Chemistry of Heterocyclic Compounds Volume 40 2004

Chemistry of Heterocyclic Compounds vol.
40
Pyrrole Oximes: Synthesis, Reactions, and Biological Activity. (Review) 1-15 Heterocyclic Quinones in ihe Nenitzescu Reaction. Synthesis of Furo- And Pyrroloquinolines from 2Methoxycarbonyl-4-oxo-5,8-quinolinequinone 16-21 Preparative Synthesis of 7-Carboxy-2-R-isoindol-1-ones 22-28 Investigations in the Area of Amines and Ammonium Compounds. 237. Synthesis of 2,2-Dialkyl-4Hydroxymethylbenzo[f]isoindolinium and 2,2-Dialkyl-4-hydroxymethylisoindolinium Salts 29-36 Synthesis and Anti-HIV-1 Activity of 2-[2-(3,5-Dimethylphenoxy)ethylthio]pyrimidin-4(3H)-ones 37-42 Multicomponent Synthesis of 2,5-Dioxo- and 4-Aryl-5-oxo-2-thioxo-1,2,3,4,5,6,7,8-octahydroquinazolines 43-46 Heterocyclization of Functionalized Heterocumulenes with C,N- and C,O-Binucleophiles. 1. Cyclocondensation of 1-Chloroalkylheterocumulenes and N-(1-Chloroalkylidene)urethanes with 2-Cyanomethylpyridine 47-57 Anomalous Beckmann Reaction in a Series of Oximes of 4-Aryl-2,7,7-trimethyl-5-oxo-5,6,7,8tetrahydroquinolines in Polyphosphoric Acid. 2. Unexpected Synthesis of 3'-Ethoxycarbonyl-4',7',7'-trimethyl-4oxo-2',6',7',8'-tetrahydrospiro(cyclohexa-2,5-diene-1,2'-pyrrolo[4,3,2-d,e]quinolines) 58-64 Trifluoromethyl-substituted Di- and Tetrahydroazolopyrimidines 65-69 Synthesis of Novel Condensed Binuclear Heterocycles Based on 1,3- and 1,5-Dicarbonyl Derivatives of 2,2Dimethyltetrahydropyran 70-74 Condensed Pyridopyrimidines. 7. Synthesis of Condensed Triazolo[4,3-c]- and Tetrazolo[1,5-c]pyrimidines 75-78 Condensed Thienopyrimidines. 19. Study of the Heterocyclization of 2-Hydrazino-6,6-dimethyl-5,6-dihydro-8Hpyranothieno[2,3-d]pyrimidin-4-one 79-83 Thiazolecarboxylic Acid Derivatives. 1. N-Substituted 2-Amino-4-methylthiazole-5-carboxylic Acid Derivatives 84-89 Synthesis of New Branched Hydrazones as Potential Hole-transporting Materials 90-93 Reactions of 3,4-Dichloro-N-R-maleimides with Substituted 2-Thiouracils 94-100 1,1-Dichloro-2,2,2-trihaloethyl Isocyanates and N-(1-Chloro-2,2,2-trihaloethylidene)urethanes in the Synthesis of 4-Trihalomethyl-2H-1,3-benzoxazin-2-ones 101-105 Synthesis and Study of the Properties of 7,8-Polymethyleneimidazo[4,5-d]-1,3,2-diazaphosphorin-2-thiones 106-113 Synthesis of Lactone from Adamantane-2-spiro-2'-oxirane 114-115 Convenient Method for Synthesis of 6-(N,N-Diethylamino)-9-(2-carboxyphenyl)-1,2,3,4-tetrahydroxanthylium Perchlorate 116-117 Spiro-bisheterocyclization of 5-Methoxycarbonyl-2,3-dihydro-2,3-pyrrolediones when Treated with Activated Enamines 118-119 Derivatives of 3,4,5,6-Tetrahydro-6a,10b-diazaindeno[1,2,3-c,d]azulene 120-122 Synthesis of 1-(2-Oxo-2-arylethyl)-3-arylcarbamoylpyridinium Bromides 123-124 Synthesis of a Novel Heterocyclic System: 7-Methyl-3-methylthio-7,8-dihydro[1,2,4]triazolo[3,4-f][1,2,4]triazine 125-126 Synthesis of 1,6-Polymethylene Pyrimidines Based on 4-(1-Azacycloalkylidene)-1,3-oxazol-5-ones 127-128 Carbon Disulfide in Synthesis of Thiazolo[3,4-a]quinoxalines Based on 3-(-Chlorobenzyl)quinoxalin-2-(1H)-ones 129-131 Synthesis, Structure, and Chemical Properties of N-Substituted 2(3)-Imino-2,3-dihydrofuran-3(2)-ones. (Review) 133-152 Isomerization of (Het)arylbenzoins in Basic Media 154-160
Investigation of the Oxidation-Reduction Characteristics of Heterocyclic Quinones 161-165 Synthesis and Some Chemical Conversions of 2-([2,2]-5-Paracyclophanyl)pyrrole 166-176 Cyclization of Dialkyl-(4-hydroxy-2-butynyl)(3-alkenylpropargyl)ammonium Salts and Recyclization of the 2,2Dialkyl-4-hydroxymethylisoindolinium Salts Obtained 177-182 Chemistry of Modified Flavonoids. 24. Synthesis of 4- Aryloxy-3-(2-hydroxy-4-hydroxy/alkoxyphenyl)pyrazoles 183-187 Heterocyclic Derivatives of Fullerene C60. 1. Synthesis of New Fulleropyrazolines by the 1,3-Dipolar Cycloaddition of Nitrile Imines 188-193 Two Directions of the Reaction of 4-Bromobenzaldehyde with Substituted Acetophenones and Urea. Synthesis of Aryl-substituted Pyrimidin-2-one and Hexahydropyrimido[4,5-d]pyrimidin-2,7-dione 194-202 Synthesis and Properties of Azoles and Their Derivatives. 52. Periselectivity of [2+3] Cycloaddition of Nitrones to trans--Cyanonitroethylene in the Light of FMO Theory 203-205 Synthesis and Properties of Azoles and Their Derivatives. 54. The Regioselectivity of [2+3] Cycloaddition Of C,C,N-Triphenyl- and Z-C,N-Diphenylnitrones With - and -Substituted Nitroethylenes in Light of Frontier Molecular Orbital Theory 203-210 Condensation of Ethyl 2-Oxoindoline-3-glyoxylate with o-Aminophenol and o-Phenylenediamine 211-213 Synthesis of 3-(3-Acetyl-5-aryl-2,3-dihydro-1,3,4-oxadiazol-2-yl)chromones 214-218 Synthesis of Some Biologically Active Pyrazole, Thiazolidinone, and Azetidinone Derivatives 219-226 Synthesis and Properties of 12(E)-Ethoxyimino Derivatives of 8-Aza-16-thiagona-12,17-diones 227-230 Novel Approaches to Synthesis of 4-Alkyl-6-amino-5-cyano-3-methyl(propyl, phenyl)-2H,4H-pyrano[2,3c]pyrazoles 231-240 4-Nitrophenyl N-(1-Aryl-2,2,2-trifluoroethylidene)urethanes: Novel 1,3-Electrophilic Components of Reactions Leading to 6- and 7-Membered Heterocycles 241-244 Characteristic Features of a Hetero DielsAlder Reaction: the Reaction of Aroylketene with Allobetulone as an Example 245-246 Regioselective Cycloaddition of Azomethines and Carbodiimides to Aroyl(quinoxalinyl)ketenes 247-248 Cyclization of o-Carboxyanilides of Aroylacetic Acids: a Route to a Novel Class of Heterocyclic Enamino Ketones 249-250 Instructions to Authors 251-256 The Pfitzinger Reaction. (Review) 257-294 Trimethylsilylcyanation of N-[3-(2-Furyl)-2-propenylidene]trifluoromethylanilines 295-300 Interaction of 5-Aryl-2,3-dihydrofuran-2,3-diones with Functionally Substituted Hydrazides and Diaminoglyoxal Diphenylhydrazone 301-307 Synthesis of Some Halogen- and Nitro-substituted Nicotinic Acids and Their Fragmentation Under Electron Impact 308-314 Regioisomeric Acetoxy Derivatives of 8-Aza-D-homogona-12,17a-dione. Annelation of 1-Methyl-3,4dihydroisoquinoline with 4-Acetoxy-2-acetylcyclohexane-1,3-dione 315-319 The Kost-Sagitullin Rearrangement in a Series of 1-Alkyl-2-(carbamoylmethyl)-4,6-dimethylpyrimidinium Iodides 320-325 Heterocyclization of Oximes of 3,5-Dimethyl(1,3,5-trimethyl)-2,6-diphenylpiperid-4-ones and N-Benzylpyrrolid-3ones with Acetylene in a Superbasic Medium 326-333 Novel Aspects of the Reaction of 3-(Benzimidazol-2-yl)-2-iminocoumarins with Aromatic Aldehydes 334-342 Synthesis of Lariat Diazacrown Ethers with Terminal Amino Groups in the Side Chains 343-350 Acylation of 3,4-Dihydropyrrolo[1,2-a]pyrazines 351-360
Conversion of Amino Group in Position 6 of Uracil 361-363 [3+2] Cycloaddition of Dimethyl Acetylenedicarboxylate, Methyl Acrylate, and Ethyl Acrylate to 4,5-Dihydro-5methyl-3H-spiro[benz-2-azepine-3,1'-cyclohexane] N-Oxide 364-369 Synthesis of 2-Trihalomethyl-3,4-dihydrothieno[2,3-d]pyrimidin-4-ones 370-376 Synthesis and Properties of Substituted Isoxazolo[3',4':4,5]thieno[2,3-b]pyridines 377-386 N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences: 70 Years 387-391 Modification of the Peripheral Substituents in Chlorophylls a and b and Their Derivatives (Review) 393-425 Phosphorylation of Furfural by Secondary Phosphine Oxides 426-429 Indole Derivatives. 142. Some Properties of [4-(2-Indolyl)phenyl]phenylmethane and 1-[4-(2-Indolyl)phenyl]-2phenylethane 430-435 Dipyrrolo[1,2-a:2',1'-c]pyrazines. 8. Electrophilic Substitution in Dipyrrolo[1,2-a:2',1'-c]pyrazines and 5,6Dihydrodipyrrolo[1,2-a:2',1'-c]pyrazines. Acylation of Dipyrrolo[1,2-a:2',1'-c]pyrazines 436-445 Synthesis and Heterocyclization of -Aroyl--diphenylphosphorylpropionic Acids 446-451 Synthesis and Antimicrobial Activity of Substituted 5-Cyano-6-oxo-2-styrylnicotinic Acids 452-455 Investigation of H-Complex Formation of Derivatives of Naphthalimide with Phenol by IR Spectroscopy 456-459 Interaction of Methyl 5,6-Dialkyl-2-amino-3-cyanopyridine-4-carboxylates with Primary Amines 460-464 Investigation of the Nucleophilic Rearrangement of 2-(Cyanomethyl)-1,4,6-trimethylpyrimidinium Iodide Into 4,6Dimethyl-2-methylaminonicotinic Acid Nitrile 465-468 Synthesis and Properties of Symmetrical and Asymmetrical Phthalocyanines with D,L-Leucine Fragments 469-474 Synthesis and Rotamerism of 9,10-Diarylsubstituted 1,2,3,4,5,6,7,8,9,10-Decahydroacridine-1,8-Diones 475-480 Acylation and Cyclodehydration of Benzofuran-, Benzothiophene-, and Indolyl-3-acetic Acid Arylamides. Synthesis of Novel Benzofuro[2,3-c]-, Benzothieno[2,3-c], and Indolo[2,3-c]pyrilium and Pyridine Derivatives 481-489 Condensation of 1-Amino-4-azafluorene with -Diketones and ,-Unsaturated Ketones 490-495 Cyclizations of N-(1-Chloro-2,2,2-trihaloethylidene)-O-methylurethanes with 5-Amino-3-methylisoxazole and 3Amino-5-methylisoxazole 496-499 New Derivatives of Thiazole with Mesomorphous Properties 500-502 Reaction of 1,2,3-Selenadiazoles with Phosphines 503-506 Psychotropic Preparations Sydnophen and Sydnocarb as Donors of Nitrogen Monoxide 507-509 Synthesis of Derivatives of 8-Cyano-6-ethoxycarbonyl-3-hydroxy-5-methylimidazo[1,2-a]pyridine and 9Alkoxycarbonyl- (or 9-Carboxy)-3-ethoxycarbonyl-2-methyl-10H-benzo[b]-1,8-naphthyridine-5-one from the Reaction of 2-Chloro-5-ethoxycarbonyl-6-methylnicotinonitrile with Amino Acids 510-515 6-Arylamino-3-methyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines: Novel N-Arylamidine Structures 516-518 Unusual Reaction of 5-Ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine with Ethyl Propiolate 519-520 Unusual Reaction of 1-Acetyl-5-bromo-1H-indole-2,3-dione with Ethyl (Triphenylphosphoranylidene)acetate 521-522 Novel Synthesis of Substituted Benzimidazoles by Reduction of Esters of 4-Alkylamino-3,5-dinitrobenzoic Acids by Tin Chloride 523-524 Novel Stereoselective Synthesis of Chiral Nonracemic cis- and trans-3-Alkyl-4-aminopiperidines 525-527 7-Oxo-3,7-dihydro- and 1,2,7-Trioxo-1,2,3,7-tetrahydropyrano[3,2-e]indoles 528-529 Unusual Condensation of 6,7-Dimethoxy-1,3,3-trimethyl-3,4-dihydroisoquinoline with 4-Antipyrylidenebarbituric Acid
530-531 Novel Synthesis Route for Pyrrolo[1,2-a]quinazolines 532-533 Novel Synthesis for 4-Hydroxy-2-phenyl-2H-benzotriazoles 534-535 Oxidation of Heterocyclic Compounds by Permanganate Anion. (Review) 537-560 Synthesis of N-Substituted -Alkoxy-3-aryl-4-methyl-2,5-dihydro-2-pyrrolones 561-569 Conditions for the Selective Conversion of Quaternary 3-Anilino-1,5-dimethylpyrazolium Salts into 3-Anilino-1,5dimethylpyrazole 570-574 Interaction of ,-Unsaturated Ketones of the Adamantane Series with N,N'-Binucleophiles 575-581 Stereodirected Catalytic Synthesis of Perhydroacridines and Their Isologs from Decahydroacridine-1,8-diones 582-593 Simple Synthesis of 6-Substituted 4a-Methyl-1,2,3,4,4a,10b-hexahydrophenanthridines and -9,10Benzophenanthridines 594-598 Synthesis of Formyl Derivatives of 2-Hetarylimidazoles Annelated with Naphthalene and Phenanthrene Rings 599-602 Condensed Isoquinolines. 16. Enamine Properties of Benzo[4,5]imidazo[1,2-b]isoquinolin-11(5H)-one in Terms of Its Acylation Reactions 603-615 Synthesis of 2-Substituted and 2,3-Disubstituted Quinazolin-4-ones Containing a Sterically Hindered Phenol Residue 616-621 Some Chemical Transformations of 4,5-Dihydro-5-methyl-3H-spiro[benz-2-azepine-3,1'-cyclohexane] N-Oxide 622-630 A Facile Synthesis of Substituted Benzodiazepines Using Solid Support 631-634 Synthesis of 3-(3-Alkyl-5-thioxo-1H-4,5-dihydro-1,2,4-triazol-4-yl)aminocarbonylchromones 635-640 Oxidative Reactions of Azines. 11. The Influence of Manganese Dioxide on the Reaction of Tetrahydropyridines with Formaldehyde: Synthesis and Molecular Structures of 3-Oxa-7-azabicyclo[3.3.1]- and 6-Oxa-2azabicyclo[3.2.1]octanes 641-649 A New Route to Partially Hydrogenated Thiazolo[3,2-a]pyridine 650-659 Halocyclization of Substituted 2-(Alkenylthio)pyrimidin-6-ones 660-666 Reaction of 2-Aminothiazoles and Their Benzo- and Naphtho Derivatives with -Sulfonyltrifluoromethylvinyldiols 667-675 Quantum-chemical Study of the Structure of 1,2,2,3,4,4-Hexachloro-1,3-diphosphetane Isomers 676-679 Third Balticum Organicum Syntheticum Conference in Riga 681-683 Heterocalixarenes. (Review) 683-700 Hydrosilylation Of (Hetero)aromatic Aldimines in the Presence of a Pd(I) Complex 701-714 Synthesis and Cytotoxic Activity of 4-Substituted 3-Cyano-6,6-dimethyl-5,6-dihydro-2-pyranones 715-724 Unnatural Amino Acids. 2. Simple Method of Obtaining Esters of Aziridine-2-carboxylic Acids by a Transesterification Reaction 725-733 Interaction of Hydroxylamine with Esters of 2-Oxobutenoic Acids. Synthesis of 1-Hydroxy-3-hydroximino-2pyrrolidinones 734-741 Synthesis and Cytotoxicity of Derivatives of Di(3-indolyl) Selenide 742-746 Nitrogen NMR Shieldings of Some Nitro Derivatives of 2-Amino-4-methylpyridine Systems 747-752 Electrochemical Oxidation of Compounds Containing 1,4-Dihydropyridine and Pyridinium Rings Analogs of Gene Transfection Agents 753-758 Activation of Pyridinium Salts for Electrophilic Acylation: a Method for Conversion of Pyridines into 3Acylpyridines 759-766
Condensation Products of 1-Aryl-3-ethoxycarbonyl-2-methyl-1,4,5,6-tetrahydro-4(1H)pyridones with Hydrazine, Phenylhydrazine, and Hydroxylamine 767-775 Synthesis of Quinoline-8-selenol, Its Complex Compounds with Metals and Their Cytotoxic Activity 776-780 Synthesis and Cyclization of N-(4-Phenoxyphenyl)--alanines 781-787 Synthesis and Reactions of (6-Methyl-2-methylsulfanyl-4-oxo-3,4-dihydro-3-pyrimidinyl)acetyl Azide 788-791 Cyclization of the Reaction Products of p-Phenylenediamine with Maleic Acid 792-796 Addition of Nitrile Oxides to Aryl Allyl Ethers 797-800 Reaction of N-Phenylbenzamidine with O-Acetylbenzeneoximoyl Chloride 801-806 Oxidative Recyclization of 4,6,7-Trichloro-5-hydroxy-2-(2-pyrimidylamino)-2,3-dihydrobenzo[b]furan 807-810 Synthesis of Substituted 5,6-Dihydro-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepines 811-815 Synthesis of Cytotoxic 4-Sulfonyl-, 4-Sulfonylthio-and 4-Sulfothioazetidinones-2 816-822 Gunars Duburs Seventieth Birthday 823-828 The Seventieth Birthday of Professor Andris Strakovs 829-830 Oleg Nikolaevich Chupakhin Seventieth Birthday 831-833 Benzo[b]tellurophene, Dibenzo[b,d]tellurophene, and Their Derivatives. (Review) 834-853 Acylation of Amines with 5-Phenyltetrazol-2-ylacetyl Chloride 854-861 Synthesis of 6-Bromomethyl-substituted Derivatives of Pyridin-2(1H)-ones and Their Reaction with Nucleophiles 862-867 Reaction of 3,5-Carbonyl-substituted 1,4-Dihydropyridines with Hydrazine Hydrate 869-875 Synthesis, Cardiovascular Activity, and Electrochemical Oxidation of Nitriles of 5-Ethoxycarbonyl-2-methylthio1,4-dihydropyridine-3-carboxylic Acid 876-887 Cyclocondensation of 2-Fluoro-5-nitrobenzaldehyde with Amidines. New Synthesis of Isoquinolines 888-894 Oxidative Addition of N-Aminophthalimide and 3-Amino-2-methylquinazolin-4(3H)-one to Conjugated Azocyclopentenes and Azocyclohexenes 895-902 Ring-Chain Tautomerism of 1,2,3,4-Tetrahydroquinazolines. The Products of Reaction of 1,3-Dicarbonyl Compounds with 2-Aminomethylaniline 903-910 Regioselectivity of Nucleophilic Attack on the Reactions of 1,2,4-Triazine 4-Oxides with Certain C-Nucleophiles 911-915 Synthesis of Derivatives of 1,3,4-Oxadiazoles Based on Monohydrazides of 2-Aryl-4-methyl-4-cyclohexen-1,2dicarboxylic Acids 916-918 Synthesis of 2-Aryl and 2-Hetaryl Derivatives of 2'-Aminospiro[(1,3-dioxane)-5,5'-thiazolin]-4'-one and Spiro[(1,3dioxane)-5,5'-thiazolidine]2',4'-dione 919-926 Tautomeric and Conformational Isomerism of Mercaptoacetylhydrazones of Methyl Alkyl Ketones 926-930 Candida Rugosa Lipase-catalyzed Kinetic Resolution of 3-(Isobutyryloxy)methyl 4-[2-(Difluoromethoxy)phenyl]-2methyl-5,5-dioxo-1,4-dihydrobenzothieno[3,2-b]pyridine-3-carboxylate 931-937 Reactions of 2-Amino-4-methyl-6-(2-pyridyl)- and 2-Amino-4-methyl-6-phenyl-7,8-dihydroindazolo[4,5-d]thiazoles with Aldehydes 938-943 10-Aryl-7,7-dimethyl-5,6,7,8,9,10-hexahydro-11H-pyrido[3,2-b][1,4]benzodiazepin-9-ones 944-948 11-Aryl-3,3-dimethyl-7- and 7,8-Substituted 1,2,3,4,10,11-Hexahydro-5H-dibenzo[b,e]-1,4-diazepin-1-ones 949-955 Selective Cyclopropanation of Chromenes with a Phenylacryloyl Substituent by Bromine-containing Zinc Enolates 956-957
Unexpected O-Methylation of N-(2-Hydroxyethyl)-1,2,3,4-tetrahydroquinoline and -1,2,3,4-Tetrahydroisoquinoline in Silylalkylation by Trimethylchloromethylsilane under Phase-transfer Catalysis Conditions 958-959 Cyclization of N,N-Bis(2-chloroethyl)methylamine in Aqueous Hydrazine 960-961 Kishner Reduction of 3,3-Dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydroindolo[2,3-c]quinolin-1-one 962-963 Transformations of 5-Amino-4-(3,4-dimethoxyphenyl)pyrazoles in the Diazotization Reaction 964-965 Synthesis and Characteristics of Tetracyclic Systems of Benzo[b]furoindoles and Their Derivatives. (Review) 967-978 Investigation in the Area of Furan Acetal Compounds. 13. Synthesis and Structure of 1,3-Dioxacyclanes Based on Furfural and Glycerol 979-985 Features of the Reaction of Heterocyclic Analogs of 2'-Alkoxychalcones with Lanthanide Shift Reagents 986-991 Reactions of Amidines with 5-Methylene-1,3-dioxolan-2-ones 992-1001 Synthesis of Arylidene Derivatives of 1-Aryl-3H-pyrrol-2-ones 1002-1006 Synthesis of Ethyl cis- and trans-4-Chloro-5-oxo-1,2-diphenylpyrrolidine-2-carboxylate 1007-1008 Synthesis, Structure, and Some Properties of Substituted 3-Carbethoxy(methoxy)-5-cyano-1,2,3,4tetrahydrospirocyclohexane-4-pyridine-2-thiones 1009-1016 Regioselective Synthesis and Properties of 6-Amino-3-carbamoyl-5-cyano-3,4-dihydrospirocyclohexane-4pyridine-2-thiol and 5-Cyano-3-thiocarbamoyl-4-spirocyclohexanepiperidine-2,6-dione 1017-1023 Reaction of Polyfluorinated -Diimines with Ketones. A Novel Method for the Synthesis of Fluorinated Pyridines 1024-1030 Characteristics of the Dissociative Ionization of 9-Aryl(hetaryl)-3,3,6,6-tetramethyldecahydroacridine-1,8-diones under the Influence of Electron Impact 1031-1035 Synthesis of 3,3-Dialkyl-1-(3-coumarinyl)-3,4-dihydroisoquinolines 1036-1038 Studies on Reactions of Cyclic Oxalyl Compounds with Hydrazines or Hydrazones. 2. Synthesis and Reactions of 4-Benzoyl-1-(4-nitrophenyl)-5-phenyl-1H-pyrazole-3-carboxylic Acid 1039-1046 Synthesis of Pyridazinone Derivatives 1047-1051 Condensed Isoquinolines. 17. Enamine Properties of Benzimidazo[1,2-b]isoquinolin-11(5H)-one in Alkylation Reactions 1052-1062 4-Oxo-3,4-dihydroquinazolinyl- and Benzimidazolylacetonitriles in Annelation Reactions of a Haloquinoline Ring 1063-1069 Interaction of Cyclic Schiff's Bases with 2-Methylthiopyrimidine-4,6-dione Enol Acetate. Synthesis of 5-(2-Acetyl6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolyl)-6-hydroxy-2-methylthio-1,4-dihydro-4-pyrimidinones 1070-1076 Study of the Products of Iodocyclization of 4-Allyl-5-phenyl-1,2,4-triazole-3-thione 1077-1082 Reactions of 1,3-Substituted Benzothieno[2,3-c]pyrylium Salts with Primary Amines 1082-1086 Reaction of Substituted 2-Allylthiopyrimidin-4(3H)-ones with Sulfenyl Chlorides 1087-1091 2-R-5-Ar(Het)-5,6-dihydro-7H-[1,2,4]triazolo[5,1-b][1,3]thiazin-7-ones 1092-1096 Substituted and Spiro-annelated Perhydro-1,2,3-oxathiazine 2,2-Dioxides and 1-Benzyl-4-methylazetidines 1097-1105 Hetarylcyanamides. (Review) 1107-1123 The Use of 4-(Bromomethylene)-5,5-dimethyl-1,3-dioxolan-2-one as Masked -Bromo-'-Hydroxy Ketone in the Synthesis of Heterocyclic Systems 1124-1130 Synthesis and Reactions of 1-(3-Chloropropyl)-6,7-dimethoxy-3-methylbenzo[c]pyrylium Perchlorate 1131-1136 Synthesis and Structure of Di-N-arylpyrrolo[1,2-c;5,6-c]cyclooctanes 1137-1141 Reactions of Hydroxyazolidines with -Donor Heterocycles. 3. Reaction of 1-Acetyl-5-hydroxypyrazolidines with Oxindoles
1142-1149 Heterocyclic Derivatives of Fullerene C60. 2. Cycloaddition to Fullerene C60 of the Products of Dehydrochlorination of N-Benzyltrifluoroacetimidoyl Chlorides 1150-1154 Interaction of 5-Acetyl(alkoxycarbonyl)-3-alkoxycarbonyl-6-methylpyridin-2(1H)-ones with Primary Aromatic Amines and Hydrazine Hydrate 1155-1161 Derivatives of sym-Triazine. 3. Synthesis and Some Conversions of Monoazides of the Triazine Series 1162-1168 Derivatives of sym-Triazines. 6. Some Special Features of the Addition of Substituted Acetylenes to Triazine Monoazides 1169-1173 Reactions of 2,3-Dioxopyrrolo[2,1-a]isoquinolines with Ammonia and Aliphatic Amines 1174-1178 Condensed Isoquinolines. 18. Enamine Properties of Benzimidazo[1,2-b]isoquinolin-11(5H)-one in the Michael Reaction 1179-1184 Studies on Pyrazine Derivatives. 38. Synthesis, Reactions, and Tuberculostatic Activity of Pyrazinyl-substituted Derivatives of Hydrazinocarbodithioic Acid 1185-1193 Synthesis of Substituted 1,2,4-Triazoles and 1,3,4-Thiadiazoles 1194-1198 Isomerization in the Oxidative Cyclocondensation of 2-Aroylmethyl-1H-benzimidazoles with o-Aminothiophenol 1199-1206 Unexpected Direction of Iodocyclization of 3-Allylthio-5-phenyl-4H-1,2,4-triazole 1207-1211 Reaction of 10-Methyl(phenyl)-5,10-dihydrophenarsazine 10-Oxides with Hydriodic Acid 1212-1215 Novel Route to 2,6-Diphenyl-1,4-dithiine 1216-1217 3-Aryl-2-chloropropanals in Hantzsch Synthesis of Pyrroles 1218-1219 Synthesis of Amino Acid Esters: Derivatives of 1,2,3,4-Tetrahydroisoquinoline 1220-1221 Novel Variant of Recyclization of N-Arylmaleimides when Reacted with Aminoazoles 1222-1223 Reductive Cyclization of N-(2,4-Dinitrophenyl)pyridinium Chloride by Tin(II) Chloride 1224-1225 Reaction of 10-Cyanotetrahydrobenzo[b][1,6]naphthyridines with Acetylenedicarboxylic Ester 1226-1227 Unexpected Reaction of Thiosemicarbazide with 3,6-Bis(vinylsulfonyl)-1,2,4,5-tetrafluorobenzene 1228-1229 Aleksei Vsevolodovich Bogatsky (75th Anniversary of his Birth) 1230-1234 Vadim Aleksandrovich Pestunovich (January 6, 1942 -- July 4, 2004) 1235-1242 Reactivity of pyrrol-2-ones. (review) 1243-1261 Phenyl-substituted porphyrins. 1. Synthesis of meso-phenyl-substituted porphyrins 1262-1270 Derivatives of indole. 143.* synthesis of photochromic derivatives of 2-arylindoles 1271-1278 Polyfunctional pyrazoles. 3.* Synthesis of 3-(3-aryl-4-formyl-1-pyrazolyl)propionic acids and their amides 1279-1282 A novel spiroheterocyclization: synthesis of 1-ethoxycarbonylmethylidene-8-(2-ethoxycarbonylmethylidene-5,5dimethyl-3-pyrrolidinylidene)-3,3,6-trimethyl-2-azaspiro[4,5]deca-6,9-diene 1283-1287 [3 + 3] Cyclocondensation of 1-alkyl-3,4-dihydroisoquinolines with -keto esters. New annelation reaction in a series of cyclic Schiffs bases 1288-1294 Chemistry of Acyl(imidoyl)ketenes. 8. Thermolysis of 3-Alkoxycarbonyl-5-phenyl-1,2,4,5-tetrahydropyrrolo[1,2-a]quinoxaline-1,2,4-triones. Structure of 2-(3-oxo-4-phenyl-3,4-dihydro-2-quinoxalinyl)-2,4-di(ethoxycarbonyl)-6phenyl-2,3,5,6-tetrahydro-1h-pyrido[1,2-a]quinoxaline-1,3,5-trione 1295-1299 Reaction of 3-acylamino- and 3-alkoxybenzo[c]pyrilium salts with hydrazine 1300-1304 Dehydration of 4-hydroxy-4-methyl-3-phenylamino-oxazolidin-2-ones 1305-1309
Regioselectivity of the interaction of (1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediol with some symmetrical ketones 1310-1314 Novel schemes for the synthesis of pyrrolocoumarins 1315-1322 Recyclization of 2-iminocoumarins using nucleophilic reagents. 6. Reaction of 2-iminocoumarin-3-carboxamides with 2-aminobenzophenones 1323-1331 Intramolecular cyclization of 5-aryl-3-arylamino-4-benzoyl-1h-3-pyrrolin-2-ones to pyrrolo[3,4-b]quinolines 1332-1334 Synthesis of 7-oxopyrrolo-[3,2-d]pyrimidine 5-oxides by the rearrangement of 6-alkynyl-5-nitropyrimidines 1335-1338 Synthesis of derivatives of 7,8-dihydrothiazolo[2,3-i]purine by halocyclization of 6-allylthiopurine 1339-1341 Condensed pyridopyridimines. 8. Synthesis of new derivatives of pyrano[3,4:6,7]pyrido[2,3-d]pyrimidine 1342-1345 Formation of the pyrroline N-oxide ring by interaction of -isonitrosoketones derivatives of tetrahydrobenzofurazan and -furoxan with aldehydes and morpholine and some of the reactions of these compounds 1346-1351 New method for the synthesis of thieno[2,3-d]pyrimidines 1352-1358 Annelation of 3,4-dihydroisoquinolines by 3-acyl-5,5-dimethylthiopyran-2,4-diones. Synthesis and properties of 8aza-17-thia-d-homogona-12,17a-diones 1359-1369 First example of hydro-thiophosphorylation of 3-thiolene 1,1-dioxide 1370-1372 Synthesis of 3-chloro-6,6-diphenyl-6,11-dihydropyrido[1,2:1,2]imidazo-[4,5-b]quinoline based on reaction of 2chloromethyl-4,4-diphenyl- 4h-3,1-benzoxazine with 2-amino-5-chloropyridine 1373-1374 A. N. Nesmeyanov Institute of Organoelement Compounds (INEOS), Russian Academy of Sciences: 50 years 1375-1379 Antibiotics produced at the G. F. Gauze Scientific-Research Institute of new antibiotics, Russian Academy of Medical Sciences (marking the fiftieth anniversary of the institute). (review) 1381-1395 Antibiotics produced at the G. F. Gauze Scientific-Research Institute of New Antibiotics, Russian Academy of Medical Sciences (marking the Fiftieth Anniversary of the Institute). (Review) 1381-1395 Self-oscillating reaction In the Furan series 1396-1401 Self-oscillating reaction in the furan series 1396-1401 Heterocyclic synthesis using Nitrile imines. 4. synthesis of 3-substituted 1-aryl-1,2,4-triazaspiroalk-2-enes 1402-1407 Heterocyclic synthesis using nitrile imines. 4. Synthesis of 3-substituted 1-aryl-1,2,4-triazaspiroalk-2-enes 1402-1407 Chemistry of 3-hetarylcoumarins. 2*. 3-(2-thiazolyl)coumarins 1408-1420 Chemistry of 3-hetarylcoumarins. 2. 3-(2-thiazolyl)coumarins 1408-1420 Reactions of 4-Cyanobenzo-[c]pyrylium salts with Nitrogen-containing nucleophiles 1421-1426 Reactions of 4-cyanobenzo[c]pyrylium salts with nitrogen-containing nucleophiles 1421-1426 Concerning the product of [2 + 2] cyclodimerization of 9-allenylcarbazole 1427-1434 Concerning the product of [2 + 2] cyclodimerization of 9-allenylcarbazole 1427-1434 New derivatives of 3-Aminoindole. Synthesis of 2-Aryl(Hetaryl)-3-(3,5-Dimethyl-1-Pyrazolyl)indoles 1435-1441 New derivatives of 3-aminoindole. Synthesis of 2-aryl(hetaryl)-3-(3,5-dimethyl-1-pyrazolyl)indoles 1435-1441 Alkylation of 3-cyano-4-methoxymethyl-6-methyl-2(1h)-pyridone by active Halomethylene compounds. The Molecular structure of 3-amino-2-benzoyl-4-methoxymethyl-6-methylfuro[2,3-b]pyridine 1442-1453 Alkylation of 3-cyano-4-methoxymethyl-6-methyl-2(1h)-pyridone by active halomethylene compounds. The molecular structure of 3-amino-2-benzoyl-4-methoxymethyl-6-methylfuro[2,3-b]pyridine 1442-1453 Synthesis and reductive reactions of 2,3-dioxo-2,3-dihydrobenzo-[b]furo[2,3-f]-, -[2,3-g]-, and -[3,2-e]indoles
1454-1459 Synthesis and reductive reactions of 2,3-dioxo-2,3-dihydrobenzo[b]furo[2,3-f]-, -[2,3-g]-, and -[3,2-e]indoles 1454-1459 Synthesis of 3,9,9,9a-tetramethyl-1,2,3,9a-tetrahydro-9h-imidazo[1,2-a]-indol-2-ones by reaction of 2,3,3trimethyl-3h-indole with 2-bromopropionamides 1460-1464 Synthesis of 3,9,9,9a-tetramethyl-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]-indol-2-ones by reaction of 2,3,3trimethyl-3H-indole with 2-bromopropionamides 1460-1464 Synthesis of 1,2,3,9a-tetrahydro-9h-imidazo[1,2-a]indole-2-thione and 1,5,6,10b-tetrahydroimidazo[2,1-a]isoquinoline-2(3h)-thione derivatives 1465-1469 Synthesis of 1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indole-2-thione and 1,5,6,10b-Tetrahydroimidazo[2,1-a]isoquinoline-2(3H)-thione derivatives 1465-1469 Reactions of 5-diazoimidazoles With steroid hydrazones 1470-1476 Reactions of 5-diazoimidazoles with steroid hydrazones 1470-1476 Synthesis of 2-r-4,5,7-trimethyl-1-vinyl-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridines 1477-1484 Synthesis of 2-R-4,5,7-trimethyl-1-vinyl-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridines 1477-1484 Synthesis of 6-aryl-1,6-dihydro-dipyrazolo[3,4-b:4,3-c]pyridines 1485-1489 Synthesis of 6-aryl-1,6-dihydrodipyrazolo[3,4-b:4,3-c]pyridines 1485-1489 A convenient one-pot synthesis of benzopyrimido[1,8]naphthyridines by knoevenagel condensation 1490-1492 A convenient one-pot synthesis of benzopyrimido[1,8]naphthyridines by Knoevenagel condensation 1490-1492 Cyclization of -[(s)-1-phenylethyl]-amino alcohols to form chiral 1,3-disubstituted phthalanes 1493-1494 Cyclization of -[(S)-1-phenylethyl]-amino alcohols to form chiral 1,3-disubstituted phthalanes 1493-1494 Efficient route to substituted 2-aminoquinoline 1495-1496 Efficient route to substituted 2-aminoquinoline 1495-1496 Novel cyclocondensation of 2-acylethynyl-1-amino- and 2-alkoxycarbonylethynyl-1-amino-anthraquinones with pyridines 1497-1498 Novel cyclocondensation of 2-acylethynyl-1-amino- and 2-alkoxycarbonylethynyl-1-amino-anthraquinones with pyridines 1497-1498 Unexpected reaction of 3-benzoyl-4-hydroxy-1-methyl-4-phenylpiperidine with 1,2-diaminobenzene 1499-1501 Unexpected reaction of 3-benzoyl-4-hydroxy-1-methyl-4-phenylpiperidine with 1,2-diaminobenzene 1499-1501 Method for synthesis of 2-amino-5-(2-thienylmethyl)thiazole 1502-1503 Method for synthesis of 2-amino-5-(2-thienylmethyl)thiazole 1502-1503 Unusual reaction of 3,6-dimethoxy-benzonorbornadiene with 2-chloro-sulfenyl-1-pyridine 1-oxide 1504-1505 Unusual reaction of 3,6-dimethoxy-benzonorbornadiene with 2-chloro-sulfenyl-1-pyridine 1-oxide 1504-1505 Novel method for synthesis of polynuclear heterocyclic systems with a pyridazine ring 1506-1507 Novel method for synthesis of polynuclear heterocyclic systems with a pyridazine ring 1506-1507 Unexpected oxidation of azafluoren-9-ones under Baeyer-Villiger conditions 1508-1509 Spirothiazolo[4,2]- and thiazolo-[3,4-a]quinoxalines based on 3-(-bromoethyl)quinoxalin-2-ones and thiourea 1510-1512 Emilija Gudriniece (August 3, 1920 October 4, 2004) 1513-1515 4,7-Dihydro-, 4,5,6,7-tetrahydro-, and octahydroisoindoles (and methanoisoindoles). (Review) 1517-1535
Synthesis of 5-amino-4-hetaryl-2,3-dihydro-1h-3-pyrrolones 1536-1542 2-(1-Adamantyl)-7-methylimidazo-[1,2-]pyridine and its reactions with N-bromosuccinimide 1543-1545 Preparation of 1-amino-4-methylpiperazine 1546-1549 Investigation of the products of interaction of cyclic diketones with nitrogen-containing 1,4-binucleophiles 1550-1559 Investigation of naphthyridines. 16. Synthesis of derivatives of 2,5-dioxo-1,2,5,6,7,8-hexahydro-1,6naphthyridine-3-carboxylic acids from anilides (hydrazides) of 6-oxo-2-styrylnicotinic acids 1560-1563 New synthesis of the dihydroindolizinoquinoline system by intramolecular cyclization of sulfur ylide 1564-1567 Quantum-chemical study of the structure and thermochemical properties of nitropiperazines and nitrosopiperazines 1568-1587 2-R-6-ethyl-7-hydroxy-3-(5-phenyl-1,3,4-thiadiazolyl-2)chromones 1588-1594 Reactions of -acetylenic ketones with n-3-amidinothioureas. 1. Synthesis and properties of new derivatives of 1,3-thiazine 1595-1599 Synthesis and properties of (thieno[2,3-b]pyridin-3-yl)iminotriphenylphosphoranes. Molecular structure of (2benzoyl-4-methoxymethyl-6-methylthieno[2,3-b]pyridin-3-yl)iminotriphenylphosphorane 1600-1608 Study of nitrogen- and sulfur-containing heterocycles. 54. Properties and conversions of pyrimido[4,5-b]-1,4benzothiazepines. Synthesis of a novel heterocyclic system: Pyrimido[5,4-c]isoquinoline 1609-1617 Study of reaction of 5-aryl-2,3-dihydro-2,3-furandiones with n-cyanotriphenylphosphinimine. Molecular and crystal structure of the solvate of 6-p-tolyl-2-triphenylphosphinimino-4H-1,3-oxazin-4-one with acetonitrile 1618-1625
Chemistry of Heterocyclic Compounds, Vol. 40, No. 1, 2004
PYRROLE OXIMES: SYNTHESIS, REACTIONS, AND BIOLOGICAL ACTIVITY. (REVIEW)

E. Abele, R. Abele, and E. Lukevics Data on the production methods and reactions of pyrrole aldoximes and ketoximes and their derivatives are reviewed. The synthesis of new heterocycles from the pyrrole oximes is examined separately. The principal results from investigation of the biological activity of pyrrole oximes are described. Keywords: oximes, pyrrole, biological activity. Pyrrole oximes are widely used as intermediates in fine organic synthesis. In the present work the methods for the production and the reactions of pyrrole oximes are reviewed. Methods for the synthesis of new heterocycles from derivatives of these oximes are dealt with in a separate section. The principal methods for investigation of the structure of pyrrole oximes with regard to isomerism are also briefly examined. The main paths for the selective production of the E- and Z-isomers of the oximes and their O-ethers are described. The last section of the paper gives the results from research into the biological activity of derivatives of pyrrole oximes.
1. SYNTHESIS AND STRUCTURE OF PYRROLE OXIMES 1.1. Synthesis of Pyrrole Oximes The classical method for the synthesis of pyrrole oximes is based on the reaction of an aldehyde or ketone with hydroxylamine hydrochloride in pyridineethanol [1, 2], sodium acetatemethanol or ethanol [3-6], sodium carbonateethanolwater [7], or potassium hydroxideethanol [8] systems. By modifying these methods it is possible to obtain the pyrrole oxime 2 from 5-bromo-2-dimethylmethylene-3,4-dimethyl-2H-pyrrole (1). Debromination of the oxime 2 in the system containing palladium on barium sulfatesodium methoxidesodium hydroxide leads to 3,4-dimethylpyrrolecarbaldehyde oxime (3) [9].
Me
Me
NH2OH .HCl MeONa
Me
Me
Me
Me
Pd, BaSO4
Br
N
Br
CHNMe2
CH=NOH
MeONa
CH=NOH
H 2
__________________________________________________________________________________________ Latvian Institute of Organic Synthesis, Riga; e-mail: abele@osi.lv. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 3-19, January, 2004. Original article submitted August 19, 2003. 0009-3122/04/4001-00012004 Plenum Publishing Corporation 1
Unexpected deiodination during the synthesis of pyrrole oxime was described in [10]. Thus, the reaction of the aldehyde 4 with hydroxylamine hydrochloride in the presence of 10% aqueous sodium hydroxide gives the oxime 5 with a yield of 81% [10].
HOOCCH2CH2 I CH2COOH
NH2OH.HCl, NaOH, H2O
HOOCCH2CH2
CH2COOH CH=NOH
N H
CHO
N H
2-Methoxy-1-pyrroline (6) and hydroxylamine in alcohol give 2-pyrrolidone oxime (7) [11].
NH2OH N 6 OMe N H NOH 7
A series of methods for the synthesis of pyrrole oximes were based on the nitrosation of indole derivatives [12-15]. For example, pyrrole (8) and alkyl nitrites in the presence of sodium alcoholates give a salt of the oxime 9 [16]. The ketoxime 11 is formed as the only product during the nitrosation of 2-acetylpyrrole (10) with amyl nitrite [17]
NOH AlkONO, AlkONa N H 8 Me N H 10 O C5H11ONO, NaOEt N H 11 O NOH N 9
The nitrosation of 2-(dimethylaminomethyl)pyrrole (12) with sodium nitrite in acetic acid gives a mixture of the oxime 13, N-nitrosodimethylamine, and formaldehyde [18].
NO O N H 12 13 NOH + MeNMe + CH2O
NMe2 N H
NaNO2, AcOH
The pyrrole oximes 16 and 17 (ratio 90:10, overall yield 74%) were obtained successfully by the reaction of pyrrole with the bromo oxime 14 in the presence of sodium carbonate. The products are formed through the cycloadduct 15 as intermediate [19].
_
PhSO2CBr=NOH (14) K2CO3
_ O N N SO2Ph 15 SO2Ph
N H 8 _
SO2Ph N H 16 + NOH N H 17
NOH
1-Methylpyrrole (18) reacts readily with the oxime of ethyl bromopyruvate in a basic medium and forms the oxime 19 with a 67% yield [20].
NOH Na2CO3 N Me 19 CO2Et
N Me 18
Br
CO2Et NOH
The condensation of 3-ethoxycarbonyl-2,4-dimethylpyrrole (20) with the -diketone monoxime 21 gives the gem-dipyrrolyl derivative 22 [21].
EtO2C Me + Me N H Me NOH O Me Me Me N H Me HN Me 20 21 22 CO2Et Me Me HON
EtO2C
The reaction of the dioxime 23 with acetone and morpholine leads to the formation of 3-hydroxy-2methyl-2-morpholino-4-hydroxyimino-2,3,4,5,6,7-hexahydro-3H-indole 1-oxide (24) with a yield of 80% [22]. 3
NOH O NOH 23
MeCOMe, O
NH
NOH OH Me N N O 24 O
1.2. The Structure of Pyrrole Oximes One of the most reliable methods for the determination of the structure of isomeric pyrrole oximes is NMR spectroscopy. In [23] the stereochemistry of the oximes of 2-carbonyl derivatives of 1-nitrophenylpyrroles was studied in detail. 2-Formyl-1-nitropyrroles readily give oximes in reaction with hydroxylamine and always as a mixture of two isomers, s-trans-syn (25) and s-trans-anti (26), which can be separated by chromatography. The ratio of the isomers amounts to 2:1 in the case of 1-(4-nitrophenyl)-2-formylpyrrole oxime and 4:1 for the 3-isomer. This means that conjugation of the nitro group with the pyrrole ring stabilizes the s-trans-syn isomer.
OH H N N NO2 25 26 OH N N H NO2
The difference between the chemical shifts of -H and OH amounts to 2.91-2.92 for the syn isomer and 4.30 ppm for the anti isomer. The 15N1H spinspin coupling constant (12.5 Hz) was determined for the anti isomer of pyrrole 2-aldoxime in acetone [24]. Several papers have been devoted to the synthesis, structure, and transformations of pyrrole aldoximes and ketoximes [25-27]. Thus, the two isomeric anti (27) (mp 164.5C) and syn (28) (mp 70-71C) products are formed in the synthesis of 2-pyrrolecarbaldehyde oxime. The syn isomer of the oxime is less stable and is readily transformed into the anti isomer on heating, during storage, during irradiation, or in the presence of HCl. In reaction with copper acetate the anti isomer 27 forms a 1:1 complex, while the syn isomer 28 forms a 1:2 complex. It was also shown that the syn isomer of 2-acetylpyrrole oxime is converted into the anti isomer in the presence of HCl.
Cu(OAc)2 N H 27 N H Cu(OAc)2 N H HON 28 N Cu N O CHO HCl NOH N NOH Cu/2
The structure of pyrrole oximes has also been investigated by UV spectroscopy [28, 29], polarography [30], spectrophotometry [30, 31], and potentiometry [31].
2. REACTIONS OF PYRROLE OXIMES 2.1. Synthesis of the Ethers of Pyrrole Oximes The chief method for the synthesis of the O-ethers of pyrrole oximes is based on the reaction of O-alkyl derivatives of hydroxylamine with carbonyl derivatives in the presence of sodium acetate in aqueous ethanol [6]. Another method for the synthesis of the O-ethers of pyrrole aldoximes is based on the reaction of the salts of the oximes with alkyl halides. It should be noted that only the E-isomers of pyrrole aldoximes give O-alkyl derivatives. Z-Aldoximes give mainly the N-alkylated products nitrones [32]. Phase-transfer catalysis systems alkyl bromide (RBr)10% aq. NaOHOct4N+BrPhH or RBrsolid K2CO318-crown-6PhH were used successfully by the authors for the O-alkylation of pyrrole oximes. The ketone oximes 29 react with hexacyanocyclopropane (30) in the presence of metallic sodium and give 2-amino-4,4-di(alkylideneaminooxy)-1,5,6,6-tetracyano-3-azabicyclo[3.1.0]hex-2-enes 31 with yields of up to 74%. The further reaction of compound 31 with the oxime (RR'C=NOH) and sodium leads to the tricyclic derivatives of oximes 32 [33].
RR'C=NO NC NC RR'C=NOH + NC NC 29 30 CN CN CN H2N N 31 R, R' = Alk Na NC CN CN ON=CRR' ON=CRR' N 29, Na H2N H2N N 32 ON=CRR' CN CN ON=CRR' ON=CRR'
The formamidoximes 33 react with aldehydes in the presence of DBU and give the tautomeric oximes 36 and 37 with yields of 29-68%. The products are formed through the intermediates 34 and 35 [34].
_ H NC NC N NOR NOR H NC NH2 _ HN O H _ _ O H NH N Ar N H2N _ _ H N N Ar 35 _ Ar H O N H N NH NOR H NOR Ar H H O N H N NH2 _ NOR H
ArCHO, DBU
H
36
33
34
N H
R = Me, CH2Ph
37
2-Acetylpyrrole O-acetyloxime was obtained by acylation of the oxime in the acetyl chloride triethylamine system [35]. The pyrrole ketoxime 38 was also acylated by acids (RCOOH) in the 4-dimethylaminopyridine (DMAP)3-(dimethylaminopropyl)-1-ethylcarbodiimide (EDCI)methylene chloride system and gave the acyl derivatives 39 with yields of up to 78% [36].
NOH N Me 38 R = Alk, Py Me RCOOH , EDCI , DMAP , CH2Cl2 N Me 39 NOCOR Me
The pyrrole oxime carbamate (41) was obtained with a yield of 67% from N-(4-nitrobutyl)pyrrole (40) in the presence of phenyl isocyanate and triethylamine [37].
N NO 2 40
PhNCO, Et3 N
N OCONHPh N
41
2.2. Reactions of Pyrrole Oxime Groups and Rings Recent advances in the chemistry of oxime derivatives were reviewed in [38]. In this section the chemistry of pyrrole oximes will mainly be discussed. The dehydration of the oximes was described extensively in the review [39]. In addition, pyrrole oximes are easily transformed into the corresponding nitriles in the presence of acetic anhydride [5, 40-45], acetic anhydridesodium acetate [46], p-toluenesulfonic acidDMF [47], or epichlorohydrinsodium methoxide [48]. Pyrrole aldoximes and ketoximes were hydrogenated to the corresponding derivatives of primary pyridine amines in the presence of Raney nickel in dioxane or ethanol [49], rhodiumaluminum oxide or Raney nickel in methanol [50], or platinum dioxideacetic acid [51]. During hydrogenation with Raney nickel 4-aryl-5formyl-3-methoxycarbonyl-1,2-dimethylpyrrole oximes (42) give a mixture of primary amines 43 (yields 32-40%) and dimeric products 44 (yields 30-35%) [52]. Pyrrole aldoximes were also reduced to primary amines in the presence of sodium amalgam [53]. The transformation of 2-pyrrolecarbaldehyde oxime to the corresponding aldehyde (yield 88%) takes place readily in the presence of cetyltrimethylammonium permanganate [54].
R MeO2C Me
Ni H2 / MeOH
R MeO2C MeO2C Me
R R
+
Me N Me
43 R = H, OAlk
CO2Me H N N Me
44
N Me
42
CH=NOH
CH2NH2
N Me
Me
It should also be noted that C-(2-pyrrolyl) N-[2-(4'-chlorophenylsulfonamido)ethyl] nitrone (46) can be generated by the reaction of the salt of the pyrrole oxime 45 with N-(4-chlorophenylsulfonyl)aziridine in the presence of sodium hydride [55].
SO2
NaH
Cl H N
N H
CH=NONa
N H
N + -O
46
SO2
Cl
45
2.3. The Synthesis of New Heterocycles from Pyrrole Oximes Advances in the synthesis of heterocyclic systems from oximes were reviewed in [56], and in this section we will dwell on the specific reactions of pyrrole oximes. In the presence of Raney nickel, generated in situ, the oximes 47 give a mixture of several pyrrolo[2,3-b]pyrrolones 48 and 49 (overall yield 16-41%) and 50 (yield 4-48%) [57].
H Ph O Ph NOH N R 47 Me Ni-Al EtOH Ph O Ph N Me + N R 48 Ph Ph Me Ph O Ph H N Me + N R 49 Me
Me
+
O N R 50 R = H, Alk Me
Several papers have been devoted to synthesis of the isoxazole derivatives of pyrrole oximes. The reaction of 3-hydroxyimino-2,5-diphenylpyrrole (51) with NH2OHHCl in methanol leads to the trioxime 52 and then to a mixture of 3-benzoyl-5-phenylisoxazole oxime (53) and 3-phenyl-4-phenylacetyl-1,2,5-oxadiazole (54). Under similar conditions 3-hydroxyimino-2-methyl-5-phenylpyrrole only gives 3-acetyl-5-phenylpyrrole oxime [58].
NOH
NH2OH.HCl, MeOH
NOH Ph Ph NOH NOH

52
NOH Ph Ph N O 53 Ph
54 +
Ph O N O N
Ph
N
51
Ph
In the presence of methylene chloride and water the meso-formylporphyrin oximes 55 give the isoxazoles 56 with a yield of ~50% [59].
R' R N Ni N R''' R'' 55 R, R', R'', R''' = Alk R' N R R'' 56 R' N CH=NOH R''' R'' R''' CH2Cl2, H2O R N Ni N N R R' R'' O N R'''
O N
The sodium salt of the oxime 9 in the hydroxylamine hydrochloridepotassium hydroxidewater system gives the oxadiazole 57 with a yield of 78% [16].
NOH NH2OH HCl, KOH, H2O N 9
.
HO O N O 57
NH2 N
The nitroxyl radical of 2,2,3,3-tetramethyl-4-phenylethynyl-2,5-dihydro-1H-pyrrole-3-carbaldehyde (58) reacts in the hydroxylamine hydrochloridepotassium carbonateethanolwater system with the formation of the pyrrolo[3,4-c]pyridine radical 60 with a yield of 82%. The product 60 is formed through the oxime 59 as intermediate [60].
Ph NH2OH, CHO K CO 2 3 Me Me N O. 58 Me Me Me Me N O. 59 Ph CH=NOH Me Me Me Me N O. 60 Me Me Ph N O
The hydroxyiminopyrroles 61 react with hydrazine with cleavage of the ring and form dihydropyridazine oximes 62 as the only product [61].
R' R' NOH NH2NH2 R'' N 61 R, R', R'' = H, Alk R R'' HN N 62 NOH
Cyclization of 2,5-diphenylpyrrole (63) with the oxime of ethyl bromopyruvate in the sodium carbonatemethylene chloride system leads to ethyl 4a,6-diphenyl-4,4a,7,7a-tetrahydropyrrolo[2,3-e]-1,2oxazine-3-carboxylate (64) with a yield of 36% [20].
CO 2Et NOH Na2 CO 3 Ph N Ph 64 CO 2Et O N
+ Ph N H 63 Ph
Br
The reaction of compound 24 with hydrazine hydrate in acetic acid leads to tetrahydrocinnoline oxime 65 with a 32% yield. The reaction of compound 24 with hydroxylamine hydrochloride gives the spiro derivative of isoxazoline 66 (yield 75%) [22].
NOH OH Me N N 65 O 24 NH2OH.HCl NOH N O NH2NH2.H2O O N N NOH Me
Me
NOH 66
The reaction of the Z-isomer of 2-pyrrolecarbaldehyde oxime 28 with 4-bromo-1-butene leads to C-2-pyrrolyl N-3-butenyl nitrone 67 with a yield of 43%. Intramolecular thermocycloaddition of 67 leads to exo-C-2-pyrrolyl-1-aza-7-oxabicyclo[2.1.1]heptane (68) with a yield of 49% [62].
_
O PhMe 110
oC
Br N H 28 CH=NOH EtONa, EtOH N H 67
+ O N
N N H H 68
The thermal cyclization of 1-allyl-2-pyrrolecarbaldehyde (69) was described in [63]. In this case in boiling xylene the oxime 69 gives the dimer 70 with a yield of 52%.
Me N CH=NOH 140 oC H N O N H N H CH=NOH
69
70
2.4. The Beckmann Rearrangement of Pyrrole Oximes The Beckmann rearrangement is one of the most characteristic reactions of oximes. In the presence of phosphorus pentachloride [27] or hydrochloric acid [7] the E- and Z-isomers of pyrrole ketoximes give acylaminopyrroles. A simple method was also developed for the synthesis of the isomeric derivatives of pyrroloazepines 73 and 74 by the rearrangement of syn- and anti-4-tosyloxyimino-4,5,6,7-tetrahydroindoles 72 [64].
SO2
Me H N HN NH
N Me 71 Me SO2O
N DMF 73 O N H N Me
N 72 Me 74
N Me
Reaction 1,3-dimethyl-1,5,6,7-tetrahydro-4H-indol-4-one oxime in polyphosphoric acid leads to 1,3-dimethyl-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one [65]. During the treatment of 3-ethoxycarbonyl-2-methyl-4,5-dioxobenzo[g]indole 5-monoxime (75) in an alkaline medium 5-(2-cyanophenyl)-3-ethoxycarbonyl-2-methyl-1-phenyl-4-pyrrolecarboxylic acid (76) was formed with a yield of 87% as a result of a Beckmann rearrangement [66].
OH N N Ph 75 76
COOEt PhSO2Cl, NaOH Me
HOOC CN N Ph
COOEt Me
3. THE BIOLOGICAL ACTIVITY OF DERIVATIVES OF PYRROLE OXIMES 3.1. Action on the Cardiovascular System The pyrrole oximes 77, which exhibited anti-serotonin 5-HT2-receptor activity, were proposed as antihypertensive and anticoagulation drugs [67, 68]. 10
HON HON N N (CH2)n O N O 77 R = H, Alk; n = 35 N R N F N Me O 78 N Ph
The oxime derivatives of pyrroloazepines also exhibited vasodilating activity. Among these compounds the oxime 78 was mentioned as one of the most active [69, 70]. The blocking action of pyrrole O-(2-alkylamino-2-hydroxypropyl)oximes 79 on -adrenoceptors has also been investigated [71].
N Me
CR=NOCH2CH(OH)CH2NHCMe2R' 79 R = H, Alk, Ar; R' = H, Me
3.2. Antidepressant Activity The tricyclic derivatives of the pyrrole oximes 80 and 81 exhibited high antidepressant activity [72, 73].
N 80
O-(CH2)n-NR'R''
N R 81
O-(CH2)n-NR'R''
R,R',R'' = H, Alk; n = 2, 3
3.3. Analgesic and Anti-inflammatory Activity Oxime derivatives containing pyrrole and pyridine fragments were studied as inhibitors of Raf kinase [74]. All these compounds can be used as analgesics and agents against migraine, and the oxime 82 is one of the most active.
11
N H HON 82 O NMe2
The O-lauroyl- and O-nicotinoyloximes of 1-methyl-2-acetylpyrrole possess anti-inflammatory activity [36].
3.4. Bactericidal Activity Derivatives of 2-pyrrolecarbaldehyde oximes have exhibited high bactericidal activity [75-77]. The pyrrole oxime fragment also enters into the structure of certain penicillin antibiotics [78]. It was recently shown that ethers of pyrrole oximes 83 have high bactericidal activity against resistant strains of bacteria [79].
Me O O O Me O N H O 83 R, R' = Alk OH Me O NOR' R
Me MeO
3.5. Pyrrole Oximes as Fungicides and Plant Growth Regulators The ethers of pyrrole oximes exhibit high fungicidal, insecticidal, and acaricidal activity [80]. Among these compounds, in particular, the ether 84 should be mentioned [81].
NOMe N MeO 2C 84 Me CHOMe
The ethers of pyrrole amidoximes [(pyrrolyl)C(NH2HCl)=NOCHR'CO2R", where R', R" = alkyl] exhibited good herbicidal activity [82].
12
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15
HETEROCYCLIC QUINONES IN THE NENITZESCU REACTION. SYNTHESIS OF FUROAND PYRROLOQUINOLINES FROM 2-METHOXYCARBONYL-4-OXO-5,8-QUINOLINEQUINONE
T. I. Mukhanova1, L. M. Alekseeva1, A. S. Shashkov2, and V. G. Granik1 Derivatives of furo[2,3-f]quinoline were synthesized by the reaction of the enamines of acetylacetone and benzoylacetone with 2-methoxycarbonyl-4-oxo-5,8-quinolinequinone. A derivative of pyrrolo[2,3-h]quinoline was obtained from N-benzyl--aminocrotonic ester. Keywords: 3-acyl-5-hydroxy-7-methoxycarbonyl-9-oxofuro[2,3-f]quinolines, 1-benzyl-3-ethoxycarbonyl-8-hydroxy-5-methoxycarbonyl-2-methyl-7-oxopyrrolo[2,3-h]quinoline, 2-methoxycarbonyl-4oxo-5,8-quinone, enamine, Nenitzescu reaction. The new path that we developed for the synthesis of tricyclic systems containing indole or benzofuran rings as fragments is based on the use of heterocyclic quinones in the Nenitzescu reaction and the use of derivatives of indazolequinone [1], benzofuranquinone [2], and isoquinolinequinone [3] for this purpose. The present work was devoted to the use of an arbitrary quinone 2-methoxycarbonyl-4-oxo-5,8-quinolinedione (1), synthesized by the method in [4]. It is known [5] that the electron density at the -positions of 4-pyridones is substantially increased and it is at these positions that the reactions with electrophilic reagents are directed. From this it can be concluded that the carbonyl at the position 5 of the quinone 1 (added to the -position of the pyridine ring) is a weaker electron acceptor than the quinone carbonyl at position 8 (structure A), while the reactions with nucleophilic reagents, which the enamines (the second component of the Nenitzescu reaction) are, will take place preferentially at position 6.
O
4 3 2 8 8a
O
6 7 5 4a
O _
_ O
N1 H 1
COOMe O
+ N H
COOMe O
+ N H
COOMe O A
+ N H
COOMe
__________________________________________________________________________________________ Federal State Unitary Enterprise "The State Scientific Center NIOPIK" (Scientific-Research Institute of Organic Intermediates and Dyes), Moscow 103787; e-mail: makar-cl@ropnet.ru. 2 N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow 117913. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 20-26, January, 2004. Original article submitted July 19, 2001. 16 0009-3122/04/4001-00162004 Plenum Publishing Corporation
1
In addition it can be supposed that, as for isoquinolines, the presence of the electron-withdrawing pyridone ring will lead to difficulty in the oxidation of the intermediate hydroquinone adducts [3], and this must give rise to the preferential formation of the furo- and not the pyrrolotricyclic systems. The reaction of the quinone 1 with the enamino ketones 2a-e leads exclusively to 3-acyl-5-hydroxy-7methoxycarbonyl-2-methyl-9-oxofuro[2,3-f]quinolines 3a,b. Compounds 3a,b were subjected to O-acetylation in order to increase the solubility, and their NMR spectra were investigated in this form 4a,b. In spite of the theoretical treatment, which determines the probability of the formation of compounds 3a,b, it is still necessary to consider the possible production of the isomeric structures 5.
Me O O COR" O R"OC AcOH Me NRR' 2ae N OH H 3a,b a R" = Ph, b R" = Me Ac2O OH
5 4 5a 9a 9 9b
+
N O 1 H COOMe
COOMe
O
6 7 8
Me R"OC COOMe
2 1 3 3a 4 5 5a
O
9b 9a
OCOMe
9 8
R"OC Me
3a 3 2 1
N H 5
OCOMe MeCOO OCOMe
COOMe
4a,b
R"OC Me
N O 5A
COOMe
a R = H, R' = R" = Me; b R = H, R' = p-MeC6H4, R" = Me; c R = R' = Me, R" = Ph; d R = H, R' = CH2Ph, R" = Ph; e R = H, R' = p-MeOC6H4, R" = Ph
The 1H NMR spectra of the obtained compounds correspond well to both structures 4 and 5 (see Experimental), and it is impossible on their basis to provide an unambiguous answer to the question as to whether annelation of the furan ring is in fact realized at the 5,6 bond of the quinoline ring. Examination of the HMBC spectra (1H13C correlations through two and three bonds, see Table 1) of the obtained acetyl derivatives shows that the derivatives 3 are in fact formed as a result of condensation of the quinone 1 and the enamines 2. Thus, in the HMBC spectrum of compound 4a the signal of the 8-H proton (8.11 ppm) has two correlation peaks with the signals of C(9a) and C(9) (112.2 and 152.6 ppm respectively), while the signal of the 4-H proton (7.72 ppm) has three correlation peaks with signals at 139.5, 142.2, and 144.6 ppm, belonging to C(9b), C(5a), and C(5). (It is not possible to assign these signals specifically, which incidentally is not important for solution of the main task, i.e., determination of the structure of the synthesized compounds.) The presence of three correlation peaks for the 4-H signal with the signals of the carbon atoms, observed in the 17
TABLE 1. The 13C NMR Chemical Shifts of Compounds 4a,b, and 8 and the Proton-Carbon Correlations in the HMBC spectrum (1H13C Correlation through Bonds 2 and 3)*
Carbon atoms 2 3 3 4 5 5 7 8 9 9 9
13
, , ppm 4b 164.1 (2-3) 117.8 (2-3) 124.4 (nc) 116.5 (nc) *3 *4 *3 115.4 (nc) 152.6 (8-) 111.9 (8-) *4
4 163.1 (2-3) 117.1 (2-3) 125.1 (nc) 115.9 (nc) *2 *2 146.9 (nc) 115.7 (nc) 152.6 (8-) 112.2 (8-) *2
Carbon atoms 2 3 3a 3b 5 6 7 7 8 9 9 1-CH2C6H5
13
, , ppm 8
2-3 3-R
5( and 9)OCOCH3
7-O3
14.5 190.4 (-2'6') CO 138.3 (-3'5') 1 128.7, 128.8 2'6'3'5' 133.1 (-2'6') 4' 168.5 (3) 169.4 (3) 20.5 CH3 20.7 CH3 164.1 (3) 52.9 3
15.3 193.4(CH3) 30.5 CH3
CO
2-3 3-OC2H5
145.8 (1-CH2, 2-CH3) 105.5 (2-CH3) 112.1 (9-H) *5 *5 112.2 (NH) 176.3 (nc) 114.3 (9-H, NH, 6-H) 145.4 9-) 102.3 (nc) 135.4 (1-2) 46.3 CH2 136.0 (3',5'-H) C1' 125.8 C2'6' 128.6 C3'5' 127.3 C4' 13.8 167.1 (2) CO 61.1 CH2 12.9 CH3 162.2 (3, 6-, NH) CO 53.1 CH3 169.0(CH3) 20.8 CO CH3
168.4 (3) 5-COOCH3 169.3 (3) 20.4 CH3 20.6 CH3 164.1 (3,8-) CO 8-OCOCH3 52.8 3
_______ * The numbers of the protons with which correlation peaks are observed in the HMBC spectrum are given in parentheses (nc = no correlation). The signals of the protonated carbon atoms were assigned by means of the HSQC spectrum. *2 139.6 (4-), 142.2 (4-), 144.6 (4-). *3 144.8 (nc), 147.0 (nc). *4 139.4 (4-), 141.8 (4-). *5 135.2 (nc), 136.7 (nc).
downfield region, indicates conclusively in favor of structure 4. If compounds with structure 5 were obtained, the signal of the proton of the pyrimidine fragment would have correlation peaks similar to those observed in the spectrum, but a correlation peak with an upfield signal for the C(5a) atom (identical with C(9a), 112.2 ppm in structure 4) would be observed for the 4-H signal in addition to the two correlation peaks with the downfield atoms C(9b) and C(5). This is the main argument in favor of the idea that structure 5 is not realized; a general correlation peak for the signals of the two aromatic protons and a signal for a carbon atom with 112.2 ppm are not observed in the spectrum. The same logic indicates that compound 4b has an analogous structure. Consequently, it is possible to state that the reaction of the quinone 1 with the enamines 2 takes place at the position 6 of the quinone with the formation of compounds having structure 3.
18
In a continuation of the present research a compound having a weaker electron-withdrawing substituent at the -position, i.e., N-benzyl--aminocrotonic ester 6, was chosen as enamine component. The reaction of the quinone 1 and the enamine 6 led to the tricyclic compound 7, which was converted into the O-acetyl derivative 8. The data from the 1H NMR spectrum, the HMBC spectra (Table 1), and also the ROESY spectrum and the results from the mass spectra make it possible to determine reliably the structure of compound 8. Its highresolution mass spectrum contains a molecular-ion peak with m/z 476.1582 and ion peaks at 434 (M+ MeCO), 388 (M+ MeCOEtOH), 343 (M+ MeCOPhCH2), and 297 (M+ MeCOEtOHPhCH2). In the ROESY spectrum there is a strong correlation peak at 5.59/7.27 ppm. This means that the PhCH2 group and the 9-H proton are sterically close. (It is not possible to imagine any other ring closure in which the benzyl substituent would be close to 6-H.) In the HMBC spectrum at 176.3 ppm there is a downfield signal not having a correlation peak with the signals of any protons and assigned to the 7-CO carbon atom. The presence of the pyridone fragment is also favored by the presence of the NH signal in the 1H NMR spectrum in the region of 14 ppm. It can be supposed on the basis of these data that the reaction in this case takes place in the unusual direction:
O COOEt 1 O
+
Me NHCH2Ph Me PhCH2NH OH H N N OH H COOEt COOMe O N OH H COOEt COOMe
OH
PhCH2
PhCH2 Me
N H COOEt 7
COOMe
Me
O
8 9 7a
O
7 6 4 5
PhCH2
9a 2 3
3b 3a
N H 8
COOMe
Me
COOEt
The HMBC spectrum supports the proposed structure; the signal of the proton at position 9 (7.27 ppm) has two correlation peaks with the upfield carbon atoms 112.1 (C(3a)) and 114.3 (C(7a)). Thanks to the presence of a correlation peak in the spectrum at 6.57/114.3 (H-6/C(7a)) it is possible to assign these signals having chemical shifts of similar value. The signal of the 9-H proton also has a correlation peak with a downfield signal at 145.4 ppm, assigned to C(8) (correlation with C(8) through two bonds). The signal of the 6-H proton (6.57 ppm) has two correlation peaks with C(7a) (114.3 ppm) and with 5-CO (162.2 ppm). (In the spectrum there is a correlation peak at 4.00/162.2 (OMe/5-CO)). For the signal of the NH proton (14 ppm) there are three correlation peaks with the following signals: 5-CO (162.2), C(6) (112.2), and C(7a) (143.3 ppm). The obtained data undoubtedly indicate that the interaction of the quinolinequinone 1 and the enamino ester 6 leads to 1-benzyl-8-hydroxy-2-methoxycarbonyl-3-ethoxycarbonyl-7-oxopyrrolo[2,3-h]quinoline (7), containing a 6-hydroxyindole fragment. Whereas the retardation of the benzofuran synthesis with decrease in 19
the electron-withdrawing strength of the substituent at the -position of the enamine does not seem unusual the benzofuran cyclization of the intermediate hydroquinone adduct depends directly on the electron deficiency at the -position of the enamine fragment the formation of 6-hydroxyindoles has until now only been observed in cases with variation of the structures of the initial enamines (but not quinones), e.g., in the transition from N-alkyl- to N-aryleneamines or to enamines having strong electron acceptors such as cyano and particularly nitro groups at the -position [6]. In view of the fact that the Nenitzescu reaction very often takes place ambiguously and the yield of the obtained 6-hydroxy derivative is low it is not possible to claim that the use of the heterocyclic quinone 1 in reaction with the enamine 6 changes the direction of this reaction completely and fundamentally and excludes the formation of the normal 5-hydroxyindoles for the Nenitzescu reaction. However, the fact that the structure of the quinone can change this direction so dramatically is a new previously unknown and unexpected phenomenon and requires further detailed investigation.
EXPERIMENTAL The 1H NMR spectra were recorded on a Bruker AC-200 spectrometer (200 MHz). The 2D HMBC NMR spectra (1H and 13C) were obtained on a Bruker DRX-500 spectrometer (at 500 and 125 MHz respectively) using the manufacturer's standard procedures. The high-resolution mass spectra were obtained on a Finnigan MAT TCQ 700 spectrometer (triple quadrupole) with direct injection of the sample into the ion source. The purity of the obtained substances was monitored on Silufol UV-254 and Kieselgel 60 F-254 (Merck) in ethyl acetate. 3-Benzoyl-5-hydroxy-7-methoxycarbonyl-2-methyl-9-oxofuro[2,3-f]quinoline (3a). A mixture of the quinone 1 (0.23 g, 10 mmol), 2-p-anisidino-3-benzoyl-2-propene (2e) (0.27 g, 10 mmol), and glacial acetic acid (4 ml) was heated to 60-70C, kept at this temperature for 5 min, and then left at room temperature. The next day the crystals that separated were filtered off, washed on the filter with petroleum ether, and dried, and 0.14 g (37.1%) of the furoquinoline 3a was obtained; mp >300C (DMF) (decomp.). High-resolution mass spectrum. Found: m/z 377.0888 [M]+. 21H15NO6. Calculated: M = 377.359. 3-Acetyl-5-hydroxy-7-methoxycarbonyl-2-methyl-9-oxofuro[2,3-f]quinoline (3b). The compound was obtained similarly to compound 3a from the quinone 1 and the enamine 2b with a yield of 59%; mp >300C (DMF) (decomp.). High-resolution mass spectrum. Found: m/z 315.077 [M]+. 1613N6. Calculated: M = 315.288. 1-Benzyl-3-ethoxycarbonyl-8-hydroxy-5-methoxycarbonyl-2-methyl-7-oxopyrrolo[2,3-h]quinoline (7). The compound was obtained similarly to compound 3a from the quinone 1 and the enamine 6 with a yield of 32%. After recrystallization from dioxane the pure pyrroloquinoline 7 was isolated with a yield of 13%, calculated on the initial quinone 1; mp 285-287C. High-resolution mass spectrum. Found: m/z 434.1487 [M]+. 2422N2O6. Calculated: M = 434.486. 5,9-Diacetoxy-3-benzoyl-7-methoxycarbonyl-2-methylfuro[2,3-f]quinoline (4a). To compound 3a (0.38 g, 10 mmol) acetic anhydride (15 ml) and three drops of sulfuric acid were added. The reaction mixture was heated until the precipitate had dissolved, kept at room temperature for 24 h, and poured into cold water (150 ml). The precipitate was filtered off, washed with water on the filter, and dried. The yield of compound 4a was 0.38 g (82%). The compound was purified by column chromatography on silica gel. The eluent was ethyl acetate. The solvent was distilled, and compound 4a was obtained with a yield of 43%; mp 192-194C (ethanol). High-resolution mass spectrum. Found: m/z 419.099 [M]+. 2317N7. Calculated: M = 357.32. 1H NMR spectrum, , ppm: 2.40 (3, s, 5(9)-3); 2.51 (3, s, 9(5)-3); 2.49 (3, s, 2-3); 3.95 (3, s, 7-C3); 7.43 (2, t, 3'-, 5'-H); 7.70 (1, t, 4'-H); 7.72 (1, s, 4-); 7.83 (2, d, 2'-, 6'-H); 8.11 (1, s, 8-). 20
5,9-Diacetoxy-3-acetyl-7-methoxycarbonyl-2-methylfuro[2,3-f]quinoline (4b). The compound was prepared similarly to compound 4a from the furoquinoline 3b and acetic anhydride with a yield of 50%. The individual compound was likewise isolated by column chromatography on silica gel. High-resolution mass spectrum. Found: m/z 357.084 [M]+. 1815N7. Calculated: M = 357.32. 1H NMR spectrum, , ppm: 2.47 (3, s, 5(9)-3); 2.58 (3, s, 9(5)-3); 2.67 (3, s, 3-C3); 2.93 (3, s, 2-3); 3.98 (3, s, 7-3); 8.13 (1, s, 8-); 8.29 (1, s, 4-). 8-Acetoxy-1-benzyl-3-ethoxycarbonyl-5-methoxycarbonyl-2-methyl-7-oxopyrrolo[2,3-h]quinoline (8). The compound was prepared similarly to compound 4a from the pyrroloquinoline 7 and acetic anhydride with a yield of 90%; mp 245-247C (methanol). High-resolution mass spectrum. Found: m/z 476.1582 [M]+. 2624N27. Calculated: M = 476.49. 1H NMR spectrum: 1.40 (3, t, 3-23); 2.27 (3, s, 8-3); 2.69 (3, s, 2-C3); 4.00 (3, s, 5-3); 4.44 (2, t, 3-23); 5.59 (2, s, C2Ph); 6.57 (1, s, 6-); 7.02 (2, d, 2'-, 6'-H); 7.27 (2, m, 9-, 4'-H); 7.32 (2, t, 3'-, 5'-H); 14.00 (1, N). The work was carried out with financial support from the Russian Fund for Fundamental Research (grant No. 99-03-32973).
REFERENCES 1. 2. 3. 4. 5. 6. V. M. Lyubchanskaya, L. M. Alekseeva, S. A. Savina, and V. G. Granik, Khim. Geterotsikl. Soedin., 1482 (2000). V. M. Lyubchanskaya, L. M. Alekseeva, S. A. Savina, and V. G. Granik, Khim. Geterotsikl. Soedin., 1012 (2003). T. I. Mukhanova, L. M. Alekseeva, and V. G. Granik, Khim. Geterotsikl. Soedin., 670 (2002). J. Baxter and W. R. Phillips, J. Chem. Soc. Perkin Trans. I, 2374 (1973). D. Barton and W. D. Ollis, Comprehensive Organic Chemistry [Russian translation], Vol. 8, Khimiya, Moscow (1985), p. 30. V. G. Granik, V. M. Lyubchanskaya, and T. N. Mukhanova, Khim.-Farm. Zh., 27, No. 6, 37 (1993).
21
PREPARATIVE SYNTHESIS OF 7-CARBOXY-2-R-ISOINDOL-1-ONES

A. V. Varlamov, E. V. Boltukhina, F. I. Zubkov, N. V. Sidorenko, A. I. Chernyshev, and D. G. Grudinin A preparative method for the synthesis of 7-carboxy-2-R-isoindol-1-ones was developed on the basis of the [4+2] cycloaddition of secondary furfurylamines to maleic anhydride. Keywords: isoindolones, furfurylamines, intramolecular DielsAlder reaction. Isoindolones, or phthalimides, can be obtained from phthalic anhydride [1] and various derivatives of phthalic acid [2, 3] by the oxidation of 2-R-1-methoxycarbonylisoindoles [4]. Functionally substituted isoindolones, from which various condensed heterocyclic systems containing an isoindole fragment can be obtained, are of interest at the synthetic level. Great promise in this direction is opened up by the recently developed method for the synthesis of 1-isoindolones based on the transformation of nitrogencontaining tricyclic compounds 2,3,7,7a-tetrahydro-3a,6-epoxy-2-R-isoindol-1-ones, which can be obtained with high yields from N-alkyl(aryl)-N-furfurylacrylamides by intramolecular [4+2] cycloaddition [5-12]. The epoxyisoindolones can also be obtained by the four-component condensation of furfural and benzylamine or furfurylamine and benzaldehyde with derivatives of maleic and fumaric acids [13]. In the context of the development and study of the applicability limits for the last method we propose a two-stage preparative method for the synthesis of 7-carboxy-2R-isoindol-1-ones 2, based on the [2+4] cycloaddition of maleic anhydride to N-substituted furfurylamines 1a-j. The initial furfurylamines 1a-j were prepared by reduction of the respective Schiff bases with sodium borohydride in ethanol. Cycloaddition of maleic anhydride to the amines 1a-j was conducted in benzene at 25C. The reaction takes place stereoselectively and in most cases with high yields (Table 1). The carboxy-substituted epoxyisoindolones 2a-j are formed through the initial formation of the N-furfurylamide of maleic acid 2*, which is then transformed through an exo transition state into the epoxy derivative 2. It is significant that N-acetyl-N-phenylfurfurylamine does not enter into [4+2] cycloaddition with maleic anhydride even after prolonged boiling in xylene, which provides indirect evidence for the described reaction path. It is interesting to note the important role of the substituent R at the nitrogen atom of the furfurylamines 1. Thus, Z-4-(2-furylmethylamino)-4-oxobut-2-enoic acid, which does not undergo an intramolecular DielsAlder reaction and does not enter into reaction with an excess of maleic anhydride even after heating to 150C, is formed with a quantitative yield during the reaction of furfurylamine with maleic anhydride.
__________________________________________________________________________________________ Russian University of the Friendship of Peoples, Moscow 117198; e-mail: avarlamov@sci.pfu.edu.ru, fzubkov@sci.pfu.edu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 27-33, January, 2004. Original article submitted December 25, 2001. 22 0009-3122/04/4001-00222004 Plenum Publishing Corporation
10
O
7 6
H O 1aj N R
O
1 2 3 5
COOH O H3PO4 70100 oC
COOH
O N R
C6H6, 25 oC
N R 2aj
3ai
O N R
O COOEt O O COOH N 2* Ph 4
COOEt
O N Ph
a R = Ph; b R = Bn; c R = C6H4Cl-m; d R = C6H4NO2-p; e R = C6H4NO2-m; f R = tetrahydrofuryl; g R = cyclohexyl; h R = methoxyethyl; i R = cyclopropyl; j R = furfuryl
In spite of existing data on the effective [4+2] cycloaddition of maleic anhydride to furfuryl alcohols [14, 15], we were unable to realize the reaction of maleic anhydride with secondary furfurylamines containing the reactive functional groups OH or NR2 in the radical R. During an attempt at cycloaddition to N-(-hydroxyethyl)-, N-(-pyridyl)-, and N-(-pyridyl)furfurylamines rapid polymerization of the reaction mixtures occurred. TABLE 1. The Characteristics of Compounds 2a-j, 3a-i, 4, and 5
Compound 1 2a 2b 2c 2d 2e 2f 2g 2h 2i 2j 3a 3b Empirical formula 2 C15H13NO4 C16H15NO4 C15H12NO4Cl C15H12N2O6 C15H12N2O6 C14H17NO5 C15H19NO4 C12H15NO5 C12H13NO4 C15H13NO5 C15H11NO3 C16H13NO3 Found, % Calculated, % 4 4.79 4.79 5.27 5.26 3.95 3.93 7.82 7.80 7.84 7.80 6.08 6.09 6.84 6.86 5.87 5.93 5.53 5.53 4.72 4.73 4.37 4.35 4.85 4.87 mp, N 5 5.18 5.17 4.93 4.91 4.59 4.58 8.84 8.86 8.90 8.86 5.03 5.01 5.04 5.05 5.27 5.53 5.93 5.96 5.05 5.09 5.52 5.53 5.26 5.24 6 184-185.5* 164 179-181* 202-204 205-207 134-136 191-192 127-128.5 168-171.5 146-148 227-230 177-178.5* Yield, % 7 86 90 89 74 80 37 90 92 35 95 46 33
C 3 66.43 66.42 67.35 67.37 58.90 58.92 56.99 56.96 56.95 56.96 60.23 60.21 64.97 64.98 56.73 56.92 61.29 61.28 65.44 65.45 71.13 71.15 71.94 71.91
23
TABLE 1 (continued)
1 3c 3d 3e 3f 3g 3h 3i 4 5 2 C15H10NO3Cl C15H10N2O5 C15H10N2O5 C14H15NO4 C15H17NO3 C12H13NO4 C12H11NO3 C17H17NO4 C17H15NO3 3 62.62 62.60 60.41 60.40 60.38 60.40 64.34 64.36 69.50 69.49 61.55 61.28 66.34 66.36 68.22 68.23 72.59 72.60 4 3.49 3.48 3.35 3.35 3.36 3.35 5.78 5.75 6.56 6.56 5.51 5.53 5.04 5.07 5.60 5.69 5.56 5.34 5 4.89 4.87 9.36 9.39 9.38 9.39 5.33 5.36 5.40 5.40 5.81 5.92 6.48 6.45 4.70 4.68 4.95 4.98 6 229.5-230* 297 (dec.)*2 239-240*2 130-132* 245-246* 168.5-170.5 213-213.5 133-134*3 106-107*
4
7 48 30 52 56 37 30 22 75 86
_______ * Recrystallization from a mixture of i-PrOH and DMF. *2 DMSO. *3 Ethyl acetate. *4 from a mixture of hexane and ethyl acetate.
TABLE 2. The Spectral Characteristics of Compounds 2a-5

Compound 2a 2b 2c 2d 2e 2f 2g 2h 2i 2j 3a 3b 3c 3d 3e 3f 3g 3h 3i 4 5 Molecular mass Found [] 271 285 305, 307 316 316 279 277 253 235 275 253 267 287, 289 298 298 261 259 235 217 299 281
+
IR, , cm-1 NCO 1669 1659 1680 1680 1675 1680 1660 1625 1630 1660 1610 1600 1583 1610 1589 1690 1615 1610 1600 1615 1610 1690 1640 COO 1729 1729 1730 1705 1728 1720 1730 1715 1710 1725 1714 1713 1710 1705 1711 1705 1700 1720 1715 1725 1715 OH 2460 2485 2480 2400 2500 2480 2400 2460 2460 2460 2300 2370 2400 2410 2380 2380 2300 2280
Calculated 271 285 305, 307 316 316 279 277 253 235 275 253 267 287, 289 298 298 261 259 235 217 299 281
24
TABLE 3. The 1H NMR Spectra of N-R-4-Oxo-10-oxa-3-azatricyclo[5.2.1.01,5]dec-8-ene-6-carboxylic Acids 2a-j and Ethyl N-Phenyl-4-oxo-10-oxa-3-azatricyclo[5.2.1.01,5]dec-8-ene-6-carboxylate (4) (TMS)
Compound 2a 2b 2c 2d 2e 2f 2A-H d 2B-H d 4.06 d 3.44 d 4.06 d 4.18 d 4.19 d 3.92 d Chemical shift, , ppm* 6-H d 7-H 8-H 2.60 d 2.51 d 5.05 d 4.98 d 6.49 dd 6.40 dd SSCC (J, Hz) 7,8 8,9 1.8 1.5 1.3 1.7 1.5 0 5.9 5.7 5.6 5.7 5.5 5.8
COOH
5-H d 3.07 d 2.84 d 3.07 d 3.15 d 3.14 d 2.89 d
9-H 6.64 d 6.54 d
Others
2, 2B
5,6 9.1 9.2 9.2 9.1 9.2 9.2
Others
12.15 br. s 4.55 d 3.89 d 4.52 d
2.59 d 5.02 br. s 6.47 br. d 6.62 d 2.67 d 2.65 d 2.80 d 5.03 d 5.07 d 5.26 6.48 dd 6.51 dd 6.45 d 6.62 d 6.66 d 6.50 d
4.58 d 12.25 br. s 4.64 d 9.41 br. s 4.23 d
2g 2h 2i 2j
3.84 d 4.05 d 3.91 d 3.96 d
3.82 d 3.62 d 3.46 d 3.78 d
2.86 s 2.74 d 2.46 d 3.20 d 2.80 d 2.79 d 2.50 d
5.32 s 4.96 d 4.97 d 5.35 d
6.48 s 6.42 dd 6.57 d 6.41 dd 6.50 dd 6.53 d 6.46 d
4.42 d
4.19 d
2.98 d
2.79 d 5.19 br. s 6.48 br. d 6.58 d
7.66 (2, d); 7.38 (2, t); 11.7 7.14 (1, t) 7.33-7.21 (2H, m); 4.42 (1H, d); 11.7 4.34 (1, l) 7.88 (1H, br. s); 7.49 (1H, d); 11.5 7.40 (1H, t); 7.17 (1H, d) 8.22 (2H, AA'); 7.91 (2H, BB') 11.6 8.76 (1H, t); 7.96 (2H, dd); 11.6 7.69 (1H, t) 4.07(1H, dd); 3.95-3.65 (3H, m); 12.5 3.16 (1H, dd); 2.10-1.75 (2H, m); 1.70-1.50 (2H, m) 3.85 (1H, m); 1.90-1.60 (10H, m) 11.5 3.60-3.40 (3H, m); 3.26 (3H, s); 11.6 3.17 (1H, m) 2.67 (1H, m); 0.66 (4H, m) 11.5 7.38 (1H, dd); 6.34 (1H, dd); 12.2 6.30 (1H, dd); 4.78 (1H, d); 4.30 (d) 7.58 (2H, d); 7.35 (2H, t); 11.4 7.14 (1H, t); 4.27 (m, 23); 1.32 (t, 23)
Jm = Jmp = 7.3 JAB = 15.3 (2Ph) J5'6' = J4'5' = 8.0 JAB 9.2 J5'6' = J4'5' = 8.2 J2'4' = J2'6' = 2.1 JAB = 14.0 JA2' = JB2' = 7.0 (2CHO) J1'2' = J1'3' 5.6 JAB = 15.6; J' = 3.4 J' = 0.8; J = 1.8 (CH2furyl) Jm = Jmp = 7.6 JCH2CH3 = 7.0
9.2 9.2 9.0
1.8 1.3 1.5
5.8 5.6 5.8
8.9
1.0
5.5
_______ * Solvent: DMSO-d6 (compounds 2a-i) and CDCl3 (compounds 2j and 4).
25
26
TABLE 4. The 1H NMR Spectra of Solutions of 2-R-7-Carboxyisoindolin-1-ones 3a-i and 7-Ethoxycarbonyl-2phenylisoindolin-1-one (5) (TMS)
Compound 3a 3b 3c 3d 3e 3f Chemical shift,, ppm* 4-H 5-H 6-H 7.85-7.70 m 7.80-7.76 m 7.88 br. d 7.82 t 8.49 dd 8.08 br. d 7.97 br. d SSCC, (J, Hz) 5,6 6.3 7.2 7.3 7.2
COOH 15.53 s 15.74 br. s
3A-H
3B-H
Others 7.76 (1H, d); 7.50 (2H, t); 7.34 (2H, t) 7.39-7.26 (5H, m); 4.57 (2H, s) 8.02 (1H, t); 7.80 (1H, dd); 7.51 (1H, t); 7.33 (1H, dd) 8.27 (2) and 8.12 (2, 'BB') 8.83 (1H, br. s); 8.23 (1H, dd); 8.09 (1H, dd); 7.78 (1H, t) 4.16 (1H, dq); 3.97 (1H, dd); 3.87 (1H, t); 3.77 (1H, dd); 3.55 (1H, dd); 2.10 (1H, dd); 1.93 (2H, ); 1.63 (1H, dd. d) 4.08 (1H, m); 1.93-1.18 (10H, m) 3.82 (2H, t); 3.64 (2H, t); 3.29 (3H, s) 3.16-3.03 (1H, m); 1.00-0.85 (4H, m) 7.83 (2H, d); 7.40 (2H, t); 7.16 (1H, t); 4.50 (m, 23); 1.43 (t, 23)
3A,3B 18.5
4,5
4,6 2.6
Others Jom = Jmp = 7.5 J5'6' = J5'4' = 7.9; J2'6' = J2'4' = 1.3 JAB 9.1 J5'6' = J5'4' = 8.2; J4'6' = 1.3
5.04 s 4.81 s 5.18 s 5.09 s 5.25 s 4.83 d 4.64 d
7.2 7.3 7.2
0 0 0
7.91 d 7.65 d
7.70-7.60 m 7.85 t 7.99 d 7.69 t 8.38 d
3g 3h 3i 5
15.94 br. s
4.69 s 4.76 s 4.63 s 4.83 s
7.88 d 7.91 dd 7.86 br. d
7.79 t 7.81 t 7.79 t 7.60 br. s
8.16 d 8.16 dd 8.15 br. d
7.4 7.6 7.3
0 1.4 0
7.4 7.6 7.3
Jom = Jmp = 7.6; JCH2CH3 = 7.2
_______ * Solvent: DMSO-d6 (compounds 3b-i) and CDCl3 (compounds 3a and 5).
To convert the epoxy derivatives 2a-j into the 7-carboxyphthalimidines 3a-i we used hydrochloric and sulfuric acids at various concentrations, 85% phosphoric acid, and boron trifluoride etherate in boiling dioxane. The largest yields of compounds 3 were obtained with BF3Et2O, but from the practical standpoint it is better to use 85% phosphoric acid in the range of 70-100C. In spite of the fact that the yield of the desired products here is reduced by 10-15% the procedure for the synthesis and the isolation of the isoindolones 3 is greatly simplified. It was not possible to select conditions for the aromatization of the N-furfuryl-substituted epoxide 2j. During esterification of the acids 2a and 3a the corresponding monoesters 4 and 5 were obtained. The mass spectra of compounds 2 and 3 (Tables 1 and 2) contain low-intensity peaks of molecular ions, corresponding to their molecular formulas. The readily occurring elimination of a CO2 molecule and retrodiene dissociation (in the case of the adducts 2) are the reason for the insufficient reliability of this method of obtaining evidence for the structure of the synthesized substances. In the IR spectra of the carboxylic acids 2a-j and 3a-i there are characteristic bands for the stretching vibrations of the amide and carboxyl groups in the regions of 1610-1690 and 1705-1730 cm-1 respectively, and there is also a broad band for the associated hydroxy in the region of 2280-2485 cm-1. In the IR spectra of the esters 4 and 5 the band of the ester group appears at 1715-1725 cm-1. The 1H NMR spectra of compounds 2a-j (Table 3) contain three characteristic signals for the interacting protons 7-H, 8-H, and 9-H with chemical shifts of 4.96-5.35, 6.40-6.51, and 6.46-6.66 ppm respectively and spinspin coupling constants 3J78 = 1.3-1.8 and 3J89 = 5.5-5.9 Hz. The absence of the 3J67-exo spinspin coupling constant in the bicyclooxaheptene fragment of the molecule indicates unambiguously the endo arrangement of the 5-H and 6-H protons (J56 = 9.0-9.3 Hz) and the exo arrangement of the carboxyl and amide substituents. The protons of the 2-CH2 group in compounds (2a-j) are chemically nonequivalent and are observed in the spectrum in the form of an AB system. Conversely, in the 1H NMR spectra of compounds 3a-e,g-i the signals of the 3-CH2 protons are equivalent and are observed in the form of a singlet at 4.63-5.25 ppm. Only in the case of the magnetically anisotropic tetrahydrofuryl substituent R do these protons become nonequivalent and appear in the form of an AB system (Table 4).
EXPERIMENTAL The IR spectra were recorded on a Specord IR-75 spectrometer in tablets with potassium bromide. The mass spectra were recorded on an HP MS 5988 mass spectrometer with direct injection of the sample into the ion source with ionizing potential 70 eV. The 1H NMR spectra were recorded in deuterochloroform and DMSO-d6 solutions on Bruker WP-200 (200 MHz) or Bruker WH-400 (400 MHz) instruments with TMS as internal standard. Silufol UV-254 plates were used for thin-layer chromatography (development with iodine vapor). 3-R-4-Oxo-3-azatricyclo[5.2.1.01,5]dec-8-ene-6-carboxylic Acids (2a-j). A mixture of maleic anhydride (0.1 mol) and N-R-furfurylamine 1a-j (0.1 mol) in benzene (100 ml) was stirred at 25C for 2-3 days. The precipitate was filtered off, washed with benzene, and dried at 90C to constant weight. Compounds 2a-j were obtained in the form of finely crystalline powders. The spectral data and physicochemical characteristics of the tricyclic compounds 2a-j are given in Tables 1-3. 2-R-Carboxyisoindolin-1-ones (3a-i). The epoxyisoindolinones 2a-i (0.01 mole) were heated at 70-100C for 1 h in 85% phosphoric acid (40 ml). The reaction mixture was cooled and poured into water. The crystals that separated were filtered off, washed with water to a neutral reaction in the wash water, dried, and recrystallized from a mixture of isopropyl alcohol and DMF. The spectral data and physicochemical characteristics of the isoindolones 3a-i are given in Tables 1-3.
27
Ethyl 4-Oxo-3-phenyl-10-oxa-3-azatricyclo[5.2.1.01,5]dec-8-ene-6-carboxylate (4) and 7-Ethoxycarbonyl-2-phenylisoindolin-1-one (5). To a suspension of compound 2a (or 3a) (0.01 mol) in ethanol (50 ml) we added concentrated hydrochloric acid (1 ml). The mixture was boiled for 10-12 h (monitored by TLC). The reaction mixture was poured into water and extracted with ether (3 50 ml), and the extract was dried with magnesium sulfate. The residue after distillation of the ether was recrystallized from ethyl acetate. The esters 4 and 5 were obtained in the form of white crystals (Tables 1-4). The work was carried out with financial support from the Russian Fundamental Research Fund (grant No. 01-03-32844).
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. D. T. Minh and J. E. Johnson, J. Org. Chem., 42, 4217(1977). J. D. White and M. E. Mann, Adv. Heterocycl. Chem., 10, 113 (1969). R. Bonnett and S. A. North, Adv. Heterocycl. Chem., 29, 341 (1981). R. Fryor, J. V. Early, and L. U. Sternbach, J. Org. Chem., 34, 649 (1969). M. S. Bailey, B. J. Brisdon, D. W. Brown, and K. M. Stark, Tetrahedron Lett., 24, 3037 (1983). D. D. Sternbach, D. H. Rossane, and K. D. Onan, Tetrahedron Lett., 26, 591 (1985). M. E. Gung and J. Gervay, Tetrahedron Lett., 29, 2429 (1988). S. C. Hirst and A. D. Hamilton, J. Am. Chem. Soc., 113, 382 (1991). M. Suzuki, T. Okada, T. Taguchi, Y. Hanzawa, and Y. Iitaka, J. Fluorine Chemistry, 57, 239 (1992). D. Prajapati, D. R. Borthakur, and J. S. Sandhu, J. Chem. Soc. Perkin Trans. I, 1197 (1993). K. H. Doetz, D. Boettcher, and M. Jendro, Inorg. Chim. Acta, 222, 291 (1994). J. B. F. N. Engberts, Pure Appl. Chem., 67, 823 (1995). K. Paulvannan, Tetrahedron Lett., 40, 1851 (1999). A. Pelter and B. Singaram, J. Chem. Soc. Perkin Trans. I, 7, 1383 (1983). A. Pelter and B. Singaram, Tetrahedron Lett., 23, 245 (1982).
28
INVESTIGATIONS IN THE AREA OF AMINES AND AMMONIUM COMPOUNDS. 237.* SYNTHESIS OF 2,2-DIALKYL-4-HYDROXYMETHYLBENZO[f]ISOINDOLINIUM AND 2,2-DIALKYL4-HYDROXYMETHYLISOINDOLINIUM SALTS
E. O. Chukhadzhyan1, A. R. Gevorkyan1, El. O. Chukhadzhyan1, K. G. Shakhatuni1, F. S. Kinoyan1, and G. A. Panosyan2 The ability of the 4-hydroxy-2-butynyl group to participate as ,-unsaturated fragment in basecatalyzed intramolecular cyclization was established. 2,2-Dialkyl-4-hydroxymethylbenzo[f]isoindolinium and 2,2-dialkyl-4-hydroxymethylisoindolinium salts were obtained by the cyclization of dialkyl(4-hydroxy-2-butynyl)(3-phenylpropargyl)- or dialkyl(4-hydroxy-2-butynyl)(3-alkenylpropargyl)ammonium salts. Keywords: alkenylpropargyl and phenylpropargyl groups, 4-hydroxy-2-butynyl group, 2,2-dialkyl-4hydroxymethylbenzo[f]isoindolinium and 2,2-dialkyl-4-hydroxymethylisoindolinium salts, base catalysis, cyclization. Under the conditions of base catalysis quaternary ammonium salts containing groups of the propargyl or allyl type together with 3-alkenyl or 3-arylpropargyl group undergo intramolecular cyclization of the diene synthesis type, forming isoindolinium and dihydroisoindolinium salts and their condensed analogs [2, 3]. In order to reveal the ability of the 4-hydroxy-2-butynyl group to participate in cyclization and in the preparation of new potentially biologically active isoindolinium salts the behavior of dialkyl(4-hydroxy-2butynyl)(3-phenylpropargyl)ammonium bromides 1a-f under the conditions of base catalysis was investigated. It was shown that in the presence of 0.2 mole of aqueous alkali to 1 mole of the salt they readily undergo cyclization, forming 2,2-dialkyl-4-hydroxymethylbenzo[f]isoindolinium bromides 2a-f with yields of 75-80%. Cyclization of the salts 1a-f, in contrast to their propargyl analogs [2, 3], requires treatment of the reaction mixture at 50-55C for 5-10 min, after which spontaneous heating is observed, and the temperature of the reaction mixture rises to 80-85C.
_______ * For Communication 236, see [1]. __________________________________________________________________________________________ Institute of Organic Chemistry, National Academy of Sciences of the Republic of Armenia, Erevan 375091. 2 Center for Research in Molecular Structure, National Academy of Sciences of the Republic of Armenia, Erevan 375014; e-mail: alexsh@msrc.am, henry@msrc.am. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 34-41, January, 2004. Original article submitted September 4, 2000; revision submitted June 28, 2001. 0009-3122/04/4001-00292004 Plenum Publishing Corporation 29
1
+ R 2N _ Hal
CH2C CCH2OH CH2C C
CH2OH _ OH + R2 N _ Hal 2af, 4af
1af, 3af
1a, 2a R = Et; 1b, 2b R = Pr; 1c, 2c R = Bu; 1d, 2d R2 = (CH2)4; 1e, 2e R2 = (CH2)5; 1f, 2f R2 = (CH2)2O(CH2)2; 3a, 4a R = Me; 3b, 4b R = Et; 3c, 4c R = Pr; 3d, 4d R = Bu; 3e, 4e R2 = (CH2)5; 3f, 4f R2 = (CH2)2O(CH2)2; 1a-f, 2a-f Hal = Br; 3a-f, 4a-f Hal = Cl
The initial salts 1a-f were prepared by the reaction of dialkyl-4-hydroxy-2-butynylamines [4] with 3-phenylpropargyl bromide. Dimethyl(4-hydroxy-2-butynyl)(3-phenylpropargyl)ammonium chloride 3a was synthesized by the reaction of dimethyl-3-phenylpropargylamine with chromatographically pure 1-chloro-4hydroxy-2-butyne, prepared by the familiar method [5]. Dialkyl(4-hydroxy-2-butynyl)(3-phenylpropargyl)ammonium chlorides 3b-f were synthesized in the same way. The latter, unlike their bromine analogs 1a-f, undergo cyclization under the conditions of base catalysis under milder conditions, forming 3-hydroxymethylbenzo[f]isoindolinium chlorides 4a-f with yields of 80-85%. It is interesting in relation to the presented results to investigate further the effect of various halide ions on the physiological activity of isoindolinium salts. As shown in the case of the salts 5a-e the 3-alkenyl analogs of the salts 1a-e and 3a-e are also capable of cyclization. The cyclic products 6a-e were obtained with yields of 70-75%.
CH2OH + R2N _ Hal CH2C CCH2OH CH2C 5ac CCX=CH2 _ OH + R2N _ Hal 6ae
5a, 6a R = Me, X = H, Hal = Cl; 5b, 6b R = Et, X = H, Hal = Cl; 5c, 6c R = Et, X = H, Hal = Br; 5d, 6d R = Et, X = Me, Hal = Cl; 5e, 6e R2 = (CH2)2O(CH2)2; X = Me, Hal = Br
Of the products 2, 4, and 6 only the salts 2d-f, 4f, and 6e were obtained in the crystalline form. The IR spectra of the initial salts 1a-f, 3a-f, and 5a-e contain characteristic absorption bands for the disubstituted acetylenic bond at 2220-2230 and for the hydroxyl group at 1020 and 3200-3400 cm-1. In the spectra of the salts 1 and 3 containing the 3-phenylpropargyl fragment there are characteristic absorption bands of the aromatic ring at 1500, 1600, and 3060 cm-1 and of the monosubstituted benzene ring at 690, 720, and 750 cm-1, while in the spectra of their 3-alkenylpropargyl analogs there are absorption bands for the CHCH2 group at 920 and 930 cm-1 or CCH2 group at 890 cm-1 and also the conjugated CC bond at 1580-1610 cm-1. In the spectra of the cyclization products 2a-f and 4a-f respectively there are no absorption bands for the disubstituted CC bond and monosubstituted benzene ring mentioned above, while in the spectra of the cyclic salts 6a-e there are no absorption bands for the CHCH2 and CCH2 fragments characteristic of the initial salts 5a-e. In the IR spectra of the cyclic salts 2a-f and 4a-f there are absorption bands for the 1,2-substituted and pentasubstituted benzene rings at 740, 750, 770, and 870 cm-1 respectively, while in the spectra of the salts 6a-e there are bands for the 1,2,3- and 1,2,3,5-substituted benzene rings at 710, 720 and 850, 860, 1960 cm-1 respectively. The spectra of salts 2a-f, 4a-f, and 6a-e also contain characteristic absorption bands for the hydroxyl group at 1050 and 3200-3500 cm-1.
30
TABLE 1. The Characteristics of the Salts 1a-f4a-f, 5a-e, and 6a-e

Compound 1 1 Empirical formula 2 C17H22BrNO Found, % Calculated, % Hal 3 23.50 23.81 21.76 21.98 20.22 20.41 23.73 23.95 N 4 4.05 4.17 3.54 3.85 3.30 3.57 4.07 4.19 5 75-76 mp, IR spectrum, , cm-1 6 700, 770, 1020, 1500, 3030, 3060, 3200-3500 690, 770, 1020, 1580, 2230, 3030, 3050, 3200-3400 700, 750, 1030, 1510, 1580, 2240, 3200-3400 690, 760, 1020, 1500, 1550, 1600, 2220, 3060, 3200-3300 UV spectrum Commax, pound* nm () 7 8 215 (4.20) 245 (4.25) 245 (4.18) 245 (4.25) 2a Found, % Hal 9 23.35 N 10 3.97 11 *
2
mp,
IR spectrum, , cm-1 12 730, 770, 870, 1050, 1510, 1600, 3060, 3200-3500 730, 760, 870, 1050, 1500, 3030, 3200-3400 750, 870, 1045, 1500, 3030, 3200-3450 730, 760, 860, 1055, 1500, 1560, 1600, 3300-3400
UV spectrum, max, nm () 13 230 (4.51), 285 (3.87), 296 (3.65), 325 (2.70) 233 (4.55), 275 (3.50), 325 (2.62) 232 (4.50), 275 (3.56), 286 (3.59), 325 (2.53) 230 (4.51), 275 (3.45), 285 (3.50), 298 (3.26), 325 (2.56)
1b
C19H26BrNO
100-102
2b
22.45
3.66
*2 *2
1c
C21H30BrNO
120-121
2c
20.15
3.24
1d
C17H20BrNO
110-112
2d
23.68
3.88
224-225
31
32
TABLE 1 (continued)
1 1e 2 C18H22BrNO 3 22.68 22.99 22.60 22.86 13.09 13.47 11.82 12.18 10.88 11.11 10.38 10.22 4 3.85 4.02 3.78 4.00 5.06 5.31 4.52 4.80 4.07 4.38 3.96 4.03 5 130-131 6 690, 720, 740, 1020, 1500, 2230, 3200-3400 690, 780, 1020, 1500, 2240, 3300-3400 700, 770, 1020, 1510, 3060, 3200-3500 700, 750, 1020, 1500, 1600, 2230, 3060, 3200-3500 700, 770, 1020, 1550, 2220, 3030, 3050, 3200-3400 700, 750, 770, 1020, 1500, 1560, 1600, 2230, 3060, 3170-3350 690, 750, 1020, 1500, 1550, 1600, 2220, 3060, 3200-3360 7 245 (4.20) 245 (4.50) 245 (4.30) 245 (4.25) 245 (4.32) 245 (4.30) 8 2e 9 22.73 10 4.21 11 240-241 12 730, 770, 860, 1050, 1510, 1550, 1600, 3060, 3200-3400 730, 770, 870, 1510, 1550, 1050, 1600, 3060, 3200-3500 730, 770, 860, 1050, 1510, 1600, 3030, 3200-3450 740, 750, 870, 1050, 1510, 1600, 3050, 3200-3500 730, 750, 770, 870, 1050, 1500, 3030, 3200-3350 750, 770, 870, 1045, 1510, 3030, 3200-3500 740, 760, 870, 1050, 1500, 1550, 1600, 3030, 3200-3350 13 232 (4.46), 275 (3.52), 285 (3.59), 327 (2.61) 232 (4.57), 275 (3.50), 287 (3.60), 297 (3.48), 322 (2.60), 327 (2.64) 230 (4.46), 287 (3.75), 300 (3.75), 325 (2.85) 230 (4.55), 285 (3.89), 296 (3.70), 325 (2.72) 233 (4.70), 275 (3.55), 325 (2.60) 232 (4.46), 275 (3.65), 286 (3.72), 325 (2.76)
1f
C17H20BrNO2
168-170 *2 *2 *2
2f
22.61
3.83
247-248
3a
C15H18ClNO
4a
13.22
5.12
Oil
3b
C17H22ClNO
4b
12.49
4.52
Oil
3c
C19H26ClNO
4c
10.93
4.23
Oil
3d
C21H30ClNO
86-87
4d
10.42
3.87
Oil
3e
C18H22ClNO
11.33 11.70
4.28 4.61
162-164
245 (4.00)
4e
11.47
4.42
Oil
232(4.60),275 (3.62), 285(3.60), 327(2.65)
TABLE 1 (continued)
1 3f 2 C17H20ClNO2 3 11.30 11.62 4 4.23 4.58 5 160-161 6 690, 720, 770, 1020, 1500, 1590, 1600, 2220, 3250, 3300-3400 920, 990, 1020, 1580, 2240, 3200-3500 920, 990, 1020, 1600, 2230, 3200-3500 920, 990, 1025, 1590, 2230, 3200-3400 890, 1020, 1600, 2230, 3200-3400 890, 1025, 1610, 2240, 3200-3400 7 245 (4.56) 8 4f 9 11.33 10 4.36 11 236-237 12 740, 750, 770, 870, 1050, 1500, 1550, 1600, 3050, 3200-3350 710, 1050, 1590, 3045, 3250-3450 720, 1045, 1600, 3030, 3250-3500 720, 1050, 1510, 1580, 3050, 3250-3500 850, 1050, 1560, 1580, 1960, 3040, 3070, 3250-3450 860, 1050, 1510, 1570, 1960, 3030, 3070, 3250-3500 13 232 (4.46), 275 (3.84), 287 (3.91), 297 (3.78), 327 (2.72) 240 (2.86)
5a
C11H16ClNO
16.21 16.63 14.33 14.70 27.66 27.97 13.49 13.89 25.13 25.48
6.28 6.56 5.55 5.80 4.58 4.90 5.18 5.48 4.14 4.46
*2 *2
225
6a
16.43
6.32
Oil
5b
C13H20ClNO
220
6b
14.38
5.47
Oil
240 (2.85)
5c
C13H20BrNO
120-122 *2
225
6c
27.58
4.48
Oil
238 (2.75)
5d
C14H22ClNO
222
6d
13.58
5.23
Oil
240 (2.86)
5e
C14H20BrNO2
105-106
225
6e
25.15
4.15
192-193
235 (2.95)
_______ * The empirical formulas of the products 2, 4, and 6 coincide with the empirical formulas of the initial compounds 1, 3, and 5. *2 The salt was hygroscopic.
33
34
TABLE 2. The 1H NMR Spectral Characteristics of the Salts 1a-f, , ppm, SSCC (J, Hz)
R CCH2OH + CH2C N R _ CH C CPh 2 Br 1'
HPh o-, m 7.61 7.60 7.60 7.58 m-, p-, m 7.48 7.47 7.47 7.40 R 1.36 (6H, t, J = 7.0, 2CH3); 3.55 (4H, q, J = 7.0, 2CH2) 0.98 (6H, t, J = 6.8, 2CH3); 1.82 (4H, m, 2CH2); 3.46 (4H, m, 2CH2N) 0.97 (6H, t, J = 7.0, 2CH3); 1.39 (4H, m, 2CH3CH2); 1.77 (4H, m, 2CH2CH2N); 3.48 (4H, t, J = 6.5, CH2N) 2.28 (4H, m, 2CH2); 3.88 (4H, br. t, J = 7.2, 2CH2N) 1.73 (2H, m, CH2); 1.98 (4H, m, 2CH2CH2); 3.79 (4H, m, J = 5.4, 2CH2N) 3.71 (4H, m, 2CH2); 4.03 (4H, m, 2CH2O)
1 4
Compound 1a 1b 1c 1d
1,1-H2 4.47 br. s 4.52 br. s 4.50 br. s 4.72 br. t, J = 2.0 4.70 br. t, J = 2.0 4.65 t, J = 2.0
4,4-H2 4.22 br. s 4.23 br. s 4.22 br. s 4.19 br. s 4.19 br. s 4.28 t, J = 2.0
1,'1'-H2 5.35 t, J = 6.0 5.27 br. s 5.25 br. s 5.26 br. s 5.34 br. s
OH, s 4.63 4.68 4.66 4.91
1e
4.91
7.60
7.40
1f*
4.81
7.52
7.36
_______ * The spectrum was recorded in CD3OD.
TABLE 3. The 1H NMR Spectral Characteristics of the Salts 2e,f and 4f, , ppm, SSCC (J, Hz)
OH
4 CH 2' 3'X 4' 5' 1' 2 5 6 7 9 8
+ N2
1 _ Hal
2e,f X = CH2, 4f X = O
Compound 2e 2f 4f* 1,1-H2 5.39 t, J = 2.6 5.22 s 5.18 s 3,3-H2 5.44 t, J = 2.6 5.47 s 5.38 s 4,4-2 br. s 4.40 5.04 5.01 5-H 8.01 q, J = 8.0 8.14 q, J = 8.1 8.16 m 6-H, m 7.53 7.55 7.58 7-H, m 7.53 7.53 7.56 8-H 7.62 m 7.90 d, J = 8.1 7.95 m 9-H, s 8.49 7.84 7.88 1',1'-H2 and 5',5'-H2 3.14 (2H) 3.44 (2H) 4.09 (4H) 4.05 (4H) 2',2'-H2 and 4',4'-H2 1.81 m (2H) 2.10 m (2H) 3.77 t (4H) J = 4.8 3.71 t (4H) J = 4.8 3',3'-H2 1.53 (1-H) 1.80 (1-H)
_______ * 13C NMR spectrum for compound 4f, , ppm: 58.16 ((4)); 58.55 ((2',4')); 61.35 ((1',5')); 65.49 ((1)); 66.33 ((3)); 121.82 ((9)); 123.94 (C(5)); 126.18 and 126.44 (C(6) and C(7)); 128.31 (C(8)); 128.81; 130.41; 130.78; 133.14 and 133.33 (C(3), C(4), C(4), C(8), C(9)).
35
In the UV spectra of the initial salts 1a-f and 3a-f there is an absorption maximum at 245 nm characteristic of the benzene ring, and for the salts 5a-e there is absorption in the region of 220-225 nm. In the spectra of the cyclization products 2a-f and 4a-f the absorption maximum is shifted upfield as a result of the presence of the naphthalene ring (275, 285, 298 nm), while in the spectra of the salts 6a-e there are absorption maxima for the benzene ring at 235-240 nm. The structure of the salts 1a-f, 2a,f, 3a-f, and 4f was confirmed by 1H NMR spectroscopy, and that of salt 4f was confirmed also by 13C NMR spectroscopy. The spectra of the compounds above agree well with the proposed structures.
EXPERIMENTAL The IR spectra were recorded on a UR-20 spectrometer in tablets with potassium bromide or in vaseline oil. The UV spectra were obtained on a Specord UV-Vis spectrophotometer for solutions in ethanol. The 1 H NMR spectra were obtained for solutions in DMSO-d6 on a Varian Mercury-300 spectrometer [300 MHz (1H) and 75 MHz (13C)] at 30C (303 K) with TMS as internal standard. The initial salts 1a-f, 3a-f, and 5a-e were obtained in quantitative yields in etheracetonitrile by reaction of dialkyl-4-hydroxy-2-butynylamines [4] with phenylpropargyl bromide 1a-f or of the corresponding amines with chromatographically pure 4-hydroxy-1-chloro-2-butyne, obtained by the method [5] 3a-f, 5a-e. The characteristics of the synthesized compounds are given in Tables 1-3. The signals in the 1H and 13C NMR spectra were assigned on the basis of the COSY, NOESY, and HMQC spectra. Cyclization of the Salts (1a-f), (3a-f), and (5a-e) (General Procedure). To solution of the salt 1, 3, or 5 (13-16 mmol) in water (5-6 ml) we added 2 N solution of potassium hydroxide (saltbase molar ratio 5:1) (1.31.6 ml). The reaction mixture was kept at 50-55C for 5-10 min. Spontaneous heating was observed, and the temperature of the reaction mixture rose to 85-90C. After cooling the reaction mixture was extracted with ether (2 30 ml) to remove the products of the side reactions. In each case 8-10% of amine of unestablished structure was detected in the extract by titration. The aqueous solution was acidified with hydrobromic acid or hydrochloric acid and evaporated to dryness. The residue was extracted with absolute ethanol. The salts 2a-c, 4a-e, and 6a-d were precipitated from the extract with ether but could not be recrystallized. The salts 2d-f, 4f, and 6e were precipitated from the aqueous solution, and the main part was isolated by filtration. The filtrate was treated as described above for the aqueous solution.
REFERENCES 1. 2. 3. 4. 5. S. T. Kocharyan, V. E. Karapetyan, and N. P. Churkina, Zh. Obshch. Khim., 70, 1169 (2000). El. O. Chukhadzhyan, E. O. Chukhadzhyan, and A. T. Babayan Zh. Org. Khim., 10, 46 (1974). A. T. Babayan, E. O. Chukhadzhyan, and L. A. Manasyan, Arm. Khim. Zh., 31, 489 (1978). E. O. Chukhadzhyan, A. R. Gevorkyan, El. O. Chukhadzhyan, and K. G. Shakhatuni, Zh. Org. Khim., 36, 1304 (2000). G. Dupont, R. Dulou, and G. Lefebvre, Bull. Soc. Chim. France, 816 (1954).
36
SYNTHESIS AND ANTI-HIV-1 ACTIVITY OF 2-[2-(3,5-DIMETHYLPHENOXY)ETHYLTHIO]PYRIMIDIN-4(3H)-ONES

M. S. Novikov1, A. A. Ozerov1, O. G. Sim1, and R. W. Buckheit2 New 2-[2-(3,5-dimethylphenoxy)ethyl]thio derivatives of pyrimidin-4(3H)-one containing various substituents at positions 5 and 6 of the pyrimidine ring were synthesized. It was shown that alkylation of 2-thiouracils with 1-bromo-2-(3,5-dimethylphenoxy)ethane in DMF takes place exclusively at the sulfur atom. The obtained 6-benzyl and 6-(2,6-difluorobenzyl) derivatives have clearly defined virus-inhibiting properties with respect to type 1 human immunodeficiency virus in vitro and suppress its reproduction by 50% at concentrations of 1.3 and 11.2 M respectively. Keywords: activity. 2-[2-(3,5-dimethylphenoxy)ethylthio]pyrimidin-4(3H)-ones, S-alkylation, anti-HIV-1
The search for new effective inhibitors of the reproduction of the human immunodeficiency virus (HIV) is the most important problem of modern medicine. A few years ago more that 15 000 new cases of HIV infection were established daily, and at present a progressive growth of the disease is being observed [1]. One of the most studied targets for chemotherapeutic action against HIV is reverse transcriptase (RT), which transforms the viral RNA into the proviral DNA. Blocking of its activity destroys the replicative cycle of HIV [2]. However, the inhibitors of reverse transcriptase employed for the treatment of HIV infection have a series of serious side effects, which restrict their clinical application. Moreover, prolonged therapy leads to the establishment of resistance in HIV to nucleosidic and nonnucleosidic inhibitors of reverse transcriptase. This gives rise to the need to search for new more selective and safer drugs [3].
O HN S N F Me Me F S HN N O O R
1
R2 Me
1322
Me
__________________________________________________________________________________________ Scientific-Research Institute of Pharmacology, Volgograd Medical University, Volgograd 400131, Russia; e-mail: ozerov@vlink.ru. 2 TherImmune Research Corp., Maryland, USA. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 42-47, January, 2004. Original article submitted August 1, 2003. 0009-3122/04/4001-00372004 Plenum Publishing Corporation 37
1
Earlier it was established that certain 2-(alkylthio)- and 2-(cycloalkylthio)pyrimidin-4(3H)-ones exhibit considerable antiviral activity against HIV-1 [4-8]. For example, the (R)-enantiomer of 5-methyl-6-(-methyl2,6-difluorobenzyl)-2-(cyclopentylthio)pyrimidin-4(3H)-one (1) inhibits by 50% the reproduction of HIV-1 in vitro at a concentration of only 0.002 M [9]. However, compounds of this series containing an aromatic fragment as S-alkyl substituent have not been described before. In this connection we undertook the synthesis of new derivatives of pyrimidin-4(3H)-one containing at position 2 an aryloxyethylthio substituent capable of conformationally imitating the benzyl fragment of the highly active compound 1 and its analogs, and we studied their anti-HIV activity in vitro. It is known that several methods have been used for the S-alkylation of 2-thiouracils: a) Treatment of an alkaline aqueous solution of 2-thiouracil with methyl iodide leads to the target 2-(methylthio)pyrimidin-4(3H)one with a yield of 88% [10]; b) Treatment of an alkaline wateralcohol solution of 2-thiouracil with methyl iodide leads to the preferential formation of 2-(methylthio)pyrimidin-4(3H)-one with a yield of 38% and the side formation of 3-methyl-2-(methylthio)pyrimidin-4(3H)-one with a yield of 8% [11]; c) Alkylation of 2-thiouracils with alkyl halides in absolute methanol in the presence of sodium methoxide gives the corresponding 2(alkylthio) derivatives with yields in the range of 50-78% [7, 12]; d) Alkylation with alkyl halides in the polar solvent DMF [12] or DMSO [13] in the presence of potassium carbonate frequently leads to the formation of a complex mixture of S-mono-, S,N(1)-, and N(3),S-dialkyl compounds.
O
HN
S
Br
Me
K2CO3
+
N H
211
R2
12
Me
O
HN
Me
R2
Me
1322
2, 5-11, 13, 1622 R1 = H; 3, 14 R1 = Me; 4, 15 R1 = CH2Ph; 2-4, 13-15 R2 = Me; 5, 16 R2 = Ph; 6, 17 R2 = CH2Ph; 7, 18 R2 = CH2(1-C10H7); 8, 19 R2 = CH2(2,6-F2C6H3); 9, 20 R2 = CH2O(4-MeC6H4); 10, 21 R2 = CH2O(4-ClC6H4); 11, 22 R2 = CH2O(2-C10H7)
We found that the treatment of the initial 6-methyl (2), 5,6-dimethyl (3), 5-benzyl-6-methyl (4), 6-phenyl (5), 6-benzyl (6), 6-(1-naphthylmethyl) (7), 6-(2,6-difluorobenzyl) (8), 6-[(4-methylphenoxy)methyl] (9), 6-[(4-chlorophenoxy)methyl] (10), and 6-[(2-naphthyloxy)methyl] (11) derivatives of 2-thiouracil, which were synthesized by the previously described methods [14, 15], in DMF solution with an equimolar amount of 1bromo-2-(3,5-dimethylphenoxy)ethane (12) in the presence of potassium carbonate at 70-80C leads to the exclusive formation of S-alkylated 2-[2-(3,5-dimethylphenoxy)ethylthio] derivatives of pyrimidin-4(3H)-one 13-22. According to TLC, the formation of S,N-dialkylation side products was not detected. The bulky 2-(3,5-dimethylphenoxy)ethyl substituent at the sulfur atom probably screens the nitrogen atom of the pyrimidine ring and prevents further alkylation under the given conditions. The physicochemical characteristics of compounds 13-22 are given in Table 1.
38
TABLE 1. The Characteristics of the Synthesized Compounds

Compound 13 14 15 16 17 18 19 20 21 22 Empirical formula C15H18N2O2S C16H20N2O2S C22H24N2O2S C20H20N2O2S C21H22N2O2S C25H24N2O2S C21H20F2N2O2S C22H24N2O3S C21H21ClN2O3S C25H24N2O3S Found, % Calculated, % 6.39 6.25 6.44 6.62 6.10 6.36 5.89 5.72 5.83 6.05 5.59 5.81 5.11 5.01 6.33 6.10 5.30 5.08 5.80 5.59 mp, N 9.36 9.65 9.01 9.20 7.07 7.36 7.77 7.95 7.90 7.64 6.94 6.73 7.21 6.96 6.87 7.06 6.50 6.72 6.77 6.48 167-169 180-181 168-169 174-176 153-155 174-175 168-169 192-194 163-164 190-192 0.37 0.22 0.72 0.46 0.48 0.40 0.52 0.32 0.24 0.18 61 72 63 58 75 61 71 61 52 33 Rf Yield, %
62.19 62.04 63.38 63.13 69.75 69.44 68.28 68.16 68.67 68.83 71.82 72.09 62.95 62.67 66.83 66.64 60.27 60.50 69.56 69.42
The antiviral properties of the synthesized compounds in vitro against HIV-1 were studied at the TherImmune Research Corporation (Maryland, USA) according to the previously described method [16]. The investigations showed that some of the new compounds 13-22 exhibited appreciable virus-inhibiting activity. The highest activity was exhibited by 2-[2-(3,5-dimethylphenoxy)ethylthio] derivatives of 6-benzylpyrimidin-4(3H)-one (17) and 6-(2,6-difluorobenzyl)pyrimidin-4(3H)-one (19), which inhibited the reproduction of HIV-1 by 50% at concentrations of 1.3 and 11.2 M and had a selectivity index of 58.0 and 8.1 respectively. The compounds containing a naphthyl fragment at position 6 proved weakly active. At concentrations of 40.8 and 123.0 M the derivatives of 6-(1-naphthylmethyl)pyrimidin-4(3H)-one (18) and 6-(naphthyloxymethyl)pyrimidin-4(3H)-one (22) blocked the reproduction of the virus by only 25% (Table 2). TABLE 2. The Anti-HIV-1 Activity of the Synthesized Compounds in Culture of CEM-SS Cells in vitro*
Compound 13 14 15 16 17 18 19 20 21 22 Antiviral activity EC50 (EC25), M >200.0 >200.0 >100.0 >100.0 1.3 (40.8) 11.2 >100.0 >100.0 (123.0) Cytotoxicity, TC50, M 39.4 46.2 >100.0 >100.0 72.9 61.7 90.0 92.7 >100.0 >200.0 Therapeutic index, TC50 / EC50 58.0 8.1
_______ * EC50 is the effective concentration securing protection of the cells against the cytopathic effect of the virus by 50%; TC50 is the cytotoxic concentration reducing the viability of the uninfected cells by 50%. 39
Investigation of the structureactivity relation showed that the compounds containing methyl (13-15) or phenyl (16) group as substituent at position 6 of the pyrimidine ring do not possess virus-inhibiting characteristics. At the same time increase in the dimensions and conformational mobility of the substituent to benzyl (17) leads to substantial increase of anti-HIV activity. Further increase in the size of the substituent to 1naphthylmethyl (18) leads to decrease in the activity of the compounds. With the symmetrical introduction of fluorine atoms at the o-position of the benzyl substituent in 19 the virus-inhibiting characteristics are reduced by an order of magnitude. The 6-(aryloxymethyl) derivatives 20-22, which have an additional oxygen atom in the substituent, are significantly less active than their 6-arylmethyl analogs. Transfer of the benzyl fragment from position 6 to position 5 in compound 15 leads to complete loss of anti-HIV-1 activity.
EXPERIMENTAL The 1H NMR spectra were recorded on a Tesla BS-567A spectrometer (100 MHz) in a 1:1 mixture of DMSO-d6 and acetone-d6 with HMDS as internal standard. The spectra were interpreted by means of the licensed ACD/HNMR Predictor Pro 3.0 software of Advanced Chemistry Development (Canada). The mass spectra were recorded on a Varian MAT-111 spectrometer (direct injection, electron impact ionization, 70 eV). Thin-layer chromatography was conducted on Silufol UV-254 plates in the 1:1 ethyl acetatehexane system with development in iodine vapor. The melting points were determined in glass capillaries on a Mel-Temp 3.0 instrument (Laboratory Devices Inc. USA). 2-[2-(3,5-Dimethylphenoxy)ethylthio]-6-methylpyrimidin-4(3H)-one (13). Mixture of 6-methyl-2thiouracil (2.3 g, 16.18 mmol) and potassium carbonate (2.3 g, 16.64 mmol) in DMF (40 ml) was stirred at 70-80C for 1 h. Solution of 1-bromo-2-(3,5-dimethylphenoxy)ethane 11 (3.7 g, 16.15 mmol) in DMF (20 ml) was added, and the mixture was stirred at the same temperature for a further 4 h. It was cooled to room temperature and filtered. The filtrate was evaporated under vacuum, and the residue was washed with cold water (100 ml). The insoluble solid residue was filtered off, dried in air, and recrystallized from ethanol (80 ml). We obtained 2.6 g (61%) of a white crystalline substance; mp 167-169C. 1H NMR spectrum (DMSO-d6), , ppm, J (Hz): 2.15 (3H, s, CH3); 2.20 (6H, s, CH3); 3.45 (2H, t, J = 7, SCH2); 4.16 (2H, t, J = 7, OCH2); 5.95 (1H, s, 5-H); 6.54 (3H, s, H arom.). Mass spectrum (m/z): 290 [M]+. Compounds 14-22 were prepared similarly. 2-[2-(3,5-Dimethylphenoxy)ethylthio]-5,6-dimethylpyrimidin-4(3H)-one (14). 1H NMR spectrum (DMSO-d6), , ppm, J (Hz): 2.16 (6H, s, 3-, 5-CH3 arom.); 2.18 (3H, s, 5-CH3); 2.32 (3H, s, 5-CH3); 2.34 (3H, s, 6-CH3); 3.46 (2H, t, J = 7, SCH2); 4.17 (2H, t, J = 7, OCH2); 6.58 (1H, s, H arom.). Mass spectrum (m/z): 304 [M]+. 5-Benzyl-2-[2-(3,5-dimethylphenoxy)ethylthio]-6-methylpyrimidin-4(3H)-one (15). 1H NMR spectrum (DMSO-d6), , ppm, J (Hz): 2.14 (6H, s, CH3 arom.); 2.32 (3H, s, CH3); 3.44 (2H, t, J = 7, SCH2); 3.71 (2H, s, CH2Ph); 4.15 (2H, t, J = 7, OCH2); 6.60 (3H, s, H arom.); 7.01-7.56 (5H, m, C6H5). Mass spectrum (m/z): 380 [M]+. 2-[2-(3,5-Dimethylphenoxy)ethylthio]-6-phenylpyrimidin-4(3H)-one (16). 1H NMR spectrum (DMSO-d6), , ppm, J (Hz): 2.09 (6H, s, CH3 arom.); 3.44 (2H, t, J = 7, SCH2); 4.17 (2H, t, J = 7, OCH2); 6.12 (1H, s, 5-H); 6.56 (3H, s, H arom.); 7.14-7.69 (5H, m, C6H5). Mass spectrum (m/z): 352 [M]+. 6-Benzyl-2-[2-(3,5-dimethylphenoxy)ethylthio]pyrimidin-4(3H)-one (17). 1H NMR spectrum (DMSO-d6), , ppm, J (Hz): 2.10 (6H, s, CH3 arom.); 3.48 (2H, t, J = 7, SCH2); 4.08 (2H, s, CH2Ph); 4.18 (2H, t, J = 7, OCH2); 5.93 (1H, s, 5-H); 6.54 (3H, s, H arom.); 6.96-7.54 (5H, m, C6H5). Mass spectrum (m/z): 366 [M]+. 2-[2-(3,5-Dimethylphenoxy)ethylthio]-6-(1-naphthylmethyl)pyrimidin-4(3H)-one (18). 1H NMR spectrum (DMSO-d6), , ppm, J (Hz): 2.10 (6H, s, CH3 arom.); 3.46 (2H, t, J = 7, SCH2); 4.11 (2H, t, J = 7, OCH2); 4.34 (2H, s, ArCH2); 5.98 (1H, s, 5-H); 6.60 (3H, s, H arom.); 6.78-7.82 (5H, m, C6H5). Mass spectrum (m/z): 416 [M]+. 40
2-[2-(3,5-Dimethylphenoxy)ethylthio]-6-(2,6-difluorobenzyl)pyrimidin-4(3H)-one (19). 1H NMR spectrum (DMSO-d6), , ppm, J (Hz): 2.11 (6H, s, CH3 arom.); 3.45 (2H, t, J = 7, SCH2); 4.12 (2H, s, ArCH2); 4.20 (2H, t, J = 7, OCH2); 5.98 (1H, s, 5-H); 6.54-7.12 (5H, m, H arom.). Mass spectrum (m/z): 402 [M]+. 2-[2-(3,5-Dimethylphenoxy)ethylthio]-6-(4-methylphenoxymethyl)pyrimidin-4(3H)-one (20). 1H NMR spectrum (DMSO-d6), , ppm, J (Hz): 2.10 (6H, s, CH3 arom.); 2.06 (3H, s, CH3); 3.44 (2H, t, J = 7, SCH2); 4.18 (2H, t, J = 7, OCH2); 5.12 (2H, s, CH2OAr); 5.84 (1H, s, 5-H); 6.50-6.87 (7H, m, H arom.). Mass spectrum (m/z): 396 [M]+. 6-(4-Chlorophenoxymethyl)-2-[2-(3,5-dimethylphenoxy)ethylthio]pyrimidin-4(3H)-one (21). 1H NMR spectrum (DMSO-d6), , ppm, J (Hz): 2.12 (6H, s, CH3 arom.); 3.46 (2H, t, J = 7, SCH2); 4.19 (2H, t, J = 7, OCH2); 5.10 (2H, s, CH2OAr); 5.82 (1H, s, 5-H); 6.55 (3H, s, H arom.); 6.61-7.21 (4H, m, H arom.). Mass spectrum (m/z): 416 [M]+. 2-[2-(3,5-Dimethylphenoxy)ethylthio]-6-(2-naphthyloxymethyl)pyrimidin-4(3H)-one (22). 1H NMR spectrum (DMSO-d6), , ppm, J (Hz): 2.11 (6H, s, CH3 arom.); 3.46 (2H, t, J = 7, SCH2); 4.18 (2H, t, J = 7, OCH2); 5.08 (2H, s, CH2OAr); 5.81 (1H, s, 5-H); 6.54 (3H, s, H arom.); 6.90-7.72 (7H, m, H arom.). Mass spectrum (m/z): 432 [M]+. Investigation of the Anti-HIV-1 Activity. CEM-SS cells were suspended in a culture medium at the rate of 105 cells/ml and infected with HIV-1 (HTLV-IIIB strain) with infection multiplication of 0.2. Immediately after infection solutions containing various concentrations of the investigated substances in DMSO were added, and incubation was carried out for 4 days at 37C. The number of live cells was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, and the concentration of the substance that protected the CEM-SS cells by 50% from the cytopathic effect of HIV-1 (EC50) was established. The cytotoxicity of the tested compounds was determined in parallel, and here the concentration of the substance that reduced the number of live CEM-SS cells by 50% (TC50) was established. The therapeutic index, equal to the ratio of the cytotoxic concentration to the inhibitor concentration (TC50/EC50), was obtained by calculation.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. J. O. Kahn and B. D. Walker, New Engl. J. Med., 339, 33 (1998). W. C. Green, New Engl. J. Med., 324, 308 (1991). J. A. Levy, Microbiol. Rev., 57, 183 (1993). A. Mai, M. Artico, G. Sbardella, S. Massa, A. G. Loi, E. Tramontane, P. Scano, and P. La Colla, J. Med. Chem., 38, 3258 (1995). A. Mai, M. Artico, G. Sbardella, S. Massa, E. Novellino, G. Greco, A. G. Loi, E. Tramontane, M. E. Marongiu, and P. La Colla, J. Med. Chem., 42, 619 (1999). A. Mai, G. Sbardella, M. Artico, R. Ragno, S. Massa, E. Novellino, G. Greco, A. Lavacchia, C. Musiu, M. La Colla, M. E. Marongiu, P. La Colla, and R. Loddo, J. Med. Chem., 44, 2544 (2001). O. S. Pedersen, L. Petersen, M. Brandt, E. B. Nielsen, and E. B. Pedersen, Monatsh. Chem., 130, 1499 (1999). E. A. Sudbeck, C. Mao, T. K. Venkatachalam, L. Tuel-Angren, and F. M. Uckun, Antimicrob. Agents Chemother., 42, 3225 (1998). M. Quaglia, A. Mai, M. Artico, G. Sbardella, R. Ragno, S. Massa, D. del Piano, G. Setzu, S. Doratiotto, and V. Cotichini, Chirality, 13, 75 (2001). J. Spychala, Synth. Commun., 27, 1943 (1997). A. R. Katritzky, G. Baykut, S. Rachwal, M. Szafran, K. C. Caster, and J. Eyler, J. Chem. Soc. Perkin Trans. 2, 1499 (1989). 41
12. 13. 14. 15. 16.
K. Danel, E. B. Pedersen, and C. Nielsen, J. Med. Chem., 41, 191 (1998). H. Todoriki, Y. Nishimura, S. Higuchi, A. Y. Hirakawa, and M. Tsuboi, Bull. Chem. Soc. Japan, 53, 1881 (1980). W. H. Miller, A. M. Dessert, and G. W. Anderson, J. Am. Chem. Soc., 70, 500 (1948). C. K. Chu, I. Wepmen, K. A. Watanabe, and J. J. Fox, J. Org. Chem., 41, 2793 (1976). R. W. Buckheit, E. L. White, V. Fliakas-Boltz, J. Russell, T. L. Stup, T. L. Kinjerski, M. C. Osterling, A. Weigand, and J. P. Bader, Antimicrob. Agents Chemother., 43, 1827 (1999).
42
MULTICOMPONENT SYNTHESIS OF 2,5-DIOXO- AND 4-ARYL-5-OXO-2-THIOXO1,2,3,4,5,6,7,8-OCTAHYDROQUINAZOLINES

N. N. Tonkikh, A. Strakovs, and M. V. Petrova Ten 2,5-dioxo- and 4-aryl-5-oxo-2-thioxo-1,2,3,4,5,6,7,8-octahydroquinazolines have been synthesized in three-component interactions of 1,3-cyclohexanedione or dimedone, urea or thiourea, and substituted benzaldehydes (3-bromo-, 4-bromo-, 4-fluoro-, 4-methoxy-, 3,4-methylenedioxy-, and 3-nitro-). 9-Aryl4,5-dioxo-1,2,3,4,5,6,7,8-octahydro-9H-xanthenes were also formed in these reactions. Keywords: 2,5-dioxo- and 5-oxo-2-thioxo-4-aryl-1,2,3,4,5,6,7,8-octahydroquinazolines, substituted benzaldehydes, ureas, 1,3-cyclohexanediones, three-component synthesis. Among the large diversity of multicomponent reactions involving 1,3-dicarbonyl compounds, aldehydes and various C- and N-nucleophiles [1-14] the variant of the Bidginelli condensation involving 1,3-cyclohexanedione, an aromatic aldehyde, and urea, leading to quinazoline derivatives is unknown. In these reactions the formation of the corresponding 9-aryl-4,5-dioxo-1,2,3,4,5,6,7,8-octahydroxanthenes might be expected as side products.
H H2N X NH2 2a,b 3a-f 4a-j O R R H N X NH O R1 R1 5a-e O O R1 R R O R R
R R O 1a,b
OH
1 a R= H; b R = Me; 2 a X= O; b X = S; 3 a R1= 3-Br, b R1 = 4-Br, c R1 = 4-F, d R1 = 4-OMe, e R1 = 3,4-OCH2O, f R1 = 3-NO2; 4 a R, R1, X = H, 4-Br, O; b H, 4-F, O; c H, 4-F, S; d H, 4-OMe, O; e H, 4-OMe, S; f H, 3,4-OCH2-O-, O; g H, 3-NO2, O; h Me, 3-Br, O; i Me, 4-F, O; j Me, 4-OMe, O; 5 a R,R1 = H, 4-F; b R,R1 = Me, 4-F; c R,R1 = H, OMe; d R,R1 = Me, OMe; e R,R1 = H, OCH2O
We used 1,3-cyclohexanedione (1a) or dimedone (1b), urea (2a) or thiourea (2b), and substituted benzaldehydes 3a-f as starting materials. Reactions were carried out by continuously (9-10 h) boiling equimolar quantities of diketone 1, aldehyde 3 and 3 equivalents of urea or thiourea 2 in ethanol in the presence of catalytic amounts of H2SO4. In the case of 4-fluoro-, 4-methoxy-, or 3,4-methylenedioxybenzaldehydes a __________________________________________________________________________________________ Riga Technical University, Riga LV-1048, Latvia; e-mail: marina@osi.lv. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 48-51, January, 2004. Original article submitted March 27, 2001. 0009-3122/04/4001-00432004 Plenum Publishing Corporation 43
precipitate of the corresponding octahydroxanthenes 5 formed from the reaction mixture on cooling. After separating it and removing a portion of the solvent a mixture of octahydroquinazolines 4 and octahydroxanthenes 5 was precipitated with water. Sequential treatment of the mixture with hot ethanol and chloroform leads to pure quinazolines 4. The structures of the quinazoline derivatives 4 were confirmed by data of 1H NMR spectra. In all cases the proton signals at the neighboring C(4) (5.09-5.32 ppm, 3J = 3 Hz) and N(3) (7.65-7.83 ppm, 3J = 3 Hz) atoms were clearly recorded. In the 2-thioxo derivatives 4c,e the signals of N(1)-H and N(3)-H were displaced towards low field (4c 10.56 and 9.61, 4e 10.58 and 9.66 ppm) compared with the 2-oxo derivatives. The signals of the protons of the carbocyclic fragment of molecules 4 and the proton at the C(4) atom, bearing an aromatic substituent, are observed in the expected regions. Absorption bands for the vibrations of the NH bonds of compound 4 were displayed in the IR spectra in the range of 3050-3370 cm-1, and the bands of the carbonyl groups at 1700-1712 for C(2)=O and at 1610-1628 cm-1 for C(5)=O. Octahydroxanthenes 5c-e formed in the reactions were obtained by the known procedures of [15,16] and the known compounds 5a,b were synthesized by the procedure [16] for the first time (Tables 1, 2).
EXPERIMENTAL The IR spectra were taken on a Specord IR 75 instrument for suspensions in nujol (1500-1800 cm-1) and in hexachlorobutadiene (2000-3600 cm-1, the absorption bands for the CH stretching vibrations at 2800-3050 cm-1 are not given). The 1H NMR spectra were recorded on a Bruker WH 90/DS (90 MHz) spectrometer for solutions in CDCl3 and DMSO-d6, internal standard was HMDS.
TABLE 1. Characteristics of the Synthesized Compounds

Compound 4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 5a 5b Empirical formula C14H13BrN2O2 C14H13FN2O2 C14H13FN2OS C15H16N2O3 C15H16N2O2S C15H14N2O4 C14H13N3O4 C16H17BrN2O2 C16H17FN2O2 C17H20N2O3 C19H17FO3 C23H25FO3 Found, % Calculated, % H N 3.92 4.08 4.87 5.03 4.61 4.74 5.80 5.92 5.66 5.59 4.99 4.93 4.49 4.56 4.77 4.91 5.81 5.94 6.60 6.71 5.40 5.49 6.77 6.84 8.51 8.72 10.61 10.76 10.02 10.14 10.11 10.29 9.59 9.71 9.73 9.79 14.70 14.63 7.81 8.02 9.60 9.72 9.12 9.33 mp, Hal (S) 24.60 24.87 (11.40) (11.60) (10.90) (11.12) 270-271 275-276 258-260 271-272 271-272 279-281 291-292 22.60 22.88 229-230 274-275 273-274 253-254 208-210 56 19 30 13 17 13 61 23 14 14 72 77 Yield, %
52.12 52.36 64.80 64.61 60.78 60.85 65.97 66.16 62.30 62.47 62.73 62.93 58.60 58.53 54.85 55.03 66.60 66.65 67.21 67.98 72.95 73.07 74.80 74.97
44
TABLE 2. Spectral Characteristics of the Synthesized Compounds

Compound 4 IR spectra, , cm-1 1712, 1674, 1616, 1500; 3350, 3260-3150 1702, 1672, 1650, 1624, 1510; 3350, 3260, 3150 1630, 1610, 1570, 1515; 3250, 3200 1700, 1650, 1606, 1515; 3240, 3100
1
NMR spectra, , ppm (coupling constant, J, Hz)
4b
4 4d
4e
1628, 1572, 1510; 3260, 3200
4f
1708, 1680, 1616, 1500; 3350-3050 1710-1700, 1652, 1610, 1530; 3350, 3260, 3100 1702, 1660, 1622, 1575, 1535; 3370, 3260, 3140 1707, 1660, 1615, 1530; 3300, 3220, 3130 1710, 1674, 1616, 1515; 3320, 3240, 3150 1680, 1660, 1622, 1602, 1510 1685, 1668, 1633, 1518
4g
DMSO-d6. 1.67-2.67 (6H, m, 3CH2); 5.16 (1H, d, 3J = 3, CH); 7.09-7.56 (4H, m, C6H4); 7.74 (1H, d, 3J = 3, NH); 9.46 (1H, br. s, NH) DMSO-d6. 1.78-2.54 (6H, m, 3CH2); 5.23 (1H, d, 3J = 3, CH); 7.07-7.43 (4H, m, C6H4); 7.83 (1H, d, 3J = 3, NH); 9.58 (1H, br. s, NH) DMSO-d6. 1.85-2.63 (6H, m, 3CH2); 5.21 (1H, d, 3J = 3, CH); 7.20-7.99 (4H, m, C6H4); 9.61 (1H, br. s, NH); 10.56 (1H, br. s, NH) DMSO-d6. 1.78-2.67 (6H, m, 3CH2); 3.69 (3H, s, CH3); 5.12 (1H, d, 3J = 3, CH); 6.81 (2H, m, 3J = 8, 64); 7.16 (2H, m, 3J = 8, C6H4); 7.65 (1H, br. s, NH); 9.38 (1H, br. s, NH) DMSO-d6. 1.78-2.58 (6H, m, 3CH2); 3.71 (3H, s, CH3); 5.16 (1H, d, 3J = 3, CH); 6.87 (2H, m, 3J = 8, 64); 7.27 (2H, m, 3J = 8, C6H4); 9.66 (1H, d, 3J = 3, NH); 10.58 (1H, br. s, NH) DMSO-d6.1.74-2.53 (6H, m, 3CH2); 5.09 (1H, d, 3J = 3, CH); 5.92 (2H, s, CH2); 6.73 (3H, center m, 64); 7.67 (1H, d, 3J = 3, NH); 9.45 (1H, br. s, NH) DMSO-d6. 1.69-2.56 (6H, m, 3CH2); 5.32 (1H, d, 3J = 3, CH); 7.52-8.07 (5H, m, 64, NH); 9.56 (1H, br. s, NH) DMSO-d6. 0.89 (3H, s, CH3); 1.07 (3H, s, CH3); 2.12 (2H, m, CH2); 2.41 (2H, m, 2); 5.18 (1, d, 3J = 3, CH); 7.23-7.49 (4H, m, 64); 7.81 (1H, br. s, NH); 9.56 (1, br. s, NH) DMSO-d6. 0.88 (3H, s, CH3); 1.07 (3H, s, CH3); 2.03 (2H, m, CH2); 2.34 (2H, m, 2); 5.18 (1, d, 3J = 3, CH); 6.98-7.36 (4H, m, 64); 7.81 (1H, br. s, NH); 9.54 (1, br. s, NH) DMSO-d6. 0.92 (3H, s, CH3); 1.05 (3H, s, CH3); 2.05 (2H, m, CH2); 2.31 (2H, m, 2); 3.72 (3H, s, CH3); 5.14 (1, d, 3J = 3, CH); 6.83 (2, m, 3J = 8, 64); 7.25 (2, m, 3J = 8, C6H4); 7.74 (1H, br. s, NH); 9.45 (1, br. s, NH) DMSO-d6.1.93-2.66 (12H, m, 6CH2); 4.58 (1H, s, CH); 6.94-7.33 (4H, m, 64, NH) DCl3. 0.96 (6H, s, 2CH3); 1.09 (6H, s, 2CH3); 2.16 (4H, s, 2CH2); 2.46 (4H, s, 2CH2); 4.94 (1H, s, CH); 6.81-7.36 (4H, m, 64)
4h
4i
4j
5a 5b
4-(4-Bromophenyl)- (4a), 4-(4-Fluorophenyl)- (4b), 4-(4-Methoxyphenyl)- (4d), 4-(3,4-Methylenedioxyphenyl)- (4f), 4-(3-Nitrophenyl)-2,5-dioxo-1,2,3,4,5,6,7,8-octahydroquinazolines (4g), 4-(4-Fluorophenyl)- (4c), 4-(4-Methoxyphenyl)-5-oxo-2-thioxo-1,2,3,4,5,6,7,8-octahydroquinazolines (4e), 4-(3-Bromophenyl)- (4h), 4-(4-Fluorophenyl)- (4i), and 4-(4-Methoxyphenyl)-7,7-dimethyl-2,5-dioxo-1,2,3,4,5,6,7,8octahydroquinazolines (4j). Solution of diketone 1 (5 mmol), aldehyde 3 (5 mmol), and urea or thiourea (15 mmol) in ethanol (30 ml) was boiled for 10 h in the presence of concentrated H2SO4 (0.15 ml). In the case of quinazolines 4b,d,e,f,i,j a precipitate of the corresponding octahydroxanthene 5 (10-15% calculated on the aldehyde, identification is given below) was formed on cooling the ethanolic solution. The xanthene 5 precipitate was filtered off, ethanol (~20 ml) was distilled from the filtrate, the residue was poured into water (70 ml), the solution neutralized to pH 7 with aqueous KOH solution, and left for 24 h. The precipitated solid, sometimes oily, was filtered off or decanted from water. The substance obtained was triturated sequentially with hot ethanol and chloroform to remove octahydroxanthene derivatives. The quinazolines 4, obtained in this way are pure substances according to TLC data. Recrystallization of them from THF or DMF led to significant loss, but the melting point did not change.
45
Octahydroxanthenes 5c, 5d, and 5e obtained in the synthesis of quinazolines 4d, 4f, and 4j gave no depression of melting point with known samples [15,16]. 9-(4-Fluorophenyl)-4,5-dioxo-1,2,3,4,5,6,7,8octahydro-9H-xanthenes 5a,b were also obtained by us for the first time by the reaction of diketones 1a,b with 4-fluorobenzaldehyde. Their characteristics are given in Tables 1 and 2.
REFERENCES 1. 2. 3. 4. 5. 6. C. O. Kappe. Acc. Chem. Res., 33, 879 (2000). C. O. Kappe, Eur. J. Med. Chem., 35, 1043 (2000). C. O. Kappe, D. Kumar, and R. S. Varma, Synthesis, 1799 (1999). M. Boisbrun, L. Jeannin, L. Toupet, and J.-Y. Laronze, Eur. J. Org. Chem., 3051 (2000). A. A. Hassanien, M. A. Zahran, M. S. A. El-Gaby, and M. M. Ghorab, J. Indian Chem. Soc., 76, 350 (1999). W. C. Wong, W. Sun, B. Lagu, D. Tian, M. R. Marzabadi, F. Zhang, D. Nagarathnam, S. W. Miao, J. M. Wetzel, J. Peng, C. Forray, R. S. L. Chang, T. B. Chen, R. Ransom, S. O'Malley, T. P. Broten, P. Kling, K. P. Vyas, K. Zhanh, and C. Gluchowski, J. Med. Chem., 42, 4804 (1999). E. H. Hu, D. R. Sidler, and U.-H. Dolling, J. Org. Chem., 63, 3454 (1998). A. J. Ortiz, A. Sanchez, and M. Nogueras, J. Heterocycl. Chem., 35, 231 (1998). J. B. Sainani, A. C. Shah, and V. P. Arya, Indian J. Chem. B, 33, 526 (1994). A. L. Mikhal'chuk and O. V. Gulyakevich, Izv. Akad. Nauk, Ser. Khim., 2353 (1996). S. G. Krivokolysko, V. D. Dyachenko, A. N. Chernega, and V. P. Litvinov, Izv. Akad. Nauk, Ser. Khim., 733 (2000). S. G. Krivokolysko, V. D. Dyachenko, and V. P. Litvinov, Khim. Geterotsikl. Soedin., 1691 (1999). S. G. Krivokolysko, V. D. Dyachenko, and V. P. Litvinov, Khim. Geterotsikl. Soedin., 230 (1999). V. D. Dyachenko, N. N. Nesterov, S. G. Krivokolysko, and V. P. Litvinov, Khim. Geterotsikl. Soedin., 785 (1997). E. C. Horning and M. G. Horning, J. Org. Chem., 11, 95 (1946). D. Vorlnder, Z. Anal. Chem., 77, 241 (1929).
7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
46
HETEROCYCLIZATION OF FUNCTIONALIZED HETEROCUMULENES WITH C,N- AND C,O-BINUCLEOPHILES. 1. CYCLOCONDENSATION OF 1-CHLOROALKYLHETEROCUMULENES AND N-(1-CHLOROALKYLIDENE)URETHANES WITH 2-CYANOMETHYLPYRIDINE
M. V. Vovk, P. S. Lebed, A. N. Chernega, V. V. Pirozhenko, V. I. Boiko, and I. F. Tsymbal The interaction of 1-chloroalkyl isocyanates, 1-chloroalkylcarbodiimides, 1,1-dichloroalkyl isocyanates, and N-(1-chloroethylidene)-O-methylurethanes with 2-cyanomethylpyridine has been investigated. An effect of organic base has been detected on the regioselectivity of the cyclocondensation of 1-chloroalkyl isocyanates, which leads to 2,3-dihydro-1H-pyrido[1,2-c]pyrimidin-1-one or the isomeric 2,3-dihydro1H-pyrido[1,2-c]pyrimidin-3-one. Irrespective of the cyclization conditions 1-chloroalkylcarbodiimides react with the formation of 1-imino-2,3-dihydro-1H-pyrido-[1,2-c]pyrimidines. One type of product, a 1H-pyrido[1,2-c]pyrimidin-1-one, was also isolated from 1,1-dichloroalkyl isocyanates and N-(1chloroalkylidene)urethanes. Keywords: 1H-pyrido[1,2-c]pyrimidines, 1-chloroalkyl isocyanates, 1-chloroalkylcarbodiimides, N-(1-chloroalkylidene)urethanes, 2-cyanomethylpyridine, cyclocondensation. Results correlated by us recently [1] on the chemical behavior of functionally 1-substituted alkylheterocumulenes (isocyanates and carbodiimides) enabled the conclusion that they are promising as 1,3-bielectrophilic [C=NC=]2+ synthons in intra- and intermolecular cyclizations with O,O-, O,S-, and N,S-bifunctional reagents. However their interaction with C,N-binucleophiles is limited to the examples of 1-cyclohexenyldialkylamines [2] and -N-methylaminocrotonic acid ethyl ester [3]. The formation in the latter case of 4-oxo(imino)tetrahydropyrimidine derivatives served as a strong reason for the involvement in similar reactions of compounds in which the nitrogen atom is the element of the heterocycle which should enable development of an efficient approach to a condensed pyrimidine system. For this reason the interaction of 1-chloroalkylheterocumulenes and some derivatives with 2-cyanomethylpyridine has been studied in the present work with the aim of obtaining new pyrido[1,2-c]pyrimidines. We note that previously the [4+2] cycloaddition reaction of 2-vinylpyridines to acyl isocyanates [4] and the electrocyclization of 2-(2-heterocumuleno)vinylpyridines [5,6] were used for the synthesis of pyrido[1,2-c]pyrimidine derivatives. Overall, the constant attention to this type of compounds is caused by the wide spectrum of their biological activity [6,7].
__________________________________________________________________________________________ Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev 02094; e-mail: mvovk@i.com.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 52-63, January, 2004. Original article submitted April 19, 2002. 0009-3122/04/4001-00472004 Plenum Publishing Corporation 47
It was established by us that 1-chloroalkyl isocyanates 1a-c react comparatively readily with 2-cyanomethylpyridine 2 with the formation of products of a pyrido[1,2-c]pyrimidine structure. In a series of reactions of 1-chloroalkyl isocyanates with binucleophilic reagents the influence of the conditions leading to the structure of the final products was discovered for the first time. The interaction of the reactants in benzene solution in the presence of triethylamine leads to 2,3-dihydro-1H-pyrido[1,2-c]pyrimidin-1-ones 3a-c and heating in this solvent in the absence of an organic base is accompanied by the formation of the isomeric 2,3-dihydro-1H-pyrido[1,2-c]pyrimidin-3-ones 4a-c (Table 1). We suggest that on mixing reactants 1 and 2 N-carbamoylation of the pyridine ring takes place with the formation of salt A. This is probably an equilibrium process, confirmation of which is the appearance and gradual increase in the 19F NMR spectra of signals at ~ -72 ppm [8], the intensity of which after 7-8 days became the same as the intensity of the signals of the initial isocyanates (~ -80 ppm). Addition of an organic base to the mixture leads to the formation of an anionic center on the cyanomethyl group, attack of which on the electrophilic azomethine bond closes the ring. On heating the reaction mixture, evidently displacement of the equilibrium towards the starting materials occurs followed by C-carbamoylation of the cyanomethyl group with the formation of intermediates of type B, which are then cyclized into 4a-c.
Ar F3 C Cl 1ac N=C=O
N 2
CN
+ _ N Cl O N A HCl
CN CF3 Ar
Et3N HCl O
N N H 3ac
CN CF3 Ar
HCl F 3C Ar
N H N B
CN F 3C O Ar
N N H 4ac
CN O
a r = Ph; b Ar = 4-MeC6H4 ; c Ar = 4-MeOC6H4
The differences between structures 3 and 4 were recorded by IR and 1H, 19F, and 13C NMR spectroscopy (Tables 2, 3). In the IR spectra of compounds 3a-c bands for the C=O group were found at 1732-1735 cm-1, but for 4a-c they were displaced to a lower frequency region (1630-1634 and 1648-1650 cm-1), which may be caused by participation in conjugation with the hexatriene bond system. A more detailed analysis of the IR spectra of compounds 3a and 4a showed that for 3a bands were observed for (C=O) at 1735, for (CN) at 2195, and for (NH) at 3261 cm-1 in the solid state. In solution in CH2Cl2 (c = 0.018 M) the frequencies of these bands appeared at 1733, 2199, and 3385 cm-1 respectively, i.e. only the band for (NH) was changed. Its shape was also changed, which is evidently caused by the participation of the NH group in the formation of intermolecular associates in the solid state between the unshared electron pair of the node nitrogen atom of one molecule and the NH group proton of another. The C=O group does not participate in such a process, consequently in the initial solutions and in solutions diluted 4.5 and 13 times its intensity and frequency are the same as in the solid state. 48
TABLE 1. Characteristics of the Synthesized Compounds 3a-c, 4a-c, 6a-c, and 9a,b
Compound 3 3b 3 4 4b 4 6 6b 6 9 9b Empirical formula 16H10F3N3O C17H12F3N3O C17H12F3N3O2 16H10F3N3O C17H12F3N3O C17H12F3N3O2 C22H17F3N4 C23H19F3N4 C23H19F3N4O C10H4F3N3O C10H4Cl3N3O Found, % Calculated, % 3.09 3.18 3.61 3.65 3.51 3.48 3.24 3.18 3.78 3.65 3.54 3.48 4.21 4.22 4.69 4.56 4.32 4.39 1.54 1.69 1.57 1.40 mp, N 13.40 13.24 12.81 12.68 12.29 12.10 13.36 13.24 12.53 12.68 11.94 12.10 14.03 13.79 13.41 13.33 12.99 12.84 17.70 17.57 14.31 14.56 188-189 187-188 185-186 230-231 228-229 214-215 116-117 125-126 156-157 207-208 220-221 Yield*, % (method) 60 71 74 44 46 39 50 (A), 40 (B) 38 43 52 (A), 37 (B) 41 (C), 30 (D) 56 (A), 47 (C)
60.79 60.57 61.37 61.63 59.07 58.79 60.29 60.57 61.50 61.63 59.92 58.79 68.20 67.97 68.47 68.56 65.76 66.05 50.36 50.22 41.80 41.63
_______ * Compounds 3a-c, 4a-c, 6a-c, and 9a were recrystallized from ethanol, compound 9b from ethanoldioxane, 2:1. In the solid state compound 4a is characterized by a broad absorption band for the C=O group at 1634 cm-1 with a high frequency shoulder at 1650 cm-1. In the region of (NH) absorption there was a broad band at 3157 cm-1. In CH2Cl2 solution (c = 0.018 M) two bands were observed for the C=O group (1641 and 1669 cm-1) and a band for the NH group at 3390 cm-1. The bands at 1669 and 3390 cm-1 are the bands for (C=O) and (NH) of monomeric molecules, which indicates the existence of intermolecular associates with two hydrogen bonds in the solid state.
N H . . . . .O O . . . . .H N
In the 1H NMR spectra of pyrido[1,2-c]pyrimidin-1-ones 3a-c the singlets for the N-H protons at 9.76-9.84 ppm are representative, as are the doublets for the 8-H protons in the low field portion of the spectrum (7.93-7.95 ppm), caused by the deshielding effect of the carbonyl group. For the pyrido[1,2-c]pyrimidin-3-ones 4a-c the analogous signals for 8-H and N-H are displaced towards high field by approximately 0.9 ppm. Comparison of the 19F NMR spectra of compounds 3a-c and 4a-c shows that the signals of the CF3 group resonate in approximately the same range (from -75 to -76 ppm) irrespective of their position in the pyrimidine ring, although in the CC(CF3)N bond system of 3a-c a high field displacement (~0.5 ppm) compared with the NC(CF3)N bond system of 4a-c is observed. The 13C NMR spectra confirm the cyclic structure of the reaction products of isocyanates 1a-c with 2-cyanomethylpyridine 2 and have distinctive features for each cyclic isomer. For compounds 3a-c the singlet for the C(1) atom (C=O group) is at 146, and the quartet for the C(3) atom is at 63 ppm (JCF = 29 Hz). However for compounds 4a-c the C(1) atom is displayed as a quartet at 81 (JCF = 30-31 Hz), but the C(3) atom (C=O group) shows as a singlet at 160 ppm. 49

Compound 3a
1
NMR spectrum, , ppm (J, Hz)
19 F NMR spectrum, , ppm
IR spectrum, , cm-1 = 1735 N 2195 NH 3261
3b
3c
4a
4b
4c
6a* 6b*2
6c*3
9a
9b
6.19-6.24 (1H, m, 7-); 6.80 (1, d, J = 9.3, 5-H); 7.09-7.15 (1, m, 6-); 7.42-7.53 (3, m, r); 7.62 (2, d, J = 8.0, HAr); 7.95 (1H, d, J = 7.3, 8-H); 9.84 (1, s, NH) 2.37 (1, s, 3); 6.30 (1, m, 7-); 6.79 (1, d, J = 9.4, 5-H); 7.10-7.24 (1, m, 6-); 7.27 (2, d, J = 8.1, HAr); 7.49 (2, d, J = 8.1, HAr); 7.93 (1, d, J = 7.4, 8-H); 9.78 (1, NH) 3.82 (3, s, 3); 6.38-6.50 (1, m, 7-); 6.82 (1, d, J = 9.4, 5-H); 6.99-7.02 (2, d, J = 9.0, HAr); 7.11-7.30 (1, m, 6-); 7.53 (2, d, J = 9.0, HAr); 7.93 (1, d, J = 7.4, 8-H); 9.76 (1, s, NH) 6.43-6.49 (1, m, 7-); 6.93-6.95 (1, d, J = 7.0, 5-H); 7.09-7.12 (1, d, J = 9.0, 8-H); 7.49-7.54 (1, m, 6-); 7.47-7.58 (3, m, r); 7.62-7.66 (2, m, r); 8.96 (1, s, NH ) 2.41 (3, s, 3); 6.43-6.48 (1, m, 7-); 6.94 (1, d, J = 7.0, 5-H); 7.09 (1, d, J = 9.1, 8-H); 7.37 (2, d, J = 8.3); 7.45-7.58 (1, m, 6-H); 7.55 (2, d, J = 8.3, HAr); 8.93 (1, s, NH) 3.84 (3, s, 3); 6.44-6.52 (1, m, 7-); 6.96 (1, d, J = 7.0, 5-H); 7.05-7.17 (3, 8- + r); 7.46-7.55 (1, m, 6-); 7.59 (2, d, J = 8.5, HAr); 8.92 (1, s, NH) 2.31 (3, s, 3); 6.13-6.17 (1, m, 7-); 7.03-7.56 (11, m, 5-H + 6-H + r); 7.70 (1, J = 7.2, 8-H); 8.98 (1, s, NH) 2.31 (6, br. s, 3); 6.09-6.21 (1, m, 7-); 7.01-7.17 (6, m, 5-H + 6- + r); 7.42-7.55 (4, m, r); 7.68 (1, d, J = 7.2, 8-H); 8.95 (1, s, NH) 2.29 (3, s, 3); 3.75 (3, s, 3); 6.08-6.19 (1, m, 7-); 6.86-7.11 (6, m, 5-H + 6-H + r); 7.42-7.45 (4, m, r); 7.67 (1, d, J = 6.8, 8-H); 8.93 (1, s, NH) 7.91-7.96 (1, m, 7-); 8.19 (1, d, J = 8.5, 5-H); 8.50-8.55 (1, m, 6-H); 9.35 (1, d, J = 6.8, 8-H) 7.82-7.87 (1, m, 7-); 8.20 (1, d, J = 8.4, 5-H); 8.43-8.48 (1, m, 6-H); 9.27 (1, d, J = 6.9, 8-H)
-76.47
-76.46
1732
2199
3259
-76.57
1734
2202
3276
-75.69
1634, 1650
2210
3157
-75.89
1630, 1647
2210
3178
-76.02
1632, 1648
2212
3163
75.44
2197
3385
-75.45
2198
3318
-75.69
2190
3318
-68.18
1709
2235
1714
2237
_______ * (C=N) 1665 cm-1. *2 (C=N) 1663 cm-1. *3 (C=N) 1659 cm-1.
The special features of the molecular and crystal structure of compound 4a were also studied by X-ray structural analysis. The overall form of the 4a molecule is shown in Fig. 1, the main bond lengths and valence angles are given in Table 4. The central bicyclic system N(1)N(2)C(1-8) is markedly non-planar, the deviation of the atoms from the mean-square plane is 0.323 . The N(1)C(2)C(5-8) ring is planar to within 0.032 , and the heterocycle N(1)N(2)C(1-4) has the conformation of a flattened half-chair (the modified CremerPople parameters [9] S, , and were 0.48, 53.4, and 5.8 respectively). By virtue of the steric conditions the benzene ring C(9-14) 50
TABLE 3. 13C NMR Spectra of the Obtained Compounds, , ppm (J, Hz)
Compound 1 3 (1) 2 146.93 (3) 3 63.66 (q, J = 29) (4) 4 68.00 (4) 5 148.09 (5) 6 119.44 (6) 7 136.21 (7) 8 108.50 (8) 9 128.98 N 10 117.49 CF3 11 125.38 (q, J = 292) CCl3 12 CAr 13 136.60 (i) 127.31 (o) 128.64 (m) 129.11 (p) 133.63 (i) 138.52 (o) 129.06 (m) 127.10 (p) 128.47 (i) 128.67 (o) 113.83 (m) 159.45 (p) 133.83 (i) 128.31 (o) 129.41 (m) 130.97 (p) CAr' 14 Other signals 15
3b
146.86
63.46 (q, J = 29)
68.18
147.91
119.38
135.96
108.32
128.84
117.38
125.30 (q, J = 290)
20.50 (CH3)
3c
63.66 (q, J = 29)
125.40 (q, J = 290)
55.23 (CH3O)
4a
81.36 (q, J = 31)
160.46
68.87
153.15
119.54
139.50
112.57
136.08
117.40
124.15 (q, J = 296)
51
52
TABLE 3 (continued)
1 4b 2 81.33 (q, J = 31) 3 160.55 4 68.86 5 153.09 6 119.48 7 139.46 8 112.49 9 136.00 10 117.39 11 124.17 (q, J = 296) 12 13 130.84 (i) 128.20 (o) 129.90 (m) 140.80 (p) 125.11 (i) 129.69 (o) 114.38 (m) 160.61 (p) 139.62 (i) 126.86 (o) 128.17 (m) 128.43 (p) 136.67 (i) 126.76 (o) 128.72 (m) 137.87 (p) 14 15 20.67 (CH3)
4c
81.14 (q, J = 30)
160.39
69.22
152.87
119.46
138.75
111.87
135.48
116.87
124.01 (q, J = 296)
55.23 (CH3O)
6a
143.00
63.52 (q, J = 27)
69.16
148.37
119.92
133.53
107.94
130.22
118.04
124.77 (q, J = 285)
6b
142.95
63.33 (q, J = 27.2)
69.30
148.27
119.91
133.39
107.87
130.23
118.05
124.83 (q, J = 285)
137.20 (i) 120.52 (o) 129.04 (m) 132.11 (p) 137.27 (i) 120.44 (o) 129.02 (m) 132.05 (p)
20.28 (CH3)
20.44 (CH3) 20.26 (CH3')
9a 9b
148.50 148.03
154.46 (q, J = 34) 163.44
81.10 79.70
149.36 150.11
123.16 121.90
143.78 142.97
123.16 122.70
133.05 132.59
112.90 113.78
154.46 (q, J = 34) 95.26
Fig. 1. Overall form of the 4a molecule with numbering of atoms. is practically orthogonal to the bicyclic system, the appropriate dihedral angle being 84.4. In the crystal the 4a molecules are joined in centrosymmetric dimers (Fig. 2) through hydrogen bonds O(1)H(2)N(2) (O(1)N(2) 2.866(2), O(1)H(2) 2.04(2) , O(1)H(2)N(2) 176.7(14)), which confirms the results of the IR spectral investigations presented above.
Fig. 2. Crystal packing of compound 4a (intermolecular hydrogen bonds N(2)H(2)O(1) are shown by dotted lines). 53
TABLE 4. Bond Lengths (d) and Valence Angles () in the Molecule of Compound 4a
Bond O(1)C(4) N(1)C(1) N(1)C(2) N(1)C(8) N(2)C(1) N(2)C(4) C(2)C(3) C(2)C(5) C(3)C(4) C(5)C(6) C(6)C(7) C(7)C(8) d, 1.234(2) 1.498(2) 1.379(2) 1.379(2) 1.437(2) 1.372(2) 1.396(2) 1.422(2) 1.436(2) 1.354(3) 1.408(3) 1.343(3) Angle C(1)N(1)C(2) C(2)N(1)C(8) C(1)N(2)C(4) N(1)C(1)N(2) N(1)C(2)C(3) N(1)C(2)C(5) C(2)C(3)C(4) N(2)C(4)C(3) C(2)C(5)C(6) C(5)C(6)C(7) C(6)C(7)C(8) N(1)C(8)C(7) , deg 119.57(13) 121.12(14) 124.13(13) 108.98(13) 119.67(14) 116.77(15) 121.00(14) 115.49(14) 121.47(16) 119.66(16) 119.32(16) 121.36(16)
The imino analogs of 1-chloroalkyl isocyanates 1a-c, the 1-chloroalkylcarbodiimides 5a-c, are systems with a less electrophilic heterocumulene group and an -carbon atom with more marked electrophilic properties. This shows up significantly in the character of their interaction with 2-cyanomethylpyridine 2.
Ar
Ar'
F3C
N=C=N
or EtN(i-Pr)2
Cl 5ac
N 2
CN
HCl
N H
Ar'
CN
N
Ar'
CN
N
C
CF3
Ar
N H
6ac
CF3
Ar
a Ar = Ph, Ar' = 4-MeC6H4; b Ar = Ar' = 4-MeC6H4;c Ar = 4-MeOC6H4, Ar' = 4-MeC6H4
It was established that 10 h heating of reactants 5a-c and 2 in boiling benzene did not give analogs of compound 4 but analogs of compound 3, viz. the 1-imino-1H-pyrido[1,2-c]pyrimidines 6a-c (see Table 1). It is most probable that in this case products of C-alkylation C are formed first, which are then cyclized intramolecularly into 6a-c. The presence in the 1H NMR spectra of compound 6a (see Table 2) of doublet signals for the 8-H protons at 7.67-7.70, and in the 13C NMR spectra (see Table 3) of compounds 6a,b of quartets for the C(3) atoms at 63 ppm (JCF = 27 Hz) reliably confirm the structure proposed. On investigating the reaction of carbodiimides 5 with 2-cyanomethylpyridine 2 in the presence of an organic base a positive result was obtained only on using N-ethyl-N,N-diisopropylamine as base. It was shown for carbodiimide 5a as an example, that on using this base 5a reacts with pyridine 2 by the scheme given above with the formation of compound 6a in 40% yield. With the aim of synthesizing unhydrogenated analogs of pyrido[1,2-c]pyrimidines 3 and 4 the interaction of 2-cyanomethylpyridine 2 with 1,1-dichloroalkyl isocyanates 7a,b and N-(1-chloro-2,2,2trihaloethylidene)-O-methylurethanes 8a,b was investigated under various experimental conditions. The results 54
obtained indicate that irrespective of the character of reactants 7 and 8 and also of the reaction conditions, one type of compound is formed, 3-trihalomethyl-1H-pyrido[1,2-c]pyrimidin-1-ones 9a,b (see Tables 1-3). It is logical to propose that thanks to the more electrophilic properties of the heterocumulene group of isocyanates 7a,b, compared with isocyanates 1a-c, the more stable pyridinium salts of type A are formed initially which, under the action of base or temperature, are dehydrochlorinated into the cyclic system 9. N-(1-Chloroethylidene)urethanes 8a,b react with nitrile 2 by a C-iminoalkylation scheme with the formation first of intermediates D, the intramolecular condensation of which also leads to heterocycle 9.
Et3 N or 2HCl
X 3 CCCl2N=C=O 7a,b
+
N 2
CN
Cl
O
+ N
N
CN
Cl
CX 3
CN
N 9a,b
O
O
CX 3
X3C
Cl
OMe
Et3 N or 2HCl
8a,b
N H MeOOC N
CN
MeOH
CX 3
D a X = F ; b X = Cl
In the IR spectra of pyrido[1,2-c]pyrimidines 9a,b there were absorption bands for the C=O group at 1709-1714 cm-1. The presence in the 1H NMR spectra of a doublet for 8-H at 9.27-9.35 ppm is in agreement with literature data [6], and in the 13C NMR spectra the signal of the C(1) atom (C=O group) at 148 ppm corresponds to that for the hydrogenated analogs 3a-c.
EXPERIMENTAL The IR spectra were recorded on a UR-20 instrument in KBr disks (for compounds 3a and 4a also in CH2Cl2 solution). The 1H and 19F NMR spectra of solutions in (CD3)2SOCCl4, 2:1 and the 13C NMR spectra of solutions in (CD3)2SO were obtained on a Varian-Gemini spectrometer (300, 188, 75 MHz respectively), internal standards were TMS (1H, 13C) and CCl3F (19F). The initial 1-chloroalkyl isocyanates 1a-c were obtained by the procedure of [10], 1-chloroalkylcarbodiimides 5a-c of [11], 1,1-dichloroalkyl isocyanates 7a,b according to [12,13], and N-(1-chloroethylidene)urethanes 8a,b according to [14]. 3-Aryl-4-cyano-3-trifluoromethyl-2,3-dihydro-1H-pyrido[1,2-c]pyrimidin-1-ones (3a-c). A solution of isocyanate 1a-c (3 mmol) in benzene (15 ml) was added dropwise with stirring to a solution of 2-cyanomethylpyridine 2 (0.354 g, 3 mmol) in benzene (5 ml), and then after 30 min triethylamine (0.31 g, 3.1 mmol) was added. The reaction mixture was stirred for 1 h, left for 24 h, and then filtered. The solid was washed with water, and dried. The filtrate was evaporated, hexane (1 ml) and 2-propanol (10 ml) were added to the oily residue, and the mixture heated to boiling. The precipitate formed on cooling was filtered off, combined with the first portion of solid, and crystallized. 55
1-Aryl-4-cyano-1-trifluoromethyl-2,3-dihydro-1H-pyrido[1,2-c]pyrimidin-3-ones (4a-c). A mixture of isocyanate 1a-c (3 mmol) and 2-cyanomethylpyridine 2 (0.354 g, 3 mmol) in benzene (20 ml) was boiled for 20 h. The solvent was evaporated, ethanol (6 ml) was added to the residue, the mixture was heated to boiling, and cooled. The resulting solid was filtered off, and dried. 3-Aryl-1-arylimino-4-cyano-3-trifluoromethyl-2,3-dihydro-1H-pyrido[1,2-c]pyrimidines (6a-c). A. A mixture of 2-cyanomethylpyridine 2 (0.354 g, 3 mmol) and carbodiimide 5a-c (3 mmol) in benzene (20 ml) was boiled for 10 h. The solvent was evaporated, and the residue purified by crystallization. B. A solution of carbodiimide 5a (0.974 g, 3 mmol) in benzene (15 ml) was added dropwise with stirring to a solution of 2-cyanomethylpyridine 2 (0.354 g, 3 mmol) in benzene (5 ml), and after 30 min N-ethylN,N-diisopropylamine (0.4 g, 3.1 mmol) was added. The reaction mixture was stirred for 1 h, left for 96 h, and then filtered. The filtrate was evaporated, ethanol (4 ml) was added to the oily residue, and the mixture heated to boiling. The precipitate formed on cooling was filtered off. 4-Cyano-3-trihalomethyl-1H-pyrido[1,2-c]pyrimidin-1-ones (9a,b). A. A solution of isocyanate 7a,b (2.5 mmol) in benzene (5 ml) was added dropwise with stirring to a solution of 2-cyanomethylpyridine 2 (0.295 g, 2.5 mmol) in benzene (5 ml). After 30 min a solution of triethylamine (0.505 g, 5 mmol) in benzene (5 ml) was added dropwise, the mixture stirred for 3 h, and left for a day. The resulting solid was filtered off, washed with water, dried, and crystallized. B. A mixture of 2-cyanomethylpyridine 2 (0.295 g, 2.5 mmol) and isocyanate 7a (2.5 mmol) in benzene (15 ml) was boiled for 15 h. The solvent was evaporated, and the residue crystallized. C. A mixture of urethane 8a,b (3 mmol) and triethylamine (0.303 g, 3 mmol) in toluene (10 ml) was added with stirring to a solution of 2-cyanomethylpyridine 2 (0.354 g, 3 mmol) in toluene (5 ml). After 3 h the precipitate of triethylamine hydrochloride was filtered off, the filtrate was left at room temperature for 3-4 days (in the case of urethane 8b) or boiled for 3 h (in the case of urethane 8a). The solvent was then evaporated, and the residue purified by crystallization. D. A mixture of 2-cyanomethylpyridine 2 (0.354 g, 3 mmol) and urethane 8a (3 mmol) in benzene (15 ml) was boiled for 12 h. The solvent was evaporated, and the residue crystallized. The X-Ray Structural Investigation of a Monocrystal of Compound 4a of linear dimensions 0.25 0.31 0.53 mm was carried out at room temperature on an Enraf-Nonius CAD-4 automatic four-circle diffractometer (CuK radiation, relative scanning rate 2/ = 1.2, max = 70, sphere segment 0 h 14, 0 k 7, -21 l 21). In all 2951 reflections were selected of which 2560 are symmetrically independent (Rint = 0.01). The crystals of 4a are monoclinic, a = 12.120(10), b = 6.320(6), c = 17.692(11) , = 94.84(6), V = 1350.5 3, M = 317.27, Z = 4, dcalc = 1.56 g/cm3, = 10.8 cm-1, F(000) = 650.3, space group P21/c. The structure was solved by the direct method and refined by the least-squares method in a full-matrix anisotropic approach using the set of programs CRYSTALS [15]. In the refinement 2325 reflections with I > 3(I) were used (248 parameters being refined, number of reflections per parameter 9.4). All the hydrogen atoms were made apparent from an electron density difference synthesis and were refined isotropically. Calculation of the absorption in the crystal was carried out by the azimuthal scanning method of [16]. In the refinement the weighting scheme of Chebyshev [17] was used with the parameters: 2.46, -0.74, 0.67, -1.16, and -0.10. The final values for the reliability factors were R = 0.044 and RW = 0.044, GOF = 0.953. The residual electron density from the Fourier difference series were 0.26 and -0.30 e/3. A full set of the crystallographic data is deposited in the Cambridge Structural Data Bank (No. CCDC 178183).
REFERENCES 1. 2. 3. 56 M. V. Vovk, Dissertation for Doctor of Chemical Sciences, Kiev, 1994. A. D. Sinitsa, L. O. Nebogatova, and S. V. Bonadyk, Zh. Org. Khim., 14, 522 (1978). M. V. Vovk and V. V. Pirozhenko, Khim. Geterotsikl. Soedin., 96 (1994).
4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.
N. N. Zobova, N. R. Rubinova, and B. A. Arbuzov, Izv. Akad. Nauk SSSR, Ser. Khim., 2608 (1975). P. Molina, A. Lorenzo, and E. Allet, Tetrahedron, 48, 4601 (1992). P. Molina, E. Allet, A. Lorenzo, P. Lopez-Cremades, I. Rioja, A. Ubeda, M. C. Terencio, and M. J. Alcoroz, J. Med. Chem., 44, 1011 (2001). R. J. Chorvat, K. A. Prodon, and G. W. Adelstein, J. Med. Chem., 28, 1285 (1985). V. N. Fetyukhin, M. V. Vovk, and L. I. Samarai, Zh. Org. Khim., 19, 1232 (1983). N. S. Zefirov and V. A. Palyulin, Dokl. Akad. Nauk SSSR, 252, 111 (1980). V. N. Fetyukhin, A. S. Koretskii, V. I. Gorbatenko, and L. I. Samarai, Zh. Org. Khim., 13, 271 (1977). V. I. Gorbatenko, V. N. Fetyukhin, and L. I. Samarai, Zh. Org. Khim., 12, 2472 (1976). V. I. Gorbatenko, Yu. I. Matveev, M. N. Gertsyuk, and L. I. Samarai, Zh. Org. Khim., 20, 2543 (1984). V. I. Boiko, M. N. Gertsyuk, and L. I. Samarai, Zh. Org. Khim., 24, 451 (1988). L. I. Samarai, V. I. Boiko, and M. N. Gertsyuk, Zh. Org. Khim., 26, 745 (1990). D. J. Watkin, C. K. Prout, J. R. Carruthers, and P. W. Betteridge, Crystals, Issue 10, Chemical Crystallography Laboratory, Univ. of Oxford, 1996. A. C. T. North, D. C. Phillips, F. Scott, and F. S. Mathews, Acta Crystallogr., A24, 351 (1968). J. R. Carruthers and D. J. Watkin, Acta Crystallogr., A35, 698 (1979).
57
ANOMALOUS BECKMANN REACTION IN A SERIES OF OXIMES OF 4-ARYL-2,7,7-TRIMETHYL5-OXO-5,6,7,8-TETRAHYDROQUINOLINES IN POLYPHOSPHORIC ACID. 2*. UNEXPECTED SYNTHESIS OF 3'-ETHOXYCARBONYL-4',7',7'-TRIMETHYL-4-OXO2',6',7',8'-TETRAHYDROSPIRO(CYCLOHEXA2,5-DIENE-1,2'-PYRROLO[4,3,2-d,e]QUINOLINES)
S. V. Tolkunov1, A. I. Khyzhan1, S. V. Shishkina2, O. V. Shishkin2, and V. I. Dulenko1 Oximes of 3-ethoxycarbonyl-4-halo(methoxy)phenyl-2,7,7-trimethyl-5-oxo-5,6,7,8-tetrahydroquinolines are converted in polyphosphoric acid (PPA) into 3'-ethoxycarbonyl-4',7',7'-trimethyl-4-oxo-2',6',7',8'tetrahydrospiro(cyclohexa-2,5-diene-1,2'-pyrrolo[4,3,2-d,e]quinoline). An X-ray structural analysis has been carried out on one of the synthesized compounds. Keywords: oximes of 4-aryl-3-ethoxycarbonyl-2,7,7-trimethyl-5-oxo-5,6,7,8-tetrahydroquinolines, 3'-ethoxycarbonyl-4',7',7'-trimethyl-4-oxo-2',6',7',8'-tetrahydrospiro(cyclohexa-2,5-diene-1,2'-pyrrolo[4,3,2-d,e]quinolines), polyphosphoric acid. We previously reported an anomalous Beckmann reaction in a series of oximes of 4-aryl-3ethoxycarbonyl-2,7,7-trimethyl-5-oxo-5,6,7,8-tetrahydroquinolines in polyphosphoric acid (PPA) [1]. It was shown that, depending on the substituent in position 4 of the quinoline ring, the reaction may proceed in three directions: with aromatization of the saturated ring (ZemmlerWolf aromatization), with the formation of azepinones, the normal Beckmann rearrangement products, and with the formation of pyridoacridines. While studying the rearrangement of oximes of 4-chloro(bromo, methoxy)phenyl-3-ethoxycarbonyl-2,7,7-trimethyl-5oxo-5,6,7,8-tetrahydroquinolines in PPA we discovered a new route for the reaction process. As it turned out on heating oximes 1a-c in PPA elimination of the substituent located at position 4 of the phenyl ring occurs and only one product is formed, viz. 3'-ethoxycarbonyl-4',7',7'-trimethyl-4-oxo-2',6',7',8'-tetrahydrospiro(cyclohexa2,5-diene-1,2'-pyrrolo[4',3',2'-d,e]quinoline) (2a). When R1 = Cl or Br hydrogen halide is evolved from the reaction mixture. _______ * For Part 1 see [1]. __________________________________________________________________________________________ L. M. Litvinenko Institute of Physical-Organic Chemistry and Coal Chemistry, National Academy of Sciences of Ukraine, Donetsk, 83114; e-mail: tolkunov@uvika.dn.ua. 2 Institute of Monocrystals, National Academy of Sciences of Ukraine, Kharkov 61001 Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 64-70, January, 2004. Original article submitted August 28, 2001; revision submitted January 31, 2002. 58 0009-3122/04/4001-00582004 Plenum Publishing Corporation
1
R1 O HO N Me Me N 1ad Me
R2 COOEt Me Me
R2 COOEt
N 2a,b
Me
1 a R1 = Cl, b R1 = Br, c R1=OMe, d R1 = Cl; a-c R2 = H, d R2 = Cl; 2 a R2 = H, b R2 = Cl
The structure of compound 2a was established by an X-ray structural investigation. The tetrahydro ring is in a half-boat conformation. The deviation of the C(3) atom from the mean-square plane of the remaining ring atoms is 0.65 . One of the methyl substituents at C(3) has an axial orientation relative to the plane of the tetrahydro ring, the second is equatorial (torsion angle C(1)C(2)C(3)C(20) is 67.4(3), C(1)C(2)C(3)C(21) 172.9(2)). Repulsion between the H(20C) atom and the ring atoms (shortened intramolecular contacts H(20C)C(1) 2.79, H(20C)C(5) 2.67, H(20C)C(6) 2.73 (total of van der Waals radii 2.87 [2])) evidently leads to lengthening of the C(3)C(4) bond to 1.557(3) compared with a mean value of 1.538 [3]. The dihydro ring spiro-linked with the tricyclic fragment is planar with a precision of 0.02 and is folded practically perpendicularly to the plane of the rings (torsion angle C(6)C(7)C(10)C(15) is 113.4(2)). The C(13)O(3) bond at 1.225(3) is extended somewhat compared with a mean value of 1.210 . The C(16) atom of the ester substituent at the C(8) atom is somewhat out of the plane of the pyridine ring (torsion angle C(6)C(7)C(8)C(16) is -171.0(2)), and the carbonyl group is folded practically perpendicularly to the plane of the tricyclic fragment (torsion angle C(7)C(8)C(16)O(1) is 118.1(3)), which is probably explained by the repulsion between this substituent and the dihydro ring. The C(18) atom is randomized with an equally probable population at two positions A and B. In conformer A the C(18) atom occupies an as-position relative to the C(16)O(2) bond and in conformer B a position close to ar (torsion angle C(16)O(2)C(17)C(18) 129.7(5) in A and 163.4(4) in B). Shortened intermolecular contacts were detected in the crystal of compound 2a O(1)H(15)' (0.5-x, y-0.5, 1.5-z) 2.43 and O(3)H(1b)' (0.5-x, 0.5+y, 1.5-z) 2.43 (total of van der Waals radii 2.46 ), which may hardly count as hydrogen bonds in view of the angles C(15)H(15)O(1)' (105) and C(19)H(19b)O(3) (74).
Fig. 1. Structure of compound 2a. 59
The 1H NMR spectra were in complete agreement with structures 2a,b. However attention is attracted by the special features of the 1H NMR spectrum of pyrroloquinoline 2b (R2 = Cl) compared with the spectrum of 2a. The protons of the CH2 group in the carboxyethyl fragment are magnetically nonequivalent and are displayed as a multiplet of ten lines. The protons of the 8-CH2 group are also magnetically nonequivalent, which is caused by the different spatial orientation of the CH bonds and by the displacement of one of them due to the influence of the magnetic anisotropy of the chlorine atom. The formation of such a condensed system is explained by the uncoordinated orientation in the substituted phenyl ring and as a result attack by the nitrene cation 3 occurs at position 1 of the phenyl substituent with the formation of cation 4, which is then converted as a result of the usual additionfission reactions into pyrroloquinolines 2a,b.
R1 R1 +
+ N 1ad Me Me 3 O R1 O P OH OH N
R2 COOEt Me Me Me
R2 COOEt N 4 Me
O HO HO P
O O O P OH OH H 2O
N Me Me 5 N
R2 COOEt Me
R1 Me Me
R2 COOEt N 6 Me
2a,b
The formation of small quantities of 1-ethoxycarbonyl-2,5,5-trimethyl-5,6-dihydro-4H-pyrrolo[2,3,4-k,l]acridine (7), in addition to pyrroloquinoline 2a, was discovered in the reaction of 4-(4-bromophenyl)-3ethoxycarbonyl-2,7,7-trimethyl-5-oxo-5,6,7,8-tetrahydroquinoline oxime (1b).
Br
N COOEt Me Me 7 N Me
60
TABLE 1. Coordinates (104) and Equivalent Isotropic Thermal Parameters (2103) of Non-hydrogen Atoms in Structure 2a
Atom N(1) N(2) O(1) O(2) O(3) C(1) C(2) C(3) C(4) C(5) C(6) C(7) C(8) C(9) C(10) C(11) C(12) C(13) C(14) C(15) C(16) C(17) C(18a) C(18b) C(19) C(20) C(21) x 1425(2) 3210(3) 3122(2) 1772(2) 4517(2) 1789(2) 1770(3) 2858(3) 2743(3) 2754(3) 2235(3) 2374(3) 2056(2) 1547(3) 3044(3) 2205(3) 2669(3) 4051(3) 4873(3) 4428(3) 2372(3) 2183(3) 914(6) 1089(7) 1105(4) 4256(3) 2652(4) y -1138(2) 2071(2) -664(2) 675(2) 3372(2) -372(2) -428(2) 249(2) 1354(2) 1382(2) 514(2) 658(2) -142(2) -1021(2) 1694(2) 2439(2) 2965(2) 2848(2) 2077(2) 1563(2) -95(2) 850(3) 944(8) 1540(6) -1917(2) -156(3) 251(3) z 10764 (2) 11184(2) 8271(1) 8017(1) 8194(2) 11386(2) 12442(2) 13087(2) 12709(2) 11658(2) 11076(2) 10150(2) 9502(2) 9847(2) 10153(2) 9477(2) 8846(2) 8747(2) 9342(2) 9995(2) 8531(2) 7112(2) 6274(4) 6504(6) 9200(2) 13107(2) 14117(2) Ueq 53(1) 61(1) 77(1) 65(1) 95(1) 45(1) 55(1) 55(1) 62(1) 52(1) 46(1) 47(1) 47(1) 50(1) 51(1) 58(1) 61(1) 63(1) 61(1) 57(1) 51(1) 93(1) 93(3) 76(2) 72(1) 77(1) 79(1)
TABLE 2. Bond Lengths (l) in the Structure of Pyrroloquinoline 2a

Bond N(1)C(1) N(2)C(5) O(1)C(16) O(2)C(17) C(1)C(6) C(2)C(3) C(3)C(21) C(4)C(5) C(6)C(7) C(7)C(10) l, 1.339(2) 1.288(3) 1.197(3) 1.466(3) 1.371(3) 1.545(4) 1.531(4) 1.498(4) 1.373(3) 1.534(4) Bond C(8)C(16) C(10)C(11) C(11)C(12) C(13)C(14) C(17)C(18b) N(1)C(9) N(2)C(10) O(2)C(16) O(3)C(13) C(1)C(2) l, 1.494(3) 1.495(4) 1.314(4) 1.457(4) 1.538(1) 1.348(3) 1.519(3) 1.317(3) 1.229(3) 1.509(4) Bond C(3)C(20) C(3)C(4) C(5)C(6) C(7)C(8) C(8)C(9) C(9)C(19) C(10)C(15) C(12)C(13) C(14)C(15) C(17)C(19a) l, 1.519(4) 1.555(4) 1.441(4) 1.391(4) 1.412(4) 1.503(4) 1.494(4) 1.460(4) 1.319(4) 1.538(1)
EXPERIMENTAL The 1H NMR spectra were recorded on a Varian VXR-300 instrument (300 MHz) and on a Gemini-200 instrument (200 MHz), internal standard was TMS. A check on the purity of the compounds obtained was carried out by TLC on Silufol UV-254 plates. Visualization was with UV light or iodine vapor.
61
TABLE 3. Valence Angles () in Structure 2a

Angle C(1)N(1)C(9) (16)O(2)(17) N(1)C(1)C(2) (1)(2)(3) (20)(3)(2) (20)(3)(4) (2)(3)(4) N(2)C(5)C(6) (6)(5)(4) (1)(6)(5) (6)(7)(8) (8)(7)(10) (7)(8)(16) N(1)C(9)C(8) (8) (9)(19) (11)(10)N(2) (11)(10)(7) N(2)(10)(7) (11)(12)(13) O(3)(13)(12) (15)(14)(13) O(1)(16)O(2) O(2)(16)(8) O(2)(17)(18) , deg. 118.4(2) 114.6(2) 123.5(2) 112.4(2) 110.1(2) 109.4(2) 111.0(2) 113.3(2) 117.5(2) 127.2(2) 117.9(2) 135.8(2) 120.8(2) 124.0(2) 121.3(2) 108.4(2) 113.8(2) 104.1(2) 121.8(3) 122.3(3) 121.5(3) 124.3(2) 111.7(2) 109.1(4) Angle C(5)N(2)(10) N(1)C(1)C(6) (6)(1)(2) (20)(3)(21) (21)(3)(2) (21)(3)(4) (5)(4)(3) N(2)C(5)C(4) (1)(6)(7) (7)(6)(5) (6)(7)(10) (7)(8)(9) (9)(8)(16) N(1)C(9)C(19) (11)(10)(15) (15)(10) N(2) (15)(10)(7) (12)(11)(10) O(3)(13)(14) (14)(13)(12) (14)(15)(10) O(1)(16)(8) O(2)(17)(18b) (18b)(17)(18) , deg. 107.6(2) 119.9(2) 116.6(2) 109.2(2) 108.8(2) 108.3(2) 110.5(2) 129.2(3) 123.2(2) 109.4(2) 105.7 (2) 116.4(2) 122.5(2) 114.7(2) 113.3(2) 107.2(2) 109.5(2) 123.0(3) 120.7(3) 117.0(2) 123.1(3) 123.9(3) 105.3(4) 32.4(4)
X-Ray Structural Investigation. The crystals of compound 2a were monoclinic, C21H22N2O3, and at 20C: a = 10.212(4), b = 13.258(5), c = 14.226(5) ; = 104.04(2); V = 1869(1) 3; M = 349.40; Z = 4, space group P21/n; dcalc = 1.242 g/cm3; (MoK) = 0.084 mm-1; F(000) = 740. Unit cell parameters and the intensities of 3174 reflections (3001 independent, Rint = 0.025) were measured on a Siemens P3/PC automatic four-circle diffractometer (MoK, graphite monochromator, 2/ scanning, 2max = 50). The structure was solved by the direct method with the SHELX97 [4] set of programs. The positions of the hydrogen atoms were made apparent from an electron density difference synthesis and were refined by a riding model with Uiso-nUeq (n = 1.5 for a methyl group and n = 1.2 for the remaining hydrogen atoms). When refining the structure, limits were imposed on the bond lengths in the randomized fragment (C(sp3)C(sp3) 1.54(1) ). The structure was refined on F2 by the full-matrix least-squares method in an anisotropic approach for the nonhydrogen atoms to wR2 = 0.155 for the 3001 reflections (R1 = 0.052 for 1827 reflections with F > 4(F), S = 0.971). The 4-aryl-3-ethoxycarbonyl-2,7,7-trimethyl-5-oxo-5,6,7,8-tetrahydroquinolines were obtained by the procedure of [5,6]. General Procedure for Obtaining Oximes of 4-Aryl-3-ethoxycarbonyl-2,7,7-trimethyl-5-oxo5,6,7,8-tetrahydroquinolines (1a-d). Hydroxylamine hydrochloride (6.9 g, 100 mmol) and pyridine (8 ml) were added to a solution of the appropriate tetrahydroquinoline (10 mmol) in ethanol (50 ml). The mixture was boiled for 6 h, poured into water, neutralized with dilute hydrochloric acid to a neutral reaction, and the product was filtered off.
62
4-(4'-Chlorophenyl)-3-ethoxycarbonyl-2,7,7-trimethyl-5-oxo-5,6,7,8-tetrahydroquinoline Oxime (1a). Yield 56.6%; mp 170C (alcohol). 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 0.95 (3H, t, J = 7.1, COOCH2CH3); 1.02 (6H, s, 7- ,7-CH3); 2.45 (3H, s, 2-CH3); 2.55 (2H, s, 8-CH2); 2.78 (2H, s, 6-CH2); 3.96 (2H, q, J = 7.1, COOCH2CH3); 7.18 (2H, d, J2,3 = 8.2, 3'- ,5'-H); 7.50 (2H, d, J5,6 = 8.2, 2' -,6'-H): 10.90 (1H, s, NOH). Found, %: C 65,33; H 6.05; Cl 9.23: N 7.35. C21H23ClN2O3. Calculated, %: C 65.20; H 5.99; Cl 9.16; N 7.24. 4-(4'-Bromophenyl)-3-ethoxycarbonyl-2,7,7-trimethyl-5-oxo-5,6,7,8-tetrahydroquinoline Oxime (1b). Yield 61.5%; mp 213C (alcohol). 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 0.95 (3H, t, J = 7.1, COOCH2CH3); 1.02 (6H, s, 7-, 7-CH3); 2.45 (3H, s, 2-CH3); 2.55 (2H, s, 8-CH2); 2.78 (2H, s, 6-CH2); 3.96 (2H, q, J = 7.1, COOCH2CH3); 7.15 (2H, d, J2,3 = 8.2, 3'-, 5'-H); 7.57 (2H, d, J5,6 = 8.2, 2'-, 6'-H); 10.90 (1H, s, NOH). Found, %: C 58.61; H 5.31; Br 18.60; N 6.30. C21H23BrN2O3. Calculated, %: C 58.48; H 5.37; Br 18.52; N 6.49. 3-Ethoxycarbonyl-4-(4'-methoxyphenyl)-2,7,7-trimethyl-5-oxo-5,6,7,8-tetrahydroquinoline Oxime (1c). Yield 77.47%; mp 190-192C (alcohol). 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 0.95 (3H, t, J = 7.1, COOCH2CH3); 1.02 (6H, s, 7-, 7-CH3); 2.45 (3H, s, 2-CH3); 2.55 (2H, s, 8-CH2); 2.78 (2H, s, 6-CH2); 3.79 (3H, s, 4'-OCH3); 4.01 (2H, q, J = 7.1, COOCH2CH3); 6.92 (2H, d, J2,3 = 8.6, 3'-, 5'-H); 7.05 (2H, d, J5,6 = 8.6, 2'-,6'-H); 10.92 (1H, s, NOH). Found, %: C 69.37; H 6.67; N 7.21. C22H26N2O4. Calculated, %: C 69.09; H 6.85; N 7.32. 4-(2',4'-Dichlorophenyl)-3-ethoxycarbonyl-2,7,7-trimethyl-5-oxo-5,6,7,8-tetrahydroquinoline Oxime (1d). Yield 57.5%; mp 158-159C (alcohol). 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 0.90 (3H, t, J = 7.1, COOCH2CH3); 0.92 (3H, s, 7-CH3); 1.03 (3H, s, 7-CH3); 2.46 (3H, s, 2-CH3); 2.50 (2H, s, 8-CH2); 2.78 (2H, s, 6-CH2); 3.93 (2H, q, J = 7.1, COOCH2CH3); 7.15 (1H, d, J5,6 = 8.2, 6'-H); 7.41 (1H, dd, J5,6 = 8.2, J3,5 = 2.2, 5'-H); 7.57 (1H, d, J3,5 = 2.1, 3'-H); 10.88 (1H, s, NOH). Found, %: C 59.91; H 5.15; Cl 16.75; N 6.45. C21H22Cl2N2O3. Calculated, %: C 59.87; H 5.26; Cl 16.83; N 6.65. General Procedure for Obtaining Compounds 2a,b, 7. A mixture of PPA (10 g) and the appropriate oxime 1a-d (1 g) was kept at 100C for 1 h. The reaction mixture was poured into water (100 ml), neutralized with aqueous ammonia solution, and the precipitated solid extracted with chloroform. Purification was by chromatography on silica gel. The eluent was chloroformalcohol, 10:0.5 for 2a and toluenechloroform alcohol, 5:1:0.4 for 2b. 3'-Ethoxycarbonyl-4',7',7'-trimethyl-4-oxo-2',6',7',8'-tetrahydrospiro(cyclohexa-2,5-diene-1,2'pyrrolo[4',3',2'-d,e]quinoline) (2a). Yield 28.4%; mp 110-112C (hexane). Rf 0.60. 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 1.07 (6H, s, 7-, 7-CH3); 1.16 (3H, t, J = 7.1, COOCH2CH3); 2.62 (3H, s, 2-CH3); 2.72 (2H, s, 6-CH2); 2.86 (2H, s, 8-CH2); 4.08 (2H, q, J = 7.1, COOCH2CH3); 6.43 (4H, s, CH=CH). 1H NMR spectrum (pyridine-d5), , ppm (J, Hz): 0.98 (6H, s, 7-, 7-CH3); 1.21 (3H, t, J = 7.1, COOCH2CH3); 2.72 (3H, s, 2-CH3); 2.89 (4H, s, 6-, 8-CH2); 4.25 (2H, q, J = 7.1, COOCH2CH3); 6.55 (2H, d, J2,3 = 10, 2,6-CH=CH); 6.75 (2H, d, J5,6 = 10, 3,5-CH=CH). Found, %: C 71.79; H 6.45; N 7.80. C21H22N2O3. Calculated, %: C 71.98; H 6.33; N 7.99. 2-Chloro-3'-ethoxycarbonyl-4',7',7'-trimethyl-4-oxo-2',6',7',8'-tetrahydrospiro(cyclohexa-2,5-diene1,2'-pyrrolo[4',3',2'-d,e]quinoline) (2b). Yield 31.4%; mp 110C (hexane). Rf 0.33. 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 1.02 (3H, s, 7-CH3); 1.16 (3H, s, 7-CH3); 1.19 (3H, t, J = 7.1, COOCH2CH3); 2.71 (3H, s, 2-CH3); 2.78 (2H, s, 6-CH2); 2.90 and 2.91 (2H, s, 8-CH2); 4.14 (2H, m, J = 7.1, COOCH2CH3); 6.48 (2H, s, 2,3-CH=CH); 6.80 (1H, s, 5-CH=). Found, %: C 65.67; H 5.65; Cl 9.05; N 7.41. C21H21ClN2O3. Calculated, %: C 65.54; H 5.50; Cl; 9.21; N 7.28. 9-Bromo-1-ethoxycarbonyl-2,5,5-trimethyl-5,6-dihydro-4H-pyrido[2,3,4-k,l]acridine (7). Yield 7%; mp 178C (alcohol). 1H NMR spectrum, , ppm (J, Hz): 1.05 (6H, s, 5-, 5-CH3); 1.34 (3H, t, J = 7.1, COOCH2CH3); 2.58 (3H, s, 2-CH3); 3.04 (4H, s, 4- and 6-CH2); 4.40 (2H, q, J = 7.1, COOCH2CH3); 7.17 (1H, dd, J10,11 = 9.2, J8,10 = 2.8, 10-H); 7.32 (1H, d, J8,10 = 2.8, 8-H); 7.95 (1H, d, J10,11 = 9.2, 11-H). Found, %: C 61.36; H 5.27; Br 19.08; N 6.67. C21H21BrN2O2. Calculated, %: C 61.03; H 5.12; Br 19.33; N 6.78.
63
REFERENCES 1. 2. 3. 4. 5. 6. S. V. Tolkunov, A. I. Khizhan, and V. I. Dulenko, Khim. Geterotsikl. Soedin., 1849 (2003). Yu. V. Zefirov and P. M. Zorkii, Usp. Khim., 58, 713 (1989). H.-B. Burgi and J. D. Dunitz, Structure Correlation, Vol. 2, VCH, Weinheim (1994), p. 741. G. M. Sheldrick, SHELX97. PC Version, A System of Computer Programs for Crystal Structure Solution and Refinement, 1998, Rev. 2. H. J. Antaki, J. Chem. Soc., 4877 (1973). E. E. Grinshtein, E. I. Stankevich, and G. Ya. Dubur, Khim. Geterotsikl. Soedin., 1118 (1966).
64
TRIFLUOROMETHYL-SUBSTITUTED DIAND TETRAHYDROAZOLOPYRIMIDINES

S. M. Desenko1, E. S. Gladkov1, V. G. Nenaidenko2, O. V. Shishkin1, and S. V. Shishkina1 The condensation of 4,4,4-trifluoro-1-phenylbut-1-en-3-one with 2-aminobenzimidazole, 3-amino-1,2,4triazole, and 5-aminotetrazole gives hydroxy-substituted tetrahydro derivatives of pyrimido[1,2-a]benzimidazole, and of 1,2,4-triazolo-, and tetrazolo[1,5-a]pyrimidine. Dehydration of them to the corresponding dihydroazolopyrimidines has been carried out. An X-ray structural investigation was carried out and the molecular structure of 5-hydroxy-7-phenyl-5-trifluoromethyl-4,5,5,7tetrahydrotetrazolo[1,5-a]pyrimidine is discussed. Keywords: azolopyrimidines, trifluoromethyl-substituted unsaturated ketones, heterocyclization, stereochemistry. The synthetic availability of trifluoromethyl-substituted unsaturated carbonyl compounds, which has been increasing for some time past, has attracted attention to heterocyclization reactions based on them [1]. In the present work the interaction has been studied of 4,4,4-trifluoro-1-phenylbut-1-en-3-one 2 with 3-amino1,2,4-triazole 1a, 5-aminotetrazole 1b, and 2-aminobenzimidazole 1c. It is known [2] that the interaction of aromatic unsaturated ketones with aminoazoles leads to the formation of dihydro derivatives of azolopyrimidine systems. However the literature data on the heterocyclization reaction of ketone 2 shows the possibility of isolating hydroxy-substituted tetrahydroheterocycles, the hemiaminal structure of which is stabilized by the strong electron-withdrawing influence of the CF3 group. In fact maintaining solutions of amines 1a-c and ketone 2 in methanol for 2 days led to the formation of hydroxy-substituted tetrahydroazolopyrimidines 3a-c. On carrying out the cyclocondensation in boiling methanol exclusively dihydro derivatives 4a-c were isolated from the reaction mixture. The desired dehydration of compounds 3a-c into dihydroazolopyrimidines 4a-c was effected by the action of p-toluenesulfonic acid (Scheme 1). The IR spectra of compounds 3 and 4 in KBr disks contain broad absorption bands at 3235-3410 cm-1 (OH, NH). An intense band was also present at 1615-1630 cm-1 (C=C) in the spectra of compounds 4. The 1H NMR spectra of the tetrahydro derivatives 3 are characterized by the presence of signals for the aromatic protons, the protons of the NH and OH groups, and also for an ABX system of protons for the CHCH2 fragment of the tetrahydropyrimidine nucleus. In the spectra of compounds 4 the singlet of the hydroxyl proton is lost, the signal of the NH proton is regularly displaced towards lower field, and the signals of the CH protons are displayed as two doublets, one of which (=CH) is broadened due to long range coupling with the imino group proton (Table 2).
__________________________________________________________________________________________ Institute for Single Crystals, National Academy of Sciences of Ukraine, Kharkov 61001, Ukraine; e-mail: desenko@isc.kharkov.com. 2 M. V. Lomonosov Moscow State University, Moscow 119899, Russia; e-mail: Nen@acylium.chem.msu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 71-76, January, 2004. Original article submitted October 2, 2001. 0009-3122/04/4001-00652004 Plenum Publishing Corporation 65
1
Scheme 1
Ph X Y H N N 1ac PhCH=CHCOCF3 X 2 Y NH
2
Ha Hb OH CF3
Ph
N N N H 3ac A Ph
Ha Hb OH CF3 <
+
N
N N H 3c
2,
TsOH
H2O
X Y N
N N H 4ac CF3
1, 3, 4 a X= N, Y = CH; b X = N, Y = N; c X+Y = o-C6H4
The presence in the molecules of 3 of two chiral centers raises the problems of the stereoselectivity of the reactions forming them and of the steric configuration of the substances obtained. It was shown previously in [1] that the condensation of ketone 2 with binucleophiles as a rule proceeds stereoselectively and leads to a heterocycle with a cis-configuration of the phenyl and trifluoromethyl substituents. In fact, in the 1H NMR spectra of compounds 3a,b (including the unpurified reaction products) there were no signs of doubling of individual groups of signals, which indicates the formation of only one of the possible diastereomers. The spectrum of compound 3c corresponds to a mixture of steric isomers A and B of this substance in a ratio of ~3:1 (according to the integrated intensities of the corresponding signals). The value of the coupling constant JAX = 11.8-13.9 Hz both for compounds 3a,b and for both diastereoisomers of compound 3c, typical for constants of a Jaa type, also indicates the equatorial orientation of the phenyl substituent in the molecules of these substances (including both diastereomeric forms of 3c). The chemical shifts of all the protons of the tetrahydropyridine ring of compounds 3a,b and of diastereoisomer A of compound 3c were close in value (see Table 2). The signal of the HB proton of diastereomer B of compound 3c was markedly displaced (by ~0.3 ppm) towards low field compared with the signal of this proton in the spectrum of isomer A and in the spectra of compounds 3a,b. This phenomenon must be linked in isomer B with a change of the spatial orientation of the hydroxyl and trifluoromethyl groups relative to the equatorial proton HB, which enables assignment of the molecules of compound 3a,b and of the predominant diastereomer A of compound 3c to one isomeric series. The formation of compound 4c on dehydration of 3c serves as additional confirmation for this. TABLE 1. Characteristics of Compounds 3a-c, 4a-c
Compound 3a 3b 3c 4a 4b 4c Empirical formula C12H11N4OF3 C11H10N5OF3 C17H14N3OF3 C12H9N4F3 C11H8N5F3 C17H12N3F3 Found, % Calculated, % 19.68 19.71 24.55 24.55 12.63 12.61 21.03 21.04 26.18 26.21 13.34 13.33 mp, 176-177 163-164 264 119-121 219-220 231-233 Yield, % 55 72 80 61 86 93
66
TABLE 2. 1H NMR Spectra of Compounds 3a-c, 4a-c in DMSO-d6

Compound 6- (1) Chemical shifts, , ppm (coupling constant J, Hz) OH 7- Aromatic (1H, (1H) protons (m) (1) br. s) 5.27 (dd) 5.54 7.29-7.44 11.9 NH (1, br. s) 8.7
3b
3c
4a 4b 4c
2.22 (dd, 2.42 (dd, J = -13.3, J = 4.7) J = 12.5) 2.35 (dd, 2.44 (dd, J = 13.2, J = 4.6) J = 12.1) 2.28 (dd, 2.47 (dd, J = -13.1, J = 4.4); J = 11.8); 2.43* (dd, 2.74* (dd, J = -14.3, J = 6.0) J = 13.9) 5.60 (1, d) 5.62 (1, d) 5.52 (1, d)
7.39-7.48
9.3
7.6 *2
5.42 5.52*
5.84-7.50
8.9
6.27 (br. d, J = 3.8) 6.57 (br. d, J = 2.6) 6.37 (br. d, J = 3.9)
7.05-7.55 7.20-7.44 6.75-7.43
10.8 11.37 11.5
_______ * Diastereomer B. Ratio A : B, 3:1. *2 Overlapped by aromatic proton signals. The structure of compound 3b (including its relative configuration) was established unequivocally by an X-ray structural investigation (Fig. 1, Table 3). The results showed the diequatorial disposition of the phenyl and trifluoromethyl substituents in the 3b molecule. In view of the features of the 1H NMR spectra of
Fig. 1. Structure of the 3b molecule (without hydrogen atoms) with bond lengths (). 67
TABLE 3. Bond Lengths (l) in the Molecule of Compound 3b

Bond F(1)C(5) F(3)C(5) N(1)C(1) N(2)C(1) N(3)N(4) N(5)C(1) C(2)C(3) C(3)C(4) C(6)C(7) C(7)C(8) C(9)C(10) l, 1.333(8) 1.336(6) 1.344(6) 1.324(7) 1.293(6) 1.337(6) 1.509(7) 1.549(7) 1.364(8) 1.403(8) 1.35(1) Bond F(2)C(5) O(1)C(4) N(1)C(4) N(2)N(3) N(4)N(5) N(5)C(2) C(2)C(6) C(4)C(5) C(6)C(11) C(8)C(9) C(10)C(11) l, 1.348(7) 1.390(6) 1.452(6) 1.366(7) 1.325(6) 1.495(6) 1.537(7) 1.516(8) 1.386(7) 1.39(1) 1.373(8)
compounds 3a-c the 3a molecule and isomer A of compound 3c must be assigned to the same isomeric series. Thus in the reactions of ketone 2 with amines 1a-c the previously noted regularity [1] of the preferential formation of tetrahydrocyclic systems with a cis-configuration of the CF3 and C6H5 groups in reactions of this ketone with binucleophiles is retained. According to the X-ray structural data the tetrahydro ring of the 3b molecule is in a distorted half-chair conformation. The C(3) and C(4) atoms deviate from the mean-square plane of the remaining ring atoms by -0.49 and 0.25 respectively. The phenyl substituent at the C(2) atom is in the equatorial position (torsion angle C(1)N(5)C(2)C(6) is -143.3(5)) and is folded relative to the N(5)C(2) bond by 43.9(7) (torsion angle N(5)C(2)C(6)C(7)). The hydroxyl group at the C(4) atom occupies an axial position, but the trifluoromethyl substituent is equatorial (torsion angles C(1)N(1)C(4)O(1) is -80.1 (5), C(1)N(1)C(4)C(5) 160.4(4)). The bond lengths in the tetrazole fragment were close to the bond lengths in related compounds [3-5]. The N(5)C(2) bond at 1.495(6) and C(2)C(6) at 1.537(7) are somewhat long compared with their mean values of 1.469 and 1.513 respectively [6], which may probably be explained by some steric strain in this fragment as indicated by the short 3a-HC(7) contact at 2.82 at a total of van der Waals radii of 2.87 [7]. In the crystal too shortened intramolecular contacts were detected for 3a-HF(1) at 2.50 , H(1N)F(3) at 2.45 (total of van der Waals radii 2.56 ) and a shortened intermolecular contact for H(2)N(3) (x-1, y, z) at 2.56 (2.66 ).
TABLE 4. Some Valence () and Torsion () Angles in the Molecule of Compound 3b

Angle N(5)C(2)C(3) N(5)C(2)C(6) O(1)C(4)N(1) O(1)C(4)C(3) N(1)C(4)C(5) C(5)C(4)C(3) C(7)C(6)C(2) C(11)C(6)C(2) , deg. 105.3(3) 110.4(4) 109.7(4) 112.3(4) 107.6(4) 109.4(4) 122.8(4) 117.9(5) Angle C(2)N(5)C(1)N(1) C(4)N(1)C(1)N(5) C(1)N(5)C(2)C(3) C(1)N(5)C(2)C(6) N(5)C(2)C(3)C(4) C(1)N(1)C(4)O(1) C(1)N(1)C(4)C(5) C(1)N(1)C(4)C(3) C(2)C(3)C(4)N(1) C(3)C(4)C(5)F(1) N(5)C(2)C(6)C(7) , deg. 8.4(7) -17.7(7) -25.2(6) -143.3(5) 50.9(5) -80.1(5) 160.4(4) 42.5(6) -62.0(5) 51.6(6) 43.9(7)
68
EXPERIMENTAL X-Ray Structural Investigation. The crystals of 5-hydroxy-7-phenyl-5-trifluoromethyl-4,5,6,7tetrahydrotetrazolo[1,5-a]pyrimidine 3b were monoclinic, C11H10F3N5O, at 20C a = 6.429(2), b = 7.334(2), c = 26.94(1) , = 95.07(3), V = 1265.2(7) 3, M = 285.24, Z = 4, space group P2(1)/c, dcalc = 1.498 g/cm3, (MoK) = 0.132 mm-1, F(000) = 584. The parameters of the unit cell and the intensities of 2194 reflections (2011 independent, Rint = 0.154) were measured on a Siemens P3/PC automatic four-circle diffractometer (MoK, graphite monochromator, 2/ scanning, 2max = 50). The structure was solved by the direct method with the set of programs SHELX97 [8]. The positions of the hydrogen atoms were calculated geometrically and were refined with a riding model with Uiso = nUeq (n = 1.5 for the hydroxyl group and n = 1.2 for the remaining hydrogen atoms). The structure was refined on F2 by the full-matrix least-squares method in an anisotropic approach for the nonhydrogen atoms to wR2 = 0.23 for 2011 reflections (R1 = 0.075 for 808 reflections with F > 4(F), S = 0.882). Final bond lengths and angles are given in Tables 3 and 4. The 1H NMR spectra were measured on a Varian Mercury-200 instrument (200 MHz) in DMSO-d6 (internal standard was TMS). The IR spectra were obtained in KBr disks on a Specord IR-75 spectrometer. The homogeneity of compounds was checked by TLC on Silufol UV-254 plates, eluent was methanol. 5-Hydroxy-7-phenyl-5-trifluoromethyl-4,5,6,7-tetrahydrotetrazolo[1,5-a]pyrimidine (3b). A mixture of 5-aminotetrazole 1b (0.85 g, 10 mmol) and 4,4,4-trifluoro-1-phenylbut-1-en-3-one 2 (2.0 g, 10 mmol) in methanol (25 ml) was stirred for 2 days at 25C. The solution was evaporated to a volume of 10 ml and after cooling, compound 3b (2.05 g, 72%) was filtered off; mp 163-164C (methanol). Compounds 3a and 3c were obtained analogously. 5-Trifluoromethyl-7-phenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine (4b). A. A solution of 3b (1.45 g, 5 mmol) and p-toluenesulfonic acid (0.1 g) in methanol (20 ml) was boiled for 2 h. The solution was evaporated to a volume of 10 ml, and compound 4b (1.25 g, 86%) was filtered off; mp 219-220C (methanol). B. A mixture of 5-aminotetrazole 1b (0.85 g, 10 mmol) and 4,4,4-trifluoro-1-phenylbut-1-en-3-one 2 (2.0 g, 10 mmol) in methanol (25 ml) was boiled for 10 h. The solution was evaporated to a volume of 10 ml, and compound 4b (2.5 g, 90%) was filtered off. Compounds 4a and 4c were obtained analogously.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. V. G. Nenaidenko, A. V. Sanin, and E. S. Balenkova, Usp. Khim., 68, 483 (1999). S. M. Desenko, Khim. Geterotsikl. Soedin., 147 (1995). G. Hajos, A. Messmer, A. Neszmelyi, and L. Parkanyi, J. Org. Chem., 49, 3199 (1984). M. M. Goodman, J. L. Atwood, R. Carlin, W. Hunter, and W. W. Paudler, J. Org. Chem., 41, 2860 (1976). J. Zabrocki, G. D. Smith, J. B. Dunbar Jr., H. Lijima, and G. R. Marshall, J. Am. Chem. Soc., 110, 5875 (1988). H. B. Burgi and J. D. Dunitz, Structure Correlation, Vol. 2, VCH, Weinheim (1994), p. 741. N. S. Zefirov and P. M. Zorkii, Usp. Khim., 58, 713 (1989). G. M. Sheldrick, SHELX97. PC Version. A System of Computer Programs for Crystal Structure Solution and Refinement. Rev. 2 (1998).
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SYNTHESIS OF NOVEL CONDENSED BINUCLEAR HETEROCYCLES BASED ON 1,3- AND 1,5-DICARBONYL DERIVATIVES OF 2,2-DIMETHYLTETRAHYDROPYRAN
N. V. Zyk1, S. Z. Vatsadze1, M. L. Kostochka1, V. P. Lezina2, and V. G. Vinokurov2 Treatment of 1,5- and 1,3-dicarbonyl derivatives of 2,2-dimethyltetrahydropyran with a series of binucleophiles gave condensed pyranopyrazole, pyranothiopyrimidine, pyranoisoxazole, and pyranopyridine systems. Keywords: 5-acyl-2,2-dimethyltetrahydropyran-4-ones, 2,2-dimethyltetrahydropyran-4-one, pyranoisoxazoles, pyranopyrimidines A number of natural antibiotics with a broad range of activity contain the perhydropyran nucleus, e.g. streptomycin, kanamycin, and neomycin. The synthetic medicinal substances in the pyran series used in contemporary medicine are fundamentally benzopyran derivatives. The most important of these is Vitamin E, or more specifically the group of substances called tocopherols e.g. -tocopherol, the basis of which constitutes tocol [1]. With the aim of studying the biological activity of novel pyran derivatives we have been interested in the possible synthesis of binuclear heterocycles which are condensed at the positions 3 and 4 of the pyran ring. One possible route for preparing similar structures is the acylation of pyran-4-ones followed by cyclization with cyanoacetamide to give 3-oxopyrano[3,4-c]pyridine [2]. 2,2-Dimethyltetrahydropyranopyrrole [3], pyrano[3',4':5,6]pyrido[2,3-d]pyrimidine [4], and pyranoisoxazolidine [5] systems are known. Since the search for novel, potentially biologically active compounds is a promising goal, the object of this work was the synthesis of novel, condensed heterocycles based on 1,3- and 1,5-dicarbonyl derivatives of 2,2-dimethylpyran. In order to prepare the -diketones we chose the method of acylation of 2,2-dimethyltetrahydropyran-4one enamines [1]. The reaction of compound 1 with morpholine gave a mixture of the isomeric enamines 2 and 3. It had been previously been reported [2] that the result of this reaction was just the single product 2. Detailed analysis of the 1H NMR spectra of the reaction product showed the presence of the two isomeric enamines 2 and 3. Evidence for the presence of compound 3 came from two additional triplet signals at 2.5 and 3.80 ppm. The enamines 2 and 3 are formed in the ratio 1:1 but they could not be separated chromatographically and were used in the subsequent syntheses as the isomeric mixture.
__________________________________________________________________________________________ M. V. Lomonosov State University, Moscow 119992, Russia; e-mail: szv@org.chem.msu.ru. Institute of Pharmacology, Russian Academy of Medicinal Science, Moscow 125315; e-mail: m_kostochka@mail.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 77-81, January, 2004. Original article submitted January 24, 2002.
2 1
70
0009-3122/04/4001-00702004 Plenum Publishing Corporation
O O O N
O N
+
O 1
N H
+
O 2 O 3
The reaction of compounds 2 and 3 with acid chlorides under Stork conditions gave the 1,3-dicarbonyl compounds 4-7 in 33-56% yields.
O 2, 3 + RCOCl NEt3 O R O + 47 R O O O
4 R = Me; 5 R = Ph; 6 R = 4-FC6H4; 7 R = 3,4-(MeO)2C6H3
TLC and GLC data for the products 4-7 point to the presence of two compounds in each case but they were very difficult to separate using preparative GLC. The compounds have very similar retention times on the column at boiling point. We consider that, as in the case of enamines 2 and 3, the diketones 4-7 exist as a mixture of two isomers, these also being in the ratio 1:1 according to GLC data. For this reason, a detailed interpretation of the 1H NMR spectra did not prove possible (it should be noted that each of the isomeric diketones exists as a mixture of the keto and enol form). The IR spectra of the compounds 4-7 show aromatic C=C absorption bands at 1580-1630 cm-1 and enol form carbonyl groups at 1640-1670 and 1710-1740 cm-1. Compound 4 exists almost wholly in the enol form as shown by the presence of a clearly defined C=C absorption band at 1630 cm-1 and OH at 3300-3500 cm-1 and by the absence of the characteristic absorption frequency for one of the carbonyl groups. Chromatographic mass spectroscopic analysis of compounds 5 and 6 confirms their composition: for 5 m/z 51, 77, 105, 147, 232 [M]+., for 6 m/z 51, 75, 123, 249, 250 [M]+.. The -dicarbonyl compounds obtained 4-7 (as the mixture of isomers) underwent heterocyclization with such binucleophiles as hydrazine hydrate, hydroxylamine hydrochloride, and thiourea. Specific reaction conditions were chosen for each of the reactions carried out. As a result, we prepared compounds 8, 9. The 1H NMR spectra of the compounds 8 and 9 show signals for the phenyl substituent and two methyl groups. The 1H NMR spectrum of compound 8 shows two singlets for the methylene groups in the pyran ring at 2.90 and 4.90 ppm and a signal for the NH group at 7.35 ppm. In the 1H NMR spectrum of compound 9 the two singlets are observed for the methylenes of the pyran ring at 2.75 and 4.90 ppm.
N O Ph O 9 NH2OH . HCl MeCOOH O
5
HN
N Ph
. R NH2NH2 H2O
EtOH O 8
The spectra of the compounds 8,9 show only one of the isomers hence it can be deduced that only the diketone with less steric hindrance takes part in the reaction. In the reactions of the diketones 4 with all of the bis nucleophiles used, the products could not be separated. 71
TABLE 1. Physicochemical Parameters for Compounds 4-7

Compound 4 Empirical formula C9H14O3 Found, % Calculated, % H 63.34 63.52 72.62 72.39 8.50 8.29 6.70 6.94 bp, (mm Hg) 80-115 (11) 138-142 (2) 135-142 (1.7) 65.41 65.74 7.00 6.90 175-180 (2) IR spectrum, , cm-1 1720 (C=O); 1630 (C=C); 3300-3500 (OH) 1710, 1680 (C=O); 3300-3510 (OH) 1740, 1640 (C=O); 3300-3500 (OH) 1710, 1670 (C=O); 3400-3510 (OH) Yield, %
37
5 6* 7
C14H16O3 C14H15FO3 C16H20O5
56 39 32.5
_______ * Found: F 7.35%; calculated: F 7.59%.
The reaction of the diketones 7 with hydrazine hydrate in the presence of a catalytic amount of sulfuric acid gave 3,4-dimethoxybenzoic acid. The previously known 1,5-dicarbonyl compound 10 [6] has been prepared by the reaction of benzalacetophenone with 2,2-dimethyltetrahydropyran-4-one as a single isomer. We have found that the diketone 10 reacts with hydroxylamine hydrochloride in glacial acetic acid and cyclises to the previously unreported 7,7-dimethyl-2,4-diphenyl-5,8-dihydropyrano[4,3-b]pyridine 11. The anticipated result was not obtained when carrying out the reaction in alcohol. The 1H NMR spectrum of the product 11 did not disagree with the proposed structure and the composition was shown by elemental analysis (see Experimental).
Ph O 1 Ph Ph KOH, EtOH O 10 O Ph O Ph NH2OH . HCl MeCOOH O 11 N Ph
EXPERIMENTAL Monitoring of the course of the reaction and the purity of the reaction products was carried out using TLC on Silufol UV-254 plates and by GLC on a Tsvet-152 chromatograph (0.7 m 3 mm column, liquid phase SE30/5% on Chromaton-N-AW 0.16-0.20 mm, nitrogen carrier, temperature program 75-300 / 22C/min). IR spectra were recorded on a Perkin-Elmer instrument using KBr. Mass spectra were obtained on an HP-5972 instrument with an electron ionization energy of 70 eV. 1H NMR spectra were recorded on a Bruker A-250 (250 MHz) instrument with TMS internal standard. Melting points for the materials were determined on a Koffler block Boetius apparatus in an open capillary and are uncorrected. 2,2-Dimethyl-4-morpholinodihydropyrans (2, 3). Morpholine (15.26 g, 175.5 mmol) in benzene (10 ml) was added dropwise to a solution of 2,2-dimethyltetrahydropyran-4-one 1 (15 g, 117 mmol) in benzene (50 ml) and refluxed in a DeanStark apparatus until the calculated amount of water had been produced. The solvent was distilled off and the residue was distilled in vacuo to give a mixture of compounds 2 and 3 72
(12.15 g); bp 109-112C (4 mm Hg). Yield 52%. 1H NMR spectrum, , ppm: isomer 2: 2.8 (4H, m, CH2N); 3.7 (4H, t, CH2O); 1.3 (6H, s, 2CH3); 2.0 (2H, s, 3-H); 4.6 (1H, t, 5-H); 4.2 (2H, m, 6-H); isomer 3: 2.8 (4H, m, CH2N); 3.7 (4H, t, CH2O); 1.3 (6H, s, 2CH3); 2.0 (2H, t, 5-H); 3.8-3.9 (2H, t, 6-H); 4.5 (1H, s, 3-H). 5-Acyl-2,2-dimethyltetrahydropyran-4-ones (5-7) (General Method). The corresponding acid chloride (54 mmol) in dry benzene (10 ml) was added dropwise with stirring to a solution of the mixture of enamines 2 and 3 (8.88 g, 45 mmol) and triethylamine (5.45 g, 54 mmol) in dry benzene (60 ml) with the reaction held at room temperature. The reaction mixture was stirred for a further 2 h, heated to reflux for 30 min, HCl (18%, 22 ml) added, and heated for a further 1 h. After cooling, the aqueous layer was separated and the benzene was washed with water to neutral reaction. The aqueous solution was basified with potassium carbonate to pH ~7 and extracted three times with benzene. The combined benzene fractions were dried over CaCl2, benzene was distilled off, and the residue was distilled twice in vacuo monitoring the purity of the product by GLC analysis. 5-Acetyl-2,2-dimethyltetrahydropyran-4-one (4) was prepared similarly but after the addition of acetyl chloride the mixture was not heated but immediately hydrolyzed with HCl (18%, 22 ml) and then worked up as described above. The physicochemical and spectrosopic properties of the compounds 4-7 are given in Table 1. 6,6-Dimethyl-3-phenyl-4,7-dihydro-(2H)-pyrano[4,3-c]pyrazole (8). A mixture of the diketones 5 (0.5 g, 2.1 mmol) and hydrazine hydrate (0.105 g, 2.1 mmol) in alcohol (6.2 ml) was refluxed for 4 h. The alcohol was evaporated off and the residue was recrystallized from i-PrOH to give compound 8 (300 mg) with mp 172-175C. Yield 65.7%. 1H NMR spectrum (CDCl3), , ppm: 1.3 (6H, s, 2CH3); 2.9 (2H, s, 7-H); 4.9 (2H, s, 4-H); 7.3 (1H, s, NH); 7.5-7.9 (5H, m, Ph). Found, %: C 73.31; H 7.25; H 12.35. C14H16N2O. Calculated, %: C 73.66; H 7.06; N 12.27 6,6-Dimethyl-3-phenyl-4,7-dihydro-(2H)-pyrano[4,3-c]isoxazole (9). A mixture of the diketones 5 (0.5 g, 2.1 mmol), hydroxylamine hydrochloride (0.21 g, 3.1 mmol), and glacial acetic acid (5 ml) was refluxed for 5 h, poured into water, and taken to neutral reaction. The obtained solution was extracted with benzene, solvent was distilled off, and the residue was recrystallized from alcohol to give compound 9 (120 mg); mp 95-97C. Yield 26%. 1H NMR spectrum (CDCl3), , ppm: 1.4 (6H, s, 2CH3); 2.8 (2H, s, 7-H); 4.9 (2H, s, 4-H); 7.4-7.7 (5H, m, Ph). Found, %: C 72.95; H 6.73; N 6.23. C14H15NO2. Calculated, %: C 73.34; H 6.59; N 6.11. 7,7-Dimethyl-2,4-diphenyl-5,8-dihydropyrano[4,3-b]pyridine (11). A mixture of the 1,5-diketone 10 (1 g, 3 mmol) (obtained according to [6]) and hydroxylamine hydrochloride (0.479 g, 6 mmol) in glacial acetic acid (10 ml) and alcohol (2 ml) was refluxed for 7 h. The reaction mixture was poured into water, basified to pH ~8-9, and extracted twice with benzene. The benzene was distilled off and the residue was recrystallized from i-PrOH. Standing the mother liquor for one week at -5C gave compound 11 (0.38 g); mp 84-85C. Yield 40%. 1H NMR spectrum (CDCl3), , ppm: 1.4 (6H, s, 2CH3); 3.0 (2H, s, 8-H); 4.7 (2H, s, 5-H); 7.2-7.9 (11H, m, Ar and Py). Found, %: C 83.90; H 6.76; N 4.21. C22H21NO. Calculated, %: C 83.78; H 6.71; N 4.44. This work was carried out with the financial support of the Russian fund for basic research (project No. 99-03-33094a).
REFERENCES 1. 2. A. T. Soldatenko, N. M. Kolyadina, and I. V. Shendrik, Basic Organic Chemistry of Medicinal Compounds [in Russian], Khimiya, Moscow (2001), p. 192. A. S. Noravyan, Yu. T. Struchkov, S. V. Lindeman, and E. G. Paronikyan, Khim. Geterotsikl. Soedin., 1137 (1989).
73
3. 4. 5. 6.
A. S. Noravyan and E. G. Paronikyan, Khim. Geterotsikl. Soedin., 1464 (1983). A. S. Noravyan and A. Sh. Oganisyan, Khim. Geterotsikl. Soedin., 1239 (1999). Sh. P. Memberyan and A. S. Norovyan, Arm. Khim. Zh., 28, 146 (1975). S. A. Shumakov and V. A. Kaminskii, Khim. Geterotsikl. Soedin., 89 (1985).
74
CONDENSED PYRIDOPYRIMIDINES. 7*. SYNTHESIS OF CONDENSED TRIAZOLO[4,3-c]- AND TETRAZOLO[1,5-c]PYRIMIDINES

A. Sh. Oganisyan, A. S. Noravyan, and M. Zh. Grigoryan Novel dihydro-5H-pyrano[3',4':5',6']pyrido[2,3-d]-1,2,4-triazolo[4,3-c]pyrimidines and 1,2,3,4-tetrazolo[1,5-c]pyrimidines have been synthesized from 2-amino-3-cyano-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine. Keywords: dihydro-5H-pyrano[3',4':5',6']pyrido[2,3-d]-1,2,4-triazolo[4,3-c]pyrimidines, dihydro-5Hpyrano[3',4':5',6'][2,3-d]-1,2,3,4-tetrazolo[1,5-c]pyrimidines, condensed pyridopyrimidines, annelation. In continuing our systematic study of condensed pyrano[4,3-b]pyridines [2] there are current and promising developments of suitable methods for the synthesis and the study of the biological activity of novel condensed pyrano[3',4':5,6]pyrido[2,3-d]pyrimidines annelated with different heterocycles along the c bond of the pyrimidine ring.
O N 1 HN O N 3 N NH2 N H RC(OEt)3 O N 5a,b N N N N H R reflux CN NH2 N2H4 reflux HC(OEt)3 O 2 N N2H4 40 oC O N 4 N CN N=CHOEt
NH N NH2 H
5 a R = H, b R = Me
_______ * For Communication 6 see [1]. __________________________________________________________________________________________ A. L. Mndzhoyan Institute of Fine Organic Chemistry, National Academy of Sciences, Armenian Republic, Yerevan 375014; e-mail: raffi@acc.am. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 82-84, January, 2004. Original article submitted September 20, 2000; revision submitted June 6, 2001. 0009-3122/04/4001-00752004 Plenum Publishing Corporation 75
Condensation of 2-amino-3-cyano-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine 1 [3] with ethyl orthoformate gave the corresponding 2-ethoxymethyleneamino derivative 2 which was refluxed with an alcoholic solution of hydrazine hydrate to give the 4-hydrazinodihydro-5H-pyranopyridopyrimidine 3. The intermediate 3-amino-4-iminodihydro-5H-pyranopyridopyrimidine 4 was also separated and this could be heated in the presence of hydrazine hydrate to give the product 3 via a Dimroth rearrangement. Condensation of compound 3 with the orthoformate and orthoacetate esters gave high yields of the products of annelation of a triazole ring along the c bond of the pyrimidine ring (5a,b).
H N N O N 6 N N H S CS2 3 NaNO2 O N 7 N
N N N N H
Treatment of compound 3 with carbon disulfide or sodium nitrite (in the presence of acetic acid) led to similar products with annelated 3-thioxotriazole and tetrazole rings 6 and 7 respectively.
EXPERIMENTAL IR spectra were taken on a UR-20 instrument using vaseline oil and 1H NMR spectra on a Varian Mercury 300 (300 MHz) instrument. TLC was carried out on Silufol UV-254 plates and revealed using iodine vapor. The parameters for the compounds 2-7 synthesized are given in Table 1.
TABLE 1. Characteristics of compounds 2-7

Compound 2 3 4 5a 5b 6* 7
2
Empirical formula C14H17N3O2 C12H15N5O C12H15N5O C13H13N5O C14H15N5O C13H13N5OS C12H12N6O
C 64.61 64.85 59.03 58.76 58.71 58.76 61.82 61.16 61.85 62.44 57.41 57.12 55.73 56.24
Found, % Calculated, % H 7.01 6.61 5.81 6.16 5.81 6.16 5.31 5.13 5.02 5.61 4.61 4.79 5.12 4.72
mp, C N 16.85 16.21 29.07 28.55 28.87 28.55 26.85 27.44 26.82 26.01 20.40 20.50 32.15 32.80 120-122 300-303 348-350 292-295 212-214 275-277 225-228
Rf *
Yield, % 85 90 87 88 78 75 86
0.63 0.56 0.62 0.57 0.61 0.70 0.64
_______ * Solvent systems: etherisooctane, 1:2 (2); pyridineether, 1:1 (3); ether chloroformpyridine, 2:1:1 (4); butanolpyridine, 4:2 (5a,b, 6), ether chloroform, 2:1 (7). *2 Found, %: S 11.17. Calculated, %: S 11.73.
76
3-Cyano-2-(ethoxymethylene)amino-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine (2). A mixture of compound 1 (2 g, 0.01 mol) and ethyl orthoformate (20 ml) was refluxed for 10 h. After distillation of the ortho ester the viscous mass was treated with ether or petroleum ether (5 ml). The precipitated crystals of product 2 were filtered off and dried. 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 8.43 (1H, s, 4-CH); 7.80 (1H, s, N=CH); 4.68 (2H, t, J = 1.8, 5,5-H2); 4.43 (2H, t, J = 7, OCH2); 2.78 (2H, t, J = 1.8, 8,8-CH2); 1.43 (3H, t, J = 7, CH2CH3); 1.28 (6H, s, 7,7-(CH3)2). 4-Hydrazino-8,8-dimethyl-8,9-dihydro-6H-pyrano[3',4':5,6]pyrido[2,3-d]pyrimidine (3). A. A mixture of compound 2 (2.59 g, 0.01 mol), hydrazine hydrate (98%, 5 ml), and ethanol (20 ml) was refluxed for 3 h. After cooling, the precipitated crystalline product 3 was filtered off, washed with cold alcohol, and recrystallized from ethanol. B. The product 3 was obtained as described above using compound 4 (2.45 g, 0.01 mol) (see below), hydrazine hydrate (98%, 2 ml), and ethanol (20 ml). IR spectrum (thin film), , cm-1: 1630 (C=N), 3200-3370 (NH, NH2). 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 14.00 (1H, br. s, NH); 8.20 (1H, s, 5-H); 7.90 (1H, s, 2-H); 6.80 (2H, br. s, NH2); 4.63 (2H, s, 6,6-H2); 2.90 (2H, t, J = 1.9, 9,9-H2); 1.30 (6H, s, 8,8-(CH3)2). 3-Amino-4-imino-8,8-dimethyl-8,9-dihydro-6H-pyrano[5',4':5,6]pyrido[2,3-d]pyrimidine (4). A mixture of compound 2 (2.59 g, 0.01 mol), hydrazine hydrate (5 ml), and ethanol (10 ml) was heated with stirring at 40C for 1 h. After cooling, the precipitated crystals of product 4 were filtered off, washed with cold alcohol, and dried. IR spectrum (thin film), , cm-1: 1630 (C=N), 3100-3350 (NH, NH2). 1H NMR spectrum (DMSO-d6), , ppm: 12.79 (1H, s, 4-NH); 8.20 (1H, s, 2-H); 7.85 (1H, s, 5-H); 7.73 (2H, s, 3-NH2); 4.62 (2H, s, 6,6-H2); 2.70 (2H, s, 9,9-H2); 1.28 (6H, s, 8,8-(CH3)2). 9,9-Dimethyl-8,9-dihydro-11H-pyrano[5',4':5,6]pyrido[3,2-e]triazolo[4,3-c]pyrimidine (5a). A mixture of compound 3 (2.45 g, 0.01 mol) and ethyl orthoformate (20 ml) was refluxed for 3 h. The precipitated crystals of product 5a were filtered off, washed with cold alcohol, and dried. 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 9.50 (1H, s, 5-H); 9.23 (1H, s, 3-H); 7.86 (1H, s, 12-H); 4.98 (2H, s, 11,11-H2); 3.32 (2H, t, J = 1.8, 8,8-H2); 1.42 (6H, s, 9,9-(CH3 )2). 3,9,9-Trimethyl-8,9-dihydro-11H-pyrano[5',4':5,6]pyrido[3,2-e]triazolo[4,3-c]pyrimidine (5b). Prepared from a mixture of compound 3 (2.45 g, 0.01 mol) and ethyl orthoacetate (20 ml) as described above to give the product 5b. 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 9.50 (1H, s, 5-H); 7.86 (1H, s, 12-H); 4.98 (2H, s, 11,11-H2); 3.32 (2H, t, J = 1.8, 8,8-H2); 2.05 (3H, s, 3-CH3); 1.42 (6H, s, 9,9-(CH3)2). 9,9-Dimethyl-3-thioxo-2,3,8,9-tetrahydro-11H-pyrano[5',4':5,6]pyrido[3,2-e]triazolo[4,3-c]pyrimidine (6). A mixture of compound 3 (2.45 g, 0.01 mol) and carbon disulfide (7.6 g, 0.1 mol) in absolute pyridine (10 ml) was refluxed for 6 h. The precipitated crystals of the product 6 were filtered off and recrystallized from pyridine. IR spectrum (thin layer), , cm-1: 1430 (C=S), 1620 (C=N), 3100-3300 (NH). 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 9.22 (1H, s, 2-NH); 8.44 (1H, s, 5-H); 8.20 (1H, s, 12-H); 4.80 (2H, s, 11,11-H2); 2.82 (2H, t, J = 1.8, 8,8-H2); 1.43 (6H, s, 9,9-(CH3)2). 9,9-Dimethyl-8,9-dihydro-11H-pyrano[5,4':5,6]pyrido[3,2-e]tetrazolo[5,1-c]pyrimidine (7). A solution of sodium nitrite (1 g, 0.015 mol) in water (3 ml) was added dropwise with stirring to a solution of compound 3 (2.45 g, 0.01 mol) in acetic acid (20 ml) at room temperature. Stirring was continued for 20 min. The precipitated crystals of the product 7 were filtered, washed with water, and recrystallized from ethanol. 1 H NMR spectrum (DMSO-d6), , ppm (J, Hz): 9.90 (1H, s, 5-H); 8.20 (1H, s, 12-H); 4.82 (2H, s, 11,11-H); 3.05 (2H, t, J = 1.8, 8,8-H2); 1.45 (6H, s, 9,9-(CH3)2). This work was completed within the scope of the International Science and Technology Union (MNTS).
77
REFERENCES 1. 2. 3. A. Sh. Oganisyan, A. S. Noravyan, and M. Zh. Grigoryan, Khim. Geterotsikl. Soedin., 1372 (2003). A. Sh. Oganisyan, A. S. Noravyan, M. Zh. Grigoryan, and Arzh. Sh. Oganisyan, Khim. Geterotsikl. Soedin., 1239 (1999). S. G. Pilosyan, Authors Abstract, Dissertations of Candidates in Chemical Sciences [in Russian], Yerevan (1986).
78
CONDENSED THIENOPYRIMIDINES. 19*. STUDY OF THE HETEROCYCLIZATION OF 2-HYDRAZINO-6,6-DIMETHYL-5,6-DIHYDRO8H-PYRANOTHIENO[2,3-d]PYRIMIDIN-4-ONE

A. Sh. Oganisyan1, A. S. Noravyan1, A. A. Karapetyan2, M. S. Aleksanyan1, and Yu. T. Struchkov2 Novel condensed pyrano[4',3':4,5]thieno[3,2-e]triazolo[3,4-b]pyrimidine derivatives have been synthesized from 2-amino-3-carbethoxy-5,5-dimethyl-4,5-dihydro-7H-thieno[2,3-c]pyran. Keywords: pyran, pyrimidine, thienopyrimidine, thienopyran, thiophene. The synthesis of 2-amino-3-carbethoxy-5,5-dimethyl-4,5-dihydro-7H-thieno[2,3-c]pyran (1) has been reported in [2]. It serves as a starting material for the development of methods for preparing novel pyranothienopyrimidines, the structures of which have been identified by X-ray analysis. The reaction of compound 1 [2] with benzoylisothiocyanate gave the corresponding 2-N'-thioureido derivative 2. Treatment of the latter with an aqueous alcoholic solution of potassium hydroxide caused an intramolecular cyclization to give the 6,6-dimethyl-2-thioxo-5,6-dihydro-8H-pyrano[4',3':4,5]thieno[2,3-d]pyrimidin-4-one (3). Condensation of this with concentrated hydrazine hydrate then gave the corresponding 2-hydrazino-substituted compound 4.
COOEt O 1 PhCONCS S NH2 O NH O S 3 N H S N2H4 O S 4 N O 2 S COOEt NHCNHCPh S O NH NHNH2 O
KOH
_______ * For Communication 18 see [1]. __________________________________________________________________________________________ A. L. Mndzhoyan Institute of Fine Organic Chemistry, National Academy of Sciences, Armenian Republic, Yerevan 375014. 2 Center for the Investigation of Molecular Structure, National Academy of Sciences, Armenian Republic, Yerevan 375014; e-mail: harkar@msrc.am. 3 A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Moscow 117813. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 85-89, January, 2004. Original article submitted November 29, 2000. 0009-3122/04/4001-00792004 Plenum Publishing Corporation 79
1
The heterocyclization of compound 4 with ethyl orthoformate gave a product which might be assigned the structure 5 or 6. Alkylation of this product with methyl iodide gave an N-methyl derivative whose X-ray analysis proved that the structure corresponded to 7. The modest accuracy of the X-ray analytical data obtained did not permit a detailed discussion of the geometrical parameters but did allow us unambiguously to solve the problem of the structure of 7.
4 O N O S 5 MeI O N O S 7 N N Me N O S 8 N N N H N O S 6 O N Me N N N O NH N N
The structure of the molecule of 7 is given in Fig. 1 together with the numbering for the non-hydrogen atoms and the bond lengths and the values of the valence angles are given in Table 2. Overall, they are in agreement with standard values and allow us to judge the nature of the valence bonds, i.e. to determine unambiguously the structure of compound studied. The tetrahydropyran ring in 7 has the configuration of a distorted half-chair with the O(2) and C(3) atoms deviating from the mean square plane of the remaining ring atoms by -0.33 and 0.42 respectively. With the exception of the O(2) and C(3) atoms of the tetrahydropyran ring, the condensed tetracyclic system is essentially planar as might be expected (the greatest deviation from the mean square plane calculated for all of the atoms in the molecule besides O(2), C(3), C(17), and C(18) being -0.14 ).
Fig. 1. Structure of the 7 molecule with bond lengths. 80
TABLE 1. Atomic Coordinates (104) and Their Equivalent Thermal Parameters

Atom C(1) O(2) C(3) C(4) C(4a) C(5) C(6) S(7) C(1a) N(8) x/a 549(3) 1149(2) 1403(3) 981(3) 285(3) -236(3) -822(3) -713(1) 107(3) -1411(2) y/b 1521(5) 1112(3) 1411(5) 1040(5) 1222(5) 1206(5) 1442(5) 1685(1) 1448(5) 1465(4) z/c 2333(8) 2724(5) 4173(7) 5423(8) 5071(8) 6114(7) 5429(7) 3525(2) 3670(8) 6069(6) Biso 2.0(2) 2.0(1) 1.8(2) 1.7(2) 1.4(2) 1.6(2) 1.3(2) 1.8(1) 1.7(2) 1.6(2) Atom C(9) N(10) C(11) N(12) N(13) C(14) C(15) O(16) C(17) C(18) x/a -1389(3) -861(2) -227(3) -1869(3) -1682(3) -1065(3) -2564(4) 218(2) 1476(3) 2053(3) y/b 1195(5) 936(4) 939(5) 1100(5) 758(5) 666(6) 1221(7) 712(4) 2478(7) 944(4) z/c Biso
7472(8) 1.912(1) 8253(6) 1.3(1) 7640(8) 1.6(2) 8420(6) 2.1(2) 9794(7) 2.4(2) 9664(8) 2.0(2) 8095(8) 3.1(2) 8461(8) 2.1(2) 4248(8) 2.5(2) 4239(9) 2.3(2)
TABLE 2. Valence Angles () (deg.)

Angle O(2)C(1)C(1a) C(1)O(2)C(3) O(2)C(3)C(4) O(2)C(3)C(17) O(2)C(3)C(18) C(4)C(3)C(17) C(4)C(3)C(18) C(17)C(3)C(18) C(3)C(4)C(4a) C(4)C(4a)C(1a) C(4)C(4a)C(5) C(1a)C(4a)C(5) () 108.6(6) 114.7(5) 109.5(5) 114.4(6) 103.5(6) 111.9(6) 110.0(6) 110.2(6) 110.5(6) 120.1(6) 126.7(6) 113.2(6) Angle C(4a)C(5)C(6) C(4a)C(5)C(11) C(6)C(5)C(11) C(5)C(6)S(7) C(5)C(6)N(8) S(7)C(6)N(8) C(1a)S(7)C(6) C(1)C(1a)C(4a) C(1)C(1a)S(7) C(4a)C(1a)S(7) C(6)N(8)C(9) N(8)C(9)N(10) () 112.3(6) 128.1(6) 119.4(6) 110.7(5) 127.9(6) 121.4(6) 91.1(3) 125.3(6) 121.9(5) 112.8(5) 111.1(6) 126.7(6) Angle N(8)C(9)N(12) N(10)C(9)N(12) C(9)N(10)C(11) C(9)N(10)C(14) C(11)N(10)C(14) C(5)C(11)N(10) C(5)C(11)O(16) N(10)C(11)O(16) C(9)N(12)N(13) C(9)N(12)C(15) N(13)N(12)C(14) N(13)N(12)C(15) N(10)C(14)N(13) () 127.3(7) 106.0(6) 123.9(6) 106.9(6) 129.2(6) 110.7(6) 130.9(6) 118.4(6) 111.5(6) 127.8(6) 104.7(6) 120.4(6) 111.0(6)
Hence we have shown that heterocyclization of the 2-hydrazino derivative 4 with ethyl orthoformate occurs regioselectively to give the product 5.
EXPERIMENTAL IR spectra were taken on a UR-20 instrument using vaseline oil and 1H NMR spectra on a Varian Mercury 300 (300 MHz) instrument. TLC was performed on Silufol UV-254 plates and revealed using iodine vapor. X-ray Analytical Investigation of Compound 7. Crystals of compound 7 were of low quality but suitable for X-ray analysis for this specific purpose. They were obtained by slow evaporation of an alcoholic solution. Unit cell parameters and intensities of 1460 independent reflections were measured on a Syntex P21, four circle, automatic diffractometer at a temperature of -120C (MoK, /2 scanning, graphite monochromator, max = 25). Crystals rhombic: a = 20.953(4), b = 14.253(3), c = 8.898(1) ; V = 2657.4(9) 3; Z = 8; dcalc = 1.451 g/cm3; space group Pccn.
81
The structure was solved by a direct method and refined in block diagonal least squares analysis in the anisotropic approximation for non-hydrogen atoms. The positions of all the H-atoms were revealed in electron density difference synthesis and included in the refinement with fixed isotropic parameters Biso = 5 2. All calculations were carried out on an IBM Eclipse-S/200 with the INEXTL program [3]. The final values for the difference factors were R = 0.080 and Rw = 0.065 for 1248 reflections with I > 7(I). The atomic coordinates are given in Table 1. 2-(N'-Benzoylthioureido)-3-carbethoxy-5,5-dimethyl-4,5-dihydro-7H-thieno[2,3-c]pyran (2). Benzoyl isothiocyanate (1.6 g, 10 mmol) was added with stirring to a solution of compound 1 [2] (2.55 g, 10 mmol) in methanol (40 ml). Stirring was continued for 3 h. The precipitated crystals were filtered off and washed with ether to give the product 2 (3.7 g, 90%); mp 208-210C (pyridine), Rf 0.65 (acetonehexane, 1:2). IR spectrum (thin film), , cm-1: 1680 (amide C=O), 1710 (C=O), 3250-3350 (NH). 1H NMR spectrum (pyridine-d5), , ppm (J, Hz): 9.15 (1H, s, HNCO); 7.35-8.20 (6H, m, C6H5, NHCS); 4.76 (2H, s, 7,7-H2); 4.50 (2H, q, J = 7, CH2CH3); 2.96 (2H, s, 4,4-H2); 1.36 (3H, t, J = 7, CH2CH3); 1.30 (6H, s, 5,5-(CH3)2). Found, %: C 57.38; H 5.22; N 6.70; S 15.38. C20H22N2O4S2. Calculated, %: C 57.41; H 5.26; N 6.69; S 15.31. 6,6-Dimethyl-2-thioxo-5,6-dihydro-8H-pyrano[4',3':4,5]thieno[2,3-d]pyrimidin-4-one (3). A mixture of compound 2 (4.18 g, 10 mmol), potassium hydroxide (1.12 g, 0.02 mol), and aqueous alcohol (50%, 50 ml) was refluxed for 2 h. After cooling, the reaction mixture was acidified with a 10% solution of hydrochloric acid to a weakly acidic reaction. The precipitated crystals were filtered off, washed with water, and dried to give the product 3 (2.4 g, 92.1%); mp 288-290C (pyridine), Rf 0.47 (chloroformpyridine, 1:1). IR spectrum (thin film), , cm-1: 1690 (C=O), 3400-3420 (NH). Found, %: C 49.28; H 4.32; N 10.39; S 23.93. C11H12N2O2S2. Calculated, %: C 49.25; H 4.47; N 10.44; S 23.88. 2-Hydrazino-6,6-dimethyl-5,6-dihydro-8H-pyrano[4',3':4,5]thieno[2,3-d]pyrimidin-4-one (4). A mixture of compound 3 (2.68 g, 10 mmol), concentrated hydrazine hydrate (5 ml), and butanol (20 ml) was refluxed for 8 h and then held for ~16 h at room temperature. The precipitated crystals were washed with water and dried to give the product 4 (2 g, 75.5%); mp 308-310C (butanol), Rf 0.50 (hexaneethyl acetate, 1:2). IR Spectrum (thin film), , cm-1: 1700 (C=O), 3200-3400 (NHNH2). 1H NMR spectrum (pyridine-d5), , ppm: 10.8 (1H, s, 3-NH); 5.70 (1H, s, NHNH2); 4.40 (4H, s, 8,8-H2, NHNH2); 2.85 (2H, s, 5,5-H2); 1.18 (6H, s, 6,6-(CH3)2). Found, %: C 49.52; H 5.18; N 21.13; S 12.09. C11H14N4O2S. Calculated, %: C 49.62; H 5.26; N 21.05; S 12.03. 7,7-Dimethyl-6,7-dihydro-9H-pyrano[4',3':4,5]thieno[3,2-e]triazolo[3,4-b]pyrimidin-5-one (5). A mixture of compound 4 (2.66 g, 10 mmol) and ethyl orthoformate (10 ml) was refluxed for 8 h and then held for ~16 h at room temperature. The precipitated crystals were filtered off, washed with ether, and dried to give the product 5 (2.2 g, 75.8%); mp 298-300C (pyridine), Rf 0.48 (hexaneethyl acetatepyridine, 2:1:1). IR spectrum (thin film), , cm-1: 1690 (C=O); 3100-3150 (NH). 1H NMR spectrum (pyridine-d5), , ppm: 10.4 (1H, s, NH); 9.20 (1H, s, 3-H); 4.42 (2H, s, 9,9-H2); 2.82 (1H, s, 6,6-H2); 1.20 (6H, s, 7,7-(CH3)2). Found, %: C 52.11; H 4.22; N 20.34; S 11.70. C12H12N4O2S. Calculated, %: C 52,17; H 4.34; N 20.28; S 11.59. 1,7,7-Trimethyl-6,7-dihydro-9H-pyrano[4',3':4,5]thieno[3,2-e]triazolo[3,4-b]pyrimidin-5-one (7). A mixture of compound 5 (2.76 g, 10 mmol), methyl iodide (1.41 g, 0.01 mol), potassium carbonate (2 g), and methyl ethyl ketone (50 ml) was refluxed for 18 h. The residue after distillation of solvent was washed with water and the precipitated crystals were filtered off and washed with ether to give the product 7 (2 g, 70.0%); mp 211-212C (ethanol), Rf 0.68 (hexaneethanolethyl acetate, 1:1:1). 1H NMR spectrum (pyridine-d5), , ppm: 8.95 (1H, s, 3-H); 4.50 (2H, s, 9,9-H2); 3.40 (3H, s, 1-CH3); 2.80 (1H, s, 6,6-H2); 1.20 (6H, s, 7,7-(CH3)2). Found, %: C 53.81; H 4.71; N 19.52; S 10.80. C13H14N4O2S. Calculated, %: C 53.79; H 4.82; N 19.31; S 11.03.
82
REFERENCES 1. 2. 3. 4. A. P. Mkrtchyan and A. S. Noravyan, Khim. Geterotsikl. Soedin., 261 (2002). A. S. Noravyan, A. P. Mkrtchyan, I. A. Dzhagatspanyan, I. M. Nazaryan, N. E. Akopyan, and S. A. Vartanyan, Khim. -Farm. Zh., 11, No. 8, 20 (1977). R. G. Gerr. A. I. Yanovskii, and Yu. T. Struchkov, Kristallografiya, 28, 1029 (1983). F. H. Allen, O. Kennard, D. Watson, L. Brammer, A. G. Orpen, and R. Taylor, J. Chem. Soc., Perkin Trans. 2, No 12, S1-S19 (1987).
83
THIAZOLECARBOXYLIC ACID DERIVATIVES. 1. N-SUBSTITUTED 2-AMINO-4-METHYLTHIAZOLE5-CARBOXYLIC ACID DERIVATIVES

V. V. Dovlatyan, K. A. Eliazyan, V. A. Pivazyan, E. A. Kazaryan, and A. P. Engoyan Acylation of the ethyl ester and anilide of 2-amino-4-methylthiazole-5-carboxylic acid gave 2-acetyl(arylsulfonyl)amino derivatives. Methylation of acetylaminothiazole and subsequent deacetylation gave 2-methylamino-4-methylthiazole-5-carboxylic acid, which was then converted into esters. The ethyl ester and anilide of thiazole-2-carboxylic acid were used as starting compounds for the synthesis of 2-dimethylaminoformimino- and 2-chlorobenzenesulfonylureido derivatives. Keywords: aminoformiminothiazole, acylaminoformiminothiazole, dimethylaminoformiminothiazole, thiazole-5-carboxylic acid, thiazole-5-carboxylate esters. In a continuation of a study of the synthesis and derivatives of thiazoline-5-carboxylic acid [1], we sought new pesticides and pharmaceuticals among products obtained from the available ethyl ester (1) and anilide 2 of 2-amino-4-methylthiazole-5-carboxylic acid [2]. In the present work, we describe several transformations of 1 and 2 at the amino group. Acylation of aromatic and heterocyclic amines may lead to the appearance or enhancement of the biological activity of these derivatives [3]. This led us to study the acylation of 1 and 2, which can undergo aminoimino tautomerization, and, thus, may react in either the amine or imine form, as in the case of their closest analog, 2-aminothiazole [4]. Methylthiazoles 1 and 2 react regioselectively in acetic anhydride or by the action of arylsulfonyl chlorides in pyridine to give exclusively acylaminothiazoles 3a-e, 4a-e, and 5. Ester 5 is an NH-acid readily methylated to give 6, which may be deacylated to give 2-methylamino-4-methylthiazole-5-carboxylic acid (7) and, then, some of its esters 8a-c. The action of thionyl chloride on 1 and 2 was studied in an attempt to obtain N,N'-thionyldi(aminothiazole), which is a possible fungicide. However, 2-N-dimethylaminoformimino derivatives 9a and 9b, which are the products of the condensation of 1 and 2 with the DMF solvent, are formed instead of the expected thionyldi(aminothiazoles). We also found that aminothiazoles 1 and 2 react with 2-chlorobenzenesulfonyl isocyanate to give 10a and 10b, which are related to the highly active herbicide, thiamethuronmethyl (harmony) [6] and, thus, may hold some interest.
__________________________________________________________________________________________ Armenian Agricultural Academy, Yerevan 375009, Armenia; e-mail: artak@dolphin.am. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 90-95, January, 2004. Original article submitted July 6, 2001. 84 0009-3122/04/4001-00842004 Plenum Publishing Corporation
O Me ArSO2Cl X N S NH2 1, 2 O Me X N S Me (MeCO)2O Me
O Me OEt N S N S
O OEt
HNCOMe 5 O
MeNCOMe 6 O Me
OH N S
RHal
OR N S
HNSO2Ar 3ae, 4ae
HNMe 7
HNMe 8ac
1, 3ae X = OEt, 2, 4ae X = NHPh; 3, 4 a Ar = Ph, b Ar = 4-MeC6H4, c Ar = 2-ClC6H4, d Ar = 2,5-Me2C6H3, e Ar = 4-AcNHC6H4; 8 a R = CH2Ph, b R = CH2COOMe, c R = (CH2)2OPh
O SOCl2 Me X N S Me N CH 1, 2 Me X N S Cl 9a,b O N Me
HNCONHSO2 10a,b
9, 10 a X = OEt, b X = NHPh
EXPERIMENTAL The 1H NMR spectra were taken in DMSO-d6 on a Mercury-300 spectrometer at 300 MHz. Thin-layer chromatography was carried out on Silufol UV-254 plates using 1:1 or 1:2 acetoneheptane as the eluent and 2% AgNO3 + 0.4% bromophenol blue + 4% citric acid as the developer. Ethyl Esters (3a-e) and Anilides (4a-e) of 2-Arylsulfamido-4-methylthiazole-5-carboxylic Acids. A sample of arylsulfonyl chloride (10 mmol) was added in portions to a solution of ethyl ester of 2-amino-4methylthiazole-5-carboxylic acid (1) (1.86 g, 10 mmol) or corresponding anilide 2 (2.33 g, 10 mmol) in pyridine (5 ml). The mixture was maintained for 48 h at 20C and, then, ice water (20 ml) was added. The precipitate formed of 3a-e or 4a-e was filtered off, washed with water, and dried in the air. The products were purified by dissolution in alkali and reacidification by adding acetic acid. 85
86
TABLE. 1. Physicochemical and Spectral Characteristics of Compounds 3a-e and 4a-e

Compound 3 3b 3c 3d 3e Empirical formula C13H14N2O4S2 C14H16N2O4S2 C13H13ClN2O4S2 C15H18N2O4S2 C15H17N3O5S2 Found, % Calculated, % N S 8.80 8.59 8.41 8.24 7.93 7.77 7.76 7.91 11.22 10.97 11.45 11.26 10.61 10.85 10.57 10.31 10.70 10.47 12.83 13.02 19.27 19.63 19.12 18.82 17.31 17.75 18.40 18.08 17.09 16.71 17.59 17.16 16.07 16.54 16.09 15.71 16.32 15.96 15.21 14.88 mp, C
1
H NMR spectrum, , ppm
Yield, %
157-158 198-200 192-194 174-175 136-137
4a 4b 4c 4d 4e
C17H15N3O3S2 C18H17N3O3S2 C17H14ClN3O3S2 C19H19N3O3S2 C19H18N4O4S2
222-224 230-231 140-141 142-143 213-214
1.38 (3H, t, J = 6.5, CH3CH2); 2.43 (3H, s, CH3); 4.27 (2H, q, J = 6.5, CH2); 7.43-7.83 (5H, m, Ph); ~12.50 (1H, v. br. s, NH) 1.36 (3H, t, J = 6.5, CH3CH2); 2.00 (3H, s, CH3Ar); 2.42 (3H, s, CH3); 4.17 (2H, q, J = 6.5, CH2); 7.22-7.75 (4H, m, Ar); 12.20 (1H, br. s, NH) 1.30 (3H, t, J = 6.5, CH3CH2); 2.50 (3H, s, CH3); 4.25 (2H, q, J = 6.5, CH2CH3); 7.60-8.20 (4H, m, Ar); 12.30 (1H, br. s, NH) 1.35 (3H, t, J = 6.5, CH3CH2); 2.08 (3H, s, CH3); 2.20 (3H, s, CH3); 2.45 (3H, s, CH3); 4.22 (2H, q, J = 6.5, CH2); 7.70-8.10 (3H, m, Ar); 12.20 (1H, br. s, NH) 1.38 (3H, t, J = 6.5, CH3CH2); 2.08 (3H, s, C(=)CH3); 2.40 (3H, s, CH3); 4.25 (2H, q, J = 6.5, CH2); 7.70 (4H, s, Ar); 10.02 (1H, s, NHC=O); 12.90 (1H, v. br. s, NHSO2) 2.45 (3H, s, CH3); 7.10-7.80 (10H, m, 2Ph); 10.10 (1H, s, NH); 12.40 (1H, br. s, NHSO2) 2.05 (3H, s, CH3Ar); 2.45 (3H, s, CH3); 6.90-7.80 (9H, m, Ar); 10.20 (1H, s, NH); 12.30 (1H, br. s, NHSO2) 2.50 (3H, s, CH3); 7.05-8.20 (9H, m, Ar); 10.15 (1H, s, NH); 12.30 (1H, br. s, NHSO2) 2.10 (3H, s, CH3); 2.25 (3H, s, CH3); 2.45 (3H, s, CH3); 6.90-8.00 (8H, m, Ar); 10.10 (1H, s, NH); 12.25 (1H, br. s, NHSO2) 2.07 (3H, s, C(=)CH3); 2.43 (3H, s, CH3); 6.95-7.80 (9H, m, Ar); 9.70 (1H, s, NHPh); 10.05 (1H, s, NHPh); 12.80 (1H, br. s, NHSO2)
77 76 80 86 79
80 94 95 96 55
TABLE 2. Characteristics of Compounds 8a-c

Compound 8 8b 8c Empirical formula C13H14N2O2S C9H12N2O4S C14H16N2O3S Found, % Calculated, % N H 11.00 10.69 11.71 11.48 9.47 9.59 12.52 12.21 13.43 13.11 11.21 10.96
1
mp, *
Yield, %
125-127 160-162 118-120
2.43 (3H, s, CH3); 2.90 (3H, d, J = 5.5, NCH3); 5.20 (2H, s, CH2); 7.23-7.38 (H, m, Ph); 7.96 (1H, br. s, NH) 2.45 (3H, s, CH3); 2.90 (3H, d, J = 5.5, NCH3); 3.75 (3H, s, CH3); 4.65 (2H, s, CH2); 8.20 (1H, br. s, NH) 2.45 (3H, s, CH3); 2.90 (3H, d, J = 5.5, NCH3); 4.25 (2H, t, J = 6.2, CH2); 4.56 (2H, t, J = 6.2, CH2Ph); 6.90-7.30 (5H, m, Ph); 8.00 (1H, br. s, NH)
61 62 55
_______ * 1:1 Heptanebenzene for 8a and 8b, heptane for 8c.
87
The physicochemical and spectral data are given in Table 1. Ethyl Ester of 2-Acetylamino-4-methylthiazole-5-carboxylic Acid (5). A suspension of 1 (1.86 g) in acetic anhydride (5 ml) was heated for 5 h at 105-110C. Excess acetic anhydride was distilled off and the residue was treated with water (10-15 ml). The precipitate of 5 was filtered off, washed with water, and dried to give 2.1 g (92%) of compound 5; mp 215-217C. 1H NMR spectrum, , ppm (J, Hz): 1.47 (3H, t, J = 6.5, CH3CH2); 2.40 (3H, s, CH3); 3.55 (3H, s, C(=O)CH3); 4.25 (2H, q, J = 6.5, CH2); 8.10 (1H, br. s, NH). Found, %: N 12.45; S 13.69. C9H12N2O3S. Calculated, %: N 12.28; S 14.04. Ethyl Ester of 2-N-Acetylamino-N-methyl-4-methylthiazole-5-carboxylic Acid (6). A sample of 5 (2.3 g, 10 mmol) was added with stirring to a solution of 84% KOH (0.7 g, 10 mmol) in DMF (10 ml). After 30 min, freshly distilled dimethyl sulfate ( 1.26 g/cm3) (1 ml, 10 mmol) was added dropwise at 0C. The mixture was maintained for 24 h at 20C and DMF was evaporated off. The precipitate was treated with water and filtered off to give 1.86 g (83%) of compound 6; mp 102-104C (octane). 1H NMR spectrum, , ppm (J, Hz): 1.38 (3H, t, J = 6.5, CH3CH2); 2.40 (3H, s, CH3); 2.57 (3H, s, C(=O)CH3); 3.67 (3H, s, NCH3); 4.25 (2H, q, J = 6.5, CH2). Found, %: N 11.39; S 13.56. C10N14N2O3S. Calculated, %: N 11.57; S 13.22. 2-Methylamino-4-methylthiazole-5-carboxylic Acid (7). A sample of 6 (2.42 g, 10 mmol) was added to a solution of 84% KOH (1.4 g, 20 mmol) in ethanol (20 ml) and the mixture was heated at reflux for 2 h. Ethanol was distilled off. The residue was dissolved in water (10 ml) and acidified by adding acetic acid. The precipitate was filtered off to give 1.1 g (64%) of compound 7; mp 159-160C, Rf 0.41. 1H NMR spectrum, , ppm: 2.40 (3H, s, CH3); 2.85 (3H, s, NCH3); 7.83 (1H, br. s, NH); ~11.0 (1H, v. br. s, OH). Found, %: N 16.47; S 18.97. C6H8N2O2S. Calculated, %: N 16.28; S 18.60. Esters of 2-Methylamino-4-methylthiazole-5-carboxylic Acid (8a-c). Benzyl chloride (1.52 g, 12 mmol) (for 8a), methyl chloroacetate (for 8b) (1.30 g, 12 mmol), or phenoxyethyl bromide (for 8c) (2.00 g, 12 mmol) was added to a solution of potassium salt (2.1 g, 10 mmol) of acid 7 and the mixture was heated for 3 h at 50-60C. The suspension was poured into a Petri dish and DMF was evaporated off. The residue was treated with 15 ml water and the precipitates of 8a-c were filtered off (Table 2). Ethyl Ester (9a) and Anilide (9b) of 2-Dimethylaminoformimino-4-methylthiazole-5-carboxylic Acid. A sample of DMF (4 ml) and, then, thionyl chloride (0.8 ml, 11 mmol) were added slowly in portions with stirring to 1 (1.86 g, 10 mmol) or 2 (2.33 g, 10 mmol) cooled to 0C. The mixture was maintained for 24 h at 20C and ice water (20 ml) was added. The solution was filtered to remove turbidity and the filtrate was neutralized by adding NaHCO3. The precipitated product was filtered off. Ethyl Ester 9a was obtained in 87% yield (2.1 g); mp 60-62C (heptane), Rf 0.51. 1H NMR spectrum, , ppm: 2.50 (3H, s, CH3); 3.07 (3H, s, N(CH3)2); 3.20 (3H, s, N(CH3)2); 6.95-7.70 (5H, m, Ph); 8.40 (1H, s, CH=N); 9.35 (1H, s, NH). Found, %: N 17.63; S 13.58. C10H15N3O2S. Calculated, %: N 17.43; S 13.28. Anilide 9b was obtained in 86% yield (2.48 g); mp 93-95C (1:1 heptanebenzene), Rf 0.45. 1H NMR spectrum, , ppm: 2.50 (3H, s, CH3); 3.10 (3H, s, N(CH3)2); 3.20 (3H, s, N(CH3)2); 6.95-7.70 (5H, m, Ph); 8.42 (1H, s, N=CH); 9.35 (1H, s, NH). Found, %: N 19.62; S 11.48. C14H16N4OS. Calculated, %: N 19.44; S 11.11. N-Thiazolyl-N'-(2-chlorobenzenesulfonyl)ureas (10a,b). A sample of 2-chlorobenzenesulfonyl isocyanate (2.2 g, 10 mmol) and five drops of pyridine were added to a solution of 1 (1.86 g, 10 mmoles) or 2 (2.33 g, 10 mmol) in absolute toluene (10 ml). The mixture was heated at reflux for 2 h and urea 10a or 10b was filtered off. Urea 10a was obtained in 93% yield (3.75 g); mp 246-247C (dec.) (heating at reflux in 50% ethanol), Rf 0.35. 1H NMR spectrum, , ppm (J, Hz): 1.30 (3H, t, J = 6.5, CH3CH2); 2.50 (3H, s, CH3); 4.0 (2H, q, J = 6.5, CH2CH3); 7.55-8.15 (4H, m, Ar). Found, %: Cl 8.80; N 10.12; S 16.17. C14H14ClN3O5S2. Calculated, %: Cl 8.80; N 10.41; S 15.86. Urea 10b was obtained in 95% yield (4.3 g); mp 292-293C (dec.), Rf 0.44. 1H NMR spectrum, , ppm: 2.45 (3H, s, CH3); 6.09-8.20 (9H, m, Ar); 9.70 (1H, s, NH); 10.20 (1H, s, NH); 12.80 (1H, br. s, NHSO2Ar). Found, %: Cl 8.17; N 12.64; S 14.65. C18H15ClN4O4S2. Calculated, %: Cl 7.88; N12.43; S 14.21. 88
REFERENCES 1. 2. 3. 4. 5. 6. V. V. Dovlatyan, K. A. Eliazyan, V. A. Pivazyan, E. A. Kazaryan, A. P. Engoyan, R. T. Grigoryan, and R. G. Mirzoyan, Khim. Geterotsikl. Soedin., No. 677 (2000). Y. Sawa and R. Maeda, J. Pharm. Soc. Jpn., 76, 301 (1956); Chem. Abstr., 13875 (1956). W. Schfer, K. Sasse, L. Eue, and H. Hack, West Ger. Pat. 1277241 (1969); Ref. Zh. Khim., 5N095P (1970). H. Martin, O. Rohr, S. Janiak, and L. Edrer, Swiss Pat. 479247 (1969), Ref. Zh. Khim., 11 N976 (1970). G. A. Melent'eva, Pharmaceutical Chemistry [in Russian], Meditsina, Moscow 91968), p. 300. Yu. A. Baskakov, Zh. Vses. Khim. Obshch. im. D. I. Mendeleeva, 33, 634 (1988).
89
SYNTHESIS OF NEW BRANCHED HYDRAZONES AS POTENTIAL HOLETRANSPORTING MATERIALS

V. Getautis, O. Paliulis, R. Degutyte, and I. Paulauskaite A new class of branched hydrazones has been prepared by the reaction of N-2,3-epoxypropylated N-phenylhydrazones containing photoconductive groups with 2,5-dimercapto-1,3,4-thiadiazole in the presence of the catalyst triethylamine. Keywords: hydrazones, epoxypropyl derivatives, dithioles, 1,3,4-thiadiazoles triethylamine. In previous works [1-4] we have reported on novel classes of branched molecules, consisting of conjugated -electron systems, which hold promise as hole-transporting materials (HTM) for various electrooptical applications. The general synthesis route of such organic photoconductors involves the addition of two molecules of oxiranes containing photoconductive groups to various binding agents, for example 2-phenylindole, aniline derivatives, and dihydroxy compounds. Furthermore, we described the synthesis of welldefined branched hydrazones obtained in the reaction of 9-ethyl-9H-3-carbazolecarbaldehyde N-2,3-epoxypropyl-N-phenylhydrazone (1a) and 4-(diethylamino)benzaldehyde N-2,3-epoxypropyl-Nphenylhydrazone (1b) with benzenediols [5]. These HTM are low-molecular glasses and can be used for preparation of electrophotographic layers [6]. Herein we report on the synthesis of a novel series of branched hydrazones analogues to the former described ones but having a 1,3,4-thiadiazole ring in the linking fragment. We felt that the 2,5-dimercapto-1,3,4thiadiazole function offers a two-fold advantage. First is the higher reactivity of the thiol group in nucleophilic oxirane ring opening as well as the commercial availability of the starting agent. Second, some derivatives of 2,5-dimercapto-1,3,4-thiadiazole are used as levelling additives for copper plating electrolytes, giving smooth surfaces [7]. The qualitative surface for the electrophotographic layer could be very important. Nucleophilic opening of the oxirane ring in hydrazone 1a according to the known method [5], i.e., by refluxing 1a with 2,5-dimercapto-1,3,4-thiadiazole (molar ratio 2:1) in 2-butanone in the presence of triethylamine (TEA), gave 2,5-bis[6-(9-ethyl-9H-carbazol-3-ylmethylene)-3-hydroxy-5-phenyl-5,6-diaza-1thiahexyl]-1,3,4-thiadiazole (2a) with 74% yield. Further investigation showed that the reaction could be carried out in mild conditions (at room temperature), thus giving a somewhat higher yield and a purer product. Based on the developed method, by the interaction of 1b, 4-(diphenylamino)benzaldehyde N-2,3-epoxypropyl-Nphenylhydrazone (1c) and 4-(4,4'-dimethyldiphenylamino)benzaldehyde N-2,3-epoxypropyl-N-phenylhydrazone (1d) with 2,5-dimercapto-1,3,4-thiadiazole, the following branched hydrazones in 66-84% yields were synthesized: 2,5-bis[6-(4-diethylaminobenzylidene)-3-hydroxy-5-phenyl-5,6-diaza-1-thiahexyl]-1,3,4-thiadiazole
__________________________________________________________________________________________ Kaunas University of Technology, LT-3028 Kaunas, Lithuania; e-mail: vgetaut@ctf.ktu.lt. Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 96-99, January, 2004. Original article submitted November 18, 2002. 90 0009-3122/04/4001-00902004 Plenum Publishing Corporation
(2b), 2,5-bis[6-(4-diphenylamino)benzylidene-3-hydroxy-5-phenyl-5,6-diaza-1-thiahexyl]-1,3,4-thiadiazole (2c), and 2,5-bis[6-(4,4'-dimethyldiphenylamino)benzylidene-3-hydroxy-5-phenyl-5,6-diaza-1-thiahexyl]-1,3,4-thiadiazole (2d).
HS N N Ht(Ar) 1ad HO N Ht(Ar) Et N 1, 2 a Ht = ; N O
S N N
SH
TEA
S N N 2ad
OH N N Ht(Ar)
1, 2 b Ar = Et2N
1, 2 c Ar =
1, 2 d Ar = Me
N Me
The structures of 2a-d were confirmed by the spectral data. The doublet of the OH group at 5.6-5.2 ppm in the H NMR spectra recorded in DMSO-d6 solutions confirmed the nucleophilic opening of the oxirane ring at the primary carbon atom. Some individual downfield peaks were assigned to characteristic protons of heterocyclic or aromatic moieties: a singlet at 8.25, a doublet at 8.12 (4-H and 2-H of carbazole ring in 2a, respectively), or a triplet at ca. 7.0 ppm (4-H of phenyl ring in 2a,b). The singlet of a proton of the CH=N fragment appears in the region of 7.6-7.8 ppm while the protons of the flexible aliphatic bridge, between the aromatic thiadiazole fragments, usually give peaks at 4.47-3.20 ppm. In the 1H NMR spectrum of 2d the most clearly defined ABX systems of the nonequivalent geminal protons of NCH2 and CH2S were observed. The resonances of NCH2 protons appeared as two doublets of doublets at 4.02 (HA) and at 3.96 ppm (HB) with JAB = 15.0, JBX = 7.0 and JAX = 5.1 Hz, due to the coupling with CH, while the protons of CH2S moiety respectively gave two dd in the region of 3.65-3.3 ppm (JAB = 14.3, JAX = 3.7, JBX = 7.3 Hz). In the 1H NMR spectrum of 2a a double set of signals of the AB part of an ABX system of CH2S is observed at 3.65-3.25 ppm, indicating that the obtained product is a mixture of diastereomers. Hence, the synthesized branched hydrazones containing two stereogenic centers were usually obtained as mixtures of diastereomers. Only in the case of 2d was one stereoisomer registered. In the IR spectra hydroxy groups participating in hydrogen bonding give rise to a broad oscillation band at 3630-3100 cm-1. The existence of several diastereomers, the possibility of intermolecular hydrogen bonding, and the flexibility of aliphatic linking chains make crystallization in the solid state difficult, so 2a-d are molecular glasses. Moreover, such compounds usually do not have definite melting points and are often characterized by their glass transition temperatures (Tg) [8]. Furthermore, after some attempts, 2a-d were crystallized from
1
91
toluene. The presence of hydroxy groups make them cross-linkable with, for example, polyisocyanates. Such cross-linked systems enable one to prepare electrophotographic photoreceptors with high solvent resistance and good mechanical properties. The newly synthesized branched hydrazones 2a-d showed high morphological stability and excellent charge transporting properties, which we reported recently in [9].
EXPERIMENTAL 2,3-Epoxypropyl derivatives of hydrazones 1a-d were prepared according to our earlier procedure [10]. The 1H NMR spectra were registered on a Bruker AC 250 (250 MHz) and Mercury-VX (400 MHz) spectrometers with TMS as the internal standard. The IR spectra were taken in KBr on a Perkin-Elmer (Spectrum BX II) spectrometer. The course of the reactions and the purity of the products were monitored by thin-layer chromatography (TLC) on Silufol UV-254 plates, using 4:1 acetone/n-hexane as the eluent. Silica gel (grade 62, 60-200 mesh, 150 , Aldrich) was used for column chromatography. 2,5-Bis[6-(9-ethyl-9H-carbazol-3-ylmethylene)-3-hydroxy-5-phenyl-5,6-diaza-1-thiahexyl]-1,3,4-thiadiazole (2a). A. To a solution of compound 1a (10.0 g, 27.1 mmol) and 2,5-dimercapto-1,3,4-thiadiazole (2.03 g, 13.55 mmol) in 25 ml of 2-butanone was added 1.9 ml (13.5 mmol) of TEA and the mixture was refluxed for 1 h. After evaporation of 2-butanone and TEA, the residue was dissolved in 25 ml of toluene and cooled till -5C. The crystals formed upon standing (24 h) were filtered off and washed with 2-propanol to give 8.9 g (74.1%) of 2a; mp 167-170.5C (toluene). 1H NMR spectrum (250 MHz, CDCl3), , ppm (J, Hz): 8.25 (2H, s, 4-H Ht); 8.12 (2H, d, J = 7.8, 1-H Ht); 7.83 (2H, d, J = 7.8, 2-H Ht); 7.81 (2H, s, CH=N); 7.50-7.14 (16H, m, Ht, Ar); 6.99 (2H, t, J = 7.0, 4-H Ar); 4.44 (2H, m, CH); 4.27 (4H, q, J = 6.8, CH2CH3); 4.06-3.82 (6H, m, OH, NCH2); 3.60 and 3.55 (2H, m, HA, double set of signals of AB part of ABX system, CH2S); 3.36 and 3.31 (2H, m, HB, double set of signals of AB part of ABX system, CH2S); 1.37 (6H, t, J = 6.8, CH2CH3). IR spectrum, , cm-1: 3368 (OH, br); 3048 (CHarom); 2972, 2930 (CHaliph); 806, 747, 730, 694 (CH=CH of carbazole, monosubstituted benzene). Found, %: C 67.39; H 5.38; N 12.72. C50H48N8O2S3. Calculated, %: C 67.54; H 5.44; N 12.60. B. TEA (1.9 ml, 13.5 mmol) was slowly added to a solution of compound 1a (10.0 g, 27.1 mmol) and 2,5-dimercapto-1,3,4-thiadiazole (2.03 g, 13.55 mmol) in 15 ml of 2-butanone, while the temperature of the reaction mixture was maintained below 30C. Then the reaction mixture was stored overnight at room temperature and the product was isolated according to procedure A. The yield of 2a was 10.1 g (84.1%). A sample of this product with the product obtained according to procedure A did not give a depressed melting point. 2,5-Bis[6-(4-diethylaminobenzylidene)-3-hydroxy-5-phenyl-5,6-diaza-1-thiahexyl]-1,3,4-thiadiazole (2b) was prepared and isolated as described for 2a (procedure B), except that compound 1b (8.7 g, 27.1 mmol) instead of 1a was used. The yield of 2b was 7.6 g (70.4%); mp 114.5-116C (toluene). 1H NMR spectrum (250 MHz, DMSO-d6), , ppm (J, Hz): 7.74 (2H, s, CH=N); 7.48-7.14 (12H, m, Ar); 6.80 (2H, t, J = 7.1, 4-H Ar); 6.64 (4H, m, J = 8.7, Ar); 5.54 (2H, d, J = 3.9, OH); 4.20-3.90 (6H, m, NCH2CH); 3.30 (8H, q, J = 6.9, CH2CH3); 3.18 (4H, m, CH2S); 1.06 (12H, t, J = 7.1, CH2CH3). IR spectrum, , cm-1: 3324 (OH, br); 3019 (CHarom); 2968, 2927, 2957 (CHaliph); 813, 749, 694 (mono- and p-disubstituted benzene). Found, %: C 63.11; H 6.46; N 14.20. C42H52N8O2S3. Calculated, %: C 63.28; H 6.58; N 14.06. 2,5-Bis[6-(4-diphenylamino)benzylidene-3-hydroxy-5-phenyl-5,6-diaza-1-thiahexyl]-1,3,4-thiadiazole (2c) was prepared as described for 2a (procedure B), except that compound 1c (11.2 g, 27.1 mmol) instead of la was used. The product was isolated by subjecting the reaction mixture to chromatography using propanone/hexane (1:4) as the eluent. After removal of the eluents, the residue was recrystallized from toluene. 8.9 g (66.4%) of 2c was filtered off and washed with 2-propanol; mp 165-167C (toluene). 1H NMR spectrum (400 MHz, CDCl3), , ppm (J, Hz): 7.61 (2H, s, CH=N); 7.53 (4H, m, J = 8.8, Ar); 7.40-6.97 (34H, m, Ar); 4.47 92
(2H, m, CH); 4.08-3.90 (6H, m, NCH2, OH); 3.62 and 3.59 (2H, m, HA, double set of signals of AB part of ABX system, SCH2); 3.41-3.32 (2H, m, HB from SCH2). IR spectrum, , cm-1: 3384 (OH, br); 3060, 3033 (CHarom); 2914 (CHaliph); 827, 752, 695 (mono- and p-disubstituted benzene). Found, %: C 70.33; H 5.28; N 11.41. C58H52N8O2S3. Calculated, %: C 70.42; H 5.30; N 11.33. 2,5-Bis[6-(4,4'-dimethyldiphenylamino)benzylidene-3-hydroxy-5-phenyl-5,6-diaza-1-thiahexyl]1,3,4-thiadiazole (2d) was prepared as described for 2a (procedure B), except that compound 1d (12.1 g, 27.1 mmol) instead of 1a was used. The target product was isolated according to the procedure described for 2c. The yield of 2d was 9.6 g (68.1%). 1H NMR spectrum (400 MHz, CDCl3), , ppm (J, Hz): 7.60 (2H, s, CH=N); 7.49 (4H, m, J = 8.2, Ar); 7.39-7.29 (8H, m, Ar); 7.08-6.96 (22H, m, Ar); 4.46 (2H, m, CH); 4.03 (2H, d, J = 3.8, OH); 4.02 (2H, dd, JAB = 15.0, JAX = 5.1, HA of NCH2); 3.96 (2H, dd, JBX = 7.0, HB of NCH2); 3.60 (2H, dd, JAB = 14.3, JAX = 3.7, HA of SCH2); 3.37 (2H, dd, JBX = 7.3, HB from SCH2); 2.29 (12H, s, 4-CH3). IR spectrum, , cm-1: 3355 (OH, br); 3024 (CHarom); 2919, 2858 (CHaliph); 815, 750, 693 (CH=CH of mono- and p-disubstituted benzene). Found, %: C 71.17; H 7.69; N 10.81. C62H60N8O2S3. Calculated, %: C 71.23; H 7.79; N 10.72.
REFERENCES 1. 2. 3. 4. 5. 6. S. Kutkevicius, A. Stanisauskaite, V. Getautis, and A. Railaite, J. Prakt. Chem., 337, 315 (1995). V. Getautis, M. Daskeviciene, and A. Stanisauskaite, Khim. Geterotsikl. Soedin., 898 (2000). V. Getautis, A. Stanisauskaite, and M. Daskeviciene, in Abstracts of 13th International Conference on Organic Synthesis, Warsaw, Poland, 2000, 336. M. Daskeviciene, V. Getautis, J. V. Grazulevicius, A. Stanisauskaite, J. Antulis, V. Gaidelis, V. Jankauskas, and J. Sidaravicius. J. Imaging Sci. Technol., 46, 467 (2002). V. Getautis, M. Daskeviciene, A. Stanisauskaite, and O. Paliulis, Khim. Geterotsikl. Soedin., 884 (2002). V. Gaidelis, J. Gavutiene, V. Getautis, J. V. Grazulevicius, V. Jankauskas, R. Kavaliunas, R. Lazauskaite, O. Paliulis, M. A. Rossman, D. J. Sidaravicius, T. P. Smith, and A. Stanisauskaite, US Pat. 6214503; Chem. Abstr., 134, 273544 (2001). S. Valiuliene and A. Rutavicius, Chemija, 10, 67, (1999). Y. Shirota, J. Mater. Chem., 10, 1 (2000). M. Daskeviciene, V. Gaidelis, V. Getautis, V. Jankauskas, O. Paliulis, and J. Sidaravicius, Lith. J. Phys., 41, 521 (2001). A. Stanisauskaite, V. Getautis, and A. Railaite, Chemija, 3, 68, (1996).
7. 8. 9. 10.
93
REACTIONS OF 3,4-DICHLORON-R-MALEIMIDES WITH SUBSTITUTED 2-THIOURACILS

Yu. M. Volovenko1, G. G. Dubnina1, and A. N. Chernega2 Reactions of 3,4-dichloro-N-R-maleimides with substituted thiouracils at 40C gave a 1:1 mixture of isomers of pyrrolothiazolopyrimidinetriones. Under conditions of thermodynamic control (100C, 5 h) only pyrrolo[3',4':4,5]thiazolo[3,2-a]pyrimidine-4,6,8-triones were formed, hydrolysis of which followed by decarboxylation gave 5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxamide. The structure of N2-phenyl-6-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxamide was confirmed by X-ray crystallography. Analogous cyclization of 3,4-dichloro-N-R-maleimides with 2-thioxoquinazol-4-one also gave a mixture of two isomers which were successfully separated by fractional crystallization. Keywords: 7-R-2-R2-3-R1-7,8-dihydro-4H,6H-pyrrolo[3',4':4.5][1,3]thiazolo[3,2-a]pyrimidine-4,6,8triones, N2-R-6-R1-5-oxo-5H[1,3]thiazolo[3,2-a]pyrimidine-2-carboxamide, nucleophilic substitution in 3,4-dichloro-N-R-maleimides. In 1989-1990 Katritzky [1,2] described the formation of the pyrrolo-[3,4-d]thiazole ring as a result of the reaction 3,4-dichloro-N-phenylmaleimide with thioamides (thiourea, thoacetamide, dithiooxamide). Japanese authors later reported other products from the reaction of substituted maleimides with dithiooxamide tetrahydro-1H,5H-[1,4]dithiino[2,3-b:6,5-b']dipyrrole [3], but in 1993 Katritzky showed that pyrrolo[3,4-d]thiazoles were only obtained in negligible quantities from the maleimides with thioamides, while the main products of the reactions are tetrahydro-1H,5H-[1,4]dithiino[2,3-b;6,5-b']dipyrroles [4]. In the present work we have studied the interaction of 3,4-dichloro-N-R-maleimides 1 with 2-thiouracils 2 which contain three nucleophilic centers: the sulfur atom and the nitrogen atoms at positions 1 and 3. In mild conditions (30-40C) the reaction did not stop at the replacement of just one chlorine atom of the imide 1 but proceeded to cyclization as a result of which a mixture of the isomers 3 and 4 was formed in approximately equal amounts (to judge from the 1H NMR spectrum) (Scheme 1). When the reactions were carried out under more vigorous conditions (100C, 5 h) only the isomers 3a-m were formed. We did not succeed to isolate isomers 4 in pure form. Calculation of the energies of the isomers with structures 3 and 4 was carried out using the AM1 method (Hyper Chem 5.0, grad = 0.01 kcal/mol, suite of programs) showed that isomer 3 has a lower energy than isomer 4 (E = 7-10 kcal/mol). Evidently in the boiling reaction mixture isomers 4 are converted to the more thermodynamically stable isomers 3 which is similar to what occurs in the Dimroth rearrangement [5].
__________________________________________________________________________________________
2
Taras Shevchenko Kiev National University, Kiev 01033, Ukraine; e-mail: otava@carrier.kiev.ua. Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev 02094, Ukraine. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 100-106, January, 2004. Original article submitted June 6, 2001. 0009-3122/04/4001-00942004 Plenum Publishing Corporation
94
Scheme 1
O R N O Cl 1 R O Cl
1
+
S
HN N H 2 O N O
R R
O ;
Et3N 100 oC
3040 oC O
1
R N S
N N S 3am
R N O
4 R = CH2Ph, Ar; R1 = H, Me, R1, R2 = CH2CH2CH2 ; R2 = H, Me, n-Pr
The IR spectra of compounds 3a-m contain two carbonyl stretching bands of the maleimide ring at 1785-1775 (as) and 1730-1715 (s) cm-1. The carbonyl stretching vibration of the pyrimidine ring is observed at 1715-1685 cm-1, which corresponds to data [6] characteristic for isomers of type 3. 2-Thioxo-1,2,3,4-tetrahydro-4-quinazolone (5), a benzo-annelated derivative of 2-thiouracil, also reacted with dichloromaleimides 1 ( R = 4-MeC6H4 or 4-MeOC6H4) under mild conditions to form a mixture of isomers 6 and 7 in equal amounts (according to the 1H NMR spectra).
O 1
+
S
HN
O
NEt3
O
N H 5 O R N O S 6a,b N N O O N S 7a,b N
+
O 1:1
R N O
6, 7 a R = 4-MeC6H4; b R = 4-MeOC6H4
However in this case heating the reaction mixture at 100C for 5h gave only a negligible increase in the quantity of isomer 7. Compounds 6b, 7a,b were isolated in pure form by fractional crystallization. The 1H NMR spectrum of isomer 6b permitted the elucidation of the positions of the resonances of the protons of isomer 6a by difference from the 1H NMR spectra of the mixture of isomers (Table 1). Isomers 6a,b are less soluble in dioxane than isomers 7a,b, they are higher melting, and are chromatographically less mobile (Rf (6) = 7.8; Rf (7) = 8.8). As a result of the angular structure of the planar molecules of isomers 6a,b, the proton in position 1 is in the same plane as the carbonyl groups of the maleimide ring. In the 1H NMR spectra of compounds 6a,b the deshielding effect of the carbonyl groups cause a considerable shift of the proton of this signal to weak field: 9.11 (6a) and 9.08 ppm (6b) (1H, d). In the 1H NMR spectra compounds 7a,b the proton at position 9 appears at weakest field at 8.31 and 8.29 ppm (1H, d). In the IR spectra of compounds 6b, 7a,b the two bands corresponding to the carbonyl groups of the maleimide ring are observed at 1785-1770 (as) and 95
1720-1715 (s) cm-1. Vibrations of the carbonyl group of the quinazoline nucleus were observed at 1700 for isomers 7a,b and at 1650 cm-1 for isomer 6b. Refluxing compounds 3 in aqueous dioxane in he presence of an equimolar amount of triethylamine led to hydrolysis and opening of the maleimide ring with subsequent decarboxylation to give compounds 8a-c.
O
O O;
H2O ; NEt3
H R N O S
R N N
CO2
8ac
6285%
The 1HNMR spectra of 8a-c include a singlet for the proton of the thiazole ring in the region of 8.99-9.14 ppm. The signal of the amide proton, which disappears on the addition of D2O, is observed in the 10.39-10.71 ppm region. The signals of the protons of the substituents R, R1, and R2 are cited in Table 1. The carbonyl stretching frequencies of the maleimide ring are absent from the IR spectra of compounds 8a-c. The stretching vibrations of the amide carbonyl group and the carbonyl group of the pyrimidine ring appear in the 1650-1640 cm-1 region. The NH stretching vibrations are in the region of 3290-3280 cm-1and the band for the CH bond of the thiazole ring is in the 3080-3060 cm-1 region. The structure of compound 8b was confirmed by X-ray crystallography (Fig. 1, Table 2) using the CAMERON method [7]. The bicyclic system S(1)N(1)N(2)C(1-6) is planar within 0.026 A, and the interfacial angle between the S(1)N(1)C(1-3) and N(1)N(2)C(3-6) rings is only 1.9. The geometric parameters of the cyclic systems indicate considerable electron density delocalization [8,9]. The exocyclic carboxamide fragment C(1)C(8)O(2)N(3)C(9) is also almost planar (torsion angles C(1)-C(8)-N(3)-C(9) and O(2)C(8)N(3)C(9) are 174.5 and 4.2) and forms an interfacial angle with the bicyclic plane S(1)N(1)N(2)C(1-6) of 7.8Atom N(3) has a planar trigonal configuration of bonds: the sum of the angles is 360. The benzene ring C(9-14) is rotated relative to the plane C(1)C(8)O(2)N(3)C(9) by 28.1. The molecules of compound 8b are connected into a zigzag chain in the crystal and form intermolecular bonds N(3)H(3)O(1) with the following parameters: N(3)O(1) 2.877(3), H(3)O(1) 2.12(3), N(3)H(3) 0.81(3) A, N(3)H(3)O(1) 157(2).
Fig. 1. Molecular structure of compound 8b.
96
TABLE 1. Characteristics of Compounds 3a-m, 6a,b, 7a,b, 8a-c

Compound 1 3a 3b CH2Ph 3-MeC6H4 R* 2 Empirical formula 3 15H9N3O3S 15H9N3O3S Found, % Calculated, % N S 4 5 13.42 13.50 13.59 13.50 13.07 12.84 13.04 12.92 13.32 13.50 12.50 12.38 12.09 11.89 12.12 11.89 12.38 12.46 12.05 11.96 11.88 11.96 10.23 10.30 10.10 10.30 9.56 9.79 9.99 9.85 10.17 10.30 9.37 9.45 9.28 9.07 9.31 9.07 9.48 9.50 9.18 9.12 9.15 9.12
1
NMR spectrum, , ppm (J, Hz) 6
mp, C 7 179-180 212-213
Yield, % 8 65 58
3c
4-MeOC6H4
15H9N3O4S
3d 3e 3f 3g
CH2Ph Ph Ph CH2Ph
16H11N3O3S 15H9N3O3S 17H13N3O3S 18H15N3O3S
3h
2-MeC6H4
18H15N3O3S
3i 3j 3k
Ph 2-MeC6H4 4-MeC6H4
17H11N3O3S 18H13N3O3S 18H13N3O3S
4.78 (2, s, 2); 6.42 (1H, d, J = 6.0, C(3)-H); 7.22-7.39 (5H, m, HAr); 8.03 (1, d, J = 6.0, C(2)-H) 2.38 (3, s, 3); 6.50 (1H, d, J = 6.0, C(3)-H); 7.19-7.22 (2H, m, 2'- and 4'-HAr); 7.30 (1H, d, J = 9.0, 6'-HAr); 7.44 (1H, t, J = 7.8, 5'-HAr); 8.04 (1, d, J = 6.0, C(2)-H) 3.80 (3, s, O3); 6.43 (1H, d, J = 6.0, C(3)-H); 7.08 (2H, d, J = 8.7, 3'- and 5'-HAr); 7.32 (2H, d, J = 8.7, 2'- and 6'-HAr); 8.05 (1, d, J = 6.0, C(2)-H) 2.30 (3, s, 3); 4.78 (2, s, 2); 6.32 (1H, s, C(3)-H); 7.2-7.3 (5H, m, HAr) 2.19 (3, s, 3); 7.2-7.4 (3H, m, 3'-, 4'- and 5'-HAr); 7.72 (2H, d, J = 7.5, 2'- and 6'-HAr); 8.03 (1H, s, C(2)-H) 0.95 (3H, t, J = 7.2, CH3); 1.68 (2H, m, CH2-CH2-CH3); 2.58 (2H, t, J = 7.2, CH2-CH2-CH3); 6.36 (1H, s, C(3)-H); 7.37.6 (5H, m, HAr) 0.93 (3H, t, J = 7.2, CH3); 1.65 (2H, m, CH2-CH2-CH3); 2.53 (2H, t, J = 7.0, CH2-CH2-CH3); 4.78 (2, s, C6H52); 6.30 (1H, s, C(3)-H); 7.2-7.4 (5H, m, HAr) 0.92 (3H, t, J = 7.3, CH3); 1.67 (2H, m, CH2-CH2-CH3); 2.19 (3H, s, CH3); 2.58 (2H, t, J = 7.2, CH2-CH2-CH3); 6.38 (1H, s, C(3)-H); 7.30-7.45 (4H, m, HAr) 2.08 (2H, m, C(7)-H); 2.76 (2H, t, J = 7.6, C(6)-H); 2.90 (2H, t, J = 7.6, C(8)-H); 7.4-7.55 (5H, m, HAr) 2.09 (2H, m, C(7)-H); 2.18 (3H, s, CH3); 2.76 (2H, t, J = 7.5, C(6)-H); 2.91 (2H, t, J = 7.5, C(8)-H); 7.3-7.45 (4H, m, HAr) 2.08 (2H, m, C(7)-H); 2.37 (3H, s, CH3); 2.75 (2H, t, J = 7.6, C(6)-H), 2.90 (2H, t, J = 7.6, C(8)-H); 7.26 (2H, d, J = 8.4, 3'- and 5'-HAr); 7.34 (2H, d, J = 8.4, 2'- and 6'-HAr)
189-190
60
185-186 193-194 191-192 151-152
61 53 62 58
214-215
59
233234 222-223 209-210
69 55 67
97
98
TABLE 1 (continued)
1 3l*2 3m*3 2 4-ClC6H4 3 17H10ClN3O3S 4 11.44 11.30 10.42 10.34 11.63 5 8.70 8.62 8.08 7.89 8.87 6 2.08 (2H, m, C(7)-H); 2.75 (2H, t, J = 7.6, C(6)-H); 2.90 (2H, t, J = 7.6, C(8)-H); 7.43 (2H, d, J = 8.7, 3'- and 5'-HAr); 7.61 (2H, d, J = 8.7, 2'- and 6'-HAr) 2.10 (2H, m, C(7)-H); 2.77 (2H, t, J = 7.6, C(6)-H); 2.91 (2H, t, J = 7.6, C(8)-H); 7.58 (2H, m, 4'- and 5'-HAr); 7.87 (1H, d, J = 9.0, 6'-HAr) 2.40 (3, s, 3); 7.26 (2, d, J = 8.2, 3'- and 5'-HAr); 7.37 (2, d, J = 7.8, 2'- and 6'-HAr); 7.75 (1H, t, J = 8.1, C(3)-H); 8.0 (1H, t, J = 8.1, (2)-); 8.26 (1H, d, J = 7.8, C(4)-H); 9.11 (1H, d, J = 9.0, C(1)-H) 3.82 (3, s, O3); 7.13 (2, d, J = 8.4, 3'- and 5'-H); 7.39 (2, d, J = 7.8, 2'- and 6'-HAr); 7.72 (1H, t, J = 8.1, C(3)-H); 7.98 (1H, t, J = 8.4, (2)-); 8.22 (1H, d, J = 8.1, C(4)-H); 9.08 (1H, d, J = 8.1, C(1)-H) 2.38 (3, s, 3); 7.29 (2, d, J = 8.1, 3'- and 5'-HAr); 7.35 (2, d, J = 7.8, 2'- and 6'-HAr); 7.62 (1, t, J = 8.1, (8)-H); 7.72 (1, d, J = 8.1, C(6)-H); 7.95 (1, t, J = 8.1, (7)-H); 8.31 (1, d, J = 8.1, C(9)-H) 3.82 (3, s, O3); 7.09 (2, d, J = 9.0, 3'- and 5'-HAr); 7.34 (2, d, J = 8.7, 2'- and 6'-HAr); 7.61 (1, t, J = 8.1, (8)-H); 7.70 (1, d, J = 7.8, C(6)-H); 7.94 (1, t, J = 7.8, (7)-H); 8.29 (1, d, J = 8.1, C(9)-H) 3.75 (3H, s, OCH3); 6.33 (1H, d, J = 6.0, C(6)-H); 6.95 (2, d, J = 8.0, 3'- and 5'-HAr); 7.61 (2, d, J = 8.0, 2'- and 6'-HAr); 8.06 (1H, d, J = 6.0, C(7)-H); 9.09 (1H, s, C(3)-H); 10.57 (1H, s, NH) 2.06 (3H, s, CH3); 7.16 (1H, t, J = 7.5, 4'-HAr); 7.39 (2H, t, 3'- and 5'-HAr); 7.71 (2H, d, J = 7.3, 2'- and 6'-HAr); 8.02 (1H, s, C(7)-H); 9.14 (1H, s, C(3)-H); 10.71 (1H, s, NH) 2.03 (2H, m, C(7)-H); 2.28 (3H, s, CH3); 2.75 (2H, t, J = 7.8, C(8)-H); 2.85 (2H, t, J = 7.8, C(6)-H); 7.17 (2H, d, J = 8.4, 3'- and 5'-HAr); 7.54 (2H, d, J = 8.4, 2'- and 6'-HAr); 8.99 (1H, s, C(3)-H); 10.39 (1H, s, NH) 7 228-29 8 53
2,3-Cl2C6H3
17H9Cl2N3O3S
232-233
58
4-MeC6H4
19H11N3O3S
6b
4-MeOC6H4
19H11N3O4S
11.19 11.13
8.54 8.50
279-280
11
7a
4-MeC6H4
19H11N3O3S
11.57 11.63
8.68 8.87
245-246
23
7b
4-MeOC6H4
19H11N3O4S
11.25 11.13
8.46 8.50
234-235
26
8a
4-MeOC6H4
14H11N3O3S
14.05 13.95 14.81 14.73 13.08 2.91
10.57 10.64 11.10 11.24 10.00 9.85
276-277
77
8b
Ph
14H11N3O2S
242-243
85
4-MeC6H4
17H15N3O2S
253-254
62
_______ * 3a-d,f-h, 8a R1 = H; 3e, 8b R1 = Me; 3i-m, 8c R1+R2 = (CH2)3; 3a-s,e, 8a,b R2 = H; 3d R2 = Me; 3f-h R2 = n-Pr. *2 Found, %: Cl 9.62; calculated, %: Cl 9.54 *3 Found, %: Cl 17.42; calculated, %: Cl 17.45.
TABLE 2. Bond Lengths (d) and Bond Angles () in the Molecule of Compound 8b
Bond S(1)C(1) S(1)C(3) O(1)C(6) O(2)C(8) N(1)C(2) N(1)C(3) N(1)C(6) N(2)C(3) N(2)C(4) C(1)C(2) C(1)C(8) C(4)C(5) C(5)C(6) N(3)C(9) N(3)C(8) d, 1.740(3) 1.731(3) 1.226(3) 1.220(3) 1.395(3) 1.373(3) 1.413(3) 1.304(4) 1.362(4) 1.337(4) 1.491(4) 1.354(4) 1.428(4) 1.419(4) 1.341(4) Angle S(1)C(3)N(1) N(1)C(3)N(2) N(2)C(4)C(5) C(4)C(5)C(6) N(1)C(6)C(5) O(2)C(8)N(3) O(2)C(8)C(1) N(3)C(8)C(1) N(1)C(2)C(1) C(3)N(1)C(6) C(3)N(2)C(4) C(8)N(3)C(9) C(2)N(1)C(3) C(1)S(1)C(3) S(1)C(1)C(2) , deg. 110.7(2) 124.7(3) 126.5(3) 119.4(3) 113.0(2) 125.9(3) 118.6(2) 115.4(2) 112.5(2) 122.1(2) 114.3(2) 127.2(2) 113.8(2) 90.31(14) 112.6(2)
EXPERIMENTAL The course of reactions and the purity of the synthesized compounds were monitored by TLC (Silufol UV-254m eluent 9:1 chloroformmethanol). IR spectra of KBr discs were recorded with UR-20, Specord IR-75, and Pye-Unicam instruments, 1H NMR spectra of DMSO-d6 solutions with TMS as internal standard were recorded with a Varian machine (300 MHz). The X-ray Crystallographic Study of a monocrystal (0.25 0.31 0.59 mm) of compound 8b was carried out at room temperature with an automatic four circle Enraf-Nonius CAD-4 diffractometer (MoK radiation, relative rate of scanning 2/ = 1.2, max = 65, segment of the sphere 0 < h < 12, 0 < k < 8, -17 < l < 17). 2306 reflexions were collected of which 2006 were symmetrically independent (Rint = 0.015). Crystals of compound 8b are monoclinic, C14H11N3O2S; M = 285.32; a = 11.476(4), b = 7.471(4), c = 15.395(7) ; = 100.62(3); V = 1297.3 A3; Z = 4; d = 1.46 g/cm3; space group P21/n; = 2.42 cm-1; F(000) = 593. The structure was solved by direct methods and refined by least squares in the complete matrix anisotropic approximation with the CRYSTALS suite of programs [10]. For the refinement 1748 reflexions with I > 3(I) were used. All hydrogen atoms were found from difference syntheses of the electron density and were included in the conclusion in fixed positions and thermal parameters (only atom H(3) was refined isotropically). Calculation of absorption in the crystal was carried out using azimuthal scanning [11]. The Chebyshev weighting scheme [12] with parameters of 1.61, 0.90, 1.51, -0.22, and 0.38 was used in the refinement. The final residual factors were R = 0.041, Rw = 0.046, GoF 1.137. The complete set of crystallographic data, including atomic coordinates and their anisotropic thermal parameters have been deposited in the Cambridge Crystal Structure Bank (CCDC 155191). 7-R-2-R2-3-R1-7,8-Dihydro-4H,6H-pyrrolo[3',4':4,5]thiazolo[3,2-a]pyrimidine-1,3,9-triones 3i-m. A solution of the corresponding dichloromaleimide 1 (10 mmol) ( R = 4-MeC6H4, 4-MeOC6H4) and 2-thioquinazolone 2 (1.78 g, 10 mmol), and triethylamine (1.52 g, 15 mmol) in dry dioxane (20 ml) was refluxed for 5h. Ethanol (10 ml) was added to the cooled solution. The precipitate was filtered off, washed with ethanol, and recrystallized from dry dioxane. Mixtures of isomers 3 and 4 were prepared in milder conditions analogous to the method used to prepare the mixtures of isomers 6a + 7a and 6b + 7b. 99
9-R,9,10-Dihydro-5H,8H-pyrrolo[3',4':4,5]thiazolo[3,2-a]quinazoline-5,8,10-triones 6a,b; 2-R-2,3-Dihydro-1H,10H-pyrrolo[3',4':4,5]thiazolo[2,3-b]quinazoline-1,3,10-triones 7a,b. To a solution of the corresponding dichloromaleimide 1 (10 mmol) ( R = 4-MeC6H4, 4-MeOC6H4) and 2-thioquinazolone 2 (1.78 g, 10 mmol) in dry dioxane (25 ml), triethylamine (1.52 g, 15 mmol) was added dropwise at 30-40C. The mixture was then stirred for 4 h at 35-45C and then kept at room temperature for 8h. The precipitate was filtered off and washed with a small amount of dioxane and water. The precipitate was a mixture of approximately equal amounts of isomers 6 and 7. The overall yields of the mixtures of isomers were 55 (6a + 7a) and 67% (6b + 7b). Compounds 6b (11%), 7a (23%), and 6a (26%) were obtained in pure form by fractional crystallization from dry dioxane. N2-R-6-R1-5-Oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxamides 8a,b; N2(4-methylphenyl-5-oxo5,6,7,8-tetrahydrocyclopenta[f]thiazolo[3,2-a]pyrimidine-2-carboxamide (8c) (Table 1). A solution of the corresponding compound 3 (3 mmol), triethylamine (0.303 g, 3 mmol), and water (1 ml) in dioxane (10 ml) was boiled for 1 h and then the reaction mixture was kept at room temperature for 8 h. The precipitate was filtered off and washed with a small amount of dioxane and water. It was recrystallized from DMF.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. A. R. Katritzky and W. Q. Fan. J. Heterocycl. Chem.,25, 901 (1988). A. R. Katritzky , W. Q. Fan, and S. Bayyuk. J. Heterocycl. Chem.,26, 885 (1989). M. Matsuoka, A. Iwamoto, and T. Kitao. J. Heterocycl. Chem.,28, 1445 (1991). A. R. Katritzky and W. Q. Fan. J. Heterocycl. Chem.,30, 1679 (1993). O. Dimroth, Liebigs Ann. Chem., 364, 183 (1909). V. A. Kovtunenko, V. V. Ishchenko, A. K. Tyltin, and F. S. Babichev. Doklad. Akad. Nauk., 294, 375 (1987). D. J. Watkin, C. K. Prout, and L. J. Pearce. CAMERON. Chemical Crystallography Laboratory, Univ. of Oxford, Oxford (1996). M. Burke-Laing and M. Laing. Acta Crystallogr., B32, 3216 (1976). V. A. Naumov and O. N. Kataeva. Molecular Structures of Organic Compounds of Oxygen and Sulfur in the Gas Phase [in Russian], Nauka, Moscow (1990), p.137. D. J. Watkin, C. K. Prout, J. R. Carruthers, and P. W. Betteridge. CRYSTALS issue 10. Chemical Crystallography Laboratory, Univ. of Oxford, Oxford (1996). A. C. T. North, D. C. Phillips, and F. S Mathews. Acta Crystallogr., A24, 351 (1968). J. R. Carruthers and D. J. Watkin. Acta Crystallogr., A35, 698 (1979).
100
1,1-DICHLORO-2,2,2-TRIHALOETHYL ISOCYANATES AND N-(1-CHLORO-2,2,2TRIHALOETHYLIDENE)URETHANES IN THE SYNTHESIS OF 4-TRIHALOMETHYL2H-1,3-BENZOXAZIN-2-ONES

M. V. Vovk, A. V. Bol'but, P. S. Lebed', and V. I. Boiko 4-Trihalomethyl-2H-1,3-benzoxazin-2-ones have been synthesized by the reaction of 1,1-dichloro-2,2,2trihaloethyl isocyanates or N-(1-chloro-2,2,2-trihaloethylidene)urethanes with 3-dialkylamino(alkoxy)phenols. The character of the products from the addition of nucleophiles has been shown to depend on the nature of the nucleophile and the trihalomethyl group. Keywords: N-alkylideneurethanes, m-dialkylamino(alkoxy)phenols, isocyanates, 4-trihalomethyl-2H1,3-benzoxazin-2-ones. In previous papers [1-3] we have shown the possibility of using thermal cyclocondensation of derivatives of 1-chloro-2-trifluoromethylalkyl isocyanates and N-alkylidene-O-arylurethanes to prepare trifluoromethyl-containing 3,4- and 2,3-dihydro-1,3-benzoxazines. With the objective of synthesizing nonhydrogenated analogs of known heterocyclic systems we have studied the reaction of 1,1-dichloro-2,2,2trihalomethyl isocyanates 1a,b, and the N-(1-chloro-2,2,2-trihaloethylidene)urethanes 2a-d made from them, with phenols 3a-d activated by dialkylamino or alkoxy groups. It was found that interaction of the isocyanates 1a,b with the m-dialkylaminophenols 3a,b in benzene in the presence of an organic base led to the formation of the N-alkylideneurethanes 4a-c, the structures of which were confirmed by the absence in the IR spectra of the reaction mixtures of the absorption band of the N=C=O groups in the 2260-2270 cm-1 region and the appearance of the absorption band of the C=O group in the 1760-1770 cm-1 region. According to the 19F NMR spectrum, measured for compound 4b, the N-alkylideneurethanes 4a-c even at 20-25C began to be converted slowly into 4-trihalomethyl-2H-1,3benzoxazin-2-ones 5a-c by intramolecular electrophilic attack of the imidoyl carbon at position 6 of the benzene ring, activated by the dialkylamino group. This process was completed by boiling the reaction mixture for 0.5 h. In the case of 1-aryl-1-chloro-2,2,2-trifluoroethyl isocyanates the analogous reaction occurred only on heating in toluene for 10 h [2]. The decrease in the nucleophilicity of the phenoxy nucleus in N-alkylideneurethanes 4d,e which resulted from replacing the dialkylamino groups by poorer donating alkoxy group led to considerably slower cyclization. The required compounds 5d,e were isolated in yields of 41 and 9% respectively only after prolonged boiling of the reaction mixture in xylene. __________________________________________________________________________________________ Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev 02094, Ukraine; e-mail: hetfos@ukrpack.net, mvovk@i.com.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 107-112, January, 2004. Original article submitted February 21, 2001. 0009-3122/04/4001-01012004 Plenum Publishing Corporation 101
R
CHal3 CCl2N=C=O 1a,b
HO
3ad
R
20 0C HCl
CHal3
HCl
O CHal3 CCl=NCO
4ad
5ae
1a Hal = F, b Cl, 3a R = Me2N, b Et2N, c MeO, d EtO, 4, 5 a R = Me2N, Hal = Cl, b R = Et2N, Hal = F, c R = Et2N, Hal = Cl, d R = MeO, Hal = F, e R = EtO, Hal = Cl
In the IR spectra of the 1,3-benzoxazinones 5 the absorption bands of the exocyclic C=O groups appear at 1735-1760 and the endocyclic C=N bond at 1630-1635 cm-1. In the 1H NMR spectra there are doublets for proton C(8)H (6.44-6.83) and proton C(5)H (7.65-8.17 ppm), and also a doublet of doublets for C(6)H (6.65-6.91 ppm) which confirms annelation at position 6 of the benzene ring. In the 19F NMR spectra of compounds 5a,b,d there are singlets for the CF3 group in the range 67.2-68.0 ppm, typical for this group attached to sp2-carbon atoms [4]. The cyclic structure of 5 was also confirmed by measuring the 13C NMR spectrum for compound 5c: 12.32 (CH3), 45.04 (CH2), 94.87 (CCl3), 95.96 (C(8)), 99.64 (C(5a)), 109.10 (C(6)), 129.53 (C(5)), 151.71 (C(8a)), 153.98 (C(4)), 161.41 (C(7)), 169.59 (C=O). To obtain the isomeric with 5 2-trihalomethyl-4H-1,3-benzoxazin-4-ones of type 6 we investigated the reaction of N-(1-chloro-2,2,2-trihalo)ethylidene-O-methylurethanes 2a,b [5] with the phenol 3b. The reason for choosing this solution was the results obtained previously for the cyclization of compounds 2a,b with arylamines [6]. However, as we had established, the products of substitution of the chlorine atom 7a,b did not undergo electrophilic attack at the o-position of the phenoxy substituent by the methoxycarbnyl group even on prolonged heating in mesitylene. Therefore N-alkylidene-O-(4-nitrophenyl)urethane 2c was chosen to increase the electrophilicity of the carbonyl group in reaction with the phenol 3b. We observed the unexpected conversion of the imidate 7c in a yield of 51% not into a structure of type 6, but into compound 5c (the reaction occurs over a day at room temperature but in just 0.5 h in boiling dioxane). We suggest that in this case a mild transphenoxylation occurs into the heterodiene system of bonds, which most probably occurs by an anionic mechanism [7] through the stage of the 1,1-diphenoxyalkyl isocyanate A, Cyclization of the intermediate rearrangement product B is evidently facilitated by the ability of the 4-nitrophenoxy group as a leaving group (Scheme 1). Reaction of alcohols with the benzoxazin-2-ones 5b,c gave stable 2,3-dihydro-4-alkoxy derivatives 10a-c which confirmed the ability of trihalomethyl group no matter what the halogen, to retain exocyclic alkoxy substituents. The increased electrophilicity of compound 5b, caused by the presence of the CF3 group, led to its reaction with ammonia occurring at both electrophilic centers with opening of the oxazine ring, as a result of which we were unable to isolate individual products of the reaction. At the same time the reaction of cyclohexylamine with compound 5c, which contains a CCl3 group, leaves the cyclic system unaffected. The initially formed 4-amino-3,4-dihydro derivative 11, like its hydroxy analog 8b, loses a molecule of chloroform and is converted into compound 12 which, according to its 1H NMR spectrum in CDCl3, exists as the 4-amino derivative 12.
102
Scheme 1
O CHal3CCl=NCOR' 2a-c NEt2 O N HCl 3b Et2N O 7a-c R'= 4-O2NC6H4 O C N Et2N A O OR' CCl3 B CCl3 R'= 4-O2NC6H4OH Et2N O N O Et2N O R'O O N CCl3 OR' CHal3 ROH Et2N O 6 O N CHal3
HO
5c 2, 7 a Hal = F, R'= Me, b Hal = Cl, R' = Me, c Hal = Cl, R' = 4-O2NC6H4
4-Trihalomethyl-2H-1,3-benzoxazin-2-ones of type 5 are little studied [8,9] benzannelated systems with two electrophilic centers the carbon atoms of the C=O and C=N groups. The reactions of benzoxazinones 5 with some nucleophilic reagents might be used as a suitable variant for the synthesis of new dihydro derivatives. In particular, mild hydrolysis of compound 5b, which contains a CF3 group, occurs by addition of water to the C=N group with the formation of the stable product 8a, whereas the CCl3 group does not stabilize its analog 8b, which undergoes haloform elimination to give the 2,4-dioxo derivative 9.
C H al3
X= OH
OH
NH
Hal = Cl CHCl3
O
NH O
Et 2 N
C H al3
N
Et 2 N
O 8a,b
AlkO
Et 2 N
9
C H al3
NH O
HX
O
X= OAlk
Et 2 N
5b,c
10a-c
RNH
CCl3
NH
CHCl3
NHR
N
X= H 2 N R
Et 2 N
11
Et 2 N
12
8 a Hal = F, b Hal = Cl; 10 a Hal = F, Alk = Me, b Hal = Cl, Alk = Me, c Hal = Cl, Alk = i-Pr; 12 R = cyclo-C6H11
103
TABLE 1. Characteristics of the Compounds Synthesized

Compound 5a 5b 5c 5d 5e 8a 9 10a 10b 10c 12 Empirical formula 119Cl3N2O2 1313F3N2O2 1313Cl3N2O2 106F3NO3 118Cl3NO3 1315F3N2O3 1214N2O3 1417F3N2O3 1427Cl3N2O3 1612l3N2O3 1825N3O2 Found, % Calculated, % H 2.69 2.95 4.39 4.58 4.24 3.90 2.32 2.47 2.69 2.61 5.18 4.97 5.92 6.02 5.27 5.38 4.41 4.66 5.11 5.35 8.27 7.99 mp, C N 9.27 9.11 10.07 9.79 8.03 8.35 5.50 5.71 4.17 4.54 9.52 9.21 12.17 11.96 8.62 8.80 7.53 7.62 6.72 7.08 13.03 13.32 187-188 155-156 185-186 97-98 125-126 134-135 206-207 119-120 180-181 168-169 211-212 Yield, % (method) 52 44 56 (A), 51 (B) 41 9 95 94 73 71 70 75
C 43.31 42.96 54.21 54.55 46.90 46.52 48.61 48.99 43.11 42.82 51.44 51.32 61.48 61.53 53.06 52.83 46.08 45.76 48.86 48.56 68.71 68.54
EXPERIMENTAL IR spectra of KBr disks or solutions in chloroform or dioxane were recorded on a UR-20 apparatus. H and F NMR spectra of CDCl3 solutions with TMS (1H) or CCl3F (19F) internal standards were recorded on Varian-Gemini machine (300 and 188 MHz respectively). The characteristics of compounds 5a-e, 8a, 9, 10a-c, and 12 are cited in Table 1. Compounds 5a,b,d were recrystallized from a benzenedioxane mixture, 5c,e, 8a, 9, 12 from dioxane, 10a,b from methanol, and 10c from 2-propanol. N-(1,2,2,2-Tetrachloro)ethylidene-O-(4-nitrophenyl)urethane (2c). Triethylamine (0.505 g, 5 mmol) in benzene (5 ml) was added dropwise to a mixture of isocyanate 1b (1.22 g, 5 mmol) and 4-nitrophenol (0.696 g, 5 mmol) and the mixture was stirred for 2h. The precipitate of triethylammonium chloride was filtered off, the filtrate was evaporated and the residue recrystallized from a 6:1 mixture of hexane and benzene. Yield 89%; mp 91-92C. IR spectrum (CH2Cl2), , cm-1: 1700 (C=N), 1780 (C=O). 1H NMR spectrum (C6D6), , ppm (J, Hz): 6.55 (2H, d, J = 9.3, 2,6-H); 7.62 (2H, d, J = 9.3, 3,5-H). Found, %: Cl 40.76; N 7.82. C9H4Cl4N2O4. Calculated, %: Cl 40.99; N 8.10 N-[1-(3-Diethylaminophenoxy)-2,2,2-trihalomethylethylidene]-O-methylurethanes (7a,b). A mixture of phenol 3a (0.826 g, 5 mmol) and triethylamine (0.505 g, 5 mmol) was added dropwise to a solution of N-alkylidenurethane 2a,b (5 mmol) in benzene (15 ml) and the mixture stirred for 2 h. The precipitate of triethylammonium chloride was filtered off, the filtrate was evaporated and the oily precipitate was purified by freezing out from a 1:10 mixture of diethyl ether and hexane at -18C. Compound 7a. Yield 85%. IR spectra (CH2Cl2), , cm-1: 1695 (C=N), 1765 (C=O). 1H NMR spectrum (C6D6): , ppm (J, Hz): 0.74 (6H, t, J = 7.2, 2CH3); 2.76 (4H, q, J = 7.2, 2CH2); 3.16 (3H, s, OCH3); 6.26 (1H, dd, J1,2 = 8.7, J1,3 = 2.1, 4-H); 6.34 (1H, dd, J1,2 = 7.8, J13 = 1.7, 6-H); 6.38 (1H, t, J = 2.1, 2-H); 6.92 (1H, t, J = 8.7, 5-H). 19F NMR spectrum (C6D6), , ppm: 71.3. Found, %: F 17.83, N 8.67. C14H17F3N2O3. Calculated, %: F 17.91; N 8.80.
1 19
104
Compound 7b. Yield 53%. IR spectrum (CH2Cl2), , cm-1: 1690 (C=N), 1770 (C=O). 1H NMR spectrum (CDCl3), , ppm (J, Hz): 1.17 (6H, t, J = 7.2, 2CH3); 3.34 (4H, q, J = 7.2, 2CH2); 3.37 (3H, s, OCH3); 6.39 (1H, t, J = 2.1, 2-H); 6.42 (1H, dd, J1,2 = 8.3, J1,3 = 2.0, 4-H); 6.54 (1H, dd, J1,2 = 8.4, J1,3 = 2.1, 6-H); 7.18 (1H, t, J = 8.3, 5-H). Found, %: Cl 29.07; N 7.71. C14H17Cl3N2O3. Calculated, %: Cl 28.93; N 7.62. 4-Trihalo-2H-1,3-benzoxazin-2-ones (5a-e). A. A mixture of phenol 3a-c (5 mmol) and triethylamine (0.505 g, 5mmol) was added to a solution of isocyanate 1a,b (5 mmol) in benzene (10 ml) and the mixture was stirred for 3 h at room temperature. The precipitate of triethylammonium chloride was separated to give benzene solutions of the N-alkylideneurethanes 4a-e. In the case of 4a-c the solution was boiled for 0.5 h. For compounds 4d,e the benzene was evaporated and xylene (15 ml) was added to the residue and boiled for 8 h (compound 4d) and for 30 h (compound 4e). After removal of the solvent, diethyl ether (20 ml) was added to the residue and the solid substance was filtered off after 24 h. B. A mixture of phenol 3b (0.826 g, 5 mmol) and triethylamine (0.505 g, 5 mmol) in dioxane (10 ml) was added to a solution of N-alkylideneurethane 2c (1.73 g, 5 mmol) in dioxane (15 ml) and the mixture was stirred for 2h. The precipitate of triethylammonium chloride was filtered off, and the filtrate was kept for 24 h or boiled for 0.5 h. The solvent was removed and diethyl ether (20 ml) was added to the residue which was kept for 24 h and the solid product formed was filtered off. 4-Hydroxy-4-trifluoromethyl-2,3-dihydro-4H-1,3-benzoxazin-2-one (8a) and 2,3-Dihydro-4H-1,3benzoxazin-2,4-dione (9). Water (0.1 ml) was added to a solution of compound 5b,c (3 mmol) in DMSO (3 ml) and the solution was kept at room temperature for 24 h. The mixture was then diluted with water (10 ml) and the precipitate formed was filtered off and recrystallized. 4-Alkoxy-4-trichloromethyl-2,3-dihydro-4H-1,3-benzoxazin-2-ones (10a-c). Compounds 5a,b were dissolved in methanol or 2-propanol (5 ml), 3 drops of triethylamine were added, and the mixture was kept for 48 h. The precipitate was filtered off and recrystallized. 4-Cyclohexylamino-2H-1,3-benzoxazin-2-one (12). Cyclohexylamine (0.198 g, 2 mmol) was added to a solution of compound 5c (0,671 g, 2 mmol) in dioxane (10 ml) and the mixture was kept for 48 h. The precipitate was filtered off and recrystallized.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. M. V. Vovk, A. A. Pokholenko, and A. V. Bol'but, Zhur. Org. Khim., 32, 476 (1996). M. V. Vovk and A. V. Bol'but, Zhur. Org. Khim., 34, 628 (1998). M. V. Vovk and A. V. Bol'but, Ukr. Khim. Zhur., 64, 46 (1998). M. V. Vovk and V. I. Dorokhov, Izv. Vuzov. Khim. i Khim. Tekhnol., 39, 15 (1996). L. I. Samarai, V. I. Boiko, and M. N. Gertsyuk, Zhur. Org. Khim., 26, 745 (1990). V. I. Boiko, V. M. Vovk, and L. I. Samarai, Ukr. Khim. Zhur., 61, 48 (1995). A. G. Catchpole and E. D. Hughes, J. Chem. Soc., 4 (1948). J. Petridou-Fischer and E. P. Papadopoulos, J. Heterocycl. Chem., 20, 1159 (1983). A. Kamal and P. B. Satur, Synth. Commun., 12, 157 (1982).
105
SYNTHESIS AND STUDY OF THE PROPERTIES OF 7,8-POLYMETHYLENEIMIDAZO[4,5-d]1,3,2-DIAZAPHOSPHORIN-2-THIONES

D. B. Nilov1, A. V. Kadushkin2, N. P. Solov'eva1, Yu. N. Sheinker1, and V. G. Granik2 In thionation of cyclic N-cyanoamidines, a four-step process occurs that leads to derivatives of novel heterocyclic systems: 7,8-polymethyleneimidazo[4,5-d]-1,3,2-diazaphosphorin-2-thiones. We have studied the chemical and spectral properties of the compounds obtained. Keywords: imidazo[4,5-d]-1,3,2-diazaphosphorins, thionation, ThorpeZiegler cyclization. phosphorus pentasulfide, N-cyanoamidines,
In the course of studying the chemical and biological properties of derivatives of 1-carbamidomethyl-2pyrrolidone (piracetam) and its analogs [1-3], it has been established that converting the amide groups to thioamide groups leads to a sharp enhancement of the antihypoxic and nootropic activity of the compounds [4, 5]. Continuing this research, we attempted to convert the carbamoyl group of 1-carbamidomethyl-2cyanoiminopyrrolidine (1a), which also exhibits nootropic and anticonvulsive action [6] to thiocarbamoyl group. However, in a study of the reaction product of carbamide 1a and phosphorus pentasulfide in pyridine, we found that the reaction did not stop at the thionation step but rather proceeded all the way to formation of a tricyclic system containing annelated pyrrole, imidazole, and 1,3,2-diazaphosphorin rings. In fact, in the IR spectrum of the product 2a obtained (isolated as a pyridine solvate), there was no absorption band from the CN group. In the 1 H NMR spectrum of compound 2a in DMSO-d6, we observed the following proton signals at , ppm (J, Hz): 2.50 (2H, m, 7-CH2); 2.84 (2H, t, 8-CH2); 4.30 (2H, t, 6-CH2); 9.30 (1H, br. d, 2J = 15.3, NH, NHP), and 9.38 (1H, br. s, NH), and pyridine protons at 7.79 (2H, t, -H); 8.26 (1H, t, -H); 8.79 (2H, d, -H).* In the mass spectrum of tricycle 2a, we observe a molecular ion peak (m/z) [M]+ 276 and ion peaks 243 [M+ - SH], 184 [M+ - SH, - CSNH2], 148 [M+ - SH, - PS2], 123 [M+ - CS - NH - PS2], 95 [PS2+]. An SH proton signal is not clearly seen in the 1H NMR spectrum, which is consistent with the data in [8] concerning a study of the spectra for such compounds. Based on all the results obtained, the isolated compound was assigned the structure of 7,8-trimethyleneimidazo[4,5-d]-1,3,2-diazaphosphorin-2-thione (2a). Similarly, 1-carbamidomethyl-2-cyanoiminopiperidine (1b) and 1-carbamidomethyl-2-cyanoiminohexahydroazepine (1c), when reacted with P2S5 in pyridine, are converted to 7,8-tetra- and 7,8-pentamethyleneimidazo[4,5-d]-1,3,2-diazaphosphorin-2-thiones 2b,c. The proposed scheme for these irreversible conversions is shown below: _______ * The tendency of 1,3,2-diazaphosphorin derivatives to form pyridine solvates of variable composition has been described in [7-12]. __________________________________________________________________________________________ Drug Chemistry Center/All-Russian Scientific Research Pharmaceutical Chemistry Institute, Moscow 119815; e-mail: nilov22@hotmail.com. 2 Federal State Unitary Enterprises. "The State Scientific Center NIOPIK", Moscow 103787, Russia; e-mail: alex111x@orc.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 113-121, January, 2004. Original article submitted July 19, 2001. 106 0009-3122/04/4001-01062004 Plenum Publishing Corporation
1
n(CH2)
N
NCN
P2S5/Py
1ac
NCN
N
CH2CONH2
n(CH 2)
n(CH 2)
N N
NH2 CSNH2
n(CH 2)
N
SH H N P S
SH
CSNH2
CH2CSNH2
n(CH 2)
N
H N
P NH
S SH
.
N
2ac
1a, 2a n = 1; 1b, 2b n = 2; 1c, 2c n = 3
In the first step, conversion of amide to thioamide occurs (as is usual under these conditions), where significant activation of the methylene unit occurs [14], making possible a ThorpeZiegler cyclization [15] with participation of this unit and the N-cyano group. 1,2-Polymethylene-4-amino-5-carbamidoimidazoles 3 formed in this case are acylated by the phosphorus pentasulfide at the primary 4-amino group, followed by cyclization of the derivative 4 obtained to tricyclic diazaphosphorins 2. We carried out an analogous cyclization within this work based on 1,2-trimethylene-4-amino-5cyanoimidazole (5) [16, 17]. In this case, as the reaction product we isolated the tricycle 2a (the reaction probably occurs via intermediate 4).
N N 5 NH2 CN P2S5/Py
H N N
SH N P S SH CN
H2S
2a
We must reiterate that in this work, as in the papers cited above [7-12], depending on the conditions under which the reaction products are isolated and the conditions under which the solvent is removed, the pyridine content (%) in the solvates fluctuates in rather broad limits (from 6 to 50 mole %, according to 1H NMR spectral data). Nevertheless, a stable compound was obtained upon heating pyridine solvate 2a with benzylamine. The high basicity of the latter makes it possible to synthesize a stable compound 6, for which we obtained not only clear spectral data but also satisfactory elemental analysis results (see Experimental). The presence of thiol and thiocarbamoyl moieties in compounds 2a-c makes possible alkylation of their anions by both alkyl halides and dialkyl sulfates. In this case, using alkyl halides we can obtain dialkyl derivatives 7a-d. When compound 2a reacts with dimethyl and diethyl sulfates, the alkylation occurs not only at the sulfur atoms but also at the NH group in the position 1, and as a result tris-alkyl derivatives 8a,b are formed:
107
2ac
RHal EtONa/EtOH
n(CH2) N
H N
P N
S SR
7ad R2SO4/NaOH (for 2a)
SR
PhCH2NH2 (for 2a)
ac n = 13, R = CH2Ph d n = 1, R = Me R N S P SR N
N n(CH2) N 6 S N H N P S PhCH2NH2 N 8a,b R = Me, Et
SH NH
SR
The next step in this work was to study the reactions of compounds 7 and 8 with nucleophilic reagents, as which we selected various amino derivatives. When compounds 7d and 8a reacted with amines, we observed an interesting fact: while diallyl derivative 7d yields 2-morpholide 9a as the major product when reacted with morpholine (the other bis-alkyl substituted derivative 7a reacts analogously, to form the derivative 9b), the reaction of tris-alkyl derivative 8a with morpholine leads to substitution at the position 4 and formation of compound 10. To refine these results using 1H NMR spectroscopy, we studied the reaction mixtures (after driving off the excess morpholine) obtained as a result of the indicated reactions. We found that after reaction of compounds 7d and morpholine, the mixture contained morpholide 9a, the starting compound 7d, and 4-morpholino derivative 11 (~6:2:1). Only 4-morpholino derivative 10 and starting 8a (24:1) were present in the reaction mass obtained when compound 8a was heated with morpholine.
HN 7d O N 9a N H N S P N N N N 11 Me N N 10 N O N P N S SMe N O H N S
+
O
N SMe
SMe
HN 8a
The compounds 9a,b and 10 were isolated in pure form. A series of reactions carried out with other amines, including aromatic amines (the mixtures thus obtained were analyzed using 1H NMR spectra) shows that for reaction of 1-unsubstituted 2,4-dialkylthiodiazophosphorins 7a,d with amines, formation of 2-phosphamides is typical (upon reaction with amines under harsher conditions (180-190C), a mixture of 2,4-diamino derivatives is formed), while for the 1-substituted compounds 8 the process of substitution at the position 4 predominates (this tendency has already been noted in the literature [18]). From our standpoint, such a direction for the change in the course of the reaction with amines is due to the fact that the presence of the
108
substituent in the position 1 of the diazaphosphorin ring leads to steric hindrances in the transition state upon attack at the phosphorus atom in the position 2, which in this case promotes the substitution process occurring exclusively at the position 4. The structure of all the synthesized compounds was studied in detail using 1H and 13C NMR spectra (most of them are given in Experimental). Here we compare the 13C NMR spectra (in DMSO-d6) of compound 2a [, ppm (J, Hz): 24.1 (C(7)); 24.6 (C(8)); 49.8 (C(6)); 113.2 (C(4a), 3J = 7.6, C(4a)P); 141.8 (C(9a)); 177.1 (C(4), d, 2 J = 11.4, CP)] and compound 7a [, ppm (J, Hz): 23.8 (C(7)); 25.0 (C(8)); 32.2 (4-CSCH2, 4J = 1.8, CP); 37.7 (PSCH2, 2J = 4.4, CP); 46.9 (C(6)); 108.9 (C(4a), 4J = 33.0, CP); 155.4 (C(9a)); 159.4 (C(8a)); 160.9 (C(4), 4 J = 17.0, CP)].* Comparison of the chemical shifts for the C(4) atom of both compounds allows us to say that tricycle 2a exists in the thione tautomeric form. For compounds 2a, 7a, 9b, and 12 (isolated from reaction of compound 7a and benzylamine at 180-190C, see Experimental), we also obtained data from 31P NMR spectra (DMSO-d6, external standard 85% H3PO4). In diazaphosphorin 2a, the 31P signal is observed at 75 ppm; in 2-S- and 4-S-dibenzyl derivative 7a, the 31P signal is shifted upfield to 63.3 ppm, while for compound 11 we observe further shift of the signal to 55.8 ppm. These results also are evidence in favor of thione structure for compound 2a. In conclusion, we need to focus on some features of the 1H NMR spectra of the synthesized compounds. 1. The signals from protons of the 2-SCH2Ph group in compounds 8a-c are nonequivalent, which is due to their spatial proximity to the asymmetric phosphorus atom: = SCHaPh SCHbPh = 0.07-0.08 ppm. These protons are represented by two triplets of equal intensity at 3.74-3.79 ppm and 3.83-3.88 ppm (2JHaHb = 3JCHa-P ~ 14 Hz). 2. The protons of the 4-thiobenzyl moiety in compounds 7a-c are spatially distant from the P atom (no spinspin coupling with the phosphorus atom appears) and form two doublets of equal intensity in the 4.26-4.35 ppm region with 2JHaHb ~ 13.5 Hz. 3. The most unexpected feature was the appearance of nonequivalence of the cyclic methylene protons in the position 6, which formally are quite distant from the phosphorus atom. This nonequivalence is even observed for the seven-membered compound 7c and is ~0.1 ppm. For compounds 9b and 8, the nonequivalence of the 6-H protons is 0.04 ppm and 0.10 ppm respectively (two symmetric 1H multiplets each). For these compounds, the nonequivalence of the 4-SCH2Ph protons is = 0.06 ppm and 0.18 ppm respectively, while for the diamino derivative 12 that was isolated in pure form we have 6-CHa,CHb = 0.20 ppm (two symmetric 1H multiplets each that are far apart from each other). For this compound, we also observe nonequivalence for the methylene protons of the 4-SCH2Ph moiety (CH2 = 0.11 ppm). The observed nonequivalence of the 4-SCH2Ph and 6-CH2 protons undoubtedly is connected with the spatial structure of the studied systems. It has been shown [8] that when benzo-1,3,2-diazaphosphorin-4-thiones are converted to S,S-dialkyl derivatives, the heterocycle becomes markedly flatter.
H N H S P SH NH N P N SR' S SR'
In the case of the studied compounds, the transition of the heterocycle to a more planar structure also should lead to the substituent at the 4 position coming appreciably closer to the 6-CH2 group. In order to assess to what extent such flattening may affect the appearance of nonequivalence of the protons of this methylene _______ * The signals from the carbon atoms of the two phenyl rings were: 127.4, 127.6, 128.7 (2C), 128.8 (4C), 129.5 (2C), 137.4, 137.7 ppm. 109
group, we studied the spectra of compound 9a in DMSO in the presence of NaOD. This transition of the heterocyclic system to a flatter state, connected with formation of the anion, led to appreciable divergence of the signals for the 6-CHa and 6-CHb protons, and 6-CHa,CHb (before addition of the base, ~0.02 ppm) increased up to 0.1 ppm.
8
N N 9a
Hb Ha
7 6
SH P N N
+NaOD O N
S P N N
O Na+
SMe
SMe
Thus we can conclude that namely specifically spatial and conformational effects are responsible for the appreciable nonequivalence of the 4-SCH2R and 6-CH2 protons observed in the 1H NMR spectra of the studied compounds.
EXPERIMENTAL The NMR spectra were recorded on XL-200 and Unity 400+ (Varian) spectrometers (400 MHz for 13C, 163 MHz for 31P), internal standard TMS. The mass spectra were recorded on a MAT-112 (Varian) and an SSQ-710 (Finnigan) spectrometer with electron impact ionization energy 70 eV. The IR spectra were recorded on a Perkin-Elmer 599 spectrometer. The melting points were determined on a Boetius heating stage. Thin layer chromatography was run on Silufol UV-254 plates, methanol as the eluent, visualization in iodine vapors. 1-Carbamidomethyl-2-cyanoiminopiperidine (1b). A stream of dry ammonia was passed through suspension of 2-cyanoimino-1-ethoxycarbonylmethylpiperidine (2.1 g, 10 mmol) in methanol (30 ml) for 2 h at room temperature. Then the reaction mass was cooled down to 0-5C and the precipitate was filtered off. Yield 1.3 g (72%); mp 222-224C (EtOHwater, 5:1). Found, %: C 53.31; H 6.69: N 31.27. C18H12N4O. Calculated, %: C 53.31; H 6.71; N 31.09. Compound 1c was obtained similarly. Yield 79%; mp 215-217C (EtOHwater, 5:1). Found, %: C 55.79; H 7.48; N 28.66. C9H14N4O. Calculated, %: C 55.65; H 7.27; N 28.85. 7,8-Trimethylene-1H-imidazo[4,5-d]-1,3,2-diazaphosphorin-2-mercapto-2,4-dithione, Pyridine Solvate (2a). A. Dry pyridine (30 ml) was added slowly and carefully with stirring to carefully ground and stirred mixture of 1-carbamidomethyl-2-cyanoiminopyrrolidine 1a (10 g, 60 mmol) and phosphorus pentasulfide (20 g, 90 mmol). The mixture was heated and changed to an oil. After addition of pyridine, the mixture was boiled for 5 min and then washed with boiling benzene (2 100 ml); water (200 ml) was added and this was boiled for 2 min and then cooled down. The precipitate was filtered off and carefully washed with water and ethanol. Yield 12.4 g (63%)*; mp > 300C (DMFwater, 3:1). 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 2.50 (2H, m, 7-CH2); 2.84 (2H, t, 8-CH2); 4.30 (2H, t, 6-CH2); 9.30 (1H, br. d, 2J = 15.3, NH-P), and 9.38 (1H, br. s, NH); pyridine: 7.85 (2H, m, -H); 8.26 (1H, t, -H), 8.79 (2H, d, -H); SH does not appear; 13C NMR spectrum (DMSO-d6), , ppm (J, Hz): 24.1 (C(7)); 24.6 (C(8)); 49.8 (C(6)); 113.2 (C(4a)), d, 3J = 7.6, C(4a)P); 141.8 (C(9a)); 153.1 (C(8a)); 177.1 (C(4), d, 2J = 11.4, C(4)P). Mass spectrum: [M]+ 276, 243 [M+ - SH], 184 [M+ - SH, - CSNH2], 148 [M+ - SH, PS2], 123 [M+ - CSNHPS2], 95 (PS2+). _______ * Here and in other cases, to calculate the product yields we assumed that the average pyridine content in the solvates was 2/3 mol/liter of pyridine per 1 mol/liter of diazaphosphorin.
110
B. Dry pyridine (3 ml) was added slowly with stirring to mixture of 1,2-trimethylene-4-amino-5cyanoimidazole 5 (1.48 g, 10 mmol) and phosphorus pentasulfide (3.33 g, 15 mmol), then the procedure was continued as in Method A. Yield 1.02 g (31%). Homologs of Compound 2a were obtained similarly. Compound 2b. Yield 45%; mp > 300C (DMFwater, 3:1), [M]+ 374. Compound 2c. Yield 54%; mp > 300C (DMFwater, 3:1), [M]+ 388. 7,8-Trimethylene-2,4-dibenzylthio-1H-imidazo[4,5-d]-1,3,2-diazaphosphorin-2-thione (7a). Pyridine solvate 2a (1.65 g, 5 mmol) was dissolved in sodium ethoxide solution prepared from Na (0.28 g, 12 mmol) and ethanol (20 ml). Then benzyl chloride (1.5 ml, 12 mmol) was added; this was boiled for 5 min and then poured into cold water (40 ml). The mixture obtained was acidified with HCl down to pH 2-3, the precipitate was filtered off and then washed with water and ethanol. Yield 1.73 g (76%); mp 187-189C (DMFwater, 3:1). 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 2.49 (2H, m, 7-CH2); 2.78 (2H, t, 8-CH2); 4.07 (2H, t, 6-CH2); 3.77 (1H, t, 2JCHaCHb = 14.0, 3JCHa-P = 14.0, 2-CHaPh), and 3.85 (1H, t, 3JCHb-P = 14.0, 2-CHbPh); 4-CH2 protons: 4.30 (1H, d, 2JCHaCHb = 13.5, CHa) and 4.31 (1H, d, CHb); 10.26 (1H, d, 2J1NH-P = 8.5, 1-NH). 13C NMR spectrum (DMSO-d6), , ppm (J, Hz); 23.8 (C(7)); 25.0 (C(8)); 32.2 (C(4)SCH2, 4Javg = 1.8); 37.7 (PSCH2, 2Javg = 4.6); 46.9 (C(6)); 108.9 (C(4a), 4Javg = 33.0); 155.4 (C(9a)); 159.4 (C(8a)); 160.9 (C(4), 4Javg = 16.7), signals from the two phenyl rings are observed at 127.4 (1C), 127.6 (1C), 128.7 (2C), 128.8 (4C), 129.5 (2C), 137.4 (1C, 3Javg = 5.1), 137.7 (1C), mass spectrum: [M]+ 456, fragmentation: 333 [M+ - SCH2Ph], 301 [M+ - SCH2Ph, - S], 211 [M+ - SCH2Ph - SCH2Ph], 124 [HSCH2Ph+], 91 [CH2Ph+]. Found, %: C 55.00; H 4.65; N 12.25. C21H21N4PS3. Calculated, %: C 55.25; H 4.64; N 12.27. Compound 7b was obtained similarly. Yield 62%; mp 214-218C (DMFwater). [M]+ 470. 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 1.77, 1.90 (4H, m, 7-CH2, 8-CH2); 2.71 (2H, t, 9-CH2); 4.07 (2H, t, 6-CH2); 3.74, 3.83 (2H, t, 2JCHaCHb = 14.1, 3JCHa-P = 14.1, 3JCHb-P = 14.1, PCHaHb); 4.26, 4.35 (2H, d, 2JCHaCHb = 13.6, 4-CSCHaHb); 7.15-7.45 (10H, m, 2Ph); 10.16 (1H, d, 2JNH-P = 8.8, 1-NH). Found, %: C 55.73; H 5.07; N 11.95; S 19.98. C22H23N4PS3. Calculated, %: C 56.15; H 4.93; N 11.91; S 20.44. Compound 7c was obtained similarly. Yield 38%; mp 182-186C (DMFwater, 3:1), [M]+ 484. 1 H NMR spectrum (DMSO-d6), , ppm (J, Hz): 1.45-1.85 (6H, m, 7-, 8-, 9-CH2); 2.82 (2H, m, 10-CH2); 4.22, 4.32 (2H, m, 6-CH2); 3.79 (1H, t, 2JCHaCHb = 14.0, 3JCHa-P = 14.0, PSCHa); 3.88 (1H, br. t, 3JCHb-P = 14.4, P SCHb); 4.27, 4.35 (2H, d, 2JH-H = 13.6, 4-CSCH2Ph); 7.15-7.50 (10H, m, 2Ph); 10.20 (1H, d, 2J1-NH-P = 9.1, 1-NH). Found, %: C 56.72; H 5.14; N 11.50; S 19.68. C23H25N4PS3. Calculated, %: C 57.00; H 5.20; N 11.56; S 19.85. Compound 7d was obtained similarly. Yield 47%; mp 249-251C (DMF), [M]+ 304. 1H NMR spectrum (DMSO-d6, 90C), , ppm (J, Hz): 2.11 (3H, d, 3JMe-P = 15.7, PSMe); 2.51 (3H, s, 4-CSMe); 2.54 (2H, m, 7-CH2); 2.80 (2H, t, 8-CH2); 4.14 (2H, t, 6-CH2); ~10 (1H, br. s, 1-NH). Found, %: C 35.65; H 4.38; N 18.47; S 31.35. C9H13N4PS3. Calculated, %: C 35.52; H 4.31; N 18.41; S 31.61. 1-Methyl-7,8-trimethylene-2,4-dimethylthio-1H-imidazo[4,5-d]-1,3,2-diazaphosphorin-2-thione (8a). Pyridine solvate 2a (3.29 g, 10 mmol) was dissolved in aqueous (1 mol/l) solution of NaOH (80 ml). The solution obtained was washed twice with benzene and cooled down to 0-5C, and then dimethyl sulfate (5 ml) was added. The reaction mixture was stirred for 30 min, the precipitate was filtered off and washed with water and ethanol. Yield 1.96 g (62%); mp 144-147C (DMFwater, 3:1). [M]+ 318, fragments 271 [M+ - SCH3], 255 [M+ - PS], 239 [M+ - SCH3 - SCH3], 198 [M+ - N=CCH3 - CH3], 79 (PSCH3+), 63 (PS+). 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 1.99 (3H, d, 3JMe-P = 15.7, PSCH3); 2.52 (2H, m, 7-CH2); 2.52 (3H, s, 4-CSCH3); 2.83 (2H, t, 8-CH2); 3.22 (3H, d, 3JMe-P = 10.1, 1-NCH3), 4.16 (2H, m, 6-CH2). Found, %: C 37.65; H 4.94; N 17.46; S 30.12. C10H15N4PS3. Calculated, %: C 37.72; H 4.75; N 17.60; S 30.21. Compound 8b was obtained similarly. Yield 54%; mp 131-134C (DMFwater, 3:1). Found, %: C 43.13; H 6.24; N 15.54; S 26.77. C13H21N4PS3. Calculated, %: C 43.32; H 5.87; N 15.54; S 26.69.
111
Reaction of 7,8-Trimethylene-1H-imidazo[4,5-d]-1,3,2-diazaphosphorin-2-thiones with Amines. General Method. Mixture of diazaphosphorin 2a, 8a, or 7d (10 mmol) and 5-fold excess of the corresponding amine was boiled for 10-30 min. 2-Propanol (50 ml) was added, the mixture was boiled for 1 min and cooled down. The precipitate was filtered off and washed with 2-propanol and hexane. Compound 6. Yield 37%; mp 236-239C (decomp., DMFwater, 3:1), [M]+ 276. 1H NMR spectrum (DMS-d6), , ppm (J, Hz): 2.43 (2H, m, 7-CH2); 2.70 (2H, t, 8-CH2); 4.19 (2H, t, 6-CH2); 8.66 (2H, br. d, 2 JNH-P = 16.4, NH); 8.92 (1H, br. d, 2JNH-P = 13.6, NH); 4.05 (2H, s, CH2Ph); 7.43 (5H, m, Ph); 8.13 (2H, br. s, NH2). 13C NMR spectrum (DMSO-d6), , ppm (J, Hz): 23.9 (C(7)); 24.9 (C(8)); 47.1 (C(6)); 115.5 (C(4a), 3 JC4a-P = 6.8); 151.2 (C(9a)); 158.8 (C(8a)); 175.8 (C(4), 2JC4-P = 12.5); 42.7 (CH2Ph); 128.8, 129.0, 129.2, 134.3 (Ph). Found, %: C 43.85; H 4.80; N 18.17; S 25.50. C14H18N5PS3. Calculated, %: C 43.85; H 4.73; N 18.27; S 25.09. Compound 9a. Yield 74%; mp 243-246C (DMF), [M]+ 343. 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 2.44 (3H, s, 4-CSCH3); 2.50 (2H, m, 7-CH2); 2.76 (2H, t, 8-CH2); 3.10 (4H, m, 3JCH2-P = 8.3, ,'-N CH2); 3.52 (4H, t, ,'-OCH2); 4.10 (2H, m, 6-CH2); 9.36 (1H, d, 3JNH-P = 6.8, NH). Found, %: C 41.98; H 5.36; N 20.40; S 18.64. C12H18N5OPS2. Calculated, %: C 41.97; H 5.28; N 20.40; S 18.68. Compound 9b. Yield 36%; mp 240-242C (DMFwater, 3:1). 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 2.49 (2H, m, 7-CH2); 2.75 (2H, t, 8-CH2); 4.07 (2H, m, 6-CH2); 3.08 (4H, m, 3JCH2-P = 8.5, ,'-NCH2); 3.51 (4H, m, ,'-OCH2); 4.32 and 4.42 (2H, d, 2JCHaCHb = 13.6, SCH2); 9.45 (1H, d, 2J1-NH-P = 6.8, NH); 7.15-7.45 (5H, m, Ph). Found, %: C 51.23; H 5.32; N 16.69; S 15.52. C18H22N5OPS2. Calculated, %: C 51.54; H 5.29; N 16.70; S 15.29. Compound 10. Yield 46%; mp 194-197C (DMFwater, 2:1), [M]+ 357. 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 1.98 (3H, d, 2JMe-P = 14.9, PSMe); 2.47 (2H, m, 7-CH2); 2.83 (2H, t, 8-CH2); 3.15 (3H, d, 3JMe-P = 10.7, 1-NMe); 3.53 (4H, t, ,'-NCH2); 3.65 (4H, t, ,'-OCH2); 4.09 (2H, m, 6-CH2). 13 C NMR spectrum (DMSO-d6), , ppm (J, Hz): 23.7 (C(7)); 25.1 (C(8)); 31.7 (SCH2); 45.4 (2C, 2JNCH2-P ~ 1, NCH2); 46.8 (C(6)); 66.7 (2C, 3JOCH2-P = 6.4, OCH2); 108.3 (C(4a), 3JC4a-P = 23.9); 155.4 (C(9a)); 158.4 (C(4), 3 JC4-P = 10.9); 158.7 (C(8a)); aromatic carbon atoms of the SCH2Ph moiety give signals at 127.4 (1C), 128.7 (2C), 129.4 (2C), 138.3 (1C). Found, %: C 43.31; H 5.71; N 19.43; S 18.13. C13H20N5OPS2. Calculated, %: C 43.69; H 5.64; N 19.60; S 17.94. Compound 12. Yield 69%; mp 225-227C (DMFwater, 3:1). 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 2.48 (2H, m, 7-CH2); 2.71 (2H, t, 8-CH2), and 4.05 and 4.25 (two symmetric multiplets 1H each, 6-CH2, 2J6-CHa,6-CHb + 3J6-CH2,7-CH2 = 24); 8.55 (1H, d, NH, 2JNH-P = 6.0); 3.75 (Ha) and 3.83 (Hb) (two doublets 1H each, PNHCH2Ph, 2JCHaCHb = 14.3, 3JNH-CHa = 3JCHb-NH = 7.4); 5.11 (1H, m, JNH-P = 14.2); 4.46 (Ha) and 4.58 (Hb) (two q 1H each, 4-CNHCH2-Ph, 2JHaHb = 15.2, 3JNHCHb = 6.2); 7.12-7.36 (10H, m, 2Ph). 13C NMR spectrum (DMSO-d6), , ppm (J, Hz): 23.4 (C(7)); 25.1 (C(8)); 43.1 (C(4)NCH2Ph); 45.5 (PNHCH2Ph, 3J = 2.7); 46.0 (C(6)); 100.8 (C(4a), 3JC4b,P = 19.9); 151.1 (C(9a)); 155.6 (C(4), 2JC4,P = 4.4); 155.7 (C(8a)); 126.5, 126.8, 127.4 (C(4)); 128.1 (C(2)); 128.4 (C(2)); 140.2, 141.3 (3Javg = 6.2, 2Ph). Found, %: C 59.52; H 5.66; N 19.78; S 7.38. C21H23N6PS. Calculated, %: C 59.70; H 5.49; N 19.89; S 7.32.
REFERENCES 1. 2. 3. 4. 112 T. M. Bargar and C. M. Riley, Synth. Commun., 479 (1980). T. V. Stezhko, V. G. Granik, R. G. Glushkov, L. E. Roshchina, A. I. Polezhaeva, and M. D. Mashkovskii, Khim.-Farm. Zh., 290 (1984). T. A. Gudasheva, R. I. Ostrovskaya, F. V. Maksimova, A. V. Chupin, S. S. Trofimov, V. P. Lezina, T. A. Voronina, and A. P. Skoldinov, Khim.-Farm. Zh., 276 (1989). V. G. Granik, T. V. Golovko, R. G. Glushkov, M. D. Mashkovskii, L. E. Roshchina, A. I. Polezhaeva, R. B. Parimbetova, Yu. G. Bobkov, A. S. Losev, and I. A. Ivanova, Khim.-Farm. Zh., 1186 (1989).
5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.
A. V. Kadushkin, T. V. Golovko, V. G. Granik, R. G. Glushkov, R. B. Parimbetova, V. A. Parshin, and M. D. Mashkovskii, Khim.-Farm. Zh., 1193 (1989). D. B. Nilov, A. V. Kadushkin, V. G. Granik, N. P. Solov'eva, V. V. Asnina, R. B. Parimbetova, V. A. Parshin, and M. D. Mashkovskii, Khim.-Farm. Zh., No. 1, 35 (1993). W. Walter, T. Fleck, J. Voss, and M. Gerwin, Liebigs Ann. Chem., 275 (1975). R. M. Acheson, C. T. Lines, M. R. Bryce, Z. Dauter, C. D. Reynolds, and A. Schmidpeter, J. Chem. Soc., Perkin Trans. 2, 1913 (1985). K. Nagarajan, S. J. Shenoy, H. Fritz, O. Hosang, and W. J. Richter, Helv. Chim. Acta, 68, 900 (1985). B. R. Shinde, S. J. Shenoy, and N. R. Pai, Indian J. Chem., 29B, 711 (1990). R. Chen and J. Wang, Gaodeng Xuexiao Huaxue Xuebao, 923 (1992); Chem. Abstr., 118, 102089 (1992). D. B. Nilov, N. P. Solov'eva, I. S. Nikolaeva, V. V. Peters, L. Yu. Krylova, T. A. Gus'kova, and V. G. Granik, Khim.-Farm. Zh., No. 7, 16 (1998). D. B. Nilov, A. V. Kadushkin, N. P. Solov'eva, and V. G. Granik, Mendeleev Commun., 67 (1995). A. S. Fissyuk, M. A. Vorontsova, and D. V. Temnikov, Tetrahedron Lett., 37, 5203 (1996). V. G. Granik, A. V. Kadushkin, and J. Liebsher, Adv. Het. Chem., 72, 79 (1998). D. B. Nilov, A. V. Kadushkin, S. G. Kalistratov, A. S. Sokolova, I. S. Nikolaeva, V. V. Peters, L. Yu. Krylova, and V. G. Granik, Khim.-Farm. Zh., No. 9-10, 63 (1992). E. N. Dozorova, A. V. Kadushkin, G. A. Bogdanova, N. P. Solov'eva, and V. G. Granik, Khim. Geterotsikl. Soedin., 754 (1991). B. R. Shinde, S. J. Shenoy, and N. R. Pai, Indian J. Chem., 29B, 721 (1990).
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LETTERS TO THE EDITOR

SYNTHESIS OF LACTONE FROM ADAMANTANE-2-SPIRO-2'-OXIRANE
A. K. Shiryaev Keywords: lactone, adamantane-2-spiro-2'-oxirane. In the Bott reaction [1], alcohols, their esters and olefins are used as the sources of the carbenium ions reacting with 1,1-dichloroethylene. With the aim of determining the ability of compounds of other classes to react with 1,1-dichloroethylene, we have studied the reaction of the latter with adamantane-2-spiro-2'-oxirane (1) in concentrated sulfuric acid, as a result of which we obtained adamantane-2-spiro-2-tetrahydro-5'-furanone (2). Under the reaction conditions, obviously oxirane 1 cannot be rearranged to aldehyde, and alkene is added to the least substituted carbon atom of the heterocycle, which is probably connected with steric hindrances and participation of the protonated form of oxirane in the reaction. Steric hindrances can also explain the fact that lactone 2 formed does not react further with olefin. Along with lactone 2, a mixture is also formed of chlorinated derivatives of adamantane that is difficult to separate. In the 1H NMR spectrum of compound 2, we observe nonequivalence of the methylene groups of the heterocycle. This is probably connected with deviation of the methylene group adjacent to the adamantane moiety from the plane formed by the remaining four atoms of the heterocycle, which is typical of five-membered lactones and allows us to study, for example, their enantiomerism [2].
O +
1
CH2=CCl2
H2SO4
O O
2
Adamantane-2-spiro-2'-tetrahydro-5'-furanone. 1,1-Dichloroethylene (1 ml, 12 mmol) and then solution of adamantane-2-spiro-2'-oxirane [3] (2 g, 12 mmol) in 1,1-dichloroethylene (9 ml, 110 mmol), at a temperature no higher than 5C, were added dropwise with stirring to concentrated sulfuric acid (30 ml, 580 mmol) cooled down to 0C . The mixture was held with cooling for 1 h, poured onto ice, and neutralized with 20% solution of sodium hydroxide up to pH 5; then the products were extracted with hexane. After chromatographing on silica gel (hexane as the eluent) and crystallization from hexane, 0.71 g (28%) of product were isolated; mp 111-112C. IR spectrum (Shimadzu FTIR-8400S, KBr), , cm-1: 1761 (C=O), 1245 (CO),
__________________________________________________________________________________________ Samara State Technical University, Samara 443100, Russia; e-mail: orgchem@sstu.edu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 122-123, January, 2004. Original article submitted May 21, 2003; revision submitted July 8, 2003. 114 0009-3122/04/4001-01142004 Plenum Publishing Corporation
1206 (CO). 1H NMR spectrum (Tesla BS-567A, 100 MHz, CDCl3), , ppm (J, Hz): 1.6-2.0 (14H, m); 2.20 (1H, dd, J = 7.3 and J = 1.8); 2.29 (1H, dd, J = 9.2 and J = 3.0); 2.60 (1H, dd, J = 9.2 and J = 3.0); 2.69 (1H, dd, J = 7.3 and J = 1.8). Found, %: C 75.57; H 8.86. C13H18O2. Calculated, %: C 75.69; H 8.80.
REFERENCES 1. 2. 3. K. Bott, Angew. Chem., 77, 967 (1965). A. F. Beecham, Tetrahedron Lett., 32, 3591 (1968). A. K. Shiryaev and I. K. Moiseev, Zh. Obshch. Khim., 58, 1680 (1988).
115
CONVENIENT METHOD FOR SYNTHESIS OF 6-(N,N-DIETHYLAMINO)9-(2-CARBOXYPHENYL)-1,2,3,4-TETRAHYDROXANTHYLIUM PERCHLORATE

Ya. A. Prostota Keywords: tetrahydroxanthylium salts, cyclocondensation, polymethine dyes. Goal-directed search for new dyes absorbing in the near IR range of the spectrum is an important problem in polymethine dye chemistry [1]. A major method for solving this problem is to search for new heterocyclic rings for assembling polymethine dyes. Some 6-(N,N-dialkylamino)-1,2,3,4-tetrahydroxanthylium salts are used as starting materials for synthesis of fluorescent polymethine dyes absorbing in the near IR region [2]. Generally synthesis of such compounds is a multistep and labor-intensive process, while the yields of the target products are insignificant [2]. At the same time, derivatives of 6-(N,N-dialkylamino)-1,2,3,4-tetrahydroxanthylium derivatives substituted at the position 9 have not been described in the literature. With the aim of obtaining new derivatives of this heterocyclic system, we have studied cyclocondensation of the easily prepared 2-hydroxy-4-(N,N-diethylamino)-(2-carboxy)benzophenone (1) and cyclohexanone. We found that carrying out the reaction in concentrated H2SO4 makes it possible to obtain the target compound 2 in rather high yield, and the isolation and purification processes are significantly simplified. Benzophenone 1 is obtained from phthalic anhydride and 3-(N,N-diethylamino)phenol according to the procedure in [3]. The proposed synthesis method allows us to obtain compound 2 in good yield. Furthermore, this method is based on using accessible and inexpensive starting materials, which makes it promising for further application.
CO2H O N 1 OH
CO2H 1. H2SO4 / 2. 70% HClO4 N + O 2 _ ClO4
+
O
__________________________________________________________________________________________ Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev 02094; e-mail: yprostota@bpci.kiev.ua, yprostota@ukr.net. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 123-124, January, 2004. Original article submitted April 7, 2003; revised November 20, 2003. 116 0009-3122/04/4001-01162004 Plenum Publishing Corporation
Freshly distilled cyclohexanone (6.6 ml, 63.7 mmol) was added dropwise to concentrated H2SO4 (70 ml) cooled down to 0C. Then compound 1 (10 g, 32 mmol) was added in portions with vigorous stirring. The reaction mixture was held for 1-1.5 h at 90C, cooled down, and poured onto ice (300 g). 70% perchloric acid (7 ml) was added to the solution formed. The precipitate was filtered off, washed with cold water (100 ml), and recrystallized from acetic acid (25 ml). Yield 9.7 g (67%); mp 214-216C (decomp.). 1H NMR spectrum (Bruker AC-250, 250 MHz, acetone-d6/TMS), , ppm (J, Hz): 1.36 (6H, t, J = 7.14, NCH2CH3); 1.81 (2H, m, CH2); 2.0 (2H, m, CH2); 2.31 (2H, m, CH2); 3.2 (2H, m, CH2); 3.78-3.87 (4H, q, J = 7.14, NCH2CH3); 7.19-7.22 (1H, m, HPh); 7.26 (1H, s, 5-H); 7.39-7.46 (2H, m, HAr); 7.81-7.97 (3H, td, J = 7.6, J = 1.34, HPh); 8.35-8.38 (1H, d, J = 8.8, 7-H). Found, %: C 60.8; H 5.7; N 3.1. C24H26ClNO7. Calculated, %: C 60.6; H 5.5; N 2.9.
REFERENCES 1. 2. 3. J. Fabian, H. Nakazumi, and M. Matsuoka, Chem. Rev., 92, 1197 (1992). P. Czerney, U.-W. Grummt, and W. Gnther, J. Prakt. Chem., 340, 214 (1998). R. R. Sauers, S. N. Husain, A. P. Piechowski, and G. R. Bird, Dyes Pigm., 8, 35 (1987).
117
SPIRO-BISHETEROCYCLIZATION OF 5-METHOXYCARBONYL-2,3-DIHYDRO2,3-PYRROLEDIONES WHEN TREATED WITH ACTIVATED ENAMINES

Yu. N. Bannikova and A. N. Maslivets Keywords: activated enamines, 2,3-dihydro-2,3-pyrrolediones, indole-spiro-pyrroles. While continuing studies of recyclization and heterocyclization of 4-acyl-5-alkoxycarbonyl-1-aryl-2,3dihydro-2,3-pyrrolediones when treated with binucleophilic reagents (o-aminophenol and N-phenyl-ophenylenediamine [1], o-phenylenediamine [2], o-aminothiophenol [3], arylhydrazines [4, 5]), we studied a reaction that has been unknown for monocyclic 2,3-dihydro-2,3-pyrrolediones, the reaction of 1-aryl-4-aroyl-5methoxycarbonyl-2,3-dihydro-2,3-pyrrolediones 1, 2 with CH-, NH-binucleophiles: activated enamines (3-alkylamino-5,5-dimethyl-2-cyclohexen-1-ones 3, 4). When pyrrolediones 1, 2 are briefly refluxed (5-10 min) in absolute benzene with enamines 3, 4 (1:1), 1-alkyl-6,6-dimethyl-2,4-dioxo-2,3,4,5,6,7-hexahydro-1H-indole-3-spiro-2-(1-aryl-3-aroyl-4-hydroxy-5-oxo2,5-dihydro-1H-pyrroles) 5, 6 are formed in practically quantitative yields. The spectral characteristics of compounds 5, 6 are quite close to those of model compounds A, the structure of which has been confirmed by Xray diffraction data [6].
O Ar1CO MeOCO N Ar2 O O 1, 2 Alk O Ar2 N MeOH O OH O COAr1 5, 6 N Me Me O OH A Me Me Ar2 3, 4 NHAlk O OH OH O N O COAr1 N O COAr1 AlkHN MeOCO Me Me
H N
Me Me
1, 5 Ar1 = p-O2NC6H4; 2, 6 Ar1 = Ph; 1, 5 Ar2 = Ph; 2, 6 Ar2 = p-ClC6H4; 3, 5 Alk = CH2Ph; 4, 6 Alk = C6H11-c
__________________________________________________________________________________________ Perm State University, Perm 614990, Russia; e-mail: koh2@psu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 124-126, January, 2004. Original article submitted June 4, 2003. 118 0009-3122/04/4001-01182004 Plenum Publishing Corporation
Probably in the first step of the reaction, addition of enamines 3, 4 occurs with participation of their activated -CH group at the 5 position of pyrroledions 1, 2, as described for reactions of these pyrrolediones with binucleophiles in [1-5], followed by intramolecular closure of the pyrrole ring due to nucleophilic attack by the alkylamino group on the ester carbonyl group and cleavage of methanol. The described reaction is a very rare example of regioselective assembly of the previously not very accessible spiro-bisheterocyclic system indole spiro-pyrrole with goal-directed variable functional substituents in several positions of both heterocycles. 1-Benzyl-6,6-dimethyl-2,4-dioxo-2,3,4,5,6,7-hexahydro-1H-indole-3-spiro-2-(4-hydroxy-3-p-nitrobenzoyl-5-oxo-1-phenyl-2,5-dihydro-1H-pyrrole) (5). A solution of pyrroledione 1 [7] (5 mmol) and enamine (5 mmol) 3 in absolute benzene (2 ml) was refluxed for 10 min and then cooled down; after 24 hours, the precipitate was filtered out. Yield 95%; mp 254-256C (with decomposition, from ethylacetate). IR spectrum (vaseline oil), , cm-1: 3250 broad (OH), 1751, 1735 (C(2)=Oindole, C(5)=Opyrrole), 1671, 1631 (C(4)=Oindole, COPh). 1 H NMR spectrum (400 MHz, DMSO-d6, HMDS), , ppm (J, Hz): 0.64 (3H, s, CH3); 0.85 (3H, s, CH3); 2.07, 2.12 (2H, two d, J = 16.2, C(7)H2); 2.18, 2.57 (2H, two d, J = 18.6, C(5)H2); 4.81, 4.95 (2H, two d, J = 16.5, CH2Ph); 6.95-7.45 (10H, group of multiplets, 2Ph); 7.86, 8.35 (4H, two d, J = 8.9,C6H4NO2-p); 12.00 (1H, br. s, OH). Found, %: C 68.66; H 4.68; N 7.31. C33H27N3O7. Calculated, %: C 68.62; H 4.71; N 7.27. 1-Cyclohexyl-6,6-dimethyl-2,4-dioxo-2,3,4,5,6,7-hexahydro-1H-indole-3-spiro-2-(3-benzoyl-1-pchlorophenyl-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole) (6). Yield 95%; mp 251-252C (with decomposition, from ethyl acetate). IR spectrum (vaseline oil), , cm-1: 3210 broad (OH), 1745 (C(2)=Oindole, C(5)=Opyrrole), 1660 broad (C(4)=Oindole, COPh). 1H NMR spectrum (400 MHz, DMSO-d6, HMDS), , ppm: 0.63 (3H, s, CH3); 0.87 (3H, s, CH3); 1.34 (2H, m, CH2cyclohexyl); 1.64 (2H, m, CH2cyclohexyl); 1.81-2.05 (6H, m, 3CH2cyclohexyl); 1.94, 2.04 (2H, two d, J = 16.1, C(7)H2); 2.52, 2.60 (2H, two d, J = 18.1, C(5)H2); 3.75 (1H, m, CH); 7.00-7.65 (9H, group of multiplets, Ph+C6H4); 12.48 (1H, br. s, OH). Found, %: C 68.69; H 5.52; Cl 6.40; N 5.00. C32H31ClN2O5. Calculated, %: C 68.75; H 5.59; Cl 6.34; N 5.01. This work was done with the financial support of the Russian Foundation for Basic Research (grants No. 01-03-32641, No. 02-03-96411).
REFERENCES 1. 2. 3. 4. 5. 6. 7. A. N. Maslivets, L. I. Smirnova, and Yu. S. Andreichikov, Zh. Org. Khim., 2141 (1992). A. N. Maslivets, L. I. Smirnova, O. I. Ivanenko, and Yu. S. Andreichikov, Zh. Org. Khim., 31, 610 (1995). A. N. Maslivets, L. I. Smirnova, O. I. Ivanenko, and Yu. S. Andreichikov, Zh. Org. Khim., 31, 765 (1995). A. N. Maslivets, T. M. Popova, and Yu. S. Andreichikov, Khim. Geterotsikl. Soedin., 1566 (1991). Z. G. Aliev, A. N. Maslivets, T. M. Gorkovets, Yu. S. Andreichikov, and L. O. Atovmyan, Izv. Akad. Nauk, Ser. Khim., 610 (1999). I. V. Mashevskaya, I. A. Tolmacheva, O. Yu. Tiunova, Z. G. Aliev, and A. N. Maslivets, Khim. Geterotsikl. Soedin., 565 (2002). Yu. S. Andreichikov, A. N. Maslivets, L. I. Smirnova, O. P. Krasnykh, A. P. Kozlov, and L. A. Perevozchikov, Zh. Org. Khim., 23, 1534 (1987).
119
DERIVATIVES OF 3,4,5,6-TETRAHYDRO6a,10b-DIAZAINDENO[1,2,3-c,d]AZULENE
K. G. Nazarenko1, T. I. Shirokaya1, K. V. Shvidenko1, A. A. Tolmachev2, A. I. Tolmachev1, and A. Ya. Il'chenko1 Keywords: benzimidazole, benzimidazolium bromide, diazaazulene. The heterocyclic system 3,4,5,6-tetrahydro-6a,10b-diazaindeno[1,2,3-cd]azulene (1) is unknown. Derivatives of the similar systems pyrrolo[1,2-a]benzimidazole [1-4] and 5,6,7,8-tetrahydro-2a,4adiazacyclopenta[c,d]azulene [5, 6] have shown themselves to be physiologically active compounds and dyes. We have developed a method for obtaining derivatives of system 1 from 1,2-pentamethylenebenzimidazoles 2, described previously in [7], using the Chichibabin reaction to form the annelated pyrrole ring. The benzimidazoles 2a,b, when heated briefly with bromo ketones in toluene, yield the quaternary salts 3a-e; substituted 3,4,5,6-tetrahydro-6a,10b-diazaindeno[1,2,3-cd]azulenes 1a-d are formed from the salts 3a-d when they are boiled in dilute NaOH solution. The structure of salts 2 and products 1 was confirmed by the 1H NMR spectra.
N R1 R 2a,b
1 10 9 10a 10b 2 4 5
COR 2
6 7 8 9
BrCH2COR2 PhMe R1
3 2
N + N
NaOH H2O
R R2
10
3ae
_ Br
N N
6 5 3 4
R1
6a
R 1ad
2
1, 3 , b R = H, R1 = F; c, d, e R = R1 = F; , c R2 = Me; b, d R = C6H4OMe-p; e R2 = C6H4F-p, 2 a R = H, R1 = F, b R = R1 = F
2-Fluoro-5-(2-oxopropyl)-7,8,9,10-tetrahydro-6H-azepino[2,1-b]benzimidazolium bromide (3a). A mixture of compound 2a (2.3 g, 11.27 mmol) and bromoacetone (1.54 g, 11.27 mmol) was refluxed in toluene for 2 h. The mixture was cooled down and the precipitate was filtered out and washed with acetone. __________________________________________________________________________________________ Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev 02094; e-mail: shyrokaya@rambler.ru, shved@i.com.ua. 2 Scientific and Industrial Chemistry and Biology Center, Taras Shevchenko Kiev National University, Kiev 01033, Ukraine; e-mail: dov@fosfor.kiev.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 126-128, January, 2004. Original article submitted June 27, 2003. 120 0009-3122/04/4001-01202004 Plenum Publishing Corporation
1
Yield 2.65 g (69%); mp > 300C (ethanolDMF). 1H NMR spectrum (300 MHz, DMSO-d6, TMS), , ppm (J, Hz): 1.73 (2H, m, 7-CH2); 1.85 (2H, m, 8-CH2); 1.93 (2H, m, 9-CH2); 2.39 (3H, s, CH3); 3.29 (2H, m, 6-CH2); 4.65 (2H, m, 10-CH2); 5.83 (2H, s, CH2); 7.53 (1H, d, J = 9.0, 4-H); 8.10 (2H, d, 1-H and m, 3-H, overlapped). Found, %: F 5.71. C15H18FBrN2O. Calculated, %: F 5.57. Compounds 3b-d were obtained as for 3a. 2-Fluoro-5-[2-(4-methoxyphenyl)-2-oxoethyl]-7,8,9,10-tetrahydro-6H-azepino[2,1-b]benzimidazolium Bromide (3b). Yield 97%; mp 254C (ethanol). 1H NMR spectrum (300 MHz, DMSO-d6, TMS), , ppm (J, Hz): 1.78 (2H, m, 7-CH2); 1.92 (4H, m, 8-, 9-CH2); 3.27 (2H, m, 6-CH2); 3.05 (3H, s, OCH3); 4.71 (2H, m, 10-CH2); 6.45 (2H, s, CH2); 7.19 (2H, d, J = 9.0, 2'-, 6'-H); 7.52 (1H, dt, J1 = 2.7, J2 = 9.0, 4-H); 8.08 (1H, d, 1-H); 8.14 (2H, d, J = 9.3, 3'-, 5'-H); 8.14 (1H, m, 3-H). Found, %: Br 18.24. C21H22FBrN2O2. Calculated, %: Br 18.40. 1,2-Difluoro-5-(2-oxopropyl)-7,8,9,10-tetrahydro-6H-azepino[2,1-b]benzimidazolium Bromide (3c). Yield 78%; mp 264-266C (i-PrOH). 1H NMR spectrum (300 MHz, DMSO-d6, TMS), , ppm (J, Hz): 1.74 (2H, m, 7-CH2); 1.96 (4H, m, 8-, 9-CH2); 2.40 (3H, s, CH3); 3.33 (2H, m, 6-CH2); 4.73 (2H, m, 10-CH2); 5.88 (2H, s, CH2); 7.80 (1H, m, 3-H); 7.95 (1H, dd, J1 = 0.9, J2 = 9.0, 4-H). Found, %: F 10.41. C15H17BrF2N2O. Calculated, %: F 10.58. 1,2-Difluoro-5-[2-(4-methoxyphenyl)-2-oxoethyl]-7,8,9,10-tetrahydro-6H-azepino[2,1-b]benzimidazolium Bromide (3d). Yield 98%; mp 176C (ethanolhexane). 1H NMR spectrum (300 MHz, DMSO-d6, TMS), , ppm (J, Hz): 1.78 (2H, m, 7-CH2); 1.99 (4H, m, 8-, 9-CH2); 3.37 (2H, m, 6-CH2); 3.93 (3H, s, OCH3); 4.79 (2H, m, 10-CH2); 6.48 (2H, s, CH2); 7.19 (2H, d, J = 8.7, 2'-, 6'-H); 7.75 (1H, m, 3-H); 7.95 (1H, dd, J = 7.8, 4-H); 8.13 (2H, d, J = 8.7, 3', 5'-H). Found, %: Br 17.86. C21H21F2BrN2O2. Calculated, %: Br 17.67. 8-Fluoro-2-methyl-3,4,5,6-tetrahydro-6a,10b-diazabenzo[a]cyclopenta[c,d]azulene (1a). Compound 3a (1.5 g, 4.40 mmol) in a 10% NaOH solution (20 ml) was refluxed for 2 h. The mixture was cooled down and the precipitated solid oil was filtered out and washed with water and then dried. Yield 1 g (94%); mp 86-87C (i-PrOHhexane). 1H NMR spectrum (300 MHz, DMSO-d6, TMS), , ppm (J, Hz): 1.91 (2H, m, 4-CH2); 2.01 (2H, m, 5-CH2); 2.07 (3H, s, CH3; 2.50 (2H, m, 3-CH2); 3.85 (2H, m, 6-CH2); 6.77 (1H, t, J = 8.6, 10-H); 6.91 (1H, s, 1-H); 7.13 (1H, d, J = 10.5, 7-H); 7.47 (1H, m, 9-H). Found, %: F 7.92. C15H15FN2. Calculated, %: F 7.84. Compounds 1b-d were obtained as for 1a. 8-Fluoro-2-(4-methoxyphenyl)-3,4,5,6-tetrahydro-6a,10b-diazabenzo[a]cyclopenta[c,d]azulene (1b). Yield 91%; mp 126-127C (ethanol). 1H NMR spectrum (300 MHz, DMSO-d6, TMS), , ppm (J, Hz): 1.92 (2H, m, 4-CH2); 2.08 (2H, m, 5-CH2); 2.75 (2H, m, 3-CH2); 3.77 (3H, s, OCH3); 3.90 (2H, m, 6-CH2); 6.84 (1H, dt, J1 = 2.7, J2 = 9.0, 10-H); 6.96 (2H, d, J = 8.4, 2'-, 6'-H); 7.21 (1H, d, 7-H); 7.31 (1H, s, 1-H); 7.39 (2H, d, J = 8.7, 3'-, 5'-H); 7.61 (1H, m, 9-H). Found, %: F 5.89. C21H19FN2O. Calculated, %: F 5.68. 7,8-Difluoro-2-methyl-3,4,5,6-tetrahydro-6a,10b-diazabenzo[a]cyclopenta[c,d]azulene (1c). Yield 98%; mp 74-75C (hexane). 1H NMR spectrum (300 MHz, DMSO-d6, TMS), , ppm (J, Hz): 1.85 (2H, m, 4-CH2); 1.97 (2H, m, 5-CH2); 2.07 (3H, s, CH3); 2.52 (2H, m, 3-CH2); 4.02 (2H, m, 6-CH2); 6.90 (1H, s, 1-H); 6.98 (1H, m, 9-H); 7.28 (1H, dd, J1 = 3.8, J2 = 8.8, 10-H). Found, %: F 14.45. C15H14F2N2. Calculated, %: F 14.60. 7,8-Difluoro-2-(4-methoxyphenyl)-3,4,5,6-tetrahydro-6a,10b-diazabenzo[a]cyclopenta[c,d]azulene (1d). Yield 86%; mp 152-154C (ethyl acetate). 1H NMR spectrum (300 MHz, DMSO-d6, TMS), , ppm (J, Hz): 1.86 (2H, m, 4-CH2); 2.06 (2H, m, 5-CH2); 2.70 (2H, m, 3-CH2); 3.78 (3H, s, OCH3); 4.07 (2H, m, 6-CH2); 6.96 (2H, d, J = 12.9, 2'-, 6'-H); 7.04 (1H, m, 9-H); 7.30 (1H, s, 1-H); 7.37 (2H, d, J = 12.9, 3'-, 5'-H); 7.42 (1H, dd, J = 5.7, 10-H). Found, %: F 10.61. C21H18F2N2O. Calculated, %: F 10.78.
121
REFERENCES 1. 2. 3. 4. 5. 6. 7. P. M. Kochergin, A. A. Druzhinina, and R. M. Palei, Khim. Geterotsikl. Soedin., 149 (1966). F. S. Babichev and A. F. Babicheva, Khim. Geterotsikl. Soedin., 917 (1967). P. M. Kochergin, R. M. Palei, and S. A. Chernyak, Khim. Geterotsikl. Soedin., 659 (1993). V. A. Anisimova, A. A. Spasov, I. A. Bocharova, O. V. Ostrovskii, T. I. Panchenko, and G. P. Dudchenko, Khim.-Farm. Zh., No. 1, 22 (1996). V. A. Kovtunenko, K. G. Nazarenko, and A. M. Demchenko, Tetrahedron, 52, 9835 (1996). V. A. Kovtunenko, K. G. Nazarenko, and A. M. Demchenko, Khim. Geterotsikl. Soedin., 1072 (1996). K. G. Nazarenko, T. I. Shyrokaya, K. V. Shvidenko, and A. A. Tolmachev Synth. Commun., in press.
122
SYNTHESIS OF 1-(2-OXO-2-ARYLETHYL)3-ARYLCARBAMOYLPYRIDINIUM BROMIDES

A. R. Khairulin, V. A. Yanchenko, and A. M. Demchenko Keywords: imidazo[1,2-a]pyridinium bromide, nicotinamide, 3-arylcarbamoyl-1-(2-oxo-2-arylethyl)pyridinium bromide, quaternary salts. Pyridine derivatives have a broad spectrum of biological action and exhibit antitubercular [1], antimicrobial [2, 3], fungicidal, and pesticidal activity [4]. Since quaternary salts, obtained by alkylation of quinoline by substituted phenacyl bromides, when fused with a two-fold excess of aromatic amine followed by treatment with 45% hydrobromic acid yield the corresponding imidazo[1,2-a]quinolinium salts [5], we attempted to carry out the analogous reaction based on nicotinamide. We also hypothesized that the presence of an electron-acceptor substituent in the position 3 of the system would promote the reaction.
NH2 O + N _ Br O NH2 + N O _ Br O N H R1
+
R1
R 1a,b
NH2 R1 + N N _ Br R 2 O
3ac
1 a R = H, b R = Br; 3 a R = H, R1 = OMe, b R = H, c R = Br, R1 = OMe
We obtained the starting 1-phenacylnicotinamide bromides 1a,b by the method in [6]. Note that in the cited paper, the reaction product of nicotinamide and phenacyl bromide is assigned a structure corresponding to alkylation at the amide nitrogen atom. The 1H NMR spectroscopy data suggest that the reaction occurs at the __________________________________________________________________________________________ T. G. Shevchenko Chernigov State Pedagogical University, Chernigov 14038, Ukraine; e-mail: demch@cn.relc.com. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 128-130, January, 2004. Original article submitted December 3, 2002; revision submitted July 21, 2003. 0009-3122/04/4001-01232004 Plenum Publishing Corporation 123
ring nitrogen atom. Thus the methylene group of compound 1a appears as a two-proton singlet in the 6.59 ppm region, while the protons from the amide group appear as two broadened singlets at 8.19 ppm and 8.65 ppm respectively. If the structure indicated in [6] were realized, then the methylene group should appear in the 1 H NMR spectrum as a two-proton doublet, while the proton from the amide group should appear as a oneproton triplet. The melting point of the compound 1a that we obtained practically coincides with the literature value (222-223C for the sample we obtained, and 224C according to [6]). The 1H NMR spectra of the products of fusion of pyridinium salts 1 with anilines and also elemental analysis data indicate that instead of the proposed formation of imidazo[1,2-a]pyridinium salts 2, transamidation in the quaternary salt 1 occurs to a substituted aniline moiety, with formation of 3-arylcarbamoyl-1-(2-oxo-2arylethyl)pyridinium bromides 3. When nicotinamide was fused with substituted anilines, we did not observe the transamidation reaction. 3-(4-Methoxyphenylcarbamoyl)-1-(2-oxo-2-phenylethyl)pyridinium Bromide (3a). A mixture of of compound 1a (3.21 g, 0.01 mol), p-anisidine (2.46 g, 0.02 mol) and acetic acid (1 ml) was heated on an oil bath under reflux at a temperature of 150C for 3 h. After cooling, the reaction mixture was ground with 45% hydrobromic acid (20 ml) and poured into water. The crystallized precipitate was filtered out, washed with water until it tested neutral, and dried. Yield 2.22 g (52%); mp 215C (EtOHDMF). 1H NMR spectrum (300 MHz, DMSO-d6/TMS), , ppm (J, Hz): 3.77 (3H, s, OCH3); 6.61 (2H, s, COCH2); 7.01 and 7.71 (4H, two d, J = 8.7, C6H4); 7.65-8.08 (5H, m, C6H5); 8.47 (1H, m, 5-HPy); 9.23 (1H, d, J = 5.7, 6-HPy); 9.31 (1H, d, J = 8.4, 4-HPy); 9.65 (1H, s, 2-HPy); 10.9 (1H, s, NH). Found, %: Br 18.5; N 6.41. C21H19BrN2O3. Calculated, %: Br 18.7; N 6.56. 1-(2-Oxo-2-phenylethyl)-3-phenylcarbamoylpyridinium Bromide (3b) was obtained as for compound 3a from compound 1a (0.01 mol) and aniline (20 mmol). Yield 1.74 g (44%); mp 231C (EtOH DMF). 1H NMR spectrum (300 MHz, DMSO-d6/TMS), , ppm (J, Hz): 6.62 (2H, s, COCH2); 7.19-8.08 (10H, m, Ar); 8.46 (1H, m, 5-HPy); 9.19 (1H, d, J = 5.7, 6-HPy); 9.29 (1H, d, J = 8.1, 4-HPy); 9.64 (1H, s, 2-HPy); 11.0 (1H, s, NH). Found, %: Br 19.9; N 7.31. C20H17BrN2O2. Calculated, %: Br 20.1; N 7.05. 3-(4-Methoxyphenylcarbamoyl)-1-[2-oxo-2-(4-bromophenyl)ethyl]pyridinium Bromide (3c) was obtained as for compound 3a. Yield 2.33 g (46%); mp 250C (EtOHDMF). 1H NMR spectrum (300 MHz, DMSO-d6/TMS), , ppm (J, Hz): 3.77 (3H, s, OCH3); 6.60 (2H, s, COCH2); 6.97 and 7.70 (4H, two d, J = 8.4, C6H4); 7.88-8.04 (4H, two d, J = 8.7, C6H4); 8.44 (1H, m, 5-HPy); 9.18 (1H, d, J = 6.0, 6-HPy); 9.28 (1H, d, J = 7.8, 4-HPy); 9.63 (1H, s, 2-HPy); 10.9 (1H, s, NH). Found, %: Br 31.3; N 5.34. C21H18Br2N2O3. Calculated, %: Br 31.6; N 5.53.
REFERENCES 1. 2. 3. 4. D. Pancechowska-Ksepko, H. Foks, M. Janowiec, and Z. Zwolska-Kwiek, Acta Pol. Pharm., 50, (2-3), 259 (1993); Chem. Abstr., 121:108637 (1994). E. Wyrzykiewicz, W. Prukala, and B. Kedzia, Pol. PL 159736; Chem. Abstr. 122:132989 (1995). W. Prukala, E. Wyrzykiewicz, and B. Kedzia, Pol. PL 175323; Chem. Abstr. 130:311702 (1999). W. Grammenos, K. Oberdorf, H. Sauter, A. Gypser, H. Bayer, M. Gewehr, T. Grote, B. Muller, A. Ptock, F. Rohl, G. Hamprecht, N. Gotz, E. Ammermann, G. Lorenz, and S. Strathmann, PCT Int. Appl. WO 99 21833; Chem. Abstr. 130:311704 (1999). U. Habermalz, B. Reinshagen, and F. Kroehnke, Chem. Ber., 108, 984 (1975). J. Shukri and H. Satlar, J. Prakt. Chem., 33, 293 (1966).
5. 6.
124
SYNTHESIS OF A NOVEL HETEROCYCLIC SYSTEM: 7-METHYL-3-METHYLTHIO7,8-DIHYDRO[1,2,4]TRIAZOLO[3,4-f][1,2,4]TRIAZINE

L. Labanauskas, V. Bucinskaite, D. Bucyte, A. Brukstus Keywords: 7,8-dihydro[1,2,4]triazolo[3,4-f][1,2,4]triazine, 4-amino-3-chloromethyl-5-methylthio-4H1,2,4-triazole, 4-amino-3-methylaminomethyl-5-methylthio-4H-1,2,4-triazole, condensation. During a study of triazoles and related condensed heterocycles [1], we synthesized 7-methyl-3methylthio-7,8-dihydro[1,2,4]triazolo[3,4-f][1,2,4]triazine (5), which is a previously unknown heterocyclic system. The amino alcohol 2 obtained by methylation of thione 1 is converted to the chlorinated derivative 3, and then to the methylamino derivative 4. Compound 5 is obtained by condensation of the latter with ethyl orthoformate. In its IR spectrum, there were no vibrational bands for the amino groups, but in the 1H NMR spectrum we observed a signal from the methine proton at 7.11 ppm.
H N N HOCH2 N NH2 1 MeNH2 MeNHCH2 N N N NH2 4 SMe Me N S MeI HOCH2 N N N NH2 2 (EtO)3CH N N N N 5 SMe SMe SOCl2 ClCH2 N N N NH2 3 SMe
The IR spectra were obtained on an FT-IR Spectrum BX II (Perkin-Elmer) spectrophotometer in nujol, while the NMR spectra were obtained on a Tesla BS-587A (80 MHz) in DMSO-d6, internal standard TMS. 4-Amino-5-methylthio-4H-1,2,4-triazol-3-ylmethanol (2). Sodium (0.5 g, 22 mmol) and then thione 1 (3 g, 21 mmol) [1] and iodomethane (1.3 ml, 22 mmol) were dissolved in methanol (50 ml). The mixture was boiled for 1.5 h, neutralized with acetic acid, and evaporated to dryness. The residue was triturated with hot toluene (20 ml), the toluene was decanted off and then it was cooled. The precipitate was recrystallized from 2-propanol and we obtained 1.2 g (37%) of compound 2; mp 135-138C. IR spectrum, , cm-1: 3378, 3290 (NH2), 3083 (OH). 1H NMR spectrum, , ppm: 2.58 (3H, s, SCH3); 4.56 (2H, s, CH2); 5.42 (1H, s, OH); 5.86 (2H, s, NH2). Found, %: C 30.28; H 4.91; N 34.88. C4H8N4OS. Calculated, %: C 29.99; H 5.03; N 34.97. __________________________________________________________________________________________ Vilnius University, Organic Chemistry Department, Vilnius 2006, Lithuania; e-mail: linas.labanauskas@chf.vu.lt. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 130-131, January, 2004. Original article submitted October 13, 2003. 0009-3122/04/4001-01252004 Plenum Publishing Corporation 125
4-Amino-3-chloromethyl-5-methylthio-4H-1,2,4-triazole (3). A solution of compound 2 (0.15 g, 0.94 mmol) in thionyl chloride (10 ml) was held for 30 min at 20C and evaporated down under vacuum without heating. The dry residue was recrystallized from 2-propanol and we obtained 0.1 g (60%) of compound 3; mp 130-133C. IR spectrum, , cm-1: 3303, 3126 (NH2). 1H NMR spectrum, , ppm: 2.68 (3H, s, SCH3); 4.82 (2H, s, CH2); 7.88 (2H, br. s, NH2). Found, %: C 26.48; H 4.21; N 31.58. C4H7ClN4S. Calculated, %: C 26.89; H 3.95; N 31.36. 4-Amino-3-methylaminomethyl-5-methylthio-4H-1,2,4-triazole (4). A solution of 4-amino3-chloromethyl-5-methylthio-4H-1,2,4-triazole 3 (0.8 g, 4.5 mmol) and methylamine (0.42 g, 13.5 mmol) in methanol (30 ml) was boiled for 1.5 h; the solvent was evaporated off under vacuum, and a crude oily product 4 was obtained. A chloroform solution of compound 4 was washed with water. IR spectrum, , cm-1: 3365, 3318, 3220 (NH, NH2). 1H NMR spectrum, , ppm: 2.70 (3H, s, SCH3); 3.98 (2H, s, CH2); 4.22 (2H, s, NH2). 7-Methyl-3-methylthio-7,8-dihydro[1,2,4]triazolo[3,4-f][1,2,4]triazine (5). Unpurified compound 4 from the previous reaction and ethyl orthoformate (5 ml) were heated for 1 h at a temperature of 130C, cooled down, filtered, and recrystallized from 2-propanol. Obtained 0.75 g (75% relative to compound 3) of compound 5; mp 234-235C. 1H NMR spectrum, , ppm: 2.67 (3H, s, SCH3); 3.08 (3H, s, NCH3); 4.66 (2H, s, CH2); 7.11 (1H, s, CH). Found, %: C 39.28; H 5.26; N 38.35. C6H9N5S. Calculated, %: C 39.33; H 4.95; N 38.22.
REFERENCES 1. 2. L. Labanauskas, V. Buchinskaite, V. Bucinskaite, A. Brukstus, and G. Urbalis, Khim. Geterotsikl. Soedin., 948 (2003). W. L. Albrecht and D. W. Jones, US Patent 4230715; Chem. Abstr. 94:121552f (1981).
126
SYNTHESIS OF 1,6-POLYMETHYLENE PYRIMIDINES BASED ON 4-(1-AZACYCLOALKYLIDENE)-1,3-OXAZOL-5-ONES

K. G. Nazarenko1, K. V. Shvidenko1, and A. A. Tolmachev2 Keywords: enamine, isothiocyanate, 1,6-polymethylene pyrimidine. We propose a novel method for obtaining derivatives of 1,6-polymethylene pyrimidines, which are intermediates in synthesis of some alkaloids [1]. The method is based on reaction of 4-(2-azacycloalkylidene)1,3-oxazol-5-ones 1a,b with isothiocyanates in DMF in the presence of sodium hydride. We hypothesize that during the reaction, the anion formed from compound 1 is added to the isothiocyanate molecule, which is followed by recyclization, leading to the 4-oxo-2-thioxo-5-benzoylamino-1,6-polymethylene pyrimidine derivatives 2a-d. The structure of compounds 2a-d has been proven based on the 1H and 13C NMR spectra and elemental analysis data. Enamines that are structurally similar to 1, containing an ester and a nitrile group in the -position, react with heterocumulenes, yielding 1,6-polymethylene pyrimidine derivatives.
(CH2)n N O 1a,b (CH2)n N _ O (CH2)n N S N R 2ad 1 a n = 1, b n = 3; 2 a n = 1, R = Ph, b n = 1, R = 2-methylpropen-2-yl, c n = 3, R = Ph, d n = 3, R = Me H N O O N Ph S N R Ph (CH2)n N _ O N O Ph H2O N Ph 1. NaH 2. RNCS
__________________________________________________________________________________________ Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev 02094; e-mail: shved@i.com.ua. 2 ChemBio Center at Taras Shevchenko Kiev National University, Kiev 01033, Ukraine. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 132-133, January, 2004. Original article submitted May 20, 2003. 0009-3122/04/4001-01272004 Plenum Publishing Corporation 127
1
General Procedure for Obtaining Compounds 2a-d. Sodium hydride (12 mmol, 60% suspension in mineral oil) was added to a solution of the appropriate oxazolone [2, 3] (10 mmol) in dry DMF. The mixture was stirred at room temperature for 30 min, the appropriate isothiocyanate was added (10 mmol), and the mixture was stirred for another 8 h. Water was added, the mixture was stirred for 1 h, and the precipitate formed was filtered out. N-(3-Oxo-2-phenyl-1-thioxo-1,2,3,5,6,7-hexahydropyrrolo[1,2-c]pyrimidin-4-yl)benzamide (2a). Yield 36%; mp 243-245C (i-PrOHEtOH). 1H NMR spectrum (DMSO-d6, 300 MHz), , ppm (J, Hz): 2.15-2.25 (2H, m, 6-CH2); 3.14 (2H, t, J = 7.8, 5-CH2); 4.33 (2H, t, J = 7.8, 7-CH2); 7.14-7.17 (2H, m, arom.); 7.38-7.59 (6H, m, arom.); 7.96-7.99 (2H, m, arom.); 9.74 (1H, s, NH). 13C NMR spectrum (DMSO-d6, 75 MHz), , ppm: 20.21 (6-C), 31.14 (5-C), 56.61 (7-C), 111.86 (4-C), 128.32, 128.39, 129.20, 129.03, 129.85, 132.45, 133.96, 140.28, 154.48, 159.59 (CO), 165.77 (NHCOPh), 174.38 (CS). Found, %: C 66.43; N 11.23. C20H17N3O2S. Calculated, %: C 66.10; N 11.56. N-[2-(2-Methylpropen-2-yl)-3-oxo-1-thioxo-1,2,3,5,6,7-hexahydropyrrolo[1,2-c]-pyrimidin-4-yl]benzamide (2b). Yield 42%; mp 202-204C (i-PrOHEtOH). 1H NMR spectrum (DMSO-d6, 300 MHz), , ppm (J, Hz): 1.76 (3H, s, CH3); 2.10-2.21 (2H, m, 6-CH2); 3.07 (2H, t, J = 7.3, 5-CH2); 4.33 (2H, t, J = 7.3, 7-CH2); 4.51 (1H, s, CH2=C); 4.75 (1H, s, CH2=C); 4.89 (2H, s, NCH2); 7.46-7.59 (3H, m, arom.); 7.95 (2H, d, J = 7.1, arom.); 9.68 (1H, s, NH). Found, %: C 63.65; N 12.17. C18H19N3O2S. Calculated, %: C 63.32; N 12.31. N-(3-Oxo-2-phenyl-1-thioxo-1,2,3,5,6,7,8,9-octahydropyrimido[1,6-a]azepin-4-yl)benzamide (2c). Yield 63%; mp 236-238C (EtOH). 1H NMR spectrum (DMSO-d6, 300 MHz), , ppm (J, Hz): 1.79 (6H, m, 6-, 7-, 8-CH2); 2.98 (2H, m, 5-CH2); 4.87 (2H, m, 9-CH2); 7.11 (2H, d, J = 7.7, arom.); 7.34-7.57 (6H, m, arom.); 7.94 (2H, d, J = 7.7, arom.); 9.65 (1H, s, NH). Found, %: C 67.34; N 10.43. C22H21N3O2S. Calculated, %: C 67.50; N 10.73. N-(2-Methyl-3-oxo-1-thioxo-1,2,3,5,6,7,8,9-octahydropyrimido[1,6-a]azepin-4-yl)benzamide (2d). Yield 62%; mp 179-181C (EtOAcheptane). 1H NMR spectrum (DMSO-d6, 300 MHz), , ppm (J, Hz): 1.74 (6H, m, 6-, 7-, 8-CH2); 2.91 (2H, m, 5-CH2); 3.68 (3H, s, NCH3); 4.88 (2H, m, 9-CH2); 7.46-7.59 (3H, m, arom.); 7.95 (2H, d, J = 6.9, arom.); 9.60 (1H, s, NH). 13C NMR spectrum (DMSO-d6, 75 MHz), , ppm: 24.85 (6-C), 25.76 (7-C), 26.73 (8-C), 27.62 (5-C), 35.36 (NCH3), 52.27 (9-C), 112.25, 127.15, 127.81, 131.24, 132.93, 155.11, 157.13 (CO), 165.78 (NHCOPh), 176.10 (CS). Found, %: C 61.64; N 12.95. C17H19N3O2S. Calculated, %: C 61.98; N 12.76.
REFERENCES 1. 2. 3. H. Taguchi, H. Yazawa, J. F. Arnett, and Y. Kishi, Tetrahedron Lett., 6, 627 (1977). R. G. Glushkov and O. Yu. Magidson, Zh. Obshch. Khim., 30, 1855 (1960). D. Cook and A. Lawson, J. Chem. Soc., Perkin Trans. 1, 465 (1973).
128
CARBON DISULFIDE IN SYNTHESIS OF THIAZOLO[3,4-a]QUINOXALINES BASED ON 3-(-CHLOROBENZYL)QUINOXALIN-2-(1H)-ONES

A. A. Kalinin and V. A. Mamedov Keywords: xanthogenates, carbon disulfide, thiazolo[3,4-a]quinoxalines, quinoxalines, thiazoles. A widely used method for obtaining thiazole derivatives is the CookHeilbron synthesis [1], in which CS and CCN moieties are used to construct the ring in condensation of carbon disulfide with -amino nitriles and -amino amides, leading to 5-aminothiazole derivatives that are either unsubstituted or substituted in the position 4. We have found that 3-(-chlorobenzyl)quinoxalin-2-(1H)-ones 1 [2], because of the -chlorobenzylimine moieties which function as a triatomic synthon C+CN, when reacted with hydrogen disulfide yield condensed thiazole derivatives: thiazolo[3,4-a]quinoxalines 2, 3. Since the reactions are carried out in the presence of KOH in methanol solution, formation of a thiazoloquinoxaline system probably occurs via xanthogenates 4, which then undergo intramolecular cyclocondensation. In order to confirm this hypothesis, we synthesized the xanthogenates 4a,b and showed that they can undergo ring closure to form thiazolo[3,4-a]quinoxalines under conditions of not only base catalysis but also acid catalysis, and the latter variant is preferred. Depending on both the reaction conditions and the nature of the aryl group of the substituent at the position 3, 1-thioxo (2) or 1-oxo (3) derivatives of thiazolo[3,4-a]quinoxalines are formed. The best yields of thiazolo[3,4-a]quinoxalines are achieved when the reactions are carried out in CF3COOH; in this case, boiling solutions of xanthogenates 4a,b in CF3COOH for two hours leads exclusively to 1-oxothiazolo[3,4-a]quinoxalines 3a,b, while boiling for half an hour makes it possible, when Ar = Ph, to obtain the 1-thioxo
X Ar N N H O MeOH, KOH, CS2 N N H 4a,b O H+ S S OMe Cl MeOH, KOH, CS2, , 7 h N N O H 2 (X = S) 3 (X = O) S Ar
Ar
4 a Ar = Ph, b Ar = 2,4-Cl2C6H3
__________________________________________________________________________________________ A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Science Center, Russian Academy of Sciences, Kazan 420088; e-mail: mamedov@iopc.kcn.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 133-135, January, 2004. Original article submitted July 23, 2003. 0009-3122/04/4001-01292004 Plenum Publishing Corporation 129
derivative 2a. We do not get good results if instead of CF3COOH we use AcOH or 6.1 M HCl, in which thiocyanate and diphenylisothioureide analogs of compound 4a readily undergo intramolecular cyclization to form 1-iminothiazoloquinoxalines [3]: we can obtain thiazoloquinoxaline 2a only if we boil xanthogenate 4a for 4 h. In the 1H NMR spectrum of thiazoloquinoxalines 2, 3, there is a diagnostic doublet signal [3-5] from the H(9) proton of the azolo[a]quinoxalines, which resonates downfield (8.8-10.5 ppm), in contrast to other protons of the aromatic rings. 3-Phenyl-1-thioxothiazolo[3,4-a]quinoxalin-4(5H)-one (2a). A. KOH (0.20 g, 3.6 mmol) and CS2 (0.9 ml) were dissolved in methyl alcohol (10 ml). Quinoxaline 1a (0.40 g, 1.5 mmol) was added to the solution and it was boiled for 7 h. The precipitated crystals were filtered out and washed with methanol. Yield 30 mg (6.5%). B. A solution of compound 4a (0.60 g, 1.8 mmol) in AcOH (10 ml) was boiled for 4 h and allowed to stand overnight. The precipitated crystals were filtered out and washed with 2-propanol. Yield 60 mg (11%). C. A solution of compound 4a (0.30 g, 0.9 mmol) in CF3COOH (5 ml) was boiled for 40 min and allowed to stand overnight. The precipitated crystals were filtered out and washed with 2-propanol. Yield 0.11 g (40%); mp 300-302C. IR spectrum (vaseline oil), , cm-1: 689, 738, 1075, 1130, 1165, 1224, 1398, 1489, 1606, 1687, 2500-3220. 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 7.13-7.63 (8H, m, C6H5, H(6-8)); 10.48 (H, d, J = 8.33, H(9)); 11.55 (1H, br. s, NH). Found, %: C 61.85; H 3.07; N 9.18; S 20.84. C16H10N2OS2. Calculated, %: C 61.91; H 3.25; N 9.03; S 20.66. 3-Phenylthiazolo[3,4-a]quinoxaline-1,4(5H)-dione (3a). A solution of compound 4a (0.30 g, 0.9 mmol) in CF3COOH (5 ml) was boiled for 2 h. The precipitated crystals was filtered out and washed with 2-propanol. Yield 0.11 g (40.5%); mp 313-315C (AcOH). The characteristics of 3a match those described in [3]. 3-(2,4-Dichlorophenyl)thiazolo[3,4-a]quinoxaline-1,4(5H)-dione (3b). Obtained as for tricycle 3a from quinoxaline 4b. Yield 41%; mp >360C (DMSO). IR spectrum (vaseline oil), , cm-1: 478, 587, 756, 814, 842, 878, 1097, 1226, 1317, 1435, 1496, 1578, 1633, 1689, 2500-3220. 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 7.16-7.24 (2H, m, H(6) or H(7), H(8)); 7.31 (1H, dd, J = 8.04, J = 6.68, H(6) or H(7)); 7.51 (1H, dd, J = 8.70, J = 2.00, H(5) in C6H3Cl2); 7.59 (1H, d, J = 8.70, H(6)); 7.73 (1H, d, J = 2.00, H(3) in C6H3Cl2); 8.83 (1H, d, J = 8.04, H(9)); 11.28 (1H, br. s, NH). Found, %: C 52.99; H 2.38; N 7.63; S 8.69; Cl 19.32. C16H8Cl2N2O2S. Calculated, %: C 52.91; H 2.22; N 7.71; S 8.83; Cl 19.52. 3-(-Methoxythiocarbonylthiobenzyl)quinoxalin-2(1H)-one (4a). KOH (0.40 g, 7.1 mmol) and CS2 (1.0 ml) were dissolved in methyl alcohol (30 ml) and then the mixture was stirred for 0.5 h. Quinoxaline 1a (1.00 g, 3.7 mmol) was added to the solution and it was stirred for 4 h and allowed to standard overnight. The crystals were filtered out and washed with 2-propanol. Yield 1.13 g (90%); mp 165-167C (i-PrOH). IR spectrum (vaseline oil), , cm-1: 698, 755, 1075, 1101, 1280, 1492, 1560, 1612, 1663, 2500-3220. 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 4.14 (3H, s, CH3); 6.63 (1H, s, PhCH); 7.25-7.38 (5H, m); 7.55-7.65 (3H, m); 7.84 (1H, d, J = 8.20, H(5)), 12.45 (1H, br. s, NH). Found, %: C 59.47; H 4.21; N 8.25; S 18.74. C17H14N2O2S2. Calculated, %: C 59.63; H 4.12; N 8.18; S 18.72. 3-(-Methoxythiocarbonylthio-2,4-dichlorobenzyl)quinoxalin-2(1H)-one (4b). Obtained as for compound 4a from quinoxaline 1b. Yield 89%; mp 217-219C (acetone). IR spectrum (vaseline oil), , cm-1: 469, 577, 749, 855, 891, 946, 1058, 1100, 1235, 1432, 1559, 1612, 1660, 2500-3220. 1H (DMSO-d6) NMR spectrum, , ppm (J, Hz): 4.14 (3H, s, CH3); 6.93 (1H, s, ArCH); 7.28-7.39 (2H, m); 7.42 (1H, dd, J = 8.58, J = 2.38, H(5) in C6H3Cl2); 7.52-7.62 (2H, m); 7.68 (1H, d, J = 2.38, H(3) in C6H3Cl2); 7.78 (1H, dd, J = 8.10, J = 0.95, H(8)); 12.64 (1H, br. s, NH). Found, %: C 49.68; H 2.88; N 6.67; S 15.97; Cl 17.32. C17H12Cl2N2O2S2. Calculated, %: C 49.64; H 2.94; N 6.81; S 15.59; Cl 17.24. This work was done with the financial support of the Russian Foundation for Basic Research (grant No. 03-03-32865). 130
REFERENCES 1. 2. 3. 4. 5. C. Roussel, in: Thiazole and Its Derivatives (J. V. Metzger, ed.), Wiley, New York (1979), Pt. 2, p. 393. V. A. Mamedov, I. A. Nuretdinov, and F. G. Sibgatullina, Izv. Akad. Nauk, Ser. Khim., 1412 (1988). V. A. Mamedov, A. A. Kalinin, A. T. Gubaidullin, I. A. Litvinov, and Ya. A. Levin, Khim. Geterotsikl. Soedin., 1664 (1999). V. A. Mamedov, A. A. Kalinin, I. Kh. Rizvanov, N. M. Azancheev, Yu. Ya. Efremov, and Ya. A. Levin, Khim. Geterotsikl. Soedin., 1279 (2002). G. W. H. Cheeseman and B. Tuck, J. Chem. Soc. (C), 13, 1164 (1967).
ERRATUM The authors of the article "1H and 13C NMR Spectra of 9H-Pyrimido[4,5-b]indoles", Vol. 39, No. 10, pp. 1348-1354, are V. P. Borovik, M. M. Shakirov, and O. P. Shkurko. The paper was presented of and on behalf of N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry. 131
SYNTHESIS, STRUCTURE, AND CHEMICAL PROPERTIES OF N-SUBSTITUTED 2(3)-IMINO2,3-DIHYDROFURAN-3(2)-ONES. (REVIEW)

V. V. Zalesov and A. E. Rubtsov Published data on the synthesis, structure, and chemical properties of N-substituted 2(3)-imino-2,3dihydrofuran-3(2)-ones to 2002 are reviewed. Keywords: 2,3-diimino-2,3-dihydrofurans, N-substituted 2-imino-2H-furan-3-ones, 3-imino-3H-furan2-ones, spectral characteristics, chemical transformations. Data on the synthesis of a furan ring containing carbonyl and imine functions respectively at positions 2 and 3 of the heterocycle were first published a hundred years ago and concerned the synthesis of 2-hydroxyimino-2H-benzo[b]furan-3-one [1]. Limited but very varied material on the synthesis and chemical transformations of the imino derivatives of furan has now appeared. This review is devoted to methods for the synthesis of N-substituted 2-imino-2H-furan-3-ones (A), 3-imino-3H-furan-2-ones (B), and the 2,3-diimino derivatives of 2,3-dihydrofuran (C).
O O A N O B N O O C N N
It includes the imino derivatives of 2,3-dihydrofurandione itself and also the imino derivatives of its condensed benzo[b], phenanthro[9,10-b], and other analogs.
1. METHODS FOR THE SYNTHESIS OF N-SUBSTITUTED 2(3)-IMINO-2(3)H-FURAN-3(2)-ONES AND 2,3-DIIMINO-2,3-DIHYDROFURANS Methods for the production of N-substituted imino derivatives of furan can be divided into two groups, i.e., methods based on the introduction of an imino function into an already existing furan ring and methods involving the construction of a furan ring with an R-imino group at position 2 or 3.
__________________________________________________________________________________________ Perm State University, Perm, Russia; e-mail: Alekhsandr.Rubtsov@psu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 163-186, February, 2004. Original article submitted March 3, 2003. 0009-3122/04/4002-01332004 Plenum Publishing Corporation 133
1.1. Syntheses Based on the Furan Heterocycle Chronologically, the first were papers on the synthesis of the 2-oximes of 2H-benzo[b]furan-3-ones 2a-c [1-4]. The 2-oximes were prepared by the reaction of coumaran-3-ones 1a-c, containing an activated methylene group, with nitrous acid.
R
1
O NaNO2 / AcOH R
2
O O 2ac N OH
O 1ac
1, 2 a R1 = H, R2 = H, b R1 = Me, R2 = H; c R1 = R2 = Br
2-Oximes unsubstituted in the aromatic ring (2a) [1], 5-methyl-substituted (2b) [2, 3], and 5,7-dibromine-substituted (2c) oximes [4] of 2H-benzo[b]furan-3-one derivatives were obtained in a similar way. 2-(4-Dimethylaminophenylimino)-2H-benzo[b]furan-3-one (3a) was obtained by the reaction of coumaran-3-one (1a) with 4-nitroso-N,N-dimethylaniline [5].
O
+
O 1a
O N
NMe2
EtOH / NaOH O N NMe2
O 3a
In 1972 2-phenylimino-2H-benzo[b]furan-3-one (3b) was obtained with a yield of 36% by the analogous reaction of coumaran-3-one (1a) with nitrosobenzene [6]. The activated methylene group of the coumaran-3-ones 1d,e takes part in a coupling reaction with benzenediazonium chloride leading to the formation of 5-methyl-2-phenylhydrazono-2H-benzo[b]furan-3-one (4a) [7] and 6-methoxy-2-phenylhydrazono-5-chloro-2H-benzo[b]furan-3-one (4b) [8] respectively.
R R
2 1
O O 1d,e
R PhN2 Cl
+
O Ph O 4a,b N N H
4 a R1 = Me, R2 = H; b R1 = Cl, R2 = MeO
More recently the reaction was used for the introduction of a hydrazone function at position 3 of the furan ring and the synthesis of 3-arylhydrazono-5-phenyl-3H-furan-2-ones 5 [9].
134
N NHAr
O
ArN2 Cl
5
The 5-aryl-2,3-dihydrofuran-2,3-diones 6a-e can be used as basic heterocycle for the synthesis of the 2-imino derivatives of furan-3-ones. Thus, reaction of the furandiones 6 with N-phenyltriphenylphosphine imine or the triphenylphosphoranylidenehydrazones of aldehydes and ketones (triphenylphosphazines) gave 5-aryl-2phenylimino-2H-furan-3-ones 7a-e [10, 11] and substituted 5-aryl-2-methylenehydrazono-2H-furan-3-ones 8a-v [12-15] respectively.
O Ph3P=NPh Ph3PO O p-R1C6H4 O O 6ae p-R1C6H4 O N Ph
7ac (8393%) O Ph3P=NN=CR2R3 Ph3PO p-R1C6H4 O N N R2 R3
8av (2487%)
6 a R1 = H, b R1 = Me, c R1 = MeO, d R1 = Cl, e R1 = Br; 7 a R1 = Me, b R1 = Cl, c R1 = Br; 8 a R1 = Me, R2 = R3 = H; b R1 = Cl, R2 = R3 = H; c R1 = Br, R2 = R3 = H; d R1 = Me, R2 = R3 = Ph; 1 e R = Cl, R2 = R3 = Ph; f R1 = Br, R2 = R3 = Ph; g R1 = Me, R2 = H, R3 = PhCO; h R1 = MeO, R2 = H, R3 = PhCO; i R1 = Cl, R2 = H, R3 = PhCO; j R1 = Br, R2 = H, R3 = PhCO; k R1 = Cl, R2 = H, R3 = PhCH2O; l R1 = Br, R2 = H, R3 = PhCH2O; m R1 = Me, R2 = H, R3 = PhCH2O; n R1 = MeO, R2 = H, R3 = PhCH2O; o R1 = Br, R2 = H, R3 = PhCH2O; p R1 = Me, 2 R = H, R3 = 1-AdCO; q R1 = Cl, R2 = H, R3 = 1-AdCO; r R1 = H, R2 = H, R3 = EtOCO; s R1 = Me, R2 = H, R3 = EtOCO; t R1 = MeO, R2 = H, R3 = EtOCO; u R1 = Cl, R2 = H, R3 = EtOCO; v R1 = Br, R2 = H, R3 = EtOCO
The formation of the 2-iminofuran-3-ones 7 and 8 by the Wittig and Staudinger types of reaction is distinguished by the fact that in the presence of a ketone carbonyl the reaction takes place at the lactone carbonyl group of the heterocycle. The authors explain such a direction of attack by the phosphine imine and triphenylphosphazines in terms of the electron density distribution in the 2,3-dioxo heterocycle. The direction of reaction of triphenylphosphazines with furandiones is the same if the hydrogen atom at position 4 of the heterocycle is replaced by a chlorine or bromine atom [16].
1.2. Construction of a Furan Ring with the R-Imino Function Preparative methods have now been developed for the construction of all three types of structures under discussion: A, B, and C. 1.2.1 Synthesis of N-Substituted 2-Imino-2H-furan-3-ones A. Iminofurans of this type are synthesized by the reaction of acylketenes with isonitriles. The various methods differ in the processes used to generate the acylketenes. Thus, in [17] the acylketenes were generated during the thermolysis of 2-diazo-1,3-diketones, and they then formed the N-substituted 2-imino-4-R1-5-R1-2H-furan-3-ones 9a-l with the isonitriles. It should be mentioned that only symmetrical diazodiketones were used. The yields of the iminofuranones 9
135
amounted to 40-96% and evidently depended both on the activity of the diene and dienophile in the [4+1] cycloaddition and on the rate of formation and the stability of the acylketenes during their formation under the conditions of a thermolytic Wolff rearrangement.
O 100C/ 0.51 h N2 O
1 2 1
1
R R
R R
C O
R R NC R
1 2
O O N R
2
Xylene ( N2)
9al (4096%)
2 1 2
9 a R = R = Ph; b R = 4-MeOC6H4, R = Ph; c R = Ph, R = 2,6-Xyl; d R1 = 4-MeOC6H4, R2 = 2,6-Xyl; e R1 = 4-ClC6H4, R2 = 2,6-Xyl; f R1 = Ph, R2 = TosCH2; 1 g R = 4-MeOC6H4, R2 = 2,6-Xyl; h R1 = 4-MeOC6H4, R2 = cyclo-C6H11; i R1 = 4-ClC6H4, R2 = cyclo-C6H11; j R1 = Ph, R2 = cyclo-C6H11; k R1+R1 = biphenyl-2,2'-diyl, R2 = 2,6-Xyl; l R1 = cyclo-C6H11, R2 = 2,6-Xyl
Under somewhat milder conditions, during the thermolysis of furandiones 6a,b,d,e in solution (carbon tetrachloride, benzene, carbon tetrachlorideoctane, etc.), aroylketenes are generated. They then react with phenyl-, tert-butyl-, tosylmethyl, and 1-adamantylisonitriles, forming N-phenyl (7a), N-tert-butyl (10a-d), N-tosylmethyl (10e-h), and N-(1-adamantyl) (10i-l) derivatives of 5-aryl-2-imino-2H-furan-3-ones [11, 18, 19].
O C 6a,b,d,e ~ 80 C CO p-R1C6H4 O R NC p-R1C6H4 O N R
2 2
7a (40%), 10al (5898%) 10 a R1 = H, R2 = t-Bu; b R1 = Me, R2 = t-Bu; c R1 = Cl, R2 = t-Bu; d R1 = Br, R2 = t-Bu; e R1 = H, R2 = TosCH2; f R1 = Me, R2 = TosCH2; g R1 = Cl, R2 = TosCH2; h R1 = Br, R2 = TosCH2; i R1 = H, R2 = Ad; j R1 = Me, R2 = Ad; k R1 = Cl, R2 = Ad; l R1 = Br, R2 = Ad
In [19] it was also shown that 2-(1-adamantylimino)-5-aryl-4-bromo-2H-furan-3-ones 10m,n are formed during the thermolysis of 5-aryl-4-bromo-2,3-dihydrofuran-2,3-diones in the presence of 1-adamantyl isocyanide (1 h, xylene).
Br Ar O O O Br Ar C O O AdNC Br Ar O O N Ad
Xylene CO
10m,n (50, 39%) 10 m Ar = Ph; n Ar = 4-ClC6H4
1.2.2. Synthesis of N-Substituted 3-Imino-3H-furan-2-ones B. This heterocycle is constructed by intramolecular cyclization of the 2-imino derivatives of o-hydroxyphenylglyoxalic acid [6, 7, 20-25] or the 2-imino derivatives of 4-R-2,4-dioxobutyric acids [26-29]. Thus, the synthesis of 2-phenylhydrazono-3Hbenzo[b]furan-2-one (12a), 5-methyl-3-phenylhydrazono-3H-benzo[b]furan-2-one (12b) [7], and 3-benzoylphenylhydrazono-5-methyl 3H-benzo[b]furan-2-one (12c) [7] by intramolecular cyclization of the respective 2-imino derivatives of o-hydroxyphenylglyoxalic acid 11a-c was described in [7, 21]. 136
Ph R R
1 2
N OH O OH H2O
R N N O O
Ph
11ac
12ac 12a (67%) [21]
11, 12 a R1 = R2 = H; b R1 = Me, R2 = H; c R1 = Me, R2 = PhCO
There are a series of papers [6, 21-24] on the synthesis and chemical transformations of 3-semicarbazido- and 3-thiosemicarbazido-3H-benzo[b]furan-2-ones 12d [21] and 12e [21-24]. The imino derivatives of acids 11d,e undergo cyclization when boiled in glacial acetic acid [21] and concentrated hydrochloric acid [22-24] respectively. An attempt at the synthesis of compound 12e by the direct reaction of benzo[b]furan-2,3-dione with thiosemicarbazide in an aqueous medium led mainly to the formation of the acid 11e [25].
X H2N N N H O OH N N H O O 12d,e 12 d (40%); e (87%) X OH NH2
HCl (MeCOOH) H2O
11d,e
11, 12 d X = O; e X = S
Intramolecular cyclization of the 2-imino derivatives of 4-R-2,4-dioxobutyric acids takes place spontaneously [26] on heating or under the influence of dehydrating agents [27-29]. Thus, when heated with arylamines (60C) pyrrolyl pyruvates form the enamino ketones 13a-e, which with stronger heating undergo cyclization to 3-arylimino-5-(1-R-aryl-3-hydroxy-2-oxo-2,5-dihydropyrrol-4-yl)-3H-furan-2-ones 14a-e [26].
OEt O O H NAr 2 HO O O Ar
1 2
OEt O N HO O H .. O. Ar
1
Ar
N Ar HO EtOH O N R 14ae (2958%) O 1 Ar O
H2O
N R
R 13be (8797%)
13, 14 a Ar1 = Ar2 = Ph, R = Me; b Ar1 = Ar2 = R = Ph; c Ar1 = 4-BrC6H4, Ar2 = R = Ph; d Ar1 = 4-O2NC6H4, Ar2 = R = Ph; e Ar1 = Ar2 = R = 4-BrC6H4
The authors were unable to isolate compound 13a since it undergoes cyclization to the iminofuranone 14a even at 20C [26]. The 2-arylamino 15a-c, 2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-ylamino) 15d-h, and 2-diphenylmethylenehydrazino 15i-m derivatives of 4-aryl-4-oxobut-2-enoic acids are more stable. 137
p-R1C6H4 O H N
O N OH R2 (MeCO)2O H 2O p-R1C6H4 O O R2
15am
16am (4590%)
15, 16 a R1 = Me, R2 = Ph; b R1 = Me, R2 = 4-ClC6H4; c R1 = H, R2 = 1-naphthyl; d R1 = H, R2 = 4-Ant; e R1 = Me, R2 = 4-Ant; f R1 = MeO, R2 = 4-Ant; g R1 = Cl, R2 = 4-Ant; h R1 = Br, R2 = 4-Ant; i R1 = H, R2 = Ph2C=N; j R1 = Me, R2 = Ph2C=N; k R1 = MeO, R2 = Ph2C=N; l R1 = Cl, R2 = Ph2C=N, m R1 = Br, R2 = Ph2C=N, Ant = 4-antipyryl
Compounds 15a-m undergo cyclization smoothly to 5-aryl-3-R-imino-3H-furan-2-ones 16a-m when heated in acetic anhydride [27-29]. Under the influence of triethylamine the acylmethyl esters of 2-arylhydrazono-2-cyanoacetic acids undergo cyclization to 4-amino-3-arylhydrazono-5-acyl-3H-furan-2-ones 17a-c [30].
NC R O O N O NHAr NEt3 DMF R H2N O N NHAr O
O 17ac (2542%)
17 a R = Ph, Ar = o-Tol; b R = Ph, Ar = 2-naphthyl; c R = Me, Ar = o-Tol
1.2.3. Synthesis of 2,3-Diimino Derivatives of 2,3-Dihydrofurans C. The reaction of isonitriles with -acylketene imines leads to the formation of the 2,3-diimino derivatives of 4,5-disubstituted 2,3-dihydrofurans 18a-k [31].
R1 C O I1 N R2 R R O N N R1 R2
N R R C
R1 CNR2 R R
18ak (3695%)
18 a R1 = 4-Tol, R2 = 2,6-Xyl, R = Ph; b R1 = 4-Tol, R2 = 2,6-Xyl, R = 4-MeOC6H4; c R1 = 4-Tol, R2 = R = Ph; d R1 = 4-Tol, R2 = Ph, R = 4-MeOC6H4; e R1 = 4-Tol, R2 = cyclo-C6H11, R = Ph; f R1 = 4-Tol, R2 = 2,6-Xyl, R = 4-ClC6H4; g R1 = 4-Tol, R2 = 2,6-Xyl, R+R = biphenyl-2,2'-diyl; h R1 = 4-Tol, R+R = biphenyl-2,2'-diyl, R2 = cyclo-C6H11; i R1 = 4-Tol, R+R = biphenyl-2,2'-diyl, R2 = Ph; j R1 = 4-Tol, R+R = biphenyl-2,2'-diyl, R2 = 2-Py; k R+R = biphenyl-2,2'-diyl, R1 = R2 = 2,6-Xyl
4,5,N(2),N(3)-tetraaryl-2,3-dihydro-2,3-furan diimines 18a-f and N(2),N(3)-diarylphenanthro[9,10-b]furan2,3-diimines 18g-k were prepared by this method with yields of 36-95% [31]. 3-Arylhydrazono-2-ethoxycarbonylimino-2,3-dihydrobenzo[b]furans 19a-c were synthesized by the diazotization of 2-ethoxycarbonyliminobenzo[b]furan [32].
138
O O N OEt
ArNH2/NaNO2/HCl O
NNHAr O N OEt
19ac (5780%) 19 a Ar = 2-NCC6H4; b Ar = 3-MeC6H4; c Ar = 1-naphthyl
In addition, the synthesis of 3-thiosemicarbazido-2-phenylimino-2,3-dihydrobenzo[b]furan 19d was described in [6] but was based on the reaction of iminofuranone 3b itself with thiosemicarbazone.
2. THE SPECTRAL CHARACTERISTICS OF IMINOFURANONES The IR spectra of the N-substituted 2-imino-2H-furan-3-ones A are characterized by the presence of an absorption band for the C(3)=O group in the region of 1690-1738 cm-1, the position of which in the spectrum depends on the character of the substituents at the imine nitrogen atom and at positions 4 and 5 of the heterocycle. Thus, the absorption band of the C(3)=O carbonyl group is present in the IR spectra at 1732 cm-1 in iminofuranone 3b [6], at 1710-1729 cm-1 in the iminofuranones 7a-c [10, 11], at 1710-1728 cm-1 in compounds 8a-v [14, 15], and at 1690-1705 cm-1 in compounds 10m,n [19]. The authors of [19] consider that the strong absorption band in the region of 1690-1705 cm-1 is due to the superimposition of the stretching vibrations of the C(3)=O and C=N bonds. In the IR spectra of compounds 9a-l the authors record the presence of a split band in the region of 1700 cm-1 but do not give its assignment [17]. The 1H NMR spectra of compounds of this type are individual in nature, and it is only possible to single out a large group of iminofuranones 7a-c, 8a-v, and 10a,n not containing a substituent at position 4 of the heterocycle. The singlet of the methine proton in the 1H NMR spectra is observed at 5.98-6.91 ppm (in carbon tetrachloride, deuterochloroform, DMSO-d6) [10, 11, 14, 15, 19]. In the 13C NMR spectrum of the iminofuranone 9b (deuterochloroform) the singlet of the C(3)=O carbon atom appears at 172.30 ppm [17]. The mass spectra of the iminofurans contain a molecular ion peak and peaks for the fragment ions [M - RNC]+ and [R - NCO]+ [11, 17]. The lactone carbonyl of N-substituted 3-imino-3H-furan-2-ones (B) gives a wide range of absorption in the IR spectra. Thus, the band for the stretching vibrations of the C(2)=O group is observed in the IR spectra of the iminofurans at 1774 cm-1 (DMSO) for 12d [21], at 1769 cm-1 for (12l) [21, 22], at 1775-1790 cm-1 for 14a-e [26], at 1773-1820 cm-1 for 16a-m [27-29], and at 1720-1740 cm-1 for 17a-c [30]. Quantum-chemical calculations in the CNDO/2 approximation were carried out for the iminofuranone 10a. According to the results, the most electron-deficient atoms in the molecule are the C(5), C(3), and C(2) carbon atoms, which provide targets for attack by nucleophilic reagents [33].
3. THE CHEMICAL PROPERTIES OF IMINOFURANONES The presence of several carbon atoms similar in electronegativity in the structure of iminofuranones provides several directions for their reactions with nucleophilic reagents. Iminofuranones are characterized by ring opening, recyclization, and a series of reactions taking place with participation of the C=N bonds and also functional groups.
139
3.1. Ring Opening Reactions of Iminofuranones Ring opening in iminofuranones takes place as a result of their hydrolysis and aminolysis. 3.1.1. Hydrolysis of Iminofuranones. Iminofuranones differ substantially in their stability in the hydrolysis process, depending on the type of structure A, B, and C and on the nature of the substituents. 2-Iminofuranones A are fairly inert toward water, but most of them are slowly hydrolyzed during storage. Thus, the iminofuranones 3a,b form the anilide and 4-dimethylaminoanilide respectively of o-hydroxyphenylglyoxalic acid during storage [6, 20, 21]. Acid hydrolysis (dioxanewater, catalytic amounts of HCl, 20-25C) of the iminofuranones 7a-c, 10e-l, and 8g-i gave the respective amides 20a-k [11, 18, 19, 34] and substituted hydrazides 21a-c [12-15] of 4-aryl-2hydroxy-4-oxo-Z-but-2-enoic acids.
O(S) p-R1C6H4 O..
.H
NHR O
O p-R1C6H4 N R
2
H2O, H (H2S)
20ak (6482 %) O N N H Ph
7ae, 8gi, 10el p-R1C6H4 O..

.H
21ac (6585 %)
20 a R = Me, R = Ph; b R = Cl, R = Ph; c R = Br, R = Ph; d R = H; R2 = TosCH2; e R1 = Me, R2 = TosCH2; f R1 = Cl, R2 = TosCH2; g R1 = Br, R2 = TosCH2; h R1 = H, R2 = Ad; i R1 = Me, 2 R = Ad; j R1 = Cl, R2 = Ad; k R1 = Br, R2 = Ad. 21 a R1 = Me; b R1 = MeO; c R1 = Cl
1 2 1 2 1 2 1
Under the influence of gaseous hydrogen sulfide the 2-iminofuranones 10i-l form the N-(1-adamantyl)amides of 4-aryl-2-hydroxy-4-oxobut-3-enoic thioacids 20h-k [35]. The iminofuranones 10m,n behave differently under these conditions and undergo strong dissociation to chloro-p-R1-acetophenones and 1-aminoadamantane hydrobromide [19].
Br
O
N Ad O 10m,n
H2O/HCl AdNH2 . HBr
p-R1C6H4COCH2Cl
p-R1C6H4
The dehydration of the acids 11a-c and 15a-n, leading to the formation of the 3-iminofuranones 12a-c and 16a-m, is reversible, and the products are easily hydrolyzed to the initial 2-imino derivatives of the acids [21-23, 27-29].
11, 15 H2O H2O 12, 16
During acid hydrolysis of the 2-iminofuranones 9c,e, having substituents at position 4 of the heterocycle, and 2,3-diiminofuranones 18b,f,g,i only recyclization products are formed [17, 35] (see section 3.2). 140
3.1.2. Ring Opening of Iminofuranones under the Influence of NH- and SH-Nucleophiles. There are examples of ring opening under the influence of ammonia and primary and secondary amines for all types of iminofuranones [11, 17, 33, 35-39]. The 2-iminofuranones 9c,e with ammonia and cyclohexylamine [17], the 2-iminofuranones 10a-d,g with benzylamine and piperidine [11, 33, 37], and the iminofuranones 8d-f with aniline and benzylamine [33, 38, 39] form the respective amides 22a-c [17] and 22d-j [11, 33, 37] and hydrazides 22k-m [33, 38, 39] of N-substituted 4-amino-4-aryl-2-oxo-3-R2-but-3-enoic acids. Under the influence of arylamines the 3-iminofuranones 16d undergo decyclization with the formation of the arylamides of 2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1Hpyrazol-4-ylamino)-4-oxo-4-phenylbut-2-enoic acid 23a-d [29]. The diiminofuran 18a reacts with cyclohexylamine and p-toluidine with the formation of the 2,6-dimethylanilides of N-substituted 4-amino-3,4diphenyl-2-(4-methylphenylamino)but-3-enoic acids 24a,b [37].
R R
1 2
O N R
3
N R Ph O
Ph Ph
NTol-p N R
1
O
16d
O
18a
9c,e, 10ad,g, 8df
R4R5NH
ArNH2
R2NH2
O R R
2
NHR O NHR R
4 5
NHAr NHR
1
O Ph Ph
NHR1 NTol-p NHR2

Ph R NH
2
NHR
NTol-p
Ph
Ph
22ac (7190%) 22dj (6075%)

Compound 22a 22b 22c 22d 22e 22f 22g 22i 22j 22k 22l 22m
23ad (6493%)
24a,b (55, 32%)
R1 Ph Ph 4-ClC6H4 Ph 4-ClC6H4 4-ClC6H4 Ph o-Tol 4-BrC6H4 o-Tol 4-ClC6H4 4-BrC6H4
R2 Ph Ph 4-ClC6H4 H H H H H H H H H
R3 2,6-Xyl 2,6-Xyl 2,6-Xyl t-Bu t-Bu TosCH2 t-Bu t-Bu t-Bu Ph2C=N Ph2C=N Ph2C=N
R4 H H H H H H
R5 H cyclo-C5H9 cyclo-C5H9 PhCH2 PhCH2 PhCH2 (CH2)5 (CH2)5 (CH2)5 Ph Ph Ph
H H H
23a R1 = 4-Ant, Ar = Ph; b R1 = 4-Ant, Ar = 4-HOC6H4; c R1 = 4-Ant, Ar = 4-MeOC6H4; d R1 = 4-Ant, Ar = 4-ClC6H4; 24 a R1 = 2,6-Xyl, R2 = cyclo-C6H11; b R1 = 2,6-Xyl, R2 = o-Tol
141
In the case of the iminofuranones A and C attack by the amine is directed at the C(5) carbon atom of the heterocycle, and this agrees fully with the quantum-chemical calculations [33].
O p-R1C6H4 O N R
2
O PhSH p-R1C6H4 PhS 25 O NHR

2
25 R2 = Ad, TosCH2
Like the amines, thiophenol attacks the C(5) atom of the iminofuranones 10e-l with the formation of the N-substituted amides of 4-aryl-4-arylthio-2-oxo-3-butenoic acids 25 [33, 40].
3.2. The Recyclization of Iminofuranones 3.2.1. Recyclization as a Result of Hydrolysis and Aminolysis. Catalytic acid hydrolysis of the iminofuranones 9c,e and diiminofuranones 18b,f leads to the formation of 1,4,5-triaryl-2,3-dihydro-2,3pyrrolediones 26a-c [17, 36].
R R O R O 9c,e NXyl -2,6 H /H2O H2O (H2NTol-p) 26ac (4789%)
+
O O Me
R Me
R R
NTol-p NXyl -2,6
O 18b,f
26 a R = Ph; b R = 4-ClC6H4; c R = 4-MeOC6H4
The pyrroledione 26b is obtained with almost identical yields from the iminofuranone 9e and the diiminofuranone 18f respectively. The recyclization of compounds 9c,e and 18b,f probably includes opening of the ring to the corresponding amides of carboxylic acids, which under the reaction conditions undergo intramolecular cyclization to derivatives of pyrroledione. Under the influence of hydroxylamine hydrochloride the diiminofuranone 18b rearranges to the 3-oxime of 1-(2,6-dimethylphenyl)-4,5-bis(4-methoxyphenyl)-2,3-dihydropyrrole-2,3-dione 27 [36].
p-MeOC6H4 18b H2NOH p-MeOC6H4 Me N NOH O Me
27 (49%)
3.2.2. Recyclization under the Influence of Hydrazines. The recyclization of iminofuranones under the influence of hydrazine and substituted hydrazines has been studied more comprehensively. 142
O R
1
O NHR
2
R H2O R1
NHR N
3
R R R
1 1
O N NH2 R
3
H2NNHR
2
I2 O R
1 3
R 28ac (7479%) R H2O R

1 1
N R O 9ad, fh, j
N NHR O NHR I3
2
O N R 29aj
2
NNHR
Compound
28a 28b 28c 29a 29b 29c 29d 29e 29f 29g 29h 29i 29j
R1 Ph 4-MeOC6H4 4-MeOC6H4 Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph
R2 2,6-Xyl 2,6-Xyl TosCH2 cyclo-C6H11 cyclo-C6H11 cyclo-C6H11 TosCH2 Ph 2,6-Xyl cyclo-C6H11 Ph 2,6-Xyl cyclo-C6H11
R3 H Me Me Ph PhCO PhNHCO PhCO Tos 2,4-(O2N)2C6H3 PhCO Tos PhCO Ph
Thus, the 2-iminofuranones 9c,d,g undergo recyclization under the influence of hydrazine and methylhydrazine to the N-substituted amides of 3-pyrazolecarboxylic acids 28a-c, while the 2-iminofuranones 9a-d,f,h,j in reactions with aryl- and acylhydrazines form the 1,4,5-trisubstituted 2-hydrazono-2H-pyrrol-3-ones 29a-j [17]. The authors consider that the formation of the pyrazole derivatives 28a-c includes attack by the amino group of the hydrazine or by the secondary amino group of the methylhydrazine at the C(5) carbon atom of the heterocycle, opening of the iminofuranone ring, and intramolecular cyclization of the intermediately formed amide (intermediate I2) on account of the primary amino group and the -carbonyl group C(2)=O. The iminofuranones 10 react similarly with hydrazine [34]. On the other hand, the opening of the ring in the iminofuranones 9a-d,f,h,i by the action of aryl- and acylhydrazines takes place as a result of attack by their primary amino group at the C(2) carbon atom of the heterocycle with the formation of the amidrazone I3 as intermediate, which then undergoes cyclization to the pyrrolone derivative 29 [17]. The reaction of 9j with N-methyl-N-phenylhydrazine leads to 4,5-diphenyl-2-(N-methyl-N-phenylhydrazono)-1-cyclohexyl-2H-pyrrol2-one 29j with a yield of 5% [17]. According to data in [40], the intermediate amidrazones of the I3 type were isolated as a result of cleavage of the 2-(1-adamantylimino)-5-aryl-4-bromo-2H-furan-3-ones by the action of 2,4-dinitrophenylhydrazine and underwent cyclization to derivatives of 2-hydrazonopyrrol-3-ones 29 on heating. Recyclization by the action of substituted hydrazines is also characteristic of 3-iminofuran-2-ones. Thus, the iminofuranones 16d-h react with alkyl- and arylhydrazines to form 6-aryl-4-(1,5-dimethyl-3-oxo-2-phenyl2,3-dihydro-1H-pyrazol-4-ylimino)-1,4-dihydro-2H-pyridazin-3-ones 30a-n and 4-[5-aryl-1-(2,4-dinitrophenylamino)-2-oxo-1,2-dihydropyrrol-3-ylideneamino]-1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-ones 31a-e [27, 41, 42]. 143
N Ant O Ant O R NHNHR Ar O

1 2
N Ar
N R O. . N .H Ant I4
2
H N
Ar R
1
N
1
R 30an (2492%) N Ant Ar O

1
O 16dh
H2O
R2 = H
H N R 31ae (4961%)
Compound 30a 30b 30c 30d 30e 30f 30g 30i 30j 30k 30l 30m 30n 31a 31b 31c 31d 31e R1 Me Me Me Me Me Et Et Et Et Ph 2,4-(NO2)2C6H3 2,4-(NO2)2C6H3 Ph 2,4-(NO2)2C6H3 2,4-(NO2)2C6H3 2,4-(NO2)2C6H3 2,4-(NO2)2C6H3 2,4-(NO2)2C6H3 R2 H H H H H H H H H H H H Ph H H H H H Ar Ph o-Tol 4-MeOC6H4 4-ClC6H4 4-BrC6H4 Ph 4-MeOC6H4 4-ClC6H4 4-BrC6H4 Ph 4-MeC6H4 4-MeOC6H4 Ph Ph o-Tol 4-MeOC6H4 4-ClC6H4 4-BrC6H4
Ring opening in the iminofuranones 16d-h probably takes place as a result of attack by the amino group of the hydrazine at the C(2) carbon atom of the heterocycle with the formation of the intermediate hydrazide of but-2-enoic acid I4, which undergoes intramolecular cyclization to a derivative of pyridazine 30a-n or pyrrolone 31a-e [41, 42]. In [43] the formation of 4-benzoyl-1,5-diphenylpyrazole-3-carboxylic acid 32 was described. In the opinion of the authors the reaction takes place through the intermediate 4-benzoyl-5-phenyl-3-phenylhydrazono3H-furan-2-one I5, formed after attack by the phenylhydrazine at the C(3)=O carbonyl group of 4-benzoyl-5phenyl-2,3-dihydrofuran-2,3-dione [43].
O Ph Ph O O O H2NNHPh Ph H 2O Ph O O N NHPh O Ph Ph N Ph I5 32 (49%) N O O OH
144
2,6-Dimethylphenylamides of 1,3,4-triphenylpyrazole-5-carboxylic (33a) and 1,4,5-triphenylpyrazole-3carboxylic acids (34a) are formed with yields of 16 and 31% respectively as a result of the recyclization of diiminofuran 18a by the action of phenylhydrazine [36].
Ph Ph O 18a N N Tol-p Xyl-2,6
H2NTol-p
H2NNHR
O Ph Ph N N N H R
Me Ph Ph N
O N H N
Me
Ph Ph Me N
N NHR O Me
Me
Me
33ad
(1623%)
R 34a,b
(31, 47%)
35ad
(3047%)
33 a R = Ph, b R = Tos, c R = PhCO, d R = EtOCO; 34 a R = Ph, b R = Me; 35 a R = 4-O2NC6H4, b R = Tos, c R = PhCO, d R = EtOCO
The formation of the two pyrazole derivatives may result from attack of the primary (compound 33) and secondary (compound 34) amino group of the substituted hydrazine at the C(5) carbon atom of the heterocycle. In the reactions of compound 18a with methylhydrazine attack by the secondary amino group mostly takes place at the C(5) carbon atom of the heterocycle (with the formation of compound 34b), while the reaction with tosyl- or acylhydrazines leads to the formation of the pyrazoles 33b-d but with yields of 17-23%, since yet another direction of recyclization with the formation of 3-hydrazono-1,4,5-triaryl-3H-pyrrol-2-ones 35b-d is realized in this reaction [36]. The reaction of compound 18a with N'-methyl-N'-phenylhydrazine leads to 1-(2,6-dimethylphenyl)-4,5-diphenyl-3-(N'-methyl-N'-phenylhydrazono)-3H-pyrrol-2-one 35e with a yield of 72% [36]. 3.2.3. Recyclization of Iminofuranones under the Influence of Vicinal Diamines. 2-Iminofuran-3ones 10a-e,g,o react with o-phenylenediamine to form N-substituted 2-amino-3-phenacylidene-3,4dihydroquinoxalines 36a-g [18, 34, 44].
H2N H2N
p-R1C6H4
2
O
p-R1C6H4
NHR N O..
NHR
p-R1C6H4 H2O
N O..
O
10ae, g, o
N R
.H
I6
O H2N
.H
36ag (5987%)
36 a R1 = H, R2 = t-Bu; b R1 = Me, R2 = t-Bu; c R1 = Cl, R2 = t-Bu; d R1 = Br, R2 = t-Bu; e R1 = H, R2 = TosCH2; f R1 = Cl, R2 = TosCH2; g R1 = H, R2 = 2,5-Xyl
The authors consider that the amino group of the o-phenylenediamine initially attacks at position 2 of the heterocycle nucleophilically. This leads to opening of the ring with the formation of substituted amidines I6, and they undergo cyclization to the quinoxaline derivatives 36 [44]. 145
Analogous attack occurs during the reaction of the iminofuranone 10p with 3,4-diaminocoumarin, but cyclization of the intermediate amidine I7 to 3-(1-adamantylamino)-1,2-dihydro-5H-chromeno[4,3-b]pyrazine2,5-dione 37 is accompanied by cleavage of the bromo-p-methylacetophenone [45].
Br p-Tol O N Ad p-Tol Br NH2 NH2 O O O I7 O HN N O 37 (89%) O NHAd NH O NAd OH O
O 10p
+
NH2
3.2.4. Recyclization under the Influence of Azomethines. The only example of such reactions was described in [46, 47]. The reaction of the iminofuranones 10e-h with substituted N-(benzylidene)benzylamines leads to the formation of 5-aryl-2-aroylacetyl-1-benzylimidazoles 38a-e [46, 47].
O 10eh 4-R2C6H4CH=NCH2Ph p-R1C6H4 N CH2Tos + N C HC6H4R2-p CH2Ph N p-R1C6H4 O H O N CH2Ph C6H4R2-p
-
O I8
TosH
38ae (6378%)
38 a R1 = H, R2 = Me2N; b R1 = Me, R2 = Me2N; c R1 = H, R2 = MeO; d R1 = Cl, R2 = MeO; e R1 = Br, R2 = MeO
The authors consider that the formation of compounds 38 begins with attack at position 2 of the heterocycle by the trigonal nitrogen atom of the azomethine with the formation of a zwitterionic adduct I8. A series of consecutive transformations of the adduct I8 (three stages of transformations) results in the elimination of toluenesulfinic acid and the formation of an imidazole system. The reaction mechanism is hypothetical, but the structure of compounds 38 was confirmed by X-ray crystallographic analysis of compound 38d [47]. 146
3.3. Reactions Taking Place with Participation of the Azomethine Bond of Iminofurans 3.3.1. Addition of OH and NH Nucleophiles at the C=N Bond. 5-Aryl-2-methylenehydrazono-2Hfuran-3-ones 8, in which the C=N bond is activated by acyl substituents, add water, alcohols, and amines at this bond [12, 14, 15, 36, 38, 48]. Thus, the iminofuranone 8i is capable of forming the product from the addition of water 2-benzoyloxymethylhydrazono-5-(4-chlorophenyl)-2H-furan-3-one (39a) even during crystallization from solvents containing water [14, 15, 48]
O H p-R1C6H4 O 8gi,l,q,s
Compound 39a 39b 39c 39d 39e 39f 39g 39h 39i 39j 39k 39l
O N R O
2
HOR
OR p-R1C6H4 O N N H
R O
39a (18%) 39bl (6590%)

R2 Ph Ph Ph Ph Ph 4-BrC6H4 Ph PhCH2 PhCH2 Ad EtO EtO R3 H Me Me Me Me Me Et Me Et Me Me D3C
R1 Cl H Me MeO Cl Cl Cl Br Br Cl Me Me
Aliphatic alcohols add vigorously at the activated C=N bond of compounds 8g-i,l,q,s with the formation of compounds 39b-e [12, 14, 15]. In [36] the addition of ethanol at the C(3)=N bond of the diiminofuran 18a, leading to the formation of 2-(2,6-dimethylphenylimino)-3-(4-methylanilino)-4,5-diphenyl-3-ethoxy-2,3dihydrofuran 40, was described.
OEt Ph Ph O 18a N N Tol-p EtOH Xyl-2,6 Ph O Ph NHTol-p N Xyl-2,6
40 (87%)
In contrast to the reactions for compounds 10 described in section 3.2.3, o-phenylenediamine reacts with compounds 8g-i by attacking with the amino group not the C(2) atom of the heterocycle but the carbon atom of the activated C=N bond. As a result the 5-aryl-2-hydrazono-2H-furan-3-ones 41a-c and 2-phenylquinoxaline are formed [12, 15, 38, 48].
147
O H p-RC6H4 O 8gi N N O Ph
H2N H2 N p-RC6H4 O
O HN N I9 H2O O N NH2 N Ph N H NH2 Ph O
p-RC6H4
+
N
41ac (5683 %) 41 a R=Me, b R=MeO, c R= Cl
The reaction probably takes place through the formation of the intermediate N,N-aminal I9, which is stabilized with the formation of the hydrazones 41 and 2-phenylquinoxaline [48]. The iminofuranone 9k reacts with an ynamine through the C=N double bond [17].
Me 9k
NEt2 O Me I10
O Me NEt2 Me
O O
NEt2 N Me Me
Me
42 (4560 %)
The initially formed [2+2]-cycloadduct I10 is transformed as a result of cleavage at the C(2)N bond into 2-(2,3-dihydro-3-oxophenanthro[9,10-b]furan-2-ylidene)-N'-(2,6-dimethylphenyl)-N,N-diethylpropionamidine 42 [17]. 3.3.2. Cycloaddition at the C=N Bond of Iminofurans. The cycloaddition of ketenes and acylketenes at the C=N bond of iminofurans of types A and C was studied. Thus, the iminofuranones 10e-g react with diphenylketene according to a [2+2]-cycloaddition scheme with the formation of 5'-aryl-3,3-diphenylspiro-1tosylmethyl[azetidine-2,2'-3'H-furan]-3',4-diones 43a-c [49].
O Ph2C=C=O N p-RC6H4 O Ph O Tos
10eg
Ph 43ac (3337%) 43 a R = H, b R = Me, c R = Cl
148
Derivatives of spiro[azetidine-2,3'-furan]-4-ones 44a-c are also formed during reaction of the diiminofurans 18a,g with diphenylketene, phenylbenzoylketene, and dimethylketene. In the last case, however, 10,11-dihydro-11,11-dimethyl-10-(2,6-dimethylphenyl)-13-(4-methylphenyl)phenanthro[9',12':2,3]furo[4,5-b]pyrazin-13H-12-one 45 is formed in addition to compound 44c with a comparable yield [36].
R
2
Tol-p O N N Tol-p
1
18a,g
R R C=C=O R
R R
O Me
+
O 45 (29%) N
N R
Me Xyl-2,6
44ac (88, 61, 27%)
44 a R1 = 2,6-Xyl, R = R2 = R3 = Ph; b R1 = 2,6-Xyl, R = R2 = Ph, R3 = PhCO; c R1 = Ph, R+R = biphenyl-2,2'-diyl, R2 = R3 = Me
The products from the alternative cyclization path through the C(2)=N bond were not isolated in these transformations. The iminofuranones 8i, 9j,m, 10e,h react with acylketene as dienophiles through their C=N bond according to a [4+2] cycloaddition scheme with the formation of derivatives of spiro[furan-2(3H),2'[2H][1,3]-oxazines] 46a-e [17, 50-52]. In the case of compound 8i, however, attack by the diene on the activated C=N bond of the azine system also occurs and leads to the formation of 2-benzoyl-3-[5-(4-chlorophenyl)-3-oxo2,3-dihydro-2-furanylideneamino]-6-(4-methylphenyl)- 3,4-dihydro-2H-1,3-oxazin-4-one (47) [52].
R 9j,m; 10e,h R R
1 2 1
O O O R
3
N O O
O C
46ad (2892%)
O 8i p-ClC6H4 Ph O O N
O N O
C6H4Me-p
+
O N N Ph O O C6H4Me-p O
46e
p-ClC6H4
O 47
46 a R1 = R2 = Ph, R3 = cyclo-C6H11; b R3 = 2,6-MeC6H4, R1+R2 = dimethylpropane-1,3-diyl; c R2 = H, R3 = TsCH2, R1 = Ph; d R2 = H, R3 = TsCH2, R1 = 4-BrC6H4
Mercaptoacetic acid adds at the C=N bond of iminofuranone 9c with the formation of 3'-(2,6-dimethylphenyl)-4,5-diphenylspiro[furan-2(3H),2'-[1,3]thiazolidine]-3,4'-dione (48) and at the C(3)=N bond of compound 18a also with the formation of a spiro product 49, but the diiminofuran rearranges to pyrrolone during the reaction [36]. 149
Ph 9c Ph
O S O
2,6-Xyl O OH SH
N O p-MeC6H4 Ph N S Ph N O O
48 (41%)
18a
Xyl-2,6 49 (65%)
Thiobenzoyl isocyanate enters into [4+2]-cycloaddition at the C(3)=N bond of the iminofurans 18a,c with the formation of derivatives of spiro[furan-3(2H),2'-[2H-1,3,5]thiadiazines] 50a,b [31].
O 18a,c R p-MeC6H4 R
1 1
O N S O N Ph
2
N Ph
C S
N R
50a,b
(76, 78%)
50 a R1 = Ph, R2 = 2,6-Xyl; b R1 = 4-MeOC6H4, R2 = Ph
3.4. Reactions Taking Place at the Functional Groups of Iminofurans The thermal intramolecular cyclization of diiminobenzofurans 19a-c to 2-arylbenzofuro[2,3-e][1,2,4]triazin-3(2H)-ones 51a-c [32] and diiminobenzofuran 19d to 1,3,4-thiadiazino[6,5-b]benzofuran 2-imine 52 [6] can be included among such transformations.
NNHAr O O 19ac S NNH N Ph NH2 HCl 52 O N N S (66%) NH N OEt N N Ar O
N O 51ac (8793%)
O 19d
51 a Ar = 2-NCC6H4; b Ar = 3-Tol; c R = 1-naphthyl
150
In addition, reactions of carbonyl compounds with 2-hydrazonofuran-3-ones 40a-c, which take place exclusively at the amino group of the latter, were described in [15, 38, 48].
CONCLUSION Analysis of the published data shows that iminofuranones and diiminofurans represent an interesting class of furan derivatives. Alternative methods of synthesis have been worked out for the iminofuranones A and B, and this gives the researcher the opportunity to choose between one or other method according to task in hand. The structure of iminofuranones gives rise to abundant synthetic potential. The presence of several electron-deficient centers in their molecules makes it possible to control the direction of attack by the nucleophilic reagent and the structure of the final reaction products by varying the substituents in the heterocycle and at the imino functions. A number of OH, SH, and NH nucleophiles have already been tested in reactions with iminofuranones. Broad synthetic possibilities are presented by the recyclization of iminofuranones and cyclization at the C=N bonds of iminofurans. The practical application of iminofuranones remains untouched, but there is reason to suppose that iminofuranones could prove no less promising in pharmacological respects than derivatives of furan itself. Thus, iminofuranones are accessible and convenient subjects for the creation of various acyclic and heterocyclic structures and are promising for further investigations in heterocyclic chemistry.
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153
ISOMERIZATION OF (HET)ARYLBENZOINS IN BASIC MEDIA

S. P. Ivonin, A. V. Lapandin, and V. G. Shtamburg The isomerization of the hetaryl analogs of unsymmetrical benzoins on heating in basic media is a convenient preparative method for the production of -hydroxyacyl derivatives of -excessive heterocycles. The motivating force here for the isomerization is the formation of a thermodynamically more stable product. It was established that isomerization is promoted by increase in the difference between the electron-donating characteristics of the (het)aryl residues. Keywords: benzoins, -excessive heterocycles, isomerization. The benzoin condensation is a convenient method for the synthesis of benzoins both with symmetrical and with unsymmetrical structures [1]. With thiazolium salts as catalysts it was possible not only to increase the overall yield and optical purity of the benzoins but also to use the reaction as a model to study the formation of the CC bond in natural systems, catalyzed by enzymes (thiamine diphosphate) [2-11]. Study of the mechanism of the benzoin condensation and determination of the role of the acyl carbanion as intermediate made it possible to obtain the less stable unsymmetrical -benzoins as a result of a two-stage reaction [12-17], which is impossible under the conditions of the classical benzoin condensation [1]. However, the -benzoins are formed here with low yields, while only the furan and pyridine derivatives are obtained from the hetaryl analogs [17]. The aldehydes of -excessive heterocycles are inactive under the conditions of the benzoin condensation [18]. Therefore, for example, electrophilic acylation, requiring a few more stages for the production of the benzoins, was used in the case of the synthesis of -hydroxyacylindoles, which have pharmacological activity [19, 20]. 4'-Dimethylaminobenzoin (the -isomer) can be isomerized to the corresponding -isomer in basic media [1], and it was interesting to use isomerization for the production of the more stable hetarylbenzoins. The starting compounds were the hetaryl analogs of -benzoins, which can be easily obtained by hydroxymethylation of the respective -excessive heterocycles with arylglyoxals [21]. We found that the isomerization of -benzoins 1-13 takes place smoothly in the presence of triethylamine as base in boiling alcohol. As a result high yields of the corresponding hetaryl analogs of -benzoins 14-26 were obtained (Scheme 1). In our opinion isomerization of benzoins takes place as intramolecular migration of a hydrogen atom between the oxygen atoms in the anion A, formed as a result of removal of a proton by the base from the carbon atom of the hydroxymethyl group. In fact, use of the O-deuterated -benzoin 27 in isomerization under the indicated conditions gave the -benzoin 28, in which the deuterium atom was preserved to the extent of 100%. The 1H NMR spectrum of the -benzoin 28 does not contain the signals in the region of 5.70 and 11.88 ppm that in the spectrum of the -benzoin 20 correspond to the OH and NH protons, while the signals of __________________________________________________________________________________________ Dnepropetrovsk National University, Dnepropetrovsk 49050, Ukraine; e-mail: ivonin@dp.ukrtel.net. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 187-194, February, 2004. Original article submitted November 14, 2003. 154 0009-3122/04/4002-01542004 Plenum Publishing Corporation
Scheme 1
HO O Het
113
NEt3 R EtOH, 78 oC Het
O OH R
1426
Het =
, N Me
1, 14
, N C6H4OEt-p
2, 15
, N C6H4Me-p
3, 16
Me
N Me
4, 17
Me
Me
Me
Me
Me
C6H4Br-p
5, 18
C6H4Me-p
6, 19
N R2
712, 2025
R1 ,
Me
O
13, 26
R = Ph (111, 1324, 26), 2-thienyl (12, 25) R1 = H (7, 12, 20, 25), Me (8, 9, 21, 22), Ph (10, 23), t-Bu (11, 24) R2 = Me (9, 22), H (all other cases)
CHOD and H(2) Ind are in the form of singlets, in contrast to the doublets in the 1H NMR spectrum of 20. In the IR spectrum of compound 28 the vibrations of the ND and OD bonds appear in the region of 2580-2490 cm-1 respectively. The presence of the deuterium at the oxygen atom and not at the carbon atom in the -benzoin 28 Scheme 2
O Ph NEt3 EtOH, 78 oC N D A O Ph Me2SO4 N D 28 DMSO, NaOH 29 N Me OMe Ph _ O + D _ O Ph
DO
N D 27 O
OD
155
TABLE 1. The Duration of the Isomerization of -Benzoins

Compound 1 2 3 4 5 Duration, h* 1.5 3.5 4 11.5 12 Compound 6 7 8 9 10 Duration, h* 12 3 5 5 9 Compound 11 12 13 27 Duration, h* 9 5 6.5 3
_______ * The duration was determined from the disappearance of the spot for the initial compound in TLC (every 30 min). was also proved by the alkylation of 28 with dimethyl sulfate in DMSO. In fact, the 1H NMR spectrum of the isolated bis-O,N-alkylated product 29 contains a singlet at 5.32 ppm as also in the 1H NMR spectrum of the -benzoin 28, indicating the presence of a proton at the carbon atom. The formation of the thermodynamically more stable -isomer, determined by the electronic nature of the hetaryl residue, is in our opinion the motivating force of the isomerization, and an increase in the duration of the isomerization is therefore observed with decrease of the electron-donating power in the following order (for R = Ph):
N Me
< N H
<<
Me
The substantial decrease in the electron-donating power of the furan ring compared with the pyrrole rings leads to the result that the -benzoin 13 is less active than the -benzoins 1 and 7. In the case of the pyrrole derivatives it was established that the decrease in the electron-donating power of the position of the heterocycle reduces the duration of isomerization in the following order (for R = Ph):
<< N Me <<
<
OEt
Me
<<
Me
N Me
Me
~ Me
Me
Me
Me
Br
Me
156
The most active is the -benzoin 1, in which the reaction center is attached to the most electrondonating group. Replacement of the alkyl group at the nitrogen atom by a less electron-donating aryl group increases the duration of isomerization, and the reaction center here is sensitive to the electronic effect of the substituent in the aryl ring. The pyrrole 2 is therefore somewhat more active than 3. In the case of the pyrroles 46 the hydroxy ketone group is attached to the less electron-donating -position of the heterocycle. The duration of isomerization is therefore increased, while the influence of the electronic effect of the substituent at the nitrogen atom is levelled out. The opposite effect from the electron-donating characteristics is observed for (het)aryl groups in the righthand part of the benzoin molecule. Thus, the isomerization rate decreases with increase in the donating power (for Het = Ind), i.e., the greater the difference in the electron-donating characteristics of the (het)aryl substituents in the benzoin molecule, the more readily the isomerization takes place.
Ph <
The increase in the size of the substituent at the o-position to the -hydroxy ketone group in the hetaryl moiety in the series of 2-alkylindole derivatives (for R = Ph) leads to a reduction in the rate of isomerization, due to steric hindrances to removal of the proton at the carbon atom by the base. In our opinion the increase in the duration of the isomerization of the 2-phenylindole derivative is due in addition to the electron-accepting effect of the phenyl ring.
R1 N R2 R1 = H < Me< Ph ~ t-Bu
In the 1H NMR spectra of the obtained -benzoins it is possible to detect the following relationship: the doublets of the o-protons of the unsubstituted phenyl ring are shifted upfield by 0.5-0.6 ppm compared with those in the spectra of the initial -benzoins [21]. This relationship can be used to determine the structure of isomeric benzoins, since the position and form of the signals of these protons are similar for isomers of the same series [22].
EXPERIMENTAL The 1H NMR spectra were obtained in DMSO-d6 on a Varian VXR-300 instrument (300 MHz) with TMS as internal standard. The reaction was monitored by TLC on Silufol UV-254 plates in the 5:1 benzene acetone system with development in iodine vapor. We described the -benzoins 1-10, 12, and 13 in [21]. The -benzoins 11 and 27 were obtained by the general procedure in [21]. 2-(2-tert-Butyl-1H-indol-3-yl)-2-hydroxy-1-phenylethanone (11). A solution of 2-tert-butylindole (5.00 mmol) in benzene (4 ml) was added to a solution of phenylglyoxal (5.00 mmol) in benzene (4 ml). The obtained solution was kept at room temperature for 24 h. The precipitate was filtered off and crystallized from benzene. Yield 66.3%, colorless crystals; mp 142-144C. 1H NMR spectrum, , ppm, J (Hz): 1.49 (s, 9H, t-Bu); 157
5.29 (d, 1H, CHOH, J = 5.4); 6.41 (d, 1H, CHOH, J = 5.4); 6.76 (t, 1H, H(6) Ind, J = 8.4); 6.92 (t, 1H, H(5) Ind, J = 8.4); 7.19 (d, 1H, H(7) Ind, J = 8.4); 7.25 (d, 1H, H(4) Ind, J = 8.4); 7.34 (t, 1H, H(3) and H(5) Ar, J = 6.9); 7.46 (d, 1H, H(4) Ar, J = 6.9); 7.82 (d, 2H, H(2) and H(6) Ar, J = 6.9); 10.72 (s, 1H, NH). Found, %: 78.11; 6.87. C20H21NO2. Calculated, %: C 78.15; H 6.89. O,N-Dideutero-2-hydroxy-2-(1H-indol-3-yl)-1-Phenylethanone (27). A solution of phenylglyoxal deuteroxide (5.00 mmol), indole (5.00 mmol), and deuterium oxide (0.1 ml) in benzene (8 ml) was boiled for 2 h and cooled. The precipitate was filtered off and crystallized from toluene. Yield 58.0%, colorless crystals; mp 180-182C. 1H NMR spectrum, , ppm, J (Hz): 6.39 (s, 1H, CHOD); 7.00 (t, 1H, H(6) Ind, J = 8.1); 7.08 (t, 1H, H(5) Ind, J = 8.1); 7.32 (d, 1H, H(7) Ind, J = 8.1); 7.35 (s, 1H, H(2) Ind); 7.40 (d, 1H, H(7) Ind, J = 8.1); 7.51 (t, 2H, H(3) and H(5) Ph, J = 7.8); 7.67 (d, 1H, H(4) Ph, J = 7.8); 8.02 (d, 2H, H(2) and H(6) Ph, J = 7.8). Found, %: 75.73; N 5.52. C16H11D2NO2. Calculated, %: C 75.87; N 5.53. General Procedure for the Isomerization of -Benzoins 1-13 and 27 (Table 1, Schemes 1 and 2). A solution of the -benzoin (1.50 mmol) and triethylamine (0.21 ml, 1.80 mmol) in ethanol (6 ml) was boiled for the time indicated in the table. The obtained solution was evaporated under vacuum, and the residue was crystallized. The following compounds were obtained in this way. 2-Hydroxy-1-(1-methyl-1H-pyrrol-2-yl)-2-phenylethanone (14). Yield 50.5%, colorless prisms; mp 107-108 (hexane). 1H NMR spectrum, , ppm, J (Hz): 3.84 (s, 3H, NMe); 5.58 (d, 1H, CHOH, J = 5.7); 5.70 (d, 1H, CHOH, J = 5.7); 6.05 (dd, 1H, H(4) Pyr, J = 3.9, J = 2.4); 7.05 (d, 1H, H(5) Pyr, J = 2.4); 7.20 (d, 1H, H(4) Ph, J = 6.9); 7.21 (d, 1H, H(3) Pyr, J = 3.9); 7.27 (t, 2H, H(3) and H(5) Ph, J = 6.9); 7.42 (d, 2H, H(2) and H(6) Ph, J = 6.9). Found, %: C 72.53; H 6.10. C13H13NO2. Calculated, %: C 72.54; H 6.09. 1-[1-(4-Ethoxyphenyl)-2-hydroxy-1H-pyrrol-2-yl]-2-phenylethanone (15). Yield 80.4%, light-yellow powder; mp 78-79C (80% ethanol). 1H NMR spectrum, , ppm, J (Hz): 1.40 (t, 3H, CH3CH2, J = 7.0); 4.10 (q, 2H, CH3CH2), J = 7.0); 5.60 (d, 1H, CHOH, J = 5.6); 5.64 (d, 1H, CHOH, J = 5.6); 5.88 (dd, 1H, H(4) Pyr, J = 3.9, J = 2.4); 6.04 (d, 1H, H(5) Pyr, J = 2.4); 6.87 (d, 1H, H(3) Pyr, J = 3.9); 7.04 (d, 2H, H(2) and H(6) Ar, J = 8.7); 7.36 (d, 1H, H(4) Ph, J = 7.8); 7.45 (d, 2H, H(3) and H(6) Ar, J = 8.7); 7.47 (t, 2H, H(3) and H(5) Ph, J = 7.8); 7.58 (d, 2H, H(2) and H(6) Ph, J = 7.8). Found, %: C 74.79; H 5.99. C20H19NO3. Calculated, %: C 74.75; H 5.96. 2-Hydroxy-1-(1-(p-tolyl)-1H-pyrrol-2-yl)-2-phenylethanone (16). Yield 70.3%, oil from hexane. 1 H NMR spectrum, , ppm, J (Hz): 2.38 (s, 3H, 4-MeAr); 5.71 (d, 1H, CHOH, J = 6.3); 5.82 (d, 1H, CHOH, J = 6.3); 6.30 (dd, 1H, H(4) Pyr, J = 3.9, J = 3.9); 6.93 (d, 2H, H(2) and H(6) Ar, J = 9.0); 7.17 (d, 2H, H(3) and H(5) Ar, J = 9.0); 7.25 (d, 1H, H(5) Pyr, J = 3.9); 7.29 (d, 1H, H(3) Pyr, J = 3.9); 7.31 (d, 1H, H(4) Ph, J = 8.1); 7.34 (t, 2H, H(3) and H(5) Ph, J = 8.1); 7.44 (d, 2H, H(2) and H(6) Ph, J = 8.1). Found, %: C 78.27; H 5.59. C19H17NO2. Calculated, %: C 78.33; H 5.88. 2-Hydroxy-1-(1,2,5-trimethyl-1H-pyrrol-3-yl)-2-phenylethanone (17). Yield 64.7%, colorless plates; mp 135-136C (benzene). 1H NMR spectrum, , ppm, J (Hz): 2.08 (s, 3H, 5-MePyr); 2.45 (s, 3H, 2-MePyr); 3.31 (s, 3H, 1-MePyr); 5.26 (d, 1H, CHOH, J = 5.7); 5.53 (d, 1H, CHOH, J = 5.7); 6.29 (s, 1H, H(4) Pyr); 7.18 (d, 1H, H(4) Ph, J = 6.9); 7.27 (t, 2H, H(3) and H(5) Ph, J = 6.9); 7.36 (d, 2H, H(2) and H(6) Ph, J = 6.9). Found, %: C 74.01; H 7.04. C15H17NO2. Calculated, %: C 74.05; H 7.04. 1-[1-(4-Bromophenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-2-hydroxy-2-phenylethanone (18). Yield 92.6%, light-yellow powder; mp 160-161C (80% ethanol). 1H NMR spectrum, , ppm, J (Hz): 1.91 (s, 3H, 5-MePyr); 2.25 (s, 3H, 2-MePyr); 5.39 (d, 1H, CHOH, J = 5.7); 5.55 (d, 1H, CHOH, J = 5.7); 6.44 (s, 1H, H(4) Pyr); 7.22 (d, 1H, H(4) Ph, J = 7.5); 7.23 (d, 2H, H(2) and H(6) Ar, J = 8.4); 7.31 (t, 2H, H(3) and H(5) Ph, J = 7.5); 7.42 (d, 2H, H(2) and H(6) Ph, J = 7.5); 7.68 (d, 2H, H(3) and H(5) Ar, J = 8.4). Found, %: C 62.53; H 4.71. C20H18BrNO2. Calculated, %: C 62.51; H 4.72. 2-Hydroxy-1-[2,5-dimethyl-1-(p-tolyl)-1H-pyrrol-3-yl]-2-phenylethanone (19). Yield 85.8%, lightyellow powder; mp 126-127C (80% ethanol). 1H NMR spectrum, , ppm, J (Hz): 1.89 (s, 3H, 5-MePyr); 2.24 (s, 3H, 4-MeAr); 2.40 (s, 3H, 2-MePyr); 5.29 (d, 1H, CHOH, J = 6.3); 5.52 (d, 1H, CHOH, J = 6.3); 6.37 (s, 158
1H, H(4) Pyr); 7.09 (d, 2H, H(2) and H(6) Ar, J = 8.1); 7.21 (d, 1H, H(4) Ph, J = 6.9); 7.28 (d, 2H, H(3) and H(5) Ar, J = 8.1); 7.30 (t, 2H, H(3) and H(5) Ph, J = 6.9); 7.41 (d, 2H, H(2) and H(6) Ph, J = 6.9). Found, %: C 78.98; H 6.65. C21H21NO2. Calculated, %: C 78.97; H 6.63. 2-Hydroxy-1-(1H-indol-3-yl)-2-phenylethanone (20). Yield 85.9%, colorless prisms; mp 194-196C (toluene). 1H NMR spectrum, , ppm, J (Hz): 5.70 (d, 1H, CHOH, J = 4.2); 5.77 (d, 1H, CHOH, J = 4.2); 7.12 (t, 1H, H(6) Ind, J = 8.1); 7.15 (t, 1H, H(5) Ind, J = 8.1); 7.20 (d, 1H, H(4) Ph, J = 7.3); 7.28 (t, 2H, H(3) and H(5) Ph, J = 7.3); 7.40 (d, 1H, H(7) Ind, J = 8.1); 7.51 (d, 2H, H(2) and H(6) Ph, J = 7.3); 8.18 (d, 1H, H(4) Ind, J = 8.1); 8.43 (d, 1H, H(2) Ind, J = 3.0); 11.88 (d, 1H, H(l) Ind, J = 3.0). Found, %: C 76.47; H 5.21. C16H13NO2. Calculated, %: C 76.48; H 5.21. 2-Hydroxy-1-(2-methyl-1H-indol-3-yl)-2-phenylethanone (21). Yield 71.4%, colorless crystals; mp 175-176C (benzene). 1H NMR spectrum, , ppm, J (Hz): 2.41 (s, 3H, Me); 5.72 (d, 1H, CHOH, J = 6.0); 5.90 (d, 1H, CHOH, J = 6.0); 7.16 (t, 1H, H(6) Ind, J = 7.2); 7.22 (t, 1H, H(5) Ind, J = 7.2); 7.24 (d, 1H, H(4) Ph, J = 7.8); 7.30 (t, 2H, H(3) and H(5) Ph, J = 7.8); 7.45 (d, 1H, H(7) Ind, J = 7.2); 7.54 (d, 2H, H(2) and H(6) Ph, J = 7.8); 7.83 (d, 1H, H(4) Ind, J = 7.2); 11.88 (s, 1H, H(l) Ind). Found, %: C 76.87; H 5.73. C17H15NO2. Calculated, %: C 76.96; H 5.70. 2-Hydroxy-1-(1,2-dimethyl-1H-indol-3-yl)-2-phenylethanone (22). Yield 73.9%, colorless crystals; mp 185C ethanol. 1H NMR spectrum, , ppm, J (Hz): 2.50 (s, 3H, 2-MeInd); 3.70 (s, 3H, l-MeInd); 5.69 (d, 1H, CHOH, J = 5.9); 5.94 (d, 1H, CHOH, J = 5.9); 7.19 (t, 1H, H(6) Ind, J = 8.1); 7.22 (t, 1H, H(5) Ind, J = 8.1); 7.27 (d, 1H, H(4) Ph, J = 6.3); 7.37 (t, 2H, H(3) and H(5) Ph, J = 6.3); 7.43 (d, 1H, H(7) Ind, J = 8.1); 7.49 (d, 2H, H(2) and H(6) Ph, J = 6.3); 8.04 (d, 1H, H(4) Ind, J = 8.1). Found, %: C 77.35; H 6.06. C18H17NO2. Calculated, %: C 77.40; H 6.13. 2-Hydroxy-2-phenyl-1-(2-phenyl-1H-indol-3-yl)ethanone (23). Yield 90.9%, white powder; mp 151-152C (benzenehexane). 1H NMR spectrum, , ppm, J (Hz): 5.79 (d, 1H, CHOH, J = 6.0); 5.83 (d, 1H, CHOH, J = 6.0); 7.17 (t, 1H, H(6) Ind, J = 6.9); 7.21 (t, 1H, H(5) Ind, J = 6.9); 7.23 (d, 1H, H(4) Ph, J = 7.9); 7.30 (t, 2H, H(3) and H(5) Ph, J = 7.9); 7.35-7.40 (m, 5H, 2-PhInd); 7.45 (d, 1H, H(7) Ind, J = 6.9); 7.53 (d, 2H, H(2) and H(6) Ph, J = 7.9); 7.77 (d, 1H, H(4) Ind, J = 6.9); 11.51 (s, 1H, H(1) Ind). Found, %: C 80.59; H 5.18. C22H17NO2. Calculated, %: C 80.71; H 5.23. 1-(2-tert-Butyl-1H-indol-3-yl)-2-hydroxy-2-phenylethanone (24). Yield 80.0%, colorless prisms; mp 222-224C (benzene). 1H NMR spectrum, , ppm, J (Hz): 1.61 (s, 9H, t-Bu); 5.97 (d, 1H, CHOH, J = 8.1); 6.22 (d, 1H, CHOH, J = 8.1); 7.17 (t, 1H, H(6) Ind, J = 7.2); 7.21 (t, 1H, H(5) Ind, J = 7.2); 7.24 (d, 1H, H(4) Ph, J = 7.9); 7.30 (t, 2H, H(3) and H(5) Ph, J = 7.9); 7.45 (d, 1H, H(7) Ind, J = 7.2); 7.54 (d, 2H, H(2) and H(6) Ph, J = 7.9); 7.83 (d, 1H, H(4) Ind, J = 7.2); 12.10 (s, 1H, H(1) Ind). Found, %: C 78.09; H 6.77. C20H21NO2. Calculated, %: C 78.15; H 6.89. 2-Hydroxy-1-(1H-indol-3-yl)-2-(2-thienyl)ethanone (25). Yield 52.7%, colorless needles; mp 162-163C (ethanol). 1H NMR spectrum, , ppm, J (Hz): 6.06 (d, 1H, CHOH, J = 4.5); 6.13 (d, 1H, CHOH, J = 4.5); 6.93 (t, 1H, H(4) Th, J = 4.8); 7.13 (d, 1H, H(3) Th, J = 4.8); 7.20 (t, 1H, H(6) Ind, J = 7.8); 7.22 (t, 1H, H(5) Ind, J = 7.8); 7.40 (d, 1H, H(5) Th, J = 4.8); 7.48 (d, 1H, H(7) Ind, J = 7.8); 8.19 (d, 1H, H(4) Ind, J = 7.8); 8.57 (s, 1H, H(2) Ind); 12.05 (s, 1H, H(1) Ind). Found, %: 65.34; 4.27. C14H11NO2S. Calculated, %: C 65.35; H 4.31. 2-Hydroxy-1-(5-methyl-2-furyl)-2-phenylethanone (26). Yield 90.3%, colorless needles; mp 150-151C (ethanol). 1H NMR spectrum, , ppm, J (Hz): 2.33 (s, 3H, 5-MeFur); 5.63 (d, 1H, CHOH, J = 3.9); 5.94 (d, 1H, CHOH, J = 3.9); 6.24 (d, 1H, H(4) Fur, J = 3.0); 7.21 (d, 1H, H(4) Ph, J = 7.5); 7.29 (t, 2H, H(3) and H(5) Ph, J = 7.5); 7.43 (d, 2H, H(2) and H(6) Ph, J = 7.5); 7.46 (d, 1H, H(3) Fur, J = 3.0). Found, %: C 72.19; H 5.62. C13H12O3. Calculated, %: C 72.21; H 5.59. O,N-Dideuterio-2-hydroxy-1-(1H-indol-3-yl)-2-phenylethanone (28). Yield 80.9%, colorless prisms; mp 198-200C (toluene). 1H NMR spectrum, , ppm, J (Hz): 5.80 (s, 1H, CHOD); 7.16 (t, 1H, H(6) Ind, J = 9.6); 7.19 (t, 1H, H(5) Ind, J = 9.6); 7.23 (d, 1H, H(4) Ph, J = 8.1); 7.30 (t, 2H, H(3) and H(5) Ph, J = 8.1); 159
7.46 (d, 1H, H(7) Ind, J = 9.6); 7.54 (d, 2H, H(2) and H(6) Ph, J = 8.1); 8.21 (d, 1H, H(4) Ind, J = 9.6); 8.54 (s, 1H, H(2) Ind). Found, %: C 75.84; N 5.49. C16H11D2NO2. Calculated, %: C 75.87; N 5.53. 2-Methoxy-1-(1-methyl-1H-indol-3-yl)-2-phenylethanone (29). To a stirred solution of the -benzoin 28 (380 mg, 1.50 mmol) in DMSO (5 ml) a 10% aqueous solution of sodium hydroxide (0.60 ml, 1.50 mmol) and dimethyl sulfate (0.57 ml, 6.00 mmol) were added successively. The obtained mixture was stirred, 20 ml of water was added, and the precipitate was filtered off and crystallized from 80% ethanol. Yield 51.8%, lightyellow powder; mp 132-133C. 1H NMR spectrum, , ppm, J (Hz): 3.40 (s, 3H, NMe); 3.88 (s, 3H, OMe); 5.33 (s, 1H, CHOMe); 7.18 (t, 1H, H(6) Ind, J = 8.4); 7.21 (t, 1H, H(5) Ind, J = 8.4); 7.25 (d, 1H, H(7) Ind, J = 8.4); 7.30 (t, 2H, H(3) and H(5) Ph, J = 7.5); 7.46 (d, 1H, H(4) Ph, J = 7.5); 7.51 (d, 2H, H(2) and H(6) Ph, J = 7.5); 8.19 (d, 1H, H(4) Ind, J = 8.4); 8.57 (s, 1H, H(2) Ind). Found, %: 77.36; H 6.10; N 5.00. C18H17NO2. Calculated, %: 77.40; H 6.13; N 5.01. The work was carried out with financial support from the Ministry of Education and Science of Ukraine (No. 0101U00159).
REFERENCES 1. W. S. Ide and J. S. Buck, in: R. Adams (editor), Organic Reactions, Wiley, New York (1948), Vol. 4, p. 269; V. Aid and I. C. Bak, in: R. Adams (editor), Organic Reactions [Russian translation], Izd. Inostr. Lit., Moscow (1948), Vol. 4, p. 229. Y.-T. Chen, G. L. Barletta, K. Haghjoo, J. T. Cheng, and F. J. Jordan, J. Org. Chem., 59, 7714 (1994). Y. Murakami, J.-i. Kikuchi, Y. Hisaeda, and O. Hayashida, Chem. Rev., 96, 721 (1996). R. Breslow and S. D. Dong, Chem. Rev., 98, 1997 (1998). M. J. White and F. J. Leeper, J. Org. Chem., 66, 5124 (2001). H. Iding, T. Dnnwald, L. Greiner, A. Liese, M. Mller, P. Segert, J. Grotzinger, A. S. Demir, and M. Pohl, Chem. Eur. J., 6, 1483 (2000). T. Dnnwald, A. S. Demir, P. Siegert, M. Pohl, and M. Mller, Eur. J. Org. Chem., 2161 (2000). A. S. Demir, M. Pohl, E. Janzen, and M. Mller, J. Chem. Soc., Perkin Trans. 1, 633 (2001). A. S. Demir, O. Sesenoglu, E. Eren, B. Hosrik, M. Pohl, E. Janzen, D. Kolter, R. Feldmann, P. Dunkelmann, and M. Mller, Adv. Synth. Catal., 344, 96 (2002). M. Pohl, B. Lingen, and M. Mller, Chem. Eur. J., 8, 5288 (2002). P. Dunkelmann, D. Kolter-Jung, A. Nitsche, A. S. Demir, P. Siegert, B. Lingen, M. Baumann, M. Pohl, and M. Mller, J. Am. Chem. Soc., 124, 12084 (2002). J. P. Kuebrich and R. L. Schowen, J. Am. Chem. Soc., 93, 1220 (1971). R. E. Koenigkramer and H. Zimmer, J. Org. Chem., 45, 3994 (1980). I. Lantos, P. E. Bender, K. A. Razgaitis, B. M. Sutton, M. J. DiMartino, D. E. Griswold, and D. T. Walz, J. Med. Chem., 27, 72 (1984). M. D. Rozwadowska, Tetrahedron, 41, 3135 (1985). T. Kurihara, K. Santo, S. Harusawa, and R. Yoneda, Chem. Pharm. Bull., 35, 4777 (1987). A. Clerici and O. Porta, J. Org. Chem., 58, 2889 (1993). M. S. Kim, J. S. Gong, and I.-S. H. Lee, J. Heterocycl. Chem., 29, 149 (1992). M. N. Preobrazhenskaya, L. M. Orlova, S. S. Liberman, G. S. Mosina, V G. Avramenko, N. P. Sorokina, and N. N. Suvorov, Khim.-Farm. Zh., 6, No. 1, 32 (1972). J. Bergman and J. E. Bckvall, Tetrahedron, 31, 2063 (1975). S. P. Ivonin, A. V. Lapandin, A. A. Anishchenko, and V. G. Shtamburg, Synth. Commun., 34, 439 (2004). S. Yoshima and K. Yamamoto, Yakugaku Zasshi, 92, 359 (1972); Chem. Abstr., 77, 5264 (1972).
2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 160
INVESTIGATION OF THE OXIDATIONREDUCTION CHARACTERISTICS OF HETEROCYCLIC QUINONES

E. Yu. Khmel'nitskaya, N. B. Grigoriev, V. M. Lyubchanskaya, T. I. Mukhanova, and V. G. Granik An electrochemical investigation was undertaken into the oxidationreduction characteristics of heterocyclic quinones including derivatives of indazole, benzimidazole, benzofuran, benzothiazole, and isoquinoline. It was established that the compounds are reduced with the successive irreversible transfer of two electrons. The effect of structural factors and the nature of the heterocycle on the ease of reduction of the compounds is examined. Keywords: heterocyclic quinones, oxidationreduction characteristics, polarographic investigation. Many derivatives containing a quinone fragment exhibit significant biological activity. Their role as cytotoxic agents resulting from enzymatic reduction and followed by oxidation by atmospheric oxygen with the formation of a superoxide radical-anion, peroxynitrite, and the initial quinone (the so-called redox cyclization) is well known. The mechanism of the Nenitzescu reaction (the reaction of quinones with enamines) [1, 2] includes a whole series of oxidationreduction stages resulting from the redox characteristics of the quinones and hydroquinones and the various quinone- and hydroquinone-containing intermediates (e.g., hydroquinone and quinone adducts, quinoneimmonium derivatives, etc.) formed in the course of the reaction. Investigation of the Nenitzescu reaction is one of the promising directions in the development of the chemistry of heterocyclic compounds, since it can be used to produce 5-hydroxybenzofurans and, particularly, 5-hydroxyindoles and their derivatives, which include the neuromediator serotonin. The discovery of the role of serotonin has led to considerable progress in neuropharmacology. The 5-hydroxyindole derivatives include a whole group of biologically highly active compounds such as melatonin, indopan, etc., and interest in the mechanism of the Nenitzescu reaction is therefore constantly increasing. As a result it seems quite natural to investigate the polarographic behavior of the initial quinones in order to examine further their possible transformations under the influence of various nucleophilic agents, including enamines. Recently a new direction, based on the use of heterocyclic quinones in condensation with enamines, was discovered in the development of the Nenitzescu reaction. In view of the fact that the electrochemical characteristics of the derivatives of benzo- and naphthoquinones have been studied in great detail while heterocyclic quinones have been investigated little in this respect, in the present work we studied the polarographic behavior of indazole-, benzimidazole-, benzothiazole-, and isoquinolinequinones, for which
__________________________________________________________________________________________ Federal State Unitary Undertaking State Scientific Center NIOPIK, Moscow 101999, Russia; e-mail: makar-cl@ropnet.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 195-200, February, 2004. Original article submitted October 24, 2001. 0009-3122/04/4002-01612004 Plenum Publishing Corporation 161
TABLE 1. The Half-Wave Potentials (E) of the Quinones in Anhydrous Dimethylformamide

Compound 1/2, V, of first wave 1/2, V, of second wave Compound 1/2, V, 1/2, V, of first of second wave wave
O N
-0.39 -1.20
O Me
-0.57 -1.32
N O O N S O O
-0.49 -1.31 -0.46 -1.23
O O 5 O
-0.61 -1.28
Me
O 6 O Ph
-0.62 -1.37
O O
N
3 COOEt Me
-0.52 -1.29
O 7 O
Ph
N N O 8 Me
-0.66 -1.38
N O 4 Me
information on the paths for their condensation with enamines is already available. A list of the investigated compounds and their half-wave potentials are given in Table 1. 1,4-Benzoquinone (3) and 1,4-naphthoquinone (6) were used as models for comparison with heterocyclic quinones. In anhydrous DMF all the listed quinones are reduced in two stages two waves of equal height are observed on the polarograms. By comparison of the proportionality factor in the Ilkovic equation for each waves of the investigated substances and model compounds it was established that both electrochemical stages correspond to the transfer of one electron. It is known that in aprotic solvents aromatic quinones form a semiquinone as a result of the transfer of one electron, and reduction takes place according to the following scheme [3]:
O O
.
+e
_
.
Solvent
OH
+
O
_ _ O Semiquinone
OH
162
In electrochemical reduction the heterocyclic quinones that we investigated also go through a semiquinone stage. Here the waves have diffusion character, and their slope corresponds to an irreversible process. Aromatic quinones behave similarly in aprotic media. Thus, even Kolthoff found that a quinhydrone electrode is not reversible in nonaqueous solutions and anodic waves for the corresponding hydroquinones are not detected at the reduction potentials of the quinones [4, 5]. Similar results were obtained by cyclic voltammetry [6]. The obtained data are largely unexpected, e.g., the fairly large hindrance of the reduction of compound 8 compared with the derivative of thiazolequinone 2 or the high negative reduction potential of the indazolequinone 7, which has phenyl substituents at positions 1 and 3. The latter is explained by the fact that the phenyl rings must be turned significantly from the plane of the bicycle for steric reasons. The previously mentioned [7] large difference between the half-wave potentials of the first stage in the reduction of the benzimidazolequinone 1 and its N-methyl derivative 8 can be explained by the presence in compound 1 of a hydrogen bond between the NH and C=O groups of the quinone fragment, which stabilizes the radical-anion (or transition state) to a greater degree than the initial molecule. It is clear that such stabilization is impossible for compound 8.
O
.
N N
.. .H
It is seen from the data in Table 1 that the difference in the half-wave potentials of the first stage of electrochemical reduction is appreciably larger that for the second, i.e., the stabilization of the dianion depends less on the nature of the annelated heterocycle. For the heterocyclic quinones that we investigated an analogy is also observed in the behavior with aromatic quinones after the addition of a proton donor to the aprotic medium. Phenol was used as proton donor. Here the second wave is shifted toward more positive potentials, and in the limit (in the transition to aqueous organic solvents) it merges with the first, forming one two-electron wave. In 40% aqueous solutions of DMF, however, in a neutral medium with Bu4NClO4 as supporting electrolyte a difference in the behavior of the model and the investigated compounds is observed. For benzo- and naphthoquinones under these conditions one clear two-electron wave is obtained on the direct-current polarogram, and the corresponding peak is observed on the alternating-current curve. For all the investigated heterocyclic quinones the two-electron wave has a tendency to split, which appears on the alternating-current polarogram as two distinct peaks. It is only possible to eliminate such splitting in an acidic DMFwater medium at a pH of about 5. This means that the semiquinones of compounds 1, 2, 4, 5, 7, and 8 are more stable than benzo- and naphthoquinones, and their complete protonation requires the presence of a stronger proton donor then water in the solution. The half-wave and peak potentials obtained in the DMFwater medium are given in Table 2. These data indicate that in all cases the annelated heterocyclic fragments stabilize the semiquinone radical-anions and hinder their protonation, i.e., exhibit distinct electron-accepting characteristics. The obtained results do not correlate entirely with the data for the Nenitzescu reaction. Apparently, the quinones that are most easily reduced should have the strongest oxidizing power, and their use (if they and not other intermediates are the oxidizing agents in the Nenitzescu reaction) should lead to an increase in the degree of indolization compared with benzofuran cyclization.
163
TABLE 2. The Peak and Half-Wave Potentials of Quinones 1-8 in 40% Dimethylformamide
Compound 1 2 4 5 6 7 8 , V, of first peak , V, second peak E1/2, V, DMFacetone buffer, ~5 Dissolution of Hg -0.06 -0.05 Maximum -0.16 -0.19
0.02 Bu4NClO4 -0.20 -0.35 -0.30 -0.21 -0.49 -0.41 -0.35 -0.62 -0.58 -0.58 -0.58 -0.55 -0.43
O N H O OH [O] HN HO Het (CH2) n OH O N HN O Het (CH2) n OH O
Het (CH2)n
Het (CH2) n Benzofurans
Het (CH2) n Indoles
This agrees well with the results obtained for compounds 1 and 2; in the first case the formation of only indole derivatives is observed, and in the second both indole and benzofuran derivatives are formed. However, for the most difficultly reduced indazolequinone 7 and for the derivatives of isoquinoline 4 and benzofuran 5 that exist in the middle range of potentials the picture remains uncertain, since for compounds 7 and 5 cyclization takes place in both directions (with the formation of 5-hydroxyindoles and 5-hydroxybenzofurans), while for the isoquinolinequinones only benzofuran cyclization is observed. Thus, the picture is more complicated when the Nenitzescu reaction occurs; the oxidizing agents are probably not only the initial quinones but also quinonecontaining intermediates that are formed (and, possibly, also other active forms of oxygen that are formed), and this requires further investigations.
EXPERIMENTAL Polarography was performed on a PY-1 polarograph with a dropping mercury electrode having the following characteristics: drop time 3.5 sec, mercury flow rate 2.9 mg/sec, 0.1 N potassium chloride solution, open circuit. The supporting electrolytes were 0.1 M solutions of Bu4NClO4 in DMF and acetate buffer solutions in mixture with DMF. The Bu4NClO4 was obtained by precipitation from solutions of Bu4NOH with 164
perchloric acid and was crystallized from ethanol. The DMF was dried over calcined potassium carbonate and was then distilled under vacuum. The half-wave potentials were reduced to the saturated calomel electrode scale by comparison with E1/2 of the K+ ion using Vlcek's method [8]. The investigated quinones were prepared by known methods: Compound 1 by the method [9], 2 [10], 4 [11], 5 [12], 7 [13], 8 [14]. The work was supported by grant No. 99-03-32973 from the Russian Fundamental Research Fund.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. G. R. Alien, Organic Reactions, Wiley Interscience, New York (1973), Vol. 20, p. 337. V. G. Granik, V. M. Lyubchanskaya, and T. I. Mukhanova, Khim.-Farm. Zh., No. 6, 37 (1993). C. Mann and K. Barnes, Electrochemical Reactions in Nonaqueous Systems [Russian translation], Khimiya, Moscow (1974), p. 187. S. Wawzonek, R. Berkey, and M. Blaha, J. Electrochem. Soc., 103, 456 (1956). I. Kolthoff and T. Reddy, J. Electrochem. Soc., 108, 980 (1961). B. Eggins and J. Chambers, Coll. Czech. Chem. Commun., 34, 232 (1969). V. D. Bezuglyi, L. Ya. Kheifets, E. R. Zakhs, and L. S. Efros, Zh. Org. Khim., 2, 1103 (1966). A. Vlcek, Coll. Czech. Chem. Commun., 20, 980 (1955). L. Weinberger and A. R. Day, J. Org. Chem., 24, 1451 (1959). K. Fries and H. Reitz, Liebigs Ann. Chem., 527, 53 (1936). G. R. Alien and M. Weiss, J. Org. Chem., 33, 198 (1968). Y. Jnouye and H. Kakisawa, Bull. Chem. Soc. Jpn., 42, 3318 (1969). V. M. Lyubchanskaya, L. M. Alekseeva, and V. G. Granik, Tetrahedron, 53, 15005 (1997). W. Middleton, H. Monney, and J. Parrick, Synthesis, 9, 740 (1984).
165
SYNTHESIS AND SOME CHEMICAL CONVERSIONS OF 2-([2,2]-5-PARACYCLOPHANYL)PYRROLE

A. V. Varlamov, T. N. Borisova, Boniface Nsabimana, A. I. Chernyshev, G. G. Aleksandrov, and L. G. Voskressensky 2-([2,2]-5-Paracyclophanyl)pyrrole has been synthesized and nitration and formylation of it have been effected. The 1--cyanoethyl derivative and 2-formyl-5-paracyclophanyl-3H-pyrrolizine have been obtained from 5-formyl-2-([2,2]-5-paracyclophanyl)pyrrole by the action of acrylonitrile and acrolein respectively under Michael reaction conditions. Keywords: paracyclophane, pyrrole, heterocyclization, addition, Trofimov reaction. The heterocyclization of ketoximes with acetylene in a superbasic medium (Trofimov reaction) is a simple and convenient method of obtaining substituted NH- and N-vinylpyrroles [1-3], tetrahydropyrrolo[3,2-c]pyridines [4], and tetrahydropyrrolo[1,2-c]pyrimidines [5]. The heterocyclization of oximes of acetophenones substituted in the aromatic ring has been described, however oximes of acetyl substituted [2,2]paracyclophanes have not been studied in this reaction. It might have been expected that the paracyclophane fragment, due to its structure and large steric bulk, will prove to have a different influence than substituted phenyl on the course of the Trofimov reaction. In the present work the heterocyclization of the oxime of 5-acetyl[2,2]paracyclophane (1) with acetylene in superbasic medium and some conversions of 2-([2,2]-5-paracyclophanyl)pyrrole (2) have been studied. The heterocyclization reaction was carried out in the systems KOHDMSO and RbOHDMSO at 85-110C and atmospheric pressure. The reaction was accompanied by resinification. In KOHDMSO the yield of substituted paracyclophane 2 was 16-22%, but its N-vinyl-substituted derivative 3 was not present in the reaction mixture. In addition to compound 2 the O-vinyl ether of oxime 1 (compound 4) and 5-acetyl[2,2]paracyclophane were isolated (6-8% yield) from the reaction mixture. The latter is formed by retro-oxime fission of the initial oxime. Thus oxime 1 behaves analogously to acetophenone oxime and its p-chloro and p-amino-substituted derivatives on heterocyclization in the presence of KOH, where the corresponding O-vinyl ethers were isolated but N-vinylpyrroles were not present in the reaction mixtures [10]. In RbOHDMSO the yield of pyrrole 2 was somewhat lower (9-14%), however in this case the N-vinylpyrrole 3 was obtained (6-8%), but the vinylic ether 4 was not present in the reaction mixture, since rubidium hydroxide is more reactive in the pyrrolization reaction and in the N-vinylation of pyrroles [11]. Certain chemical conversions of the newly synthesized pyrrole 2 have been studied, formylation according to WilsmeierHaack and nitration with copper nitrate in acetic anhydride according to Menke.
__________________________________________________________________________________________ Russian People's Friendship University, Moscow 117198; e-mail: avarlamov@sci.pfu.edu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 201-211, February, 2004. Original article submitted January 24, 2001. 166 0009-3122/04/4002-01662004 Plenum Publishing Corporation
2 1 12 11 10 9
3 4 13 14 15 16 7 5 6
Me
NOH
1
3
4 5
N1 H
+
3 DMF / POCl3
+
4
C NO
Me
2 Cu(NO3)2 Ac2O
O N CH2 O 7 CH2=CHCN H Triton B CH2CN C H
N H 6
NO2
N H 5 CH2=CHCHO
Triton B
O
1 2
4N 3
N CHO CH2
C H
CH2CHO
Both electrophilic substitution reactions proceeded at the -position of the pyrrole ring. The 2-formyl substituted pyrrole 5 was obtained in 69% yield for which a 4 to 5-fold excess of phosphorus oxychloride was required. The nitro derivative 6 was obtained in significantly lower yield (13%) due to marked resinification of the reaction mixture. On alkylation of pyrrole 2 with acrylonitrile under Michael reaction conditions in the presence of Triton B, 1-(-cyanoethyl)-5-formyl-2-(2,2]-5-paracyclophanyl)-pyrrole 7 was obtained. In the case of acrolein the Michael addition adduct underwent further intramolecular cyclization into 2-formyl-5-([2,2]-5paracyclophanyl)-3H-pyrrolizine (8). The possibility of intramolecular cyclization in the latter case is caused by the strong electron-withdrawing effect of the carbonyl group of the -formylethyl fragment. In the IR spectra of compounds 2, 5, and 6 there were bands for NH stretching vibrations at 3284-3434 cm-1. The intense band for the CO stretching vibrations in compounds 5, 7, and 8 was displayed at 1660, 1646, and 1727 cm-1 respectively. The stretching vibrations of the NO2 group in compound 6 and the CN group in compound 7 were observed at 1500, 1373, and 2260 cm-1 respectively. Signals were present for all the required protons in the 1H NMR spectra of compounds 1-8 (Table 1). A broadened signal was observed for the oxime group proton (8.9 ppm), a singlet for the methyl group protons (2.26 ppm), and complex multiplets for the aromatic and methylenic protons. The pyrrole ring in compound 2 167
168
TABLE 1. 1H NMR Spectra of [2,2]Paracyclophanyl-substituted Oximes 1, 4, Pyrroles 2, 3, 5-7, and Pyrrolizine 8

Compound 1 2 3 Chemical shifts, , ppm (coupling constants, J, Hz) NR 8.9, br. s ()* 8.16, br. s (NH) 6.68, dd, 4.52, dd, 5.07, dd, J = 8.9; 15.9; 1.2 (NCH=CH2) 7.14, dd, 4.22, dd, 4.75 dd, J = 6.7; 14.3; 1.5 (OCH=CH2)*3 9.15, br. s (NH) 9.27, br. s (NH) 2.39, m (2); 4.27, td (HB); 4.77, td (), JAB = 13.1, JACH2 = 6.9, JBCH2 = 7.3 (NCHHBCH2CN) 1- 7.45, br. s*5 H3 6.43, m, JNH,3 = 2.5, J3,4 = 3.4, J3,5 = 1.5 *2 H4 6.37, m, JNH,4 = 2.8, J3,4 = 3.4, J4,5 = 2.8 *2 5R1 5-H, 6.91, m, JNH,5 = 2.8, J3,5 = 1.5, J4,5 = 2.8 7.17, m paracyclophanyl 2 2.9-3.5, m 2.7-3.6, m 2.75-3.2, m Ar 6.4-6.75, m 6.45-6.75, m 6.35-6.85, m
4 5 6 7
6.54, dd, JNH,3 = 2.8, J3,4 = 4.0 6.51, dd, JNH,3 = 2.8, J3,4 = 4.3 6.61, d, J3,4 = 3.4*4
7.08, dd, JNH,4 = 2.8, J3,4 = 4.0 7.27, dd, JNH,4 = 2.8, J3,4 = 4.3*4 7.18, d, J3,4 = 4.3
9.55, s (CHO) 9.85, s ()
2.8-3.6, m 2.6-3.25, m 3.45-3.7, m 2.65-3.25, m 3.4-3.6, m 2.65-3.25, m
6.3-6.85, m 6.4-6.65, m 6.4-6.7 6.4-6.75, m
3- 4.75, d, 4.40, d, JA, = 20.5
6- *2
7- *2
2.85-3.20, m
6.4-6.8, m
_______ * 2.26, s, Me. *2 Overlapped by signals of aromatic protons. *3 2.25, s, Me. *4 Measured by the double resonance difference spectrum {4-H} or {NH}.
causes the appearance in its spectrum of a broadened signal for the NH proton (8.16 ppm), and three multiplets for the 3-H, 4-H, and 5-H protons with coupling constants characteristic of a pyrrole ring J1,5 = 2.8, J1,4 = 2.8, J1,3 = 2.5, J3,4 = 3.4, J3,5 = 1.5, and J4,5 = 2.8 Hz. Signals were recorded in the spectrum of the N-vinyl substituted derivative 3 for a three-spin system for the protons of the vinyl fragment with vicinal coupling constants Jcis = 8.9, Jtrans = 15.9, and geminal Jcis,trans = 1.2 Hz. In the spectrum of O-vinyl ether 4 a singlet was present for the methyl group (2.25 ppm) and three double doublets for the O-vinyl fragment. The spectra of the 5-formyl and 5-nitro substituted compounds 5 and 6 were characterized by the absence of the H-5 signal, but the vicinal coupling constant between H-3 and H-4 was 4.0 (5) and 4.3 Hz (6). In the low field portion of the spectrum of these compounds broadened signals were observed for the NH protons at 9.15 (5) and 9.27 (6) and for the formyl group of compound 5 at 9.55 ppm. In difference to compound 5, the broadened signal for the NH proton was absent from the spectrum of its N- cyanoethyl derivative 7, but three multiplets for the methylene protons were recorded at 4.77, 4.27, and 2.39 ppm with integrated intensities of 1H, 1H, and 2H respectively. The protons belonging to the first two multiplets have geminal coupling constant J = 13.1 Hz. In the spectrum of pyrrolizine 8 a singlet signal was observed at 9.70 ppm for the formyl proton, broadened due to long range coupling with the singlet for the H-1 proton at 7.45 ppm, and also two double doublet signals for the nonequivalent H-3 protons (A 4.75, B 4.40 ppm) with geminal coupling constant 20.5 Hz. In the mass spectra of compounds 2, 3, 5-8 (Table 2) there were peaks of various intensities for the molecular ions.The main decomposition path of the M+ ions of all the compounds is linked with the breakdown of the [2,2]paracyclophene fragment into two, as a result of which fragment ions are formed with m/z 104 and 1. In the case of pyrroles 6-8, having a functional group at C(2) of the pyrrole or pyrrolizine fragment, a second breakdown pathway for M+ is linked with elimination of the functional group and the formation of fragment 2.
N R + M 2, 3, 58
R1 CH2
+.
CH2
+.
R1 2 CH2 m/z 104 +. N H
+
CH2 1
N R
R1
R1 (R1 = H) N +
R1 (R = H)
m/z 167
m/z 168
On dissociation of the M+ ion of compound 7 fission of CH2CN was observed, characteristic of N-ethyl substituted pyrroles [12]. In the second stage of decomposition the 1 ion eliminates either R or R1 with the formation of a fragment ion with m/z 168, probably having the structure of a tropiliumpyrrolizine cation. This ion then eliminates H. In the case of the formyl and nitro-substituted pyrroles 5-7 the 1 ion ejects CO and OH respectively.
169
TABLE 2. Fragment Ions in the Mass Spectra of Compounds 2, 3, 5-8

Compound 2 3 5 6 7 M+ 273 (30) 299 (100) 301 (10) 318 (8) 354 (31) 339 (3) 1 169 (38) 195 (40) 197 (3) 214 (4) 250 (13) 235 (4) 2 m/z (Irel, %) 168 (100) (6) (10) 272 (46) 326 (5) 310 (5) (31) (18.7)
104 (100) (8) (100) (100) (100)
167 (25) (10) (10) (23) (25)
Other ions
[1]+ 194 (90) [1O]+ 169 (10) [1H]+ 197 (15) [1O]+ 222 (35) [1]+ 249 (17) [MCH2CN]+ 314 (5) [2CO]+ 206 (7)
(31)
(15)
(13)
The molecular and crystal structures of 2-paracyclophanyl-1-vinylpyrrole 3 were established by X-ray structural analysis. The crystal structure of compound 3 contains two crystallographically independent molecules A and B packed together (see Fig. 1). The numbering of the atoms in the A and B molecules is the same. In Tables 3, 4 and 5 are given the coordinates of atoms, bond lengths, and valence angles existing in the A and B molecules. The paracyclophane fragment has the common geometric parameters for this system [13,14]. The deviation of the tertiary atoms C(1), C(4), C(9), and C(12) from the plane of the benzene rings was 0.16 , as for other [2,2]paracyclophanes. As a result of this the benzene rings take on a boat configuration. The pyrrole ring is turned from the paracyclophane plane by 44.8 in molecule A and by 42.5 in molecule B. Molecules A and B differ in the angle of turn of the vinyl group relative to the pyrrole ring. The appropriate dihedral angle is 5.81 in molecule A and 22.83 in molecule B. The C(21)=C(22) bond lengths in the vinyl group are 1.263(9) and 1.308(7) respectively, i.e. shorter than the length of this bond in alkenes. The N(1)C(21) bond lengths in both molecules were close to one another and were 1.414(5) and 1.410(5) , shorter than in amines (1.470 ). This indicates the displacement of electron density from the pyrrole ring to the vinyl group. The X-ray structural analysis data correlate well with the data obtained from other physicochemical methods [1]. The pyrrole ring is flat, the - (C(17)C(20)), '-' (C(18)C(19)), and -' (C(19)C(20)) bonds in the pyrrole rings of both molecules are shorter
Fig. 1. General form of molecule A and numbering of atoms. 170
than in pyrrole (1.382 and 1.417 respectively). The lengths of the N(1)- and N1-' bonds were different in both molecules. The N(1)C(17) bond has the same length (1.370 ), but the N(1)C(18) bond at 1.387(4)-1.384(4) , is longer than in pyrrole.
TABLE 3. Coordinates of Atoms in Fractions of the Unit Cell Axes and Thermal Corrections Uiso and Ueq for Compound 3
Atom 1 x 2 y 3 Molecule N(1) C(1) C(2) C(3) C(4) C(5) C(6) C(7) C(8) C(9) C(10) C(11) C(12) C(13) C(14) C(15) C(16) C(17) C(18) C(19) C(20) C(21) C(22) H(2) H(3) H(5) H(6) H(71) H(72) H(81) H(82) H(11) H(13) H(14) H(151) H(152) H(161) H(162) H(18) H(19) H(20) H(21) H(221) H(222) 0.1533(2) 0.2170(4) 0.3130(4) 0.3622(4) 0.3185(3) 0.2395(3) 0.1905(4) 0.1348(5) 0.0663(4) 0.0781(2) 0.1580(2) 0.1995(3) 0.1654(3) 0.0689(3) 0.0273(3) 0.2406(4) 0.3356(5) 0.2108(2) 0.2288(3) 0.3321(3) 0.3221(3) 0.0361(3) -0.0171(5) 0.335(3) 0.415(3) 0.211(3) 0.134(3) 0.076(4) 0.174(3) -0.009(4) 0.084(3) 0.262(2) 0.045(3) -0.032(3) 0.197(4) 0.281(4) 0.395(5) 0.337(4) 0.207(2) 0.395(3) 0.380(3) -0.001(3) 0.009(6) -0.095(5) 0.9276(1) 0.8737(2) 0.8658(3) 0.8028(4) 0.7431(3) 0.7544(3) 0.8182(3) 0.9311(2) 0.9183(2) 0.8458(2) 0.8288(2) 0.7616(2) 0.7107(2) 0.7247(2) 0.7906(2) 0.6511(2) 0.6729(3) 0.8806(2) 0.9662(2) 0.9449(2) 0.8915(2) 0.9297(2) 0.9710(4) 0.904(2) 0.791(2) 0.715(2) 0.823(2) 0.930(2) 0.978(2) 0.926(2) 0.957(2) 0.750(1) 0.689(2) 0.803(2) 0.617(2) 0.632 (2) 0.670(3) 0.637(2) 1.003(2) 0.965(2) 0.863(2) 0.899(2) 1.006(4) 0.973(3) 0.3113(2) -0.0114(2) 0.0425(3) 0.0547(3) 0.0126(3) -0.0563 (3) -0.0681(3) 0.0055(3) 0.0917(3) 0.1295(2) 0.1991(2) 0.2018(2) 0.1413(2) 0.0887(2) 0.0830(2) 0.1187(4) 0.0529(4) 0.2593(2) 0.3629(3) 0.3434(3) 0.2797(2) 0.3186(3) 0.3678(5) 0.077(2) 0.101(3) -0.091(2) -0.110(2) -0.056(4) 0.019(3) 0.075(3) 0.144(2) 0.242(2) 0.048(2) 0.037(2) 0.085(3) 0.179(3) 0.089(4) 0.003(3) 0.404(2) 0.376(2) 0.251(2) 0.274(3) 0.405(4) 0.369(3) 0.0617(7) 0.075(1) 0.084(1) 0.086(1) 0.079(1) 0.077(1) 0.076(1) 0.094(1) 0.071(1) 0.0492(8) 0.0447(7) 0.0504(8) 0.0606(9) 0.0624(9) 0.0567(9) 0.092(1) 0.105(2) 0.0480(7) 0.070(1) 0.069(1) 0.0564(8) 0.086(1) 0.174(3) 0.07(1) 0.10(1) 0.09(1) 0.08(1) 0.15(2) 0.12(1) 0.12(2) 0.09(1) 0.057(8) 0.07(1) 0.08(1) 0.13(2) 0.13(2) 0.16(2) 0.13(2) 0.07(1) 0.09(1) 0.08(1) 0.09(1) 0.22(3) 0.16(2) z 4 Uiso/Ueq 5
171
TABLE 3 (continued)
1 N(1) C(1) C(2) C(3) C(4) C(5) C(6) C(7) C(8) C(9) C(10) C(11) C(12) C(13) C(14) C(15) C(16) C(17) C(18) C(19) C(20) C(21) C(22) H(2) H(3) H(5) H(6) H(71) H(72) H(81) H(82) H(11) H(13) H(14) H(151) H(152) H(161) H(162) H(18) H(19) H(20) H(21) H(221) H(222) 2 0.3517(2) 0.1620(3) 0.1664(3) 0.2539(4) 0.3397(3) 0.3221(4) 0.2338(4) 0.1022(5) 0.1762(3) 0.2938(3) 0.3816(2) 0.4672(3) 0.4685(3) 0.3975(3) 0.3111(3) 0.5292(4) 0.4557(4) 0.3782(2) 0.3513(3) 0.3776(3) 0.3950(3) 0.3359(3) 0.2816(4) 0.114(4) 0.262(3) 0.375(3) 0.228(2) 0.037(7) 0.097(6) 0.144(5) 0.173(3) 0.522(2) 0.403(2) 0.258(3) 0.550(4) 0.584(4) 0.497(5) 0.452(4) 0.344(2) 0.386(3) 0.409(3) 0.367(3) 0.272(4) 0.246(3) 3 Molecule B 1.4072(1) 1.1854(2) 1.1194(3) 1.0754(2) 1.0964(2) 1.1558(2) 1.1997(2) 1.2438(4) 1.2843(3) 1.2558(2) 1.2787(1) 1.2318(2) 1.1653(2) 1.1514(2) 1.1963(2) 1.1067(2) 1.0662(3) 1.3448(2) 1.4584(2) 1.4298(2) 1.3589(2) 1.4157(2) 1.4672(3) 1.108(2) 1.032(2) 1.168(2) 1.243(2) 1.232(4) 1.278(4) 1.287(3) 1.333(2) 1.245(1) 1.106(2) 1.184(1) 1.070(2) 1.127(2) 1.066(3) 1.019(2) 1.505(2) 1.453(2) 1.323(2) 1.375(2) 1.467(2) 1.503(2) 4 0.1992(2) 0.1312(3) 0.1659(3) 0.1492(3) 0.0955(3) 0.0444(3) 0.0618(3) 0.1783(6) 0.2452(4) 0.2602(2) 0.2070(2) 0.1907(2) 0.2256(2) 0.2945(2) 0.3111(2) 0.1807(4) 0.1091(4) 0.1581(2) 0.1345(3) 0.0549(4) 0.0697(3) 0.2930(3) 0.3290(5) 0.220(3) 0.185(2) 0.004(2) 0.034(2) 0.204(5) 0.131(4) 0.302 (4) 0.236(3) 0.150(2) 0.323(2) 0.354(2) 0.234(3) 0.148(3) 0.049(4) 0.134(3) 0.155(2) -0.000(3) 0.024(2) 0.333(3) 0.393(3) 0.287(2) 5 0.0594(7) 0.083(1) 0.083(1) 0.074(1) 0.070(1) 0.079(1) 0.083 (1) 0.125(2) 0.085(1) 0.0553(8) 0.0453(7) 0.0487(8) 0.0555(8) 0.068(1) 0.067(1) 0.079(1) 0.096(1) 0.0490(7) 0.074(1) 0.079(1) 0.0623(9) 0.075(1) 0.104(2) 0.12(1) 0.08(1) 0.08(1) 0.06(1) 0.24(4) 0.20(4) 0.17(2) 0.10(1) 0.049(8) 0.07(1) 0.066(9) 0.13(2) 0.12(2) 0.18(2) 0.12(2) 0.06(1) 0.11(1) 0.08(1) 0.11(1) 0.13(2) 0.09(1)
The pyrrole fragments of molecules A and B differ in bond length [C(17)C(20), 1.374(4) and 1.351(5) respectively] and the size of the valence angle [C(18)N(1)C(21), 125.4(3) and 126.9(3) respectively]. It is possible that these differences are caused by the sizes of the dihedral angles between the paracyclophane, pyrrole, and vinyl fragments.
172
TABLE 4. Bond Lengths (d, ) in Molecules A and B

Bond N(1)C(18) N(1)C(17) N(1)C(21) C(1)C(2) C(1)C(6) C(1)C(7) C(2)C(3) C(3)C(4) C(4)C(5) C(4)C(16) C(5)C(6) C(7)C(8) C(8)C(9) A 1.376(4) 1.387(4) 1.414(4) 1.381(6) 1.384(5) 1.507(6) 1.356(6) 1.396(6) 1.380(5) 1.485(6) 1.367(5) 1.557(6) 1.506(4) B 1.370(4) 1.384(4) 1.410(4) 1.368(5) 1.389(6) 1.514(7) 1.377(5) 1.382(5) 1.379(5) 1.514(6) 1.386(6) 1.517(7) 1.522(5) Bond C(9)C(14) C(9)C(10) C(10)C(11) C(10)C(17) C(11)C(12) C(12)C(13) C(12)C(15) C(13)C(14) C(15)C(16) C(17)C(20) C(18)C(19) C(19)C(20) C(21)C(22) A 1.390(4) 1.415(4) 1.384(4) 1.461(4) 1.374(4) 1.395(5) 1.503(5) 1.363(5) 1.580(7) 1.374(4) 1.346(5) 1.393(5) 1.263(6) B 1.378(5) 1.407(4) 1.394(4) 1.461(4) 1.378(4) 1.375(5) 1.508(5) 1.378(5) 1.556(6) 1.351(4) 1.343(6) 1.395(5) 1.308(5)
TABLE 5. Valence Angles (, deg) in Molecules A and B

Angle C(18)N(1)C(17) C(18)N(1)C(21) C(17)N(1)C(21) C(2)C(1)C(6) C(2)C(1)C(7) C(6)C(1)C(7) C(3)C(2)C(1) C(2)C(3)C(4) C(5)C(4)C(3) C(5)C(4)C(16) C(3)C(4)C(16) C(6)C(5)C(4) C(5)C(6)C(1) C(1)C(7)C(8) C(9)C(8)C(7) C(14)C(9)C(10) C(14)C(9)C(8) C(10)C(9)C(8) A 109.0(3) 125.4(3) 125.2(3) 115.4(5) 121.5(4) 121.8(4) 121.6(4) 121.4(4) 115.6(5) 121.2(5) 121.7(4) 121.0(4) 121.7(4) 112.8(3) 113.7(3) 116.9(3) 119.4(3) 122.3(3) B 108.3(3) 126.9(3) 124.7(3) 116.3(4) 121.9(6) 120.5(6) 121.4(4) 120.8(4) 116.9(4) 120.9(4) 120.7(4) 120.4(4) 121.0(4) 113.7(4) 115.2(4) 117.5(3) 119.8(3) 121.1(3) Angle C(11)C(10)C(9) C(11)C(10)C(17) C(9)C(10)C(17) C(12)C(11)C(10) C(11)C(12)C(13) C(11)C(12)C(15) C(13)C(12)C(15) C(14)C(13) C(12) C(13) C(14)C(9) C(12)C(15)C(16) C(4)C(16)C(15) C(20) C(17)N(1) C(20)C(17)C(10) N(1)C(17)C(10) C(19)C(18)N(1) C(18)C(19)C(20) C(17)C(20)C(19) C(22)C(21)N(1) A 118.0(3) 118.1(3) 123.2(3) 123.2(3) 116.3(3) 121.2(3) 121.2(3) 120.5(3) 121.8(3) 112.7(4) 113.3(4) 106.2(3) 129.2(3) 124.5(3) 108.1(3) 108.1(3) 108.6(3) 125.8(5) B 117.8(3) 119.0(3) 122.6(3) 122.3(3) 117.2(3) 120.1(4) 121.9(3) 120.0(4) 121.5(3) 113.6(3) 113.1(3) 107.1(3) 130.2(3) 122.7(3) 108.5(4) 107.6(4) 108.6(4) 124.9(5)
EXPERIMENTAL The 1H NMR spectra were recorded for ~2% solutions of compounds in CDCl3 on a Bruker WP 200 (200 MHz) spectrometer, and the 13C NMR spectra for 10% solutions on a Bruker WM 400 (100 MHz) instrument at 30C. Chemical shifts were measured relative to TMS and to solvent CDCl3 (13C, 77.0 ppm) as internal standard. The mass spectra were obtained on MX 1303 and Kratos MS 2 SRF instruments. The IR spectra were recorded on a UR 20 spectrophotometer in KBr disks. Aluminum oxide of Brockmann activity grade II was used for preparative chromatography and plates with a bound layer of aluminum oxide and silica gel of types Alufol and Silufol UV 254 were used for TLC. X-Ray Structural Analysis of Compound 3. The crystals were monoclinic, space group P21/C: a = 11.997(3), b = 19.222(6), c = 14.721(6) ; V = 3392(2) 3; Z = 8; dcalc = 1.172 g/cm3; (MoK) = 0.067 mm-1. The diffraction experiment was carried out on a Cad-4 diffractometer (MoK radiation, graphite 173
monochromator, scanning, 2max = 48, 3237 reflections with F2 3(I). The structure was solved by the direct method with the SHELXL-93 [16] program to R 0.041 (wR2 = 0.098). Oxime of 5-Acetyl[2,2]paracyclophane (1). 5-Acetyl[2,2]paracyclophane (10 g, 0.04 mol), hydroxylamine hydrochloride (5.56 g, 0.08 mol), and sodium acetate (9.84 g, 0.12 mol) in 2-propanol (150 ml) were boiled for 3 h (check by TLC). The mixture was cooled, the solid was filtered off, and washed with water. Oxime 1 (9.96 g, 94%) was obtained as colorless crystals of mp 173-175C (ethyl acetate), Rf 0.53 (Alufol, chloroformheptane, 1.5:1). IR spectrum, , cm-1: 3330 (OH). 13C NMR spectrum (100 MHz, CDCl3), , ppm: 157.3 (C=N); 139.6, 139.5, 139.3 (C(5), C(4), C(7)); 138.0, 137.6 (C(1), C(10)); 135.8 (d, C(6)); 133.4, 132.8 (d, C(15), C(16)); 132.7, 132.4, 132.3, 131.2 (d, C(11), C(12), C(13), C(14)); 35.5, 35.3, 35.2 (t, C(2), C(8), C(9)); 34.8 (m, C(3)); 15.8 (q, CH3). Mass spectrum, m/z (Irel, %): 265 (30), 248 (3), 161 (35), 160 (32), 144 (100), 143 (20), 142 (5), 128 (5), 115 (13), 105 (20), 104 (28), 103 (19), 91 (10), 78 (16), 77 (18). Found, %: C 80.00; H 7.40; N 5.10. M+ 265. C18H19NO. Calculated, %: C 80.02; H 7.20; N 5.30. M 265. 2-([2,2]-5-Paracyclophanyl)pyrrole (2), 2-([2,2]-5-Paracyclophanyl)-1-vinylpyrrole (3), and 5-(1-Vinyloxyiminoethyl)[2,2]paracyclophane (4). A. Acetylene was bubbled through a solution of oxime 1 (5 g, 19 mmol) and potassium hydroxide (0.11 g, 19 mmol) in DMSO (50 ml) at 95-100C for 4 h (check by TLC). The mixture was poured onto ice and extracted with ether (5 100 ml). The ether extract was dried over magnesium sulfate. After distillation of the solvent the residue (4.7 g) was chromatographed on a column (2.5 55 cm) of aluminum oxide, eluent being ethyl acetateheptane, 1:40. Initially the oxime vinyl ether 4 (0.31 g, 5.6%) was washed off, white crystals mp 86-87C (ethyl acetateheptane), Rf 0.75 (silufol, ethyl acetateheptane, 1:3). Mass spectrum, m/z (Irel, %): 291 (25) M+, 263 (20), 248 (100), 144 (80), 104 (7). Found, %: C 82.61; H 7.22; N 4.99. M+ 291. C20H21NO. Calculated, %: C 82.50; H 7.20; N 4.81. M 291. Then pyrrole 2 (1.14 g, 22%) was washed off as colorless crystals, becoming pink on standing, mp 135-137C (ethyl acetate heptane), Rf 0.60 (silufol, ethyl acetateheptane, 1:3). IR spectrum, , cm-1: 3434 (NH). Mass spectrum, m/z (Irel, %): 273 (30) M+, 169 (38), 168 (100), 167 (25), 142 (8), 141 (13), 131 (28), 115 (16), 104 (100), 69 (70). Found, %: C 87.89; H 6.98; N 5.10. M+ 273. C20H19N. Calculated, %: C 87.91; H 6.95; N 5.12. M 273. Finally 5-acetyl[2,2]paracyclophane (0.14 g) was washed off. Colorless crystals, mp 104-105C (heptane). A mixing test with an authentic sample gave no depression of melting point. B. The procedure described above using oxime 1 (5 g, 19 mmol) and rubidium hydroxide (0.99 g, 19 mmol) in DMSO (50 ml) at 95-100C gave compound 2 (0.73 g, 14%), mp 136-137C (ethyl acetate heptane), a sample of which gave no depression of melting point in a mixing test with the sample obtained in A; the N-vinyl-substituted pyrrole 3 (0.8 g:14%), colorless crystals, mp 74-76C (ethyl acetateheptane), mass spectrum, m/z (Irel, %): 299 (100), 195 (40), 194 (90), 180 (22), 168 (6), 167 (10), 152 (8), 141 (6), 128 (6), 104 (8), and 5-acetyl[2,2]paracyclophane (0.33 g), mp 103-104C. 5-Formyl-2-([2,2]-5-paracyclophanyl)pyrrole (5). Pyrrole 2 (1 g, 3.7 mmol) in DMF (5 ml) was added dropwise to Vilsmeier reagent obtained from DMF (2.7 g, 37 mmol) and freshly distilled phosphorus oxychloride (2.3 g, 14 mmol) at -5C. The mixture was left at 20C for 2 h (check by TLC), made alkaline to pH 8 with 10% aqueous sodium carbonate solution, extracted with chloroform (3 20 ml), and the extract dried over magnesium sulfate. After distillation of the chloroform the residue (1.42 g) was chromatographed on a column (2.9 20 cm) of aluminum oxide, eluting with chloroform. Compound 5 (0.76 g, 69%) was isolated as yellow crystals, mp 152-153C (ethyl acetateheptane), Rf 0.67 (silufol, ethyl acetateheptane, 1:4). IR spectrum, , cm-1: 3284 (NH), 1660 (CO). Mass spectrum, m/z (Irel, %): 301 (10) M+, 197 (3), 196 (3), 169 (10), 168 (10), 115 (17), 104 (100), 103 (70), 102 (23), 101 (16), 91 (18), 86 (61), 78 (22). Found, %: C 84.03; H 6.51; N 5.19. M+ 301. C21H19NO. Calculated, %: C 83.70; H 6.31; N 4.65. M 301. 5-Nitro-2-([2,2]-5-paracyclophanyl)pyrrole (6). Compound 2 (0.2 g, 0.73 mmol) in acetic anhydride (5 ml) was added dropwise to a suspension of Cu(NO3)2.3H2O (0.18 g, 0.73 mmol) in acetic anhydride (5 ml) at -12C. After 1 h (check by TLC) the reaction mixture was treated with saturated sodium carbonate solution to pH 8, and extracted with ether (4 20 ml). The extract was dried over magnesium sulfate. After distillation of 174
ether the residue (0.18 g) was chromatographed on a column (3.2 19 cm) of aluminum oxide, eluting with ethyl acetateheptane. Pyrrole 6 (80 mg, 34.5%) was obtained as yellow crystals, mp 168-170C (ethyl acetate heptane), Rf 0.79 (Silufol, ethyl acetateheptane, 1:4). IR spectrum, , cm-1: 1570 and 1360 (NO2). Mass spectrum, m/z (Irel, %): 318 (8) [M]+, 288 (2), 272 (46), 214 (4), 197 (15), 168 (31), 167 (23), 166 (15), 149 (15), 146 (23), 145 (11), 144 (11), 141 (15), 115 (19), 105 (38), 104 (100), 91 (50). Found, %: C 75.83; H 5.32; N 9.05. M+ 318. C20H18N2O2.. Calculated, %: C 75.47; H 5.66; N 8.81. M 318. 1-(-Cyanoethyl)-5-formyl-2-([2,2]-5-paracyclophanyl)pyrrole (7). A solution of formylpyrrole 5 (0.3 g, 0.99 mmol) and acrylonitrile (0.053 g, 1.9 mmol) in absolute benzene (25 ml) was heated at 65C for 5 h in a current of nitrogen in the presence of Triton B (5 drops) (check by TLC). The benzene was distilled off, water (10 ml) was added, the mixture was extracted with chloroform, and the extract dried over magnesium sulfate. After distilling off the chloroform the residue (0.43 g) was purified on a column (2.9 22 cm) of aluminum oxide, eluent being chloroform. Compound 7 (0.26 g, 65%) was obtained as pink crystals of mp 166-168C, Rf 0.51 (Silufol, ethyl acetateheptane, 1:4). IR spectrum, , cm-1: 2260 (CN), 1660 (CO). Mass spectrum, m/z (Irel, %): 354 (31) M+, 314 (5), 250 (13), 249 (17), 222 (35), 221 (32), 182 (20), 181 (31), 180 (27), 168 (19), 167 (25), 166 (16), 149 (40), 105 (100), 104 (100), 91 (43). Found, %: C 81.53; H 5.87; N 8.05. M+ 354. C24H22N2O. Calculated, %: C 81.36; H 6.21; N 7.91. M 354. 2-Formyl-5-([2,2]-5-paracyclophanyl)-3H-pyrrolizine (8). A solution of formylpyrrole 5 (0.3 g, 0.99 mmol) and acrolein (0.12 g, 1.9 mmol) in absolute benzene (25 ml) was heated at 50C for 1.5 h in a current of nitrogen in the presence of Triton B (5 drops) (check by TLC). The benzene was distilled off, water (10 ml) was added, the mixture was extracted with chloroform, and the extract dried over magnesium sulfate. After distilling off the chloroform the residue (0.32 g) was purified on a column (1.2 40 cm) of aluminum oxide, eluting with ethyl acetateheptane, 1:10. Pyrrolizine 8 (40 mg, 36%) was isolated as yellow crystals of mp 128-129C (ethyl acetateheptane), Rf 0.67 (Silufol, ethyl acetateheptane, 1:4). IR spectrum, , cm-1: 1770 (CO). Mass spectrum, m/z (Irel, %): 339 (3) M+, 338 (8), 310 (5), 235 (4), 206 (7), 169 (16), 168 (15), 167 (58), 105 (42), 104 (31), 97 (100), 91 (31). Found, %: C 85.10; H 6.51; N 3.92. M+ 339. C24H21NO. Calculated, %: C 84.96; H 6.19; N 4.13. M 339.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. B. A. Trofimov and A. I. Mikhaleva, N-Vinylpyrroles [in Russian], Nauka, Novosibirsk (1984). B. A. Trofimov, in R. A. Jones (editor), The Chemistry of Heterocyclic Compounds, Vol. 48, Pt II, Wiley, New York (1992), p. 131. B. A. Trofimov and A. I. Mikhaleva, Zh. Org. Khim., 32, 1127 (1996). T. N. Borisova, A. V. Varlamov, N. D. Sergeeva, A. T. Soldatenkov, O. V. Zvolinskii, A. A. Astakhov, and N. S. Prostakov, Khim. Geterotsikl. Soedin., 973 (1987). N. S. Prostakov, A. V. Varlamov, T. N. Borisova, and N. D. Sergeeva, Khim. Geterotsikl. Soedin., 1287 (1987). B. A. Trofimov, S. E. Korostova, L. N. Balabanova, and A. I. Mikhaleva, Zh. Org. Khim., 14, 1733 (1978). S. E. Korostova, L. N. Sobenina, L. N. Nesterenko, I. A. Aliev, and A. I. Mikhaleva, Zh. Org. Khim., 20, 1960 (1984). B. A. Trofimov, S. E. Korostova, L. N. Balabanova, and A. I. Mikhaleva, Khim. Geterotsikl. Soedin., 489 (1978). S. E. Korostova, S. G. Shevchenko, and M. V. Sigalov, Khim. Geterotsikl. Soedin., 187 (1991). S. E. Korostova, A. I. Mikhaleva, L. N. Sobenina, S. G. Shevchenko, and V. V. Sherbanov, Khim. Geterotsikl. Soedin., 1501 (1985). 175
11. 12. 13. 14. 15. 16.
S. E. Korostova, S. G. Shevchenko, E. A. Polubeshchev, A. I. Mikhaleva, and B. A. Trofimov, Khim. Geterotsikl. Soedin., 770 (1989). N. S. Vul'fson, V. G. Zaikin, and A. I. Mikaya, Mass Spectrometry of Organic Compounds [in Russian], Khimiya, Moscow (1986). P. Gautzel and T. Krueblood, Acta Crystallogr., 18, 958 (1965). M. Sheehan and D. Y. Gram, J. Am. Chem. Soc., 91, 3953 (1969). G. M. Sheldrick, SHELXS 86. Program for the Solution of Crystal Structures. Univ. of Gttingen, Gttingen, Germany (1985). G. M. Sheldrick, SHELXS 93. Program for the Refinement of Crystal Structures. Univ. of Gttingen, Gttingen, Germany (1993).
176
CYCLIZATION OF DIALKYL-(4-HYDROXY2-BUTYNYL)(3-ALKENYL-PROPARGYL)AMMONIUM SALTS AND RECYCLIZATION OF THE 2,2-DIALKYL-4HYDROXYMETHYLISOINDOLINIUM SALTS OBTAINED

A. R. Gevorkyan1, E. O. Chukhadzhyan1, El. O. Chukhadzhyan1, and G. A. Panosyan2 2,2-Dialkyl-4-hydroxymethylisoindolinium chlorides, like benzisoindolinium salts, readily undergo intramolecular recyclization under conditions of aqueous alkaline decomposition, comprising fission of the isoindolinium ring and formation of a dihydrofuran ring leading to (1,3-dihydro-4isobenzofuranylmethyl)dialkylamines. Keywords: 4-hydroxy-2-butynyl group, dialkyl(3-alkenylpropargyl)-(4-hydroxybutyn-2-yl)ammonium salts, (1,3-dihydro-4-isobenzofuranylmethyl)dialkylamines, base catalysis, recyclization, cyclization. Chloride and bromide salts of dialkyl(4-hydroxy-2-butynyl)(3-alkenylpropargyl)ammonium of type 1 and of -(3-phenylpropargyl)ammonium undergo intramolecular cyclization in the presence of catalytic amounts of aqueous alkali with the formation of 2,2-dialkyl-4-hydroxymethylisoindolinium salts 2 and -benz[f]isoindolinium salts [1]. When studying the aqueous alkaline decomposition of 2,2-dialkyl-4-hydroxymethylbenzCH 2OH CH 2C C R 2N l CH 2C C C 1ag X O CH 2 CH 2 CH 2OH OH OH R 2N
l
X 2ag O
R 2N l X
OH R 2N 3ag X
1a, 2a, 3a; 1b, 2b, 3b R = Et; 1c, 2c, 3c R = Pr; 1d, 2d, 3d R = Bu; 1e, 2e, 3e R2 = (CH2)4; 1f, 2f, 3f R2 = (CH2)5, 1g, 2g, 3g R2 = (CH2)2O(CH2)2
In all cases X = H, 1b, 2b, 3b X = Me
__________________________________________________________________________________________ Institute of Organic Chemistry, National Academy of Sciences of the Armenian Republic, Erevan 375091; e-mail: hasulik4@mail.ru. 2 Centre for the Investigation of Molecular Structure, National Academy of Sciences of the Armenian Republic, Erevan 375014; e-mal: henry@msrc.am. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 212-217, February, 2004. Original article submitted November 12, 2003. 0009-3122/04/4002-01772004 Plenum Publishing Corporation 177
1
178
TABLE 1. Physicochemical Characteristics and Yields of Amines 3a-g

Compound Empirical formula Found, % Calculated, % H 76.38 76.06 76.97 76.67 77.56 77.21 78.44 78.11 77.10 76.81 77.73 77.38 71.57 71.21 9.47 9.33 9.02 9.65 9.83 9.93 10.60 10.41 8.68 8.43 9.06 8.81 7.56 7.81 Bp., (mm Hg.) mp, 110 (2) 114 (2) 140 (1) 82 (1) 107 (1) 127 (1) 145 (2) 50-51 (hexane) nD20 Mp picrate, Mp hydrochloride, C (ethanol) C (abs. ethanol) IR spectrum, , cm-1 Yield, % 61 3 3b 3c 3d 3e 3f 3g C13H19NO C14H21N C15H23N C17H27N C13H17NO C14H19NO C13H17NO2 6.05 6.82 6.60 6.39 6.25 6.00 5.07 5.36 7.04 6.89 6.23 6.45 6.14 6.39 1.5238 1.5290 1.5110 1.5070 1.5440 1.5410 137 * 145-146 * 155 186-187 174-175 140-141 *2 152-154 *2 193 224-225 194-195 705, 760, 1050, 1200, 1550, 1600, 3030 840, 1030-1070, 1200, 1590, 1600 705, 770, 1050, 1200-1240, 1540, 1590, 3040 700, 770, 1050, 1200, 1550, 1600, 3040 705, 770, 1050, 1200-1240, 1540, 1590, 3040 700, 750-770, 1050, 1200, 1550, 1600, 3040 705, 760, 1050, 1200, 1550, 1590, 3050 64 59 60 60 68 69
_______ * No picrate formed. *2 Hygroscopic.
TABLE 2. Physicochemical Characteristics of Amines 4c,d,f and Salts 1c,d,f,g

Compound Empirical formula C11H19N C13H23N C10H15N C15H24ClNO C17H28ClNO C14H20ClNO C13H18ClNO2 Found, % Calculated, % H l 11.84 11.59 12.29 11.99 10.36 10.13 9.12 8.97 9.65 9.47 8.14 7.94 7.30 7.09 Bp, C (mm Hg) N 8.26 8.47 6.92 7.25 9.70 9.39 4.98 5.19 4.96 4.70 5.77 5.52 5.50 5.48 64-65 (3) 84 (3) 83-85 (2) * * * * 1.4662 1.4690 1.5020 nD20 Mp hydrochloride, C (abs. ethanol) *2 83 137-138 Yield, % 58 55 58 ~100 ~100 ~100 ~100
80.24 79.94 81.21 80.76 80.85 80.48 67.02 66.77 68.75 68.5 66.51 66.26 61.33 61.05
4c 4d 4f 1c 1d 1f 1g
13.48 13.14 11.58 11.90 13.62 13.97 13.53 13.86
_______ * Salts 1c,d,f,g were honey-like. *2 Salts were hygroscopic.
179
180
TABLE 3. 1H NMR Spectra of Amines 3a-g in DMSO-d6+CCl4, , ppm, Coupling Constants (J, Hz)
O 3b* R = C2H5, X = CH3; 3a, cg R = C2H5, C3H7, C4H9, (CH2)4, (CH2)5, (CH2)2O(CH2)2, X=H
R 1.01 (6H, t, J = 7.2, 2CH3); 2.45 (4H, q, J = 7.2, 2CH2) 0.85 (6H, t, J = 7.3, 2CH3); 1.45 (4H, m, 2CH3CH2); 2.32 (4H, t, J = 7.3, N(CH2)2) 0.87 (6H, t, J = 7.2, 2CH3); 1.27 (4H, m, 2CH3CH2); 1.41 (4H, m, 2CH3CH2CH2); 2.34 (4H, t, J = 7.1, N(CH2)2) 1.70-1.80 (4H, m, 2CH2); 2.41-2.48 (4H, m, N(CH2)2) 1.44 (2H, m, CH2); 1.55 (4H, quintet, J = 5.1, 2CH2); 2.32 (4H, t, J = 5.1, N(CH2)2) 2.36 (4H, m, N(CH2)2); 3.59 (4H, m, O(CH2)2)
R2N
Compound 3a 3c 3d 3e 3f 3g NCH2, s 3.46 3.44 3.43 3.52 3.36 3.41 H2COCH2, t 4.97, 5.03, J = 2.2 4.98, 5.02, J = 2.3 4.99, 5.02, J = 2.3 4.99, 5.02, J = 2.3 4.98, 5.03, J = 2.3 5.00, 5.05, J = 2.2
X
HAr, m 7.05-7.15 7.06-7.17 7.05-7.17 7.05-7.17 7.06-7.16 7.05-7.20
_______ * 1H NMR spectrum of amine 3b (CDCl3), , ppm (J, Hz): 1.03 (6H, t, J = 7.2, 2CH3); 2.36 (3H, s, CH3); 2.48 (4H, q, J = 7.2, 2CH2); 3.45 (2H, s, NCH2); 5.08 (2H, br. s, OCH2); 5.14 (2H, br. s, OCH2); 6.92 and 7.01 (2H, br. s, HAr). 13 C NMR spectrum of amine 3f (DMSO-d6+CCl4), , ppm: 23.90 (CH2); 25.49 (2CH2); 53.90 [N(CH2)2]; 61.38 (NCH2); 72.04 (OCH2); 72.34 (OCH2); 118.76, 126.52, and 126.81 (3CHAr); 132.41, 137.99, and 138.83 (3CAr). 13 C NMR spectrum of amine 3g (DMSO-d6+CCl4), , ppm: 52.98 [N(CH2)2]; 60.91 (NCH2); 65.94 [O(CH2)2]; 71.93 (OCH2); 72.31 (OCH2); 118.97, 126.49, and 126.92 (3CHAr); 131.25, 137.99, and 138.86 (3CAr).
[f]isoindolinium chlorides and bromides it was discovered that intramolecular recyclization occurred [2]. With the aim of establishing the general nature of this reaction, the behavior of 2,2-dialkyl-4-hydroxymethylisoindolinium salts under conditions of aqueous alkaline decomposition has been studied in the present work. Since salts 2a-g, formed by the cyclization of dialkyl(4-hydroxy-2-butynyl)(3-alkenylpropargyl)ammonium salts 1a-g, are not successfully obtained in the crystalline state, we studied their decomposition without isolating them. The recyclization of salts 2a-g, unlike the benzisoindolinium analogs, is effected on extended heating. The recyclization products, (1,3-dihydro-4-isobenzofuranylmethyl)dialkylamines 3a-g, were obtained in 60-68% yield (Table 1). Based on the investigations carried out it may be said that the intramolecular recyclization detected by us in [2] has a general character and opens broad possibilities for making potentially bioactive amines containing a dihydrofuran ring. The hydrogenated furan ring is found in the composition of many natural alkaloids. Amines 3a-g were also obtained in 5-10% yield on cyclization of salts 1a-g under base catalyzed conditions. In the IR spectra of the initial dialkyl(3-vinylpropargyl)amines 4c,d,f, synthesized for the first time, there were characteristic absorption bands for a doubly substituted acetylenic bond at 2220-2230, for CH=CH2 at 920, 930, and a conjugated C=C bond at 1580-1610 cm-1 (Table 2). In the IR spectra of the initial salts 1c,d,f,g, which have been obtained for the first time, characteristic absorption bands were detected for a doubly substituted acetylenic bond at 2220, for a hydroxyl group at 1020 and 3200-3400, for CH=CH2 at 920, 930, and also for a conjugated C=C bond at 1580-1610 cm-1 (Table 2). In the IR spectra of amines 3a-g absorption bands were detected characteristic of 1,2,3- and 1,2,3,5-substituted benzene rings at 700 and 760, and at 840 cm-1 respectively, for the aromatic ring at 1550, 1600, and 3050, and for an ether grouping at 1050 and 1200 cm-1. The structures of amines 3a-g were confirmed by 1H NMR spectroscopy, and the structures of 3f,g also by the 13C NMR method (Table 3). The spectra of the compounds indicated were in agreement with the proposed structures.
EXPERIMENTAL The IR spectra were taken on a UR 20 spectrometer in KBr disks or in nujol mulls. The 1H and 13C NMR spectra were obtained on a Varian Mercury 300 spectrometer (300 MHz for proton and 75 MHz for carbon nuclei) at 30C (303 K). Internal standard was TMS. The initial dialkyl(3-alkenylpropargyl)amines were synthesized by the Mannich reaction [3]. Salts 1a-g were obtained in quantitative yield in acetonitrile by the interaction of dialkyl(3-alkenylpropargyl)amines 4a-g with chromatographically pure 1-chloro-4-hydroxy-2-butyne obtained by the procedure of [4]. The characteristics of amines 3a-g and the data of 1H and 13C NMR spectra are given in Tables 1 and 3. The characteristics of amines 4c,d,f and of salts 1c,d,f,g are given in Table 2. Cyclization of Salts 1a-g and the Direct Aqueous Alkaline Decomposition of Salts 2a-g (General Method). A 2N KOH solution (1.8 ml) was added to a solution of the initial salt 1a-g (18 mmol) (molar ratio salt : base = 5 : 1). The reaction mixture was heated at 50-55C for 5-10 min, then self-heating of the reaction mixture occurred to 75-85C. The reaction mixture was extracted with ether (2 30 ml) to remove products of side reactions. In each case amines 3a-g (5-10%) were detected in the ether extract by titration, the picrates of which gave no depression of melting point with picrates of amines 3a-g obtained on aqueous alkaline decomposition of salts 2a-g. A twofold molar quantity of potassium hydroxide dissolved in water (2-3 ml) was then added to the reaction mixture without isolating the cyclization products 2a-g. The reaction mixture was boiled for 3-3.5 h at 85-90C. The mixture was extracted with ether (3 50 ml), the ether extract was washed with water, and dried over MgSO4. After removing the ether, amines 3a-g were obtained by vacuum distillation.
181
REFERENCES 1. 2. 3. 4. E. O. Chukhadzhyan, A. R. Gevorkyan, El. O. Chukhadzhyan, K. G. Shakhatuni, F. S. Kinoyan, and G. A. Panosyan, Khim. Geterotsikl. Soedin., 34 (2004). E. O. Chukajian, H. R. Gevorkyan, E. O. Chukhajian, K. G. Shakhatuni, H. A. Panosyan, and R. A. Tamazyan, J. Heterocycl. Chem., 40, 1059 (2003). E. O. Chukhadzhyan, A. R. Gevorkyan, El. O. Chukhadzhyan, and K. G. Shakhatuni, Zh. Org. Khim., 36, 9 (2000). G. Dupont, R. Dulou, and G. Lefebvre, Bull. Soc. Chem. France, 816 (1954).
182
CHEMISTRY OF MODIFIED FLAVONOIDS. 24*. SYNTHESIS OF 4- ARYLOXY-3-(2-HYDROXY4-HYDROXY/ALKOXYPHENYL)PYRAZOLES

V. V. Arkhipov, M. M. Garazd, M. N. Smirnov, and V. P. Khilya 3-Aryloxychromones are recyclized under the action of hydrazine into derivatives of 4-aryloxy-3-(2,4dihydroxyphenyl)pyrazole. Keywords: 3-aryloxychromones, 4-aryloxy-3-(2-hydroxy-4-hydroxy/alkoxyphenyl)pyrazoles, recyclization. The interaction of hydrazine and its derivatives with compounds containing the chromone system may be effected in two main directions, with the formation of hydrazones or by recyclization of the chromone fragment. It is known that isoflavones and 3-hetarylchromones are readily recyclized under the action of hydrazine exclusively into 4-aryl- and 4-hetarylpyrazole derivatives [2-5]. In the present work we have studied the interaction of 7-hydroxy- and 7-alkoxy-3-aryloxychromones 1a-j with hydrazine. The synthesis of 3-phenoxychromones 1a-d by the heterocyclization of the corresponding -aryloxy-2,4-dihydroxyacetophenones under conditions of acid and base catalysis has been described previously [6-7]. Like the preparation of chromone 1b [7], the use of the modified KostaneckiRobinson method and subsequent acid hydrolysis of the resulting acetate led to compound 1e. The 7-alkoxy derivatives 1f-j were obtained by the alkylation of the corresponding 7-hydroxy derivatives with alkyl halides in acetone in the presence of potassium carbonate by the known procedure of [7]. The physicochemical properties of the new chromone derivatives 1e-j are given in Tables 1 and 2.
R2O R2O
7 4' 2" 4"
R1 O
4' 2'
R3 NH2NH2
2'
HO
O
5
R3
O 1aj
N1 H 2aj
R1
1, 2 a R1 = R2 = R3 = H, b R1 = Me, R2 = R3 = H, c R1 = CF3, R2 = R3 = H, d R1 = COOH, R = R3 = H, e R1 = Me, R2 = H, R3 = OEt, f R1 = R2 = Me, R3 = H, g R1 = Me, R2 = Et, R3 = H, h R1 = Me, R2 = Bu, R3 = H, i R1 = Me, R2 = CH2Ph, R3 = H, j R1 = R2 = Me, R3 = OEt
2
_______ * For Part 23 see [1]. __________________________________________________________________________________________ Kiev Taras Shevchenko University, Kiev 02033, Ukraine; e-mail: ishchenko@mail.univ.kiev.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 218-222, February, 2004. Original article submitted November 27, 2001; revision submitted January 10, 2003. 0009-3122/04/4002-01832004 Plenum Publishing Corporation 183
TABLE 1. Physicochemical Properties of Compounds 1e-j and 2a-j

Compound Empirical formula C18H16O5 C17H14O4 C18H16O4 C20H20O4 C23H18O4 C19H18O5 15H12N2O3 16H14N2O3 16H11F3N2O3 16H12N2O5 18H18N2O4 17H16N2O3 18H18N2O3 20H22N2O3 23H20N2O3 19H20N2O4 Found, % Calculated, % H 5.0 5.16 4.92 5.00 5.38 5.44 6.18 6.21 5.0 5.06 5.52 5.56 4.47 4.51 4.85 5.00 3.27 3.30 3.90 3.87 5.52 5.56 5.48 5.44 5.90 5.85 6.57 6.55 5.35 5.41 5.98 5.92 mp, N 10.21 10.44 9.98 9.92 8.19 8.33 8.82 8.97 8.51 8.58 9.35 9.45 9.17 9.03 8.28 8.48 7.69 7.52 7.99 8.23 184 168 160 131 135 126 179 171 169 185 163 155 142 105 135 116 87 91 88 81 76 87 89 90 48 60 94 93 94 96 95 96 Yield, %
C 69.18 69.22 72.28 72.33 72.94 72.96 74.0 74.06 76.99 77.08 69.90 69.93 67.14 67.16 67.00 67.18 57.08 57.15 61.50 61.54 66.15 66.25 68.94 68.91 69.68 69.66 71.02 70.99 74.00 74.18 67.15 67.05
1e 1f 1g 1h 1i 1j 2a 2b 2c 2d 2e 2f 2g 2h 2i 2j
As a result of brief heating of alcoholic solutions of compounds 1a-j with an excess of hydrazine, opening of the pyrone ring occurs with subsequent cyclization into 4-aryloxy-3-(2-hydroxy-4hydroxy/alkoxyphenyl)pyrazoles 2a-j. Their structure was confirmed by the results of elemental analysis (Table 1), data of 1H NMR spectra (Table 2) etc. The pyrazoles obtained were dissolved in dilute alkali and with an alcoholic solution of ferric chloride they form blue-green chelate complexes by means of the phenolic hydroxyl and a nitrogen atom of the pyrazole ring. In their 1H NMR spectra, measured in DMSO-d6, signals characteristic of such structures were observed in the 9.4-13.2 ppm region. The protons of the pyrazole ring NH group were displayed as strongly broadened peaks at lowest field (12.9-13.2 ppm). A singlet was observed for the 2'-OH group proton at 10.8-11.3, and for the 4'-OH group proton at 9.1-9.6 ppm. In the case of compounds 2f-j in place of the singlet for the 4'-hydroxy group signals were present in the spectrum for the corresponding alkoxy substituent. Displacement of the 6'-H proton signal in the spectra of pyrazoles 2 by 1.0-1.2 ppm towards high field, compared with the position of the peak of the same proton in the spectra of the initial chromones 1 (found in position 5 in them), is explained by the formation of the chelate structure [8]. 3-Phenoxychromones, like other isoflavones, are therefore readily cyclized in high yield into the corresponding pyrazoles, which enables this reaction to be used for preparative purposes for the synthesis of derivatives of 4-aryloxy-3-(2,4-dihydroxyphenyl)pyrazole unavailable by other methods.
184
TABLE 2. 1H NMR Spectra of 3-Aryloxychromones 1e-j

Compound 5-H (1H, d, J = 8.0) 7.97 8.00 8.00 8.00 6-H (1H, dd, J = 2.0; 8.0) 7.10 7.10 7.10 7.10 Signals of protons, , ppm, coupling constants (J, Hz)* 8-H 2'-H, (1H, d, 6'-H 7-OR2 J = 2.0) (2H, m) 10.65 (1H, s, ) 3.97 (3H, s, CH3) 4.23 (2H, q C2); 1.44 (3H, t, J = 7.0, CH3) 3.88 (2H, t, OCH2); 1.59 (2H, m, OCH2CH2); 1.36 (2H, m, CH2CH3); 0.89 (3H, t, J = 7.0, C3) 7.50 (5H, m, Ph); 5.33 (2H, s, C2) 3.95 (3H, s, CH3) 7.30 7.20 7.20 7.20 6.83 (s) 7.05 7.00 7.05 3'-H, 5'- (2H, m) 6.83 (s) 7.00 6.95 7.00
2-Me (3H, s) 2.36 2.39 2.39 2.39
4'-R3 1.28 (3H, t, CH3); 3.93 (2H, q, CH2) 7.00 (1H, m, H) 6.95 (1H, m, H) 7.00 (1H, m, H)
1e*2 1f 1g 1h
1i 1j
2.38 2.38
8.00 8.00
7.15 7.00
7.20 7.20
7.05 6.90 (s)
7.00 6.90 (s)
7.00 (1H, m, H) 3.95 (2H, q CH2); 1.33 (3H, t, CH3)
_______ * In (CD3)2CO. *2 In DMSO-d6.
185
186
TABLE 3. 1H NMR Spectra of Substituted Pyrazoles 2a-j

Compound 3'-H (1H, d, J = 2.0) 6.36 6.38 6.41 6.36 6.21 6.48 6.43 6.45 Signals of protons, , ppm, coupling constants (J, Hz) 5'-H 6'-H (1H, dd, (1H, d, 4'-OR2 J = 2.0; 8.0) J = 8.0) 9.15 (1H, s) 8.40 (1H, s) 9.63 (1H, s) 9.49 (1H, s) 9.45 (1H, s) 3.74 (3H, s, CH3) 1.31 (3H, t, J = 7.0); 3.98 (2H, q, J = 7.0, CH2) 3.88 (2H, t, J = 7.0, OCH2); 1.59 (2H, m, OCH2CH2); 1.36 (2H, m, CH2CH3); 0.89 (3H, t, J = 7.0, CH3) 7.40 (5H, m, Ph); 5.05 (2H, s, CH2) 3.69 (3H, s, CH3) 6.22 6.25 6.17 6.18 6.18 6.32 6.32 6.31 7.45 7.58 7.28 7.28 7.38 7.65 7.65 7.65 3''-H, 5''-H, (2H, m) 7.00 7.00 6.90 6.84 6.84 (s) 7.00 7.00 7.00
Solvent
1-H (1H, s) 12.90 12.09 13.40 13.00 12.75 12.13 12.13 12.17
5-R1 (s) 7.78 2.17 (3H, CH3) 13.00 (1H, COOH) 2.07 (3H, CH3) 2.19 (3H, CH3) 2.18 (3H, CH3) 2.17 (3H, CH3)
2'-OH (1H, s) 10.76 11.11 10.25 10.19 10.95 11.18 11.15 11.14
2''-H, 6''-H, (2H, m) 7.28 7.28 7.20 7.28 6.84 (s) 7.28 7.28 7.28
4''-R3 7.00 (1H, m) 7.00 (1H, m) 6.90 (1H, m) 6.84 (1H, m) 1.29 (3H, t, CH3), 3.95 (2H, q, CH2) 7.00 (1H, m) 7.00 (1H, m) 7.00 (1H, m)
2a 2b 2c 2d 2e 2f 2g 2h
DMSO-d6 (CD3)2CO DMSO-d6 (CD3)2CO DMSO-d6 (CD3)2CO (CD3)2CO (CD3)2CO
2i 2j
DMSO-d6 DMSO-d6
12.70 12.86
2.08 (3H, CH3) 2.07 (3H, CH3)
11.15 11.08
6.55 6.41
6.43 6.36
7.48 7.51
7.28 6.83 (s)
7.00 6.83 (s)
7.00 (1H, m) 1.29 (3H, t, CH3), 3.95 (2H, q, CH2)
EXPERIMENTAL The progress of reactions and the purity of compounds obtained were checked by TLC on Silufol UV 254 plates in the systems chloroformmethanol, 9 : 1 and 19 : 1. The 1H NMR spectra were measured on Bruker WP 100SY and Varian VXR 300 instruments (100 and 300 MHz respectively) in DMSO-D6 and (CD3)2CO relative to TMS (internal standard). 3-(4-Ethoxyphenoxy)-7-hydroxy-2-methylchromone (1e). A mixture of -(4-ethoxyphenoxy)-2,4dihydroxyacetophenone (2.58 g, 10 mmol), acetic anhydride (4.7 ml: 50 mmole), and triethylamine (5.6 ml, 40 mmol) was maintained at 125-130C for 4 h. After cooling, the reaction mixture was poured into cold water (200 ml), the precipitated solid 7-acetoxy derivative was filtered off, washed thoroughly on the filter with water, and crystallized from ethanol. The crystals obtained were dissolved in the minimum amount of ethanol, concentrated hydrochloric acid (1 ml) was added to the solution, and the mixture boiled until disappearance of the starting material (TLC). The crystals of product 1e, precipitated on cooling, were separated and crystallized from ethanol. 7-Alkoxy-3-aryloxy-2-methylchromones (1f-j) (General Method). The appropriate alkyl halide (5.5 mmol) was added to a solution of chromone 1b,e (5 mmol) in absolute acetone (50 ml) containing powdered freshly calcined potassium carbonate (2.07 g, 15 mmol) with vigorous stirring and heating. The reaction mixture was maintained at 50-60C for 1-3 h (the end of the reaction was determined by TLC). After cooling, the mixture was transferred to 1 N sulfuric acid solution (100 ml), the solid product was filtered off, and crystallized from 2-propanol. 4-Aryloxy-3-(2-hydroxy-4-hydroxy/alkoxyphenyl)pyrazoles (2a-j) (General Procedure). A solution of 85% hydrazine hydrate (0.5 ml) in ethanol (5 ml) was added to a hot solution or suspension of the appropriate 3-aryloxychromone 1a-j (4 mmol) in ethanol (20 ml). The reaction mixture was boiled for 5-30 min (the end of the reaction was determined by TLC) and transferred to ice water (200 ml) (in the case of acid 2d the resulting mixture was acidified with dilute hydrochloric acid to pH 6). The precipitate of product 2 was filtered off, and crystallized from 50% ethanol.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. M. M. Garazd, V. V. Arkhipov, N. K. Proskurka, and V. P. Khilya, Khim. Geterotsikl. Soedin., 744 (1999). V. P. Khilya, L. G. Grishko, and F. S. Babichev, Khim. Geterotsikl. Soedin., 1474 (1976). V. P. Khilya, T. M. Tkachuk, I. P. Kupchevskaya, and G. M. Golubushina, Dokl. Akad. Nauk UkSSR, Ser. B, No. 5, 61 (1980). N. V. Gorbulenko, G. M. Golubushina, I. P. Kupchevskaya, and V. P. Khilya, Dokl. Akad. Nauk UkSSR, Ser. B, No. 7, 623 (1978). I. P. Kupchevskaya and V. P. Khilya, Dokl. Akad. Nauk UkSSR, Ser. B, No. 2, 119 (1979). V. G. Pivovarenko, V. P. Khilya, and S. A. Vasil'ev, Khim. Prir. Soedin., 639 (1989). S. A. Vasil'ev, M. S. Luk'yanchikov, G. I. Molchanov, V. D. Turubarov, and V. P. Khilya, Khim.-farm. Zh., No. 7, 34 (1991). V. P. Khilya and V. V. Ishchenko, Khim. Geterotsikl. Soedin., 1019 (2002).
187
HETEROCYCLIC DERIVATIVES OF FULLERENE C60. 1. SYNTHESIS OF NEW FULLEROPYRAZOLINES BY THE 1,3-DIPOLAR CYCLOADDITION OF NITRILE IMINES
M. V. Reinov, M. A. Yurovskaya, D. V. Davydov, and A. V. Streletskii New stable [6,6]-closed cycloadducts, fulleropyrazolines containing aryl, hetaryl, trifluoromethyl, and other substituents in the five-membered ring, have been obtained by the 1,3-dipolar cycloaddition of nitrile imines to C60. Two methods of generating nitrile imines in situ have been used, the dehydrohalogenation of the corresponding hydrazonoyl halides by the action of triethylamine and the thermal decomposition of 2,5-diaryltetrazoles. Keywords: hydrazonoyl halides, 2,5-diaryltetrazoles, [6,6]-closed cycloadducts, nitrile imines, fullerene C60, fulleropyrazolines, 1,3-dipolar cycloaddition. 1,3-Dipolar cycloaddition of nitrile imines to C60 is the standard method for annelating the pyrazoline ring to the fullerene sphere (see review [1] and cited literature). Further development of investigations in this direction may be connected primarily with the synthesis of new representatives of this class of compounds or secondly with the application of new methods of generating nitrile imines. Both aspects have been studied in the present work. The known method of generating nitrile imines in situ (route A), the dehydrohalogenation of substituted hydrazonoyl halides by the action of triethylamine, has made possible a significant expansion of the variety of 1,3-disubstituted fulleropyrazolines. The cycloadducts 5a-i synthesized contain aryl and trifluoromethyl substituents in the five-membered heterocyclic fragment. The starting materials for generating nitrile imines 4a-c in situ, the hydrazonoyl chlorides 3a-c, were obtained by the action of PCl5 [2] on the hydrazides of the appropriate acids 1a-c. The preparation of nitrile imine precursors 4d-i by this method was unsuccessful. Good results were obtained on generating nitrile imines, not from the corresponding hydrazonoyl chlorides but from the bromides 3d-i, which, in turn, were synthesized by the bromination of hydrazones 2d-i by the action of NBS [3]. An interesting fact may be noted that on bromination of p-ethoxybenzaldehyde phenylhydrazone (2e) under these conditions the p-bromophenylhydrazonoyl bromide of p-ethoxybenzaldehyde (3f) is formed in parallel. This was indicated by the isolation of cycloadduct 5f together with fulleropyrazoline 5e from the reaction mixture obtained on interacting the unexpected bromination product, fullerene, and triethylamine.
__________________________________________________________________________________________ Moscow M. V. Lomonosov State University, Moscow 119234, Russia; e-mail: yumar@org.chem.msu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 223-228, February, 2004. Original article submitted November 1, 2003. 188 0009-3122/04/4002-01882004 Plenum Publishing Corporation
O R1 C 1ac R1 CH 2di NNHR2 NHNHR2 NBS
PCl5
R1 X
N N H 3ac, X=Cl 3di, X=Br
R2
Et3N route A
R2 N N R1
R1 + 4ai
N N _
R2
C60 PhBr, 120 oC, 2x 5am
PhBr, 155 oC, 3 x N R1 N N N 6jm R2 route B PhBr, 155 oC R1 + 4jm N N _ R2
14 a R1= p-O2NC6H4, R2= Ph; b R1=Ph, R2= p-O2NC6H4; c R1= Ph, R2=2,4-Cl2C6H3; d R1= R2= p-O2NC6H4; e R1= p-EtOC6H4, R2=Ph; f R1= p-EtOC6H4, R2= p-BrC6H4; g R1= CF3, R2= Ph; h R1= CF3, R2= p-MeC6H4; i R1= CF3, R2= -MeOC6H4; 35 j R1= 2-thienyl, R2= p-MeC6H4; k R1= R2=Ph; l R1= 4-Py, R2= Ph; m R1= Ph, R2= -OC6H4
All the hydrazonoyl halides 3a-i synthesized were used for generating in situ the corresponding nitrile imines 4a-i by the action of triethylamine directly in the reaction mixture already containing C60. Reaction was carried out in bromobenzene. The cycloaddition of nitrile imines 4a-i leads smoothly to the formation of stable [6,6]-closed monofulleropyrazolines 5a-i. Literature data indicate that mainly monoadducts are formed as a result of cycloaddition of nitrile imines [3]. However, there is a reference [4] that on interacting 1,3-diphenylnitrile imine with C60 under similar conditions the monoadduct is not formed but the main compound isolated is the bisadduct. In our case the addition of practically all the nitrile imines 4a-i leads to the formation of monoadducts as the chief product, when using nitrile imine 4h the bisadduct was recorded as a side product (according to data of MALDI mass spectrometry). In addition to the described standard method we used for the first time a procedure (route B), preparatively simple, for generating nitrile imines by the thermal decomposition of 2,5-diaryltetrazoles. Cycloadducts 5j-m, containing aryl and hetaryl substituents such as thienyl and pyridyl in the pyrazoline fragment, were synthesized by this method. The availability of 2,5-diaryltetrazoles of various structure generates a greater possibility for functionalization of the fullerene spheroid than route A, which is limited by the availability of the appropriate hydrazonoyl halides. 5-(2-Thienyl)-2-p-tolyltetrazole (6j) was obtained by the known procedure of [5]. For the synthesis of the remaining diaryltetrazoles 6k-m we developed a new original procedure. Several methods of obtaining 2,5-diaryltetrazoles are known. It is possible to synthesize them by regioselective arylation of 5-aryltetrazoles under the action of diaryliodonium salts in the presence of palladium and copper catalysts in DMF [6], or on
189
oxidation of stannylated 5-aryltetrazoles with Cu(II) acetate in the presence of Ar2I+X- in CH2Cl2 [7]. Our method comprises the regioselective arylation of 5-aryltetrazoles by various diaryliodonium salts in water using metallic copper catalyst.
H N Ar N N
1
N Ar
2
1 Ar2 I + X
Cu, KOH H2O, 100 oC Ar
N
2
N N
Ar1 = Ph, p-MeO-64; Ar2 = Ph, 4-Py
The simplicity of carrying out the experiment (reaction in water), the ease of isolating the desired compounds, and the fairly high yields (60-85%), depending on the structure of the iodonium salt, serve as an irrefutable advantage of the proposed method of synthesis of diaryltetrazoles 6. Thermal decomposition of tetrazoles 6 at a temperature of the order of 150C in bromobenzene solution in the presence of fullerene-60 leads to the intermediate formation in situ of the corresponding nitrile imines 4j-m and their subsequent cycloaddition. Bromobenzene is the optimum solvent for carrying out the reaction. The reaction also proceeds in chlorobenzene and toluene but the yields of the cycloadducts were far less. Assignment of the synthesized fulleropyrazolines 5a-m to the [6,6]-closed isomers was made on the basis of 13C NMR data. Analysis of all the obtained adducts was unsuccessful, because of the difficulties linked with the long time for accumulation of 13C NMR spectral signals due to the low solubility of adducts. Two signals were present in the spectra of adducts 5b and 5h in the 75-110 ppm region which correspond to the C(3) and C(4) nuclei of the pyrazoline ring. When forming [5,6]-open fulleroid structures the signals of the C(3) and C(4) atomic nuclei will not be present in the aliphatic portion of the spectrum. The 1H NMR spectral data indicate the presence in adducts 5a-m of an annelated five-membered heterocyclic fragment. The main characteristics are the signals in the 7.6-8.3 region assigned to the ortho protons of the N-aryl substituent, and in the 8.1-8.4 ppm region assigned to the ortho protons of the C-aryl substituent. Such a large displacement towards low field compared with the initial hydrazonoyl halides is caused by intramolecular charge-transfer between the fullerene fragment and the aryl substituents of the fulleropyrazoline ring [3,8]. The MALDI spectra confirm that monocycloaddition proceeds under the indicated conditions.
EXPERIMENTAL The 1H and 13C NMR spectra were recorded on a Varian XL 400 instrument (1H at 400 and 13C at 100 MHz), internal standard was TMS. The NMR spectra of the fullerene adducts 5 were obtained for solutions in CS2acetone-d6, 5:1. Mass spectral analysis by the MALDI method was carried out on a Vision 2000 instrument with a N2 laser, the wavelength of the radiation of which was 336 nm, and a time of flight mass analyzer. As matrices we successfully used orthorhombic sulfur, [3-(4-tert-butylphenyl)-2-methylprop-2-enylidene]malononitrile (DCTB), and 9-nitroanthracene. Both negative and positive ions were recorded. Each mass spectrum was obtained by summing the signals of 20 to 50 laser impulses. The order of preparing samples of substances for analysis was as follows: several drops (less than 1 l) of a saturated toluene solution of the matrix were applied to a metallic target with the aid of a fine capillary to form, after evaporation of the solvent, a thin film. A fraction of the substance being analyzed, obtained by TLC, was also dissolved in toluene, after which the surface of the matrix film was moistened with several drops of this solution with the aid of a fine capillary. The best conditions for analysis were achieved on using this procedure with a matrix of sulfur or DCTB when recording negative ions. In the mass range of the substance being analyzed the molecular radical-anion [M]- had the greatest intensity, while the intensity of the C60- fragment ion was low. 190
A check on the progress of reactions and the purity of the compounds obtained was effected by TLC on Silufol UV 254 plates. Separation and purification of substances were carried out on columns of silica gel L 40/100, eluting with hexanebenzene, 3:1. Hydrazides 1a-c and hydrazonoyl halides 2a-c were synthesized by the procedure of [2]. Phenylhydrazonoyl Chloride of p-Nitrobenzaldehyde (3a). Yield 55%; mp 184-188C. 1H NMR spectrum (CDCl3), , ppm: 7.10 (1H, t, 4-H); 7.35 (2H, m, 3-, 5-H); 7.48 (2H, d, 2-, 6-H); 8.23 (2H, d, 2'-, 6'-H); 8.40 (2H, d, 3'-, 5'-H); 10.56 (1H, s, NH). Found, %: C 56.76; H 3.66; N 15.61. C13H10ClN3O2. Calculated, %: C 56.64; H 3.66; N 15.24. p-Nitrophenylhydrazonoyl Chloride of Benzaldehyde (3b). Yield 70%; mp 190-195C. Found, %: C 56.70; H 3.64; N 15.35. C13H10ClN3O2. Calculated, %: C 56.64; H 3.66; N 15.24. 2,4-Dichlorophenylhydrazonoyl Chloride of Benzaldehyde (3c). Yield 47%; mp 90C. IR spectrum (nujol), , cm-1: 1600 (C=N), 3330 (NH). 1H NMR spectrum (CDCl3), , ppm (J, Hz): 7.16 (1H, dd, oJ = 8.8, m J = 2.3, 5-H); 7.26 (1H, d, mJ = 2.3, 3-H); 7.35 (3H, m, 3'-, 4'-, 5'-H); 7.45 (1H, d, J = 8.8, 6-H); 7.86 (2H, m, 2'-, 6'-H); 8.63 (1H, s, NH). Phenylhydrazone of p-Ethoxybenzaldehyde (2d). p-Ethoxybenzaldehyde (1.39 g, 9.3 mmol) was added to a solution of phenylhydrazine (1 g, 9.3 mmol) in methanol (10 ml) and the mixture was heated until the beginning of solid precipitation, after which the reaction mixture was cooled. The solid was filtered off and used directly in the next stage. p-Nitrophenylhydrazone of p-Nitrobenzaldehyde (2e). A solution of p-nitrobenzaldehyde (0.99 g, 6.5 mmol) was added with stirring to a hot solution of p-nitrophenylhydrazine (1 g, 6.5 mmol) in methanol (20 ml). The mixture was heated for several minutes and cooled. The precipitated solid was filtered off. Phenylhydrazone of Trifluoroacetaldehyde (2g), p-Tolylhydrazone of Trifluoroacetaldehyde (2h), and o-Methoxyphenylhydrazone of Trifluoroacetaldehyde (2i). CF3CH(OH)2 (15 mmol), obtained by the procedure of [9], was added to a solution of freshly distilled arylhydrazine (10 mmol) in methanol (10 ml), and the mixture was stirred at ~20C for 1 h in an inert atmosphere. After the end of the reaction the methanol was distilled off at ~20C, benzene (20 ml) was added to the reaction mixture, and the solution dried over sodium sulfate. A large portion of the benzene was distilled off at ~20C, hexane (10 ml) was added, and the mixture cooled. The resulting crystals were filtered off, and used in the next stage without further purification. Hydrazonoyl Halides (3d-i). N-Bromosuccinimide (NBS) (36 mg, 0.2 mmol) was added to a solution of hydrazone 2 (0.21 mmol) in bromobenzene (10 ml), and the mixture was stirred for 20 min. The synthesis of compounds 3e and 3f was carried out at 0C, of compound 3d at 70-80C, and of the remaining hydrazonoyl halides at room temperature. The precipitated succimide was filtered off and the solution obtained was used in the next stage. 5-(2-Thienyl)-2-(p-tolyl)tetrazole (6j) was obtained by the procedure of [5]. Diaryltetrazoles (6k-m) (General Method). Potassium hydroxide (1 mmol) was added as aliquots of a titrated aqueous solution with stirring to 5-aryltetrazole (1 mmol) in water (10 ml), then diaryliodonium salt (1.5 mmol) and freshly activated metallic copper (1.5 mmol) were added after homogenization of the solution. The reaction mixture was boiled for 16 h in a stream of argon. After the end of the reaction the solution was extracted three times with chloroform. The extract was dried over Na2SO4 and passed through a layer of Al2O3 (separation from the initial 5-aryltetrazole and salts). The solution obtained was evaporated, and the residue crystallized from CCl4 or CHCl3. 2,5-Diphenyltetrazole (6k). Yield 60%; mp 100C. UV spectrum (EtOH), max (log ): 272 nm (4.24). Mass spectrum, m/z (I, %): 223 (2) [M+H]+, 222 (<1) [M]+, 194 (40) [M-N2]+, 103 (10) [M-N2-C6H5N]+, 91 (100) M-N2-C7H5N]+. 1H NMR spectrum (acetone-d6), , ppm: 7.54-7.62 (4H, m, m-HPh); 7.67-7.71 (2H, m, p-HPh); 8.20-8.24 (4H, m, o-HPh). 2-(p-Methoxyphenyl)-5-phenyltetrazole (6l). Yield 85%; mp 101-102C. UV spectrum (EtOH), max (log ): 300 nm (4.10). Mass spectrum, m/z (I, %): 253 (3) M+H]+, 252 (<1) [M]+, 224 (20) [M-N2]+, 121 191
(100) [M-N2-C6H5N]+, 106 (25) [M-N2-C6H5N-CH3]+, 103 (10) [M-N2-C7H7NO]+. 1H NMR spectrum (acetone-d6), , ppm: 2.88 (3H, s, CH3O); 7.45 (2H, d, 2-, 6-HArl); 7.55-8.10 (5H, m, Ph); 8.20 (2H, d, 3-, 5-HArl). 2-Phenyl-5-(4-pyridyl)tetrazole (6m). Yield 72%; mp 146C. UV spectrum (EtOH), max (log ): 270 nm (4.41). Mass spectrum, m/z (I, %): 224 (1) [M+H]+, 223 (<1) [M]+, 195 (20) [M-N2]+, 104 (5) [M-N2-C6H5N]+, 91 (100) [M-N2-C6H4N2]+, 64 (40) [M-N2-C6H4N2-HCN]+. 1H NMR spectrum (DMSO-d6), , ppm: 7.30-7.90 (5H, m, Ph); 7.60 (2H, d, 4-Py); 8.10 (2H, d, 4-Py). Fulleropyrazolines (5a-i) (General Method). A solution of hydrazonoyl halide 3 (0.21 mmol) in bromobenzene (10 ml) was added with stirring during 1.5 h to a solution of fullerene C60 (50 mg, 0.07 mmol) and triethylamine (50 l) in bromobenzene (20 ml) at 120-130C. The mixture was stirred at this temperature for a further 2 h, the solvent was distilled off, and the residue treated with methanol. The resulting solid was filtered off, and washed several times with methanol. The adduct was isolated from the mixture obtained by column chromatography. Eluents were benzenehexane, 1:1 (for adducts 5a-c), benzenehexane, 1:3 (for compounds 5d-f), and benzenehexane 1:10 (for adducts 5g-i). Fulleropyrazolines (5j-m) (General Method). A solution of fullerene C60 (50 mg, 0.07 mmol) and tetrazole 6 (0.2 mmol) in bromobenzene was boiled for 3 h. The mixture was then treated analogously to the previous procedure. Eluents were benzenehexane, 1:3 (for adducts 5j,k,m), and benzeneethyl acetate, 10:1 (for 5l). 3-(p-Nitrophenyl)-1-phenylpyrazolo[4',5':1,2]fullerene[60] (5a). 1H NMR spectrum, , ppm (J, Hz): 7.47 (3H, m, 3-, 4-, 5-HPh); 7.93 (2H, d, 2-, 6-HPh); 8.30 (2H, d, J = 9.1, 2-, 6-Hp-NO2C6H4); 8.60 (2H, d, J = 9.1, 3-, 5-Hp-NO2C6H4). MALDI mass spectrum: [M]- 959.7. 1-(p-Nitrophenyl)-3-phenylpyrazolo[4',5':1,2]fullerene[60] (5b). 1H NMR spectrum, , ppm: 7.54 (3H, m, 3-, 4-, 5-HPh); 8.25 (6H, m, 2-, 3-, 5-, 6-Hp-NO2C6H4; 2-, 6-HPh). 13C NMR spectrum, , ppm: 75 (Csp3); 106 (Csp3); 129, 135, 138.5, 139, 140, 141, 145.5, 146.5, 149, 151.4, 152, 152.5, 152.6, 153, 153.8, 154, 154.5, 155, 155.2, 155.5, 155.7, 156, 156.8, 157.3, 159, (Csp2). MALDI mass spectrum: [M]- 960. 1-(2,4-Dichlorophenyl)-3-phenylpyrazolo[4',5':1,2]fullerene[60] (5c). 1H NMR spectrum, , ppm (J, Hz): 7.42 (1H, dd, oJ = 8.47, mJ = 2.36, 5-H); 7.47 (3H, 3-, 4-, 5-HPh); 7.60 (1H, d, mJ = 2.36, 3-HC6H3Cl2); 7.88 (1H, d, oJ = 8.47, 6-HC6H3Cl2); 8.23 (2H, d, 2-, 6-HPh). MALDI mass spectrum: [M]- 983.7. 1-(p-Nitrophenyl)-3-(p-nitrophenyl)pyrazolo[4',5':1,2]fullerene[60] (5d). 1H NMR spectrum, , ppm (J, Hz): 8.31 (2H, d, J = 6.8, 2-, 6-Hp-NO2C6H4); 8.33 (2H, d, J = 6.8, 3-, 5-Hp-NO2C6H4); 8.39 (2H, d, J = 9, 2'-, 6'-Hp-NO2C6H4); 8.62 (2H, d, J = 9, 3'-, 5'-Hp-NO2C6H4). 3-(p-Ethoxyphenyl)-1-phenylpyrazolo[4',5':1,2]fullerene[60] (5e). 1H NMR spectrum, , ppm (J, Hz): 1.46 (3H, t, J = 6.9, CH2CH3); 4.10 (2H, q, J = 6.9, CH2CH3); 6.95 (2H, d, J = 8.6, 3-, 5-Hp-EtOC6H4); 7.17, (1H, t, 4-HPh); 7.40 (2H, t, 3-, 5-HPh); 7.88 (2H, d, 2-, 6-HPh); 8.14 (2H, d, J = 8.6, 2-, 6-Hp-EtOC6H4). MALDI mass spectrum: [M]- 958.2. 1-(p-Bromophenyl)-3-(p-ethoxyphenyl)pyrazolo[4',5':1,2]fullerene[60] (5f). 1H NMR spectrum, , ppm (J, Hz): 1.46 (3H, t, J = 6.9, CH2CH3); 4.10 (2H, q, J = 6.9, CH2CH3); 6.96 (2H, d, J = 8.9, 3-, 5-Hp-EtOC6H4); 7.52 (2H, d, J = 9, 3-, 5-HPh); 7.84 (2H, d, J = 9, 2-, 6-HPh); 8.14 (2H, d, J = 8.9, 2-, 6-Hp-EtOC6H4). MALDI mass spectrum: [M]- 1038. 1-Phenyl-3-trifluoromethylpyrazolo[4',5':1,2]fullerene[60] (5g). 1H NMR spectrum, , ppm: 7.29 (1H, m, 4-HPh); 7.38 (2H, m, 3-, 5-HPh); 7.56 (1H, d, 2-, 6-HPh). MALDI mass spectrum: [M]- 907. 1-(p-Tolyl)-3-trifluoromethylpyrazolo[4',5':1,2]fullerene[60] (5h). 1H NMR spectrum, , ppm (J, Hz): 2.41 (3H, s, CH3); 7.26 (2H, d, J = 8.6, 3-, 5-Hp-CH3C6H4); 7.69 (2H, d, J = 8.6, 2-, 6-Hp-CH3C6H4). 13C NMR spectrum, , ppm: 31.7 (CH3); 83.8 (Csp3); 96.3 (Csp3); 129.5 (CF3); group of signals 135-161 (Carom and Cful); 179 (C=N). MALDI mass spectrum: [M]- 920.7. 1-(o-Methoxyphenyl)-3-trifluoromethylpyrazolo[4',5']fullerene[60] (5i). 1H NMR spectrum, , ppm: 3.90 (3H, s, CH3O); 7.06 (2H, m, 3-, 5-Ho-CH3OC6H4); 7.41 (1H, m, 4-Ho-CH3OC6H4); 7.65 (1H, m, 6-Ho-CH3OC6H4). MALDI mass spectrum: [M-H]- 935. 192
3-(2-Thienyl)-1-p-tolyl)pyrazolo[4',5':1,2]fullerene[60] (5j). 1H NMR spectrum, , ppm (J, Hz): 7.10 (1H, m, 4-HThienyl); 7.22 (2H, d, J = 8, 3-, 5-HPh); 7.48 (1H, d, 3-HThienyl); 7.72 (2H, d, J = 8, 2-, 6-HPh); 7.91 (1H, d, 5-HThienyl). MALDI mass spectrum: [M]- 935. 1,3-Diphenylpyrazolo[4',5':1,2]fullerene[60] (5k). 1H NMR spectrum, , ppm: 7.43 (6H, m, 3-, 4-, 5-HPh; 3'-, 4'-, 5'-HPh); 7.89 (2H, d, 2-, 6-HPh); 8.23 (2H, d, 2', 6'-HPh). MALDI mass spectrum: [M]- 915. 1-Phenyl-3-(4-pyridyl)pyrazolo[4',5':1,2]fullerene[60] (5l). MALDI mass spectrum: [M]- 916. 1-(p-Methoxyphenyl)-3-phenylpyrazolo[4',5':1,2]fullerene[60] (5m). 1H NMR spectrum, , ppm (J, Hz): 3.81 (3H, s, CH3O); 6.94 (2H, d, J = 9.5, 3-, 5-Hp-CH3OC6H4); 7.45 (3H, m, 3-, 4-, 5-HPh); 7.73 (2H, d, J = 9.5, 2-, 6-Hp-CH3OC6H4); 8.23 (2H, d, 2-, 6-HPh). MALDI mass spectrum: [M-H]- 944.3. The authors are grateful to O. V. Boltalina for helpful comments. A. V. Streletskii is grateful to the Volkswagen Fund (Project No. I-77/855) and the RFFI fund (Project No. 03-03-32855) for material support.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. M. A. Yurovskaya and I. V. Trushkov, Izv. Ross. Akad. Nauk, Ser. Khim., 343 (2002). H. V. Pechmann and L. Seeberger, Chem. Ber., 27, 2122 (1894). P. Cruz, A. Diaz-Ortiz, J. J. Garcia, M. J. Gomez-Escalonilla, A. Hoz, and F. Langa, Tetrahedron Lett., 40, 1587 (1999). S. Muthu, P. Maruthamuthu, R. Ragunathan, P. R. Vasudeva Rao, and C. K. Mathews, Tetrahedron Lett., 35, 1763 (1994). A. S. Shawali and A. A. Fahmi, J. Heterocyclic Chem., 16, 123 (1979). D. V. Davydov, I. P. Beletskaya, and M. S. Gorovoy, Tetrahedron Lett., 43, 6221 (2002). D. V. Davydov, I. P. Beletskaya, B. B. Semenov, and Y. A. Smushkevich, Tetrahedron Lett., 43, 6217 (2002). Y. Matsubara, H. Tada, S. Nagase, and Z. Yoshida, J. Org. Chem., 60, 5372 (1995). K. Tanaka, H. Masuda, and K. Mitsuhashi, Bull. Chem. Soc. Jpn., 57, 2184 (1984).
193
TWO DIRECTIONS OF THE REACTION OF 4-BROMOBENZALDEHYDE WITH SUBSTITUTED ACETOPHENONES AND UREA. SYNTHESIS OF ARYL-SUBSTITUTED PYRIMIDIN-2-ONE AND HEXAHYDROPYRIMIDO[4,5-d]PYRIMIDIN-2,7-DIONE
V. F. Sedova and O. P. Shkurko Condensation of 4-bromobenzaldehyde, urea, and 4-alkyl-substituted acetophenones gave substituted hexahydro-1H,8H-pyrimido[4,5-d]pyrimidin-2,7-diones or 1H-pyrimidin-2-ones, depending on the substituent on the acetophenone ring and the nature of the solvent (i-PrOH, BuOH, AcOH). The corresponding 5-bromopyrimidin-2-ones were formed on bromination of these compounds. The structures of these compounds were confirmed by IR, UV, and 1H NMR spectroscopy. Keywords: 4-alkylacetophenones, aminopyrimidines, 4-bromoacetaldehyde, 5-bromo-1H-pyrimidin-2ones, hexahydro-1H,8H-pyrimido[4,5-d]pyrimidin-2,7-diones, 4,6-diaryl-1H-pyrimidin-2-ones, chloropyrimidines, bromination, condensation. A revived interest in the Biginelli reaction the three component condensation of aromatic aldehydes, ureas, and carbonyl compounds (-keto esters, -diketones, etc.) which permits the preparation of hydrogenated pyrimidin-2-ones, among which are compounds with high biological activity [1-4], is the reason for our continuation of the investigation of the modification of the Biginelli reaction using aromatic ketones. To synthesize hydrogenated pyrimidin-2-ones [5] we used 4-bromobenzaldehyde (1) and a series of aromatic ketones with the aim of preparing 4-bromophenyl derivatives of pyrimidin-2-one. Acetophenone (2a), 4-methylacetophenone (2b), and 4-butylacetophenone (2c)were chosen as the aromatic ketones. Condensation of the aldehyde 1, acetophenone 2a, and urea in a mole ratio of 1:1:4 in 2-propanol in the presence of concentrated HCl did not give the expected products 4-(4-bromophenyl)-6-phenyl-3,4-dihydro-1Hpyrimidin-2-one (3a) or 4-(4-bromophenyl)-6-phenyl-1H-pyrimidin-2-one (4a). The product of the reaction under these conditions was 4,5-bis(4-bromophenyl)-8a-phenyl-3,4,4a,5,6,8a-hexahydro-1H,8H-pyrimido[4,5-d]pyrimidin-2,7-dione (5) (scheme 1, Table 1). Its composition ans structure were confirmed by microanalysis, IR, UV, and 1H NMR spectra. For example, two carbonyl stretching frequencies at 1695 and 1668 cm-1 were observed in the IR spectrum and absorptions above 260 nm were absent from the UV spectrum. The latter indicates the presence of unconjugated aromatic groups in the molecule. When the concentration of the solution was increased and the ratio of the reactants change to 1.5:1:3 the pyrimidinone 4a (Table 1) was isolated from the reaction mixture in addition to compound 5.
__________________________________________________________________________________________ N. N. Vorozhstsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Novosibirsk 630090; e-mail: oshk@nioch.nsc.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, 229-238, February, 2004. Original article submitted July 6, 2001. 194 0009-3122/04/4002-01942004 Plenum Publishing Corporation
Scheme 1
H 4-BrC6H4CHO 1 C6H4Br- 4 N N H 3a Ph O N H 4a Ph C6H4Br- 4
i-PrOH H +
HN O
4-RC6H4COMe
+
+
2ac
R=H i-PrOH
NH2CONH2 H R = Me, Bu
4 -BrH4C6 HN O
H C H Br- 4 6 4 NH
C6H4Br -4 N O
N H 5
Ph
N H
6b
+7
BuOH (AcOH)
4a + 5 + 4-RC6H4COCH=CHC6H4Br-4 (6a) + (4-BrC6H4CH2NH)2CO (7)
N C6H4Br -4 H 4b,c
2, 4, 6 a R = H, b R = Me, c R = Bu
When the reaction was carried out in butanol the yield of compound 4a increased, but the main product remained the pyrimidopyrimidine 5 (Table 1). 4-Bromochalcone 6a was also isolated and the formation of N,N'-bis(4-bromobenzyl)urea (7) was shown by 1H NMR spectroscopy. Increasing the reaction time led to decrease in the yield of 5a and an increase in the yield of the chalcone 6a which may be associated with hydrolytic decomposition of the pyrimidopyrimidine 5. It was shown that when compound 5 was boiled in butanol containing concentrated HCl it was converted completely into the pyrimidine 4a and the chalcone 6a (cf. [6]). Condensation of compounds 1, 2a, and urea in acetic acid led to the preferential formation of the pyrimidin-2-one 4a (Table 1). This compound was also obtained from the addition of urea to chalcone 6a in acid catalysis conditions analogous to those reported in [7, 8]. The behavior of acetophenones 2b and 2c in the three component condensations differed from that of acetophenone 2a. The reaction products obtained were, respectively 4-(4-bromophenyl)-6-(4-tolyl)-1Hpyrimidin-2-one (4b) and 4-(4-bromophenyl)-6-(4-butylphenyl)-1H-pyrimidin-2-one (4c), together with disubstituted ureas 7 and the chalcone (6b) (see Scheme 1) (Table 1, experiments 6-8). Pyrimidopyrimidines analogous to compound 5 were not isolated from these experiments. TABLE 1. Condensation of 4-Bromobenzaldehyde (1) with Acetophenones (2) and Urea (U)
Expe- Acetoriment phenone 1 2 3 4 5 6 7 8 2a 2a 2a 2a 2a 2b 2c 2c Reaction conditions Reaction Reagent ratio Medium time, h 1:2:U i-PrOH/HCl i-PrOH/HCl BuOH/HCl BuOH/HCl AcOH/HCl i-PrOH/HCl i-PrOH/HCl BuOH/HCl 6 6 6 14 5 8 6 6 1:1:4 1.5 : 1 : 3 1.5 : 1 : 3 1.5 : 1 : 3 1.5 : 1 : 3 1.5 : 1 : 3 1.5 : 1 : 3 1.5 : 1 : 3 Reaction products and yields, % 4 13 (4a) 21 (4a) 17 (4a) 34 (4a) 48 (4b) 15 (4c) 25 (4c) 5 63 49 42 25 5 6 16 (6a) 23 (6a) 4 (6a) 10 (6b) 7
7 21 7 10
195
A scheme for this reaction can be proposed in agreement with data from [5, 9]. In the first stage an acid catalysed condensation of the aldehyde with urea occurs to give an intermediate immonium ion. This ion reacts further with the acetophenones to give an open chain intermediate which cyclizes stepwise into the dihydropyrimidinones 3 (Scheme 2). Scheme 2
+ 4-BrC6H4CHNHCONH2 1 + NH2CONH2 H + + 4-BrC6H4CH=NHCONH2 H2NCONHCHC6H4Br-4 ArCOCH H2NCONHCHC6H4Br-4 ArCOMe
4-BrC6H4 ArCOCH2CH H2NCONH 4 [O] 3
Depending on the reaction conditions and the increased reactivity of the immonium ion and the relatively low reactivity of the carbonyl groups in the intermediates diureidoalkylation may occur at the same time as formation of compound 3 with subsequent cyclization to the pyrimidopyrimidines 5. During the reaction the immonium ion is the hydrogen acceptor for the dehydrogenation of the dihydropyrimidinones 3 which are converted in this way into the substituted benzyl- or dibenzylureas 7 [10]. Scheme 3
C6H4R'-4 N O N H 4a,d,e Br2 / AcOH 4 -BrH4C6 HN O N H 5 N H H H C H Br- 4 H 6 4 NH O Br2 / AcOH 120 oC 4a, 8a R' = Br, R" = Ph; 4d, 8b R' = H, R" = Ph; 4e, 8c R' = R" = H 25 oC R" Br2 / AcOH O N N H 8a,b,c C6H4R '-4 Br R"
4a
8a
Ph
8a
196

Compound 1 4 4b 4c 5 6b 7 8a 8d Empirical formula 2 C16H11BrN2O C17H13BrN2O C20H19BrN2O C24H20Br2N4O2 C16H13BrO C15H14Br2N2O C16H10Br2N2O C16H11BrN2O Found, % Calculated, % Br (Cl) 5 24.30 24.43 23.50 23.42 20.40 20.85 29.30 28.73 27.60 26.53 39.90 40.15 39.06 39.35 25.10 24.43 mp, (solvent) 8 272-275 (EtOHdioxane) 335-337 (EtOHDMF) 310-312 (EtOHDMF) 327-329 (80% AcOH) 157-159 (EtOH) 265267 [14] (EtOH) 268-272 (EtOHdioxane) 246-251 (EtOH) Yield, % 9 34 47 25 63 23 21 55 57
C 3 58.44 58.73 59.98 59.83 62.57 62.67 51.42 51.82 62.97 63.80 45.52 45.25 47.47 47.32 58.43 58.73
H 4 3.40 3.39 3.76 3.84 4.86 4.99 3.71 3.62 4.40 4.35 3.52 3.54 2.69 2.48 3.44 3.39
N 6 8.42 8.56 8.49 8.21 7.19 7.31 9.77 10.07 6.79 7.04 6.36 6.90 8.79 8.56
[M]+*, m/z 7 326.0055 326.0055 340.0199 340.0212 382.0675 382.0681 * 300.0 300.0 395.9499 395.9474 403.9185 403.9161 326.0066 326.0055
197
198
TABLE 2 (continued)
1 8e 9a 9b 9c 9d 10a 10b 10c 10d 2 C10H7BrN2O C16H10BrClN2 C17H12BrClN2 C20H18BrClN2 C16H9Br2ClN2 C21H20BrN3 C22H22BrN3 C25H28BrN3 C21H19Br2N3 3 47.35 47.83 55.67 55.59 56.96 56.77 60.10 59.79 45.74 45.26 64.32 63.96 64.08 64.71 67.16 66.66 53.31 53.30 4 2.74 2.81 2.83 2.92 3.33 3.36 4.61 4.51 2.37 2.14 5.18 5.11 5.28 5.43 6.19 6.26 4.07 4.05 5 32.00 31.83 (10.00) (10.26) (10.08) (9.86) (9.02) (8.82) (8.20) (8.35) 20.99 20.27 19.20 19.57 17.40 17.74 33.90 33.76 6 10.82 11.16 8.01 8.11 7.68 7.79 6.99 6.97 6.40 6.60 10.80 10.66 10.42 10.29 9.46 9.33 8.85 8.88 7 249.9741 249.9742 343.9715 343.9716 357.9873 357.9873 400.0343 400.0342 421.8818 421.8822 393.0837 393.0841 407.0989 407.0997 449.1474 449.1467 470.9939 470.9947 8 207-211 (EtOH) 154-155 (EtOH) 156-159 (EtOH) 74-76 (EtOH) 205-207 (EtOH) 159-161 (EtOH) 178-180 (EtOH) 112-113 (EtOH) 170-174 (EtOH) 9 68 74 68 50 70 75 94 88 80
_______ * High resolution mass spectra, except for compound 6b. In addition to [M+] (m/z 554), compound 5 gave a fragment ion (m/z 327.0113), calculated for C16H12BrN2O [ M - BrC6H4CH=NHCONH2]+ m/z 327.0133.
Bromination of pyrimidine derivatives at position 5 of the ring occurred readily in the presence of donor substituents [11]. An example of bromination of unsubstituted pyrimidin-2-one is known [12]. It was shown that preliminary covalent hydration facilitated bromination. There are no reports of the behavior of aryl-substituted pyrimidin-2-ones in the literature. We have established that ready bromination of aryl-substituted pyrimidinones is a general phenomenon. For example, 4,6-diphenyl- (4d) and 4-phenyl-1H-pyrimidin-2-ones (4e) are brominated to give the corresponding 5-bromoderivatives 8b and 8c (Scheme 3). Compound 5 underwent no change on treatment with bromine in chloroform. It appeared to be unstable to bromination in acetic acid and two products which appeared to be aryl-substituted pyrimidin-2-ones were isolated from the reaction mixture. One of these was compound 4a while the second was the product of bromination of 4a which was confirmed by bromination of 4a. The structure 5-bromo-4-(4-bromophenyl)-6phenyl-1H-pyrimidin-2-one (8a) was assigned to this compound on the basis of its 1H and 13C NMR spectra. The signal of the carbon atom C(5)Br of the pyrimidine ring was observed to strong field at 101.59 ppm in the 13C NMR spectrum. The 4,6-diaryl-5R'-2-chloropyrimidines 9a-d were obtained by treatment of compounds 4a-c and 8a with POCl3. Compounds 9a-d were converted into the 4,6-diaryl-5'-2-piperidinopyrimidines 10a-d by nucleophilic substitution with piperidine (Scheme 4). Scheme 4
4-BrC6H4 R' 4-RC6H4 4ac, 8a N H N O 4-BrC6H4 R' 4-RC6H4 9ad N H N Cl 4-BrC6H4 R' N 4-RC6H4 10ad N N
9a, 10a R = R' = H, 9b,10b R = Me, R' = H, 9c, 10c R= Bu, R' = H; 9d, 10d R= H, R' = Br
We have shown that acetophenone and its 4-alkyl-substituted analogs behave differently in condensation with 4-bromobenzaldehyde and urea. It has been established that bromination of aryl-substituted pyrimidin-2ones with bromine in acetic acid occurs readily and identically to give the corresponding 5-bromopyrimidin-2ones.
TABLE 3. Spectroscopic Characteristics of the Compounds Synthesized

Compound 1 4 4b UV spectrum IR (EtOH), spectrum, =, cm-1 max, nm (log ) 2 3 1625 1618 278.6 (4.062), 348.4 (3.994) 7.6 (3.928), 349.9 (3.880) 7.1 (4.310), 349.4 (4.272)
1
NMR spectrum, , ppm (J, Hz) in CF3COOH 4
4c
1615
7.74 (1H, s, C(5)H); 7.87 (2H, d, J = 8.0, o,o'-H, p-BrC6H4); 8.02 (5H, s, Ph); 8.16 (2H, d, J = 8.0, m,m'-H, p-BrC6H4) 2.66 (3H, s, CH3); 7.70 (2H, d, J = 8.0, o,o'-H, p-BrC6H4); 7.77 (1H, s, C(5)H); 8.02 (4H, s, p-CH3C6H4); 8.12 (2H, d, J = 8.0, m,m'-H, p-BrC6H4) 1.08 (3H, t, J = 7.0, CH3); 1.56 (2H, m, CH2); 1.83 (2H, m, CH2); 2.95 (2H, t, J = 8.0, CH2); 7.72 (2H, d, J = 8.0, o,o'-H, p-BrC6H4); 7.78 (1H, s, C(5)H); 7.96-8.10 (4H, m, p-C4H9C6H4); 8.15 (2H, d, J = 8.0, m,m'-H, p-BrC6H4)
199
TABLE 3 (continued)
1 5* 2 1695, 1668 3 253.5 (3.336) 4 2.91 (1H, t, J = 6.0, ArCHCHCHAr); 4.21 (2H, d, J = 6.0, ArCH); 6.76 (2H, s, 2NH); 6.94 (4H, d, J = 8.5, o,o'-H, 2p-BrC6H4); 6.997.01 (5H, m, m,m'-H, p-H, C6H5, NH); 7.11-7.19 (2H, m, o,o'-H, C6H5); 7.27 (4H, d, J = 8.5, m,m'-H, 2p-BrC6H4) 2.56 (3H, s, CH3); 7.48 (2H, d, J = 8.0, o,o'-H, p-BrC6H4); 7.58-7.76 (5H, m, p-CH3C6H4, COCH=CH); 7.97 (1H, d, J = 15.0, COCH=CH); 8.01 (2H, d, J = 8.0, m,m'-H, p-BrC6H4) 4.55 (4H, s, 2CH2); 7.16 (4H, d, J = 8.0, o,o'-H, 2p-BrC6H4); 7.56 (4H, d, J = 8.0, m,m'-H, 2p-BrC6H4) 7.95 (2H, d, J = 8.0, o,o'-H, p-BrC6H4); 7.94 (2H, d, J = 7.5, o,o'-H, C6H5); 7.83 (2H, d, J = 8.0, m,m'-H, p-BrC6H4); 7.74-7.94 (3H, m, m,m'-H, p-H, C6H5) 7.75-7.97 (6H, m, m,m'-H, p-H, 2C6H5); 7.99 (4H, d, J = 8.0, o,o'-H, 2C6H5) 7.76-7.96 (3H, m, m,m'-H, p-H, C6H5); 8.00 (2H, d, J = 8.0, o,o'-H, C6H5); 9.09 (1H, s, C(6)H) 7.83 (2H, d, J = 7.0, o,o'-H, p-BrC6H4); 7.908.10 (3H, m, m,m'-H, p-H, C6H5); 8.22 (2H, d, J = 7.0, m,m'-H, p-BrC6H4); 8.26 (2H, d, J = 8.0, o,o'-H, C6H5); 8.57 (1H, s, C(5)H) 2.62 (3H, s, CH3); 7.63 (2H, d, J = 8.0, o,o'-H, p-BrC6H4); 7.93 (2H, d, J = 8.5, o,o'-H, p-CH3C6H4); 8.13 (2H, d, J = 8.0, m,m'-H, p-BrC6H4); 8.23 (2H, d, J=8.5, m,m'-H, p-CH3C6H4); 8.51 (1H, s, C(5)H) 1.09 (3H, t, J = 7.0, CH3); 1.56 (2H, m, CH2); 1.83 (2H, m, CH2); 2.91 (2H, t, J = 8.0, CH2); 7.67 (2H, d, J = 8.0, o,o'-H, p-BrC6H4); 7.93 (2H, d, J = 8.5, o,o'-H, p-C4H9C6H4); 8.18 (2H, d, J = 8.0, m,m'-H, p-BrC6H4); 8.25 (2H, d, J = 8.5, m,m'-H, p-C4H9C6H4); 8.54 (1H, s, C(5)H) 7.68-7.83 (3H, m, m,m'-H, p-H, C6H5); 7.86 (4H, s, o,o'-H, m,m'-H, p-BrC6H4); 7.87 (2H, d, J = 8.0, o,o'-H, C6H5) 1.98 (6H, s, 3CH2); 4.17 (4H, s, 2CH2); 7.58 (1H, s, C(5)H); 7.74 (2H, d, J = 7.5, o,o'-H, p-BrC6H4); 7.75-7.91 (3H, m, m,m'-H, p-H, C6H5); 8.00 (2H, d, J = 7.5, m,m'-H, p-BrC6H4); 8.08 (2H, d, J = 8.0, o,o'-H, C6H5) 1.98 (6H, s, 3CH2); 2.58 (3H, s, CH3); 4.16 (4H, s, 2CH2); 7.48 (2H, d, J = 8.0, o,o'-H, p-BrC6H4); 7.57 (1H, s, C(5)H); 7.73 (2H, d, J = 8.5, o,o'-H, p-CH3C6H4); 8.02 (2H, d, J = 8.0, m,m'-H, p-BrC6H4); 8.17 (2H, d, J = 8.5, m,m'-H, p-CH3C6H4) 1.07 (3H, t, J = 7.5, CH3); 1.52 (2H, m, CH2); 1.77 (2H, m, CH2); 1.99 (6H, , 3CH2); 2.88 (2H, t, J = 8.0, CH2); 4.18 (4H, , 2CH2); 7.57 (1H, s, C(5)H); 7.58 (2H, d, J = 8.0, o,o'-H, p-BrC6H4); 7.84 (2H, d, J = 8.5, o,o'-H, p-C4H9C6H4); 7.93 (2H, d, J = 8.0, m,m'-H, p-BrC6H4); 8.08 (2H, d, J = 8.5, m,m'-H, p-C4H9C6H4) 1.94 (6H, s, 3CH2); 4.08 (4H, s, 2CH2); 7.63-7.76 (4H, m, C6H4); 7.76-7.98 (5H, m, C6H4)
6b
1658
225 (3.436), 317 (3.700)
7 8a*2
1665
1675
261 (3.070), 270 (3.070), 276 (2.861) 248 (4.062), 343 (3.725)
8d 8e 9a
1668 1662
244 (4.110), 345 (3.844) 228 (4.045), 338 (3.616) 257 (4.395), 313 (4.410) 261 (4.075), 285 (3.994), 316 (4.125) 262 (4.376), 285 (4.298), 317 (4.420)
9b
9c
9d*2
256 (4.243), 304 (4.130) 229 (4.527), 270 (4.660), 366 (3.855)
10a
10b
232 (4.399), 270 (4.453), 366 (3.710)
10c
232 (4.466), 267 (4.560), 366 (3.854)
10d
267 (4.535), 360 (3.667)
_______ * 1H NMR spectrum recorded in DMSO-d6. *2 1H NMR spectrum at 400.13 MHz.
200
EXPERIMENTAL IR spectra of the compounds synthesized were recorded in KBr disks on a Bruker Vector 22 spectrophotometer. UV spectra of ethanol solutions were recorded on Specord M-40 spectrophotometer. Mass spectra were recorded with a Finnigan MAT-8200 by direct insertion of samples into the ion source. 1H NMR spectra in trifluoroacetic acid with CH2Cl2 as internal standard (5.32 ppm) were recorded on Bruker AC-200 (200 MHz) and Bruker WP-200 SY (200 MHz) instruments. The spectra of compounds 8a and 8d were recorded with a Bruker AM-400 (400 MHz) instrument. The 13C NMR spectrum of compound 8a in DMSO-d6 was recorded on a Bruker AM-400 spectrometer (100 MHz). The course of reactions and the purity of the compounds obtained were monitored by TLC on Silufol UV-254 strips with CHCl3 as eluent. Data for new compounds are cited in Tables 2 and 3. 4,5-Bis(4-bromophenyl-8a-phenyl-3,4,4q,5,6,8-hexahydro-1H,8H-pyrimido[4,5-d]pyrimidin-2,7-dione (5) and 4-(-bromophenyl)-6-phenyl-1H-pyrimidin-2-one (4a). 4-Bromobenzaldehyde (9.2 g, 50 mmol) was added to a solution of urea (9.0 g, 150 mmol) in 2-propanol (70 ml) and conc. HCl (5 ml). The reaction mixture was stirred and kept at room temperature overnight. A voluminous precipitate formed. Acetophenone (6.0 g, 50 mmol) was added to the reaction mixture which was boiled for 3 h, more urea (3.0 g, 50 mmol) was added and boiling was continued for 3 h. The precipitate was removed after cooling, and was washed successively with methanol, NaHCO3 solution, water, and ethanol, and then dried to give the pyrimidopyrimidine 5 (6.9 g). A further amount of 5 (1.85 g) was obtained by dilution of the filtrate with methanol or ethanol. Overall yield 8.75 g (63%) (experiment 1, Table 1). Experiments 2-4 were carried out analogously. In experiment 2 treatment of the filtrate with ethanol gave compound 4a (2.5 g, 13%). In experiments 3 and 4 the precipitate consisted of a mixture of compounds 4a, 5, and 6a. The precipitate was boiled with methanol (75 ml) and filtered. A precipitate of 4-bromochalcone 6a, mp 127-129C [13], was formed from the filtrate. An additional quantity of the chalcone was precipitated from the methanol filtrate with water. The solid which did not dissolve in methanol was heated with 2:1 ethanol dioxane (50 ml) and filtered. The pyrimidine 4a precipitated from the filtrate. The insoluble residue was dissolved on boiling in 1:2 ethanolacetic acid. The precipitate which formed on cooling was filtered off, washed with NaHCO3 solution, water, and ethanol, then dried to give compound 5. More 5 can be obtained by adding an equal volume of ethanol to the filtrate. When the reaction was carried out in acetic acid (experiment 5), the precipitate obtained was substituted dibenzylurea 7. The precipitate obtained by addition of an equal volume of methanol to the filtrate was filtered off and washed with methanol to give pyrimidine 4a. Water (150 ml) was added to the filtrate, the precipitate which formed was separated, boiled with ethanol and filtered. Chalcone 6a precipitated from the ethanol filtrate. The residue insoluble in ethanol was a mixture of compounds 5 and 7 according to the 1H NMR spectrum 4-4-Bromophenyl)-6-phenyl-1H-pyrimidinone (4a). A. A mixture of 4-bromochalcone 6a (4.6 g, 16 mmol) and urea (3.0 g, 50 mmol) in 2-propanol (30 ml) and conc. HCl (5 ml) was boiled for 7.5 h. The precipitate was filtered off, washed with ethanol, NaHCO3 solution, water, and again with ethanol to give pyrimidine 4a (3.0 g, 49%). B. Compound 5 (10.0 g, 18 mmol) was boiled in butanol (60 ml) and conc. HCl (10 ml) for 13 h. The precipitate was filtered off and washed with water to give chalcone 6a (1.1 g). Methanol (100 ml) was added to the filtrate and further chalcone (1.2 g) precipitated. Overall yield of chalcone 6a 45%. Pyrimidine 4a (2.6 g, 44%) precipitated on addition of water (150 ml) to the methanol filtrate. 4-(4-Bromophenyl)-6-(4-tolyl)-1H-pyrimidin-2-one (4b). The reaction was carried out analogously to experiments 1 and 2 above. A mixture (12.8 g) of pyrimidine 4b, chalcone 6b, and urea 7 (63:13:24 from 1 H NMR spectroscopic data) was obtained. The residue was boiled in ethanol (50 ml) and filtered. Chalcone 6b separated from the filtrate. Crystallization of the insoluble residue from a mixture of ethanol and DMF gave the pyrimidine 4b. 201
4-(4-Bromophenyl)-6-(4-butylphenyl)-1H-pyrimidin-2-one (4c) was prepared analogously to compound 4b (experiments 7 and 8, Table 1). Bromination of Compound 5. A. Bromine (10.4 g, 65 mmol) was added dropwise to a solution of compound 5 (18.0 g, 320 mmol) in acetic acid (90 ml) and the mixture was stirred for 8 h at room temperature. The reaction mixture was evaporated, methanol (100 ml) and pyridine (20 ml) added, the mixture boiled for 1 h, cooled, the precipitate filtered off and washed with water and methanol to give pyrimidine 4a (6.8 g). An equal volume of water was added to the filtrate. The precipitate was filtered off and washed with ethanol to give 5-bromo-4-(4-bromophenyl)-6-phenyl-1H-pyrimidin-2-one (8a) (3.0 g, 24%). 13C NMR (100.61 MHz), DMSO-d 6, , ppm: 101.59 (C(5)), 122.44 (C-Br, C6H4Br), 127.44 (Cm,m',C6H5), 128.52 (Co,o', C6H5) 128.85 (Cp, C6H5), 130.52, 130.71 (Co,o, Cm,m', C6H4Br), 137.93 (Ci, C6H4Br), 138.66 (Ci, C6H5), 158.82 (C(4)), 164.86 (C(6)), 166.16 (C=O). B. The reaction mixture obtained by adding bromine to compound 5 in acetic acid, as in the preceding experiment, was boiled for 0.5 h and treated analogously to give compound 8a (7.1 g, 55%). 5-Bromo-4,6-diphenyl-1H-pyrimidin-2-one (8b). A solution of bromine (0.8 g, 5 mmol) in acetic acid (5 ml) was added to a solution of compound 4d (1.0 g, 4 mmol) in acetic acid (10 ml). A precipitate formed in 1-2 min. The mixture was boiled for 1 h, cooled, and the precipitate was filtered off. Methanol (15 ml) and pyridine (1 ml) were added to the residue, the mixture was heated for 15 min, cooled, and 10% HCl added until the solution was acidic. The precipitate was filtered off, washed with water and dried to give pyrimidine 8d (0.75 g). Compounds 8a and 8c were made analogously. 2-Chloro-4-(4-bromophenyl)-6-phenylpyrimidine (9a). A mixture of pyrimidine 4a (21.0 g, 64 mmol) and POCl3 (75 ml) was boiled for 4h, the excess of POCl3 was evaporated in vacuum, the residue was poured onto ice, triturated, and kept for several hours at room temperature. The precipitate was filtered off, washed with NaHCO3 solution and water to give chloropyrimidine 9a (16.4 g, 74%). Compounds 9b,c, and d were made analogously. 4-(4-Bromophenyl)-6-phenyl-2-piperidinopyrimidine (10a). A mixture of chloropyrimidine 9a (1.0 g, 2.9 mmol), piperidine (0.8 g, 9.0 mmol), and ethanol (10 ml) was boiled for 5 h, the precipitate was filtered off and washed with water and ethanol to give compound 10a (0.85 g, 75%). Compounds 10b, c, and d were prepared analogously.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 202 C. O. Kappe, Molecules, 3, 1 (1998). C. O. Kappe, Acc. Chem. Res., 33, 879 (2000). C. O. Kappe, K. Peters, and E.-M. Peters, J. Org. Chem., 62, 3109 (1997). D. Nagarathnam, G. Chiu, T. G. Dhar, W. C. Wong, M. R. Marzabadi, C. Gluchowski, B. Lagu, S. Miao, PCT Int. Appl. WO 96 14846; Chem. Abstr., 125, 142759 (1996). V. P. Mamaev and V. F. Sedova, Izv. SO AN SSSR. Ser. Khim. Nauk, No. 3, 87 (1969). V. F. Sedova and V. P. Mamaev, Khim. Geterotsikl. Soed., 691 (1970). G. Zigeuner, W. Nischk, and B. Juraczovits, Monatsh., B97, 1611 (1966). G. Zigeuner, M. Rauer, F. Paltauf, and E. Fuchs, Monatsh., B98, 22 (1967). C. O. Kappe, J. Org. Chem., 62, 7201 (1997). V. F. Sedova, V. A. Samsonov, and V. P. Mamaev, Izv. SO AN SSSR. Ser. Khim. Nauk, No. 2, 112 (1972). D. J. Brown, The Pyrimidines. Wiley, N.Y. (1994), p. 349. O. S. Tee and S. Banerjee, J. Chem. Soc., Chem. Commun., 1032 (1972). W. B. Black and R. E. Lutz, J. Am. Chem. Soc., 77, 5134 (1955). A. Bakibaev, Zhur. Org. Khim., 30, 1684 (1994).
SYNTHESIS AND PROPERTIES OF AZOLES AND THEIR DERIVATIVES. 52*. PERISELECTIVITY OF [2+3] CYCLOADDITION OF NITRONES TO trans--CYANONITROETHYLENE IN THE LIGHT OF FMO THEORY
R. Jasinski, A. Ciezkowska, and A. Baranski [2+3] Cycloaddition reaction of nitrones with trans--cyanonitroethylene may theoretically lead to regioisomeric nitroisoxazolidines and isomeric oxadiazoles. However, 4- and 5-nitroisoxazolidines were really obtained as only reaction products. Periselectivity of this reaction is rationalized in terms of the FMO theory. Keywords: periselectivity, FMO, nitrone, nitroalkene, AM1 calculations. Some years ago, Padwa et al. [2, 3] showed that in the [2+3] cycloaddition reaction of N-methyl-Cphenylnitrone (1a) and C-phenyl-N-(t-butyl)-C-phenylnitrone (1b) with trans--cyanonitroethylene (2) the alkene C=C bond participated, while the much less shielded CN bond remained unchanged. Consequently, regioisomeric nitroisoxazolidines 3a,b and 4a,b were formed as the only products. The corresponding isomeric oxadiazoles 5a,b and 6a,b were not found in the reaction mixture. The reaction of 2 with C,N-diphenylnitrone (1c) proceeds in the same way [4]. This work is an attempt to explain the observed phenomenon on the basis of Frontier Molecular Orbitals (FMO) theory [5].
H C6H5 C C NO2 H H R C N
+
C6H5 R N O 3ac C6H5 R N O 4ac
NO2 C N N C NO2
N R N O 5ac C6H5 N H
C6H5
+
O N
C C 2
NO2 H
R N O 6ac
C NO 2 C H
1ac
a R = Me, b R = CMe3, c R = Ph _______ * Part 51 see [1]. __________________________________________________________________________________________ Institute of Organic Chemistry and Technology. Cracow University of Technology, 31-155 Cracow, Poland; e-mail: pcbarans@usk.pk.edu.pl. Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 239-242, February, 2004. Original article submitted January 21, 2003. 0009-3122/04/4002-02032004 Plenum Publishing Corporation 203
We began analysis of the molecular orbital interactions with the characterization of the structures of reactants 1a-c and 2 using the AM1 method within the MOPAC 93 program package [6]. The calculations were preformed on a Pentium III (733 MHz) personal computer. In the case of nitrones and nitroalkenes, this method provides good agreement between calculated and experimental data [1, 7-9]. As shown in Table 1, the HOMO energy of 1a is -8.45 eV. This orbital is localized on the the C, N, and O atoms of the >C=N(O) fragment and is perpendicular to the molecular plane. LUMO has the energy -0.30 eV and is localized in the same way. Both in the case of HOMO and LUMO, the 2pz coefficient on the oxygen atom is slightly higher than that on the carbon atom of the >C=N(O) fragment. The FMO properties of 1b are similar to those of 1a. In this case the HOMO energy is -8.36 eV, while the LUMO energy is -0.19 eV. However, when the alkyl substituent on the nitrogen atom of the >C=N(O)- fragment is replaced by the phenyl group, the electronic structure of the FMO significantly changes. The LUMO energy decreases. Simultaneously, the 2pz amplitude on the oxygen atom goes down remarkably. The HOMO of cyanonitroethylene 2 is localized on the carbon atoms of the ethylene fragment and on the carbon and nitrogen atoms of the cyano group, perpendicularly to the molecular plane. Its energy is -12.01 eV. The 2pz amplitude on the >C=C< fragment is higher than that on the CN group. The corresponding LUMO, with the energy -1.81 eV, is localized in the same way. Also in this case, the 2pz amplitude on the carbon atoms of the >C=C< fragment is higher than that on the carbon and nitrogen atoms of the CN group. Figure 1 shows the FMO interaction diagram of the reactions studied, elaborated on the basis of the electronic properties of the addends. As shown, in the case of all of the nitrones studied, the HOMOnitroneLUMOalkene energy gap is significantly smaller than the HOMOalkeneLUMOnitrone gap. Hence, according to the Sustmann classification [10], these are the reactions with normal orbital control. According to the Fukui and Fujimoto rule [11], in the cycloaddition reactions new -bonds are formed between those atoms where the difference between atomic orbital (AO) coefficients is the lowest. As shown in Fig. 1, the AO coefficients of the HOMO of nitrone 1a are 0.480 and -0.513 for carbon and oxygen atoms of the >C=N(O) fragment, respectively. When these data are compared with the corresponding data for the LUMO of cyanonitroethylene 2, it can be noticed that the values of the HOMO coefficients are clearly much closer to the LUMO coefficients on carbon atoms of the ethylene fragment, than to the coefficients on the atoms of the CN group. Comparison of the AO coefficients of the LUMO of alkene 2 with those of the HOMO of nitrones 1b and 1c leads to similar conclusion. Hence, in all of the cases analyzed, the C=C bond in the ethylene fragment of the alkene should react preferentially in the cycloaddition reaction. This conclusion is perfectly consistent with the periselectivity observed experimentally [2-4]. The FMO method, which is a simplification of the Molecular Orbital Perturbation method [12, 13], does not take into account all of the factors that influence reactivity of chemical compounds. It happens in practice that beside the orbital effects, sometimes the reaction periselectivity is controlled by steric effects and/or by charge distribution on reagents. The [2+3] cycloaddition reactions of diarylnitrones and tetracyanoethylene are examples of such control [14]. However, the FMO method predicts well the periselectivity of the reactions of trans--cyanonitroethylene with N-alkyl-C-phenylnitrones and C,N-diphenylnitrone. TABLE 1. Essential Properties of Frontal Molecular Orbitals of Nitrones 1ac and Cyanonitroethylene 2
Compound 1a 1b 1c 2 HOMO Eigenvectors N/C O/CCN 0.279 0.277 0.280 0.558 -0.513 -0.515 -0.492 -0.234 LUMO Eigenvectors N/C O/CCN -0.499 -0.492 -0.338 -0.589 0.390 0.372 0.266 -0.164
C/C 0.480 0.499 0.481 0.653
NCN -0.394
E [eV] -8.45 -8.36 -8.40 -12.01
C/C 0.350 0.346 0.382 0.513
NCN 0.308
E [eV] -0.30 -0.19 -0.73 -1.81
204
Fig. 1. FMO interaction diagram for [2+3] cycloaddition of nitrones 1a-c to cyanonitroethylene 2. Data for diagram taken from Table 1. The authors are grateful to the Polish State Committee for Scientific Research for financial support of this work (Grants C-2/338/BW/02 and C-2/121/DS/02). REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. A. Baranski, R. Jasinski, and K. Zurowski, J. Phys. Org. Chem., 16, 279 (2003). A. Padwa, L. Fisera, and K. F. Koehler, J. Org. Chem., 49, 276 (1984). A. Padwa, K. F. Koehler, and A. Rodriguez, J. Am. Chem. Soc., 103, 4974 (1981). M. Kosman and R. Jasinski, in: Materiay Uczelnianej Sesji Studenckich Kol Naukowych, Politechnika Krakowska, Krakow 2002, p. 201. I. Fleming, Frontier Orbitals and Organic Chemical Reactions, Wiley, Chichester (1976). J. J. J. Steward, MOPAC 93 Manual, Fujitsu Limited, Tokyo, 1993. A. Baranski, M. Olszanska, and K. Baranska, J. Phys. Org. Chem., 13, 489 (2000). R. Jasinski and A. Baranski, Czasopismo Techniczne PK (Chemia), 4, 1 (2001). A. Baranski, R. Jasinski, and M. Bujak, Polish J. Chem., 76, 145 (2002). R. Sustmann, Tetrahedron Lett., 2717 and 2721 (1971). K. Fukui, Theory of Orientation and Selection, Springer-Verlag, Berlin (1975). E. G. Klopmann, in: E. G. Klopmann (editor) Chemical Reactivity and Reaction Paths, Wiley, N. Y. (1974). R. Jasinski, A. Markowska, and A. Baranski, Wiad. Chem., 56, 9 (2002). Yu. D. Samuilov, S. E. Solov'eva, and A. I. Konovalov, Zh. Obsch. Khim., 50, 138 (1980).
205
SYNTHESIS AND PROPERTIES OF AZOLES AND THEIR DERIVATIVES. 54*. THE REGIOSELECTIVITY OF [2+3] CYCLOADDITION OF C,C,N-TRIPHENYL- AND Z-C,N-DIPHENYLNITRONES WITH - AND -SUBSTITUTED NITROETHYLENES IN LIGHT OF FRONTIER MOLECULAR ORBITAL THEORY
R. Jasinski, A. Ciezkowska, A. Lyubimtsev, and A. Baranski Using quantum-chemical calculations we have carried out an analysis of frontier molecular orbital interactions in the [2+3] cycloaddition reactions of C,C,N-triphenyl- and Z-C,N-diphenylnitrones with - and -substituted nitroethylenes. In all of the examples studied the orbital effects lead to the formation of the corresponding 4-nitroisoxazolidines. Keywords: nitroalkenes, nitrones, regioselectivity, [2+3] cycloaddition, frontier molecular orbitals. The greatest contribution towards the stabilization of transition states in [2+3] cycloaddition reactions is the contribution of the effects related to overlap of the frontier molecular orbitals of the reagents (FMO) [2, 3]. Hence, by analysis of the molecular properties of the stationary states of the 1,3-dipole and the dipolarophile it might be possible to predict which of the theoretically possible regioisomers in the reaction route might be kinetically preferred. As follows from the work [4-7], in the case of nitrones and conjugated alkenes the predictions made on the basis of FMO theory correlate well with the observed experimental data regarding selectivity hence we have used the indicated route to describe the [2+3] cycloaddition involving C,C,N-triphenylnitrone (1) and Z-C,N-diphenylnitrone (2) with the - and -substituted nitroethylenes 3a-e and 4a-d which are the targets of our systematic investigations [4-6, 8-10]. In theory, these reactions can lead to a mixture of the corresponding regioisomeric adducts. Our work is an attempt to establish the most likely route for the reaction studied. Since literature data regarding the electronic structure of the nitrones 1, 2 and the nitroolefins 3a-e, 4a-d is absent we have used the AM1 method [11, 12] from the MOPAC-93 program package to describe these properties. The choice of method was dictated by the better correlation of the obtained results with experimental data as compared with alternative methods [4-6, 8, 10].
_______ * For Communication 53 see [1]. __________________________________________________________________________________________ Institute of Organic Chemistry and Technology, Cracow University of Technology 31-155 Cracow, Poland; e-mail: pcbarans@usk.pk.edu.pl. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 243-248, February, 2004. Original article submitted June 16, 2003. 206 0009-3122/04/4002-02062004 Plenum Publishing Corporation
R C6H5 R C6H5 N 1, 2 C6H5 O _ R2 C NO2 C6H5 N
NO2 R2
R1 O 5ai, 6ai R R1 R2 O NO2
+
R1 C H C6H5 C6H5 3ae, 4ad
7ai, 8ai
1 R = C6H5; 2 R = H, 3 a R = CH3, R = H, b R = H, R = H, c R = Cl, R = H, d R = COOCH3, R2 = H, e R1 = CCl3, R2 = H; 4 R1 = H, R2 = CH3, b R1 = H, R2 = Cl, c R1 = H, R2 = COOCH3, d R1 = H, R2 = CCl3; 1 5 a R = C6H5, R = CH3, R2 = H, b R = C6H5, R1 = H, R2 = H, c R = C6H5, R1 = Cl, R2 = H, d R = C6H5, R1 = COOCH3, R2 = H, e R = C6H5, R1 = CCl3, R2 = H, f R = C6H5, R1 = H, R2 = CH3, g R = C6H5, R1 = H, R2 = Cl, h R = C6H5, R1 = H, R2 = COOCH3, i R = C6H5, R1 = H, R2 = CCl3; 6 a R = H, R1 = CH3, R2 = H, b R = H, R1 = H, R2 = H, c R = H, R1 = Cl, R2 = H, d R = H, R1 = COOCH3, R2 = H, e R = H, R1 = CCl3, R2 = H, f R = H, R1 = H, R2 = CH3, g R = H, R1 = H, R2 = Cl, h R = H, R1 = H, R2 = COOCH3, i R = H, R1 = H, R2 = CCl3
1 2 1 2 1 2 1
The study of the reactivity of the reagents was started with a determination of the basic parameters of their electronic structures. The data in Table 1 indicates that the electronic structures of the nitrones 1 and 2 are similar. Their HOMO energies are -8.44 and -8.39 eV respectively. In both cases the HOMO's are located on the 2pz orbitals of the carbon, nitrogen, and oxygen perpendicular to the plane defined by the >C=N(O) fragment. The amplitude on the oxygen atom is slightly larger than the value for the carbon atom. In contrast, the difference between the LUMO energy is more marked. For the nitrone 2 ELUMO it is -0.86 eV. Including a third phenyl substituent in the molecule leads to an increase in this energy to -0.43 eV. The HOMO energy of nitroethylene is -11.95 eV. This orbital is localized on the carbon atom perpendicular to the vinyl fragment of the olefin molecule. The HOMO has a slightly smaller amplitude on the -carbon atom (0.628) when compared with the -atom (0.684). The LUMO levels were localized similarly but, in this instance, the energy is -0.90 eV and the amplitude on the -carbon atom (0.435) markedly less than on the -atom (0.625). The introduction of a methyl group into the -position of the nitroethylene caused the HOMO energy to increase by 0.68 eV. The LUMO energy also undergoes a minimal change. The presence of electron acceptor substituents slightly changes the HOMO level with a simultaneous significant decrease in the LUMO energy. Specifically, the LUMO energy is -1.27 eV for -chloronitroethylene (3c), -1.74 eV for carbomethoxynitroethylene (3d), and -1.69 eV for trichloromethylnitroethylene (3e). A similar kind of FMO energy change is seen when introducing a substituent into the - position of the molecule of nitroethylene. Thus the HOMO level for -methylnitroethylene (4a) exceeds the HOMO for nitroethylene (3b) by 0.74 eV and is -11.21 eV. For the alkene 4a the LUMO increases by 0.11 eV when compared with the nitroethylene 3b and is -0.79 eV. When exchanging an electron donor substituent in the -position of the nitroolefine for a powerful electron acceptor the HOMO energy does not undergo a marked change. At the same time, the LUMO energy decreases to -1.37 eV when R2 = COOCH3 and to -1.44 eV for R2 = CCl3. Using the obtained parameters for the stationary states of the reagents we have carried out an analysis of the FMO interaction. As is apparent in the FMO diagram (Fig. 1) in the case of the nitrones and also nitroethylene and its - substituted analogs the HOMOnitrone - LUMOalkene difference (E1) is significantly less that the alternative HOMOalkene - LUMOnitrone difference (E2). Hence we are concerned with so called normal electron control processes [13]. Similar types of orbital effects are observed for the same nitrones and -substituted analogs of nitroethylene (Fig. 2). As might be expected, in both cases the preference for the HOMOnitrone - LUMOalkene interaction (E = E2 - E1) increases with an increase in the electron acceptor properties of the substituent in the alkene molecule. 207
TABLE 1. Basic Molecular Properties of the Stationary States of the Nitrones 1,2 and Nitroalkenes 3a-e, 4a-d from the Semiempirical AM1 Method
Compound 1 2 3 3b 3c 3d 3e 4a 4b 4c 4d AO Coefficients for the HOMO C/C O/C 0.505 0.481 0.649 0.684 0.652 0.487 0.642 0.619 0.533 0.298 0.640 -0.524 0.490 0.551 0.628 0.474 0.463 0.591 0.632 0.506 0.265 0.572 EHOMO, eV -8.44 -8.39 -11.27 -11.95 -11.38 -12.20 -12.09 -11.21 -11.26 -12.08 -11.90 AO Coefficients for the LUMO C/C 0.349 0.382 0.432 0.435 0.463 0.522 0.503 0.433 0.446 0.441 0.441 O/C 0.274 0.266 -0.628 -0.625 -0.639 -0.562 -0.585 -0.619 -0.635 -0.705 -0.683 ELUMO, eV -0.43 -0.86 -0,87 -0.90 -1.27 -1.74 -1.69 -0.79 -1.12 -1.37 -1.44
In the fundamental process of cycloaddition, novel -bonds are formed between atoms little differentiated in the atomic coefficient values (the Fukui and Fujimoto rule [2]). Hence by comparing the AO coefficient values we can propose that, in the reactions involving diphenyl- and triphenylnitrones with the nitroolefins 3a-b, the formation of adducts with a nitro group in position 4 of the azolidine ring would be
E1 = [EHOMO nitrone 1 ELUMO alkene] E2 = [EHOMO alkene ELUMO nitrone 1] E = E2 E1
7.57 7.52 10.84 10.41 3.27 2.89
7.54 7.49 11.52 11.09 3.98 3.60
7.17 7.12 10.95 10.52 3.78 3.40
6.70 6.65 11.77 11.34 5.07 4.69
6.75 6.70 11.66 11.23 4.92 4.53
Fig. 1. Diagram of the FMO interaction for the [2+3] cycloaddition of C,C,N-triphenyland Z-C,N-diphenylnitrones with the nitroalkenes 3a-e.
208
7.65 7.60 10.78 10.35 3.13 2.75
7.32 7.27 10.83 10.40 3.51 3.13
7.07 7.02 11.65 11.22 4.58 4.20
7.00 6.95 11.47 11.04 4.47 4.09
Fig. 2. Diagram of the FMO interaction for the [2+3] cycloaddition of C,C,N-triphenyland Z-C,N-diphenylnitrones with the nitroalkenes 4a-d.
preferred. This suggestion found support in the studies [8, 10] in which it was shown that the reaction investigated occurs regioselectively in most cases to give the corresponding 4-nitroisoxazolidines. Hence the theoretical calculations correlate well with the observed experimental results. The authors express their thanks to the Polish Committee for Scientific Research for financial support of this work (grant C-2/209/DS/03 and C-2/79/BW/03).
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. A. Markowska, R. Jasinski, and A. Baranski, Czasopismo Techn. PK (Chemia), No. 1, 28 (2003). K. Fukui, Theory of Orientation and Stereoselection, Springer-Verlag, Berlin (1975). I. Fleming, Hranicni Orbitaly a Reakce v Organicke Chemii, NTL, Prague (1983). R. Jasinski, A. Ciezkowska, and A. Baranski, Khim. Geterotsikl. Soedin., 239 (2004). A. Baranski, R. Jasinski, and M. Bujak, Polish J. Chem., 76, 145 (2002). R. Jasinski and A. Baranski, Czasopismo Techn. PK (Chemia), No. 4, 1 (2001). K. N. Houk, A. Bimanand, D. Mukherjee, J Sims, Ch. Yau-Ming, D. C. Kaufman, and L. N. Domelsmith, Heterocycles, 7, 293 (1977). A. Baranski, R. Jasinski, and K. Zurowski, J. Phys. Org. Chem., 16, 279 (2003). A. Baranski and R. Jasinski, Khim. Geterotsikl. Soedin., 1670 (2001).
209
10.
11. 12. 13.
A. Baranski, R. Jasinski, and A. Markowska in Abstract of Papers of the Fifth International Conference. Theoretical and Experimental Backgrounds of Development of New High Performing Chemical Technologies and Equipment, Ivanovo (Russia) (2001), p. 118. J. J. P. Steward, MOPAC-93 Manual, Fujitsu Limited, Tokyo (1993). M. J. Dewar, E. G. Zoebisch, E. F. Haely, and J. J. P. Steward, J. Amer. Chem. Soc., 107, 3902 (1985). R. Sustmann, Tetrahedron Lett., 2117 (1971).
210
CONDENSATION OF ETHYL 2-OXOINDOLINE3-GLYOXYLATE WITH o-AMINOPHENOL AND o-PHENYLENEDIAMINE

V. V. Bolotov, S. N. Kovalenko, S. V. Kovaleva, and V. I. Stepanenko A method is presented for the synthesis of 3-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)-1,4dihydroquinoxalin-2-one and 2-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2H-1,4-benzoxazin-3(4H)-one by the reaction of ethyl 2-oxoindoline-2-glyoxylate with o-aminophenol and o-phenylenediamine. Proposed reaction mechanisms are presented. Keywords: 2H-1,4-benzoxazin-3(4H)-one, 1,4-dihydroquinoxalin-2-one, 2-oxo-1,2-dihydro-1H-indole, cis-trans izomerism. In continuing our study of the reactivity of ethyl 2-oxoindoline-3-glyoxylate (1) [1] it was of interest to introduce o-substituted anilines 2 containing a second nucleophilic group (o-aminophenol, o-phenylenediamine) into the scope of the investigation. The presence of the two electrophilic centers in the ethoxalyl residue in ester 1 gives the possibility of reaction with the amines indicated to give the 1,4-dihydroquinoxalin-2-one and 2H-1,4-benzoxazin-3(4H)-one rings respectively. The ester 1 needed for this target was prepared by a Claisen reaction of 2-oxoindoline with diethyloxalate in absolute ethanol in the presence of sodium ethylate [2]. We have previously shown [1] that the ester 1 reacts with arylamine ester groups to give the corresponding 2-oxoindoline-3-glyoxylic acid arylamides. In this respect the reaction of o-phenylenediamine and o-aminophenol with the ester 1 can be represented by the following scheme:
HO
O OEt O
NH2 XH
HX .. HO NH O X NH O O H 4, 5 4 X = NH, 5 X = O N
+
2 X = NH, O
N 1
O N H 3
__________________________________________________________________________________________ Ukraine National Pharmaceutical Academy, Kharkov 61002; e-mail: igor@uiv.kharkov.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 249-251, February, 2004. Original article submitted May 17, 2001. 0009-3122/04/4002-02112004 Plenum Publishing Corporation 211
According to this scheme the first stage of the reaction is the formation of the intermediate arylamides 3 which then undergo an intramolecular cyclization to give the heterocycles 4 and 5. In the reaction with o-aminophenol it is theoretically possible to suggest the formation of compound 6 which is an isomer of compound 5.
O O N H O N H 6
However, bearing in mind that in the o-aminophenol the amino group is a better nucleophile than the hydroxy group, it might be expected that the arylamide 3 is formed in the first stage of the reaction and that this is then converted to compound 5. The correctness of this proposal is confirmed also by the reaction of ester 1 with p-aminophenol in which the product is the 2-oxo-1,2-dihydro-3H-indoline-3-glyoxylic acid 4-hydroxyphenylamide [1]. The presence of the double bond between the heterocyclic rings in compounds 4 and 5 leads to the possibility of forming their cis and trans isomers.
H N O X O N H
trans isomer
NH O O
N H
cis isomer
Calculations of the overall energy of two of the possible isomers of compound 4 (X = NH) were carried out using the SCF LCAO MO quantum-chemical method in the MNDO semiempirical approximation with PM3 parameterization [4, 5] and this has shown that the trans isomer of compound 4 is energetically more favored than the cis isomer with an overall energy difference of 4.391 kcal/mole. If in the trans isomer the deviation from ring coplanarity is 5.3 then it is increased to 14.6 in the cis isomer due to the steric interaction between the carbonyl groups. These results give a basis for assuming that compounds 4, 5 are formed in the trans configuration in the course of the reaction.
EXPERIMENTAL H NMR spectra were measured on a Bruker WP-300 SY instrument (300 MHz) using DMSO-d6 solvent and TMS internal standard. Mass spectra were taken on a Finnigan MAT-4615B instrument with ballistic heating of the sample and ionization energy of 70 eV. 212
1
3-(2-Oxo-1,2-dihydro-3H-indol-3-ylidene)-1,4-dihydroquinoxalin-2-one (4). o-Phenylenediamine (5.0 mmol) was added to the ethyl ester 1 (5.0 mmol) in DMF (3 ml). Within 5 min of the start of refluxing a red colored precipitate was formed and this was filtered off and crystallized from DMF. Yield 1.1 g (76%); mp 298-299C. 1H NMR spectrum, , ppm: 14.11 (1H, s, NH); 11.91 (1H, s, NH); 10.77 (1H, s, NH); 8.65 (1H, d, Ar); 6.78-7.22 (7H, m, Ar). Mass spectrum, m/z (Irel, %): 277 (100) [M]+, 279 (21) [M-CO]+, 220 (41), 144 (24), 90 (29), 76 (32), 65 (41), 44 (89). Found %: C 69.28; H 3.98; N 15.18. C16H11N3O2. Calculated, %: C 69.31; H 4.02; N 15.15. 2-(2-Oxo-1,2-dihydro-3H-indol-3-ylidene)-2H-1,4-benzoxazin-3(4H)-one (5). o-Aminophenol (5.0 mmol) was added to the ethyl ester 1 (5.0 mmol) in DMF (3 ml) and the product was refluxed for 1 h. The reaction mixture was diluted with water and acidified using hydrochloric acid to pH 3-4. The bright orange colored precipitate formed was filtered off, washed with water to pH 7, and crystallized from aqueous DMF to give 0.82 g (61%) of product with mp 310-311C. 1H NMR spectrum, , ppm: 13.61 (1H, s, NH); 11.07 (1H, s, NH); 8.48 (1H, d, Ar); 6.75-7.26 (7H, m, Ar). Mass spectrum, m/z (Irel, %): 278 (64) [M]+, 250 (100) [M-CO]+, 221 (35), 193 (47), 167 (15), 157 (22), 125 (18), 103 (36), 76 (46), 63 (74), 51 (53). Found, %: C 69.12; H 3.59; N 10.12. C16H10N2O3. Calculated, %: C 69.06; H 3.62; N 10.07.
REFERENCES 1. 2. 3. 4. V. V. Bolotov, S. V. Kovaleva, V. I. Stepanenko, and D. Yu. Matvienko, Fiziologicheski Akt. Veshchestva, No. 1, 51 (1999). L. Horner, Liebigs Ann. Chem., 548, 117 (1941). J. J. P. Stewart, J. Comput. Chem., 10, 209 (1989). J. J. P. Stewart, J. Comput. Aided Mol. Design, 4, 1 (1990).
213
SYNTHESIS OF 3-(3-ACETYL5-ARYL-2,3-DIHYDRO-1,3,4OXADIAZOL-2-YL)CHROMONES
L. Cao, L. Zhang, and J. J. Liu A method is proposed for the synthesis of 3-(3-acetyl-5-aryl-2,3-dihydro-1,3,4-oxadiazol-2-yl)chromones which consists of the conversion of 3-formylchromones to aroylhydrazones and their subsequent heterocyclization using acetic anhydride. Keywords: 3-hetarylchromones, 1,3,4-oxadiazolines. 3-Hetarylchromones show a broad range of biological actions. They show high antiallergic, anticholesteremic, hypolipidemic, antimicrobial, fungicidal, and antiblastic activity, as well they are stimulators of the central nervous system [1]. For this reason much attention has been paid to the synthesis of novel compounds in recent times. Methods for the synthesis of 3-hetarylchromones has been collected in the review [1]. Two proposed basic routes have been identified. The first is the construction of the chromone system from substituted -hetaryl-2-hydroxyacetophenones and the second is the introduction of the heterocycle into a prepared chromone system. In the present work we have selected the second approach to the synthesis of the previously unknown 3-(3-acetyl-5-aryl-2,3-dihydro-1,3,4-oxadiazol-2-yl)chromones 1a-l using the available 3-formylchromones 2a-l [2, 3].
R1 O CHO O 2al (MeCO)2O reflux R2 O 1al
13 a R1 = H, R2 = Me, Ar = Ph; b Ar = o-ClC6H4, Ar = p-MeOC6H4, d Ar = p-O2NC6H4, e R1 = H, R2 = Br, Ar = Ph; f Ar = o-ClC6H4, g Ar = p-MeOC6H4, h Ar = p-O2NC6H4, i R1 = R2 = Cl, Ar = Ph; j Ar = o-ClC6H4, k Ar = p-MeOC6H4, l Ar = p-O2NC6H4
R1 ArCONHNH2 R2
O CH=NNHCOAr O
R2
3al
R1
COMe N O N Ar
__________________________________________________________________________________________ Chemistry Faculty, Xinjiang University, Urumchi 830046, Peoples Republic of China; e-mail: clhx@xju.edu.cn. State Central Laboratory, Nankai University, Tianjin 300070, Peoples Republic of China. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 252-256, February, 2004. Original article submitted October 21, 2002. 214 0009-3122/04/4002-02142004 Plenum Publishing Corporation
Treatment of the 3-formylchromones with aroylhydrazines gave the corresponding aroylhydrazones 3a-l. In the presence of acetic anhydride these undergo heterocyclization to give the 3-(3-acetyl-5-aryl-2,3-dihydro1,3,4-oxadiazol-2-yl)chromones 1a-l. The structures of compounds 1a-l and 3a-l were confirmed by elemental analytical data and from IR, 1 H NMR, and mass spectra. The characteristics of compounds 1a-l and 3a-l are given in Table 1 and the 1 H NMR and mass spectra in Tables 2 and 3.
TABLE 1. Characteristics of Compounds 1a-l and 3a-l

Compound 1a 1b 1c 1d 1e 1f 1g 1h 1i 1j 1k 1l 3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l Empirical formula C20H16N2O4 C20H15ClN2O4 C21H18N2O5 C20H15N3O6 C19H13BrN2O4 C19H12ClBrN2O4 C20H15BrN2O5 C19H12BrN3O6 C19H12Cl2N2O4 C19H11Cl3N2O4 C20H14Cl2N2O5 C19H11Cl2N3O6 C18H14N2O3 C18H13ClN2O3 C19H16N2O4 C18H13N3O5 C17H11BrN2O3 C17H10ClBrN2O3 C18H13BrN2O4 C17H10BrN3O5 C17H10Cl2N2O3 C17H9Cl3N2O3 C18H12Cl2N2O4 C17H9Cl2N3O5 Found, % Calculated, % 4.65 4.63 3.96 3.95 4.81 4.79 3.86 3.84 3.19 3.17 2.72 2.70 3.43 3.41 2.65 2.64 3.02 3.00 2.56 2.53 3.24 3.26 2.48 2.47 4.64 4.61 3.87 3.85 4.77 4.79 3.71 3.73 2.97 2.99 2.49 2.48 3.28 3.27 2.44 2.42 2.80 2.79 2.30 2.29 3.07 3.09 2.24 2.23 mp, N 8.07 8.04 7.35 7.32 7.36 7.40 10.71 10.68 6.81 6.78 6.29 6.26 6.35 6.32 9.19 9.17 6.92 6.95 6.44 6.40 6.49 6.47 9.39 9.37 9.13 9.15 8.24 8.22 8.40 8.33 12.04 11.96 7.58 7.55 6.94 6.91 7.01 6.98 10.08 10.10 7.70 7.76 7.11 7.08 7.18 7.16 10.39 10.35 173-174 187-188 248-249 222-224 215-216 206-207 233-234 228-229 136-137 204-205 239-241 212-214 209-210 234-235 214-216 235-236 217-218 197-198 207-208 195-196 211-213 176-177 188-190 283-284 80 52 47 43 79 51 47 42 83 52 44 54 85 75 60 57 88 72 62 70 82 60 55 51 Yield, %
68.91 68.96 62.70 62.75 66.60 66.66 61.06 61.07 55.20 55.23 51.01 50.98 54.23 54.19 49.85 49.80 56.66 56.60 52.16 52.14 55.47 55.45 50.89 50.91 70.54 70.58 63.40 63.44 67.90 67.85 61.60 61.54 55.11 55.01 50.40 50.34 53.92 53.89 49.09 49.06 56.58 56.53 51.58 51.61 55.30 55.26 50.24 50.27
215
TABLE 2. 1H NMR Spectra of Compounds 1a-l and 3a-l

Compound 1a 1b 1c 1d 1e 1f 1g 1h 1i 1j 1k 1l 3 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l
1
NMR spectrum, , ppm
8.83 (1H, s, 2-H); 8.39-7.28 (8H, m, 5, 7, 8-H, ArH); 7.01(1H, s, 2'-H); 2.33 (3H, s, CH3); 2.37 (3H, s, COCH3) 8.89 (1H, s, 2-H); 8.29-7.25 (7H, m, 5, 7, 8-H, ArH); 7.07 (1H, s, 2'-H); 2.30 (3H, s, CH3); 2.35 (3H, s, COCH3) 8.92 (1H, s, 2-H); 8.23-7.16 (7H, m, 5, 7, 8-H, ArH); 7.09 (1H, s, 2'-H); 2.28 (3H, s, CH3); 2.37 (3H, s, COCH3); 3.59 (3H, s, OCH3) 8.81 (1H, s, 2-H); 8.39-7.28 (7H, m, 5, 7, 8-H, ArH); 7.12 (1H, s, 2'-H); 2.28 (3H, s, COCH3) 8.87 (1H, s, 2-H); 8.31-7.22 (7H, m, 5, 7, 8-H, ArH); 7.07 (1H, s, 2'-H); 2.37 (3H, s, COCH3) 8.79 (1H, s, 2-H); 8.35-7.18 (7H, m, 5, 7, 8-H, ArH); 7.12 (1H, s, 2'-H); 2.28 (3H, s, COCH3) 8.95 (1H, s, 2-H); 8.28-7.12 (7H, m, 5, 7, 8-H, ArH); 7.09 (1H, s, 2'-H); 2.28 (3H, s, COCH3); 3.62 (3H, s, OCH3) 8.91 (1H, s, 2-H); 8.25-7.10 (7H, m, 5, 7, 8-H, ArH); 7.03 (1H, s, 2'-H); 2.39 (3H, s, COCH3) 8.88 (1H, s, 2-H); 8.13-7.22 (7H, m, 5, 7-H, ArH); 7.15 (1H, s, 2'-H); 2.37 (3H, s, COCH3) 8.91 (1H, s, 2-H); 8.28-7.23 (6H, m, 5, 7-H, ArH); 7.09 (1H, s, 2'-H); 2.28 (3H, s, COCH3) 8.91 (1H, s, 2-H); 8.19-7.18 (6H, m, 5, 7-H, ArH); 7.03 (1H, s, 2'-H); 2.38 (3H, s, COCH3); 3.65 (3H, s, OCH3) 8.94 (1H, s, 2-H); 8.25-7.13 (6H, m, 5, 7-H, ArH); 7.00 (1H, s, 2'-H); 2.31 (3H, s, COCH3) 12.21 (1H, br. s, NH); 8.87 (1H, s, 2-H); 7.24-7.98 (9H, m, CH=N, 5, 7, 8-H, ArH); 2.31(3H, s, CH3) 12.15 (1H, br. s, NH); 8.77 (1H, s, 2-H); 7.23-7.92 (8H, m, CH=N, 5, 7, 8-H, ArH); 2.31(3H, s, CH3) 12.08 (1H, br. s, NH); 8.70 (1H, s, 2-H); 7.28-8.10 (8H, m, CH=N, 5, 7, 8-H, ArH); 2.31(3H, s, CH3); 3.56(3H, s, OCH3) 11.89 (1H, br. s, NH); 8.76 (1H, s, 2-H); 7.12-8.21 (8H, m, CH=N, 5, 7, 8-H, ArH) 11.98 (1H, br. s, NH); 8.79 (1H, s, 2-H); 7.22-8.19 (9H, m, CH=N, 5, 7, 8-H, ArH) 11.89 (1H, br. s, NH); 8.76 (1H, s, 2-H); 7.12-8.21 (8H, m, CH=N, 5, 7, 8-H, ArH) 12.00 (1H, br. s, NH); 8.52 (1H, s, 2-H); 7.23-8.25 (8H, m, CH=N, 5, 7, 8-H, ArH); 3.66 (3H, s, OCH3) 11,95 (1H, br. s, NH); 8.92 (1H, s, 2-H); 7.23-8.25 (8H, m, CH=N, 5, 7, 8-H, ArH) 12.02 (1H, br. s, NH); 8.58 (1H, s, 2-H); 7.23-8.33 (8H, m, CH=N, 5, 7-H, ArH) 11.83 (1H, br. s, NH); 8.97 (1H, s, 2-H); 7.21-8.17 (7H, m, CH=N, 5, 7-H, ArH) 11.98 (1H, br. s, NH); 8.97 (1H, s, 2-H); 7.13-8.32 (7H, m, CH=N, 5, 7-H, ArH); 3.66 (3H, s, OCH3) 12.10 (1H, br. s, NH); 8.95 (1H, s, 2-H); 7.22-8.38 (7H, m, CH=N, 5, 7-H, ArH)
The IR spectra of the aroylhydrazones 3a-l show characteristic absorption bands at 3100-3200 (NH), 1660-1670 (C=O), 1620-1640 (C=N), and 1590-1610 cm-1. The 1H NMR spectra of aroylhydrazones 3a-l show signals in the range 8.5-9.0 ppm for the 2-H of the pyrone ring and at 11.8-12.2 ppm for the NH group proton. Due to the instability of the aroylhydrazones the molecular ion peak in their mass spectra was of low intensity. The appearance of peaks for [M-ArCO]+ shows that the amide CN bond undergoes fission readily. The chromone ring is broken via a retro DielsAlder reaction and is then stabilized by a stepwise fission at the single CO group. The IR spectra of the 3-(3-acetyl-5-aryl-2,3-dihydro-1,3,4-oxadiazol-2-yl)chromones 1a-l show the absence of the absorption bands at 3100-3200 cm-1. Instead there are found bands characteristic of chromones (1592-1620 and 1475-1510 cm-1) and an acetyl group (1750-1760 cm-1). The signal for the NH in the region 11.8-12.2 ppm is absent in the 1H NMR spectra. 216
TABLE 3. Mass Spectra of Compounds 1a-l and 3a-l

Compound 1a 1b 1c 1d 1e 1f 1g 1h 1i 1j 1k 1l 3 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l Mass spectrum, m/z (%) 348 (M+, 3), 305(100), 187, 160, 135, 91, 77, 51, 43(48) 384 ([M+2]+, 1), 382 (M+, 3), 341(33), 339(100), 187, 160, 135, 91, 77, 51, 43(52) 378 (M+, 4), 335(100), 187, 160, 135, 91, 77, 51, 43(60) 393 ((M+, 6), 350(100), 187, 173, 160, 135, 91, 77, 65, 43(50) 414 ([M+2]+, 2), 412 (M+, 2), 371, 369(100), 266, 264, 252, 250, 240, 238, 224, 215, 213, 121,119, 43(62) 450 ([M+4]+, 1), 448 ([M+2]+, 4), 446 (M+, 3), 407, 405, 403(100), 253, 251, 226, 224, 201, 199, 121, 119, 43(38) 444 ([M+2]+, 2), 442 (M+, 2), 401(98), 399(100), 253, 251, 226, 224, 201, 199, 43(49) 459 ([M+2]+, 3), 457 (M+, 4), 416(97), 414(100), 253, 251, 226, 224, 201, 199, 43(60) 402 (M+, 1), 363(12), 361(67), 359(100), 245, 243, 241, 218, 216, 214, 189, 43(49) 436 (M+, 2), 397(10), 395(66), 393(100), 245, 243, 241, 218, 216, 214, 189, 43(51) 432 (M+, 1), 393(11), 391(67), 389(100), 245, 243, 241, 218, 216, 214, 189, 43(46) 451 ([M+4]+, 1), 449 ([M+2]+, 5), 447 (M+, 8), 408, 406, 404(100), 245, 243, 241, 218, 216, 214, 189, 43(53) 306 (M+,10), 278, 262, 260, 201, 173, 172, 160, 135, 105(100), 91, 77, 65 342 ([M+2]+, 6), 340 (M+,19), 298, 296, 173, 172, 160, 141(30), 139(100), 135, 91, 77, 65 336 (M+,5), 292, 173, 172, 160, 135(100), 91, 77, 65 351 (M+,7), 323, 307, 305, 173, 172, 150(100), 135, 91, 77, 65 372 ([M+2]+, 9), 370 (M+, 10), 344, 342, 326, 324, 239, 237, 173, 172, 135(100), 77, 65 408 ([M+6]+, 1), 406 ([M+4]+, 4), 404 ([M+2]+, 3), 360, 239, 237, 141(32), 139(100) 402 ([M+2]+, 5), 400 (M+, 6), 374, 372, 358, 356, 239, 237, 202, 135(100) 417 ([M+2]+, 4), 415 (M+, 5), 389, 387, 373, 371, 239, 237, 201, 199, 150(100) 364 ([M+4]+, 0.7), 362 ([M+2]+, 4), 360 (M+, 6), 336, 334, 332, 227, 172, 135, 105(100) 400 ([M+6]+, 0.1), 398 ([M+4]+, 1), 396 ([M+2]+, 3), 394(M+, 3), 350, 229, 141(32), 139(100 394 ([M+4]+, 0.5), 392 ([M+2]+, 3), 390 (M+, 4), 348, 231, 229, 227, 202, 135(100) 409 ([M+4]+, 0.4), 407 ([M+2]+, 3), 405 (M+, 4), 381, 379, 377, 229, 227, 150(100)
The 2-H proton of the pyrone ring is seen as a sharp signal in the region 8.8-8.9 ppm [4] in the spectra of the products 1a-l. The mass spectra of the products 1a-l show a low intensity peak for the molecular ion (generally less than 10%), the main peak being for [M-COCH3]+. Subsequent fragmentation is similar to that described above for the aroylhydrazones 3a-l.
EXPERIMENTAL Thin-layer chromatographic analysis was carried out on GF-254 plates. Melting points were measured on an MP-S3 heating table (Japan). Elemental analysis was carried out using an MT-3 automatic analyzer. IR spectra were taken on a Bruker EQUINOX-55 FT-IR machine using KBr and 1H NMR spectra on a Bruker AX 80 (80 MHz) machine using CDCl3 or DMSO-d6 solvent and TMS internal standard. Mass spectra were recorded on an HP 5988 AMS instrument. General Method for Preparing the Aroylhydrazones (3a-l). Equal amounts of compounds 2a-l and the aroylhydrazines (obtained as in [2, 5]) were mixed and dissolved in 95% alcohol. Several drops of glacial acetic acid were added and the mixture was refluxed for 5-6 h with use of a reflux condenser. After cooling, the crystals formed were filtered off and recrystallized from absolute alcohol to give the aroylhydrazones 3a-l. 217
General Method for Preparing 3-(3-Acetyl-5-aryl-2,3-dihydro-1,3,4-oxadiazol-2-yl)chromones (1al). Acetic anhydride was added to the aroylhydrazone 3a-l (2 mmol) and refluxed for 2 h. After cooling, the reaction mixture was poured into iced water. The precipitate was filtered off, washed with water, dried, and recrystallized from DMFEtOHH2O to give the products 1a-l. The authors express their thanks for the financial support of the State Fund for Natural Science, Peoples Republic of China (29962002) and to the Nankai University State Central Organoelemental Laboratory, Peoples Republic of China.
REFERENCES 1. 2. 3. 4. 5. M. S. Frasinyuk and V. P. Khilya, Khim. Geterotsikl. Soedin., 3 (1999). A. Nohara, T. Umetani, and Y. Sanno, Tetrahedron Lett., 22, 1995 (1973). L. Cao and V. Van, Khim. Geterotsikl. Soedin., 1227 (2003). A. L. Kazakov, V. P. Khilya, V. V. Mezheritskii, and Yu. Litkei, Naturally Occurring and Modified Isoflavonoids [in Russian], Rostov University Publishing House (1985) p. 129. L. M. Chen, Z. Y. Zhang, X. Zhang, D. X. Cai, and D. Yan, Chem. J. Chinese Univ., 9, 283 (1988).
218
SYNTHESIS OF SOME BIOLOGICALLY ACTIVE PYRAZOLE, THIAZOLIDINONE, AND AZETIDINONE DERIVATIVES

R. B. Pawar and V. V. Mulwad Pyrazole, thiazolidinone, and azetidinone derivatives were synthesized from chalcones of 4-hydroxycoumarin. The structures of all the synthesized compounds were confirmed on the basis of spectral and analytical data. The compounds were screened in vitro for their antibacterial activity against various bacterial strains. Keywords: azetidinones, biologically active pyrazoles, thiazolidinones. 1-Benzopyran-2-(2H)-ones are well known for their various biological activities [1, 2]. Pyrazoles and several N-substituted pyrazoles are known to possess neuroleptic [3], analgesic and anti-inflammatory, antipyretic [4], antiarrhythmic [5], sedative-hypnotic effect [6], and antimicrobial activity [7]. They are inhibitors and deactivators of liver alcohol dehydrogenase [8], while 3,5-substituted pyrazoles are known for hypoglycemic activity [4] in glucose primed and diabetic rats. 4-Thiazolidinones have been reported to demonstrate a wide range of pharmacological activities such as hypnotic-sedative, analgesic activity, anticonvulsant [9], antifungal [10], antibacterial [11], and antitubercular activity against M. tuberculosis H37Rv [12]. -Lactamase is generally considered to be responsible for microbial resistance against a broad spectrum of -lactam antibiotics [13]. In continuation of our work [14] we report here for the first time on the synthesis of some dihydropyrazole, thiazolidinone, and azetidinone derivatives, and on estimation of their biological properties. For this purpose chalcones of 4-hydroxy-1-benzopyran-2-(2H)-one and 3-(2H-4-hydroxy-2-oxobenzopyran-3yl)--arylethenyl ketones 1a,b were treated with hydrazine hydrate in the presence of piperidine to yield dihydropyrazole derivatives 2a,b. The 1H NMR spectrum of compound 2a showed the presence of a doublet at 1.95 (J = 7 Hz) for two protons at C(4) and a triplet at 2.48 for one proton at C(5). It showed the presence of a singlet at 3.68 for three protons of OCH3 along with signals at 7.188.41 for eight aromatic protons. It also exhibited singlets at 8.74 and 10.04 for one proton each for the NH and OH groups, which were D2O exchanged. Dihydropyrazoles 2a,b were treated with chloroacetyl chloride in the presence of triethylamine in 1,4-dioxane to give N-chloroacetyl derivatives 3a,b. The 1H NMR spectra of 3a,b did not show the signal at 8.74 for NH, but a singlet at 4.11 for two protons of CH2CI was present along with other signals. Chlorides 3a,b were treated with hydrazine hydrate in ethanol in the presence of piperidine to give N-acetylhydrazines 4a,b. The 1H NMR spectra of 4a and 4b showed a signal at 4.46 for two protons of CH2NH and a broad signal at 4.30 for two protons of NH2 and 8.50 for one proton of NH, which are D2O exchanged. Compounds 4a,b when treated with benzaldehyde gave the corresponding hydrazones 5a,b which __________________________________________________________________________________________ Department of Chemistry, The Institute of Science, 15, Madam Cama Road, Mumbai 400 032, India; e-mail: vinata_mulwad@indiatimes.com, roops_pawar@hotmail.com. Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 257-264, February, 2004. Original article submitted December 26, 2002. 0009-3122/04/4002-02192004 Plenum Publishing Corporation 219
Scheme 1
O
O
R
8 9
NH2NH2
O
2 3
7 6 5
O
3 2N 4 5
5' 6' 1' 4' 3' 2'
10
OH
O
1a,b
OH
2a,b
NH
1
ClCH2COCl
8 7 6 5 9
O
2 3
O
4 5
5' 6' 1' 4' 3' 2'
R
7
O
2 3
O
4 5 3 2
10
NH2NH2
6 5 10 4
3 2
OH
N
1
4a,b
N H
NH2
OH
3a,b
N1
O
CH2Cl
PhCHO
8 7 6 5 9
O
2 3
O
4 5 3 2
5' 6' 4' 3' 2'
R
5' 6' 4' 3' 2'
10
1'
OH
N
1
5a,b
HSCH2COOH
N H
1'
8 7 6 5
O
2 3
O
4 5
5' 6' 1' 4' 3' 2'
10
3 2
OH
N
1
6' 1'
5' 4'
ClCH2COCl
6a,b
N H
O
N S
2'
3'
8 7 6 5
O
2 3
O
4 5
5' 6' 1' 4' 3' 2'
10
3 2
OH
N
1
6'
5' 4'
7a,b
N N H
O
1'
CI
2'
3'
27 a R = OMe, 27 b R = H
220
TABLE 1. Spectral Data of Compounds 2a,b-7a,b

Compound 1 2a IR spectra, , cm-1, KBr 2 3426 (OH and NH), 2927 (CH), 1724 (C=O), 1620 (C=N), 1544, 1440, 1373, 1257, 1027, 778
1
H NMR spectra (, ppm), DMSO-d6 (J, Hz) 3
13
C NMR spectra (, ppm), DMSO-d6 4
Mass spectra, m/z (%) 5 M+ 336 m/z 319, 305, 292, 280, 265, 254, 240, 223, 216, 200, 185, 176, 161, 152, 144, 135, 121, 105, 91, 77, 65,43, 42 M+ 306, m/z 278, 270, 229, 221, 207, 201, 175, 161, 145,133, 121, 104, 90, 85, 77, 67, 57 M+ 412, M+2 414, m/z 384, 353, 335, 323, 305, 290, 268, 251, 237, 223, 204, 175, 161, 144, 121, 107 M+ 382, M+2 384, m/z 354, 339, 315, 305, 276, 270, 247, 227, 221, 207, 199, 175, 161, 145, 133, 121, 105, 90, 85, 77, 67, 56
2b
1.95 (2H, d, J = 7, 4-, 4-H2); 2.48 (1H, t, 5-H, CHNH), 3.68 (3H, s, OCH3); 7.18 (1H, d, J = 6, 8-H); 7.40 (2H, d, J = 8, 2'- and 6'-H); 7.59 (2H, d, J = 8.5, 3'- and 5'-H); 7.80 (1H, d, J = 7.5, 5-H), 8.11 (1H, t, 6-H); 8.41 (1H, t, 7-H); 8.74 (1H, s, NH, D2O exchanged); 10.04 (1H, s, OH, D2O exchanged) 3420 (OH and NH), 2928 (CH), 1.90 (2H, d, J = 7, 4-, 4-H2); .42 (1H, t, 5-H); 1723 (C=O), 1614 (C=N), 1511, 7.05 (3H, m, 3'-, 4'- and 5'-H); 7.32 (2H, d, J = 8.5, 1459, 1380, 1250, 1177, 1031, 823 2'- and 6'-H); 7.50 (1H, d, J = 7, 8-H); 7.67 (1H, t, 6-H); 7.80 (1H, d, J = 7, 5-H); 8.60 (1H, s, NH, D2O exchanged); 10.40 (1H, s, OH, D2O exchanged) 3300 (OH), 2959 (CH), 1707 (C=O), 1621 (C=N), 1510, 1447, 1253, 1099, 1027, 806 2.01 (2H, d, J = 6, 4-, 4-H2); 2.50(1H, t, H(5)), 3.56 (3H, s, OCH3); 4.11 (2H, s, ClCH2C=O); 6.49 (2H, d, J = 6, 2'- and 6'-H); 6.73 (1H, t, 6-H), 6.91(1H, t, 7-H); 7.13(1H, d, J = 7, 8-H); 7.16 (2H, d, J = 6, 3'- and 5'-H); 7.39 (1H, d, J = 6, 5-H); 10.92 (1H, s, OH, D2O exchanged) 2.20 (2H, d, J = 6.5, 4-, 4-H2); 2.75 (1H, t, 5-H); 4.15 (2H, s, CH2C=O); 6.60 (2H, t, 6- and 7-H); 6.75 (1H, d, J = 7, H-8); 6.85 (1H, d, J = 7.5, 5-H); 7.15 (2H, d, J = 7, 2'- and 6'-H); 7.35 (3H, m, 3'-, 4'-H and 5'-H); 10.40 (1H, s, OH, D2O exchanged)
41.3 (C(4)), 53.8 (OCH3), 56.1 (C(5), 100.2 (C(3)), 111.9 (C(10)), 116.4 (C(2')), 118.2 (C(8)), 119.9 (C(6')), 127.6 (C(5)), 128.6 (C(6)), 132.7 (C(7)), 136.0 (C(3')), 137.1 (C(1')), 151.2 (C(9)), 154.3 (C-4')), 158.1 (C(3)), 162.0 (C(4)), 166.2 (C(2)) 42.0 (C(4)), 51.2 (C(5)), 103.9 (C(3)), 111.9 (C(10)), 117.0 (C(2')), 118.2 (C(8)), 119.8 (C(6')), 120.9 (C(2')), 124.0 (C(6')), 127.4 (C(5)), 128.6 (C(6)), 132.5 (C(7)), 136.0 (C(3')), 137.0 (C(5')), 145.0 (C(1')), 151.2 (C(9)), 158.0 (C(3)), 163.6 (C(4)), 166.8 (C(2)) 43.0 (C(4)), 54.2 (OCH3), 57.7 (C(5)), 61.0 (CICH2C=O), 100.5 (C(3)), 111.0 (C(10)), 116.5 (C(2')), 118.2 (C(8)), 119.9 (C(6')), 127.6 (C(5)), 128.6 (C(6)), 132.7 (C(7)), 136.0 (C(3')), 137.1 (C(1')), 151.2 (C(9)), 154.3 (C(4')), 158.1 (C(3), 162.0 (C(4)), 166.2 (C(2)), 169.1 (NC=O) 41.2 (C(4)), 56.0 (C(5)), 61.0 (CICH2C=O), 99.5 (C(3)), 111.9 (C(10)), 117.2 (C(2')), 118.2 (C(8)), 119.8 (C(6')), 120.9 (C(3')) and C(5')), 127.5 (C(5)), 128.6 (C(6)), 132.6 (C(7)), 136.0 (C(4')), 137.1 (C(1')), 151.2 (C(9)), 158.0 (C(3)), 161.8 (C(4)), 163.5 (C(2)), 166.9 (NC=O)
3a
3b
3432 (OH), 3017 (CH), 1721 (>C=O), 1623 (C=N), 1553, 1442, 1249, 1136, 1111, 996, 833
221
222
TABLE 1 (continued)
1 4a 2 3433 (OH, NH and NH2), 2955(CH), 1727 (C=O), 1617, 1541, 1444, 1378, 1259, 1159, 1115, 992, 778 3 2.34 (2H, d, J = 6, 4,- 4-H2); 2.77 (1H, t, 5-H); 3.48 (3H, s, OCH3); 4.30 (2H, b, NH2); 4.46 (2H, s, CH2C=O); 7.06 (2H, d, J = 8.5, 2'- and 6'-H); 7.10 (1H, t, 6-H); 7.27 (1H, t, 7-H); 7.90 (2H, d, J = 7.5, 3- and 5'-H); 7.82 (1H, d, J = 7, 8-H); 8.00 (1H, d, J = 7.5, 5-H); 8.50 (1H, s, NH, D2O exchanged); 10.42 (1H, s, OH, D2O exchanged) 2.10 (2H, d, J = 6, 4-, 4-H2); 2.42 (1H, t, 5-H, CHNH); 4.20 (2H, b, NH2); 4.45 (2H, s, CH2C=O); 7.04 (2H, d, J = 8.5, 6- and 7-H); 7.25 (1H, d, 8-H); 7.49 (3H, m, 3'-H, 4'- and 5'-H); 7.75 (1H, d, J = 7, 5-H); 8.00 (2H, d, 2'- and 6'-H); 8.80 (1H, s, NH, D2O exchanged); 10.43 (1H, s, OH, D2O exchanged) 2.09 (2H, d, J = 8, 4-, 4-H2); 2.75 (1H, t, 5-H); 3.48 (3H, s, OCH3); 4.33 (2H, s, CH2C=O); 6.55 (1H, s, N=CHPh); 7.02 (2H, d, J = 7.5, 2''- and 6''-H); 7.07 (3H, m, 3''-, 4''- and 5''-H); 7.19 (2H, d, J = 9, 2'- and 6'-H); 7.34 (2H, t, 6- and 7-H); 7.45 (1H, d, J = 7.5, 8-H); 7.57 (1H, d, J = 7, 5-H); 7.69 (2H, d, J = 8, 3'- and 5'-H); 8.27 (1H, s, NH, D2O exchanged), 10.30 (1H, s, OH, D2O exchanged) 2.05 (2H, d, J = 8, 4-, 4-H2); 2.49 (1H, t, 5-H); 4.38 (2H, s, CH2C=O); 6.60 (1H, s, N=CHPh); 7.35 (2H, t, 6- and 7-H); 7.57 (3H, m, 3''-, 4''- and 5''-H); 7.73 (2H, d, J = 8.5, 2''- and 6''-H); 8.00 (3H, m, 3'-, 4'- and 5'-H); 8.25 (3H, d, J = 8.5, 2'-, 6'- and 8-H); 8.55 (1H, d, J = 7, 5-H); 9.04 (1H, s, NH, D2O exchanged); 10.41 (1H, s, OH, D2O exchanged) 4 43.2 (C(4)), 54.7 (OCH3), 56.9 (C(5)), 58.9 (NHCH2C=O), 104.1 (C(3)), 111.5 (C(10)), 118.0 (C(8)), 120.7 (C(6')), 120.8 (C(2')), 123.9 (C(5)), 124.3 (C(6)), 132.2 (C(7)), 137.6 (C(3') and C(5')), 140.5 (C(1')), 150.0 (C(9)), 154.0 (C(4'), COCH3), 159.4 (C(3)), 163.4 (C(4)), 164.6 (C(2)), 170.0 (NC=O) 42.0 (C(4)), 56.8 (C(5)), 60.0 (CICH2C=O), 98.8 (C(3)), 112.0 (C(10)), 117.3 (C(2')), 118.3 (C(8)), 119.9 (C(6')), 121.0 (C(3') and C(5')), 127.5 (C(5)), 128.6 (C(6)), 132.6 (C(7)), 135.9 (C(4')), 137.0 (C(1')), 151.3 (C(9)), 158.0 (C(3)), 161.9 (C(4)), 163.6 (C(2)), 167.0 (NC=O) 42.5 (C(4)), 52.9 (OCH3), 53.9 (C(5)), 55.4 (NHCH2C=O), 98.1 (C(3)), 111.5 (C(10)), 112.2 (C(3'') and C(5'')), 117.3 (C(4'')), 118.0 (C(8)), 120.7 (N=CHPh), 120.8 (C(2'), C(6'), C(2'') and C(6'')), 123.9 (C(5)), 124.3 (C(6)), 132.2 (C(7)), 137.6 (C(3') and C(5')), 140.5 (C(1')), 152.0.0 (C(9)), 154.2 (C(4')), 159.4 (C(3)), 160.0 (C(4)), 165.0 (C(2)), 172.0 (NC=O) 41.3 (C(4)), 53.8 (OCH3), 56.1 (C(5)), 59.9 (NHCH2C=O), 100.2 (C(3)), 111.9 (C(10)), 116.4 (C(2') and C(6')), 118.2 (C(8)), 119.9 (C(2'') and C(6'')), 121.0 (N=CHPh), 127.6 (C(5)), 128.6 (C(6)), 132.7 (C(7)), 136.0 (C(3'), C(4') and C(5')), 137.1 (C(3''), C(4'') and C(5'')), 140.2 (C(1') and C(1'')), 151.2.0 (C(9)), 158.1 (C(3)), 162.0 (C(4)), 166.2 (C(2)), 169.1 (NC=O) 5 M+ 408, m/z 380, 354, 331, 305, 287, 270, 247, 241, 227, 221, 175, 161, 133, 121, 104, 90, 84, 77, 67, 56
4b
3420 (OH, NH and NH2), 2928 (CH), 1725 (>C=O), 1613, 1511, 1459, 1250, 1177, 1031, 823
5a
3479 (OH and NH), 2877 (CH), 1719 (>C=O), 1623, 1556, 1453, 1313, 1213, 999, 784
5b
3440 (OH and NH), 3081 (CH), 1711 (>C=O), 1613, 1546, 1438, 1380, 1207, 1135, 1021, 824
M+ 466, m/z 434, 300, 280, 251, 238, 228, 204, 190, 175, 145, 135, 121, 105, 91, 77, 43
TABLE 1 (continued)
1 6a 2 3464 (OH and NH), 2897 (CH), 1710 (>C=O), 1607, 1511, 1442, 1251, 1176, 1031, 829 3 2.31 (2H, d, J = 7, 4-, 4-H2); 2.76 (1H, t, 5-H); 3.48 (3H, s, OCH3); 3.73 (2H, s, SCH2C=O); 4.53 (2H, s, NCH2C=O); 4.90 (1H, s, NCHS); 6.82 (2H, d, J = 7.5, 2'- and 6'-H); 6.87 (2H, d, J = 7.5, 2''- and 6''-H); 7.00 (2H, d, J = 7, 3'- and 5'-H); 7.17 (1H, t, 6-H); 7.44 (3H, t, 3''-, 4''- and H-5''); 7.58 (1H, d, J = 7, 8-H); 7.76 (1H, t, 7-H); 8.06 (1H, d, J = 8, 5-H); 8.67 (1H, s, NH, D2O exchanged); 10.52 (1H, s, OH, D2O exchanged) 1.99 (d, 2H, J = 7, 4-, 4-H2); 2.53 (1H, t, 5-H); 3.80 (2H, s, SCH2C=O); 4.42 (2H, s, NCH2C=O); 4.80 (1H, s, NCHS); 7.42 (3H, m, 3'-, 4'- and 5'-H); 7.72 (2H, d, J = 7.5, 2'- and 6'-H); 8.00 (2H, m, 6- and 7-H); 8.20 (1H, d, J = 7, 8-H); 8.40 (3H, m, 3''-, 4''- and 5''-H); 8.60 (2H, d, 2''- and 6''-H); 8.80 (1H, d, J = 7.5, 5-H); 9.61 (1H, s, NH, D2O exchanged); 10.85 (1H, s, OH, D2O exchanged) 2.20 (2H, d, J = 7, 4-, 4-H2); 2.63 (1H, t, 5-H); 3.38 (1H, d, J = 6, CICHC=O); 3.55 (3H, s, OCH3); 4.46 (2H, s, NCH2C=O); 4.47 (1H, d, J = 6, NCHAr); 6.68 (1H, d, J = 7.5, 8-H); 6.95 (2H, d, J = 7.5, 2''-H, 6''-H); 7.10 (2H, m, 6- and 7-H); 7.27 (3H, t, 3''-, 4''- and 5''-H); 7.49 (2H, d, J = 7.5, 2'- and 6'-H); 7.85 (1H, d, J = 7, 5-H); 7.91 (2H, d, J = 7, 3'- and 5'-H); 8.67 (1H, s, NH, D2O exchanged); 10.52 (1H, s, OH, D2O exchanged) 1.80 (2H, d, J = 7, 4-, 4-H2); 2.60 (1H, t, 5-H); 3.40 (1H, d, J = 6, CICHC=O); 4.20 (2H, s, NCH2C=O); 4.49 (1H, d, J = 6, NCHPh); 7.05 (2H, t, 6-H and 7-H); 7.22 (3H, m, 3'-, 4'- and 5'-H); 7.38 (1H, d, J = 8, 8-H); 7.50 (1H, d, J = 7.5, 5-H); 7.67 (3H, m, 3''-, 4''- and 5''-H); 7.80 (4H, m, 2'-H, 6'-, 2''- and 6''-H); 8.50 (1H, s, NH, D2O exchanged); 10.51 (1H, s, OH, D2O exchanged) 4 41.6 (NCHS), 45.1 (C(4)), 53.5 (OCH3), 55.4 (C(5)), 59.0 (SCH2C=O), 62.5 (NHCH2C=O), 102.8 (C(3)), 111.5 (C(10)), 112.2 (C(2'), C(6'), C(2''') and C(6''')), 117.3 (C(3'''), C(4''') and C(5''')), 118.0 (C(8)), 123.9 (C(5)), 124.3 (C(6)), 132.2 (C(7)), 137.7 (C(3') and C(5')), 140.5 (C(1') and C(1''')), 150.2 (C(9)), 152.2 (C(4'), COCH3), 158.0 (C(3)), 162.4 (C(4)), 163.0 (C(2)), 166.0 (SC=O), 172.0 (NC=O) 41.9 (NCHS), 45.5 (C(4)), 53.3 (C(5)), 56.8 (SCH2C=O), 61.0 (NHCH2C=O), 99.0 (C(3)), 111.9 (C(10)), 117.2 (C(2') and C(6')), 118.2 (C(8)), 119.8 (C(2''') and C(6''')), 127.5 (C(5)), 128.6 (C(6)), 132.6 (C(7)), 136.0 (C(3'), C(4') and C(5')), 137.1 (C(3'''), C(4''') and C(5''')), 142.2 (C(1') and C(1''')), 151.3 (C(9)), 158.0 (C(3)), 161.9 (C(4)), 163.6 (C(2)), 166.7 (SC=O), 170.0 (NC=O) 31.6 (NCHPh), 40.5 (CICHC=O), 45.1 (C(4)), 53.5 (OCH3), 55.4 (C(5)), 59.0 (SCH2C=O), 62.5 (NHCH2C=O), 102.8 (C(3)), 111.5 (C(10)), 112.2 (C(2'), C(6'), C(2''') and C(6''')), 117.3 (C(3'''), C(4''') and C(5''')), 118.0 (C(8)), 123.9 (C(5)), 124.3 (C(6)), 132.2 (C(7)), 137.7 (C(3') and C(5')), 140.5 (C(1') and C(1''')), 150.2 (C(9)), 152.2 (C(4')), 158.0 (C(3)), 162.4 (C(4)), 163.0 (C(2)), 166.0 (SC=O), 172.0 (NC=O) 29.9 (NCHPh), 39.1 (CICHC=O), 45.0 (C(4)), 53.0 (C(5)), 62.3 (NHCH2C=O), 102.5 (C(3)), 113.4 (C(10)), 114.2 (C(2'), C(6'), C(2''') and C(6''')), 119.2 (C(8)), 119.3 (C(3''), C(4'') and C(5'')), 122.8 (C(3'), C(4') and C(5')), 125.0 (C(5)), 125.4 (C(6)), 133.0 (C(7)), 140.1 (C(1''')), 142.2 (C(1')), 151.1 (C(9)), 162.6 (C(3)), 164.0 (C(4)), 167.3 (C(2)), 172.2 (NC=O) 5 M+ 570, m/z 550, 493, 450, 392, 361, 284, 252, 232, 204, 190, 175, 144, 134, 115, 105, 91, 77
6b
3431 (OH and NH), 2928 (CH), 1727 (C=O), 1607, 1542, 1445, 380, 1260, 1159, 1023, 779
7a
3464 (OH and NH), 2897 (CH), 1710 (>C=O), 1607, 1511, 1442, 1251, 1176, 1031, 829
M+ 572 M+2 574 m/z 550, 495, 464, 434, 392, 361, 300, 284, 251, 232, 204, 190, 175, 145, 134, 115, 105, 91, 77, 43
7b
3433 (OH and NH), 2927 (CH), 1726 (>C=O), 1606, 1541, 1445, 1375, 1261, 1115, 1025, 779
223
did not show signals at 4.46 for NH2 but showed the presence of a signal at 6.55 for one proton of N=CHPh. Hydrazones 5a,b on further treatment with either mercaptoacetic acid or chloroacetyl chloride gave thiazolidinones 6a,b or azetidinones 7a,b respectively. The 1H NMR spectra of 6a,b showed the presence of signals at 3.73 for two protons of SCH2 and at 4.90 for SCHN, which confirm the formation of the thiazolidinone ring. Also the 1H NMR spectra of 7a,b showed the presence of doublets at 3.38 (J = 6 Hz) for one proton of CICH and 4.47 (J = 6 Hz) for one proton of NCHPh along with other signals, which confirm the formation of the azetidinone ring. The structures of all the above-synthesized compounds are confirmed on the basis of spectral (Table 1) and analytical data (Table 2). All compounds were screened in vitro for their antibacterial activity against a variety of bacterial strains (Table 3). Antimicrobial activity. The minimum inhibition concentration (MIC) was determined using the Tube Dilution method according to the standard procedure [15]. All the compounds were screened in vitro for their antimicrobial activity against a variety of bacterial strains such as Staphylococcus aureus, Salmonella paratyphi, and Escherichia coli (Table 3). The standard drugs used for comparison were ciprofloxacin (MIC 5 g/ml), cloxacillin (MIC 10 g/ml), and gentamycin (MIC 5 g/ml). The antimicrobial data of the above compounds reveal that compounds having the methoxy group have increased antibacterial activity while azetidinones are found to be more biologically active than thiazolidinones.
TABLE 2. Physical and Analytical Data of Compounds 2a,b-7a,b

Compound 2a 2b 3a* 3b*2 4a 4b 5a 5b 6a*
3
Empirical formula C19H16N2O4 C18H14N2O3 C21H17N2O5Cl C20H15N2O4Cl C21H20N4O5 C20H18N4O4 C28H24N4O5 C27H22N4O4 C30H26N4O6S C29H24N4O5S C30H25N4O6Cl C29H23N4O5Cl
C 68.10 67.85 70.15 70.58 60.87 61.16 63.10 62.82 61.95 61.76 63.85 63.49 67.87 67.74 69.86 69.52 63.40 63.15 64.67 64.44 63.05 62.93 64.35 64.20
Found, % Calculated, % H 8.43 8.33 4.69 4.69 4.33 4.12 4.05 3.92 5.05 4.90 4.70 4.76 4.55 4.83 4.50 4.72 4.65 4.56 4.23 4.44 4.49 4.37 4.15 4.24
mp, C N 4.76 4.55 9.15 9.45 6.85 6.79 7.15 7.32 13.85 13.72 14.90 14.81 11.36 11.29 11.86 12.01 9.70 9.82 10.25 10.37 9.53 9.79 10.21 10.33 190 168 238 225 256 265 213 226 245 >300 >300 287
Yield, %
75 70 72 68 76 80 79 77 67 70 65 63
6b*4 7a*
5
7b*6
_______ * Found, %: Cl 9.03. Calculated, %: Cl 9.16. *3 Found, %: S 5.43. Calculated, %: S 5.61. *4 Found, %: S 5.98. Calculated, %: S 4.81. *5 Found, %: Cl 6.13. Calculated, %: Cl 6.11. *6 Found, %: Cl 6.30. Calculated, %: Cl 6.45. 224
TABLE 3. Antibacterial Activity of 2a,b-7a,b

Compound 2a 2b 3a 3b 4a 4b Activity, g/ml S. aureus S. typhi E. coli 50 50 100 100 100 150 50 100 50 50 100 100 50 50 100 100 50 50 Compound 5a 5b 6a 6b 7a 7b Activity, g/ml S. typhi E. coli 50 50 100 100 25 100 50 100 25 50 25 50
S. aureus 25 50 50 100 25 50
EXPERIMENTAL Melting points were taken in open capillaries and are uncorrected. IR spectra (max, cm-1) were recorded on PerkinElmer FTIR, and NMR (1H and 13C) were recorded on Bruker AMX (500 MHz) and AC (200 MHz) using TMS as standard. Mass spectra were recorded on Shimadzu GC-MS. 5-Aryl-3-[2H-4-hydroxy-2-oxobenzopyran-3-yl]-4,5-dihydropyrazole (2a,b). Chalcones of 4-hydroxybenzopyran-2-one 1a,b (0.01 mol) and hydrazine hydrate (0.01 mol, 0.5 ml) in the presence of piperidine (1.0 ml) in alcohol were refluxed for 7-8 h. The reaction was monitored on TLC. On the completion of the reaction the reaction mixture was poured onto crushed ice and neutralized with dilute HCI to give a solid product, which was then crystallized from alcohol to afford 2a,b in 70-75% yield. 5-Aryl-1-chloroacetyl-3-[2H-4-hydroxy-2-oxobenzopyran-3-yl]-4,5-dihydropyrazole (3a,b). 5-p-Methoxyphenyl-3-[2H-4-hydroxy-2-oxobenzopyran-3-yl]-4,5-dihydropyrazoles 2a,b (0.01 mol) were taken in hot benzene, and chloroacetyl chloride (0.015 mol, 1.68 ml) was added dropwise. The reaction mixture was stirred at room temperature for 8 h and was then cooled to give a pale yellow solid. This solid was recrystallized from methanol to give 3a,b in 65-72% yield. 5-Aryl-1-hydrazinoacetyl-3-[2H-4-hydroxy-2-oxobenzopyran-3-yl]-4,5-dihydropyrazole (4a,b). A mixture of compound 3a,b (0.01 mol) and hydrazine hydrate (0.01 mol, 1.40 ml) in alcohol was refluxed for 7-8 h. The reaction mixture was then poured onto crushed ice to give a solid product, which was then recrystallized from alcohol to give hydrazines 4a,b in 75-80% yield. 5-Aryl-1-[(benzylidenehydrazino)acetyl]-3-[2H-4-hydroxy-2-oxobenzopyran-3-yl]-4,5-dihydropyrazole (5a,b). An equimolar mixture of hydrazines 4a,b (0.01 mol) and benzaldehyde (0.01 mol, 1.06 ml) in ethanol (30 ml) containing acetic acid (0.5 ml) was refluxed for 6 h. The excess solvent was distilled off and the residue was poured onto crushed ice to give a solid. The separated solid was filtered off and recrystallized from methanol to give hydrazones 5a,b in 77-79% yield. 5-Aryl-3-[2H-4-hydroxy-2-oxobenzopyran-3-yl]-1-[(2-phenyl-4-oxothiazolidin-3-ylamino)-acetyl]4,5-dihydropyrazole (6a,b). A mixture of hydrazones 5a,b (0.01 mol) and thioglycolic acid (0.02 mol, 1.84 ml) in DMF was refluxed for 12 h. The reaction mixture was cooled and poured into ice-cold sodium bicarbonate solution to remove traces of acid, if any. Finally the solid obtained was filtered off, dried, and recrystallized from alcohol to give 6a,b in 65-70% yield. 5-Aryl-N-[(3-chloro-2-oxo-4-phenylazetidin-1-ylamino)acetyl]-3-[2H-4-hydroxy-2-oxo-benzopyran3-yl]-4,5-dihydropyrazoles (7a,b). To the hydrazones 5a,b (0.01 mol) in 1,4 dioxane (40 ml) was added chloroacetyl chloride (0.01 mol, 1.12 ml) and triethylamine (0.01 mol, 1 ml) while stirring at 0-5C. The reaction mixture was stirred at this temperature for 1 h and then refluxed for 7 h. The excess solvent was removed and the residue was poured onto crushed ice to afford a solid product. The solid was filtered off, washed, and recrystallized from methanol to give 7a,b in 77-82% yield.
225
The authors are thankful to Mumbai University for financial assistance. The authors are grateful to National Facility for High Field NMR, TIFR Mumbai. The authors are also grateful to the Padmaja Occupational Hygiene & Diagnostic Centre, Navi Mumbai, and Prof. Vaidya, Head of the Microbiology Dept., Institute of Science, Mumbai for biological testing. The authors are also thankful to Mr. S. V. Chiplunkar, UDCT, Mumbai for elemental analysis.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. M. A. Stahmann, M. Ikawa, and K. P. Link, US Pat. 2427579; Chem. Abstr., 42, 603 (1948). R. B. Arora and C. N. Mathur, Brit. J. Pharmacol., 20, 29 (1963). Burgers Medicinal Chemistry, Wiley, N. Y. (1980), p. 291. The Merck Index, ed. M. Windholz, Merck and Co., Rahway, New Jersey, 11th ed. (1989), p. 161. R. W. Hamilton, J. Heterocycl. Chem., 13, 545 (1976). L. S. Goodman and A. Gilman, The Pharmacological Basis of Therapeutics, Macmillan, N. Y. (1980), p. 295. K. Ramalingam, G. X. Thyvelikakath, K. D. Berlin, R. W. Chesnul, R. P. Brown, N. N. Durham, S. E. Ealick, and D. Vander Helm, J. Med. Chem., 20, 847 (1977). R. W. Fries, D. P. Bohlken, and B. V. Plapp, J. Med. Chem., 22, 356 (1979). E. Ylhan and N. Ergenc, Arch. Pharm. (Weinheim), 325, 453 (1992). N. Cesur, Z. Cesur, N. Ergenc, M. Uzun, M. Kiraz, and O. Kasymodlu, D. Kaya, Arch. Pharm. (Weinheim), 327, 271 (1994). The Merck Index, 11th Edition, 6233 (1989). Z. Cesur, H. Guner, and G. Otuk, Eur. J. Med. Chem., 29, 981 (1994). Eunhee Kim, Jongsook Bang, Han-Young Kang, Ae Nim Pae, Hun Yeong Kob, and Moon HO Chang, Korean J. Med. Chem., 2, 45 (1992). V. V. Mulwad and R. B. Pawar, Ind. J. Het. Chem., 10, 241 (2001). S. Frankle, S. Reitman, and A. C. Sonnenwirth, Gradwols Clinical Laboratory Methods and Diagnosis, II, 7th ed., C. V. Mosby Company, Germany (1970), p. 1406.
226
SYNTHESIS AND PROPERTIES OF 12(E)-ETHOXYIMINO DERIVATIVES OF 8-AZA-16-THIAGONA-12,17-DIONES

M. V. Budnikova, A. L. Mikhal'chuk, and D. B. Rubinov The reaction of 8-aza-16-thiagona-1,3,5(10),13-tetraene-12,17-dienes with ethoxyimine in dimethyl sulfoxide yields the corresponding 12(E)-ethoxyimino derivatives. The physicochemical properties of these compounds were studied. Keywords: 8-aza-16-thiagona-12,17-diones, heterosteroids, 12(E)-ethoxyimino-8-aza-16-thiagona-17ones, 12(E)-ethoxyimino-1H-thieno[3',4':5,6]pyrido[2,1-a]isoquinolin-1-ones. 8-Azasteroids, their D-homoanalogs, and heteroanalogs with oxygen, nitrogen, sulfur atoms at the 16(17) position of the tetracyclic 8-azasteroid skeleton display biological properties [1-4] and, thus, have been studied in the search for new pharmacological agents for the regulation of biological function and control of the biochemical homeostasis of man and farm animals. 8-Aza-16-thiagona-12,17-diones [5, 6] have received special attention due to the biophoric properties related to their nitrogen and sulfur atoms [7, 8]. However, the extremely low solubility of these azathiasteroids severely limits their possible modification and biological screening. Thus, these compounds must be transformed to increase their solubility while retaining their basic structural elements. The replacement of the 12-carbonyl group in 1-azagona-12,17-D-homodiones by imino or hydroxyimino functions, on the whole, does not alter the biological activity of these compounds and, in some cases, even enhances it. On the other hand, such derivatives, as a rule, are more soluble than their dioxo precursors. Hence, we attempted to obtain imino or hydroxyimino derivatives of 8-aza-16-thiagona-12,17-diones to study their chemical and biological properties. The first attempts to obtain hydroxyimino derivatives of 8-aza-16-thiagona-12,17-diones under the conditions used for transforming 8-aza-16-oxagona-12,17-diones [9], proved unsuccessful [6, 10]. In further work, we found that 8-aza-16-thiagona-12,17-diones 1a,b are quite soluble in DMSO at 80-100C and remain chemically stable under these conditions over a long period. This finding was used in the synthesis of ethoxyimino derivatives 2a,b. The condensations of 8-aza-16-thiagona-12,17-diones 1a,b with ethoxyamine were carried out in solutions of these reagents in DMSO at 80-100C with monitoring by thin-layer chromatography. At the end of the reaction upon the complete consumption of substrates 1a,b, the reaction mixtures were diluted with water and the precipitates filtered off. Usual work-up of the crude products gave analytical samples of 12(E)-ethoxyimino derivatives 2a,b.
__________________________________________________________________________________________ Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, 220141 Minsk, Belarus; e-mail: rubinov@ns.iboch.ac.by. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 265-269, February, 2004. Original article submitted June 6, 2001. 0009-3122/04/4002-02272004 Plenum Publishing Corporation 227
O S
11
NOEt C N
O D S
15
R R 1a,b
EtONH2 DMSO,
R R
A
3
B 2a,b
a R = H, b R = OMe
Under these conditions for the reaction of substrates 1a,b with ethoxyamine, we might have expected the formation of pyrido[2,1-a]isoquinoline derivatives 3 or 17-ethoxyimino derivatives 4 in addition to desired products 2a,b. These additional products could be formed as the result of attack of nucleophilic ethoxyamine at the electrophilic thiolactone group C(17)=O. On the other hand, the formation of 12-ethoxyimino derivatives 2a,b as mixtures of E-(anti)- and Z-(syn)-stereoisomers is very likely. However, the thin-layer chromatographic monitoring of the reaction course and spectral investigation of 2a,b indicated that there were no other products of the reaction of substrates 1a,b with ethoxyamine.
O H OEt O O R R 3 N SH R R 4 N NOEt S
The composition and structure of products 2a,b are in accord with the elemental analysis data and physicochemical data. The IR spectra of 12-ethoxyimino derivatives 2a,b, on the whole, support their proposed structure. A number of specific features are found, which would be difficult to explain without additional spectral investigation. Thus, in the 1700-1600 cm-1 region, the spectrum of 2a shows strong bands (85%) at 1680 and 1610 cm-1 and a medium-strength band (55%) at 1650 cm-1, while, in this region, 2b has only one strong band (85%) at 1652 cm-1 but two medium-strength bands (60-70%) at 1695 and 1620 cm-1. All these bands are broadened and asymmetrical, indicating the presence of various components. While the high-frequency bands at 1695 and 1685 cm-1 may be reliably assigned to C=O group vibrations, it is difficult to assign the bands at lower frequencies to C=N or C=C bonds. We should note that one strong broadened and symmetrical band is found for 2b at 1500-1400 cm-1 at ~1470 cm-1, while two medium-strength bands are found in this region for 2a at 1488 and 1460 cm-1 due to vibration of the C=C bonds of the aromatic ring A [10]. The electronic absorption spectra of 2a,b, as in the case of starting 1a,b [5, 6], show strong bands at ~320 and ~280 nm, which, in general, indicates that there are only slight differences in the electronic structures of these compounds. On the other hand, a very broad, low-intensity band with maximum at ~410 nm is noted in the UV spectrum of 2b, which may be assigned to n* electronic transitions [11]. The 1H NMR spectra of ethoxyimino derivatives 2a,b show signals for all the protons of their proposed structures. Thus, in the 4.50-4.70 ppm region, the signal for 9-H appears as the X-part of the C(9)HC(11)H2 ABXspin system. The signals for C(15)H2 appear at 3.95-4.06 ppm as a strongly coupled AB-spin system [12]. In contrast to the 1H NMR spectra of starting 1a,b [5, 6], the spectra of derivatives 2a,b have characteristic ethyl group signals as a three-proton triplet (at ~1.30 ppm) and two-proton quartet (at ~4.18 ppm). Two three-proton singlets are found for 2b, which has 2- and 3-OMe substituents in ring A, as well as singlets for 1-H and 4-H shifted upfield. We should note that no 1H NMR signals were found corresponding to the Z-(syn)-configuration of the OEt group of the 12-ethoxyimino substituent. Support for the E-configuration of the ethoxy group is 228
found in the position of the signals of the ABX-system for the protons at C(9) and C(11). Thus, in contrast to 1a,b [5, 6], the signals for the protons in 2a,b are shifted upfield by about 160 and 180 Hz for C(9)HX and C(11)HA, respectively, and by 80 Hz for C(11)HB. Such a displacement cannot be attributed only to the change in electronegativity upon replacing the oxygen atom by an ethoxyimino group but is quite clear taking account of the anisotropic effect of an ethoxy substituent with E-configuration. The 13C NMR spectra of derivatives 2a,b show the corresponding number and type of 13C signals for the assigned structures. In particular, the ethoxyimino substituent methyl groups are found in the region up to 20 ppm, while the signals for the 13C(17)-thiolactone carbonyl groups are found at 190-200 ppm. The signals for the 13C-azomethine fragment are found at ~167 ppm, while the 13C atoms of the C(13)=C(14) vinyl fragment are found at ~104 and ~148 ppm, respectively. The 13C NMR spectra also support the assigned E-configuration of the ethoxyimino group in 2a,b: the signals for 13C(9) and 13C(11) are shifted upfield by ~4 and ~10 ppm, respectively, relative to the corresponding signals in 1a,b [5, 6]. We should note that products 2a,b are much more soluble and have much lower melting points in comparison with their 12,17-dioxo precursors. Thus, 2a melts at about 100C lower than precursor 1a, while 2b melts at 70C lower than 1b [5, 6]. Thus, ethoxyimino derivatives of 8-aza-16-thiagona-12,17-diones 2a,b appear to be more convenient for further chemical transformations and biological testing, while the reported method provides for the preparation of other hydroxyimino and alkoxyimino derivatives of 8-aza-16-thiagona-12,17-diones 1. We should note that the formation of ethoxyimino derivatives 2a,b exclusively as E-isomers indicates the great significance of coulombic interactions in the stereochemistry of such imino compounds.
EXPERIMENTAL Samples of 8-aza-16-thiagona-1,3,5(10),13-tetraene-12,17-diones 1a,b were obtained by fusing the corresponding 3,4-dihydroisoquinolines using 3-acetylthiotetronic acid according to our previous procedures [5, 6]. The reaction course and purity of the products were monitored by thin-layer chromatography on Silufol UV-254 plates using 9:1 chloroformmethanol as the eluent. The melting points were determined on a Boetius block. The IR spectra were taken on a UR-20 spectrometer using KBr pellets. The UV spectra were taken on a Bruker AC-200 spectrometer for CDCl3 solutions at 200 MHz for the 1H NMR spectra and 50 MHz for the 13 C NMR spectra using TMS as the internal standard. rac-12(E)-Ethoxyimino-8-aza-16-thiagona-1,3,5(10),13-tetraen-17-one (2a). Ethoxyamine (0.11 ml, 1.5 mmol) was added to a solution of 8-aza-16-thiagona-12,17-dione 1a (0.27 g, 1 mmol) in dimethylsulfoxide (30 ml) and the mixture obtained was maintained at 80C for 24 h. Then, additional 0.07 ml (1 mol) of ethoxyamine was added, maintaining the mixture at the indicated temperature. Further samples of ethoxyamine (0.07 ml) were added after each additional 24 h period until the complete consumption of the starting azasteroid. The total reaction time was 80 h. The total amount of ethoxyamine used was 0.32 ml (4.5 mmol). At the end of the reaction, the desired product was precipitated from the reaction mixture by adding water, filtered off, and dissolved in chloroform. The solution obtained was dried over sodium sulfate and then evaporated to dryness. The residue was then recrystallized from ethyl acetate to give 0.26 g of ethoxyimino derivative 2a in 82% yield as light-yellow crystals; mp 199-203C (dec). IR spectrum, , cm-1: 3080-2830, 1680, 1650, 1610, 1565, 1488, 1460, 1415, 1380, 1357, 1340, 1295, 1215, 1125, 1056, 1020, 943, 900, 875, 847, 772, 760, 685. UV spectrum, max, nm (): 273.6 (13150), 316.8 (17900); min, nm (): 233 (8040), 292.1 (9625). 1H NMR spectrum, , ppm (J, Hz): 1.28 (3H, t, J1,2 = 7.0, CH3); 2.16 (1H, dd, J1 = 13.0, J2 = 16.0, 11-HB); 2.81 (1H, tt, J1 = 16.0, J2,3 = 3.0, 6-He); 3.11 (1H, dtd, J1 = 3.0, J2 = 12.0, J3 = 16.0, 6-Ha); 3.42 (1H, ddd, J1 = 3.0, J2 = 12.0, J3 = 16.0, 7-Ha); 3.86 (1H, dd, J1 = 3.0, J2 = 16.0, 11-HA); 3.95 (1H, tt, J1,2 = 3.0, J3 = 16.0, 7-He); 3.98 (1H, d, J = 17.0, 15-HB); 4.10 (1H, d, J = 17.0, 15-HA); 4.22 (2H, q, J1,2,3 = 7.0, NOCH2); 4.64 (1H, dd, J1 = 3.0, J2 = 13.0, 9-HX); 229
7.17-7.42 (4H, m, 1-H, 2-H, 3-H, 4-H). 13C NMR spectrum, , ppm: 15.323 (CH3), 30.071 (C(6)), 30.464 (C(11)), 31.683 (C(15)), 44.363 (C(7)), 56.750 (C(9)), 70.257 (NOCH2), 104.653 (C(13)), 126.788 (CH), 127.843 (CH), 127.963 (CH), 129.434 (CH), 133.976 (C(10)), 135.053 (C(5)), 147.287 (C(14)), 167.437 (C(12)), 195.218 (C(17)). Found, %: C 65.00, 64.79; H 5.89, 5.73; N 9.03, 8.84; S 10.02, 10.01. C17H18N2O2S. Calculated, %: C 64.95; H 5.77; N 8.91; S 10.20. M 314.40. rac-12(E)-Ethoxyimino-2,3-dimethoxy-8-aza-16-thiagona-1,3,5(10),13-tetraen-17-one (2b). The reaction of 8-aza-16-thiagona-12,17-dione 1b (0.33 g, 1 mmol) with ethoxyamine according to a procedure analogous to the synthesis of 2a gave 0.26 g (70%) of ethoxyimino derivative 2b as light-yellow crystals; mp 245-250C (dec.). IR spectrum, , cm-1: 3100-2830, 1695, 1652, 1620, 1525, 1480-1455, 1398, 1358, 1320, 1282, 1234, 1225, 1140, 1062, 1050, 954, 936, 887, 861, 796. UV spectrum, max, nm (): 210.5 (25730), 290 (23730), 317.3 (28760), 410 (1765); min, nm (): 201.8 (25285), 253.2 (12745), 298.7 (20915), 368.2 (1400). 1 H NMR spectrum, , ppm (J, Hz): 1.30 (3H, t, J1,2 = 7.5, CH3); 2.17 (1H, dd, J1 = 13.0, J2 = 16.5, 11-HB); 2.82 (1H, tt, J1,2 = 3.0, J3 = 15.5, 6-He); 3.06 (1H, dtd, J1 = 4.0, J2 = 15.5, J3 = 17.0, 6-Ha); 3.39 (1H, ddd, J1 = 4.0, J2,3 = 17.0, 7-Ha); 3.78 (1H, dd, J1 = 4.0, J2 = 16.5, 11-HA); 3.88 (3H, s, OCH3); 3.92 (3H, s, CH3); 3.96 (1H, tt, J1,2 = 4.0, J3 = 17.0, 7-He); 3.98 (1H, d, J = 17.5, 15-HB); 4.06 (1H, d, J = 17.5, 15-HA); 4.14 (2H, q, J1,2,3 = 7.5, NOCH2); 4.58 (1H, dd, J1 = 4.0, J2 = 13.0, 9-HX); 6.66 (1H, s, 4-H); 6.74 (1H, s, 1-H). 13C NMR spectrum, , ppm: 14.734 (CH3), 29.363 (C(6)), 30.002 (C(11)), 31.269 (C(15)), 43.902 (C(7)), 55.991 (C(9)), 55.991 (OCH3), 56.298 (OCH3), 69.587 (NOCH2), 103.972 (C(13)), 109.004 (C(4)), 111.402 (C(1)), 125.683 (C(10)), 126.235 (C(5)), 143.314 (C(2)), 146.762 (C(3)), 148.314 (C(14)), 166.963 (C(12)), 198.495 (C(17)). Found, %: C 60.78, 60.75; H 6.03, 5.98; N 7.34, 7.41; S 8.51, 8.43. C19H22N2O4S. Calculated, %: C 60.94; H 5.92; N 7.48; S 8.56. M 374.46. The authors express their profound gratitude to Academician Afanasii Andreevich Akhrem for his interest in our work and helpful comments in a discussion of the experimental data and theoretical considerations.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 230 A. A. Akhrem, B. B. Kuz'mitskii, F. A. Lakhvich, V. A. Khripach, and Yu. L. Zhuravkov, Chemistry and Biology of Immunoregulators [in Russian], Zinatne, Riga (1985), p. 265. N. A. Konoplya, O. V. Gulyakevich, A. L. Mikhal'chuk, and B. B. Kuz'mitskii, Vestsi Akad. Navuk Belarusi, Ser. Khim. Navuk, No. 3, 91 (1994). G. S. Lyubin, I. G. Dad'kov, O. V. Gulyakevich, and B. B. Kuz'mitskii, Vestsi Akad. Navuk Belorussk. SSR, Ser. Khim. Navuk, No. 2, 93 (1990). A. A. Akhrem, F. A. Lakhvich, L. G. Lis, and B. B. Kuz'mitskii, Vestsi Akad. Navuk Belorussk. SSR, Ser. Khim. Navuk, No. 6, 81 (1982). M. V. Budnikova, L. G. Lis, D. B. Rubinov, and A. L. Mikhalchuk, Mendeleev Commun., 208 (1999). M. V. Budnikova, D. B. Rubinov, and A. L. Mikhal'chuk, Khim. Geterotsikl. Soedin., 107 (2003). N. K. Kochetkov (editor), General Organic Chemistry (Nitrogen-containing Heterocycles) [in Russian], Vol. 8, Khimiya, Moscow (1985), pp. 196, 255, 286. E. R. Uzhdavini, Toxicology of Organic Sulfur Compounds [in Russian], Zinatne, Riga (1986), p.195. A. A. Akhrem, F. A. Lakhvich, L. G. Lis, and V. N. Pshenichnyi, Zh. Org. Khim., 15, 1396 (1979). A. Cross, Introduction to Practical Infrared Spectroscopy [Russian translation], Nauka, Moscow (1961), p. 111. O. V. Sverdlova, Electronic Spectra in Organic Chemistry [in Russian], Khimiya, Leningrad (1973), p. 248. R. Bible, Interpretation of Nuclear Magnetic Resonance Spectra [Russian translation], Atomizdat, Moscow (1969), p. 224.
NOVEL APPROACHES TO SYNTHESIS OF 4-ALKYL-6-AMINO5-CYANO-3-METHYL(PROPYL, PHENYL)2H,4H-PYRANO[2,3-c]PYRAZOLES

V. D. Dyachenko1 and E. B. Rusanov2 We have obtained 4-alkyl-6-amino-5-cyano-3-methyl(propyl, phenyl)-2H,4H-pyrano[2,3-c]pyrazoles by reaction of 4-alkylmethylene-3-substituted 5-pyrazolones with malononitrile or cyanothioacetamide. We have used X-ray diffraction to study the structure of 6-amino-5-cyano-4-isopropyl(hexyl)-3-phenyl2H,4H-pyrano[2,3-c]pyrazoles. Keywords: 4-alkylmethylene-3-substituted 5-pyrazolones, 4-alkyl-6-amino-5-cyano-3-methyl(propyl, phenyl)-2H,4H-pyrano[2,3-c]pyrazoles, malononitrile, cyanothioacetamide, Michael reaction. 4-Aryl(hetaryl)-substituted pyrano[2,3-c]pyrazoles have been obtained by reaction of aryl(hetaryl)methylenemalononitriles with 5-pyrazolone [1-4]. We have proposed a modified method for synthesis of 4-alkylsubstituted pyrano[2,3-c]pyrazoles, involving three-component condensation of aliphatic aldehydes, malononitrile, and 3-methyl-5-pyrazolone [5] (Scheme 1). In this paper, we consider novel variants of the synthesis of 4-alkyl-6-amino-5-cyano-3-methyl(propyl, phenyl)-2H,4H-pyrano[2,3-c]pyrazoles 1, involving the reaction of 4-alkylidene-substituted 5-pyrazolones 2 with cyanothioacetamide 3 (method A) or malononitrile 4 (method B) in ethanol in the presence of morpholine. Both routes probably include formation of the corresponding Michael adducts 5 and 6, regioselectively undergoing ring closure under the reaction conditions to form the substituted pyrano[2,3-c]pyrazoles 1. Condensation of 3-methyl-4-(3'-pentylmethylene)-5-pyrazolone (7) with cyanothioacetamide 3 leads to formation of substituted 1H,4H-pyrano[2,3-c]pyrazole (8) (Scheme 2). Physicochemical and spectral study methods support the structure of compound 8 (Tables 1, 2) specifically as a 1H,4H-pyranopyrazole structure. At the same time, these arguments are not convincing as evidence for the structure of systems 1, because the 1H NMR spectra obtained are not inconsistent with either structures 1A or their prototropic isomers 1B. We have discussed this problem earlier in [5]. In order to establish the regioselectivity of the condensation of 4-alkylmethylidene-3-methyl(propyl, phenyl)-5-pyrazolones 2 with CH-acids 3 and 4 and to unambiguously resolve the question concerning the structure of its products 1, we used X-ray diffraction to study 6-amino-5-cyano-4-hexyl-3-phenyl-2H,4Hpyrano[2,3-c]pyrazole (1a) and 6-amino-5-cyano-4-isopropyl-3-phenyl-2H,4H-pyrano[2,3-c]pyrazole (1k).
__________________________________________________________________________________________ Taras Shevchenko Lugansk State Pedagogical University, Lugansk 91011, Ukraine; e-mail: dvd_lug@online.lg.ua. 2 Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev 02094; e-mail: iochkiev@ukrpak.net. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 270-281, February, 2004. Original article submitted June 13, 2001; revision submitted February 20, 2003. 0009-3122/04/4002-02312004 Plenum Publishing Corporation 231
1
Scheme 1
CN H2N 3 R R
1
O S
NH ( )
R1 CN
R HN H2S N
R1 CN O 1ax (A) NH2
HN N OH S 5
NH2
N N H 2ax
O CN 4 CN (B) , O NH R R1 CN HN N 6 OH C N R N N H O 1ax (B) NH2 R1 CN
1, 2 a, b, kq,u,v R = Ph, ch,t,w, x R = Me, i, j, r R = Pr; a R1 = Me(CH2)5, b R1 = Me2CHCH2, c R1 = cyclohexyl, d R1 = 2-butyl, e R1 = 2-pentyl, f R1 = Me(CH2)8, g R1 = Ph(CH2)2, h R1 = Me(CH2)10, i R1 = Me2CH, j R1 = cyclohexyl, k R1 = Me2CH, l R1 = MeCHPh, m R1 = Me(CH2)8, n R1 = Et2CH, o R1 = cyclohexyl, p R1 = 3-cyclohexyl, q R1 = PhCH2, 1 r R = 3-cyclohexyl, s R1 = Ph(CH2)2, t R1 = 3-cyclohexyl, u R1 = 2-pentyl, v R1 = 2-butyl, w R1 = MeCHPh, x R1 = PhCH2
Scheme 2
Me Me Me Me Me N 7 N Ph O 3, O NH N H2S N Ph 8 O NH2 CN Me
A general view of molecules 1a and 1k is shown in Figs. 1 and 2; the basic geometric parameters are given in Tables 3 and 4. The central bicyclic system O(1)N(3)N(4)C(1-5,7) for both compounds is practically flat: the deviations of the atoms from the mean-square plane are no greater than 0.123(3) , the dihedral angle between the five-membered heterocycle N(3)N(4)C(4)C(5)C(7) and the six-membered ring O(1)C(1-5) is only 5.8 for 1a and 3.5 for 1k. The N(1), C(6), C(8), and C(14), C(10) atoms deviate from the central plane respectively by -0.067 , -0.290 , 1.462 , and 0.048 for 1a, and by 0.051 , -0.483 , 1.434 , and 0.073 for 1k. 232
TABLE 1. Characteristics of Compounds 1a-x, 8

Compound 1a 1b 1c 1d 1e 1f 1g 1h 1i 1j 1k 1l 1m 1n 1o 1p 1q 1r 1s 1t 1u 1v 1w 1x 8 Empirical formula C19H22N4O C17H18N4O C14H18N4O C12H16N4O C13H18N4O C17H26N4O C16H16N4O C19H30N4O C13H18N4O C16H22N4O C16H16N4O C21H18N4O C22H28N4O C18H20N4O C19H20N4O C19H18N4O C20H16N4O C16H20N4O C21H18N4O C14H16N4O C18H20N4O C17H18N4O C16H16N4O C15H14N4O C19H22N4O Found, % Calculated, % H 6.98 6.88 6.10 6.16 6.88 7.02 7.15 6.94 7.41 7.37 8.60 8.67 5.64 5.75 8.96 9.15 7.50 7.37 7.82 7.74 5.80 5.75 5.19 5.30 7.82 7.74 6.60 6.54 6.15 6.29 5.69 5.70 5.06 4.91 6.94 7.09 5.34 5.30 6.31 6.29 6.63 6.54 5.95 6.16 5.61 5.75 5.44 5.30 7.01 6.88 mp, N 17.47 17.38 18.87 19.03 21.54 21.69 23.96 24.12 22.58 22.75 18.44 18.53 20.14 19.99 17.14 16.95 22.59 22.75 19.48 19.56 20.04 19.99 16.48 16.36 15.25 15.37 18.02 18.17 17.32 17.49 17.63 17.60 15.87 17.06 19.82 19.70 16.29 16.36 21.70 21.86 17.98 18.17 19.24 19.03 20.14 19.99 20.96 21.04 17.18 17.38 153-155 194-196 191-192 193-195 178-180 155-157 177-179 148-149 183-185 202-203 228-230 170-172 144-145 228-230 223-225 218-220 182-183 201-203 193-195 207-209 203-205 228-230 188-190 171-173 188-190 Yield, % (method A, B) 88 (A), 79 (B) 95 (A), 84 (B) 91 (A), 88 (B) 78 (A), 81 (B) 70 (A), 73 (B) 91 (A), 83 (B) 84 (A), 70 (B) 76 (A), 89 (B) 92 (A), 76 (B) 75 (A), 83 (B) 74 (A), 80 (B) 79 (A), 74 (B) 90 (A), 88 (B) 81 (A), 84 (B) 88 (A), 90 (B) 68 (A), 72 (B) 70 (A), 74 (B) 92 (A), 88 (B) 95 (A), 81 (B) 72 (A), 73 (B) 84 (A), 81 (B) 79 (A), 85 (B) 94 (A), 95 (B) 70 (A), 64 (B) 70 (A)
C 70.59 70.78 69.45 69.37 65.22 65.09 61.87 62.05 63.28 63.39 67.63 67.52 68.49 68.55 68.87 69.05 63.42 63.39 66.90 67.11 68.41 68.55 73.54 73.67 72.41 72.50 69.88 70.11 71.29 71.23 71.54 71.68 73.22 73.15 67.42 67.58 73.58 73.67 65.54 65.61 69.95 70.11 69.20 69.37 68.63 68.55 67.49 67.65 70.87 70.78
The geometric characteristics of molecule 1k are rather close to those found for molecule 1a. In particular, in these molecules the corresponding bond lengths for the central bicyclic system match within experimental error limits, and the conformations of these molecules are only slightly different. The benzene ring C(14-19) in compound 1a is rotated by only 8.2 relative to the central plane, while in compound 1k the corresponding dihedral angle is 22.8. The (CH2)5CH3 group in 1a in fact is orthogonal to this plane: the vector C(3)CEN (where CEN is the center of gravity of the system of C(8-13) atoms) makes an 84.4 angle with it. The shortened intramolecular contact N(1)C(6) of 2.828(5) (the sum of the van der Waals radii 233
234
TABLE 2. Spectral Characteristics of Compounds 1a-x, 8

Compound 1a 1b 1c 1d 1e 1f 1g 1h 1i 1j 1k 1k 1l 1m 1n 1o 1p 1q 1r 1s 1t 1u 1v 1w 1x 8 IR spectrum, , cm-1 CN 2165 2174 2170 2185 2189 2190 2184 2187 2184 2188 2195 2195 2174 2202 2188 2195 2190 2187 2190 2186 2193 2177 2180 2194 2185 2193 NH, NH2 3300, 3342, 3440 3212, 3333, 3466 3315, 3364, 3458 3331, 3372, 3465 3272, 3310, 3476 3254, 3311, 3483 3297, 3384 3455 3318, 3389, 3476 3240, 3325, 3472 3242, 3300, 3486 3173, 3210, 3488 3173, 3210, 3488 3150, 3300, 3451 3148, 3217, 3495 3192, 3284, 3490 3147, 3210, 3485 3210, 3274, 3499 3256, 3364, 3410 3180, 3247, 3496 3155, 3246, 3450 3146, 3250, 3477 3163, 3254, 3510 3154, 3229, 3498 3185, 3241, 3476 3147, 3352, 3420 3152, 3345, 3448 NH (br. s) 12.65 12.64 11.83 11.82 11.99 11.90 12.02 11.89 11.98 11.99 12.69 12.69 12.58 12.63 12.64 12.62 12.69 12.63 12.02 12.77 11.82 12.65 12.69 11.70 11.92 C(4)H 4.07, t 4.00, t 3.28, d 3.42, d 3.40, d 3.52, t 3.68, t 3.55, t 3.37, d 3.38, d 3.89, d 3.89, d 4.17, d 4.03, t 4.11, d 3.81, d 3.99, d 4.35, t 3.49, d 4.11, t 3.41, d 4.00, d 4.01, d 3.50, d 3.77, t 3.70, d N2 (br. s) 6.79 6.73 6.52 6.44 6.68 6.58 6.77 6.48 6.55 6.74 6.81 6.81 6.60 6.67 6.72 6.74 6.83 6.66 6.78 6.85 6.49 6.82 6.80 6.34 6.66 7.00
1
NMR spectrum, , ppm Other protons
7.59 (2H, d, Ph); 7.45 (2H, t, Ph); 7.37 (1H, t, Ph); 1.50 (2H, m, CH2); 1.00 (8H, m, (CH2)4); 0.73 (3H, t, CH3) 7.51 (2H, d, Ph); 7.49 (2H, t, Ph); 7.38 (1H, t, Ph); 1.65 (1H, m, CH); 1.32 (2H, m, CH2); 0.88 (3H, t, CH3); 0.59 (3H, t, CH3) 2.19 (3H, s, CH3); 0.91-1.80 (11H, m, cyclohexyl) 2.17 (3H, s, CH3); 1.18 (1H, m, CH); 1.15 (2H, m, CH2); 0.92 (3H, t, CH3); 0.79 (3H, d, CH3) 2.18 (3H, s, CH3); 1.62 (1H, m, CH); 0.63-1.42 (10H, m, (CH2)2 and (CH3)2) 2.15 (3H, s, CH3); 1.60 (2H, m, CH2); 1.22 (14H, m, (CH2)7); 0.84 (3H, t, CH3) 7.04-7.32 (5H, m, Ph); 2.24 (2H, m, CH2); 2.19 (3H, s, CH3); 1.90 (2H, m, CH2) 2.12 (3H, s, CH3); 1.16 (2H, m, CH2); 1.20 (18H, m, (CH2)9); 0.86 (3H, t, CH3) 1.83 (1H, m, CH); 1.60 (2H, m, CH2); 0.91 (8H, m, (CH3)2 and CH2); 0.72 (3H, d, CH3) 1.02-1.83 (15H, m, (CH2)2 and cyclohexyl); 0.85 (3H, t, CH3) 7.33-7.54 (5H, m, Ph); 1.72 (1, m, CH); 0.86 (3H, d, CH3); 0.50 (3H, d, CH3) 7.33-7.54 (5H, m, Ph); 1.72 (1, m, CH); 0.86 (3H, d, CH3); 0.50 (3H, d, CH3) 6.91-7.72 (10H, m, Ph2); 2.88 (1H, m, CH); 0.89 (3H, d, CH3) 7.36-7.58 (5H, m, Ph); 1.49 (2H, m, CH2); 1.11 (14H, m, (CH2)7); 0.93 (3H, t, CH3) 7.37-7.70 (5H, m, Ph); 1.42 (1H, m, CH); 0.95 (4H, m, (CH2)2); 0.58 (6H, t, (CH3)2) 7.36-7.69 (5H, m, Ph); 0.68-1.81 (11H, m, cyclohexyl) 7.35-7.70 (5H, m, Ph); 5.48 (2H, m, CH=CH); 0.92-1.93 (7H, m, cyclohexenyl) 7.04-8.11 (10H, m, Ph2); 2.75, (2H, dd, CH2) 5.50 (2H, m, CH=CH); 1.08-2.07 (11H, m, (CH2)2 and cyclohexenyl); 0.88 (3H, t, CH3) 7.02-7.59 (10H, m, Ph2); 2.11 (1H, m, CH2); 2.41 (1H, m, CH2); 1.75 (2H, m, CH2) 5.61 (2H, m, CH=CH); 2.20 (3H, s, CH3); 1.24-2.09 (7H, m, cyclohexenyl) 7.33-7.64 (5H, m, Ph); 1.50 (2H, m, CH2); 1.29 (2H, m, CH2); 1.12 (1H, m, CH); 0.78 (3H, t, CH3); 0.50 (3H, d, CH3) 7.36-7.68 (5H, m, Ph); 1.50 (2H, m, CH2); 1.14 (1H, m, CH); 0.82 (3H, t, CH3); 0.49 (3H, d, CH3) 6.99-7.28 (5H, m, Ph); 2.87 (1H, m, CH); 1.89 (3H, s, CH3); 1.32 (3H, d, CH3) 6.93-7.15 (5H, m, Ph); 1.86 (3H, s, CH3); 2.90 (1H, d. d, CH2); 2.75 (1H, d. d, CH2) 7.75 (2H, d, Ph); 7.48 (2H, t, Ph); 7.30 (1H, t, Ph); 2.28 (3H, s, CH3); 1.50 (1H, m, CH); 1.42 (2H, m, CH2); 1.19 (2H, m, CH2); 1.00 (3H, t, CH3); 0.85 (3H, t, CH3)
Fig. 1 General view of a molecule of compound 1a.
Fig. 2 General view of a molecule of compound 1k.
of the N and C atoms is 3.20 [6]) leads to substantial nonequivalence of the exocyclic angles at the C(1) atom; in both compounds, the bond angle N(1)C(1)C(2) is significantly increased compared with the N(1)C(1)O(1) angle: for 1a it is 128.0(3) and 109.9(3), while for 1k it is 127.2(3) and 110.3(3) respectively. Similarly, the repulsion between the rather bulky Ph and Alk substituents causes an increase in the bond angle C(4)C(7)C(14)C(11) up to 133.6(3)-133.1(3), compared with the angle N(4)C(7)C(4) of 105.6(3). The atoms N(1) and N(4) in compound 1a have a trigonal planar configuration of the bonds. In this case, the orientation of the NH2 group is quite favorable for conjugation between the unshared electron pair of the N(2) atom and the system of the C(1)C(2) double bond: the angle between them is no greater than 4. In fact, the
235
TABLE 3 Bond Lengths (d) and Bond Angles () in the Molecule of Compound 1a
Bond O(1)C(1) O(1)C(5) N(1)C(1) N(1)H(1NA) N(1)H(1NB) N(2)C(6) N(3)N(4) N(3)C(5) N(4)C(7) N(4)H(4N) C(1)C(2) C(2)C(6) C(2)C(3) C(3)C(4) C(4)C(5) C(4)C(7) d, 1.368(3) 1.369(4) 1.331(5) 0.89(4) 0.78(4) 1.158(4) 1.355(4) 1.326(4) 1.361(4) 0.92(4) 1.369(5) 1.409(4) 1.532(5) 1.506(4) 1.384(5) 1.392(4) Angle C(1)O(1)C(5) N(4)N(3)C(5) N(3)N(4)C(7) N(1)C(1)O(1) N(1)C(1)C(2) O(1)C(1)C(2) C(1)C(2)C(6) C(1)C(2)C(3) C(3)C(2)C(6) C(2)C(3)C(4) C(5)C(4)C(7) C(3)C(4)C(5) C(3)C(4)C(7) N(3)C(5)O(1) N(3)C(5)C(4) O(1)C(5)C(4) N(2)C(6)C(2) N(4)C(7)C(4) N(4)C(7)C(14) C(4)C(7)C(14) , deg. 115.6(3) 101.9(2) 113.9(3) 109.9(3) 128.0(3) 122.1(3) 116.6(3) 125.5(3) 117.5(3) 106.6(3) 103.5(3) 121.2(3) 135.3(3) 118.1(3) 115.1(3) 126.8(3) 179.0(3) 105.6(3) 120.8(3) 133.6(3)
TABLE 4 Bond Lengths (d) and Bond Angles () in the Molecule of Compound 1k
Bond O(1)C(1) O(1)C(5) N(1)C(1) N(1)H(1N) N(1)H(2N) N(2)C(6) N(3)N(4) N(3)C(5) N(4)C(7) N(4)H(4N) C(1)C(2) C(2)C(6) C(2)C(3) C(3)C(4) C(4)C(5) C(4)C(7) d, 1.364(4) 1.366(4) 1.321(5) 0.84(6) 0.87(4) 1.139(4) 1.352(4) 1.315(4) 1.355(4) 0.92(4) 1.373(5) 1.409(5) 1.512(5) 1.509(5) 1.385(5) 1.381(4) Angle C(1)O(1)C(5) C(5)N(3)N(4) N(3)N(4)C(7) N(1)C(1)O(1) N(1)C(1)C(2) O(1)C(1)C(2) C(1)C(2)C(6) C(1)C(2)C(3) C(6)C(2)C(3) C(2)C(3)C(4) C(7)C(4)C(5) C(5)C(4)C(3) C(7)C(4)C(3) N(3)C(5)O(1) N(3)C(5)C(4) O(1)C(5)C(4) N(2)C(6)C(2) N(4)C(7)C(4) N(4)C(7)C(11) C(4)C(7)C(11) , deg. 115.4(3) 102.4(3) 113.4(3) 110.3(3) 127.2(3) 122.5(3) 114.7(3) 125.0(3) 120.3(3) 106.8(3) 103.7(3) 121.2(3) 134.9(3) 119.0(3) 114.6(3) 126.4(3) 178.2(4) 105.8(3) 121.0(3) 133.1(3)
bond N(1)C(1) of 1.331(5) is considerably shortened compared with the standard range of 1.43-14.5 for an N(sp2)C(sp2) single bond [7,8], while the bond C(1)C(2) of 1.369(5) is appreciably elongated compared with the value of 1.33 typical of a C(sp2)C(sp2) double bond [8]. 236
The corresponding parameters for compound 1k are close. The N(1) and N(4) atoms in compound 1k have a trigonal planar configuration of the bonds, where the sums of the bond angles at these atoms are respectively 360.0(1.0) and 360.0(2.4), the orientation of the N(1)H2 group is quite favorable for conjugation between the unshared electron pair of the N(1) atom and the -system of the C(1)C(2) double bond: the dihedral angle between the planes O(1)N(1)C(1)C(2)C(3)C(6) and N(1)H(1N)H(2N) is 17.1. As a result of this conjugation, the N(1)C(1) bond of 1.321(5) , as in the 1a case, is considerably shortened, while the C(1)C(2) bond of 1.373(5) is appreciably elongated. In both compounds, in the five-membered heterocycle N(3)N(4)C(4)C(5)C(7), all the endocyclic interatomic distances correspond to a bond multiplicity of approximately 1.5, which indicates significant delocalization of the electron density in this system. In the crystal, the molecules of compound 1a, as a result of the hydrogen bonds N(1)H(11)N(3) (N(1)N(3) 3.025(4) , N(1)H(11) 0.89(4) , N(3)H(11) 2.141(4) , N(1)H(11)N(3) 176(2)), are organized into centrosymmetric dimers. In turn, these dimers, via the hydrogen bonds N(4)H(4)N(2) (N(4)N(2) 3.024(4) , N(4)H(4) 0.92(4) , N(2)H(4) 2.189(4) , N(4)H(4)N(2) 150(2)) form an infinite network (Fig. 3). In the crystal of compound 1k, as a result of the hydrogen bonds N(1)H(1N)N(3) (N(1)N(3) 2.999(4) , N(1)H(1N) 0.84(6) , N(3)H(1N) 2.17(6) , N(1)H(1N)N(3) 172(3)), the molecules are also organized into centrosymmetric dimers which in turn, via the the hydrogen bonds N(4)H(4N)N(2) (N(4)N(2) 2.913(4) , N(4) H(4N) 0.92(4) , N(2)H(4N) 2.01(4) , N(4)H(4N)N(2) 167(2)) form an infinite chain along the a crystallographic axis (Fig. 4). For H bonds of the type NHN, the statistical mean of the interatomic distance NN is 2.98 for = 0.16 2 [9]. Thus, the N(1)-unsubstituted pyrano[2,3-c]pyrazoles 1 exist in the crystalline state as the 2H,4H-isomers 1A rather than the 1H,4H-isomers 1B, as maintained in earlier papers [13-16]. From literature data on the isomerism of 4H-pyrans condensed with six-membered carbon rings, we know that the boat conformation is typical in the crystalline form [17, 18]. In the structures of 1a,k studied in this work, the 4H-pyran ring, like the pyrazole ring, is practically flat. This fact is probably also responsible for the stability of the 2H,4H-isomers 1A.
Fig. 3. Crystal packing for compound 1a (bc projection). The dotted lines indicate hydrogen bonds. 237
Fig. 4. Crystal packing for compound 1k (the Ph and (CH2)5CH3 substituents are not shown).
EXPERIMENTAL An X-ray Diffraction Study of a Single Crystal of Compound 1a with linear dimensions 0.11 0.31 0.32 mm was carried out at -133C on an Enraf-Nonius DIP2000 diffractometer (MoK radiation, scanning, 90 frames every 2, 600 sec/frame, crystaldetector distance 75 mm, max = 26, spherical segment 22 h 23, -21 k 23, 22 l 23). The unit cell parameters were determined from 124 reflections and refined using the entire data file. We collected a total of 18366 reflections, of which 2350 were symmetry independent (Rint = 0.028). The crystals of compound 1a were trigonal, a = 18.744(1) ; = 117.77(1); V = 2520.2(2) 3; M = 327.45; Z = 6; dcalc = 1.295 g/cm3; = 0.82 cm-1; space group R-3. The structure was deciphered by the direct method and refined by the least squares method in the full-matrix anisotropic approximation using the programs SHELXS and SHELXL93 [10, 11]. Refinement was carried out using 2341 reflections with I > 2(I) (303 refined parameters, number of reflections times the parameter 7.73). Practically all the H atoms were determined from a difference electron density synthesis and isotropically refined. Only the hydrogen atoms for the disordered C(12) and C(13) atoms were placed geometrically and included in the calculation with fixed positions and thermal parameters. We used the weighting scheme = 1/[2(Fo2) + (0.0117P)2 + 6.1294], where P = (Fo2 + 2Fc2)/3. Correction for absorption in the crystal was taken into account by scaling 90 frames using the SCALEPACK program [12]. The final values of the R factors were R1(F) = 0.0597 and Rw(F2) = 0.1271, GOF = 1.001. The residual electron density from a difference Fourier series was 0.27 and -0.42 e/3.
238
X-ray Diffraction Study of a Single Crystal of Compound 1k with linear dimensions 0.16 0.25 0.34 mm was carried out at room temperature on an automatic four-circle Enraf-Nonius CAD-4 diffractometer (MoK radiation, graphite monochromator, ratio of /2 scanning rates = 1.2, max = 23, spherical segment 0 h 7, -11 k 11, -13 l 13). We collected a total of 2373 reflections, of which 2192 were independent (averaging R factor 0.040). The crystals of compound 1k were triclinic, a = 6.537(4), b = 9.844(3), c = 11.540(4) ; = 92.89(3), = 92.03(4), = 103.88(4); V = 719.1(6) 3, Z = 2, dcalc = 1.295 g/cm3, = 0.085 mm-1, F(000) = 296, space group P-1 (No. 2). The structure was deciphered by the direct method and refined by the least-squares method in the full-matrix anisotropic approximation using the programs SHELXS and SHELXL93 [10, 11]. In the refinement, we used 1871 reflections with I > 2(I) (254 refined parameters, number of reflections times the parameter 7.37, weighting scheme = 1/[2(Fo2) + (0.0731P)2], where P = (Fo2 + 2Fc2)/3, the ratio of the maximum/mean shift of the error in the last cycle was 0.033/0.005). A correction for anomalous scattering was included; no corrections for absorption were made. All the hydrogen atoms were determined objectively and isotropically refined. The final values of the R factors were R1(F) = 0.0612 and Rw(F2) = 0.1322, GOF = 1.045. The residual electron density from a difference Fourier series after the last refinement cycle was 0.22 and -0.23 e/3. The IR spectra of the synthesized compounds were recorded on an IKS-29 in vaseline oil. The 1H NMR spectra were recorded on a Bruker WM-250 (250 MHz) (for compounds 1a-q, 8), a Bruker AM-300 (300 MHz) (for compounds 1r-w), and a Bruker WP-100 SY (100 MHz) (for compound 1x) in DMSO-d6, internal standard Me4Si. The mass spectra were taken on a Kratos MS-890 (70 eV). The melting points were determined on a Kofler apparatus. The course of the reaction was monitored by TLC (Silufol UV-254; acetonehexane, 3:5; visualizing agent, iodine vapors). 4-Alkyl-6-amino-5-cyano-3-methyl(propyl, phenyl)-2H,4H-pyrano[2,3-c]pyrazoles (1a-x). (General Method). A. Cyanothioacetamide 3 (1.0 g, 10 mmol) and morpholine (3 drops) were added to a mixture of the corresponding compound 2 (10 mmol) in ethanol (15 ml) at 20C, after which they were stirred for 2 h and allowed to stand for 24 hours. The precipitate formed was filtered out and then washed with ethanol and hexane. We obtained compounds 1a-x, which were recrystallized from ethanol (see Tables 1 and 2). B. Morpholine (3 drops) was added to a mixture of substituted pyrazolone 2 (10 mmol) and malononitrile 4 (0.66 g, 10 mmol) in ethanol (15 ml) at 20C; this was stirred for 20 min and then was allowed to stand for 24 hours. The precipitate formed was filtered out and washed with ethanol and then hexane, and recrystallized from ethanol. We obtained compounds 1a-x with chromatography data, melting points, and IR spectra identical to those obtained by method A. The characteristics of pyrazolopyrans 1a-x are given in Tables 1 and 2. The mass spectral data for compounds 1k,q, m/z (Irel, %): 1k 297 [M]+ (8), 238(25), 237(100), 214(14), 77(47); 1q 328 [M]+ (5), 262(43), 238(35), 237(100), 220(41), 219(88), 91(45), 77(40), 58(61). 6-Amino-3-methyl-4-(3'-pentyl)-1-phenyl-1H,4H-pyrano[2,3-c]pyrazole (8) was obtained similarly to compounds 1 by method A, starting from pyrazolone 7 (see Tables 1 and 2). Mass spectrum, m/z (Irel, %): 322 [M]+ (4), 252(40), 251(100), 118(28), 79(25), 77(83), 58(49).
REFERENCES 1. 2. 3. 4. 5. B. Y. Riad, A. O. Abdelhamid, F. A. Khalifa, and Y. E. Saleh, Arch. Pharmacol. Res., 12, 201 (1989). Yu. A. Sharanin, L. G. Sharanina, and V. V. Puzanova, Zh. Org. Khim., 19, 2609 (1983). H. F. Zohdi, A. H. H. Elghandour, N. M. Rateb, and M. M. M. Sallam, J. Chem. Res. (S), No. 12, 396 (1992). F. F. Abdel-Latif and R. M. Shaker, Indian J. Chem. (B), 29, 322 (1990). G. V. Klokol, S. G. Krivokolysko, V. D. Dyachenko, and V. P. Litvinov, Khim. Geterotsikl. Soedin., 1363 (1999). 239
6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.
L. Pauling, The Nature of the Chemical Bond, Cornell University Press, New York (1960). R. W. Alder, N. C. Goode, T. J. King, J. M. Mellor, and B. W. Miller, J. Chem. Soc. Chem. Commun., No. 5, 173 (1976). M. Burke-Laing and M. Laing, Acta Crystallogr., B32, 3216 (1976). L. N. Kuleshova and P. M. Zorkii, Acta Crystallogr., B37, 1363 (1981). G. M. Sheldrick, SHELXS-86. Program for the Solution of Crystal Structures, University of Gottingen, Gottingen, Germany (1986). G. M. Sheldrick, SHELXS-93. Program for the Refinement of Crystal Structures, University of Gottingen, Gottingen, Germany (1993). Z. Otwinowski and W. Ninor, Methods Enzymol., 276, 307 (1997). L. G. Sharanina, V. P. Marshtupa, and Yu. A. Sharanin, Khim. Geterotsikl. Soedin., 1420 (1980). F. F. Latif and A. K. M. H. Gohar, Bull. Soc. Chim. Belg., 95, 21 (1986). H. Junec and H. Aigner, Chem. Ber., 106, 914 (1973). G. Tacconi, G. Gafti, and G. Desimoni, J. Prakt. Chem., 322, 831 (1980). G. V. Klokol, L. G. Sharanina, V. N. Nesterov, V. E. Shklover, Yu. A. Sharanin, and Yu. T. Struchkov, Zh. Org. Khim., 23, 412 (1987). M. Suarez, E. Salfran, Y. Verdecia, E. Ochoa, L. Alba, N. Martin, R. Martinez, M. Quinteiro, C. Seoane, H. Novoa, N. Blaton, O. M. Peeters, and C. De Ranter, Tetrahedron, 58, 953 (2002).
240
4-NITROPHENYL N-(1-ARYL-2,2,2-TRIFLUOROETHYLIDENE)URETHANES: NOVEL 1,3-ELECTROPHILIC COMPONENTS OF REACTIONS LEADING TO 6- AND 7-MEMBERED HETEROCYCLES
M. V. Vovk, V. I. Dorokhov, and L. I. Samarai We propose an approach to synthesis of N,O,S-containing 6- and 7-membered heterocycles based on using 4-nitrophenyl N-(1-aryl-2,2,2-trifluoroethylidene)urethanes as the electrophilic components in heterocyclizations with bifunctional nucleophilic reagents. Keywords: N-alkylideneurethanes, bifunctional nucleophiles, 5-oxoimidazo[2,3-b]-1,3,5-thiadiazines, 2-oxo-1,5,3-oxathiazepines, 2-oxo-1,5,3-benzoxathiazepines. N-Alkylideneurethanes have been used as 1,2- or 1,4-components in cycloaddition reactions with electron-rich reagents [1].
H N X 24 N X 6 C O X 79 5 H N Y O O OR YH ROH
N OR 1
HX
YH
YH
We have significantly expanded the synthetic possibilities of N-alkylideneurethanes by using them as 1,3-electrophilic components in heterocyclizations with bifunctional nucleophilic substrates. The proposed approach essentially involves addition of bifunctional nucleophiles 2-4 to N-alkylideneurethanes 1, which leads to formation of acyclic products 5, followed by generation under the reaction conditions of isocyanates of type 6 and their intramolecular cyclization to hetero systems 7-9.
__________________________________________________________________________________________ Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev 02094; e-mail: hetfos@ukrpack.net; mvovk@i.com.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 282-285, February, 2004. Original article submitted June 26, 2001. 0009-3122/04/4002-02412004 Plenum Publishing Corporation 241
Ar CF3 N
O O 1a,b ON 2 OH SH OH NO2
H N N H 2 N N S
SH S OH 3 CF3 Ar S O CF3 Ar NH 8a,b O O 9a,b S 4
CF3 Ar NH O
NH O 7a,b
1, 79 a Ar = Ph, b Ar = 4-MeC6H4
The pronounced electrophilicity of the azomethine group in urethanes 1 helps the reaction occur regioselectively as a result of the formation of urethanes 5, which cannot always be successfully achieved in cyclizations with participation of 1-chloroalkyl isocyanates [2]. A necessary condition for the heterocyclization is the ability of urethanes 5 to generate synthons 6, which first of all depends on the nature of the substituent R. We have established that such a requirement is satisfied by 4-nitrophenyl N-alkylideneurethanes 1, since under mild conditions (benzene, 80C) the corresponding urethanes 5 tend to readily eliminate 4-nitrophenol with formation of isocyanates 6, which is detected by IR spectroscopy. Such properties are lacking in 4-nitrophenyl N-alkylideneurethanes 1 (R = CH3, CH2C6H5), and for this reason they cannot be used as components for cyclizations, since the corresponding urethanes 5 do not undergo further conversions either at 80C or at higher temperatures (110-140C). The approach considered above for synthesis of hetero systems 7-9 is illustrated by the examples of cyclocondensations of 4-nitrophenyl N-(1-aryl-2,2,2-trifluoroethylidene)urethanes 1a,b with bifunctional nucleophiles: 2-imidazoline thione 2, 2-mercaptoethanol 3, and 2-mercaptophenol 4. We have shown that when the reagents are heated in benzene, we obtain the target products in high yields: derivatives of 3-aryl-5-oxo-3trifluoromethyl-6,7-dihydroimidazo[2,3-b]-1,3,5-thiadiazines 7a,b [3], 4-aryl-2-oxo-4-trifluoromethyl-1,5,3oxathiazepines 8a,b, and 4-aryl-2-oxo-4-trifluoromethyl-1,5,3-benzoxathiazepines 9a,b. Compounds 7a,b-9a,b (Table 1) are colorless crystalline compounds, the individual purity of which was shown by TLC while their composition was determined by elemental analysis results and their structure was proven by IR, 1H and 19F NMR spectra (Table 2). The IR spectra of compounds 7a,b are characterized by absorption bands for the carbonyl groups of the ureide moiety in the 1660-1680 cm-1 region, while compounds 8a,b, 9a,b are characterized by absorption bands for the carbonyl groups of the urethane moiety in the 1740-1770 cm-1 region. In the 1H NMR spectra of all the compounds, along with signals from methyl, methylene, and aromatic protons, we see broadened singlets for the NH protons at 7.80-8.50 ppm. The presence of the same signals in the 19F NMR spectra for both the reaction mixtures and the end products is evidence for the regioselectivity of the cyclization process. The region where we see the 74-77 ppm signals indicates that the CF3 groups are located on the sp3-hybridized carbon atom of the SCN moiety, and supports a cyclic structure for the compounds obtained [4].
242
TABLE 1. Characteristics of Synthesized Compounds

Compound 7 7b 8 8b 9 9b Empirical formula 1210F3N3OS 1312F3N3OS 1110F3NO2S 1212F3NO2S 1510F3NO2S 1612F3NO2S Found, % Calculated, % C H S 47.98 47.84 50.01 49.52 47.39 47.65 49.30 49.47 55.69 55.38 56.68 56.63 3.11 3.35 3.91 3.84 3.78 3.63 4.45 4.15 3.34 3.10 3.30 3.56 10.74 10.64 10.50 10.17 11.27 11.56 11.12 11.01 9.57 9.85 9.56 9.45 mp, C (solvent for crystallization) 146-147 (hexanebenzene, 2:1) 179-180 (hexanebenzene, 1:8) 56-57 (hexanediethyl ether, 2:1) 69-70 (hexanediethyl ether, 2:1) 88-89 (hexanebenzene, 8:1) 77-78 (hexanebenzene, 5:1) Yield, %
69 78 64 70 57 68
TABLE 2. Spectral Characteristics of Compounds 7-9

Compound 7 7b 8 8b IR spectrum, , cm-1 = 1665 1660 1750 1745 NH 3240 3220 3250 3400 3250 3400 3290 3380 3190 3360
19 1
H NMR spectra, , ppm
F NMR spectra, , ppm 76.2 76.2 74.5 75.7
9 9b
1750 1765
3.80-3.98 (4, m, 2); 7.37-7.41 (5, m, Harom.); 9.84 (1, br. s, NH) 2.29 (3, s, 3); 3.78-3.95 (4, m, C2); 7.15-7.54 (4, m, 64); 9.67 (1, br. s, NH) 2.72-2.87 (2, m, 2S); 4.22-4.38 (2, m, CH2O); 7.42-7.61 (5, m, 6H5); 8.15 (1, br. s, NH) 2.38 (3, s, 3); 2.95-3.17 (2, m, C2S); 4.15-4.35 (2, m, 2O); 7.18-7.47 (4H, m, 64); 8.00 (1, br. s, NH) 7.12-7.50 (9, m, arom); 7.80 (1, br. s, NH) 2.28 (3, s, 3); 7.16-7.41 (8, m, arom); 8.21 (1, br. s, NH)
74.1 74.7
EXPERIMENTAL The IR spectra were recorded on a UR-20 in KBr disks. The 1H NMR spectra were measured on a Varian Gemini spectrometer (200 MHz) in CDCl3 solution, internal standard HMDS. The 19F NMR spectra were obtained on a Bruker WP-200 (188 MHz) in CDCl3 solution, internal standard CCl3F. TLC was done on Silufol UV-254 plates. 4-Nitrophenyl N-(1-Aryl-2,2,2-trifluoroethylidene)urethanes (1a,b). 4-Nitrophenol (1.39 g, 0.01 mol) and triethylamine (1.01 g, 0.01 mol) were added to a solution of the corresponding 1-aryl-1-chloro-2,2,2trifluoroethyl isocyanate [5] (0.01 mol) in benzene (45 ml). The mixture was stirred at room temperature for 2 h. The triethylamine hydrochloride precipitate was filtered out, the filtrate was refluxed for 1 h, the solvent was evaporated, and the residue was recrystallized from a 1:3 hexanebenzene mixture. Compound 1a. Yield 85%; mp 73-74C. IR spectrum, , cm-1: 1790 (C=O), 1720 (C=N). 1H NMR spectrum, , ppm: 7.96-8.09 (4H, m, C6H4); 7.49-7.60 (5H, m, C6H5). 19F NMR spectrum, , ppm: 69.23 s. Found, %: C 53.16; H 2.59; N 8.34. C15H9F3N2O4. Calculated, %: C 53.27; H 2.68; N 8.28. 243
Compound 1b. Yield 86%; mp 97-98C. IR spectrum, , cm-1: 1800 (C=O), 1725 (C=O). 1H NMR spectrum, , ppm: 7.41-8.03 (8H, m, C6H4); 2.29 (3H, s, CH3). 19F NMR spectrum, , ppm: 70.08 s. Found, %: C 54.12; H 3.25; N 8.17. C16H11F3N2O4. Calculated, %: C 54.55; H 3.15; N 7.95. 3-Aryl-3-trifluoromethyl-3,4,7,8-tetrahydro-5H-imidazo[2,3-b]-1,3,5-thiadiazin-5-ones (7a,b), 4-Aryl4-trifluoromethyl-3,4-dihydro-2H-1,5,3-(benzo)oxathiazepin-2-ones (8a,b, 9a,b). Triethylamine (4-5 drops) was added to a mixture of N-alkylideneurethane 1a,b (0.005 mol) and the nucleophilic reagent 2-4 (0.005 mol) in benzene (50 ml), and the mixture was heated at the boiling point for 3 h. After the solvent was evaporated, the residue was washed with a saturated solution of Na2CO3 (50 ml), dried, and purified by crystallization.
REFERENCES 1. 2. 3. 4. 5. B. S. Drach, V. S. Brovarets, and O. B. Smolii, in: Syntheses of Nitrogen-Containing Heterocyclic Compounds Based on Amidoalkylating Agents [in Russian], Naukova Dumka, Kiev (1992), p. 33. M. V. Vovk, V. I. Dorokhov, and L. I. Samarai, Zh. Org. Khim., 25, 2390 (1989). M. V. Vovk, Yu. I. Davidyuk, and L. I. Samarai, Ukr. Khim. Zh., 58, 54 (1992). M. V. Vovk, V. I. Dorokhov, and L. I. Samarai, Zh. Org. Khim., 25, 2394 (1989). V. N. Fetyukhin, A. S. Koretskii, and V. I. Gorbatenko, Zh. Org. Khim., 13, 271 (1977).
244

CHARACTERISTIC FEATURES OF A HETERO DIELSALDER REACTION: THE REACTION OF AROYLKETENE WITH ALLOBETULONE AS AN EXAMPLE
D. D. Nekrasov, A. E. Rubtsov, and A. G. Tolstikov Keywords: allobetulone, benzoylketene, spiro-1,3-dioxin-4-one, 5-phenyl-2,3-dihydrofuran-2,3-dione, [4+2] cycloaddition. 5-Phenyl-2,3-dihydrofuran-2,3-dione (1) is a convenient synthon for generation of benzoylketene [1]. In reactions with ketones, benzoylketene (2) forms 2,2-disubstituted 6-phenyl-1,3-dioxin-4-ones [2]. In the reaction of benzoylketene 2 (obtained in situ from furandione 1) with allobetulone (3-oxo-19,28-epoxyoleane) (3) [3], two stereoisomeric spiro adducts 4, 5 were unexpectedly isolated.
O O Ph O C Ph 2 O O O O 3
O 1
+
O O O Ph 4 O 5 Ph O O
__________________________________________________________________________________________ Perm State University, Perm 614990, Russia; e-mail: Alekhsandr.Rubtsov@psu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 286-287, February, 2004. Original article submitted December 30, 2003. 0009-3122/04/4002-02452004 Plenum Publishing Corporation 245
Based on the integrated intensity of the singlet for the CH group of the dioxinone ring in the 1H NMR spectrum of the reaction mixture, the optical isomers are formed in 1:2 ratio. The studied conversion occurs according to a hetero DielsAlder reaction with reversed electronic effects in the addends, where benzoylketene 2 acts as the heterodiene while the keto group of allobetulone 3 acts as the heterodienophile. The optical isomers were separated by column chromatography. We obtained colorless crystalline compounds with Rf 0.55 and 0.50, which have similar spectral characteristics. In the 1H NMR spectrum of compounds 4,5, there is a set of signals from the aromatic protons with center at 7.45 ppm, a singlet from the methine proton of the dioxinone ring in the 5.78 ppm and 5.82 ppm region, and also a set of protons from the condensed oleane system. Spiro[(6-phenyl-3,4-dihydro-2H-1,3-dioxin)-2R(S),3'-(19',28'-epoxyolean)]-4-ones (4, 5). A solution of compound 1 (0.01 mol) and compound 3 (0.01 mol) in anhydrous benzene (50 ml) was refluxed for 5 h. The solvent was removed, the tarry residue was chromatographed on a column (Silicagel L 100/250), and eluted with a 1:5 ethyl acetatehexane mixture. It was recrystallized from hexane. Compound 4, Rf 0.55 (Silufol UV-254, 1:5 ethyl acetatehexane), mp 200-202C (hexane), []D18 = 17.5 (chloroform). IR spectrum, , cm-1, 1715 (C=O), 1615 (C=C). 1H NMR spectrum, , ppm: 7.45 (5H, m, Ph); 5.78 (1H, s, =CH); 3.71 (1H, d, 28-H); 3.71 (1H, s, 19-H); 3.38 (1H, d, 28-H); 2.48 (1H, t, 2-H); 2.44 (1H, t, 2-H); 1.84 (2H, td, 1-H); 0-1.8 (42H, set of signals from aliphatic protons). Found: m/z 586 [M]+. C39H54O4. Calculated: M = 586.86. Compound 5, Rf 0.50 (Silufol UV-254, 1:5 ethyl acetatehexane), mp 149-151C (hexane), []D18 = 52.2 (chloroform). IR spectrum, , cm-1: 1725 (C=O), 1615 (C=C). 1H NMR spectrum, , ppm: 7.45 (5H, m, Ph); 5.81 (1H, s, =CH); 3.72 (1H, d, 28-H); 3.46 (1H, s, 19-H); 3.39 (1H, d, 28-H); 2.48 (1H, t, 2-H); 2.43 (1H, 5, 2-H); 1.90 (2H, td, 1-H); 0-1.8 (42H, set of signals from aliphatic protons). Found: m/z 587 [M]+. C39H54O4. Calculated: M = 585.86 The IR spectra were recorded on a UR-20 in vaseline oil; the 1H NMR spectra were recorded on a MERCURYplus 300 (300 MHz) in CDCl3, internal standard HMDS. The mass spectra were obtained on an MKh-1310 with emission current 1000 mA, electron ionizing energy 70 eV, vaporizer temperature 120C, source temperature 200C. The angle of rotation was determined on a PerkinElmer 341 polarimeter (c1 CHCl3).
REFERENCES 1. 2. 3. D. D. Nekrasov, Khim. Geterotsikl. Soedin., 291 (2001). D. D. Nekrasov, Khim. Geterotsikl. Soedin., 1011 (2001). H. Schulze and H. Pieron, Ber., 2, 2332 (1922).
246
REGIOSELECTIVE CYCLOADDITION OF AZOMETHINES AND CARBODIIMIDES TO AROYL(QUINOXALINYL)KETENES

N. Yu. Lisovenko and A. N. Maslivets Keywords: aroyl(imidoyl)ketenes, 2,3-dihydro-2,3-furandiones, 1,3-oxazin-4-ones, cycloaddition. 3-Aryl-2-quinoxalinyl(aroyl)ketenes 1a,b, generated in thermolysis of 3-aryl-2-(2-aryl-4,5-dioxo-4,5dihydro-3-furyl)quinoxalines 2a,b, in the absence of other partners undergo the reaction of [4+2] cyclodimerization, where one ketene molecule participates in the reaction as the dienophile by means of the C=C bond of the ketene moiety, while another ketene molecule participates as the diene by means of the conjugated C=CC=N bond system of the imidoylketene moiety [1]. In contrast to the cyclodimerization reaction, attempts at "capturing" the aroyl(imidoyl)ketenes 1a,b by cyclic ketones lead to formation of the corresponding [4+2] cycloadducts with participation of the C=O bond of the ketones in the conjugated system of bonds C=CC=O of the aroylketene moiety [2]. Both of the reactions described, judging from TLC data for the reaction mixture, occur practically regioselectively.
N N Ar 2a,b
R CH N R'
Ar O -CO O O
N N
Ar
Ar O
N N Y X N R 5
Ar Ar O
O 1a,b
N N
O N O
R'
N N
O N O N
3a,b R
1, 2 a Ar = Ph, b Ar = p-MeC64; 3 a R = Br, R' = OMe, b R = OMe, R' = Br
__________________________________________________________________________________________ Perm State University, Perm 614990, Russia; e-mail: koh2@psu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 288-289, February, 2004. Original article submitted June 20, 2003. 0009-3122/04/4002-02472004 Plenum Publishing Corporation 247
We have found that "capture" of aroyl(imidoyl)ketenes 1a,b by Schiff's bases or dicyclohexylcarbodiimide also leads practically regioselectively to formation of the corresponding [4+2] cycloadducts 3a,b,4. The spectral characteristics of compounds 3a,b, 4, in particular the characteristic form of the multiplet for the four protons of the quinoxaline moiety, practically coinciding with that for model cycloaddition products of cyclic ketones in [2], the structure of which has been confirmed by X-ray diffraction, allow us to reject the isomeric structure 5 for compounds 3a,b, 4 and suggest that the C=N bond of azomethines or carbodiimides and the conjugated system of bonds C=CC=O of aroyl(imidoyl)ketenes 1a,b participate in the [4+2] cycloaddition reaction. 2-(2-p-Bromophenyl-3-p-methoxyphenyl-4-oxo-6-p-tolyl-3,4-dihydro-2H-1,3-oxazin-5-yl)-3-p-tolylquinoxaline (3a). A solution of furandione 2b (1 mmol) and N-p-bromobenzylidene-p-anisidine (1.1 mmol) in absolute p-xylene (5 ml) was held for 20 min at 138-140C and then cooled down, and the precipitate was filtered out. Yield 78%; mp 210-211C (CH3CN). IR spectrum (vaseline oil), , cm-1: 1665 (C=O). 1H NMR spectra (400 MHz, DMSO-d6, HMDS), , ppm: 2.19 (3H, s, CH3); 2.38 (3H, s, CH3); 3.71 (3H, s, OCH3); 6.81-7.68 (17H, m, 4C6H4+CH); 7.86 (2H, m, 6-, 7-Hquinox); 8.07, 8.11 (2H, m, 5-, 8-Hquinox). Found, %: C 70.01; H 4.66; Br 12.07; N 6.21. C39H30BrN3O3. Calculated, %: C 70.06; H 4.52; Br 11.95; N 6.28. 2-(3-p-Bromophenyl-2-p-methoxyphenyl-4-oxo-6-p-tolyl-3,4-dihydro-2H-1,3-oxazin-5-yl)-3-p-tolylquinoxaline (3b). Obtained analogously. Yield 80%; mp 171-172C (CH3CN). IR spectrum (vaseline oil), , cm-1: 1650 (C=O). 1H NMR spectrum (400 MHz, DMSO-d6, HMDS), , ppm: 2.19 (3H, s, CH3); 2.38 (3H, s, CH3); 3.77 (3H, s, OCH3); 6.80-7.51 (17H, m, 4C6H4+CH); 7.86 (2H, m, 6-,7-Hquinox); 8.06, 8.12 (2H, m, 5-,8-Hquinox). Found, %: C 70.07; H 4.09; Br 11.77. N 6.31. C39H30BrN3O3. Calculated, %: C 70.06; H 4.52; Br 11.95; N 6.28. 2-(3-Cyclohexyl-2-cyclohexylimino-4-oxo-6-phenyl-3,4-dihydro-2H-1,3-oxazin-5-yl)-3-phenylquinoxaline (4). Obtained analogously. Yield 92%; mp 168-170C (acetonitrile). IR spectrum (vaseline oil), , cm-1): 1675 (C=O). 1H NMR spectrum (400 MHz, DMSO-d6, HMDS), , ppm: 1.01-1.80 (20H, m, 10CH2); 3.70 (1H, m, NCH); 4.56 (1H, m, NCH); 7.00-7.45 (10H, m, 2Ph); 7.93 (2H, m, 6-,7-Hquinox); 8.12, 8.15 (2H, m, 5-,8-Hquinox). Found, %: C 77.90; H 6.67; N 10.25. C36H36N4O2. Calculated, %: C 77.67; H 6.52; N 10.06. This research was done with the financial support of the Russian Foundation for Basic Research (grant No. 01-03-32641).
REFERENCES 1. 2. N. Yu. Lisovenko, O. P. Krasnykh, Z. G. Aliev, E. S. Vostrov, O. P. Tarasova, and A. N. Maslivets, Khim. Geterotsikl. Soedin., 1429 (2001). N. Yu. Lisovenko, A. N. Maslivets, and Z. G. Aliev, Khim. Geterotsikl. Soedin., 140 (2003).
248
CYCLIZATION OF o-CARBOXYANILIDES OF AROYLACETIC ACIDS: A ROUTE TO A NOVEL CLASS OF HETEROCYCLIC ENAMINO KETONES
E. S. Vostrov, N. N. Mokhnatkina, O. M. Popova, M. V. Andrakovskiy, and A. N. Maslivets Keywords: 2-aroylmethylene-3,1-benzoxazin-4-ones, o-carboxyanilides of aroylacetic acids. A convenient method for obtaining amides of aroylacetic acids is aroylacylation of amines [1] and amides [2] by aroylketenes, generated in thermolysis of 6-aryl-2,2-dimethyl-4H-1,3-dioxin-4-ones. Use of anthranilic acid as the amine is of interest because of the possibility of using the carboxyl functional group in further conversions. In thermolysis of 6-aryl-2,2-dimethyl-4H-1,3-dioxin-4-ones 1a,b in the presence of anthranilic acid, we obtained o-carboxyanilides of aroyl acetic acids 2a,b, which undergo ring closure when treated with dicyclohexylcarbodiimide to form E-2-aroylmethylene-2,4-dihydro-1H-3,1-benzoxazin-4-ones 3a,b.
O O Ar O 1a,b Me Me N H 4a,b O O Ar O 2a,b
14 a Ar = Ph, b Ar = p-MeOC6H4
O Ar O
Me2CO COOH H N
COOH NH2
(C6H11N)2C (C6H11NH)2CO 3a,b
N H .
.. O
Ar
Based on spectral data, we can eliminate the structure of the isomeric 3-aroyl-1,2,3,4tetrahydroquinoline-2,4-diones 4a,b for the products of intramolecular cyclization, but the described reaction is a preparative method for obtaining representatives of a novel class of heterocyclic enamino ketones. o-Carboxyanilide of Benzoylacetic Acid (2a). A solution of dioxinone 1a (1.00 g, 4.9 mmol) and anthranilic acid (0.67 g, 4.9 mmol) in m-xylene (2 ml) was boiled for 10-15 min and then cooled down, and the precipitate was filtered out. Yield 1.10 g (79%); mp 177-178C (ethanol). IR spectrum (vaseline oil), , cm-1: __________________________________________________________________________________________ Perm State University, Perm 614990, Russia; e-mail: koh2@psu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 290-291, February, 2004. Original article submitted January 19, 2004. 0009-3122/04/4002-02492004 Plenum Publishing Corporation 249
3160 broad (NH, COOH), 1698 (COOH), 1685 broad (CONH, COPh), 1540 ("amide II"). 1H NMR spectrum (400 MHz, DMSO-d6), , ppm: 4.31 (2H, s, CH2); 7.18-8.44 (9H, m, C6H4+C6H5); 11.26 (1H, s, NH); 13.60 (1H, br. s, COOH). Found, %: C 67.76; H 4.60; N 5.00. C16H13NO4. Calculated, %: C 67.84; H 4.63; N 4.94. o-Carboxyanilide of 4-Methoxybenzoylacetic Acid (2b). Synthesized analogously. Yield 1.07 g (70%); mp 175-176C (ethanol). IR spectrum (vaseline oil), , cm-1: 3145 broad (NH, COOH), 1703 (COOH), 1670 broad (CONH, COC6H4), 1533 ("amide II"). 1H NMR spectrum (400 MHz, DMSO-d6), , ppm: form (A): 3.86 (3H, s, MeO); 4.22 (2H, s, CH2); 7.05-8.44 (8H, m, 2C6H4); 11.26 (1H, s, NH), 13.58 (1H, br. s, COOH). Found, %: C 65.25; H 4.80; N 4.45. C17H15NO5. Calculated, %: C 65.17; H 4.83; N 4.47. E-2-Phenacylidene-2,4-dihydro-1H-3,1-benzoxazin-4-one (3a). A solution of anilide 2a (0.95 g, 3.35 mmol) and dicyclohexylcarbodiimide (0.69 g, 3.35 mmol) in 1,2-dichloroethane (20 ml) was boiled for 1 h and then cooled down, and the precipitate of dicyclohexylurea was filtered out. The mother liquor was evaporated and the residue was crystallized from 2-propanol. Yield 0.89 g (100%); mp 141-142C (2-propanol). IR spectrum (vaseline oil), , cm-1: 3050 broad (NH in the intramolecular hydrogen bond); 1762 (C(4)=O); 1634 broad (COPh in the intramolecular hydrogen bond). 1H NMR spectrum (400 MHz, CDCl3), , ppm: 5.95 (1H, s, CH); 7.37-8.15 (9H, m, C6H5 + C6H4); 14.26 (1H, s, NH). Found, %: C 72.39; H 4.15; N 5.30. C16H11NO3. Calculated, %; C 72.45; H 4.18; N 5.28. E-2-(4-Methoxybenzoylmethylene)-2,4-dihydro-1H-3,1-benzoxazin-4-one (3b). Synthesized analogously. Yield 0.99 g (100%); mp 164-165C (2-propanol). IR spectrum (vaseline oil), , cm-1: 3040 broad (NH in the intramolecular hydrogen bond); 1750 (C(4)=O), 1630 broad (COC6H4 in the intramolecular hydrogen bond). 1H NMR spectrum (400 MHz, CDCl3), , ppm: 3.88 (3H, s, MeO); 5.88 (1H, s, CH); 6.95-8.13 (8H, m, 2C6H4); 14.27 (1H, s, NH). 13C NMR spectrum (100 MHz, CDCl3), , ppm: 55.48 (MeO); 83.93 (C(2)=CH); 114.10 (C(4a)); 121.25-129.35 (ArH); 137.00 (C(8a)); 162.12 (C(4)); 162.56 (C(2)); 177.30 (COC6H4). Found, %: C 69.17; H 4.48; N 4.75. C17H13NO4. Calculated, %: C 69.15; H 4.44; N 4.74. The research was done with the financial support of the Russian Foundation for Basic Research (grants Nos. 04-03-33024, 04-03-96033) and the Ministry of Education of the Russian Federation (grant A03-2.11-55); the NMR spectra were taken at the Ural Regional NMR Spectroscopy Center (URAL-NMR) (Russian Foundation for Basic Research grant No. 00-03-40139).
REFERENCES 1. 2. Yu. S. Andreichikov, V. L. Gein, A. P. Kozlov, and O. V. Vinokurova, Zh. Org. Khim., 24, 210 (1988). Yu. S. Andreichikov, O. V. Vinokurova, and V. L. Gein, Zh. Org. Khim., 25, 2431 (1989).
250
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acetonitrile; h, phenol; hl, chlorobenzene; h, toluene; i-PrOH, isopropyl alcohol; THF, tetrahydrofuran etc. Reagents, radicals, ligands, protecting groups: , acetyl; cc, acetylacetonate; Ad, adamantyl; Alk, alkyl; All, allyl; Ar, aryl; Bn, benzyl (PhCH2); Bu, butyl (s-Bu, i-Bu, t-Bu, respectively), Bz, benzoyl (PhCO); Cbm, carbamoyl; Cp, cyclopentadienyl; en, ethylenediamine (as ligand only); Et, ethyl; Hacac, acetylacetone; Hal, halogen; Het, hetaryl; , methyl; Mes, mesityl (1,3,5-trimethylphenyl); Ph, phenyl; Pr, propyl; i-Pr, isopropyl; y, pyridine; Tf, trifluoromethanesulfonyl; s, p-toluenesulfonyl (tosyl); Vin, vinyl as well as common designations for amino acids, carbohydrates, and protecting groups. 3.14. Reference citations in the text should be given in square brackets; the numbering of references in the list should correspond to the order in which they are mentioned in the text. Only one source should be noted under one reference number. The abbreviations for the titles of journals and handbooks for papers in Russian should correspond to those used in Referativnyi Zhurnal Khimiya (Chemistry Journal of Abstracts) or to the style of Kluwer Academic/Plenum Publishers (available from the editorial office). References to unpublished results and private communications may be given only as footnotes but should neither mentioned in the reference list nor numbered. The only exceptions are papers of the authors previously sent in Khimiya Geterotsiklicheskikh Soedinenii but yet not published; these may be included in the reference list with full title of the paper mentioned. 3.15. The list of references should be on a separate sheet and should include the names and initials of all authors ("et al." is not allowed). The references are given in the Latin transcription (see Chem. Abstr.). The reference section should be written as follows: Books: A. F. Pozharskii, A. T. Soldatenkov, and A. R. Katritzky, Heterocycles in Life and Science, J. Wiley a. Sons, Chichester, etc., 1997. L. M. Yagupolskii, Aromatic and Heterocyclic compounds with Fluorine-Containing Substituents [in Russian], Naukova Dumka, Kiev, 1988. In discussing particular problems, concrete pages or chapters should be cited. Papers in Collections and Handbooks: A. K. Sarkar, in Rodds Chemistry of Carbon Compounds, S. Coffey (Ed.), Elsevier Science Publishers Co, Amsterdam, 1974, IIIb, p. 236. H. Glaser, in Houben-Weil Methoden der Organischen Chemie, Georg Thieme Verlag, Stuttgart, 1957, XI, Teil 1, S.108. Journals: For journals with through volume or annual pagination, the issue number may not be noted. O. Neilands, Khim. Geterotsikl. Soed., 1763 (2003). N. S. Zefirov, Dokl. Akad. Nauk, 252, 111 (1980). E. Lukevics, N. P. Erchak, L. E. Demicheva, Khim.-Farm. Zh., 26, No. 1, 45 (1992). V. Yu. Kotov, A. B. Nikol'skii, A. M. Popov, Vestn. Leningrad Univ., 25, issue 4, 39 (1985). R. Maroni, G. Melloni, G. Modena, J. Chem. Soc. Perkin Trans. 1, 353 (1974). T. Sato, Yakugaku zasshi, 77, 771 (1957); Chem. Abstr., 51, 17941 (1957). Abstracts of Papers: Kh. M. Minachev, V. I. Avaev, E. S. Shapiro, M. A. Ryashentseva, G. V. Antoshin, in Nanesennye metallicheskie katalizatory prevrashcheniya uglevodorodov. Tezisy Vsesoyuz. Soveshch., Nauka, Novosibirsk, 1978, 131. L. Brandsma, B. A. Trofimov, N. A. Nedolya, A. Malkina, in Abstracts of 17th International Symposium on the Organic Chemistry of Sulfur, Tsukuba, Japan, 1996, 233. 255
Authors sertificates, Patents: O. E Nasakin., E. G. Nikolaev, USSR Authors Certif. 1168554; Byul. Izobret., No. 27, 90 (1985) [in Russian]. J. E. Dunbar, J. W. Zemba, US Pat. 3764608; hem. bstr., 80, 14852 (1974). Theses: D. A. Maiboroda, Abstract of Diss. Cand. Sc. (Chem.), Moscow, 1998. L. A Rodinovskaya, Theses Dr. Sc. (Chem.), Moscow, 1994. Manuscripts that do not follow the above rules will not be accepted. 4. THE PUBLISHING PROCESS 4.1. If required, manuscripts and/or proofs are sent to the authors for checking before publication. Manuscripts retained for correction for more than two months or those requiring another revision will be considered as new manuscripts. The date when a manuscript was received by the editorial office and the date when the manuscript was accepted for publication after revision are indicated at the end of the paper. Upon receipt of the proof, a thorough checking of figures and captures, formulas, equations, and all numeral data is recommended. References should be checked against the original publications. A manuscript sent to the authors for revision should be returned in the revised form (in duplicate) together with the original version containing editors remarks. The revised manuscript should be added by a letter of the authors containing requests on all remarks and comments and interpreting all introduced alterations. It is necessary to present (on diskette or by e-mail) a file with revised manuscript. In the case of delay of receipt of the proof from the author, the Editors reserve the right to print the paper without the authors corrections. 5. SENDING OF MANUSCRIPTS Manuscripts for publication should be sent to the Editorial office of the Journal Khimiya Geterotsiklicheskikh Soedinenii, Latvian Institute of Organic Synthesis, Aizkraukles, 21, Riga LV-1006, Latvia. phone: (371) 7555918 fax / phone: (371) 7550338 e-mail: hgs@osi.lv For speed of publication, authors (especially those from the CIS countries) are advised to send the manuscripts to any of the Regional Editors and to correspond directly with them: Prof. L. I. Belenkii, N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prosp., 47, 117913 Moscow, Russia; phone: (7-095) 135-8838, fax: (7-095) 135-5328, e-mail: lb@1september.ru. Prof. M. A. Yurovskaya, Department of Chemistry, M. V. Lomonosov Moscow State University, Vorob'evy Gory, 119899 Moscow, B-235, Russia; tel.: (7-095) 939-5376, fax: (7-095) 932-8846, e-mail: yumar@org.chem.msu.su. The same manuscript should not be sent to more than one address. The manuscripts will not be returned. When the paper is published, the copyright is transferred to the Publisher. Information concerning the journal Khimiya Geterotsiklicheskikh Soedinenii and its English version Chemistry of Heterocyclic Compounds, Contents of the journal issues, Annual Author Indexes as well as Instructions to Authors may be found in Internet: http:/www.osi.lv/hgs/hgs.html 256
THE PFITZINGER REACTION. (REVIEW)

M. G.-A. Shvekhgeimer Published data on the Pfitzinger reaction and its modifications, leading to quinoline-4-carboxylic acids, are reviewed, analyzed, and classified. Keywords: isatin, isatin derivatives, ketones, 4-quinolinecarboxylic acid derivatives, condensation, cyclization, Pfitzinger reaction, recyclization. The formation of derivatives of 4-quinolinecarboxylic (cinchoninic) acid as a result of the reaction of isatin or its derivatives with ketones containing the CH2CO group in the presence of sodium hydroxide or potassium hydroxide was first discovered at the end of the nineteenth century by Pfitzinger [1] and is known in organic chemistry as the Pfitzinger reaction. In the ensuing years this reaction, in which isatin and its derivatives on the one hand and various ketones on the other were used, has attracted the attention of many authors. The interest in this reaction was due to the possibility of synthesizing prospective biologically active substances simply and with good yields from readily available materials. In spite of numerous papers in this field the literature does not contain any publications summarizing the enormous amount of data that has accumulated over more than a century. Individual and poor-quality data on the Pfitzinger reaction have only appeared in monographs [2-4] and in a review [5]. The present review covers all the available published data on the Pfitzinger reaction beginning from the time of its discovery. The investigated material has been classified on the basis of the structure of the initial ketones; separate sections cover the reactions of isatins with dialkyl ketones, keto acids, alkyl aryl ketones, and alkyl hetaryl ketones and also with cyclic ketones. Papers describing the synthesis of 4-quinolinecarboxylic acids by methods related to the Pfitzinger reaction are discussed in a separated section. The reaction of isatins with ketones leading to 4-quinolinecarboxylic acids is carried out in the presence of strong nucleophiles (sodium hydroxide or potassium hydroxide). For this reason the generally accepted mechanism of the process is the following. The isatins 1 are converted by the action of alkalis into the salts of
O O O R 1 N H O _ COO M+ R1 R N 4 R2 5 2 + R N R2 MOH R + O _ M CCO R1CH2CR2 O O R 3 COOH H R1 N=CCH2R 1 R2 _ CCO M+
NH2
H2O
__________________________________________________________________________________________ A. N. Kosygin Moscow State Textile University, Moscow 117918, Russia; e-mail: office@msta.ac.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 323-365, March, 2004. Original article submitted January 15, 2001. 0009-3122/04/4003-02572004 Plenum Publishing Corporation 257
isatoic acids 2, which condense with ketones with the release of water, forming the salts 3. The latter undergo cyclization through the CO and CH2 groups and are converted into the salts of 4-quinolinecarboxylic acids 4, the treatment of which with acids (usually acetic) gives the required compounds 5. Subsequently only the initial isatins and ketones and also the final products will be presented in the texts and in the schemes without mention of the intermediate formation of the salts 2-4. As a rule the conditions and the yields of the reactions will be indicated in the schemes and in the tables.
1. REACTIONS WITH DIALKYL KETONES Pfitzinger first reported the synthesis of 2-methyl-4-quinolinecarboxylic acid (6) as a result of the reaction of isatin (7) with acetone in the presence of an aqueous solution of alkali in a paper published in 1886 [1].
COOH O O
+
N H 7 O
MeCMe
OH
_ N 6 Me
In subsequent papers [6, 7] he refined the reaction conditions (33% NaOH, 100C, 8 h) and reported that the acid 6 can be obtained with a yield of up to 80% while with more dilute sodium hydroxide solutions the yield was reduced to 50-53% [8-11]. Pfitzinger also studied the reaction of 5-methylisatin with acetone in the presence of a 5% aqueous solution of sodium hydroxide (boiling for several hours) and obtained 2,6-dimethyl-4-quinolinecarboxylic acid with a yield of 80% [6, 7]. The acids 8 substituted in the benzene ring were synthesized by condensation of the appropriately substituted isatins 9 with acetone in the presence of a dilute aqueous solution of sodium hydroxide [12], a 33% alcohol solution of potassium hydroxide [13], a 3.2% aqueous solution of sodium hydroxide [14], a 10% aqueous solution of sodium hydroxide [15], an 18% alcohol solution of potassium hydroxide [16], and a 20% wateralcohol solution of potassium hydroxide [17].
COOH R1 N H R2 9 O O
+
O
MeCMe
OH
R1 N R2 8 Me
boiling
R1, R2 (time, h), yield, %: OMe, H (6), n/d [12]; H, H (72), 70; H, Br (72), 75; Br, Br (72), 70 [13]; F, H (12), n/d [14]; H, Br (16), 51 [15, 16]; H, I (24), 87 [17]
The reaction of -naphthisatin 10 with acetone in a boiling wateralcohol solution of potassium hydroxide gave a 70% yield of the benzo[f]quinoline derivative 11 [18]. The tetracyclic compound 13 was obtained from acetone and -acenaphthisatin 12 under analogous conditions (yield 81%) [19].
258
COOH R R N H 10, 12 10, 11 R = H [18]; 12, 13 R+R = CH2CH2 [19] O O O R KOH, H2OEtOH boiling 36 h (10), 30 h (12) R N 11, 13 Me
MeCMe
As in the reactions with acetone, in the reaction of isatin 7 with symmetrical ketones in the presence of sodium hydroxide [20] or potassium hydroxide [21, 22] in a wateralcohol medium only one product of type 14 is formed each time.
COOH O 7 R N 14 CH2R
RCH2CCH2R
NaOH / KOH, H2OEtOH boiling
A single product is also formed in the case of unsymmetrical ketones of the MeCOCHR1R2 or RCH2COCHR1R2 type, since for the Pfitzinger reaction to occur the ketone must contain either a methyl group or a methylene group next to the carbonyl group. For example, only one appropriate cyclopropyl-substituted acid 16 is formed from methyl cyclopropyl ketone 15 and isatins 9 [23, 24].
COOH O 9 R1 N R2 16
MeC 15
KOH, H2OEtOH boiling
R1, R2, time, h: , , 5-7, (yield 84%) [23]; H, Me, 24; Cl, H, 24; Br, H, 24 [25]
The prolonged action of heat on the isatins 9 with the keto acid 17 gave the diacids 18 [25].
O 9 O CH2COH Me 17
1 2
R1 KOH, H2OEtOH boiling, 48 h R2
COOH O N Me 18 Me CH2COH
MeC Me
R , R , yield, %: , , 89.0; Me, , 59.0; H, Me, 76; Br, Br, 42.5
Methyl and ethyl -methoxyethyl ketones 19 and 20 condense with isatin 7 when heated in the presence of sodium hydroxide in water, and 2-(-methoxyethyl)-substituted acids 21 and 22 are formed with yields of 74 or 60% respectively [26]. Their analog isopentyl -methoxyethyl ketone 23 with a bulky substituent does not react with isatin 7 under the same conditions, but under more severe conditions the corresponding derivative of 4-quinolinecarboxylic acid 24 is formed with a yield of 46% [27]. 259
O 7
COOH NaOH, H2O, 100C, 24 h (19, 20) 40% aq. KOH, 115120C, 24 h (23) N 21, 22, 24 R CHMe OMe
RCH2CCHMe OMe 19, 20, 23
19, 21 R = H; 20, 22 R = Me; 23, 24 R = CH2CHMe2
As a result of prolonged boiling with the isatin 7 in the presence of potassium hydroxide in water and alcohol the diethoxy-substituted ketones 25 form the acids 26 [28].
COOH O 7 R N 26 CH(OEt)2
KOH, H2OEtOH boiling 72 h
RCH2CCH(OEt)2 25
R, yield, %: Et, 25; Bu, 94
The condensation of 5-bromoisatin with methyl -phenylvinyl ketone in a waterbenzene medium in the presence of sodium hydroxide and the phase-transfer catalyst Et4N+Br- takes place readily, and 6-bromo-2-(phenylvinyl)-4-quinolinecarboxylic acid is formed with an 85% yield [29]. If unsymmetrical ketones of the RCH2COCH2R1 type 27 are used in the Pfitzinger reaction, the process may be nonregioselective. Thus, careful study of the products from the reaction of isatin 7 with methyl ethyl ketone showed that 2,6-dimethyl-4-quinolinecarboxylic acid (mainly) and 2-ethyl-4-quinolinecarboxylic acid (and not only the former, as supposed earlier [8]) are obtained [22, 30]. It should be noted that from the halogen-substituted isatins 9 (R = H, R' = Br and R = R1 = Cl) and methyl ethyl ketone only one product (8-bromo- or 6,8-dichloro-substituted 2,3-dimethyl-4-quinolinecarboxylic acid) was obtained in both cases [16]. A probable mechanism for the formation of the two regioisomers as a result of the condensation of isatin 7 with unsymmetrical ketones of the MeCOCH2R type was presented in [31].
O O CCO 7 _ OH O O _ CCO O MeCCH2R H + O O +H + _ _ O O O _ CCO H R Me COOH R N Me
_ N=CCHR Me
_ CCO _ O O O CCO H H _ COOH
NH2
N=CCH2R Me +H +
H +
_ CCO _ N=CCH2 CH2R
OO
CH2R
CH2R
260
During a systematic study of the reaction of isatin 7 with ketones of type 27 it was shown that either two products 28 and 29 (minor) or only one product 28 are formed depending on the structure of the initial ketone [28].
COOH
O
COOH
R1
R1CH2CCH2R2 27
KOH, H2O
100 oC
+
N
29
CH2R1 R2
N
28
CH2R2
R1, R2 (time, h), total yield, %, products: H, Me (7), 85, 28, 29; H, Et (72), 92, 28; H, Pr (70), 93, 28; H, Bu (78), 80, 28; H, C5H11 (96), 92, 28; H, C8H17 (n/d), n/d, 28; H, Ph, (n/d), n/d, 28, 29; H, CH2Ph, (n/d), n/d, 28; Me, Ph, (n/d), n/d, 28, 29
It was found that from the ketones R3CH2COCH2R4 30, in which R3 < R4, and the isatins 9 only one compound 31 is formed in each case, i.e., the reaction takes place through the groups with smaller molecular mass CH2R3 [16, 24]. Such a reaction path can clearly be explained by steric factors and, to some degree, by the inductive effect of the alkyl radicals.
COOH R1 N H 7, 9 O O O R1 KOH, H2OEtOH boiling 18 h [16], 24 h [24] R2 N 31 R3 CH2R4
R3CH2CCH2R4 30
R2
R1 = H, Me, Bu, Cl, Br; R2 = H, Me, Cl; R3 = H, Me, Et, Pr; R4 = Alk (C1C6, C11, C15, C19). Yields 37-86%
The condensation of -naphthisatin 32 with the ketones 33 takes place through the methyl group of the latter. Here the tricyclic condensed compounds 34 are formed with almost quantitative yields [24].
COOH O O
+
32 N H O
MeCR 33
KOH, EtOH N 34 R
R = C6H13, C9H19
Unsymmetrical ketones containing Ar and OAr substituents in the alkyl radicals behave differently in the Pfitzinger reaction. Thus, methyl -phenylethyl ketone reacts with isatin 7 in the presence of potassium hydroxide in water and alcohol through the methyl group a single product 2-(-phenylethyl)-4quinolinecarboxylic acid is formed with a yield of 79% [22, 32]. The direction of the reaction of the isatin 7 with ketones of the 35 type under the same conditions depends on the nature of the substituent Ar. Thus, if R = Ph, C6H4OMe-4, OPh, or OC6H4OMe-4, a mixture of compounds 36 and 37 in ratios of 38:62, 40:60, 38:62, or 29:71 respectively was formed each time. On the other hand, with R = C6H4NO2-4 or OC6H4NO2-4 only the acids 37 (Ar = C6H4NO2-4 or OC6H4NO2-4) were obtained [31]. 261
+
7 N H O
MeCCH2Ar 35
KOH, H2OEtOH COOH COOH
+
N 36 CH2Ar 37 N
Ar Me
Ar : Ph, C6H4OMe-4 (36, 37); C6H4NO2-4 (37)
The reaction of the isatin 7 with the keto alcohol CH3COCH2OH also gave a single product 3-hydroxy2-methyl-4-quinolinecarboxylic acid [31]. Different regioselectivity was observed in the reaction of isatin 7 with the ketones 38 and 39, resulting in the synthesis of the acids 40 and 41 with yields of 35 and 41% respectively [22].
COOH Me 33% KOH, H2OEtOH boiling, 6 h N CH2Ph
O 7
PhCH2CCH2Me 38
O 7
40 COOH Ph 10 N KOH, H2OEtOH boiling, 7 h N 41 Me
PhCH2CMe 39
In a series of papers [33-39] it was found that the reaction of isatins 7 and 42 with alkoxy- and aroxysubstituted ketones 43 takes place with the participation of the CH2 group in CH2OR2, leading to compounds 44.
R1 N H 7, 42 O O COOH KOH, H2OEtOH R1 N 44 OR3 R2 boiling 4-6 h [35, 36], 1012 h [34, 39], 3036 h [37, 39], 48 h [33]
+
O
R2CCH2OR3 43
R1: H, Me; R2: Alk (C2C5); R3: Alk (C2C4), C6H4R4 (R4: 4-Me, 3-Me, 2-Me, 4-OMe, 4-OEt, 4-OPr, 4-OBu, 2-OMe), C6H3Me2-2,4, 1-naphthyl, 2-naphthyl. Yields 20-93%
It should be noted that other authors later obtained two products each 46 and 47 from methyl aroxymethyl ketones 45 and isatin 7 [31].
COOH O 7 OAr KOH, H2O boiling 46 N Me 47 N CH2OAr COOH
MeCCH2OAr 45
Ar, (ratio 46:47): Ph, (62:38); C6H4OMe-4, (71:29)
262
However, only the analogs of compounds 46, i.e., the acids 48, were synthesized from the sulfur analogs of the ketones 45 and isatins 11 [38, 40].
COOH O 7/42 R1 KOH, H2O 100C, 12-23 h [38] 8 h [40] N 48 Me SAr
MeCCH2SAr
R1: H, Me; Ar: C6H4R2 (R2: H, 2-Me, 3-Me, 4-Me). Yields 60-90%
Japanese researchers [41] have patented a method for the synthesis of 2,3-dimethyl-4quinolinecarboxamide (yield 61.8%) by heating the isatin 7 and methyl ethyl ketone with an aqueous solution of ammonia in a tube at 100C for 8 h. Under the conditions of the Pfitzinger reaction secondary alcohols are capable of being oxidized to ketones and entering into condensation with isatins with the formation of derivatives of 4-quinolinecarboxylic acid. Thus, the product 50 was obtained with a yield of 81% from the hydroxylactone 49 and isatin 7 [25].
Me Me 7 O C O KOH, H2OEtOH boiling, 24 h 49 50 N COOH
Me Me (CH2)2 O C O
2MeCH(CH2)2 OH
The behavior of aliphatic diketones in the investigated reaction has been studied little. Two sets of conditions (A, B) for the reaction of the diketones 51 with isatin 7 were described in [42]. According to method A, a mixture of isatin and the diketone 51 was boiled in the presence of potassium hydroxide in water and alcohol, resulting in the synthesis of the keto acid 52. From acetylacetone under similar conditions the authors of [43] obtained the product from in situ cyclization of the acid 52, i.e., the lactone 53. In method B the isatin was first converted by the action of potassium hydroxide into the salt 54, which was then isolated and brought into reaction with 2,5-hexanedione in the dry form. In this case the reaction product was the acid 55 (yield 33%).
COOH O O A: 7 O
KOH, H2OEtOH boiling N 52
CR2 R1
R1CCH2CR2 51
R1, R2, (time, h), yield, %: Me, Me, (6), 73; Me, Ph, (8), 67 [42]
263
O O 7 O
MeCCH2CMe
15% KOH, H2OEtOH boiling, 6 h
52 N 53 O O
Me COOH CH2 N R1
[43] O CR2
B: 7
KOH, H2OEtOH 54
COCOOK NH2
R1C(CH2)2CR2 55
R1, R2, (time, h, , ), yield, %: Me, Me, (3, boiling), 80; Me, Et, (1, 100, 20 min, 150), 67; Me, Ph, (10, 120), 42; Ph, Ph, (10, 140-150), 63; Me, Me, (2, 160-180), 33 [42]
There are also examples of the use of compounds that are converted into diketones under the conditions of the Pfitzinger reaction and then react with isatins. Thus, the diacid 56 (yield 58%) was obtained from 2-hydroxy-3-butanone and isatin 7 in the presence of potassium hydroxide in water [26], while the dicarboxylic acids 58 were synthesized from 3-chloro-2-butanone and isatins 57 [44]. The initial chloro ketone is clearly saponified to 2-hydroxy-3-butanone under the reaction conditions. As in the reaction with isatin 7, the product is then oxidized to 2,3-butanedione, which reacts with two molecules of isatin.
COOH OH O 2 . 7 + MeCHCMe KOH, H2O 100C, 24 h N 56 COOH R
1
COOH
N COOH R1 N R
3
O N H O
Cl O + MeCHCMe
KOH, H2O boiling, 2-4 h
R R
R2 R
3
N 58 R3
R2
57 R1, R2, R3: Me, H, H; H, Me, H; H, H, Me
2. REACTIONS WITH KETO ACIDS In this section we will concentrate on papers in which the reactions of isatins with keto acids having various arrangements of the carbonyl and carboxyl groups, leading to quinolinedicarboxylic and quinolinetricarboxylic acids, are described. Pyruvic acid (an -keto acid), its derivatives at the methyl group, and its esters in the Pfitzinger reaction have been studied in greatest detail. In the search for antimalarial products and other biologically active compounds unsubstituted isatin 7 and its derivatives 59 were brought into condensation with pyruvic acid, resulting in the synthesis of the diacids 60 [7, 15, 45-47].
264
R1 R2 R3 R4 7, 59 N H O O O NaOH / KOH, H2O R2 R3
R1
COOH
MeCCOOH
N R4 60
COOH
R1, R2, R3, R4, (conditions), yield, %: H, H, H, H, (33% KOH, H2O, 20C, 48 h) n/d [7]; H, OMe, H, H, (KOH, K2CO3, 20C, 2 days), n/d [12]; H, OMe, OMe, OMe, (KOH, H2O, 95C, 6 ), n/d [45]; H, Cl, H, H, (KOH, H2O, 37C, 48 h), 62 [15, 46]; H, H, Cl, H, (NaOH, H2O, boiling, 8 h), 95; Cl, H, H, H, (NaOH, H2O, boiling, 48 h), 30 [47]; H, H, H, Cl, (KOH, H2O, 37C, 48 h), 54 [15]; H, Cl, H, Cl, (KOH, H2O, 37C, 48 h), 97 [15]
The reaction of isatins 9 with halogen-substituted acids or their esters 61 takes place even at room temperature. The obtained dicarboxylic acids 62 are decarboxylated in situ, and the final products are derivatives of 3-hydroxy-4-quinolinecarboxylic acid 63 [48, 49].
R1 N H 7, 9 R1 N R2 62 O O O KOH, H2O, N2 20C, 6 days
XCH2CCOOR3 61 COOH OH COOH
R2
R1 CO2
COOH OH N R2 63
X: Cl, Br; R1: H, Me, OMe, Cl, Br, I; R2: H, Cl, COOH; R3: H, Et. yields, %: 14-79
Structures 64 and 65 were proposed in [7] for the product from the condensation of isatin 7 with acetoacetic acid (a -keto acid). The first must clearly be preferred, since the CH2 group must be more active than CH3 under the conditions of the Pfitzinger reaction. Actually in [21] the structure of the product 64 was proved by its oxidation to the tricarboxylic acid 66, which was also synthesized from the keto dicarboxylic acid 67 and isatin 7.
COOH O 7 COOH
33% aq. KOH 20C, 48 h 64 COOH N
COOH
MeCCH2COOH
+
Me 65 N CH2COOH
[O] 64 N 66
COOH COOH
O 7
HOOCCCH2COOH 67
265
The 6-methoxy derivative of the acid 66 was obtained from the keto diacid 67 and 5-methoxyisatin (potassium hydroxide in water and alcohol, 20C, 48 h) [12]. The reaction of the isatins 7 and 40 with -keto acids and their esters 68 under analogous conditions led to the corresponding dicarboxylic acids 69 [21, 50-52]. The tricarboxylic acid 71 was synthesized from acetonedicarboxylic acid 70 and the isatin 7 [21].
O O COOH KOH, H2O 2025 oC R N 69 COOH R1
R N H 7, 40
+
O
R1CCH2COOR2 68
R, R1, R2, (time, h), yield, %: H, Ph, H, (24), n/d; Me, Me, H, (24), n/d [21]; Me, Me, Et, (48), 90 [50]; H, Me, Et, (24), 88; Me, Ph, Et, (75), 82; Me, C6H3(OMe)2-3, 4, Et, (75), 71; Me, C6H4OMe-4, Et, (75), 75 [51]; H, Ph, Et, (48), 44; H, CH2Ph, Et, (78), 64 [52]
COOH O 7 + HOOCCH2CCH2COOH 70 KOH, H2O 20C, 24 h N 71 COOH CH2COOH
A series of dicarboxylic acids 73 were synthesized as a result of a systematic study of the condensation of isatin 7 with keto acids 72 in the presence of potassium hydroxide or sodium hydroxide (Table 1) [53-59].
COOH O O KOH / NaOH, H2O boiling N 73 (CH2)n1COOH R RC(CH2)nCOOH 72 O
N H 7
TABLE 1
R Me Ph Ph 4-MeC6H4 4-ClC6H4 Ar 2-Naphthyl 2-Thienyl 3-Indolyl n 3 2 3 2 2 2 2 2 2 Yield of References 73, % 62.5 65.0 93.0 53.0 66.0 n/d n/d 70.0 n/d 58* 53*2 59*2 53*2 53*2 54*3 54*3 55*4 54*3 R 3-Indolyl 3-Indolyl 3-Indolyl 1-Methyl-3-indolyl 1-Methyl-3-indolyl 2-Methyl-3-indolyl 2-Methyl-3-indolyl 2-Methyl-3-indolyl 1,2-Dimethyl-3-indolyl n 2 3 4 2 3 2 3 4 2 Yield of References 73, % 56.0 45.0 45.0 55.0 40.0 53.0 41.0 53.0 53.0 56, 57*5 56, 57*5 57*5 56, 57*5 56, 57*5 56, 57*5 56, 57*5 56, 57*5 56, 57*5
_______ * 33% aq. KOH, 72 h. *2 33% aq. KOH, boiling 12 h. *3 Heating. *4 KOH, H2OEtOH, boiling 12 h. *5 33% aq. NaOH, boiling 50 h. 266
3. REACTIONS OF ISATINS WITH ALKYL ARYL KETONES Alkyl aryl ketones are most often used in the Pfitzinger reaction. In view of the large number of publications and the variety of the obtained compounds this material is examined in condensed form and is in a number of cases presented in tabular form. In one of the first papers [7] it was reported that when isatin 7 was heated (100C, 6 h) with acetophenone 74 in the presence of potassium hydroxide in water and alcohol 2-phenyl-4-quinolinecarboxylic acid (cinchophen) was formed with a yield of 65%. Later on [60-69] the isatins 59, containing substituents in the benzene ring, were used in the Pfitzinger reaction with the same ketone, and the similarly substituted quinolinecarboxylic acids 75 were obtained (Table 2) [12, 14, 28, 31, 60-69].
R1 R2 R3 R4 59 N H O O R1 KOH, H2OEtOH boiling R2 R3 R4 75 N Ph COOH
+
O
MeCPh 74
TABLE 2
Substituent (reaction time, h), yield of product (72), % [reference] R ,R ,R =H R 1, R 3, R 4 = H R 1, R 4 = H R 1, R 3 = H R 1, R 2, R 3 = H
2 3 4
R = COOH (n/d), n/d [60]; R1 = Cl (8), 57 [61]; R1 = SO3K (24), 76* [62] R2 = Me (n/d), n/d [63]; R2 = OMe (12*2), n/d [12]; R2 = COOH (7) n/d [64]; R2 = F (1*2), n/d [14]; R2 = Cl (24), 90 [31]; R2 = Br (5*3), 78 [28]; R2 = I (n/d), 83 [65, 66]; R2 = NHAc (4), n/d [67] R2 = R3 = Cl (8), 86 [61]; R2 = R3 = Me (8), 85 [68] R2 = R4 = Br (8), 65 [69] R4 = COOH (7), n/d [64]
_______ * The product was 5-hydroxy-4-quinolinecarboxylic acid. *2 NaOH, H2O. *3 NaOH, Et4N+Br-, H2OPhH. The reaction of 7-nitroisatin with the ketone 74 by heating with a concentrated aqueous solution of ammonia in an autoclave gave the amide 76 (yield 8%) [70].
CONH2 O
+
NO2 N H 59 O
74
NH3, H2O, autoclave 130C, 8 h NO2 76 N Ph
2-Aryl-4-quinolinecarboxylic acids 78 (Table 3) were synthesized by the condensation of isatin 7 with monosubstituted acetophenones 77 [24, 63, 69, 71-80].
267
COOH O 7
KOH, H2OEtOH boiling N 78
MeC 77
TABLE 3
R 4-Me 4-Pr-i 4-C7H15 4-C8H17 4-C9H19 4-C12H25 4-Br 3-Cl 2-OH/4-OH 2-Cl/4-Cl 3-Me 4-OMe 4-OEt 4-OPr Reaction Yield of References time, h 78, % 48 48 24 24 24 24 8 8 48 48 48 6-8 8 8 n/d n/d 95 92 96 90 65 n/d n/d n/d n/d 85.9 70.8 67.1 63 71 72 72 72 72 24, 73 69 74 24, 74 74 75 24, 75 75 R 4-OBu 4-OC5H11 4-SEt 4-OPh/4-SPh 4-(C6H4OMe-4) 4-NEt2 4-NO2 3-NO2 4-Ph 4-(CH2)2Ph 4-(C6H3Cl-3, Me-4) 4-(2,5-Dimethylpyrrol-1-yl) 4-Et Reaction time, h 8 48 24 24 24 8 8-10* 8-10* 12-15 12 68 24 48 Yield of References 78, % 68 66 n/d n/d n/d n/d 7 8 100 95 85 98 n/d 75 75 24 24 24 69 76 76 77 78 79 80 24
_______ * NH3 was used instead of KOH. Data on the reaction of di- and trisubstituted acetophenones with isatin 7 are given in Table 4 [24, 69, 74, 79, 81-83] and with isatins 57 in Table 5 [14, 24, 29, 65, 69, 79, 84, 85].
R1 R2 R3 80 KOH, H2OEtOH boiling N 79 COOH R1 R2 R3
O 7
MeC
TABLE 4
R1 2-Me 2-Me 2-Me 2-Me 3-Me R2 4-Me 5-Me 4-Bu-t 4-Me R3 H/5-Me H 6-Me H (Reaction time, h), yield, % [references] (24), 53/54 [81] (24, 8, 48) n/d [24, 69, 74 resp.] (24), 0 [81] (24), 0 [81] (24, 48), n/d [24, 74] R1 2-Cl 3-Cl R2 4-Cl/ 5-Cl 4-Cl (Reaction time, h), R3 yield, % [references] H H H H H H (8), n/d [69] (24, 19), 82 [24,79] (24), n/d [82] (24), n/d [82] (14), 71 [79] (3), n/d [83]
3-Cl/ 3-Br 4-OMe 3-Cl 4-Cl 3-NO2 4-OEt 5-Cl 4-NHAc
4-OMe 6-Bu
268
COOH R1 R2 R3 57 N H O O O
MeC 82
R4 R5
KOH, H2OEtOH
R1 R4 R2 R3 81 N R5
TABLE 5
R1 H H H Me Me, Br, I F Cl Cl Cl Cl Cl Cl Br Br Br Br R2 H OMe Cl H H H H H H H OMe Cl H H H H R3 Cl H H H H H H H Cl Cl H H H H H Br R4 4-Cl 3-Cl 4-Cl 4-Cl 3-Me 4-F 4-Me 3-OMe 4-Cl 3-Cl 4-OMe/4-Cl 4-OMe 3-Me/4-OMe*3 3-Me, 4-Pr-i, 4-Ph, 4-Cl, 4-Br, 4-I 2-Me 4-OMe R5 H 4-Cl H/5-Cl* H 4-I H H 4-OMe H 4-Cl H H H H 4-Me/5-Me H (Reaction time, h), yield of 80, % [references] (10), 51 [79] (42.5), 82 [85] (30/28), 86/45 [79] (24), n/d [24] (n/d), n/d [65] (1*2), n/d [14] (24), n/d [24] (22), 95 [85] (24-48), 85-87 [79, 84] (21), 53 [79] (24/40), 75/76 [85] (40), 75 [85] (24/5), n/d /82 [24, 29] (24), n/d [24] (24), n/d [24] (8), 65 [69]
_______ * There is also a 2-Me substituent in the benzene ring. *2 NaOH, H2O. *3 NaOH, Et4N+Br-, H2OPhH. The schemes presented below illustrate investigations into the reaction of acetophenone 74 [18, 19, 68, 86, 87] and more complex methyl aryl ketones [19, 88] with annelated isatins 10, 12, 32, 83, and 84, leading to various polycyclic systems 85-88.
COOH O (CH2)n 83 N H O
33% aq. KOH 74 100C, 8-10 h (CH2)n N 85 Ph
n, yield, %: 1, 40; 2, 53 [68]
COOH O N H O
74
NaOH, H2O boiling, 8-10 h R 86 N Ph
R 84
R, yield, %: Cl, 70 [86]; H, n/d [87]
269
R R
COOH O
N H 10, 12
MeCAr
KOH, H2OEtOH boiling R
R N Ar
87 R or R+R, Ar (time, h): H, Ph (36) [18]; CH2CH2, Ph (30-36) [19]; C6H4Ph-4 (24); H, 2-naphthyl (8); , 4-methyl-1-naphthyl (8); , 2-anthracenyl (8); , 2-acenaphthenyl (8); , 1-pyrenyl (8) [88]; CH2CH2, 2-phenanthrenyl (24) [19]
COOH O O
+
N H 32 O
MeCAr
KOH, H2OEtOH boiling N 88 Ar
Ar: C6H4Ph-4; 4-methyl-1-naphthyl; 2-fluorenyl; 2-anthracenyl; 5-acenaphthenyl; 1-pyrenyl; 6-benzo(a)phenanthrenyl
In [88] it was shown that the ketones 81 and 82 react with the isatins 10 and 32 only if the Ar does not contain substituents at the o-position to the carbonyl group; the products 87 and 88 here are obtained with almost quantitative yields. By replacing the methyl group in the acetophenones by RCH2 [in ketones of type 89] it is possible to obtain 2,3-disubstituted quinolinecarboxylic acids with structure 90, many examples of the synthesis of which are summarized in Table 6 [24, 80, 82, 89, 90-97].
COOH O R N H 1 O O R2 R3 89 KOH, H2OEtOH R1 R N 90 R2 R3
R1CH2C
TABLE 6
R 1 R1 2 Me (68), 90; Et, (2), 18; Ph, (100), 80 Me, Et Bu (24), 30; C6H4Me-4, (48), 37; C6H3Me2-2,4, (48), 12; C6H2Me3-2,4,6, (48), 0 OMe, (6-8), 96; NH2 (6-8), n/d -C10H7NH, (n/d), n/d Ph, (12) R2 3 3-Cl, C6H4Me-4 3-Cl; 3-Br 3-Cl H R3 4 H 4-OMe 4-OEt H References 5 89 82 82 90
H H 4-Me, 65; 4-Et, 55 4-CH2Ph, 44; CHPh2, 68 2-Me, 21; 2-Cl, 24 H 5-Me
H H H 4-Me H 2-Cl
92 94 91 91 93 91
6- Me, 65 7- Me, 70 8-Me, 80 8-Me
NH2, (6-8) Ph, (12), 55
270
TABLE 6 (continued)
1 5-F 6-F 2 Me, (18) Me, (12) Me, (n/d) Me, (24) Me, (24) Me, Et (24) Me, Et Me, Et, Ph, (24) Me, Et, Ph, CH2COOH (24) Et, (24) Ph, (24) Ph, (24) Me (n/d) Ph, (12) Ph, (12) 3 4-Ph, 58 4-C6H13, 56 C6H4F-2, n/d H; 4-Et, 4-Bu 2-Me 4-Pr; 4-Ph 6-Tetralinyl (24), n/d 4-Cl 4-Br 3-OMe 2-OMe 2-Me 4-(2,5-Dimethyl-1-pyrrolyl), n/d 2-Me, 46.5 4-Me, 69; 2-Me, 17 2-Cl, 43 4 H H H H 5-Me H H H H 4-OMe 4-OMe 5-Me H 5-Me H 4-Me 5 96 95 97 24 24 24 24 24 24 24 24 24 80 91 91 91
6-Br
6-Cl
It is well known, however, that ketones Me(CH2)nCOAr (n > 2) hardly react at all with isatin 7 under the usual conditions of the investigated reaction even when boiled for 36 h [24]. On the other hand, in the reaction of the isatins 40 with the ketones 91, in which the Ar groups are condensed systems, the corresponding acids 92 are as a rule formed with high yields (Table 7) [19, 24, 29, 72, 81, 91, 98].
COOH R N H 40 O O
+
O
R1CH2CAr 91
R N 92
R1 Ar
TABLE 7
R 1 H H R1 2 Ar 3 2-Naphthyl 2-Methyl-1-naphthyl, 4-methyl-1-naphthyl 2-Methoxy-1-naphthyl, 2-fluorenyl* 5-Indanyl* 2-Naphthyl 2-Fluorenyl 3-Phenanthrenyl 1-Benzpyrenyl 5-Acenaphthenyl 2-Naphthyl (Reaction time, h), product yield, % [reference] 4 (96), 96 [101] (24), 90-100 [72*, 81]
Me, Et Me, Et, Pr Et Me Me, Et Bu-i, C5H11, C6H13, C7H15, C4H19, C11H23
(24), 80 [72] (48/96), 90/90, 62 (R1 = Et) [81, 98] (24), 0 (Pr), 89 (Me) [81] (24), 78 [81] (24), 35 [19] (48), 78,75 [81] (96), 33 (i-Bu), 46-56, 28 (C9H19) 16 (C11H23) [98]
271
TABLE 7 (continued)
1 H Ph 2 3 2-Naphthyl, 7-methyl-1- and 7-methyl2-naphthyl 4-Methoxy-1-naphthyl, 6-chloro-1naphthyl 5-Acenaphthenyl 1-Naphthyl 4-Methyl-1-naphthyl, 5-acenaphthenyl 3-Pyrenyl 4 (12), 63-78 [91] (12), 15, 60 [91] (12), n/d [91] (5)*2, 78 [29] (24), n/d [24] (24), n/d [24]
Br
H Me H, Me, Et
_______ * At 70-80C. *2 NaOH, Et4N+Br-, H2OPhH.
Under similar conditions the condensation of isatin 7 with 11-propionyl[3,4]benzpyrene 93 leads to the acid 94 with a yield of 71% [19].
COOH O EtC KOH, H2OEtOH boiling, 24 h 93 94 N Me
When the isatins 1 and the acetates of -hydroxy ketones 95 are heated in the presence of potassium hydroxide [99] or sodium hydroxide [100] in water and alcohol, hydrolysis of the OAc group occurs in addition to recyclization, and the reaction products are 2-aryl-3-hydroxy-4-quinolinecarboxylic acids 96, recommended as antiarhythmic agents and immunodepressants.
COOH O
O R N H 1 O
KOH/ NaOH, H2OEtOH boiling
OH R N 96 Ar
AcOCH2CAr 95
R: H, 8-Me, 6-OMe, 6-Cl; Ar: C6H4R1 (R1: H, 4-Br, 4-OMe, 4-NH2, 4-Ph), CH2Ph, C6H3Me2-2,4. Time, h: 10 [99]; 4 (for R = 6-OMe, Ar = CH2Ph [99]; 2.5 [100]. Yields 11-100%
The diketones 97 react with two molecules of isatin 7, forming the dicarboxylic acids 98 [77, 78].
272
O 2. 7
O (CH2)n 97 COOH R N (CH2)n 98 CCH2R
RCH2C
KOH, H2OEtOH boiling COOH R N
R, n, (time, h), yield,%: H, 0, (3), 41.5 [77]; H, 2, (18), n/d [78]; Me, 2, (18), 20.0 [78]
The benzyl CH2 group takes part in the reaction of isatin 7 with the ketones RCOCH2Ar 99 and 100, and the analogs of compounds 90, i.e., the acids 101 and 102, are formed. For these reactions the effects of the position and size of substituents in the benzene ring and alkyl radical of the ketone on the formation of the products 101 and 102 were investigated [101, 102]. According to the reactivity in the investigated examples the ketones 99 and 100 were separated into the three groups indicated in the schemes below.
COOH O 7 R1 R2 99 KOH, H2OEtOH boiling, 48 h N 101 R R1 R2
RCCH2
1.
Ketones reacting normally with isatin: for R = H, Me, Et, Ph R1 = 3-Me, R2 = 4-OMe; then indicated R, R1, R2: H, 2-Me, 4-OMe; Me, 2-Me, 4-OMe; Ph, 2-Me, 4-OMe; H, 2-Me, 4-OPr; Me, 2-Me, 4-OPr; Ph, 2-Me, 4-OPr; H, 2-Me, 4-OBu-i; Me, 2-OMe, 3-Me; H, 2-OC5H11-i, 3-Me [97]; H, 2-Me, 5-OEt; Me, 2-Me, 5-OEt; H, 2-Me, 4-OBu [98]. Ketones reacting with isatin to an insignificant degree: for R = Me, Et, Ph R1 = 3-Me, R2 = 4-OC5H11-i; then indicated R, R1, R2: 2-Me, 4-OBu; Et, 2-Me, 4-OMe; Et, 2-Me, 4-OPr; Et, 2-Me, 4-OBu; Ph, 2-Me, 4-OBu-i; Ph, 2-Me, 4-OBu [97]. Ketones not reacting with isatin: R = Et, R1 = 2-C5H11, R2 = Me [97].
COOH R2 R3 100 KOH, H2OEtOH boiling, 48 h N 102 R R1 R2 R3
2.
3.
O 7
R1
RCCH2
1.
Ketones reacting normally with isatin: for R = H, Me, Ph R1 = 2-OMe, 2-OC5H11-i, 4-OPr, R2 = 2-Me; R3 = 5-Me; then indicated R, R1, R2, R3: H, 2-Me, 4-OEt, 4-Pr-i; Me, 2-Me, 4-OEt, 5-Pr-i; Me, 2-Me, 4-OEt, 5-Pr-i; Me, 2-Me, 3-Bu-i, 4-Me [98]. Ketones reacting with isatin to an insignificant degree: R, R1, R2, R3: Et, 2-Me, 4-OPr, 5-Me; 2-Me, 4-OBu, 5-Me; Et, 2-Me, 4-OBu, 5-Me; Ph, 2-Me, 4-OBu, 5-Me [98]. Ketones not reacting with isatin: R = Me, Ph; R1 = 2-Me; R2 = 4-OMe; R3 = 6-Me [98].
2.
3.
273
It follows from the data in [101, 102] that the Pfitzinger reaction is sensitive to steric factors arising not only from the effect of substituents at the ortho positions of the benzene ring but to some degree also from the size of the substituent at the para position.
4. REACTIONS OF ISATINS WITH ALKYL HETARYL KETONES By the reaction of isatins with alkyl hetaryl ketones it is possible to obtain various 2-hetaryl-substituted 4-quinolinecarboxylic acids. Thus, in the presence of aqueous solutions of alkalis ketones of the furan series 103 react with isatins 59 with the formation of acids 104 containing a furyl substituent [12, 103, 104].
R1 R2 N H R3 59 R2 N R3 (CH=CH)n 104 O R4 O O O R4 O 103 R1 COOH (CH=CH)n CMe
KOH / NaOH, H2O
R1 = H, Cl; R2 = H, Me, OMe, Cl; R3 = H, Cl; R4 = H, NO2; n = 0, 1. Yields 46-86%
The thienyl-substituted acids 105 were synthesized by the condensation of isatins 9 with acylthiophenes 106 [104-106].
R1 N H R2 7, 9 R1 N R2 105 O O
O R3 S 106 CR4
NaOH, H2O boiling
COOH R5 S R3
R1 = H, Me, C8H17; R2 = H, Cl, C7H15; R3 = H, NO2, Ph; R4 = H, Alk (C1-C7, C9-C11), CH2Ph; R5 = H, Alk (C1-C6, C8-C10), Ph. For R1 = R2 = R5 = H, R3 = R4 = Me yield 60%
During study of the behavior of alkyl 2,5-dimethylthienyl ketones 107 in the Pfitzinger reaction it was found that their reaction with isatin 7 under normal conditions, leading to compounds 108, only takes place with R = Me, Ph; with R = Pr, Bu the corresponding products could not be isolated [107]. This is clearly due to steric hindrances brought about by the groups 2-Me and R containing two or more carbon atoms.
274
O O CCH2R
COOH R KOH, H2OEtOH N 108 Me S Me
+
N H 7 O Me S 107 Me
R, yield, %: Me, 50; Ph, 41
Compounds 109 and 110, containing two uncondensed or condensed thiophene rings, were synthesized with high yields from the corresponding ketones 111 and 112 and isatin 7 [77, 108]. The bithiophene 117-119 [77, 108] or dibenzothiophene 120 [109] derivatives, containing two 4-quinolinecarboxylic acid residues as substituents, were easily obtained in the same way from the ketone 113 and the diketones 114-116 by condensation with isatin 7.
O 7 COOH KOH, H2OEtOH boiling 3 h (111), 24 h (112) N 109, 110 X
MeCX 111, 112
X= S S (109, 111) COOMe O 7 KOH, H2OEtOH boiling 113 COOH O 2 O KOH, H2OEtOH boiling 6 h (114), 24 h (116), 100-110C, 24 h (115) N Z 117120 N N S S (110, 112) COOH COOMe
MeCZ
Z 117
COOH
.7 +
MeCZCMe 114116
Z =
S S
Me
Me
(113, 114, 117, 118)
(115, 119)
(116, 120)
The schemes below give the available data on the synthesis of derivatives of 4-quinolinecarboxylic acid 121-123 with substituted indole [110], pyridine [13, 104, 111, 113], or substituted quinoxaline [113] residues at position 2. It should be noted that compounds 122 with a pyridyl substituent were synthesized in the search for substances having antimalarial activity.
275
O R N H 40 COOH R N R2 121 N H R1 O CCH2R1 KOH, H2OEtOH heat
+
O N H
R2
R: H, Me, Br; R1 = H, Me; R2 = H, Me, Ph [110]

COOH R1 N H R2 9 O O R1 KOH, H2OEtOH boiling R2 N 122 N
+
O N
CMe
R1 = H, Cl, Br; R2 = H, Me, Cl, Br. Time, h: 22/72 [13], 6 [104], 2 [111, 112]. Yields 50-70%
O N 7 CMe R COOH KOH, H2OEtOH boiling N R 123 N N
+
N
R = H, Me [113]
The condensation of isatin 7 with 2-acetyl-4-phenylquinoline (sodium hydroxide or potassium hydroxide, water, boiling, 1 h) gave an 80% yield of 2-(4-phenyl-2-quinolinyl)quinoline-4-carboxylic acid [114, 115]. The reaction of isatin 7 with acylated dibenzothiophene [81, 109, 116], dibenzofuran [116], and dibenzopyran [72] with the general formula 124 and also the reaction of the isatins 59 with acetylphenothiazine [72] and acetylthianthrene [117] with the general formula 125 gave the corresponding quinolinecarboxylic acids 126 and 127, having a tricyclic condensed system with a heterocycle as substituent at position 2.
COOH O 7 + R1CH2C X 124 R2 KOH, H OEtOH 2 boiling 2448 h N R1 R2 X 126
R1, position of COCH2R1, R2, X, yield, %: H, 3, H, NH, (70-80 C, 24 h), 78 [72]; Me, 2, H, S, 90 [81]; H, 2, H, S, (12 h), 80 [109, 116]; H, 2, H, O, 78; Et, 2, H, O, 31; Ph, 2, H, O, 68; H, 2, Br, S, 30; Ph, 2, Br, S, 27 [116]
276
R1 R2 R3 R4 59 N H O S COMe KOH, EtOH 24 h X 125 R1 R2 R3 R4

1 2 3 4
+
O
COOH S N 127 X
R , R , R , R , position of COMe, X, temperature, C: H, H, H, H, 3, NH, 70-80 (yield 88%) [72]; Me, H, Me, H, 2, S, 100; H, Me, H, Me, 2, S, 100 [117]
5. REACTIONS OF ISATINS WITH CYCLIC KETONES AND DIKETONES The Pfitzinger reaction provides a simple and convenient method for the synthesis of condensed polycyclic compounds containing a heterocycle from readily obtainable starting materials. Cyclic ketones and, more rarely, diketones are often used as starting compounds. The condensation of isatins 42 with cyclopentanone and its derivatives 128 has been investigated in a fair amount of detail [13, 19, 118-120]. It was found that the size of the substituent adjacent to the carbonyl group of the ketones has a significant effect on the yield of the condensation products 129. Thus, in the case of 2-methylpentanone the yield of the acid 129 (R1 = Me, R = H) amounted to 78%; in the case of 2-ethylcyclopentanone the yield was 1% (R = H, R1 = Et), and with 2-propylcyclopentanone the reaction did not occur [119].
COOH R R N H O NaOH /KOH, H2OEtOH boiling O 128 N 129 R1
+
O 42
R1
R, R1, (time, h), yield, %: Br, H, (22), 55 [13]; F, H, (1), n/d [14]; H, Me, (24), 75 [19]; H, H, (5), 57 [13]; H, H, (22), 89 [20]; H, H, (8), 62-87 [118-120]; H, Et, (72), n/d; H, Pr, (72), 0 [119]
Derivatives of 2-cyclopentenone 130 enter readily into reaction with isatin to form the corresponding tricyclic compounds 131 [121, 122].
O R1 7 COOH KOH, H2OEtOH boiling, 6-7 h N 131 R1 R2
+
R2 130
R, R1: H, Ph [121]; CH2COOH, Ph [122]
277
The reaction of the isatins 9 with cyclohexanones 132 leads to the formation of derivatives of 1,2,3,4-tetrahydro-9-acridinecarboxylic acid 133. If R = H the yields of the products 133 amount to 75-100% [19, 20, 65, 118, 123-125]. However, it was noticed in [19] that cyclohexanone does not react with -naphthisatin 10 under the conditions of the Pfitzinger reaction.
R1 KOH, H2OEtOH COOH R3 N R2 133
R1 N H R2 7, 9, 42
O O
+
132
R3
boiling, 24-72 h
R2 = H, R1, R3, position of R3 in 132 and 133, (time, h), yield, %: H, Me, 2 and 4, (60) [19, 119]; H, Et, 2 and 4, (72), <1; H, Pr, 2 and 4, (72), O; H, (CH2)nMe (n = 3-7), 2 and 4, (24), 80 [24]; H, Me, 3 and 3, (72), 80; H, Me, 4 and 2, (72), 85; H, C6H11, 4 and 2, (72), 85 [119]; R3 = H, R1, R2: H, H [20, 118, 123-125]; Cl, Cl; Me, Me [19]; H, H [65]; Br, H; Br, Br [118]; Cl, H; Me, H [123]
The position and size of the substituent R2 in the cyclohexanone derivatives has a significant effect on their reaction with isatins. Thus, if R2 is at position 3 or 4, high yields of the products from condensation with isatins 42 are formed. On the other hand, from the ketones with various substituents R2 at position 2 under the same conditions good yields are only observed with R2 = Me [13, 19, 24, 119]. The reactions of isatins 7 [118, 126] and 42 [13, 82, 127-129] with ketones 134 containing seven and 7-17 CH2 units respectively in the ring have also been described.
COOH R NaOH/KOH, H2OEtOH CH2 boiling N 135 (CH2)n
R N H 7, 42
+
O
(H2C)n
134
R = H, n = 6, base, yield, %: NaOH, n/d [126]; KOH, 47 [118]. Base KOH, R, n, (time, h): H, 5-6, (72); Br, 5, (24); Br, 6, (72) [13]; H, 5, (72); Br, 5, (24), Br, 6, (72) [13]; H, 11, (24) [82]; Me, 6-8, (24) [127]; H, 6, (15); Cl, 6, (15); Br, 6, (15); Br, 13, (15) [128]; H, 12, (24); H, 15, (24); Me, 13, (24) [129]
Compounds 136 containing an unsaturated macrocycle were obtained with yields of up to 85% from civetone 135 and isatins 42 [128, 129].
HC(CH2)7 42 COOH C=O HC(CH2)7 135 KOH, H2OEtOH boiling, 24 h R N (CH2)6 (CH2)7 136 CH CH
R: Br [128]; H [129]
The reaction of isatins 7 and 9 with substituted benzannelated ketones 137 led to tetracyclic and pentacyclic (with R3 + R4 = CH2CH2) acids 138 [130-134].
278
R1 N H R2 7, 9
R3 O R4
R1 ( )n NaOH/KOH boiling R2
COOH ( )n N H R6 138 R5 R3 R4
+
O R5 R6 137 O
R3 = H, n = 1, time 12 h, R1, R2, R4, R5, R6: H, H, H, H, H, (yield 85%) [130]: H, H, H, Bu-t, H; H, Br, H, Bu-t, H; H, OMe, H, H, Me; Br, OMe, H, H, Me; H, Pr-i, OMe, Me, H; Me, H, (CH2)4, H [131]; n = 2, R1, R2, R3, R4, R5, R6, (time, h), yield, %: H, H, H, H, Bu-t, H, (12), n/d; H, H, Me, H, OMe, Pr-i, (12), n/d; Me, H, H, H, Bu-t, H, (12) n/d [131]; H, H, H, H, H, H, (100), 65; Br, H, H, H, H, H, (100), n/d; Br, Br, H, H, H, H, (100), n/d [132]; F, H, H, Ph, H, H, (12), 78 [133]; F, H, H, Ph, C6H4F-4, H, (n/d), 68 [134]
Compound 138 with R = F, R3 = Ph, and R1 = R2 = R4 = R5 = H was patented as a product active against leukemia and melanoma [133]. Attempts at the reaction of isatins with menthone, pulegone, camphor [118], isopulegone, dihydroisopulegone, tetrahydrocarvone, or norcamphor [19] were unsuccessful even with prolonged heating (potassium hydroxide, water, ethanol, 100C, 3 days). In [135, 136] the behavior of ketones of the steroid series in the Pfitzinger reaction was also studied. From dehydroepiandrosterone 139 and isatin 7 compound 140 was synthesized with a yield of 20%, and the reaction was accompanied by isomerization of the double bond [135]. The reaction of estrone 141 and isatin 7 leads to the acid 142 [136].
Me 7 + HO Me O KOH, EtOH boiling 24 h 139 Me N 140 Me COOH OH
Me 7 +
O KOH, H2OEtOH boiling 12 h
COOH
OH
HO 141
N 142
Me
Compounds 144 were synthesized from cholestanone 143 and isatins 7 and 42 under the same conditions, but the reaction of the same isatins with testosterone (with R = H in the isatin) or chlolestenone (with R = Me) could not be realized [136].
Me R N H 7, 42 O O Me KOH, H2OEtOH boiling, 12 h O 143 Me Me COOH R N 144 Me Me Me Me Me
Me
R: H [135, 136]; Me (yield 100%) [136]
279
Among the ketones examined in this section it is also possible to include the di- and trihydroxy derivatives of benzene, which are capable under the reaction conditions of forming tautomers containing a keto group. Thus, 3-hydroxy-9-acridinecarboxylic acid 145 was obtained by heating isatin 7 with resorcinol in the presence of alkali in water [137]. Other derivatives of 9-acridinecarboxylic acid 146 were synthesized with yields of 72-92% from phloroglucinol (used in the form of the dihydrate) and isatins 1. The reactions were conducted in the presence of sodium hydroxide [137, 138] or potassium hydroxide [139] in water.
O R 1, 7 N H O O COOH X NaOH / KOH, H2O OH boiling R N OH
+
X
145, 146 145 X = H [137]; 146 X = OH, time 5 h, R = H [137, 139]; 5-F, 6-F, 7-F [138]
Heterocyclic ketones 147 [130, 140], 148 [52], 149 [141, 142], and 150 [143] have also been studied in the Pfitzinger reaction. Their structure, the structure of the obtained products 151-154, and the reaction conditions are given in the schemes (see below). Among the obtained the acids 153 (yields ~70%), which inhibit the ignition of cotton induced by oils, should be mentioned.
_ OH , H2O heat COOH ( )n1 S N 151 147, 151 n = 1, 2, R = H, Me
COOH R1 N H 9 O O R
1
O 7, 42 + S 147 ( )n
+
O
KOH, H2OEtOH S 148 boiling, 12 h R

2
N 152 S
R1, R2: H, H; Me, H; Me, Me; Br, H. Yields 90-100%

O R N H 42 O O R COOH O N 153 KOH, H2OEtOH heat
+
149
R: H, Cl, Br, Me
COOH O N H 7 O
R1 R
2
KOH, H2OEtOH N 150 O 154 boiling, 8 h N N R2 R

1
R1 + R2: (CH2)4, CH=CHCH=CH. Yields up to 78%
280
There are a few examples of the use of cyclic diketones in the Pfitzinger reaction. In all the described cases the products from reaction of only one carbonyl group in these compounds with the isatin were obtained. Thus, the keto acids 156 were formed as a result of the reaction of the salt 54 (previously obtained from the isatin 7) with the diketones 155 [42].
COOH O KOH, H2OEtOH 135-140C, 0.5 h Me N 156 R
COCOOK
+
NH2 54 Me 155 R
R: H, Me
The keto carboxylic acid 158 was obtained from 1,3-indanedione 157 and isatin 7 [130].
COOH O NaOH, H2O heat 157 O N 158
O 7
A compound of the triterpenoid series, ketomethyl glycyrrhetate 159, which contains seven condensed six-membered rings, is formed with a yield of 42% as a result of the condensation of isatin 7 with the diketone 160 [144]. If the reaction is carried out in butanol instead of ethanol, the reaction takes place more quickly, but the yield of compound 159 is lower on account of resinification processes.
Me O 7 + O Me Me Me Me Me 160 H Me KOH, EtOH boiling, 24 h; 20C, 12 h N Me 159 Me Me COOH Me COOMe O Me Me H Me COOMe
The condensation product 162 is formed with yields of 71% or 84% [145] when isatin 7 is heated with the N-derivatives of pyrrolidine-2,3-dione 161.
COOH O 7
KOH, EtOH boiling, 12 h N 162 O N R
N R 161
R (yield, %): C6H11 (71), CH2Ph (84)
281
6. REACTIONS RELATED TO THE PFITZINGER REACTION This section reviews the results of investigations on other methods for the synthesis of 4-quinolinecarboxylic acid derivatives, including various 2-quinolone-4-carboxylic acids. The transformations were mostly based on various substituted hydroxyindoles or isatins. A well-known method for the synthesis of 4-quinolinecarboxylic acid derivatives involves the aldol condensation of isatins with ketones having an activated CH2 group in the presence of bases, followed by recyclization of the condensation products (or some of their subsequent transformations) to the desired compounds. Thus, the ketols 164 are formed with good yields from the ketones 163 and isatin 7 in the presence of ammonia and are transformed into 2-substituted quinolinecarboxylic acids 165 when heated in an acidic medium [23, 76].
O 7+ MeCR 163 OH NH3, H2O, EtOH boiling N H O CH2CR O 164
COOH AcOH, H2SO4, H2O boiling N 165 R = C6H4R1; R1 (time, h): H, 3-NH2 (5), 3-NO2, 4-NO2 (16), 4-Ph (20), 4-C6H4NO2-p (16); R = R1, 2-thienyl, R1 (time, h): H, 2-thienyl (5), 2-thienyl (9), 4-NO2, 5-NO2 (12), 1-adamantyl (3-5). Yields 52-92% R
However, the ketols 166 and 167, which are similar to compounds 164 and are the products from the condensation of isatin 7 with malononitrile or phenylacetic ester respectively, were transformed into 2-quinolone-4-carboxylic acid 168 or its 3-phenyl derivative 169 [146].
OH X N H 166, 167 O boiling N H 168, 169 COOH R O
166 X = CH(CN)2 (10% aq. NaOH), 168 R = H; 167 X = CH(Ph)COOEt (conc. HCl, EtOH), 169 R = Ph
The acid 168 was also obtained by acidification of the diammonium salt 170 (X = NH4) with HCl or by boiling the silver salt 170 (X = Ag) with sulfuric acid [147].
C(COOX)2 N H 170 O 7% aq. H2SO4 boiling 168
X = NH4, Ag
282
Derivatives of compound 168, i.e., the 3-carboxy- and 3-mercapto-substituted compounds 171 [146] and 172 [148] were synthesized from oxindoles with the general formula 173.
COOH X N H 173 O conc. HCl, EtOH NaOH, H2O (172) N H 171, 172 Y O
For X = C(R) CN (R = CONH2, CN), Y = COOH (171); S S , Y = SH (172) For X = NH O
If the substituent at position 3 in the oxindoles 174 or benzoxindole 175 is a CHCOPh group, 2-phenylsubstituted 4-quinolinecarboxylic acids 176 [149] or 4-benzoquinolinecarboxylic acids 177 [150] respectively are formed when they are heated with concentrated hydrochloric acid in alcohol. Compound 174 (R = H) is not transformed into the corresponding acid 176 under the conditions of the Pfitzinger reaction [149].
R R2 N H 174, 175
1
O CHCPh O conc. HCl, EtOH 120C (176), boiling (177) R

2
R1
COOH
N 176, 177
Ph
174, 176 R1 = H, R2 (time, h), yield, %: H (2.0), 72; Me (2.0), 95; Cl (12.5), 65; Br (6.0), 85
When heated in acidic medium the oxindole derivatives 178 (R = H) undergo recyclization to 2-aryl-1,4dihydro-4-quinolinecarboxylic acids 179 or to 2-phenyl-4-quinolinecarboxylic acid (cinchophen) [151].
R=H R O CHCAr 179 N H 178 O R = NHCOPh EtOH, 110-120C, 9 h N Ar: Ph (yield 98%), 6H4R1-4 (R1 = Me, Cl, Br) Ph AcOH, boiling, 1 h N H Ar COOH
COOH
Papers in which the reactions of isatins with various reagents leading mainly to derivatives of 2-quinolone-4-carboxylic acid were studied are discussed below. The condensation of isatins 180 with diketene gave quinolonecarboxylic acids 181 acylated at position 3 [152]. 283
COOH O N 180 R
1
H2C H2C=
C O
NaOH, H2O
COMe N 181 R1 O
R1, R2, yield, %: H, H, 43; H, Me, 47; Me, H, 8
According to existing data, the reaction of isatins with phenylacetic acid under various conditions leads to various products. Thus, the reaction of this acid with isatin 7 in the presence of sodium acetate was first described in 1893 [153], and the product was assigned the formula 182. The reaction of the same reagents with heat in acetic acid led to 2-hydroxy-3-phenyl-4-quinolinecarboxylic acid 183 [154]. In later papers [155-157] substituted quinolonecarboxylic acids 185 were obtained by heating the isatins 1 or 7 with the above-mentioned acid or its derivatives in the presence of sodium acetate.
Ph R = R1 = H, AcONa H2O, 200-220C, 0.5 h N H 182 CCOOH O
COOH O R 1, 7 N H O R
1
R = R1 = H, AcOH 100C, 0.5 h 183 N
Ph OH
PhCHCOOH 184
COOH AcONa 190-200C, 30-60 h R N H 185 O R

1
185, R, R1, yield, %: 5-I, H, n/d [155]; H, OMe, 52 [156]; 5-F, OMe, 49; 5-Cl, OMe, 47; 5-Br, OMe, 35; 5-I, OMe, 26; 6-F, OMe, 58; 6-Cl, OMe, 54; 6-Br, OMe, 81; 6-I, OMe, 81 [157]
In the reaction of the isatins 7 [154, 155], 54 [17, 154, 155], or 186 [155, 158, 159] with malonic acid in the presence of sodium acetate [155, 158] or in acetic acid [17, 154, 155, 159] the reaction products were 2-hydroxy-4-quinolinecarboxylic acids, which usually exist in the form of the 2-quinolone derivatives 187, as a result of decarboxylation of the initially formed dicarboxylic acids. Compound 187 with R = R1 = R2 = H and R3 = Me was patented as a plant growth regulator (Aureorysin) [158].
COOH R R
1 2
O N R
3
R CH2(COOH)2
1 2
R4
N R
3
O
4
7, 54, 186 187 R4 = H, R1, R2, R3, yield, %: I, H, H, 100 [17]; H, H, H, 100; Br, H, H, 100; Br, H, Br, 100; Br, H, Br, 88 [154]; I, H, H (boiling, 5 h), 65 [155]; R1 = R2 = R3 = H, R4 = Me [155]; R4 = CH2CH2CN [159]
284
The recyclization of N-acylisatins is often used for the transformation of isatins into derivatives of 4-quinolinecarboxylic acid. The N-acylisatins are obtained by the treatment of the isatins with carboxylic acid chlorides or anhydrides. Published data on the transformation of acyl derivatives with the general formula 188 into quinolonecarboxylic acids 189 are summarized below [12, 14, 155, 160-168].
R
1
COOH O N R
2
NaOH / KOH boiling
X N H 189 O
COCH2X
188
X, R1, R2, (time): H, H, H, (1-4 h) [160-163]; H, F, H, (1 h); H, OMe, H, (1 h); H, H, OMe, (1 h) [12, 14, 155, 164]; Ph, H, H, (5 min) [155]; CH=CH2, H, H, (30 min) [165-167]; Me, H, H, (1 h) [170]
The described recyclization was used for the synthesis of 2-quinolone-4-carboxylic acid labeled with the C isotope at position 2 or 3 from the products of the acylation of isatin 7 by the acid chlorides CH313COCl or H313CCOCl respectively [168]. A completely different reaction product is formed from the N-chloroacetyl derivative 190 under the conditions described above. When it was boiled in an aqueous solution of sodium hydroxide, 2,4-dihydroxyquinoline 191 was obtained with a yield of 56-70% [169].
13
OH O N 190 O NaOH, H2O boiling, 2 h 191 N OH
COCH2Cl
According to data from other authors [170], the reaction results in the formation of a mixture of 3-hydroxy-2-quinolone (15%) and 4-hydroxy-2-quinolone (15%). The transformation of the N-acylquinolines 192 (the products from the acylation of isatins with methoxyacetic anhydride) into the 3-methoxy-substituted quinolonecarboxylic acid 193 was realized under different conditions; compounds 192 were converted into the salts 194, the cyclization of which by heating with potassium tert-butoxide in DMF led to compounds 193 [171].
_ + CCO K NHCCH2OMe R COOH
t-BuOK, DMF
OO
O N R 192 O
K2CO3, H2O boiling, 1 h
COCH2OMe
194 OMe
100C, 5 h R
N H 193
R, yield (%) 192, 193: H, 77, 75; Cl, 71, 76
285
The synthesis of derivatives of quinoline from isatins and carboxylic acid anhydrides can also be realized without isolating the intermediate N-acyl derivatives. Thus, unsubstituted 2-quinolonecarboxylic acid containing the 14C isotope at position 3 was synthesized by the condensation of isatin 7 with the anhydride (H314CCO)2O [172]. The unsubstituted acid 168 [163] and its 3-aryl derivatives 195 [173, 174] were obtained by heating the isatin 7 directly with the respective anhydrides.
COOH X 7 + (XCH2CO)2O N H 168, 195 X (reaction conditions): H (NaOAc, autoclave, 180-190C, 5-10 h, 210-220C, 1-2 h) [163]; Ph (180-190C, 3 h) [173]; C6H4NO2-4 (180-190C, 5 h in PhNO2) [174] O
Since the Pfitzinger reaction requires a large excess of alkali, aliphatic aldehydes, which readily polymerize under these conditions, cannot be used in the reaction. However, it was possible to overcome these difficulties by using the aldoximes. Thus, Pfitzinger heated the isatin 7 with acetaldehyde oxime in the presence of potassium hydroxide in water and obtained 4-quinolinecarboxylic acid together with the oxime of isatinic acid 196 [175].
COOH 7 COOH C=NOH
MeCH=NOH
40% aq. KOH heat N
+
196
NH2
3-Alkyl-substituted 4-quinolinecarboxylic acids 197 were synthesized by the condensation of isatin 7 with the aldoximes 198 [176].
COOH 7
RCH2CH=NOH 198
50% aq. KOH N 197
R, temperature, C, (time, h), yield, %: C5H11, 105-110, (62), 19; C8H17, 115-120, (24), 28
Ketoximes containing a CH2 group adjacent to the oxime group are also capable of entering into the Pfitzinger reaction. Thus in the reaction of the isatin 7 with the ketoxime 199 3-cyano-2-methylquinoline-4carboxylic acid 200 is formed with a 50% yield [177].
COOH NOH 7 + NCCH2CMe 199 NaOH, H2O heat, 4-5 h N 200 CN Me
286
The condensation of isatin 7 with the oximes of cyclic diketones 201 led to the dicarboxylic acids 202 (yields 22-23%) [178].
HOOC NOH 2 . 7 + (CH2)n NOH 201 201, 202: n = 1, 2 30% aq. KOH 180C, 24 h N 202 N (CH2) n COOH
The isatins 7 and 54 react with the imines 203 in boiling dioxane with the formation of the products from aldol condensation 204, which recyclize when heated in ethylene glycol or glycerol to the amides of 4-quinolinecarboxylic acids 205 [179].
OH dioxane R
1
R4 ethylene glycol/ CHCPh glycerol O NH heat R1 R2 R3
CONH2 R4 N 205 Ph
R R
1 2
O N H O
NH
R4CH2CPh 203
boiling, 0.5-3 h R2 R
3
R 7, 54
N H
204
R1, R2, R3, R4, solvent (temperature, C), yield of product 205, %: H, H, H, Me, ethylene glycol, (197), 82; Cl, H, Cl, Me, glycerol, (290), 65; H, Cl, Me, Me, glycerol, (230), 81; NO2, H, H, Me, glycerol, (245), 95; H, H, H, Et, ethylene glycol, (197), 75
The 2-methoxy-substituted amides 206 were synthesized by the reaction of the imidic esters 207 with isatin 7 [179]. A mechanism for the reaction is proposed in the same paper.
NH 7 CONH2 dioxane boiling, 0.5-3 h N 206 R OMe
RCH2COMe 207
R, yield, %: Me, 58; (CH2)3CN, 44; Ph, 71; 4-NHC6H4CH2COOH, 62; 4-NHC6H4SO3H; 35; Cl, 26; CH2CN, 58; (CH2)2CN, 29
O N H 7 OH RO N H C=O NH O
NH
OH O CH2 C-OR NH CONH2
MeCOR 207a 204 HO
N H
CONH2 H H N OR
H2O
OR
287
In the case of the condensation of the isatins 208 with the imidic esters 209 with a large excess of the latter it was found that the amides 210 are only formed with isatins not having substituents at position 4 (R = H). If R H the process stops at the first stage, and compounds 211 are formed [180, 181].
R1 R R R
2 1 2
CONH2
R1 = H O N H O NH N R
3
OR
MeCOR4 209 R1 = H R
2
210 OH NH CH2COR1 N H O 211
208
R
1 2 3 4
R = H, R = H, Cl, Br, NO2, Me; R = H, Cl, Br; R = Me, Et. Time, min: 5-10 [180]; 30 [181]. Yield of product 209 46-71%
The schemes presented below also illustrate the synthesis of various amides of substituted quinolineand quinolonecarboxylic acids 212-214 by the reaction of isatins 7, 9, 54, and 180 with amides 215 [179], acylated amino acids 216 and isothiocyanates [182], and enamines 217 [183].
CONH2 R4 N NH2
R1 R2 R3 N H
NH
+
O
R4CH
2C
dioxane boiling, 0.5-3 h
R1 R2
NH2 215
R3 212 7, 54 1 2 3 4 R = H, Cl, Br, NO2; R = H, Cl; R = H, Cl, Br, Me; R = H, Me, Ph. Yields 46-94%
CONHR1 O O O pyridine heat, 0.5 h N NHCOAr O
+
N O
ArCNHCH2COH 216
+ R1NCS
213 R R 7, 180 R, R1, Ar, temperature, C: H, Me, Ph, 130-140; H, Ph, Ph, 140-150; Me, Ph, Ph, 140-150; H, Ph, C6H4Me-4, 140-150. Yields 29-49%
CONHR R1 N H R2 9 O O NHR3
3
+ R4C=CHCOOEt
217
HCl, dioxane 20C, 24 h
R1 N R2
COOEt R4
214 R1 = Cl, Br, NO2; R2 = H, Cl, Br; R3 = H, Me; R4 = Me, Ph. Yields 25-85%
288
The action of 50% aqueous potassium hydroxide on equimolar amounts of isatin and nitromethane leads to the formation of the acid 218 and the oxime 219. With a twofold excess of nitromethane only 219 is obtained [184].
COOH 7 NOH
aq. KOH MeNO2 50-55C N 218
NO2
+
219 N H O
The condensation of isatins 7 and 42 with derivatives of oxazolone 220 in the presence of potassium hydroxide in water gave the dicarboxylic acids 221 (yields 55-88%) [185].
R N H 7, 42 R N 221 COOH O R2 H C N 220 COOH R2 O O R1
+
O
KOH, H2O heat, 6 h
R = H, Me, Br; R1 = Me, Ph; R2 = H, Me, OMe
In conclusion it is necessary to mention papers in which the recyclization of isatin derivatives 222 and 223 to 4-cinnolinecarboxylic [186-188] or 4-quinazolinecarboxylic [189] acids 224, 225, and 226 was studied. These transformations are presented in the schemes below.
R1 O NaOH / KOH, H2O N 222 O R2 boiling, 0.5-1 h 224 N CH COOH R1 R2 N N
R1, R2: H, H, (yield 75-80%); Me, H, (5 h, yield 100%) [186]; H, Me; H, OMe; H, F; Me, Cl; OMe, H [187]; H, Cl [188]
COOH O NH3, EtOH, ampule N
2 223 COR
R1
R1 100C, 3 h N 225
N R2
R, R1 (yield, %): H, H, (70); F, H, (80)
289
O O 223 1) NaOH, H2O 2) aq. HCl to pH 1-2 R1 CCOH NHCOR2 NH3, EtOH, ampule R1
_+ COO NH4 N N 226 R2
R, R1 (yield, %): H, H (85); F, Me (70)
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294
TRIMETHYLSILYLCYANATION OF N-[3-(2-FURYL)-2-PROPENYLIDENE]TRIFLUOROMETHYLANILINES
I. Iovel, L. Golomba, S. Belyakov, A. Kemme, J. Popelis, and E. Lukevics The addition of Me3SiCN to N-[3-(2-furyl)-2-propenylidene]trifluoromethylanilines, differing in the position of the CF3 group in the benzene ring and in the presence or absence of a methyl group in the heterocycle, was studied in the presence of aluminum bromide as catalyst. The direction of the process (1,2-addition in all cases) was determined, and certain other features of the reactions were discovered. A series of the corresponding unsaturated heterocyclic -amino nitriles were synthesized. The molecular and crystal structures of one of them were determined by X-ray crystallographic analysis. Keywords: -Amino nitriles, N-[3-(2-furyl)-2-propenylidene]anilines, Lewis acid, trimethylsilyl cyanide, catalysis. Recently we synthesized a series of new N-[3-(2-furyl)-2-propenylidene]trifluoromethylanilines [1-3] by the condensation of furylacroleins with 2-, 3-, and 4-trifluoromethylanilines. In a continuation of the previous investigations [4-6] in the present work we studied the trimethylsilylcyanation of a series of new aldimines by the reaction of trimethylsilyl cyanide with various azomethines. There are no published data on the reaction of trimethylsilyl cyanide with propenylideneamines. During investigation of the hydrosilylation of furylacrolein and its derivatives and analogs containing conjugated O=CC=C bonds it was shown that 1,2- and 1,4-addition products are formed in these processes [7]. On the basis of this it seemed of interest to determine the direction of the processes in the trimethylsilylcyanation of the system of N=CC=C bonds. It was established in [4, 5] that among the employed Lewis acids the most active catalyst of the addition of trimethylsilyl cyanide to various heterocyclic aldimines is aluminum bromide in the presence of 4A molecular sieves. This catalytic system was therefore also used in the present investigation. The reaction of the 2-, 3-, and 4-trifluoromethyl derivatives of N-(3-hetaryl-2-propenylidene)anilines 1a-f (where hetaryl = 2-furyl and 5methyl-2-furyl) with trimethylsilyl cyanide was studied. The reactions were conducted in methylene chloride or acetonitrile at 40 or 65C with the substrate and silyl cyanide in a molar ratio of 1:1.2 and the catalyst at a concentration of 20 mole %. During study of the reaction of the substrates 1a-f with trimethylsilyl cyanide it was found that compounds containing a 4-CF3 group in the benzene ring have the highest reactivity. The methyl group of the furan ring has practically no effect on the rate of the process on account probably of the distance from the reacting bond. During trimethylsilylcyanation of the aldimines 1a-f after hydrolysis and separation of the reaction mixtures by preparative liquid column chromatography the 1,2-addition products, i.e., the respective -amino nitriles of N-(1-cyano-3-hetaryl-2-propenyl)trifluoromethylanilines 3a-f, were obtained in all cases with yields of 57-85% (Scheme 1, Table 1). It should be noted that in contrast to trimethylsilylated azomethines __________________________________________________________________________________________ Latvian Institute of Organic Synthesis, Riga, LV-1006; e-mail: iovel@osi.lv. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 366-373, March, 2004. Original article submitted February 22, 2003. 0009-3122/04/4003-02952004 Plenum Publishing Corporation 295
Scheme 1
CF3 R O C C C N H H H
1af
Me3SiCN AlBr3 + 4A MS CH2Cl2 40C H H R O H CN SiMe3 N or MeCN 65C
4 3
CF3
H2O R
H H O H CN N H
2'
3'
CF3
4' 6' 5'
2af
R = H, Me position of CF3: 2'-, 3'-, 4'-
3af
hydrolysis of the NSi bond in the intermediate products 2a-f takes place under very mild conditions by the action of moist acetone at room temperature. Thus, in the investigated processes the trimethylsilyl cyanide adds selectively at the N=C bond of the initial imines without affecting the C=C double bond. All the obtained compounds were oily or crystalline yellow substances, and their 1H NMR spectra (Table 2) and the elemental analysis of the solid compounds (Table 1) corresponded to the structure of the required products. In the 1H NMR spectra of all the synthesized nitriles 3a-f the spinspin coupling constant of the protons at the HC=CH double bond amounted to 15.4-15.8 Hz, indicating the trans position for the indicated hydrogen atoms. The GLC mass spectra of compounds 3a-f could not be recorded as a result probably of the thermal instability of the synthesized -amino nitriles, as reflected in the loss of gaseous HCN by these molecules and the formation of the corresponding amines under the conditions of analysis. In order to obtain additional information revealing the structure of the substances an investigation by 2D-COSY and 13C NMR methods was undertaken for compound 3b. The results fully supported the proposed structure of the final product (see Scheme 1).
TABLE 1. The Characteristics of the Reactions and the Products

Compound 3a 3b 3c 3d 3e 3f R Position , C/ Time, Empirical of CF3 h (solvent) formula (Mcalc) 23423440/25, 65/6 (MeCN) 40/6 (CH2Cl2) 40/4 (CH2Cl2) 40/15 (CH2Cl2) 65/5 MeCN) 40/3 (CH2Cl2) C15H11N2OF3 (292.26) C15H11N2OF3 (292.26) C15H11N2OF3 (292.26) C16H13N2OF3 (306.29) C16H13N2OF3 (306.29) C16H13N2OF3 (306.29) Found, % Calculated, % C H N 61.70 61.65 61.50 61.65 62.47 62.74 3.89 3.79 3.74 3.79 4.34 4.28 9.05 9.58 9.36 9.58 8.90 9.15 mp, oC Yield, % 71 72 85 57 70 75
H H H Me Me Me
Oily liquid 87-88 136-137 Oily liquid Oily liquid 115-116
296
TABLE 2. The 1H NMR Spectra of the Synthesized Compounds

Compound CH3, s 3a Chemical shift (CDCl3), , ppm, SSCC (J, Hz) CHN, dd H, dd H, dd Ring protons 5.08 (J = 5.4, 7.8) 5.05 (J = 5.4, 8.6) 6.19 (J = 5.4, 15.7) 6.17 (J = 5.4, 15.6) 6.91 (J = 15.7) 6.42 (2H, s, H-3, H-4), 6.9-7.0 (2H, m, H-5, H-6), 7.40 (1H, s, H-5), 7.5-7.6 (2H, m, H-3, H-4) 6.40 (2H, s, H-3, H-4), 6.9-7.0 (2H, m, H-2, H-6), 7.12 (1H, d, J = 8.0, H-5), 7.35 (1H, s, H-5), 7.39 (1H, m, H-2) 6.42 (2H, s, H-3, H-4), 6.81 (2H, d, J = 8.4, H-2, H-6), 7.41 (1H, s, H-5), 7.51 (2H, d, J = 8.4, H-3, H-5) 6.02 (1H, d, J = 3.0, H-4), 6.31 (1H, d, J = 3.0, H-3), 6.9-7.0 (2H, m, H-5, H-6), 7.5-7.6 (2H, m, H-3, H-4) 6.01 (1H, d, J = 3.1, H-4), 6.30 (1H, d, J = 3.1, H-3), 6.9-7.0 (2H, m, H-2, H-6), 7.12 (1H, d, J = 7.4, H-5), 7.35 (1H, m, H-2) 6.01 (1H, d, J = 3.4, H-4), 6.29 (1H, d, J = 3.4, H-3), 6.75 (2H, d, J = 8.4, H-2, H-6), 7.54 (2H, d, J = 8.4, H-3, H-5)
NH, d 4.51 (J = 7.8)
3b
4.53 (J = 8.6)
6.83 (J = 15.6)
3c
4.20 (J = 8.4)
5.09 (J = 5.3, 8.4) 5.06 (J = 5.2, 7.2) 5.05 (J = 4.8, 8.2)
6.20 (J = 5.3, 15.8) 6.12 (J = 5.2, 15.8) 6.10 (J = 4.8, 15.4)
6.86 (J = 15.8)
3d
2.32
4.50 (J = 7.2)
6.80 (J = 15.8)
3e
2.32
4.07 (J = 8.2)
6.77 (J = 15.4)
3f
2.31
4.20 (J = 8.8)
5.04 (J = 5.4, 8.8)
6.09 (J = 5.4, 15.6)
6.80 (J = 15.6)
The 13C NMR spectrum of compound 3b contained the following chemical shifts, , ppm (SSCC, CF, J, Hz): 47.18 , 110.76 (4.0) C(2'), 111.18 and 111.70 (3) and (4), 116.68 (4.0) (4'), 116.95 (1.1) C(5'), 117.04 CN 118.21 C(6), 123.31 C, 123.93 (272.2) CF3, 130.07 C, 131.85 (32.1) C(3'), 143.31 C(5), 144.67 C(1'), 150.35 C(2). The spectrum confirms the presence of the C=C double bond and the presence of the NC substituent at the C atom. In addition, the recorded spectrum agrees with the conclusion reached for the structure of 3b by means of the HOSE (Hierarchical Ordered Spherical Description of Environment) codes [8]. In order to establish the structure of compound 3f conclusively single crystals were prepared, and X-ray crystallographic analysis was performed. A three-dimensional model of the molecule showing the designations of the atoms and the ellipsoids of the thermal vibrations is shown in Fig. 1. Table 3 give the principal bond lengths and bond angles. In the molecule of 3f it is possible to distinguish two approximately planar fragments: The furan ring together with the C(7) and C(8) atoms and the phenyl ring with the N(12), C(9), C(10), and N(11) atoms. The C(7)C(8)C(9)N(12) torsion angle, characterizing the mutual rotation of the planar fragments, is 117.1(8)C. The results of the X-ray investigation indicate the syn-trans configuration for the compound, and this agrees with 1H NMR data concerning the arrangement of the protons at the C=C double bond. In the structure of 3f the fluorine atoms are randomly arranged, like the structures 5b and 5c in [3]. The g values for all six fluorine atoms are 0.5. In the crystal structure there is a forked hydrogen atom of the NHN type with bond lengths 3.207(5) (N(12)H(12)N(11) = 148(4), H(12)N(11) = 2.45(6)) and 3.136(5) (N(12)H(12)N(11) = 121(4), H(12)N(11) = 2.61(6)). These lengths are somewhat longer than the statistical mean value for the length of a hydrogen bond of this type 2.98 [9]. Figure 2 shows a fragment of the molecular packing and indicates the positions of the hydrogen bonds in the crystal. The crystals of compound 3f are centrosymmetric and contain equal amounts of the molecules of the S- and R-enantiomers.
297
Fig. 1. A three-dimensional model of the molecule of N-[1-cyano-3-(5-methyl-2-furyl)-2-propenyl]4-trifluoromethylaniline (3f).
Fig. 2. A fragment of the crystal structure of compound 3f. TABLE 3. The Principal Bond Lengths (d) and Bond Angles () in the Molecules of Compound 3f
Bond 1 O(1)C(5) O(1)C(2) C(18)C(13) C(18)C(17) C(9)N(12) C(9)C(10) d, 2 1.371(5) 1.375(5) 1.403(5) 1.389(6) 1.451(5) 1.489(6) Angle 3 C(5)O(1)C(2) C(13)C(18)C(17) N(12)C(9)C(10) N(12)C(9)C(8) C(10)C(9)C(8) C(9)N(12)C(13) , deg. 4 106.6(4) 120.0(4) 111.5(3) 110.5(3) 111.4(3) 123.6(3) Angle 5 F(3)C(19)F(2') F(3)C(19)F(3') F(1')C(19)F(2') F(1')C(19)F(3') F(2')C(19)F(3') C(19)F(2)F(1') , deg. 6 61.4(14) 50.(2) 100.0(14) 113.(2) 102.(2) 64.0(11)
298
EXPERIMENTAL The 1H and 13C NMR spectra were investigated on a Varian Mercury spectrometer at 200 and 50.3 MHz respectively for solutions in deuterochloroform with TMS as internal standard. The acetonitrile (special purity) was used without further purification, and the methylene chloride was distilled over phosphorus pentoxide. Trimethylsilyl cyanide (Aldrich) was used without further purification. Aluminum bromide (Fluka), 4A molecular sieves (VEB Laborchemie Apolda), and silica gel for column chromatography (Kieselgel 60, 0.063-0.200 mesh, Merck) were used. Analyses by TLC were conducted on Kieselgel 60 F254 (Merck) plates. General Procedure for Trimethylsilylcyanation. A 5-cm3-Pierce reaction tube was blown with argon, and dry solvent (2 ml), the initial amine (0.5 mmol), aluminum bromide (0.1 mmol), and the molecular sieves (0.5 g) were placed in it. Trimethylsilyl cyanide (0.6 mmol) was then added to the mixture with a syringe. The reaction was conducted at 40 or 65C, and samples were taken periodically and analyzed by TLC and GLC-MS. At the end of the reaction (the reaction times are given in Table 1) the mixture was filtered and evaporated at reduced pressure (30C/15 mm Hg), and acetone was added. A white precipitate of compounds containing the Me3Si group separated. The mixture was filtered and evaporated, and ether was added. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by liquid chromatography on a column of silica gel with 9.5:0.2 benzeneethyl acetate as eluent. X-ray Crystallographic Analysis. Single crystals of compound (3f) were grown from a 1:3 mixture of benzene and ethyl acetate. The diffraction pattern was recorded at 20C on an automatic Nonius Kappa CCD diffractometer (MoK radiation) to 2max = 51. The crystals belong to the monoclinic system and have the following parameters: a = 22.4388(8), b = 5.9784(2), c = 22.758(1) ; = 90.745(1); V = 3052.7(2) 3; d = 1.333 g/cm3; Z = 8; F(000) = 1264; = 0.11 mm-1. The structure was interpreted by the direct method and refined by full-matrix least-squares treatment in anisotropic approximation. The hydrogen atoms were found from a difference synthesis and refined anisotropically. Of 3050 symmetrically independent reflections 1536 reflections with I > 3(I) were used in the calculations. The final divergence factor was 0.094. All the calculations were performed using software in [10, 11]. The authors are grateful to the Latvian Science Council for financing the work (grant No. 181).
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. I. Iovel, L. Golomba, J. Popelis, A. Gaukhman, and E. Lukevics, Khim. Geterotsikl. Soedin., 324 (2000). I. Iovel, L. Golomba, S. Belyakov, J. Popelis, A. Gaukhman, and E. Lukevics, Khim. Geterotsikl. Soedin., 361 (2003). I. Iovel, L. Golomba, S. Belyakov, J. Popelis, and E. Lukevics, Khim. Geterotsikl. Soedin., 1642 (2003). I. Iovel, L. Golomba, S. Belyakov, J. Popelis, S. Grinberga, and E. Lukevics, Appl. Organomet. Chem., 14, 721 (2000). I. Iovel, L. Golomba, S. Belyakov, A. Kemme, and E. Lukevics, Appl. Organomet. Chem., 15, 733 (2001). I. Iovel, L. Golomba, J. Popelis, A. Gaukhman, and E. Lukevics, Khim. Geterotsikl. Soedin., 847 (2003). I. Iovel, J. Popelis, A. Gaukhman, and E. Lukevics, J. Organomet. Chem., 559, 123 (1998). W. Bremser, B. Franke, and H. Wagner, Chemical Shift Ranges in Carbon-13 NMR Spectroscopy, Verlag Chemie, Weinheim, Deerfield Beach-Florida, Basel (1982), p. 890. 299
9. 10. 11.
L. N. Kuleshova and P. M. Zorkii, Acta Crystallogr., B37, 1363 (1981). A. Altomare, M. C. Burla, M. Camalli, G. L. Cascarano, C. Giaccovazzo, A. Guagliardi, A. G. G Moliterni, and R. Spagna, J. Appl. Crystallogr., 32, 115 (1999). S. Mackay, C. J. Gilmore, C. Edwards, N. Stewart, and K. Shankland, maXus Computer Program for the Solution and Refinement of Crystal Structures, Bruker Nonius, The Netherlands, MacScience, Japan & The University of Glasgow (1999).
300
INTERACTION OF 5-ARYL-2,3-DIHYDROFURAN-2,3-DIONES WITH FUNCTIONALLY SUBSTITUTED HYDRAZIDES AND DIAMINOGLYOXAL DIPHENYLHYDRAZONE

D. D. Nekrasov1, S. V. Kol'tsova1, and M. A. Radishevskaya2 The reaction of 5-aryl-2,3-dihydrofuran-2,3-diones with cyanoacetylhydrazide, o-(hydrazinocarbonyl)phenylthiourea, and the diphenylhydrazone of diaminoglyoxal leads to the synthesis of the corresponding N-cyanoacetylhydrazides of aroylpyruvic acids, 2-(N-aroylpyruvoylhydrazinocarbonyl)phenylthioureas, and 5,6-bis(phenylhydrazono)-3-aroylmethylenepiperazin-2-ones. The results of the primary investigation of the biological activity of N-cyanoacetylhydrazides of aroylpyruvic acids are given. Keywords: 5-aryl-2,3-dihydrofuran-2,3-diones, aroylpyruvoylhydrazides, 5,6-bis(phenylhydrazono)-3aroylmethylenepiperazin-2-ones, biological activity, decyclization, recyclization. Study of the interaction of 4-substituted and unsubstituted 5-aryl-2,3-dihydrofuran-2,3-diones with hydrazines and their derivatives [1-9] has shown that the direction of the reaction is determined by the presence of methyl, phenyl, and benzoyl substituents in position 4 of the furandione ring and by the structure of the reagent. In addition the ratio of the components and the synthetic conditions influence the course of the process. To investigate the reaction of 4-unsubstituted furandiones with functional derivatives of hydrazine we used cyanoacetylhydrazine, o-(hydrazinocarbonyl)phenylthiourea, and diaminoglyoxal phenylhydrazone. Interest in this reaction is also linked with the biological activity of the products formed [10-14]. As has been established, the reaction of 5-aryl-2,3-dihydrofuran-2,3-diones 1 with cyanoacetic acid hydrazide proceeds in anhydrous dioxane at room temperature. The N-cyanoacetylhydrazides of aroylpyruvic acids 2a-f were formed in high yield in this way, and are the products of fission of the furan ring at the OC(2) bond by the primary amino group of the reactant. A broad intense band is observed in the IR spectra of compounds 2a-f corresponding to the stretching vibrations of the NH bond at 3190-3320 cm-1. Absorption bands caused by the stretching vibrations of the CH= group at 3070-3090, and also by the CN group at 2267-2270 cm-1 were also observed. There were two absorption bands in the 1667-1710 cm-1 region for the amide carbonyls, and at 1580-1620 cm-1 an intense band caused by the absorption of the aromatic ring and of the C=O group involved in an intramolecular hydrogen bond.
__________________________________________________________________________________________ Institute of Technical Chemistry, Urals Branch, Russian Academy of Sciences, Perm 614990, Russia; e-mail: cheminst@mpm.ru. 2 Perm D. N. Pryanishnikov Agricultural Academy, Perm 614990, Russia. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 374-380, March, 2004. Original article submitted October 16, 2001; revision submitted May 19, 2002. 0009-3122/04/4003-03012004 Plenum Publishing Corporation 301
1
O p -RC6H4 O 1af O
H2N
H N O
CN p -RC6H4 O. O H
O N H
H N
C
O
CN
..
2af
CONHNH2 NHCSNH2
O N H
H N
O
. ..
H O C6H4R-p
NHCSNH2 H2N H2N NNHC6H5 NNHC6H5 O p-RC6H4CCH2

O
4ad NH NNHC6H5 NNHC6H5
O H2N
O H2O p-RC6H4 O.
H N N
NNHC6H5 NNHC6H5 5a,b
. .H
1, 2, 4 a R = H, b R = Me, c R = Et, d R = Cl, e R = Br, f R = F; 5 a R = Me, b R = Cl
In the 1H NMR spectra a singlet was present for the protons of the methylene group at 3.77-3.82, a singlet for the methine proton at 6.76-7.10, a multiplet for the aromatic protons with center at 7.53-7.83 ppm, and also a broadened signal for the NH group at 10.48-10.69 ppm. No signal was observed for the proton of the enolic hydroxyl, probably due to broadening by rapid exchange. The spectral characteristics of compounds 2a-f agree well with the literature data for similar compounds [11-14]. The interaction of compound 2d with o-phenylenediamine was carried out to confirm by chemical methods the structure of the compounds formed.
NH2 NH2
H N N H 3
O CHCOC6H4Cl- p
2d
NH2NHCOCH2CN
Heating the reactants in absolute ethanol for 30 min leads to the formation of a bright-yellow product, soluble with difficulty in alcohol, but well soluble in dioxane. Study of the IR and 1H NMR spectra, and also the absence of a depression of melting point when mixed with an authentic specimen of the product, confirmed the formation of 3-p-chlorophenacylidene-3,4-dihydro-2-quinoxalone [15]. It is evident that in the course of the reaction fission of cyanoacetylhydrazine occurs with the formation of quinoxaline 3. On interacting furandiones 1 with 2-(hydrazinocarbonyl)phenylthiourea reaction in several directions is possible: at the thiourea fragment with the formation of a 3-substituted 5-phenacylidene-4-oxoimidazolidine-2thione ring [16] and at the hydrazinocarbonyl fragment with the fission of the furandiones 1 ring [14]. However 302
investigations showed that on reacting compounds 1 with the indicated reactant (dioxane, 100C, 30 min), the sole products were the 1-(N-aroylpyruvoylhydrazino-carbonyl)phenylthioureas 4a-d. The constants, yields, and data of elemental analysis of these compounds are given in Table 1. Absorption bands were detected in the IR spectra of compounds 4a-d for carbonyl groups at 1615-1710, for NH groups at 3150-3340, and for NH2 at 3403-3485 cm-1. The 1H NMR spectra of the indicated compounds contain a singlet for the methine group proton at 7.2 ppm, signals for the aromatic protons at 6.70-7.80, singlets for the NH group protons at 8.46-8.56, 9.40-9.46, 10.66-10.80, and a singlet for the OH group proton at 12.23-12.40 ppm. The molecular ion was absent from the mass spectrum of compound 4a, however the presence of the fragment ions indicated below agree with the proposed structure.
204 196 151 179 176 147 119 105
CONHNHCOCOCH2COC6H5 NHCSNH2
The scheme of forming compounds 4a-d is analogous to the scheme of forming compounds 2a-f and includes nucleophilic attack at the C(2) atom of furandiones 1 by the primary amino group of the hydrazinocarbonyl fragment of the molecule with ring opening of the latter, which leads to products 4a-d. Attempts to cyclize compounds 4a-d involving the residue of thiourea and the hydrazide fragment were unsuccessful.
TABLE 1. Characteristics of the Synthesized Compounds 2a-f, 4a-d, and 5a,b

Compound 2a 2b 2c 2d 2e 2f 4 4b 4c 4d 5a 5b Empirical formula C13H11N3O4 C14H13N3O4 C15H15N3O5 C13H10ClN3O4 C13H10BrN3O4 C13H10FN3O4 C18H16N4O4S C19H18N4O4S C20H20N4O5S C18H15ClN4O4S 25H22N6O2 C24H19ClN6O2 Found, % Calculated, % N (Hal) 3.9 4.0 4.5 4.5 4.6 4.7 3.3 3.3 2.9 2.8 3.8 3.4 4.3 4.2 4.6 4.5 4.8 4.7 3.5 3.6 5.2 5.1 4.4 4.2 15.3 15.4 14.3 14.6 13.1 13.3 13.7 (11.6) 13.7 (11.5) 12.0 (22.5) 11.9 (22.7) 14.3 14.4 14.7 14.6 14.2 14.1 13.0 13.1 13.5 (8.5) 13.4 (8.5) 19.3 19.2 18.4 (7.8) 18.3 (7.7) mp, Yield, %
57.0 57.0 57.9 58.5 56.7 56.8 50.8 50.7 44.2 44.3 53.9 53.6 56.3 56.2 57.3 57.2 56.2 56.0 51.7 51.6 68.5 68.4 62.9 62.8
190-192 203-204 205-206 194-195 208-209 210-212 224-225 225-226 228-230 220-222 166-168 187-189
96 94 97 98 98 98 85 82 80 85 81 80
303
TABLE 2. Spectral Characteristics of Compounds 2a-f, 4a-d, and 5a,b

Compound 2 2b 2c IR spectrum, , cm-1 1590, 1667-1695, 2270, 3080, 3190-3320 1600, 1668-1695, 2270, 3070, 3260-3312 1605, 1680-1710, 2268, 3078, 3270-3310 1590, 1675-1707, 2270, 3090, 3265-3308 1590, 1683-1710, 2270, 3090, 3260-3308 1600, 1670-1700, 2267, 3078, 3270-3305 1615, 1665, 1705, 3200-3340, 3480 1620, 1660, 1700, 3150-3340, 3460 1610, 1670, 1700 (sh), 3200-3310, 3400 1625, 1660, 1700, 3200-3320, 3460 1585-1650, 1690, 3135-3280, 3350-3475 1580-1645, 1690, 3135-3275, 3350-3470
1
NMR spectrum, , ppm
2d 2e 2f 4
4b
4c
4d 5a
5b
3.77 (2H, s, CH2); 6.76 (1H, s, CH); 7.53 (5H, m, C6H5); 10.48 (2H, br. s, 2NH) 2.04 (3H, s, CH3); 3.78 (2H, s, CH2); 7.02 (1H, s, CH); 7.60 (4H, m, 6H4); 10.62 (2H, br. s, 2NH) 1.30 (3H, t, CH3CH2O); 3.78 (2H, s, CH2); 4.17 (2H, q, CH3CH2O); 7.05 (1H, s, CH); 7.60 (4H, m, C6H4); 10.55 (2H, br. s, 2NH) 3.82 (2H, s, CH2); 6.97 (1H, s, CH); 7.66 (4H, m, C6H4); 10.59 (2H, br. s, 2NH) 3.80 (2H, s, CH2); 7.10 (1H, s, CH); 7.83 (4H, m, C6H4); 10.69 (2H, br. s, 2NH) 3.78 (2H, s, CH2); 7.07 (1H, s, CH); 7.65 (4H, m, C6H4); 10.54 (2H, br. s, 2NH) 7.20 (1H, s, CH); 7.40-8.13 (11H, m, C6H4, C6H5, NH2); 8.56 (1H, d, NH); 9.46 (1H, s, NH); 10.70 (1H, s, NH); 12.40 (1H, s, OH) 2.33 (3H, s, CH3); 7.20 (1H, s, CH); 7.26-8.16 (10H, m, 2C6H4, NH2); 8.56 (1H, m, NH); 9.46 (1H, s, NH); 10.70 (1H, s, NH); 12.40 (1H, s, OH) 1.23 (3H, s, CH3CH2O); 4.03 (2H, q, CH3CH2O); 6.83-8.06 (11H, m, 2C6H4, CH, NH2); 8.46 (1H, m, NH); 9.4 (1H, s, NH); 10.8 (1H, s, NH); 12.23 (1H, s, OH) 7.05-8.26 (11H, m, 2C6H4, CH, NH2); 8.46 (1H, m, NH); 9.46 (1H, s, NH); 10.66 (1H, s, NH); 12.33 (1H, s, OH) 2.36 (3H, s, CH3); 6.11 (1H, s, NH); 6.67-8.06 (15H, m, 2C6H5, C6H4, CH); 8.36 (1H, s, NH); 8.73 (1H, s, NH) 6.10 (1H, s, NH); 6.70-8.00 (15H, m, 2C6H5, C6H4, CH); 8.40 (1H, s, NH); 8.70 (1H, s, NH)
5,6-Bis(phenylhydrazono)-3-aroylmethylenepiperazin-2-ones 5a,b were formed on heating equimolar quantities of furandiones 1 and diaminoglyoxal diphenylhydrazone for 1 h in anhydrous toluene (Table 2). Absorption bands were present in the IR spectra of these compounds for the C=O group in position 2 of the piperazine ring at 1690-1693 cm-1. The broad unresolved band at 1585-1650 cm-1 is caused by the overlap of absorptions of the C=C bonds of the phenyl rings and the C=O of the aroylmethylene substituent linked as a sixmembered H-chelate ring. Bands for the stretching vibrations of the NH bonds are in the ranges 3135-3280 and 3350-3475 cm-1. The 1H NMR spectrum of compound 5a contains a singlet for the three protons of the methyl group of the tolylmethylene substituent at 2.36, and signals for the NH group protons at 6.11, 8.36, and 8.73 ppm. The signals for the protons of the aromatic rings and the CH group overlap one another and are found in the range 6.67-8.06 ppm. The signal for the NH group proton of the H-chelate ring was not detected, probably due to broadening as a result of rapid exchange. The 1H NMR spectrum of compound 5b has a similar picture. The data given are in good agreement with the spectral data of structurally close piperazinones [17]. The scheme of forming compounds 5a,b, as in the case of aromatic and heterocyclic 1,2-diamines [18-21], includes attack of the C(2) atom of furandiones 1 by a primary amino group of diaminoglyoxal diphenylhydrazone with opening of the furan ring and subsequent cyclization of the intermediate product in the second stage as a result of attack by the primary amino group of the C(2) atom on the acid residue. The possibility of diaminoglyoxal diphenylhydrazone participating in the reaction as a 1,3-diamine does not take place. Analogous processes were observed in the reaction of furandiones 1 with thiocarbohydrazide in [22]. On heating furandiones 1 with 1,2-bis(1-cyanocyclohexyl)hydrazine, 4-hydroxy-2H-pyran-2-ones 6 [23] and the initial hydrazine were isolated from the reaction mixture. 304
CN 1
N H
H N CN CO p -RH4C6
H..
O C6H4R- p
O 6
The low reactivity of the hydrazine used is probably linked, on the one hand, with steric difficulties connected with the cyclohexyl rings, and on the other, with the electron-withdrawing influence of the cyano groups. While continuing the study of the anti-inflammatory, analgesic, and antiviral activity of acylpyruvic acid hydrazides with various substituents in the acyl portion of the molecule and at the nitrogen atoms [11-14], we have investigated compounds 2a-f on these forms of activity. Assessment of primary activity was carried out according to standard procedures of carrageenan inflammation [24], the hot plate test [25], and protection from viral infection [26]. It was established that hydrazides 2 possessed a marked anti-inflammatory action with inhibition of exudates in the range 42.0-62.1%. Compound 2c displays an effect analogous to orthofen, and compound 2b surpasses the standard in activity by almost 7%. The remaining compounds of this series were surpassed somewhat by orthofen in anti-inflammatory activity. The analgesic effect of compounds 2a, 2b, and 2f were practically the same (22.2-24.2 sec), which indicates the lack of influence of the substituents in the aryl ring on the action displayed. Amidopyrine surpassed the investigated compounds 2 in the strength of effect displayed. Antiviral testing of hydrazide 2a showed that this compound suppresses the reproduction of type A group influenza virus in developing chicken embryos, however in experiments on mice the compound is inactive in relation to this type of virus. The investigated hydrazide 2a is exceeded in activity by the medicinal preparations rimantadine and adapromine, which makes the search for compounds with antiviral activity of little promise in this series.
EXPERIMENTAL The IR spectra of compounds 2-5 were taken on a UR-20 instrument in nujol mulls. The 1H NMR spectra were recorded on a PC-60 spectrometer (60 MHz) in DMSO-d6 solution. HMDS was used as internal standard ( 0.05 ppm). The mass spectra were obtained on a MX-1310 instrument, ionizing voltage was 50 V. The homogeneity of compounds was confirmed on Silufol-254 plates in the system benzeneether, 1:1, visualizing with iodine. The characteristics of compounds 2-5 are given in Tables 1 and 2. N-Cyanoacetylhydrazides of Aroylpyruvic Acids (2a-f). Cyanoacetylhydrazine (10 mmol) was added to a solution of the appropriate furandione 1 (10 mmol) in dioxane (20 ml), and the mixture stirred at room temperature for 30 min. The solid was filtered off and recrystallized from acetonitrile. 2-(N-Aroylpyruvoylhydrazinocarbonyl)phenylthioureas (4a-d). Furandione 1 (5 mmol) and the o-hydrazinocarbonylphenylthiourea (5 mmol) were dissolved in dioxane (15 ml), and the mixture was boiled for 30 min. The precipitated solid was filtered off, and recrystallized from DMF. 5,6-Bis(phenylhydrazono)-3-aroylmethylenepiperazin-2-ones (5a,b). A mixture of furandione 1 (5 mmol) and diaminoglyoxal diphenylhydrazone (5 mmol) in anhydrous toluene (20 ml) was heated for 1 h. The solution was cooled, the precipitated solid was filtered off, and recrystallized from toluene. The work was carried out with the support of the Russian Fund for Fundamental Investigations (Project No. 02-03-96411).
305
REFERENCES 1. 2. 3. 4. 5. Yu. S. Andreichikov and D. D. Nekrasov, Zh. Org. Khim., 21, 684 (1985). A. N. Maslivets, O. P. Tarasova, I. S. Berdinskii, and Yu. S. Andreichikov, Zh. Org. Khim., 28, 1039 (1989). Y. Akcamur, G. Penn, E. Ziegler, H. Sterk, G. Kollenz, K. Peters, E.-M. Peters, and H. G. Schnering, Monatsh. Chem., 117, 231 (1986). S. N. Shurov, L. N. Karpova, E. Yu. Posyagina, Yu. V. Ionov, T. N. Somova, N. G. Shilova, and Yu. S. Andreichikov, Zh. Org. Khim., 35, 1232 (1999). N. N. Trapeznikova, V. O. Koz'minykh, E. S. Berezina, and E. N. Koz'minikh, Strategy and Tactics of Organic Synthesis. Abstracts of the 3rd All-Russian Symposium on Organic Chemistry, Yaroslavl (2001), p. 104. A. N. Maslivets, N. Yu. Lisovenko, E. S. Vostrov, and O. P. Tarasova, Strategy and Tactics of Organic Synthesis. Abstracts of the 3rd All-Russian Symposium on Organic Chemistry, Yaroslavl (2001), p. 17. O. P. Tarasova and A. N. Maslivets, Prospects for Developing Natural Sciences in Colleges. Proceedings of the International Scientific Conference, Perm (2001), Vol. 1, p. 126. T. M. Shironina, E. N. Koz'minykh, N. M. Igidov, and V. O. Koz'minykh, Prospects for Developing Natural Sciences in Colleges. Proceedings of the International Scientific Conference, Perm (2001), Vol. 1, p. 145. V. O. Koz'minykh, A. O. Belyaeva, and E. N. Koz'minykh, Khim. Geterotsikl. Soedin., 1263 (2003). D. D. Nekrasov, Khim. Geterotsikl. Soedin., 291 (2001). V. O. Koz'minykh, N. M. Igidov, V. I. Il'enko, A. V. Milyutin, V. E. Kolla, Z. N. Semenova, and Yu. S. Andreichikov, Khim.-farm. Zh., No. 7-8, 28 (1992). V. O. Koz'minykh, N. V. Safonova, A. V. Milyutin, V. G. Armaginova, V. E. Kolla, S. A. Shelenkova, I. V. Yakovlev, G. N. Novoselova, Yu. S. Andreichikov, and V. I. Il'enko, Khim.-farm. Zh., No. 3, 42 (1994). N. M. Igidov, E. N. Kozminykh, A. V. Milyutin, E. S. Berezina, G. A. Shavkunova, I. B. Yakovlev, S. A. Shelenkova, V. E. Kolla, E. V. Voronina, and V. O. Koz'minykh, Khim.-farm. Zh., No. 11, 21 (1996). A. V. Milyutin, N. V. Safonova, V. P. Chesnokov, F. Ya. Nazmetdinov, E. V. Voronina, I. V. Krylova, Yu. S. Andreichikov, V. E. Kolla, and Yu. V. Kozhevnikov, Khim.-farm. Zh., No. 5, 26 (1996). Yu. S. Andreichikov, Yu. A. Nalimova, S. P. Tendryakova, and G. D. Plakhina, USSR Inventor's Certificate 482453; Byull. Izobret., No. 25 (1975). Yu. S. Andreichikov, D. D. Nekrasov, M. A. Rudenko, and Yu. A. Nalimova, Khim. Geterotsikl. Soedin., 1411 (1988). D. D. Nekrasov, S. V. Kol'tsova, and Yu. S. Andreichikov, Zh. Org. Khim., 31, 591 (1995). I. V. Krylova, D. D. Nekrasov, and Yu. S. Andreichikov, Khim. Geterotsikl. Soedin., 1457 (1988). D. D. Nekrasov, S. N. Shurov, O. I. Ivanenko, and Yu. S. Andreichikov, Zh. Org. Khim., 30, 126 (1994). O. A. Sof'ina, N. M. Igidov, E. N. Koz'minykh, N. N. Trapeznikova, Yu. S. Kasatkina, and V. O. Koz'minykh, Zh. Org. Khim., 37, 1067 (2001). Yu. S. Andreichikov, D. D. Nekrasov, S. G. Pitirimova, A. S. Zaks, M. I. Korsheninnikova, A. N. Plaksina, Z. N. Semenova, and V. A. Kopeikin, Khim.-farm. Zh., 946 (1989). Yu. S. Andreichikov, S. V. Kol'tsova, I. A. Zhikina, and D. D. Nekrasov, Zh. Org. Khim., 35, 1567 (1999). Yu. S. Andreichikov, Yu. A. Nalimova, A. P. Kozlov, and I. A. Rusakov, Zh. Org. Khim., 14, 2436 (1978).
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13.
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Methodological Recommendations in the Experimental Study of Nonsteroidal Anti-inflammatory Agents [in Russian], Farmkomitet, Moscow (1982). N. B. Eddi and D. Leimbakh, Farmakol. Toksikol., 311 (1960). V. I. Il'enko, Methods of Testing and Assessment of the Antiviral Activity of Chemical Compounds Against Influenza Virus [in Russian], All-Union Research Institute (VNII) for Influenza, Leningrad (1977), 35 pp.
307
SYNTHESIS OF SOME HALOGENAND NITRO-SUBSTITUTED NICOTINIC ACIDS AND THEIR FRAGMENTATION UNDER ELECTRON IMPACT
L. V. Dyadyuchenko1, V. D. Strelkov1, S. N. Mikhailichenko1, and V. N. Zaplishny2 Features of electrophilic and nucleophilic substitution under chlorination and nitration reactions conditions have been investigated for 6-hydroxy- and 6-methyl-substituted derivatives of 3-cyano-4methyl-2(1H)-pyridones. The polychloro- and nitro-substituted 3-cyano-4-methylpyridines obtained were used as synthons in the synthesis of some polyhalo- and nitro-substituted nicotinic acids and their amides. The fragmentation pathways of the synthesized compounds under electron impact have been studied. Keywords: halo and nitro derivatives, nicotinic acids, fragmentation under electron impact. Substituted nicotinic acids and their functional derivatives attract the attention of investigators as potential physiologically active substances belonging to a group in which compounds are known possessing a broad spectrum of pharmacological [1-3], and also pesticidal [4, 5] activity. However there is no information in the literature on nicotinic acids containing 3-4 identical or different substituents in the pyridine ring. In the present work the synthesis is described of new polysubstituted derivatives of nicotinic acid starting from 3-cyano-4-methyl-2(1H)-pyridones 1a,b, containing methyl or hydroxyl groups in position 6 of the ring, by the conversions given in the scheme. Electrophilic substitution of the hydrogen atom in position 5 of the ring of compounds 1a,b and also nucleophilic substitution of the 2-OH group and the 6-OH of the enolic form of pyridones 1 by a chlorine atom and a nitro group depends on the substituent in position 6, and also on the type of chlorinating or nitrating agent. Thus 6-methylpyridine 1a on chlorination with an excess of SO2Cl2 in CCl4 forms the product of electrophilic substitution, the 5-chloro derivative 2a, in 94% yield. Nitration with nitric acid also proceeds selectively at the same position, leading to the 5-nitro derivative 2b. Treatment with an excess of POCl3 at ~105C leads to substitution of the 2-OH group of the enolic form of pyridone 1a by an atom of chlorine, with aromatization of the ring and the formation of 2-chloro-3-cyano-4,6-dimethylpyridine (3a). The 5chloro and 5-nitro derivatives 2a,b react analogously with POCl3 and lead to the 2,5-dichloro- and 2-chloro-5nitro-substituted products 3c,d respectively (in the case of nitro compound 2b chlorination was conducted at 180C). 2,6-Dichloro-3-cyanopyridine 3b is formed from 3-cyano-6-hydroxy-4-methyl-2(1H)-pyridone (1b) with POCl3 (1b : POCl3, 1:2) after 6 h at 120C.
__________________________________________________________________________________________ All-Russian Research Institute for Biological Plant Protection, Krasnodar 350039, Russia. 2 Kuban State Agricultural University, Krasnodar 350044, Russia; e-mail: vlad_zpl@mail.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 381-388, March, 2004. Original article submitted March 23, 2001; revision submitted January 10, 2002. 308 0009-3122/04/4003-03082004 Plenum Publishing Corporation
1
Me Cl O N H 5b CN Cl O Cl
Me CN N H 5a O (1b) (1a) CN Me Cl HO N H 4 CN O (3b) Me R1 R2 N 7af COOH Cl R1 R2 (1b) R N H 1a,b O R1 Me
Me CN N H 2a,b O
Cl O
Me
Me (1a) R1 R2 CN N Cl 3ae Me CONH2 N 6ae Cl
1 R = CH3, b R = OH; 2 a R1 = Cl, b R1 = NO2; 3, 6, 7 a R1 = H, R2 = Me; b R1 = H, R2 = Cl; c R1 = Cl, R2 = CH3; d R1 = NO2, R2 = Me; e R1 = Cl, R2 = Cl; f R1 = NO2, R2 = Cl
The behavior of pyridone 1b, in position 6 of which an OH group possessing a +M effect is found in place of a methyl group possessing a marked +I effect, differs markedly in the reactions described above. Its chlorination with sulfuryl chloride or the direct action of chlorine does not lead to the desired 5-chloro-6hydroxypyridone 4, but is completed by the formation of a mixture of isomeric dichlorides 5a and 5b (varying the reaction conditions affects only the ratio of isomers), which is in agreement with the data of [6]. Reduction of this mixture with zinc dust in a protic solvent proceeds smoothly with the formation only of 5-chloro-3-cyano-6hydroxy-4-methyl-2(1H)-pyridone (4). On treating the latter with an excess of POCl3 the trichloro-substituted pyridine derivative 3e is formed. Attempts to nitrate pyridone 1b, in spite of a wide variation of the conditions (HNO3 of various concentrations, mixtures of it with AcOH, Ac2O, and H2SO4, and also HNO2 and isoamyl nitrate [7]), were unsuccessful. Even at reduced temperature (-91C) the reaction was accompanied by resinification, destruction of the 2-pyridone ring, and the formation of a complex mixture of colored resinous products, which it was not possible to identify. Acid hydrolysis of halogen-substituted cyanopyridines 3a-e with aqueous 80% sulfuric acid solution leads smoothly and in maximum yield to the corresponding amides of nicotinic acid 6a-e. Subsequent diazotization of these difficultly hydrolyzable amides 6a-e with nitrous acid by the known method of Bouveault [8] led to the target substituted acids 7a-e. The halonitro-substituted acid 7f was successfully obtained only by the nitration of nitrile 3b with a mixture of conc. HNO3 and H2SO4 at ~100C. It transpired that hydrolysis of the cyano group to carboxyl occurs simultaneously with the introduction of the nitro group. All the synthesized compounds were amorphous or white finely crystalline powders. The aromatic nitriles 3a-e (mp 67-110C) were readily soluble in the usual organic solvents. Amides 6a-e and acids 7a-e were high-melting substances, soluble with difficulty or not at all in the usual organic solvents, soluble in some highly polar solvents, except for of DMF and DMSO. The characteristics of the synthesized compounds are given in Tables 1 and 2. 309
TABLE 1. Characteristics of Compounds 2a,b, 3a-e, 6a-e

Compound 2a Empirical formula C8H7ClN2O Found, % Calculated, % H Cl 3.69 3.87 3.72 3.66 4.32 4.24 2.04 2.16 3.18 3.01 2.77 2.86 mp, C* N 260-261 Mass spectrum, m/z (Irel) [M]+ 182 (100); 154 (39); 119 (29); 92 (8) [M]+ 193 (68); 176 (100); 148 (21); 119 (53); 92 (28) [M]+ 166 (100); 130 (21); 131 104 (13); 132 77 (7) [M]+ 186 (60); 151 (100); 125 (41); 105 (32) [M]+ 200 (100); 164 (15); 129 (21); 102 (11) [M]+ 21 (59); 194 (100); 165 (32); 139 (69); 130 (45); 102 (23) [M]+ 184 (89); 168 (100); 140 (33); 104 (13); 78 (30) [M]+ 184 (89); 140 (33); 104 (13); 78 (30) [M]+ 204 (74); 188 (100); 160 (23); 124 (24); 99 (14) [M]+ 218 (86); 202 (100); 183 (12); 174 (38); 147 (26); 133 (9) [M]+ 229 (29); 213 (21); 196 (16); 168 (24); 140 (100) [M]+ 238 (41); 222 (100); 194 (14); 187 (18); 159 (28); 133 (9) Yield, % 94
C 52.84 52.61 50.01 49.74 57.94 57.66 44.78 44.95 47.68 47.96
19.53 15.40 19.41 15.34 21.94 21.76 21.58 17.01 21.28 16.82 37.72 14.75 37.91 14.98 35.44 13.60 35.26 13.96 16.61 19.50 16.75 19.86
2b
C8H7N3O3
265-266
54
3a
C8H7ClN2
95-96
95
3b
C7H4Cl2N2
107-108
98
3c
C8H6Cl2N2
67-68
76
3d
C8H6ClN3O2 45.12 45.40
90-91
61
3e
C7H3Cl3N2
38.14 37.96 51.95 52.04
1.24 1.37 5.04 4.92 2.84 2.96 3.64 3.69
47.94 12.49 48.02 12.65 19.28 15.01 19.20 15.18 34.65 13.49 34.58 13.66 32.51 12.87 32.36 12.79
110-111
69
6a
C8H9ClN2O
154-155
89
6b
C7H6Cl2N2O 40.79 41.00 C8H8Cl2N2O 43.61 43.86
170-171
93
6c
146-147
91
6d
C8H8ClN3O3 42.00 41.84 C7H5Cl3N2O 35.31 35.10
3.46 3.52 2.13 2.11
15.68 18.26 15.44 18.30 44.67 11.73 44.41 11.70
188-189
47
6e
167-168
69
_______ * Solvents for crystallization: acetone (compound 2a), EtOH (compounds 2b, 6a-e), cyclohexane (compounds 3a,b,d), hexane (compound 3c). The dissociation constants pKa of the substituted nicotinic acids 7a-f were within the range 2.55-2.79 (Table 2), which enables them to be assigned to the strong acids, exceeding the strength of nicotinic acid by two orders of magnitude. There were broadened absorption bands in the IR spectra of the synthesized acids for the carboxyl OH group at 3200-3600 with maxima at 3430-3448 cm-1 (see Table 2). Medium and strong sharp absorption bands for the C=C and C=N bonds of the conjugated pyridine ring were found at 1539-1603 cm-1. At 1715-1734 cm-1 there was an absorption band for the C=O group, which is characteristic of strong acids existing as dimers [9]. In the spectra of the acids containing a nitro group there were also intense bands at 1540-1545 and 1339-1348 cm-1 which may be interpreted as being characteristic for NO2. It is not expedient to give and discuss the 1H NMR spectra of the synthesized compounds because they were not very informative. 310
TABLE 2. Characteristics of the Synthesized Compounds 7a-f

Compound 7a 7b 7c 7d 7e 7f Empirical formula C8H8ClNO2 C7H5Cl2NO2 C8H7Cl2NO2 C8H7ClN2O4 C7H4Cl3NO2 C7H4Cl2N2O4 Found, % Calculated, % H Cl 4.50 4.34 2.31 2.45 2.43 2.31 3.21 3.06 1.52 1.68 1.52 1.61 19.2 19.1 34.3 34.4 32.4 32.5 15.3 15.4 44.3 44.2 28.2 28.3 mp, C* N 7.42 7.54 6.83 6.79 6.35 6.42 12.28 2.15 5.73 5.82 11.25 11.16 139-140 119-120 159-160 170-171 150-151 168-169 2.79 2.64 2.72 2.57 2.64 2.55 60 88 96 76 75 60 pKa Yield, %
C 51.55 51.77 40.66 40.81 47.21 47.07 41.79 41.67 34.78 34.95 33.35 33.49
_______ * Solvents for crystallization: EtOAc (compounds 7a,b,e) and EtOH (compounds 7c,d,f). Study of the behavior of the synthesized acids under the action of electron impact showed that their molecular ions [M]+ were characterized by enhanced stability and relative intensity (54-100%), while the directions of their primary fragmentation were fairly diverse. It is known [10] that as a result of the primary fragmentation of M+ of nicotinic acid under electron impact there is loss of COOH, hydroxyl, or a H2O molecule. This turned out to be characteristic also for the substituted nicotinic acids 7a-e, in the mass spectra of which peaks for [M-H2O]+ ions were detected with a relative intensity (Irel) of 10-46%. Elimination of the COOH group and the formation of highly stable [M-COOH]+ ions also takes place (Irel 18-100%). In addition ejection of a molecule of CO2 was observed in the mass spectra of acids 7a-e, as indicated by the presence of peaks for [MCO2]+ ions (Irel 21-31%). We note that the 5-nitro-substituted acid 7f loses an NO2 group in the initial stage of decomposition and elimination of CO2 is a characteristic only for the secondary processes of fragmentation. The formation of [M-HCl]+ fragments (Irel 20-100%) is characteristic of the primary fragmentation processes of the molecular ions of all the halogen-substituted nicotinic acids with the exception of compounds 7d,f containing a 5-nitro group. The latter probably split off a chlorine atom in the later stages of fragmentation. In the fragment ions from electron impact of the majority of the 2-chloronicotinic acids being discussed, it is probable that migration of the hydroxyl group occurs to the position where the positive charge is localized, i.e. to carbon atom 2, which corresponds to the fragmentation pathway of o-nitrobenzoic acids [11], with subsequent elimination of CO.
Me C N + O OH Me N Me C OH O+ CO N OH Me +
OH Me
CO Me N H
311
TABLE 3. Spectral Characteristics of Compounds 7a-f

Compound Mass spectrum: molecular and characteristic ions, m/z (Irel, % of maximal) [M]+ 185 (93); [MOH]+ 168 (20); [MH2O]+ 167 (10); [MHCl]+ 149 (100); [168-CO]+ 140 (12); [149CH3, CH2]+ 120 (25); [149CO]+ 105 (17) [M]+ 205(100); [MOH]+ 188 (68); [MH2O]+ 187 (44); [MHCl]+ 168 (41); [MCO2]+ 161 (31); [MCOOH]+ 160 (19); [169CO]+ 141 (33) [M]+ 219 (100); [MHOH]+ 201 (32); [MHCl]+ 183 (75); [MCOOH]+ 174 (18); [183Cl]+ 148 (81); [183COOH]+ 138 (15); [148CO]+ 120 (22) [M]+ 230(64); [MOH]+ 213 (52); [MOH,H2O]+ 195 (11); [MNO2]+ 184 (13); [213Cl,CN]+ 142 (27); [184CO2]+ 140 (33); [140Cl]+ 105 (44) [M]+ 239 (100); [MOH]+ 222 (28); [MH2]+ 221 (35); [MHl]+ 203 (20); [MCO2]+ 192 (10); [MCOOH]+ 194 (12); [203Cl]+ 168 (55); [203COOH]+ 158 (16); [168CO2]+ 124 (19) [M]+ 250 (54); [MOH]+ 233 (49); [MOH,H2O]+ 205 (100); [MNO2,Cl]+ 169 (45); [MCO2,NO2]+ 160 (68); [169CO]+ 141 (28); [169Cl]+ 134 (28); [141OH]+ 124 (28) IR spectrum, max, cm-1 3600, 3300 (3443) 3600, 3000 (3430) 3600, 3300 (3431) 3600, 3200 (3430) 3600 2200 (3448) = 1725 =, =N 1603 NO2 Yield, %
60
7b
1717
1570 1539
88
7c
1734
1576
96
7d
1726
1589
1540 1348
76
7e
1718
1545
75
7f
3600 3200 (3430)
1715
1576
1545 1389
60
In the later stages of fragmentation, elimination of a hydroxyl group or one further CO fragment is possible with the formation of more stable five-membered heterocyclic ions with a relative intensity of 17-33%. The features of the electrophilic and nucleophilic substitution in 6-oxo- and 6-methyl-substituted 3-cyano-4-methyl-2(1H)-pyridones have been studied. Accessible routes have been developed for the synthesis of polysubstituted nicotinic acids, which are potentially biologically active substances.
EXPERIMENTAL The IR spectra were recorded on a Bruker IFS-45 spectrometer with an analyzing Aspekt-1000 computer for compounds in KBr disks. The mass spectra were recorded on an LKB-2091 chromato-mass spectrometer with direct insertion of samples into the ion source (energy of ionizing electrons 70 eV). The elemental analysis of the synthesized compounds was carried out on a Carlo Erba model 1106 analyzer. The dissociation constants of acids 7a-f were determined on a type I130.2M.1 ionomer. The homogeneity of the synthesized compounds was confirmed by TLC on Silufol UV-vis plates, solvent was hexaneacetone, 1:1, visualizing with iodine vapor. The solvents used were purified and dried by known methods [14]. The initial 3-cyano-4,6-dimethyl-2(1H)-pyridone 1a and 3-cyano-6-hydroxy-4-methyl-2(1H)-pyridone 1b were obtained and purified as described previously in [12, 13]. The synthesis of mixtures of isomeric nitriles 5a and 5b and their reduction to 5-chloro-3-cyano-6-hydroxy-4-methyl-2(1H)-pyridone 4 was carried out analogously to [6]. Their physicochemical characteristics are given in the cited work. 312
5-Chloro-3-cyano-4,6-dimethyl-2(1H)-pyridone (2a). A mixture of cyanopyridone 1a (5 g, 33.7 mmol) and sulfuryl chloride (18.25 g, 135.2 mmol) in dry CCl4 (50 ml) was boiled under reflux for 6 h. After cooling, the precipitated solid was filtered off, washed with CCl4, and dried. Product 2a (5.8 g) was obtained as a white, finely crystalline powder. 3-Cyano-4,6-dimethyl-5-nitro-2(1H)-pyridone (2b). A solution of HNO3 (d = 1.51 g/cm3, 2.1 ml) in Ac2O (1.8 ml) was added slowly with stirring to a suspension of cyanopyridone 1a (3.48 g, 18 mmol) in Ac2O (12 ml) at 01C. The reaction mixture was maintained at 5C for 0.5 h, then at 20C for 0.5 h, and poured onto ice. The precipitated solid was filtered off, washed with ice water (3 50 ml), and dried in vacuum. Product 2b (2.5 g) was obtained as a white powder. 2-Chloro-4,6-dimethylnicotinic Acid Nitrile (3a). A mixture of cyanopyridone 1a (5.0 g, 33.7 mmol) and POCl3 (5.17 g, 33.7 mmol) was heated in a sealed ampule at 120C for 5.5-6.0 h. The ampule was opened and the contents were poured onto crushed ice (30 g). The resulting solid was filtered off, washed with ice water (3 50 ml), and dried under reduced pressure. Nitrile 3a (5.35 g) was obtained as a white, finely crystalline powder. Nitriles 3b-e were obtained analogously from compounds 1b, 2a,b, and 4 respectively. 2,6-Dichloro-4-methylnicotinic Acid Amide (6b). A mixture of nitrile 3b (1 g, 5.35 mmol) and 80% H2SO4 (15 ml) was stirred at 982C for 6 h. The cooled reaction mixture was poured onto crushed ice (30 g), and aqueous ammonia solution added to pH ~5. The resulting solid was filtered off, washed thoroughly with water, and dried in a vacuum desiccator. Amide 6b (1 g) was obtained as a white, finely crystalline powder. Amides 6a,c-e were obtained analogously, but at a hydrolysis time of 10 h. 2,6-Dichloro-4-methylnicotinic Acid (7b). A mixture of amide 6b (5 g, 24 mmol) and conc. H2SO4 (d = 1.84 g/cm3, 21.4 ml) was heated slowly until complete solution of the amide. A solution of NaNO2 (3.9 g, 56.5 mmol) in water (20 ml) was slowly added dropwise to the cooled solution at ~0C. The reaction mixture was kept for 40-60 min at 20-25C, then poured onto crushed ice (50 g). The solid which separated was filtered off, and purified by reprecipitation from 10% NaOH solution by acidifying with 10% HCl solution. The solid was washed with water, dried at 20C, and the crystallohydrate of 7b (4.8 g) was obtained; mp 108-110C. After additional drying in vacuum at 80C for 1.5 h, the anhydrous 7b acid (4.4 g) was obtained as a white powder. Substituted nicotinic acids 7a,c-d were obtained analogously from amides 6a,c-d respectively. 2,6-Dichloro-4-methyl-5-nitronicotinic Acid (7f). A solution of nitrile 3b (1 g, 5.35 mmol) in a mixture of HNO3 (d = 1.51 g/cm3, 7 ml) and H2SO4 (d = 1.84 g/cm3, 7 ml) was heated at ~100C for 10 h. The mixture was cooled to 0C and added dropwise to ice (30 g) powdered and cooled to -40C. The precipitated solid was filtered off, washed with water, reprecipitated from saturated NaHCO3 solution, washed with water to pH 7, and dried. Acid 7f (0.81 g, 60%) was obtained as a white, finely crystalline powder.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. A. I. Mikhalev, V. K. Kudryashova, and M. E. Konshin, Khim.-farm. Zh., No. 5, 7 (1973). Australian Patent 4593111975; Ref. Zh. Khim., 12 O92P (1980). V. P. Chesnokov, M. E. Konshin, V. S. Zalesov, and V. K. Kudryashova, Khim.-farm. Zh., No. 11, 7 (1973). A. D. Gutman, US Patent 4251263; Ref. Zh. Khim., 17 O339P (1973). A. D. Gutman, US Patent 4327218; Ref. Zh. Khim., 4 O431P (1983). L.V. Dyadyuchenko, V. D. Strelkov, and V. N. Zaplishnii, Khim. Geterotsikl. Soedin., 1641 (1999). I. Guben, in: Methods of Organic Chemistry [in Russian], Vol. IV, Goskhimizdat, Moscow (1949), Book 1, p. 251. K. V. Vatsuro and G. L. Mishchenko, in: Named Reactions in Organic Chemistry [in Russian], Khimiya, Moscow (1976), p. 84. 313
9. 10. 11. 12. 13. 14.
K. Nakanishi, in: Infrared Spectra and Structure of Organic Compounds [Russian translation], Mir, Moscow (1965), p. 53. O. N. Porter, Mass-spectrometry of Heterocyclic Compounds, New York (1984). B. P. Terentiev, in: Mass-spectrometry in Organic Chemistry [in Russian], Vyssh. shkola, Moscow (1979), p. 120. H. Jahine, H. A. Zaher, F. A. Sayed, and M. Sayed, J. Prakt. Chem., 316 (1974). R. C. Elderfield (editor), Heterocyclic Compounds, Vol. 1, Wiley, New York (1950). A. Weissberger, E. Proskauer, J. A. Riddick, and E. E. Toops, Organic Solvents [Russian translation], Izd. Inostr. Lit., Moscow (1958).
314
REGIOISOMERIC ACETOXY DERIVATIVES OF 8-AZA-D-HOMOGONA-12,17a-DIONE. ANNELATION OF 1-METHYL-3,4-DIHYDROISOQUINOLINE WITH 4-ACETOXY2-ACETYLCYCLOHEXANE-1,3-DIONE

O. V. Gulyakevich, V. G. Zaitsev, and A. L. Mikhal'chuk Annelation ([2+4] cyclocondensation) of 1-methyl-3,4-dihydroisoquinoline with 4-acetoxy-2-acetylcyclohexane-1,2-dione leads to a mixture of regioisomeric acetoxy derivatives of 9-methyl-8-aza-Dhomogona-12,17a-dione. Keywords: 8-aza-D-homogonanes, 8-azasteroids, 2-acylcyclohexane-1,3-diones, isoquinolines, cyclic Schiff's bases, annelation, regioselectivity, stereochemistry. 3,4-dihydro-
Annelation reactions of cyclic Schiff's bases with -di- and ,'-tricarbonyl compounds or their enolic derivatives is an exceptionally simple and effective approach to the construction of an ABCD tetracyclic system of steroid heteroanalogs [1-4]. The interest in compounds of such a series is caused by the appearance of biological activity [5, 6] and the prospect linked with this of developing new pharmacological agents from them for medical and veterinary use [7]. It was shown previously that cyclocondensation of 3,4-dihydroisoquinolines with 4-substituted 2-acetyldimedones and 2-acetylcyclohexane-1,3-diones is effected regio- and stereoselectively leading to the 9,17-trans-diastereomer of 8-aza-D-homogonanes [3, 8-11]. In the case of 2-acetyl-4-hydroxycyclohexane-1,3dione mixtures are formed of the regioisomeric 15- and 17-hydroxy derivatives of 8-aza-D-homogonanes [12], but with 1-alkyl-substituted 3,4-dihydroisoquinolines 15-hydroxy derivatives are formed exclusively. This indicates a reverse of the regiochemistry of this reaction. The reasons for such a change on going from 4-substituted derivatives of 2-acyldimedones [3, 8, 9] to a 4-substituted derivatives of 2-acetylcyclohexane-1,3dione [10-12] are still not completely clear. At the same time the special features of the annelation of cyclic Schiff's bases with ,'-tricarbonyl compounds is of both practical and theoretical interest, raising the possibility of directing their regio- and stereochemical results and of obtaining new derivatives of 8-azasteroids of the required structure for physicochemical and medico-biological investigations. In view of what has been stated it seemed important to clarify how the presence of a methyl group at the azomethine carbon atom of 3,4-dihydroisoquinoline 1 influences its annelation by 4-acetoxy-2-acetylcyclohexane-1,3-dione (2).
__________________________________________________________________________________________ Institute of Bioorganic Chemistry, National Academy of Sciences, Belarus, Minsk 220141; e-mail: mikhalch@imaph.bas-net.by. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 389-394, March, 2004. Original article submitted January 19, 2001. 0009-3122/04/4003-03152004 Plenum Publishing Corporation 315
O N 1 O O OAc
17 D 9 C N H A B H H H H H H
O OAc
+
O 2 O O
+
H Ha
He
15 He OAc He Ha
The condensations of isoquinoline 1 with triketone 2 were effected by boiling equimolar mixtures of them in alcohols or by keeping the mixtures indicated at room temperature in accordance with known conditions [8, 9]. It was shown in this way that in all the cases studied a mixture was formed of the 17- and 15-acetoxy derivatives of 8-aza-D-homogonanes 3 and 4 respectively in approximately the same ratio. As noted previously [2, 8, 13], the first event of the interaction of the 3,4-dihydroisoquinolines displayed basic properties with the ,'-triketones displayed acidic properties is salt formation, which enables reactions to proceed as a result of coulombic interactions of the ionized reactants. It is evident that in this case dilution of the reaction medium must affect the reaction rate to a lesser extent than in the case of the interaction of nonionized reactants. Nonetheless a significant reduction of reaction rate on dilution was established for the interactions of azomethine 1 with ,'-triketone 2. Thus, for completion of the reaction at a ratio (1 + 2) : solvent equal to ~1:50, ~5 h is required, at a component ratio ~1:100 the reaction time amounted to ~25 h, and at a ratio ~1:200 the reaction was not complete after 72 h boiling. Such a dependence of reaction rate on the extent of dilution might be caused, in particular, by conformational and/or tautomeric conversions of the interacting compounds, when not every collision of molecules leads to the formation of products. Heating in the studied experiments therefore shows up insignificantly on the reaction rate if the ratio indicated above is 1:50. According to the data obtained the acetoxy derivatives 3 and 4 were isolated as the 9,17- and 9,15-transdiastereoisomers, which may point in favor of the stereospecificity of the studied reaction. However, since products 3 and 4 were isolated chromatographically in an overall yield of ~57%, and the minor cis-diastereoisomers may have been lost in the process of isolation, it is only possible to speak with confidence about the stereoselectivity of the process. The composition and structure assigned to acetoxy derivatives 3 and 4 are in agreement with the results of elemental analysis and spectral data. In the mass spectra of acetoxy derivatives 3 and 4 signals were present corresponding to the molecular ions and accompanying them were signals of the [M+1]+ ion-radical, characteristic of nitrogen-containing heterocycles, and also a [M-15]+ peak corresponding to the product of ion fragmentation with fission of a methyl group. The fragmentation pathways of the molecular ions of compounds 3 and 4 are therefore different. For the first the most intense (40%) were the ion-radicals with masses 264, 253, 238, 210, and 144, and for the second the ion-radicals with masses 324, 280, 264, 236, and 115. Absorption bands (AB) were present in the IR spectra of acetates 3 and 4 at ~1750 and ~1240 cm-1 caused by the vibrations of C=O and COC bonds and confirmed the presence of ester groupings in the structures of these compounds [9]. Intense asymmetric AB were located at 1680-1710 cm-1 linked with the
316
presence of carbonyl groups at positions 12 and 17a [9], and an AB of medium intensity (35-40%) at ~1630 cm-1 was assigned to the vibrations of the C(13)=C(14) bond. Differentiation of the spectral contours in the 1670-1715 cm-1 region showed that the AB located in this region of the spectrum are composite and are caused by contributions of 4-6 components of different intensity. The two most intense are probably linked with the symmetric and antisymmetric stretching vibrations of the C=O groups, and the components of low intensity with the deformation vibrations of the same groups. However a strict assignment of these AB is still difficult. In the IR spectra AB of medium intensity were also present at 740-790 cm-1 characteristic of the vibrations of CN bonds. Combination of the data considered therefore confirms the presence in the molecules of derivatives 3 and 4 both of acetoxy groups and of the N(8)C(14)=C(13)( C(12)=O)C(17a)=O fragments. As with the 8-azasteroids described previously, which contain aminovinyldicarbonyl fragments [3, 6, 8, 9], in the electronic absorption spectra of derivatives 3 and 4 two intense (log >4) asymmetric AB were present caused by * electronic transitions. Differentiation of the spectral contours showed that the long wave AB (300-320 nm) have a composite character and are caused by contributions of several components with maxima at 291.8 and 308.8 nm in the case of compound 3 and 291.2, 310, and 324.7 nm in the case of compound 4. At the same time the short wave AB (260-270 nm) retained their shape after differential treatment procedure enabled their more precise positions to be established as 264.7 for acetate 3 and 262.7 for acetate 4. The significant difference of the 15-acetoxy derivative 4 from its 17-substituted isomer 3 is the presence in the electronic absorption spectrum of a weak long wave AB at ~380 nm and a yellow-green luminescence of solutions in alcohol. These properties of derivative 4 may be caused by contaminants formed for example as a result of its decomposition to phenol 5.
H O O
N 5
However proof of such a hypothesis has still not been successfully obtained, since acetates 3 and 4 do not survive the conditions of chromato-mass spectrometry, and methods of TLC and NMR are insufficiently sensitive. The differences in the position of the long wave AB of compounds 3 and 4 are extremely eloquent and of principal importance for structural assignments. The indicated AB is located at ~312 nm for the 15-acetoxy derivative 4 and at ~305 nm for the 17-acetoxy derivative 3. An analogous difference in the position of the long wave AB is also observed in the case of the corresponding 15- and 17-hydroxy derivatives [12]. The 1H NMR method turned out to be most informative when studying the structure of compounds 3 and 4, and enabled convincing stereostructural assignments to be carried out on the basis of the observed spectral differences (IR, UV, 1H NMR, and mass spectrum). In the 1H NMR spectra of both compounds there were signals for the protons of the isoquinoline (AB) and quinolone (CD) fragments confirming their common nature with the previously described derivatives of the 8-aza-D-homogona-12,17a-dione series [3, 9]. A characteristic of the spectra of derivatives 3 and 4 is the presence of three-proton singlets for the resonance of the 9-Me group and the 15- and 17-acetoxy substituents. An important difference in the spectra of compounds 3 and 4 is the size of the chemical shift and form of the signal of the methine proton found in the same position as the acetoxy group. In the case of acetate 3 the 15H signal is found at 5.20 ppm and is a doublet of doublets with coupling constants J1 = 5.0 and J2 = 13.0 Hz, indicating its quasiaxial disposition. The 17-H signal of acetate 4 is however found at 6.01 ppm and has the form of a triplet with coupling constant J1,2 = 3.0 Hz, indicating its quasiequatorial situation. 317
The difference in chemical shifts of the 7-He protons of compounds 3 and 4 of 0.33 ppm is also important. It is linked with the differences in the stereoelectronic environment of the protons mentioned. In the spectrum of acetate 3 the chemical shift of the 7-He proton corresponds to the chemical shift of analogous protons of 15-unsubstituted 8-azasteroids ( 4.05-4.30 ppm [3, 9]). In the spectrum of acetate 4 the signal of the analogous proton is displaced towards high field by 0.33 ppm, which may be explained by the anisotropic influence of the quasiaxial 15-acetoxy group. The data of NOE for compound 4 showed the presence of long range spin-spin interactions of the C(7)H2 group protons with the 15-He proton both in direct and in reverse experiments. In the case of compound 3 long range spin-spin interactions were observed for the protons of the C(7)H2 and C(15)H2 groups. The long range spinspin interactions for other groups of protons are shown in the Scheme. EXPERIMENTAL The 3,4-dihydroisoquinoline 1 used in the investigation was obtained by the cyclodehydration of homoveratrylacetamide with phosphorus oxychloride according to BischlerNapieralski [14], and the ,'-triketone 2 by the known procedure of [15]. A check on the progress of reactions and the homogeneity of products was effected by TLC on silica gel F60 254 plates (Merck), eluent was chloroformmethanol, 9.5:0.5, visualizing in UV light or iodine vapor with subsequent calcining at 250-350C. Melting points were determined on a Boetius heating block. The IR spectra were obtained on a UR-20 instrument for KBr disks. The UV spectra were taken on a Specord M-400 spectrophotometer for solutions in ethanol. The mass spectra were obtained on a Shimadzu MS QP-5000 mass spectrometer (direct insertion of samples, energy of ionizing electrons 70 eV). The 1 H NMR spectra were recorded on a Bruker AC-200 (200 MHz) radiospectrometer, solvent was CDCl3, internal standard TMS, precision of measurement was 0.5 Hz. rac-17-Acetoxy-9-methyl-8-aza-D-homogona-1,3,5(10),13-tetraene-12,17a-dione (3) and rac-15Acetoxy-9-methyl-8-aza-D-homogona-1,3,5(10),13-tetraene-12,17a-dione (4). A mixture of isoquinoline 1 (131 mg, 1 mmol) and ,'-triketone 2 (191 mg, 1 mmol) in ethanol (4 ml) was boiled for 5 h in an atmosphere of argon, following the progress of the reaction by TLC. The reaction mixture was then evaporated, the dry residue washed with ether, dissolved in chloroform, and subjected to flash chromatography on silica gel 5/40 (Chemapol) (8 g), eluting with chloroformmethanol, 9.5:0.5. According to chromato-mass spectrometry the first eluates contained a mixture of low molecular byproducts (up to 180 mass units), among which 2,6-dihydroxyacetophenone was present (2-acetylresorcinol, [M]+ 152.15). From the second portion of eluate, after evaporation and crystallization of the obtained residue from alcoholether, the 15-acetoxy derivative 4 (77 mg, 25%) was obtained (Rf 0.3) as yellow prismatic crystals; mp 235-242C (decomp.). IR spectrum, , cm-1: 2850-3020, 1751, 1680-1710, 1630, 1518-1542, 1500, 1459, 1385, 1360, 1340, 1212-1244, 1146, 1045, 740780. UV spectrum, max, nm (): 261.6 (13275), 311.6 (14390), 377.3 (1035); min nm (): 230.4 (3760), 280.4 (5560), 359.3 (955). 1H NMR spectrum, , ppm (J, Hz): 1.60 (3H, s, 9-CH3); 2.20 (3H, s, 15-COCH3); 2.04-2.30 (2H, m, 16,16-H2); 2.30-2.64 (2H, m, 17,17-H2); 2.68 (1H, d, J = 16.0, 11-HB); 2.80 (1H, d, J = 16.0, 11-HA); 2.91 (1H, tt, J = 3.0, J = 3.0, J = 15.0, 6-He); 3.13 (1H, dtd, J = 3.0, J = 13.0, J = 15.0, 6-Ha); 3.32 (1H, ddd, J = 3.0, J = 13.0, J = 13.0, 7-Ha); 3.94 (1H, tt, J = 3.0, J = 3.0, J = 13.0, 7-He); 6.01 (1H, t, J = 3.0, J = 3.0, 15-He); 7.09-7.36 (4H, m, 1-, 2-, 3-, 4-H). Mass spectrum, m/z (Irel, %): 340.35 (5.60) [M+1]+; 339.35 (23.65) [M]+; 325.30 (11.04); 324.30 (46.47); 296.30 (13.72); 282.30 (9.67); 281.30 (20.01); 280.30 (83.25); 279.25 (9.63 ); 278.30 (6.88); 269.25 (8.82); 268.25 (6.00); 266.25 (15.58); 265.25 (20.05); 264.25 (91.89); 262.25 (6.88); 254.25 (35.45); 252.25 (11.54); 249.20 (8.71); 238.25 (7.27); 237.25 (11.46); 236.25 (58.54); 208.25 (16.76); 196.20 (9.42); 194.25 (6.71); 182.20 (7.61); 180.20 (10.26); 168.15 (8.70); 167.15 (10.56); 152.10 (6.40); 146.15 (8.60); 145.15 (8.19); 144.15 (20.18); 143.15 (16.42); 142.15 (6.63); 141.10 (7.21); 132.25 (9.40); 131.20 (10.97); 130.10 (12.81); 129.15 (17.32); 128.10 (33.31); 127.10 (12.87); 118 (7.11); 117.15 (14.00); 116.15 (12.00); 115.10 (40.24); 110.45 (6.18); 108.70 (8.41); 105.05 (10.00); 104.05 (7.88); 103.10 318
(18.18); 102.10 (12.97); 95.60 (6.43); 90.80 (31.05); 89.10 (9.94); 85 (7.17); 83 (10.32); 79.05 (12.16); 78.05 (10.09); 77.05 (33.83); 76.05 (7.36); 67.05 (7.37); 66.05 (8.55); 65.05 (27.38); 64.05 (7.79); 63.05 (14.72); 60 (18.39); 55.05 (24.00); 53.05 (20.10); 52.05 (9.65); 51.05 (17.58); 45.10 (25.50); 44.10 (16.83); 43.10 (100); 42.10 (13.77); 41.10 (21.17); 39.10 (32.06); 36.05 (7.77). Found, %: C 70.83, 70.72; H 6.22, 6.28; N 4.05, 4.11. C20H21NO4. Calculated, %: C 70.78; H 6.24; N 4.13. M 339.39. The 17-acetoxy derivative 3 (99 mg, 32%) was isolated from the third portion of eluate in the form of pale-yellow needles (Rf = 0.19); mp 213-216C (decomp.). IR spectrum, , cm-1: 2830-3000, 1753, 1680-1715, 1630, 1530, 1504, 1447-1470, 1420, 1386, 1222-1262, 1141, 1053, 789, 778. UV spectrum, max, nm (): 265 (15190); 304.6 (16065); min, nm (): 229.3 (995); 280 (8250). 1H NMR spectrum, , ppm (J, Hz): 1.60 (3H, s, 9CH3); 1.94-2.40 (3H, m, 16-H2, 15-H); 2.18 (3H, s, 17-COCH3); 2.62-2.95 (1H, m, 15-H); 2.64 (1H, d, J = 16.0, 11-HB); 2.77 (1H, d, J = 16.0, 11-HA); 2.95 (1H, tt, J = 3.5, J = 3.5, J = 15.0, 6-He); 3.13 (1H, dtd, J = 3.5, J = 13.0, J = 15.0, 6-Ha); 3.42 (1H, ddd, J = 3.5, J = 13.0, J = 13.0, 7-Ha); 4.27 (1H, tt, J = 3.5, J = 3.5, J = 13.0, 7He); 5.20 (1H, dd, J = 5.0, J = 13.0, 17-Ha); 7.08-7.36 (4H, m, 1-, 2-, 3-, 4-H). Mass spectrum, m/z (Irel, %): 340.35 (6.72) [M+1]+; 339.35 (24.31) [M]+; 324.30 (14.15); 296.30 (10.20); 280.30 (12.08); 266.20 (9.31); 265.30 (13.25); 264.25 (68.19); 254.20 (9.04); 253.20 (47.31); 252.25 (8.42); 239.20 (9.45); 238.20 (75.77); 236.25 (8.33); 225.20 (12.60); 224.25 (9.80); 211.25 (9.77); 210.25 (60.40); 208.25 (6.42); 197.25 (22.51); 196.25 (15.33); 182.20 (27.41); 180.20 (6.81); 170.20 (11.19); 168.15 (6.59); 167.15 (9.42); 146.15 (7.74); 145.15 (7.64); 144.15 (47.29); 143.15 (13.12); 141.10 (6.77); 131.15 (6.94); 130.10 (15.15); 129.15 (16.61); 128.10 (28.99); 127.10 (10.11); 117.15 (10.05); 116.15 (8.22); 115.10 (28.89); 103.10 (13.80); 102.15 (6.09); 91.05 (16.87); 79.05 (7.70); 78.10 (6.24); 77.05 (20.48); 67.05 (10.19); 66.05 (6.90); 65.05 (15.95); 63.05 (8.34); 60.00 (12.12); 55.05 (14.14); 54.10 (6.83); 53.05 (27.71); 52.05 (6.98); 51.05 (12.25); 45.10 (16.70); 44.10 (21.38); 43.10 (100); 42.15 (12.57); 41.10 (19.96); 39.10 (20.00). Found, %: C 70.69, 70.81; H 6.20, 6.24; N 4.11, 4.07. C20H21NO4. Calculated, %: C 70.78; H 6.24; N 4.14. M 339.39. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. A. A. Akhrem and Yu. A. Titov, Total Steroid Synthesis, Plenum Press, New York, London (1970), p. 362. M. von Strandtmann, M. Cohen, and J. Shavel jr, J. Org. Chem., 33, 797 (1966). O. V. Gulyakevich, A. L. Mikhal'chuk, A. I. Verenich, D. B. Rubinov, A. A. Zenyuk, and A. A. Akhrem, Enamines in Organic Synthesis [in Russian], UrO RAN, Ekaterinburg (1996), p. 111. F. A. Lakhvich, L. G. Lis, and A. A. Akhrem, Usp. Khim., 53, 1014 (1984). A. A. Akhrem, B. B. Kuz'mitskii, F. A. Lakhvich, V. A. Khripach, and Yu. L. Zhuravkov, Chemistry and Biology of Immunoregulators [in Russian], Zinatne, Riga (1985), p. 265. N. A. Konoplya, O. V. Gulyakevich, A. L. Mikhal'chuk, and B. B. Kuz'mitskii, Vestsi Akad. Navuk Belarus., Ser. Khim. Navuk, No. 3, 91 (1994). B. B. Kuz'mitskii, Ya. E. Kenisberg, B. Ya. Birman, V. P. Golubnichii, and O. V. Gulyakevich, USSR Inventor's Certificate 1225083 (1984); Byull. Izobret., No. 39-40, 194 (1993). A. L. Mikhal'chuk, O. V. Gulyakevich, A. A. Zenyuk, A. V. Korchik, L. G. Lis, L. I. Ukhova, and V. A. Khripach, Dokl. Akad. Nauk, 317, 1397 (1991). A. L. Mikhal'chuk, O. V. Gulyakevich, D. B. Rubinov, and A. A. Akhrem, Khim. Geterotsikl. Soedin., 374 (1993). O. V. Gulyakevich, V. G. Zaitsev, and A. L. Mikhal'chuk, Zh. Obshch. Khim., 69, 1041 (1999). O. V. Gulyakevich, V. G. Zaitsev, and A. L. Mikhal'chuk, Khim. Geterotsikl. Soedin., 1092 (2000). O. V. Gulyakevich, V. G. Zaitsev, and A. L. Mikhal'chuk, Zh. Obshch. Khim., 70, 1581 (2000). A. L. Mikhal'chuk, O. V. Gulyakevich, Yu. V. Shklyaev, V. S. Shklyaev, and A. A. Akhrem, Khim. Geterotsikl. Soedin., 681 (1998). W. M. Whaley and T. R. Govindachari, Organic Reactions, Vol. 6, Wiley, New York (1951), p.151. V. G. Zaitsev, G. I. Polozov, and F. A. Lakhvich, Tetrahedron, 50, 6377 (1994). 319
THE KOSTSAGITULLIN REARRANGEMENT IN A SERIES OF 1-ALKYL-2-(CARBAMOYLMETHYL)4,6-DIMETHYLPYRIMIDINIUM IODIDES

G. G. Danagulyan and L. G. Sahakyan The rearrangement of 1-alkyl-2-(carbamoylmethyl)pyrimidinium iodides into substituted 2-alkylaminonicotinamides occurring in alcoholic solutions of amines has been studied. It was shown that in the presence of water the rearrangement of 2-(carbamoylmethyl)-1,4,6-trimethylpyrimidinium iodide is accompanied by the formation of a derivative of 2-oxo-1,2-dihydronicotinic acid, and under the action of ethylamine a "rearrangement and transamination" occurs leading to 2-ethylamino-4,6dimethylnicotinamide. Keywords: 2-alkylaminonicotinamide, alkylamines, nucleophiles, pyrimidinium salt, KostSagitullin rearrangement. We recently reported the rearrangement of 2-(carbamoylmethyl)-4,6-dimethylpyrimidinium iodomethylate into 4,6-dimethyl-2-methylaminonicotinamide [1]. The present communication continues this investigation and is also devoted to a study of the KostSagitullin rearrangement in a series of 1-alkyl-2(carbamoylmethyl)-4,6-dimethylpyrimidinium iodides, i.e. pyrimidinium salts containing an acetic acid amide (or alkylamide) in position 2 of the heterocycle. In a previously published series of studies on the recyclization of pyrimidinium salts into derivatives of 2-alkylaminopyridine [2-6] the influence was investigated of individual amine reactants and also certain substituents in the pyrimidine ring on the possibility and direction of conversion. In the present communication the effect has been studied of the amide group in the side chain of the heterocycle on the course of the transformation. The models for the rearrangement, salts 3a-e, were synthesized by the reaction of 2-(ethoxycarbonylmethyl)-4,6-dimethylpyrimidine with ammonia or alkylamines and subsequent quaternization of the obtained 2-(carbamoylmethyl)-4,6-dimethylpyrimidines 2 with alkyl iodides.
Me N Me N 1 COOEt RNH2 Me N 2 Me N CONHR Me R1I
Me
N 3ae
+ R1 _ I N CONHR
a R = H, R1= Me; b R = H, R1 = Et; c R = Me, R1 = Me; d R = Me, R1 = Et; e R = Et, R1 = Me
__________________________________________________________________________________________ Institute of Organic Chemistry, National Academy of Sciences of the Armenian Republic, Erevan 375094; e-mail: gdanag@email.com. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 395-400, March, 2004. Original article submitted August 28, 2001. 320 0009-3122/04/4003-03202004 Plenum Publishing Corporation
On heating iodides 3b-e in a sealed glass ampule with alcoholic solutions of alkylamines the products of rearrangement, 2-alkylaminonicotinamide 4, and of dealkylation, pyrimidines 2, were isolated though in all conversions the main reaction product was the corresponding nicotinamide 4.
Me
3be
R1NH
CONHR
Me
N
4be
NHR
It is proposed that the rearrangement, beginning with attack of the amine at position 6 of the pyrimidine ring of iodide 3 (route A in the scheme), leads to fission of the C(6)N(1) bond of the ring and subsequent recyclization of the acyclic intermediate with the formation of a new CC bond. It should be noted that the rearrangement may also be represented by attack at position 2 of the heterocycle, which however requires separate discussion. The alternative direction of attack of the nucleophile at the alkyl group located at the quaternized nitrogen atom (route B) leads to the dealkylation product 2, although in this case it is impossible to exclude other schemes of carrying out the reaction.
A R1NH2 Me + N N 3 B Me N Me N 2 X Me N H X = CONHR NHR
1
B R1 _ I X
R1NH2 A HI Me
Me
NHR 1 R1 N N X Me
Me
NR 1 NHR1 N H X H
Me
Me
NR
Me X R1NH2 Me N 4 NHR
1
In the reaction of iodide 3a, containing a methyl group at the quaternized nitrogen atom, with an alcoholic solution of ethylamine a "rearrangement with transamination" might be expected, similar to the conversion described by us previously in a series of iodoalkylates of 4,6-dimethylpyrimidinylacetic acid ester [5, 6]. In reality it turned out that here also the main reaction product was the substance obtained by including a fragment of the amine reactant (ethylamine) into the final structure, namely 2-ethylamino-4,6dimethylnicotinamide (4b), although the recyclization is accompanied partially by the formation of the products of the normal rearrangement 4a and demethylation (pyrimidine 2). In the presence of water the rearrangement of the same iodide 3a with methylamine led to 4,6-dimethyl2-oxo-1,2-dihydronicotinamide (5) in 83% yield and partially to pyridine 4a. We note that the formation of a pyridone derivative (analogous in structure to compound 5) was observed previously by us on rearranging 2-(ethoxycarbonylmethyl)-1,4,6-trimethylpyrimidinium iodide in aqueous alcoholic solutions of amines [7], which indicates the regularity of such conversions and their general character. In the IR spectrum of compound 321
Me EtNH2 Me 3a MeNH2 EtOH / H2O Me N H 5 (83%) CONH2 N NHEt 4b (55%) Me CONH2 O
Me
Me CONH2
+
Me N
+
N
N CONH2
NHMe Me
4a (7%)
2a (7%)
4a (10%)
5 absorption was noted at 3580 cm-1 corresponding to an intramolecular hydrogen bond. This possibly explains the fact of the appearance in the 1H NMR spectrum of the amide group protons as two separate (in different regions of the spectrum) broadened signals.
TABLE 1. Characteristics of 1-Alkyl-2-(carbamoylmethyl)-4,6-dimethylpyrimidinium Iodides 3b-e*

Compound 3b Empirical formula C8H11N3OC2H5I Found, % Calculated, % 37.11 37.40 4.72 5.02
1
mp,
NMR spectrum (DMSO-d6), , ppm (J, Hz)
Yield, % 40
172-173
3c
C9H13N3OCH3I
37.14 37.40
4.73 5.02
158-160
3d
C9H13N3OC2H5I
39.56 39.42
5.16 5.41
3e
C10H15N3OCH3I
39.22 39.42
5.12 5.41
161-162
1.55 (3, t, J = 8.2, 23); 2.73 (3, s, 4(6)-3); 2.97 (3, s, 6(4)-3); 4,31 (2, s, 2NH2); 4.63 (2, q, J = 8.2, 23); 7.3 (1, br. s, NH); 7.8 (1, br. s, NH); 8.15 (1, s, 5-) 2.67 (3H, s, 4-CH3); 2.85 (3H, s, 6-CH3); 2.90 (3H, d, J = 4.8, NHCH3); 4.05 (3H, s, 1-CH3); 4.3 (2H, s, CH2); 7.35 (1H, br. s, NH); 8.01 (1H, s, 5-H) 1.53 (3H, t, J = 7.1, 1-CH2CH3); 2.7 (3H, s, 4-CH3); 2.85 (3H, s, 6-CH3); 2.95 (3H, d, J = 4.8, NHCH3); 4.35 (2H, q, J = 7.1, 1-CH2CH3); 4.41 (2H, s, CH2); 7.81 (1H, br. s, NHCH3); 8.09 (1H, s, 5-H) 1.17 (3H, t, J = 7.1, CH2CH3); 2.75 (3H, s, 4-CH3); 2.9 (3H, s, 6-CH3); 3.19 (3H, d, J = 7.1, CH2CH3); 4.13 (3H, s, N-CH3); 4.35 (2H, s, CH2); 8.07 (1H, s, 5-H); 8.33 (1H, br. s, NH)
83
70
74
_______ * The data on iodide 3a are given in [1].
322
Me C Me N H O. .
O .. N
.H
The structure was confirmed by 1H NMR spectroscopy. In the 1H NMR spectra of all the recyclization products signals were present for the protons of the 4- and 6-CH3 groups, the alkylamine and amide fragments, and also the signals for the 5-H protons. It is noteworthy that the signal for the latter is displayed at significantly higher field (6.09-6.26 ppm) than the signals of the 5-H protons of the pyrimidinium salts (7.98-8.15 ppm) or even of the corresponding pyrimidines 2 (6.9-7.0 ppm), which enables the formation of the rearrangement product to be established unequivocally, based on NMR spectra. We add that the appearance of a white spot on spraying chromatograms with Ehrlich reagent is also a qualitative sign characteristic of all the recyclization products, including those described previously in [1-7]. This makes it possible to control the process of forming recyclization products chromatographically.
EXPERIMENTAL The NMR spectra were obtained on a Varian Mercury-300 (300 MHz) spectrometer in the Center for the Investigation of Molecular Structure of the National Academy of Sciences of Armenia (program US CRDF RESC 17-5). Silufol UV-254 plates were used for thin-layer chromatography (to determine Rf), visualizing with iodine vapor and Ehrlich's reagent. Preparative separation was carried out by column chromatography on silica gel (Silica gel L 5/40 Merck). 2-(Alkylcarbamoylmethyl)-4,6-dimethylpyrimidine (2). A solution of 2-pyrimidinylacetic acid ester 1 (1 g, 5 mmol) in a 13% alcoholic solution of alkylamine (10 ml) was heated at 90-100C in a sealed ampule for 20 h. The solvent was distilled off, hexane was added, the precipitated crystals were filtered off, washed with hexane, and dried. Compounds 2b,c were obtained. 4,6-Dimethyl-2-(methylcarbamoylmethyl)pyrimidine (2b). Yield 0.8 g (88%); mp 106-107C, Rf 0.17 (acetone). 1H NMR spectrum (CDCl3), , ppm (J, Hz): 2.46 (6H, s, 4- and 6-CH3); 2.83 (3H, d, J = 3, NHCH3); 3.85 (2H, s, CH2); 6.94 (1H, s, 5-H); 7.5 (1H, br. s, NHCH3). Found, %: C 59.94; H 6.97; N 23.69. C9H13N3O. Calculated, %: C 60.31; H 7.31; N 23.45. 2-(Ethylcarbamoylmethyl)-4,6-dimethylpyrimidine (2c). Yield 0.85 g (89%); mp 90-91C, Rf 0.16 (acetone). 1H NMR spectrum (CDCl3), , ppm (J, Hz): 1.29 (3H, t, J = 7.2, CH2CH3); 2.44 (6H, s, 4- and 6-CH3); 2.78 (2H, dq, J1 = 3, J2 = 7.2, NHCH2CH3); 3.84 (2H, s, CH2); 6.98 (1H, s, 5-H); 7.25 (1H, br. s, NHCH2CH3). Found, %: C 61.79; H 8.07; N 21.57. C10H15N3O. Calculated, %: C 62.15; H 7.82; N 21.74. The synthesis of 2a was described previously in [1]. 1-Alkyl-2-(carbamoylmethyl)-4,6-dimethylpyrimidinium Iodides (3a-e). General procedure. The appropriate pyrimidine 2 (10 mmol) and alkyl iodide (10 ml) were heated in a sealed glass ampule in a boiling water bath. After 10 h the precipitated crystals were filtered off, washed with a small quantity of hexane, and dried in the air (Table 1). 2-Ethylamino-4,6-dimethylnicotinic Acid Amide (4b). A. Iodide 3a (0.75 g, 2.4 mmol) was mixed with 13% alcoholic ethylamine solution (8 ml) and heated in a sealed glass ampule at 95-100C for 35 h. The precipitated crystals were then filtered off, washed with cold hexane, and dried. Water (3 ml) was added to the crystals, the solution was made alkaline with dilute KOH solution, extracted with chloroform, and the extract dried over magnesium sulfate. After distilling off the solvent, the residue was chromatographed on a column 323
(silica gel L 5/40, eluent was acetone). Pyridine 4b (0.25 g, 55%) was obtained; mp 161-162C, Rf 0.7 (benzene acetone, 1:3). 1H NMR spectrum (CDCl3), , ppm (J, Hz): 1.25 (3H, t, J = 7.2, NHCH2CH3); 1.61 (1H, br. s, NH), 2.35 (3H, s, 4(6)-CH3); 2.38 (3H, s, 6(4)-CH3); 3.45 (2H, dq, J1 = 7.2, J2 = 5.0, NHCH2CH3); 5.75 (1H, br. s, NH); 5.94 (1H, br. s, NH); 6.25 (1H, s, 5-H). Mass spectrum, m/z (Irel, %): 194 (8), 193 (65) [M]+, 178 (13), 176 (35), 175 (13), 165 (14), 161 (82), 149 (14), 148 (47), 147 (100), 134 (47), 133 (12), 122 (20), 121 (12), 119 (8), 108 (11), 107 (61), 106 (46). Found, %: C 62.34; H 7.59; N 21.98. C10H15N3O. Calculated, %: C 62.15; H 7.82; N 21.74. Amide 4a (0.03 g, 7%) and the demethylation product, pyrimidine 2 (0.03 g, 7%), were isolated by preparative separation and were identical in mp and by TLC with known samples [1]. B. Analogously, according to the general procedure, the reaction of iodide 3b (0.6 g, 1.8 mmol) with 13% ethanolic ethylamine solution (10 ml) gave nicotinamide 4b (0.2 g, 58%) [mp 161-162C, Rf 0.7 (benzene acetone, 1:3)] and amide 2a (0.06 g, 19%) [mp 126-127C, Rf 0.16 (benzeneacetone, 1:3)]. 4,6-Dimethyl-2-methylaminonicotinic Acid Methylamide (4c). A mixture of iodide 3c (0.65 g, 2 mmol) and a 15% ethanolic methylamine solution (10 ml) was heated in a sealed ampul at 95-100C for 15 h. The solvent was then removed and the residue washed with benzene. After evaporating the solvent from the benzene extract the residual mass was separated on a column of silica gel (eluent acetonebenzene, 2:1). Nicotinamide 4c (0.15 g, 40%) was obtained; mp 128-130C and Rf 0.75 (acetone) or Rf 0.66 (benzeneacetone, 1:2) and compound 2 (R = Me) (0.04 g, 10%), which was identical to a known sample in mp and by TLC. 1 H NMR spectrum of compound 4c (CDCl3), , ppm (J, Hz): 2.23 (3H, s, 4(6)-CH3); 2.35 (3H, s, 6(4)-CH3); 2.94 (3H, d, J = 4.8, NHMe); 2.98 (3H, d, J = 5.1, NHCH3); 5.61 (1H, br. s, NH); 5.76 (1H, br. s, NH); 6.23 (1H, 5-H). Mass spectrum, m/z (Irel, %): 194 (7), 193 (54), 178 (19), 163 (27), 150 (9), 136 (19), 119 (8), 108 (17), 107 (100), 106 (19), 79 (11), 77 (13). Found, %: C 61.94; H 7.56; N 21.51. C10H15N3O. Calculated, %: C 62.15; H 7.82; N 21.74. 2-Ethylamino-4,6-dimethylnicotinic Acid Methylamide (4d). A solution of iodide 3d (0.5 g, 1.5 mmol) in 13% alcoholic ethylamine solution (8 ml) was heated in a sealed ampule at 90-100C for 25 h. The solvent was distilled off, and the residue was passed through a column of silica gel (L 5/40), eluting with benzeneacetone, 2:1. The rearrangement product, pyridine 4d (0.14 g, 45%), and pyrimidine 2 (R = Me) (0.03 g, 10%) were obtained. Compound 4d: mp 104-105C, Rf 0.66 (benzeneacetone, 1:2). 1H NMR spectrum (CDCl3), , ppm (J, Hz): 1.23 (3H, t, J = 7.2, NHCH2CH3); 2.23 (3H, s, 4(6)-CH3); 2.33 (3H, s, 6(4)-CH3); 3.0 (3H, d, J = 5.1, NHCH3); 3.2 (2H, dq, J = 7.2, NHCH2CH3); 5.54 (1H, br. s, NH); 5.69 (1H, br. s, NH); 6.23 (1H, s, 5-H). Found, %: C 63.88; H 8.51; N 20.08. C11H17N3O. Calculated, %: C 63.74; H 8.27; N 20.27. 4,6-Dimethyl-2-methylaminonicotinic Acid Ethylamide (4e). The interaction of 2-(ethylcarbamoylmethyl)-1,4,6-trimethylpyrimidinium iodide 3e (1 g, 3 mmol) with 15% alcoholic methylamine solution (15 ml), according to the general rearrangement procedure (20 h, 90-100C) and subsequent column resolution (eluent benzeneacetone, 2:1), gave pyridine 4e (0.2 g, 35%) and pyrimidine 2 (R = Et) (0.06 g, 10%). The latter was identical with a known sample by mp (172-173C) and TLC. Compound 4e: oil, Rf 0.5 (acetone). 1H NMR spectrum (CDCl3), , ppm (J, Hz): 1.25 (3H, t, J = 7.2, NHCH2CH3); 2.37 (3H, s, 4(6)-CH3); 2.65 (3H, s, 6(4)-CH3); 3.43 (2H, dq, J1 = 7.2, J2 = 5.1, NHCH2CH3); 3.58 (3H, d, J = 5.0, NHCH3); 5.63 (1H, br. s, NH); 6.09 (1H, s, 5-H); 9.58 (1H, br. s, NH). Found, %: C 63.94; H 8.47; N 20.02. C11H17N3O. Calculated, %: C 63.74; H 8.27; N 20.27. Conversion of 2-(Carbamoylmethyl)-1,4,6-trimethylpyrimidinium Iodide (3a) in Aqueous Alcoholic Methylamine Solution. Water (2 ml) was added to a solution of iodide 3a (0.4 g, 1.3 mmol) in 15% alcoholic methylamine solution (10 ml) and the mixture was heated in a sealed ampule at 90-100C for 20 h. The solution was then evaporated to dryness under reduced pressure, and hexane was added to the residue. The precipitated crystals were filtered off, washed with hot hexane, and then with several drops of water, and dried. 3-Carbamoyl-4,6-dimethyl-1,2-dihydro-2-pyridone (5) (0.18 g, 83%) was obtained; mp 214-215C, Rf 0.3 324
(acetone). The solvent was distilled from the hexane solution, and nicotinamide 4a (20 mg, 10%) was obtained, which corresponded with a known sample in 1H NMR spectrum, TLC, and melting point. 1H NMR spectrum of compound 5 (CDCl3), , ppm: 2.35 (3H, s, 4(6)-CH3); 2.70 (3H, s, 6(4)-CH3); 5.95 (1H, br. s, NH); 6.1 (1H, s, 5-H); 9.35 (1H, br. s, NH); 12.6 (1H, br. s, NH). Found, %: C 58.09; H 6.21; N 16.71. C11H17N3O. Calculated, %: C 57.82; H 6.07; N 16.86. The work was carried out within the framework of scientific theme 00-405b of the Ministry of Science and Education of the Armenian Republic, and also jointly with Prof. A. R. Katritzky (University of Florida) grant No. ACH-006 98/ACI-955 of the National Fund for Science and Advanced Technology of Armenia (NFSAT), and the US Civil Research and Development Fund (US CRDF).
REFERENCES 1. 2. 3. 4. 5. 6. 7. G. G. Danagulyan, L. G. Sahakyan, and G. A. Panosyan, Khim. Zh. Armen., 53, 62 (2000). G. G. Danagulyan, L. G. Sahakyan, A. R. Katritzky, and S. N. Denisenko, Heterocycles, 53, 419 (2000). G. G. Danagulyan and L. G. Sahakyan, Khim. Geterotsikl. Soedin., 698 (2000). G. G. Danagulyan, L. G. Sahakyan, and G. A. Panosyan, Khim. Geterotsikl. Soedin., 351 (2001). G. G. Danagulyan and L. G. Sahakyan, Khim. Geterotsikl. Soedin., 1434 (1999). G. G. Danagulyan and L. G. Sahakyan, Khim. Zh. Armen., 53, 147 (2000). G. G. Danagulyan, L. G. Sahakyan, A. R. Katritzky, and S. N. Denisenko, Khim. Geterotsikl. Soedin., 1572 (1999).
325
HETEROCYCLIZATION OF OXIMES OF 3,5-DIMETHYL(1,3,5-TRIMETHYL)2,6-DIPHENYLPIPERID-4-ONES AND N-BENZYLPYRROLID-3-ONES WITH ACETYLENE IN A SUPERBASIC MEDIUM

L. G. Voskressensky, T. N. Borisova, and A. V. Varlamov It has been established that on heterocyclization of 3,5-dimethyl-2,6-diphenylpiperid-4-one oxime with acetylene in a superbasic medium migration of the 3a-CH3 group to the anionic nitrogen atom occurs, leading to the formation of 5,7-dimethyl-4,6-diphenyl-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridine. The formation of the N-anion causes aromatization of the tetrahydropyridine ring. Tetrahydropyrrolo[1,2-c]pyrimidines are formed in the Trofimov reaction as a result of decomposition of the intermediate 3H-pyrrole in a retro-Mannich reaction. Keywords: oxime, pyrrole, pyrrolidine, tetrahydropyrrolo[3,2-c]pyridine, heterocyclization. The heterocyclization of oximes of piperid-4-ones with acetylene in a superbasic medium (the Trofimov reaction) has enabled preparative methods to be developed for obtaining 4,5,7-trimethyl-4,5,6,7tetrahydropyrrolo[3,2-c]pyridine [1] and 2,4,5-trimethyl-1,2,3,4-tetrahydropyrrolo[1,2-c]pyrimidine [2] and a systematic study to begin on the reactivity of these heterocyclic structures containing two pharmacophoric rings [3-6]. Meanwhile many aspects of the Trofimov reaction in a series of nitrogen-containing cyclic ketones remain unclarified. In particular the effect of the ring size of the heterocyclic ketone and the mutual disposition of the nitrogen atom and the oxime grouping on the course of the Trofimov reaction have not been studied. The chemical mechanism of the formation of tetrahydropyrrolo[1,2-c]pyrimidines under the conditions of the Trofimov reaction remains unclear. On heterocyclization of 3,5-dimethyl-2,6-diphenylpiperid-4-one (1) in the presence of KOH the expected main product of heterocyclization, 4,5-dimethyl-1,3-diphenyl-1,2,3,4-tetrahydropyrrolo[1,2-c]pyrimidine (2), was not isolated [7]. Depending on the reaction conditions either 4,5-dimethyl-1,3diphenylpyrrolo[1,2-c]pyrimidine (3), the product of aromatization of compound 2 (atmospheric pressure, 90-95C) was obtained, or 2-ethynyl-7a-hydroxy-3a,7-dimethyl-4,6-diphenylperhydropyrrolo[3,2-c]pyridine (4) was formed as a mixture of four isomers according to the mutual disposition of the 3a-CH3 and 2-ethynyl groups and the junction of the piperidine and pyrrolidine rings (autoclave, 80-90C). Results are correlated in the present communication on the study of the heterocyclization of oxime 1 with acetylene at 70C, of 1,3,5-trimethyl-2,6-diphenylpiperid-4-one oxime (5) and of the oximes of 1-benzyl(6), 1-benzyl-2-methyl- (7), and 1-benzyl-4-methylpyrrolid-3-ones (8). The pyrrolid-3-ones required for carrying out this work were synthesized by the intramolecular condensation of esters of the corresponding 3-benzylaminohexane-1,6-dicarboxylic acids under conditions of the Dieckmann reaction [8]. __________________________________________________________________________________________ Russian People's Friendship University, Moscow 117198; e-mail: rpfu@orc.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 401-409, March, 2004. Original article submitted March 2, 2001. 326 0009-3122/04/4003-03262004 Plenum Publishing Corporation
It was established by us that on heterocyclization of oxime 1 in the system RbOHDMSO the expected tetrahydropyrrolo[1,2-c]pyrimidine 2 was aromatized at 70C to pyrrolo[1,2-c]pyrimidine 3 [9], the presence of which was shown by TLC. In addition, under these conditions migration occurs in the intermediate compound [a 3H-pyrrole (A)] of the methyl group from position 3a to the anionic nitrogen atom. As a result of this 5,7-dimethyl-4,6-diphenyl-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridine (9) is formed, identical with that obtained previously on heterocyclization of 1,3-dimethyl-2,6-diphenylpiperid-4-one oxime [9]. On chromatographic resolution of the reaction mixture isomers of tetrahydropyrrolo[3,2-c]pyridine 4 were isolated, one in the pure state, and three others as a mixture, analysis of which was carried out with the aid of chromato-mass spectrometry.
Me N Me 1 OH
R=H
Me N N Me A
Me Me N N
+H
N
Me
+
C CH
Me N N H
Me 3
N H OH
Me 9
It is logical to suggest that aromatization of the expected tetrahydropyrrolo[1,2-c]pyrimidine 2 in superbasic medium also occurs through the formation of an anion with the charge on a nitrogen of the tetrahydropyrimidine fragment. In order to confirm this hypothesis we studied the heterocyclization of the oxime of the pentasubstituted piperid-4-one 5 under the same conditions as for oxime 1. According to the data of chromato-mass spectrometry there were twenty one compounds in the reaction mixture, among which were 1,3,5-trimethyl-2,6-diphenylpiperid-4-one (28%), tetrahydropyrrolo[1,2-c]pyrimidine 10 (16%), and three isomers of perhydropyrrolo[3,2-c]pyridine 11 (16%). The product of aromatization of compound 10, pyrrolopyrimidine 3, was absent from the reaction mixture (Scheme 1). A mixture of isomeric tetrahydropyrrolopyrimidines 10a and 10b and an individual isomer 10b were isolated chromatographically from the reaction mixture. The isomer 10b has a pseudoequatorial disposition of substituents in the tetrahydropyrimidine fragment, which follows from the size of the coupling constant 3 J3,4 = 10.1 Hz. In the 1H NMR spectrum of compound 10b signals were observed for all the protons in the molecule with the appropriate coupling constants. The signal of the 1-H proton was a singlet with 5.01, the signal of the 3-H proton was a doublet with 3.31, and the signal of the 4-H proton was a multiplet at 3.15 ppm. Analysis of the 1H NMR spectrum of the mixture of isomers of 10a and 10b showed that in both isomers the chemical shifts of the pyrrole fragment and N-CH3 protons coincided. The signals of the protons of 327
Scheme 1
Me
Me N Me 5 OH
Me
..
Me A
Me
Me + N 1
Me
3 2 1' Me
2'
_N
Me Me Me N N H OH 10b C
Me
5
+
CH Me Me
Me
6
Me
N
2 1
N
7
+
Me
11ac
10a
the 1-, 3-, and 4-H in the spectrum of isomer 10a have the same multiplicity as in the spectrum of compound 10b, but were observed at 4.95, 3.84, and 3.05 ppm respectively. The size of the coupling constant 3J3,4 = 3.7 Hz permits the assumption that in pyrrolopyrimidine 10a the 4-CH3 group is disposed pseudoaxially. The formation of pyrrolopyrimidine 10 as a mixture of isomers and the fact that for 3,3-disubstituted 3Hpyrroles migration of a radical from position 3 to the nitrogen atom does not occur under heterocyclization conditions, shows that pyrrolopyrimidines are formed under the conditions of the Trofimov reaction as a result of a retro-Mannich reaction. This process is accompanied by aromatization of the pyrrole ring as a result of a [1,3]-sigmatropic shift. Intramolecular cyclization of the resulting zwitter-ion B leads to tetrahydropyrrolopyrimidine 10. Rotation around the C'(1)C'(2) bond may occur in the process of cyclization, which is also a reason for the formation of two isomers of compound 10. The structures of compounds 10 and 11 were confirmed by mass spectrometry. In the mass spectrum of tetrahydropyrrolopyrimidine 10b there was a high intensity peak for the M+-ion, corresponding to its empirical formula. The dissociation of the molecular ion is characterized by two main breakdown pathways. The first of these is linked with aromatization of the tetrahydropyrrolopyrimidine fragment of the molecule and is accompanied by elimination of CH3, H, and Ph radicals in various sequences. As a result fragments with m/z 223 and 285 are formed, having the structure of cation-radicals of substituted pyrrolopyrimidines. The second decomposition pathway is caused by fission of the tetrahydropyrrolopyrimidine ring in three directions, a, b, and c. On breakdown by direction a fragments [PhCH=NCH3]+ [119 (16)] and [PhC=NCH3] [118 (100)] are eliminated from the M+-ion. As a result ions with m/z 197 (68) and 198 (23) are formed, which then eliminate CH3 and H. Decomposition by directions b and c leads to the formation of fragment ions with the structure of a substituted aziridine and azirine (Scheme 2). The fragmentation of N-methyl-substituted perhydropyrrolopyrimidines 11a-c under electron impact (Table 1) is analogous to the fragmentation of NH perhydropyrrolopyrimidines 4 [3]. As a result of their lability under electron impact conditions there are no peaks for their molecular ions in their mass spectra, but in the high mass region peaks are present for the fragment ions [M-H2O]+, which have a higher intensity than the 328
Scheme 2
a b Me Me N N Me Me CH3, Ph, H
+.
+.
. . .
Me
N c
Me N
+
223 (18)
+.
Me N N
Me M + 316 (92) 132 (3)
PhC=NMe
285 (4) Me Me Me 183 (9) H Me Me N 197 (68) H PhCH=NMe + N 198 (28) 209 (10) N Me a
+.
.
+.
Me . 182 (33)
+
Me
196 (19)
208 (17)
analogous peaks in the mass spectrum of compound 3 [3]. The fragment ion 306 (2.8), observed in the mass spectrum of compound 11b, is linked with the existence of ring-chain tautomerism and the elimination of a NH2C3H2 particle as a result of -fission in the ketonic form (Scheme 3). On the basis of [3] it may be assumed that an axial-equatorial linkage of the piperidine and pyrrolidine rings occurs in compound 11b, and there is an equatorial-equatorial linkage in compounds 11a and 11c. The heterocyclization of pyrrolid-3-one oximes 6-8 with acetylene was carried out at 95C in the system DMSOKOH with 100 mol % of the latter. It was established by TLC in the example of oxime 7 that heterocyclization begins at a temperature of 90C. The reaction of oximes 6-8 with acetylene was accompanied by severe resinification and the formation of a multicomponent reaction mixture, from which only unreacted oxime was successfully isolated (10-23%) by column chromatography and identified. The formation of the 329
[MNH2C3H2-3]+ 291
[MNH2C3H2]+ 306
PhCH=N+H3 120
Compound
N
214
N Ph 147
0.8 0.9 2.8
PhCN+3 118
N+ Ph 146
PhCH=N3 + 119
[MH2O]+ 342
330
TABLE 1. Peak Intensities of the Main Fragment Ions in the Mass Spectra of Perhydropyrrolopyrimidines
Intensity of ions, %
CH3
+.
CH3 N+
Ph Ph 208
5.1 3.4 7.1
CH3
+.
CH3
117
Ph Ph 209
15.4 9.6 11.4 1.5 2.1 2.8
PhCH2+ 91
Ph+ 77
68
11a 11b 11c
12.2 5.9 8.6
2.8
3.3 1.0 4.3
1.0 1.7 4.3
100 100 100
5.0 4.0 11.4
38.3 30.8 37.5
16.9 14.1 17.1
28.0 28.8 31.4
16.6 4.8 17.1
3.4 3.3 8.6
TABLE 2. Physicochemical Constants, Data of IR and NMR Spectroscopy, and Mass Spectroscopy of Oximes of Substituted 1-Benzylpyrrolid-3-ones 5-7
Compound 5 6 Empirical formula 11H14N2O 12H16N2O Found, % Calculated, % H 7.52 7.37 7.63 7.84 7.48 7.84 mp, N 92 69.09 69.47 70.42 70.59 70.08 70.59 15.00 14.74 13.65 13.73 13.58 13.73 153-154 78-79 190 204 990 (NO), 1680 (C=N) 3200-3400 (OH) 940 (NO), 1680 (C=N) 2850-3100 (OH) 935 (NO), 1670 (C=N) 3200-3500 (OH) 2.50-2.70 (4-H); 2.72-2.83 (5-H); 3.20 (2-H); 3.67 (CH2Ph) 1.34 (3); 2.10-2.62 (4-H); 2.92-(-3.12) (5-H); 3.0 (2-H); 3.25 and 4.09 (CH2Ph) 1.23 (3); 2.50-2.74 (2-H, 4-, 5-); 3.71 (CH2Ph) []+, m/z IR spectrum (KBr), cm-1 NMR spectrum (CDCl3), , ppm Yield, %
90
11H16N2O
150-151
204
20
Scheme 3
Me Me Me N NH C CH Me OH H2O
Me N N Me 342 C CH
11
Me N
Me NH2 C O Me CH
Me N O+ Me 306
expected pyrrolopyrrolidines was also not successfully shown by chromato-mass spectrometry. Probably decomposition of the pyrrolidine ring occurs in the process of heterocyclization, with a condensation reaction at the 2-CH2 group, and also reaction at the N-benzyl radical. Decomposition of cyclic ketones containing a heteroatom in the position to the oxime function was described in [10]. It should be noted that B. A. Trofimov and collaborators did not successfully effect heterocyclization of cyclopentanone oxime. It has therefore been established that the formation of tetrahydropyrrolo[1,2-c]pyrimidines occurs by a retro-Mannich reaction under the conditions of the Trofimov reaction. It has been shown that the formation of an N-anion causes the aromatization of tetrahydropyrrolo[1,2-c]pyrimidines, but the Trofimov reaction may not be used for converting -pyrrolidone oximes into pyrrolopyrrolidines.
EXPERIMENTAL The IR spectra were recorded on a UR-20 spectrometer in KBr disks. Chromato-mass spectra were obtained on an HPMS-5988 instrument. NMR spectra were recorded on Bruker WM-400 and WP-200 spectrometers (400 and 200 MHz) at 20C in CDCl3. Aluminum oxide of Brockmann activity grade II (Fluka) was used for column chromatography, and Silufol plates for TLC. Visualization was with iodine vapor. 5,7-Dimethyl-4,6-diphenyl-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridine (9) and 2-Ethynyl-7a-hydroxy3a,7-dimethyl-4,6-diphenylperhydropyrrolo[3,2-c]pyridines (4). Acetylene was bubbled through a solution of oxime 1 (4.5 g, 15 mmol) and RbOH (0.77 g, 7.5 mmol) in DMSO (50 ml) at 70C. After 2h, further RbOH (0.31 g, 3 mmol) was added and the reaction was conducted for 4 h (check by TLC). The mixture was cooled, poured into ice water (150 ml), and extracted with ether (5 100 ml). The extract was dried over MgSO4. After distilling off the solvent, the residue (3.1 g) was chromatographed on a column of aluminum 331
oxide (1.9 52 cm). Initially a mixture (8 mg) of pyrrolopyrimidine 3 with 3,5-dimethyl-2,6-diphenylpiperid-4one (Rf 0.63, ethyl acetatehexane, 1:4) was eluted with hexane. A characteristic green spot, identical with a standard spot, appeared on TLC [3]. Then 3,5-dimethyl-2,6-diphenylpiperid-4-one (0.11 g, 3.6%) was eluted; white crystals, mp 128-130C (hexane). A sample mixed with a standard melted with no depression of melting point. A mixture of hexaneethyl acetate, 30:1, eluted pyrrolopyridine 9 (75 mg, 2.5%); yellow crystals, mp 126128C (ethyl acetatehexane), Rf 0.64 (ethyl acetateheptane, 1:3). Lit. data [1]: mp 128-131C (hexane), Rf 0.63. Found, %: C 83.63; H 6.61; N 9.40. [M]+ 302. C21H22N2. Calculated, %: C 83.43; H 7.31; N 9.33. [M]+ 302. A more polar mixture of ethyl acetatehexane, 1:10, eluted a single isomer of 4, yellow crystals; mp 170-171C (ethyl acetatehexane), Rf 0.58 (Silufol, ethyl acetateheptane, 1:3). Lit. data [3] for an isomer with an axialequatorial linkage of rings; mp 172-173C (hexane), Rf 0.58 (Silufol, ethyl acetatehexane, 1:3). Found, %: N 8.34. [M-H2O]+ 328. C23H26N2O. Calculated, %: N 8.13. [M-H2O]+ 328. Three isomers of 4 were eluted (75 mg, 2.5 %); white crystals, mp 136-145C, Rf 0.53, 0.2, and 0.17 (Silufol, ethyl acetateheptane, 1:3). Their chromatographic mobility was identical to a standard sample [3]. Found, %: N 8.24. [M-H2O]+ 328. C23H26N2O. Calculated, %: N 8.13. [M-H2O]+ 328. Finally a mixture of ethyl acetatehexane, 1:4, eluted dimethylhydroxysulfimide (80 mg); colorless crystals, mp 105-106C (ethyl acetatehexane). Found, %: N 15.53. [M]+ 93. C2H7NOS. Calculated, %: N 15.05. [M]+ 93. 5,7-Dimethyl-4,6-diphenyl-4,5,6,7-tetrahydropyrrolo[1,2-c]pyrimidines (10) and 2-Ethynyl-7ahydroxy-3a,5,7-trimethyl-4,6-diphenylpyrrolo[3,2-c]pyridines (11). Acetylene was bubbled through a solution of oxime 5 (5 g, 16 mmol) and RbOH (0.83 g, 8 mmol) in DMSO (50 ml) at 70C. After 2 h, further RbOH (0.4 g, 4 mmol) was added and the reaction conducted to the end (check by TLC). The mixture was cooled, poured into ice water (150 ml) , extracted with ether (5 100 ml), and the extract dried over MgSO4. After distilling off the ether a dark resinous mass (5.14 g) was obtained. Part of this residue (2.7 g) was chromatographed on a column of aluminum oxide (1.9 50 cm). Initially a mixture of compounds 10a and 10b (20 mg, 1.32%) was eluted with hexane. NMR spectrum of compound 10a (CDCl3), , ppm (J, Hz): 1.17 (3H, d, 3 JCH3 = 6.7, 4-CH3); 1.75 (3H, s, NCH3); 2.12 (3H, s, 5-CH3); 3.05 (1H, m, 4-H); 3.84 (1H, d, 3J34 = 3.7, 3-H); 4.95 (1H, s, 1-H); 5.78 (1H, d, 3J67 = 2.8, 6-H); 5.86 (1H, d, 3J67 = 2.8, 7-H); 7.30-7.45 (10H, m, 2-C2H5). Pyrrolopyrimidine 10b (35 mg, 2.3%) was then eluted, white crystals of mp 111-112C (hexane), Rf 0.7 (Silufol, ethyl acetateheptane, 1:2). NMR spectrum of 10b (CDCl3), , ppm (J, Hz): 1.17 (3H, d, 3JCH3 = 6.7, 4-CH3); 1.75 (3H, s, N-CH3); 2.12 (3H, s, 5-CH3); 3.15 (1H, d, 3J3,4 = 10.1, 3-H); 3.31 (1H, m, 4-H); 5.01 (1H, s, 1-H); 5.78 (1H, d, 3J67 = 2.8, 6-H); 5.86 (1H, d, 3J67 = 2.8, 7-H); 7.30-7.45 (10H, m, 2-C2H5). Mass spectrum, m/z (Irel, %): 316 (92) [M]+, 315 (57), 302 (6), 301 (24), 288 (32), 287 (10), 286 (6), 285 (4), 240 (13), 239 (72), 224 (12), 223 (18), 210 (5), 209 (10), 208 (17), 198 (28), 197 (68), 196 (19), 194 (8), 183 (9), 182 (33), 180 (9), 167 (13), 129 (14), 128 (19), 120 (44), 119 (16), 188 (100), 116 (14), 115 (37), 91 (75), 89 (15), 82 (15), 77 (57), 65 (16), 51 (14), 42 (17). Found, %: N 8.98. C22H24N2. Calculated, %: N 8.85. At the end of the chromatography, 1,3,5-trimethyl-2,6-diphenylpiperid-4-one (40 mg) was isolated as white crystals; mp 105-106C (heptane). A mixing test with a standard sample gave no depression of melting point. The reaction mixture was analyzed on the chromato-mass spectrometer. The formation of three isomers of perhydropyrrolopyridine 11 was established. The mass spectra were characterized by the presence of a peak for the [M-H2O]+ ion with m/z 342. Oximes of 1-Benzyl-, 1-Benzyl-2-methyl-, and 1-Benzyl-4-methylpyrrolid-3-ones (5-7). A solution of 1-benzyl-, 1-benzyl-2-methyl-, or 1-benzyl-4-methylpyrrolid-3-ones (0.1 mol), obtained by Dieckmann cyclization from (-ethoxycarbonylethyl)-methoxycarbonylmethylbenzylamine, (-ethoxycarbonylethyl)-ethoxycarbonylethylbenzylamine, and (-ethoxycarbonylpropyl)methoxycarbonylmethylbenzylamine respectively [8], hydroxylamine hydrochloride (0.2 mol), and potassium hydroxide (0.3 mol) in ethanol (200 ml) was boiled for 5-6 h (check by TLC). After distilling off the alcohol the residue was extracted with chloroform 332
(4 100 ml), and the extract dried over MgSO4. The solid mass obtained after distilling off the chloroform was crystallized from heptane. Oximes 5-7 were obtained, the physicochemical and spectral characteristics of which are given in Table 2.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. T. N. Borisova, A. V. Varlamov, N. D. Sergeeva, A. T. Soldatenkov, O. V. Zvolinskii, A. A. Astakhov, and N. S. Prostakov, Khim. Geterotsikl. Soedin., 973 (1987). N. S. Prostakov, A. V. Varlamov, T. N. Borisova, and N. D. Sergeeva, Khim. Geterotsikl. Soedin., 1286 (1987). A. E. Aliev, T. N. Borisova, I. A. Stazharova, A. A. Sinitsyna, A. I. Mikaya, N. S. Prostakov, and A. V. Varlamov, Khim. Geterotsikl. Soedin., 903 (1992). A. V. Varlamov, T. N. Borisova, A. E. Aliev, I. A. Stazharova, and E. A. Sakhnova, Khim. Geterotsikl. Soedin., 681 (1993). T. N. Borisova, A. E. Aliev, E. A. Sakhnova, A. A. Sinitsyna, and A. V. Varlamov, Khim. Geterotsikl. Soedin., 137 (1993). A. V. Varlamov, T. N. Borisova, S. B. Barge, L. G. Voskressensky, A. I. Chernyshev, and E. M. Semenova, Khim. Geterotsikl. Soedin., 1670 (1998). A. V. Varlamov and T. N. Borisova, Khim. Geterotsikl. Soedin., 849 (1991). E. A. Pril and F. McElvain, J. Am. Chem. Soc., 55, 1234 (1933). T. N. Borisova, L. G. Voskressensky, and A. V. Varlamov, Khim. Geterotsikl. Soedin., 136 (1995). V. A. Trofimov, in R. A. Jones (editor), The Chemistry of Heterocyclic Compounds, Vol. 48, Pt. 2, Wiley, New York (1992), p. 131. B. A. Trofimov and A. I. Mikhaleva, N-Vinylpyrroles [in Russian], Nauka, Novosibirsk (1984), p. 271.
333
NOVEL ASPECTS OF THE REACTION OF 3-(BENZIMIDAZOL-2-YL)-2-IMINOCOUMARINS WITH AROMATIC ALDEHYDES

N. Yu. Gorobets, V. V. Abakumov, A. V. Borisov, and V. M. Nikitchenko The reaction of 3-(benzimidazol-2-yl)-2-iminocoumarins with aromatic aldehydes has been studied. The condensation products 7-aryl-7H-benzo[4,5]imidazo[1,2-c]benzopyrano[3,2-e]pyrimidines or 3-(benzimidazol-2-yl)coumarins are formed depending on the nature of the substituent in the starting 2-iminocoumarin and aldehyde. In DMF medium, 7-aryl-7H-benzo[4,5]imidazo[1,2-c]benzopyrano[3,2-e]pyrimidines isomerize to the corresponding 7-aryl-14H-benzo[4,5]imidazo[1,2-c]benzopyrano[3,2-e]pyrimidines. The effect of the substituent on the isomerization process has been studied and the reaction mechanisms are discussed. Keywords: 7-aryl-7H-benzo[4,5]imidazo[1,2-c]benzopyrano[3,2-e]pyrimidine, 7-aryl-14H-benzo[4,5]imidazo[1,2-c]benzopyrano[3,2-e]pyrimidine, aromatic aldehyde, 3-(benzimidazol-2-yl)-2-iminocoumarin, 3-(benzimidazol-2-yl)coumarin, substituent effect, isomerization, proton transfer, equilibrium. The considerable attention of investigators to 2-iminocoumarin derivatives is connected with their high reactivity, potentially reacting both with electrophilic and with nucleophilic substituents [1-4]. Special interest in this program has focused on reactions which form novel heterocyclic systems [5, 6]. In previous work [7] we reported the reaction of the 3-benzimidazol-2-yl-2-iminocoumarins 1a-c with an excess of aromatic aldehydes 2b-f,k in refluxing n-propanol or n-butanol in the presence of catalytic amounts of piperidine to give the 7-aryl-7H-benzo[4,5]imidazo[1,2-c]benzopyrano[3,2-e]pyrimidines 3a,i-k. In several cases the condensation product could not be separated due to a side reaction involving the hydrolysis of the 2-imino group to give 3-(benzimidazol-2-yl)coumarins [8, 9] (see Scheme 1). With the aim of a detailed examination of the effect of the reaction conditions and nature of the substituent on the course of the studied reaction for the 3-(benzimidazol-2-yl)-2-iminocoumarins and the corresponding aromatic aldehydes in n-pentanol or n-butanol in the presence of pyridine, the 7-aryl-7Hbenzo[4,5]imidazo[1,2-c]benzopyrano[3,2-e]pyrimidines 3a-m were prepared (Table 1). The effect of increasing the reaction temperature of the medium (exchanging n-butanol for n-pentanol) in the case of the difficultly soluble starting unsubstituted 3-(benzimidazol-2-yl)-2-iminocoumarin 1a and the methoxy derivative 1b was significant to decrease the time to carry out the reaction and to increase the yield, however in the case of the 7-dialkyl derivatives 1c,d the use of n-butanol was optimal.
__________________________________________________________________________________________ V. N. Karazin National University, Kharkov 61077, Ukraine; e-mail: nic@univer.kharkov.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 410-420, March, 2004. Original article submitted April 14, 2003. 334 0009-3122/04/4003-03342004 Plenum Publishing Corporation
Scheme 1
12
N
5 4 3
R2 N H 2ad,fk AlkOH piperidine 2ae
13
11 10
CHO
2
N N8
9
R1
6 7 8
14
R1
3 4
O
1
NH
O
5
N
6
1ad AlkOH piperidine
3am
R2
N R1 O 4ac
6 7
N H O
1 a R1 = H, b R1 = 6-MeO, c R1 = 7-NEt2, d R1 =
2 a R2 = H, b R2 = 4-Cl, c R2 = 4-Br, d R2 = 4-OMe, e R2 = 4-NO2, f R2 = 4-NMe2, g R2 = 4-OH, h R2 = 2-OH, i R2 = 4-OH-3-OMe, j R2 = 2-OH-3-OMe, k R2 = 2-OH-5-OMe; 3 ae R1 = H, a R2 = 4-NMe2, b R2 = 4-OH, c R2 = 2-OH, d R2 = 2-OH-3-OMe, e R2 = 4-OH-3-OMe, f, g R1 = 2-MeO, f R2 = 2-OH, g R2 = 2-OH-3-OMe, hk R1 = 3-NEt2, h R2 = H, i R2 = 4-Cl,
2
j R2 = 4-OCH3, k R2 = 2-OH-5-OMe, l, m R1 =
, l R2 = H, m R2 = 4-Br; 4 a R1 = H,
b R1 = 6-MeO, c R1 = 7-NEt2
The substituents in the starting 2-iminocoumarins 1a-d and the aromatic aldehydes proved to have a significant effect on the reaction course. Hence in the case of the 2-iminocoumarins which contain a dialkylamino group in position 7 (compounds 1c,d) the reaction occurs in good yield, even in n-butanol. For completion of the reaction 15-60 min is sufficient, moreover it is possible to obtain the condensation products with virtually all of the aromatic aldehydes 2a-d,k. However, the reaction of the 2-iminocoumarin 1c with para-nitrobenzaldehyde 2e gave only the 3-benzimidazolylcoumarin 4c. The reaction time increases to 2 h when using the unsubstituted 3-benzimidazol-2-yl-2-iminocoumarin 1a and the 6-methoxy derivative 1b. In these conditions, the condensation products (Table 1) are only formed when using the aromatic aldehydes 2f-j with donor substituents in the aromatic ring. The presence of only one para-methoxy group in the benzaldehyde 2d does not allow the condensation. The benzaldehydes 2a-e give the 3-benzimidazolylcoumarins 4a,b in almost quantitative yield. In order to explain the effect reported above on the effect of the substituent one should bear in mind that a donor substituent in position 7 of the 2-iminocoumarin increases the electron density both at the nitrogen atoms of the benzimidazole and also on the 2-imino group nitrogen thus increasing the overall nucleophilicity of the heterocyclic system. This makes possible the condensation of the 7-dialkylamino derivatives 1c,d with aromatic aldehydes containing a different kind of substituent. Not so evident are the reasons why aromatic aldehydes containing donor substituent take part in condensation with the 2-iminocoumarins 1a,b and those not containing them don't.
335
336
TABLE 1. Characteristics of the Compounds 3b-h,l,m

Compound 3b Empirical formula C23H15N3O2 Found N, % Calculated N, % 11.50 11.62 11.50 11.66 10.63 10.79 mp, 244-246 IR spectrum, , cm-1 1452, 1520, 1560 (C=C); 1600, 1660 (C=N); 2830, 3008, 3060 (); ~3400 (OH) 1456, 1508, 1524 (C=C); 1600, 1672 (C=N); 2860, 3036 (); ~3450 (OH) 1452, 1492, 1528 (C=C); 1600, 1680 (C=N); 2830, 2912, 3056 (); ~3450 (OH) 1540, 1560, 1576 (C=C); 1604,1676 (C=N);2932,3064 () ; ~3300 (OH) 1460, 1528, 1584 (C=C); 1604, 1672 (C=N); 2936, 2972, 3064 (); ~3450 (OH)
1
Yield, % 52
3c
C23H15N3O2
257-259
3d
C24H17N3O3
247-248
3e
C24H17N3O3
10.63 10.69 10.63 10.50
261-262
3f
C24H17N3O3
272-273
3g
C25H19N3O4
9.88 10.06
289-290 1458, 1482, 1580 (C=C); 1623, 1667 (C=N); 2837, 2942, 2994, 3057 (); ~3450 (OH) 261-263 1512, 1532, 1549 (C=C); 1612, 1668 (C=N); 2896, 2928, 2972, 3052, 3080 () 1542, 1564 (C=C); 1608, 1676 (C=N); 2932, 2952, 3004, 3024, 3044 ()
3h
C27H24N4O
13.32 13.24
3l
C27H24N4O
12.60 12.45
271-273
3m
C29H23BrN4O
10.70 10.63
>300
1452, 1528, 1568 (C=C); 1608, 1672 (C=N); 2848, 2892, 2932, 3048 ()
6.7 (2H, d, J = 8.5, 3',5'-H); 7.1-7.3 (8H, m, 2,3,4,7,9,11,2',6'-H); 7.5 (1H, td, J = 7.9, J = 1.5, 10-H); 7.6-7.8 (2H, m, 1,12-H); 8.3 (1, s, 14-H); 9.4 (1, s, O) 6.7-6.8 (2H, m, 3',5'-H); 7.0-7.3 (7H, m, 2,3,4,9,11,2',6'-H); 7.4 (1, s, 7-H); 7.5 (1H, td, J = 7.9, J = 1.5, 10-H); 7.6-7.8 (2H, m, 1,12-H); 8.3 (1, s, 14-H); 9.7 (1, s, O) 3.7 (3H, s, OMe); 6.7-6.8 (2, m, 4'- or 6',5'-H); 6.9 (1, dd, J = 7.6, J = 2.1, 4'- or 6'-H); 7.0-7.3 (5, m, 2,3,4,9,11-H); 7.5 (1, s, 7-H); 7.5 (1H, td, J = 7.9, J = 1.5, 10-H); 7.6-7.8 (2, m, 1,12-H); 8.3 (1, s, 14-H); 8.9 (1, s, ) 6.6-6.8 (2H, m, 5',6'-H); 7.0 (1H, d, J = 1.2, 2'-H); 7.0-7.3 (6H, m, 2,3,4,7,9,11-H); 7.5 (1H, td, J = 7.9, J = 1.5, 10-H); 7.6-7.8 (2H, m, 1,12-H); 8.3 (1, s, 14-H); 9.0 (1, s, O) 3.8 (3H, s, OMe); 6.7-6.8 (2H, m, 3',5'-H); 7.0-7.3 (7H, m, 3,4,9,10,11,4',6'-H); 7.3 (1H, d, J = 2.7, 1-H); 7.4 (1, s, 7-H); 7.7 (1H, d, J = 7.9, 12-H); 8.2 (1, s, 14-H); 9.7 (1, s, ) 3.73 (3H, s, 3'-OMe); 3.79 (3H, s, 2-OMe); 6.6-6.8 (2, m, 4'- or 6',5'-H); 6.9 (1H, dd, J = 7.6, J = 2.7, 4'- or 6'-H); 7.07.2 (5, m, 3,4,9,10,11-H); 7.3 (1, d, J = 2.7, 1-H); 7.4 (1, s, 7-H); 7.7 (1, d, J = 7.9, 12-H); 8.2 (1, s, 14-H); 8.9 (1, s, ) 1.1 (6H, t, J = 7.3, N(CH2CH3)2); 3.4 (4H, q, J = 7.3, N(CH2CH3)2); 6.4 (1H, d, J = 2.4, 4-H); 6.6 (1H, dd, J = 8.9, J = 2.4, 2-H); 7.0-7.2 (3H, m, 9,10,11-H); 7.27.4 (6H, m, 7,2',3',4',5',6'-H); 7.5 (1H, d, J = 8.9, 1-H); 7.6 (1H, d, J = 7.9, 12-H); 8.1 (1H, s, 14-H) 1.9 (4H, q, J = 6.0, N(CH2CH2CH2)2); 2.7 (4H, t, J = 6.0, N(CH2CH2CH2)2); 3.3 (4H, m, N(CH2CH2CH2)2); 7.0-7.2 (4H, m, 1,9,10,11-H); 7.27.4 (5H, m, 2',3',4',5',6'-H); 7.3 (1H, s, 7-H); 7.2-7.4 (5H, m, 2',3',4',5',6'-H); 7.6 (1H, d, J = 7.9, 12-H); 8.0 (1H, s, 14-H) 1.8 (4H, q, J = 6.0, N(CH2CH2CH2)2); 2.7 (4H, t, J = 6.0, N(CH2CH2CH2)2); 3.3 (N(CH2CH2CH2)2); 6.9-6.2 (4H, m, 1,9,10,11-H); 7.2 (1H, s, 7-H); 7.3 (2H, d, J = 8.2, 2',6'-H); 7.5 (2H, d, J = 8.2, 3',5'-H); 7.6 (1H, d, J = 7.9, 12-H); 8.0 (1H, s, 14-H)
71
67
71
58
79
66
72
45
When considering a possible reaction mechanism it should be noted that, while not appearing possible to determine which of the nitrogen atoms (the nitrogen of the 2-imino group or one of the nitrogen atoms of the benzimidazole ring) undergoes initial attack by the electrophilic carbonyl group of the aromatic aldehyde, a necessary stage after the formation of the intermediate hemiaminal (a or b) is the fission of a molecule of water.
N a 1+2 C O N H b N
N OH Ar or C O N HO N .. H H Ar _ 3
..
H
OH
H +
In both possible transition states for the second stage, the methine carbon atom is surrounded by three electron-acceptor atoms (the two nitrogen atoms and the oxygen atom) and must be markedly electron deficient. Electron-donor substituents in the aryl radical can partially compensate for the deficit of electron density for this atom, lowering the energy of the transition state for the irreversible terminal stage of the departure of a hydroxyl group (typical of substitution reactions occurring via an SN1 mechanism). In the reactions with the aldehydes 2a-e which give the 2-iminocoumarin hydrolysis products (the 3-benzimidazolylcoumarins 4a-c) it can be stated with confidence that the aldehyde participates in the hydrolysis process. This is confirmed by the fact that a blank experiment (refluxing the 3-benzimidazolyl-2-iminocoumarin 1a in n-pentanol in the presence of piperidine for 10 h) shows no production of the corresponding coumarin 4a. Evidently the function of the aldehyde is to form an aldimine. When using DMF as reaction medium the unsubstituted 2-iminocoumarin 1a and 5-methoxysalicylaldehyde 2k give the isomer 7-(2-hydroxy-5-methoxyphenyl)-14H-benzo[4,5]imidazo[1,2-c]benzopyrano[3,2-e]pyrimidine (5a) but the para-dimethylaminobenzaldehyde 2f leads to a mixture of the isomers 5b and 3a in the ratio 1:2 (method A).
12 13 11 10
14
2k
2 3 4
N8 O
5
N
6
Me
N N H O 1a NH
DMF piperidine H 2f Method A O H
5a
HO
N N N
+
Me
3a
5b
N Me
These facts caused us to turn our investigation to the effect of solvent on the reaction course. It was found that the 7H-derivatives 3a-k obtained in n-pentanol behaved differently, depending on the substituent, when heated in DMF in the presence of piperidine. If the aryl radical contains hydroxy and methoxy groups 337
together, as occurs in compounds 3d,e,g, the isomerization occurs fully to give the 14H-isomers 5e,f,h respectively (Table 2). Completion of this reaction needs about 2 h refluxing. If the aryl radical contains only one donor substituent (a hydroxy or dimethylamino group, compounds 3a-c,f, method B) then after 2 h refluxing in DMF in the presence of piperidine a new product is found in the reaction medium (TLC analysis) which does not increase upon subsequent, prolonged reflux. Such behaviour points to the presence of an equilibrium between the two isomers of 3a-c,f and 5b-d,g respectively.
N N O 5bh N R2
N R1 O N R2 N H 3d,e,g 3ac,f 3hk
H Method B R1
5 bf R1 = H, b R2 = 4-NMe2, c R2 = 4-OH, d R2 = 2-OH, e R2 = 2-OH-3-OMe, f R2 = 4-OH-3-OMe, g, h R1 = 2-MeO, g R2 = 2-OH, h R2 = 2-OH-3-OMe
The 1H NMR spectra of the precipitates formed upon cooling the mixtures also supported the presence of a mixture of the two isomers of 5b-d,g and 3a-c,f while in the case of the para-dimethylamino derivatives 5b and 3a a mixture of the same composition (1:2, method B) is formed as in the direct reaction of para-dimethylaminobenzaldehyde with 2-iminocoumarin 1a in DMF (method A). The pure 14H-derivatives 5d,g can be prepared in good yield by a double recrystallization of the equilibrium mixture from DMF (Table 2). In the case of the 3-diethylamino derivatives 3h-k the isomerization is not observed. Basic catalysis of the isomerization infers separation of a methine proton. In view of the absence of isomerization in alcohol medium it can be proposed that the anion is unstable under these conditions and can be rapidly protonated. On the other hand, in the aprotic dimethylformamide the anion is more stable and can exist for quite a long time thus bringing about a proton addition at position 14 and hence we were able to separate the thermodynamically more stable isomer or to observe the equilibrium. Based on such a mechanism we favored the proposal that acid may also serve as catalyst. In fact, in the protic n-butanol in the presence of sulfuric acid an equilibrium between the isomers of 5b and 3a is also observed but with a rather different ratio of isomers (3:4, method B). The position of the equilibrium depends on the relative thermodynamic stability of the isomers and the properties of the medium, hence the nature of the substituent in the coumarin and aryl fragments determines the ability of the 7H-derivatives 3a-k to undergo isomerization. The presence in the 7H-derivatives of a donor substituent in position 3 (compounds 3h-k) evidently stabilizes the 7H-isomer due to conjugation of the dimethylamino group with the acceptor benzimidazole and iminolactone heterocyclic system fragments hence these derivatives do not isomerize. On the other hand, donor substituents in the aryl radical stabilize the 14H-isomer thanks to their conjugation with the acceptor pyrimidine ring. The 1H NMR spectra of the synthesized compounds fully agree with the structure proposed (see Tables 1 and 2 and also [7]). The singlet for the methine proton at position 7 in the 7H-derivatives 3a-m appears in the aromatic proton resonance region (7.0-7.5 ppm) but, none the less, its chemical shift can be identified in the majority of cases. To a significant extent the position of this signal depends on the nature of the substituent in the coumarin and aryl fragments of the molecules (see Table 1). The chemical shift of the singlet for the proton at position 14 depends only on the nature of the substituent R1. This signal is subsequently shifted to high field with an increase in the donor strength of the substituent R1 when going from the compounds unsubstituted in the coumarin fragment of the compounds 3b-e to the julolidine derivatives 3l,m. The multiplet for the ABCD spin system of the four benzimidazole protons is seen at 7.0-7.8 ppm. In several cases the signals for the protons in positions 10 and 12 appear, respectively, as a triplet of doublets at 7.5 and a doublet at 7.6-7.7 ppm with the 338
TABLE 2. Characteristics of the Compounds 5a,d-h

Compound 5a Empirical formula C24H17N3O3 Found N, % Calculated N, % 10.63 10.75 11.50 11.38 10.63 10.65 10.63 10.48 10.63 10.54 mp, 281-283 IR spectrum, , cm-1 1456, 1500, 1572 (C=C); 1636, 1667 (C=N); 2837, 2960, 3004, 3040 (); ~3400 (OH) 1454, 1560, 1584 (C=C); 1598, 1630 (C=N); 2848, 2910, 3018, 3050 (); ~3450 (OH) 1455, 1488, 1560 (C=C); 1622, 1648 (C=N); 2832, 2925, 2950 (); ~3550 (OH) 1491, 1573, 1590 (C=C); 1602, 1632 (C=N); 2828, 2890, 2955 (); ~3450 (OH) 1490, 1570, 1590 (C=C); 1604, 1642 (C=N); 2832, 2929, 3006 (); ~3450 (OH) 1455, 1487, 1582 (C=C); 1628, 1640 (C=N); 2828, 2890, 2930, 2982 (); ~3450 (OH)
1
NMR spectrum, , ppm. (J, Hz)
Yield, % 48
5d
C23H15N3O2
291-293
5e
C24H17N3O3
269-271
5f
C24H17N3O3
300-302
5g
C24H17N3O3
288-290
5h
C25H19N3O4
9.88 9.95
299-302
3.8 (3H, s, OMe); 4.3 (2H, s, CH2); 6.7 (1H, d, J = 7.9, 9-H); 7.0-7.3 (6, m, 1,2,4,10,3',6'-H); 7.3 (1H, m, 3-H); 7.4-7.5 (2H, m, 11,4'-H); 7.8 (1, d, J = 7.9, 12-); 9.5 (1, s, ) 4.3 (2H, s, CH2); 6.7 (1H, d, J = 7.9, 9-H); 6.9-7.7 (10, m, 1,2,3,4,10,11,3',4',5',6'-H); 7.8 (1, d, J = 7.9, 12-); 10.1 (1, s, ) 3.9 (3H, s, OMe); 4.3 (2H, s, CH2); 6.6 (1H, d, J = 7.9, 9-H); 7.0-7.3 (5, m, 2,4,10,5',4'- or 6'-H); 7.2-7.4 (2H, m, 3, 4'- or 6'-H); 7.4-7.5 (2H, m, 1,11-H); 7.8 (1, d, J = 7.9, 12-); 9.3 (1, s, ) 3.8 (3H, s, OMe); 4.2 (2H, s, CH2); 6.8 (1H, d, J = 7.9, 9-H); 6.7-7.5 (9H, m, 1,2,3,4,10,11,2',5',6'-H); 7.7 (1, d, J = 7.9, 12-); 9.7 (1, s, ) 3.8 (3H, s, OMe); 4.3 (2H, s, CH2); 6.6 (1H, d, J = 7.9, 9-H); 6.8 (1, dd, J = 8.9, J = 2.7, 3-H); 6.9-7.2 (5, m, 1,4,10,3',5'-H); 7.4 (1, t, J = 7.9, 11-H); 7.5-7.6 (2H, m, 4',6'-H); 7.8 (1, d, J = 7.9, 12-); 10.0 (1, s, ) 3.8 (3H, s, 2-OMe); 3.9 (3H, s, 3'-OMe); 4.3 (2H, s, CH2); 6.6 (1H, d, J = 7.9, 9-H); 6.9 (1, dd, J = 8.9, J = 2.7, 3-H); 7.0-7.2 (5, m, 1,4,10,4'- or 6',5'-H); 7.3 (1, dd, J = 6.4, J = 3.1, 4'- or 6'-H); 7.4 (1, t, J = 7.9, 11-H); 7.8 (1, d, J = 7.9, 12-); 9.3 (1, s, )
63
55
70
60
45
339
Fig. 1. Resulting calculated structures for compounds 3g (a) and 5h (b) using the method of molecular mechanics (MM+). single large spin-spin coupling of J = 7.9 Hz. The signal for the methylene group closest to the nitrogen in the julolidine derivatives 3l,m is partially (for compound 3l) or fully (for 3m) obscured by the signal for the water in the DMSO-d6. In the 1H NMR spectra of the 14H-derivatives 5a-h a singlet is observed in the region 4.2-4.3 ppm for the two protons of the methylene group. Additionally, the characteristic signal for the proton at position 14 in the range 8.2-8.3 ppm is not observed. For a precise and proven assignment of the aromatic proton signals in the spectrum of the derivative 5h we have used the COSY 2D 1H NMR spectroscopic method. The presence of three cross peaks for the doublet at 6.6 ppm shows that this signal lies at an anomalously high field position for a benzimidazole [10], none the less it is assigned to position 9. Such a shift is attributable to the magnetic anisotropy of the aryl radical in position 7. The fact that this proton is found over the plane of the aryl radical in position 7 in the molecule 5h (in contrast to the isomer 3g) is confirmed by structural calculations made by molecular mechanics (Figure 1). Strong bands for a C=N bond are observed in IR spectra of the 7H-derivatives 3b-h,l,m in the region 1600-1680 cm-1. The spectra of the 14H-isomers 5a,d-h show two C=N vibrations at 1598-1667 cm-1. In both series of isomers bands of varying intensity for the C=C bonds in the aromatic and heterocyclic rings are found in the range 1452-1590 cm-1. CH Alkyl bond bands are seen at 2828-2972 cm-1 and weak bands for the aromatic and heterocyclic CH vibrations appear in characteristic regions of the spectrum at 2994-3080 cm-1 (see Tables 1 and 2). Hence the reactivity of 3-(benzimidazol-2-yl)-2-iminocoumarins with aromatic aldehydes is controlled by the nature of the substituent and the conditions for carrying out the reaction. The 7H-derivatives 3h-j,l,m contain a dialkylamino group at position 3 and are high efficiency fluorophores. As was shown in our work [11], they can be used as laser dyes, the generation energy parameters of which exceed the corresponding value for the structurally similar laser dye coumarin 7 (compound 4c).
EXPERIMENTAL IR spectra were measured for KBr tables on a Specord M82 spectrophotometer in the range 400 to 4000 cm-1 and 1H NMR spectra on a Varian Mercury 200 (200 MHz) instrument using DMSO-d6 solvent and TMS internal standard. The purity of all of the products was monitored by TLC using Silufol UV-254 plates and with ethyl acetate as eluent. 340
7-Aryl-7H-benzo[4,5]imidazo[1,2-c]benzopyrano[3,2-e]pyrimidine (3a-m) (General Method). A mixture of the 3-(benzimidazol-2-yl)-2-iminocoumarin 1a-d (3.5 mmol) and the aromatic aldehyde 2a-k (5 mmol) in n-pentanol (10-15 ml) (or the same volume of n-butanol for the 7-dialkylamino derivatives 1c,d) was heated to reflux, piperidine (3-4 drops) was added, and the product was refluxed for 2 h, cooled, and left overnight. The precipitated solid was filtered off, washed with ethanol, and recrystallized from n-butanol or a mixture of n-butanol and DMF (see Table 1). 7-(Hydroxy-5-methoxyphenyl)-14H-benzo[4,5]imidazo[1,2-c]benzopyrano[3,2-e]pyrimidine (5a). A mixture of the 3-(benzimidazol-2-yl)-2-iminocoumarin 1a (2 mmol) and 5-methoxysalicylaldehyde 2k (3 mmol) in DMF (3 ml) was heated to reflux, piperidine (4 drops) added, refluxed for 3 h, cooled, and left overnight. The precipitated solid was filtered off, washed with ethanol, and recrystallized from DMF (Table 2). Equilibrium Mixture of 7-(4-Dimethylaminophenyl)-14H-benzo[4,5]imidazo[1,2-c]benzopyrano[3,2-e]-pyrimidine (5b) and 7-(4-Dimethylaminophenyl)-7H-benzo[4,5]imidazo[1,2-c]benzopyrano[3,2-e]pyrimidine (3a). A. A mixture of 3-(benzimidazol-2-yl)-2-coumarin 1a (2 mmol) and paradimethylaminobenzaldehyde 2f (3 mmol) in DMF (3 ml) was heated to reflux, piperidine (4 drops) added, refluxed for 2 h, cooled, and left overnight. The precipitated solid was filtered off and washed with ethanol. According to 1H NMR data the mixture contains the products 5b and 3a in the ratio of about 1:2. The equilibrium mixture for 5c and 3b was obtained similarly (about 3:5). Recrystallization from DMF and/or AcOH did not lead to the separation of a single product. B. Piperidine (4 drops) was added to 7-(4-dimethylamino)-7H-benzo[4,5]imidazo[1,2-c]benzopyrano[3,2-e]pyrimidine 3a (2 mmol) in DMF (3 ml) and the product was refluxed for 2 h, cooled, and left overnight. The precipitated solid was filtered off and washed with ethanol. According to the 1H NMR data the mixture contains the products 5b and 3a in the ratio of about 1:2. C. Freshly prepared H2SO4 solution in n-butanol (5%, 4 drops) was added to 7-(4-dimethylamino)-7Hbenzo[4,5]imidazo[1,2-c]benzopyrano[3,2-e]pyrimidine 3a (2 mmol) in n-butanol (8 ml), and the product was refluxed for 2 h, cooled, and left overnight. The precipitated solid was filtered off and washed with ethanol. According to the 1H NMR data the mixture contains the products 5b and 3a in the ratio of about 3: 4. 7-Aryl-14H-benzo[4,5]imidazo[1,2-c]benzopyrano[3,2-e]pyrimidine (5d-h) (General Method). Piperidine (4 drops) was added to the 7-aryl-7H-benzo[4,5]imidazo[1,2-c]benzopyrano[3,2-e]-pyrimidine 3c-g (2 mmol) in DMF (3 ml) and the product was refluxed for 2 h, cooled, and left overnight. The precipitated solid was filtered off, washed with ethanol, and recrystallized from a mixture of n-butanol and DMF. In the case of the ortho-hydroxy derivatives 3c and 3f the initially formed precipitate is a mixture of the isomers 5d and 3c or 5g and 3f respectively. A double recrystallization of these precipitates from DMF led to separation of the products 5d and 5g respectively (see Table 2).
REFERENCES 1. 2. 3. 4. 5. 6. 7. C. N. O'Callaghan, T. B. H McMurry, and J. E. O'Brien, J. Chem. Soc., Perkin Trans. 2, 425 (1998). A. A. Karasev, L. L. Lukatskaya, V. I. Rubtsov, O. K. Zhikol, S. N. Yarmolenko, and O. A. Ponomarev, Zh. Obshch. Khim., 65, 1547 (1995). S. M. Kovalenko, I. E. Bylov, K. M. Sytnik, V. P. Chernykh, and Y. V. Bilokin, Molecules, 5, 1146 (2000). http://www.mdpi.org/molecules/papers/51001146.pdf. C. Mhiri, R. El Gharbi, and Y. Le Bigot, Synth. Commun., 29, 3385 (1999). Y. V. Bilokin, M. V. Vasylyev, O. V. Branytska, S. N. Kovalenko, and V. P. Chernykh, Tetrahedron, 55, 13757 (1999). W. Kuzmierkiewicz, Liebigs Ann. Chem., 541 (1987). N. Yu. Gorobets and V. V. Abakumov, Khim. Geterotsikl. Soedin., 1719 (2002). 341
8. 9. 10. 11.
R. M. Christhie and C. H. Lui, Dyes and Pigments, 47, 79 (2000). S. N. Kovalenko, M. V. Vasil'ev, I. V. Sorokina, V. P. Chernykh, A. V. Turov, and S. A. Rudnev, Khim. Geterotsikl. Soedin., 1664 (1998). R. Benassi, R. Grandi, U. M. Pagnoni, and F. Taddei, Magn. Reson. Chem., 24, 420 (1986). V. V. Maslov, N. Yu. Gorobets, A. V. Borisov, and V. M. Nikitchenko, Zh. Prikl. Spektrosk., 70, 698 (2003).
342
SYNTHESIS OF LARIAT DIAZACROWN ETHERS WITH TERMINAL AMINO GROUPS IN THE SIDE CHAINS
N. G. Lukyanenko, T. I. Kirichenko, and S. V. Shcherbakov Treatment of diazacrown ethers with N-(haloalkyl)- and N-(haloethoxy)phthalimides gives the corresponding N,N'- substituted diazacrown ether. Hydrazinolysis of the latter then gives diazacrown ethers with terminal primary amino groups in the side chain. Their reductive methylation using formaldehyde in formic acid gives the dimethylamino derivatives. The presence of a lariat effect was demonstrated by treating the compounds obtained with picrates of alkali and alkaline-earth metals. Keywords: diazacrown ethers, N,N'-substituted, terminal amino groups, lariat effect. Crown ethers with functional donor groups in the side chain (lariat crown ethers) form, in many cases, stronger complexes with metal cations than their unsubstituted analogs and show highly selective complex formation [1-3]. As a rule this is due to the participation of a donor group side chain in the complex formation with the cation. For specific structural compliances this can react with the cation found in the crown ether cavity involving axial positions (the lariat effect) and establish a three dimensional ligand environment around it [4-6]. One of the factors deciding the complex forming properties of the lariat crown ethers is the nature of the side chain donor groups. Among the large group of synthesized lariat azacrown ethers the least studied are compounds having a terminal amino group in the side chain [4]. Such compounds form stable complexes both with hard alkali and alkaline-earth ions and also with weak transition and certain other metal ions [7-10]. In this connection we have synthesized novel substituted diazacrown ethers with terminal amino groups in the side chain and qualitatively assessed the existence of the lariat effect in their reaction with alkali and alkaline-earth metal picrates. Lariat azacrown ethers with amino groups in the side chain are usually prepared by the acylation of azacrown ethers with activated derivatives of -amino acids, by alkylation with -halo acid N,N-dialkylamides and subsequent reduction of the obtained compounds with lithium aluminium hydride or diborane [7, 8], by alkylation of primary amine or secondary diamines with the corresponding dihalides or ditosylates [11, 12], and also by the addition of azacrown ethers to acrylonitrile and reduction of the nitrile group [10]. An interesting method for the preparation of lariat aza- and diazacrown ethers based on compounds with a benzotriazole group in the side chain has been presented [6]. All of the listed methods are not comprehensive since they do not allow the introduction of side chains with varying bond length and nature of functional group. We propose a synthetic route which, in our view, is the most rational and general method for the preparation of substituted azacrown ethers with terminal amino groups in the side chain.
__________________________________________________________________________________________ A. V. Bogatsky Physico-Chemical Institute, Odessa 65080; e-mail: physchem@paco.net. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 421-431, March, 2004. Original article submitted February 14, 2001. 0009-3122/04/4003-03432004 Plenum Publishing Corporation 343
[ N O
]n N O
[ X Y
]m
O N O Na2CO3
2ag 1. N2H4 2. HCl 3. LiOH
1a,b O [ N O Y ]m [ N O 3ae [ H2N Y ]m [ N O 4ae [ Me2N Y ]m [ N O O 5ae O ]n N [ Y ]m NMe2 O O ]n N [ Y ]m NH2 O O ]n N [ Y ]m O N O
CH2O HCOOH
1, 35 a n = 1, b n = 2; 2a,b5a,b m = 0; 2c5c m = 1, Y = (CH2)2; 2d5d m = 1, Y = 0; 2e5e m = 2, Y = 0; 2a X = Br, bd X = Cl, eg X = I
The synthesis of the N,N'-substituted diazacrown ethers 3a-e was carried out by treating diaza-15-crown5 (1a) or diaza-18-crown-6 (1b) with N-(2-bromoethyl)- (2a), N-(6-iodohexyl)- (2e), N-[2-(2-iodoethoxy)ethyl](2f), and N-{2-[2-(iodoethoxy)ethoxy]ethyl}phthalimides (2g). Reaction of diazacrown ethers 1a,b with phthalimide 2a in acetonitrile in the presence of sodium carbonate gives the N,N'-[(2-phthalimido)ethyl]diaza15-crown-5 (3a) and N,N'-[(2-phthalimido)ethyl]diaza-18-crown-6 (3b) in low yield. Carrying out the same reaction without solvent at 100C gives a markedly higher yield of compounds 3a,b. By contrast, this alkylation of the diazacrown ethers 1a,b by the iodides 2f-g under similar conditions did not give satisfactory results. Good yields were obtained when this reaction was carried out in refluxing acetonitrile over 18 h in the presence of sodium carbonate. The increased heating time lowers the yield of the target products, evidently as a result of the partial quaternization of the alkylation product. The starting iodides 2e-g were synthesized from N-(6-chlorohexyl)- (2b), N-[2-(2-chloroethoxy)ethyl](2c), and N-{2-[2-(chloroethoxy)ethoxy]ethyl}phthalimides (2d) by refluxing them with sodium iodide in acetonitrile. The bromide 2a and chlorides 2b-d were prepared by treating potassium phthalimide with dibromoethane, 1,6-dichlorohexane, 1-chloro-2-(2-chloroethoxy)ethane, and 1-chloro-2-[2-(chloroethoxy)ethoxy]ethane respectively. Treatment of hydrazine hydrate with the diazacrown ethers 3a-e gave 70-85% yields of the lariat diazacrown ethers 4a-e which contain terminal primary amino groups in the side chains. The diazacrown ethers with terminal dimethylamino groups 5a-e were prepared by reductive methylation of compounds 4a-e via reaction with formaldehyde in formic acid. 344
TABLE 1. Characteristics of the N,N'- Substituted Diazacrown Ethers 3-5

Compound 3a 3b 3c 3d 3e 4a 4b 4c 4d 4e 5a 5b 5c 5d 5e Empirical formula C30H36N4O7 C32H40N4O8 C40H56N4O8 C36H48N4O10 C40H56N4O12 C14H32N4O3 C16H36N4O4 C24H52N4O4 C20H44N4O6 C24H52N4O8 C18H40N4O3 C20H44N4O4 C28H60N4O4 C24H52N4O6 C28H60N4O8 Found, % Calculated, % H 6.43 6.52 6.62 6.69 7.83 7.85 6.94 6.93 7.19 7.13 10.59 10.62 10.41 10.37 11.38 11.43 10.16 10.12 9.99 9.95 11.18 11.25 10.96 10.89 11.70 11.76 10.64 10.71 10.41 10.43 Mass spectrum, m/z 564 608 720 696 784 304 348 460 436 524 360 404 516 492 580
1
H NMR spectrum(CDCl3), , ppm, spin-spin coupling (J, Hz)
C 63.82 63.74 63.14 63.13 66.64 66.70 62.06 62.11 61.21 61.27 55.24 55.16 55.15 55.20 62.57 62.63 55.02 55.05 54.94 54.93 59.97 59.91 59.37 59.44 65.07 65.11 58.51 58.47 57.90 57.85
N 9.92 9.86 9.20 9.17 7.77 7.72 8.04 8.02 7.14 7.16 18.40 18.50 16.08 16.13 12.16 12.11 12.83 12.75 10.68 10.59 15.54 15.48 13.85 13.87 10.84 10.77 11.37 11.32 9.65 9.62
Yield, % 61 87 40 65 48 84 75 85 70 79 85 63 77 75 63
2.6 (8H, m, NCH2); 2.9 (4H, t, J = 6.9, NCH2); 3.4 (8H, m, OCH2); 3.5 (4H, s, OCH2); 3.6 (4H, t, J = 6.9, CH2N); 7.7 (8H, m, C6H4) 2.7 (8H, t, J = 6.1, NCH2); 2.9 (4H, t, J = 7.0, NCH2); 3.4 (8H, m, OCH2); 3.5 (8H, s, OCH2); 3.7 (4H, t, J = 7.0, CH2N); 7.7 (8H, m, C6H4) 1.4 (16H, m, CH2); 2.6 (12H, m, NCH2); 3.5 (16H, m, OCH2); 3.8 (4H, t, J = 7.2, CH2N); 7.7 (8H, m, C6H4) 2.7 (12H, m, NCH2); 3.5 (24H, m, OCH2); 3.8 (4H, t, J = 5.8, CH2N); 7.7 (8H, m, C6H4) 2.7 (12H, m, NCH2); 3.5 (32H, m, OCH2); 3.8 (4H, t, J = 5.8, CH2N); 7.7 (8H, m, C6H4) 1.5 (4H, br. s , NH); 2.5 (12H, m, NCH2); 2.8 (4H, m, CH2NH2); 3.4 (8H, m, OCH2); 3.6 (4H, s, OCH2) 1.6 (4H, br. s , NH); 2.6 (12H, m, NCH2); 2.8 (4H, m, CH2NH2); 3.4 (8H, t, J = 6.2, OCH2); 3.5 (8H, s, OCH2) 1.1 (4H, br. s , NH); 1.3 (16H, m, CH2); 2.4 (12H, m, NCH2); 2.6 (4H, m, CH2NH2); 3.5 (16H, m, OCH2) 1.5 (4H, br. s , NH); 2.5 (8H, t, J = 6.2, NCH2); 2.6 (4H, t, J = 5.8, NCH2); 2.8 (4H, t, J = 5.8, CH2NH2); 3.3 (8H, t, J = 6.2, OCH2); 3.5 (16H, m, OCH2) 1.9 (4H, br. s , NH); 2.5 (8H, t, J = 6.2, NCH2); 2.6 (4H, t, J = 5.8, NCH2); 2.8 (4H, t, J = 5.8, CH2NH2); 3.3 (8H, t, J = 6.2, OCH2); 3.5 (24H, m, OCH2) 2.2 (12H, s, CH3); 2.5 (16H, m, NCH2); 3.4 (8H, m, OCH2); 3.5 (4H, s, OCH2) 2.2 (12H, s, CH3); 2.5 (16H, m, NCH2); 3.4 (8H, t, J = 6.2, OCH2); 3.5 (8H, s, OCH2) 1.3 (16H, m, CH2); 2.1 (12H, s, CH3); 2.4 (16H, m, NCH2); 3.4 (8H, t, J = 6.2, OCH2); 3.5 (8H, s, OCH2) 2.2 (12H, s, CH3); 2.5 (12H, m, NCH2); 2.7(4H, t, J = 5.8, NCH2); 3.4 (8H, t, J = 6.2, OCH2); 3.5 (16H, m, OCH2) 2.2 (12H, s, CH3); 2.5 (8H, t, J = 6.2, NCH2); 2.6 (4H, t, J = 5.8, NCH2); 2.8 (4H, m, NCH2); 3.4 (8H, t, J = 6.2, OCH2); 3.5 (24H, m, OCH2)
345
346
TABLE 2. Maximum Positions (max) and Relative Shifts (max)* of the Metal Picrate Absorption Bands in the Presence of One Hundred Fold Excess of Compounds 1b, 4, 5b-e and 6 in THF.
Compound 1b 4b 4c 4d 4e 5b 5c 5d 5e 6 LiPi max 357 379 380 378 378 370 378 349 max 10 32 33 31 31 17 32 3 max 380 380 376 380 368 379 358 NaPi max 27 27 23 27 20 26 5 max 364 380 380 379 378 370 379 KPi max 5 21 20 19 18 11 21 max 359 376 380 380 377 375 358 370 376 356 MgPi max 32 49 53 53 50 47 31 43 48 30 max 358 378 390 380 379 378 373 374 352 CaPi max 23 43 45 45 44 43 38 39 17
_______ * max is the difference in position of the metal picrate absorption band in the presence and absence of the ligand.
The value of the induced shift of the absorption maximum of picrate anion (Pi) in low polarity media [13] can serve as a test for the presence of the lariat effect. The method is based on the known dependence of the Pi on the degree of separation of the ion pair of the studied metal picrate. Evidently, the greater the shielding of the metal cation by the lipophilic envelope of the ligand the greater will be the degree of separation of the ion pair of the picrate and, in turn, this will lead to an increase in the bathochromic shift of the picrate anion band. In fact, the crown ether gives rise to a two dimensional ligand around the cation and this leads to a markedly smaller value of Pi than for cryptands which have a three dimensional intramolecular cavity. With the creation of the lariat effect the value of Pi markedly exceeds the shift observed for the unsubstituted compounds and approaches that observed for cryptands and this is quite understandable since, in this case, a three dimensional environment is created around the cation. A spectrophotometric study of the reaction of the substituted azacrown ethers 4b-e and 5b-e with lithium, sodium, potassium, magnesium, and calcium picrates was carried out in tetrahydrofuran. In most cases the addition to the picrate solution of one hundred fold excesses of the ligand gave a maximal possible shift of the picrate absorption (Pi 376-380 nm) and this points to the formation of separated ion pairs. It probably indicates a high stability for the complex since the value of Pi is only slightly sensitive to the ratio of the picrate-ligand concentration to the extent of 1/(2-5) (Table 2). In contrast to this, the unsubstituted diaza-18-crown-6 (1b) and N,N'-dibenzyldiaza-18-crown-6 (6), which cannot show the lariat effect, show a much smaller shift in the absorption maximum of the picrate anion (Pi 349-364 nm) (Table 2). This points to the presence of a lariat effect in compounds 4b-a5b-e. Since the side chains of these diazacrown ethers differ in length, number, and nature of the donor atoms evidently, in each specific example, the participation of particular heteroatoms in complex formation will be determined by the possibility of achieving a structural and electronic maximization for the cation and crown ether side chain respectively. The side chains in compound 4c contain six methylene groups and the lariat effect can be achieved only with the participation of the side amino groups in complex formation. The appearance of gem-dimethyl substituents on the nitrogen atoms in compound 5c evidently hinders their participation in interaction with a cation and as a result, in this case, the shift observed (Pi 358 nm) is similar to that of the unsubstituted diazacrown ether (see Table 2). A markedly smaller shift in the absorption maximum of the picrate anion is observed for the crown ether 5d (Pi 368-373 nm) when compared with its unsubstituted analog 4d (Pi 380 nm). In compounds with a short (4b) or longer (4e) side chain the introduction of methyl substituents at the amino groups does not influence the shift values. Evidently, the observed differences in the spectroscopic behavior of the studied crown ether complexes is due to the possible coordination of the ion with both the nitrogen and the oxygen atoms of the side chain and also the possibility of realizing complexes of different structure. Unfortunately, the data for the values of the induced shifts of picrate anion point only to the participation of the heteroatoms of the side chains in complex formation but do not allow one to make more specific conclusions about the structure of the complexes formed.
EXPERIMENTAL H NMR spectra were recorded on a Bruker AM-250 (250 MHz) instrument using CDCl3 and HMDS internal standard. Mass spectra were obtained on a Varian MAT 112 instrument with an electron impact ionization of 40 and 70 eV. UV spectra were taken on a Specord M40 UV-vis spectrophotometer. The purity of all of the compounds obtained was monitored chromatographically. Thin-layer chromatography was carried out on glass plates with an applied layer of basic aluminium oxide (L 5/40, Chemapol) and using Silufol UV-254 bound layer silica gel plates. GLC was performed on a Chrom-5 apparatus, 3 1500 mm column, 5% SP 2100 on Chromaton N-Super. 1,2-Dibromoethane, 1,6-dichlorohexane, 1,5-dichloro-3-oxapentane, and 1,8-dichloro347
1
3,6-dioxaoctane were used as commercial products. The diazacrown ethers 1a,b were obtained according to the method in [14]. N,N'-Dibenzyldiaza-18-crown-6 (6) was prepared by the method in [5]. N-(2-Bromoethyl)phthalimide (2a). A suspension of potassium phthalimide (43 g, 0.23 mol) in 1,2-dibromoethane (284 g, 1.5 mol) was refluxed for 20 h with vigorous stirring. The excess dibromoethane was distilled off under reduced pressure. The residue was dissolved in benzene (200 ml) and the unreacted potassium phthalimide and 1,2-diphthalimidoethane were filtered off. The benzene was distilled off and the residue was recrystallized from ethanol (55 ml). Yield 43.8 g (75%); mp 82-83C which agrees with that reported [15]. N-(6-Chlorohexyl)phthalimide (2b). A suspension of potassium phthalimide (21 g, 0.11 mol) and 1,6-dichlorohexane (177.7 g, 1.14 mol) has stirred at 130C for 20 h. The cooled product was filtered and the excess 1,6-dichlorohexane was distilled off under reduced pressure. The residue was crystallized from pentane (200 ml). Yield 23.7 g (78%); mp 38-39C. 1H NMR spectrum, , ppm (J, Hz): 1.5 (8H, m, CH2); 3.4 (2H, t, J = 6.2, CH2Cl); 3.6 (2H, t, J = 7.2, CH2N); 7.8 (4H, m, C6H4). Found, %: C 63.17; H 6.11; N 5.19. C14H16ClNO2. Calculated, %: C 63.28; H 6.07; N 5.27. N-[2-(2-Chloroethoxy)ethyl]phthalimide (2c) was prepared similarly from potassium phthalimide (200 g, 1.08 mol) and 1,5-dichloro-3-oxapentane (1522 g, 10.6 mol). After distillation of solvent the residue was crystallized by the addition of pentane (100 ml). The precipitate was filtered off and the product was purified by extraction with pentane in a Soxhlet apparatus for 50 h. Yield 250 g (91.5%); mp 71-72C. 1H NMR spectrum, , ppm (J, Hz): 3.6 (4H, m, CH2O); 3.8 (2H, t, J = 6.6, CH2Cl); 3.9 (2H, t, J = 5.8, CH2N); 7.6 (4H, m, C6H4). Found, %: C 56.87; H 4.83; N 5.44. C12H12ClNO3. Calculated, %: C 56.82; H 4.77; N 5.52. N-{2-[2-(Chloroethoxy)ethoxy]ethyl}phthalimide (2d) was prepared similarly from potassium phthalimide (185 g, 1.0 mol) and 1,8-dichloro-3,6-dioxaoctane (1870 g, 10 mol). Yield 89% as an oil. 1H NMR spectrum, , ppm: 3.5 (8H, m, CH2O); 3.8 (4H, m, CH2Cl, CH2N); 7.5 (4H, m, C6H4). Found, %: C 56.41; H 5.50; N 4.65. C14H16ClNO4. Calculated, %: C 56.48; H 5.42; N 4.70. N-(6-Iodohexyl)phthalimide (2e). A mixture of N-(6-chlorohexyl)phthalimide 2b (23.7 g, 0.09 mol) and freshly ignited sodium iodide (30 g, 0.2 mol) in dry acetonitrile (200 ml) was refluxed for 10 h with vigorous stirring. The precipitated NaCl was filtered off and washed with acetonitrile. The filtrate was evaporated under reduced pressure, the residue was dissolved in chloroform (100 ml), and the solution was washed with a 5% solution of sodium thiosulfate and dried over calcium chloride. Chloroform was distilled off and the residue was recrystallized from pentane (300 ml). The precipitated crystals were filtered off and dried in air. Yield 28.6 g (89.7%); mp 75-76C. 1H NMR spectrum, , ppm (J, Hz): 1.5 (8H, m, CH2); 3.1 (2H, t, J = 6.5, CH2I); 3.6 (2H, t, J = 7.2, CH2N); 7.7 (4H, m, C6H4). Found, %: C 47.12; H 4.48; N 3.88. C14H16INO2. Calculated, %: C 47.08; H 4.51; N 3.92. N-[2-(2-Iodoethoxy)ethyl]phthalimide (2f) was prepared similarly from the phthalimide 2c (91 g, 0.36 mol) and NaI (120 g, 0.8 mol) in acetonitrile (500 ml). After distillation of chloroform the product was crystallized from a mixture of hexane (1250 ml) and benzene (375 ml). Yield 120 g (97%); mp 84-86C. 1 H NMR spectrum, , ppm (J, Hz): 3.2 (2H, t, J = 7.0, CH2I); 3.6 (2H, t, J = 6.0, CH2CH2N); 3.7 (2H, t, J = 7.0, CH2CH2I); 3.9 (2H, t, J = 6.0, CH2N); 7.6 (4H, m, C6H4). Found, %: C 41.82; H 3.56; N 4.02. C12H12INO3. Calculated, %: C 41.76; H 3.50; N 4.06. N-{2-[2-(Iodoethoxy)ethoxy]ethyl}phthalimide (2g) was prepared similarly from the phthalimide 2d (89.1 g, 0.3 mol) and NaI (105 g, 0.7 mol). After distillation of chloroform the product was extracted from the residue with refluxing heptane (1.0 l). The heptane was evaporated to give compound 2g as a light-yellow oil. Yield 113 g (96%). 1H NMR spectrum, , ppm (J, Hz); 2.9 (2H, t, J = 6.9, CH2I); 3.5 (4H, m, CH2O); 3.6 (2H, t, J = 5.8, CH2CH2N); 3.7 (2H, t, J = 7.0, CH2CH2I); 3.9 (2H, t, J = 5.8, CH2N); 7.6 (4H, m, C6H4). Found, %: C 43.15; H 4.21; N 3.67. C14H16INO4. Calculated, %: 43.21; H 4.14; N 3.60. 348
2-(2-{13-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1,4,10-trioxa-7,13-diazacyclopentadecan7-yl}ethyl)-1H-isoindole-1,3(2H)-dione (3a). A mixture of the diaza-15-crown-5 1a (2.18 g, 10 mmol), phthalimide 2a (12.7 g, 50 mmol), and freshly ignited sodium carbonate (5.3 g, 50 mmol) was stirred for 10 h at 100C. Chloroform (30 ml) was added dropwise to the hot solution which was then cooled and the precipitate formed was filtered off and the chloroform evaporated under reduced pressure. The residue was dissolved in a 1:1 mixture of benzene and HCl (1 N). The benzene layer was separated and the aqueous extracted with benzene (50 ml). The aqueous solution was treated with sodium carbonate to pH 9-10 and extracted with benzene (2 50 ml). After distillation of benzene 3a was obtained as a light-yellow oil. Yield 4.0 g. 2-(2-{16-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl}ethyl)-1H-isoindole-1,3(2H)-dione (3b) was prepared similarly from diaza-18-crown-6 1b (2.62 g, 10 mmol) and phthalimide 2a (12.7 g, 50 mmol). After distillation of benzene the residue was recrystallized from a 1:1 mixture of heptane and benzene (70 ml). Yield 5.0 g; mp 116-117C. 2-(6-{16-[6-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)hexyl]-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl}hexyl)-1H-isoindole-1,3(2H)-dione (3c). A mixture of diaza-18-crown-6 1b (7.86 g, 30 mmol), phthalimide (28.6 g, 0.08 mol), and freshly ignited sodium carbonate (32 g, 0.3 mol) in dry acetonitrile (150 ml) was refluxed with stirring for 18 h. After cooling, the precipitate was filtered and the acetonitrile was distilled from the filtrate under reduced pressure. Benzene (100 ml) and 1N HCl (100 ml) were added to the residue. The oily lower layer separated in this way crystallized over 10-12 h. The crystals were filtered off, washed with benzene, and treated with a saturated solution of sodium carbonate (100 ml) at 60C. The product was removed using benzene and the extract was dried over anhydrous sodium sulfate and the solvent distilled off. The residue was crystallized from heptane (400 ml). Yield 9.2 g; mp 41-42C. 2-{2-[2-(16-{2-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]ethyl}-1,4,10,13-tetraoxa-7,16diazacyclooctadecan-7-yl}ethyl)-1H-isoindole-1,3(2H)-dione (3d) was prepared similarly by refluxing diaza18-crown-6 1b (1.05 g, 4 mmol) and the phthalimide 2f (3.45 g, 10 mmol) in the presence of lithium carbonate (3.0 g, 40 mmol) in acetonitrile (20 ml) for 30 h. After distillation of benzene the residue was crystallized from an 18:11 mixture of heptane and benzene. Yield 1.8 g; mp 96-97C. 2-[2-(2-{2-[16-(2-{2-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]ethoxy}ethyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl]ethoxy}ethoxy)ethyl]-1H-isoindole-1,3(2H)-dione (3e) was prepared similarly from diaza-18-crown-6 1b (1.05 g, 4 mmol) and phthalimide 2g (3.9 g, 10 mmol) in the presence of lithium carbonate (3.0 g, 40 mmol). Distillation of benzene gave 3e as a light-yellow oil. Yield 1.5 g. 2-[13-(2-Aminoethyl)-1,4,10-trioxa-7,13-diazacyclopentadecan-7-yl]ethylamine (4a), 2-[16-(2-Aminoethyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl]ethylamine (4b), 6-[16-(6-Aminohexyl)-1,4,10,13tetraoxa-7,16-diazacyclopentadecan-7-yl]hexylamine (4c), 2-(2-{16-[2-Aminoethoxy)ethyl]-1,4,10,13tetraoxa-7,16-diazacyclooctadecan-7-yl]ethoxy)ethylamine (4d), and 2-{2-[2-(16-{2-[2-(2-Aminoethoxy)ethoxy]ethyl}-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl)ethoxy]ethoxy}ethylamine (4e). (General Method). Hydrazine hydrate (67 mmol) was added dropwise with vigorous stirring to a refluxing solution of the diazacrown ether 3 (33 mmol) in ethanol (100 ml). The mixture was refluxed for 7 h and diluted with HCl (6 N, 22 ml). The precipitate was filtered off and ethanol was removed at reduced pressure. Water (120 ml) was added to the residue and the precipitate was filtered off. A saturated aqueous solution of LiOH was added to the filtrate to pH 10-11. The product was extracted with chloroform over 10 h. Distillation of the chloroform gave the diazacrown ether 4 as a light-yellow oil. N-(2-{13-[2-(Dimethylamino)ethyl]-1,4,10-trioxa-7,13-diazacyclopentadecan-7-yl}ethyl)-N,N-dimethylamine (5a), N-(2-{16-[2-(Dimethylamino)ethyl]-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7yl}ethyl)-N,N-dimethylamine (5b), N-6-{16-[6-(Dimethylamino)hexyl]-1,4,10,13-tetraoxa-7,16-diazacyclopentadecan-7-yl}hexyl)-N,N-dimethylamine (5c), N-{2-[2-(16-{2-[2-dimethylamino)ethoxy]ethyl}-1,4,10,13tetraoxa-7,16-diazacyclooctadecan-7-yl)ethoxy]ethyl}-N,N-dimethylamine (5d), and N-[2-(2-{2-[16-(2-{2[2-(dimethylamino)ethoxy]ethoxy}ethyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl]ethoxy}ethoxy)ethyl]-N,N-dimethylamine (5e). (General Method). An aqueous solution of formaldehyde (40%, 5 ml) was 349
added to a solution of the diazacrown ether 4 (1.5 mmol) in formic acid (5 ml). The mixture was refluxed for 10 h, diluted with conc. HCl (10 ml), and evaporated to dryness under reduced pressure. This operation was repeated once more. The residue was dissolved in water (10 ml), diluted with a saturated solution of LiOH to pH 10-11, and extracted with chloroform (5 5 ml). After distillation of chloroform, the product was removed from the residue using refluxing hexane (3 10 ml). The hexane was evaporated to give the diazacrown ether 5 as a light-yellow oil. Method for Determining the Value of the Induced Shift () of the Absorption Band of Metal Picrates in the Presence of Diazacrown Ethers. A sample of the diazacrown ether (5 mmol) was dissolved in a solution of the appropriate metal picrate (5 ml, 0.05 M) in THF. Subsequent dilution with the metal picrate solution then gave solutions with the diazacrown ether:picrate ratios of 50, 10, 2, 1, 0.75, 0.5, and 0.2. Measurements were carried out over 12 h in order to reach system equilibrium. The value of was calculated as the difference between the max of the picrate with a one hundred fold excess of the diazacrown ether and the picrate max in its absence. The results are given in Table 2.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. G. W. Gokel, Chem. Soc. Rev., 39 (1992). K. E. Krakowiak, J. S. Bradshaw, D. J. Zameska-Krakowiak, and R. M. Izat, Chem. Rev., 89, 929 (1989). J. S. Bradshaw and R. M. Izat, Accounts Chem. Res., 30, 338 (1997). J. S. Bradshaw, K. E. Krakowiak, and R. M. Izat, Aza-Crown Macrocycles, John-Wiley and Sons, New York (1993). V. J. Gatto, K. A. Arnold, A. M. Viscariello, S. R. Miller, C. R. Morgan, and G. W. Gokel, J. Org. Chem., 51, 5373 (1986). A. R. Katritzky, O. V. Denisko, S. A. Belyakov, O. F. Schall, and G. W. Gokel, J. Org. Chem., 61, 7578 (1996). D. J. Chadwick, I. A. Cliffe, I. O. Sutherland, and R. F. Newton, J. Chem. Soc., Perkin Trans. 1, 1707 (1984). H. Tsukube, T. Inoue, and K. Hori, J. Org. Chem., 59, 8047 (1994). A. R. Katritzky, S. A. Belyakov (Belykov), A. E. Sorochinsky, P. J. Steel, O. F. Schall, and G. W. Gokel, J. Org. Chem., 61, 7585 (1996). M. W. Hosseini, A. J. Blacker, and J. M. Lehn, J. Chem. Soc., Chem. Commun., 596 (1988). B. D. White, D. M. Dishong, C. Minganti, K. A. Arnold, D. M. Goll, and G. W. Gokel, Tetrahedron Lett., 26, 151 (1985). J. S. Bradshaw, K. E. Krakowiak. H. An, and R. M. Izat, Tetrahedron, 46, 1163 (1990). Y. Inoue, C. Fujiwara, K. Wada, A. Tai, and T. Hakushi, J. Chem. Soc., Chem. Commun., 393 (1987). A. V. Bogatsky, N. G. Lukyanenko, S. S. Basok, and L. K. Ostrovskaya, Synthesis, No. 2, 138 (1984). B. A. Kazanskii (editor), Synthesis of Organic Preparations [Russian translation], Vol. 1, Inostr. Lit., Moscow (1949), p. 143.
350
ACYLATION OF 3,4-DIHYDROPYRROLO[1,2-a]PYRAZINES*
V. I. Terenin, E. V. Kabanova, N. A. Tselishcheva, M. A. Kovalkina, A. P. Pleshkova, and N. V. Zyk The direction of trifluoroacetylation with trifluoroacetic anhydride of 3,4-dihydropyrrolo[1,2-a]pyrazines containing an alkyl or aralkyl substituent in position 1 depends on both the structure of the 3,4-dihydropyrrolo[1,2-a]pyrazine starting materials and on the ratio of reagent:substrate. It may lead to both mono- and disubstituted products. Trifluoroacetylation of 1-methyl-3,4-dihydropyrrolo[1,2-a]pyrazines occurs at the methyl group. Acetylation of 3,4-dihydropyrrolo[1,2-a]pyrazines leads only to N-acetyl-substituted reaction products. Keywords: 3,4-dihydropyrrolo[1,2-a]pyrazine, acetylation, trifluoroacetylation. Organic compounds containing fluorine atoms are of considerable interest to the pharmaceutical, agrochemical, and polymer fields of chemistry [2]. In this paper a method for the preparation of new heteroaromatic trifluoromethyl ketones is described. We have shown previously that formylation of 3,4-dihydropyrrolo[1,2-a]pyrazines, which are analogs of pyrrole with an imino group in the -position of the pyrrole ring, occurs ambiguously and depends on the structure of the 3,4-dihydropyrrolo-[1,2-a]pyrazine starting materials [3]. Acylation of pyrroles with trifluoroacetic anhydride occurs rapidly at 0C [4], but dipyrrolo[1,2-a;2',1'-c]pyrazines gave ditrifluoroacetyl derivatives as the principal reaction products at room temperature [5]. In a continuation of the behavior under electrophilic substitution conditions of pyrrolo[1,2-a]pyrazine [6] and its dihydroanalog, 3,4-dihydropyrrolo[1,2-a]pyrazine, we studied the reaction the 3,4-dihydropyrrolo-[1,2a]pyrazines 1-8, containing alkyl or aralkyl substituents at positions 1 and 6 of the heterocycle, with trifluoroacetic anhydride Reaction of 1-methyl- and 1,6-dimethyl-3,4-dihydropyrrolo[1,2-a]pyrazines 1 and 2 with a 2.5 fold excess of trifluoroacetic anhydride in benzene (method A) led respectively to the formation of trifluoroacetyl derivatives at the methyl group in position 1, 1,1.1-trifluoro-3-(1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yliden)acetone (9) and its 6-methyl-substituted analog 10 with yields of 47-48%.
Me N 1, 2 1, 9 R = H; 2, 10 R = Me CF3 NH 9, 10 O
method A
_______ * For previous Communication, see [1]. __________________________________________________________________________________________ M. V. Lomonosov Moscow State University, Moscow 119899, Russia; e-mail: vter@org.chem.su.ru. Translated from Khimia Geterotsiklicheskikh Soedinenii, pp. 431-442, March 2004. Original paper submitted August 27, 2001. 0009-3122/04/4003-03512004 Plenum Publishing Corporation 351
Analogous results of trifluoroacetylation formation of trifluracetonyl-substituted derivatives have been obtained with a number of methyl-substituted azines [7] such as pyridine, pyrimidine, quinoline, oxazole, benzoxazole, benzimidazole, and benzothiazole, on treatment with a three-fold excess of trifluoroacetic anhydride in the presence of pyridine at room temperature. Pyridine was shown to promote the reaction. It is interesting that the reaction of a 2:1 mixture of 2,6-, 2,4-, or 3,4-dimethylpyridines with acetic anhydride in benzene required refluxing for 6 h, and addition of pyridine reduced the yield of the reaction products. Compounds 9 and 10, which are nitrogen-containing analogs of 1,3-diketones, can exist in three tautomeric forms, in the case of compound 9 as isomers 9a-c:
N N 9a H O
CF3
N N 9b O
CF3
N N 9c H O
CF3
It was confirmed from the 1H and 13C NMR spectra that the imino ketone forms 9b and 10b do not exist in deuterochloroform solution ( signals of the methylene group in position 1 were not observed). The differences between the tautomeric forms 9a and 9c are negligible because the transformation of one into the other consists of the small shift of the acid proton relative to the oxygen and nitrogen and the energy of the barrier between them is not large. Compounds similar to 9 and 10 exist in solution predominantly (to 95%) in the an amino ketone form, depending on the solvent [8]. In the 1H NMR spectra of compound 9, signal of only one form are observed, presumably the enamino ketone form 9a, whereas in the spectra of compound 10 the signals of the two tautomeric forms 10a and 10c, are observed. If the treatment of compound 1 with excess trifluoroacetic anhydride was carried out in the presence of pyridine (method B), the yield of compound increased to 75%. When the reaction of the substrate was with an equimolar amount of trifluoroacetic anhydride in the presence of pyridine (method C) the direction of the reaction changed to give a 62% yield of 1-methylene-2-trifluoroacetyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (11), i.e., the product of acylation at the nitrogen atom of the pyrazine ring, N(2).
method C
N N 11
CH2 CF3 O
method A or B
Unlike the trifluoroacetonyl derivatives 9 and 10, compound 11 is unstable and rapidly polymerizes in the air and in solution. On treatment with an excess of trifluoroacetic anhydride compound 11 is converted into the more stable compound 9. In the case of 1,6-dimethyl-3,4-dihydropyrrolo[1,2-a]pyrazine (2) trifluoroacetylation in the presence gave only compound 10 (the yield of the reaction product dropped from 44 to 12% with an equimolar ratio of the reagents). Reaction of the 3,4-dihydropyrrolo[1,2-a]pyrazines 3-7, which have substituents other than methyl at position 1, with excess trifuoroacetic anhydride gave disubstitution at N(2) and in the pyrrole ring. For example, compounds 3-5, in which the -position of the pyrrole ring is free for electrophilic attach, gave ditrifluoroacetyl derivatives at N(2) and at C(6) respectively 1-ethyliden-, 1-propyliden-, and 2,6-di(trifluoroacetyl)-1-(1phenylmethyliden)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines 12-14. The presence of pyridine in the reaction led 352
TABLE 1. Yields of Trifluoroacetyl Derivatives of 3,4-Dihydropyrrolo[1,2-a]pyrazines

Compound 9 10 11 12 13 14 15 Yield, % Method B 75 45 81 73 83 76 Compound 16 17 18 19 20 21 22 Yield, % Method B
Method A 47 48 58 64 62
Method C
Method A
Method C 72 49
12 62
28 39
43 46 41 46
52
to a considerable increase (up to 70-80%) in the yields of the reaction products (see Table 1). Trifluoroacetylation with an equimolar ratio of substrate:reagent in the presence of pyridine led to formation of monosubstituted derivatives at N(2) of the pyrazine ring 15-17:
F3 C
N
N
1517
method C
CF3
O
N
N
35
CH2R
method A or B
N
O
R
N
O
1214
CF3
3, 12, 15 R = Me; 4, 13, 16 R = Et; 5, 14, 17 R = Ph
It should be noted attempts to obtain the N-monosubstituted trifluoroacetyl derivatives 15-17 by treatment of 3,4-dihydropyrrolo[1,2a]pyrazines with trifluoroacetic anhydride in the absence of pyridine were unsuccessful the change to an equimolar ratio of substrate:reagent only led to a considerable decrease in the yields of theditrifluoroacetyl derivatives. When the -position of the 3,4-dihydropyrrolo[1,2-a]pyrazine starting materials was occupied by a methyl group, acylation in the presence of pyridine with an excess of reagent occurred at N(2) and at carbon atoms C(7) or C(8) of the pyrrole ring with the formation of compounds 18 and 19, while with an equimolar ratio of substrate:reagent the N(2) monosubstituted products 20 and 21 were formed. In contrast to the analogous formylation products [4] the exact position of the trifluoroacetyl groups in the pyrrole rings of compounds 18 and 19 could not be established.
COCF3 Me N N 20, 21 O R CF3 6, 7 6, 18, 20 R = Me, 7, 19, 21 R = Et method C Me N N 18, 19 CH2R method A or B Me N N O R CF3
The 1H NMR spectra of the trifluoroacetyl derivatives 12-21 present a complex picture because the compounds are mixtures of the Z- and E-isomers with respect to the double bond at position 1. Moreover each of them may exist as the two configurational isomers relative to the C-N amide bond. In the case of compounds 353

Compound 9 Empirical formula C10H9F3N2O Found, % Calculated, % H N 52.40 52.18 52.88 54.10 51.93 52.18 45.91 45.89 4.08 3.94 4.21 4.54 4.02 3.94 2.76 2.96 11.89 12.17 10.90 11.47 11.86 12.17 8.37 8.23 Mass spectrum, m/z (Irel, %) 230 (M+, 67.6), 162 (12.35), 161 (100), 106 (8.86), 105 (4.86), 104 (6.92), 93 (7.93), 78 (6.52), 77 (4.71) 244 (M+, 55), 176 (10.47), 175 (100), 147 (6.73), 118 (7.63), 107 (9.78), 87 (12.69), 69 (7.61), 44 (15.3) 230 (M+,100), 161 (70.5), 134 (38.38), 133 (86.13), 106 (58.82), 104 (62.49), 93 (53.75), 92 (42.33), 69 (57.64), 51 (50.91) 340 (M+, 55.35), 271 (100), 272 (14.75), 243 (15.98), 174 (10.66), 146 (13.08), 145 (9.87), 69 (24.23), 77 (7.76) 354 (M+, 45.92), 339 (48.94), 285 (100), 257 (58.91), 161 (56.28), 148 (79), 118 (30.29), 69 (92.12), 45 (36.46), 44 (81.46) 402 (M+, 100), 333 (53.20), 332 (17.35), 305 (42.43), 304 (25.24), 208 (35.54), 207 (27.58), 206 (19.09), 105 (25.99) 244 (M+, 89.56), 175 (97.88), 149 (26.34), 148 (54.80), 147 (100), 120 (31.06), 106 (26.30), 92 (40.88), 69 (66.97), 51 (33.13) 258 (M+, 56.84), 243 (100), 230 (21.74), 189 (53.42), 174 (23.81), 161 (62.14), 145 (22.90), 118 (21.73), 117 (17.70), 69 (34.76) 306 (M+, 100), 238 (14.18), 237 (80.44), 209 (44.64), 208 (32.56), 207 (11.38), 180 (20.79), 167 (10.70), 104 (12.43) 354 (M+, 39.06), 285 (100), 257 (58.45), 188 (23.26), 160 (23.20), 159 (15.42), 132 (14.10), 94 (18.57), 69 (40.93), 44 (15.70) 368 (M+, 49.62), 366 (19.81), 353 (65.60), 339 (26.10), 299 (100), 284 (24.52), 273 (18.08), 69 (33.00) 258 (M+, 98.96), 257 (21.25), 231 (27.60), 189 (100), 175 (17.13), 162 (26.43), 161 (78.82), 159 (20.06), 118 (18.26), 69 (22.97) 197 (M+, 14.48), 196 (100), 195 (91.89), 194 (10.86), 193 (7.54), 169 (5.90), 168 (29.97), 167 (26.65), 69 (9.42) 190 (M+, 41.65), 178 (12.23), 175 (19.32), 163 (32.95), 148 (25.15), 147 (100), 136 (12.44), 121 (13.03), 120 (21.53), 119 (11.57) 204 (M+, 51.35), 189 (71.19), 175 (21.15), 161 (51.68), 147 (100), 137 (17.92), 134 (31.25), 121 (18.65), 94 (17.69), 44 (68.98) 252 (M+, 57.93), 211 (12.52), 210 (71.84), 209 (68.55), 208 (21.81), 207 (12.71), 205 (13.63), 180 (17.67), 137 (100) 204 (M+, 73.49), 189 (34.01), 162 (38.90), 161 (100), 147 (5.80), 135 (11.41), 134 (12.89), 133 (7.21), 120 (7.23), 118 (5.41) 218 (M+, 39.38), 203 (58.27), 175 (55.22), 162 (13.34), 161 (100), 159 (11.69), 149 (11.71), 148 (37.28), 135 (12.23), 44 (36.98)
10
C11H11F3N2O
11
C10H9F3N2O
12
C13H10F6N2O2
13
C11H11F3N2O
14
C18H12F6N2O2
51.91 53.74
2.82 3.01
7.01 6.96
15
C11H11F3N2O
16
C12H13F3N2O
17
C16H13F3N2O
62.71 62.74 47.78 47.47 49.24 48.92
4.12 4.28 3.17 3.41 3.94 3.83
8.95 9.15 8.02 7.91 7.59 7.61
18
C14H12F6N2O2
19
C15H14F6N2O2
20
C12H13F3N2O
22
C15H12F3N2O
23
C11H14N2O
24
C12H16N2O
25
C16H16N2O
26
C12H16N2O
27
C13H18N2O
354
14 and 17, which contain a benzylidene group at position 1, the 1H NMR spectra show that compound 14 consists of a mixture of one E- and two Z-isomers relative to the double bonds at position 1, whereas compound 17 is a mixture of E- and Z-isomers. The signal of the proton at position 8 in the pyrrole ring of the E-isomers (5.84-5.89 ppm) is at considerably stronger field than that of the Z-isomers (6.53-6.69 ppm) because it falls into the field of screening by the phenyl substituent. It may be proposed that the interaction of 3,4-dihydropyrrolo[1,2-a]pyrazines with trifluoroacetic anhydride begins with attack of the electrophile on the nitrogen atom of the imino group, N(2), of the 3,4-dihydropyrrolo[1,2-a]pyrazine starting material with formation of an iminium cation, which is stabilized by loss of a proton from a methyl or methylene group in position 1. Disappearance of the imino group deactivates the pyrrole ring and prevents the possibility of electrophilic substitution in the latter.
N N
CH2R
(CF3CO)2O
N +N
CH2R CF3 O COCF3 H+
_ N +N CHR COCF3 N N CHR COCF3
(CF3CO)2O
N N
CHR COCF3
Confirmation of this mechanism is the fact that treatment of 1-phenyl-3,4-dihydripyrrolo[1,2-a]pyrazine (8), which does not have a methyl group in position 1, with an excess of trifluoroacetic anhydride gave a 1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazinium salt (probably a trifluoroacetate) (22) and not a product of acylation of the pyrrole ring:
N N 8
Ph
method A
N +N 22
Ph CF3 O
Acylation of 3,4-dihydropyrrolo[1,2-a]hydrazines 3-7 with acetic anhydride, a weaker electrophile than trifluoroacetic anhydride, led to the formation of only the N-acetylated reaction product ( in the presence of magnesium perchlorate as Lewis acid). Separation of the products of acetylation of 1-methyl and 1,6-dimethyl3,4-dihydropyrrolo[1,2-a]pyrazines 1 and 2 was not successful.
CH2R' N 37 CHR' N 2327 O Me
(MeCO)2O Mg(ClO4)2
3, 23 R = H, R' = Me (65%); 4, 24 R = H, R' = Et (56%); 5, 25 R = H, R' = Ph (25%); 6, 26 R = Me, R' = Me (87%); 7, 27 R = Me, R' = Et (67%)
355
356
TABLE 3. NMR Spectra of the Compounds Synthesized

Compound 1 9 mp, 2 142-143
1
H NMR spectrum (CDCl3), , ppm (J, Hz) 3
13
NMR spectrum (CDCl3), , ppm (J, Hz) 4
10
171
3.76 (2, m, -3(4)); 4.17 (2, m, -4(3)); 5.77 (1, s, =F3); 6.30 (1, dd, J76 = 2.53, J78 = 3.99, H-7); 6.86 (1, dd, J87 = 3.96, J86 = 1.47, H-8); 6.91 (1H, dd, J68 = 1.39, J67 = 2.46, H-6); 11.05 (1H, br. s, NH) 2.30 (3H, s, CH3-6); 3.75 (2H, m, H-3(4)); 4.03 (2H, m, H-4(3)); 5.73 (1H, s, =CHCOCF3); 6.08 (1H, d, J = 3.79, H-7(8)); 6.82 (1H, d, J = 4.2, H-8(7)); 11.05 (1H, s, NH) 4.00-4.13 (4, 2m, -3,4); 5.01-5.60 (2, 2m, =2); 6.17 (1, dd, J78 = 3.80, J76 = 2.77, H-7); 6.44 (1H, dd, J87 = 3.65, J86 = 1.41, H-8); 6.60 (1H, dd, J68 = 1.35, J67 = 2.75, H-6) Acetone-d6: 4.15 (4H, m, H-3,4); 5.15.6 (2H, 2m, = 2); 6.10 (1, dd, J78 = 3.82, J76 = 2.41, H-7); 6.48 (1H, dd, J87 = 3.88, J86 = 1.76, H-8); 6.72 (1H, dd, J68 = 1.50, J67 = 2.67, H-6) Isomer 1: 2.08 (3, d, J = 7.10, =CHCH3); 4.05-4.30, 4.48-4.70 (4H, 2m, H-3,4); 6.08-6.16 (1H, m, =3); 6.58 (1H, m, H-8); 7.30 (1H, dq, JCF3 = 2.18, H-7) Isomer 2: 1.74 (3, d, J = 7.27, =CHCH3); 4.05-4.3, 4.48-4.7 (4H, 2m, H-3,4); 6.42 (1H, q, J = 7.34, =3); 6.52 (1H, d, J = 4.64, H-8); 7.22 (1H, dq, JCF3 = 2.17, H-7) Isomer 1: 1.20 (3, t, J = 7.49, =CH2CH3); 2.48 (2, m, J = 7.28, =CH2CH3); 4.10-4.28 (2H, m, H-3(4)); 4.50-4.61 (2H, m, H-4(3)); 6.00 (1H, t, J = 7.29, =23); 6.53 (1H, m, H-8); 7.28 (1H, dq, JCF3 = 2.19, H-7) Isomer 2: 1.13 (3, t, J = 7.57, =CH2CH3); 2.09 (2, m, J = 7.39, =CH2CH3); 4.10-4.28 (2H, m, H-3(4)); 4.50-4.61 (2H, m, H-4(3)); 6.27 (1H, t, J = 7.28, =23); 6.53 (1H, m, H-8); 7.23 (1H, dq, JCF3 = 2.14, H-7)
11
142
39.74, 43.35 (C-3,4); 83.11 (=CHCOCF3); 110.85, 113.80 (C-7,8); 118.01 (JC-F=288, CF3); 122.53 (C-8a); 126.15 (C-6); 155.92 (C-1); 175.09 (JC-F=32, =) 11.50 (CH3); 39.54, 40.30 (C-3,4); 82.68 (=CHCOCF3); 110.37, 113.98 (C-7, 8); 118.00 (q, JC-F=288, CF3); 121.76, 135.62 (C-6, 8a); 155.87 (C-1), 174.31 (q, JC-F=32, C=O) 44.00-44.22 (m, C-3,4); 103.01, 105.44, 109.63, 120.84 (C-6,7,8,=CH2), 116.21 (q, JC-F = 288.2, CF3); 124.93, 128.17 (C-1,8a); 156-156.2 (C=O)
12
13
TABLE 3 (continued)
1 14 2 * 3 Isomer 1: 3.55.2 (4H, 4m: 3.55, 4.35, 4.70, 5.09, H-3,4); 6.69 (1H, d, J = 4.70, H-8); 7.09 (1H, s, =CHPh); 7.26-7.28 (1H, m, H-7); 7.28-7.45 (5H, m, Ph) Isomer 2: 4.25, 4.52 (4H, 2m, H-3,4); 5.89 (1H, d, J = 4.92, H-8); 6.987.00 (1H, m, H-7); 7.28-7.45 (6H, m, =HPh) Isomer 3: 4.00-4.75 (4H, m, H-3,4); 6.64 (1H, d, J = 4.84, H-8); 7.00 (1H, s, =CHPh); 7.28-7.45 (6H, m, -7, Ph) Isomer 1: 1.95 (3, d, J = 7.31, =CHCH3); 4.09 (4H, m, H-3, 4); 5.68 (1H, q, J = 7.16, =CHCH3); 6.26 (1H, dd, J76 = 2.76, J78 = 3.71, H-7); 6.34 (1H, d, J = 2.61, H-8); 6.66 (1H, m, H-6) Isomer 2: 1.63 (3, d, J = 7.17, =CHCH3); 4.09 (4H, 4m, H-3, 4); 6.01 (1H, q, J = 7.35, =CHCH3); 6.16 (1H, dd, J76 = 2.75, J78 = 3.65, H-7); 6.31 (1H, dd, J86 = 1.46, J87 = 3.85, H-8); 6.57 (1H, dd, J68 = 1.72, J67 = 2.07, H-6) Isomer 1: 1.14 (3H, t, J = 7.53, CH2CH3); 2.38 (2H, m, J = 7.29, CH2CH3); 4.09-4.15 (4H, m, H-3, 4); 5.57 (1H, t, J = 7.01, =CHCH2CH3); 6.24 (1H, dd, J78 = 3.77, J76 = 2.81, H-7); 6.32 (1H, d, J67 = 2.76, H-6); 6.65 (1H, dd, J87 = 2.46, J86 = 1.60, H-8) Isomer 2: 1.06 (3H, t, J = 7.56, CH2CH3); 1.98 (2H, m, J = 7.66, CH2CH3); 3.9-4.3 (4H, 4m, H-3,4); 5.86 (1H, t, J = 7.28, =CHCH2CH3); 6.13 (1H, dd, J78 = 3.70, J76 = 2.95, H-7); 6.30 (1H, m, H-8); 6.54 (1H, dd, J67 = 2.64, J68 = 1.58, H-6) Isomer 1: 3.97-4.27 (4, m, -3,4); 5.84 (1, dd, J86 = 1.36, J87 = 3.82, H-8); 5.98 (1H, dd, J76 = 2.69, J78 = 3.93, H-7); 6.57 (1H, m, H-6); 7.207.40 (6H, m, =CHPh) Isomer 2: 3.00-5.10 (4, 4m, -3,4); 6.24 (1, dd, J76 = 2.92, J78 = 3.50, H-7); 6.53 (1H, dd, J86 = 1.43, J87 = 3.90, H-8); 6.65 (1H, m, H-6); 6.83 (1H, s, =CHPh), 7.207.40 (5H, m, Ph) Isomer 1: 2.00 (3H, d, J = 7.12, =CHCH3); 2.59 (3H, s, CH3-6); 4.01, 4.20 (4H, 2m, H-3,4); 5.85 (1H, m, =CHCH3); 6.75 (1H, s, H-7(8)) Isomer 2: 1.91 (3H, d, J = 7.31, =CHCH3); 2.22 (3H, s, CH3-6); 3.42-5.02 (4H, 4m, H-3,4); 6.47 (1H, s, H-7(8)); 7.31 (1H, q, J = 7.21, =CHCH3) Isomer 3: 1.75 (3H, d, J = 6.94, =CHCH3); 2.24 (3H, s, CH3-6); 3.42-5.02 (4H, 4m, H-3,4); 6.52 (1H, s, H-7(8)); 7.78 (1H, q, J = 7.04, =CHCH3) 4
15
16
Isomer 1: 13.32(CH3); 21.47 (CH2); 43.65, 44.11 (C-3,4); 108.49, 109.47, 120.70, 126.38 (C-6,7,8, =CHCH2CH3); 124.24, 126.93 (C-1,8a); 116.36 (q, JCF = 287, CF3); 156.20 (JCO = 35, C=O)
17
18
357
358
TABLE 3 (continued)
1 19 2 * 3 Major isomer : 1.17 (3H, t, J = 7.58, =CHCH2CH3); 2.38 (2H, m, =CHCH2CH3); 2.59 (3H, s, CH3-6); 4.00, 4.20 (4H, 2m, H-3,4); 5.73 (1H, t, J = 6.88, =CHCH2CH3); 6.71 (1H, s, H-7(8)) Major isomer: 1.93 (3H, d, J = 7.45, =CHCH3); 2.21 (3H, s, CH3-6); 3.90, 4.16 (4H, 2m, H-3, 4); 5.59 (1H, q, J = 7.19, =CHCH3); 5.99 (1H, d, J78 = 3.43, H-7(8)); 6.27 (1H, d, J87 = 3.34, H-8(7)) Major isomer: 1.13 (3H, t, J = 7.38, =CHCH2CH3); 2.21 (3H, s, CH3-6); 2.37 (2H, m, J = 7.38, =CHCH2CH3); 3.91, 4.21 (4H, 2m, H-3,4); 5.49 (1H, t, J = 7.00, =CHCH2CH3); 5.98 (1H, d, J78 = 3.48, H-7(8)); 6.24 (1H, d, J87 = 3.33, H-8(7)) 4.26 (2, m, -3(4)); 4.38 (2, m, -4(3)); 6.53 (1, dd, J76 = 2.49, J78 = 4.35, H-7); 6.99 (1, dd, J87 = 3.98, J86 = 1.35, H-8); 7.30 (1H, dd, J68 = 1.37, J67 = 2.43, H-6); 7.59 (2H, t, J = 7.61, m-Ph); 7.70 (1H, t. m, J = 7.45, p-Ph); 7.87 (2H, d. m, J = 8.45, o-Ph) DMSO-d6: 4.09 (2, m, -3(4)); 4.46 (2, m, -4(3)); 6.57 (1, dd, J76 = 2.33, J78 = 4.26, H-7); 7.02 (1, dd, J87 = 4.13, J86 = 1.26, H-8); 7.65 (2H, t, J = 7.7, m-Ph); 7.76-7.83 (4H, m, -6, o-Ph, p-Ph) Isomer 1: 1.77 (3H, d, J = 7.54, =CHCH3); 2.06 (3H, s, CCH3); 3.0-5.0 (4H, 4m: 3.15, 3.85, 4.11, 4.97, H-3, 4); 5.84 (1H, q, J = 7.24, =CHCH3); 6.13 (1H, dd, J78 = 3.47, J76 = 2.71, H-7); 6.27 (1H, dd, J87 = 3.74, J86 = 1.38, H-8); 6.56 (1H, d, J68 = 1.22, H-6) Isomer 2: 1.97 (3H, d, J = 7.46, =CHCH3); 2.15 (3H, s, CCH3); 3.98 (2, m, -3(4)); 4.08 (2H, m, H-4(3)); 5.46 (1H, q, J = 7.39, =CHCH3); 6.24 (1H, dd, J78 = 3.68, J76 = 2.74, H-7); 6.35 (1H, dd, J87 = 3.70, J86 = 1.44, H-8); 6.65 (1H, d, J68 = 1.2, H-6) Isomer 1: 1.16 (3H, t, J = 7.56, CH2CH3); 2.17 (3H, s, COCH3); 2.41 (2H, m, J = 7.53, =CHCH2CH3); 4.00 (2, m, -3(4)); 4.10 (2H, m, H-4(3)); 5.35 (1H, t, J = 7.20, =CHCH2CH3); 6.24 (1H, dd, J78 = 3.96, J76 = 2.73, H-7); 6.33 (1H, dd, J87 = 3.66, J86 = 1.57, H-8); 6.66 (1H, dd, J67 = 2.50, J68 = 1.71, H-6) 4
20 21
* *
22
165-167 (decomp.)
DMSO-d6: 41.76, 42.31 (C-3,4); 117.30 (JCF = 299, CF3); 113.66, 125.09, 133.79, 134.33 (C-6,7,8, p-Ph); 129.24, 130.18 (o-Ph, m-Ph); 121.87, 129.77 (C-8a, i-Ph); 158.57 (JCO = 31, =);161.01 (C-1)
23
24
TABLE 3 (continued)
1 25 2 * 3 Isomer 1: 1.80 (3H, s, CCH3); 3.25-5.2 (4H, 4m: 3.32, d. t, 3.90, dd, 4.12, d. t, 5.08, dd, H-3, 4); 6.21 (1H, dd, J78 = 3.55, J76 = 2.59, H-7); 6.49 (1H, dd, J87 = 3.86, J86 = 1.69, H-8); 6.64 (1H, m, H-6); 6.64 (1, s, CHPh); 7.19 (1H, t, J = 7.37, p-Ph); 7.31 (2H, t, J = 7.69, m-Ph); 7.39 (2H, d, J = 7.37, -Ph) Isomer 1: 2.36 (3H, s, CCH3); 4.00 (2, m, -3(4)); 4.18 (2H, m, H-4(3)); 5.87 (1H, dd, J87 = 3.82, J86 = 1.57, H-8); 5.97 (1H, dd, J78 = 3.92, J76 = 2.44, H-7); 6.28 (1, s, CHPh); 6.57 (1H, m, H-6); 7.29-7.43 (5H, m, Ph) Isomer 1: 1.95 (3H, d, J = 7.41, =CHCH3); 2.15 (3H, s, CH3-6); 2.21 (3H, s, CCH3); 3.81 (2H, m, -3(4)); 4.10 (2H, m, -4(3)); 5.39 (1H, q, J = 7.43, =CHCH3); 5.99 (1H, dd, J = 3.54, J = 0.52, H-7(8)); 6.28 (1H, d, J = 3.80, H-8(7)) Isomer 2: 1.76 (3H, d, J = 7.54, =CHCH3); 2.07 (3H, s, CH3-6); 2.17 (3H, s, CCH3); 3.1-5.1 (4H, 4m: 3.14, 3.75, 3.86, 5.02, H-3, 4); 5.77 (1H, q, J = 7.23, =CHCH3); 5.87 (1H, dd, J = 3.57, J = 0.79, H-7(8)); 6.35 (1H, d, J = 3.63, H-8(7)) Isomer 1: 1.14 (3H, t, J = 7.63, 2CH3); 2.16 (3H, s, CH3-6); 2.20 (3H, s, CCH3); 2.39 (2, m, J = 7.40, =CHCH2CH3); 3.81 (2H, m, -3(4)); 4.10 (2H, m, -4(3)); 5.27 (1H, t, J = 7.21, =CH2CH3); 5.97 (1H, d, J = 3.39, H-7(8)); 6.26 (1H, d, J = 3.83, H-8(7)) Isomer 2: 1.05 (3H, t, J = 7.60, 2CH3); 2.06 (3H, s, CH3-6); 2.18 (3H, s, CCH3); 2.20-2.25 (2, m, =CHCH2CH3); 3.1-5.1 (4H, 4m: 3.15, 3.76, 3.85, 5.02, H-3, 4); 5.66 (1H, m, =CH2CH3); 5.87 (1H, d, J = 3.00, H-7(8)); 6.26 (1H, d, J = 3.54, H-8(7)) 4 Isomer 1: 21.59(CH3); 41.38, 44.04 (C-3, 4); 104.06, 109.40, 116.19 (C-6,7,8); 121.26 (CHPh); 126.80, 130.73, 135.45 (C-1,8a, i-Ph); 127.18 (p-Ph); 127.84, 128.76 (m,o-Ph); 170.46 (C=O)
26
27
_______ * Mixture of isomers.
359
EXPERIMENTAL H and 13C NMR spectra were recorded on a Varian VXR-400 instrument with TMS as internal standard. Mass spectra were recorded with an MS Kratos instrument (ionization energy 70 eV). The course of reactions was monitored by TLC on Silufol UV-254 strips. The 3,4-dihydropyrrolo[1,2-a]pyrazine starting materials were synthesized by a known method [9]. Elemental analyses and mass spectra are cited in Table 2, NMR spectra in Table 3. Trifluoroacetylation of 3,4-Dihydropyrrolo[1,2-a]pyrazines (General Method). A. A solution 3,4-dihydropyrrolo[1,2-a]pyrazine (3 mmol) in benzene (10 ml) was cooled in ice and then a solution of trifluoroacetic acid (7.5 mmol) in dry benzene (5 ml) was added dropwise with stirring. The reaction mixture was stirred for 3-5 h at room temperature, after which the solvent and excess trifluoroacetic anhydride were removed in a rotary evaporator. The reaction mixture was chromatographed on a silica gel (100/160) column with benzene as eluent. The product was recrystallized from heptane. B. Trifluoroacetic anhydride (3 mmol) in ether (10 ml) was added dropwise to a mixture of 3,4-dihydropyrrolo[1,2-a]pyrazine (3 mmol) and pyridine (3 mmol) in dry ether (10 ml) at room temperature. The reaction mixture was stirred for 3-5 h, poured into cold water, extracted three times with ether, and dried over 4 A molecular sieves. The ether was evaporated in a rotary evaporator and the residue was chormatographed on a silica gel (100/160) column with benzene as eluant. The product was recrystallized from heptane. C. Trifluoroacetic anhydride (7.5 mmol) in dry ether (10 ml) was added dropwise at room temperature to a mixture of 3,4-dihydropyrrol0[1,2-a]pyrazine (3 mmol) and pyridine (7.5 mmol) in dry ether (10 ml). (Further work up was according to method B). Acetylation of 3,4-Dihydropyrrol[1,2-a]pyrazines. Mg(ClO4)2 (30 mg) was added to a solution of 3,4-dihydropyrrolo[1,2-a]pyrazine (5 mmol) and acetic anhydride (120 mmol) in toluene (30 ml). The reaction mixture was kept for a day at room temperature. The solvent and the excess acetic anhydride were evaporated and the residue was chromatographed on a silica gel (100/160 column) with 1:1 heptaneethyl acetate as eluent.
1
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. V. I. Terenin, E. V. Kabanova, M. A. Kovalkina, and A. V. Borisov, Khim. Geterotsikl. Soed., 1272 (1998). J.-P. Begue and D. Bonnet-Delpon, Tetrahedron, 47, 3207 (1991). V. I. Terenin, N. A. Tselishcheva, E. V. Kabanova, A. P. Pleshkova, and N. V. Zyk, Khim. Geterotsikl. Soed., 1395 (2000). W. Cooper, J. Org. Chem., 23, 1382 (1958). V. I. Terenin, E. L. Ruchkina, K. V. Karapetyan, V. I. Mamaev, and Yu. G. Bundel', Khim. Geterotsikl. Soed., 1566 (1995). J. Minguez, M. Castellote, J. Vaquero, J. Garsia-Navio, J. Alvares-Builla, and O. Castano, J. Org. Chem., 61, 4655 (1996). M. Kawase, M. Teshima, S. Saito, and S. Tani, Heterocycles, 48, 2103 (1998). G. O. Dudek and R. H. Holm, J. Am. Chem. Soc., 84, 2691 (1962). V. I. Terenin, E. V. Kabanova, and Yu. G. Bundel', Khim. Geterotsikl. Soed., 763 (1991). S. E. Korostova, A. I. Mikhaev, L. N. Sobenina, S. G. Shevchenko, M. G. Sigalov, I. M. Karataeva, and B. A. Trofimov, Khim. Geterotsikl. Soed., 48 (1989).
360
CONVERSION OF AMINO GROUP IN POSITION 6 OF URACIL

A. A. Yavolovskii and E. I. Ivanov The possibility of substituting amino groups in position 6 of 5-R-uracils (R = H, NO) by hydroxylamine and phenylhydrazine has been demonstrated. The products of substitution 6-hydroxyaminouracil, 5,6-dihydroxydiiminouracil, and 5-nitroso-6-phenylhydrazinouracil are readily oxidized into 1,2,5-oxadiazolo- and 1,2,3-triazolo[3,4-d]pyrimidine N-oxides respectively. Keywords: 5,6-dihydroxydiiminouracil, 6-hydroxyaminouracil, 5-nitroso-6-phenylhydrazinouracil, 1,2,5-oxadiazolo- and 1,2,3-triazolo[3,4-d]pyrimidine N-oxides, nucleophilic substitution, oxidation. The most widely used method for the preparation of pyrimidines with nitrogen-containing functional groups in positions 2,4 (or 6) is the nucleophilic substitution on chloropyrimidines [1-3]. Transamination [4, 5] has received considerably less attention although in some cases aminopyrimidines are much more available than the corresponding 4(6)-chloro derivatives.
O HN + NH3OH O HN O N H 1a,b R = NO O HN O N H 5a,b NO NH NH R [O] HN O N H 6a,b R NH2 R=H O N H 2 NHOH O NOH N H 3 O O N N N R NOH [O] HN O N H 4 O N O N
O + NH3OH R = NO + NHNH3 HN O
1 a R = H, b R = NO; 5 a R = H, b R = t-Bu; 6 a R = H, b R = t-Bu
__________________________________________________________________________________________ A. V. Bogatsky Physico-Chemical Institute, Ukraine National Academy of Sciences, Odessa 65080, Ukraine; e-mail: ivanov.u@paco.net. Translated from Khimiya Geterotsiklicheskikh Soedinenii, pp. 443-446, March, 2004. Original article submitted July 27, 2001. 0009-3122/04/4003-03612004 Plenum Publishing Corporation 361
TABLE 1 . Spectral Characteristics of the Compounds Synthesized

Compound 2 3 4 5a Mass spectrum, m/z (Irel, %) 143(83), 100(100), 68(12), 58(39), 57(14) 154(39), 111(12), 70(10), 68(15), 58(8), 54(10), 53(13), 43(100) 170(100), 154(10), 140(76), 97(10), 70(15), 69(31), 68(7), 67(59), 54(22), 53(14) 247(20), 245(8), 231(18), 229(33), 213(8), 202(8), 200(6), 186(18), 105(24), 92(13), 91(14), 77(100) 303(15), 301(8), 287(59), 285(25), 272(45), 270(95), 149(61), 132(71), 133(100), 119(53), 117(31), 110(30), 105(35), 103(15), 93(20), 91(78), 77(41) 245(28), 229(4), 139(9), 105(27), 96(6), 77(100), 51(19) 301(51), 285(12), 270(35), 230(5), 222(6), 207(11), 161(13), 133(100), 117(16), 105(25), 91(37), 77(21) IR spectrum, , cm-1 3400, 3230-3000, 1730, 1710, 1680, 1660 3320-3000, 1720, 1680, 1600 3510, 3480, 3300-3000, 1750, 1700, 1680, 1660, 1590, 1540, 1520 3250-3000, 1710, 1700, 1680, 1660, 1645, 1590, 1570, 1550, 1530 3250-3000, 1730, 1720, 1700, 1690, 1670, 1650, 1600, 1570, 1630, 1510, 15000 3200-3000, 1720, 1705, 1695, 1690, 1670, 1600, 1560 3240-3000, 1715, 1680, 1590, 1560
5b
6 6b
We have established that 6-aminouracil (1a) and its 5-nitroso derivative (1b) readily undergo acid catalyzed substitutions with hydroxylamine and phenylhydrazine. Use of the free bases or their salts with weak acids does not always lead to the satisfactory results which were achieved by using a mixture of acetate and hydrochloride salts as the nucleophile. We obtained 6-hydroxyaminouracil (2) by refluxing 6-aminouracil (1a) [6,7] for a short time with an excess of a mixture of hydroxylaminium acetate and chloride in water. Substitution of the amino group in 6-amino-5-nitrosouracil 1b by hydroxylamine at 65-75C was completed in 1.5-2 h to give 5,6-dihydroxydiiminopyrimidin-2,4-dione (3). Dioxime 3 is a colorless compound, which dissolves poorly in organic solvents and water, but well in aqueous solutions of amines and alkalis. The molecular ion is absent from the mass spectrum of oxime 3. The heaviest ion in the mass spectrum of 3 corresponds to the loss of water from the molecular ion [M - 18]+. Dioxime 3 is converted to 1,2,5-oxadiazolo[3,4-d]pyrimidin-5(4H),7(6H)-dione (4) by oxidation with concentrated nitric acid. The accessibility of the starting materials and the high yields of this synthesis for furoxanopyrimidine 4 is more effective than methods published previously [8-10]. It should be noted that the dioximes are not formed on nitrosation of 1-R-6-hydroxyamino-3-methyluracils [8,9] but instead the products of oxidative cyclization, furoxanopyrimidines, the mass spectra of which contain intense peaks at [M + 2]+. The authors attributed the presence of these peaks to the addition of two hydrogen atoms as a result of adsorption of water under the spectrometric conditions. In our case the intensity of the [M + 2]+ peaks corresponded to the isotopic composition of 4 which is apparently connected with the low stability of the hydrogenated form 3. In reaction conditions similar to those with hydroxylamine, the substitution of the amino group in 1b by phenylhydrazine gave 5-nitrosophenylhydrazones 5a and 5b. Subsequent oxidation under mild conditions with K3[Fe(CN)6] in alkaline media gave the 1,2,3-triazolopyrimidine N-oxides 6a and 6b. Although the N-oxides 6a and 6b appeared to be stable with respect to 30% hydrogen peroxide, use of H2O2 to oxidize the nitrosohydrazines 5a and 5b was accompanied by side reactions and consequently gave impure 6a and 6b as final products. EXPERIMENTAL Purity of compounds was monitored by TLC on Silufol UV-254 strips. Mass spectra were recorded on a Varian MAT-112 with an ionizing voltage of 70 eV and a chamber temperature of 220C. IR spectra of nujol mulls were recorded with Specord-80 instrument 362
6-Hydroxyaminopyrimidin-2,4-(1H,3H)-dione (2). A mixture of 6-aminouracil 1a (1.0 g, 8 mmol), hydroxylamine hydrochloride (2 g, 30 mmol), and sodium acetate (1.6 g, 20 mmol) was boiled in water (75 ml) until it dissolved. The mixture was slowly evaporated under normal conditions until crystallization began. The precipitate was separated and recrystallized from water. Yield 0.9 g (80%); mp 320C (dec.). Found, %: C 33.62; H 3.48; N 29.11. C4 H5N3O3. Calculated, %: C 33.57; H 3.50; N 29.37. 5,6-Dihydroxydiiminopyridin-2,4-(1H,3H)-dione (3). A mixture of 6-amino-5-nitrosouracil (1.4 g, 9 mmol), hydroxylamine hydrochloride (2 g, 30 mmol), and sodium acetate (1.6 g, 20 mmol) in water (50 ml) was heated to 65-70C with intense stirring to give a colorless solution. The precipitate was filtered off, washed with cold water, and dried in the air. Yield 1.4 g (91%); mp >250C. Found, %: C 30.12; H 2.36; N 32.40. C4H4N4O4. Calculated, %: C 27.90; H 2.33; N 32.56. 1,2,5-Oxadiazolo[3,4-d]pyrimidin-5,7-(4H,6H)dione N-Oxide (4). A solution of compound 3 (1.7 g, 100 mmol) in nitric acid (10 ml) and sulfuric acid (1 ml) was cautiously heated at 40-50C until solution occurred. The reaction mixture was cooled diluted with twice as much water, and neutralized with cold ammonia solution. The precipitate was filtered off, washed with water, and dried in a desiccators over P2O5. Yield 1.48 g (87%); mp 260C. Found, %: C 28.12; H 1.22; N 32.99. C4H2N4O4. Calculated, %: C 28.24; H 1.18; N 32.94. 6-[2-(4-R-Phenylhydrazino)pyrimidin-2,4-(1H,3H)-diones, (5a,b). A mixture of 6-amino-5nitrosouracil 1b , phenylhydrazine hydrochloride (20 mmol), and sodium acetate (15 mmol) in water (150 ml) was heated for 2 h at 70C with intense stirring. The precipitate was filtered off, washed twice with hot water , dried in the air, and washed with toluene until the washing were no longer colored. It was dried in air again to give a yield of 1.98 g (80%) of chromatographically pure 5a; mp 250C. Found, %: C 48.50; H 3.66; N 28.37. C10H9N5O3. Calculated, %: C 48.58; H 3.64; N 28.34. Yield of compound 5b, 2.33 g (77%); mp 232-238C. Found, %: C 55.43; H 5.63; N 23.09. C14H17N5O3. Calculated, %: C 55.45; H 5.61; N 23.10. 1-Oxides of 2-(4-R-Phenyl)-1,2,3-triazolo[4,5-d]pyrimidin-5,7-(4H,6H)diones (6a,b). Compound 5a (10 mmol) and small portions of a saturated aqueous solution of sodium hydroxide (60 mmol) were added with stirring to a solution of K3[Fe(CN)6] (60 mmol) in water (100 ml). Stirring was continued until the color of the initial solution had disappeared. The solution was then neutralized with acetic acid. The precipitate was filtered off, washed with water, and recrystallized from ethanol to give compound 6a (1.84 g, 75%); mp >300C. Found, %: C 48.95; H 2.8; N 28.56. C10H7N5O. Calculated, %: C 48.98; H 2.86; N 28.57. Yield of compound 6b, 1.8 g (60%); mp 250-255C. Found, %: C 55.80; H 4.95; N 23.27. C14H15N3O3. Calculated, % : C 55.81; H 4.98; N 23.25.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. A. V. Ivashenko and O. N. Garicheva, Khim. Geterotsikl. Soedin., 579 (1982). W. Pfleiderer and K. H. Schundehutte, Liebig Ann. Chem., 612, 158 (1958). F. Yoneda and T. Nagamatsu, Synthesis, 177 (1975). G. W. Whitehead and J. J. Traverso, J. Am. Chem. Soc., 82, 3971 (1960). H. Sun, Ch. Zhi, G. E. Wright, D. Ubiali, M. Pregnolato, A. Verri, F. Focher, and S. Spadari, J. Med. Chem., 42, 2344 (1999). W. Traube, Ber., 3035 (1900). K. Burger, Talanta, 8, 77 (1961). F. Yoneda, Y. Sakuma, and M. Ueno, J. Heterocycl. Chem., 10, 415 (1973). F. Yoneda, and Y. Sakuma, J. Heterocycl. Chem., 10, 993 (1973). C. Temple, C. L. Kussner, and J. A. Montgomery, J. Org. Chem., 10, 2086 (1967).
363
[3+2] CYCLOADDITION OF DIMETHYL ACETYLENEDICARBOXYLATE, METHYL ACRYLATE, AND ETHYL ACRYLATE TO 4,5-DIHYDRO-5-METHYL-3H-SPIRO[BENZ2-AZEPINE-3,1'-CYCLOHEXANE] N-OXIDE
A. V. Varlamov1, A. I. Chernyshev1, F. I. Zubkov1, K. F. Turchin2, and A. N. Levov1 The cycloaddition of methyl acrylate and ethyl acrylate to 4,5-dihydro-5-methyl-3H-spiro[benz-2azepine-3,1'-cyclohexane] N-oxide proceeds without either regiospecificity or stereospecificity. Eight geometrical isomers of spiro[isoxazolidino[3,2-a]benz-2-azepine-5,1'-cyclohexane] were formed, of which several were isolated as pure samples. The cycloaddition of dimethyl acetylenedicarboxylate proceeds stereoselectively, leading to spiro[isoxazolino[3,2-a]benz-2-azepine-5,1'-cyclohexane] with cis arrangement of the protons at C(7) and C(11b). Keywords: benz-2-azepines, monosubstituted alkenes, cyclic nitrones, [3+2] cycloaddition. We have already developed a simple synthesis of 3-substituted and 3-spirofused 4,5-dihydrobenz-2azepine N-oxides [1, 2], which provides the first opportunity to carry out a systematic study of the [3+2] cycloaddition of alkenes and alkynes to benz-2-azepine nitrones. In particular, acrylonitrile was found to add to 4,5-dihydro-5-methyl-3H-spiro[benz-1-azepine-3,1'-cyclohexane] N-oxide (1) without regiospecificity or stereospecificity to give all eight theoretically possible isomers of 1-cyano- and 2-cyanotetrahydro-5Hspiro[isoxazolidino[3,2-a]benz-2-azepine-5,1'-cyclohexanes] [3]. On the other hand, the addition of styrene and trimethylvinylsilane to nitrone 1 proceeded regiospecifically to give a ~1:1 mixture of two diastereomers of 2-phenyl- and 2-trimethylsilyltetrahydro-5H-spiro[isoxazolidino[3,2-a]benz-2-azepine-5,1'-cyclohexanes] [4, 5]. In the present work, we studied the addition of dimethyl acetylenedicarboxylate, methyl acrylate, and ethyl acrylate to nitrone 1. Dimethyl acetylenedicarboxylate adds to nitrone 1 even at 0C in dichloromethane to give 1,2-dimethoxycarbonyl-7-methyl-4,6,7,11b-tetrahydro-5H-spiro[isoxazolino[3,2-a]benz-2-azepine-5,1'-cyclohexane] (2). 1H NMR spectroscopy (Table 1) showed that 2 is formed as a ~13:1 mixture of two diastereomers. This conclusion is indicated by finding two signals for H-11b and the methoxy group protons in these spectra. Predominant isomer 2b was isolated in 63% yield as a pure sample by recrystallization of the reaction mixture.
__________________________________________________________________________________________
2
Russian People's Friendship University, 117198 Moscow; e-mail: fzubkov@sci.pfu. edu.ru. Pharmaceutical Chemical Center, All-Russian Pharmaceutical Chemistry Institute, 119815 Moscow; e-mail: turchin@drug.org.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 447-454, March, 2004. Original article submitted June 26, 2001. 0009-3122/04/4003-03642004 Plenum Publishing Corporation
364
TABLE 1. Chemical Shifts (, ppm) and Coupling Constants (J, Hz) in the 1H NMR Spectra of Cycloadducts 2-4 in CDCl3 with TMS as Internal Standard
Compound 2b 3a trans-trans 3b cis-trans 4a trans-trans 4b trans-cis 4c cis-trans 4d trans-trans Compound 2b 3a 3b 4a 4b 4c 4d Protons 1 3.55 q 4.07 q 3.55 q 3.14 ddd 4.03 dt 3.24 ddd 1 2.60 ddd 2.69 ddd 2A 2B 6 2.25 d 2.08 dd 2.19 d 2.08 dd 2.02 dd 2.18 d * 6 1.26 dd 1.42 dd 1.25 dd * * * * 7 3.31 dq 3.47 m 3.30 m 3.47 m * 3.30 m * 7-M 1.40 d 1.35 d 1.39 d 1.37 d 1.30 d 1.38 d 1.37 d 11b 6.31 s 5.03 d 5.09 d 5.03 d 4.73 t 5.09 d 4.71 dd 64 7.50-7.21 m 7.30-7.05 m, 7.28 d 7.30-7.10 m, 7.37 d 7.30-7.05 m, 7.27 m 7.25-7.05 m 7.40-7.10 m 7.40-7.10 m other*2 3.92 s (3) 3.71 s (3) 3.79 s (3) 3.75 s (3) 4.26 q (2) 1.32 t (3) 4.26 q (2) 0.80 t (3) 4.15 q (2) 1.23 t (3) 4.23 q (2) 1.31 t (3)
4.11 4.01 t t 4.18 4.18 d d 4.13 4.01 t t 4.50 dd 4.20-4.10 dd 4.58 dd
1,1 12.4 12.0
1,2 7.6 7.5 7.6 7.0
1,2 7.6 7.5 7.6 8.0
2,1 2.8 2.5
2,1 9.2 8.5
1,11b 7.3 7.5 7.3 8.6 8.0 6.0
Coupling constants 1,11b 2,2 8.6 10.0 7.6 7.2 7.6 11.0
6,6 14.3 14.3 14.0 14.4 14.0 15.0 14.7
6,7 0 2.1 0 2.2 3.0 0 *
6,7 11.5 10.4 11.0 * * * *
7,M 6.7 7.3 7.0 7.2 7.0 7.5 7.3
other 7.0 (Et) 7.0 (Et) 7.1 (Et) 7.1 (Et)
_______ * Protons are masked by the signals of other groups. The chemical shift and coupling constant could not be determined. *2 The broad multiplet of the cyclohexane ring protons in 2-4 seen at ~2.0-1.2 ppm (10H, m, C6H10).
365
Me
5 4 3
Me MeO2CC CCO2Me H MeO2C

1 7
H
5 11b
Me
+ N _ O
020 oC
+
MeO2C
N O
2 3
N O
2a
CO2Me
CO2Me 2b
The stereochemistry of adducts 2 was found using the dependence of the J6e,7a coupling constant on the cis or trans arrangement of H-7 and H-11b of the benz-2-azepine fragment reported in our previous work [1, 6]. The finding of J6a,7a = 11.3 Hz and lack of the corresponding J6e,7a in the spectrum of the major isomer 2b indicated cis arrangement of H-7 and H-11b. In the case of trans arrangement of these protons, the value of the J6e,7a coupling constant would have been found in the range 1.5-3.0 Hz. Protons H-7 and H-11b in the minor isomer clearly have trans arrangement. Thus, the minor isomer 2a and major isomer 2b are formed upon the approach of MeO2CCCCO2Me to the nitrone fragment from the trans and cis position, respectively, relative to the methyl group of N-oxide 1. The cycloaddition of methyl acrylate and ethyl acrylate to nitrone 1 was carried out under thermodynamic control at 110C in toluene and at 80C in benzene, respectively, in the presence of a ten-fold excess of alkene. The yield of the cycloadduct mixture in both cases was close to quantitative. The addition of methyl acrylate and ethyl acrylate, similar to the addition of acrylonitrile [3], proceeds without specificity. Analysis of the 1H NMR spectra of the reaction mixtures in the range 5.9-3.3 ppm, featuring the signals for H-1, H-2, H-7, and H-11b, showed that the cycloaddition yields all eight theoretically possible isomers of 1-alkoxycarbonyl- and 2-alkoxycarbonyl-4,6,7,11b-tetrahydro-5H-spiro[isoxazolidino[3,2-a]benz-2azepine-5,1'-cyclohexanes] (3 and 4). Since complete chromatographic separation of the reaction mixtures proved impossible, we were unable to obtain a quantitative determination of the composition of these mixtures. Two isomers of 1-methoxycarbonylisoxazolidino[3,2-a]benz-2-azepine, namely 3a with trans,trans orientation of the protons at C(7), C(11b), and C(1) in 15% yield and 3b with cis,trans orientation of these protons in 16% yield, were isolated as pure samples upon chromatography of the reaction mixture in the cycloaddition of methyl acrylate. Both these diastereomers are formed through the exo-transition state.
Me
5 4 3
Me + N
1
H
7 5 11b
Me
CO2Me 110 oC H MeO2C

1
+
MeO2C
N O3
2
N O
3a
H 3b
1-Ethoxycarbonylisoxazolidino[3,2-a]benz-2-azepine 4a with trans,trans arrangement of protons H-7, H-11b, and H-1 was isolated as a pure sample in 34% yield and 2-ethoxycarbonyl isomer 4b with trans,cis arrangement of these protons was isolated in 7% yield in the [3+2] cycloaddition of ethyl acrylate. Isomer 4a is formed through an exo-transition state, while 4b is formed through an endo transition state. Furthermore, a ~55:45 mixture of adducts 4c and 4d was isolated in total yield 23%. Adducts 4c and 4d are both formed through an exo transition state.
366
Me
7
H
5 11b
Me
+
H H
H EtO2C CO2Et 80 oC Me
1
N O3
2
N O 4b CO2Et
H 4a H
Me
N O
+
H EtO2C
N O H 4d
EtO2C
H 4c
The three-dimensional structure of methoxycarbonyl isomers 3a and 3b was established using 1H NMR spectroscopy and the nuclear Overhauser effect for H-1, H-7, and H-11b. Protons H-1 and H-11b in both isomers have trans arrangement, while H-7 and H-11b have trans arrangement in adduct 3a but cis arrangement in 3b. We should also note the close similarity of the chemical shift values for the protons in the 1H NMR spectra of isomers 3a and 3b (see Table 1) to the shifts of their cyano analogs [3]. The greatest difference in the chemical shifts is found for H-11b: = 0.15 ppm for isomer 3a and 0.13 ppm for 3b. These differences do not exceed 0.08 ppm for the other protons. The arrangement of H-7, H-11b, and H-1 in 1-ethoxycarbonyl adducts 4a and 4c was found by pairwise comparison of the chemical shift and coupling constants as well as the multiplicities of the corresponding 1 H NMR signals with those for the methoxycarbonyl (3a and 3b) and nitrile analogs [3]. The greatest chemical shift difference for isomers 3a and 4a = 0.07 ppm is observed for H-1, while for the other protons does not exceed 0.04 ppm. The chemical shift differences in the spectra of analogs 3b and 4c also do not exceed 0.04 ppm. The arrangement of H-7, H-11b, and H-2 in 4b and 4d was established analogously. Since the methoxy analogs of these isomers were not isolated, comparison of the 1H NMR spectral data of 4b and 4d was carried out with their nitrile analogs [3]. In this case, the chemical shift differences were found to be significantly greater and reached 0.3 ppm for H-1. In all cases, the J6e,7a coupling constants were taken into account for establishing the arrangement of H-7 and H-11b. This constant varies in the range 1.6-3.0 Hz for trans arrangement of these protons but is equal to zero for cis arrangement (see Table 1). Thus, our findings on the regio- and stereoselectivity of the [3+2] cycloaddition of acrylic acid derivatives to benz-2-azepine nitrone 1 are in accord with the results obtained for other cyclic nitrones [7, 8].
EXPERIMENTAL The IR spectra were taken on a UR-20 spectrometer in KBr pellets for crystalline samples and neat for oils. The mass spectra were taken on a Varian MAT-112 mass spectrometer with direct inlet of the sample into the ion source or on an HP MS 5988 GC/MS at 70 eV ionizing voltage. The 1H NMR spectra were taken on a Bruker WP-200 spectrometer at 200 MHz or Bruker WH-400 spectrometer at 400 MHz in CDCl3 solutions at 25C with TMS as the internal standard. The chemical shifts were measured in ppm on the -scale. Silufol 367
UV-254 plates were used for the thin-layer chromatography with development by iodine vapor. Column chromatography was carried out on Brockmann 0 activity alumina. 1,2-Dimethoxycarbonyl-7-methyl-4,6,7,11b-tetrahydro-5H-spiro[isoxazolino[3,2-a]benz-2-azepine5,1'-cyclohexane] (2). A solution of dimethyl acetylenedicarboxylate (1.50 ml, 12.34 mmol) in dichloromethane (5 ml) was added to a solution of nitrone 1 (3.00 g, 12.34 mmol) in dichloromethane (50 ml) at 0C. The reaction mixture was maintained at 0C for 0.5 h and overnight at 20C. Dichloromethane was distilled off. The residue was recrystallized twice from pentaneether to give 3.00 (63%) 2 as white crystals, which rapidly turn yellow in the air; mp 115-119C (dec.), Rf 0.64 (1:2 ethyl acetatehexane). IR spectrum, , cm-1: 1221 (COC), 1645 (C=C), 1713 and 1759 (C=O). Mass spectrum, m/z (Irel, %): 385 (M+, 15), 326 (100), 298 (39), 294 (29), 266 (13), 238 (8), 226 (36), 211 (21), 198 (22), 172 (23), 155 (19), 143 (24), 130 (40), 115 (38), 91 (18), 81 (22), 77 (19). Found, %: C 68.67; H 7.25; N 3.85%. C22H27NO5. Calculated, %: C 68.57; H 7.01; N 3.64; M+ 385. 1-Methoxycarbonyl-7-methyl-4,6,7,11b-tetrahydro-5H-spiro[isoxazolidino[3,2-a]benz-2-azepine5,1'-cyclohexanes] (3). A mixture of nitrone 1 (2.00 g, 8.20 mmol) and methyl acrylate (7.5 ml, 82 mmol) in toluene (70 ml) was heated at reflux for 20 h with monitoring by thin-layer chromatography. Toluene and excess methyl acrylate were distilled off in vacuum. The residue was subjected to chromatography on a 551.5-cm alumina column with 1:30 ethyl acetatehexane as the eluent. The following pure samples were isolated. Spiro Product 3a was obtained in 14.8% yield (0.40 g) as a yellow oil, Rf 0.55 (1:4 ethyl acetate hexane). IR spectrum, , cm-1: 1735 (C=O). Mass spectrum, m/z (Irel, %): 329 (M+, 86), 314 (25), 300 (15), 286 (100), 273 (6), 270 (30), 256 (6), 240 (11), 226 (36), 218 (21), 202 (15), 172 (9), 156 (9), 143 (59), 129 (41), 115 (20), 97 (53), 82 (30), 54 (33), 40 (32). Found, %: C 73.12; H 8.49; N 4.10. C20H27NO3. Calculated, %: C 72.94; H 8.26; N 4.25; M+ 329. Spiro Product 3b was obtained in 16.3% yield (0.44 g) as white crystals, mp 84-86C (hexane), Rf 0.38 (1:4 ethyl acetatehexane). IR spectrum, , cm-1: 1738 (C=O). Mass spectrum, m/z (Irel, %): 329 (M+, 73), 314 (13), 300 (43), 286 (100), 273 (8), 256 (2), 240 (4), 226 (15), 172 (5), 143 (14), 129 (17), 115 (9), 97 (8), 82 (9), 54 (13), 40 (12). Found, %: C 73.19; H 8.33; N 4.15. C20H27NO3. Calculated, %: C 72.94; H 8.26; N 4.25; M+ 329. 1- and 2-Ethoxycarbonyl-7-methyl-4,6,7,11b-tetrahydro-5H-spiro[isoxazolino[3,2-a]benz-2-azepine5,1'-cyclohexanes] (4). A mixture of nitrone 1 (0.50 g, 2.00 mmol) and ethyl acrylate (2.00 g, 20 mmol) in benzene (10 ml) was heated at reflux for 10 h with monitoring by thin-layer chromatography. Benzene and excess ethyl acrylate were distilled off in vacuum. The residue was subjected to chromatography on a 401.5-cm alumina column with 1:5 ethyl acetatepetroleum ether as the eluent. The following compounds were separated. Spiro Product 4a was obtained in 34% yield (0.23 g) as white crystals; mp 90-91C (from hexane), Rf 0.75 (1:4 ethyl acetatepetroleum ether). IR spectrum, , cm-1: 1731 (C=O). Mass spectrum, m/z (Irel, %): 343 (M+, 79), 328 (26), 314 (16), 300 (100), 287 (4), 270 (16), 240 (4), 232 (25), 226 (42), 216 (10), 196 (5), 184 (7), 172 (9), 156 (8), 143 (51), 129 (34), 115 (16), 98 (38), 91 (12), 77 (11), 55 (46). Found, %: C 73.22; H 8.61; N 4.00. C21H29NO3. Calculated, %: C 73.47; H 8.45; N 4.08; M+ 343. Spiro Product 4b was obtained in 7% yield (0.05 g) as a light yellow oil, Rf 0.60 (1:4 ethyl acetate petroleum ether). IR spectrum, , cm-1: 1733 (C=O). Mass spectrum, m/z (Irel, %): 343 (M+, 70), 328 (26), 314 (10), 300 (100), 287 (6), 270 (16), 271 (7), 232 (38), 226 (50), 224 (12), 216 (7), 172 (9), 156 (8), 143 (39), 129 (39), 115 (18), 113 (12), 98 (31), 91 (19), 77 (11), 55 (40). Mixture of Isomers 4c and 4d was obtained in 23% yield (0.16 g) as a mixture of ~55% 4c and 45% 4d, white crystals; mp 73-75C (hexane), Rf 0.42-45 (1:4 ethyl acetatepetroleum ether). IR spectrum, , cm-1: 1730 (C=O). Mass spectrum, m/z (Irel, %): 343 (M+, 36), 328 (7), 314 (6), 300 (36), 270 (24), 243 (26), 226 (100), 211 (10), 184 (11), 172 (5), 143 (30), 132 (61), 115 (18), 98 (28), 91 (15), 77 (18), 67 (8), 55 (59). Found, %: N 4.05. C21H29NO3. Calculated, %: N 4.08%; M+ 343. The total yield of all cycloadducts 4 after column chromatography was 78%. 368
This work was carried out with the financial support of the Russian Basic Research Fund (Grant 99-03-32942a).
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. A. Varlamov, V. Kouznetsov, F. Zubkov, A. Chernyshev, G. Alexandrov, A. Palma, L. Vargas, and S. Salas, Synthesis, 849 (2001). V. Kouznetsov, A. R. Palma, S. Salas, L. Y. Vargas, F. I. Zubkov, A. V. Varlamov, and J. R. Martinez, J. Heterocycl. Chem., 34, 1591 (1997). A. V. Varlamov, F. I. Zubkov, K. F. Turchin, A. I. Chernyshev, and R. S. Borisov, Khim. Geterotsikl. Soedin., 1360 (2001). A. V. Varlamov, K. F. Turchin, A. I. Chernyshev, F. I. Zubkov, and T. N. Borisova, Khim. Geterotsikl. Soedin., 703 (2000). A. V. Varlamov, F. I. Zubkov, K. F. Turchin, A. I. Chernyshev, and A. N. Levov, Khim. Geterotsikl. Soedin., 1144 (2000). V. V. Kuznetsov, S. V. Lantsetov, A. E. Aliev, A. V. Varlamov, and N. S. Prostakov, Zh. Org. Khim., 28, 74 (1992). P. N. Confalone and E. M. Huie, Organic Reactions, 36, 1 (1988). J.-G. Shvekhgeimer, Khim. Geterotsikl. Soedin., 435 (1998).
369
SYNTHESIS OF 2-TRIHALOMETHYL3,4-DIHYDROTHIENO[2,3-d]PYRIMIDIN-4-ONES
M. V. Vovk, A. V. Bolbut, V. I. Boiko, V. V. Pirozhenko, A. N. Chernega, and A. A. Tolmachev At room temperature, N-(1-chloro-2,2,2-trihaloethylidene)-O-methyl urethanes react with 2-aminothiophenes to form N-(2-thienyl)-N'-(methoxycarbonyl)trihaloacetamidines, which when heated in boiling toluene undergo ring closure to form 2-trihalomethyl-3,4-dihydrothieno[2,3-d]pyrimidin-4ones. Keywords: 2-aminothiophenes, N-(2-thienyl)-N'-methoxycarbonylamidines, 2-trihalomethyl-3,4dihydrothieno[2,3-d]pyrimidin-4-ones, N-(1-chloro-2,2,2-trihaloethylidene)-O-methyl urethanes, intramolecular cyclization. Among the derivatives of thieno[2,3-d]pyrimidines, substances have been observed that have antiviral, fungicidal, and insecticidal activity [1], antibacterial and antiparasitic properties [2], antihypertensive [3], antitumor [4], and antihistaminic [5] action. Two methods are most often used to synthesize the indicated condensed heterocyclic system. The first method includes annelation of 6-chloro-5-formyl(cyano)pyrimidines by 2-mercaptoacetates [6, 7]. The second method is based on condensation of 3-alkoxycarbonyl-2-aminothiophenes with amides [8] and guanidines [9], and proves to be an effective way to obtain 3,4-dihydro[2,3-d]pyrimidin-4ones which in turn are the basic compounds for functionalization of the position 4 with various nucleophilic groups [10, 11]. 3,4-Dihydrothieno[2,3-d]pyrimidin-4-ones with trihalomethyl substituents in the position 2 have not been described in the literature so far, although we should expect that introducing a trifluoromethyl group on the pyrimidine ring should increase the lipophilic properties of the molecule [12]. We have proposed a novel and convenient approach to synthesis of such compounds, based on reaction of N-(1-chloro-2,2,2-trihaloethylidene)-O-methyl urethanes 1a,b [13] with 2-aminothiophenes 2a,b. A detailed study of the discovered reaction allowed us to establish that, despite the biphilic nature of the reagents, the reaction is regioselective and at room temperature proceeds according to the scheme involving N-iminoalkylation of aminothiophenes to form N-(2-thienyl)-N'-(methoxycarbonyl)trihaloacetamidines 3a-d (Table 1). The structure of the latter is consistent with the results of measurements of the 1H NMR spectra (Table 2), in which for compounds 3a,b there are doublets for the C(3)H and C(4)H protons in the ranges 7.03-7.15 ppm and 7.68-7.70 ppm, while for compounds 3c,d we see singlets in the 6.91-7.04 ppm region from the C(3)H proton of the thiophene ring. The IR spectra are characterized by absorption bands for the bonds NH (3230-3300 cm-1), C=O (1690-1750 cm-1), while for compounds 3b,d we also see an absorption band for the C=N bond (1650 cm-1). __________________________________________________________________________________________ Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev 02094; e-mail: hetfos@ukrpack.net, mvovk@i.com.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 455-461, March 2004. Original article submitted June 26, 2001. 370 0009-3122/04/4003-03702004 Plenum Publishing Corporation
Compounds 3a-d, when heated in boiling toluene (3 h), undergo intramolecular cyclization to form thieno[2,3-d]pyrimidin-4-ones 4a-d (see Table 1) as a result of electrophilic attack by the carbonyl group at the -electron-rich C(3) atom of the thiophene ring. The factor determining the cyclization process is probably the increased electrophilicity of the carbonyl group, due to a significant degree to the effect of the trihaloamidine moiety. In the case of aminal 3e with a less electrophilic C=O group, obtained from N-ethylidene urethane 1c [14] and aminothiophene 2b, we did not observe formation of compound 4e either at the temperature indicated in the scheme or at a higher temperature (140C).
Hal3C Cl 1a,b MeO O N Hal3C N H 3ad S R C(O)OR' 110
oC
O N C OMe
+
H2N S 2a,b C(O)OR'
20 oC HCl
O HN Hal3C N 4ad S
R C(O)OR'
1 Hal = F, b Hal = Cl; 2 a R = H, R' = Me; b R = Me, R' = Et; 3, 4 a Hal = F, R = H, R' = Me; b Hal = Cl, R = H, R' = Me; c Hal = F, R = Me, R' = Et; d Hal = Cl, R = Me, R' = Et
O F 3C Ph 1c O N C OMe
O Me C(O)OEt F 3C Ph HN N H S 4e
2b
20
oC
MeO F 3C Ph
Me C(O)OEt
NH N H 3e S
HCl
TABLE 1. Characteristics of Synthesized Compounds 3a-d, 4a-d

Compound 3a 3b 3c 3d 4a 4b 4c 4d Empirical formula 109F3N2O4S 109Cl3N2O4S 1213F3N2O4S 1213Cl3N2O4S 95F3N2O3S 95Cl3N2O3S 119F3N2O3S 119Cl3N2O3S Found, % Calculated, % N Hal 9.29 9.03 7.60 7.79 8.45 8.28 7.58 7.23 9.72 10.07 8.85 8.55 8.86 9.15 8.17 7.88 17.84 18.37 29.23 29.58 17.07 16.85 27.89 27.44 20.63 20.49 32.74 32.47 18.97 18.61 30.27 29.91 mp, C Yield, %
110-111 107-108 118-119 97-98 227-228 238-239 159-160 220-221
78 73 84 80 76 79 74 77
371
The IR and 1H, 19F (Table 2), and 13C (Table 3) NMR spectral data provide support for a cyclic structure for the synthesized compounds, but do not give an unambiguous answer concerning the location of the proton in the amidine system of bonds, which may be substantially affected by a strong acceptor trihalomethyl group. For this reason, we carried out an X-ray diffraction study of compound 4d and established that in the crystal, the proton is located on the nitrogen atom in the position 3, i.e., the target compounds have the structure of 3,4-dihydrothieno[2,3-d]pyrimidin-4-ones.
TABLE 2. Spectral Characteristics of Compounds 3a-d, 4a-d

Compound 3a IR spectrum, , cm-1 NH CO 3285 1690 1730 1650* 1700 1735 1700 1750 1650* 1700 1730 1700 1735 1700 1740 1675 1720 1720 1735
1
NMR spectrum, , ppm, spin-spin coupling constant (J, Hz)
F NMR spectrum, , ppm 72.3
19
3b
3230
3.76 (3H, s, 3); 3.90 (3H, s, 3); 7.03 (1H, d, J = 3.8, CH); 7.18 (1H, s, NH); 7.70 (1H, d, J = 3.8, CH) 3.73 (3H, s, 3); 3.89 (3H, s, 3); 7.19 (2H, m, + NH); 7.68 (1H, d, J = 3.9, CH) 1.37 (3H, t, J = 7.1, CH3); 2.51 (3H, s, 3); 3.78 (3H, s, 3); 4.32 (2H, q, J = 7.1, OCH2); 6.91 (1H, s, (3)); 7.08 (1H, s, NH) 1.36 (3H, t, J = 7.2, CH3); 2.51 (3H, s, 3); 3.74 (3H, s, 3); 4.32 (2H, q, J = 7.2, OCH2); 7.04 (1H, s, (3)); 7.08 (1H, s, NH) 3.90 (3H, s, 3); 8.04 (1H, s, (5)); 14.5 (1H, br. s, NH) 3.90 (3H, s, 3); 8.05 (1H, s, (5)); 14.0 (1H, br. s, NH) 1.33 (3H, t, J = 7.1, CH3); 2.83 (3H, s, 3); 4.35 (2H, q, J = 7.1, OCH2); 13.8 (1H, br. s, NH) 1.37 (3H, t, J = 7.1, CH3); 2.86 (3H, s, 3); 4.33 (2H, q, J = 7.1, OCH2); 13.3 (1H, br. s, NH)
3c
3250
71.8
3d
3300
4a 4b 4c 4d
3110 3200 3200 3200
69.0
68.9
_______ * (C=N). TABLE 3. 13C NMR Spectra, , ppm, Spinspin Coupling Constant (J, Hz) of Compounds 4a-d
Compound 4a 4b 4c 4d R 14.52 14.61 OR' 52.88 52.88 61.36 (2) 13.92 (3) 61.39 (2) 14.00 (3) C(2) 147.13 (q, 2JCF = 37.8) 155.92 146.41 (q, 2JCF = 37.6) 154.88 CHal3 118.02 (q, 1JCF = 276.1) 92.98 117.87 (q, 1JCF =276.3) 92.46 C(4a) 124.47 122.76 123.75 124.76 C(5) 126.89 126.92 142.21 142.24
Compound 4a 4b 4c 4d
C(6) 131.53 131.42 124.66 122.31
C (7a) 159.86 160.36 160.11 160.49
C=O 161.14 161.20 161.35 161.49
C (4) 165.36 165.22 163.69 163.46
372
We observed that in the crystal of compound 4d, there are two symmetrically independent molecules (A and B) having quite complex geometric parameters. A general view of these molecules is shown in Fig. 1; the principal bond lengths and bond angles are given in Table 4. The central bicyclic system in the A and B
TABLE 4. Principal Bond Lengths (d) and Bond Angles () in a Molecule of Compound 4d
Bond S(1)C(1) S(1)C(4) S(2)C(12) S(2)C(15) O(1)C(6) O(4)C(16) N(1)C(4) N(1)C(5) N(2)C(5) N(2)C(6) N(3)C(15) N(3)C(17) N(4)C(16) N(4)C(17) C(1)C(2) C(2)C(3) C(3)C(4) C(3)C(6) C(12)C(13) C(13)C(14) C(14)C(15) C(14)C(16) d, 1.745(6) 1.690(6) 1.721(5) 1.714(5) 1.226(7) 1.235(6) 1.384(7) 1.279(7) 1.364(7) 1.385(8) 1.356(6) 1.290(7) 1.377(6) 1.354(7) 1.354(8) 1.433(8) 1.383(8) 1.430(8) 1.365(8) 1.423(7) 1.379(7) 1.437(8) Angle C(1)S(1)C(4) C(12)S(2)C(15) C(4)N(1)C(5) C(5)N(2)C(6) C(15)N(3)C(17) C(16)N(4)C(17) S(1)C(1)C(2) C(1)C(2)C(3) C(2)C(3)C(4) C(4)C(3)C(6) S(1)C(4)C(3) N(1)C(4)C(3) N(1)C(5)N(2) N(2)C(6)C(3) S(2)C(12)C(13) C(12)C(13)C(14) C(13)C(14)C(15) C(15)C(14)C(16) S(2)C(15)C(14) N(3)C(15)C(14) N(4)C(16)C(14) N(3)C(17)N(4) , deg. 90.7(3) 90.2(2) 114.9(5) 123.7(5) 113.8(5) 124.3(5) 113.4(4) 110.6(5) 112.7(5) 118.5(5) 112.7(4) 124.9(5) 124.6(5) 113.4(5) 114.6(4) 109.7(4) 113.6(5) 116.8(4) 112.0(4) 127.4(5) 113.3(5) 124.3(5)
Fig. 1 General view of two symmetrically independent A and B molecules of compound 4d (of the hydrogen atoms, only the H(2) and H(4) atoms are shown). 373
Fig. 2 Fragment of the crystal packing of compound 4d. The dotted lines indicate intermolecular hydrogen bonds NHO.
molecules is in fact planar: the deviations of the atoms from the mean-square plane are not greater than 0.039 and 0.023 respectively, and the dihedral angle between the 6-membered and 5-membered rings is only 2.4 and 1.2. The geometric parameters of the bicyclic system suggest substantial delocalization of the electron density [15, 16]. The exocyclic system of bonds (C(1)C(9)(=O(2))O(3) in the A molecule and C(12)C(20)(=O(5))O(6) in the B molecule) lies in the plane of the bicycle: the corresponding dihedral angles are 3.1 and 8.2. In the crystal of compound 4d, the molecules are joined into centrosymmetric dimers AA' and BB' by means of a relatively strong [17] hydrogen bond NHO (Fig. 2). The principal geometric parameters of these H bonds are as follows: N(2)O(1) 2.759(7), H(2)O(1) 1.86(6), N(2)H(2) 0.91(6) , N(2)H(2)O(1) 169(4); N(4)O(4) 2.816(6), H(4)O(4) 2.02(5), N(4)H(4) 0.82(5) , N(4)H(4)O(4) 163(4).
EXPERIMENTAL The IR spectra were recorded on a UR-20 in KBr disks. The 1H, 13C, and 19F NMR spectra were obtained on a Varian VXR-300 spectrometer (300 MHz, 75.5 MHz, and 282 MHz respectively) in CDCl3 solutions for compounds 3a-d, (CD3)2SO for compounds 4a-d, internal standards TMS (1H, 13C) and CCl3F (19F). An X-ray Diffraction Study of a Single Crystal of Compound 4d with linear dimensions 0.28 0.38 0.50 mm was carried out at room temperature on an Enraf-Nonius CAD-4 automatic four-circle diffractometer (CuK radiation, ratio of scanning rates /2 = 1.2, max = 70C, spherical segment 0 h 9, -13 k 13, -17 l 17). 374
We collected a total of 5105 reflections, of which 4782 were symmetrically independent (averaging R factor 0.051). The crystals of compound 4d were triclinic, a = 10.615(2), b = 11.213(3), c = 14.440(2) ; = 95.67(2), = 111.39(1), = 107.23(2); V = 1486.5(6) 3; M = 369.63; Z = 4; dcalc = 1.69 g/cm3; = 73.02 cm-1; space group P 1 (N 2). Absorption in the crystal was taken into account by the azimuthal scanning method [18]. The structure was deciphered by the direct method and least-squares refined in the fullmatrix anisotropic approximation using the CRYSTALS software package [19]. In the refinement, we used 3117 reflections with I > 3 (I) (369 refined parameters, number of reflections times the parameter 8.4). All the hydrogen atoms were determined from a difference electron density synthesis and included in the calculation with fixed positions and thermal parameters; only the H(2) and H(4) atoms were refined isotropically. In the refinement, we used the Chebyshev weighting scheme [20] with parameters 2.75, -0.74, 0.87, and -1.08. The final values for the R factors were R = 0.069 and Rw = 0.073, GOF = 1.090. The residual electron density from a difference Fourier series was 0.45 and -0.48 e/3. The complete set of crystallographic data was deposited in the Cambridge Structural Database (No. 165118). N-(2-Thienyl)-N'-(methoxycarbonyl)trihaloacetamidines (3a-d). A solution of aminothiophene 2a,b (5.0 mmol) and triethylamine (0.5 g, 5.0 mmol) in benzene (10 ml) was added with stirring at room temperature to a solution of N-ethylidene urethane 1a,b (5.0 mmol) in benzene (10 ml). After 2 h of stirring, the reaction mixture was heated to boiling and the precipitate of triethylamine hydrochloride was filtered out; the target products precipitated from the filtrate as it cooled. 1-(N-Methoxycarbonylamino)-1-(5-ethoxycarbonyl-4-methyl-2-thienylamino)-1-phenyl-2,2,2-trifluoroethane (3e). Aminothiophene 2b (0.93 g, 5.0 mmol) was added to a solution of N-ethylidene urethane 1c (1.15 g, 5.0 mmol) in benzene (10 ml); the reaction mixture was allowed to stand at room temperature for 12 h, and then it was refluxed for 1 h. The residue after evaporation of the solvent was crystallized from a 1:3 hexane benzene mixture. Yield 72%; mp 150C. IR spectrum, , cm-1: 1720-1760 (C=O), 3300, 3340 (NH). 1H NMR spectrum, , ppm (J, Hz): 1.24 (3H, t, J = 7.2, CH3); 2.29 (3H, s, CH3); 3.53 (3H, s, CH3); 4.13 (2H, q, J = 7.2, CH2O); 6.09 (1H, s, CH); 7.42 (3H, m, Harom); 7.66 (2H, m, Harom); 7.88 (1H, s, NH); 8.59 (1H, s, NH). 19F NMR spectrum, , ppm: -78.1 (s). Found, %: C 52.13; H 4.72; N 6.58. C18H19F3N2O4S. Calculated, %: C 51.92; H 4.60; N 6.73. 2-Trihalomethyl-3,4-dihydrothieno[2,3-d]pyrimidin-4-ones (4a-d). A solution of compound 3a-d (3.0 mmol) in toluene (10 ml) was refluxed for 3 h. The product precipitating after cooling was filtered out and crystallized from ethanol.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. J. M. Cox, J. H. Marsden, R. A. Burrell, and N. S. Elmure, German Offen Patent 2654090; Chem. Abstr., 87, 128906 (1977). P. Schmidt and K. Eichenberger, Ger. Offen Patent 2060968; Chem. Abstr., 75, 88638 (1971). J. B. Press and R. K. Russel, US Patent 4670560; Chem. Abstr., 107, 115604 (1987). V. D. Patil, D. S. Wise, and L. B. B. Townsend, J. Chem. Soc. Perkin Trans. 1, 1853 (1980). F. F. Janssens, L. E. J. Kennis, J. F. Hens, J. L. G. Torremans, and G. S. M. Diels, US Patent 4695575; Chem. Abstr., 109, 37821 (1988). H. Kosaku, S. Mitsuomi, and S. Shigeo, J. Heterocycl. Chem., 27, 717 (1990). J. Clark and M. S. Shanhet, J. Heterocycl. Chem., 30, 1065 (1993). V. I. Shvedov, V. K. Ryzhkova, and A. I. Grinev, Khim. Geterotsikl. Soedin., 459 (1967). H. Link, Helv. Chim. Acta, 73, 797 (1990). A. I. Grinev and N. V. Kaplina, Khim. Geterotsikl. Soedin., 925 (1985). R. Boehm, R. Rech, G. Houbold, and E. Hanniy, Pharmazie, 41, 23 (1986). H. A. McClinton, Tetrahedron, 48, 6555 (1992). 375
13. 14. 15. 16. 17. 18. 19. 20.
L. I. Samarai, V. I. Boiko, and M. N. Gertsyuk, Zh. Org. Khim., 26, 745 (1990). V. N. Fetyukhin, A. S. Koretskii, V. I. Gorbatenko, and L. I. Samarai, Zh. Org. Khim., 13, 271 (1977). M. Burke-Laing and M. Laing, Acta Crystallogr., B32, 3216 (1976). F. H. Allen, O. Kennard, D. G. Watson, L. Brammer, A. G. Orpen, and R. Taylor, J. Chem. Soc. Perkin Trans. 2, 1 (1987). L. N. Kuleshova and P. M. Zorkii, Acta Crystallogr., B37, 1363 (1981). A. C. T. North, D. C. Phillips, F. Scott, and F. S. Mathews, Acta Crystallogr., A24, 351 (1968). D. J. Watkin, C. K. Prout, J. R. Carruthers, and P. W. Betteridge, CRYSTALS, Issue 10, Chemical Crystallography Laboratory, University of Oxford (1996). J. R. Carruthers and D. J. Watkin, Acta Crystallogr., A35, 698 (1979).
376
SYNTHESIS AND PROPERTIES OF SUBSTITUTED ISOXAZOLO[3',4':4,5]THIENO[2,3-b]PYRIDINES

V. K. Vasilin1, E. A. Kaigorodova1, S. I. Firgang2, and G. D. Krapivin1 We synthesized derivatives of a novel heterocyclic system, isoxazolo[3',4':4,5]thieno[2,3-b]pyridine by sequential conversions in three steps: isomerization of 2-(2-R-ethylthio-2-oxo)-3-pyridyl cyanides obtained by alkylation from substituted 3-cyano-2(1H)-pyridinethiones by -halomethyl ketones in alkaline medium, to form 3-aminothieno[2,3-b]pyridines; diazotization of the amino group followed by nucleophilic substitution of the diazonium group by an azido group, bypassing the step of isolating the diazonium salts; and thermolysis of the azides formed. Keywords: 3-aminothieno[2,3-b]pyridines, 3-azidothieno[2,3-b]pyridines, isoxazolo[3',4':4,5]thieno[2,3-b]pyridines, 2-(2-R-ethylthio-2-oxo)-3-pyridyl cyanides, 3-cyano-2(1H)pyridinethiones. 3-Cyano-2(1H)-pyridinethiones are widely used for synthesis of polycondensed heteroaromatic systems [1-4]. We previously obtained compounds containing pyridine, thiophene, and oxazole rings in their structure [5]. The aim of this work was directed synthesis of isoxazolo[3',4':4,5]thieno[2,3-b]pyridines and a study of their physicochemical characteristics. As the starting materials for constructing the tricyclic system, we used substituted 3-cyano-2(1H)pyridinethiones 1-3 and -halomethyl ketones 4a-g. The reaction of pyridinethiones 1-3 with ketones 4a-g was carried out in the presence of a two-fold amount of KOH to bind the evolved hydrogen halide and to ensure ThorpeZiegler cyclization of intermediates 5 to form thienopyridines 6. The alkylation products 5, as shown in our papers [6, 7], can be isolated in pure form and characterized, but in this case they were not the object of our investigation. 3-Aminothieno[2,3-b]pyridines 6 are bright yellow crystals which are quite soluble in polar solvents, and insoluble in water and alkanes; their physicochemical characteristics are given in Table 1. The characteristics of compounds 6a,d,g, which we synthesized earlier, are given in [6-8]. The IR and 1H NMR spectral data were the most informative for establishing the structure of thienopyridines 6 (Table 1). Thus in the IR spectra of compounds 6, there are no absorption bands for the nitrile group in the 2240-2215 cm-1 region or from the C=S group of the thioamide at 1215-1220 cm-1, typical of compounds 1-3, and two absorption bands appear for the stretching vibrations of the NH bond of the amino group at 3520-3340 cm-1 and 3315-3230 cm-1, and also an absorption band for the conjugated carbonyl group at 1605-1590 cm-1. In the 1H NMR spectra there are signals from all the protons, and a broadened singlet for the protons of the amino group is observed in the 7.32-8.17 ppm region. __________________________________________________________________________________________
2
Kuban State Technological University, Krasnodar 350072, Russia; e-mail: organics@kubstu.ru. N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow 119991. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 462-472, March 2004. Original article submitted August 5, 2001. 0009-3122/04/4003-03772004 Plenum Publishing Corporation 377
R2
R2 O X 4ag R
3
N R3 O
+
R
1
N H 13
N 5
NH2 O
S 6ag
1, 6a, 6d-g R1 = Me, R2 = CH2OMe; 2, 6b R1 = CH2OMe, R2 = Me; 3, 6c R1 = R2 = Me; 4-c, 6-c R3 = Ph; 4d, 6d R3 = C6H4Br-4; 4e, 6e R3 = C6H3Cl2-2,4; 4f, 6f R3 = C6H3F2-2,4; 4g, 6g R3 = Ad1
Diazotization of 3-aminothienopyridines 6 was carried out in acetic acid medium in the presence of conc. H2SO4, which ensured good solubility of the starting components at sufficiently low temperatures (5-7C). The low basicity of 2-acyl-substituted aminothienopyridines in the diazotization reaction enables a sufficiently large amount of free amine to exist in the equilibrium mixture, as needed for efficient reaction. The diazonium salts 7a-g obtained in the solutions, immediately after removal of the excess nitrous acid, underwent a nucleophilic substitution reaction with a concentrated aqueous solution of sodium azide.
R2
NH2
R2
O
NaNO2 H2SO4
R
1
+ N2
_ HSO4 O
R3
NaN3
R1
S N 6ag
R3
R2
N3 O
R1
R3
8ag
8a, 8dg R1 = Me, R2 = CH2OMe; 8b R1 = CH2OMe, R2 = Me; 8 R1 = R2 = Me; 8c R3 = Ph; 8d R3 = C6H4Br-4; 8e R3 = C6H4Cl2-2,4; 7f, 8f R3 = C6H4F2-2,4; 8g R3 = Ad1
The 2-acyl-3-azidothieno[2,3-b]pyridines (8) obtained are crystalline compounds ranging from pale cream to light yellow in color and darkening in air, with decomposition temperatures in the range 114-128C (Table 2). The structure of pyridines 8 is supported by the IR, 1H NMR, and mass spectral data (Tables 2, 3, 6). In the IR spectra of products 8, we see the typical very intense absorption band for the azide group at 2105-2125 cm-1. Replacing the amino group with an azide group leads to a shift of the absorption bands for the carbonyl group toward the higher frequency region by 40 cm-1 on the average, to 1625-1660 cm-1 (Table 4). In the 1H NMR spectra, compared with the spectra for the starting aminothienopyridines 6, the signal from the protons of the amino group are missing; the signal from the proton of the pyridine cycle is shifted downfield ( = 0.25-0.35 ppm). 378
TABLE 1. Physicochemical Characteristics of Substituted 3-Aminothieno[2,3-b]pyridines 6a-g

Compound 6 6b 6c 6d Empirical formula C17H16N2O2S C17H16N2O2S C16H14N2OS C17H15BrN2O2S Found, % Calculated, % H N 65.25 65.36 65.20 65.36 68.20 68.06 52.01 52.18 53.64 53.55 58.72 58.61 5.15 5.16 5.14 5.16 5.01 5.00 3.81 3.86 3.69 3.70 4.05 4.05 8.94 8.97 9.05 8.97 9.94 9.92 7.12 7.16 7.37 7.35 8.05 8.04 mp, IR spectrum, , cm-1 C=O NH2 3465 3260 3480 3305 3520 3310 3340 3230 3400 3298 3410 3310 1595 1590 1590 1605
1
NMR spectrum, , ppm (J, Hz) HPy, s 7.01 7.22 7.05 7.00 NH2, s 8.10 7.98 7.96 8.17 Other protons 7.27-7.90 (5H, m, HPh) 7.50-7.76 (5H, m, HPh) 7.50-7.75 (5H, m, HPh) 7.62 (2H, d, 3J = 8.1, 2,6-HAr); 7.82 (2H, d, 3 J = 8.1, 3,5-HAr) 7.50-7.55 (2H, m, 5,6-HAr); 7.71 (1H, d, 4 J = 2.2, 3-HAr) 7.20 (1H, d. d, 4J = 2.7, 3-HAr); 7.33 (1H, d, 3 J = 8.6, 4J = 2.7, 5-HAr); 7.63 (1H, d, 3J = 8.6, 6-HAr) 1.79-1.90 (6H, m, HAd); 2.06-2.20 (9H, m, HAd)
CH3, s 2.66 2.84 2.53 2.78 2.66
OCH3, s 3.45 3.41 3.45
CH2O, s 4.80 4.53 4.80
Yield, % 92 90 89 93
137-138 126-127 203-204 135-136
6e
C17H14Cl2N2O2S
185-186
1595
2.57
3.42
4.86
7.28
8.11
90
6f
C17H14F2N2O2S
169-170
1595
2.58
3.43
4.87
7.28
8.07
92
6g
C21H26N2O2S
68.22 68.08
7.11 7.07
7.50 7.56
176-177
3370 3250
1600
2.80
3.48
4.63
7.13
7.32
96
379
TABLE 2. Some Physicochemical Characteristics of 2-Acyl-3-azidothieno[2,3-b]pyridines 8a-g

Compound 8a 8b 8c 8d 8e 8f 8g Empirical formula C17H14N4O2S C17H14N4O2S C16H12N4OS C17H13BrN4O2S C17H12Cl2N4O2S C17H12F2N4O2S C21H24N4O2S Found, % Calculated, % C H N 60.55 60.34 60.39 60.34 62.39 62.32 49.00 48.93 50.32 50.13 54.70 54.54 63.81 63.61 4.19 4.17 4.18 4.17 3.93 3.92 3.16 3.14 2.98 2.97 3.25 3.23 6.13 6.10 16.50 16.56 16.52 16.56 18.10 18.17 13.36 13.43 13.60 13.69 14.91 14.97 14.06 14.13 . decomp., C 115-117 114-115 118-119 126-128 122-124 118-119 120-122 IR spectrum, , cm-1 N3 2110 2110 2115 2105 2125 2125 2125 C=O 1625 1625 1630 1625 1640 1640 1635 Yield, % 74 79 78 75 83 73 82
The carbonyl group located adjacent to the azide group accelerates the process of decomposition of the azide in the presence of -conjugation, due to formation of a transition state in which nucleophilic attack by the unshared electron pair of the oxygen atom occurs at the nitrogen atom in the plane of the molecule, which promotes formation of oxazoles [9, 10]. A similar pattern is observed in the case of thermolysis of 2-acyl-3azidothienopyridines 8a-g, leading to formation of derivatives of a novel heteroaromatic system: isoxazolo[3',4':4,5]thieno[2,3-b]pyridine 9.
R2 N3 O R1 N 8ag S R3 R1 N 9ag S R3 R2
N O
8, 8d-g, 9a, 9d-g R1 = Me, R2 = CH2OMe; 8b, 9b R1 = CH2OMe, R2 = Me; 8c, 9c R1 = R2 = Me; 8a-c, 9a-c R3 = Ph; 8d, 9d R3 = C6H4Br-4; 8e, 9e R3 = C6H3Cl2-2,4; 8f, 9f R3 = C6H3F2-2,4; 8g, 9g R3 = Ad1
TABLE 3. 1H NMR Spectra of Some of the Synthesized 2-Acyl-3azidothieno[2,3-b]pyridines 8

Compound 8a 8d 8e
1
CH3, s CH3O, s CH2O, s 2.50 2.64 2.63 3.38 3.51 3.50 4.76 5.05 5.03
NMR spectrum, , ppm (J, Hz) Py, s Other protons 7.26 7.46 7.46 7.07-7.62 (5H, m, HPh) 7.80 (2H, d, 3J = 8.1, 2,6-HAr); 7.87 (2H, d, 3J = 8.1, 3,5-HAr) 7.63 (1H, d, 3J = 8.3, 6-HAr); 7.74 (1H, dd, 3J = 8.3, 4J = 2.2, 5-HAr); 7.79 (1H, d, 4J = 2.2, 3-HAr) 7.24-7.90 (3H, m, HAr) 1.70-1.82 (6H, m, HAd), 2.00-2.15 (9H, m, HAd)
8f 8g
2.62 2.62
3.49 3.47
5.03 4.98
7.45 7.40
380
TABLE 4. Physicochemical Characteristics of Compounds 9

Compound 9a 9b 9c 9d 9e 9f 9g Empirical formula C17H14N2O2S C17H14N2O2S C16H12N2OS C17H13BrN2O2S C17H12Cl2N2O2S C17H12F2N2O2S C21H24N2O2S Found, % Calculated, % H 4.50 4.55 4.52 4.55 4.29 4.31 3.36 3.37 3.18 3.19 3.50 3.49 6.55 6.56 mp, N 9.07 9.03 9.05 9.03 10.02 9.99 7.18 7.20 7.39 7.39 8.11 8.09 7.58 7.60 183-184 176-177 202-203 259-260 242-243 233-234 191-192 81 77 84 83 72 78 83 Yield, %
65.93 65.79 65.95 65.79 68.66 68.55 52.29 52.45 53.72 53.84 59.00 58.95 68.30 68.45
The reaction of decomposition of azides 8a-g was carried out in m-xylene at the boiling point of the solvent. The process was completed with approximately 30 min of boiling (according to TLC data). The isoxazolothienopyridines 9a-g were isolated from the reaction mixture in 72 to 83% yields. Products 9 are colorless crystalline compounds that are insoluble in water, alkanes, and ether and are soluble in haloalkanes. Some physicochemical characteristics of compounds 9 are given in Tables 4 and 5. We note that the sets of major lines in the mass spectra of isoxazolothienopyridines 9 and the corresponding azides 8 are identical (Table 6). This allows us to say that extrusion of the nitrogen molecule from the molecular ion of the azides is accompanied by rearrangement to the corresponding isoxazole radical ion (1). Further M+ fragmentation processes do not depend on the route by which this species is obtained: directly from the isoxazolothienopyridine molecule, or as a result of decomposition of the azide molecular ion. The major directions of fragmentation of the molecular ion for compounds 8 and 9 are given in Fig. 1. Some of the priority directions for decomposition of isoxazolo[3',4':4,5]thieno[2,3-b]pyridines containing a methoxymethyl fragment is ejection of a formaldehyde molecule, accompanied by formation of an 2 radical cation (M+ for the compound 9c). Upon abstraction of a methoxymethyl group, the cations 3 (CH2=O+CH3) and 4 are formed. Further fragmentation of the 2 radical cation can occur along two routes: a) cleavage of a methyl radical to form the 4 cation; b) dissociation, leading to the cation 5, the decomposition products of which (the cations 6, 7, 8) give the most intense signals in the mass spectrum. Another direction for fragmentation of M+ (1) includes cleavage of a methyl radical, rearrangement of the cation 9 formed with transfer of a portion to the pyridine nitrogen atom (the rearranged ion 9a) followed by extrusion of a carbon monoxide molecule. Fragmentation of the 10 cation leads to formation of methylnicotinonitrile and the unstable cation 5. Thus the mass spectral fragmentation of 2-acyl-3-azidothieno[2,3-b]pyridines 8 and isoxazolo[3',4':4,5]thieno[2,3-b]pyridines 9 occurs according to a common scheme. In the initial fragmentation step, the methoxymethyl group of the molecule undergoes decomposition. According to a quantum chemical study of the structure of 6-methyl-8-methoxymethyl-3phenylisoxazolo[3',4':4,5]thieno[2,3-b]pyridine (9a) (AM1 method), combining three different types of heterocycles in the same molecule leads to significant changes in the interatomic distances in the aromatic system compared with the corresponding bonds of the isolated rings. An interesting feature is the fact that the common bonds for the heterocycles become longer than in the isolated systems (Fig. 2, Table 7).
381
382
TABLE 5. Spectral Characteristics of 3-R-Isoxazolo[3',4':4,5]thieno[2,3-b]pyridines 9

Compound 9a UV spectrum, max, nm (log ) 212(4.33), 221(4.26) 245(4.19), 254(4.18) 288(4.53), 335(3.90) 212(4.32), 222(4.26) 245(4.13), 257(4.07) 287(4.43), 337(3.87) 210(4.12), 227(3.96) 247(3.90), 256(3.93) 292(4.34), 336(4.14) 207(4.54), 225(4.24) 242(4.16), 253(4.03) 287(4.56), 388(3.89) 212(4.02), 221(4.10) 238(4.00), 244(4.06) 275(4.39), 322(3.57) IR spectrum, , cm-1, =, =N 1600
1
NMR spectrum, , ppm (J, Hz) HPy, s 7.41 7.45-7.83 (5, m, Ph) Other protons
CH3, s 2.65
OCH3, s 3.54
CH2O, s 4.87
9b
1605
2.81
3.46
4.60
7.46
7.51-7.84 (5, m, Ph)
9c 9d
1600 1605
2.60 2.75 2.72
3.61
5.01
7.30 7.28
7.52-7.83 (5, m, Ph) 7.42 (2H, d, 3J = 8.1, 3,5-HAr); 7.71 (2H, d, 3J = 8.1, 2,6-HAr) 7.67 (1H. dd, 3J = 8.3, 4J = 2.2, 5-HAr); 7.89 (1H, d, 3J = 8.3, 6-HAr); 7.95 (1H, d, 4J = 2.2, 3-HAr) 7.33 (1H, d, 4J = 2.7, 3-HAr); 7.48 (1H, dd, 3J = 8.6, 4 J = 2.7, 5-HAr); 8.08 (1H, d, 3J = 8.6, 6-HAr) 1.83 (6H, m, HAd); 2.24 (9H, m, HAd)
9e 9f
1600 1605
2.64 2.66
3.50 3.52
4.91 4.91
7.46 7.46
9g
1603
2.67
3.58
4.93
7.38
TABLE 6. Values of m/z (Irel, %) and Basic Characteristics of Ions in Mass Spectra of 3-Azidothieno[2,3-b]pyridines (8) and Isoxazolothienopyridines (9)
Compound 8a 8d* 8f 8g 9a 9b 9c 9d* 9f 9g M+ (azide) 338 (1.4) 417 () 374 (5.4) 396 (4.0) 1 310 (5.1) 388 (5.5) 346 (8.0) 368 (30.6) 310 (22.1) 310 (31.5) 280 (100) 388 (35.5) 346 (54.4) 368 (64.6) 2 280 (9.8) 359 (8.0) 316 (14.1) 338 (22.0) 280 (16.5) 280 (100) 280 (100) 359 (18.0) 316 (38.1) 338 (49.0) 3 45 (13.0) 45 (37.8) 45 (13.6) 45 (14.9) 45 (11.5) 45 (5.4) 45 (7.0) 45 (7.0) 45 (13.0) 4 265 () 344 () 301 () 323 () 265 () 265 (3.0) 265 (2.2) 344 () 301 (7.0) 323 (3.9) 5 149 (1.0) 228 () 185 () 207 () 149 () 149 (0.4) 149 (0.4) 228 () 185 () 207 () 6 105 (78.0) 183 (100) 141 (100) 163 () 105 (81.9) 105 (24.4) 105 (18.5) 183 (100) 141 (100) 163 (6.7) 7 121 (18.5) 199 (28.7) 157 (16.6) 179 () 121 (17.3) 121 (6.8) 121 (7.4) 199 (20.4) 157 (17.6) 179 () 8 77 (100) 155 (54.5) 113 (34.4) 135 (100) 77 (100) 77 (24.1) 77 (25.8) 155 (70.0) 113 (29.8) 135 (100) 9 295 (36.6) 373 (17.8) 331 (51.3) 353 (16.6) 295 (51.2) 373 (29.0) 331 (97.0) 353 (27.8) 10 267 () 342 () 303 (10.2) 325 (9.7) 267 (5.1) 342 () 303 (19.8) 325 (17.5)
_______ * The m/z values are given for fragments containing the lighter bromine isotope.
383
_ O N O N R S + M (for 8f,d,f,g) N2 O N O S R + . + N N
.
HO + H N O S R O H N O + N H + S 4 CH3 N O R CO S 9a R
CH3
.
+ O 3
N 9
CH2O
1 M+ (for 9f,d,f,g) CH2O N O S 2
H2CO N
.
N O S 10 R
+ . R +N H
M + (for 9c)
N _ N
CH2O N O O S R M + (for 9b) R 6 CO + . CS + O
R O 5
+ S
CO + S 7 + R 8 CS
Fig. 1. Major fragmentation routes for 3-azidothieno[2,3-b]pyridines 8 and isoxazolothienopyridines 9. TABLE 7. Interatomic Distances (d, ) in the Isoxazolothienopyridine 9a Molecule
Bond N(1)C(1) C(1)C(2) C(2)C(3) C(3)C(4) C(4)C(5) C(5)N(1) C(4)C(6) Heterocyclic system 1.357 1.416 1.398 1.398 1.435 1.343 1.438 Isolated heterocycle 1.347 1.407 1.396 1.396 1.407 (Py) 1.377 (Tf) 1.347 1.342 Bond C(6)C(7) C(7)S SC(5) C(6)N(2) N(2)O(1) O(1)C(8) C(8)C(7) Heterocyclic system 1.490 1.667 1.736 1.341 1.320 1.428 1.381 Isolated heterocycle 1.377 (Tf) 1.462 (Isox) 1.672 1.672 1.342 1.320 1.411 1.379
384
N (2) C(3) C(4) C(2) C(1) C(5) C(7) C(6) O(1) C(8)
N (1)
Fig. 2. Projection of the spatial structure of compound 8a, obtained by the AM1 method.
EXPERIMENTAL The UV spectra were recorded on a Specord UV-vis and a Specord M-40 in the 200-700 nm range in quartz cuvets of thickness 10 mm in ethanol; the IR spectra were recorded on a Specord 71 IR-20 in the 3600-650 cm-1 range, NaCl prisms, KBr. The crystalline substances were recorded as a suspension in vaseline oil. The 1H NMR spectra were recorded on a Bruker WM-250 (250 MHz) in DMSO-d6, internal standard HMDS. The mass spectra were obtained on a Varian CH-6 with ionizing potential 70 eV and temperatures 50-180C. 3-Amino-2-benzoyl-6-methoxymethyl-4-methylthieno[2,3-b]pyridine (6b). An 10% aqueous solution of KOH (5.6 ml, 0.01 mol) was added to a suspension of 3-cyano-2(1H)-pyridinethione 2 (1.94 g, 0.01 mol) in DMF (20 ml). Then phenacyl bromide (1.99 g, 0.01 mol) was added with stirring; the mixture was held for 10-15 min at room temperature. Then another 5.6 ml of a 10% aqueous KOH solution was added, and the reaction mixture was stirred for 20 min; then the precipitate formed was separated, washed successively with water and a 1:1 ethanolwater mixture, and dried in air. The filtrate was diluted with a two-fold amount of water, the flocculent precipitate was separated and washed with water and then recrystallized from ethanol. Compounds 6a,c-g were obtained similarly. 3-Azido-2-benzoyl-4-methoxymethyl-6-methylthieno[2,3-b]pyridine (8a). Conc. H2SO4 (0.6 ml) was added to a solution of compound 6a (1.69 g, 0.005 mol) in glacial acetic acid (12 ml). The reaction mixture was cooled in an ice bath down to +5 to +8C and a solution of sodium azide (0.48 g, 0.007 mol) in water (2 ml) was slowly added in small portions. The mixture was stirred for 20 min and then the excess nitrous acid was neutralized with urea (monitored using starch/iodide indicator paper), and a solution of sodium azide (0.46 g, 0.007 mol) in water (2 ml) was added dropwise over a 10 min period. Stirring was continued for one hour. Then the reaction mass was slowly poured into water with finely shaved ice. The precipitate of azide 6a was separated, washed on the filter with cold water until the wash water tested neutral, and then it was dried over concentrated sulfuric acid. The 2-acyl-3-azidothieno[2,3-b]pyridines 8b-g was obtained similarly. 8-Methoxymethyl-6-methyl-3-phenylisoxazolo[3',4':4,5]thieno[2,3-b]pyridine (9a). Compound 8a (1.69 g, 0.005 mol) was boiled for 30 min in m-xylene (30 ml). Then the solution was cooled down to room temperature, diluted with hexane (40 ml) (petroleum ether). The precipitated crystals of isoxazolothienopyridine were separated, washed with hexane, and dried in air. They were purified by recrystallization from DMF. Compounds 9b-g were obtained by a similar procedure. 385
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. V. A. Artemov, V. A. Ivanov, A. V. Koshkarov, A. M. Shestopalov, and V. P. Litvinov, Khim. Geterotsikl. Soedin., 104 (1998). V. A. Artemov, A. M. Shestopalov, and V. P. Litvinov, Khim. Geterotsikl. Soedin., 512 (1996). V. A. Ivanov, V. A. Artemov, L. A. Rodinovskaya, A. M. Shestopalov, V. I. Nesterov, Yu. T. Struchkov, and V. P. Litvinov, Khim. Geterotsikl. Soedin., 115 (1996). E. A. Kaigorodova, L. D. Konyushkin, E. Yu. Kambulov, and G. D. Krapivin, Khim. Geterotsikl. Soedin., 1024 (1997). V. K. Vasilin, E. A. Kaigorodova, and G. D. Krapivin, Khim. Geterotsikl. Soedin., 565 (2000). E. A. Kaigorodova, L. D. Konyushkin, S. N. Mikhailichenko, V. K. Vasilin, and V. G. Kul'nevich, Khim. Geterotsikl. Soedin., 1432 (1996). E. A. Kaigorodova, L. D. Konyushkin, S. N. Mikhailichenko, V. K. Vasilin, and V. G. Kul'nevich, Khim. Geterotsikl. Soedin., 337 (1999). S. N. Mikhailichenko, N. Ya. Gubanova, E. A. Kaigorodova, V. A. Kovardakov, L. G. Bogachuk, and V. N. Zaplishnyi, Izv. VUZov, Khim. i Khim. Tekhnologiya, 41, No. 1, 63 (1998). L. K. Dyall and N. J. Dickson, Austral. J. Chem., 33, 91 (1980). T. L. Gilchrist, Heterocyclic Chemistry [Russian translation], Mir, Moscow (1996), p. 378.
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ANNIVERSARIES AND DATES

N. D. ZELINSKY INSTITUTE OF ORGANIC CHEMISTRY, RUSSIAN ACADEMY OF SCIENCES: 70 YEARS
The N. D. Zelinsky Institute of Organic Chemistry (Russian Academy of Sciences), or IOC as it is of course called for short by the hundreds of people who are working or have worked at the Institute and their thousands of colleagues, was 70 years old on February 23, 2004. Far beyond Russia's borders, the IOC is known as the N. D. Zelinsky Institute (where the field of science it covers is obvious to all). The very widespread fame of the IOC is quite understandable: it is one of the largest scientific centers in the world in the field of organic chemistry, organic catalysis, and the chemistry of natural and biologically active compounds. When and how the Institute was organized decided its destiny. The IOC was created during the period when the Academy of Sciences was moving from Leningrad to Moscow, by bringing together representatives of the leading scientific schools active in those cities: the cream of Russian organic chemistry. The framework of the Institute included laboratories directed by A. E. Favorsky, N. D. Zelinsky and his students: A. A. Balandin, B. A. Kazanskii, and A. N. Nesmeyanov, and also representatives of the V. N. Ipatiev and A. E. Chichibabin schools. In addition to these groups, back at its very beginning the Institute combined the laboratories of N. Ya. Demjanov and M. A. Ilinsky, N. M. Kishner's group, and a number of students of P. P. Schorigin. Outstanding chemists of the younger generation included Academicians I. N. Nazarov, I. L. Knunyants, A. E. Porai-Koshits, V. V. Korshak, L. F. Vereshchagin, M. M. Shemyakin, M. I. Kabachnik, and Kh. M. Minachev; Corresponding Members A. D. Petrov, N. I. Shuikin, S. S. Novikov, B. M. Mikhailov, V. A. Ponomarenko, A. M. Moiseenkov; Professors Ya. L. Gol'dfarb, A. M. Rubinshtein, and many others. The constellation of these names promised not only success for the "newborn" but also a special role for the Institute in training highly qualified chemists for all the republics of the USSR (now sovereign states) and other countries, and also in creating new scientific approaches and groups. In 1954, several laboratories of the IOC became the basis for creation of the Institute of Organoelement Compounds and the Institute of High Pressure Physics; in 1959, likewise for the Institute of the Chemistry of Natural Compounds (now the Institute of Bioorganic Chemistry). A number of academic institutes were organized with direct participation of leading IOC scientists: the Irkutsk Institute of Organic Chemistry (now the A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences), the Institute of Bioorganic Chemistry in Minsk, the Institutes of Organic Chemistry in Bishkek and Dushanbe, and the Institute of Chemistry in Ashkhabad. The Institute has a concentration of highly qualified scientists on its staff, who in many cases shaped the countenance of domestic and international chemistry. Nearly 550 scientific staff actively work at the Institute, including 5 Academicians and 5 Corresponding Members of the Russian Academy of Sciences, 95 Doctors and 280 Candidates in the sciences; their productive activity has been celebrated by high-level awards and honorary titles. Among those now working at the IOC, there are about 30 laureates of the Lenin and State prize, named prizes of the Academy of Sciences, the Demidov prize and others; 8 individuals have been awarded the title of __________________________________________________________________________________________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 473-477, March 2004. 0009-3122/04/4003-03872004 Plenum Publishing Corporation 387
"Honored Scientist of the Russian Federation." Leading IOC scientists are members of a number of foreign academies, domestic and international scientific societies, science councils of the Russian Academy of Sciences, ministries, and departments, and actively work on editorial boards of domestic and international journals. From within the walls of the Institute have issued thousands of scientific papers and reports, about 200 monographs and collected works, and more than 10 textbooks and laboratory manuals, many of which have gone through several editions and have been translated into foreign languages. IOC staff members have been the inventors on hundreds of patents. A huge contribution to the formation and development of the IOC has come from the remarkable scientists who have headed it over the course of 70 years: Academicians A. E. Favorsky, internationally known for his classic papers on molecular rearrangements and the chemistry of unsaturated compounds (1934-1939); A. N. Nesmeyanov, who initiated new directions in chemistry: heteroorganic chemistry and the chemistry of synthetic food products (1939-1959); B. A. Kazansky, the author of basic papers on various aspects of petrochemistry and heterogeneous catalysis (1954-1955); N. K. Kochetkov, founder and leader of the domestic scientific school of the chemistry and biochemistry of carbohydrates and nucleotides (1966-1988); V. A. Tartakovsky, an outstanding scientist conducting basic research on the chemistry of nitro and heterocyclic compounds and also in the area of industrial synthesis, which is of tremendous theoretical and practical importance (1988-2002). Since 2003, the Institute has been headed by M. P. Egorov (Corresponding Member, Russian Academy of Sciences), who is a well known scientist in the field of physical organic and heteroorganic chemistry. Institute staff have achieved a number of major scientific results. P. P. Shorygin discovered a new physical phenomenon: resonance Raman light scattering, which is currently being used successfully in studying organic compounds. They have designed and successfully applied methods for studying the structure and reactivity of organic compounds under normal and extreme conditions, including reactions at ultrahigh pressures (M. G. Gonikberg, V. M. Zhulin, B. S. l'yanov, A. A. Zharov), low-temperature stabilization and study of unstable particles (carbenes, free radicals) in inert matrices (O. M. Nefedov, A. K. Mal'tsev, M. P. Egorov), phase transfer catalysis (L. A. Yanovskaya, S. S. Yufit), electrochemical processes (S. G. Mairanovskii, V. A. Petrosyan, V. P. Gul'tyai, G. I. Nikishin). The achievements of the Institute have been universally recognized in the field of the chemistry of unsaturated compounds (the A. E. FavorskyI. N. Nazarov school), indeed demonstrating the unlimited possibilities for synthesis of diverse aliphatic, alicyclic, and heterocyclic systems, including natural compounds. Research on the chemistry of carbenes and their analogs, the chemistry of small rings, and diazo compounds at the Institute is widely known. A significant contribution has been made to the study of problems of double bonds involving silicon and germanium (O. M. Nefedov and colleagues). One of the most important directions taken in the activity of the IOC has been studies in heterocyclic chemistry. In the early years of the Institute, research in this area was mainly conducted by students of A. E. Chichibabin. We should mention the synthesis of pilocarpine (N. A. Preobrazhensky and colleagues), broad studies in the chemistry of amino-substituted pyridines, nicotine, anabasine (O. A. Zeide, Ya. L. Gol'dfarb, M. M. Katsnel'son), synthesis of acrichine (I. L. Kunyants and colleagues), synthesis of vitamin B1 (G. V. Chelintsev, Z. V. Benevolenskaya), hydrogenation/hydration of sylvan, leading to acetopropyl alcohol (K. S. Topchiev, L. N. Pavlov), cleavage of saturated oxygen-containing heterocycles (Ya. L. Gol'dfarb, L. M. Smorgonskii). In the 1950s, Ya. L. Gol'dfarb and colleagues carried out internationally recognized research in the field of thiophene chemistry, including study of diverse reactions of both substitution and conversion of thiophenes to form compounds in other series. During the same years, heterocycles became the objects of study for many IOC laboratories that seemed at first glance to be working rather far away from this field. G. Ya. Kondrat'eva discovered conversion of oxazoles according to a diene type synthesis, which now is the basis for industrial methods for obtaining vitamin B6. Studies of homolytic reactions (G. I. Nikishin and colleagues) conducted at the Institute in recent decades have discovered new options for preparative synthesis of thiacrown ethers and 388
lactones, including macrocyclic lactones. Regioselective and stereoselective syntheses have been carried out for polyfunctional pyridines, their hydrogenated and condensed analogs, including those using the cascade heterocyclization method (V. P. Litvinov, A.M. Shestopalov). We also note catalytic syntheses of thiophenes on rhenium-containing catalysts (M. A. Ryashentseva, Kh. M. Minachev), and syntheses of pyrazines and imidazoles on oxide catalysts (K. M. Gitis, G. V. Isagulyants). Excellent successes have been achieved in the chemistry of organoboranes; research in this area includes study of problems in both synthesis and properties of these compounds, and their diverse application in organic synthesis. In recent years, Yu. N. Bubnov and colleagues discovered very interesting reactions of reductive allylation of nitrogen-containing heterocycles (pyridine, quinoline, isoquinoline, pyrrole, indole) when treated with triallylboron and related reagents, opening up possibilities for further conversions to form compounds similar to alkaloids. V. A. Dorokhov developed efficient syntheses for nitrogen-containing heterocycles with participation of chelates of boron and transition metals. Especially significant successes in heterocyclic synthesis and conversions have been achieved by the internationally very prominent school (founded by S. S. Novikov) of the chemistry of nitro compounds (including high-energy compounds), which has been active in the Institute for half a century. V. A. Tartakovsky and colleagues observed and made broad studies of the ability of nitrone esters to act as dipoles in reactions of 1,3-dipolar cycloaddition. L. I. Khmel'nitskii and colleagues conducted comprehensive studies in the chemistry of furoxan and furazan, and also bicyclic bisureas, one representative of which: 2,4,6,8-tetramethyl-2,4,6,8tetraazabicyclo[3.3.0]octane-3,7-dione (mebicar), has been adopted in medical practice as an effective daytime tranquilizer. Broad studies have been conducted at the Institute on chemical conversion of explosives. In particular, a number of fundamental problems have been solved in the chemistry of the very high-tonnage explosive trinitrotoluene (TNT), which makes it possible to convert it to polyfunctional benzannelated O-, S-, and N-heterocycles, including such civilian products as polymer materials, new dyes, and biologically active compounds (S. A. Shevelev and colleagues). Multitargeted studies, discovering new ways to use aliphatic and aromatic nitro compounds in organic synthesis, in particular for obtaining heterocycles (V. A. Tartakovsky and colleagues), have been conducted at the Institute. New options have been discovered for synthesis of polysulfur/nitrogen-containing heterocycles based on the reaction of a complex of sulfur monochloride and a nitrogen-containing base (O. A. Rakitin and colleagues). In the area of the chemistry of natural compounds, IOC scientists have made a substantial contribution to development of the chemistry, biochemistry, and immunochemistry of carbohydrates and carbohydratecontaining biopolymers, and also the chemistry of physiologically active steroids. Research on carbohydrate chemistry (N. K. Kochetkov and his school) has created a scientific basis for understanding the biological functions of carbohydrate-containing biopolymers, which has opened up routes to obtaining new diagnostic and medicinal drugs. Research on steroid synthesis (A. A. Akhrem, A. V. Kamernitskii) has led to the creation of previously unknown hormonal drugs with separate biological functions. At the Institute, basic research has been conducted in the theory of organic catalysis (A. A. Balandin); the elementary events of a number of catalytic reactions have been studied (G. V. Isagulyants) as well as the structure and physics of the surface of a number of catalysts, including the use of quantum chemistry methods and a combination of modern instrumental methods (A. M. Rubinshtein, A. A. Slinkin, E. S. Shpiro, V. I. Yakerson, G. M. Zhidomirov, V. B. Kazansky, and N. D. Chuvylkin); priority studies have been conducted in the field of catalytic conversions of hydrocarbons (B. A. Kazansky, A. F. Plat, A. L. Liberman, O. V. Bragin), synthesis based on carbon monoxide and other monocarbon molecules (Ya. T. idus, A. L. Lapidus), asymmetric catalysis (E. I. Klabunovskii); the scientific principles have been developed for preparation of new catalysts based on domestic zeolites (Kh. M. Minachev); kinetic, physical, and mathematical models have been created for designing industrial processes and reactors (S. L. Kiperman). Many developments by the Institute have been brought to realization in the basic organic synthesis industry and the petroleum refining industry. The Institute has developed new high-efficiency, environmentally friendly catalytic processes for obtaining isopentane, high-octane gasolines, alkylaromatic hydrocarbons; 389
designed catalysts for obtaining styrene, allylacetate, acetopropyl acetate, conversion of hydrocarbons to motor fuel components etc. Industry has successfully used catalysts developed at IOC together with industrial organizations for hydrogenation of fats, purification of syngas in ammonia production, purification of inert and waste gases, synthesis of liquid hydrocarbons and ceresine from carbon monoxide and hydrogen, obtaining acetic acid by carbonylation of methanol, etc. Basic research at the Institute has been the foundation for designing many industrial processes for obtaining vitamins, medicinal drugs, and pesticides, in particular vitamins A, B1, B6, -ionone (a key intermediate for synthesis of vitamins A and E), acrichine, Hemodez (a blood substitute with detoxifying action), Vinylin (Shostakovskii balsam), Octitsil, potassium orotate, promedol, tsigerol, metaprogerol, mebicar, tribenol, lysocym, and other medicinal drugs and intermediates for their manufacture. An efficient method for isolation and purification of the antibiotic streptomycin has also been developed and put into operation. Considerable attention has been focused on synthesis of plant protectants, including insect pheromones and juvenile hormone analogs. A novel technology has been developed for obtaining insecticides with a broad spectrum of action from a group of synthetic pyrethroids (permethrin and its analogs). A major role in development of domestic scientific instrumentation has been played by joint work during 35 years of scientists at the Institute and IOC Special Design Bureau in design and industrial application of various instruments, especially chromatographs,In recent years, at the Institute mathematical chemistry and computer-assisted synthesis have been successfully developed and the use of modern information technology has expanded. The Russian international nodes of the FREEnet computer networks and the National Joint Network Coordination Center, the Moscow Information Center of the Russian Academy of Sciences/STN International, the NMR Research Center of the Russian Academy of Sciences all are successfully operating within IOC. Considerable attention has been focused on the education of new scientists and students at all levels. Post-grad and doctoral programs have existed at the Institute since its inception. Many of those who completed their graduate work at the IOC (about 1000 individuals) became major scientists, have had and continue to have key positions in science, are heads of institutes and departments, and are members of the Russian Academy of Sciences and the national academies of other countries. Today, more than half of the laboratory heads at IOC are former Institute graduate students. Institute graduates also work at prestigious scientific centers in many countries of the world. At the present time, 60 graduate students are being trained at the IOC: this is the largest group of graduate students in any chemical institute of the Russian Academy of Sciences. With the aim of training highly qualified research chemists and attracting the most talented among them to work within the Academy of Sciences system, the Institute provided the initiative for creating a Chemical Lyceum in Moscow: a new type of educational institution for training high school students (the Lyceum was founded in 1990). A Scientific Education Center was set up in 1991 within IOC for special training of the Lyceum students in the field of organic chemistry. IOC staff participate in training young research chemists, working as lecturers or laboratory instructors in the Higher Chemical College of the Academy of Sciences, which was created in 1991 within D. I. Mendeleev Moscow Chemical Engineering University. Thus, a continuous system of education operates within the Institute: Chemical Lyceum to Higher Chemical College to graduate program to doctoral program. The editorial boards of a number of leading chemical journals operate at the Institute with active participation of its staff: Izvestiya Akademii Nauk, Seriya Khimicheskaya [Russian Chemical Bulletin]; Uspekhi Khimii [Russian Chemical Reviews]; Kinetika i Kataliz [Kinetics and Catalysis]; and also Mendeleev Communications, published jointly with the Royal Chemical Society (UK). L. I. Belen'kii
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Our journal has very close ties with the IOC. Almost forty years ago, Professor Yakov Lazarevich Gol'dfarb became one of the initiators creating the journal Khimiya Geterotsiklicheskikh Soedinenii [Chemistry of Heterocyclic Compounds]; he was a very active member of the Editorial Board from the first issue to the last day of his life. For many years his student, Professor Leonid Isaakovich Belen'kii, has been a regional editor of the journal and has devoted considerable labor, effort, knowledge and skill, and good will to working with authors and editors, including not a few IOC staff members. Academician Nikolai Konstantinovich Kochetkov is a member of the Editorial Board. We can confidently say that in every issue of this journal, there is not a single paper that has not been either written or edited by "IOC'ers". We have found more than once that we can always obtain detailed and highly professional advice and support from members of the Institute and editors related to it (and to us). Our thanks to all. Our wishes for the brilliant IOC group are for new accomplishments and new achievements to benefit our favorite science: organic chemistry. Editor-in-chief of the Journal Academician E. Lukevics (Latvian Academy of Sciences)
391
MODIFICATION OF THE PERIPHERAL SUBSTITUENTS IN CHLOROPHYLLS a AND b AND THEIR DERIVATIVES (REVIEW)
V. Yu. Pavlov and G. V. Ponomarev The extensive published data on methods for the modification of peripheral substituents in chlorophylls a and b and their various semisynthetic derivatives are classified and analyzed. Special attention is paid to specific transformations arising from the presence of the unique macrocyclic tetrapyrrole fragment. Data on certain main pathways to modification of the exocyclic fragment of chlorophylls are also presented. Keywords: pyropheophorbide, porphyrin, rhodin g7, pheophetin, pheophorbide, chlorin e6, chlorophyll, fluorescent diagnostics, photoinduced electron transfer, photosensitizer, photosynthesis. This article reviews the extensive published data on the principal methods for modification of the peripheral substituents of chlorophyll and their derivatives and also some methods of modifying the exocyclic fragment, based on the classical papers of R. Willsttter, G. Fischer, and the most up-to-date investigations in this field. The great interest in modification of the peripheral substituents in chlorophyll is due to the broad spectrum of useful characteristics found in their specifically modified derivatives [1]. In particular, they have been used as models for the study of photosynthesis [2, 3]. The unique ability of chlorophyll derivatives to accumulate in tumorous tissues and to cause a photodynamic effect under laser radiation has been successively used in photodynamic therapy (PDT) and fluorescent diagnosis of malignant neoplasms [4-8]. Fundamental data on the chemistry of chlorophylls have been presented in books [9-15] and reviews [16-28], and some pathways to the modification of chlorophylls were discussed in [1, 4, 7, 29-47].
Nomenclature and Classification of the Basic Derivatives of Chlorophylls a and b Chlorophylls a and b are customarily regarded as derivatives of porphin, containing a cyclopentanone ring (exocycle) condensed with a porphyrin macrocycle, various peripheral substituents, a partially hydrogenated pyrrole ring, and a central magnesium atom. Fischer [10, 11] and IUPAC [28, 48] nomenclature are used for numbering the carbon and nitrogen atoms forming the chlorophyll molecule. In the present review the IUPAC numbering system is used except for some trivial names proposed, mainly by Fischer, for certain derivatives of chlorophylls.
__________________________________________________________________________________________ V. N. Orekhovich State Scientific-Research Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Moscow; e-mail: gelii@softel.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 483-519, April, 2004. Original article submitted October 22, 2002. 0009-3122/04/4004-03932004 Plenum Publishing Corporation 393
The structural features of chlorophylls and their derivatives make it possible to divide them into two main groups. The first group includes chlorophylls 1 and 2 and the derivatives 3-12, containing an exocyclic fragment (the so-called phorbin derivatives) (Scheme 1). The second group includes the derivatives 14-22 not containing an exocyclic fragment (the so-called nonphorbin derivatives) (Scheme 2).
1 chlorophyll a: M = Mg, R1 = Me, R2 = COOMe, R3 = Phytyl 2 chlorophyll b: M = Mg, R1 = CHO, R2 = COOMe, R3 = Phytyl 3 pheophetin a: M = 2H, R1 = Me, R2 = COOMe, R3 = Phytyl 4 pheophorbide a: M = 2H, R1 = Me, R2 = COOMe, R3 =H 5 methylpheophorbide a: M = 2H, R1 = R3 = Me, R2 = COOMe 6 pyropheophorbide a: M = 2H, R1 = Me, R2 = R3 = H 7 methylpyropheophorbide a: M = 2H, R1 = R3 = Me, R2 = H 8 pheophetin b: M = 2H, R1 = CHO, R2 = COOMe, R3 = Phytyl 9 pheophorbide b: M = 2H, R1 = CHO, R2 = COOMe, R3 =H 10 methylpheophorbide b: M = 2H, R1 = CHO, R2 = COOMe, R3 =Me 11 pyropheophorbide b: M = 2H, R1 = CHO, R2 = R3 = H 12 methylpyropheophorbide b: M = 2H, R1 = CHO, R2 = H, R3 = Me
31 3 1 20 24 19 N 18 16 17 171 172 5 4 21 6 7
R1
N M
22 23
9 10
N 11
15 132 14 13
12
131
CO 2R 3
R2 H 112
13
HO
Phytyl the residue of the alcohol phytol 13
Scheme 1. The nomenclature, names, and structural formulas of chlorophylls a and b and their main phorbin derivatives.
R1
NH
HN
R3 R4 1422
R2
14 chlorin e6: R1 = Me, R2 = R4 = COOH, R3 = CH2COOH 15 chlorin e6 trimethyl ester: R1 = Me, R2 = R4 = COOMe, R3 = CH2COOMe 16 chlorin e4: R1 = R3 = Me, R2 = R4 = COOH 17 chlorin e4 dimethyl ester: R1 = R3 = Me, R2 = R4 = COOMe 18 isochlorin e4: R1 = Me, R2 = H, R3 = CH2COOH, R4 = COOH 19 isochlorin e4 dimethyl ester: R1 = Me, R2 = H, R3 = CH2COOMe, R4 = COOMe 20 phyllochlorin e6: R1 = R3 = Me, R2 = H, R4 = COOH 21 rhodin g7: R1 = CHO, R2 = R4 = COOH, R3 = CH2COOH 22 rhodin g7 trimethyl ester: R1 = CHO, R2 = R4 = COOMe, R3 = CH2COOMe
Scheme 2. The names and structural formulas of the main non-phorbin derivatives of chlorophylls a and b.
Pathways to Modification of the Vinyl Group The vinyl group readily enters into reduction, oxidation, addition, substitution, and elimination. Under neutral and alkaline conditions it behaves like an isolated double bond, but under acidic conditions its behavior is largely determined by conjugation with the macrocycle.
394
Reduction of the Vinyl Group Reduction of the vinyl group to ethyl is realized by means of a wide range of reagents (B2H6, N2H4H2O [22, 28], PtO2 [22], Pd/C [49-52], and Raney nickel [53]). The choice of most effective reducing system is determined by the structure of the tetrapyrrole substrate being reduced. Thus, the reduction of the nickel complex 23 at Raney nickel in the Et2O/EtOH system leads to the formation of three main compounds 24-26 ([53] and the literature cited therein), while during reduction of the free base 7 at Pd/C in acetone the derivative 27 is formed with a yield of more than 90% [52] (Scheme 3).
Et
N M N
pM e
N N
()
N M N
pM e
N N
N Ni N
pM e
+
N
N
Ni
N N
7 M = 2H 23 M = Ni
pM e
24 M = Ni 27 M = 2H
25
26
A: Raney nickel in Et2O/EtOH (for the production of 24-26 from 23). B: Pd/C in Me2CO (for the production of 27 from 7).
Scheme 3. Reduction of the peripheral vinyl group*
Oxidation of the Vinyl Group Potassium permanganate [22, 54], ozone [55], and noncatalytic [56] and catalytic [57-62] oxidation with osmium tetroxide have been proposed for oxidation of the vinyl group to a formyl substituent. Thus, the reaction of 1 eq. of chlorin 15 with 1 eq. of OsO4 in pyridine led to the diol 28 with a 100% yield [56]. This was converted by treatment with NaIO4 in aqueous dioxane into the aldehyde 29 with a yield of 84%. An alternative effective method for the production of the aldehyde 29 is the oxidation of vinylchlorin 15 by means of the OsO4/NaIO4 system [61] (Scheme 4).
HO
OH
NH N pMe
N HN COOMe COOMe
NH N pMe
N HN COOMe COOMe
NH N pMe
N HN COOMe COOMe
A: OsO4Py B: NaIO4H2Odioxane C: OsO4NaIO4
15
28
29
Scheme 4. Transformation of a peripheral vinyl group into a formyl substituent.
_______ * Here and subsequently the abbreviation p = CH2CH2CO2 is used in the formulas, i.e., pMe = CH2CH2CO2Me. 395
The vinyl group of pyropheophorbide 7 is oxidized by potassium permanganate to a carboxyl group with the formation of the acid 30 with yields between 3% [63] and 30% [64]. According to data in [63], the low yield of the acid 30 is due to the parallel formation of the glycol 31. Two-stage oxidation of the pyropheophorbide 7 was proposed for the production of the derivative 30 with an acceptable yield. The vinylchlorin 7 was first oxidized with high yield to the aldehyde 32, from which the acid 30 was obtained (yield 81%) by the action of NaClO2 and NH2SO3H in the presence of 2-methyl-2-butene [63] (Scheme 5).
HO OH H R
NH N pMe
N HN
NH
N HN
NH N pMe
N HN
BC
NH N
N HN
pMe
pMe
31
A: KMnO4
30
30 R = OH 32 R = H
B: OsO4NaIO4 (for the production of 32 from 7); C: NH2SO3HNaClO2MeC(Me)CHMe (for the production of 30 from 32)
Scheme 5. Various versions of the oxidation of a peripheral vinyl group. The vinyl group of the chlorin 15 is oxidized by Tl(NO3)3 in MeOH/CH2Cl2 to the acetal 33, which is hydrolyzed in an acidic medium to the aldehyde 34. Reduction of the derivative 34 with NaBH4 leads to the formation of the hydroxyethyl derivative 35 [65]. The sequence of transformations described above can be regarded formally as a method for hydration of the vinyl group in chlorophyll derivatives against the Markovnikov rule [28, 56, 65, 66]. Nucleophilic substitution of the hydroxy group in the 3-(2-hydroxyethyl) substituent of chlorin 35 by a chlorine atom with the formation of the chlorine derivative 36 takes place readily in the Ph3P/Cl3CCN system [56]. Recently an effective method was proposed for protection of the vinyl group of chlorophylls using the organoselenium reagent o-O2NC6H4SeCNO [67]. The vinyl group can be regenerated from the derivative 37 with a yield of ~100% under the conditions used for isolation of the chlorin 15 (Scheme 6).
MeO
NH N pMe N HN COOMe COOMe
OHC
MeO
NH
NH
33
34
15 Se NO2
NH N
C
HO Cl
A: Tl(NO3)3CH2Cl2MeOH B: H3O+ C: NaBH4 D: Ph3PCl3CCN E: o-NO2C6H4SeCNOn-Bu3P CH2Cl2 F: 30% H2O2, THFH2O
NH
NH
37
35
36
Scheme 6. The synthesis and pathways to modification of the 32-hydroxyethyl substituent. 396
Addition to the Vinyl Group If the vinylchlorin 4 is heated with HI in PH4I/AcOH, the ethylporphyrin 38 is formed. The principle of the transformation of vinylchlorins into ethylporphyrins (the so-called "HI-isomerization) presumably implies the initial formation of the intermediate 39, which is then transformed into compound 38 in several stages. Treatment of the chlorin 4 in the HI/AcOH system at room temperature in the presence of oxygen gives the acetylporphyrin 40 with a yield of 20-40% (the so-called "oxo reaction") (for greater detail, see [69]) (Scheme 7). Hydrobromination of the vinyl group in chlorins 5-7, 15 is realized by the action of a solution of hydrobromic acid in acetic acid. Treatment of the respective perbromides 41-44 with alcohol [60, 69], water, or thiol [70] leads to the alkoxy derivatives 45-47, the alcohol 48, and the mercapto derivative 49 (Scheme 7).
+ IN N N NH HN N COOM e COOM e N p HN
+
B A
NH N N HN
NH N
N HN
pM e
15
R
O OOM e
pH COOMe
pH COOMe
C, D
A
NH N N HN
39
38
Br
40
R1
NH X pMe
X HN COOM e COOM e
NH X pR 2
X HN
NH N pR 3
N HN
pR 2
R1
R1
R2
44, 47
47
4143
45, 46, 48, 49
4 R1 = COOMe, R2 = H; 5 R1 = COOMe, R2 = Me; 6 R1 = R2 = H; 7 R1 = H, R2 = Me; 14 R1 = R2 = R3 = H; 41 X = NHBr, R1 = COOMe, R2 = Me; 42 X = NHBr, R1 = R2 = H; 43 X = NHBr, R1 = H, R2 = Me; 44 X = NHBr, R = Br; 45 R1 = OAlk, R2 = COOMe, R3 = Me; 1 46 R = OAlk, R2 = H, R3 = Me; 47 R = OAlk, X = N; 48 R1 = OH, R2 = R3 = H; 49 R1 = SR4 (R4 sugar residue), R2 = R3 = H A: HIPH4+IAcOHheat (for the production of compound 38 from 4 through the initial formation of 39); B: HIAOHoxygenroom temperature (for the production of 40 from 4); C: HBrAcOH; D: ROH (R = Alk) for the production of 45-47 from 41 and 43-44 respectively, 41, 43-44; (R = H) for the production of 48 from 42; R4SH (R4 sugar residue) for the production of 49
Scheme 7. Modification of a peripheral vinyl group with hydrohalogens. It was noted that functionalization of the vinyl group of chlorophyll derivatives by alcohols is a suitable method for the construction of products for PDT ([6, 7, 60] and the references therein). Thus, compound 50 (commercial name Photochlor) is undergoing clinical trials in the USA as a prospective product for PDT of cancer ([5, 6] and references therein) (Scheme 8).
397
NH N
N HN
pH
50 Photochlor
Scheme 8 Various pathways have been proposed for the transformation of 31-alkoxyethyl [69, 71, 72] and 3 -hydroxyethyl [22, 70, 73-76] substituents in chlorophyll derivatives. Thermolysis of 31-Alkoxyethyl Derivatives. When heated under high vacuum the alkoxyethyl derivative 47 forms the vinylchlorin 15. Under more rigorous conditions (1,2-dichlorobenzene, 165C, 5 h) the elimination of alcohol and water occurs in the bacteriochlorins 51 and 52 while decarboxymethylation also occurs in compound 52, and the corresponding chlorins 53 and 54 are formed. The transformation was discovered during an attempt to realize double dehydration at positions 7 and 8 of bacteriochlorins 51 and 52 in order to produce the easily functionalized 8-vinyl group of compounds 55 and 56. It was noted that the divinylporphyrin 57 is formed as a result of pyrolysis of the bacteriochlorin 51 [69]. Modification of the 31-Alkoxyethyl Substituent by CH-Acids. In the presence of zinc acetate compounds 46 and 47 readily react with the CH acid acetylacetone, forming the zinc complexes 58 and 59 with high yields [71, 72]. Alkaline treatment of the chlorin 59 leads to ketone cleavage of its -diketonate residue with the formation of the ketone 60, the reduction of which with NaBH4 gives the alcohol 61 [72]. Demetallation of the metal complexes 58-61 with 6 N hydrochloric acid [71, 72] followed by esterification of the intermediates 62 and 63 leads to the free bases 64-67, while acetylation of the hydroxy group of the chlorin 67 gives the acetate 68 [72]. Glycosylation of the 31-Hydroxyethyl Substituent. The production of the glycoside pyropheophorbide compound 69 by glycosylation of the 31-hydroxyethyl of chlorin 70 with the carbohydrate 71 in the presence of boron trifluoride etherate was reported in [70]. The acetyl groups of the carbohydrate fragment of compound 69 were removed at room temperature in the MeONaMeOH system, and the O-glycoside derivative 72 was obtained with a yield of 87% (Scheme 9). Creation of a Stereogenic Center Based on the 31-Hydroxyethyl Substituent. In the reaction of a racemic mixture of the 31R and 31S isomers 70 with vinyl acetate (donor of the acyl group) in toluene in the presence of Amano PS or Toyobo lipase the corresponding acetate 73 is formed. Its methanolysis in the presence of potassium carbonate leads to a mixture of the initial alcohols rich in the 31R isomer 70. The small diastereomeric excess (44%) of the vinyl acetate 73 is due to the fact that on account of the large size of the chlorin fragment the 3-(1-hydroxyethyl) group of the chlorin 70 cannot bond effectively with the active center of the enzyme, as a result of which the catalytic activity of the lipase is significantly reduced [73] (Scheme 10). Oxidation of the 31-Hydroxyethyl Group in an Acetyl Substituent. With KMnO4 in Me2CO [22], with (PyH)2Cr2O7 [74], and most effectively with the Pr4NRuO4Me(O)N(CH2CH2)2O system [73, 75] the 31-hydroxyethyl group is oxidized to acetyl. Thus, treatment of the chlorin 70 with the Pr4NRuO4 Me(O)N(CH2CH2)2O system gives a high yield of the acetyl derivative 74 [73]. It is interesting to note that treatment of the chlorin 75, containing a 3-(1-hydroxyethyl) substituent in the presence of an 8-hydroxymethyl substituent, with (PyH)2Cr2O7 leads to the formation of the corresponding 8-formyl derivative 76 with a yield of 79% [76]. In all probability the inertness of the 3-(1-hydroxyethyl) group toward (PyH)2Cr2O7 is due to steric hindrances during coordination of the bulky (PyH)2Cr2O7 molecule with the relatively inaccessible hydroxy group at position 31 of the pyropheophorbide 75 (Scheme 11).
1
398
O O
47 D,E B
15
OC6 H13 OH OH OC6 H13
M
N pR 3 N COOR 1 COOR 2 OR 1
M
N pMe N
NH N pMe
N HN COOM e COOM e
NH N
N HN
G,H
COOM e COOM e
pM e
60, 62, 66
59, 65
51
COOM e COOM e
55
NH N
M
N pR 4 N COOR 2 COOR 3 HN
+
pM e COOM e COOM e pM e
NH N
N HN
NH N
N HN
OOM e
COOM e
pMe
61, 63, 67, 68

O O
53
OR 1
OC6 H13
57
OH OH
54 C C
OC6 H13
M
N pMe N
D,E
NH N pR 3
N HN
NH N
N HN
NH N pMe
N HN
58, 64
R2
pMe COOM e O
45, 46, 70
52
OR
56
OR
O OR
I,J
O OR RO OR
OR
RO
OR NH N pMe N HN
71
69, 72
45 R1 = C6H13, R2 = COOMe, R3 = Me; 46 R1 = Et, R2 = H, R3 = Me; 58-61 M = Zn; 60 R1 = R2 = R3 = K; 61 R1 = H, R2 = R3 = R4 = K; 62 M = 2H, R1 = R2 = R3 = H; 63 M = 2H, R1 = R2 = R3 = R4 = H; 64, 65 M = 2H; 66 M = 2H, R1 = R2 = R3 = Me; 67 M = 2H, R1 = H, R2 = R3 = R4 = Me; 68 M = 2H, R1 = Ac, R2 = R3 = R4 = Me; 69, 71 R = Ac; 70 R1 = R2 = H, R3 = Me; 72 R = H A: Heat under high vacuum; B: OsO4H2S; C: 1,2-Dichlorobenzene, 165, 5 h; D: AcetylacetoneZn(OAc)22H2O, 40-70 min; E: 6N HCl; F: KOHdioxane, 55, 4 h, then 6N l, 4% H2SO4 in MeOH; G: NaBH4MeOH, 40, a few hours, 6N Hl, H2N2 in Et2O; H: Ac2Opyridine, 6 h; I: BF3Et2O, 71; J: MeONaMeOH
Scheme 9. Pathways for modification of the 31-alkoxy- and 31-hydroxyethyl substituent of chlorophyll derivatives. The acetyl readily enters into reduction [73, 75, 77] and nucleophilic addition [75, 77, 78]. Reduction of the Acetyl Group to a 31-Hydroxyethyl Substituent. The reduction of the acetyl fragment of chlorin 74 to the 3-(1-hydroxyethyl) derivative 70 takes place readily under the influence of sodium borohydride in methylene chloride/methanol [75]. The alcohol 70 is formed as a mixture of diastereomers. 399
OH
OA c H
H OH
NH N
N HN
NH N
NH
N HN
+
HN N
pMe
pMe
pMe
70 A: vinyl acetatelipase B: K2CO3MeOH
B 31R-73 31R-70
31S-70
Scheme 10. The creation of a stereogenic center based on the 31-hydroxyethyl group. The asymmetric reduction of the acetyl group in chlorin 74 with borane in the presence of the chiral oxaborolidines 77 and 78 leads to the selective formation of the chiral derivatives 70. Oxaborolidines are effective chiral components in such transformations. It was noticed that reduction on the tetrapyrrole substrate in the presence of (S)-oxaborolidines leads to the formation of the (311S)-alcohol 70 as the main compound, although reduction of "normal" prochiral ketones ArCOX, on the other hand, leads to the formation of the R alcohols. Such "inversion" of the stereoselectivity is due to the multifunctional nature of the tetrapyrrole chromophore, the different steric effects, and the unusual interactions between the tetrapyrrole and the reducing agents [73] (Scheme 11).
OM e
OMe
OH
OH
OH
N HN
NH N
N HN
F G
NH N
N HN
A D
NH N pMe
N HN
NH N pMe
pMe
pMe
79
H
OH
74
E

70
75
H
OH O
NH N pMe
1
N HN
NH N
N HN
NH N
N HN
NH N
N HN
pMe
pMe
pMe
3 S-70
A: Pr4NRuO4 Me(O)N B: (PyH)2Cr2O7C6H6 C: EtMgBrTHF D: NaBH4MeOHCH2Cl2 O
80
E: BH3PhNEt277PhMe or BH3Me2S78PhMeTHF F: CH(OMe)3CH2Cl2, HClMeOH G: 5% HCl
81
H N Ph Ph B R 77, 78
76
31S-77 R = Me 31S-78 R = H
Scheme 11. Oxidation of the 31-hydroxyethyl group to an acetyl group and its modification pathways. 400
Nucleophilic Addition to the Acetyl Group. The acetyl group readily forms diketals [75, 78]. Thus, by the action of CH(OMe)3/CH2Cl2 and HCl/MeOH the chlorin 74 is transformed into the derivative 79 [75], brief treatment of which with 5% hydrochloric acid leads to the formation of the initial acetylchlorin 74 with a yield of 100%. This sequence of transformations can be regarded at a method for the protection of the acetyl group. The acetyl group of 3-acetylchlorins is not very reactive towards Grignard reagents. Thus, during the action of ethylmagnesium bromide on the chlorin 80 the alcohol 81, i.e., the product from attack of the Grignard reagent on the 8-CHO group of the chlorin 80, is formed with a yield of 60%. According to the 1H NMR spectra, the chlorin 81 is formed as an equimolar mixture of diastereomers. Thus, the ethylmagnesium bromide attacks selectively the most active 8-formyl group in the presence of three other potential points of attack (the 3,13-carbonyls and COOMe in the 17-propionic residue) [77] (Scheme 11). Substitution at the Vinyl Group Vinylchlorins react with various organomercury molecules under the conditions of the Heck reaction [79-81]. Thus, treatment of the zinc complex 82 with the modified nucleoside 83 leads to the formation of the trans and gem isomers 84 and 85 with yields of 29 and 13% respectively; the metal-free pyropheophorbide 7 gives mainly the trans isomer 86 with a yield of 17% and only traces of the gem isomer 87, while the introduction of the zinc complex the 131-deoxy derivative 88 into the reaction leads to the trans and gem isomers 89 and 90 in practically equivalent amounts (8 and 9.6% respectively) [81]. In all probability, the yield and the ratio of the obtained isomers are determined mainly by the structure of the original tetrapyrrole (Scheme 12). It is known that N,N-dimethylmethyleneimmonium iodide (Eschenmoser's salt) is an effective reagent for the introduction of a dimethylaminomethyl group into the pyrrole heterocycle [82]. Thus, if compounds 15 and 82 are used as pyrrole substrates, the corresponding derivatives 91 and 92 are formed with good yields. Investigation of the 1H NMR spectra of the adducts 91 and 92 showed that the dimethylaminomethyl group condenses with the vinyl group only in the trans position. Quaternization of the amines 91 and 92 with methyl iodide leads to the water-soluble methiodides 93 and 94 [83, 84] (Scheme 12).
R R
NH
N HN
M
N pMe N
A,B
M
N pMe N COOM e COOM e
N pMe
COOM e COOM e R
COOM e COOM e
7, 15, 84, 91, 93 M = 2H 82, 88, 92, 94 M = Zn 7, 86, 87 X = O 88-90 X = H2 84-87, 89, 90 R = 83 91, 92 R = CH2NMe2 93, 94 R = CH2NMe3+I
O NH
15, 82
84, 9194
85
R
83 R
N N
AcO
N N
NH N
NH
N HN
+
HN N
AcO
OAc
pMe
pMe
pMe
7, 88 86, 89 87, 90 A: RHgCl (R = 83)LiPdCl3 (for the production of 84 and 85, 86 and 87, and 89 and 90 from 82, 7, and 88 respectively); H2C=NMe2+I (for the production of 91 and 92 from 15 and 82 respectively) B: MeI (for the production of 93 and 94 from 91 and 92 respectively)
Scheme 12. The introduction of nucleoside residues and a dimethylaminomethyl group along the periphery of the chlorin macrocycle. 401
The enhanced electron density at the peripheral vinyl group gives rise to activity in the Vilsmeier reaction. Thus, during brief heating to 100C in a mixture of phosphorus oxychloride and DMFA followed by demetallation of the intermediates 97 and 98, and 99 respectively the metal complexes 95 and 96 give the respective formyl derivatives 100 and 101 and 102. It was noted that if the metal complex 95 is used as substrate the products from monoformylation 100 and diformylation 101 are formed. Under analogous conditions the metal complex 96 forms compound 102 the result of exclusive attack at the vinyl group of the chlorin 96 [85]. Selective functionalization of the vinyl group can also be achieved in the case where the Vilsmeier reaction is conducted at a copper complex. Thus, the formyl derivative 100 is obtained during formylation of the metal complex 103 by the POCl3/DMF system after demetallation of the intermediate 104 [50, 56] (Scheme 13).
OH C OH C
N M N
N N
A,B
N M N
N N
N M N
+
R
OH C
N
pM e
R
COOM e
pM e
pM e
COOM e
COOM e
COOM e
95, 96, 103 95 M = FeCl, R = COOMe 96 M = FeCl, R = H 97 M = FeCl, R = COOMe 98 M = FeCl
97, 99, 100, 102, 104, 105 99 M = FeCl, R=H 100 M = 2H, R = COOMe 101 M = 2H 102 M = 2H, R = H
98, 101 103 M = Cu, R = COOMe 104 M = Cu, R = COOMe
A: POCl3/DMF (for the production of compounds 97 and 98, 99, and 104 from 95, 96, and 103 respectively). B: Acid treatment (for the production of 100, 101, 102 from 97 and 104, 98, and 99 respectively).
Scheme 13. Versions of the introduction of an aldehyde along the periphery of the chlorin macrocycle using the Vilsmeier reaction. Elimination of the Vinyl Group Electrophilic elimination of the vinyl group of vinylchlorins (so-called devinylation) is easily realized by heating them in molten resorcinol. The main side processes occurring during devinylation are 132-demethoxycarbonylation (see the section on "Demethoxycarbonylation at Position 132 of the Exocycle),
R R
Fe Cl N N
Fe Cl N N
pM e
COOM e O
pM e
105 R = Me 107 R = CHO
106 R = Me 108 R = H
A: Heating in molten resorcinol
Scheme 14: The elimination of a peripheral vinyl group. 402
oxidation of the chlorin macrocycle to the thermally more stable porphyrin derivative, and additional deformylation in the case of the devinylation of derivatives of the b series. Thus, when the metal complex 105 is heated in molten resorcinol the divinylchlorin 106 is formed, while if the metal complex of the b series 107 is used 3-devinyl-7-deformylchlorin 108 is formed [22] (Scheme 14).
Pathways for Modification of a Formyl Group Versions of the Introduction of a Formyl Group The main methods for the introduction of a formyl group into the chlorin macrocycle include oxidation of the vinyl group (for greater detail, see the section on "Oxidation of the Vinyl Group"), oxidation of the 15-CH2COOH group (see the section on "Pathways for Modification of the Carboxyl Groups of the Products from Opening of the Exocycle"), and the Vilsmeier reaction (see [52, 65, 67, 87-89] and the section on "Substitution at the Vinyl Group"). Photochemical modification of the peripheral substituents has also been proposed for the introduction of a formyl [90, 91]. Thus, the formyl derivative 111 is obtained with a good yield by irradiation of the chlorin 109 in carbon tetrachloride solution followed by hydrolysis of the intermediate dichloromethyl derivative 110. It is assumed that the mechanism of formation of the intermediate 110 rests on sensitization of the carbon tetrachloride, partial photolysis to the Cl radical, and possible stereospecific substitution of the methyl group of the chlorin 109 at position 7 (Scheme 15).
CHCl2
NH N N HN COOMe COOMe NH N N HN COOMe COOMe
CHO
NH N N HN COOMe COOMe
pMe
pMe
pMe
109
A: CCl4/hv
110
B: hydrolysis
111
Scheme 15. The photochemical method of introduction of a formyl group.
Reduction of the Formyl Group The formyl group is easily reduced to a hydroxymethyl group by the action of NaBH4 or Al(O-i-Pr)3 [22]. With the use of these reducing agents on a tetrapyrrole substrate containing several carbonyl groups it is difficult to achieve selectivity in the reduction of the formyl group [28]. The selective reduction of the formyl group of the pyropheophorbide 32 to a hydroxymethyl substituent with the formation of the derivative 112 is achieved by the action of t-BuNH2BH3 [92], Bu4NBH(OAc)3 [55], or NaBH3CN [63]. The reductive alkylation of the aldehyde group of the chlorin 32 to the methoxymethyl derivative 113 can be achieved is conducted with an acceptable yield by the action of the MeOH/H2SO4/Et3SiH system [92]. The aldehyde 29 is transformed by the action of sodium borohydride into the alcohol 114 [71]. The reduction of the aldehyde group in the meso position by means of sodium borohydride under the conditions of high acidity leads to a methyl group [50, 65]. Thus, treatment of the metal complex 115 with the NaBH4/AcOH system gives a high yield of the derivative 116
403
[65]. Reductive amination of the aldehyde group in chlorins has also been described [93, 94]. Thus, treatment of the chlorophyll 2 with the NH4OcNaBH3CNMeO system gives the aminomethyl derivative 117 with a yield of 80% [94] (Scheme 16).
N H2 N Mg N N N
R1
R2
N M N N N
RO
A(B)
NH N
N HN
pPhytyl
COOM e O
pR 4
R3
pMe
117
HO
NH N N HN
2, 32
R1
112, 113
Cl
R2
N
M
N COOM e COOM e
Cu
N pMe N COOM e COOM e
pMe
COOM e COOM e
pMe
114
29, 115
116
2 M = Mg, R1 = CH=CH2, R2 = CHO, R3 = COOMe, R4 = Phytyl; 29 M = 2H, R1 = CHO, R2 = H; 32 M = 2H, R1 = CHO, R2 = R4 = Me, R3 = H; 112 R = H; 113 R = Me; 115 M = Cu, R1 = CH2CH2Cl, R2 = CHO A: t-BuNH2BH3, Bu4N+BH(OAc)3 or NaBH3CN (for the production of 112 from 32); B: MeOHH2SO4Et3SiH (for the production of 113 from 32); C: NaBH4 (for the production of 114 from 29); D: NaBH4AcOH (for the production of 116 from 115); E: NH4OAcNaBH3CNMeOH (for the production of 117 from 32)
Scheme 16. The various versions of reduction of the aldehyde group. Methods for modification of the hydroxymethyl group in chlorins 112 and 114 were proposed. Thus, the acetoxy derivative 118 was obtained by treating the alcohol 112 with acetyl chloride in pyridine [63]. The reaction of the chlorins 112 and 114 with the CH-acid acetylacetone in the presence of zinc acetate gave the metal complexes 119 and 120, the brief treatment of which with 6 N hydrochloric acid led to the free bases 121 and 122 [71] (Scheme 17).
O O AcO O O
NH N
N HN
112
B (C)
M
N N N
M
N COOM e COOM e
B (C)
114
pMe
118
119, 120 M = Zn 121, 122 M = 2H
pMe
pMe
119, 121
120, 122
A: Zn(OAc)22H2Oacetylacetone, 110C (for the production of 119 and 120 from 112 and 114 respectively); AcClpyridine (for the production of 118 from 112) B: 6N hydrochloric acid (for the production of 121 and 122 from 119 and 120 respectively)
Scheme 17. Pathways for modification of the hydroxymethyl group. 404
Oxidation of the Formyl Group By oxidizing the aldehyde groups of chlorophylls it is possible to introduce a carboxyl group at various positions of the chlorin ring. Thus, the aldehydes 12 and 32 are oxidized to the carboxy derivatives 123 and 30 by the action of NH2SO3H and NaClO2 in the presence of 2-methyl-2-butene [63] (Scheme 18).
R1
NH N N HN
R2
R1
NH N N HN
R2
12 R1 = CH=CH2, R2 = CHO 30 R1 = COOH, R2 = Me 32 R1 = CHO, R2 = Me 123 R1 = CH=CH2, R2 = COOH
pM e
pM e
12, 32
30, 123
A: NH2SO3HNaClO2H3CC(Me)=CHMe (for the production of 30 and 123 from 32 and 12 respectively)
Scheme 18. Oxidation of the formyl groups of chlorophyll derivatives to carboxyl substituents. The insertion of a carboxyl group at position 3 or 7 of the chlorophyll macrocycle opens up wide possibilities for its further modification. Thus, it can be easily transformed into an amide [63, 95-97], ester, or anhydride [63, 97] group. Nucleophilic Addition to the Formyl Group The aldehyde group of the chlorophyll 2 and other formylchlorins contains a powerful nucleophilic center, giving rise to the ease of its reaction with a wide range of nucleophiles. The Production of Imino Derivatives The reaction of the aldehyde 10 with NH2OHHCl in pyridine at room temperature leads to the formation of the aldoxime 124 [98]. By increasing the temperature it is possible to obtain oximes at position 131 in various chlorophyll derivatives. Under these conditions compound 10 forms the 3,131-dioxime 125 [98], while the derivative 5 forms the 131-monoxime 126 [99]. Under analogous conditions the aldehyde 22 is transformed into the aldoxime 127, the heating of which in acetic anhydride gives the cyano derivative 128 [85]. The production of the oxime 129 was reported in [100]. A method was proposed for separating the chlorins of series a and b using the Girard T reagent [49, 101]. Thus, the hydrazide 130 is formed regioselectively during the action of this reagent on a mixture of the chlorins 5 and 10 in the presence of acetic acid. In view of the high polarity of the hydrazide 130 compared with compound 5 the compounds are easily separated by column chromatography. Acid solvolysis of the hydrazide 130 with a MeOH/Me2CO/H2SO4 mixture leads to the initial aldehyde 10. Thus, with the Girard T reagent it is possible to separate phorbin derivatives of the a and b series effectively [49] (Scheme 19). Imino derivatives are also obtained on the basis of the formyl group at position 15 (see the section on "Pathways for Modification of the Carboxyl Groups of the Products from Opening of the Exocycle").
Production of Vinyl Derivatives With the right strategy by the Wittig [51, 55, 56, 58, 102-106], Knoevenagel [104], McMurry [107-109], and other condensations [57, 105, 110] it is possible to construct effectively various vinyl derivatives based on the formyl group of chlorophylls. 405
R1
NH N N HN
R1
A,B, D
NH N
N HN
pR 2
COOM e O
pR 3
COOM e R 2
5, 10
R1
NH N N HN COOM e COOM e
124126, 130
R2 R1 R2
5 R1 = R2 = Me 10 R1 = CHO, R2 = Me 22 R1 = CH=CH2, R2 = CHO 124 R1 = CH=NOH, R2 = O, R3 = Me 125 R1 = R2 = CH=NOH, R3 = Me 126 R1 = R3 = Me, R2 = CH=NOH 127 R1 = CH=CH2, R2 = CH=NOH 128 R1 = CH=CH2, R2 = CN 130 R1 = CH=NNHCOCH2N+Me3Cl, R2 = O, R3 = Me
HON
N Zn N
pMe O
129
A,B,
Girard T reagent: [NH2NHCOCH2N+Me3]Cl
pM e
pM e
22 127, 128 A: NH2OHHClpyridine, room temperature (for the production of 124 from 10) B: NH2OHHClpyridine, 100C (for the production of 125-127 from 10, 5, and 22 respectively) C: Ac2O, heat (for the production of 128 from 127); Girard T reagent AcOH (for the production of 130 from 10) D: MeOHMe2COH2SO4 (for the production of 10 from 130)
Scheme 19. The production of imino derivatives based on the formyl group of chlorophyll derivatives.
The Wittig Reaction. Treatment of the metal complex 131 with phosphorane (Ph3P=CH2) leads to the formation of the vinyl derivative 132 with a yield of 32% [55], but if the chlorophyll 2 is used as formyl substrate the 7-vinyl derivative 133 is formed with a yield of 60% [102]. The metal-free derivatives of chlorophylls also react with phosphorane [55, 56, 103, 104] and its homologs [51, 104], and here the phorbin derivatives 10, 12, 32, and 134 form the respective ethylidenechlorins 135, 136, 7, and 5 with low yields, while the nonphorbin chlorin 137 forms the derivative 53 with a yield of more than 80% [56, 103]. Two effective pathways were proposed for the production of vinylphorbin derivatives. The first involves preliminary construction of the divinylchlorin 53 from the formylchlorin 137 by the Wittig reaction, and its cyclization with a strong base leads to the phorbin structure 138 with a yield of 82% (see the section on "Recyclization of the Exocycle") [56]. The second approach involves transformation of the aldehyde group of the phorbin chlorins 32 and 134 into the reactive phosphonium salts 139 and 140, which are converted into the derivatives 7 and 5 with good yields by the action of paraformaldehyde in the presence of epoxypropane. For this the aldehyde group of the chlorins 32 and 134 is reduced to the hydroxymethyl derivatives 112 and 141, treatment of which with the Ph3P/CBr4 system gives the phosphonium salts 139 and 140 [55] (Scheme 20). The Wittig reaction was studied in greatest detail for the formyl substrate 32 in [104]. The Knoevenagel Reaction. The base-catalyzed reaction of the aldehyde 32 with malononitrile, dimethyl malonate, and methyl cyanoacetate leads to the corresponding vinyl derivatives 142-145 [104]. It was shown that the yields of compounds 142-145 are determined by the nucleophilic activity of the employed activated methylene components and by the steric effects during the joint coordination of the bulky aldehyde molecule 32 with the nucleophile (Scheme 21). The McMurry Reaction. An effective method for the synthesis of homodimers [107-109] and heterodimers [108] of various tetrapyrroles whose monomers are linked by a system of double bonds is the McMurry reaction [112, 113]. Tetrapyrroles containing a carbonyl group, which can be at various positions of 406
OH C
R1
R2 R3
N M N N N
R1
R2
N M N N N
A, B, C, D
pM e
pM e
pR 5
R4
pR 4 O R3 O
137
53
5, 7, 132,133, 135,136, 138
2, 10, 12, 32, 112, 131, 134, 139141
2 M = Mg, R1 = CH=CH2, R2 = CHO, R3 = COOMe, R4 = Phytyl; 5 M = H, R1 = CH=CH2, R2 = R5 = Me, R3 = Et, R4 = COOMe; 7 M = 2H, R1 = CH=CH2, R2 = R5 = Me, R3 = Et, R4 = H; 10 M = 2H, R1 = CH=CH2, R2 = CHO, R3 = COOMe, R4 = Me; 12 M = 2H, R1 = CH=CH2, R2 = CHO, R3 = H, R4 = Me; 32 M = 2H, R1 = CHO, R2 = R4 = Me, R3 = H; 112 M = 2H, R1 = CH2OH, R2 = R4 = Me, R3 = H; 131 M = Zn, R1 = CHO, R2 = R4 = Me, R3 = H; 1 132 M = Zn, R = CH=CH2, R2 = R5 = Me, R3 = Et, R4 = H; 133 M = Mg, R1 = R2 = CH=CH2, R3 = Et, R4 = COOMe, R5 = Phytyl; 134 M = 2H, R1 = CHO, R2 = R4 = Me, R3 = COOMe; 135 M = 2H, R1 = CH=CH2, R2 = CH=CHMe, R3 = Et, R4 = COOMe, R5 = Me; 136 M = 2H, R1 = CH=CH2, R2 = CH=CHMe, R3 = Et, R4 = H, R5 = Me; 138 M = 2H, R1 = R3 = CH=CH2, R2 = R5 = Me, R4 = COOMe; 139 M = 2H, R1 = Ph3P+CH2Br, R2 = R4 = Me, R3 = H; 140 M = 2H, R1 = Ph3P+CH2Br, R2 = R4 = Me, R3 = COOMe; 141 M = 2H, R1 = CH2OH, R2 = R4 = Me, R3 = COOMe
A: Ph3P=CH2 (for the production of 5, 7, 53, 132, and 133 from 134, 32, 137, 131, and 2 respectively) Ph3P=CHMe (for the production of 135 and 136 from 10 and 12 respectively); B: NaN(SiMe3)2 (for the production of 138 from 53); Bu4NBH(OAc)3 (for the production of 112 and 141 from 32 and 134 respectively); C: Ph3PCBr4 (for the production of 139 and 140 from 112 and 141 respectively); D: paraformaldehyde1,2-epoxypropane (for the production of 5 and 7 from 140 and 139 respectively)
Scheme 20. Functionalization of the aldehyde groups of chlorophylls and their derivatives using the Wittig reaction.
R2 O H R1 H
NH N
N HN
NH N
N HN
142 R1 = R2 = CN (76%) 143 R1 = R2 = COOMe (52%) 144 R1 = CN, R2 = COOMe (78%) 145 R1 = COOMe, R2 = CN (0%)
pMe
pMe
A: NCCH2CN (for the production of 142 from 32) MeOOCCH2COOMe, Et3N (for the production of 143 from 32) NCCH2COOMe, Et3N (for the production of 144 and 145 from 32)
O
32
142145
Scheme 21. Reaction of the aldehyde group of chlorophyll derivatives with CH-acids in the Knoevenagel reaction.
the macrocycle, are most often used as substrates for the production of such dimers. Thus, the corresponding symmetrical trans-ethylene dimers 148 and 149 are formed when the nickel complexes 146 and 147 are heated with TiCl3(1,2-dimethoxyethane)1.5 and a zinc-copper couple in 1,2-dimethoxyethane [107] (Scheme 22).
407
H OC
pM e N N
Ni
N N COOM e COOM e
M eOOC M eOOC
N N N Ni N N
Ni N
N pM e
COOM e COOM e
pM e
146
148
N N
OH C
N
Ni
N
Ni
N N
Ni
N N
pM e pM e COOM e COOM e M eOOC M eOOC pM e
COOM e COOM e
147
149
A: TiCl3(1,2-dimethoxyethane)1.5Zn-Cu (for the production of 148 and 149 from 146 and 147 respectively)
Scheme 22. Reductive dimerization of the formyl derivatives of chlorins under the conditions of the McMurry reaction. Production of Cyanohydrins and Acetals The formyl group of chlorophyll 2 reacts with HCN and methanol with the formation of the cyanohydrin 150 and the acetal 151 respectively [22]. The aldehyde groups of the metal-free derivatives of chlorophylls also form acetals in reaction with active nucleophilics [56, 78, 103, 114, 115]. Thus, treatment of the chlorin 32 with 2,2-dimethyl-1,3-propanediol in the presence of p-MeC6H4SO3H leads to the formation of the cyclic acetal 152 with a quantitative yield, but if the polycyclic diol 153 is used as nucleophile the stereoisomeric acetals 154 and 155 are formed with yields of 79% [114]. The dimethyl acetal 156 is formed with a yield of 92% when the aldehyde 29 is treated with trimethyl orthoformate in methanol in the presence of toluenesulfonic acid [56].
R1
N M N pR 4 R3 O N N
R2
R1
R2
N M N pR 4 R3 O N N
2, 150, 151 M = M g, R 1 = CH =CH 2,

R 3 = COOM e , R 4 = P hytyl
2 R 2 = CH O 150 R 2 = CH (CN )2 151 R 2 = CH (OM e ) 2 32, 152, 154, 155, 157, 158
M = 2H , R 2 = R 4 = M e , R 3 =H
32 R 1 = CH O
O
2, 32
150152, 154, 155, 157159

M eO OM e
152 R 1= 153
O O C 6H13 N O O
O OH N OH O O O N O O O O N O O
OHC NH N N HN COOMe COOMe
NH N
N HN COOMe COOMe
A: HCN (for the production of 150 from 2); MeOH (for the production of 151 from 2); p-MeC6H4SO3HHOCH2C(Me2)2CH2OH (for the production of 152 from 32); p-MeC6H4SO3H153 (for the production of 154 and 155 from 32); HC(OMe)3MeOHTsOH (for the production of 156 from 29); MeMgI (for the production of 157 from 32); 13 CH3MgI (for the production of 158 from 32); CD3MgI (for the production of 159 from 32)
154 R 1=
C6 H 13 N O O
pMe
pMe
29
156
155 R 1=
C 6H13 N O
157 R 1 = MeCHOH; 158 R 1 = 13CH 3CHOH; 159 R 1 = CD 3CHOH
Scheme 23. The production of cyanohydrins and acetals based on the formyl group and their chemical characteristics. 408
Strong polarization of the C=O group of chlorophylls facilitates its reaction with the Grignard reagent. Thus, during the action of methylmagnesium iodide on the formyl derivative 32 the corresponding alcohols 157-159 are formed regioselectively with yields of 75-81% in the form of a racemic mixture of diastereomers [116] (Scheme 23). Other Condensations. A method proposed by Prato and coworkers was used for the synthesis of fullerenepyropheophorbide dimers [117]. It involves the addition of an azomethine ylide at the 66 bond of fullerene. Thus, heating of the formylchlorin 32 with fullerene and N-methylglycine in toluene leads to the formation of the epimers 160 with a yield of 49%, and their treatment with zinc acetate in chloroform/methanol gives the zinc complex 161 with a yield of 86% [118] (Scheme 24).
M
N N
pMe
160 M=2H
161 M=Zn
Scheme 24. The fullerenepyropheophorbide dimer.
Pathways for Modification of the 17-2-Alkoxycarbonylethyl) Group of Chlorophylls Reduction of the Ester Group Under the influence of lithium aluminum hydride both carbonyl fragments of the chlorin 27 are reduced with the formation of compounds 162 and 163. It was noted that here the 17-CH2CH2COOMe group is reduced smoothly to a 17-CH2CH2CH2OH group, while the 132-carbonyl fragment is reduced both to an alcohol and to a methylene group, and it is this that secures the presence of the two main reduction products 162 and 163 from the chlorin 27. Previous protection of the 132-carbonyl fragment of the chlorin 27 in the form of the ketal 164 makes it possible by the action of lithium aluminum hydride to realize the regioselective reduction of the ester group of the chlorin 27 to the hydroxy derivative 165 [119] (Scheme 25). Pathways were also proposed for the transformation of the alcohol groups of the chlorins 163 and 165 to methyl groups with the formation of compounds 166 and 167. For this purpose the alcohols 163 and 165 are first treated with the MsCl/Et3N system in methylene chloride with the formation of the mesityl derivatives 168 and 169, and they are then reduced with lithium aluminum hydride, giving the methyl derivatives 166 and 167 with a yield of more than 50%. The protecting group in the chlorin 170 is removed by treatment with hydrochloric acid in acetone, leading to the formation of the chlorin 167 [119] (Scheme 25). The transformation of the carboxyl group of the chlorin 6 into the aminoethyl derivative 171 was realized by the Curtius reaction under mild conditions: The carboxy derivative 6 was heated with t-BuOH in the presence of diphenylphosphoryl azide and triethylamine. By losing a molecule of nitrogen the corresponding 409
azide 172 rearranges to the isocyanate 173, which in reaction with t-BuOH in situ forms the tert-butylurethane 174. The yield of the urethane 174 was increased to 30% after replacement of triethylamine by the significantly more effective proton acceptor 175, which prevented the formation of NH3 and on this account reduced the yield of the side compounds. The quaternized amine 171 was obtained with a yield of 65% by acid hydrolysis of the urethane 174 in ethyl acetate [120] (Scheme 25).
R1
NH N N HN
A,B
NH N pR 2
N HN
E,F
NH N
N HN
R1 C 2 OR 2
A,B
162,163, 168 C
NH N N HN
6, 27, 164
171174
NH N
N HN
C,D
NH N
N HN
X CH 2 OR
166
167, 170
165, 169
6 R1 = CH=CH2, R2 = H, X = O; 27 R1 = Et, R2 = Me, X = O; 162 R1 = OH, R2 = H; 163 R1 = R2 = H; 164 R1 = Et, R2 = Me, X = O(CH2)2O; 165 R = H, X = O(CH2)2O; 167 X = O; 168 R1 = H, R2 = Ms; 169 R = Ms, X = O(CH2)2O; 170 X = O(CH2)2O; 171 R =
NH3+Cl;
172 R = N3; 173 X = NCO; 174 R = NHC(O)Bu; 175
Me Me N
Me N Me
A: LiAlH4, 0C (for the production of 162 and 163 from 27); LiAlH4, -78C (for the production of 165 from 164); B: MsClEt3N (for the production of 168 and 169 from 163 and 175 respectively); C: LiAlH4, 0C (for the production of 166 from 168); LiAlH4, -7C (for the production of 167 from 169); D: HClacetone (for the production of 170 from 167); E: N3PO(OPh)2t-BuOH175 (for the production of 172-174 from 6); F: 3M HClEtOAc (for the production of 171 from 174)
Scheme 25. Various versions of the reduction of the ester group
Hydrolysis of the Ester Group Effective hydrolysis of the ester group takes place in an acidic and an alkaline medium and also under the influence of enzymes. Acid Hydrolysis. If an ether solution of the chlorophyll 1 is shaken with 30% hydrochloric acid for 5-30 min the phytylpropionate residue is hydrolyzed, and the magnesium atom is removed from the chlorophyll molecule with the formation of the pheophorbide 4 [121, 122]. Hydrolysis of the chlorophyll 2 to the pheophorbide 9 requires a higher concentration of hydrochloric acid than the hydrolysis of chlorophyll 1 to pheophorbide 4. This fact and also the difference in the distribution coefficients etherhydrochloric acid has been successfully used for the separation of compounds of series a and b [123]. According to data in [124], the 410
hydrolysis of the phytol residue of pheophetins 3 and 8 in the hydrochloric acidether system is accompanied by hydrolysis of the 132-CO2Me fragment to a 132-CO2H group and its subsequent elimination with the formation of the corresponding derivatives 6 and 11. It was proposed to use 80% aqueous trifluoroacetic acid at 0C for regioselective hydrolysis of the phytylpropionate residue of the chlorins 3 and 8, and this made it possible to obtain the chlorins 4 and 9 with a yield of more than 90% [124] (Scheme 26).
R
N M N N N
R1
N N NH N N HN
Mg
N N COOH COOH
M
N N
pPhytyl
O COOM e
pH
pH R2
pN a
O COOM e
13, 8
178,179
4, 6, 9, 11, 176,177, 180
181
1 M = Mg, R = Me; 2 M = Mg, R = CHO; 3 M = 2H, R = Me; 4 M = 2H, R1 = Me, R2 = COOMe; 6 M = 2H, R1 = Me, R2 = H; 8 M = 2H, R= CHO; 9 M = 2H, R1= CHO, R2 = COOMe; 11 M = 2H, R1= CHO, R2 = H; 176 M = Mg, R1 = Me, R2 = COOH; 1 177 M = Mg, R = CHO, R2 = COOH; 178 R = Me; 179 R = CHO; 180 M = Mg, R1 = Me, R2 = COOH
A: hydrochloric acidether (for the production of 4 and 9 from 1 and 2 respectively; the side formation of 6 and 11 from 3 and 8 respectively); 80% CF3COOH, 0C (for the production of 4 and 9 from 3 and 8 respectively); a cold solution of alkali (for the production of 176 and 178 and 177 and 179 from 1 and 2 respectively); the enzyme chlorophyllaseaqueous acetone (for the production of 180 from 1). B: a dilute solution of sodium hydroxide (for the production of 181 from 4).
Scheme 26. The various versions of the hydrolysis of the ester group. Alkaline Hydrolysis. Treatment of the chlorophylls 1 and 2 in a cold solution of alkali leads to elimination of the phytol residue with retention of the magnesium ion in the macrocycle. Side reactions are hydrolysis of the 132-CO2Me group to a carboxy group with the formation of the chlorophyllins 176 and 177 and the products from opening of the exocycle 178 and 179 [37] (Scheme 26). The methylpropionate residue of chlorophyll derivatives 7 is hydrolyzed by the action of an aqueous solution of lithium hydroxide in THF methanol to a carboxyl group with a yield of 80-82% [60]. Enzymatic Hydrolysis. The highly effective hydrolysis of the phytylpropionate residue of chlorophylls is achieved by the action of the enzyme chlorophyllase ([125] and the references therein), discovered by Willsttter and Stoll more than 90 years ago [126]. According to data in [127], incubation of chlorophyll 1 with chlorophyllase in aqueous acetone at 22C leads after 70 min to the formation of the chlorophyllide 180 with a yield of 96% [see the section on "Various Versions of the Production of Esters Based on the 17-(2-hydroxy(alkoxy)carbonylethyl) Group of Chlorophylls"]. The 17-(2-Hydroxycarbonylethyl) group readily forms salts with strong bases. Thus, under the influence of a dilute solution of sodium hydroxide the pheophorbide 4 and its various derivatives are converted into the corresponding water-soluble sodium salts 181 with high yields [128, 129] (Scheme 26). Various Versions of the Production of Esters Based on the 17-2-Hydroxy(alkoxy)carbonylethyl) Group of Chlorophylls The pheophetins 3 and 8 are converted by the action of methanol in the presence of sulfuric acid [49] into the corresponding methyl esters 5 and 10. Esterification of the acid 4 with diazomethane gives the methyl ester 5 [52]. 411
Transesterification of the methyl esters to their C(5)C(10) homologs is realized by the action of ROH/H2SO4 [59]. In order to obtain esters containing long-chain and/or labile fragments the strategy of preliminary activation of the ester (carboxyl) group is used, or the reaction is conducted with highly active esterifying systems under mild conditions [59, 66, 97, 124, 130-133]. Thus, the reaction of the pheophorbide 6 with the polyene alcohol fucoxanthin 182 in the presence of 2-chloro-1-methylpyridinium iodide and 4-dimethylaminopyridine leads to the formation of the ester 183 with an acceptable yield [97]. With the enzyme chlorophyllase (see the section on "Hydrolysis of the Ester Group") as transesterification catalyst it is possible to obtain esters under mild conditions, starting from chlorophylls and their derivatives ([127, 134] and references cited therein). Thus, the incubation of chlorophyll 1 in the presence of chlorophyllase with the methyl ester of the amino acid serine leads to the formation of the ester 184 with a yield of 70-80% [134]. It was shown that the derivative 184 exhibits high anticancer activity [134] (Scheme 27).
R1
N N
R1
N N
M
N N
M
N N
pR3
R2
pR3 R2
1 M = Mg, R1 = Me, R2 = COOMe, R3 = Phytyl 3 M = 2H, R1 = Me, R2 = COOMe, R3 = Phytyl 4 M = 2H, R1 = Me, R2 = COOMe, R3 = H 5 M = 2H, R1 = R3 = Me, R2 = COOMe 6 M = 2H, R1 = Me, R2 = R3 = H 8 M = 2H, R1 = CHO, R2 = COOMe, R3 = Phytyl 10 M = 2H, R1 = CHO, R2 = COOMe, R3 = Me
1, 3, 4, 6, 8
5, 10, 183, 184

OH O O O
O H O 182
183 M = 2H, R1 = Me, R2 = H, R3 = fucoxanthin residue 182; 184 M = Mg, R1 = Me, R2 = COOMe, R3 = CH2CH(NH2)COOMe
A: MeOHacid (for the production of 5 and 10 from 3 and 8 respectively); CH2N2Et2O (for the production of 5 from 4); 1822-chloro-1-methylpyridinium iodide4-dimethylaminopyridine (for the production of 183 from 6); enzyme chlorophyllaseHOCH2CH(NH2)COOMe (for the production of 184 from 1)
Scheme 27. Esterification of the 172-carboxyl and transesterification of the 172-ester group.
The Production of Amide Derivatives Based on the 17-2-Hydroxycarbonylethyl) Group of Chlorophylls The creation of an amide bond on the basis of the 17-(2-hydroxycarbonylethyl) group of chlorophylls and their derivatives is an effective method for the production of prospective compounds for use in medicine ([132, 135-137] and references therein) and in industry [158]. The optimum strategy for such bioconjugates is to use the procedures of peptide chemistry. Thus, compound 185 is obtained in the reaction of the chlorin 14 with di-tert-butyl aspartate in the presence of dicyclohexylcarbodiimide. The protection of the carboxyl groups in the amino acid residue of the adduct 185 is removed by the action of trifluoroacetic acid, and the amide derivative 186 is obtained ([4] and references therein); this is an effective product (commercial name NPe6) for the treatment of various forms of cancer by PDT ([4-6, 8, 142] and references therein). It was noted that the diamide 187 is a side product in the production of the amide 185 (Scheme 28). 412
N N
N N COO COOH
N N
N N COO COOH
14
N N
N N COO COOtBu
C O NH COOH COOH O
C NH COOtBu COOtBu
C O O NH
C NH
COOtBu COOtBu COOtBu
186 "NPe6"
185
187
A: H2NCH2CH(COO-t-Bu)2dicyclohexylcarbodiimide; B: CF3COOH
Scheme 28. The strategy for the synthesis of the effective product "NPe6" for the treatment of various forms of cancer by PDT. An alternative approach was also developed for the production of 172-amide derivatives. Thus, treatment of various chlorophyll derivatives 4, 6, 188-190, containing a free 172-carboxyl group, with 2,3-dichloro-5,6dicyano-1,4-benzoquinone leads to the formation of the lactones 191-195 [159, 160]. Opening of the lactone 195 with N-nucleophiles gives good yields of the amides 196-198 [161] (Scheme 29).
R NH N N HN O O O
NH N
N HN
NH N
N HN
A
O
NH N
N HN
pH O
pH
H R
O O H R O
188,189
193,194
4, 6
191,192
NH N
N HN
A
O
NH N
N HN
B
HO
NH N
N HN
pH
CO OMe O CO OMe
CO OMe CO OMe RHN
CO OMe CO OMe O
4, 191 R = COOMe 6, 192, 196 R = H 188, 193 R = CH=CH 189, 194 R = Ac 197 R = NH 2 198 R = (CH 2)3OH
190
195
196198
A: 2,3-Dichloro-5,6-dicyanobenzoquinone (for the production of 191-195 from 4, 6, and 188-190 respectively); B: NH3, N2H4, or HO(CH2)3NH2 (for the production of 196-198 respectively from 195).
Scheme 29. Stereoselective synthesis of the lactone cycle in ring D and production of 172-amide derivatives by its opening with N-nucleophiles. Pathways for the Modification of the Exocyclic Fragment The main problem in the isolation and modification of chlorophylls is the high reactivity of their exocyclic fragment. The strong activation of the hydrogen atom at position 132 by the two carbonyl groups gives rise to the ease of enolization with the participation of the C(131)C(132) bond. For specific modification of the 413
exocycle it is necessary to take account of the ability of its enolate anion to undergo rapid and irreversible oxidation by atmospheric oxygen (the so-called "allomerization" process [9]) in the presence of bases and/or metals (for greater detail, see [22, 28]). In this review some of the basic pathways for the modification of the exocycle without the participation of atmospheric oxygen are examined in greatest detail.
Opening of the Exocyclic Fragment Mechanisms of Opening of the Exocycle. The exocycle in chlorophylls and their derivatives is easily opened with cleavage of the C(131)C(132) bond by the action of various nucleophiles. The ease of opening of the exocycle is due to the presence of a resonance-stabilized and sterically accessible nucleophilic center at carbon atom 131. The mechanism of opening of the exocycle without the involvement of oxygen is regarded as basecatalyzed nucleophilic addition to the 131-carbonyl group of the phorbin 4, which is transformed into compound 200 through the intermediate formation of the carbanion 199 [28, 162]. The key stage in the opening of the exocycle with the participation of oxygen is probably fragmentation of the initially formed hydroperoxide 201 under the acidic conditions with the formation of the so-called "unstable chlorin" 202 [11]. Evaporation of the solvent leads to cyclization of the chlorin 202 to the purpurin 188, while during esterification of compound 202 with diazomethane its exocyclic fragment is opened with the formation of the derivative 203 [49] (Scheme 30).
NH N N HN
NH N N HN
NH N N HN
pK O
HO
OH OOM e
pH OOM e
Nu
pH HC CON u
COOMe NH N N HN
201
D
N
199
pH
NH
CON u COOMe
NH
NH
200
COOM e
N HN
N HN
N HN
pH O
pH HO
HOOC
pM e O
OOM e
188
202
203
A: Nu; B: NuH; C: atmospheric oxygen, KOH; D: Acidification. E: Evaporation.; F: CH2N2Et2O
Scheme 30. Versions of the opening of the exocyclic fragment. Opening of the Exocycle by the Action of O-Nucleophiles. Alkaline hydrolysis of the chlorophylls 1 and 2 in the absence of oxygen leads to the formation of the magnesium complexes 178 and 179 respectively [22, 25]. The chlorins 14 and 21 are obtained similarly from the free bases 4 and 9 [22]. Opening of the pheophorbides 5 and 10 by the action of the methoxide ion leads to the formation of the chlorins 15 and 22. Thus, the chlorins 15 and 22 are formed when the pheophorbides 5 and 10 are kept in an atmosphere of nitrogen for 24 h in the Py/CH2N2/MeOH system [22]. Methanolysis of the exocyclic fragment of the pheophorbides 5 and 10 in the MeONa/THF/MeOH system makes it possible to obtain good yields of the trimethyl esters of the chlorins 15 [50] and 22 [51]. Brief treatment of the pheophorbides 5 and 10 with a 0.5% 414
solution of potassium hydroxide in methanol in the presence of pyridine leads to the formation of the triesters 15 and 22 respectively with yields of more than 70% [162] (Scheme 31). Opening of the Exocycle by the Action of N-Nucleophiles. Under the influence of a wide range of amines the exocycle of chlorophylls 1 and 2 and their derivatives 3, 5, and 8 open readily with the formation of the corresponding 131-carboxamides 204-208 [22, 25, 147, 163-167]. It was shown that the effectiveness of aminolysis of the exocycle is determined by the basicity of the employed amine and by steric effects during coordination of the nucleophilic center 131 with the nitrogen-containing nucleophilic [22, 25, 163]. It was noted that the rate of formation of the 131-carboxamides in most cases is increased in the presence of water or ethanol [166] (Scheme 31).
R1
N M N N N
R1
M
N N COR2 COOR3
pR2
COOMe O
pR4
15, 810
14, 15, 21, 22, 178, 179, 204208
1 M = Mg, R1 = Me, R2 = Phytyl; 2 M = Mg, R1 = CHO, R2 = Phytyl; 3 M = 2H, R1 = Me, R2 = Phytyl; 4 M = 2H, R1 = Me, R2 = H; 5 M = 2H, R1 = R2 = Me; 8 M = 2H, R1 = CHO, R2 = Phytyl; 9 M = 2H, R1 = CHO, R2 = H; 10 M = 2H, R1 = CHO, R2 = Me; 14 M = 2H, R1 = Me, R2 = OH, R3 = R4 = H; 15 M = 2H, R1 = R3 = R4 = Me, R2 = OMe; 21 M = 2H, R1 = CHO, R2 = OH, R3 = R4 = H; 22 M = 2H, R1 = CHO, R2 = OMe, R3 = R4 = Me; 178 M = Mg, R1 = Me, R2 = OH, R3 = R4 = H; 179 M = Mg, R1 = CHO, R2 = OH, R3 = R4 = H; 204 M = Mg, R1 = Me, R2 = NR5R6, R3 = Me, R4 = Phytyl; 205 M = Mg, R1 = CHO, R2 = NR5R6, R3 = Me, R4 = Phytyl; 206 M = 2H, R1 = R3 = Me, R2 = NR5R6, R4 = Phytyl; 207 M = 2H, R1 = R3 = R4 = Me, R2 = NR5R6; 208 M = 2H, R1 = CHO, R2 = NR5R6, R3 = Me, R4 = Phytyl; 204-208 R5, R6 = H, Alk, Ar, Hetero
A: Alkali, absence of O2 (for the production of 14, 21, 178, and 179 from 4, 9, 1, and 2 respectively); pyridineCH2N2MeOH, MeONaTHFMeOH or KOHMeOHpyridine (for the production of 15 and 22 from 5 and 10 respectively); R1R2NH (for the production of 204-208 from 1-3, 5, and 8 respectively).
Scheme 31. Nucleophilic opening of the exocycle without the participation of oxygen.
Pathways for Modification of the Carboxyl Groups of the Products from Opening of the Exocycle The carboxyl groups of the chlorins 14 and 21 can be easily transformed into ester groups. Thus, the reaction of the chlorins 14 and 21 with diazomethane leads to the trimethyl esters 15 and 22 respectively. Esterification of the chlorin 14 with bromomethyl acetate in the presence of N,N-diisopropylethylamine gives the triester 209 [168]. It was shown that compound 209 has significant anticancer activity ([169] and references therein). The free carboxyl groups of the chlorin 14 are decarboxylated in the order 15-CH2COOH > 13-COOH, and the chlorins 16 and 20 are formed in succession. During pyrolysis of the chlorin 20 the stable phylloporphyrin XV 210 is formed [37]. The monoacid 211 is produced by selective hydrolysis of the triester 15 [22]. By activation of the 13-COOH group of the chlorin 211 with dicyclohexylcarbodiimide it is possible to obtain the biologically active amides 212 [170]. During hydrolysis the 13-COOH group of the chlorin 211 is eliminated with the formation of the chlorin 19. Hydrolysis of the diester 19 gives the diacid 18, pyrolysis of which in pyridine gives the chlorin 20 and the porphyrin 210 [22] (Scheme 32). 415
R1
NH N N HN
R2
R1
R2
NH N N HN
B, D, E F, G, H
NH N
N HN
, H
NH N
N HN
pR 5
COOR 3 COOR 4
pR 5
COOR 3 COOR 4
pR 3
R2 R1
pH
15, 22, 209
14, 21
16, 1820, 211, 212
210
14 R 1 = CH =CH 2, R 2 = M e , R 3 = R 4 = R 5 =H 15 R 1 = CH =CH 2, R 2 = R 3 = R 4 = R 5 = M e 16 R 1 = COOH , R 2 =M e , R 3 =H 18 R 1 = R 3 = H , R 2 = CH 2COOH 19 R 1 = H , R 2 = CH 2COOM e , R 3 = M e 20 R1 = R3 = H, R2 = Me
21 R 1 = CH =CH 2, R 2 = CH O, R 3 = R 4 = R 5 = H 22 R 1 = CH =CH 2, R 2 = CH O, R 3 = R 4 = R 5 = M e 209 R 1 = CH =CH 2, R 2 = M e , R 3 = R 4 = R 5 = CH 2OC(O)M e 211 R 1 = COOH , R 2 = CH 2COOM e , R 3 = M e 212 R 1 = C(O)N H R, R 2 = CH 2COOM e , R 3 = M e , R is a residue of steroids and other hormones
A: CH2N2 (for the production of 15 and 22 from 14 and 21 respectively); AcOCH2BrEtN(i-Pr)2 (for the production of 209 from 14. B: Hydrolysis (for the production of 16 and 20 from 14). C: Pyrolysis (for the production of 210 from 20). D: Hydrolysis (for the production of 211 from 15). E: dicyclohexylcarbodiimideRNH2 (for the production of 212 from 211). F: Pyrolysis (for the production of 19 from 211). G: Hydrolysis (for the production of 18 from 19). H: Pyrolysis (for the production of 20 and 210 from 18).
Scheme 32. Esterification and pyrolysis of the carboxyl groups of the products from opening of the exocycle.
The final product from pyrolysis of the chlorins of the b series is the porphyrin 210, indicating reduction of the 7-CHO group in chlorins of the b series under rigorous conditions [11]. In spite of the similarity of the structures of chlorins 14 and 18 their chemical characteristics different significantly. Thus, treatment of the chlorin 14 with potassium permanganate followed by esterification of the intermediate 213 leads to the formation of the formyl derivative 214 with a yield of less than 10%. Under similar conditions the chlorin 18 is not transformed into the analogous formyl derivative 215, but the chlorin 216, i.e., the product from oxidation of the vinyl and 13-CH2COOH groups of the chlorin 18, is formed with a yield of more than 20%. When heated with hydroxylamine hydrochloride in aqueous pyridine the aldehyde 214 undergoes deformylation with the formation of rhodochlorin 217. In the case of the formyl derivative 216 the aldoxime 218 is obtained, and this gives a good yield of the nitrile 219 when heated with acetic anhydride [85]. It was noted that the nitromethylene derivative 220 is formed in the reaction of nitromethane with the formyl derivative 214 in the presence of pyridine and ethylamine [22] (Scheme 33). The presence of three C-nucleophilic centers, situated on one side of the chlorin macrocycle, opens up great possibilities for its further modification. It is important to note that planned modification of the chlorin 214 is possible both in the pyrrole ring C and in ring D. Thus, under the influence of the sodium methoxide/methanol system the chlorin 214 enters into intramolecular aldol condensation with the formation of the pentacyclic derivative 221, and here modification of pyrrole ring D is realized [22]. The principle of the construction of an additional ring on the basis of ring C was used by Woodward as one of the last stages in the total synthesis of chlorophyll 1 [171-174]. Thus, the cyanolactone 222 is produced during treatment of the chlorin 214 with hydrogen cyanide, and its reduction by the zinc/acetic acid system followed by esterification of the intermediate 223 gives the nitrile 224. The derivative 15 is formed during solvolysis of the nitrile 224 by the acetic acid methanol system (Scheme 33).
416
R1
NH N N HN R COOH
A, B
NH N
N HN
NH N
N HN
pH
pR 4
R3 R2
pM e
14, 18
213219 F
220
N O2
NH N
N HN R1
G, H, I
NH N
N HN
NH N
N HN COOM e
pM e
R2
pM e NC
COOM e
15, 223, 224
222
221
14 R = COOH; 15 R1 = R2 = COOMe; 18 R = H; 213 R1 = CH=CH2, R2 = COOH, R3 = CHO, R4 = H; 214 R1 = CH=CH2, R2 = COOMe, R3 = CHO, R4 = Me; 215 R1 = CH=CH2, R2 = H, R3 = CHO, R4 = Me; 216 R1 = COOMe, R2 = H, R3 = CHO, R4 = Me; 217 R1 = CH=CH2, R2 = COOMe, R3 = H, R4 = Me; 218 R1 = COOMe, R2 = H, R3 = CH=NOH, R4 = Me; 219 R1 = COOMe, R2 = H, R3 = CN, R4 = Me; 223 R1 = COOH, R2 = CN; 224 R1 = COOMe, R2 = CN
A: KMnO4 (for the production of 213 from 14); esterification (for the production of 214 from 213); KMnO4, esterification (for the production of 216 from 18). B: NH2OHHCl, heat (for the production of 217 and 218 from 214 and 216 respectively). C: Ac2O, heat (for the production of 219 from 218). D: MeNO2EtNH2pyridine (for the production of 220 from 214). E: MeONaMeOH (for the production of 221 from 224). F: HCN (for the production of 222 from 214). G: ZnAcOH (for the production of 223 from 222). H: Esterification (for the production of 224 from 223). I: AcOHMeOH (for the production of 15 from 224).
Scheme 33. Further versions of modification of the carboxyl groups in the products from opening of the exocycle. Recyclization of the Exocycle Base-Catalyzed Recyclization of the Exocycle. By the action of strong bases under anaerobic conditions various derivatives of chlorophylls 15, 35, 53, and 225-227, containing 13-COOMe and 15-CH2COOMe fragments, undergo smooth cyclization to the respective pheophorbides 5, 228, 138, and 229-231 [50, 51, 56, 65]. Thus, brief heating of the chlorin 226 with t-BuOK in the t-BuOHPy system leads to the pheophorbide 230 with a yield of 97% [65]. It is assumed that recyclization of the exocycle takes place according to the mechanism of the Dieckmann condensation [51] (Scheme 34). Recyclization of the exocycle is the best method for the production of phorbins 138, 228-321, the direct synthesis of which from the pheophorbides 5 and 10 is ineffective (see also "Production of Vinyl Derivatives"). Photolytic Recyclization of the Exocycle. An alternative way of constructing the exocyclic fragment of chlorophyll is based on the use of the chlorin 232, containing a 13-COOH fragment and a vacant position 15, as starting compound [175]. Thus, treatment of the chlorin 232 with N,N'-carbonyldiimidazole leads to the carboxyimidazole 233, the reaction of which with the chelate 234 gives the -keto ester 235. Cyclization of the 417
nonphorbin chlorin 235 to the phorbin metal complex 236 is achieved by the successive treatment of 2 eq. of Tl(CF3COO)3 and photolysis. The metal complex 236 is demetallated by the action of SO2 and hydrochloric acid, resulting in the formation of the pheophorbide 5. It is important to note that this multistage path for the construction of the exocyclic fragment was previously developed and optimized for model porphyrin systems [176-180] (Scheme 34).
R1 N N N pM e N R2 R3 R4 R1 R2
R5
N N N N COOR 3
N N N pMe N N
O COOM e
pM e R 4
5, 138, 228231
15, 35, 53, 225227, 232
233
N N pMe
N N
N N N pM e N
O COOMe
O COOM e
236
1
235
5 R1 = CH=CH2, R2 = Me, R3 = Et, R4 = H; 15 R1 = CH=CH2, R2 = Et, R3 = Me, R4 = CH2COOMe, R5 = H; 35 R = CH2CH2OH, R2 = Et, R3 = Me, R4 = CH2COOMe, R5 = H; 53 R1 = R2 = CH=CH2, R3 = Me, R4 = CH2COOMe, R5 = H; 138 R1 = R3 = CH=CH2, R2 = Me, R4 = H; 225 R1 = Et, R2 = CH=CH2, R3 = Me, R4 = CH2COOMe, R5 = H; 226 R1 = CH2CH2Cl, R2 = Et, R3 = R5 = Me, R4 = CH2COOMe; 227 R1 = R2 = Et, R3 = R5 = Me, R4 = CH2COOMe; 228 R1 = CH2CH2OH, R2 = Me, R3 = Et, R4 = H; 229 R1 = Et, R2 = Me, R3 = CH=CH2, R4 = H; 230 R1 = CH2CH2Cl, R2 = R4 = Me,
O
O
R3 = Et; 231 R1 = R3 = Et, R2 = R4 = Me; 232 R1 = CH=CH2, R2 = Et, R3 = R4 = R5 = H; 234 Mg
; 236 M = Tl3+CF3COO
OMe
A: Base (for the production of 5, 228, 138, and 229-231 from 15, 35, 53, and 225-227 respectively). B: N,N'-Carbonyldiimidazole (for the production of 233 from 232). C: 234 (for the production of 235 from 233). D: Tl(CF3COO)3, photolysis (for the production of 236 from 235). E: SO2 and hydrochloric acid (for the production of 5 from 236).
Scheme 34. Pathways for recyclization of the exocyclic fragment. Demethoxycarbonylation at Position 132 of the Exocycle. When heated in high-boiling solvents, phorbin-containing derivatives of chlorophylls containing a COOMe group in the cyclopentanone fragment 1, 3-5, 10, 228, 230, 231, and 237 readily lose it and form the corresponding stable pyro derivatives 238, 239, 6, 7, 12, and 240-243. The 132-COOMe fragment is easily eliminated both on the metal complexes 1 and 237 [181, 182] and on the nonmetal derivatives 3-5, 10, 228, 230, and 231 [11, 43, 49, 50, 65, 181]. It was noted that thermal isomerization of the pyro derivative 6 to the stable phylloerythrin 244 occurs as a side reaction during prolonged heating of the pheophorbide in pyridine [11].
418
A universal solvent for the demethoxycarbonylation of pheophorbides of series a and b is collidine (2,4,6-trimethylpyridine) [49]. Thus, the use of collidine makes it possible to obtain the pyropheophorbide 7 with a yield of more that 90%. The pyrolysis time of the pheophorbide amounts to 90 min, and the formation of side products is not observed. Under analogous conditions the pheophorbide 10 is transformed into the pyropheophorbide 12 with a yield of more than 80% [49]. An effective method for demethoxycarbonylation of compound 5 was proposed in the patent [183]. Thus, pyrolysis of the chlorin 5 in a two-phase system consisting of water and a high-boiling solvent leads to the formation of the pyro derivative 7 with a quantitative yield, and the use of a two-phase system has been applied to the large-scale production of the pyro derivative 7 (Scheme 35).
R1 N N pR 3 N N R2 R1 R2 N N NH N N pH HN
R4
R4
N N pR 3
O COOMe
1, 35, 10, 228, 230, 231, 237
6,7, 12, 238243
244
1, 238 M = Mg, R1 = CH=CH2, R2 = Me, R3 = Phytyl, R4 = H; 3, 239 M = 2H, R1 = CH=CH2, R2 = Me, R3 = Phytyl, R4 = H; 4, 6 M = 2H, R1 = CH=CH2, R2 = Me, R3 = R4 = H; 5, 7 M = 2H, R1 = CH=CH2, R2 = R3 = Me, R4 = H; 10, 12 M = 2H, R1 = CH=CH2, R2 = CHO, R3 = Me, R4 = H; 228, 240 M = 2H, R1 = CH2CH2OH, R2 = R3 = Me, R4 = H; 230, 241 M = 2H, R1 = CH2CH2Cl, R2 = R3 = R4 = Me; 231, 242 M = 2H, R1 = Et, R2 = R3 = R4 = Me; 237, 243 M = Mg, R1 = Et, R2 = R3 = Me, R4 = H
A: Heating in a high-boiling solvent (for the production of 238, 239, 6, 7, 12, and 240-243 from 1, 3-5, 10, 228, 230, 231, and 237 respectively; side formation of 244 during the pyrolysis of 4)
Scheme 35. Demethoxycarbonylation at position 132 of chlorophylls and their phorbin derivatives. Analysis of the data on methods for modification of the peripheral substituents of chlorophylls a and b demonstrates their truly boundless synthetic potential and the promise of these reactions in the development of designed methods for the synthesis of derivatives possessing a wide range of useful characteristics. The authors express their sincere gratitude to A. S. Lermontov and A. E. Voronkov (Chemical Faculty, M. V. Lomonosov Moscow State University) for practical assistance in classifying the published data.
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425
PHOSPHORYLATION OF FURFURAL BY SECONDARY PHOSPHINE OXIDES

N. I. Ivanova, N. K. Gusarova, E. A. Nikitina, S. A. Medvedeva, M. L. Al'pert, and B. A. Trofimov Nucleophilic addition of secondary phosphine oxides to furfural takes place under mild conditions and gives quantitative yields of 2-(diorganylphosphorylhydroxymethyl)furans, which are polyfunctional building blocks for organic synthesis and prospective amphiphilic ligands for the design of metal complex catalysts. Keywords: diorganylphosphine phosphorylation. oxides, 2-(diorganylphosphorylhydroxymethyl)furans, furfural,
Information on the use of furfural in organophosphorus synthesis for the formation of a CP bond is apparently limited to its reaction with phosphine [1, 2]. This reaction takes place in the presence of acids or the salts of transition metals and leads to tris(1-hydroxy-1-furylmethyl)phosphine, which is a valuable synthon and a promising ligand. Furylphosphines have been used successfully for the production of catalysts for many important organic reactions [3], and the development of new convenient approaches to the synthesis of phosphines and phosphine oxides with furan rings is therefore an urgent task. For this purpose in the present work we studied for the first time the reaction of furfural with readily obtainable secondary phosphine oxides 1, which can be easily prepared from elemental phosphorus [4-6]. It was found that furfural reacts with the phosphine oxides 1a-d at room temperature or with gentle heating (50-65C) in THF, forming 2-(diorganylphosphorylhydroxymethyl)furans 2a-d with almost quantitative yields.
H O C O O R P H 1ad R O 2ad O P CH OH R R
1, 2 a R = n-Bu; b R = n-C6H13; c R = Ph(CH2)2; d R = 4-Py(CH2)2
The reaction was monitored by 31P NMR from the disappearance of the signal for the initial secondary phosphine oxides 1a-d in the region of 30-32 ppm and from the appearance of signals in the region of 47-50 ppm, belonging to the tertiary phosphine oxides.
__________________________________________________________________________________________ A. E. Favorsky Institute of Chemistry, Irkutsk; e-mail: n_iva@irioch.irk.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 520-523, April, 2004. Original article submitted November 6, 2002. 426 0009-3122/04/4004-04262004 Plenum Publishing Corporation
TABLE 1. The 1H, 13C, and 31P NMR Spectra of Compounds 2a-d
Compound 2a Formula
4 3 2
1
Chemical shifts (DCl3), , ppm. (coupling constants, J, Hz) 13 H C 12.84, 12.89 (11), 22.53 (10), 23.65, 23.81 (9), 23.94 (d, (8), 1JPC = 59.0), 24.14 (d, (8), 1JPC = 61.7), 65.48 (d, (6), 1JPC = 80.1), 107.93 (d, (4), 3JPC = 6.1), 110.01 (3), 141.62 (2), 150.69 (5) 13.98 C(13), 21.22 C(12), 22.42 C(11), 24.66 (d, C(8), 1JPC = 62.1), 25.56 (d, C(8),1JPC = 60.8), 30.85 (d, C(9),2JPC = 13.7), 30.88 (d, C(9), 2JPC = 13.8), 31.24 (d, C(10), 3 JPC = 5.1), 66.49 (d, C(6),1JPC = 77.9), 108.68 (d, C(4), 2JPC = 5.6), 110.78 C(3), 142. 31 C(2), 151.08 C(5) 26.50 (d, C(8), 1JPC = 58.7), 27.80 (d, C(8), 1 JPC = 59.1), 26.96 (d, C(9), 2JPC = 3.8), 66.67 (d, C(6), 1JPC = 75.4), 108.73 (d, C(4), 3 JPC = 6.0), 110.60 C(3), 125.95, 126.05 C-p, 127.66 -o, 128.18, 128.24 -m, 136.67 C(2), 142.31 (d, -ipso, 3JPC = 2.1), 149. 86 C(5) 25.59 (d, C(8), 1JPC = 60.8), 26.13 (d, C(8), 1 JPC = 59.1), 26.29 (d, C(9), 2JPC = 4.0), 65.87 (d, C(6), 1JPC = 81.0), 108.76 (d, C(4), 3 JPC = 7.0), 110.69 C(3), 123.06, 123.14 C(11), C(15), 142.53 C(2), 149.05, 149.17 C(12), C(14), 149.75, 149.89 C(10), 150.15 C(5)
31
(CH3CH2CH2CH2)2P O
2b
13 12
11
10
CH OH
0.87 (6, t, 11-H); 1.32 (4, m, 10-H); 1.50 (4, m, 9-H); 1.57-1.88 (4, m, 8-H); 5.05 (1, d, 2JPH = 7.8, 6-H); 6.35 (1, t, 4-H); 6.42 (1, t, 3-H); 6.52 (1, br. s, 6-H); 7.37 (1, s, 2-)
3 2
48.81
(CH3CH2CH2CH2CH2CH2)2P
11
10
CH
OH
0.86 (6, t, 13-H); 1.25 (4, m, 12-); 1.33 (4, m, 11-); 1.56 (4, m, 8-); 1.67 (4, m, 9-H); 1.83 (4, m, 10-); 5.06 (1, d, 2JPH = 7.48, 6-H); 5.95 (1, br. s, 6-H); 6.35 (1, t, 4-H); 6.42 (1, t, 3-H); 7.24 (1, s, 2-H) 2.03 (4, m, 8-H); 2.90 (4, m, 9-H); 5.16 (1, d, 2JPH = 8.0, 6-H); 6.38 (1, t, 4-H); 6.48 (1, t, 3-H); 6.63 (1, br. s, 6-H); 7.23 (10, m, Ph); 7.40 (1, s, 2-)
48.92
2c
9 8
3 2
(PhCH2CH2)2P O
2d
12 11 10 15
49.84
CH OH
3 2
N
14
CH2CH2 P
2O
CH OH
2.03 (4, m, 8-H); 2.86 (4, m, 9-H); 5.18 (1, d, 2JPH = 8.8, 6-H); 6.40 (1, t, 4-H); 6.47 (1, t, 3-H); 6.93 (1, br. s, 6-H); 7.11, (4, d. d, 12-, 14-); 7.42 (1, s, 2-); 8.45 (4H, t, 11-, 15-)
47.58
427
For the case of the dibutyl- and bis(2-phenylethyl)phosphine oxides 1a,c it was shown that the secondary phosphine oxides react with furfural even at 25-26C (THF); here their degree of conversion after 24 h amounted to 80-86%. Subsequent heating of the reaction mixtures (50C) for 2-3 h led to quantitative conversion of the phosphine oxides 1a,c into the corresponding phosphorylfurans 2a,c. The reaction of furfural with dihexyl- and bis[2-(4-pyridyl)ethyl]phosphine oxides 1b,d was conducted at ~50-65C; quantitative conversion of these phosphine oxides to phosphorylfurans 2b,d was observed after 20-24 h. The most characteristic in the 1H and 13C NMR spectra of compounds 2a-d are the signals of the CH group of the OCHP=O fragment: A doublet at 5.05-5.18 ppm with a geminal 31P1H spinspin coupling constant of 7.45-8.80 Hz (1H NMR) and a doublet in the region of 65.48-66.67 ppm (1JPC ~75-81 Hz; 13C NMR). The anisochronism of the two chemically equivalent substituents at the phosphorus atom in the 1H and 13C NMR spectra is due to their diastereotopy. The same nonequivalence was observed in the 1H and 13C NMR spectra of 2-(diorganylphosphorylhydroxymethyl)-1-organylimidazoles [7]. In the IR spectra of 2a-d the band for the stretching vibrations of the hydroxyl group appears in the region of 3118-3146 cm-1, which is evidently due to the presence of an intramolecular hydrogen bond involving the phosphoryl fragment. A similar long-wave shift of the band for the stretching vibrations of the hydroxyl group was also observed for the analogous products from addition of secondary phosphine oxides to 3-(trialkylsilyl)- and 3-(trialkylgermyl)-2-propynals [8]. Thus, the reaction of furfural with secondary phosphine oxides is a convenient and effective method for the synthesis of new polyfunctional 2-(organylphosphorylhydroxymethyl)furans, which are highly reactive building blocks and prospective polydentate lipophilic ligands.
EXPERIMENTAL The IR spectra were obtained on a Specord IR-75 spectrometer in microlayers and in tablets with potassium bromide. The 1H, 13C, and 31P NMR spectra were recorded on a Bruker DPX-400 spectrometer at 400, 100, and 161 MHz respectively in deuterochloroform with HMDS as internal standard and 85% phosphoric acid as external standard. General Procedure. A mixture of furfural (11 mmol) and the diorganylphosphine oxide (10 mmol) in THF (10 ml) was stirred at 50-55C for 20-24 h while the reaction was monitored by 31P NMR spectrometry. The solvent was removed at reduced pressure, and the residue was reprecipitated from chloroform with pentane (for compounds 2a,b,d) or recrystallized from hexane (compound 2c). Compounds 2a-d were obtained after evaporation of the solvent. 2-(Dibutylphosphorylhydroxymethyl)furan (2a). The product was a viscous nondistilling liquid. Yield 2.5 g (97%). IR spectrum (microlayer), , cm-1: 1145 (P=O), 3136 bs (OH). Found %: C 60.45; H 8.97; P 11.99. C13H23O3P. Calculated %: C 60.22; H 8.91; P 11.90. 2-(Dihexylphosphorylhydroxymethyl)furan (2b). The product was a viscous nondistilling liquid. Yield 3.1 g (97%). IR spectrum (microlayer), , cm-1: 1146 (P=O), 3146 bs (OH). Found %: C 64.53; H 10.19; P 9.63. C17H31O3P. Calculated %: C 64.94; H 9.84; P 9.82. 2-[Bis(2-phenylethyl)phosphorylhydroxymethyl]furan (2c). Yield 3.5 g (98%); mp 82-84C (hexane). IR spectrum (potassium bromide), , cm-1: 1144 (P=O), 3123 bs (OH). Found %: C 71.17; H 6.54; P 8.74. C21H23O3P. Calculated %: C 71.14; H 6.88; P 8.90. 2-{Bis[2-(4-pyridyl)ethyl]phosphorylhydroxymethyl}furan (2d). The product was a viscous nondistilling liquid. Yield 3.4 g (95%). IR spectrum (microlayer), , cm-1: 1156 (P=O), 3118 bs (OH). Found %: C 63.97; H 5.89; N 7.72; P 8.43. C19H21N2O3P. Calculated %: C 64.04; H 5.94; N 7.86; P 8.69. The 1H, 13C, and 31P NMR spectra for compounds 2a-d are given in Table 1. 428
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. M. Reuter and L. Orthner, Ger. Patent 1075610; Ref. Zh. Khim., L83 (1961). B. A. Trofimov, N. K. Gusarova, and S. N. Arbuzova, Usp. Khim., 68, 240 (1999). N. G. Andersen and B. A. Keay, Chem. Rev., 101, 997 (2001). B. A. Trofimov, N. K. Gusarova, and L. Brandsma, Main Group Chem. News, 4, 18 (1996). N. K. Gusarova, S. F. Malysheva, S. N. Arbuzova, and B. A. Trofimov, Izv. Akad. Nauk. Ser. Khim., 1695 (1998). N. K. Gusarova, L. Brandsma, S. N. Arbuzova, S. F. Malysheva, and B. A. Trofimov, Zh. Org. Khim., 32, 269 (1996). N. K. Gusarova, S. N. Arbuzova, A. M. Reutskaya, I. I. Ivanova, L. V. Baikalova, L. M. Sinegovskaya, N. N. Chipanina, A. V. Afonin, and I. A. Zyryanova, Khim. Geterotsikl. Soedin., 72 (2002). N. K. Gusarova, A. M. Reutskaya, N. I. Ivanova, A. S. Medvedeva, M. M. Demina, P. S. Novopashin, A. V. Afonin, A. I. Albanov, and V. A. Trofimov, J. Organomet. Chem., 659, 172 (2002).
429
INDOLE DERIVATIVES. 142.* SOME PROPERTIES OF [4-(2-INDOLYL)PHENYL]PHENYLMETHANE AND 1-[4-(2-INDOLYL)PHENYL]-2-PHENYLETHANE

I. Sh. Chikvaidze, Sh. A. Samsoniya, and T. G. Narindoshvili The reactions of 2-arylindoles with strong electrophiles take place with significant resin formation. It was shown that electrophilic substitution is directed into the indole ring and into the side chain. 1,7-Migration of the substituent is observed in the investigated systems. Keywords: arylindoles, rearrangement, nitration, N-alkylation. Earlier [1] we reported on the synthesis of new 2-arylindoles and their reactions with weak electrophiles (azocoupling, formylation, and nitrosation), as a result of which the corresponding 3-substituted derivatives are formed. In the present communication we describe the nitration, bromination, alkylation, and 1,7-migration of the substituent in these 2-arylindoles. It is known that the nitration reaction of the simplest indoles is ambiguous on account of complications caused by the strong acids used as components of the usual nitrating mixtures [2, 3]. For the nitration of [4-(2-indolyl)phenyl]phenylmethane (1) we used a KNO3H2SO4 mixture at 0C and a Ac2O50% HNO3 mixture at 2-7C. In both cases there was considerable resinification of the reaction mixture. From the each obtained multicomponent mixtures we were able to isolate and characterize two compounds, i.e., 2, 3 and compounds 4 and 5, with yields of 18, 31, 19, and 39% respectively (Scheme 1). In the strongly acidic medium the formation of the product from cleavage of the side chain of compound 2 can be explained by protonation of the nearest 2-phenyl ring, and this probably favors removal of the benzyl or p-nitrobenzyl group. In a weakly acidic medium the reaction is characterized by higher selectivity. Substitution in [4-(2-indolyl)phenyl]phenylmethane takes place at the positions of the indole ring that are rich in electron density. In the 1H NMR spectra of the three 5-nitro derivatives 2-4 there are signals characteristic of the 4-, 6-, and 7-H protons of 5-substituted indole. We assigned doublets at 8.52 (compound 2), 8.51 (compound 3), and 8.27 ppm (compound 4) with Jm = 2 Hz to the 4-H protons and doublets at 7.41 (compound 2), 7.53 (compound 3), and 7.68 ppm (compound 4) with Jo = 8 Hz to the 7-H protons. The signals of the 6-H protons appear in the form of quadruplets at 8.00 (2), 7.98 (3), and 7.89 ppm (4), while the signals of the 3-H protons appear in the form of singlets at 7.20 (2), 7.21 (3), and 7.06 ppm (4). The analogous signal of the 3-H proton is absent in the spectrum of compound 5. In the spectrum of compound 3 the presence of two pairs of doublets at 7.55, 8.16 and at 7.40 and 7.84 ppm (Jo = 8 Hz), which we assigned to the protons of the 4,4'-disubstituted diphenylmethane, _______ * For Communication 141, see [1]. __________________________________________________________________________________________ Iv. Javakhishvili Tbilisi State University, Tbilisi 0128, Georgia; e-mail: shsam@wanex.net. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 524-529, April, 2004. Original article submitted February 24, 2003. 430 0009-3122/04/4004-04302004 Plenum Publishing Corporation
Scheme 1
O2N N H O2N N H 3 CH2 N H 1 O2N Ac2O HNO3 N H N H CH2 4 NO2 CH2 5 CH2 NO2
KNO3 H2SO4
and also singlet signals for the NH and CH2 groups at 12.22 and 4.16 ppm respectively, confirms conclusively the proposed structure. In the spectra of compounds 2, 4, and 5 there are multiplets for the terminal monosubstituted phenyl rings (Table 1). The alkylation of the indole 1 and 1-[4-(2-indolyl)phenyl]-2-phenylethane 6 was carried out by the method described in [4] under the conditions of phase-transfer catalysis. During benzylation of the indole 1 the 1,3-dibenzylation product 7 was unexpectedly obtained.
(CH2)n 1, 6 N R 79 RX Cat. / 50% KOH R' (CH2)n
N H
7 R = R' = CH2Ph; 8 R = CH2Ph, R' = H; 9 R = CH2CH2Me, R' = H; 1, 7, 9 n = 1, 6, 8 n = 2; X = Cl, Br
The 1H NMR spectrum of compound 7 does not contain a signal for the 3-H proton, and the signals for the protons of the NCH2 and 3-CH2 groups appear in the form of two singlets in the region of 5.23 and 3.99 ppm respectively (Table 1). In the mass spectrum of compound 7 maximum intensity is observed in the molecular ion peak at 464, the fragmentation of which takes place with successive removal of the two benzyl groups.* _______ * The m/z values are given with the relative intensities at the maximum ion current in parentheses. 431
TABLE 1. The Spectral Data of the Compounds

Compound 2 IR spectrum, , cm-1 3400 (NH), 1520, 1335 (NO2) 3390 (NH), 1510, 1340 (NO2) UV spectrum, max, nm (log ) 207 (4.30), 230 (4.09) sh, 297 (4.40) 207 (4.50), 220 (4.00) sh, 300 (4.54)
1
NMR spectrum, , ppm
J, Hz J46 = 2.00; J13 = 1.35; J67 = 7.20 J46 = 2.20; J13 = 1.37; JAB = 7.84; JA,B' = 8.72
3395 (NH), 1525, 1345 (NO2)
210 (4.61), 257 (4.41), 377 (4.21)
3400 (NH), 1515, 1337 (NO2)
209 (4.95), 261 (4.61), 333 (4.47)
213 (4.51), 227 (4.52), 301 (4.16)
214 (4.55), 218 (4.52) sh, 227 (4.64), 241 (4.51) sh, 300 (4.44) 209 (4.58), 222 (4.53) sh, 238 (4.37) sh, 297 (4.26)
14
3410 (NH)
210 (4.61), 249 (4.33), 311 (4.39)
7.20 (1H, d, 3-H); 7.41 (1H, d, 7-H); 7.48-7.58 (3H, m, HPh); 7.98 (2H, d, A-H); 8.00 (1H, dd, 6-H); 8.52 (1H, d, 4-H); 12.21 (1H, s, NH) 4.16 (2H, s, CH2); 7.12 (1H, d, 3-H); 7.40 (2H, d, B-H); 7.53 (1H, d, 7-H); 7.55 (2H, d, A'-H); 7.84 (2H, d, A-H); 7.98 (1H, dd, 6-H); 8.16 (2H, d, B'-H); 8.51 (1H, d, 4-H); 12.22 (1H, s, NH) 4.01 (2H, s, CH2); 7.06 (1H, d, 3-H); 7.24-7.31 (5H, m, HPh'); 7.38 (1H, d, B-H); 7.68 (1H, d, 7-H); 7.84 (1H, d, A-H); 7.89 (1H, d, 6-H); 8.27 (1H, d, 4-H); 12.21 (1H, s, NH) 12.66 (1H, s, NH); 8.21 (1H, d, 4-H); 4.05 (2H, s, CH2); 7.30-7.43 (10H, m, 5-, 7-, 13-H, HPh'); 7.67 (2H, d, A-H); 8.21 (1H, d, 4-H); 12.66 (1H, s, NH) 7.36 (1H, d, 4-H); 6.96 (1H, dt, 5-H); 7.07 (1H, dt, 6-H); 7.32 (1H, d, 7-H); 7.17 (2H, d, A-H); 6.83 (2H, d, B-H); 5.29 (2H, s, NCH2); 7.08-7.33 (15H, m, HPh', HPh'', HPh'''); 3.99 (2H, s, C(3)CH2); 3.98 (2H, s, CH2) 3.05 (4H, s, CH2CH2), 5.47 (2H, s, NCH2); 6.74 (1H, s, 3-H); 7.14 (2H, d, B-H); 7.22-7.41 (13H, m, 5-, 7-H, HPh', HPh''); 7.46 (2H, d, A-H); 7.77 (1H, dd, 4-H) 0.64 (3H, t, CH3); 1.56 (2H, sextet, CH2); 4.02 (2H, s, CH2); 4.13 (2H, t, NCH2); 6.46 (1H, s, 3-H); 7.03 (1H, t, 5-H); 7.14 (1H, t, 6-H); 7.17-7.53 (5H, m, HPh'); 7.36 (2H, d, B-H); 7.45 (2H, d, A-H); 7.50 (1H, d, 7-H); 7.53 (1H, d, 4-H) 2.93 (4H, s, CH2CH2); 4.32 (2H, s, C(7)CH2); 6.80 (1H, d, 6-H); 6.84 (1H, d, 3-H); 6.91 (1H, t, 5-H); 7.15-7.33 (12H, m, B-H, HPh', HPh''); 7.36 (1H, d, 4-H); 7.83 (2H, d, A-H); 11.09 (1H, s, NH)
J46 = 1.90; J67 = 8.80; JAB = 8.22; J13 = 1.48 JAB = 8.20
Jo = 7.96; Jm = 0.88; JAB = 7.92
JAB = 8.40; J45 = 8.40; J46 = 2.0
J67 = 7.92; JAB = 7.96; J45 = 1.32
J45 = 7.52; J13 = 2.24; J56 = 7.08; JAB = 8.40
M + 464 (34)
PhMe 92
372 (4.05)
PhCH2Ph 168
204 (3.85)
CH2Ph 91
113 (2.32)
CN 26
178 (4.89)
During propylation of the same arylindole 1 with propyl bromide under analogous conditions a single reaction product, [4-(1-propyl-2-indolyl)phenyl]phenylmethane (9), was obtained. Alkylation of the 2-arylindoles 1 and 6 with benzyl chloride under FriedelCrafts conditions led to complete resinification of the reaction mixture. 432
In both cases bromination with dioxane dibromide in dioxane gave complex mixtures of products. Earlier we reported that when a mixture of N-benzylphenylhydrazine and certain ketones was heated in polyphosphoric acid the corresponding N-unsubstituted indoles and their 7-benzyl derivatives were formed instead of the expected 2-substituted N-benzylindoles [5, 6]. We obtained a similar result during the synthesis of the N-benzyl derivatives 8 and 12.
O Me C 10, 11 R Me
Ph
NH2
Ph
CH2Ph
CH2Ph
R N 8, 12 CH2Ph
1, 6
+
CH2Ph 13, 14
R N H
10, 12, 13 R = C64CH2Ph; 8, 11, 14 R = C6H4(CH2)2Ph
Compounds 6 and 14 were likewise obtained when 1-[4-(N-benzyl-2-indolyl)phenyl]-2-phenylethane was treated in polyphosphoric acid at 125C, indicating 1,7-migration of the substituent. In the IR spectrum of the 7-benzyl derivative 14 there is a band characteristic of the indole NH group in the region of 3410-3430 cm-1, which is absent in the spectrum of the corresponding N-benzyl derivative 8.
(CH2)2 N H 8 (CH2)2 N H CH2Ph 14 6
The position to which the benzyl group migrates was established by comparing the 1H NMR spectra of the N-benzyl derivative 8 and the product from migration of the benzyl group 14 (Table 1). In particular, the spectrum of 1-[4-(1-benzyl-2-indolyl)phenyl]-2-phenylethane (8) does not contain a signal for the 1-H proton. A signal in the form of a doublet of doublets at 7.77 ppm can be assigned to the 4-H proton, while the signals for the 5-, 6-, and 7-H protons are included in the multiplet at 7.22-7.41 ppm. In the 1H NMR spectrum of 1-[4-(7-benzyl-2-indolyl)phenyl]-2-phenylethane (14) a signal for 1-H appears at 11.09 ppm, while the signal of the 7-H proton disappears. The signal for 6-H appears at 6.80 ppm in the form of a doublet, the signal for 5-H appears at 6.91 ppm in the form of a triplet, and the signal for 4-H appears at 7.36 ppm in the form of a doublet. In addition, for compounds 8 and 14 there are signals in the form of two doublets characteristic of the A-H and B-H protons of p-disubstituted benzenes, singlets for the bridging group (CH2CH2), and signals for the protons of the benzyl group. In the mass spectrum of compound 14 maximum intensity is observed in the peak of the molecular ion at 387.
433
TABLE 2. The Characteristics of the Compounds

Compound 2 3 4 5 7 8 9 14 Empirical formula C14H10N2O2 C21H15N3O4 C21H16N2O2 C21H16N2O2 C35H29N C29H25N C24H23N C29H25N Found, % Calculated, % H 4.38 4.20 4.21 4.02 4.72 4.88 4.69 4.88 6.12 6.26 6.22 6.46 7.23 7.08 6.37 6.46 M, Found, % Calculated, % 238 238 373 373 328 328 328 328 463 463 387 387 325 387 387 Rf * mp, Yield, % 19 31 19 39 45 47 49 *2
C 70.71 70.59 67.68 67.56 76.91 76.83 76.95 76.83 90.08 90.71 89.72 89.92 88.41 88.62 89.95 89.92
N 11.61 11.76 11.22 11.26 8.32 8.54 8.65 8.54 3.18 3.02 3.45 3.62 4.22 4.31 3.48 3.62
0.46 0.41 0.64 0.35 0.58 0.50 0.50 0.56
194-195 218-219 157-158 167-168 129-130 114-115 97-98 139-140
_______ * System for chromatography: hexaneether, 1:1 (compounds 2-5); benzenehexane, 1:3 (compounds 7 and 8); heptane (compound 9); hexaneether, 6:1 (compound 14). *2 Yield 6% (by method B) and 18% (by method A).
EXPERIMENTAL The IR spectra were recorded in Vaseline oil on a UR-20 instrument. The UV spectra were obtained in ethanol on a Specord spectrometer. The 1H NMR spectra were obtained on a Bruker AM-400 spectrometer at 400 MHz with TMS as internal standard. The mass spectra were obtained on an MS-Varian, Mat-311, EL-MS spectrometer at 70 eV. The reactions and the purity of the compounds were monitored and the Rf values were determined on Silufol UV-254 plates. 5-Nitro-2-phenylindole (2) and [4-(5-Nitro-2-indolyl)phenyl](4-nitrophenyl)methane (3). A solution of potassium nitrate (0.44 g, 5.2 mmol) in sulfuric acid (5 ml) was slowly added dropwise to a suspension of [4-(2-indolyl)phenyl]phenylmethane (0.2 g, 0.7 mmol) in sulfuric acid (10 ml), cooled to -2C, while keeping the temperature at 0C. The reaction mixture was stirred for 5 min and poured onto crushed ice (100 g). The product was extracted with ethyl acetate, and the extract was washed with an aqueous solution of sodium carbonate and with water and dried with sodium sulfate. The mixture was separated on a column of silica gel with 6:1 hexaneether as eluent. We isolated 0.03 g of compound 2 and 0.082 g of compound 3 in the form of yellow crystals. [4-(5-Nitro-2-indolyl)phenyl]phenylmethane (4) and [4-(3-Nitro-2-indolyl)phenyl]phenylmethane (5). 50% Nitric acid (0.07 ml, 1.4 mmol) and then a solution of [4-(2-indolyl)phenyl]phenylmethane (1) (0.19 g, 0.67 mmol) in acetic anhydride (5-7 ml) were added dropwise to acetic anhydride (25 ml), cooled to 0C, while keeping the temperature at 0C. The reaction mixture was stirred at 5-7C for 30 min, poured onto ice (100 g), and extracted with ether. The extract was washed with an aqueous solution of sodium carbonate and with water and dried with sodium sulfate. The mixture was separated on a column of silica gel (hexaneether, 4:1). We isolated 0.04 g of compound 4 and 0.85 g of compound 5 in the form of yellow crystals.
434
[4-(1,3-Dibenzyl-2-indolyl)phenyl]phenylmethane (7). To a solution of the indole 1 (0.28 g, 1 mmol) in benzene (30 ml) we added a 50% aqueous solution of potassium hydroxide (5 ml), tetrabutylammonium bromide (0.035 g), and benzyl chloride (0.63 g, 5 mmol). The mixture was stirred at 60C for 4 h, cooled, diluted with water, and extracted with benzene. The extract was washed with water and dried with sodium sulfate. The mixture was separated on a column of silica gel (heptane). We isolated 0.21 g of compound 7 in the form of colorless crystals. 1-[4-(1-Benzyl-2-indolyl)phenyl]-2-phenylethane (8). This compound was obtained by the method described for compound 7 from 1-[4-(2-indolyl)phenyl]-2-phenylethane (6) (0.30 g, 1 mmol) and benzyl chloride (0.63 g, 5 mmol). We isolated 0.18 g of compound 8 as colorless crystals. [4-(1-Propyl-2-indolyl)phenyl]phenylmethane (9). This compound was obtained by the method described for compound 7 from the indole 1 (0.28 g, 1 mmol) and propyl bromide (0.62 g, 5 mmol). We isolated 0.16 g of compound 9 in the form of colorless crystals. 1-[4-(2-Indolyl)phenyl]-2-phenylethane (6) and 1-[4-(7-Benzyl-2-indolyl)phenyl]-2-phenylethane (14). A. A mixture of 4-acetyldiphenylmethane (11) (2.24 g, 10 mmol), N-benzylphenylhydrazine hydrochloride (2.57 g, 10 mmol), and polyphosphoric acid (50 g) was stirred at 100-110C for 45 min. The mixture was cooled and poured as a thin stream into water (200 ml). The product was extracted with ether, and the extract was washed with water and dried. The mixture was separated on a column of silica gel (heptaneether, 50:1). We isolated 0.7 g (18%) of compound 14 and 1.18 g (40%) of compound 6 in the form of colorless crystals. B. A mixture of compound 8 (0.15 g, 0.3 mmol) and polyphosphoric acid (7 ml) was stirred at 125C for 30 min. The mixture was cooled and poured into water (30 ml). The precipitate was filtered off, washed with water, and dried. The mixture was separated on a column of silica gel (heptaneether, 20:1). We isolated 0.16 g (6%) of compound 14 in the form of colorless crystals.
REFERENCES 1. 2. 3. 4. 5. 6. Sh. A. Samsoniya, I. Sh. Chikvaidze, T. G. Narindoshvili, and N. N. Suvorov, Khim. Geterotsikl. Soedin., 899 (2001). A. D. Settimo and M. F. Saettone, Tetrahedron, 21, 823 (1965). E. N. Wayland, R. R. Kent, and R. S. Lowell, J. Org. Chem., 31, 65 (1966). N. N. Suvorov, Yu. I. Smushkevich, V. S. Velezheva, V. S. Rozhkov, and S. V. Simakov, Khim. Geterotsikl. Soedin., 191 (1976). Sh. A. Samsoniya, I. Sh. Chikvaidze, and E. O. Gogrichiani, Khim. Geterotsikl. Soedin., 1146 (1994). Sh. A. Samsoniya, I. Sh. Chikvaidze, E. O. Gogrichiani, N. N. Machaidze, and Z. E. Saliya, Khim. Geterotsikl. Soedin., 611 (1997).
435
DIPYRROLO[1,2-a:2',1'-c]PYRAZINES. 8*. ELECTROPHILIC SUBSTITUTION IN DIPYRROLO[1,2-a:2',1'-c]PYRAZINES AND 5,6-DIHYDRODIPYRROLO[1,2-a:2',1'-c]PYRAZINES. ACYLATION OF DIPYRROLO[1,2-a:2',1'-c]PYRAZINES

V. I. Terenin1, E. A. Sumtsova1, E. V. Kabanova1, A. P. Pleshkova2, and N. V. Zyk1 Esters, nitriles, and amides of dipyrrolo[1,2-a:2',1'-c]pyrazines have been synthesized by the acylation of dipyrrolo[1,2-a:2',1'-c]pyrazines and 5,6-dihydrodipyrrolo[1,2-a:2',1'-c]pyrazines with trichloroacetic acid chloride, p-tosyl isocyanate, and isocyanatophosphoric acid dichloride (Kirsanov isocyanate). Keywords: dipyrrolo[1,2-a:2',1'-c]pyrazines, 5,6-dihydrodipyrrolo[1,2-a:2',1'-c]pyrazines, acylation. Dipyrrolo[1,2-a:2',1'-c]pyrazines readily react by electrophilic substitution, such as acylation, nitration, aminomethylation, and formylation [2]. In continuing these investigations, the reactivity of dipyrrolopyrazines 1a,b and their 5,6-dihydro analogs 1c,d has been studied under conditions of trichloroacetylation with trichloroacetyl chloride. The free -position of the pyrrole ring is the initial point of attack by the trichloroacetyl cation. Products of monosubstitution 2b,d were obtained in high yield in the reaction of 2,8-dimethyldipyrrolo[1,2-a:2',1'-c]pyrazine (1b) and its dihydro analog 1d with an equimolar quantity of trichloroacetyl chloride.
Me Me N X X 1b,d N X X 4b,d N O N CCl3COCl Me N X X 2b,d Me Me OMe N O Me CCl3 NaOH MeOH
1, 2, 4 b XX = CH=CH; d XX = CH2CH2
_______ * For Part 7 see [1]. __________________________________________________________________________________________

2
Moscow M. V. Lomonosov State University, Moscow 119899, Russia; e-mail: vter@org.chem.msu.ru. A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences (RAN), Moscow 119991. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 530-540, April, 2004. Original article submitted March 19, 2003. 436 0009-3122/04/4004-04362004 Plenum Publishing Corporation
In the case of 2-methyldipyrrolopyrazines 1a,c, having two free -positions in the pyrrole rings, acylation products may be formed at both one and two pyrrole rings in the molecule. The result of the reaction depends on the substrate : reactant ratio. According to quantum-chemical calculations, the -orbital densities in the HOMO of positions 3 and 8 are practically identical in dipyrrolopyrazine 1a, but the cations formed on electrophilic attack at position 3 are thermodynamically more stable. However the formation of 8-substituted derivatives is less sterically hindered. On trichloroacetylation of pyrrolopyrazine 1a with an equimolar ratio of reactants 2-methyl-8trichloroacetyldipyrrolo[1,2-a:2',1'-c]pyrazine (2a) was isolated in addition to the disubstitution product 3a in a ratio of 1 : 2. 2-Methyl-3-trichloroacetyldipyrrolo[1,2-a:2',1'-c]pyrazine was formed in only trace amounts (based on 1H NMR spectral analysis of the reaction mixture), which may be explained by the dominance of the steric factor. On trichloroacetylation of dipyrrolopyrazines 1a,c with a twofold excess of reactant the disubstitution products were isolated, 2-methyl-3,8-trichloroacetyldipyrrolo[1,2-a:2',1'-c]pyrazine (3a) and 2-methyl-3,8-ditrichloroacetyl-5,6-dihydrodipyrrolo[1,2-a:2',1'-c]pyrazine (3c) respectively.
Me CCl3COCl 1 eq. Cl3C O Me N X X 1a,c N CCl3COCl 2 eq. Cl3C O N X X 3a,c N O Me MeO O N X X 4a,c N O OMe N 2a N Me N traces Me CCl3 NaOH MeOH N O CCl3 + 3a
1, 3, 4 a XX = CH=CH; c XX = CH2CH2
In the majority of cases trihaloacetylpyrroles undergo the haloform reaction under the action of hydroxide ion with the formation of pyrrolecarboxylic acids and trihalomethane. Trifluoroacetylpyrrole does not react with alcohols, however its trichloro analog was converted under base catalysis conditions into ester in more than 80% yield [3]. On treating trichloroacetyldipyrrolopyrazines with an alcoholic alkaline solution they readily undergo a haloform reaction and are converted into the corresponding dipyrrolopyrazine ester derivatives 4a-d. Arenesulfonyl isocyanates are used for C-acylation of electron-rich nitrogen heterocycles. However the literature data on such reactions are extremely contradictory. According to [4] pyrrole reacts with p-tosyl isocyanate at position 3, the -position of the pyrrole ring. In later studies [5,6] it was demonstrated on the basis of 1H NMR spectral data that pyrrole and N-methylpyrrole react with o-chlorobenzenesulfonyl isocyanate at the -position. As a reagent we chose p-tosyl isocyanate as one of the most reactive isocyanates in electrophilic substitution reactions [6]. Dipyrrolopyrazines undergo acylation, giving substitution products at the -position of the pyrrole rings. The disubstitution products 5a,c were obtained from 2-methyldipyrrolo[1,2-a:2',1'-c]-pyrazine (1a) and the 5,6-dihydro analog 1c at a reactant ratio of 1 : 2 in yields of the order of 90%. At an equimolar reactant ratio a complex mixture was obtained of mono- and disubstituted products and the initial 437
dipyrrolopyrazine. In the reaction of compound 1b and 2,8-dimethyl-5,6-dihydrodipyrrolo[1,2-a:2',1'-c]pyrazine (1d) with p-tosyl isocyanate at an equimolar reactant ratio monosubstitution products were obtained, viz. N1-[(2,8-dimethyldipyrrolo[1,2-a:2',1'-c]pyrazin-3-yl)carbonyl]-4-toluenesulfonamide (5b) and N1-[(2,8-dimethyl5,6-dihydrodipyrrolo[1,2-a:2',1'-c]pyrazin-3-yl)carbonyl]-4-toluenesulfonamide (5d). On using an excess of p-tosyl isocyanate a mixture of disubstituted products was obtained, the separation of which was unsuccessful.
Me O2S H N O N X X N O H N SO2
OCNTos 1a,c
Me
5a,c
Me
Me
1b,d
OCNTos
Me
N X X 5b,d
N O
H N
SO2
Me 5 a, b XX = CH=CH; c, d XX = CH2CH2
Another reactive C-acylating reagent is the dichloride of isocyanatophosphoric acid (Kirsanov isocyanate) which interacts, for example, with N-methylpyrrole, indole, and 2-methylfuran forming dichlorides of N-hetarylamidophosphoric acids [7]. N-(2,8-Dimethyl-5,6-dihydrodipyrrolo[1,2-a:2',1'-c]pyrazine-3-carboxy)aminophosphoric acid dichloride (6d) was obtained by the interaction of compound 1d with Kirsanov isocyanate. The signal of the phosphorus atom was recorded at 7.503 ppm in the 31P NMR spectrum of this compound in CDCl3.
Me Me N 1d CH2Cl2 HOPOCl2 Me N 7d N N OCNPOCl2 Me N 6d N O Me H Cl N P Cl O Me CN
The dichloride obtained is an extremely unstable compound and is converted in methylene chloride solution at room temperature into 2,8-dimethyl-5,6-dihydrodipyrrolo[1,2-a:2',1'-c]pyrazine-3-carbonitrile (7d). The intermediate dichlorides 6a-c in the reaction of dipyrrolopyrazines 1a-c with Kirsanov isocyanate were not isolated. 438
TABLE 1. Physicochemical Characteristics of the Compounds Synthesized

Compound 1 2a 2b 2d 3a 3c 4a 4b 4c 4d Empirical formula 2 13H9Cl3N2O 14H11Cl3N2O 14H13Cl3N2O 15H8Cl6N2O2 15H10Cl6N2O2 15H14N2O4 C14H14N2O2 15H16N2O4 15H16N2O4 62.31 62.93 69.79 69.41 62.59 62.49 68.83 68.83 50.91 50.70 + 327.993710 327.993693 3.62 3.95 + 457.872440 457.871694 + 459.888670 459.887344 5.06 4.93 6.42 5.82 5.57 5.59 6.51 6.60 9.65 9.78 6.32 5.78 9.65 9.72 11.30 11.47 8.25 8.45 142 (dec.) 172 159-160 196 188 150 186 154 Found, % Calculated, % H 4 mp, N 5 6 Mass spectrum, m/z (Irel,%) 7 M+ 314 (21), 280 (12), 253 (12), 251 (19), 217 (7), 198 (26), 197 (100), 170 (15), 169 (77), 168 (14) + 328 (24), 294 (5), 265 (12), 212 (15), 211 (100), 183 (41), 115 (2), 106 (6), 92 (4), 91 (7) M+ 330 (8), 296 (9), 267 (14), 233 (12), 214 (15), 213 (77), 186 (12), 185 (60), 183 (13) M+ 458 (3), 397 (6), 345 (17), 343 (45), 341 (46), 309 (19), 307 (31), 250 (15), 196 (36), 168 (10), 115 (12), 112 (44) + 460 (2), 399 (8), 345 (40), 343 (41), 311 (15), 309 (24), 252 (10), 198 (18), 170 (9), 142 (19), 115 (20), 113 (46) + 286 (100), 225 (41), 228 (45), 227 (41), 168 (18), 142 (10), 140 (11), 112 (29), 63 (15) M+ 242 (100), 241 (43), 211 (15), 184 (44), 183 (52), 182 (13), 181 (11), 121 (11), 91 (21), 57 (11) M+ 288 (100), 258 (9), 257 (23), 230 (20), 229 (19), 214 (3), 197 (2), 169 (7), 144 (8), 142 (4), 116 (3), 115 (6), 89 (4), 59 (4) M+ 244 (100), 243 (25), 228 (4), 213 (14), 186 (28), 185 (34), 169 (6), 122 (8), 92 (9), 71 (10), 57 (17), 43 (28) Yield, % 8 11 69 88 72 64 47 59 52 68
C 3
439
440
TABLE 1 (continued)
1 5a 5b 5c 5d 6d 7a 7b 7c 7d 8c 2 C27H24N4O6S2 C20H19N3O3S C27H26N4O6S2 C20H19N3O3S C13H14Cl2N3O2P C12H9N3 C13H11N3 C12H11N3 C13H11N3 C13H10N4 73.97 73.83 74.59 74.62 73.26 73.07 73.71 73.91 4.81 4.65 5.34 5.30 5.92 5.62 5.99 6.20 21.51 21.52 19.94 20.08 21.54 21.30 19.64 19.89 3 57.37 57.43 62.44 62.97 57.31 57.23 4 4.09 4.28 4.97 5.02 4.70 4.62 + 383.130364 383.132200 5 9.66 9.92 10.75 11.02 9.73 9.89 6 246-247 198-200 202 192-194 123 (dec.) 132 161 126 162-163 7 [M+197] 367 (4), 197 (28), 170 (55), 169 (44), 155 (53), 92 (12), 91 (100), 89 (10), 65 (27), 63 (13), 40 (20) M+ 381 (26), 211 (21), 197 (26), 184 (77), 183 (100), 155 (48), 92 (13), 91 (96), 65 (20), 63 (10), 39 (11) [M+197] 369 (3), 197 (16), 172 (38), 171 (27), 155 (38), 92 (11), 91 (100), 65 (24), 63 (10), 39 (11) M+ 383 (7), 197 (18), 187 (13), 186 (100), 185 (75), 144 (32), 93 (12), 92 (16), 91 (44), 65 (9) 8 91 79 82 98 87 M+ 195 (100), 194 (61), 193 (11), 169 (7), 140 (7), 115 (4), 97 (15), 63 (12) M+ 209 (86), 208 (100), 207 (10), 193 (6), 127 (3), 103 (13), 77 (5), 63 (5) M+ 197 (100), 196 (29), 194 (4), 181 (7), 169 (6), 142 (5), 115 (4), 98 (10), 97 (4) M+ 211 (100), 210 (70), 195 (5), 186 (5), 185 (5), 105 (7), 104 (11) 42 67 34 (14) 63 6
_______ * High resolution mass spectra are given for compounds 2b, 3a,c, and 5d.
TABLE 2. 1H NMR Spectra of Compounds 2-8

Compound 1 2a Chemical shifts, , ppm (coupling constants, J, Hz) Protons and substituents of the pyrrole rings Protons of the pyrazine nucleus R (2) H(R) (8) H (9) H(R) (10) H (5) H (6) 3 4 5 6 7 8 2.31 (3H, br. s) 2.73 (3, br. s) 2.45 (3, br. s) 7.88 (1, d, J9,10 = 4.8) 6.43 (1, dd, J9,10 = 3.8; J,3 = 0.8) 5.98 (1, dd, J9,10 = 3.7; J,3 = 0.7) 7.95 (1, d, J9,10 = 4.8) 7.58 (1, d, J9,10 = 4.8) 7.33 1, d, (J9,10 = 4.5) 6.61 (1, d, J10,9 = 4.8) 6.94 (1, d, J10,9 = 3.8) 6.41 (1, d, J10,9 = 3.7) 6.87 (1, dd, J10,9 = 4.8 J10,6 = 0.5) 6.55 (1, d, J10,9 = 4.8) 6.63 (1, dd, J10,9 = 4.2; J10,6 = 0.6) 7.34 (1, d, J5,6 = 6.3) 8.59 (1, d, J5,6 = 6.3) 4.63 (2, m) 8.74 (1, d, J6,5 = 6.1) 7.13 (1, d, J6,5 = 6.4) 4.09 (2, m)
H (1) 2 6.68 (1, br. s) 6.47 (1, br. s.)
Other protons 9 7.07 (1, br. s, H-3)
2b
2d
6.20 (1, d, J,3 = 0.7) 6.79 (1, s)
2.56 (3H, br. s)
2.29 (3H, br. s)
3a
2.78 (3H, br. s)
8.75 (1, d, J5,6 = 6.4) 4.63 (2, m) 8.58 (1, d, J5,6 = 6.6)
8.90 (1, d, J6,5 = 6.4) 4.86 (2, m) 8.68 (1, d, J6,5 = 6.6) 3.90 (3, s, OCH3 -8); 3.93 (3, s, OCH3-3)*2
4a
6.46 (1, d, JH,CH3 = 0.8) 6.55 (1, br. s)
2.57 (3, br. s) 2.50 (3, br. s) *
441
442
TABLE 2 (continued)
1 4b 2 6.39 (1, br.) 3 2.49 (3, br. s) 4 2.45 (3, br. s) 5 6.35 (1, dd, J5,10 = 3.5; J,3 = 0.6) 6.97 (1, d, J5,10 = 4.1) 5.93 (1, dd, J9,10 = 3.6; J,3 = 0.6) 7.81 (1, d, J5,10 = 4.7) 6.37 (1, d, J5,10 = 3.7) 6.91 (1, d, J5,10 = 4.4) 5.93 (1, d, J5,10 = 3.6) 6 6.59 (1, dd, J10,9 = 3.7; J10 ,6 = 0.4) 6.35 (1, d, J10,9 = 4.1) 6.29 (1, d, J10,9 = 3.5) 6.96 (1, d, J10,9 = 4.5) 6.60 (1, d, J10,9 = 3.9) 6.31 (1, d, J5,10 = 4.5) 6.31 (1, d, J10,9 = 3.5) 7 8.60 (1, d, J5,6 = 6.3) 4.73 (4 , s) 4.72 (2, m) 4.04 (2, m) 8 7.19 (1, d, J6,5 = 6.2; J6,10 = 0.4) 9 3.91 (3, s, OCH3-3)
4c
6.26 (1, br. s) 6.09 (1, br. s)
2.34 (3, br. s) 2.33 (3H, br. s)
3.83 (3, s, OCH3 -8); 3.86 (3, s, OCH3-3)*2 3.83 (3, s, OCH3-3)
4d
2.26 (3H, d, J3, = 0.7) *
5a
6.88 (1, br. s) 6.36 (1, br. s) (1, br. s)
8.49 (1, d, J5,6 = 6.2) 8.51 (1, d, J5,6 = 6.3) 4.50 (2, m)
8.09 (1, d, J6,5 = 6.0) 7.03 (1, d, J6,5 = 6.2) 4.56 (2, m)
5b
2.42 (3, s) *
5c
5d
6.07 (1, br.)
2.24 (3, s)
4.63 (2, m)
3.96 (2, m)
2.35, 2.38, 2.46 (9H, 3s, CH3-2, 2CH3Tos)*2; 7.52 (4H, m, m-Tos); 7.95-8.00 (4H, m, o-Tos) 2.44, 2.58 (6H, 2s, CH3-2, CH3Tos)*2; 7.36 (2H, d, J = 8.2, m-Tos); 8.06 (2H, d, J = 8.2, o-Tos) 2.41, 2.43, 2.44 (9H, 3s, CH3-2, 2CH3-Tos)*2; 7.34 (4H, m, m-Tos); 7.98-8.01 (4H, m, o-Tos) 2.43, 2.44 (6H, 2s, CH3-2, CH3-Tos)*2; 7.35 (2H, d, J = 8.2, m-Tos); 8.02 (2H, d, J = 8.2, o-Tos)
TABLE 2 (continued)
1 6d 2 6.06 (1, s) 6.32 (1, br. s) 3 2.27 (3, s) 2.35 (3, d, J3, = 0.7) 2.44 (3, d, J3, = 0.8) 2.24 (3, br. s) 4 2.23 (3, s) 7.08 (1, dd, J8,9 = 2.5; J8,10 = 1.6) 2.38 (3, br. s) 5 5.94 (1, d, J9,10 = 3.2) 6.59-6.60 (2, m) 6 6.29 1, d, J10,9 = 3.5 7 4.22 (2, m) 7.20 (1, d, J5,6 = 6.1) 6.56 (1, d, J10,9 = 3.9) 6.37 (1, dd, J10,9 = 3.9; J10,8 = 1.3) 6.29 (1, d, J10,9 = 3.6) 6.37 (1, d, J10,9 = 4.1) 7.14 (1, d, J5,6 = 6.0) 4.25 (4, s) 8 4.11 (2, m) 7.17 (1, d, J6,5 = 6.1) 7.27 (1, d, J6,5 = 6.0) 9 4.40 (1H, br. s, NH)
7a
7b
6.33 (1, br. s)
7c*3
6.11 (1, d, J,3 = 0.5) 6.06 (1, s)
7d
2.27 (3, br. s)
6.68 (1, dd, J8,9 = 2.3; J8,10 = 1.2) 2.23 (3, br. s)
6.27 (1, d, J,C3 = 0.4)
2.26 (3, br. s)
6.35 (1, dd, J9,10=3.9; J,3 = 0.8) 6.21 (1, dd, J9,10 = 3.9; J9,8 = 2.3) 5.94 (1, dd, J9,10 = 3.6; J,3 = 0.7) 6.85 (1, d, J9,10 = 4.1)
4.22 (2, m)
4.10 (2, m)
4.25-4.38 (4, m)
_______ * Chemical shifts are given in the "Other protons" column. *2 The reverse assignment of protons is possible. *3 13C NMR spectra, , ppm: 11.77 (H3); 42.91, 43.81 (CH2-5,6); 104.18, 105.15, 109.44, 120.81 (CH-1,8,9,10); 100.61, 114.17, 123.19, 130.28, 132.95 (C-2,3,11,12); 114.17 (CN).
443
Me R N 1a,b N OCNPOCl2 R N 6a,b N
Me H Cl N P Cl O Me R N 7a,b N CN O
1, 6, 7 a R = H; b R = Me
Products of monosubstitution at position 3, nitriles 7a,b, were isolated from the reaction of Kirsanov isocyanate with dipyrrolopyrazines 1a,b. In addition, according to data of TLC and chromato-mass spectrometry, in the reaction of 2-methyldipyrrolo[1,2-a:2',1'-c]pyrazine (1a), having two free -positions on the pyrrole rings, with Kirsanov isocyanate the dinitrile was formed in trace amounts. However the reaction did not proceed so unequivocally for 2-methyl-5,6-dihydrodipyrrolo[1,2-a:2',1'-c]pyrazine (1c). At an equimolar ratio of substrate to reactant the dominant reaction product was 2-methyl-5,6dihydrodipyrrolo[1,2-a:2',1'-c]pyrazine-3-carbonitrile (7c) in 34% yield. At a twofold excess of reactant two reaction products were isolated. In addition to compound 7c 2-methyl-5,6-dihydrodipyrrolo[1,2-a:2',1'-c]pyrazine-3,8-dicarbonitrile (8c) was obtained in a ratio of 2:1. The overall yield of product was 20%.
Me OCNPOCl2
CH2Cl2
Me
Me
N
1c
N
7c
+
CN
NC
N
8c
CN
EXPERIMENTAL The 1H NMR spectra were recorded on a Varian VXR-400 spectrometer (operating frequency 400 MHz) in CDCl3 solution at 28C. Internal standard was TMS. The 31P NMR spectra (operating frequency 160 MHz) were recorded relative to H3PO4 as external standard. The mass spectra of compounds were recorded on a Kratos MS-90 instrument at an ionizing energy of 70 eV. High resolution mass spectra were obtained using perfluorokerosene (PFK) as standard, by peak-matching at a resolution 8000 (at the 10% level) on a VG ZabSpec instrument (VG Analytical, Manchester, UK). A check on the progress of reactions was effected by TLC on Silufol-254 plates. Yields, constants, and spectral characteristics of the compounds investigated are given in Tables 1 and 2. Trichloroacetylation of Dipyrrolopyrazines (General Method). Trichloroacetyl chloride (1 mmol / 2 mmol) was added with stirring to a solution of dipyrrolopyrazine (1 mmol) in dry methylene chloride (5 ml). The reaction mixture was heated for 1 h, poured into water, the organic layer was separated, and the solvent evaporated. The residue was chromatographed on a column of neutral Al2O3, eluting with ethyl acetate.
444
Ester Derivatives of Dipyrrolopyrazines (General Method). The trichloroacetyldipyrrolopyrazine (1 mmol) was treated with 5N NaOH (in 50% MeOH: 10 ml) and kept at room temperature for 1 h. The solid was filtered off, washed with water, and dried. The product was chromatographed on a column of SiO2, 100/160, eluting with ethyl acetate. Acylation of Dipyrrolopyrazines with p-Toluenesulfonyl Isocyanate (General Method). p-Toluenesulfonyl isocyanate (1 mmol / 2 mmol) was added with stirring to a solution of dipyrrolopyrazine (1 mmol) in dry benzene (5 ml). The mixture was stirred for 1 h, the solid filtered off, and washed with heptane. Acylation of Dipyrrolopyrazines with Kirsanov Isocyanate, Nitrile Preparation (General Method). The dichloride of isocyanatophosphoric acid [8] (Kirsanov isocyanate) (1 mmol / 2 mmol) was added with stirring and cooling to the dipyrrolopyrazine (1 mmol) in dry hexane (5 ml). The mixture was stirred for 1 h, the solid filtered off, and washed with heptane. The solid was then dissolved in dry methylene chloride, left for 1 h at room temperature, the solvent evaporated, and the dry residue extracted with hot heptane.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. V. I. Terenin, E. A. Sumtsova, M. A. Kovalkina, S. Z. Vatsadze, E. V. Kabanova, I. F. Leshcheva, A. P. Pleshkova, and N. V. Zyk, Khim. Geterotsikl. Soedin., 1688 (2003). V. I. Terenin, E. L. Ruchkina, I. F. Leshcheva, A. P. Pleshkova, and Yu. G. Bundel', Khim. Geterotsikl. Soedin., 52 (1997). J. W. Harbuk and H. Rapoport, J. Org. Chem., 37, 3618 (1972). M. Seefelder, Chem. Ber., 96, 3243 (1963). N. L. Nam, I. I. Grandberg, and V. I. Sorokin, Khim. Geterotsikl. Soedin., 46 (1994). N. L. Nam, I. I. Grandberg, and V. I. Sorokin, Khim. Geterotsikl. Soedin., 205 (1996). A. A. Tolmachev, A. A. Chaikovskaya, R. V. Smaliy, T. N. Kudrya, A. A. Yurchenko, and A. M. Pinchuk, Heteroatom Chem., 10, 343 (1999). A. V. Kirsanov, Zh. Obshch. Khim., 24, 1033 (1954).
445
SYNTHESIS AND HETEROCYCLIZATION OF -AROYL--DIPHENYLPHOSPHORYLPROPIONIC ACIDS

R. A. Khachatryan, R. J. Khachikyan, N. V. Karamyan, G. A. Panosyan, and M. G. Indzhikyan It has been established that diphenylphosphine oxide reacts smoothly with -aroylacrylic acids with the formation of -aroyl--diphenylphosphorylpropionic acids, which were cyclized under the action of hydroxylamine, hydrazine hydrate, and phenylhydrazine hydrochloride into phospho derivatives of dihydrooxazinone and tetrahydropyridazinone respectively. It was shown that imidazole may serve as nucleophilic protection for the synthesis of dihydropyridazinone derivatives from -aroylacrylic acids. Keywords: -aroylacrylic acids, dihydropyridazinones, diphenylphosphine oxide, diphenylphosphoryldihydrooxazinones, diphenylphosphoryltetrahydropyridazinones, imidazole, pyrazolinecarboxylic acids. Due their high electrophilicity aroylacrylic acids react readily with nucleophiles, including primary and secondary amines, but, as was shown by one of us, do not interact with diethyl phosphite in the absence of catalysts. The reaction was successfully effected in an alcoholic solution of sodium ethylate or under conditions of interphase catalysis [1]. A conclusion on the order of addition has been made by analogy with amines and on the basis of the results of quantum chemical calculations [2]. The present work is devoted to the study of the interaction of aroylacrylic acids 1a-c with diphenylphosphine oxide. It was established that the reaction proceeded smoothly on heating the reactants and the addition products 2a-c are formed in high yield (70-81%, Table 1). The structures of the latter were established on the basis of the exclusive formation of -(benzoylethyl)diphenylphosphine oxide (3), on decarboxylation of acid 2a and not the isomeric -(benzoylethyl)diphenylphosphine oxide.
ArCCH=CHCOOH O 1ac
Ph2PH O
ArCCH2CHCOOH O O=PPh2 2ac
2a
ArCCH2CH2PPh2 O 3 O
Here and subsequently: a Ar = Ph, b Ar = C6H4Me-4, c Ar = C6H4Br-4
__________________________________________________________________________________________ Institute of Organic Chemistry, National Academy of Sciences (NAN) of Armenia, Erevan 375091; e-mail: MVM@lx2.yerphi.am. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 541-546, April, 2004. Original article submitted March 15, 2002; revision submitted March 4, 2003. 446 0009-3122/04/4004-04462004 Plenum Publishing Corporation

Compound 2 2b 2 3 4 4b 4 5 5b 5 6 6b 6 7 7b 7 9b 9 10 10b 10 Empirical formula C22H19O4P C23H21O4P C22H18BrO4P 21192 C22H20 NO4P C23H22NO4P C22H19BrNO4P C22H18NO3P C23H20NO3P C22H17BrNO3P C22H19N2O2P C23H21N2O2P C22H18BrN2O2P C28H23N2O2P C29H25N2O2P C28H22BrN2O2P C11H10N2O C10H7BrN2O C10H10N2O2 C11H12N2O2 C10H9BrN2O2 Found, % Calculated, % N 4.98 5.03 5.28 5.36 3.89 3.94 5.71 5.69 5.11 5.09 5.39 5.41 3.98 4.03 4.69 4.80 5.09 5.14 3.79 3.74 5.11 5.08 5.39 5.41 3.94 3.97 5.09 5.11 5.35 5.39 4.09 4.16 5.29 5.37 2.81 2.79 5.29 5.26 5.89 5.88 3.38 3.35 3.49 3.56 3.46 3.44 3.01 2.96 3.76 3.73 3.58 3.60 3.12 3.08 7.46 7.49 7.19 7.22 6.16 6.18 6.18 6.22 6.00 6.03 5.27 5.29 14.95 5.05 11.14 11.15 14.72 14.74 13.69 13.72 10.42 10.41 mp, 8.16 8.20 7.93 7.91 6.81 6.78 9.32 9.28 7.88 7.89 7.67 7.62 6.54 6.57 8.30 8.27 7.89 7.97 6.85 6.83 8.26 8.29 7.94 7.99 6.82 6.84 6.84 6.88 6.68 6.68 5.89 5.86 154-155 190-192 204-205 131-133 211-212 214-216 210-211 172-173 179-180 176-177 240-241 231-232 245-246 201-203 195-197 204-205 242-243 235-237 203-204 173-175 205-206 81 70.5 76.5 48 81.5 87.3 76 54 52 71 57.7 78.6 65.7 93.1 78 74.4 64.5 51.6 53.1 56.2 46.3 Yield, %
69.79 69.84 70.36 71.41 57.72 57.76 75.38 75.45 67.21 67.17 67.79 67.81 55.89 55.93 70.43 70.40 70.91 70.95 57.98 58.15 70.54 70.59 71.17 71.13 58.26 58.28 74.62 74.66 74.96 75.00 63.49 63.52 70.93 70.97 47.76 47.81 63.12 63.15 64.74 64.71 44.59 44.61
It is known that heterocyclic compounds with a phosphorus atom in the side chain possess high biological activity and belong to a new generation of pesticides. With the aim of transferring to compounds of this type we have obtained oximes 4a-c of the synthesized -aroyl--diphenylphosphorylpropionic acids 2a-c and have heterocyclized them by heating with a catalytic amount of sulfuric acid. As a result phospho derivatives of 3-aryl-4,5-dihydro-1,2-oxazin-6-one 5a-c were obtained in 52-71% yield (Table 1).
O H + Ar N O 5ac PPh2 O
ArCCH2CHCOOH HO N O=PPh2 4ac
447
The similarly constructed 6-aryl-2,3,4,5-tetrahydropyridazin-3-ones 6a-c and 7a-c were obtained by heating the same -phosphorylaroylpropionic acids 2a-c with hydrazine hydrate or phenylhydrazine hydrochloride respectively.
O NH2NH2 . H2O Ar N N R 6ac, 7ac PPh2 O
2ac
or PhNHNH2 . HCl
6 R = H; 7 R = Ph
Interesting results were obtained by us on boiling -aroyl--(N-imidazolyl)propionic acids 8b,c, synthesized by one of us previously [3], with an aqueous solution of hydrazine. In place of the expected aminotetrahydropyridazinones the reaction products proved to be the 6-aryl-2,3-dihydropyridazin-3-ones 9b,c.
N N ArCCH2CHCOOH O 8b,c NH2NH2 . H2O Ar N N H 9b,c O
The latter might have been formed as a result either of preliminary fission of imidazole with subsequent heterocyclization or by initial heterocyclization with subsequent fission of imidazole. Specially designed experiments showed that the interaction of aroylacrylic acids 1a-c with hydrazine hydrate leads not to the formation of pyridazinone derivatives but to pyrazolinecarboxylic acids 10a-c.
Ar 1ac
NH2NH2 . H2O
COOH N H 10ac
Analogous results have been obtained by several authors studying the reaction of aroylacrylic acids and their esters with phenylhydrazine [4-6]. It can therefore be assumed that dihydropyridazinones 9 owe their origin to the fission of imidazole from the initially formed imidazolo derivatives of tetrahydropyridazinone. The results obtained permit the conclusion that imidazole may serve as nucleophilic protection for the synthesis of pyridazinone derivatives from aroylacrylic acids. The composition and structure of all the compounds obtained were confirmed by the results of elemental analysis (Table 1) and data of NMR spectra (Table 2, the spectra of compounds 8b,c missing from [3] are also given in this Table).
448
TABLE 2. 1H, 13C* , and 31P*2 NMR Spectra of the Synthesized Compounds
Compound 1 2 Chemical shifts, , ppm (coupling constants, J, Hz)*3 2 12.35 (1, br. s, 2); 7.91 (6, m, C6H5); 7.40-7.58 (9, m, C6H5); 4.26 (1, ddd, J1 = 13.5, J2 = 11.0, J3 = 2.7, CH); 3.81 (1, ddd, J1 = 18.3, J2 = 11.0, J = 5.4, CH2); 3.03 (1, ddd, J1 = 18.3, J2 = 9.0, J3 = 2.8, CH2) 12.37 (1, br. s, ); 7.90 (4, m, C6H5); 7.80 (2, d, J = 8.1, Ar); 7.51 (6H, m, C6H5); 7.23 (2, d, J = 8.1, Ar); 4.23 (1, ddd, J1 = 13.2, J2 = 11.1, J3 = 2.8, PCH); 3.76 (1, ddd, J1 = 18.0, J2 = 11.1, J3 = 5.4, CH2); 2.98 (1, ddd, J1 = 18.0, J2 = 9.0, J3 = 2.8, CH2); 2.40 (3, s, CH3) 12.3 (1, br. s, 2); 7.91 (4, m, C6H5); 7.84 (2, d, J = 8.5, Ar); 7.60 (2, d, J = 8.5, Ar); 7.45-7.55 (6, m, C6H5); 4.26 (1, ddd, J1 = 13.2, J2 = 10.5, J3 = 2.9, CH); 3.78 (1, ddd, J1 = 18.3, J2 = 10.5, J3 = 5.7, CH2); 3.01 (1, ddd, J1 = 18.3, J2 = 8.7, J3 = 2.9, CH2) 7.91 (2H, d, J = 8.1, C6H5); 7.80 (4H, m, C6H5); 7.40-7.57 (9H, m, C6H5); 3.20 (2H, m, CH2); 2.66 (2H, m, CH2) 12.19 (1, br. s, 2); 11.27 (1, s, N); 7.79-7.94 (4, m, C6H5); 7.43-7.59 (8, m, C6H5); 7.22-7.35 (3, m, C6H5); 4.09 (1, td, J1 = 10.8, J2 = 3.3, CH); 3.32 (1, ddd, J1 = 13.8, J2 = 11.1, J3 = 6.3, CH2); 2.90 (1, ddd, J1 = 13.8, J2 = 10.2, J3 = 3.3, CH2) 12.18 (1, br. s, 2); 11.14 (1, s, N); 7.86 (4, m, C6H5); 7.45-7.57 (6, m, C6H5); 7.42 (2, d, J = 8.2, Ar); 7.06 (2, d, J = 8.2, Ar); 4.06 (1, td, J1 = 10.8, J2 = 3.2, PCH); 3.31 (1, ddd, J1 = 13.8, J2 = 11.1, J3 = 6.0, CH2); 2.87 (1, ddd, J1 = 13.8, J2 = 10.2, J3 = 3.2, CH2); 2.33 (3, s, CH3) 12.17 (1, br. s, 2); 11.23 (1, s, N); 7.91 (4, m, C6H5); 7.83 (2, d, J = 8.5, Ar); 7.62 (2, d, J = 8.5, Ar); 7.45-7.56 (6, m, C6H5); 4.05 (1, td, J1 = 10.8, J2 = 3.2, PCH); 3.32 (1, ddd, J1 = 13.8, J2 = 11.1, J3 = 6.2, CH2); 2.89 (1, ddd, J1 = 13.8, J2 = 10.2, J3 = 3.2, CH2) 7.91 (2, d, J = 8.1, C6H5); 7.80 (4, m, C6H5); 7.40-7.57 (9, m, C6H5); 4.29 (1, ddd, J1 = 15.0, J2 = 8.3, J3 = 4.2, PCH); 3.68 (1, ddd, J1 = 17.3, J2 = 12.5, J3 = 4.2, CH2); 3.19 (1, ddd, J1 = 26.4, J2 = 17.3, J3 = 8.3, CH2) 8.00-7.78 (6H, m, C6H5); 7.60-7.40 (6H, m, C6H5); 7.20 (2H, m, Ar); 4.25 (1H, ddd, J1 = 15.0, J2 = 8.4, J3 = 3.6, PCH); 3.80 (1H, ddd, J1 = 17.3, J2 = 12.8, J3 = 4.2, CH2); 3.05 (1H, ddd, J1 = 27.3, J2 = 17.3, J3 = 8.3, CH2) 7.60-7.85 (6H, m, C6H5); 7.40-7.62 (9H, m, C6H5); 4.39 (1H, ddd, J1 = 15.0, J2 = 8.4, J3 = 3.6, PCH); 3.85 (1H, ddd, J1 = 17.3, J2 = 12.9, J3 = 3.6, CH2); 3.15 (1H, ddd, J1 = 27.3, J2 = 17.3, J3 = 8.4, CH2) 10.87 and 10.73 (1H, s, NH); 7.00-8.00 (15, m, C6H5); 4.70 (0.5H, dd, J1 = 11.7, J2 = 8.4, PCH); 4.02 (0.5H, ddd, J1 = 13.8, J2 = 8.1, J3 = 5.4, CH2); 3.35 (0.5, ddd, J1 = 17.1, J2 = 12.9, J3 = 5.4, CH2); 3.78-3.16 (1H, m, CH2); 2.53 (0.5H, dd, J1 = 17.1, J2 = 13.2, PCH) 11.01 (1H, s, NH);7.89 (2H, m, C6H5);7.73 (2, m, C6H5); 7.37-7.65 (6, m, C6H5); 7.40 (2H, d, J = 8.4, Ar); 7.19 (2H, d, J = 8.4, Ar); 4.26 (1, m, ); 2.95-3.25 (2, m, 2); 2.32 (3, s, CH3) 10.93 and 10.81 (1, s, NH); 7.97 (2, m, Ar); 7.10-7.70 (12, m, Ar and C6H5); 4.71 and 4.02 (1, m, ); 2.43-3.41 (2, m, 2) 8.05 (2, m, C6H5); 7.12-7.76 (18, m, C6H5); 4.29 (1, ddd, J1 = 15.0, J2 = 8.3, J3 = 4.2, PCH); 3.69 (1, ddd, J1 = 17.3, J2 = 12.5, J3 = 4.2, CH2); 3.29 (1, ddd, J1 = 26.4, J2 = 17.3, J3 = 8.3, CH2) 8.20 (2, m, C6H5); 7.72 (2, d, J = 8.1, Ar); 7.44-7.64 (6, m, C6H5); 7.15-7.35 (7, m, C6H5); 7.06 (2, m, Ar); 3.96-4.11 (2, m, 2); 3.24 (1, m, ); 2.43 (3, s, CH3) 8.03 (2, dd, J1 = 11.7, J2 = 7.8, Ar); 7.46-7.66 (10, m, C6H5); 7.08-7.39 (7, m, C6H5 and Ar); 4.31 (1, ddd, J1 = 15.0, J2 = 8.4, J3 = 3.6, PCH); 3.65 (1, ddd, J1 = 17.3, J2 = 12.9, J3 = 3.6, CH2); 3.30 (1, ddd, J1 = 27.3, J2 = 17.3, J3 = 8.4, CH2) 7.35-7.78 (7, m, Ar, et); 5.75 (1, dd, J1 = 8.4, J2 = 4.2, CH); 4.05 (1, dd, J1 = 18.9, J2 = 8.4, CH2); 3.89 (1, dd, J1 = 18.9, J2 = 4.2, CH2); 2.35 (3, s, CH3) 7.38-7.71 (7, m, Ar, et); 5.78 (1, dd, J1 = 8.4, J2 = 4.2, CH); 4.07 (1, dd, J1 = 18.9, J2 = 8.4, CH2); 3.91 (1, dd, J1 = 18.9, J2 = 4.2, CH2)
2b
3 4
4b
5b
6b
6 7
7b
8b 8
449
TABLE 2 (continued)
1 9b 9 10 2 12.97 (1, br. s, NH); 7.80 (1, d, J = 9.9, Het) 7.68 (2, d, J = 8.1, Ar); 7.20 (2, d, J = 8.1, Ar); 6.86 (1, d, J = 9.9, Het); 2.38 (3, s, CH3) 13.09 (1, br. s, NH); 7.87 (1, d, J = 9.9, Het); 7.77 (2, d, J = 8.4, Ar); 7.56 (2, d, J = 8.4, Ar); 6.89 (1, d, J = 9.9, Het) 9.00 (1H, br. s, NH); 7.59 (2, d, J = 7.5, C6H5); 7.32 (2, t, J = 7.5, C6H5); 7.25 (1, t, J = 7.2, C6H5); 4.23 (1, dd, J1 = 10.5, J2 = 9.5, CH); 3.21 (1, m, J1 = 16.5, J2 = 10.5, CH2); 3.19 (1, m, J1 = 16.5, J2 = 9.5, CH2) 8.95 (1, br. s, NH); 7.47 (2, d, J = 8.1, Ar); 7.11 (2, d, J = 8.1, Ar); 4.20 (1, dd, J1 = 11.1, J2 = 9.3, CH); 3.18 (1, m, J1 = 16.5, J2 = 11.1, CH2); 3.16 (1, m, J1 = 16.5, J2 = 9.3, CH2) 9.03 (1, br. s, NH); 7.51 (2, d, J = 8.7, Ar); 7.46 (2, d, J = 8.7, Ar); 4.24 (1, t, J = 10.2, CH); 3.18 (2, d, J = 10.2, 2)
10b
10
_______ * 13C NMR spectrum of 6b (DMSOCCl4, 1:3), , ppm (J, Hz): 163.07 (CO, d, J = 3.0); 147.94 (d, J = 5.0); 138.92 (4-CAr); 132.95 (2C, 4-CPh); 132.19 (d, J = 99.5); 131.89 (d, J = 99.1); 131.92 (d, J = 2.7); 131.65 (d, J = 2.7); 130.99 (2C, d, J = 9.4); 130.90 (2C, d, J = 9.4); 128.95 (2C, 3-, 5-CAr); 128.66 (2C, d, J = 11.7); 128.04 (2C, d, J = 12.0); 125.45 (2C, 2-, 6-CAr); 37.41 (CH, d, J = 62.8); 22.53 (CH2, d, J = 2.4); 20.76 (CH3). *2 31P NMR spectrum (DMSOCCl4, 1:3), , ppm: 6a 33.84 and 33.03 (1:1 mixture of two tautomers); 6c 34.03 and 32.91 (1:1 mixture of two tautomers). *3 Solvents: DMSOCCl4, 1:3 (2-7a, 9, 10); CDCl3 (7b); DMSO CF3COOD, 1:3 (8b,c).
EXPERIMENTAL The 1H, 13C, and 31P NMR spectra of the synthesized compounds were taken on a Varian Mercury-300 instrument (300, 75, and 121 MHz respectively). -Aroyl--(diphenylphosphoryl)propionic Acids (2a-c). A solution of diphenylphosphine oxide (10 mmol) and -aroylacrylic acid (10 mmol) in dry benzene (10 ml) was boiled for 6 h. After cooling, the resulting precipitate of product 2 was filtered off, washed with benzene, and dried in vacuum. Decarboxylation of -Benzoyl--(diphenylphosphoryl)propionic Acid 2a. Compound 2a (1 g) was kept at 140C (5 mm Hg) for 5-10 min. After cooling, the resulting product was recrystallized from acetone. (-Benzoylethyl)diphenylphosphine oxide (3) (0.4 g) was obtained. Oximes of -Aroyl--(diphenylphosphoryl)propionic Acids (4a-c). A solution of hydroxylamine hydrochloride (36 mmol) in the minimum amount of water was added to a saturated solution of compound 2a-c (3 mmol) in methanol and the mixture obtained was boiled for 30 h. The resulting precipitate of oxime 4a-c was filtered off, washed sequentially with methanol, and with water, and dried in vacuum. 3-Aryl-5-diphenylphosphoryl-4,5-dihydro-1,2-oxazin-6-one (5a-c). A solution of compound 4a-c (15 mmol) in acetone (8 ml) containing a catalytic amount of conc. H2SO4 was boiled for 3 h. After cooling, the reaction mixture was poured into water, the precipitate of product 5a-c formed was filtered off, washed with water, and recrystallized from acetone. 6-Aryl-4-diphenylphosphoryl-2,3,4,5-tetrahydropyridazin-3-ones (6a-c). A solution of compound 2a-c (2.9 mmol) and 60% aqueous hydrazine hydrate solution (4 ml) in alcohol (5 ml) was boiled for 8 h. After cooling, the resulting solid was filtered off, washed with alcohol, and dried in vacuum. 450
6-Aryl-4-diphenylphosphoryl-N-phenyl-2,3,4,5-tetrahydropyridazin-3-ones (7a-c). A solution of compound 2a-c (1.5 mmol) and phenylhydrazine hydrochloride (1.5 mmol) in alcohol (10 ml) was boiled for 6 h. The reaction mixture was treated similarly to that described above for compounds 6a-c. 6-Aryl-2,3-dihydropyridazin-3-ones (9b,c). A mixture of acid 8b,c (2.5 mmol) and 60% aqueous hydrazine hydrate solution (4 ml) was boiled for 4 h. After cooling, the precipitate of product 9b,c formed was filtered off, washed with alcohol, and dried in vacuum. 3-Aryl-2-pyrazoline-5-carboxylic Acids (10a-c). A mixture of acid 1a-c (5 mmol), 60% aqueous hydrazine hydrate solution (3 ml), and alcohol (3 ml) was boiled for 6 h. After cooling, the precipitate of product 10a-c was filtered off, washed with alcohol, and dried in vacuum.
REFERENCES 1. 2. 3. 4. 5. 6. R. J. Khachikyan, S. Yu. Kotikyan, and S. G. Agbalyan, Khim. Zh. Armen., 52, 90 (1999). N. P. Churkina, N. P. Gambaryan, D. A. Bochvar, and S. G. Agbalyan, Arm. Khim. Zh., 30, 370 (1977). R. J. Khachikyan, G. V. Grigoryan, and S. G. Agbalyan, Arm. Khim. Zh., 39, 373 (1986). E. A. Soliman, Rev. Roum. Chem., 23, 159 (1978). A. A. Nada, Egypt. J. Chem., 19, 621 (1978). A. W. Nineham and R. A. Raphael, J. Chem. Soc., 118 (1949).
451
SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF SUBSTITUTED 5-CYANO6-OXO-2-STYRYLNICOTINIC ACIDS

A. B. Deyanov and M. E. Konshin Derivatives of the anilide or ethyl ester of 5-cyano-6-oxo-2-styrylnicotinic acid are formed in the reaction of the anilide or ethyl ester of 5-cyano-2-methyl-6-oxonicotinic acid with aromatic aldehydes. On interaction with hydrazine hydrate the products are converted into hydrazides of 5-cyano-6-oxo-2styrylnicotinic acid derivatives. Keywords: anilides, hydrazides, 5-cyano-6-oxo-2-(substituted styryl)nicotinic acid, esters, antimicrobial activity, synthesis. Amides and hydrazides of 2-styrylnicotinic acids are of interest as intermediates for the synthesis of 1,6-naphthiridines [1] and also as potential biologically active substances. The present work was undertaken with the aim of clarifying the possibility of synthesizing derivatives of 5-cyano-6-oxo-2-styrylnicotinic acid by reacting the ethyl ester and anilide of 5-cyano-2-methyl-6-oxonicotinic acid with aromatic aldehydes and studying their antimicrobial activity. The investigations showed that the ethyl ester and anilide of 5-cyano-2-methyl-6-oxonicotinic acid 1a,b react with aromatic aldehydes on boiling (3 h) a solution of the starting materials in xylene in the presence of piperidine as catalyst or on boiling (8 h) in acetic anhydride.
NC O N H 1a,b NC O N H 3ad COR Me NC O N H 2aj CONHNH2 C6H4R COR
R'C6H4CHO
NH2NH2 C6H4R'
1 a R = Et, b R = PhNH; 2 a-e R = Et, f-j R = PhNH; a R' = 4-MeO, b R' = 4-Me2N, c R' = 4-Br, d R' = 3-Br, e R'= 2-F, f R'= 4-MeO, g R' = 4-Me2N, h R' = 4-Br, i R' = 3-Br, j R' = 2-F; 3 a R = 4-MeO, b R = 4-Me2N, c R = 4-Br, d R = 3-Br
__________________________________________________________________________________________ Perm State Pharmaceutical Academy, Perm 614990, Russia; e-mail: pfa@degacom.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 547-550, April, 2004. Original article submitted June 22, 2001. 452 0009-3122/04/4004-04522004 Plenum Publishing Corporation

Compound 2a 2b 2c 2d 2e 2f 2g 2h 2i 2j 3a 3b 3c 3d Empirical formula C18H16N2O4 C19H19 N3O3 C17H13BrN2O3 C17H13BrN2O3 C17H13FN2O3 C22H17N3O3 C23H20N4O2 C21H14BrN3O2 C21H14BrN3O2 C21H14 FN3O2 C16H14N4O3 C17H17N5O2 C15H11BrN4O2 C15H11BrN4O2 Found, % Calculated, % H N 4.97 4.92 5.68 5.96 3.51 3.40 3.51 3.36 4.20 4.01 4.61 4.44 5.24 5.37 3.36 3.69 3.36 3.23 3.93 4.18 4.55 4.82 5.30 5.28 3.09 2.90 3.09 2.87 8.64 8.89 12.45 12.32 7.51 7.52 7.51 7.40 8.97 8.94 11.31 11.45 14.57 14.46 10.00 10.28 10.00 9.73 11.69 12.00 18.05 18.27 22.57 22.41 15.60 15.66 15.60 15.85 mp, Hal 262-263 296-297 21.41 21.30 21.41 21.67 6.08 6.32 309-311 292-294 260-262 277-279 210-212 19.01 19.30 19.01 19.28 5.29 5.00 274-276 291-293 244-247 183-185 233-236 22.24 22.53 22.24 22.30 322-325 240-243 53 62 40 67 48 56 72 71 66 41 89 86 90 92 Yield, %
C 66.66 66.42 67.64 67.78 54.71 55.03 54.71 54.95 65.38 65.50 71.15 71.20 71.86 72.13 60.02 59.81 60.02 60.31 70.19 69.97 61.93 62.10 63.15 63.29 50.16 49.92 50.16 50.48
In both cases ethyl esters or anilides of substituted 5-cyano-6-oxo-2-styrylnicotinic 2a-j are formed (see Table 1), but in the first case the reaction products were obtained in higher yield. In the 1H NMR spectra of compounds 2, in difference to the spectra of compounds 1 (see Experimental), the signal for the methyl group protons disappeared and a multiplet for the aromatic protons was displayed (in the case of compounds 2f-j the integrated intensity of this multiplet was increased) as were signals for the two protons of the ethylenic fragment at 7.28-7.60 ppm. In the mass spectrum of compound 2g a peak was observed for the molecular ion* with mass 384. Breakdown of the molecular ion was linked with fission of hydrogen and with conversion into a 382 ion which probably is obtained on cyclization due to the ortho-positioning of the dimethylaminostyryl residue and the heterocyclic nitrogen atom of the 384 ion, and has the structure of a benzo[1,2-b]quinolizine. Fission of a molecule of isocyanate from the 382 ion gives a 263 ion or eliminates aniline, undergoing a McLafferty rearrangement [2], and forms a 289 ion. The latter subsequently either splits off a molecule of CO or a dimethylamine fragment with the formation of 261 or 245 ions respectively. It was shown that the synthesis of hydrazides of 5-cyano-6-oxo-2-styrylnicotinic acids 3a-d may be carried out successfully on boiling ethyl esters 2a-d with hydrazine hydrate in ethanol for 5-6 h. Only the ester group reacts and the nitrile is unchanged. Four bands were observed in the IR spectrum of these compounds for the stretching vibrations of the N-H bond at 3250-3290, 3285-3315, 3310-3355, and 3405-3420 cm-1. In the 1H NMR spectrum of compounds 3a-d, compared with the initial esters 2a-d, the ethyl group signals had disappeared. A broadened signal appeared at 4.42-5.48 (1H, NH) and also a signal at 8.18-8.24 ppm (2H, NH2). _______ * Here and subsequently values of m/z are given for peaks. 453
The presence of antimicrobial activity for the hydrazides of 2-methyl-6-phenylnicotinic acid [3] was the basis for determining the activity of compounds 2f-j and 3a-d*. The investigations were carried out in relation to standard strains of Escherichia coli and Staphylococcus aureus by serial dilution [4]. All the compounds studied displayed antimicrobial activity towards Escherichia coli and Staphylococcus aureus at concentrations of 500-1000 g/ml, but hydrazide 3b inhibited growth of the former culture at a dilution of 250 g/ml, which is double the activity of ethacridine lactate. However it is half as active as the comparison standard on the culture of Staphylococcus aureus.
EXPERIMENTAL The IR spectra were recorded on a UR-20 instrument for compound 3a in CCl4 (c = 0.05 M), for 3b,c in CHCl3 (c = 0.05 M), and for the remainder in nujol. The 1H NMR spectra were obtained on a RS-60 (60 MHz) spectrometer for compounds 2b,d in CDCl3, and for the remainder in DMSO-d6, internal standard was HMDS. The mass spectra were obtained on a MX-1303 instrument with direct insertion of samples into the ion source at an ionizing voltage of 70 eV, the standard for comparison was 200Hg. 5-Cyano-2-methyl-6-oxonicotinic Acid. Compound 1 (20.6 g, 0.1 mol) was boiled in a 15% NaOH solution in alcohol for 4 h. The mixture was poured into water (200 ml), and the solution acidified with acetic acid to a weakly acid reaction. The solid was filtered off, and crystallized from aqueous DMF. Yield 15.1 g (85%); mp 273-274C. 1H NMR spectrum, , ppm: 10.62 (1H, s, COOH); 8.38 (1H, s, =C(4)H); 8.20 (1H, s, NH); 2.58 (3H, s, Me). IR spectrum, , cm-1: 3520 (O-H), 3445 (NH), 2240 (CN), 1675 (C(3)C=O), 1625 (C(6)=O). Found, %: C 53.94; H 3.39; N 15.72. C8H6N2O3. Calculated, %: C 54.13; H 3.26; N 16.01. Anilide of 5-Cyano-2-methyl-6-oxonicotinic Acid (1b). Aniline (9.3 g, mol) and phosphorus oxychloride (10 ml, 16.7 g, 0.11 mol) was added to a solution of 5-cyano-2-methyl-6-oxonicotinic acid (17.8 g, 0.1 mol) in anhydrous dioxane (50 ml). The mixture was heated for 30 min, cooled, and poured into water (200 ml). The solution was neutralized with ammonia solution, the solid was filtered off, and crystallized from aqueous DMF. Yield 14.7 g (58%); mp 216-218C. 1H NMR spectrum, , ppm: 10.58 (1H, s, CONH); 8.68 (1H, s, =C(4)H); 7.78 (1H, s, NH); 7.45 (5H, m, Ph); 2.65 (3H, s, Me). IR spectrum, , cm-1: 3270 (CONH), 3390 (NH), 2240 (CN), 1645 (C(3)C=O), 1620 (C(6)=O). Found, %: C 66.40; H 4.38; N 16.59. C14H11N3O2. Calculated, %: C 66.27; H 4.22; N 16.46. Ethyl Esters and Anilides of 5-Cyano-6-oxo-2-styrylnicotinic Acids (2a-j). A. A solution of compound 1a or 1b (0.01 mol) and substituted benzaldehyde (0.015 mol) in a mixture of xylene (10 ml) and piperidine (1 ml) was boiled for 3 h. The solvent and the excess of the benzaldehyde were steam distilled off, the solid was recrystallized from aqueous DMF (compounds 2a-g,i) or a mixture of DMFdioxanewater, 5:2:1 (compounds 2h,j). 1H NMR spectrum, , ppm: compounds 2a-e, 8.42-8.52 (1H, s, =C(4)H); 7.78-7.91 (1H, s, NH), 7.42-7.60 (6H, m, Ph, CH=CH); 4.22-4.30 (2H, q, CH2 in COOEt); 1.28-1.32 (3H, t, Me in COOEt); compounds 2f-j, 10.32-10.40 (1H, s, CONH); 8.32-8.48 (1H, s, =C(4)H); 7.65-7.86 (1H, s, NH); 7.28-7.57 (11H, m, Ph, CH=CH). IR spectrum, , cm-1: compounds 2a-e, 3310-3340 (NH), 2235-2240 (CN), 17001715 (C(3)C=O), 1650-1660 (C(6)=O); compounds 2f-j, 3290-3310 (NH), 3260-3275 (PhNH), 2230-2240 (CN), 1620-1630 (C(3)C=O), 1645-1660 (C(6)=O). Mass spectrum of compound 2g, m/z (Irel, %): 384 (97) [M]+, 382 (100), 289 (99), 273 (17), 263 (68), 261 (49), 245 (20), 234 (45), 207 (36), 191 (45), 146 (33). B. A solution of compound 1a or 1b (0.01 mol) and 3-bromobenzaldehyde (1.3 ml, 2.06 g, 0.011 mol) in acetic anhydride (5 ml) was boiled for 8 h. The mixture was poured into water (100 ml), the solution was neutralized, and the precipitated solid was crystallized sequentially from acetic acid and aqueous DMF. Compounds 2d (yield 0.37 g, 10%) and 2i (yield 1.97 g, 44%) were obtained. _______ * Tests were carried out by G. N. Novoselova. 454
Hydrazides of 5-Cyano-6-oxo-2-styrylnicotinic Acids (3a-d). Hydrazine hydrate (7.5 ml, 0.1 mol) was added to a solution of the appropriate compound 2a-d (0.01 mol) in ethanol (20 ml) and the mixture boiled for 6 h. The mixture was then poured into water (150 ml), the precipitated solid was filtered off, and crystallized from DMF. 1H NMR spectrum, , ppm: 8.32-8.39 (1H, s, =C(4)H); 8.18-8.24 (2H, s, NH2); 7.40-7.64 (1H, s, NH); 6.95-7.58 (6H, m, Ph, CH=CH). IR spectrum, , cm-1: 3405-3420, 3310-3355, 3250-3290 (NHNH2), 32853315 (NH), 2230-2240 (CN), 1600-1620 (C(3)C=O), 1630-1635 (C(6)=O).
REFERENCES 1. 2. 3. 4. V. I. Sigova and M. E. Kon'shin, Zh. Obshch. Khim., 34, 2083 (1984). P.V. Terentiev and A. P. Stankevicius, Mass Spectrometric Analysis of Biologically Active Nitrogen Bases [in Russian], Mokslas, Vilnius (1987). V. I. Sigova, V. S. Zalesov, N. V. Semyakina, M. E. Kon'shin, and A. V. Atavina, Dep. in TsBNTI Medprom, No. 195-MP-84. G. N. Pershin, Methods of Experimental Chemotherapy [in Russian], Meditsina, Moscow (1959), pp. 109-111, 456-460.
455
INVESTIGATION OF H-COMPLEX FORMATION OF DERIVATIVES OF NAPHTHALIMIDE WITH PHENOL BY IR SPECTROSCOPY

V. M. Shershukov, R.A. Minakova, A. I. Bedrik, and Yu. N. Surov The H-complex-forming reaction of naphthalimide derivatives with phenol has been investigated by IR spectroscopy. It was shown that for the majority of compounds studied the carbonyl group is the main center of basicity. In the case of amino-substituted imides of naphthalic acid transfer is possible of the reaction center from the carbonyl group to the nitrogen atom of the substituent introduced into the naphthalene ring. However because of steric hindrance this occurs only for amino- and methylaminosubstituted naphthalimide. Keywords: naphthalic acid imides, H-complex formation, proton donor, reaction center, IR spectroscopy. The spectralluminescence and electrochemical characteristics of N-imide derivatives of 4-aminosubstituted naphthalic acid were investigated in [1 ] with the aim of studying their structure. Analysis showed that at significant differences in the electron-donating properties of the 4-amino component the fluorescence of these compounds lies in close spectral regions. The value of the electrochemical characteristics (oxidation reduction potentials) also proved to be close together [2]. Such a leveling of the properties of substituents is probably explained by the different degree of flattening of the molecules caused by steric hindrance arising between the atoms of the substituents and the -hydrogen atoms of the naphthalene ring. Consequently information obtained from the investigations can hardly be considered adequate. In addition, the lack discovered by us of a linear correlation between the spectral and electrochemical characteristics in the series of 4-aminosubstituted imides of naphthalic acid [3] indicates that differences in the properties of the investigated compounds exist and may be detected with appropriate methods of investigation. Since the electron density distribution is the result of the mutual influence of all the possible effects in a molecule (which is naturally the overall result and our investigations reflect this), we considered it expedient to study its change in one fragment of the molecule, the carbonyl group, as a function of the nature of the substituent in the naphthalene ring, the effect of which is transmitted mainly by the conjugation mechanism. It is possible to obtain a comparative assessment of the electron density at a C=O group by studying its proton accepting ability. Infrared spectroscopy is a convenient method for this, enabling the determination of the values of frequency shifts of hydroxyl group stretching vibrations of the proton donor (OH), forming the H-complex with the compound being studied [4]. This method seems of interest since it displays a high sensitivity towards a factor of the molecular structure, which is very valuable when studying series of compounds with a varying structural parameter. It is sufficiently reliable since OH is determined with a low relative error compared with other methods. The change in shift (OH) is sufficiently large and exceeds the error of measurement. __________________________________________________________________________________________ Institute of Monocrystals, National Academy of Sciences (NAN) of Ukraine, Kharkov 61001; e-mail: shershukov@isc.kharkov.com. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 551-554, April, 2004. Original article submitted June 20, 2000; revision submitted August 26, 2002. 456 0009-3122/04/4004-04562004 Plenum Publishing Corporation
However in view of the inadequate solubility of many of the compounds being studied, it was not possible to carry out measurements in the known system (proton donorbasecarbon tetrachloride). We therefore considered the possibility of investigating such compounds in the proton donor without a solvent, and consequently the choice of proton donor proved to be an important factor in our investigations. It must be a sufficiently weak proton donor, capable of dissolving the compound under investigation. We proceeded from studies on the investigation of carbonyl compounds, according to which the use of the weak proton donor phenol has enabled a solution to problems of the fine structure of organic compounds, the mutual influence of centers of basicity, and other problems having important theoretical significance [4,5]. With the aim of clarifying such a possibility we carried out a comparative study of the compounds of this series, readily soluble in carbon tetrachloride and in a phenol melt. A good linear dependence was obtained between the values of OH in solution and in the melt: OHs = OHm0.9-9.36 (correlation coefficient 0.965). The results obtained agree completely with the literature data. Proceeding from this, samples of the compounds 1-15 being investigated were prepared by dissolving them in a phenol melt (mp 41C).
CO N CO 115 R2
R1
We successfully obtained samples of composition 1 : 1 sufficiently homogeneous and transparent in the region of the spectrum being investigated. Consequently the spectrograms taken enabled reliable determination of the values of OH (Table 1). As is evident from the structure the studied compounds have several centers of basicity and consequently the problem of the point of addition of phenol requires proof. A carbonyl group is the chief center of basicity for some (compounds 1-3), since the imide nitrogen atom, due to the acceptor influence of the two carbonyl groups, is practically devoid of basic properties. The sensitivity of the method to the structure of the studied compounds is easily overlooked in these compounds for which the problem of the reaction center is not in doubt. Changes in the imide portion of the molecule, in which conjugation with a C=O group is practically absent, are clearly consolidated in the shifts of the stretching vibrations of the phenolic hydroxyl group. The same may be said about compounds 6 and 15, although in them, unlike the previous compounds, addition of proton occurs at the nitrogen of the amino group. It is known that amines are more strongly basic than carbonyl compounds, and in the presence of nitrogen-containing substituents separated from the carbonyl group, interaction at the nitrogen atom of the substituent is also possible. However in the case of conjugation of amino-containing substituents and carbonyl groups in the composition of one compound, transfer of the reaction center to the oxygen atom of the carbonyl group is possible. To clarify such a possibility, additional investigations were carried out allowing for the circumstance that on forming an H-complex at a carbonyl group its absorption band must be displaced in the direction of low frequencies. If complex formation occurs at an atom of the substituent, the value of C=O must remain practically unchanged or even slightly increased. Analysis of the obtained results (Table 1) shows that for the amino-containing compounds 5 and 8 C=O in the melt, compared with C=O in KBr disks, is either unchanged or slightly increased. This is caused by certain acceptor properties, which the amino group acquires on adding a molecule of phenol. The same picture is also observed for 4-methylamino-substituted compound 9. It is as if the structure of the methylamino group, undergoing partial rehybridization from the sp2 to the sp3 state [6], i.e. while acquiring any intermediate structure between these states, remains free to conjugate with the -electron system of naphthalene and sufficiently available to the proton donor. In the case of compounds 7 and 10, with two methyl groups, the probability of forming a bond at the nitrogen atom falls sharply, probably due to steric hindrance, and addition 457
TABLE 1. Data on OH and IR Spectra of Compounds 1-15

Compound 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 R1 H H H Cl NH2 H NMe2 NH2 MeNH NMe2 Piperidyl Morpholyl Morpholyl Morpholyl H R2 H Ph 4-BuC6H4 4-BuC6H4 Ph 4-H2NC6H4 Ph 4-BuC6H4 4-BuC6H4 4-BuC6H4 4-BuC6H4 4-BuC6H4 MeNH NHCOMe NH2 , cm-1 =, cm-1 KBr Melt 1673, 1697 1688, 1656 1687, 1653 1700, 1651 1707, 1674 1700, 1676 1690, 1644 1684, 1658 1684, 1658 1688, 1654 1698, 1655 1689, 1656 1700, 1675 1720, 1692, 1667 1708, 1660
174 179 198 304 221 264 308 235 228 224 201 234 225 239
1692, 1656 1698, 1663 1706, 1663 1650, 1693 1678, 1696 1648, 1695 1683, 1656 1656, 1683 1655, 1695 1656, 1702 1658, 1697 1657, 1695 1685, 1705, 1745 1660, 1705
occurs at the carbonyl group, which is displayed as a reduction of its frequency. It should be mentioned that imides containing cycloaliphatic amines as substituents (compounds 11, 12) behave analogously and the influence exerted by them on the stability of the hydrogen bond corresponds to their electronic character. For example, a very small shift of frequency of the hydroxyl group stretching vibrations of phenol, i.e. a very low basicity for the carbonyl group, is observed for the morpholine substituted imide 12 and this substituent exerts a very weak influence on the absorption spectrum [1]. For the compounds in which additional centers of basicity are introduced into the imide portion of the molecule (compounds 13 and 14), proceeding from the grounds given above it may be stated that in compound 13 protonation occurs at the nitrogen atom of the amino group in the imide portion of the molecule, and in compound 14 at the oxygen atom of the acetyl group. Such a conclusion is in good agreement with the position of the absorption band of the carbonyl group. The fact discovered by us, that transfer of the reaction center from the nitrogen atom of the substituent in compounds 5, 8, and 9 to a carbonyl group in all the remaining amino-substituted imides, confirms indirectly the conclusions made previously that only compounds 5, 8, and 9 have a planar structure, while all the remaining substituted imides experience significant steric difficulties. The deviation from the correlation line describing the linear dependence between the transition energy (maxabs) and the difference in oxidationreduction potentials, characteristic of just 8 and 9, indicate that the transfer of reaction center observed by us in the H-complexforming reaction is also characteristic of oxidationreduction reactions. In agreement with literature data, together with steric effects, the change in reaction mechanism is the main reason for the disturbance of the linear correlation [7].
EXPERIMENTAL The IR spectra were obtained on a Specord IR 75 spectrometer in a phenol melt in the range 3000-3700 cm-1. Compounds 1-15 were synthesized according to known procedures [2,8].
458
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. L. Ya. Malkes, R. A. Minakova, and A. I. Bedrik, Zh. Prikl. Spektrosk., 55, 820 (1991). A. I. Bedrik, Author's Summary of Dissertation for Candidate of Chemical Sciences, Kharkov (1997). R. A. Minakova, A. I. Bedrik, L. Ya. Malkes, and N. N. Rozhitskii, in XVII Ukrainian Conference on Organic Chemistry, Abstracts, Kharkov (1995), p. 482. L. A. Kutulya, L. P. Pivovarevich, Yu. N. Surov, L. M. Satanovskii, and S. V. Tsukerman, Zh. Org. Khim., 11, 2094 (1975). S. V. Tsukerman, L. A. Kutulya, Yu. N. Surov, and V. F. Lavrushin, Khim. Geterotsikl. Soedin., 204 (1968). N. G. Korzhenevskaya, Ukr. Khim. Zh., 55, 1311 (1989). S. G. Mairanovskii, Ya. P. Stradyn', and V. D. Bezuglyi, Polarography in Organic Chemistry [in Russian], Khimiya, Leningrad (1976), p. 352. B. M. Krasovitskii, E. A. Shevchenko, and V. B. Distanov, Zh. Org. Khim., 19, 1305 (1983).
459
INTERACTION OF METHYL 5,6-DIALKYL-2-AMINO-3-CYANOPYRIDINE4-CARBOXYLATES WITH PRIMARY AMINES

A. N. Vasiliev, A. N. Lyshchikov, O. E. Nasakin, and Ya. S. Kayukov An unusual direction has been found for the interaction of alkyl 5,6-dialkyl-2-amino-3-cyanopyridine-4carboxylates with primary amines leading to the formation of 2,6,7-trialkyl-4-amino-2,3-dihydro-1Hpyrrolo[3,4-c]pyridine-1,3-diones. Keywords: amide, amines, aminopyrimidines, 1,3-diones, enamines, carboxamides, nucleophiles, pyridines. The previously synthesized alkyl 5,6-dialkyl-2-amino-3-cyanopyridine-4-carboxylates 1a-c, being structural analogs of isonicotinic acid, are of particular interest for their further modification [1]. The presence of different functional groups, ester and cyano, affords the possibility of studying the interaction of pyridines 1a-c with various nucleophiles. It was noted previously that the interaction of compounds 1 with amines and organic acids, outstanding as O-nucleophiles, leads to the formation of the corresponding 6,7-dialkyl-4-amino-2,3dihydro-1H-pyrrolo[3,4-c]pyridine-1,3-diones 4j-l [1]. The unusual course of the reaction with O-nuclepohiles presumes the need to study the interaction of such pyridines with N-nucleophiles. It was thus discovered that the interaction of pyridines 1a-c with alcoholic ammonia solution leads to the formation of pyrrolo[3,4-c]pyridine1,3-diones 4j-l, as in the case of interaction with O-nucleophiles, but under milder conditions. The absolute identity of the IR (Table 1), mass, and 1H NMR spectra is proof of this. The interaction of pyridines 1a-c with primary aliphatic amines in a sealed ampul on heating in an absolute medium leads to the formation of the corresponding 2-alkyl-substituted analogs 4a-i, which are yellow crystalline substances with a clearly marked yellow-green fluorescence in solution. Intense absorption bands were observed in the IR spectra of the obtained pyrrolo[3,4-c]pyridine-1,3-diones 4a-i (Table 1) at 3280-3450 for the asymmetric and symmetric stretching vibrations of the amino group, and medium intensity bands at 1675-1740 and 1630-1645 cm-1 corresponding to the stretching vibrations of the carbonyl group and the deformation vibrations of the amino group respectively. The molecular masses of the pyrrolo[3,4-c]pyridine-1,3-diones 4, found with the aid of high resolution mass spectra, corresponded to calculated values. In addition it was discovered that carrying out the reaction of pyridine 1a with benzylamine in a shorter time interval enabled N-benzyl-2-amino-3-cyano-5,6,7,8tetrahydroquinoline-4-carboxamide (2) and N(3),N(4)-dibenzyl-2-amino-5,6,7,8-tetrahydroquinoline-3,4dicarboxamide (3) to be obtained in a pure state. In the IR spectrum of 3-cyanotetrahydroquinolinamide 2, as in the spectra of the initial compounds 1, an intense absorption was present for the conjugated cyano group at 2215, and intense bands at 3285-3425 and 1615 cm-1 indicating the presence of stretching and deformation vibrations of an amino group. Absorption bands at 1640 and 1570 cm-1, representing amide I and amide II bands, __________________________________________________________________________________________ Chuvash I. N. Ulyanov State University, Department of Organic Chemistry, Cheboksary 428015, Russia; e-mail: caesar7@mail.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 555-559, April, 2004. Original article submitted January 6, 2002; revision submitted August 26, 2002. 460 0009-3122/04/4004-04602004 Plenum Publishing Corporation
indicate the associated form of compound 2. The main characteristic absorption bands in the IR spectrum of dicarboxamide 3 are analogous to those of the monoamide 2, except for the absence of the absorption band of the cyano group. Attempts to isolate analogous compounds on interaction with other amines gave no positive result. We established that further heating of carboxamide 2 and dicarboxamide 3 in benzylamine leads to their conversion into the final compound 4g. Extended storage or heating of a solution of dicarboxamide 3 leads to the same result. These additional data enabled us to assume the following scheme for the course of the reaction of the investigated pyridines 1 with primary aliphatic amines and ammonia.
Me O R1 R2 O CN N NH2 1ac R3NH2 ROH R2 N 2 R3 O R1 R2 N 3
1
R3 O R1 NH CN NH2 R3NH2 R1 R2 O
R3 NH NH N H A O N R3 R1 R3NH
2
R3
H2O NH3
NH2
NH O N H NH2
R3 O
R2
N 4al
NH2
1 R1 + R2 = (CH2)4, b R1 = R2 = Me, c R2 = Me, R1 = H; 2, 3 R1 + R2 = (CH2)4, R3 = CH2Ph; 4 a R + R2 = (CH2)4, R3 = Me, b R1 = R2 = R3 = Me, c R1 = H, R2 = R3 = Me, d R1 + R2 = (CH2)4, R3 = C5H11, e R1 = R2 = Me, R3 = C5H11, f R1 = H, R2 = Me, R3 = C5H11, g R1 + R2 = (CH2)4, 3 R = CH2Ph, h R1 = R2 = Me, R3 = CH2Ph, i R1 = H, R2 = Me, R3 = CH2Ph, j R1 + R2 = (CH2)4, R3 = H, k R1 = R2 = Me, R3 = H, l R1 = R3 = H, R2 = Me
TABLE 1. IR Spectra of Compounds 2, 3, and 4a-l

Compound 2 3 4 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l IR spectrum, cm-1 NH 3400, 3425, 3285 3430, 3300, 3255 3450, 3300 3445, 3300 3400, 3280 3450, 3285 3450, 3300 3400, 3280 3455, 3285 3445, 3285 3410, 3285 3307, 3185 3310, 3180 3315, 3190 NH 1615 1620, 1640 1630 1645 1650 1625 1635 1635 1635 1645 1630 1686 1685 1686 C=O 1737, 1680 1700, 1738 1715, 1675 1730, 1675 1740,1680 1710, 1675 1740, 1700 1745, 1695 1740, 1710 1705, 1726 1705, 1727 1702, 1720 CN 2215 Amide I and II (associated form) 1640, 1570 1645, 1575
461
TABLE 2. Characteristics of Compounds 2, 3, and 4a-l

Compound 2 3 4 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l Empirical formula C18H18N4O C25H26N4O2 C12H13N3O2 C10H11N3O2 C9H9N3O2 C16H21N3O2 C14H19N3O2 C13H17N3O2 C18H17N3O2 C16H15N3O2 C15H13N3O2 C11H11N3O2 C9H9N3O2 C8H7N3O2 Found, % Calculated, % H 7.73 5.92 6.30 6.32 5.65 5.67 5.39 5.40 4.78 4.74 7.35 7.37 7.31 7.33 6.95 6.93 5.55 5.57 5.38 5.37 4.92 4.90 5.05 5.07 4.72 4.71 3.93 3.92 mp, N 17.90 18.29 13.54 13.52 18.16 18.17 20.47 20.48 21.97 21.98 14.60 14.62 16.10 16.08 16.97 16.99 13.65 13.67 14.96 14.94 15.70 15.72 19.36 19.35 22.01 21.99 23.72 23.71 254 236 224 186 192 125 112 185 172 187 201 223 269 235 98 76 94 87 91 78 84 76 85 92 87 99 96 98 Yield, %
C 70.22 70.57 72.42 72.44 62.31 62.33 58.55 58.53 56.52 56.54 66.85 66.88 64.33 64.35 63.12 63.14 70.37 70.34 68.29 68.31 67.42 67.41 60.85 60.83 56.53 56.54 54.25 54.23
Probably the corresponding N-alkyl-5,6-dialkyl-2-amino-3-cyanoisonicotinamides 2 are formed initially, which then add a second molecule of amine at the nitrile group with the formation of the corresponding intermediate A. Under the reaction conditions the latter is readily hydrolyzed into 5,6-disubstituted N(3),N(4)-dialkyl-2-aminopyridine-3,4-dicarboxamides 3. Subsequent heating of them leads to intramolecular cyclization of the vicinal carboxamide groups into the imide fragment of compounds 4. It is necessary to mention that water is required to participate in the formation of compounds 3. Since these reactions are carried out in an absolute medium it is probable that under the process conditions alkylation of the amine occurs by the methyl alcohol formed with elimination of water, which participates in the hydrolysis. In this case methylalkylamine and dimethylalkylamine must be formed in the reaction mixture as side products and were identified by us by GLC in the case of reaction with benzylamine. Aromatic (aniline) and secondary amines (diethylamine) do not participate in this reaction, which is probably linked with their low nucleophilicity and with steric hindrance.
EXPERIMENTAL A check on the progress of reactions and the purity of the compounds synthesized was effected by TLC on Silufol UV 254 plates, visualizing with UV light (365 nm) and with iodine vapor. The IR spectra were obtained in thin films (nujol suspensions) on a UR 20 instrument. The NMR spectra were recorded on Bruker WM 250 (250 MHz) and AM 300 (300 MHz) instruments. Solvent was DMSO-d6, internal standard HMDS ( 0.05 ppm). The high and low resolution mass spectra were obtained on a Varian MAT-212 instrument at an ionizing energy of 70 eV. Chromatographic investigations were carried out on a LKhM 8MD chromatograph, 462
thermal conductivity detector, with a column (3000 3 mm) packed with chromaton N-AW-DMCS, particle size 0.250-0.315, liquid phase SP 2100, 5%; column temperature 115C, carrier gas helium, 40 ml/min, detector current 140 A, sensitivity 10, volume of test sample 0.5 l, tape flow rate 240 mm/h. Reactants and solvents used in the work were purified by standard methods [2]. N-Benzyl-2-amino-3-cyano-5,6,7,8-tetrahydroquinoline-4-carboxamide (2). Pyridine 1a (0.231 g, 1 mmol) was suspended in benzylamine (3 ml, 27 mmol) at room temperature. The suspension was placed in an ampul and sealed. The ampule was heated at 130 C for 12 h. The end of the reaction was determined by TLC (Rf 0.35, eluent ethyl acetate, violet fluorescence on UV irradiation). After cooling, the ampul was opened carefully. The contents were diluted with 1,4-dioxane (5 ml), The white solid was filtered off, washed with 1,4-dioxane (10 ml), recrystallized from 2-propanol, and dried in a vacuum desiccator over P2O5. Compound 2 (0.306 g, 98%) was obtained. 1H NMR spectrum, , ppm: 1.65 (2H, m, CH2CH2CH2); 1.72 (2H, m, CH2CH2CH2); 2.43 (2H, t, CH2CH2); 2.62 (2H, t, CH2CH2); 4.00 (2H, s, CH2NHC(O)); 5.97 (2H, s, NH2); 7.45 (5H, m, C6H5); 8.39 (1H, s, NHCH2). N(3),N(4)-Dibenzyl-2-amino-5,6,7,8-tetrahydroquinoline-3,4-dicarboxamide (3) (Table 2) was synthesized analogously by heating pyridine 1a (0.231 g, 1 mmol) in benzylamine (3 ml, 27 mmol) for 18 h. 1 H NMR spectrum, , ppm: 1.67 (2H, m, CH2CH2CH2); 1.76 (2H, m, CH2CH2CH2); 2.43 (2H, t, CH2CH2); 2.62 (2H, t, CH 2CH2); 4.20 (2H, d, CH2N(CO)); 4.28 (2H, d, CH2NHC(O)); 5.85 (2H, s, NH2); 7.25 (5H, m, Ph); 7.30 (5H, m, Ph); 7.81 (1H, s, NHCH2); 8.74 (1H, s, NHCH2). 6,7-Dialkyl-4-amino-2-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-1,3-diones (4a-c) (Table 2). A suspension of pyridine 1a-c (1 mmol) in a saturated solution of methylamine in dioxane (5 ml) was heated at 130C in a sealed ampul for 48 h. The end of the reaction was determined by TLC (eluent ethyl acetate, the compound fluoresces yellow-green on UV irradiation). After cooling to -10C the ampul was opened carefully. The contents were diluted with 1,4-dioxane (5 ml), the yellow solid was filtered off, washed with 1,4-dioxane (10 ml), and purified by vacuum sublimation or recrystallization from DMF. The product was dried in a vacuum desiccator over P2O5. 1H NMR spectrum, , ppm: 4a, 1.78 (2H, m, CH2CH2CH2); 1.85 (2H, m, CH2CH2CH2); 2.75 (2H, t, CH2CH2); 2.93 (2H, t, CH2CH2); 2.97 (3H, s, CH3); 6.50 (2H, s, NH2); 4b, 2.48 (3H, s, CH3); 2.49 (3H, s, CH3); 2.95 (3H, s, CH3); 6.50 (2H, s, NH2); 4c, 2.4 (3H, s, CH3); 2.95 (3H, s, CH3); 6.83 (1H, s, CH); 6.59 (2H, s, NH2). 6,7-Dialkyl-4-amino-2-pentyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-1,3-diones (4d-f) were synthesized analogously by heating pyridines 1a-c (1 mmol) in pentylamine (0.5 ml) at 130C for 36 h. 1H NMR spectrum, , ppm: 4e, 0.79 (3H, t, CH3CH2); 1.25 (2H, m, CH2CH2CH3); 1.34 (2H, m, CH2CH2CH2); 1.58 (2H, m, CH2CH2CH2); 2.42 (3H, s, CH3); 2.43 (3H, s, CH3); 3.50 (2H, t, CH2CH2); 6.50 (2H, s, NH2). Mass spectrum, m/z (Irel, %): 4d, 287 (100), 269 (10), 258 (7), 230 (67), 216 (28), 202 (14), 174 (6), 145 (20), 84 (5), 41 (14) (the molecular ion and 9 intense fragment ion peaks are given); 4f, 247 (77), 230 (14), 218 (100), 190 (46), 177 (46), 160 (58), 92 (21), 66 (17), 42 (25) (the molecular ion and 8 intense fragment ion peaks are given). 6,7-Dialkyl-4-amino-2-benzyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-1,3-diones (4g-i) were synthesized analogously by heating pyridines 1a-c (1 mmol) in benzylamine (0.6 ml, 5.7 mmol) at 160C for 36 h. 1H NMR spectrum, , ppm: 4g, 1.78 (2H, m, CH2CH2CH2); 1.85 (2H, m, CH2CH2CH2); 2.78 (2H, t, CH2CH2); 2.95 (2H, t, CH2CH2); 4.69 (2H, s, CH2); 6.55 (2H, s, NH2); 7.28 (5H, m, Ph); 4h, 2.43 (3H, s, CH3); 2.44 (3H, s, CH3); 4.69 (2H, s, CH2); 6,57 (2H, s, NH2); 7.30 (5H, m, Ph); 4i, 2.48 (3H, s, CH3); 6.87 (1H, s, CH); 4.70 (2H, s, CH2); 4.88 (2H, s, NH2); 7.31 (5H, m, Ph). Compound 4g was obtained under analogous conditions by heating amide 2 (0.306 g, 1 mmol) or amide 3 (0.400 g, 1 mmol) with benzylamine (0.6 ml, 5.7 mmol) at 160C for 36 h. To demonstrate the formation of methylbenzylamine and dimethylbenzylamine in the reaction a fraction with bp 75-85C (12 mm Hg) was distilled from the filtrate. The presence of the amines in this mixture was demonstrated by GLC. 6,7-Dialkyl-4-amino-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-1,3-diones (4j-l) were obtained analogously by heating pyridines 1a-c (1 mmol) with a solution (10 ml) of ammonia in 2-propanol, saturated at room temperature, at 50C for 12 h. 463
REFERENCES 1. 2. A. N. Vasiliev, Ya. S. Kayukov, O. E. Nasakin, A. N. Lyshchikov, V. N. Nesterov, O. V. Kayukova, and O. V. Pul'kherovskaya, Khim. Geterotsikl. Soedin., 338 (2001). A. J. Gordon and R. A. Ford, Chemist's Companion, Handbook of Practical Data, Techniques and References, Wiley-Interscience, New York (1972), 560 pp.
464
INVESTIGATION OF THE NUCLEOPHILIC REARRANGEMENT OF 2-(CYANOMETHYL)1,4,6-TRIMETHYLPYRIMIDINIUM IODIDE INTO 4,6-DIMETHYL-2-METHYLAMINONICOTINIC ACID NITRILE
G. G. Danagulyan, L. G. Sahakyan, and D. A. Tadevosyan 2-(Cyanomethyl)-1,4,6-trimethylpyrimidinium iodide is rearranged into 4,6-dimethyl-2-methylaminonicotinic acid nitrile by interaction with alcoholic solutions of sodium ethylate, methylamine, and also glycine and -alanine ethyl esters. This conversion was also observed for the first time for pyrimidinium salts during the process of recording 1H NMR spectra in CD3OD solution containing CD3ONa. After the rearrangement deuterium exchange of the protons of the pyridine ring methyl groups was noted spectrally. It was demonstrated experimentally that for carrying out and completing the recyclization a quantity of nucleophilic reagent must convert the molar equivalent quantity of pyridinium salt. Keywords: 2-alkylaminonicotinonitrile, pyrimidinium salt, deuterium exchange, KostSagitullin nucleophilic rearrangement. The present communication, devoted to the study of the influence of a nitrile group located in the side chain of a pyrimidinium salt, on the KostSagitullin rearrangement, continues the series of studies on the recyclization of pyrimidinium salts into 2-alkylaminopyridine derivatives [1-4]. The model for investigation, 2-(cyanomethyl)-1,4,6-trimethylpyridinium iodide (3), was synthesized by the reaction of 2-(carbamoylmethyl)4,6-dimethylpyrimidine (1) with P2O5 and subsequent methylation of the obtained nitrile 2 with methyl iodide. As was shown by our experiments, the introduction of an electron-withdrawing group (nitrile) into the side chain of a pyrimidinium salt enables the rearrangement to take place. In alcoholic sodium ethylate solution salt 3 is rearranged in a few minutes into 4,6-dimethyl-2-methylaminonicotinonitrile (4) in close to quantitative yield. On heating in alcoholic methylamine solution the same recyclization occurs in 72% yield. It is appropriate to note that under analogous conditions the iodoalkylates of esters and amides of the corresponding substituted 2-pyrimidinylacetic acids are rearranged in an overall yield of 30-55% [3-5]. It is also interesting that isomerization of salt 3 into pyridine 4 was observed by us even under the action of such amines as glycine and -alanine ethyl esters. However under these conditions "rearrangement and transamination" [1], i.e. with the inclusion of an amino acid fragment into the reaction product, was not recorded.
__________________________________________________________________________________________ Institute of Organic Chemistry, National Academy of Sciences (NAN) of the Republic of Armenia, Erevan 375094; e-mail: gdanag@email.com. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 560-563, April, 2004. Original article submitted October 26, 2001. 0009-3122/04/4004-04652004 Plenum Publishing Corporation 465
Me N Me N 1 CONH2 MeI Me + Me _ N I Me N 3 Nu C N Me P2O5 Me
Me N N 2 C N
Me CN N 4 NHMe
Nu = EtONa, MeNH2, H2NCH2COOEt, H2NCH2CH2COOEt
The ease with which the rearrangement of iodide 3 occurs in alcoholic sodium ethylate solution (rapid process and high yield of reaction product) stimulated us to study the process of converting salt 3 into pyridine 4 in CD3OD solution containing CD3ONa within the dynamics of NMR spectral changes. It turned out that after adding a small quantity of CD3ONa to a solution of iodide 3 in CD3OD the recyclization product was already formed after 5-10 min. This was indicated by the appearance in the 1H NMR spectrum of signals belonging to the protons of the reaction product. In particular there were singlets at 2.17 and 2.26 (4- and 6-CH3), 5.94 (5-H), and 3.15 ppm (N-CH3). However it is necessary to note that the signals of the protons of the initial salt were retained in the spectrum even on the following day, and the ratio of the intensities of the signals of both substances were practically unchanged over the course of time. On adding a large quantity of CD3ONa to the ampul disappearance of the proton signals of salt 3 from the 1H NMR spectrum was noted already after 5 min, while the signals of the recyclization product protons were retained. The shape of the spectrum indicated completion of the rearrangement and was confirmed chromatographically. We consider that the incomplete conversion described above of the initial salt in the experiment with CD3ONa (insufficiency of the latter) possibly indicates the formation at the first reaction step of an anhydro form as a result of fission of proton from the methylene group. Such a deprotonation leads to binding of the CD3Oalkoxide ion acting as recyclization initiator, and consequently to dying out of the rearrangement. At the same time the addition of a new portion of CD3ONa (above the equimolar amount) enables completion of the rearrangement. It was thereby shown that the course of the rearrangement depends on the amount of nucleophilic reagent. For the progress and the important completion of the recyclization it is necessary that the amount of the nucleophilic reagent exceeds the molar quantity of the pyrimidinium salt. On subsequent (after recyclization) recording of the 1H NMR spectra of the same sample we observed a gradual reduction (in the first 45-60 min) and then complete disappearance of the signals of the methyl group protons (4- and 6-CH3 of pyridine 4). This is probably linked with basic deuterium exchange of protons. It is necessary to stress that we recorded no deuterium exchange of the 5-H proton (of the pyridine nucleus) or of the N-methyl group protons. There are literature data on basic deuterium exchange of protons of pyrimidine and pyridine nuclei [6]. Previously we noted deuterium exchange for protons in pyrimidine derivatives [7,8] and considered that it might be an actual process of nucleophilic rearrangement. In the case examined in the present paper, due to the rapid course of the rearrangement (which was also confirmed by NMR spectra), basic exchange of protons occurs after completion of the recyclization and consequently does not hinder it and may not compete with it. It occurs after completion of the rearrangement and consequently is only noticed in the rearrangement product.
466
Me + N Me N Me I H H CN 3 CD ONa 3 NaI CD3OH Me
Me N N
OCD3 OCD
3
Me
OCD3 Me N CN
Me CN
Me
CD3O
Me CN 4 Me N H NMe OCD3 Me
Me
OCD3 CN N NMe
EXPERIMENTAL The 1H NMR spectra were obtained on a Varian Mercury 300 (300 MHz) spectrometer in the Center for Investigation of Molecular Structure, National Academy of Sciences (NAN) of Armenia (program US CRDF RESC 17-5). The mass spectra were recorded on a chromato-mass spectrometer (HP 6890 Series Gas Chromatograph, HP 5973 Mass Selective Detector), obtained with grant AR1-991 US CRDF. Silufol UV 254 plates were used for TLC, visualizing with iodine vapor and Ehrlich's reagent. Preparative separation was carried out by column chromatography on silica gel (Silicagel L 5/40 m). 2-(Cyanomethyl)-4,6-dimethylpyrimidine (2). A mixture of amide 1 [5] (10.0 g, 0.06 mol) and P2O5 (7.1 g, 0.05 mol) was carefully heated for 10-15 min until homogeneous. After cooling the reaction mixture was transferred to a sublimation apparatus and sublimed at 85-100C (3-5 mm Hg). Nitrile 2 (2.9 g, 33%) was obtained having mp 75-77C, Rf 0.47 (Silufol UV 254, benzeneacetone, 3:1). 1H NMR spectrum (CDCl3), , ppm: 2.48 (6H, s, 4- and 6-CH3); 3.99 (2H, s, CH2); 6.98 (1H, s, 5-H). Found, %: C 65.59; H 6.45; N 28.39. C8H9N3. Calculated, %: C 65.29; H 6.16; N 28.55. 2-(Cyanomethyl)-1,4,6-trimethylpyrimidinium Iodide (3). A solution of nitrile 2 (1.47 g, 0.01 mol) in MeI (5 ml, 11.36 g, 8-fold excess) was heated in a sealed glass ampul at 90-100C for 10 h. The resulting solid was filtered off, washed with a small quantity of hexane, and air dried. Salt 3 (1.76 g, 61%) was obtained having mp 158-160C. 1H NMR spectrum (DMSO-d6), , ppm: 2.78 (3H, s, 4 or 6-CH3); 2.85 (3H, s, 6 or 4-CH3); 4.08 (3H, s, N-CH3); 5.03 (2H, s, CH2); 8.19 (1H, s, 5-H). Rearrangement of 2-(Cyanomethyl)-1,4,6-trimethylpyrimidinium Iodide (3) into 4,6-Dimethyl-2methylaminonicotinonitrile (4). A. Iodide 3 (0.6 g, 2.0 mmol) was dissolved in an alcoholic solution of sodium ethylate [sodium (0.06 g, 2.7 mmol) in EtOH (10 ml)] and the solution was left at room temperature for 30 min. After neutralizing with an alcoholic solution of HCl, the precipitated salt was filtered off. A portion of the solvent was removed, the precipitated solid was filtered off, and washed with hexane. The yield of pyridine 4 was 0.3 g (90%) of mp 216-217C, Rf 0.3 (benzeneacetone, 3:1). 1H NMR spectrum (CDCl3), , ppm: 2.21 (3H, s, 4 or 6-CH3); 2.25 (3H, s, 6 or 4-CH3); 3.1 (3H, s, N-CH3); 3.6 (1H, s, NH); 5.71 (1H, s, 5-H). Mass spectrum, m/z (Irel, %): 162 (7), 161 (100 ) [M]+, 121 (13), 120 (21), 119 (20), 108 (9), 105 (9), 94 (10), 93 (12), 81 (10), 80 (47), 79 (9), 66 (15), 55 (18), 53 (12). Found, %: C 67.34; H 6.59; N 25.98. C9H11N3. Calculated, %: C 67.06; H 6.87; N 26.07. B. A solution of iodide 3 (0.5 g, 1.7 mmol) in 15% ethanolic methylamine solution (5 ml) was heated in a sealed ampul at 90-100C for 10 h. The resulting solid was filtered off, dried, and recrystallized from hexane acetone, 5:1. The yield of pyridine 4 was 0.16 g (58%). After removing the solvent from the filtrate and separation of the residue on a column (silicagel L 5/40, benzeneacetone 3:1), further compound 4 (0.04 g, 14%) and pyrimidine 2 (0.025 g, 10%) were obtained. Mass spectrum, m/z 161. 467
C. A mixture of iodide 3 (0.6 g, 2 mmol) and an alcoholic solution (10 ml) of aminoacid ethyl ester (6-8 mmol) was heated for 15 h at 90-100C in a sealed glass ampule. The ethanol was removed, and the residue was washed with hot hexane. After distilling off the hexane the residue was put onto a column (silicagel, acetonebenzene, 2 : 1). Pyridine 4 (0.08 g, 52%) was obtained. Pyrimidine 2 was also isolated (with glycine ester 0.04 g (14%), with -alanine ester 0.06 g (21%)). The work was carried out within the framework of scientific theme 00-405b of the Ministry of Science and Education of the Armenian Republic, and also jointly with Prof. A. R. Katritzky (University of Florida) grant No. ACH-006 98/ AC1-955 of the National Fund for Science and Advanced Technology of Armenia (NFSAT) and the US Civil Research and Development Fund (USCRDF). The authors are grateful to A. G. Panosyan for assistance in carrying out the spectral investigations.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. G. G. Danagulyan and L. G. Saakyan, Khim. Geterotsikl. Soedin., 1434 (1999). G. G. Danagulyan, L. G. Saakyan, A. R. Katritzky, and S. N. Denisenko, Khim. Geterotsikl. Soedin., 1572 (1999). G. G. Danagulyan, L. G. Sahakyan, A. R. Katritzky, and S. N. Denisenko, Heterocycles, 53, 419 (2000). G. G. Danagulyan, L. G. Saakyan, and G. A. Panosyan, Khim. Geterotsikl. Soedin., 351 (2001). G. G. Danagulyan, L. G. Saakyan, and G. A. Panosyan, Khim. Zh. Armen., 53, 62 (2000). B. Nowak-Wydre and M. Szafran, J. Org. Chem., 48, 2327 (1983). G. G. Danagulyan, M. G. Zalinyan, and R. S. Sagitullin, Khim. Geterotsikl. Soedin., 996 (1987). G. G. Danagulyan, L. G. Saakyan, and M. G. Zalinyan, Khim. Geterotsikl. Soedin., 225 (1992).
468
SYNTHESIS AND PROPERTIES OF SYMMETRICAL AND ASYMMETRICAL PHTHALOCYANINES WITH D,L-LEUCINE FRAGMENTS
A. O. Naumov, E. V. Kudrik, and G. P. Shaposhnikov Nucleophilic substitution of the nitro group in 4-nitrophthalocyanine by the D,L-leucine fragment yields N-(3,4-dicyanophenyl)-D,L-leucine possessing a chiral site. This product was used to synthesize new symmetrical and asymmetrical phthalocyanines. Keywords: N-(3,4-dicyanophenyl)-D,L-leucine, D,L-leucine, phthalocyanine. The synthesis and study of phthalocyanines possessing an 18-electron macrosystem and displaying unique properties is a rapidly developing field in the chemistry of macroheterocyclic compounds. Promising research in this field involves the synthesis of asymmetrically substituted phthalocyanines and study of these compounds for application in nonlinear optics, thin-film electronics, and liquid crystals [1-8]. There is no information in the literature on the synthesis and properties of phthalocyanines containing covalently bonded residues of natural products, especially, amino acids. A nonconventional approach to deciphering DNA sequences involves use of porphyrins modified with a short peptide chain specific for precisely determined sites in the intercalation region as anchor structures [9]. Thus, for example, leucine and isoleucine can bind by means of van der Waals forces to the methyl group of thymine [10]. All amino acids can bind nonspecifically by means of ionic interactions with the frame of the DNA molecule. On the other hand, porphyrins with amino acid residues have been studied extensively for use in photodynamic cancer therapy [11] as in model systems with intermolecular electron transfer [12]. N-(3,4-Dicyanophenyl)-D,L-leucine (1) was used to synthesize 4-(N-D,L-leucyl)-8,11,15,18,22,25hexa(pentyloxy)phthalocyanine (2) of the A3B type where A is an isoindole fragment with two OC5H11 fragments and B is an analogous fragment with substituent X and the nickel complex of tetra-(N-D,Lleucyl)phthalocyanine (3). Starting dinitrile 1 was obtained by the nucleophilic substitution of the nitro group in 4-nitrophthalonitrile (4) upon the reaction of this nitro derivative with D,L-leucine in DMF in the presence of freshly roasted potassium carbonate (Scheme 1). Dinitrile 1 was purified by column chromatography. The composition and structure of this product were supported by elemental analysis and IR spectroscopy. The IR spectra of 1 were taken for KBr pellets and nujol suspensions, which permitted reliable determination of the stretching bands of the various bonds and the groups participating in intermolecular hydrogen bonding characteristic for amino acids. We should note that, in comparison with the spectra of nitrophthalodinitrile 4, the spectra of dinitrile 1 lack bands corresponding to asymmetric and symmetric __________________________________________________________________________________________ Ivanovo State University of Chemistry and Technology, 153460 Ivanovo, Russia; e-mail: ttos@isuct.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 564-570, April, 2004. Original article submitted June 15, 2001; revision submitted June 4, 2002. 0009-3122/04/4004-04692004 Plenum Publishing Corporation 469
Scheme 1
O2N CN CN 4 OC5H11 CN XH DMF, K2CO3 1 X CN CN
, C5H11OH
, 190200 oC
CN OC5H11 5 (C H O) Mg 5 11 2
(AcO)2Ni . 2H2O
X H11C5O N NH N H11C5O 2 X = D,L-NHCH(COOH)Bu-i N N OC5H11 N HN N OC5H11 OC5H11 X N N N N Ni N N N N X
OC5H11 X 3
stretching of the N=O bonds (at 1540 and 1336 cm-1) but display the CN band at 2224 cm-1. The spectra of 1 also have a series of new bands, primarily, a band at 1718 cm-1 corresponding to stretching of the carboxyl C=O bond and also bands at 3460 and 3320 cm-1 (in the spectrum of the nujol suspension) for stretching of the amino acid OH and NH fragments. The broadening and displacement of these bands toward lower frequencies indicates the participation of these groups in intermolecular hydrogen bonding [13]. Furthermore, new bands are found in the spectrum taken for a KBr pellet at 2960-2940 cm-1, corresponding to stretching of aliphatic CH fragments. The doublet at 1384 and 1320 cm-1 in this spectrum may be assigned to CMe groups [13], while the band at 1350 cm-1 may be assigned to stretching of CN bonds. Phthalocyanine 2 was obtained by random condensation upon heating dinitrile 1 and 3,6-di(pentyloxy)phthalodinitrile (5) in 1:5 mole ratio with an excess of magnesium 1-pentylate in 1-pentanol at reflux (see Scheme 1). After demetalation by treatment with acetic acid, the phthalocyanines were separated by column chromatography. The already reported symmetrical octa(pentyloxy)phthalocyanine [14] was not formed, as shown by the results of a control experiment involving the heating of dinitrile 5 under the same conditions in the absence of 1. A bright green zone was isolated when 1:1 benzeneCHCl3 was used as the eluent. Thin-layer chromatography indicated that this zone consisted of two phthalocyanine products 2 and an unknown impurity. Phthalocyanine 2 was isolated as a pure sample upon recrystallization from DMF. The structure of phthalocyanine 2 was indicated by its 1H NMR spectrum in CDCl3. The singlet for the CO2H group proton is at lowest field (9.1 ppm). The aromatic protons appear as multiplets at 8.2-7.8 ppm (for three protons of fragment B) and 7.8-7.3 ppm (for six protons of fragments A). The signals of the CH2 group protons are seen as four multiplets: at 4.8-4.6 ppm (four equivalent OCH2 groups), 4.9-3.9 ppm (two CH2 groups closest to fragment B), 3.7-3.4 ppm (CH2 group of the amino acid residue), and 2.4-1.4 ppm (other CH2 groups). 470
400 600 800 , nm Fig. 1. Electronic absorption spectra of 2: 1) solution in CHCl3 and 2) same solution with added pyridine.
The amino acid CH protons and eight CH3 groups are seen as a singlet at 3.1 ppm and multiplet at 1.2-0.7 ppm, respectively. The most significant differences are observed for the signals of the ring and amino acid NH protons. The ring NH protons are seen as a singlet shifted upfield (0.4 ppm) due to the shielding of the large ring. The amino acid NH group singlet is at much lower field (5.9 ppm), which, along with its broadened shape, indicates the participation of this group in hydrogen bonding. The electronic absorption spectrum of phthalocyanine 2 (Fig. 1) has three bands, two of which appear as inflections (763 and 712 nm). These bands account specifically for the green color of solutions of 2. The strongest band has a maximum at 790 nm, i.e., is found in the near-IR region. We should note that this band is shifted bathochromically by about 25 nm in comparison to the analogous band in the spectrum of the octa(pentyloxy)phthalocyanine reported by Dewar et al. [14] and dilute solutions of 2 do not obey the Lambert BouguerBeer law. This finding along with the 1H NMR spectral data indicate that phthalocyanine 2 is aggregated in solution due to intermolecular hydrogen bonding similar to starting dinitrile 1. In this regard, we carried AM1 quantum chemical calculations for 1 with full optimization of all geometrical parameters. Figure 2 shows the PLUTO representation of the dimer form of dinitrile 1. Dimer 6 is formed due to two bridging NHO=C hydrogen bonds with length 2.17 . The OHN bond angles are 161.22 and 165.57. The dimerization of 1 does not lead to a significant change in the geometry of this molecule but the hydrogen bonds are very strong, as found by comparing the enthalpies of formation of dinitrile 2 and dimer 6. In the former case, H0298 = -10.82 kcal/mol, while, in the latter, H0298 = -37.78 kcal/mol. Thus, 8.48 kcal/mol are expended on the formation of each hydrogen bond. We might assume that such dimerization is also characteristic for phthalocyanine 2. The following experiment was carried out to support this hypothesis. Salts are known to form upon the addition of bases such as pyridine to solutions of carboxylic acids, leading to destruction of the hydrogen bonds involving the carboxyl groups. This behavior would be expected for 2. However, the addition of a small amount of pyridine to a chloroform solution of 2 led to a significant drop in the strength of the band at longest wavelength at 792 nm in the electronic spectrum of this compound with a concurrent increase in intensity of the band at 731 nm assigned to absorption of the associated form of phthalocyanine 2 [16] (see Fig. 1). In chloroform solution, phthalocyanine 2 probably tends to dimerize due to the formation of intermolecular hydrogen bonds involving the carboxyl groups of the amino acid residue. The addition of pyridine to this solution leads to a pyridinium salt, which, as indicated by the change in the spectral curves, has a greater tendency to undergo intermolecular interactions due to both an increase in the molecular dipole moment as a whole (dipoledipole interaction) and the greater tendency of the salt to undergo -interactions of macroaromatic ring.
471
Fig. 2. PLUTO representation of dimer 6 of dinitrile 1 from an AM1 calculation. The synthesis of phthalocyanine 3 was carried out by a reported procedure employing the reaction of dinitrile 1 with nickel diacetate dihydrate at 190-200C, leading probably to formation of mixture of isomers differing in the position of the amino acid residue. Phthalocyanine 3 was purified by reprecipitation from sulfuric acid with subsequent washing with acetone in a Soxhlet apparatus. The composition and structure of this product were supported by elemental analysis and electronic spectroscopy. We should note that introduction of four amino acid fragments into the phthalocyanine molecule does not lead to a significant change in its spectrum. Two bands characteristic for the spectra of metal complexes of unsaturated phthalocyanine are seen in the electronic spectrum taken for a DMF solution. The position of the short-wavelength B-band (Soret band) at 334 nm is retained, while the long-wavelength Q-band, which is more sensitive to the nature of the substituents in the isoindole fragments of the macroheterocycle, is shifted bathochromically by 5 nm (maximum at 672 nm) and somewhat broadened, which indicates the existence of 3 as a mixture of isomers since band broadening is a characteristic of all tetrasubstituted phthalocyanines. Such a weak substituent effect on the electronic absorption spectra of phthalocyanine 3 results, in our view, from compensation of the electron-donor effect of the secondary amino group of the substituent by the electron-withdrawing effect of its carboxyl group and the substituent as a whole becomes electroneutral. Thus, in the case of D,L-leucine, nucleophilic substitution of the nitro group in 4-nitrophthalonitrile by the amino acid residue yields new chiral derivatives, which may be used for the synthesis of symmetrical and asymmetrical phthalocyanines.
EXPERIMENTAL
1
The electronic absorption spectra of the products were taken on a Hitachi UV-2000 spectrometer and the H NMR spectra were taken on a Bruker AM-200 spectrometer at 200 MHz. Samples of phthalodinitriles 4 and 5 were prepared according to reported procedures [14, 17] and were identified by elemental analysis and comparison of their melting points with the reported data.
472
A sample of 2,3-dicyanohydroquinone, required for the preparation of dinitrile 5, was obtained from Aldrich and used without further purification. N-(3,4-Dicyanophenyl)-D,L-leucine (1). A sample of D,L-leucine (0.76 g, 5.8 mmol) and K2CO3 (0.5 g) were added to a solution of dinitrile 4 (1 g, 5.8 mmol) in DMF (20 ml) and heated at reflux for 4 h with stirring. After cooling, water (50 ml) was added and the mixture was extracted with two 20-ml chloroform portions. The extract was evaporated to dryness. The residue was dissolved in benzene (30 ml) and subjected to chromatography on an alumina column using 1:1 benzeneCHCl3 as the eluent, collecting the first, light yellow zone. Evaporation of the eluate gave 0.32 g (21.5%) 1 as a light yellow powder; mp 148-151C. IR spectrum (nujol), , cm-1: 3460 (OH), 3320 (NH), 2223 (CN), 1718 (C=O), 1674 (C=N), 1600 (C=C), 1384, 1320 (C Me), 1092 (CC). Found, %: C 64.48; H 6.32; N 15.91. C14H15N3O2. Calculated, %: C 65.36; H 5.88; N 16.33. 4-(N-D,L-Leucyl)-8,11,15,18,22,25-hexa(pentyloxy)phthalocyanine (2). A sample of dinitrile 1 (0.2 g, 0.78 mmol) and 1,4-dipentoxyphthalonitrile 5 (1.17 g, 3.9 mmol) were added to a suspension of magnesium 1pentylate obtained by dissolving magnesium (0.5 g) in 1-pentanol (20 ml) and heated at reflux with stirring for 6 h. The solvent was evaporated off and the solid residue was dissolved in acetic acid (50 ml). The solution obtained was diluted with water (100 ml). The precipitate formed was filtered off, washed with water until the wash water was neutral, dried at 120C, and extracted with benzene. The extract was subjected to chromatography on an alumina column using 1:1 CHCl3benzene as the eluent, collecting the first bright green zone. The eluate was evaporated and the residue was recrystallized from 15 ml DMF to give 0.068 g (7.5%) 2 as green needles; mp 198-203C. 1H NMR spectrum (CDCl3), , ppm: -0.41 (2H, s, NH); 0.68-1.22 (24H, m, CH3); 1.43-2.44 (36H, m, CH2); 3.12 (1H, s, CH); 3.39-3.71 (2H, m, NCH2); 3.92-4.23 (4H, m, OCH2); 4.61-4.82 (8H, m, OCH2); 5.94 (1H, s, NH); 7.29-7.81 (6H, m, Harom); 7.83-8.24 (4H, m, Harom); 9.11 (1H, s, CO2H). UV spectrum (CHCl3), max, nm (log ): 790 (2.504), 763 (1.746), 731 (0.86), 461 nm (0.425); (CHCl3+Py), max, nm (log ): 793 (1.234), 731 (1.164), 460 (0.423). Found, %: C 70.12; H 7.88; N 10.93. C68H89N9O8. Calculated, %: C 70.36; H 7.73; N 10.87. Nickel Complex of Tetra-(N-D,L-leucyl)phthalocyanine (3). A thoroughly ground mixture of dinitrile 1 (0.2 g, 0.77 mmol) and nickel acetate dihydrate (0.06 g, 0.28 mmol) was maintained in a quartz test tube for 2 h at 190-200C. The reaction mixture was then dissolved in conc. sulfuric acid (10 ml). The solution obtained was poured into water (100 ml). The precipitate formed was filtered off, washed consecutively with 3% ammonium hydroxide, 3% aq. acetic acid, and water until the wash water was neutral. Then, the precipitate was dried at 120C. The dry precipitate was purified by extraction of impurities in a Soxhlet apparatus to give 0.11 g (55%) 3 as a blue powder, which does not melt up to 250C. UV spectrum (DMF), max, nm (log ): 672 (1.21), 612 sh (0.21), 335 (0.43). Found, %: C 61.17; H 5.77; N 14.98. C56H60N12O8Ni. Calculated, %: C 61.83; H 5.56; N 15.45.
REFERENCES 1. 2. 3. 4. 5. 6. 7. H. S. Nalva and S. Miyata (editors), Nonlinear Optics of Organic Molecules and Polymers, CRC Press, Boca Raton, Florida (1997). T. Yamada, H. Hoshi, K. Ishikawa, H. Takezoe, and A. Fukuda, Nonlinear Opt., 15, 131 (1996). M. A. DiazGarcia, J. M. Cabrera, F. AgulloLopez, J. A. Duro, G. de la Torre, T. Torres, F. FernandezLazaro, F. Delhaes, and C. Mingotaud, Appl. Phys. Lett., 69, 293 (1996). G. J. Bryant, M. J. Cook, M. J. Haslam, R. M. Richardson, T. G. Ryan, and A. J. Thorne, J. Mat. Chem., 4, 209 (1994). K. E. Treacher, G. J. Clarkson, and N. B. McKeown, Mol. Cryst. Liq. Cryst., 260, 255 (1995). E. V. Kudrik, I. U. Nikolaev, G. P. Shaposhnikov, N. V. Usol'tseva, and V. V. Bykova, Mendeleev Commun., 6, 222 (2000). G. de la Torre, P. Vazques, F. AgulloLopez, and T. Torres, J. Mater. Chem., 8, 1671 (1998). 473
8. 9. 10. 11. 12. 13. 14. 15. 16. 17.
Y. B. Shim, C. S. Jin, Z. Q. Feng, and K. Niki, Electroanalysis, 8, 1023 (1996). M. PerreeFauvet, K. VerchcreBeaur, E. Tarnaud, G. AnneheimHerbelin, N. Bone, and A. Gaudemer, Tetrahedron, 52, 13569 (1996). O. A. Golubchikov (editor), Advances in Porphyrin Chemistry [in Russian], St. Petersburg Gos. Univ., St. Petersburg, Russia (1999), p. 70. G. Kargianis, G. A. Reiss, and D. A. Scourides, Austral. J. Chem., 46, 1755 (1993).). S. E. Matthews, C. W. Pouton, and M. D. Thraadgi, J. Chem. Soc., Chem. Commun., 1809 (1995). J. Brand and G. Eglinton, Application of Spectroscopy in Organic Chemistry [Russian translation], Mir, Moscow (1967), p. 279. M. J. S. Dewar, E. G. Zoebisch, E. Healy, and J. J. P. Stewart, J. Am. Chem. Soc., 107, 3092 (1985). N. V. Usol'tseva, Lyotropic Liquid Crystals: Chemical and Superchemical Structure [in Russian], Izd. Ivanovsk. Gos. Univ., Ivanovo, Russia (1994), p. 66. W. Thiel and G. Knoth, J. Prakt. Chem., 328, 497 (1986). M. G. Cook, S. D. Dunn, S. D. Howe, and A. J. Thomson, J. Chem. Soc., Perkin Trans. 1, 2453 (1988).
474
SYNTHESIS AND ROTAMERISM OF 9,10-DIARYL-SUBSTITUTED 1,2,3,4,5,6,7,8,9,10-DECAHYDROACRIDINE-1,8-DIONES

V. A. Chebanov1, V. E. Saraev1, K. M. Kobzar'1, S. M. Desenko1, V. D. Orlov2, and E. A. Gura1 Condensation of aromatic aldehydes with 5,5-dimethylcylohexane-1,3-dione and primary arylamines gave 9,10-diaryl-3,3,6,6-tetramethyl-1,2,3,4,5,6,7,8,9,10-decahydroacridine-1,8-diones. Several stereochemical features of the synthesized compounds are discussed. Dynamic NMR was used to determine the inversion barriers for the rotamers formed. Keywords: diaryl-substituted decahydroacridinediones, heterocyclization, rotamerism. 9,10- Disubstituted decahydroacridine-1,8-diones are generally prepared through a Hanztsch synthesis with a wide variety of reaction conditions [1-5]. The synthesis of the target products consists of two stages: the reaction of cyclic ketones with aldehydes and the separation of the Michael adducts followed by their heterocyclization using primary amines. Moreover, the Michael adducts are quite readily cyclized to octahydroxanthones and the second stage of the reaction is almost always accompanied by the formation of quite large amounts of oxygen containing heterocycles. One of the problems in this work was the development of a single stage method for obtaining the target 9,10-disubstituted decahydroacridine-1,8-diones. Based on general and systematized data [1-8] and certain experimental data we propose a single stage method for the synthesis of diaryl substituted decahydroacridinediones which is more convenient to carry out and gives a higher yield of the final products than does the two stage. The procedure consists of the reaction of 5,5-dimethylcyclohexane-1,3-dione (1, dimedone) with the aldehydes 2a-i and the primary amines 3a-i. The selection of reaction conditions (in particular the solvent and the catalyst) appears to the most critical. The reactions in alcohols and slow boiling solvents is independent of the type of catalyst and gives difficult to separate mixtures of the reaction products and the starting materials. The use of the high boiling, polar DMF as solvent appears optimal. It was found that the basic catalysts given in the literature (triethylamine, N-methylmorpholine, piperidine) have little effect and the reaction products are mainly the Michael adducts 4. At the same time, a large amount of acid catalyst (acetic, trifluroacetic, hydrochloric acid) leads to a heavy contamination of the target compounds 5a-o by the xanthones 6. In the method proposed by us a small amount of concentrated hydrochloric acid is used.
__________________________________________________________________________________________
2
NTK Institute for Single Crystals, Kharkov 61001, Ukraine e-mail: chebanov@isc.kharkov.com. Kharkov National University, Kharkov 61077, Ukraine e-mail: orlov@univer.kharkov.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 571-576, April, 2004. Original article submitted October 23, 2002; revision submitted October 29, 2003. 0009-3122/04/4004-04752004 Plenum Publishing Corporation 475
O O Me Me 1 O + Ar H 2ai + R2
NH2 R1 3ai Ar DMF, AcOH,
OH Me Me
OH Me
OO 4ai
Me
O Me Me R2
Ar
O Me + Me
Ar
O Me
N R1 5ao
Me
Me
O 6ai
Me
2, 4, 6 a Ar = Ph; b Ar = 3-FC6H4; c Ar = 4-MeC6H4; d Ar = 4-BrC6H4; e Ar = 4-ClC6H4; f Ar = 4-O2NC6H4; g Ar = 2-MeO-5-BrC6H3; h Ar = 4-FC6H4; i Ar = 4-MeOOCC6H4; 3 ac,h,i R1 = H, a R2 = H, b R2 = 4-OEt, c R2 = 2-F, h R2 = 3-CO2H, i R2 = 3-F; d R1 = 6-F, R2 = 2-F; e R1 = 3-Cl, R2 = 2-Cl; f R1 = 4-Cl, R2 = 2-Cl; g R1 = 4-OMe, R2 = 2-OMe; 5 a-g,n,o R1 = H; a Ar = Ph, R2 = H, b Ar = 3-FC6H4, R2 = 4-OEt, cg R2 = 2-F, c Ar = Ph, d,l Ar = 4-MeC6H4, e Ar = 4-BrC6H4, f,i,k,m Ar = 4-ClC6H4, g Ar = 4-O2NC6H4, n Ar = 4-FC6H4, R2 = 3-CO2H, o Ar = 4-MeOOCC6H4, R2 = 3-F; h Ar = 2-MeO-5-BrC6H3, R1 = 6-F, R2 = 2-F; il R2 = 2-Cl, i, j R1 = 3-Cl, j Ar = 2-MeO-5-BrC6H3, k,l R1 = 4-Cl, m R1 = 4-OMe, R2 = 2-OMe
The composition and structure of the synthesized 9,10-diaryl-3,3,6,6-tetramethyl-1,2,3,4,5,6,7,8,9,10decahydroacridine-1,8-diones 5a-o were confirmed by elemental analytical data (Table 1) and by 1H NMR spectroscopy (Table 2). The reaction products 4a-i and 6a-i were not specifically separated from the reaction mixture but their presence was revealed using TLC and 1H NMR. Samples of compounds 4a-i and 6a-i were prepared for comparison by known methods [2-5]. The 1H NMR spectra of compounds 5a-o show singlets at 0.68 and 0.90 ppm which are assigned to the protons of the four methyl groups in positions 3 and 6, multiplets for the CH2 group protons of the cyclohexane rings in the range 1.42-2.40 ppm, a singlet for the methine proton at 4.93-5.28 ppm, and signals for the aromatic protons in the range 6.60-8.10 ppm, and also for the substitutent in Ar and R1, R2. At room temperature the spectra of the compounds 5c-g, i-m with one ortho substituent in NAr (R1 = H, 2-R2 H) show a doubling of virtually all of the signals, in particular the methine proton and the methyl group protons. This led us to infer the presence of two diastereomers differing in the relative orientation of the substituents Ar and R2 relative to the plane of the acridine framework, hence showing that the rotamers A and B have quite a high inversion barrier:
476
Ar
9 10
Ar
N R2
N R2 B
In order to verify this proposal we have studied the dependence of the 1H NMR spectra for the synthesized compounds on temperature. With a temperature increase we have found that the plotted doubling of the signals in the spectra of the acridinediones 5c-g, i-m is gradually lost until they coalesce completely. Measurement of the spectra at -60C for the acridinediones 5n,o (R1 = H and 3-R2 H) gives a doubling of the signals which is not seen at room temperature. In the case of compounds 5a,b an increase (from -60 to 160C) and lowering of the temperature does not affect the appearance of the spectrum. For compound 5h (2-R1 = 6-R2 H) the existence of rotamers is not possible and a doubling of signals is not observed in the temperature range indicated above. The dependence of the 1H NMR spectra of compounds 5c-g on temperature allowed an experimental determination of their energetic inversion barriers G1 in kJ/mol as 825 (5c,d), 826 (5e), 816 (5f), and 845 (5g). This high barrier is not typical of biphenyls and its hetero analogs [9]. In particular, they allow observation of doubled signals even for compounds 5n,o which contain the R2 substituent in a meta position.
TABLE 1. Parameters for Compounds 5a-o

Compound 5a 5b 5c 5d 5e 5f 5g 5h 5i 5j 5k 5l 5m 5n 5o Empirical formula C29H31NO2 C31H34FNO3 C29H30FNO2 C30H32FNO2 C29H29BrFNO2 C29H29ClFNO2 C29H29FN2O4 C30H30 BrF2NO3 C29H28Cl3NO2 C30H30BrCl2NO3 C29H28Cl3NO2 C30H31Cl2NO2 C31H34ClNO4 C30H30FNO4 C31H32FNO4 Found N, % Calculated N, % 3.21 3.29 2.82 2.87 3.15 3.16 3.10 3.06 2.62 2.68 3.01 2.93 5.72 5.70 2.50 2.46 2.61 2.65 2.40 2.32 2.71 2.65 2.81 2.75 2.73 2.69 2.91 2.87 2.83 2.79 mp, 209-210 219-221 192-194 178-179 212-214 275-276 273-274 262-264 274-275 260-262 280-281 248-250 229-230 305-308 268-270 Yield, % 67 92 78 58 62 69 89 75 70 76 62 80 68 55 81
477
478
TABLE 2. 1H NMR Spectra of Compounds 5a-o

Compound* 5a 5b 5c 5d 5e 5f 5g 5h 5i 5j 5k 5l 5m 5n 5o 4CH2 (8, m) 1.62-2.36 1.8-2.32 1.56-2.35 1.57-2.37 1.59-2.36 1.57-2.35 1.61-2.40 1.69-2.29 1.46-2.30 1.42-2.26 1.42-2.33 1.45-2.28 1.53-2.29 1.45-2.35 1.63-2.35 Chemical shift, , ppm (spin-spin coupling, J, Hz) CH Harom, m (s / two s) 5.06 5.05 5.01; 5.04 4.97; 5.00 4.97; 5.00 5.01; 5.02 5.14 5.10 5.00; 5.02 4.97; 5.28 4.98 5.02 4.93; 4.99 5.02 5.06 6.97-7.72 (10) 6.75-7.45 (8) 6.95-7.74 (9) 6.92-7.75 (8) 7.16-7.76 (8) 7.13-7.76 (8) 7.36-8.22 (8) 6.76-7.86 (6) 7.14-7.98 (7) 6.76-7.97 (6) 7.10-8.10 (7) 6.83-8.00 (7) 6.60-7.50 (7) 6.88-7.78 () 7.25-8.04 (8)
(CH3)2C*
R1, R2 1.37 (3, t, J = 7.3, H3) 4.01 (2, q, J = 7.3, CH2) 2.21 (3, s, H3) 3.77 (3, s, H3) 2.15 (3, s, H3) 3.80 and 3.84 (3, two s, OH3) 2.75 and 2.78 (3, two s, H3) 3.85 and 3.90 (3, two s, H3) 3.79 (3, s, OH3)
0.70; 0.87 0.72; 0.87 0.73; 0.88; 0.89; 0.72; 0.75; 0.89 0.72; 0.75; 0.89 0.71; 0.74; 0.88 0.72; 0.74; 0.90 0.76; 0.88 0.75; 0.88; 0.90 0.73; 0.86 0.73; 0.87; 0.89 0.71; 0.73; 0.86; 0.88 0.68; 0.73; 0.86 0.75; 0.89 0.68; 0.87
_______ * Compounds 5c-g, i-m are a mixture of rotamers. *2 Singlet signals observed with an overall intensity corresponding to 12 protons.
To explain the results obtained we have carried out a quantum-chemical analysis of the process of the conformational transformation of the rotamers. Calculation of equilibrium geometries and the geometry of the transition state using the AM1 method showed that the cyclohexanone ring sterically hinders the rotation of the aryl substituent around the CN bond. The high steric loading for compounds 5c-g, i-m infers that, in the process of the conformational transition, simultaneously with rotation of the 10-Ar substituent the dihydropyridine ring has to undergo a complete inversion. The initially planar disposition of bonds around the nitrogen atoms becomes pyramidal and the cyclohexanone rings are strongly distorted. A direct result of the occurrence of this combination of energetically unfavored processes is the high (~82 kJ/mol) barrier to inversion.
EXPERIMENTAL H NMR spectra were measured on a Varian Mercury VX-200 spectrometer (200 MHz) using DMSO-d6 solvent and TMS internal standard. The purity of the compounds prepared was monitored using TLC on Silufol UV-254 plates with chloroform, ethyl acetate or their mixture as solvent. Melting points were measured on a Koffler stage. The nitrogen content in the prepared compounds corresponded with that calculated (Table 1). Determination of the rotational barriers was carried out using an overall line shape method and its comparison with the practical, least squares numerical value as in the method [10]. To determine the effective time T2 in solution an equimolar amount of the corresponding 9-aryl-3,3,6,6-tetramethyl-2,3,4,5,6,7,8,9octahydro-1H-1,8-xanthenedione was added (for which T2 had been measured). Calculations were carried out on the methyl group signals. The obtained values for the rate of rotation constant were used for calculation of H and S as line shape coefficients in the Eyring equation. Quantum-chemical calculations were performed using the GAMESS program package [11]. The parameters for the different atoms used in the AM1 calculation method were taken from [12, 13]. 3,3,6,6-Tetramethyl-9,10-diphenyl-1,2,3,4,5,6,7,8,9,10-decahydroacridine-1,8-dione (5a). Two drops of concentrated hydrochloric acid were added to a solution of dimedone 1 (0.42 g, 3 mmol), benzaldehyde 2a (0.16 g, 1.5 mmol), and aniline (0.14 g, 3 mmol) in dry DMF (1 ml) and the mixture was refluxed for 3 h. The precipitate formed on cooling was filtered off and crystallized from aqueous ethanol (80%) to give compound 5a (0.43 g). Compounds 5b-o were prepared similarly from dimedone 1, the aldehydes 2b-i, and the amines 3b-i.
1
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11.
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M. W. Schmidt, K. K. Baldridge, J. A. Boatz, S. T. Elbert, M. S. Gordon, J. H. Jensen, S. Koseki, N. Matsunaga, K. A. Nguyen, S. J. Su, T. L. Windus, M. Dupuis, and J. A. Montgomery, J. Comput. Chem., 14, 1347 (1993). M. J. S. Dewar, E. G. Zoebisch, E. F. Healey, and J. J. P. Stewart, J. Amer. Chem. Soc., 107, 3902 (1985). M. J. S. Dewar and E. G. Zoebisch, Theorchem, 180, 1 (1988).
480
ACYLATION AND CYCLODEHYDRATION OF BENZOFURAN-, BENZOTHIOPHENE-, AND INDOLYL-3-ACETIC ACID ARYLAMIDES. SYNTHESIS OF NOVEL BENZOFURO[2,3-c]-, BENZOTHIENO[2,3-c], AND INDOLO[2,3-c]PYRILIUM AND PYRIDINE DERIVATIVES
S. V. Tolkunov, V. S. Tolkunov, and V. I. Dulenko The acylation of benzo[b]furan-, benzo[b]thiophene, and indolyl-3-acetic acid arylamides using acetic anhydride in the presence of 70% perchloric acid occurs at the -position of the heterocycle to give 2-acetylbenzo[b]furan-, 2-acetylbenzo[b]thiophene, and 2-acetylindolyl-3-acetic acid arylamides. Depending on the amount of perchloric used in the reaction they undergo cyclodehydration to 3-arylamino-1-methylhetero[2,3-c]pyrilium salts and to N-aryl-1-methyl-3(2H)hetero[2,3-c]pyridones. Keywords: 2-acetylbenzo[b]thiophene-3-acetic acid arylamides, 2-acetylbenzo[b]furan-3-acetic acid arylamides, 2-acetylindolyl-3-acetic acid arylamides, 3-arylamino-1-methylhetero[2,3-c]pyrilium, N-aryl-1-methyl-3(2H)hetero[2,3-c]pyridones, cyclodehydration. o-Acylation and subsequent dehydration of -oxoalkyl derivatives of aromatic and heterocyclic systems give condensed pyrilium salts [1]. This reaction has been used by us previously in the benzofuran, benzothiophene, and indole series [2-4]. The acylation and cyclodehydration of benzofuran-, benzothiophene-, and indolyl-3-acetic acid arylamides has not been studied previously. This reaction is of interest since the amides described above have two reactive nucleophilic centers (CO and NH) and hence acylation-cyclodehydration can occur by two routes to yield pyrilium salts and pyridine bases. We have studied the acylation of the arylamides of the benzo[b]furan-3-acetic acid 1a-e, benzo[b]thiophene-3-acetic acids 2a,b, and indolyl-3-acetic acids 3a-c in the system acetic anhydride70% perchloric acid with different perchloric acid content. The acylation takes place at the -position of the heterocycle. The intermediately formed 2-acetylheteryl-3-acetic acid arylamides 4-6 are cyclodehydrated to the corresponding 3-arylamino-1-methylpyrilium perchlorates 7-9. We have found that the yields of the pyrilium salts 7-9 depend on the amount of perchloric acid taken in the reaction. The maximal yields for the pyrilium salt (90%) are observed with a two fold excess of perchloric acid. It was interesting to find that the NH group in the 3-arylaminopyrilium salts is not acylated, even upon prolonged holding of compounds 7-9 in the acylating mixture.
__________________________________________________________________________________________ L. M. Litvinenko Institute of Physical Organic and Carbon Chemistry, National Academy of Sciences of Ukraine, Donetsk 83114; e-mail: tolkunov@uvika.dn.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 577-585, April, 2004. Original article submitted March 1, 2001. 0009-3122/04/4004-04812004 Plenum Publishing Corporation 481
CH2CONHAr R Ac2O X 1ae, 2a,b, 3ac HClO4
NHAr 4ae, 5a,b, 6ac Ac2O HClO4 R + X Me 7ae, 8a,b, 9ac O _ ClO4
O ArNH 2 R X 10ac Me O R X
CH2CONHAr O
HClO4
Me 4ae, 5a,b, 6ac
AcOH, TEA O
R X Me
Ar
11ae, 12a,b, 13ac

1, 4 = , R = 6-Me; a Ar = Ph, b Ar = 4-MeC6H4, c Ar = 4-ClC6H4, d Ar = 4-BrC6H4, e Ar = 4-CH3OC6H4; 2, 5, X = S, R = 5-Me, a Ar = 4-MeC6H4, b Ar = 4-MeOC6H4; 3, 6, 9 X = NH, R = H; a Ar = Ph; b Ar = 4-MeC6H4; c Ar = 4-MeOC6H4; 7, 11 X = O, R = 7-Me, a Ar = Ph, b Ar = 4-MeC6H4, c Ar = 4-ClC6H4, d Ar = 4-BrC6H4, e Ar = 4-CH2OC6H4; 8, 12 X = S, R = 6-Me, a Ar = 4-MeC6H4, b Ar = 4-MeOC6H4; 10 a X = O, R = 7-Me, b X = S, R = 6-Me, c X = NH, R = H; 13 X = NH, R = H; a Ar = Ph, b Ar = 4-MeC6H4, c Ar = 4-MeOC6H4
In contrast to the acylation of the benzo[b]furan-3-acetic acid arylamides 1a-e and the benzo[b]thiophene-3-acetic acid arylamides 2a,b that of the indolyl-3-acetic acid arylamides occurs with significant tarring. Since we could not prepare the corresponding pyrilium salts in the pure state, we carried out an alternative method for their synthesis consisting of the cyclization of the 2-acetylindolyl-3-acetic acid arylamides 6a-c in a mixture of acetic anhydride and 70% perchloric acid. The 2-acetylheteryl-3-acetic acid arylamides 4-6 were prepared by the reaction of the 1-methylhetero[2,3-c]pyrones 10a-c with anilines in DMF. Cyclodehydration of the keto amides 4a-e, 5a,b, 6a-c in an acylating mixture with an excess of 70% perchloric acid gave the corresponding pyrilium salts 7a-e, 8a,b, 9a-c in greater than 90% yield. The pyrilium perchlorates 7-9 synthesized by this method were identical to the pyrilium salts obtained by the acylation of the benzofuranand benzothiophene-3-acetic acid arylamides. The structure of the 3-arylamino-1-methylpyrilium perchlorates 7-9 was confirmed using elemental analytical analysis and from their 1H NMR spectra (Tables 1 and 2). A study of the cyclodehydration of the keto amides 4a-e, 5a,b, 6a-c in the acylating mixture with an equivalent amount of 70% perchloric acid showed that, along with the pyrilium salts 7a-e, 8a,b, 9a-c, the reaction mixture contained the corresponding N-aryl-1-methyl-3(2H)hetero[2,3-c]pyridones 11-13. Thus a chromatographic investigation of the composition of the reaction mixture (after separation of the pyrilium salt) showed that the product of cyclodehydration of the 2-acetyl-6-methyl-(4-methylphenyl)amide of benzo[b]furan3-acetic acid (4b) using 70% perchloric acid in acetic anhydride gave both the pyrilium salt 7b (yield 40%) 482

Compound 1 1a 1b 1c 1d 1e 2a 2b 3a 3b 3c 4a 4b 4c 4d 4e 5a 5b 6a 6b 6c 7a 7b 7c 7d 7e 8a 8b 9a Empirical formula 2 C17H15NO2 C18H17NO2 C17H14ClNO2 C17H14BrNO2 C18H17NO3 C18H17NOS C18H 17NO2S C16H14N2O C17H16N2O C17H16N2O2 C19H17NO3 C20H19NO3 C19H16ClNO3 C19H16BrNO3 C20H19NO4 C20H19NO2S C20H19NO3S C18H16N2O2 C19H18N2O2 C19H18N2O3 C19H16ClNO6 C20H18ClNO6 C19H15Cl2NO6 C19H15BrClNO6 C20H18ClNO7 C20H18ClNO5S C20H18ClNO6S C18H15ClN2O5 Found, % Calculated, % Hal N 4 5 6 5.79 5.70 6.21 6.13 4.62 4.71 4.29 4.10 5.67 5.80 5.70 5.80 5.67 5.50 5.57 5.64 6.21 6.10 5.67 5.75 5.63 5.58 5.83 5.96 4.63 4.72 4.12 4.18 5.56 5.68 5.53 5.68 5.35 5.42 5.67 5.52 6.02 5.92 5.74 5.63 4.24 4.14 4.58 4.49 3.68 3.56 3.37 3.23 4.48 4.32 4.48 4.32 4.02 4.16 4.17 4.03 11.65 11.83 23.38 23.21 10.45 10.37 20.56 20.69 5.32 5.28 5.15 5.01 4.55 4.67 4.21 4.07 4.59 4.74 4.51 4.74 4.61 4.50 11.31 11.19 10.69 10.60 9.83 9.99 4.41 4.56 4.21 4.36 4.17 4.10 3.67 3.63 4.25 4.15 4.21 4.15 4.10 3.96 9.42 9.58 9.03 9.14 8.78 8.69 3.45 3.59 3.57 3.47 3.44 3.30 3.14 2.99 3.28 3.34 3.25 4.34 3.15 3.21 7.51 7.47 mp, S 7 10.69 10.85 10.56 10.30 9.36 9.50 9.26 9.07 7.58 7.64 7.28 7.36 8 159-160 149-150 172-173 180-181 173-174 157-158 171-172 186-187 187-188 184-185 187-188 173 175-176 192-193 193 205-206 198-200 235-237 229-230 224-225 224-225 (with dec.) 240 (with dec.) 227-228 (with dec.) 248-249 (with dec.) 223-224 (with dec.) 240 (with dec.) 232-233 (with dec.) 235 (with dec.) Rf 9 0.55 0.75 0.81 0.64 0.57 0.93 0.86 0.42 0.43 Yield, % (method) 10 75 (A), 77 (B) 76 (A), 76 (B) 70 (A), 75(B) 76 (A), 75 (B) 67 (A), 68 (B) 65 (A) 67 (B) 63 (A), 69 (B) 75 (B) 80 (B) 78 (B) 88 95 80 83 93 80 87 95 98 93 90 86 83 90 85 90 97 80
3 76.80 76.96 77.28 77.40 68.00 68.12 59.15 59.32 73.00 73.20 73.05 73.19 69.62 69.43 77.56 76.78 77.38 77.25 72.65 72.84 74.37 74.25 74.86 74.75 66.85 66.77 58.95 59.08 71.36 71.20 71.28 71.19 67.81 67.97 73.81 73.96 74.40 74.49 70.65 70.79 58.51 58.55 59.43 59.49 53.67 53.79 48.56 48.69 57.34 57.22 57.32 57.21 55.23 55.11 57.55 57.69
9.11 9.10 8.69 8.78 16.63 16.71 17.13 17.05 8.35 8.44 8.38 8.44 8.21 8.13 9.33 9.46
483
TABLE 1 (continued)
1 9b 9c 10a 10b 10c 10d 10e 11a 11b 12a 12b 12c 13a 13b 2 C19H17ClN2O5 C19H17ClN2O6 C19H15NO2 C20H17NO2 C19H14ClNO2 C19H14BrNO2 C20H17NO3 C20H17NOS C20H17NO2S C18H14N2O C19H16N2O C19H16N2O2 C13H10O3 C13H10O2S 3 58.76 58.69 56.29 56.38 78.73 78.87 79.25 79.19 70.33 70.48 61.83 61.97 75.37 75.22 75.06 75.20 71.45 71.62 78.65 78.81 79.26 79.14 75.14 74.98 72.78 72.89 67.71 67.80 4 4.52 4.41 4.15 4.23 5.35 5.23 5.47 5.65 4.23 4.36 3.98 3.83 5.51 5.37 5.49 5.36 5.04 5.11 5.27 5.14 5.68 5.59 5.47 5.30 4.63 4.71 4.44 4.38 5 8.98 9.12 8.91 8.76 10.78 10.95 21.61 21.70 6 7.13 7.20 7.10 6.92 4.66 4.84 4.57 4.62 4.45 4.33 3.68 3.80 4.27 4.39 4.52 4.38 4.31 4.18 10.34 10.21 9.56 9.71 9.18 9.20 7 8 9 10 90 96 100 100 100 100 100 100 100 100 100 100 100 100
254-255 (with dec.) 233-234 (with dec.) 192-193 0.36 193-194 226-227 229-230 0.33 0.45 0.38 0.31 0.27 0.41 0.32 0.50 0.44
191-192
9.95 214-215 10.04 9.42 254-255 9.56 (with dec.) 284-285 (with dec.) 290 (with dec.) 288-289 (with dec.) 160 13.85 13.92 187-188
together with 16.5% of the starting keto amide 4b and 26% of the 1,7-dimethyl-2-N-(4-methylphenyl)3(2H)benzofuro[2,3-c]pyridone (11b). The alternative direction of cyclodehydration of the keto amides 4-6 is achieved by heating them in acetic acid in the presence of triethylamine. In this way the N-aryl-1-methyl3(2H)hetero[2,3-c]pyridones 11-13 are formed in good yields.
EXPERIMENTAL H NMR spectra were taken on a Gemini-200 instrument (200 MHz) using DMSO-d6 as solvent and TMS as internal standard. Monitoring of the purity of the products obtained was carried out using TLC on Silufol UV-254 plates and the system tolueneethanol (4:1). Analysis of the reaction products was performed by HPLC on a Laboratory pristroje chromatograph (Prague) with an RIDK-102 differential refractometer detector and 3 150 mm column using Separon C18 stationary phase and methanolwater (7:3) mobile phase. The parameters for the compounds synthesized are given in Tables 1 and 2. 6-Methylbenzo[b]furan-3-acetic acid and 5-methylbenzo[b]thiophene-3-acetic acids were prepared by the methods [5, 6]. Preparation of the Arylamides (1a-e, 2a,b, 3a-c) (General Method). A. Pyridine (1 ml) and the corresponding arylamine (0.01 mol) were added with cooling to a benzene solution (20 ml) of the 6-methylbenzo[b]furan-3-acetic acid chloride or 5-methylbenzo[b]thiophene-3-acetic acid chloride which had been obtained from the corresponding acid (0.01 mol) and PCl5 by the standard method. The product was held at room temperature for 4 h. The precipitate was filtered off and washed with aqueous alcohol and hexane. Crystallization from isopropanol gave the arylamides 1a-e, 2a,b. 484
1
TABLE 2. 1H NMR Spectra of Compounds Synthesized

Compound 1 1a Chemical shift, , ppm (spin spin coupling, J, Hz) R, substituent in Ar (3H, s) (3, s) 2 2.41 (6-3) CH3 (3, s) 3 CH2 (2, s) 4 3.73 arom. in Het 5 7.08 ( 1, d, J = 8.0, 5-); 7.37 (1, s, 2-); 7.54 (1, d, J = 8.0, 4-); 7.81 (2, s, 7-) 7.14 ( 1, d, J = 8.0, 5-); 7.36 (1, s, 2-); 7.56 (1, d, J = 8.0, 4-); 7.80 (1, s, 7-) 7.08 (1, d, J = 8.0, 5-); 7.36 (1, s, 2-); 7.60 (1, d, J = 8.0, 4-); 7.81 (1, s, 7-) 7.08 (1, d, J = 8.0, 5-); 7.37 (1, s, 2-); 7.57 (1, d, J = 8.0, 4-); 7.81 (1, s, 7-) 7.08 (1, d, J = 8.0, 5-); 7.36 (1H, s, 2-); 7.54 (1, d, J = 8.0, 4-); 7.80 (1, s, 7-) 7.20 (1, d, J = 8.2, 6-); 7.53 (1, s, 2-); 7.69 (1, s, 4-); 7.83 (1, d, J = 8.2, 7-) 7.21 ( 1, d, J = 8.2, 6-); 7.53 (1, s, 2-); 7.70 (1, s, 4-); 7.85 (1, d, J = 8.2, 7-) arom. in Ar 6 7.00 (1, t, J = 8.0, 4'-); 7.28 (2, t, J = 8.0, 3',5'-); 7.60 (2, d, J = 8.0, 2',6'-) 7.04 (2, d, J = 8.0, 3',5'-); 7.52 (2, d, J = 8.0, 2',6'-) 7.34 (2, d, J = 8.0, 2',6'-); 7.61 (2, d, J = 8.0, 3',5'-) 7.52 (2, d, J = 8.0, 2',6'-); 7.54 (2, d, J = 8.0, 3',5'-) 6.87 (2, d, J = 8.9, 3',5'-); 7.51 (2, d, J = 8.9, 2',6'-) 7.09 (2, d, J = 8.2, 3',5'-); 7.48 (2, d, J = 8.2, 2',6'-) 6.88 (2, d, J = 8.6, 3',5'-); 7.51 (2, d, J = 8.6, 2',6'-) NH (NH in Het); (1, s) 7 10.12
1b 1c 1d 1e 2a 2b
2.20 (4'-3); 2.42 (6-3) 2.42 (6-3) 2.40 (6-3) 2.41 (6-3); 3.71 (4'-O3) 2.23 (4'-3); 2.42 (5-3) 2.43 (5-3); 3.71 (4'-O3)
3.71 3.72 3.72 3.68 3.86 3.85
10.06 10.37 10.41 10.12 10.14 10.11
485
486
TABLE 2 (continued)
1 3a 2 3 4 3.69 5 6.98 (1, t, J = 7.5, 6-); 7.07 ( 1, t, J = 7.5, 5-); 7.24 (1, d, J = 2.0, 2-); 7.36 (1, d, J = 8.0, 7-); 7.62 (1, d, J = 8.0, 4-) 6.98 (1, t, J = 7.5, 6-); 7.07 ( 1, t, J = 7.5, 5-); 7.24 (1, d, J = 2.0, 2-); 7.36 (1, d, J = 8.0, 7-); 7.62 (1, d, J = 8.0, 4-) 6.98 (1, t, J = 7.5, 6-); 7.07 (1, t, J = 7.5, 5-); 7,24 (1, d, J = 2.0, 2-); 7.35 (1, d, J = 8.0, 7-); 7.61 (1, d, J = 8.0, 4-) 7.17 (1, d, J = 8.0, 5-); 7.47 (1, s, 7-); 7.68 (1, d, J = 8.0, 4-) 7.14 ( 1, d, J = 8.0, 5-); 7.45 (1, s, 7-); 7.66 (1, d, J = 8.0, 4-) 7.18 (1, d, J = 8.1, 5-); 7.36 (1, s, 7-); 7.70 (1, d, J = 8.1, 4-) 7.16 (1, d, J = 8.1, 5-); 7.40 (1, s, 7-); 7.70 (1, d, J = 8.1, 4-) 7.16 (1, d, J = 8.1, 5-); 7.44 (1, s, 7-); 7.66 (1, d, J = 8.1, 4-) 7.38 ( 1, d, J = 8.3, 6-); 7.86 (1, d, J = 8.3, 7-); 7.92 (2, s, 4-) 7.37 ( 1, d, J = 8.4, 6-); 7.84 (1, d, J = 8.4, 7-); 7.90 (1, s, 4-) 6 7.10 (1, t, J = 8.0, 4'-); 7.30 (2, t, J = 8.0, 3',5'-); 7.56 (2, d, J = 8.0, 2',6'-) 7.09 (2, d, J = 8.4, 3',5'-); 7.53 (2, d, J = 8.4, 2',6'-) 6.85 (2, d, J = 9.0, 3',5'-); 7.51 (2, d, J = 9.0, 2',6'-) 7.02 (1H, t, J = 8.0, 4'-); 7.27 (2, t, J = 8.0, 3',5'-H); 7.57 (2H, d, J = 8.0, 2',6'-H) 7.04 (2, d, J = 8.0, 3',5'-); 7.42 (2, d, J = 8.0, 2',6'-) 7.34 (2, d, J = 8.0, 2',6'-); 7.61 (2, d, J = 8.0, 3',5'-) 7.34 (2, d, J = 8.0, 2',6'-); 7.55 (2, d, J = 8.0, 3',5'-) 6.82 (2, d, J = 8,9, 3',5'-); 7.46 (2, d, J = 8.9, 2',6'-) 7.08 (2, d, J = 8.0, 3',5'-); 7.46 (2, d, J = 8.0, 2',6'-) 6.86 (2, d, J = 8.8, 3',5'-); 7.44 (2, d, J = 8.8, 2',6'-) 7 9.95 (10.92) 9.95 (10.92) 9.93 (10.90) 10.16
3b
2.20 (4'-3)
3.69
3c
3.70 (4'-O3)
3.69
4a
2.46 (6-3)
2.57
4.19
4b 4c 4d 4e 5a 5b
2.20 (4'-3); 2.42 (6-3) 2.45 (6-3) 2.45 (6-3) 2.48 (6-3); 3.71 (4'-OCH3) 2.22 (4'-3); 2.43 (5-3) 2.43 (5-3); 3.70 (4'-O3)
2.53 2.56 2.57 2.57 2.61 2.61
4.15 4.12 4.12 4.14 4.36 4.32
10.06 10.37 10.20 9.95 10.19 10.15
TABLE 2 (continued)
1 6a 2 3 2.63 4 4.18 5 7.04 (1, t, J = 8.0, 6-); 7.24 (1, t, J = 8.0, 5-); 7.46 (1, d, J = 8.0, 7-); 7.75 (1, d, J = 8.0, 4-) 7.06 (1, t, J = 8.0, 6-); 7.28 (1, t, J = 8.0, 5-); 7.46 (1, d, J = 8.0, 7-); 7.75 (1, d, J = 8.0, 4-) 7.07 (1, t, J = 8.0, 6-); 7.29 (1, t, J = 8.0, 5-); 7.45 (1, d, J = 8.0, 7-); 7.75 (1, d, J = 8.0, 4-) 7.45 (1, d, J = 8.0, 6-); 7.48 (1, s, 8-); 7.58 (1, s, 4-); 8.29 (1, d, J = 8.0, 5-) 7.40 (1, d, J = 8.0, 6-); 7.61 (2, m, 4,8-); 8.34 (1, d, J = 8.0, 5-) 7.36 (1, d, J = 8.0, 6-); 7.47 (1H, s, 8-); 7.60 (1, s, 4-); 8.31 (1, d, J = 8.0, 5-) 7.49 (1, d, J = 8.0, 7-); 7.75 (1, s, 4-H); 8.07 (1, d, J = 8.0, 8-); 8.44 (1, s, 5-) 7.46 (1, d, J = 8.0, 7-); 7.70 (1, s, 4-); 8.00 (1, d, J = 8.0, 8-); 8.36 (1, s, 5-) 7.21 (1, t, J = 8.0, 7-); 7.31 (1, d, J = 8.0, 8-); 7.60 (1, s, 4-); 7.73 (1, t, J = 8.0, 6-); 8.31 (1, d, J = 7.8, 5-) 7.21 (1, t, J = 8.0, 7-); 7.49 (1, d, J = 8.0, 8-); 7.56 (1, s, 4-); 7.74 (1, t, J = 8.0, 6-); 8.31 (1, d, J = 7.8, 5-) 6 7.10 (1, t, J = 8.0, 4'-); 7.30 (2, t, J = 8.0, 3',5'-); 7.56 (2, d, J = 8.0, 2',6'-) 7.08 (2, d, J = 8.0, 3',5'-); 7.46 (2, d, J = 8.0, 2',6'-) 6.85 (2, d, J = 8.7, 3',5'-); 7.48 (2, d, J = 8.7, 2',6'-) 7.34 (2, d, J = 8.0, 3',5'-); 7.45 (2, d, J = 8.0, 2',6'-) 7.61 (4, m, 2',3',5',6'-) 7.10 (2, d, J = 8.8, 3',5'-); 7.49 (2, d, J = 8.8, 2',6'-) 7.40 (2, d, 3',5'- J = 8.0); 7.54 (2, d, J = 8.0, 2',6'-) 7.10 (2, d, J = 8.6, 3',5'-H); 7.50 (2, d, J = 8.6, 2',6'-) 7.457.53 (5H, m, 2',3',4',5',6-H) 7 10.07, (10.64) 10.07, (10.64) 10.03 (11.62) 12.23 12.38 12.19 12.38 12.25 11.56 (11.85) 11.59 (11.90)
6b 6c 7b 7c 7e 8a 8b 9a
2.22 (4'-3) 3.70 (4'-O3) 2.35 (4'-3); 2.50 (7-3) 2.54 (7-3) 2.52 (7-3); 3.80 (4'-3) 2.41 (4'-3); 2.52 (6-3) 2.46 (6- 3); 3.81 (4'-3)
2.63 2.63 2.74 2.79 2.74 2.81 2.75 2.91
4.18 4.16
9b
2.34 (4'-3)
2.86
7.29 (2, d, J = 8.6, 3',5'-); 7.42 (2, d, J = 8.6, 2',6'-)
487
488
TABLE 2 (continued)
1 10a 10b 11a 11b 11c 11d 11e 12a 12b 13b 2 2.42 (7-3) 2.40 (6-3) 2.48 (7-3) 2.39 (4'-3); 2.47 (7-3) 2.46 (7-3) 2.47 (7-3) 2.45 (7-3); 3.81 (4'-3) 2.38 (4'-3); 2.42 (6-3) 2.43 (6-3); 3.82 (4'-3) 2.36 (4'-3) 3 2.42 2.40 2.12 2.10 2.10 2.11 2.09 2.08 2.12 2.14 4 5 6.56 (1, s, 4-H); 7.50 (1, s, 8-); 7.61 (1H, d, J = 8.2, 6-H); 7.93 (1, d, J = 8.2, 5-H) 6.78 (1, s, 4-H); 7.42 (1, d, J = 8.2, 7-); 7.63 (1H, d, J = 8.2, 8-H); 7.96 (1, s, 5-H) 6.74 (1, s, 4-); 7.14 (1, d, J = 8.0, 6-); 7.59 (1, s, 8-H); 7.88 (1, d, J = 8.0, 5-) 6.80 (1, s, 4-); 7.19 (1, s, 8-H); 7.34 (1, d, J = 8.0, 6-); 7.94 ( 1, d, J = 8.0, 5-) 6.82 (1, s, 4-); 7.17 (1, d, J = 8.0, 6-); 7.39 (1, s, 8-); 7.95 (1, d, J = 8.0, 5-) 6.83 (1, s, 4-); 7.18 (1, d, J = 8.0, 6-); 7.39 (1, s, 8-) 7.95 (1, d, J = 8.0, 5-) 6.79 (1, s, 4-); 7.16 (1, d, J = 7.8, 6-); 7.37 (1, s, 8-); 7.94 ( 1, d, J = 7.8, 5-) 7.10 (1, s, 4-); 7.38 (1, d, J = 8.0, 7-H); 7.72 (1, d, J = 8.0, 8-); 8.02 (1, s, 5-) 7.03 (1, s, 4-); 7.42 (1, d, J = 8.0, 7-); 7.76 (1, d, J = 8.0, 8-); 8.04 (1, s, J = 8.0, 5-) 6.82 (1, s, 4-); 7.00 (1, t, J = 8.0, 7-); 7.25 (1, d, J = 8.0, 8-); 7.44 (1, t, J = 8.0, 6-); 7.87 (1, d, J = 8.0, 5-) 6.87 (1, s, 4- ); 7.03 (1, t, J = 7.6, 7-); 7.29 (1, d, J = 8.0, 8-); 7.48 (1, t, J = 7.6, 6-); 8.02 (1, d, J = 8.0, 5-) 6 7.24-7.55 (5H, m, 2',3',4',5',6'-H) 7.16 (2, d, J = 8.0, 3',5'-); 7.34 (2, d, J = 8.0, 2',6'-) 7.37 (2, d, J = 8.6, 3',5'-); 7.61 (2, d, J = 8.6, 2',6'-) 7.31 (2, d, J = 7.5, 3',5'-); 7.75 (2, d, J = 7.5, 2',6'-) 7.06 (2, d, J = 8.4, 3',5'-); 7.20 (2, d, J = 8.4, 2',6'-) 7.15 (2, d, J = 8.0, 3',5'-); 7.33 (2, d, J = 8.0, 2',6'-) 7.10 (2, d, J = 8.8, 3',5'-); 7.22 (2, d, J = 8.8, 2',6'- ) 7.10 (2, d, J = 8.0, 3',5'-); 7.29 (2, d, J = 8.0, 2',6'-) 7.08 (2, d, J = 8.8, 3',5'-); 7.20 (2, d, J = 8.8, 2',6'-) 7 (10.41)
13c
3.84 (4'-3)
2.20
(10.53)
B. Carbonyldiimidazole (1.62 g, 0.01 mol) was added to a solution of the corresponding heteryl-3-acetic acid (0.01 mol) in anhydrous dioxane. The solution was stirred for 1.5 h at room temperature and the arylamine (0.01 mol) was added. The mixture was stirred for 4 h and poured into a 5% aqueous solution of NaHCO3 (50 ml). The precipitated crystals were filtered off, washed with water, and crystallized from isopropanol to give the arylamides 1a-e, 2a,b, 3a-c. Preparation of the Pyrilium Salts (7a-e, 8a,b, 9a-c) (General Method). Perchloric acid (70%, 2 ml) was added with cooling to a solution of the arylamides 1a-e, 2a,b or the corresponding keto amide 4-6 (0.01 mol) in acetic anhydride (10 ml). The mixture was held at room temperature for 2 h. The precipitate formed was filtered off, washed with acetic acid and then water, dried, and crystallized from acetic acid to give the pyrilium salts 7a-e, 8a,b, 9a-c. 1,7-Dimethylbenzofuro[2,3-c]-3-pyrone (10a) was prepared from 1,7-dimethyl-3-hydroxybenzofuro[2,3-c]pyrilium fluoroborate [7] by a method similar to that for 10c [8]. 1,6-Dimethylbenzothieno[2,3-c]-3-pyrone (10b) was prepared from 1,6-dimethyl-3hydroxybenzothieno[2,3-c]pyrilium fluoroborate [7] by a method similar to that for 10c [8]. Preparation of 2-Acetylheteryl-3-acetic Acid Arylamides (4a-e, 5a,b, 6a-c) (General Method). The arylamine (0.15 mol) was added to a solution of the pyrone 10a (0.01 mol) in isopropanol (for pyrones 10b,c in DMF). The mixture was refluxed for 0.5 h (for 10b,c refluxed for 2 h), cooled, and poured into water. The precipitate formed was filtered off, washed with water, and dried to give the arylamides 4a-e, 5a,b, 6a-c. Compounds 4a-e were crystallized from isopropanol and 5a,b, 6a-c were crystallized from aqueous DMF. Preparation of N-Aryl-1-methyl-3(2H)hetero[2,3-c]pyrid-3-ones (11a-e, 12a,b, 13a-c) (General Method). Triethylamine (0.05 mol) was added to a solution of the 2-acetylheteryl-3-acetic acid arylamides 4a-e, 5a,b, 6a-c (0.01 mol) in acetic acid. The mixture was refluxed for 1.5 h, cooled, poured into water, and a solution of ammonia was added to pH 7. The precipitate was filtered off, washed with water, dried, and crystallized from alcohol to give the pyridones 11a-e, 12a,b, 13a-c.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. Y. P. Stradyn', Khim. Geterotsikl. Soedin., 1412 (1981). V. I. Dulenko, S. V. Tolkunov, and N. N. Alekseev, Khim. Geterotsikl. Soedin., 1351 (1981). V. I. Dulenko, S. V. Tolkunov, and N. N. Alekseev, Khim. Geterotsikl. Soedin., 37 (1983). V. I. Dulenko and S. V. Tolkunov, Khim. Geterotsikl. Soedin., 889 (1987). B. B. Dey and Y. Sankaranarayanan, J. Indian Chem. Soc., 687 (1934). F. Sauter and F. Ecker, Monats. Chem., 99, 610 (1968). S. V. Tolkunov, M. N. Kal'nitskii, and E. A. Zemskaya, Khim. Geterotsikl. Soedin., 1552 (1991). H. Pleninger, W. Muller, and K. Weinerth, Chem. Ber., 97, 667 (1964).
489
CONDENSATION OF 1-AMINO4-AZAFLUORENE WITH -DIKETONES AND ,-UNSATURATED KETONES

A. V. Varlamov, A. N. Levov, F. Toze, and A. I. Chernyshev Condensation of 1-amino-4-azafluorene with -diketones and with unsaturated ketones in basic medium gives novel substituted 1,4-diazafluoranthenes and also dihydro-4-azafluoreno[9,9a,1-b,c]cyclohexano[2',3'-e]- and indano[1',2'-e]azepines. Keywords: 4-azafluorenocyclohexanoazepines, 1-amino-4-azafluorene, diazafluoranthenes, -diketone, unsaturated ketones. We have previously used the Chichibabin reaction to prepare 1-amino-4-azafluorene (1) and studied some of its chemical reactions [1]. Azafluorene 1, with an active methylene group in position 9 and an amino group in position 1, is a promising synthon for the construction of condensed nitrogen-containing compounds with a 4-azafluorene fragment, which are of interest for biological screening. In this communication we report the results of a study of the condensation of the azafluorene 1 with -diketones and chalcones, prepared from cyclic ketones. Condensation of azafluorene 1 with benzil, furil, and p-anisil in alcoholic medium (KOH in alcohol or sodium ethylate in alcohol) gives the 1,4-diazafluoranthenes 2-4.
O O N RCCR
3 2 1N
5 6
R R
NH2
10 9 8
24
2 R = Ph, 3 R = p-MeOC6H4, 4 R = 2-furyl
The low yields of diazafluoranthenes 2-4 (30-40%) are apparently associated with the fact that the -diketones can undergo a benzil rearrangement in these reaction conditions. The use of an excess of the -diketones does not have an effect on the yield of compounds 2-4 but complicates their separation. A similar condensation of compound 1 with acenapthoquinone gives the acenaphthodiazafluoranthene 5.
__________________________________________________________________________________________ Russian People's Friendship University, Moscow 117198; e-mail: avarlamov@sci.pfu.edu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 586-591, April, 2004. Original article submitted June 14, 2002. 490 0009-3122/04/4004-04902004 Plenum Publishing Corporation
O 1
O N
The condensation of the unsaturated ketones of 2,6-bisarylidenecyclohexanone and 2-benzylideneindan1-one with compound 1 was also carried out in basic medium in alcohol. The carbonyl group of the chalcone condensed with the methylene group of the azafluorene and the amino group adds to the double bond (Michael addition) to give the dihydroazepines 6-9 which are condensates of the 4-azafluorene with the cyclohexane or indane fragments.
O CHPh O 1 RHC CHR
+
3 2 1 4
N
5 6 7
NH Ph 9
H C R
12 11 10 13
NH CH R
68 6 R = Ph, 7 R = p-MeOC6H4, 8 R = 2-furyl
The IR spectra of compounds 6-9 show a broad stretching band for the NH group in position 8 in the range 3400-3200 cm-1 and this confirms the proposed cyclization scheme. The 1H NMR spectra of compounds 2-9 (Tables 1 and 2) show signals for all of the protons present in these molecules and the absence of signals for the C(9) methylene protons found in the spectrum of the starting material 1. The mass spectra of compounds 2-9 show strong molecular ion peaks corresponding to their empirical formulae. In the mass spectra of the diazafluoranthenes 4 and 5 the [M]+ ion peak is maximal whereas in the spectra of the 5,6-disubstituted compounds 2 and 3 it is the [M-H]+ ion peak and this is a feature of the dissociation of -phenyl-substituted azines [2]. The high aromaticity of the diazafluoranthene system is the reason of the small number of decomposition pathways. The basic route for fragmentation of the molecular ion peaks for compounds 3 and 4 is associated with the fission of methoxyphenyl and furyl radicals. For [M]+, compound 3 is characterized by elimination of the radicals CH3 and OCH3 and the formation of the fragments 401 (30) and 385 (25) respectively*. Successive elimination in the ion [M]+ of the radicals CHO and CO gives the fragments 307 (19) and 279 (34) respectively. The dissociation of the acenaphthenyl-substituted diazafluoranthene 5 is characterized by the loss of HCN (301 (14)) and breakup of the [M]+ in half to form the fragments 164 (40). _______ * Here and subsequently the values m/z (Irel, %) are quoted for the molecular ion peaks. 491
492

Compound 2 3 4 5 Chemical shift, , ppm (J, Hz)* 10- 8.06 8.06 8.03 (m, J109 = 7.6) 5-R, 6-R*2
2-, d 8.81 (J23 = 6.1) 8.79 (J23 = 5.1) 8.78 (J23 = 6.1) 8.83 (J23 = 6.1)
3-, d 7.78 (J32 = 6.1) 7.75 (J32 = 5.1) 7.77 (J32 = 6.1) 7.91 (J32 = 6.1)
7- 9- 7.0-7.5 7.0-7.5 7.20-7.47, m 7.65-8.74
7.0-7.5 7.36, 7.23 (o-H); 6.96, 6.79 (m-H); 3.89 (s, 23); 3.80 s 7.75 (d, J23 = 1.5, 2-H); 6.73 (dd, J34 = 3.1, 3-H); 6.44 (dd, J34' =3.7); 6.67 (d, J34 = 3.1, 4-H); 6.05 (d, J34' = 3.7) 7.65-8.74
_______ * The 1H NMR spectrum was recorded in CDCl3 at 30C (compounds 2-4) and DMSO-d6 at 40C (compound 5). *2 The furyl substituent signals are given for compound 4. TABLE 2. 1H NMR Spectra of Compound 6-9
Compound 6 7 Chemical shift, , ppm (J, Hz)* 1-, m 7.74*2 (J12 = 7.0) 7.73*2 (J12 = 7.0) 2-, m 3-, m 4-, m 7.89*2 (J34 = 7.0) 7.91*2 (J34 = 7.0) 6-, d 8.20 (J67 = 5.5) 8.19 (J67 = 5.8) 7-, d 6.50 (J67 = 5.5) 6.50 (J67 = 5.8) 9-, d 4.48*2 (J99 = 3.4) 4.42*2 (J99 = 3.1) 9-, d 4.43*2 (J99 = 3.4) 3.38*2 (J99 = 3.1) 10-; 11-; 12- 1.6-1.9; 2.3-2.7; 2.9-3.0, m 1.2-3.0, m RCH=, s 6.16 6.19 R 6.7-6.9, m; 7.3-7.5, m R = p-3OC6H4, 6.35 (m, o-H); 6. 93 (m, m-); 6.05, m; 7.25, m 7.41, 7.40 (dd, J23 = 1.8, 2-); 6.55 (dd, J23 = 1.8, 3-H); 5.93 (dd, J34' = 3.4, 4-H) 6.7-6.9, m; 7.15-7.50, m
6.7-6.9 7.3-7.5 7.2-7.5
7.8 7.72*2 (J12 = 7.0)
7.80
7.80
7.80 7.84*2 (J34 = 7.0)
8.12 (J67 = 5.8) 8.32 (J67 = 5.5)
6.96 (J67 = 5.8) 6.74 (J67 = 5.5)
5.20 (J99 = 3.1) 4.94*2 (J99 = 3.7)
4.63 (J99 = 3.1) 4.53 (J99 = 3.7)
1.6-1.8; 2.55-2.7, m 10-2 3.55, s
5.93
7.2-7.5
______ * The 1H NMR spectrum was recorded in CDCl3 at 30C (compounds 6,7,9) and DMSO-d6 at 40C (compound 8). *2 Possible reversal of assignments.
The breakdown of the [M]+ ions for the azepines 6-9 is characterized by the existence of several joint fragmentation routes (see Scheme 1) connected with the loss of the radicals H, CH2R, and R. Moreover, for the fission of CH2R and R, the charge is localized on both fragments. Hence the intensities of the ion peak for [CH2R]+ in the mass spectra of compounds 6-9 are 50, 100, 100, and 8% respectively. Scheme 1
N N
.CH2R
+ NH [ M CH2R ] + 6 m/z 347 (7%) 7 m/z 377 (7%) 8 m/z 337 (20%) 9 m/z 293 (30%) H NH R M+ 6 m/z 438 (98%) 7 m/z 498 (49%) 8 m/z 418 (41%) 9 m/z 384 (100%)
.
[ M H ]+ 6 m/z 437 (32%) 7 m/z 497 (18%) 8 m/z 417 (7%) 9 m/z 383 (30%)
R N + N [ M R ]+ 6 m/z 361 (100%) 7 m/z 391 (40%) 8 m/z 351 (2%) 9 m/z 307 (88%)
TABLE 3. Mass Spectra of Compounds 2-9

Compound 2 3 m/z (Irel, %) 365 [M]+ (51), 355 (100), 354 (8), 353 (11), 327 (2), 251 (2), 250 (1), 224 (2), 178 (6), 177 (10), 176 (2), 108 (3), 107 (4), 88 (4), 77 (3), 32 (4), 28 (8) 416 [M]+ (80), 415 (100), 401 (30), 385 (25), 372 (30), 358 (10), 342 (100), 329 (40), 303 (10), 213 (25), 201 (20), 187 (18), 171 (31), 164 (35), 151 (20), 133 (15), 103 (20), 90 (25), 77 (5), 63 (15), 51 (3), 33 (2) 336 [M]+ (100), 333 (4), 320 (13), 319 (63), 307 (19), 279 (34), 278 (14), 251 (4), 250 (3), 226 (2), 210 (1), 196 (1), 187 (9), 186 (4), 185 (3), 181 (1), 140 (9), 139 (6), 126 (4), 111 (2), 99 (2), 94 (6), 91 (4), 87 (3), 86 (2), 77 (2), 76 (1), 75 (2), 74 (2), 65 (3), 63 (3), 51 (3), 50 (2), 45 (3), 44 (1), 43 (2), 40 (1), 39 (8), 38 (3) 328 [M]+ (100), 327 (15), 273 (5), 164 (40), 150 (21), 149 (20), 137 (20), 136 (21), 124 (5), 100 (2), 74 (1), 55 (2) 438 [M]+ (98), 437 (32), 361 (100), 360 (12), 347 (7), 319 (2), 269 (6), 242 (1), 219 (4), 165 (6), 138 (5), 115 (11), 91 (61), 77 (10), 57 (7), 43 (60) 498 [M]+ (49), 497 (18), 391 (40), 380 (1), 377 (7), 351 (1), 350 (10), 269 (3), 255 (5), 240 (5), 218 (10), 197 (11), 196 (21), 182 (11), 153 (21), 135 (70), 121 (100), 108 (20), 91 (30), 77 (37), 65 (5), 55 (7), 39 (5) 418 [M]+ (41), 417 (7), 389 (10), 375 (1), 351 (2), 337 (25), 321 (5), 309 (10), 293 (10), 281 (10), 269 (11), 255 (15), 242 (10), 231 (15), 218 (10), 196 (15), 181 (40), 165 (60), 153 (40), 138 (50), 127 (30), 115 (30), 107 (20), 91 (50), 81 (100), 65 (30), 53 (50), 39 (51) 384 [M]+ (100), 383 (35), 307 (88), 306 (25), 293 (30), 281 (3), 254 (4), 236 (3), 217 (1), 203 (20), 184 (10), 164 (8), 153 (30), 138 (10), 115 (2), 91 (5), 77 (4), 43 (2)
5 6 7
493
EXPERIMENTAL H NMR spectra were recorded on a Bruker WP-200 spectrometer (200 MHz) with TMS as internal standard. IR spectra were obtained on an IR-75 spectrometer for KBr tablets. Mass spectra were recorded on a MAT-112 instrument with direct introduction of the sample into the ion source and an ionizing voltage of 70 eV. TLC was carried out on Silufol UV-254 plates (revealed using iodine vapor) and column chromatography on Woelm grade 32-63 silica gel. 5,6-Diphenyl-1,4-diazafluoranthene (2). A solution of sodium ethylate, prepared from Na (0.5 g, 21 mmol), and the azafluorene 1 (0.2 g, 1 mmol) in absolute alcohol (20 ml) was heated to 60C, benzil (0.21 g, 1 mmol) added, and refluxed for 2 h with monitoring by TLC. The alcohol was distilled off and the residue was transferred to a silica gel column (1.5 30 cm). A mixture of ethyl acetate and hexane (1:1) eluted the diazafluoranthene 2 (0.15 g, 42%), yellow crystals; mp 199-201C (ethyl acetatehexane), Rf 0.58 (ethyl acetate). Found, %: C 87.61; H 4.53; N 7.84; M+ 356. C26H16N2. Calculated, %: C 87.60; H 4.50; N 7.80; M 356. 5,6-Di(p-methoxyphenyl)-1,4-diazafluoranthene (3) was prepared similarly from anisil (0.70 g, 2.75 mmol) and the aminofluorene 1 (0.5 g, 2.75 mmol) in the presence of sodium ethylate prepared from Na (1.0 g, 42 mmol). Yield 0.26 g (22%), yellow crystals; mp 220-221C (ethyl acetatehexane ), Rf 0.57 (ethyl acetate). Found, %: C 80.71; H 4.81; N 6.74; M+ 416. C28H20N2O2. Calculated, %: C 80.70; H 4.80; N 6.73; M 416. 5,6-Di(2-furyl)-1,4-diazafluoranthene (4) was prepared similarly from furil (0.53 g, 2.75 mmol) and the aminofluorene 1 (0.5 g, 2.75 mmol) in the presence of sodium ethylate prepared from Na (1.0 g, 42 mmol). Yield 0.21 g (24%), yellow crystals; mp 196-198C (ethyl acetatehexane), Rf 0.50 (ethyl acetate). Found, %: C 78.61; H 3.61; N 8.35; M+ 336. C22H12N2O2. Calculated, %: C 78.60; H 3.60; N 8.34; M 336. 1,4-Diazaacenaphtho[1,2-f]fluoranthene (5) was prepared similarly to that reported above from acetonaphthoquinone (0.5 g, 2.75 mmol) and the azafluorene 1 (0.5 g, 2.75 mmol) in the presence of sodium ethylate prepared from Na (1.0 g, 42 mmol). Yield 0.28 g (35%), yellow crystals; mp 277-279C (ethyl acetate hexane), Rf 0.75 (ethyl acetate). Found, %: C 87.81; H 3.66; N 8.54; M+ 328. C24H12N2. Calculated, %: C 87.80; H 3.65; N 8.53; M 328. 13-Benzylidene-9-phenyl-4-aza-9,9a-dihydrofluoreno[9,9a,1-b,c]cyclohexano[2',3'-e]azepine (6). A solution of the azafluorene 1 (0.3 g, 1.65 mmol), 2,6-dibenzylidenecyclohexanone (0.42 g, 1.65 mmol), and NaOH (0.3 g, 7.5 mmol) in ethanol (20 ml) was refluxed for 2 h with TLC monitoring. The alcohol was distilled off and the residue was chromatographed on a silica gel column (1.5 30 cm). A mixture of ethyl acetate and hexane (1:2) eluted the azepine 6. Yield (0.17 g, 25%), yellow crystals; mp 216-217C (ethyl acetatehexane), Rf 0.50 (ethyl acetate). IR spectrum, , cm-1: 3210 (NH). Found, %: C 82.01; H 5.51; N 6.34; M+ 438. C32H26N2. Calculated, %: C 82.00; H 5.50; N 6.42; M 438. 9-Anisyl-13-(p-methoxybenzylidene)-4-aza-9,9a-dihydrofluoreno[9,9a,1-b,c]cyclohexano[2',3'-e]azepine (7) was prepared similarly from the azafluorene 1 (0.3 g, 1.65 mmol), 2,6-di(p-methoxybenzylidene)cyclohexanone (0.55 g, 1.65 mmol), and NaOH (0.3 g, 7.5 mmol) in ethanol (20 ml). Yield 0.12 g (15%), yellow crystals; mp 158-160C (ethyl acetatehexane), Rf 0.45 (ethyl acetate). IR spectrum, , cm-1: 3350 (NH). Found, %: C 81.91; H 6.10; N 5.61; M+ 498. C34H30N2O2. Calculated, %: C 81.90; H 6.0; N 5.6; M 498. 13-Furfurylidene-9-(2-furyl)-4-aza-9,9a-dihydrofluoreno[9,9a,1-b,c]cyclohexano[2',3'-e]azepine (8) was prepared similarly from the azafluorene 1 (0.3 g, 1.65 mmol), 2,6-difurfurylidenecyclohexanone (0.42 g, 1.65 mmol), and NaOH (0.3 g, 7.5 mmol) in ethanol (20 ml) as described in the above method. Yield 0.19 g (27%), yellow crystals; mp 132-135C (ethyl acetatehexane), Rf 0.48 (ethyl acetate). IR spectrum, , cm-1: 3380 (NH). Found, %: C 76.71; H 5.4; N 6.71; M+ 418. C28H22N2O2. Calculated, %: C 76.70; H 5.30; N 6.70; M 418. 9-Phenyl-4-aza-9,9a-dihydrofluoreno[9,9a,1-b,c]indeno[1',2'-e]azepine (9) was prepared similarly from the azafluorene 1 (0.3 g, 1.65 mmol), 2-benzylideneindanone (0.4 g, 1.65 mmol), and NaOH (0.3 g, 494
1
7.5 mmol) in ethanol (20 ml) as described in the above method. Yield 0.19 g (33%), yellow crystals; mp 182-184C (ethyl acetatehexane), Rf 0.78 (ethyl acetate). IR spectrum, , cm-1: 3200 (NH). Found, %: C 87.48; H 5.18; N 7.28; M+ 384. C28H20N2. Calculated, %: C 87.50; H 5.20; N 7.30; M 384.
REFERENCES 1. 2. A. V. Varlamov, A. N. Levov, F. Toze, A. N. Chernyshev, V. V. Davydov, M. A. Ryabov, and O. A. Egorova, Khim. Geterotsikl. Soedin., 1682 (2002). Q. N. Porter and A. Balcas, Mass Spectrometry of Heterocyclic Compounds, Wiley, New York (1971), p. 376.
495
CYCLIZATIONS OF N-(1-CHLORO2,2,2-TRIHALOETHYLIDENE)-O-METHYLURETHANES WITH 5-AMINO-3-METHYLISOXAZOLE AND 3-AMINO-5-METHYLISOXAZOLE

M. V. Vovk, A. V. Bolbut, and V. I. Dorokhov N-(1-Chloro-2,2,2-trihaloethylidene)-O-methylurethanes undergo cyclization with 5-amino-3methylisoxazole and 3-amino-5-methylisoxazole to give respectively 6-trihalomethylisoxazolo[5,4-d]pyrimidin-4(5H)-ones and 2-trihalomethyl-4H-isoxazolo[2,3-a]-1,3,5-triazin-4-ones. Keywords: 5- and 3-aminoisoxazoles, N-(isoxazolyl)-N'-carbomethoxyamidines, 6-trihalomethylisoxazolo[5,4-d]pyrimidin-4(5H)-ones, 2-trihalomethyl-4H-isoxazolo[2,3-a]-1,3,5-triazin-4-ones, N-(1-chloro-2,2,2-trihaloethylidene)-O-methylurethanes, cyclization. We have previously reported [1, 2] that the N-(1-chloro-2,2,2-trihaloethylidene)-O-methylurethanes 1a,b are convenient synthon units for the construction of trihalomethyl-substituted condensed pyrimidine systems. In particular, the reaction of the urethanes 1 with arylamines gives 2-trihalomethylquinazol-4-ones [1] and with 2aminothiophenes the 2-trihalomethyl-3,4-dihydrothieno[2,3-d]pyrimidin-4-ones [2]. With the target of annelating an isoxazole ring we have continued our initial investigations and studied the reaction of the urethanes 1a,b with 5-amino-3-methylisoxazole (2a) and 3-amino-5-methylisoxazole (2b). We have found that compounds 1a,b, under mild conditions (benzene, 20C) and in the presence of triethylamine, selectively imidoylate the aminoisoxazole 2a to give the N-(isoxazol-5-yl)-N'carbomethoxytrihaloacetamidines 3a,b. Their 1H NMR spectra show singlets for the CH3O groups (3.83 and 3.73 ppm respectively) and C(4)H protons of the isoxazole ring (6.13 and 6.03 ppm respectively). Compounds 3a,b are of low thermal stability and when refluxed in toluene for 3 h undergo cyclization to the trihalomethyl isoxazolo[5,4-d]pyrimidin-4(5H)-ones 4a,b, evidently due to an intramolecular interaction of the carbomethoxy group of the urethane fragment and the -electron excessive C(4) center of the isoxazole nucleus. The IR spectra of compounds 4a,b show absorption bands for the C=O group in the range 1700-1705 cm-1 and for NH at 3170-3180 cm-1. The 1H NMR spectra show the NH protons as broad singlets in the range 11-12 ppm. Comparison of this data with the spectroscopic data for 3,4-dihydrothieno[2,3-d]pyrimidin-4-ones [2] allows us to assign the compounds 4a,b a 4,5-dihydro structure. The method of synthesis proposed by us differs basically from those reported in the literature [3-6], in which bifunctional 5-amino-4formyl(carbamoyl, thiocarbamoyl) isoxazoles are used for the construction of the pyrimidine ring.
__________________________________________________________________________________________ Organic Chemistry Institute, Ukraine National Academy of Sciences, Kiev 02094; e-mail: hetfos@ukrpack.net. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 592-595, April, 2004. Original article submitted July 23, 2001. 496 0009-3122/04/4004-04962004 Plenum Publishing Corporation
Hal3C Cl HCl NH2 Me O 2b MeO(O)C N Hal3C N O N H 3c,d 144 oC O N Hal3C N 4c,d N O Me Me N
C(O)OMe
1a, b 20 oC Me H2N 2a N O Me N N H 3a,b O N
MeO(O)C Hal3C
110 oC O HN Hal3C N 4a,b O Me N
1 a Hal = F, b Hal = Cl; 3, 4 a, c Hal = F; b, d Hal = Cl
The reaction of the N-ethylideneurethanes 1a,b with 3-aminoisoxazole 2b occurs at room temperature similarly to the reaction with amine 2a and gives the amidines 3c,d which tend to form cyclic products when heated in refluxing o-xylene. However, in contrast to amidines 3a,b, the position of attack of the carbonyl group is not a carbon atom but the nitrogen atom of the isoxazole ring and this causes the formation of the

Compound 3a* 3b 3c 3d 4a 4b 4c 4d Empirical formula C8H8F3N3O3 C8H8Cl3N3O3 C8H8F3N3O3 C8H8Cl3N3O3 C7H4F3N3O2 C7H4Cl3N3O2 C7H4F3N3O2 C7H4Cl3N3O2 Found, % Calculated, % Hal N 22.52 22.69 35.59 35.39 22.41 22.69 35.64 35.39 25.80 26.01 39.32 39.61 26.33 26.01 39.44 39.61 17.04 16.73 14.17 13.98 16.59 16.73 13.75 13.98 19.05 19.18 15.87 15.65 19.43 19.18 15.92 15.65 mp, C Yield, %
71 135-136 (benzene) 69-70 (benzenehexane, 3:1) 168-169 (2-propanol) 191-192 (benzene) 168-169 (benzene) 140-141 (benzene) 215-216 (benzene) 78 94 92 69 73 46 53
_______ * Viscous oil, purified by reprecipitation from ether using hexane. 497
TABLE 2. Spectroscopic Characteristics of Compounds 3a-d, 4a-d

Compound 3a 3b 3c 3d 4a 4b 4c 4d IR spectrum, , cm-1 NH CO 3165 3150 3180 3195 3170 3180 1775 1760 1765 1755 1700 1705 1755 1750
1
H NMR spectrum, , ppm*
19 F NMR spectrum, , ppm
2.33 (3H, s, CH3); 3.83 (3H, s, CH3); 6.13 (1H, s, (4)); 8.60 (1H, s, NH) 2.31 (3H, s, CH3); 3.73 (3H, s, CH3); 6.03 (1H, s, (4)); 7.68 (1H, s, NH) 2.46 (3H, s, CH3); 3.84 (3H, s, CH3); 6.17 (1H, s, (4)); 9.36 (1H, s, NH) 2.43 (3H, s, CH3); 3.68 (3H, s, CH3); 6.02 (1H, s, (4)), 8.38 (1H, s, NH) 2.53 (3H, s, CH3); 11.33 (1H, s, NH) 2.52 (3H, s, CH3); 11.65 (1H, s, NH) 2.70 (3H, s, CH3); 7.18 (1H, s, (8)); [2.75 (3H, s, CH3); 6.70 (1H, s, C(8)H)] 2.70 (3H, s, CH3); 7.12 (1H, s, (8)); [2.73 (3H, s, CH3); 6.62 (1H, s, C(8)H)]
69.7
68.7
69.2 71.1
_______ * The 1H and 19F NMR spectra were recorded in CDCl3 (compounds 3a-d) and DMSO-d6 (compounds 4a-d). For compounds 4c,d the values obtained in CDCl3 are given in square brackets.
2-trihalomethyl-4H-isoxazolo[2,3-c]-1,3,5-triazin-4-ones 4c,d. The signals for the C(8) protons appear in the 1 H NMR spectra in CDCl3 solution at 6.70 (4c) and 6.62 ppm (4d) and in DMSO-d6 solution at 7.18 (4c) and 7.12 ppm (4d) and do not disappear upon addition of water, thus confirming the presence of the triazine structure. Compounds 4c,d are members of the little studied condensed isoxazolo[2,3-a]-1,3,5-triazine system. There is evidence in the literature [7] for the synthesis of just isoxazolo[2,3-a]-1,3,5-triazine-2,4-diones in low yield by treating 3-aminoisoxazole with phenyl- or phenoxycarbonylisocyanates.
EXPERIMENTAL IR spectra were recorded on a UR-20 instrument (in CH2Cl2 solution for compound 3a and as KBr tablets for compounds 3b-d and 4a-d). 1H NMR and 19F spectra were taken on a Varian Gemini spectrometer (300 and 282 MHz respectively) using TMS internal standard (1H) or CCl3F (19F). N-(3-Methyl-5-isoxazolyl)-N'-carbomethoxytrihaloacetamidines (3a,b) and N-(5-Methyl-3isoxazolyl)-N'-carbomethoxytrihaloacetamidines (3c,d) (Tables 1 and 2). A solution of the aminoisoxazole 2a,b (5 mmol) and triethylamine (0.5 g, 5 mmol) in benzene (15 ml) was added with stirring at room temperature to a solution of the N-ethylideneurethane 1a,b (5 mmol) in benzene (15 ml). After stirring for 3 h, dioxane (10 ml) was added to the reaction mixture, the precipitated triethylamine hydrochloride was filtered off, and the solvent evaporated. The product was purified by crystallization or reprecipitation. 6-Trihalomethyl-3-methylisoxazolo[5,4-d]pyrimidin-4(5H)-ones (4a,b) and 2-Trihalomethyl-7methyl-4H-isoxazolo[2,3-a]-1,3,5-triazin-4-ones (4c,d) (Tables 1 and 2). A solution of compound 3a,b (3 mmol) in toluene (15 ml) or of the amidine 3c,d (3 mmol) in o-xylene (15 ml) was heated at reflux for 3 h. Solvent was then evaporated and the residue was purified by crystallization.
498
REFERENCES 1. 2. 3. 4. 5. 6. 7. V. I. Boiko, M. V. Vovk, and L. I. Samarai, Ukr. Khim. Zh., 61, 48 (1995). M. V. Vovk, A. V. Bol'but, V. I. Boiko, V. V. Pirozhenko, A. N. Chernega, and A. A. Tolmachev, Khim. Geterotsikl. Soedin., 455 (2004). T. Sakamo, H. Yamanaka, A. Shiozawa, W. Tanara, and H. Miyazari, Chem. Pharm. Bull., 28, 1832 (1980). C. B. Vicentini, A. C. Veronese, T. Poli, M. Guarneri, and P. Giori, J. Heterocycl. Chem., 27, 1481 (1990). C. O. Kappe, R. Flammang, and C. Wentrup, Heterocycles, 37, 1615 (1994). A. Miyashita, K. Fujimoto, T. Okada, and T. Higashino, Heterocycles, 42, 691 (1996). M. M. El-Kerdawy, S. H. Bayomi, I. A. Shehata, and R. A. Glennon, J. Heterocycl. Chem., 24, 501 (1987).
499
NEW DERIVATIVES OF THIAZOLE WITH MESOMORPHOUS PROPERTIES

Z. Kh. Kuvatov, M. G. Safarov, and M. M. Murza Azomethines containing a thiazole ring have been synthesized and their liquid crystal properties have been investigated. The influence of the central group and substituents in the azomethine component on the type and temperature range of the mesomorphous properties of the compounds synthesized has been elucidated. Keywords: azomethines, thiazole ring, liquid crystal properties. We have previously investigated the effect of the structure of azomethines with thiazole rings on the type of mesomorphism and its temperature range, with introduction of alkoxy groups with varying length of the aliphatic chain into the benzylidene component [1, 2]. In continuation of the study of the liquid crystal properties of azomethine derivatives of 2-aminothiazole, we have obtained compounds 1-14, which contain substituents of various types (halogens, nitro, dimethylamino, and methoxy groups) in the benzylidene unit using the following scheme:
O2N X 15, 16 O O2N X CHO S 114 N N C H R CH2Cl H2N S 17, 18 O2N X S N NH2
NH2
17, 15, 17 X = O; 814, 16, 18 X = NH; 1, 8 R = 2-F, 2, 9 R = 3-Br; 3,10 R = 4-Cl; 4, 11 R = 2-NO2; 5,12 R = 4-NO2; 6, 13 R = 4-NMe2; 7, 14 R = 2,4-(OMe)2
__________________________________________________________________________________________ Bashkir State University, Ufa 450074, Russia; e-mail: KuvatovZK@ic.bashedu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, 596-598, April 2004. Original article submitted March 30, 2001. 500 0009-3122/04/4004-05002004 Plenum Publishing Corporation
Sodium p-nitrophenoxide, which was quantitatively acylated with chloroacetyl chloride in alkaline medium, was used as the starting material for the preparation of compounds 1-7. Chloroacetyl derivative 15 reacted with thiourea in absolute ethanol to give the corresponding 2-aminothiazole 17, which condensed with aromatic aldehydes in absolute ethanol in the presence of a catalytic amount of piperidine to give compounds 1-7. The Schiff's bases 8-14 were obtained analogously. In this case p-nitroaniline was used as the starting material: chloroacetylation was carried out in ether, but condensation with aldehydes in dry THF. Investigation of the mesophase properties of azomethines prepared showed that all of the compounds 1-14 possess nematic liquid crystal properties. It should be noted that with X = O the mesophase existed over about twice the range as with X = NH (Table 1), however when nitro group was introduced into the ortho position in the benzylidene component (compound 11) the mesophase interval was 81 for X = NH too, i.e., it was comparable with the temperature ranges for compounds 1-7 (X =O). Evidently there are intramolecular hydrogen bonds between the proton of the N=CH group and the NO2 group in the ortho-position of the benzylidene component of compounds 4 and 11, thanks to which the intermolecular interactions in these crystals are not very strong and therefore the temperature range of the mesophase is increased and for the compound with X=O it is maximal (Table 1). Compounds 8-14 are more stable and show enantiotropic mesomorphism (the liquid crystal state is retained on super-cooling the crystalline modification), whereas compounds 1-7 decompose above 200C and possess monotropic mesomorphism. TABLE 1. Characteristics of Compounds 1-13, 17, and 18
Compound 1 2 3 4 5 6 7 8 9 10 11 12 13 14 17 18 Empirical formula 16H10FN3O3S 16H10BrN3O3S 16H10ClN3O3S 16H10N4O5S 16H10N4O5S 18H16N4O3S 18H16N3O5S 16H11FN4O2S 16H11BrN4O2S 16H11ClN4O2S 16H11N5O4S 16H11N5O4S 18H17N5O2S 18H16N4O4S 9H7N3O3S 9H8N4O2S Found, % Calculated, % H 2.55 2.92 2.24 2.49 2.45 2.80 2.36 2.72 2.48 2.72 4.10 4.35 3.92 4.15 3.04 3.22 2.35 2.53 2.84 3.07 2.70 2.98 2.64 2.98 4.42 4.63 3.96 4.17 2.64 2.95 3.24 3.40 , * N 12.04 12.24 10.10 10.39 11.52 11.70 14.88 15.13 15.04 15.13 14.96 15.22 10.72 10.88 16.14 16.37 12.62 12.87 15.44 15.62 18.80 18.97 18.64 18.97 18.86 19.07 14.32 14.58 17.48 17.72 23.45 23.73 n.m. 47 80 62 49 70 77 85 100 125 120 43 64 76 114 i.m. 116 112 152 146 158 148 132 133 152 150 124 129 137 161 56 62 58 55 61 68 65 52 64 68 56 57 63 57 Yield, %
55.82 55.97 47.12 47.54 53.06 53.40 51.64 51.89 51.48 51.89 58.30 58.69 55.58 55.96 56.02 56.14 43.88 44.15 53.22 53.56 51.84 52.03 51.76 52.03 58.50 58.86 55.92 56.25 45.32 45.57 45.40 45.76
_______ * Temperatures at which the nematic (n.m.) and isotropic (i.m.) modifications exist. 501
EXPERIMENTAL Phase transition temperatures were measured on MIN-10 polarizing microscope with a thermal adapter in a heating regime. The individuality and purity of all the compounds described were monitored by TLC on aluminum oxide with toluenechloroform (1:3) as eluent. o-Chloroaceto-4-nitroaniline (15) and N-chloroaceto-4-nitroaniline (16) were synthesized by a known method [3]. N-(2-Aminothiazol-4-yl)-4-nitroaniline (18). Solution of compound 16 (14.2 g, 0.06 mol) and thiourea (4.6 g, 0.06 mol) in absolute ethanol (100 ml) was boiled for 8 h. At the end of the reaction the solvent was evaporated and the residue was neutralized with 20% sodium carbonate solution. The precipitate was filtered off and crystallized from water. Compound 17 was prepared analogously. 4-[Amino-p-(4-nitrophenyl)]-2-benzylidenaminothiazoles (8-14). Mixture of compound 18 (1 g, 0.042 mol) and aromatic aldehyde (0.0042 mol) in dry THF (40 ml) was boiled for 4 h in the presence of a catalytic quantity of piperidine. The solvent was evaporated and the residue was crystallized from ethanol. The Benzylidene Derivatives 1-7 were prepared analogously from compound 17.
REFERENCES 1. 2. 3. M. M. Murza, A. S Golovanov, and M. G. Safarov, Khim. Geterotsikl. Soed., 546 (1996). M. M. Murza, A. S Golovanov, and M. G. Safarov, Zh. Org. Khim., 31, 1701 (1995). I. A. Khrizman (Ed.), Advances in Organic Synthesis in the Chemization of the Agricultural Industry [in Russian], Ufa, 113 (1970).
502
REACTION OF 1,2,3-SELENADIAZOLES WITH PHOSPHINES

P. Arsenyan, K. Oberte, K. Rubina, S. Belyakov, and E. Lukevics Nucleophilic attack of tributyl- and triphenylphosphines on 4-phenyl- and 5-ethoxycarbonyl-4-methyl1,2,3-selenadiazoles leads to the quantitative formation of selenophosphoranes and substituted acetylenes. The molecular structure of 4-phenyl-1,2,3-selenadiazole was confirmed by X-ray crystallography. Keywords: selenadiazole, selenium, phosphine, crystal structure, nucleophilic attack. 1,2,3-Selenadiazole and its derivatives play an important role in the solution of many theoretical and practical questions in organic chemistry [1] which explains the great interest of researchers in these compounds. Compounds containing the selenadiazole ring show aromatic character, but they have a considerable tendency to eliminate molecules of nitrogen and selenium with ring opening with formation of both acyclic compounds and new heterocycles [2, 3], therefore they are promising materials for the investigation of the mechanism of some reactions and for the synthesis of many compounds interesting in a practical sense [4]. A number of methods for the preparation of selenophosphoranes have been described in the literature. Boiling of triphenylphosphine with metallic selenium in THF gave triphenylselenophosphorane in 66% yield [5], while use of toluene increased the yield to 88% [6]. When selenium black was used in boiling toluene for 6 h the yield increased to 100% [7]. Selenophosphorane was also formed by keeping triphenylphosphine and tetrachloroselenotungsten (WCl4Se) in toluene for 2 days [8]. Benzhydrylidenetriphenylphosphorane underwent an exchange reaction with metallic selenium to give selenophosphorane in 71% yield [9, 10]. Triphenylselenophosphorane was formed on heating triphenyl(phenyl-p-tolylmethylene)-5-phosphorane with selenium in toluene at 85C for 4 h [11]. In this work a method is developed for the preparation of selenophosphoranes from 4-phenyl- and 5-ethoxycarbonyl-4-methyl-1,2,3-selenadiazoles. 4-Phenyl-1,2,3-selenadiazole (1) reacted with tributylphosphine in benzene at room temperature. In the first stage the SeN bond is broken as a result of nucleophilic attack by tributylphosphine. Elimination of a molecule of nitrogen follows. A molecule of phenylacetylene is released from the intermediate and tributylselenophosporane (3) is produced. When triphenylphosphine is used, triphenylselenophosphorane (4) is formed in quantitative yield only after boiling for one hour. In the case of 5-ethoxycarbonyl-4-methyl-1,2,3selenadiazole (2) selenophosphoranes 3 and 4 are formed in 100% yield. Ethyl but-2-ynecarboxylate (6) was isolated from the reaction mixtures in 92% yield.
__________________________________________________________________________________________ Latvian Institute of Organic Synthesis, Riga, LV -1006; e-mail: pavel.arsenyan@lycos.com. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, 599-603, April 2004. Original article submitted October 7, 2003. 0009-3122/04/4004-05032004 Plenum Publishing Corporation 503
N N Se R' 1, 2
R R''3P N2 R'
+ PR''3 Se R''3P 3, 4 Se
R 5, 6
R'
1, 5 R = Ph, R' = H; 2, 6 R = Me, R' = COOEt; 3 R" = Bu; 4 R" = Ph
When trimethyl- or triethyl phosphite was used the reaction stopped at the first stage to give selenophosphates [12]. Destruction of the selenadiazole ring with phosphines is an alternative method for the preparation of substituted acetylenes under mild conditions. The molecular structure of compound 1 was determined by X-ray diffractometry (Fig. 1). In the crystalline state the molecule of selenadiazole 1 is practically planar with a torsion angle C(5) C(4)C(6)C(7) of 178.6. The C(5)Se(1) bond (1.814 A) is shorter than the N(2)Se(1) bond (1.878 A), and the C(5)Se(1)N(2) angle equals to 86.41 (Tables 1 and 2). There are 8 independent molecules in the unit cell. TABLE 1. Bond Lengths and Intermolecular Contacts (l) in Compound 1
Bond Se(1)C(5) C(6)C(7) C(6)C(4) C(7)C(8) N(3)C(4) C(8)C(9) C(5)H(5) C(11)H(11) C(9)H(9) Contact Se(1)Se(1) Se(1)Se(1) l, 1.814(3) 1.405(4) 1.472(5) 1.371(4) 1.387(4) 1.391(5) 1.07(3) 0.96(3) 1.03(4) l contact, 3.8062(8) 3.6294(8) Bond Se(1)N(2) C(6)C(11) C(5)C(4) C(11)C(10) N(3)N(2) C(9)C(10) C(7)H(7) C(8)H(8) C(10)H(10) Contact Se(1)N(2) N(2)H(5) l, 1.878(3) 1.391(4) 1.355(4) 1.389(4) 1.265(4) 1.367(5) 0.990(3) 1.04(4) 1.10(3) l contact, 3.379(3) 2.59(3)
Fig. 1. Molecular structure of 4-phenyl-1,2,3-selenadiazole (1). 504
Fig. 2. Crystal Packing of Compound 1: Projections Along the Y (a) and Z (b) Axes. TABLE 2. Torsion Angles () in Compound 1
Angle C(5)Se(1)N(2) C(7)C(6)C(4) Se(1)C(5)C(4) C(6)C(11)C(10) C(7)C(8)C(9) C(11)C(10)C(9) C(6)C(4)N(3) Se(1)N(2)N(3) C(4)C(5)H(5) C(8)C(7)H(7) C(10)C(11)H(11) C(9)C(8)H(8) C(10)C(9)H(9) C(9)C(10)H(10) , deg. 86.41(12) 120.6(2) 111.0(2) 120.8(3) 120.9(3) 120.2(3) 119.3(2) 110.9(2) 126.(2) 125.(2) 119.(2) 118.(2) 125.(2) 123.7(13) Angle C(7)C(6)C(11) C(11)C(6)C(4) C(6)C(7)C(8) C(4)N(3)N(2) C(8)C(9)C(10) C(6)C(4)C(5) C(5)C(4)N(3) Se(1)C(5)H(5) C(6)C(7)H(7) C(6)C(11)H(11) C(7)C(8)H(8) C(8)C(9)H(9) C(11)C(10)H(10) , deg. 118.4(3) 121.0(3) 120.1(3) 117.3(3) 119.7(3) 126.4(3) 114.3(3) 122.(2) 115.(2) 121.(2) 121.(2) 115.(2) 116.0(14)
There are intermolecular contacts between selenium atoms of neighbouring molecules of selenadiazole 1 crystal within the limits of 3.63-3.81 , which is less than the sum of the van der Waals radii [13]. In addition to Se(1)Se(1) contacts there are Se(1)N(2) and N(2)H(5) contacts of 3.38 and 2.59(3) respectively.
EXPERIMENTAL For the X-ray Structural Analysis 1961 reflections were measured with a Nonius KappaCCD diffractomer using molybdenum radiation, MoK (0.7103 ). Monocrystals of compound 1 (mp 76-77C) grown from acetonewater (60:40) were monoclinic with unit cell parameters: a = 36.833(2), b = 5.7406(2), c = 7.3839(4) ; = 92.975(2); V = 1559.44(13) 3; Dx = 1.781 g/cm3; = 4.74 cm-1; coefficient of absorption 505
4.74 mm-1; space group P21/a; Z = 8. In the calculations 1114 independent reflections with |F| > 2F were used for 124 refined parameters. The final residual factor was 0.057. Calculations were carried out using a suite of programs [14-16]. Selenophosphoranes 3, 4 (General Method). Mixture of equimolar amounts of 1,2,3-selenadiazole and phosphine was dissolved in benzene and stirred for 1 h (it was necessary to boil the mixture for triphenylphosphine). The reaction mixture was evaporated and selenophosphoranes separated in quantitative yield from the substituted acetylenes by crystallization from hexane. The structure of the products was confirmed by mass and NMR spectra [6, 8]. The authors express their sincere thanks to the Latvian Committee on Science (grant no. 189) for financial support.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. P. Arsenyan, K. Oberte, O. Pudova, and E. Lukevics, Khim, Geterotsikl. Soed., , 1627 (2002). D. H. Reid, in: R. C. Storr (ed.), Comprehensive Heterocyclic Chemistry II: A Review of the Literature 1982-1995. Pergamon, Oxford (1996), Vol. 4, 743-777. M. Regitz and S. Krill, Phosphorus, Sulfur, Silicon Relat.Elem., 99, 15 (1996). R. Mugesh, W.-W. Du Mont, and U. Sies, Chem. Rev., 101, 2125 (2001) S. R. Foley and D. S. Richeson, Chem. Commun., 1391 (2000). R. K. Bhardwaj and R. S. Davidson, Tetrahedron, 43, 4473 (1987). J. A. Malito and C. Almer, Phosphorus, Sulfur, Silicon Relat.Elem., 54, 95 (1990). M. G. B. Drew, E. M. Page, and D. A. Rice, J. Chem. Soc., Dalton Trans., 61 (1983). K. Okuma, J. Sakata, Y. Tachibana, T. Honda, and O. Takumi, Tetrahedron Lett., 28, 6649 (1987). K. Okuma, I. Kaneko, H. Ohta, and Y. Yokomori, Heterocycles, 31, 2107 (1990). R. Hock, S. Hillenbrand, G. Erker, C. Krueger, and S. Werner, Chem. Ber., 126, 1895 (1993). W. Ando, Y. Kumamoto, H. Ishizuka, and N. Tokitoh, Tetrahedron Lett., 28, 4707 (1987). J. D. Dunitz, X-Ray Analysis and the Structure of Organic Molecules, Basel (Switzerland), 1995, 339. S. Mackay, C. J. Gilmore, C. Edwards, N. Stewart, and K. Shankland, maXus Computer Program for the Solution and Refinement of Crystal Structures. Bruker Nonius, The Netherlands; MacScience, Japan, and the University of Glasgow, 1999. C. K. Johnson, ORTEP-II. A Fortran Thermal-Ellipsoid Plot Program. Report ORNL-5138. Oak Ridge National Laboratory, Oak Ridge, Tennessee, USA, 1976. A. Altomare. M. C. Burla, M. Camilli, G. L. Cascarano, C. Giacovazzo, A. Guagliardi, A. G. G. Moliterni, and R. Spagna, J. Appl. Cryst., 32, 115 (1999).
15. 16.
506
PSYCHOTROPIC PREPARATIONS SYDNOPHEN AND SYDNOCARB AS DONORS OF NITROGEN MONOXIDE

V. Levina, N. V. Grigor'ev, and V. G. Granik The metabolic chain of the antihypertensive drug Molsydomin, which belongs to the group of sydnonimine derivatives, was modelled in vitro with the psychotropic drugs Sydnophen and Sydnocarb, which are also derivatives of sydnonimine. Like Molsydomin, Sydnophen and Sydnocarb are hydrolyzed to N-nitroso compounds which liberate nitrogen monoxide, NO, on subsequent oxidation which may be related to the pharmacological effects of these drugs. Keywords: nitroprusside anion, nitrogen monoxide NO, Sydnocarb, Sydnophen, hydrolysis, polarographic detection, oxidation. Among the derivatives of sydnonimine there are a large number of pharmacologically active substances, from which the drugs Molsydomin, Sydnophen, and Sydnocarb (Mesocarb) can be distinguished:
Me O N N _ + N O CH2CH N COOEt Sydnophen CH2CH Me N N N _ N + O
. HCl
NH
Molsydomin
_ + O
N CO
NH
Sydnocarb
Molsydomin is an effective antihypertensive, the pharmacological activity of which has been connected recently [1] to its ability to release nitrogen monoxide in vivo. This ability to act as an NO donor arises from hydrolysis of the side chain of Molsydomin, accompanied by decarboxylation, and opening of the sydnonimine ring under these conditions to give N-nitroso derivative. It is known [2] that N-nitroso compounds are readily oxidized in the organism, the final result of which is the liberation of nitrogen monoxide. The suggested degradation of Molsydomin occurs as follows:
__________________________________________________________________________________________ "NIOPIK" State Science Center of the Russian Federation, Moscow 103787; e-mail: makar-cl@ropnet.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, 604-607, April, 2004. Original article submitted March 21 2000. 0009-3122/04/4004-05072004 Plenum Publishing Corporation 507
N N N
OH _ + O N CO2Et
_ O N N N OH _ + O N
N N CH2CN N O
O2
.+ N N CH2CN
N O
+ H
N N CHCN
NO
The vasodilatory ability of NO donors is well-known [2], and it is no wonder that drugs with these properties are antihypertensive drugs. That Sydnophen and Sydnocarb, which have clearly expressed psychotropic activities [3], should also have similar properties is not directly based on the scheme shown above. On the other hand, the presence of sydnonimine unit in all three compounds, and the known properties of sydnonimines, related to their ability to be converted to N-nitroso compounds under appropriate conditions, provide a perfectly reasonable suggestion that preparations Sydnophen and Sydnocarb may act as NO donors. Despite their similar structures, Sydnophen and Sydnocarb belong to different pharmacological groups. The first is a sufficiently strong inhibitor of monoaminoxidase (MAO) which explains its antidepressive activity. Sydnocarb is an effective psychostimulator (considerably exceeding Sydnophen in this respect), showing an indirect sympathomimetic effect, probably based on the inhibition of the reverse capture of noradrenaline. On the other hand, the known neuromediating properties of NO in no way exclude that compounds capable of liberating it in the living organism should also possess psychotropic properties. The ability of these drugs to act as NO donors is studied using a method developed earlier, connected with the polarographic determination of the nitroprusside anion formed by the reaction of the liberated nitrogen monoxide with the ferrocyanide anion. It is known that sydnonimines are readily hydrolyzed in alkaline media into N-nitroso compounds [4,5]. The kinetic characteristics of the process differ considerably depending on the nature of the substituent on the endocyclic nitrogen atom of the sydnonimine nucleus. We have studied the hydrolysis of Sydnophen (3-phenylisopropylsydnonimine) by polarography in deaerated solutions. The results obtained agree partially with published results [5] for 3-isopropylsydnonimine, however the hydrolysis of Sydnophen is easier than that of 3-isopropylsydnonimine. For example, 3-isopropylsydnonimine is absolutely stable at pH 1-7, while at pH 7.15-8.60 an equilibrium of 3-isopropylsydnonimine with N-nitroso-3-isopropylaminoacetonitrile was observed. We observed hydrolysis of Sydnophen in concentrated electrolyte solutions at low pH (to pH 5), but even at pH 8.2 Sydnophen was completely hydrolyzed in contrast to 3-isopropylsydnonimine. Under these conditions the half-wave potential E1/2 for Sydnophen equals to -0.87 V (saturated calomel electrode) and for N-nitroso-N-phenylisopropylaminoacetonitrile E1/2 = -1.32 V (saturated calomel electrode). In 0.1 M phosphate buffer at pH 8.2 the half-wave potentials E1/2 for Sydnophen and its hydrolysis product are -0.87 and -1.32 (saturated calomel electrode) respectively. The difference in the half-wave potentials for Sydnophen and its hydrolysis product is 0.45 V which is close to the generally observed difference for N-substituted sydnonimines and the corresponding N-nitrosoaminoacetonitriles [4, 5], so the product of the Sydnophen hydrolysis under deaeration conditions at physiological pH is identified as N-nitroso-Nphenylisopropylaminoacetonitrile, which corresponds to the scheme for the metabolism of Molsydomin. Further, when N-nitroso-N-phenylisopropylaminoacetonitrile was heated in anaerobic conditions with 508
potassium ferrocyanide to 80C under either acidic or basic conditions evolution of NO from this compound did not occur in the absence of an oxidant. On additional heating in the presence of potassium ferricyanide and further treatment as described in [6, 7] practically quantitative formation of nitroprusside anion was observed, which also corresponds to the scheme for the metabolism of Molsydomin. It has been established that the chemical degradation of Sydnocarb can also follow the same scheme if an initial stage of hydrolysis is carried out in 0.1 N sulfuric acid. In this way the phenylcarbamoyl group is removed, since in the polarogram both the initial Sydnocarb and Sydnophen are observed. In 0.1 N sulfuric acid with 20% of ethanol E1/2 value for Sydnocarb is -0.58 V (saturated calomel electrode) and for Sydnophen E1/2 = -0.90 V (saturated calomel electrode). Even in these vigorous conditions hydrolysis of Sydnocarb proceeds slowly: after 1.65 h the relative ratio of the concentrations of Sydnocarb and Sydnophen in solution was 1.85 and after 6 h it was 0.35. Thus we have modelled in vitro the metabolization chain of Molsydomin for Sydnophen and Sydnocarb, although the conditions for carrying out the different stages, particularly the first, are different for these drugs. The vigorousness of the conditions necessary to carry out these conversions in vitro for Sydnophen and Sydnocarb do not rule out the possibility that they could occur in vivo, which follows from a comparison of the corresponding data for Molsydomin. It may be proposed that under the organism conditions Sydnophen and Sydnocarb are capable of liberating NO, which may contribute to the pharmacological effects of these drugs. This is not a basis for confirming that the pharmacological activity of these drugs is connected to a large degree with the liberation of NO, rather than to general scheme for the effect of indirect sympathomimetics [3]. To estimate the contribution of this or any mechanism of the psychotropic activity of Sydnophen and Sydnocarb special pharmacological and biochemical studies are required.
EXPERIMENTAL Polarographic measurements at a dropping mercury electrode were carried out according to generally accepted methods [8]. Determination of NO at the oxidation of the compounds studied was carried out according to [6,7].
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. H. Bohn and K. Schonafinger, J. Cardiovasc. Pharm., 14 (Suppl. II), 1 (1989). V. G. Granik, S. Yu. Ryabova, and N. B. Grigor'ev, Uspekhi Khimii, 65, 792 (1997). M. D. Mashkovskii, Medicinals [in Russian], Meditsina, Moscow (1993), 1. L. E. Kholodov, E. V. Borisov, and V. G. Yashunskii, Khim. Geterotsikl, Soed., 702 (1968). V. G. Yashunskii, L. E. Kholodov, and E. M. Peresleni, Zh. Obshch. Khim., 33, 3699 (1963). V. I. Levina, D. A. Grigor'ev, and N. B. Grigor'ev, Khim.-Pharm. Zh., No. 8, 55 (1995). V. I. Levina, A. V. Danilov, and N. B. Grigor'ev, Khim-Pharm. Zh., No. 4, 53 (1998). S. G. Mairanovskii, Ya. P. Stradyn', and V. D. Bezuglii, Polarography in Organic Chemistry [in Russian]. Khimiya, Leningrad (1975), 352.
509
SYNTHESIS OF DERIVATIVES OF 8-CYANO6-ETHOXYCARBONYL-3-HYDROXY-5-METHYLIMIDAZO[1,2-a]PYRIDINE AND 9-ALKOXYCARBONYL(OR 9-CARBOXY)-3-ETHOXYCARBONYL-2-METHYL10H-BENZO[b]-1,8-NAPHTHYRIDINE-5-ONE FROM THE REACTION OF 2-CHLORO-5-ETHOXYCARBONYL6-METHYLNICOTINONITRILE WITH AMINO ACIDS
A. B. Deyanov and M. E. Konshin 2-Substituted 8-cyano-6-ethoxycarbonyl-3-hydroxy-5-methylimidazo[1,2-a]pyridine was formed from the interaction of 2-chloro-5-ethoxycarbonyl-6-methylnicotinonitrile with -amino acids in DMF. The same nitrile on boiling with anthranilic acid or its esters in butanol gave, respectively, 2-(2-carboxyanilino)- or (2-(2-alkoxycarbonylanilino)-5-ethoxycarbonyl-6-methylnicotinonitriles which cyclized on heating in PPA to give 9-alkoxycarbonyl(or 9-carboxy)-3-ethoxycarbonyl-2-methyl-10Hbenzo[b]-1,8-naphthyridin-5-ones. Keywords: 10H-benzo[b]-1,8-naphthyridin-5-ones, nicotinonitriles. imidazo[1,2-a]pyridines, 2-(2carboxyanilino)-
We have shown previously that the reaction of 2-chloro-5-ethoxycarbonyl-6-methylnicotinonitrile (1) with arylamines can be used to prepare biologically active derivatives of nicotinic acid [1] and also intermediates for the synthesis of pyrido[2,3-d]pyrimidines (Scheme 1) [2, 3]. In this work, with the objective of extending these studies and elucidating the possibility of using nitrile 1 in the synthesis of functionally substituted imidazo[1,2-a]pyridines, pyrido[2,1-b]quinazolines and benzo[b]1,8-naphthyridines, we have studied the reactions of compound 1 with -amino acids, anthranilic acid and its esters. As a result of the investigations it was found that the reaction of nitrile 1 with -amino acids did not result in substitution of chlorine atom by the amino acid residue, instead an intramolecular cyclization of the intermediate N-(2-pyridyl) derivative of the amino acid occurred to give 2-substituted 8-cyano-6ethoxycarbonyl-3-hydroxy-5-methylimidazo[1,2-a]pyridines 2a-d (Table 1). This was indicated by the failure of compounds 2a,b to dissolve in aqueous sodium hydrogencarbonate, and the absence of the characteristic signals of the carboxy group protons in their 1H NMR spectra (Table 2).
__________________________________________________________________________________________ Perm State Pharmaceutical Academy, Perm 614990, Russia; e-mail: pfa@degacom.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, 608-613, April, 2004. Original article submitted June 22, 2001; revision submitted March 20, 2002. 510 0009-3122/04/4004-05102004 Plenum Publishing Corporation
Scheme 1
Me EtO2C N N CN 2ad EtO2C Me N CN N H 3ac R1 PPA Me CO2R
2
OH R
NH2 RCHCO2H
EtO2C Me N 1
CN Cl
R1
CO2R 2 NH2
O EtO2C N N H 5ac R1
CO2R
POCl3 3a EtO2C
Me N
N CN 4
2 a R = H, b R = CH2OH, c R = CH2CO2H, d R = CH2CH2CO2H; 3, 5 a R1 = R2 = H, b R1 = H, R2 = Et, c R1 = R2 = Me
In the IR spectra of imidazopyridines 2a-d stretching bands of the 3-OH were observed at 3510-3580 cm-1, and signals of hydroxyl protons appeared at 3.67-3.82 ppm in their 1H NMR spectra. These data, and also the absence of signals of the NH group protons permitted the conclusion that compounds 2a-d evidently exist in the enol form, and not the carbonyl form which is in agreement with some results presented in the review [4]. TABLE 1. Characteristics of the Compounds Synthesized
Compound 2a 2b 2c 2d 3a 3b 3c 4 5a 5b 5c Empirical formula C12H11N3O3 C13H13 N3O4 C14H13N3O5 C15H15N3O5 C17H15N3O4 C19H19N3O4 C19H19N3O4 C17H13N3O3 C17H15N2O5 C19H19N2O5 C19H19N2O5 Found, % Calculated, % H 4.52 4.41 4.76 5.03 4.32 4.27 4.77 4.75 4.65 4.79 5.42 5.58 5.42 5.65 4.26 4.53 4.62 4.74 5.39 5.11 5.39 5.09 mp, N 17.13 17.38 15.27 15.60 13.86 14.06 13.24 13.00 12.92 13.09 11.89 12.15 11.89 11.92 13.67 13.52 8.56 8.53 7.88 8.17 7.88 8.02 89-92 100-102 97-99 93-96 236-237 208-209 168-169 135-137 242-244 224-226 216-217 35 46 41 42 71 74 65 35 58 61 76 Yield, %
C 58.77 59.02 56.72 56.64 55.45 55.70 56.78 57.16 62.76 62.98 64.58 64.30 64.58 64.74 66.44 66.57 62.38 62.60 64.22 64.24 64.22 64.10
511
512
TABLE 2. Spectroscopic Characteristics of the Compounds Synthesized

Compound 2 2b 3 (3H, s) 2.58 2.58 N (1, s) H NMR spectrum, , ppm 23 23 H pyridine, s (3, q) (3, t)
1
IR spectrum, , cm-1* other protons 3.28 (1, s, 2-), 3.67 (1, s, 3-) 3.22 (2, d, 2), 3.71 (1, s, 3-), 2.45 (1, d, 2) 3.28 (2, s, 2), 3.82 (1, s, 3-) 3.25 (4, m, 2), 3.76 (1, s, 3-) 11.65 (1H, s, COOH) 2.26 (3H, s, R), 3.97 (3H, s, R') 9.43 (1H, s, COOH) 3.85 (3H, s, COOMe), 2.32 (3H, s, R) C=O 1720 1722 CN 2234 2230 NH other 3580 () 3565 ()
arom., m
8.25 8.18
1.30 1.25
4.22 4.18
2c 2d 3a 3b 3c 4 5a 5b 5c
2.48 2.48 2.68 2.81 2.70 2.55 2.65 2.62 2.62 8.68 11.68 11.43 8.78 9.18, 11.92 11.98
7.02-8.15 7.42-8.26 7.23-8.18 7.01-8.05 7.45-8.30 6.97-8.29 7.47-8.32
8.12 8.18 8.28 8.42 8.39 8.30 8.46 8.58 8.55
1.28 1.32 1.25 1.38 1.35 1.28 1.35 1.30 1.35
4.18 4.20 4.32 4.35 4.21 4.26 4.32 4.32 4.28
1726 1726 1720 1716 1710 1718 1718 1714 1716
2232 2228 2230 2228 2230 2234
3330
3520 () 3510 () 1700 (=), 3550 () 1692 (C=O) 1694 (C=O) 1660 (C=O) 1696 (C=O), 1676 (C(5)=) 1700 (C=O), 1652 (C(5)=) 1698 (C=O), 1652 (C(5)=O)
3330 3336 3412
_______ * The IR spectra of compounds 3a and 5 were obtained in CCl4 (c = 0.05 mol/l), those of compounds 3b, 3c in CHCl3 (c = 0.05 mol/l), the others as nujol mulls.
It might be expected that anthranilic acid and its esters would react with nitrile 1 to give substituted pyrido[2,1-b]quinazolin-10-one since this was observed in the case of the reaction of 2-chloronicotinamides with anthranilic acid [5]. However 2-(2-carboxyanilino)-3a or 2-(2-alkoxycarbonyl-4-R-anilino)-5-ethoxycarbonyl-6methylnicotinonitriles 3b,c were obtained as a result of this reaction. Compound 3a has a free carboxyl group and dissolves in aqueous sodium hydrogencarbonate solution. In the IR spectrum of compound 3a in carbon tetrachloride solution stretching vibrations were observed at 3550 (COOH) and 3300 cm-1(NH). The 1H NMR spectrum of this compound has signals at 8.68 (1H, NH) and 11.65 ppm (1H, COOH) which correspond to suggested structure. This reaction stops at the acid 3a which does not cyclize to derivative of pyrido[2,1-b]quinazoline, which is probably connected with steric hindrance by the methyl group at position 6. As a confirmation of this idea we carried out the reaction between 2-chloro-6methylnicotinonitrile and anthranilic acid to give 2-(2-carboxyanilino)-6-methylnicotinonitrile. When acid 3a was boiled with an excess of phosphorus oxychloride for 1.5 h 4-cyanopyrido-2ethoxycarbonyl-1-methyl[2,1-b]quinazolin-10-one (4) was obtained in 35% yield. Attempts to cyclize acid 3a by boiling for 12 h in ethylene glycol or glacial acetic acid were unsuccessful. Compound 4 is a crystalline substance insoluble in aqueous sodium hydrogencarbonate solution, but soluble in general organic solvents. In distinction from the spectrum of the starting acid 3a, the IR and 1H NMR spectra of compound 4 do not contain signals for the secondary amino group or OH of a carboxyl group. The IR and 1H NMR spectra of the esters 3b and 3c differ somewhat from the spectra of 2-arylamino-5ethoxycarbonylnicotinonitriles [1]. For example, in the IR spectra of compounds 3b,c in Nujol mulls or chloroform the stretching frequency due to a secondary amino group is missing and the stretching vibration band of one of the ester carbonyl groups is shifted to low frequency. In the 1 NMR spectra a signal for one proton is observed at 11.43 or 11.68 ppm, whereas the signal for the proton of NH group in 2-arylaminonicotinonitriles is usually observed at 9.21-9.55 ppm. The absence of stretching vibration bands in the 3100-3600 cm-1 region of the IR spectra and the weak field shift of the signal of the NH proton in the 1 H NMR spectra of esters 3b,c indicate that they exist in the form of chelates with an intramolecular hydrogen bond between the NH groups and the neighbouring carbalkoxy group. In the mass spectra of compounds 3b,c the molecular ions correspond to the molecular mass. Decomposition of the molecular ions of these compounds evidently proceeds in two directions: either with elimination of alcohol and intramolecular cyclization into the ion 307 (321)* [M - AlkOH]+ , having the structure of pyrido[2,1-b]quinazolin-10-one, or by loss of alkoxycarbonyl radical with formation of the ion 280 (294) [M - COOAlk]+. The preference for the second route of decomposition is indicated by the 100% intensity of the peaks of ions 280 (294), the stability of which is explained by redistribution of the positive charge onto the heterocyclic system. Fragmentation of the ions 307 (321) is related to the loss of CO molecule or the isocyanic acid radical with the formation of the ions 279 (293) and 265 (289) respectively. The ions 280 (294) lose H and are also converted into ions 279 and 293. The latter either lose the nitrile radical or are converted by ortho-splitting with loss of a molecule of ethanol. Further fragmentation is connected with breakdown of the heterocyclic system. Heating of 2-arylaminonicotinonitriles in concentrated acids led to cyclization into derivatives of benzo[b]-1,8-naphthyridin-10-one [6]. Because under the electronic impact from the molecular ion of compounds 3b,c ion was formed which had the structure of pyrido[2,1-b]quinazolin-10-one, and also that possibility of cyclization of compound 3a was confirmed preparatively, it seemed of interest to discover which route would follow the reactions on heating these compounds in PPA. It was established that when compounds 3a-c were heated in PPA at 135-145C for 2h they cyclized into 9-alkoxycarbonyl(carboxy)-3-ethoxycarbonyl-2-methyl-7H-(methyl)-10H-benzo[b]-1,8-naphthyridin-5-ones _______ * Here and below we use the value m/z for ion peaks. 513
5a-c in yields of 58-76%. Compound 5b was also obtained by prolonged standing of compound 3b at room temperature in concentrated sulfuric acid. Compounds 5a-c are yellow crystalline compounds, soluble in DMF and concentrated acetic acid. In their IR spectra, in contrast with the spectra of starting materials 3a-c the nitrile stretching frequency has disappeared and there is one more carbonyl group band at 1652-1676 cm-1. These data, and also the presence of the signal of one proton at 11.70 (11.93) ppm and a weak signal at 9.18 ppm in the 1H NMR spectra of naphthyridones 5b,c indicate the existence of compounds 5b,c in both the chelate and non-chelate forms.
EXPERIMENTAL IR spectra were recorded on UR-20 spectrometer. 1H NMR spectra were recorded on a PC-60 (60 MHz) spectrometer for solutions of compounds 2b, 2d, 5a-c in CDCl3, the rest in DMSO-d6 with HMDS as internal standard. Mass spectra were recorded on MX-1303 apparatus with direct inlet of the sample into the ion source, ionizing voltage 70 eV, standard for comparison 200Hg. 2-Substituted 8-Cyano-6-ethoxycarbonyl-3-hydroxy-5-methylimidazo[1,2-a]pyridines (2a-d). Compound 1 (2.25 g, 0.01 mol) was dissolved in DMF (10 ml), the corresponding -amino acid (0.015 mol) was added and the mixture was heated to complete solution of the latter and then for a further 1 h. The cooled solution was poured into water (100 ml). The precipitate was filtered off and crystallized from 2-propanolwater mixture. 2-(2-Carboxyanilino)- (3a) or 2-(2-Alkoxycarbonyl-4-R-anilino)-5-ethoxycarbonyl-6-methylnicotinonitriles (3b,c). Solution of compound 1 (2.25 g, 0.01mol) and anthranilic acid or its ester (0.015 mol) in butanol (25 ml) was boiled for 6 h. The precipitate formed on cooling was filtered off and crystallized (compound 3a from a DMF water mixture, 3b,c from 2-propanol). Mass spectra, m/z (Irel, %): 3b 353 [M]+ (47), 307 (15), 280 (100), 279 (60), 265 (10), 253 (25), 234 (10), 233 (12), 207 (12), 179 (9); 3c 353 [M]+ (77), 321 (23), 294 (100), 293 (87), 279 (10), 267 (24), 247 (16), 221 (10), 193 (3). 2-(2-Carboxyanilino)-6-methylnicotinonitrile (3a). Solution of nitrile 1 (1.53 g, 0.01 mol) and anthranilic acid (2.06 g, 0.015 mol) in 50% acetic acid (15 ml) was boiled for 4 h. The precipitate was filtered off, dried, and crystallized from 1:1 benzenehexane. M.p. 140C. Yield 1.81 g (71%). 1H NMR spectrum, , ppm: 10.27 (1H, s, COOH); 8.63 (1H, s, NH); 7.25 (6H, m, arom. prot.); 2.19 (3H, s, CH3). Found, %: C 66.6; H 4.3; N 16.4. C14H11N3O2. Calculated, %: C 66.4; H 4.4; N 16.6. 4-Cyanopyrido-2-ethoxycarbonyl-1-methyl[2,1-b]quinazolin-10-one (4). Solution of compound 3a (3.25 g, 0.01 mol) in phosphorus oxychloride (25 ml, 0.28 mol) was boiled for 1.5 h. The mixture was cooled and poured into water (100 ml) and carefully alkalized with ammonia solution to pH 8. The precipitate was filtered off, dried, and crystallized from 85% acetic acid. M.p. 135-137C, yield 1.07 g (35%). 9-Alkoxycarbonyl(carboxy)-3-ethoxycarbonyl-2-methyl-7H-(methyl)-10H-benzo[b]-1,8-naphthyridin5-ones (5a-c). Solution of the corresponding compound 3a-c (0.01 mol) in PPA was heated for 2 h at 135-145C. The mixture was poured into water (100 ml), the precipitate was filtered off and crystallized from aqueous acetic acid. 3,9-Di(ethoxycarbonyl)-2-methyl-10H-benzo[b]-1,8-naphthyridin-5-one (5b). Compound 3b (3.53 g, 0.01 mol) was dissolved in concentrated H2SO4 (25 ml) and kept at 18-22C for 240 h. The solution was poured into water (100 ml) and carefully neutralized with ammonia solution. The precipitate was filtered off, dried and crystallized. Yield 3.02 g (89%). Melting point of mixed sample with compound 5b, prepared in the previous experiment, gave no depression.
514
REFERENCES 1. 2. 3. 4. 5. 6. A. B. Deyanov, R. Kh. Niyazov, V. E. Kolla, and M. E. Kon'shin, Khim.-Pharm. Zh., 27, No. 2, 36 (1993). A. B. Deyanov, M. Yu. Gavrilov, and M. E . Kon'shin, Khim. Geterotsikl. Soed., 535 (1992). A. B. Deyanov, V. E. Kolla, F. Ya. Nazmetdinov, L. P. Drovosekova, and M. E. Kon'shin, Khim.Pharm. Zh., 27, No. 9, 29 (1993). E. Suloeva, M. Yure, and E. Gudriniece, Khim. Geterotsikl. Soed., 1299 (1999). A. I. Mikhalev, L. A. Ovodenko, A. S. Zaks, and M. E. Kon'shin, Khim.-Pharm. Zh., 29, No. 4, 40 (1995). N. I. Shramm and M. E. Kon'shin, Khim. Geterotsikl. Soed., 674 (1982).
515
6-ARYLAMINO-3-METHYL-7H[1,2,4]TRIAZOLO[3,4-b][1,3,4]THIADIAZINES: NOVEL N-ARYLAMIDINE STRUCTURES

V. A. Yanchenko1, A. M. Demchenko1, and M. O. Lozinskii2 We propose a method for obtaining derivatives of 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine by alkylation of 4-amino-5-methyl-4H-1,2,4-triazole-3-thiol by substituted -chloroacetanilides, followed by cyclization of the intermediate by phosphorus oxychloride. Keywords: 4-amino-5-methyl-4H-1,2,4-triazole-3-thiol, N1-aryl-2-(4-amino-5-methyl-4H-1,2,4-triazolyl3-thio)acetamide, 6-arylamino-3-methyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine, -chloroacetanilide, intramolecular cyclization. Condensed derivatives of 1,2,4-triazolo[3,4-b][1,3,4]thiadiazines have a broad spectrum of biological action, including antibacterial [1,2], antiviral, anti-inflammatory, and other types of activity [3]. Recently interest has considerably increased in heterocyclic N-arylamidines, connected with using them as the basis for obtaining the next generation of analgesics [4]. So we have attempted to obtain N-arylamidines with a 1,2,4-triazolo[3,4-b][1,3,4]thiadiazine ring. It was shown earlier that 4-amino-5-alkyl-4H-1,2,4-triazole-3-thiols react with such alkylating reagents as methyl iodide [1], chloroacetonitrile [2], chloroacetic acid [5], and substituted phenacyl bromides [5-8].
N Me N NH2 N Me N NH2 3ac 1 N S O H N N SH H N
Cl O
K2CO3
R1 R2
R3 2ac R3 R2 POCl3 R1 N Me N N S N N H 4ac R3 R1 R2
24 a R1 = OEt, R2 = R3 = H; b R1 = Cl, R2 = R3 = H; c R1 = H, R2 = R3 = Me
__________________________________________________________________________________________ T. G. Shevchenko Chernigov Pedagogical University, Chernigov 14038, Ukraine; e-mail: demch@cn.relc.com. 2 Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev 02094. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 614-616, April, 2004. Submitted May 28, 2002. 516 0009-3122/04/4004-05162004 Plenum Publishing Corporation
1
We propose a new method for obtaining derivatives of 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine by alkylation of 4-amino-5-methyl-4H-1,2,4-triazole-3-thiol (1) with substituted -chloroacetanilides 2, followed by cyclization of the intermediate by phosphorus oxychloride. Reaction of thiol 1 with substituted -chloroacetanilides in the presence of potassium carbonate occurs with formation of substituted N1-aryl-2-(4-amino-5-methyl-4H-1,2,4-triazolyl-3-thio)acetamides 3. When the latter are boiled with phosphorus oxychloride, intramolecular cyclization occurs and 6-arylamino-3-methyl-7H[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines 4 are formed. The structure of the synthesized compounds was confirmed by 1H NMR spectroscopy data. Thus in the spectra of compounds 3a-c, a three-proton singlet from the methyl group is found in the 2.28-2.34 ppm region, a two-proton singlet from the methylene group SCH2CONH appears in the 3.94-4.02 ppm region, and a twoproton singlet from the N-amino group resonates in the 5.71-5.89 ppm region. When the spectrum is recorded again in the presence of small amounts of D2O, this signal disappears due to deuteron exchange. The NH-amide proton signal is observed in the range of 9.66-10.36 ppm. A distinctive feature of the spectra of compounds 4a-c compared with acetanilides 3a-c is the disappearance of the two-proton singlet from the N-amino group and the signal from the acetamide proton, with the appearance of an one-proton singlet from the imino group in the position 6 of the system at 8.93-9.87 ppm.
EXPERIMENTAL The 1H NMR spectra were taken on a Bruker-300 (300 MHz) in DMSO-d6, internal standard TMS. N1-(4-Ethoxyphenyl)-2-(4-amino-5-methyl-4H-1,2,4-triazolyl-3-thio)acetamide (3a). Solution of 4-ethoxyanilide of chloroacetic acid (2.13 g, 10 mmol) in ethanol (20 ml) was added to solution of compound 1 (1.3 g, 10 mmol) in aqueous ethanol (40 ml) containing K2CO3 (1.38 g, 10 mmol). The reaction mixture was boiled for 30 min and cooled down, then water (50-60 ml) was added. The colorless precipitate was filtered off, washed with water, and dried. Yield 2.85 g (93%); mp 226C (ethanol). 1H NMR spectrum, , ppm: 1.30 (3H, t, OCH2CH3); 2.28 (3H, s, CH3); 3.96 (2H, q, OCH2CH3); 4.02 (2H, s, CH2CO); 5.89 (2H, s, NH2); 6.85 and 7.43 (4H, dd, C6H4); 10.16 (1H, s, NH). Found, %: N 23.0. C13H17N5O2S. Calculated, %: N 22.8. N1-(4-Chlorophenyl)-2-(4-amino-5-methyl-4H-1,2,4-triazolyl-3-thio)acetamide (3b) was obtained similarly to compound 3a, from equimolar (10 mmol each) amounts of compound 1 and 4-ethoxyanilide of chloroacetic acid. Yield 2.71 g (91%); mp 211C (ethanol). 1H NMR spectrum, , ppm: 2.31 (3H, s, CH3); 4.02 (2H, s, CH2CO); 5.83 (2H, s, NH2); 7.31 and 7.58 (4H, dd, C6H4); 10.36 (1H, s, NH). Found, %: N 23.2. C11H12ClN5OS. Calculated, %: N 23.5. N1-(2,3-Dimethylphenyl)-2-(4-amino-5-methyl-4H-1,2,4-triazolyl-3-thio)acetamide (3c) was obtained similarly to compound 3a, from equimolar (10 mmol each) amounts of compound 1 and 2,3-dimethyl-chloroacetanilide. Yield 2.45 g (84%); mp 173C (ethanol). 1H NMR spectrum, , ppm: 2.11 (3H, s, CH3); 2.28 (3H, s, CH3); 2.34 (3H, s, CH3); 3.94 (2H, s, CH2CO); 5.71 (2H, s, NH2); 6.92-7.31 (3H, m, C6H3); 9.66 (1H, s, NH). Found, %: N 24.2. C13H17N5OS. Calculated, %: N 24.0. 6-(4-Ethoxyphenylamino)-3-methyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine Hydrochloride (4a). Acetamide 3a (2 g, 6.5 mmol) in phosphorus oxychloride (30 ml) was boiled for 2-3 h; the excess oxychloride was evaporated under vacuum to dryness. The oily residue was triturated with ether. The crystallized precipitate was filtered off, washed with water, and dried. Yield 1.75 g (83%); mp >250C (ethanolDMF). 1H NMR spectrum, , ppm: 1.31 (3H, t, OCH2CH3); 2.46 (3H, s, CH3); 3.98 (2H, q, OCH2CH3); 4.01 (2H, s, SCH2); 6.95 and 7.63 (4H, dd, C6H4); 9.87 (1H, s, NH). Found, %: N 21.3. C13H15N5OSHCl. Calculated, %: N 21.5. 6-(4-Chlorophenylamino)-3-methyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine Hydrochloride (4b) was obtained similarly to compound 4a, from acetamide 3b (2 g, 6.7 mmol). Yield 1.97 g (93%); mp >250C (ethanolDMF). 1H NMR spectrum, , ppm: 2.46 (3H, s, CH3); 3.88 (2H, s, SCH2); 7.27 and 7.71 (4H, dd, C6H4); 9.75 (1H, s, NH). Found, %: N 22.4. C11H10ClN5SHCl. Calculated, %: N 22.1. 517
6-(2,3-Dimethylphenylamino)-3-methyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (4c). Acetamide 3c (2 g, 6.9 mmol) in phosphorus oxychloride (30 ml) was boiled for 2-3 h; the excess oxychloride was evaporated under vacuum to dryness and the oily residue was triturated with 10% NaOH solution (50 ml). The crystallized precipitate was filtered off, washed with water, and dried. Yield 1.38 g (74%); mp >250C (ethanol DMF). 1H NMR spectrum, , ppm: 2.14 (3H, s, CH3); 2.19 (3H, s, CH3); 2.26 (3H, s, CH3); 3.92 (2H, s, SCH2); 7.05-7.27 (3H, m, C6H3); 8.93 (1H, s, NH). Found, %: N 25.5. C13H15N5S. Calculated, %: N 25.6.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. M. C. Hosur, M. B. Talawar, U. V. Laddi, Rajani S. Bennur, and S. C. Bennur, Indian J. Chem., 34B, 707 (1995). N. F. Eweiss and A. A. Bahajaj, J. Heterocycl. Chem., 24, 1173 (1987). Zi-Yi Zhang and Xiao-Wen Sun, Heterocycles, 48, 561 (1998). A. M. Demchenko, T. A. Bukhtiarova, K. G. Nazarenko, and M. O. Lozinskii, in: Nitrogen-Containing Heterocycles and Alkaloids [in Russian], Iridium Press, Moscow (2001), Vol. 1, p. 291. Jag Mohan and Vinntt Kumar, Indian J. Chem., 37B, 183 (1998). P. Vainilavicius, R. Smicius, V. Jakubkiene, and S. Tumkevicius, Monatsh. Chem., 132, 825 (2001). N. N. Kolos, V. D. Orlov, E. Yu. Slobodina, E. Yu. Yur'eva, S. P. Korshunov, and Ziong Van Tue, Khim. Geterotsikl. Soedin., 267 (1992). O. V. Dyablo and A. F. Pozharskii, Khim. Geterotsikl. Soedin., 1155 (1997).
518

UNUSUAL REACTION OF 5-ETHYL4,5,6,7-TETRAHYDROTHIENO[3,2-c]PYRIDINE WITH ETHYL PROPIOLATE
L. G. Voskressensky, T. N. Borisova, S. V. Akbulatov, A. I. Chernyshev, and A. V. Varlamov Keywords: thienopyridine, ethyl propiolate, Hofmann reaction. Earlier we carried out tandem transformations of tetrahydropyrrolo[3,2-c]pyridines treated with acetylenedicarboxylic ester [1]. We showed that the direction of these transformations is strongly affected by the properties of the solvent. In nonpolar solvents, 2- and 3-vinyl-2(3)-dimethoxycarbonylvinylaminoethyl(isopropyl)pyrroles are formed [2]; in polar solvents, a mixture of these pyrroles with tetrahydropyrrolo[2,3-d]azocines is formed [3]; and in protic solvents, 3-alkoxy(hydroxy)alkyl-2-dimethoxycarbonylvinylaminoalkylpyrroles are formed [4].
H _ CO2Et +N S
N S 1 OEt
CO2Et
H2C H2C
EtO2C N CO2Et A 2 S N S
In continuing our study of the synthetic limits for tandem transformation of condensed tetrahydropyridines, we have studied the reaction of 5-ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (1) [5] with ethyl propiolate in ethanol. The reaction occurs readily at 20C. However, instead of the expected ethoxymethylthiophene A, we find that the ethyl ester of (E)-3-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acrylic acid (2) is formed in 52% yield, probably due to Hofmann cleavage in the initially formed zwitterion. In __________________________________________________________________________________________ Russian People's Friendship University, Moscow 117198; e-mail: lvoskressensky@sci.pfu.edu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 617-618, April, 2004. Original article submitted February 2, 2004. 0009-3122/04/4004-05192004 Plenum Publishing Corporation 519
the 1H NMR spectrum of compound 2, we observe signals from all the protons in the molecule. The signals from the 4-CH2 protons have the form of an AB spectrum at 4.90 and 4.50 ppm (2J = 15.5 Hz). The protons from the N-vinyl group resonate at 6.45 and 6.03 ppm. The spinspin coupling constant 3J = 13.5 Hz indicates a trans configuration for the enamine moiety. In the mass spectrum, there is a low-intensity molecular ion peak with m/z 237 (6%). The maximum peak with m/z 110 is due to retrodiene decomposition of the M+ ion [6], which leads to formation of a thiatropylium cation.
EtO2C N S
.+
S
+. S
Thus we have established a novel direction for tandem conversions of condensed tetahydropyridines with activated alkynes. (E)-3-(6,7-Dihydro-4H-thieno[3,2-c]pyridin-5-yl)acrylic Acid Ethyl Ester (2). A mixture of compound 1 (3 mmol) and ethyl propiolate (3.5 mmol) in absolute ethanol (15 ml) was stirred for 5 h at 20C. The solvent was evaporated down to 2/3 volume and cooled, and the precipitated crystals were filtered out. Yield 0.37 g (52%); mp 203-204C. Mass spectrum, m/z (Irel, %): 237 [M]+ (6), 192 (18), 167 (25), 152 (20), 111 (20), 110 (100), 44 (35). 1H NMR spectrum (400 MHz, DMSO-d6), , ppm (J, Hz): 7.51 (1H, d, J = 5.4, 2-H); 6.91 (1H, d, J = 5.4, 3-H); 6.44 (1H, d, J = 13.5, =CHN); 6.00 (1H, d, J = 13.5, =CHO2Et); 4.93 (1H, d, J = 15.5, 4-H); 4.52 (1H, d, J = 15.5, 4-H); 4.04 (1H, m, 6-H); 3.79 (1H, m, 6-H); 3.63 (2H, q, J = 7.3, CH2CH3); 3.17 (1H, m, 7-H); 2.90 (1H, m, 7-H); 1.23 (3H, t, J = 7.3, CH2CH3). Found, %: C 60.43; H 6.12; N 5.92. C12H15NO2S. Calculated, %: C 60.76; H 6.33; N 5.90. We would like to thank the Russian Foundation for Basic Research for financial support (grant No. 02-03-32941).
REFERENCES 1. 2. 3. 4. 5. 6. A. V. Varlamov, T. N. Borisova, L. G. Voskressensky, B. Nsabimana, and A. I. Chernyshev, Heterocycl. Commun., 7, 461 (2001). L. G. Voskressensky, A. V. Varlamov, and T. N. Borisova, in: Abstracts of the 18th International Congress of Heterocyclic Chemistry, Yokohama, Japan (2001), p. 294. A. V. Varlamov, T. N. Borisova, L. G. Voskressensky, T. A. Soklakova, L. N. Kulikova, A. I. Chernyshev, and G. G. A1exandrov, Tetrahedron Lett., 43, 6767 (2002). L. G. Voskressensky, T. N. Borisova, A. V. Varlamov, L. N. Kulikova, and T. A. Soklakova, Molecular Diversity, 6, 207 (2003). O. W. Gooding, C. C. Beard, Heterocycles, 32,1777 (1991). E. E. Stashenko, P. I. Zakharov, T. N. Borisova, A. V. Varlamov, B. S. Subbotin, N. S. Prostakov, Khim. Geterotsikl. Khim., 212 (1988).
520
UNUSUAL REACTION OF 1-ACETYL5-BROMO-1H-INDOLE-2,3-DIONE WITH ETHYL (TRIPHENYLPHOSPHORANYLIDENE)ACETATE

V. O. Kozminykh, K. Sh. Lomidze, E. N. Kozminykh, and A. N. Berezin Keywords: 1-acetyl-5-bromo-1H-indole-2,3-dione, diethyl ester of 2,1'-diacetyl-5,5'-dibromo-1,2'dioxo-1,1',2,2',7,8,8a-heptahydrospiro{benzo[cd]indole-6,3'-indole}-7,8-dicarboxylic acid, ethyl (triphenylphosphoranylidene)acetate. Isatins readily react with methylene triphenylphosphoranes to form 3-methylene-1,3-dihydro-2H-indol2-ones, which are of practical importance [1-5]. As a result of reaction of 1-acetyl-5-bromo-1H-indole-2,3-dione with the ethyl ester of triphenylphosphoranylidene acetic acid (ethoxycarbonylmethylene triphenylphosphorane), in addition to the usual Wittig reaction product (the yellow ethyl ester of (2Z)-(2-oxo-1,2-dihydro3H-indol-3-ylidene)acetic acid (1)), we unexpectedly isolated a colorless "dimer": the diethyl ester of 2,1'diacetyl-5,5'-dibromo-1,2'-dioxo-1,1',2,2',7,8,8a-heptahydrospiro{benzo[cd]indole-6,3'-indole}-7,8-dicarboxylic acid (2).
Br N O Me COMe OEt Br O N O 1 Me O N Br O CO2Et N O CO2Et COMe 2 O O Ph3P=CHCO2Et Ph3P=O
Br
Thus a mixture of 1-acetyl-5-bromo-1H-indole-2,3-dione (1.34 g, 5 mmol) and the ethyl ester of triphenylphosphoranylidene acetic acid (1.74 g, 5 mmol) was boiled in benzene (70 ml) for 2.5 h. The solvent was evaporated and the residue was recrystallized from alcohol (compound 1 was obtained) and dioxane (spiro compound 2 was obtained). __________________________________________________________________________________________ Perm State Pedagogical University, Perm 614990, Russia; e-mail: kvo@pi.ccl.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 619-620, April, 2004. Submitted January 3, 2004. 0009-3122/04/4004-05212004 Plenum Publishing Corporation 521
Ethyl Ester of (2Z)-(1-Acetyl-5-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)acetic Acid (1). Yield 0.96 g (57%); mp 150-151C (ethanol). 1H NMR spectrum (300 MHz, DMSO-d6), , ppm: 1.37 (3H, t, OCH2CH3); 2.63 (3H, s, COCH3); 4.34 (2H, q, OCH2CH3); 6.82 (1H, s, CH); 7.63 (1H, d, 7-H); 8.15 (1H, d, 6-H); 8.78 (1H, s, 4-H). Found, %: C 50.11; H 3.30; Br 23.37; N 3.85. C14H12BrNO4. Calculated, %: C 49.73; H 3.58; Br 23.63; N 4.14. Diethyl Ester of 2,1'-Diacetyl-5,5'-dibromo-1,2'-dioxo-1,1',2,2',7,8,8a-heptahydrospiro{benzo[cd]indole-6,3'-indole}-7,8-dicarboxylic Acid (2). Yield 0.50 g (30%); mp 236-237C (dioxane). 1H NMR spectrum (500 MHz, DMSO-d6), , ppm: 0.83 (3H, t, OCH2CH3); 1.28 (3H, t, OCH2CH3); 2.60 (3H, s, COCH3); 2.67 (3H, s, COCH3); 3.60 (2H, q, OCH2CH3); 3.63 (1H, t, 8-H); 3.68 (1H, d, 7-H); 4.19 (2H, q, OCH2CH3); 4.30 (1H, d, 8a-H); 7.47 (1H, d, 3-H); 7.52 (1H, s, 4'-H); 7.56 (1H, d, 7'-H); 7.87 (1H, d, 4-H); 8.02 (1H, d, 6'-H). Mass spectrum, m/z (Irel, %): 676 [M]+ (11), 632 [M - CO2]+ or [M - CH3CO - H]+ (2), 602 [M - CO2Et H]+ (8), 588 [M - 2CO2]+ or [M - 2CH3CO - 2H]+ (2), 560 (4), 538 (3), 517 (3), 500 (2), 471 (3), 444 (7), 427 (2), 409 (3), 382 (2), 366 (8), 337 [1/2 M - H]+ (5), 309 (3), 284 (5), 269 (3), 243 (3), 229 (6), 214 (8), 201 (5), 188 (3), 164 (2), 140 (2), 115 (2), 82 (5), 55 (3), 43 [CH3CO]+ (100). Found, %: C 49.56; H 3.24; Br 23.82; N 4.33. C28H24Br2N2O8. Calculated, %: C 49.73; H 3.58; Br 23.63; N 4.14.
REFERENCES 1. 2. 3. 4. 5. H. A. Brandman, J. Heterocycl. Chem., 10, 383 (1973). G. Tacconi, A. G. Invernizzi, and G. Desimoni, J. Chem. Soc., Perkin Trans. 1, 1872 (1976). E. N. Kozminykh, E. S. Berezina, and V. O. Kozminykh, Zh. Obshch. Khim., 66, 1128 (1996). E. N. Kozminykh, E. S. Berezina, V. E. Kolla, S. A. Shelenkova, E. V. Voronina, and V. O. Kozminykh, Khim.-Farm. Zh., 31, No. 2, 31 (1997). F. H. Osman and F. A. El-Samahy, Phosphorus, Sulfur, Silicon Relat. Elem., 134/135, 437 (1998).
522
NOVEL SYNTHESIS OF SUBSTITUTED BENZIMIDAZOLES BY REDUCTION OF ESTERS OF 4-ALKYLAMINO-3,5-DINITROBENZOIC ACIDS BY TIN CHLORIDE
A. V. Vlaskina and V. P. Perevalov Keywords: esters of 4-alkylamino-3,5-dinitrobenzoic acids, esters of 7-amino-6-chloro-2-R-1Hbenzimidazole-5-carboxylic acids, tin chloride, reduction of nitro group. We have established that in reduction of isopropyl esters of 4-benzylamino-, 4--phenethylamino-, and 4-butylamino-3,5-dinitrobenzoic acids 1-3 by tin chloride in isopropyl alcohol in the presence of hydrogen chloride, closure of the imidazole ring occurs, leading to formation of isopropyl esters of 7-amino-6-chloro-2-R1H-benzimidazole-5-carboxylic acids 4-6.
NO2 Cl RNH2 i-PrO2C NO2 i-PrO2C 13 NO2 NO2 NHR SnCl2 Cl NH2 i-PrOH, i-PrO2C HCl 46 H N R N
1, 4 R = Ph, 2, 5 R = Bn, 3, 6 R = Pr
Under the same conditions, the substituted benzimidazole is not formed from the methyl ester of 2-benzylamino-3,5-dinitrobenzoic acid. We hypothesize that, in accordance with the data in [1, 2], in compounds 1-3 initially intermediate reduction of the nitro group to the hydroxylamine occurs, followed by its rearrangement accompanied by introduction of a chlorine atom into the position ortho to the amino group formed. In the second step, intramolecular cyclization of the intermediate o-nitroso-N-alkylamino compound when treated with tin chloride occurs more rapidly than further reduction to the amino compound. The 1H NMR spectra were recorded on a Bruker WP-200 (200 MHz) spectrometer in DMSO-d6 solutions; chromato-mass spectral studies of the isolated compounds were conducted using a Hewlett Packard 6890 gas chromatograph/mass spectrometer with a 5973 mass spectrometric detector, an HP-5MS column (30 m 0.25 mm), phase layer thickness 0.25 m, helium as the carrier gas (40 cm/s), 20:1 flow splitter, source temperature 150C, injector temperature 230C, temperature gradient from 40C to 320C (25C/min), ionization by electron impact. 3,5-Dinitro-4-chlorobenzoic acid was obtained according to the procedure in [3]; the isopropyl ester was obtained as for the methyl ester in [3]. __________________________________________________________________________________________ D. I. Mendeleev Russian Chemical Technological University, Moscow 125047; e-mail: sark@muctr.edu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 620-622, April, 2004. Submitted October 17, 2003. 0009-3122/04/4004-05232004 Plenum Publishing Corporation 523
Isopropyl Ester of 4-Benzylamino-3,5-dinitrobenzoic Acid (1). A solution of benzylamine (1.8 ml, 16.5 mmol) in i-PrOH (10 ml) was poured into a boiling solution of the isopropyl ester of 3,5-dinitro-4chlorobenzoic acid (5.0 g, 16.5 mmol) and Et3N (2.3 ml, 16.5 mmol) in i-PrOH (50 ml). This was held for 20 min, and then the suspension formed was poured into hot water and boiled for 20 min, then acidified with a 10% HCl solution (pH 6), and cooled down. The yellow precipitate was filtered out. After recrystallization from i-PrOH, we obtained 5.2 g (88%) of compound 1; mp 93-95C. Compounds 2 (yield 98%; mp 112-115C) and 3 (yield 67%; mp 64-65C) were obtained by a similar procedure. Isopropyl Ester of 7-Amino-6-chloro-2-phenyl-1H-benzimidazole-5-carboxylic Acid (4). A reducing solution was prepared by passing HCl through a suspension of SnCl22H2O (4.3 g, 16.0 mmol) in i-PrOH (15 ml) until the precipitate was completely dissolved. Compound 1 (1.5 g, 4.0 mmol) in i-PrOH (20 ml) was dissolved by heating; the solution was saturated with HCl, and the reducing solution was slowly added dropwise over a period of 1.5 h. The reaction mass first had a dark red color, and then the color became lighter. When the reaction was complete, the solvent was distilled off under vacuum and the residue was mixed with a 10% HCl solution, and then the precipitated flocs were filtered out. After recrystallization from dilute AcOH, we obtained 0.6 g (44%) of compound 4; mp 202-205C. 1H NMR spectrum, , ppm (J, Hz): 8.30-8.33 (2H, m, Ph); 7.667.69 (3H, m, Ph); 7.23 (1H, s, Harom); 5.14 (1H, m, J = 6.48, CH); 1.35 (6H, d, J = 6.48, CH3). Mass spectrum, m/z: 329, 331 [M]+. Found, %: C 61.70; H 4.90; N 12.70. C17H16ClN3O2. Calculated, %: C 61.91; H 4.86; N 12.75. Compound 5 was obtained similarly. Yield 22%; mp 211-214C. 1H NMR spectrum, , ppm (J, Hz): 7.37-7.46 (5H, m, Ph); 7.20 (1H, s, Harom); 5.15 (1H, m, J = 6.01, CH); 4.49 (2H, s, CH2); 1.33 (6H, d, J = 6.01, CH3). Mass spectrum, m/z: 343, 345 [M]+. Found, %: C 62.90; H 5.22; N 12.20. C18H18ClN3O2. Calculated, %: C 62.88; H 5.24; N 12.23. Compound 6 was obtained as for compound 4. Yield 11%; mp 189-192C. 1H NMR spectrum, , ppm (J, Hz): 7.18 (1H, s, Harom); 5.15 (1H, m, J = 6.48, CH); 3.04 (2H, t, J = 7.40, CH2CH2CH3); 1.91 (2H, q, J = 7.40, CH2CH2CH3); 1.34 (6H, d, J = 6.48, CH3); 0.97 (3H, t, J = 7.40, CH2CH2CH3). Mass spectrum, m/z: 295, 297 [M]+. Found, %: C 56.88; H 6.00; N 14.20. C14H18ClN3O2. Calculated, %: C 56.85; H 6.09; N 14.21.
REFERENCES 1. 2. 3. C. C. Price, D. B. Guthrie, J. Am. Chem. Soc., 68, 1592 (1946). H. E. Heller, E. D. Hughes, C. K. Ingold, Nature, 168, 909 (1951). F. Ullmann, Ann., 366, 82 (1909).
524
NOVEL STEREOSELECTIVE SYNTHESIS OF CHIRAL NONRACEMIC cis- AND trans-3-ALKYL-4-AMINOPIPERIDINES

E. R. Lukyanenko, A. A. Borisenko, and G. V. Grishina Keywords: 4-aminopiperidines, cis and trans isomers, stereoselective synthesis. We have shown that previously unknown optically pure trans-(3R,4R) isomers 4a-d with diastereomeric excess de > 99% and the diastereomeric pair of cis-(3S,4R),-(3R,4S) isomers 3a-d with de < 71% of N-[(1S)-1-phenylethyl]-4-amino-1,3-dialkylpiperidine are formed in 46%-90% yield by sequential lithiation and alkylation by alkyl halides of the chiral imines 1a,b, with formation of Z-(3S)-3-alkyl- and Z-(3R)-3-alkylimines 2a-d followed by their reduction by sodium borohydride in ethanol. The entire reaction sequence is carried out with no isolation of intermediates. The cis isomers 3a-d and the trans isomers 4a-d were separated by column chromatography on aluminum oxide; their structure and diastereomeric purity were established from elemental analysis, chromatomass spectrometry, and 1H, 13C NMR spectra. The cis and trans structure of isomers 3a-d and 4a-d was established by analysis of the vicinal spinspin coupling constants for the 3-H and 4-H protons of the piperidine ring, using high-resolution one-dimensional and two-dimensional 1H NMR spectroscopy. Formation of only the
Me O (S)-PhCH(Me)NH2 N R Me N Ph R N R Z-2ad
1
Ph 1. LiNEt2 2. R1Hal
N R 1a,b Me N Ph R N R
1
Me 3. NaBH4 HN Ph R N R 3ad
1
Me HN Ph R N R 4ad
1
1 R = Bn, b R = Me; 24 a R = Bn, R1 = Me; b R = Me, R1 = Me; c R = Me, R1 = Allyl; d R = Me, R1 = CH2OMe
__________________________________________________________________________________________ M. V. Lomonosov Moscow State University, Moscow 119899, Russia; e-mail: grishina@org.chem.msu.su. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 622-624, April, 2004. Submitted February 4, 2004. 0009-3122/04/4004-05252004 Plenum Publishing Corporation 525
Z-form of the diastereomeric imines 2a-d is supported by the presence in the 13C NMR spectra of reaction samples (after completion of the alkylation process) of signals from the C(4) atoms of only the Z-form of the (3S)and (3R)-isomers of imine 2b; signals from the E-form of these isomers appear after these samples have been held for 10 h at room temperature, which is quite consistent with the data in [1-3]. Key factors determining the diastereoselectivity of the process are the ratio of the Z-(3S)- and Z-(3R)-imines 2a-d formed and the subsequent preference for hydride attack on one side of the prochiral C=N bond. The absolute configuration of the target 1,3-dialkyl-4-aminopiperidines was determined by the stereochemical correlation method, in line with the configuration of (3R,4S)-cis-N-[(1S)-1-phenylethyl]-4-amino-1-methyl-3-(4-methylbenzyl)piperidine, as established by X-ray diffraction. The stereoselective synthesis we developed is the first general approach to optically pure trans isomers and enriched cis isomers of 3-alkyl-4-aminopiperidines, which are chiral synthons for obtaining next-generation analgesics. Synthesis of the Compounds 3a-d and 4a-d, Using as an Example the cis and trans Isomers of N-[(1S)-1-phenylethyl]-4-amino-1,3-dimethylpiperidine (3b, 4b) (General Procedure). The reaction was carried out under an argon atmosphere using a septum and a syringe procedure. (1S)-N-(1-Methylpiperidin-4ylidene)-1-phenylethylamine (3 g, 13.9 mmol) in absolute THF (5 ml) was added to a solution of lithium diethylamide, obtained at -10C by stirring for 10 min a mixture of solutions of HNEt2 (1.32 g, 18 mmol) in absolute THF (20 ml) and a 1.6 N BuLi solution in hexane (11.3 ml, 18 mmol). The reaction mixture was stirred for 30 min at -10C, then cooled down to -80C; then MeI (2.56 g, 18 mmol) was added and the mixture was stirred for 1 h at -80C. Then in sequence we added absolute ethanol (2 ml) and NaBH4 (0.68 g, 18 mmol) and then stirred this mixture for another hour at -80C. Then the reaction mixture was allowed to stand with vigorous stirring in order to warm up to room temperature. The solvents were evaporated off, the residue was decomposed by careful addition of 6 N HCl until evolution of hydrogen stopped; then water (10 ml) was added, and a 20% NaOH solution was added up to pH 12-13 and it was extracted with CH2Cl2 (2 30 ml). The organic extracts were combined and dried with anhydrous Na2SO4, and then the solvent was evaporated off. The residue was chromatographed on a column with Al2O3 in the hexaneEtOAc system with a gradient from 30:1 to 1:1. We obtained 1.42 g (44%) of the cis-(3S,4R) and (3R,4S) diastereomeric pair 3b and 1.45 g (45%) of the trans-(3R,4R) diastereomer 4b of N-[(1S)-1-phenylethyl]-4-amino-1,3-dimethylpiperidine. (3S,4R),(3R,4S)-3b: de 29%, Rf 0.6 (Alufol, hexaneacetone 1:1), []D20 -59 (c 2.0, benzene). Chromato-mass spectrum (retention time), m/z (Irel, %): (3R,4S)-3b: (12.08 min) 232 [M]+ (1); 127 [M - CH(CH3)C6H5]+ (100); 105 [CH(CH3)C6H5]+ (49); 96 (64); (3S, 4R)-3b: (12.20 min) 232 [M]+ (1); 127 [M - CH(CH3)C6H5]+ (100); 105 [CH(CH3)C6H5]+ (61); 96 (88); (3R,4R)-4b: de > 99%, Rf 0.2 (Alufol, hexaneacetone 1:1), []D20 -108 (c 2.0, benzene). 1 H NMR spectrum (400 MHz, CDCl3, TMS), , ppm (J, Hz): 0.89 (3H, d, J = 6.2, 3-CH3); 1.04 (1H, br. s, NH); 1.26 (1H, m, J = 4.0, J = 11.0, J = 12.4, J = 12.6, 5a-H); 1.31 (3H, d, J = 6.4, CH(CH3)C6H5); 1.49 (1H, t, J = 10.8, J = 10.8, 2a-H); 1.53 (1H, m, J = 2.1, J = 10.8, J = 6.2, J = 12.0, 3a-H); 1.71-1.78 (2H, m, J = 11.8, J = 12.4, J = 3.0, J = 11.0, J = 4.1, J = 11.1, 4a-,6a-H); 2.04 (1H, d of pseudo q, J = 3.0, J = 12.7, J = 4.1, J = 2.9, 5e-H); 2.17 (3H, s, 1-CH3); 2.69 (1H, dd, J = 7.3, J = 2.1, 2e-H); 2.78 (1H, m, J = 4.0, J = 4.1, J = 11.1, J = 1.0, 6e-H); 3.95 (1H, q, J = 6.4, CH(CH3)C6H5); 7.19-7.33 (5H, m, CH(CH3)C6H5). 13C spectrum (CDCl3, 100 MHz, TMS), , ppm: 16.3; 25.7; 31.9; 37.2; 46.1; 54.1; 55.1; 57.3; 63.0; 126.6, 126.6, 128.2, 146.0. Chromato-mass spectrum (retention time), m/z (Irel, %): (12.09 min) 232 [M]+ (1); 127 [M-CH(CH3)C6H5]+ (44); 105 [CH(CH3)C6H5]+ (48), 96 (100). Found, %: C 47.10; H 4.37; N 16.06. C15H24N22C6H3N3O7 (dipicrate). Calculated, %: C 46.96; H 4.38; N 16.23. This work was carried out with the financial support of the Russian Foundation for Basic Research, grant No. 01-03-32781a.
526
REFERENCES 1. 2. 3. G. V. Grishina, E. L. Gaidarov, and A. E. Aliev, Khim. Geterotsikl. Soedin., 1369 (1992). R. R. Fraser, J. Banville, and K. L. Dhawan, J. Am. Chem. Soc., 100, 7999 (1978). A. I. Meyers, D. R. Williams, G. W. Erickson, S. White, and M. Druelinger, J. Am. Chem. Soc., 103, 3081 (1981).
527
7-OXO-3,7-DIHYDRO- AND 1,2,7-TRIOXO1,2,3,7-TETRAHYDROPYRANO[3,2-e]INDOLES

T. E. Khoshtariya, L. T. Bochoidze, and K. T. Batsikadze Keywords: pyranoindoles. Various coumarin compounds are found in plants and have high biological activity, including anticoagulating, spasmolytic, antitumor, and other properties [1-3]. The importance of the bicyclic indole system is well known; many of its derivatives have valuable therapeutic properties (indomethacin, mexamine, methisazone, etc.) [4]. We have synthesized tricyclic condensed systems in which indole (or isatin) and coumarin moieties are combined. We used the E. Fischer and Sandmeyer reaction to "add" the pyrrole ring onto the bicyclic coumarin system. From 6-aminocoumarin 1 [5], we obtained the hydrazine 2 [5], converted by reaction with pyruvic acid to hydrazone 3, the indolization of which followed by decarboxylation of the unpurified acid 4 lead to the target product 5 in acceptable yield.
O
4 3 2 5 6
NH2 O
4 3 2
5 6
H N
7
C=O
8 7
9 d e
b c a
O
1
7 8
NH
3
O
1
HC=NOH O
4 3 2 5 6
1
4 3 2 5 6 7
6 + N2Cl O COOH N C Me
1 9 8 7 d e c b 2 a 9 8 7 d e
O
6
4 5
H N
7
7 NH2. HCl
O
1
O
1
2
c
1 b a 3 2
4 3 2
5 6
H N
7
COOH NH
O
1
O
6
4 5
NH
3
O
6
4 5
__________________________________________________________________________________________ Georgian Technical University, Tbilisi 380075; e-mail: t_khoshtaria@yahoo.com. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 624-626, April, 2004. Submitted August 3, 2003; revision submitted October 17, 2003. 528 0009-3122/04/4004-05282004 Plenum Publishing Corporation
The same starting amine 1 was converted, via the isonitroso acetamide of coumarin 6, to 1,2,7-trioxo1,2,3,7-tetrahydropyrano[3,2-e]indole (7). This is the first time that a coumarin-based synthesis of a tricyclic condensed system with an indole moiety in the molecule has been carried out. No analogs of the compounds we obtained have yet been observed in nature. It is certainly of interest to study the pharmacological properties of such condensed heterocycles because of the many diverse types of physiological activity they exhibit, which is typical for the derivatives of each of them individually [6, 7]. 7-Oxo-3,7-dihydropyrano[3,2-e]indole (5). 6-Coumarinyl hydrazine hydrochloride 2, obtained by diazotization of 6-aminocoumarin 1 followed by reduction of the diazo solution by SnCl22H2O in hydrochloric acid by the method in [5], was converted by reaction with pyruvic acid to hydrazone 3, which when heated up to 90C in the ethyl ester of polyphosphoric acid yields 7-oxo-3,7-dihydropyrano[3,2-e]indolyl-2-carboxylic acid (4). With no additional purification, 1 g (4 mmol) of the unpurified acid 4 was held at a temperature of 150-160C under a stream of inert gas until evolution of CO2 stopped (~2-3 min). The residue was purified on a column with aluminum oxide (eluent etherhexane 3:1). Yield of compound 5: 0.4 g (50%); mp 146-147C. IR spectrum, , cm-1: 3410 (NH). UV spectrum, max, nm (log ): 249 (4.33), 255 (4.66), 263 (4.88), 279 (4.91), 295 (4.95), 315 (4.55), 320 (4.35). 1H NMR spectrum (250 MHz, DMSO-d6), , ppm: 11.52 (NH); 6.90 (1H); 7.54 (2H); 7.65 (4H); 7.11 (5H); 6.45 (8H); 8.45 (9H), J4,5 = 9.0; J8,9 = 9.8; J1,2 = 3.0; J1,3 = 2.2; J2,3 = 2.6 Hz. Found, %: C 71.2; H 4.0; N 7.4. C11H7NO2. Calculated, %: C 71.4; H 3.8; N 7.6. 6-Isonitrosoacetamidocoumarin (6). Crystalline sodium sulfate (180 g), 6-aminocoumarin 1 (100 mmol) in water (100 ml) with addition of hydrochloric acid (10 ml) and hydroxylamine hydrochloride (330 mmol) in water (50 ml) were added successively to a solution of chloral hydrate (100 mmol) in water (50 ml). The mixture was heated to boiling and held for 3 h. The hot solution was filtered, the precipitate was washed with cold water and dried. Yield 76%; mp 175-177C. IR spectrum, , cm-1: 1680 (C=O); 3290 (NH). UV spectrum, max, nm (log ): 244 (4.49), 288 (4.10), 295 (4.15), 333 (4.25), 350 (4.00). 1H NMR spectrum (250 MHz, DMSO-d6), , ppm: 10.4 (NH); 7.67 (CH); 12.2 (OH); 7.79 (7H); 7.40 (8H); 8.09 (3H); 6.49 (4H), J3,4 = 9.0; J7,8 = 9.0; J6,8 = 2.3 Hz. Found, %: C 57.1; H 3.3; N 12.4. C11H8N2O4. Calculated, %: C 56.9; H 3.4; N 12.1. 1,2,7-Trioxo-1,2,3,7-tetrahydropyrano[3,2-e]indole (7). Compound 6 (100 mmol) was added in small portions with stirring to 95% sulfuric acid heated up to 50C. When addition was complete, the temperature was brought up to 90C and held there for another 2 h. The reaction mixture was cooled down, transferred to a beaker with crushed ice (200 g), and allowed to stand overnight. The precipitated crystals were filtered out, carefully washed with water, and dried. Yield 70%; mp 255-257C. IR spectrum, , cm-1: 3415 (NH); 3250 (NHO=C); 1700 (C=O). 1H NMR spectrum (250 MHz, acetone-d6), , ppm: 11.29 (NH); 7.29 (4H); 7.59 (5H); 6.69 (8H); 8.48 (9H); J4,5 = 9.0; J8,9 = 9.8; J9,5 = 0.4 Hz. Found, %: C 61.3; H 2.2; N 6.2. C11H5NO4. Calculated, %: C 61.4; H 2.3; N 6.5.
REFERENCES 1. 2. 3. 4. 5. 6. 7. V. I. Malikov and A. I. Saidkhodzhaev, Khim. Prirod. Soedin., 250 (1998). V. I. Malikov and A. I. Saidkhodzhaev, Khim. Prirod. Soedin., 560 (1998). M. D. Mashkovskii, in: Medicinal Drugs [in Russian], Meditsina, Moscow (1993), Pt. 2, pp. 82, 84. M. D. Mashkovskii, in: Medicinal Drugs [in Russian], Meditsina, Moscow (1993), Pt. 1, pp. 216, 367; Pt. 2, pp. 394, 527. G. T. Morgan and F. M. G. Micklethwait, J. Chem. Soc., 85, 1230 (1904). J. K. Sugden and T. O. Yoloye, Pharm. Acta Helv., 53, No. 3/4,65 (1978). N. N. Suvorov, Zh. Vses. Khim. Obshch. im. D. I. Mendeleeva, 21, 144 (1976). 529
UNUSUAL CONDENSATION OF 6,7-DIMETHOXY-1,3,3-TRIMETHYL3,4-DIHYDROISOQUINOLINE WITH 4-ANTIPYRYLIDENEBARBITURIC ACID

Yu. V. Shklyaev Keywords: antipyrin-4-carbaldehyde, barbituric acid, 6,7-dimethoxy-1,3,3-trimethyl-3,4-dihydroisoquinoline. The reaction of arylidene barbituric acids with 1-methyl-3,4-dihydroisoquinolines, leading to the corresponding 8-azasteroid derivatives, has been described [Ref. 1, p. 208]. This reaction can be carried out both with the arylidene barbituric acid itself and in the three-component variant: by heating a mixture of the aldehyde, barbituric acid, and 1-methyl-3,4-dihydroisoquinoline in DMF [Ref. 1, p. 426]. Since 8-azasteroids with substituents in the 7 position have not yet been described, it was of interest to carry out the analogous reaction with 6,7-dimethoxy-1,3,3-trimethyl-3,4-dihydroisoquinoline. However, as we have established, the reaction of 6,7-dimethoxy-1,3,3-trimethyl-3,4-dihydroisoquinoline (1) with a mixture of 4-antipyrin aldehyde 2 and barbituric acid 3, or with the product 4 obtained by condensation of compounds 2 and 3, leads to formation of only 1-(6,7-dimethoxy-3,3-dimethyl-1,2,3,4tetrahydro-1-isoquinolylidene)-2-(3,5-diaza-2,4,6-trioxo-1-cyclohexylidene)ethane (5), which judging from the spinspin coupling constant of the vicinal protons (~15 Hz), exists in the trans conformation.
MeO MeO 1 Me N Me Me OHC Me N 2 Ph N Me O O NH 3 O
HN
MeO MeO
1
Me Me NH
2
MeO MeO Me N
Me Me
H N
O Me
O HN 5 O
O NH
+O
N H 4
N Ph
Me
__________________________________________________________________________________________ Institute of Technical Chemistry, Urals Branch of the Russian Academy of Sciences, Perm 614990; e-mail: cheminst@mpm.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 627-628, April, 2004. Submitted June 10, 2003; revision submitted January 29, 2004. 530 0009-3122/04/4004-05302004 Plenum Publishing Corporation
Probably in the first step of the reaction, the antipyrylidene barbituric acid 4 undergoes Michael addition to the enamine form of 3,4-dihydroisoquinoline 1, but the product 6 proves to be unstable under the reaction conditions and eliminates the antipyrin moiety.
MeO MeO
Me Me NH
150 oC
CH2
MeO MeO
Me Me NO H N
NH
O
O
O
5
Me
N N Ph Me 6
1-(6,7-Dimethoxy-3,3-dimethyl-1,2,3,4-tetrahydro-1-isoquinolylidene)-2-(3,5-diaza-2,4,6-trioxo-1cyclohexylidene)ethane (5). Dry DMF (10 ml) was added to a mixture of compound 1 (2.21 g, 0.01 mol), barbituric acid (1.28 g, 0.01 mol), and antipyrin carbaldehyde (2.16 g, 0.01 mol); the mixture was heated to boiling. The mixture become homogeneous at first, but after 1-2 min abundant precipitation began. The mixture was heated for 15 min, cooled down, and poured into 100 ml water; the red precipitate was collected, dried, and crystallized from alcohol. Yield 59%, decomposes at ~217C. IR spectrum, , cm-1: 3300 (NH); 1730, 1660 (C=O); 1615 (C=N). The 1H NMR spectrum was taken on a Bruker AM 300 (300 MHz) in DMSO-d6, internal standard Me4Si, , ppm: 1.31 (6H, s, gem-CH3); 2.87 (2H, s, CH2-4); 3.83 (3H, s, OCH3-6); 3.89 (3H, s, OCH3-7); 6.96 (1H, s, 5-H); 7.28 (1H, s, 8-H); 7.55 (1H, d, H(1) vinyl); 8.30 (1H, d, H(2) vinyl); 9.70 (1H, s, NHisoquin); 10.01 (1H, br. s, NHbarb); 10.12 (1H, br. s, NHbarb). The mass spectrum was taken on a Finnigan MAT under standard conditions (electron impact, 70 eV), m/z (Irel, %): 371 [M]+ (100); 356 [M - Me] (90); 341 [M - 2Me] (23); 296 (68); 283 [M-NHCONH] (20); 270 (45); 244 [M - barbituric acid] (50); 233 (60); 218 [M - barbituric acid CH=CH] (70); 191 [methoxy-3,3-dimethyl-1,2,3,4-tetrahydroisoquinoline] (40); 128 [barbituric acid] (38). This work was done with partial financing from a Russian Federation Presidential Grant for support of the leading scientific schools NSh-2020.2003.3 and the program of the Presidium of the Russian Academy of Sciences on "New principles and methods for directed synthesis of compounds with specific properties."
REFERENCES
1.
A. L. Mikhal'chuk and O. V. Gulyakevich, in: Nitrogen-Containing Heterocycles and Alkaloids [in Russian], Iridium Press, Moscow (2001), Vol. 2.
531
NOVEL SYNTHESIS ROUTE FOR PYRROLO[1,2-a]QUINAZOLINES

E. S. Vostrov, D. V. Gilev, and A. N. Maslivets Keywords: 2-aroylmethylene-3-aryl-4-quinazolones, hetereno[a]-2,3-dihydro-2,3-pyrrolediones. 3-Phenacylidene-1,2,3,4-tetrahydro-2-quinoxalones react with oxalyl chloride to form substituted 3-aroyl-1,2,4,5-tetrahydropyrrolo[1,2-a]quinoxaline-1,2,4-triones [1], while 2-phenacylidene-1,2-dihydroquinoxalines react to form 5-aryl-4-quinoxalinyl-2,3-dihydro-2,3-furandiones [2]. With the aim of extending the data so we can predict which of the two directions indicated above will occur, we undertook the synthesis of 2-phenacylidene-3-aryl-1,2,3,4-tetrahydro-4-quinazolones 2a,b and studied their reaction with oxalyl chloride. The structure of the substituted quinazolones 2a,b is the limiting factor for realization of one of the alternative directions for reaction of a heterocyclic enaminoketone with oxalyl chloride. Usually 2-acylmethylene-3-aryl-4-quinazolones are obtained by reaction of 2-(methyl lithium)-3-aryl-4quinazolones with esters [3] or ester condensation of 2-(methyl lithium)-3-aryl-4-quinazolones in the presence of sodium hydride [4]. We propose a novel and simple method for obtaining substituted quinazolones 2a,b by reaction of 2-phenacylidene-3,4-dihydro-1H-3,1-benzoxazin-4-one (1) with aromatic amines. When substituted quinazolones 2a,b react with oxalyl chloride under conventional conditions for synthesis of five-membered 2,3-dioxo heterocycles [1, 2], instead of the expected 3-aryl-2-(4,5-dioxo-2-phenyl-4,5-dihydro-3-furyl)-3,4dihydro-4-quinazolones (3a,b), we get 4-aryl-3-benzoyl-1,2,4,5-tetrahydropyrrolo[1,2-a]quinazoline-1,2,5triones (4a,b).
O O N H. N O N Ar O O Ph 3a,b O N N H. Ar (COCl)2 N Ph 24 a Ar = Ph, b Ar = o-MeC6H4 O O 4a,b N Ar COPh O
1 O
..O
Ph
ArNH2
.. O
2a,b
__________________________________________________________________________________________ Perm State Pedagogical University, Perm 614990, Russia; e-mail: koh2@psu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 629-630, April, 2004. Submitted November 21, 2003. 532 0009-3122/04/4004-05322004 Plenum Publishing Corporation
In the indicated reaction, probably closure of the pyrroledione ring occurs due to its greater thermodynamic stability compared with the alternative furandione ring, while in our case steric hindrances leading to closure of the furandione ring are not as important as in the case described in [2]. The described reaction is a novel route to constructing a heterocyclic system of a substituted pyrrolo[1,2-a]quinazoline. E-2-Phenacylidene-3-phenyl-1,2,3,4-tetrahydro-4-quinazolone (2a). A solution of benzoxazinone 1 (0.50 g, 1.88 mmol) and aniline (0.17 ml, 1.88 mmol) in decane (1 ml) was boiled for 1 h and then cooled down. The precipitate was filtered out. Yield 0.60 g (93%); mp 212-214C (2-propanol). IR spectrum (vaseline oil), , cm-1: 3040 broad (NH in the intramolecular hydrogen bond), 1685 (C(4)=O), 1610 broad (COPh in the intramolecular hydrogen bond). 1H NMR spectrum (250 MHz, DMSO-d6), , ppm (J, Hz): 5.04 (1H, s, C(2)=CH); 7.30-7.85 (13H, m, ArH); 8.07 (1H, d, J = 8.0, C(5)H); 15.60 (1H, s, NH). Found, %: C 77.67; H 4.73; N 8.25. C22H16N2O2. Calculated, %: C 77.63; H 4.74; N 8.23. E-2-Phenacylidene-3-o-tolyl-1,2,3,4-tetrahydro-4-quinazolone (2b) was synthesized similarly. Yield 0.60 g (90%); mp 218-219C (2-propanol). IR spectrum (vaseline oil), , cm-1: 3060 broad (NH in the intramolecular hydrogen bond), 1683 (C(4)=O), 1615 broad (COPh in the intramolecular hydrogen bond). 1 H NMR spectrum (400 MHz, DMSO-d6), , ppm (J, Hz): 2.12 (3H, s, Me); 4.96 (1H, s, C(2)=CH); 7.30-7.90 (12H, m, ArH); 8.05 (1H, d, J = 7.9, C(5)H); 15.38 (1H, s, NH). Found, %: C 77.95; H 5.05; N 7.94. C23H18N2O2. Calculated, %: C 77.97; H 5.08; N 7.91. 3-Benzoyl-4-phenyl-1,2,4,5-tetrahydropyrrolo[1,2-a]quinazoline-1,2,5-trione (4a). A solution of quinazolone 1a (0.10 g, 0.29 mmol) and oxalyl chloride (0.03 ml, 0.29 mmol) in absolute chloroform (3 ml) was boiled for 30 min under reflux and then cooled down. The precipitate was filtered out. Yield 0.10 g (95%); mp 255-256C (with decomposition, from chloroform). IR spectrum (vaseline oil), , cm-1: 1790 (C(1)=O), 1728 (C(2)=O), 1716 (C(5)=O) 1648 (COPh). 1H NMR spectrum (500 MHz, DMSO-d6), , ppm (J, Hz): 7.03-7.95 (12H, m, ArH); 8.11 (1H, d, J = 7.9, C(6)H); 8.68 (1H, d, J = 8.0, C(9)H). Found, %: C 73.07; H 3.52; N 7.10. C24H14N2O4. Calculated, %: C 73.10; H 3.55; N 7.11. 3-Benzoyl-4-o-tolyl-1,2,4,5-tetrahydropyrrolo[1,2-a]quinazoline-1,2,5-trione (4b) was synthesized similarly. Yield 0.11 g (93%); mp 230-232C (with decomposition, from chloroform). IR spectrum (vaseline oil), , cm-1: 1783 (C(1)=O), 1725 (C(2)=O), 1712 (C(5)=O), 1650 (COPh). 1H NMR spectrum (400 MHz, CDCl3), , ppm (J, Hz): 2.23 (3H, s, Me); 7.11-7.85 (11H, m, ArH); 8.23 (1H, d, J = 7.9, C(6)H); 8.82 (1H, d, J = 8.0, C(9)H). 13C NMR spectrum (100 MHz, CDCl3), , ppm: 17.79 (Me); 114.32 (C(9)); 126.25-137.21 (Ar); 156.78 (C(1)); 157.49 (C(5)); 161.71 (C(3a)); 173.49 (C(2)), 186.50 (COPh). Found, %: C 73.50; H 3.95; N 6.88. C25H16N2O4. Calculated, %: C 73.53; H 3.92; N 6.86. This work was carried out with the financial support of the Russian Foundation for Basic Research (grants Nos. 01-03-32641, 02-03-96411, 03-03-06634). The NMR spectra were taken at the Ural Regional NMR Spectroscopy Center, URAL-NMR (Russian Foundation for Basic Research grant No. 00-03-40139).
REFERENCES 1. 2. 3. 4. I. V. Mashevskaya, R. R. Makhmudov, G. A. Aleksandrova, O. V. Golovnina, A. V. Duvalov, and A. N. Maslivets, Khim.-Farm. Zh., 35, 20 (2001). A. N. Maslivets, N. Yu. Lisovenko, O. V. Golovnina, E. S. Vostrov, and O. P. Tarasova, Khim. Geterotsikl. Soedin., 556 (2000). T. L. Rathman, M. C. Sleevi, M. E. Krafft, and J. F. Wo1fe, J. Org. Chem., 45, 2169 (1980). J. F. Wo1fe, T. L. Rathman, M. C. Sleevi, J. A. Campbell, and T. D. Greenwood, J. Med. Chem., 33, 161 (1990).
533
NOVEL SYNTHESIS FOR 4-HYDROXY2-PHENYL-2H-BENZOTRIAZOLES

G. L. Artamonov and V. P. Perevalov Keywords: 6-amino-7-chloro-2-phenyl-2H-benzotriazole-4-carboxylic acid, 4-hydroxy-7-nitro-2phenyl-2H-benzotriazole, 7-hydroxy-2-phenyl-2H-benzotriazole-4-carboxylic acid, diazotization. We have established that in diazotization of 6-amino-2-phenyl-7-chloro-2H-benzotriazole-4-carboxylic acid (1) in aqueous sulfuric acid using a large excess of NaNO2, followed by holding the mixture at the boiling point, the compound 5-diazo-7-nitro-2-phenyl-2H-benzotriazol-4-one (2) is formed. In diazotization with an equimolar amount of NaNO2, from compound 1 we obtain 6-diazo-7-oxy-2-phenyl-2H-benzotriazole-4carboxylic acid (3). When quinonediazides 2 and 3 are treated with sodium hydroxide in aqueous ethanol, respectively 7-nitro-2-phenyl-2H-benzotriazol-4-ol (4) and 7-hydroxy-2-phenyl-2H-benzotriazole-4-carboxylic acid (5) are formed. For compound 4, the signals in the 1H and 13C spectra were assigned using the two-dimensional heteronuclear techniques HSQC and HMBC.
N NaNO2, excess H2SO4, H2O, Cl H2N N N Ph N COOH 1 NaNO2 H2SO4, H2O, COOH 3 N N + O N N Ph N NaOH, soln. in EtOH COOH 5 OH N N Ph N NO2 2 N + O N N Ph N NaOH, soln. in EtOH NO2 4 OH N N Ph N
The 1H and 13C NMR spectra were recorded on a Bruker DRX-500 (500 MHz and 125 MHz respectively) in DMSO-d6 at 30C. Two-dimensional HSQC and HMBC spectra were obtained using the gradient technique. __________________________________________________________________________________________ D. I. Mendeleev Russian University of Chemical Technology, Moscow 125047; e-mail: sark@muctr.edu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 631-632, April, 2004. Submitted October 17, 2003. 534 0009-3122/04/4004-05342004 Plenum Publishing Corporation
5-Diazo-7-nitro-2-phenyl-2H-benzotriazol-4-one (2). A solution of sodium nitrite (4.00 g, 58 mmol) in water (20 ml) was poured in portions into a suspension (cooled down to 20C) of 6-amino-7-chloro-2-phenyl2H-benzotriazole-4-carboxylic acid 1 (1.00 g, 3.47 mmol) in water (16 ml) and 95% sulfuric acid (20 ml); the reaction was monitored to make sure that nitrogen oxides were not evolved too vigorously. After 15 min, the reaction mass was brought to the boiling point, held there for 1.5 h, cooled, and poured over ice. The precipitate was filtered out and recrystallized from ethanol. Yield 0.31 g (32%); mp 220-222C (decomp.). IR spectrum (KBr), , cm-1: 2160 (=N+=N-); 1540, 1344 (NO2). 1H NMR spectrum, , ppm: 9.11 (1H, s, 6-H); 8.20 (2H, m, 2'-, 6'-H); 7.61 (3H, m, 3'-,4'-, 5'-H). Mass spectrum, m/z: [M]+ 282. Found, %: C 51.03; H 2.19; N 29.74. C12H6N6O3. Calculated, %: C 51.07; H 2.14; N 29.78. 6-Diazo-7-oxy-2-phenyl-2H-benzotriazole-4-carboxylic Acid (3). A solution of (0.24 g, 3.47 mmol) sodium nitrite in water (20 ml) was poured in portions into a suspension (cooled down to 20C) of compound 1 (1.00 g, 3.47 mmol) in water (16 ml) and 95% sulfuric acid (20 ml). After 15 min, the reaction mass was brought to 60C, held there for 1.5 h, and poured over ice. The precipitate was filtered out and recrystallized from ethanol. Yield 0.50 g (52%); mp 185-186C (decomp.). IR spectrum (KBr), , cm-1: 2148 (=N+=N-); 1700 (C=O). 1H NMR spectrum (DMSO-d6), , ppm: 8.45 (1H, s, 5-H); 8.20 (2H, m, 2'-, 6'-H); 7.61 (3H, m, 3'-, 4'-, 5'-H). 13C NMR spectrum, , ppm: 172.0 (7-C); 164.6 (COOH); 148.0 (8-C); 141.8 (9-C); 140.0 (1'-C); 132.7 (5-C); 130.9 (3'-, 5'-C); 130.6 (4'-C); 121.0 (2'-, 6'-C); 109.9 (4-C); 84.4 (6-C). Mass spectrum, m/z: [M]+ 281. Found, %: C 55.56; H 2.54; N 24.74. C13H7N5O3. Calculated, %: C 55.52; H 2.51; N 24.90. 4-Hydroxy-7-nitro-2-phenyl-2H-benzotriazole (4). A 50% NaOH solution (5 ml) was added to a solution of compound 2 (0.50 g, 1.77 mmol) in ethyl alcohol (100 ml), and the mixture was heated to the boiling point. After 15 min, the reaction mass was cooled and then made slightly acidic with 10% HCl. The precipitate obtained was filtered out and recrystallized from ethanol. Yield 0.17 g (38%); mp 211-212C. IR spectrum (KBr), , cm-1: 3616, 3428 (OH); 1530, 1356 (NO2). 1H NMR spectrum, , ppm (J, Hz): 8.45 (1H, d, J = 7.0, 6-H); 8.32 (2H, m, 2'-H, 6'-H); 7.63 (3H, m, 3'-,4'-, 5'-H); 6.85 (1H, d, J = 7.0, 5-H). 13C NMR spectrum, , ppm: 157.2 (4-C); 139.9 (9-C); 139.2 (1'-C); 138.2 (8-C); 131.3 (6-, 4'-C); 130.1 (3'-, 5'-C); 128.6 (7-C); 120.7 (2'-, 6'-C); 107.4 (5-C). Mass spectrum, m/z: [M]+ 256. Found, %: C 56.13; H 3.08; N 21.81. C12H8N4O3. Calculated, %: C 56.25; H 3.15; N 21.87. 7-Hydroxy-2-phenyl-2H-benzotriazole-4-carboxylic Acid (5). Obtained as for compound 4, from compound 3 (0.5 g, 1.78 mmol) in ethyl alcohol (100 ml) and 50% NaOH (5 ml). The compound was recrystallized from dilute acetic acid. Yield 0.15 g (33%); mp 203-204C. IR spectrum (KBr), , cm-1: 1685 (C=O). 1H NMR spectrum, , ppm (J, Hz): 11.60 (1H, br. s, OH); 8.32 (2H, m, 2'-, 6'-H); 8.04 (1H, d, J = 7.8, 5-H); 7.65 (3H, m, 3'-, 4'-, 5'-H); 6.81 (1H, d, J = 7.8, 6-H). Mass spectrum, m/z: [M]+ 255. Found, %: C 61.23; H 3.48; N 16.43. C13H9N3O3. Calculated, %: C 61.18; H 3.55; N 16.46.
535
OXIDATION OF HETEROCYCLIC COMPOUNDS BY PERMANGANATE ANION. (REVIEW)

A. T. Soldatenkov, A. V. Temesgen, and N. M. Kolyadina Data on the oxidative transformations of heterocyclic compounds with permanganate anion are reviewed. Keywords: permanganate anion, oxidation. The oxidation reactions of organic compounds make up one of the most important regions of chemistry, the principal objective of which is the synthesis of oxygen-containing substances. Among the various oxidizing agents currently used in synthesis [1, 2] the most widespread are manganese compounds, which make it possible both to introduce oxygen-containing functions into the initial molecules and to realize dehydrogenation, aromatization, decyclization, cyclization, and coupling reactions. The literature on the use of the variablevalence compounds of manganese in organic synthesis, and this includes reviews, is very comprehensive [3-10], and a considerable proportion of it has been devoted to the oxidation of organic substances by permanganates. Potassium permanganate, as the most readily available of these reagents, is most often used for oxidation. Apart from this compound, however, it is also possible to use the sodium, copper(II), magnesium, silver, zinc, and ammonium salts. On account of their suitable solubility in organic solvents tetraalkylammonium, benzyltrialkylammonium, and triarylphosphonium permanganates make it possible to oxidize substrates in nonaqueous media [2, 7]. Analysis of the literature shows that there are hardly any reviews that deal systematically with the oxidation of heterocyclic compounds in the presence of permanganates. In order to fill this gap the present review was undertaken in order to analyze research of the last 15-20 years on the main types of controlled oxidative transformation of heterocyclic compounds under the influence of the permanganate anion. Transformation of side substituents in the heterocycle, the production of oxo groups at the ring atoms, the dihydroxylation of partially hydrogenated heterocycles, dehydrogenation and aromatization, oxidative coupling, and decyclization and the formation of heterocycles are discussed.
1. TRANSFORMATIONS OF SIDE SUBSTITUENTS IN HETEROCYCLES This section contains data on oxidative transformations in alkyl, alkenyl, hydroxyalkyl, formyl, and thiol groups present in the initial heterocyclic compounds. During oxidation of 5-methyl-substituted 2-(2-benzimidazolyl)furan 1 in the KMnO4H2O system (30C, 1.5 h) it is possible to obtain the corresponding furancarboxylic acid with a 21% yield only in the form of __________________________________________________________________________________________ Russian Peoples' Friendship University, Moscow; e-mail: nKolyadina@sci.pfu.edu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 643-669, May, 2004. Original article submitted October 4, 2000. 0009-3122/04/4005-05372004 Plenum Publishing Corporation 537
the potassium salt 2, since acidification leads to complete decarboxylation [11]. (The yield of the furan 3 amounted to 44%.) At the same time the thienyl derivative 1 (X = S, 80C) is converted into the stable free acid 4 (yield 27%).
KMnO4 R S 4 COOH R X 1 Me R O 2 HCl COOK CO2 R O 3
X = O, S; R = 1-methyl-2-benzimidazolyl
Methyl groups in the triazole rings of bis-1,2,4-triazolo[3,4-d]-1,2,4-triazolo[3,4-f]furazano[3,4-b]pyrazines are oxidized to carboxyl groups by the action of potassium permanganate in aqueous solutions [12]. In certain cases dealkylation of the alkyl-substituted heterocycles is observed under the conditions of oxidation, and this makes it possible to synthesize the unsubstituted heterocycles. For example, the methyl and dimethylaminoethyl group at position 5 of the tetrazoles 5 undergo oxidative cleavage on heating with potassium permanganate (60-98C) [13, 14]. This reaction is recommended as a convenient method for the production the un substituted tetrazole 6.
N N R N N
N N N N H H 6 5 5 R = Me; Me2NCH2CH2
The methyl group in 2-halopicoline N-oxides is oxidized to carboxyl, and the presence of the halogen reduces the resistance of the heterocycle to oxidation [15]. The oxidation of 5,5'-dimethyl-2,2'-bipyridine gave a carboxylic acid that had a powerful inhibiting effect on the propylhydroxylase responsible for the deposition of collagen in the human organism [16]. On heating potassium permanganate oxidizes the dimethyl-substituted xanthones 7 [17] or phenoxaphosphine 10-oxides 8 [7] with the formation of dicarboxylic acids 9 or 10. According to data in [18], the methyl group in the 6-methyluracil derivative is not oxidized by aqueous potassium permanganate. Instead of the expected carboxylic acid the N-oxide of the iminol tautomer of the initial substrate was isolated.
X Me O 7, 8 7, 9 X = C=O, 8, 10 X = O=PPh Me HOOC O 9, 10 X COOH
The methylene group in bis(2-benzodiazolyl)methanes is oxidized by potassium permanganate to a secondary alcohol and/or ketone group [19]. During study of the transformations of alkenyl substituents at the nitrogen atom in -lactams 11 it was established that they are eliminated under very mild conditions with the formation of the N-unsubstituted heterocycle 12 [20].
538
R1 N O 11
R2
R1 N
R2
R3
12
R1 = OPh; R2 = Ph; R3 = CH=CH2, CH=CHMe
2-Phenyl-5-phenylethynylfuran 13 is oxidized by potassium permanganate with a satisfactory yield to the dicarbonyl derivative 14 [1].
OO Ph O 13 C CPh Me2CO / H2O Ph O 14 CCPh 5371%
The hydroxylation of the cis-tetrahydropyranyl-substituted alkene 15 was realized [21]. It is assumed that the double bond is attacked by the electrophilic permanganate from the side opposite to the pyran ring, in which the C(5)O bond must be in the s-cis conformation in order to form the single glycol 16.
H O O O O O 15 16 C C Me H C O H
OH C Me OH
In [22] the O-cyclopentenyl fragment in the hydroxyquinazoline 17 was successfully hydrogenated with potassium permanganate in the THFH2OKOH system. The obtained 4-(trans-3,trans-4-dihydroxycyclopentanr-yloxy)quinazoline 18 and its quaternary salts were promising as anticancer agents.
O N N 17 N NH
HO
OH
O 18 54%
During synthesis of the antibiotics fuzarinic acid and its analogs 19 potassium permanganate was used for oxidation of the -styryl group to a carboxyl group in the pyridines 20 without affecting the n-butyl substituent at the C(5) atom [23]. 539
R2 Bu N 20 R1 Bu
R2
N 19
COOH
R1 = CH=CHPh, CH2OH; R2 = H, Me, NO2, OMe, Cl
If bis(pyridine)silver permanganate is used hydroxymethyl groups can be oxidized to carbaldehyde groups [2]. Thiophene-2,5-dimethanol was converted quantitatively by this reagent into the dialdehyde 22 [24]. During an attempt at the analogous oxidation of furan-2,5-dimethanol, however, furan-2,5-dicarboxylic acid 23 was isolated with a yield of 56%. Hydroxymethyl substituents in xanthones of type 7 [17] and in pyridines 20 [23] are converted into carboxyl groups by the action of potassium permanganate.
Ph S 22 Ph
X = S, R = Ph
R X 21
AgMnO4
X = O,
OHC
CHO
HOH2C
CH2OH R = H HOOC
O 23
COOH
The 1-hydroxyethyl group in 1,2,3-1H-benzotriazoles was oxidized into a hydroxycarbonylmethyl group (potassium permanganate in aqueous acetic acid) [25]. The benzotriazolylacetic acids obtained here exhibit herbicidal characteristics. The oxidation of carbaldehyde substituents to carboxyl groups takes place particularly readily. Thus, an almost quantitative yield of 2-furancarboxylic acid is obtained during the oxidation of furfural with permanganate anion generated in a diaphragm-free electrochemical cell from an alkaline solution of manganese dioxide [26]. In the case of the oxidation of 2-pyrrolecarbaldehyde with potassium permanganate in aqueous acetone at 40C the yield of the corresponding acid amounted to 69% [27]. When the reaction temperature was reduced to 25C the oxidation rate decreased by 2.5 times, and when the temperature was raised above 40C decarboxylation occurred. It is also possible to obtain the corresponding hetarenecarboxylic acids with yields of 58-90% by the analogous oxidation of 2-formylthiophene [28], 3-formylindole [29], 3-formyl--carbolin [30], and 3-quinolinecarbaldehyde [31, 32]. 2-Nitrophenylthio-substituted benzimidazoles and benzothiazoles were oxidized to their sulfonyl derivatives with good yields with the aim of producing antimicrobial agents [33]. A series of 5-alkylthio- and arylthiotetrazoles 24 were converted into the corresponding sulfonyl derivatives 25 by oxidation under the conditions of phase-transfer catalysis (tetrabutylammonium bromide chloroformaq. acetic acid) [34, 35]. In the case of R1 = H and R2 = Ph only the disulfide is formed.
O R 2S N N N 24 N N N 25 R1 R2 S O N N
R1
R1 = H, Me, Et, CH2Ph; R2 = Me, Et, n-Bu, CH2Ph, C6H4Me-p, C6H4NO2-m
540
In the synthesis of activated haptenes, which are used in the production of monoclonal antibodies, potassium permanganate is effective for oxidation of the sulfide side group in the pyridine 26 to methylsulfonyl (aqueous acetic acid). The yield of the sulfone 27 amounted to 87% [36].
NO2 MeS N 26 O MeS O N 27 NO2
Arylthio groups in benzo[f]quinolines are oxidized by a 1% aqueous solution of potassium permanganate to the corresponding sulfones, which were tested as antibacterial agents [37]. Alkylthio groups in 1,5naphthiridines and arylthio groups in uracils [33] were converted by the potassium permanganate/acetic acid system into sulfonyl groups. According to data in [38], sulfenamide groups in 1,2,4-triazole are successfully oxidized to sulfonamide groups. A similar synthesis was realized with the aim of studying the inhibition of anhydrases and reducing ocular pressure. A series of heterocyclic bissulfonamides, which proved to be good inhibitors of zinc-containing anhydrases, were synthesized by analogous oxidation [39].
2. THE FORMATION OF OXO GROUPS AT THE RING ATOMS OF A HETEROCYCLE In a number of cases potassium permanganate deposited on aluminum oxide secures high selectivity of oxidation and simplifies isolation of the products. 1,3-Dihydrobenzofuran 28 is easily oxidized to the lactone 29 by this reagent [40].
O 28 29 O O 91%
At the same time its isomer 2,3-dihydrobenzofuran was found to be stable under these conditions even during prolonged oxidation (up to 217 h). In an analogous system derivatives of benzopyran 30 and dibenzopyran 31 are converted with high yields into the lactone 32 [41] and the ketone 33 [40] respectively.
O O O
Me 30
Me
R 32
R = H, Me, Et, CH2Ph O O
31
33
541
1,4-Disubstituted tetrahydropyridines 34 were converted into the unsaturated lactams 35 by the brief action of aqueous potassium permanganate in acetonitrile at 20C [42-44].
R2 R2
N R1 34
R1 35 R1 = Me, CH2Ph, CH2C6H4Cl-p; R2 = Ph, 4-Py, CH=CHPh
The N-acetyltetrahydroisoquinolines 36 and the quaternary salts of dihydroisoquinolines 37 were oxidized with good yields to tetrahydro-1-isoquinolinones 38 by potassium permanganate under the conditions of phase-transfer catalysis (crown ether) [45]. Isoquinolinium and quinolinium quaternary salts are also converted into the corresponding N-substituted 1-isoquinolones and 2-quinolones.
R R1 37 N _ X + R2 R1 38 O R N R2 R R1 36 N R2
R, R1 = H, OMe, NO2 ; R2 = Me, Et, CH2Ph, COEt, COMe, COPh, CHO
It was found that 4H-selenopyrans 39 are easily oxidized by potassium permanganate (heating in acetone/acetonitrile) to -selenopyrones 40 (yields 45-65%) [46].
O R1 R1 Se 39 R = Ph; R1 = H, Me R R1 R1 Se 40 R
Silaazaanthracenes 41 are oxidized with high yields by potassium permanganate in acetone at 20C to silaazaanthrones 42 [47].
Me Si N 41 R = Ph, Me O 42 R Me Si N 90% R
In [48, 49] a series of 2-thiazolidinethiones 43 were oxidized with potassium permanganate to thiazolidinones 44 and their S,S-dioxides 45 under the conditions of phase-transfer catalysis. The authors note a marked increase in the effectiveness of oxidation to the dioxides 45 if benzoic acid is added to the reaction mixture. 542
R1 R2 S 43 N
CH2Ph S
R1 R2 S 44 N
CH2Ph
R1
+
O
R2 S O
CH2Ph N O O 3370%
45
R1 = H, Et; R2 = H, CH2Ph, i-Pr
3. DIHYDROXYLATION OF PARTIALLY HYDROGENATED HETEROCYCLES Aqueous solutions of potassium permanganate were used for the dihydroxylation of partially reduced heterocycles containing a C=C double bond (the Wagner method). The reaction is usually conducted in the cold in a neutral or weakly alkaline medium, while the cis-1,2-diols are formed with moderate yields. Oxidation in an acidic medium or without cooling often leads to the products from more profound transformations. 3,4-Dehydrobutyrolactone 46 is converted with a good yield into the 3,4-dihydroxylactone 47, in which the cis isomer is formed with 60% selectivity [50].
H BnO O 46 O HO H BnO O 47 O OH
It was established that in aqueous THF only cis-2,5-dimethoxy-2,5-dihydrofuran (48) undergoes dihydroxylation, giving the product 49 [1, 51]. The trans isomer 48 only forms the diol 50 if the THF is replaced by ethanol.
HO OH MeO H H O 50 OMe HO EtOH / H2O MeO O 48 H OMe KMnO4TFHH2O H O MeO 49 OH H OMe
Oxidation of the unsaturated five-membered lactam 51 in the KMnO418-crown-6CH2Cl2 system gives the diol 52 with a yield of 65% [52].
OTBS O N O BOC 51 O O HO N BOC 52 O OH OTBS O
TBS = tert-butyldimethylsilyl, BOC = tert-butoxycarbonyl
The Wagner reaction was used successfully for the cis dihydroxylation of the dihydropyrans 53 (in a neutral medium) [53-55]. The ratio of the diastereomeric glycols 54 is determined by the nature of the substituent R1. 543
R2 R3 R4 R3
R2
OH
OH
R1
R4
R1
53 54 R1 = H, Me, CH2Ac, OMe, OEt, OCH2Ph, NHCOOEt; R2 = H, Me; R3 = H, OAc; R4 = H, Me, CH2OH, CONH2, OMe, OAc
In the synthesis of analogs of the antibiotic griseusin 55 cetyltrimethylammonium potassium permanganate was used successfully for the cis dihydroxylation of the spirofused dihydropyran ring in the initial compound 56 (20C, 3 h) [56].
Me O O O HO HO O O 56 O 55 O Me
The N-alkoxycarbonyltetrahydropyridines 57 are dihydroxylated smoothly by an aqueous solution of potassium permanganate in the cold to the diols 58 [57]. However, the simultaneous presence of two methyl groups at the double bond or replacement of the N-alkoxycarbonyl substituent by an N-methyl greatly reduces the yield of the diols (by two or more times). The introduction of a phenyl radical at the C(4) atom completely deactivates the piperideine ring in compound 59.
R3 R2 N R1 57 N R1 58 R1 = COOMe, COOEt, Me; R2, R3 = H, Me R3 OH OH R2 N COOMe 59 Ph
It was later established [58-61] that a slight modification of the conditions for the Wagner reaction (its realization not in the cold but at 25-35C) activates the 4-arylpiperideines 60. Here, however, the latter are converted not into the expected piperidinediols but into the dihydroxylactams 61. It was found that this oxohydroxylation reaction takes place through preliminary oxidation of the initial tetrahydropyridines 60 to their 2-oxo derivatives, which are then easily dihydroxylated [44, 62].
Ar R2 R2 N R1 60 N R1 61 Ar OH OH O
R1 = Me, Et, CH2Ph; R2 = H, CH2OAc; Ar = Ph, 4-Py
544
During the action of potassium permanganate on oligonucleotides or on DNA (62, where R is the nucleotide or DNA residue) under mild conditions it was established that of all the purine and pyrimidine bases only thymine reacts selectively, being converted into the cis-glycol of dihydrothymine 63 [63].
O HN O N R 62 Me HN O N R 63 O Me OH OH
4. DEHYDROGENATION AND AROMATIZATION OF HETEROCYCLES The permanganate ion has found fairly widespread use in the chemistry of heterocyclic compounds as a dehydrating and aromatizing agent. Thus, with potassium permanganate 2,9-dimethyldihydrodibenzofuran 64 undergoes dehydration with simultaneous oxidation of the methyl groups to carboxyl groups [64]. With phenylenediamine the obtained diacid 65 forms a highly heat-resistant polymer.
Me
Me
HOOC COOH
O
64
O
65
The substituted pyrazolines 66 are converted by potassium permanganate into good yields of the corresponding pyrazoles 67 [65].
Ar R2 N H 66 N R1 Ar R2 N H 67
1 2
R1 N
Ar = Ph, C6H4Me-p; R , R = COPh, COC6H4Me-p, COC6H4OMe-p, COOEt
The substituted triazolines 68 readily undergo aromatization with potassium permanganate in the presence of phase-transfer catalysts. The yields of the triazoles 69 were 50-70% [66].
R3 N N N R1 68 R2 N N N R1 69 R2 R3
R1 = Me, C6H4Cl-p, C6H4Me-p, R2 = 4-Py, 2-quinolyl, COOEt, R3 = H, Me, Ph
In [67] it was established that the diazoline 70 is oxidized by potassium permanganate in acetic acid at room temperature after only 1 h. The main reaction path here is aromatization of the heterocycle to compound 71 as a result of removal of the N-acetyl group and dehydrogenation. The structure of the minor products 72 and 545
73 makes it possible to assume that oxidation of the thiomethyl side group to sulfonyl occurs at the first stage. Similar results were obtained with the introduction of various substituents (Me, OMe, Cl, CN, NO2) at the para position.
Ac N N Ph S 70 SMe Ph Ac N N S 71 SO2Me 50% Ac N N Ph S 72 SO2Me 12% N N Ph O 73 S O SO2Me 6%
Under the influence of potassium permanganate tetrahydropyridine fragments may be converted into their dihydro derivatives or are fully aromatized. Thus, 3-hydroxymethyl-1-methyl-4-phenyl-1,2,3,6tetrahydropyridine is oxidized with removal of the hydroxymethyl and N-methyl groups to 4-phenylpyridine (yield 10%) [61]. It was established that oxidation of the unsubstituted 1,2,3,4-tetrahydroisoquinoline by potassium permanganate in acetone or acetonitrile at 20C is a fast exothermic aromatization reaction, leading after 20 min to isoquinoline (yield 50%) [45]. At 0C, however, dehydrogenation of the tetrahydroisoquinolines 74 occurred after a few minutes with the formation of a mixture of 3,4-dihydroisoquinolines 75 (yield 80%) and isoquinolines 76 (yield 20%). If catalytic amounts of 18-crown-6 were used high selectivity in the dihydroisoquinoline was achieved.
R2 R2 R1
74 75
R2 NH R2 R1 N
R2
+
R2 R1
76
R1 = H, Ph, C6H4NO2-p, R2 = H, OMe
In dry THF potassium permanganate can have a mild dehydrating effect. Thus, 1,2,3,4-tetrahydrocarbolins 77 are transformed selectively into the 3,4-dihydro derivatives 78 with yields of 28-94%. In some cases the nature of the substituent at the C(1) atom gives rise to complete aromatization of the heterocyclic fragment [68].
N H 77
NH R R = Ph, C6H4Hal, hetaryl
N H 78
N R
Potassium permanganate has also been used satisfactorily in the aromatization of N-unsubstituted 1,4-dihydropyridines [70, 71] in addition to the oxidation agents such as HNO3, CrO3, MnO2, and 2,3-dichloro5,6-dicyano-1,4-benzoquinone usually employed for this purpose [69]. The oxidative aromatization of 1,4-dihydropyridines 79 by the action of potassium permanganate under various conditions was studied in detail in [71]. Thus, boiling of Hantsch esters in dry benzene in the presence of potassium permanganate deposited on montmorillonite led only to the dealkylation products 80, while in the case of 4-aryl substituents only the 4-substituted pyridines 81 were formed. The use of moist benzene under analogous conditions gave a mixture of compounds 80 and 81 in ratios between 1.0:1.5 and 1.5:1.0 (total yield 80-100%). Crown ethers and TEBAC 546
catalyze the oxidation with aqueous potassium permanganate also with the formation of a mixture of pyridines 80 and 81. At the same time the oxidation of dihydropyridines with a solution of potassium permanganate in acetone or acetic acid is selective only the pyridines 81 are formed (but with lower yields of 40-45%). Irradiation of the reaction mixture with ultrasound makes it possible to reduce the reaction time to a few minutes. The dealkylationaromatization reaction presumably begins with homolytic cleavage of the NH bond with transfer of a single electron to the pyridine ring. The alkyl radical at C(4) is then removed and dimerizes. Such a mechanism is confirmed by isolation of the dimerization product and also by successful oxidation of the initial dihydropyridines even with the use of small (catalytic) amounts of potassium permanganate. The dehydrogenation products 81 are formed by a concurrent ionic mechanism.
R2 R1 Me N H 79 R1 Me R1 Me N 80 R1 R1 R2 R1 N 81 Me
+
Me Me
R1 = COOEt, R2 = H, Et, n-Pr, n-Bu, Ph, C6H4NO2-p, C6H4OMe-p
In the last 10-15 years a relatively new system containing liquid ammonia or alkylamine in mixture with potassium permanganate has been widely used for the introduction of an amino group into six-membered nitrogen heterocycles [72, 73]. Derivatives of pyridine [74, 75], quinoline [76], naphthiridines [77, 78], quinoxalines [79], and other azines [72, 73] enter into the reaction. It was established by NMR that nucleophilic addition of the ammonia or alkylamine to the heterocycle occurs at the first stage at a position determined not by the electron density but by the thermodynamic stability of the intermediate Meisenheimer adduct. The second stage involves oxidative dehydrogenation of the complex with generation of the aromatic system and the formation of amino- or alkylamino-substituted heterocycles. The sequence of transformations in 3-nitro-1,8naphthiridines 82, which are effectively aminated by methylamine at -7C at position 4 through the complex 83 and the 1,4-dihydro derivative 84 with the formation of the methylaminonaphthiridines 85 [78], is presented below. In the case where R = Cl substitution of the halogen by the methylamino group is also observed.
H NO2 N 82 N R _ N 83 + NH2Me NO2 R H NHMe NO2 N H 84 R NHMe NO2 N 85 R
R = H, NHPh, NHMe, NH2, OH, OMe, Cl
In [80] it was established that pyrimido[4,5-d]pyrimidine-2,4-dione 86 undergoes nucleophilic amination (at +7 to -75C) mostly at position 7 with subsequent oxidation by potassium or silver permanganate to the amino derivatives 87 (yields 51-83%).
O NHR1R2
HN O N Me N 86
N N 87
N NR1R2
NR1R2 = NH2, NHMe, NHEt, NHBu-t, piperidyl, morpholyl
547
It was recently established that apart from amines the 2-phenylpropionitrile carbanion, generated in situ, can add to nitro-substituted pyridine 88 (and also thiophene, furan, pyrrole, and thiazole) rings in the NH3 KMnO4 system at -70C [81]. The adducts formed here are then oxidized to the products from nucleophilic substitution of hydrogen 89. Diphenylacetonitrile and triphenylacetonitrile only give the analogous substitution products with five-membered heterocyclic nitroarenes.
R2 NO2 Me R2 NO2 Me Ph R1 = H, Cl; R2 = H, OEt CN 89 N R1
+
N 88 R1
PhCHCN
Potassium permanganate was used during the development of a one-pot method for the synthesis of 2,5-dimethylhydrazine 90 from hydroxyiminoacetone 91, where its role involved oxidative dehydrogenation of the intermediate dihydropyrazine 92 [82].
N Me N 92 Me Me N N 90 24% Me
2 MeCOCH=NOH 91
1. SnCl2, HCl 2. NaOH, KMnO4, 0 oC
Full aromatization was observed during the oxidation of tetrahydropyrimidine 93 with potassium permanganate [83].
R2 HN R1 N H 93 COOEt Me R1 N N R2 COOEt Me
R1 = C6H4NO2-o; R2 = C6H4NO2-m
The tetrahydro-2-triazinethiones 94 are gently dehydrogenated by potassium permanganate to the corresponding triazinethiones 95 under the conditions of phase-transfer catalysis [84].
Ar HN Ar N R 94 NH S Ar N
Ar N N R 95 R = Me, Et; Ar = Ph, C6H4OMe-p S
548
5. OXIDATIVE COUPLING The permanganate anion has recently found use for various intermolecular condensations, which can be classified as NN, CN, and CC oxidative coupling. Amino-substituted heterocycles having primary amino groups readily enter into NN coupling with the formation of azo compounds. The, the oxidation of 1-aminoindole with potassium permanganate in an acidic medium gave azoindole [85]. The authors point out that the reaction path depends on pH inasmuch as deamination of the aminoindole is mainly observed in a neutral medium. An analogous azo product was isolated with a good yield during the oxidation of 5-aminopyrrolopyrimidine-2,4-dione. 3-Amino-5-nitro-1,2,4-triazole in the form of the potassium salt was converted by potassium permanganate into the high-energy stable azotriazole [86]. At 20C in an acidic medium 5-amino-1-(2hydroxypropyl)-3-nitro-1,2,4-triazole 96 is converted selectively into the azo compound 97 with a yield of 75% [87]. It was noted that the use of chromium(VI) oxide leads only to oxidation of the secondary alcohol group to ketone.
O2N N N
N H2N N N
NO2
N N 2
CH2CH(OH)Me 96
Me(OH)CHCH2 97
4-Amino-3-cyanofurazan 98 is transformed after 10 min (20C) into the azafurazan 99 during oxidation with an aqueous solution of potassium permanganate [88]. In the case of 3,4-diaminofurazan trifurazans linked by azo bridges were synthesized [89]. Such high-energy molecules are of interest as a new type of potentially powerful explosive.
NC N N N 2 86%
NC N
NH2 O 98 N
O 99
A secondary cyclic amino group can also participate in NN coupling under the influence of an oxidizing agent. The possibility of oxidative N- and S-dialkylamination of benzimidazolinethiones 100 by diethylamine was demonstrated in [90].
R H N N H 100 R = Me, Cl, NO2 S HNEt2 N NEt2 R H N S NEt2
549
The condensation of pyridine with theophylline can be included among the CN coupling reactions of heterocyclic compounds [91]. Oxidation of theophylline 101 with potassium permanganate was realized in a waterpyridine solution and led to the formation of the 8-pyridiniotheophyllinate 102. It was stressed that this ylide is not formed in the absence of water.
O Me O N N Me 101 H N N O Me
+
N O
N N Me 102
N _ N
+ N
The intermolecular condensation of 4-aryl-1,2,3,6-tetrahydropyridines 103 with primary arylamines, leading to 2-aryliminotetrahydropyridines 104, was observed in [43, 92]. The key stage of this CN coupling reaction is probably removal of a hydride ion from the methylene group of the allylamine fragment of the heterocycle. The carbocation 103a), stabilized in the form of the cycloiminium ion 103b), is then attacked by the nucleophilic amine with the formation of the imine 104.
R MnO4 N Me 103 R = Ph, ; _ N Me 103a + + N Me 103b NH2Ar N Me 104 NAr R R R
2 HOMnO3
Ar = C6H4NO2-p, C6H4Br-p, C6H4N=NPh
Heterocyclic compounds containing activated CH2 or CH groups enter into oxidative CC coupling reactions. 2,4-Disubstituted 5(4H)-thiazolinones 105 were effectively dimerized by the action of potassium permanganate in acetic acid [93]. Here high yields of the symmetrical 4,4'-bithiazolones 106, the structure of which was confirmed by X-ray crystallographic analysis, were obtained. In certain cases it was possible to isolate the isomeric products from 2,2' and 2,4' cross coupling 107 and 108 respectively, indicating a free-radical mechanism for this reaction.
H R2 O S 105 O R2 N O S 106 R1 R1 2 S R2 O S 107 = Et, Ph, OEt, SEt; R2 = Me, CH2Ph, Ph N N R1 R2 KMnO4
N R1 2
R2 O S 108
R1 N R1
550
Bis(2-benzodiazolyl)methanes and also their oxaaza and thia analogs 109 enter very readily into reaction with potassium permanganate at the methylene group with the formation of compounds having various degrees of oxidation, including CC coupling products [19]. It was established that the yield of the oxidation products and the ratio depended to a significant degree on the nature of the second heteroatom in the fivemembered heterocycle and on the reaction conditions. Since compounds 110 and 111 could also be obtained in the absence of the oxidizing agent [during an attempt to synthesize complexes of the initial 109 with manganese diacetate], the authors indicated the possibility not only of radical but also of carbanionic paths for their oxidation.
R2CH2 109 R= (R2CH )2 110 N X
R2C=CR2 111
R2CHOH
R2CO
; X = O, S, NMe, NCH2Me, NCH2Ph
Recently a new oxidative CC coupling reaction of 4-aryltetrahydropyridines 112 was realized with certain CH acids 113 (acetone, methyl aryl ketones, nitromethane, and dicyanomethane) [60, 61, 94, 95]. Under the influence of potassium permanganate under mild temperature conditions these substrates undergo intermolecular reaction with the formation of 2-methylenetetrahydropyridines 114. The preferred E-configuration of the enamine fragment in compounds 114 (with R2 R3) was established by X-ray crystallographic analysis and NMR.
Ar Ar
+
N R1 112 R1
CH2R2R3 113
N R1 114
R2 R3
= Me, Et; Ar = Ph, 4-Py, paracyclophan-4-yl;
R2 = R3 = CN; R2 = H, R3 = NO2, COMe, COPh
6. DECYCLIZATION REACTIONS The potassium permanganate anion as a hard oxidizing agent can be used in the decyclization of heterocycles. This makes it possible to synthesize a series of difficultly obtainable compounds with specific arrangements of the substituents and compounds of practical significance. During the oxidation of compound 115 with potassium permanganate two products 116 and 117 from cleavage of the four-membered lactam ring were isolated [96]. The thiazolidine ring proved more stable on account of its aromaticity.
O R2 N 115 N R1 S R1 116 R1 = CH2OPh; R2 = MeOOCCMe2 S N CONHR2 CONH2
S R1 117
551
2-Acetamidomethyltetrahydrofuran 118 was oxidized to the aminolevulinic acid 119 with a high yield by potassium permanganate in a dilute aqueous solution of sulfuric acid [97].
OMe MeO O 118 CH2NHAc 1. KMnO4 / H + 2. H + / H2O
HOOC O NH2
119
The method was recommended as a convenient method for the synthesis of this selective herbicide and plant growth regulator. During oxidation with alkaline potassium permanganate at 95C the phthalide 120 was converted into the disubstituted benzoic acid 121 with a yield of 97% [98].
OMe Ar O 120 O 1. KMnO4 / KOH 2. H + 121 OMe COAr COOH
The tetrasubstituted pyridine 122 contains several potential oxidizable substituents. When its solution in acetone or aqueous butanol was heated with potassium permanganate only the furyl radicals were oxidized to carboxyl groups [18 h, yield of acid 123 70-95%] [99].
Ar Me N O 122 O Ar = C6H4OMe-p HOOC N 123 Ar Me COOH
The oxidative decyclization of substituted tetrahydropyridines 124 was studied in [43, 100]. It was found that increase in the temperature for oxidation with potassium permanganate (to 50-60C), the introduction of electron-donating substituents at C(4), the use of phase-transfer catalysis, and quaternization of the substrates resulted in cleavage of the tetrahydropyridines 124 to 1-(formylamino)alkan-3-ones 125 with yields of 43-85%. With increase in the length of the process deformylation of the amides 125, leading to the amino ketones 126, became possible.
R2 O R2CCH2CH2N(R1)CHO N R1 124 R1 = Me, Et, CH2Ph, CH2C6H4Cl-p; R2 = Me, Ph, C6H4Me-p, C6H4OMe-p, 4-Py 125 O R2CCH2CH2NHR1 126
552
The sequence of oxidation in the tetrahydropyridines 124 was studied. They are first transformed into 3,4-dihydroxy-2-piperidinones, which then undergo cyclization with the elimination of one carbon atom and the formation of amido ketones [62, 101]. The action of heat on 2,3-dichloroquinoxaline in aqueous potassium permanganate in a neutral medium led to oxidation of the benzene fragment and the formation of dichlorine-substituted pyrazinedicarboxylic acid [102]. An aqueous alkaline solution of potassium permanganate oxidizes 4,7-dihydro-1,3-dioxepins 127 destructively in the cold, giving high yields of the salts of biscarboxymethyl acetals 128 [103].
KOOC O R O R 127 O R R = H, Me COOK O R 128
During the action of potassium permanganate under the conditions of phase-transfer catalysis oxazabicyclooctene 129 underwent oxidative cleavage at the double bond. As a result a high yield of the racemic tetrahydrooxazine acid 130 was obtained [104].
R2 O N R1 R2 COOH O N
R1 COOH 129 130 R1 = COOCH2Ph; R2 = CH2NHCOCH2Cl
7. CYCLIZATION REACTIONS Such a strong oxidizing agent as potassium permanganate can be used not only for the cleavage of cyclic bonds but also for the formation of heterocycles. An example of cyclization with the formation of a threemembered nitrogen heterocycle is the oxidation of a wateracetone solution of the oxime derivative 131 with potassium permanganate. The reaction gives a high yield of the substituted 2H-aziridine 132 [105].
MeNOC O H N t-Bu
SMe
t-BuCCH(SMe)2 131
132 SO2Me
During oxidation of the tricyclic diene 133 with triethylbenzylammonium permanganate at -50C a mixture of two products was formed the expected diol 134 (yield 70%) and the oxirane derivative 135 (yield 20%) [106].
553
Me
Me
Me HO HO
Me O
Me Me
HO HO
133
TBS
134
TBS
135
TBS
The authors attributed the unusual activation of the inert exocyclic double bond to a rare case of epoxidation by the permanganate anion, which in this reaction probably occurred by intramolecular transfer of an oxygen atom in the diester 133a to its exo-double bond through the intermediate products 133b and/or the radical 133c.
Me O 133 _ O Mn O O 133a Me _ Me Me O _ O Mn O 133b O Me Me
. Mn
O O
134
O 133c
Another case of epoxidation was discovered during oxidation of the homoallyl alcohols 135 in a multiphase heterogeneous system (KMnO4CuSO4, CH2Cl2t-BuOH; 20C; 3-6 h) [107]. Here the keto lactones 137 were also isolated in addition to the oxiranes 136.
R1 R2 ( )n 135 OH ( )n 136 R1, R2 = H, Me; n = 13 O R1 R2 OH O
+
( )n O O 137
R1 R2
Presumably, the oxiranes are formed directly from the organomanganese compound 135a, while the ketolactone is preceded by the formation of the diester 135b, the ketodiol 135c, and the intramolecular cyclization products 135d.
135 R ( )n _ MnO3 135a 137 O R O O OH _ MnO2 R ( )n 135c R = CH2C(R1R2)OH O ( )n O OH 135d OH R1 R2 136
( )n
135b
554
In an analogous system the alcohols 138 undergo oxidative cyclization to the spirosubstituted -lactones 139, which were isolated with yields of 33-62% [108]. In all cases the formation of diols was not observed, which the authors attribute to the chemoselectivity of permanganate deposited on a solid support.
R R R 138 R = H, Me OH R R 139 R O O
Under the conditions of phase-transfer catalysis the dibenzylidene derivative of 2,3-diamino-2,3dimethylbutane 140 was oxidized by potassium permanganate (24 h, yield 45%) to the imidazoline 141 [109]. This imidazoline, the structure of which was confirmed by X-ray crystallographic analysis, was probably formed through transformation of the ester 142 into the zwitterion 143, which underwent cyclization to the imidazolidine 144. The latter then underwent oxidative dehydrogenation to the stable product 141.
Me Me Me Me N=CHPh N=CHPh 140 _ O O _ O Me Me Me Me N=CPh + N=CHPh H 143 Me Me Me Me COPh N Ph N H 144 COPh N Ph N Mn O O CPh H
Me Me Me Me
N N
Me Me Me Me 141
CHPh 142
A new method was proposed for the synthesis of 1,2,4-oxadiazoles 145 by oxidative heterocyclization of the oximes 146 [110]. These oximes are presumably oxidized to the nitrosimines 147. The latter are tautomers of the imino oximes 148, which undergo cyclization to the oxadiazolines 149. During oxidation the latter undergo aromatization to oxadiazoles.
R CNHCH2Ph N OH 146 R RCN=CH2Ph N O 147 RCN=CHPh N OH 148 R = C6H4NO2-p N H N O 149 Ph KMnO4 H2O / OH _
R N N O 145 Ph
555
It was shown for the case of a large series of 1,3,5-trisubstituted formazans 150 that potassium permanganate is the best oxidizing agent for their cyclization to 2,3,5-trisubstituted tetrazolium salts 151 [111, 112]. The yield of the salts 151 under the conditions of phase-transfer catalysis amounted to 70-80%. However, addition of the catalyst was evidently superfluous, since its role can be fulfilled by the tetrazolium permanganate formed from the tetrazolium hydroxide as a result of double decomposition. The stability of the salts is increased if the synthesis is conducted in an acidic aqueous medium.
R2 N N N R3 150 _ _ R1 = Ph; R2 = Alk> Ar, R3 = Ar, X = Cl , OH N H R1 KMnO4 CH2Cl2H2O / HCl (5%) R2 N N + N N R1 R3 151 _ X
A typical example of pH control of the direction of oxidative transformations is the oxidation of methadone 152 by potassium permanganate [113]. In an alkaline medium this tertiary amine undergoes effective degradation to benzophenone. However, oxidation in a neutral medium (in acetone) led to its cyclization with the formation (with high yields) of both five- and six-membered heterocycles 2-pyrrolidone 153 and 2,3-dioxopiperidine 154 (in a ratio of 4:1).
Ph Ph O Ph pH 9 Me Et NMe2 152 Ph O pH 7 Me N Me 153 Ph Ph O Ph Ph O
+
Me N Me O 154
In [114] an original method was demonstrated for transition from the carbocyclic compound 155 to the heterocyclic compound 156 by oxidation of the former with potassium permanganate in acetic anhydride. Initially the -keto dicarboxylic acid 157 is formed the cyclohexenone 155, and it is then decarbonylated with subsequent cyclization to the anhydride 156.
Ph Me Ph Me COOH COOH O 155 O 157 CO O 156 O Ph Me O
During study of the effect of the heterogeneity of the medium on the direction of oxidation of the 1,2-, 1,4-, and 1,5-dithioalkanes 158 with permanganate it was established that in solution the oxidizing agent leads to the formation of linear sulfonic acids, whereas under heterogeneous conditions (potassium permanganate, deposited on a solid support) these thiols are oxidized to five-, six-, and seven-membered 1,2-dithiocycloalkanes 159 with yields of 45-97% [115].
556
HSCH2(CH2)nCH2SH 158
KMnO4 / CuSO4 . 5H2O CH2Cl2 n = 13
S S
( )n 159
During the oxidation of the tetrahydropyrimidine 160, which has an ortho-nitrophenyl substituent at C(2), with potassium permanganate intramolecular heterocyclization, resulting in the formation of pyrimido[1,2-b]indazole 161, was observed [23].
Ar HN N H NO2 160 N COOEt Me N Me N Ar COOEt
161
Thus, the examination of recent publications has made it possible to conclude that the potential of such a well known oxidizing agent as the permanganate anion has been far from exhausted. New directions for its use both as a powerful oxidizing agent for the effective introduction of various functional groups and as an agent with oxidizing capability which can even be used for the formation of heterocycles have appeared. The work was carried out with support from the Russian Fundamental Research Fund (project 99-0332940a).
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560
SYNTHESIS OF N-SUBSTITUTED 5-ALKOXY-3-ARYL-4-METHYL2,5-DIHYDRO-2-PYRROLONES

K. V. Nikitin and N. P. Andryukhova 5-Alkoxy-1-aralkyl-3-aryl-4-methyl-2,5-dihydro-2-pyrrolones and the corresponding alkylthio derivatives were synthesized for the first time through the intermediate formation of unsymmetrical maleimides. The possibility of wide variation of the substituents at positions 1, 3, and 5 of the 2-pyrrolones was demonstrated. Keywords: amido alcohols, herbicides, pyrrolones, ethers. The interest in substituted 2,5-dihydro-2-pyrrolones 1 is due primarily to their application as components of herbicides [1-5]. However, in spite of the fact that many 3,4-homosubstituted pyrrolones 1 (R1 = R2) have been described [3-5], there is little information on compounds with different substituents at positions 3 and 4 (R1 R2) and a functional group at position 5 [6]. Two main methods are usually employed for the production of such pyrrolones. The first involves successive acylation of the amine RNH2 2 by the action of R1CH2COCl followed by alkylation of the obtained amide with the -halo ketone R2COCHR3X and, finally, condensation of the product of the last reaction to the corresponding pyrrolone.
R1CH2COCl H N O O R N R3 R1 O R2 1 MeONa O R1 N R2 R3 R R2COCHR3X
RNH2 2
R1
However, the method cannot be used for the synthesis of 5-alkoxy- or 5-alkylthio-substituted pyrrolones. The second method is used for the production of these compounds [3-5], i.e., the symmetrical cyclic anhydride 3 is converted into the symmetrical imide 4 by the action of the amine RNH2 2. The obtained imide 4 is then reduced to the hydroxypyrrolone 5, and the 5-hydroxy group of the latter is esterified with the corresponding alcohol (X = O) or thiol (X = S) R3XH 6. __________________________________________________________________________________________ M. V. Lomonosov Moscow State University, Moscow, Russia; e-mail: newscientist@mtu-net.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 670-678, May, 2004. Original article submitted January 24, 2000; revision submitted April 9, 2001. 0009-3122/04/4005-05612004 Plenum Publishing Corporation 561
O R1 O R2 O 3 O R1 R1 2 R2
O N R O 4 R1 N R 6 R2 N R O NaBH4
R2 OH 5
XR3 1 X = O, S
The production of pyrrolones 1 through the stage of 3,4-heterosubstituted pyrroles [6] is probably less widely used. In the present work we describe a new convenient and more general method for the synthesis of 3,4-heterosubstituted pyrrolones 1 that makes it possible to vary widely the substituents at positions 1, 3, and 5 of this heterocycle. The synthesis was conducted by successive arylation of the monosubstituted cyclic anhydride 7a,b, imidation of the obtained unsymmetrical anhydride 8 with the primary amine 2, reduction of the obtained imide 9 to the N-substituted 3-aryl-5-hydroxy-4-methyl-2,5-dihydro-2-pyrrolone 10, and finally substitution of the hydroxyl in the latter by the OR3 or SR3 group by the action of alcohol or thiol 6 on the hydroxypyrrolone 5 with the formation of the final pyrrolone 1.
O O R2 O 7a,b R1 R2 OH 10 7 a R2 = H, b R2 = Me O N R 6, H + 1 1. R1N2Cl 2. Ac2O R1 O R2 O 8af O 2 R1 N R R2 O 9aj O NaBH4
The unsymmetrical anhydrides 8a-f were obtained in the Meerwein reaction [7] by the reaction of arenediazonium chloride with monosubstituted anhydrides 7a,b in acetone with copper salts as catalysts (Table 1). The intermediately formed 3-aryl-4-chloro-4-methylsuccinic anhydrides were not isolated but were subjected directly to elimination of HCl in boiling acetic anhydride. The obtained unsymmetrical maleic anhydrides 8a-f were purified by vacuum distillation. It should be noted that alternative methods for the synthesis of the anhydrides 8 have been described in the literature. One of them is based on pyrolysis of the relatively inaccessible 1-ethoxyalkenyl esters of -keto acids [8]. In our case methods based on the condensation of arylacetonitriles R1CH2CN and -keto acids [9] or phenylacetic acids with -keto acids [10] did not give the desired results. 562
TABLE 1. The Characteristics of the Unsubstituted Maleic Anhydrides 8a-f

Compound* 8a 8b 8c 8d 8e 8f Ph 2-FC6H4 2-FC6H4 3-FC6H4 3-Cl-4-FC6H3 4-Cl-2F-C6H3 R1 Empirical formula 1183 105FO3 C11H7FO3 C11H7FO3 C11H6ClFO3 C11H6ClFO3 Found, % Calculated, % C H 62.30 62.51 64.42 64.08 63.88 64.08 55.09 54.91 55.34 54.91 2.77 2.62 3.13 3.42 3.44 3.42 2.70 2.51 2.66 2.51 bp, C (0.01 mm Hg) 130-135 120 127 125 145-150 148-155 mp, IR spectrum , cm-1 (CO) 1750 1758 1755 1750 1758 1760
1
Yield, %
92 (94 [8]) 68 45 44
2.3 (3H, s); 7.6 (5H, m) 7.18-7.38 (3H, m); 7.50-7.65 (1H, m); 8.34 (1H, s) 2.18 ( 3H, s); 7.2-7.6 (4H, m) 2.33 (3H, s); 7.1-7.6 (4H, m) 2.33 (3H, s); 7.0-7.8 (3H, m) 2.27 (3H, s); 7.0-7.7 (3H, m)
32 41 65 58 31 38
_______ * 8 a,c-f R2 = Me, b R2 = H.
563
564
TABLE 2. The Characteristics of the Unsubstituted Maleimides 9a-j, Obtained from the Anhydrides 8a-f and Amines 2
Compound* 9a 9b 9c 9d 9e 9f 9g 9h 9i H Ph 2-FC6H4 2-FC6H4 2-FC6H4 3-FC6H4 4-Cl-2FC6H3 Ph H R1 R Empirical formula C12H11NO2 C18H15NO2 C18H14FNO2 C20H17ClFNO2 C20H16Cl2FNO2 C20H16Cl2FNO2 C20H15Cl3FNO2 C20H17Cl2FNO2 Found, % Calculated, % H 5.60 5.45 4.89 4.78 5.00 4.79 4.50 4.11 4.24 4.11 3.44 3.54 4.90 4.58 2.69 2.76 3.51 3.34
1
mp, N 4.97 5.05 4.66 4.74 3.97 3.91 3.55 3.57 3.43 3.57 3.23 3.28 4.02 3.74 5.26 5.48 4.27 4.22 171 106 108 *3 70 74
C 77.68 77.96 73.31 73.21 67.28 67.14 60.93 61.24 60.99 61.24 56.12 56.30 64.00 64.18 51.60 51.66 61.61 61.55
H NMR spectrum, , ppm (J, Hz)
Yield, % (method)*2 90 (A) 82 (A) 86 (A) 45 (B), 78 () 55 (B) 50 (B) 48 (B) 84 () 75 (A)
PhCH2 PhCH2 PhCH2 3-ClC6H4CMe2 3,5-Cl2C6H3CMe2 3,5-Cl2C6H3CMe2 3,5-Cl2C6H3CMe2 3,5-Cl2C6H3CMe2
2.03 (3H, s); 4.6 (2H, s); 6.28 (1H, s); 7.3 (5H, m) 2.03 (3H, s); 4.73 (2H, s); 7.1-7.5 (10H, m) 2.06 (3H, s); 4.73 (2H, s); 7.1-7.50 (9H, m) 1.96 (6H, s); 2.02 (3H, s); 7.05-7.5 (8H, m) 1.94 (6H, s); 2.03 (3H, s); 7.2 ( 5, m); 7.6 (2H, m) 1.95 (6H, s); 2.02 (3H, s); 7.2-7.6 (7H, m) 1.93 (6H, s); 2.02 (3H, s); 7.2-7.5 (6H, m) 1.93 (6H, s); 2.15 (3H, s); 7.22 (3H, s); 7.4-7.6 (5H, m) 2.18 (3H, s); 5.72 (1H, s); 6.53 (1H, s); 6.90 (1H, d, J = 6.5); 7.23 (1H, d, J = 9.1) 2.30 (3H, s); 5.7 (1H, br. s); 6.99 (1H, d, J = 6.5); 7.33 (1H, d, J = 7.9); 7.5-7.7 (5H, m)
2-F-4-Cl-5-HOC6H2 C11H7ClFNO3
9j
Ph
2-F-4-Cl-5-HOC6H2 C17H11Cl3FNO3
166
50 (A)
_______ * 9a-j R2 = Me. *2 A is the method described in [1]; B is 2 mol of acetic acid in dioxane; C is 1 mol of acetic acid and 1 mol of triethylamine in benzene. *3 bp 130C (1 mm Hg); the boiling point was not given in [11].
The transition from the unsymmetrical anhydrides 8a-f to the maleimides 9 is usually realized with good yields [3-5, 11] by refluxing them with amines 2 in acetic acid. Direct alkylation of the maleimides 9 (R = H) with alcohols in the presence of triphenylphosphine also gives good results. It is surprising that the authors of [11] used alkylation of the silver salt of citraconimide for the synthesis of the N-benzylimide of citraconic acid 9a with a yield of 24%, whereas we obtained the imide 9a by the usual method (with a yield of 88%). The imidation of arylmethylmaleic anhydrides 8a-c with benzylamine also does not give rise to any complications (Table 2), but the corresponding acetanilide is formed as side product if substituted anilines are used in the reaction. In the reaction of the anhydride 8c with ,-dimethyl-3-chlorobenzylamine in acetic acid (method A [11]) the corresponding imide is hardly formed at all, and the reaction takes place with a satisfactory yield only if 2 eq. of acetic acid in dioxane is used (method B). With the use of 1 mol of triethylamine and 1 mol of acetic acid to 1 mol of the anhydride in benzene (method C) the yield of the imide becomes high. The restricted formation of the imides from amines in which the NH2 group is attached to a tertiary carbon atom can probably be explained by steric hindrances to nucleophilic attack by such an amine on the carbonyl groups of the anhydride. The reduction of the imides 9a-j to the corresponding hydroxypyrrolones was realized with sodium borohydride in methanol [3-5], since it is known that the same reaction in THF [11] leads to the formation of side products. Reduction of the imides 9 under our conditions leads to the formation of a mixture of two regioisomeric cyclic N-substituted amido alcohols: 3-Aryl-4-methyl-1,5-dihydro-2H-pyrrol-2-one 10 and 4-aryl3-methyl-1,5-dihydro-2H-pyrrol-2-one 11. During reduction of the imide 9a the succinimide 12 is formed in addition.
OH R1 9a NaBH4 10a + R2 O 11a N R + R2 O 12 R1 N R O
The structure of the individual isomeric pyrrolones 10a and 11a was established by 2D 1H NMR and 1H NOE. The acyclic aldehyde form was not found in the reaction mixture.
TABLE 3. The Reduction of the Imides 9a-j by Sodium Borohydride in Methanol

Imide 9a 9b 9c 9d 9e 9f 9g 9h 9i 9j NaBH4, mol 0.5 1 0.5 1 1 1 1 1 1 1.5 10 : 11 8:1 1:1 2:1 3.5:1 3.5:1 4:1 3.5:1 3.5:1 5:1 2:1 Yield, % 10aj 76 43 61 62 58 66 53 76 70 55 11aj 10* 53 34 18 16 17 15 23 14 25
_______ * In addition, 12% of N-benzylmethylsuccinimide is formed. 565
566
TABLE 4. Characteristics of the Synthesized Substituted 4-Methyl-1,5-dihydro-2H-pyrrol-2-ones 1a-l*

Compound*2 1a 1b 1c 1d 1e 1f PhCH2 PhCH2 PhCH2 3,5-Cl2C6H3CMe2 3,5-Cl2C6H3CMe2 3,5-Cl2C6H3CMe2 R R3 Empirical formula C13H15NO2 C14H16ClNO2 C19H19NO2 C21H21Cl2NO2 C22H23Cl2NO2 C23H25Cl2NO2 Found, % Calculated, % C H 71.55 71.87 63.40 63.28 77.59 77.79 64.77 64.62 65.60 65.35 65.91 66.03 70.03 70.27 63.00 62.85 66.08 65.81 62.28 62.34 42.44 42.83 72.92 73.29 7.07 6.96 6.22 6.07 6.68 6.53 5.30 5.42 5.49 5.73 6.17 6.02 6.11 5.90 5.45 5.51 6.06 6.16 5.62 5.45 3.10 3.32 5.63 5.83
1
H NMR spectrum, , ppm (J, Hz)
N 6.33 6.45 5.20 5.27 4.85 4.77 3.60 3.59 3.64 3.46 3.29 3.35 3.88 4.10 3.25 3.33 3.00 2.95 2.80 3.03 3.91 3.84 4.26 4.50 1.95 (3H, s); 2.98 (3H,s); 4.04 (1H, d, J = 14.8); 4.95 (1H, d, J = 14.8); 5.02 (1H, s); 5.95 (1H, s); 7.29 (5H, s) 1.92 (3H, s); 3.23.5 (4H, m); 4.12 (1H, d, J = 15); 4.8 (1H, d, J = 15); 5.06 (1H, s); 5.89 (1H, s); 7.25 (5H, s) 2.07 (3H, s); 3.03 (3H, s); 4.13 (1H, d, J = 14.8); 5.05 (1H, d, J = 14.8); 5.11 (1H, s); 7.27.6 (10H, m) 1.74 (3H, s); 1.84 (3H, s); 2.14 (3H, s); 3.17 (3H, s); 5.6 (1H, s); 7.2-7.6 (8H, m) 1.26 (3H, m); 1.7 (3H, s); 1.85 (3H, s); 2.15 (3H, s); 3.2-3.5 (2H, m); 5.6 (1H, s); 7.2-7.6 (8H, m) 1.18 (3H, d, J = 6.1); 1.27 (3H, d, J = 6.1); 1.75 (3H, s); 1.87 (3H, s); 2.19 (3H, s); 3.97 (1H, m); 5.6 (1H, s); 7.15-7.6 (8H, m) 2.11 (3H, s); 3.3-3.6 (4H, m); 4.30 (1H, d, J = 14.5); 4.98 (1H, d, J = 14.5); 5.22 (1H, s); 7.2-7.6 (10H, m) 1.16 (3H, t, J = 7.5); 1.87 (3H, s); 1.94 (3H, s); 2.14 (2H, q, J = 7.5); 2.23 (3H, s); 5.18 (1H, s); 7.2-7.5 (8H, m) 1.1-1.5 (6H, m); 1.5-1.8 (4H, m); 1.87 (3H, s); 1.95 (3H, s); 2.24 (3H, s); 2.25 (1H, m); 5.20 (1H, s); 7.2-7.4 (8H, m) 1.30 (3H, t, J = 7); 1.80 (3H, s); 1.87 (3H, s); 2.17 (3H, s); 3.76 (1H, d, J = 14); 4.02 (1H, d, J = 14); 5.79 (1H, s); 7.2-7.5 (8H, m) 2.15 (3H, s); 3.3-3.7 (4H, m); 5.85 (1H, s); 6.1 (1H, s); 7.0-7.2 (2H, m); 7.4 (1H, s) 1.94 (3H, s); 3.06 (3H, s); 4.16 (1H, d, J = 14.6); 5.04 (1H, d, J = 14.6); 5.16 (1H, s); 7.05-7.50 (9H, m)
Yield, % 92 97 90 92 90 87
Me CH2CH2Cl Me Me Et i-Pr
1g 1h 1i 1j
PhCH2 3,5-Cl2C6H3CMe2 3,5-Cl2C6H3CMe2 3,5-Cl2C6H3CMe2
CH2CH2Cl Et C6H11-cyclo CH2COOEt
C20H20ClNO2 C22H23Cl2NOS C26H29Cl2NOS C24H25Cl2NO4
95 95 96 70
1k 1l
2F-4Cl-5HOC6H2 PhCH2
CH2CH2Br Me
C13H12BrClFNO3 C19H18FNO2
91 90
_______ * Compounds 1a-l are thick oils. *2 1a,b,k R1 = H, c-j R1 = Ph, l R1 = 2-FC6H4; a-l R2 = Me.
In order to avoid inaccuracies in the separation of the isomeric pyrrolones 10 and 11 the ratio of the reduction products was determined by 1H NMR spectroscopy from the ratio of the signals for the protons at position 5 of the pyrrolone ring. For compounds 10 the position of this signal is 0.5-0.6 ppm downfield from the signal for compounds 11. The ratio of the hydroxypyrrolones 10 and 11, determined by NMR, agrees well with the yields of the individual 5-alkoxypyrrolones 1 isolated from mixtures of the isomers 10 and 11 (Table 3). During investigation of this reaction we established that the pyrrolones 10 are mostly formed, but the selectivity of reduction is low, and sometimes the pyrrolone 11 (reduction of the imide 9b) predominates in the mixture. The reduction of the citraconimides 9a and 9i is most selective. These imides, which do not have substituents at position 3, probably have the most symmetric distribution of electron density of the -system, characterized by a relatively low electron density at position 5, to which attack by the reducing agent is mostly directed. Conversely, reduction of N-benzyl-3-methyl-4-phenylmaleimide 9b, where the phenyl substituent has a +M effect, gives mostly the pyrrolone 11b. Nevertheless, all the imides with tertiary benzyl or aromatic substituents at the nitrogen atom 9d-j are reduced fairly selectively with the formation of the isomeric pyrrolones 10d-j and 11d-j in ratios (3:1)-(5:1). The target products the pyrrolones 1 (Table 4) are easily formed during treatment of the respective compounds 10 with an excess of the primary or secondary alcohol with protic acids (HCl, TsOH) as catalysts. Tertiary alcohols do not enter into the reaction, as we demonstrated for the case of tert-butyl alcohol. The transformation of the pyrrolones 11 into the alkylated derivatives 1 takes place readily under the same conditions. It is possible, therefore, not to separate the highly polar compounds 10 and 11 but to separate their isomeric alkoxylation products 1. An interesting feature of the NMR spectra of compounds 1a-c,g,l should be mentioned (Table 4). The signals of the diastereotopic protons of the methylene group of the benzyl radical in these compounds are separated from each other by 0.8-1.0 ppm with spinspin coupling constant 14-15 Hz in spite of the fact that the asymmetric carbon atom is three bonds away from these protons. A possible explanation of the such a strong effect of the asymmetry on the chemical shift may be that the nitrogen atom in these systems has a nonplanar configuration and itself becomes asymmetric. The formation of the alkylthiopyrrolones 1 in the reaction of hydroxypyrrolones 10 with thiols is similar to the reaction of the latter with alcohols but takes place noticeably more readily. A small excess of the thiol is sufficient to complete the reaction. The ease of substitution of the hydroxyl at position 5 in the investigated 1,5-dihydro-2H-pyrrol-2-ones is probably due to the formation an intermediate carbenium-immonium cation during the action of the acids on them. Nevertheless, in a number of cases alkylation of the free hydroxyl of the 5-hydroxy-1,5-dihydro-2Hpyrrol-2-one with the respective halide (ClCH2COOEt) proved more successful for the introduction of a substituent at position 5 (for example OCH2COOEt). Thus, it is possible by the proposed method to produce a wide range of compounds 1 by varying the substituents at positions 1, 3, and 5.
EXPERIMENTAL The 1H NMR spectra were measured on a Varian GEMINI-200 instrument (200 MHz) in deuterochloroform with TMS as internal standard. The mass spectra were obtained on a GCMS-OP 1000 instrument. The IR-FT spectra were recorded on a Mattson Genesis II spectrophotometer. Chromatographic separation of the mixtures was performed on Merck silica gel 40/63 . The eluant was hexaneethyl acetate. The melting points were determined on Thomas-Hoover capillary equipment and were not corrected. The commercial reagents and solvents were used without further purification. The characteristics of the synthesized compounds are given in Tables 1-4. 567
Unsymmetrical Maleic Anhydrides (8a-f) (General Procedure). To conc. hydrochloric acid (8 ml, 0.1 mol) we added water (15 ml) and substituted aniline (50 mmol). The mixture was cooled to 3C, and a saturated aqueous solution of sodium nitrite (3.45 g, 50 mmol) was added drop by drop. Then a solution of copper chloride (1.34 g, 10 mmol) and the anhydride 7 (5.6 g, 50 mmol) in a mixture of water (2 ml) and acetone (20 ml) was added. The reaction mixture was stirred at 5C for 2 h and then at room temperature for 20 h. The bottom layer was rejected, and the top layer was evaporated under vacuum, and 30 ml of acetic anhydride was added to the residue. The mixture was refluxed for 12 h and submitted to fractional distillation under vacuum, and the last fraction was collected. Unsymmetrical Maleimides (9a-j). A. To a solution of the anhydride 8 (1 mmol) in acetic acid (1 ml) we added the amine 2 (1 mmol). The mixture was refluxed for 12 h, and the reaction product was isolated by vacuum distillation or chromatography. B. To a solution of the anhydride 8 (1 mmol) in dioxane (2 ml) we added acetic acid (2 mmol) and then the amine 2 (1 mmol). The mixture was refluxed for 12 h, and the reaction product was isolated by vacuum distillation or chromatography. C. To a solution of the anhydride 8 (1 mmol) in benzene (2 ml) we added acetic acid (1 mmol), triethylamine (1 mmol), and then the amine 2 (1 mmol). The mixture was refluxed for 12-24 h, and the reaction product was isolated by vacuum distillation or chromatography. 3,4-Disubstituted 5-Hydroxy-1,5-dihydro-2H-pyrrol-2-ones (10a-j, 11a-j) (General Procedure). In methanol (80 ml) in an atmosphere of nitrogen at 40C we dissolved the hydroxypyrrolone 9 (10 mmol). With stirring we then added slowly sodium borohydride (0.38 g, 10 mmol). The reaction mixture was evaporated under vacuum, and water (10 ml) was added. The product was extracted with ethyl acetate (for compounds 9i,j the pH of the aqueous phase was previously brought to 6-7), washed with ammonium chloride solution, dried, and evaporated. The mixture of isomers 10 and 11 was used without further purification. They can be isolated in the individual form by chromatography on silica gel. 3,4-Disubstituted 5-Alkoxy-1,5-dihydro-2H-pyrrol-2-ones and 3,4-Disubstituted 5-Alkylthio-1,5dihydro-2H-pyrrol-2-ones (1a-l). General Procedure for the Volatile Alcohols. To compound 10 (1 mmol) (containing the isomer 11 as impurity) we added the respective alcohol (5 ml) and p-toluenesulfonic acid (0.019 g, 0.1 mmol). The mixture was refluxed for 1 h, and triethylamine (0.1 ml, 0.72 mmol) was added. The mixture was evaporated under vacuum, and ethyl acetate (10 ml) was added. The mixture was washed with water, dried, and evaporated, and the reaction product (1) was purified by chromatography. General Procedure for the Nonvolatile Alcohols and Thiols. To compound 10 (1 mmol) we added benzene (5 ml), the respective alcohol (2 mmol) (1.1 mmol of the thiol), and p-toluenesulfonic acid (0.019 g, 0.1 mmol). The mixture was refluxed for 4 h, and triethylamine (0.1 ml, 0.72 mmol) and ethyl acetate (10 ml) were added. The product was washed with water, dried, evaporated, and purified by chromatography.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 568 K. Moriyasu, H. Akieda, H. Aoki, M. Suzuki, S. Matsuto, Y. Iwasaki, S. Koda, and K. Tomiya, US Patent 5409886; Chem. Abstr., 124, P8680 (1995). N. Ohba, A. Ikeda, K. Matsunari, Y. Yamada, M. Hirata, Y. Nakamura, A. Takeuchi, and H. Karino, US Patent 5006157; Chem. Abstr., 114, 247145 (1991). B. Boehner and M. Baumann, Swiss. Pat. 633678; Chem. Abstr., 98, 121386 (1983). B. Boehner and M. Baumann, German Patent 2735841; Chem. Abstr., 88, 152415 (1978). T. Kume, T. Goto, M. Honmachida, A. K. Amochi, A. Yanagi, S. Yagi, and S. Miyachi, European Patent 0286816 (1988); Chem. Abstr., 110, 135246 (1989). H. Kinoshita, Y. Hayashi, Y. Murata, and K. Inomata, Chem. Lett., 1437 (1993). C. S. Rondestvedt and O. Vogl, J. Am. Chem. Soc., 77, 2313 (1955).
8. 9. 10. 11. 12.
M. S. Newman and W. M. Stallick, J. Org. Chem., 38, 3386 (1973). W. D. Dean and D. M. Blum, J. Org. Chem., 58, 7916 (1993). E. K. Fields, S. J. Behrend, S. Meyerson, M. L. Winzenburg, B. R. Ortega, and H. K. Hall, J. Org. Chem., 55, 5165 (1990). G. B. Gill, G. D. James, K. V. Gates, and G. Pattenden, J. Chem. Soc. Perkin Trans. 1, 2567 (1993). F. Farina, M. V. Martin, and M. C. Paredes, Heterocycles, 22, 1733 (1984).
569
CONDITIONS FOR THE SELECTIVE CONVERSION OF QUATERNARY 3-ANILINO1,5-DIMETHYLPYRAZOLIUM SALTS INTO 3-ANILINO-1,5-DIMETHYLPYRAZOLE
I. B. Dzvinchuk1, S. A. Kartashov1, A. V. Vypirailenko1, U. Doller2, and M. O. Lozinskii1 The possibility has been studied of converting quaternary 3-anilino-1,5-dimethylpyrazolium salts into 3-anilino-1,5-dimethylpyrazole, the first representative of the 1-alkyl-3-arylaminopyrazoles. The dependence of the reaction direction on the nature of the substituent at position 2 has been clarified. The most effective result was obtained with a cyanoethyl substituent. On boiling the initial salt with aqueous ammonia the target product is isolated in quantitative yield. Syntheses of the initial salts are described. C-Sulfonation was detected on interacting 3-anilino-1-benzoyl-3-methylpyrazole and dimethyl sulfate, with the formation of p-(3-amino-1,2,5-trimethylpyrazolio)benzenesulfonate. Keywords: hydrazines, pyrazoles, dehaloalkylation, quaternization, selectivity, C-sulfonation, cyanoethylation. Arylamino-substituted pyrazoles have been known for more than a hundred years [1]. Up to the present time efficient pesticides [2], antipyretics [3], disperse dyestuffs [4], and anti-inflammatory [5] and hypotensive [6] agents have appeared among their derivatives. However 1-alkyl-3-arylaminopyrazoles have not been described until now. Their synthesis is expedient for the search for new substances of practical use, but problematical from a methodological point of view. In particular, according to the data of the Michaelis school [7-9], on thermal dehalogenalkylation of quaternary 3-arylaminopyrazolium salts the alkyl group bound to the ring nitrogen atom in position 1 is split off and 5-arylaminopyrazoles are formed. We assumed that this reaction may be converted into a method of synthesizing 3-arylaminopyrazoles. A necessary condition must probably be the presence of a readily leaving substituent in position 1 of the initial salts. Experimental verification of the hypothesis and selection of a suitable substituent has been carried out on quaternary 3-anilino-1,5dimethylpyrazolium salts and is presented in this work. First we contemplated synthesizing and testing quaternary pyrazolium salts containing such readily leaving groups as benzoyl in position 1. The interaction of acetothioacetanilide (1) and benzoylhydrazine (2a) with the formation of the initial 5-anilino-1-benzoylpyrazole (3a) has been described by us previously [10]. Quaternization of compound 3a with dimethyl sulfate proceeds, as we found, ambiguously and did not stop at the stage of forming the expected quaternary salt 4a. The subsequent conversion is probably effected through a series of intermediate compounds 5-7. After treatment of the reaction mixture with aqueous ammonia a compound with a betaine structure 8 was obtained in low yield. The result indicates that the benzoyl group is __________________________________________________________________________________________ Institute of Organic Chemistry, National Academy of Sciences of the Ukraine, Kiev 02094; e-mail: iochkiev@ukrpack.net. 2 Aventis CropScience Gmbh, D-65926, Frankfurt-on-Main, Germany. Translated from Khimiya Geterotsiklicheskikh Soedinenii, Vol. 40, No. 5, pp. 679-684, May, 2004. Original article submitted November 19, 2001. 570 0009-3122/04/4005-05702004 Plenum Publishing Corporation
1
unsuitable for the solution of the problem being investigated. It leaves the nitrogen atom even under the conditions for obtaining the initial salt under the action of the nascent, low reactivity nucleophile, methylsulfate anion. Probably a mixed anhydride of methyl sulfate and benzoic acid is formed, which then sulfonates the aniline fragment at the para position. The possibility also appears of methylating the second ring nitrogen atom, which has been carried out.
MeCOCH2CSNHPh 1 NH2NHR 2ac Me Me R = Et: 170 oC Me Me N N _ R I 4b,c R = (CH2)2CN: H2O, NH4OH , 23 min, NH4I, H2N(CH2)2CN Me R = COPh: Me2SO4 120 oC, 5 h Me + N N R _ MeOSO3 4a Me 5 Me2SO4 Me N N Me _ MeOSO3 6 Me Me N N Me _ MeOSO3 + H N + NHPh NHPh MeOSO2OCOPh + EtI, MeI NHPh N N 5 NHPh
3b
Me N N 3ac R
NHPh
R = Et, (CH2)2CN MeI
MeOSO2OCOPh PhCOOH
SO3Me
H2O, NH4OH
7 Me Me + N N Me 8 H N _ SO3
2 4 a R = COPh, b R = Et, c R = (CH2)2CN
571
Proceeding from the results presented it was necessary to test more stable substituents. Ethyl and cyanoethyl were tested. By interacting reactant 1 with ethyl- and cyanoethylhydrazines 2b,c by the procedure of [11] we obtained the corresponding previously undescribed pyrazoles 3b,c. These compounds were more nucleophilic than the N-benzoyl analog 3a mentioned above. Quaternization took place under the action of an excess of methyl iodide on extended refluxing in acetone and gave the starting salts 4b,c in high yield. The ethyl-substituted salt 4b underwent dehaloalkylation on refluxing in diglyme. However the process occurred nonselectively with fission of ethyl and methyl iodides. As was established by 1H NMR, a mixture was formed of the desired compound 5 and the ethylpyrazole 3b mentioned already in a molar ratio of 2:3. The mixture was not successfully separated either by crystallization or chromatographically (compounds 4c and 5 have practically coincident Rf values). As we revealed, the cyanoethyl group possesses optimal properties for an efficient solution to the problem being investigated. In difference to benzoyl it was retained on obtaining the quaternary salt, and, in difference to ethyl, was readily removed from the salt regioselectively. The reaction occurred on boiling salt 4c in aqueous ammonia and was complete after 2-3 min. The conversion is probably fission of hydriodic acid and transcyanoethylation. Ammonium iodide and 3-aminopropionitrile, the formation of which must be expected, are soluble in water and do not impede the isolation of the desired product. Compound 5 crystallized from the reaction mixture in practically quantitative yield in an analytically pure state. The compounds 3b,c, 4b,c, 5, and 8 synthesized by us were colorless crystalline substances. Salts 4b,c and 8 were soluble in hot water, poorly in cold, and in acetone. The remaining compounds were soluble in acetone, chloroform, and ethyl acetate, worse in alcohol (with the exception of product 5), and insoluble in hexane and water. On extended storage iodides 4b,c acquire a yellow color, but the remaining compounds were unchanged. Pyrazoles 3b,c and salts 4b,c were obtained by us by standard methods and their structures were confirmed by the investigations carried out. The formation of betaine 8 was unexpected. This is the first example known to us of C-sulfonation on interaction with dimethyl sulfate. Nonetheless the structure of 8 followed readily from the data of 1H NMR spectra. The chemical shifts of the -4 proton, and of the protons of the methyl and amino groups linked to the heterocycle were extremely close in size to those detected for the quaternary salts 4b,c. The appearance of the aromatic protons of the aniline fragment was typical for a 1,4-disubstituted benzene ring. Comparison of the 1H NMR spectra of 3-arylaminopyrazole 5 and 5-arylaminopyrazoles 3b,c clearly indicates the energetically more favorable conjugation system between the nitrogen atom of the aniline fragment and the ring C=N bond in the first compound. This is caused by the fact that the conjugation system is one multiple bond shorter. As a result the electron density is increased at the heterocycle and reduced at the extracyclic amino group. The signal of the H-4 proton of compound 5 was displaced by 0.16-0.20 ppm towards high field, but the amino group proton was displaced by 0.29-0.47 ppm towards low field. The appearance of the aromatic protons of the aniline fragment was extremely noteworthy. In compounds 3b,c and the quaternary salts 4b,c the extracyclic nitrogen atom exerts an electron-donating influence on the phenyl fragment, and the signals of its protons appeared in the sequence m, o, and p from low to high field. For compound 5 the sequence of the o- and p-signals was different going towards high field and the signal of the o-protons was displaced (compared with compounds 3b,c) by 0.40-0.50 ppm towards low field. The effect is probably caused by the deshielding effect of the lone pair of electrons of the pyrazole nitrogen atom. Deshielding of the aniline fragment is of course possible only for structure 5 as it exerts maximum effect on the spatially closely disposed o-protons. The selective N-decyanoethylation of pyrazolium salts, shown by us, probably has a general character. In view of the availability of cyanoethylhydrazine [12] this reaction may be used for the directed synthesis of new 1-alkyl-3-arylaminopyrazoles. It is also expedient to study the N-decyanoethylation of a series of 1,2- and 1,3-diazolium salts as a method of synthesis of previously unknown or difficultly available compounds.
572
TABLE 1. Physicochemical and Spectral Characteristics of Compounds 3b,c, 4b,c, 5, and 8

Compound 3b 3c 4b 4c 5 8 Empirical formula C12H15N3 C13H14N4 C13H18IN3 C14H17IN4 C11H13N3 C12H15N3O3S*2 Found, % Calculated, % 7.56 7.51 6.14 6.24 5.27 5.29 4.58 4.65 7.07 7.00 5.45 5.37 mp, C* N 20.81 20.88 24.60 24.76 12.18 12.24 15.18 15.22 22.40 22.44 14.79 14.94 113-114 121-121.5 135-136 201-202 101-103 345-347 IR spectrum, , cm-1 3210 (NH) 2255 (CN), 3240 (NH) 3225 (NH) 2260 (CN), 3110 (NH) 3250 (NH) 3215, 3490 (NH) Yield %
71.45 71.61 69.16 69.00 45.55 45.49 45.61 45.66 70.39 70.56 51.29 51.23
67 75 98 97 97 38
_______ * Compounds were crystallized from 2-propanol (3c, 4b), water2-propanol, 1:2 (3b, 4c), hexaneethyl acetate, 4:1 (5), wateracetic acid, 4:1 (8). *2 Found, %: S 11.49. Calculated, %: S 11.40. TABLE 2. 1H NMR Spectra of Compounds 3b,c, 4b,c, 5, and 8
Compound 3b Chemical shifts (DMSO-d6), , ppm (J, Hz) 1.24 (3H, t, J = 7.2, 3CH2); 2.11 (3H, s, 3Het); 3.89 (2H, q, J = 7.2, 2CH3); 5.76 (1H, s, -4); 6.73 (1H, t, J = 7.2, p-ptoton 65); 6.79 (2H, d, J = 7.8, o-protons 65); 7.16 (2H, dd, J1 = 7.2, J2 = 7.8, m-protons 65); 7.78 (1H, s, NH) 2.12 (3H, s, 3Het), 2.96 (2H, t, J = 6.3, CH2CN), 4.15 (2H, t, J = 6.3, 2N), 5.81 (1H, s, -4), 6.78 (1H, t, J = 7.5, p-ptoton 65), 6.88 (2H, d, J = 7.8, o-protons 65), 7.19 (2H, dd, J1=7.2, J2 = 7.8, m-protons 65), 7.96 (1H, s, NH) 1.29 (3H, t, J = 6.9, 3CH2), 2.37 (3H, s, 3Het), 3.84 (3H, s, CH3N), 4.42 (2H, q, J = 6.9, 2CH3), 6.25 (1H, s, -4), 7.14 (1H, t, J = 6.9, p-ptoton 65), 7.26 (2H, d, J = 7.5, o-protons 65), 7.41 (2H, dd, J1=6.9, J2 = 7.5, m-protons 65), 9.26 (1H, s, NH) 2.37 (3H, s, 3Het), 3.11 (2H, t, J = 6.9, CH2CN), 3.84 (3H, s, CH3N), 4.74 (2H, t, J = 6.9, 2N), 6.27 (1H, s, -4), 7.15 (1H, t, J = 7.6, p-ptoton 65), 7.26 (2H, d, J = 7.8, o-protons 65), 7.43 (2H, dd, J1 = 7.6, J2 = 7.8, m-protons 65), 9.47 (1H, s, NH) 2.18 (3H, s, 3Het), 3.60 (3H, s, CH3N), 5.60 (1H, s, -4), 6.67 (1H, t, J = 7.2, p-ptoton 65), 7.14 (2H, dd, J1 = 7.2, J2 = 7.5, m-protons 65), 7.29 (2H, d, J = 7.5, o-protons 65), 8.25 (1H, s, NH) 2.36 (3H, s, 3Het), 3.79 (3H, s, CH3N), 3.83 (3H, s, CH3N), 6.30 (1H, s, -4), 7.08, 7.60 (4H, dd, J = 8.4, p-64), 9.31 (1H, s, NH)
3c
4b
4c
EXPERIMENTAL The IR spectra were recorded on a UR 20 instrument in KBr disks. The 1H NMR spectra were recorded on a Varian VXR 300 (300 MHz) spectrometer, internal standard was TMS. A check on the progress of reactions and the homogeneity of the compounds synthesized was effected by TLC on Silufol UV 254 plates in the solvent system benzeneethanol, 9:1 (visualization in UV light). The characteristics of the synthesized compounds are given in Tables 1 and 2. 573
1-Substituted 5-Anilino-3-methylpyrazoles (3b,c). A solution of hydrazine 2b or 2c (12 mmol) in 2-propanol (2 ml) was added dropwise during 5 min to a boiling solution of compound 1 (1.93 g, 10 mmol) in 2-propanol (3 ml). Boiling was continued for a further 15 min to complete the reaction. The mixture was stirred until crystallization commenced (in the synthesis of compound 3b the reaction mixture was first diluted with water (5 ml)), then maintained at 15-20C for 2 h, and at -5C for 1 h. The solid was filtered off, and washed with aqueous 2-propanol, 1:1. 2-Substituted 3-Anilino-1,5-dimethylpyrazolium Iodides (4b,c). Mixtures of pyrazole 3b or 3c (3 mmol), methyl iodide (4.43 g, 30 mmol), and acetone (1.5 ml) were refluxed for 9 or 45 h respectively. After cooling, the solid was filtered off, and washed with acetone. Compound 4b was recrystallized from 2-propanol. Compound 4c was obtained in an analytically pure state. 3-Anilino-1,5-dimethylpyrazole (5). A mixture of salt 4c (0.74 g, 2 mmol) and 20% aqueous ammonia (2 ml) was stirred and refluxed for 2-3 min. Water (2 ml) was then added and the mixture stirred until the resulting oil crystallized. After cooling, the solid was pulverized, filtered off, washed with water, and dried at 80C. p-(3-Amino-1,2,5-trimethylpyrazolio)benzenesulfonate (8). A mixture of pyrazole 3a (1.38 g, 5 mmol) and freshly distilled dimethyl sulfate (1.51 g, 12 mmol) was maintained at 115-120C for 5 h. After cooling, water (3 ml) and 20% aqueous ammonia (3 ml) were added. The mixture was stirred and refluxed for 2-3 min. After cooling, the solid was filtered off, washed with water, with 2-propanol, and with ether. Dehaloalkylation of 3-Anilino-2-ethyl-1,5-dimethylpyrazolium Iodide. Compound 4b (0.2 g) was refluxed in diglyme (1 ml) for 8 h. The solvent was evaporated in the vacuum of a water-jet pump with heating on a boiling water bath. The residue was dissolved in methylene chloride (5 ml) and passed through a column of Al2O3 (d = 1 cm, h = 4 cm), eluting with methylene chloride, and discarding eluate in front of the running colorless fraction. The solvent was evaporated. The residue was dried from traces of diglyme in a Fischer pistol at 115C in a water-jet pump vacuum for 3 h. The oil obtained was dissolved in DMSO-d6 (1.5 ml) and the 1 H NMR spectrum taken. The spectrum was interpreted by comparison with the spectra of compounds 3b and 5. The dehaloalkylation product obtained was mainly a mixture of compounds 3b and 5 in a molar ratio of 3:2 (the composition was estimated from the integrated intensities of the C-methyl group signals). We are grateful to Aventis CropScience for financial support.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 574 E. Silberstein, Germ. Patent 113384; Chem. Zbl., 2, 654 (1900). M. Heil, C. Erdelen, U. Wachendorff-Neumann, Ger. Offen. DE 19544798; Chem. Abstr., 127, 65764 (1997). R. A. Appleton, S. C. Burford, D. N. Hardern, and D. N. Wilkinson, Eur. Patent 178035; Chem. Abstr., 105, 42796 (1986). M. A. Metwally, Y. M. Darwish, M. M. El-Hussini, and F. A. Amer, J. Indian Chem. Soc., 65, 54 (1988). Fisons Corp., Jpn. Kokai Tokkyo Koho JP 62267269; Chem. Abs., 109, 149523 (1987). A. Ranise, F. Bondavalli, P. Schenone, A. Bargagna, M. Scafuro, A. Marfella, L. Berrino, and E. Marmo, Farmaco, Ed. Sci., 38, 101 (1983). A. Michaelis and E. Gunkel, Chem. Ber., 34, 723 (1901). A. Michaelis and E. Hepner, Chem. Ber., 36, 3271 (1903). A. Michaelis and A. Lachwitz, Chem. Ber., 43, 2106 (1910). I. B. Dzvinchuk, S. A. Kartashov, A. V. Vypirailenko, and M. O. Lozinskii, Khim. Geterotsikl. Soedin., 703 (2002). A. N. Borisevich and P. S. Pel'kis, Khim. Geterotsikl. Soedin., 312 (1969). M. Mugno and M. Bornengo, Gazz. Chim. Ital., 86, 451 (1956).
INTERACTION OF ,-UNSATURATED KETONES OF THE ADAMANTANE SERIES WITH N,N'-BINUCLEOPHILES

A. A. Pimenov, N. V. Makarova, I. K. Moiseev, and M. N. Zemtsova The influence has been established of the structure of the initial ketone, the reactants, and the reaction conditions on the direction of the interaction of ,-unsaturated ketones of the adamantane series with hydrazine, phenylhydrazine, semicarbazide, thiosemicarbazide, urea, and thiourea. It was found that on interaction with hydrazine and phenylhydrazine both intermediate hydrazones and the final cyclization products, pyrazolines, were formed. Reaction with semicarbazide and thiosemicarbazide leads only to the synthesis of derivatives at the carbonyl group, semicarbazones and thiosemicarbazones, but with urea and thiourea leads to products of addition at the double bond. Keywords: hydrazones, ,-enones, ureas, ,-unsaturated ketones, pyrazolines, semicarbazones, thioureas, thiosemicarbazones, addition. ,-Unsaturated ketones serve as starting materials for the synthesis of a large number of heterocyclic compounds [1,2]. In addition their use in the synthesis of heteryl-substituted adamantanes is rarely met in the literature [3-5]. The interaction of 3-(1-adamantyl)-1-aryl-1-propen-3-ones with hydroxylamine was described in [6]. The authors succeeding in isolating a substituted isoxazole only in the case of Ar = 4-O2NC6H4. We previously described the synthesis of 4-(1-adamantyl)-1-R-buten-3-ones from (1-adamantyl)acetone [7]. With the aim of studying the chemical properties of ,-unsaturated ketones of the adamantane series synthesized by us we reacted 3-(1-adamantyl)-1-phenyl-1-propen-3-one (1) [6], 4-(1-adamantyl)-1-phenyl-1buten-3-one (2) [7], and 3-(1-adamantyl)-1-(4-nitrophenyl)-1-propen-2-one 3 [6] with hydrazines. The choice of starting materials was determined by the following factors. 1) Compared with unsaturated ketones 1 and 3 ketone 2 has a methylene group between the adamantyl residue and the carbonyl which enables assessment of the degree of influence of the adamantyl residue on the cyclization process. 2) Compound 3 contains a nitro group in the phenyl residue exerting an influence on the conjugated system C(=O)CH=CH. Reactions were carried out with 99% hydrazine and freshly distilled phenylhydrazine. Under acidic conditions (acetic acid, sulfuric acid) ketones 1-3 give cyclic products with 99% hydrazine, viz. 5-(1-adamantyl)3-phenylpyrazoline (4a), 5-(1-adamantylmethyl)-3-phenylpyrazoline (4b), and 5-(1-adamantyl)-3-(4nitrophenyl)pyrazoline (4c). Under alkaline conditions (ethyl alcohol, KOH) the reaction of ketone 3 with hydrazine leads to the synthesis of hydrazone 5. Refluxing hydrazone 5 in acetic acid in the presence of sulfuric
__________________________________________________________________________________________ Samara State Technical University, Samara 443010, Russia; e-mail: moiseev@dp.sstu.samara.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, Vol. 40, No. 5, pp. 685-692, May, 2004. Original article submitted January 23, 2001. 0009-3122/04/4005-05752004 Plenum Publishing Corporation 575
acid also leads to the synthesis of pyrazoline 4c. On reacting the ,-unsaturated ketones 1-3 with phenylhydrazine both under alkaline (ethyl alcoholKOH, ethyl alcoholEtONa, DMSOKOH, ethyl alcohol piperidine) and under acidic conditions (acetic acidsulfuric acid) only hydrazones 6a-c were obtained.
AcOH/H2SO4 N 4ac N H AcOH/H2SO4 n = 0, 1 R = H, NO2 EtOH/KOH n = 0, R = NO2 NH2NH2 O (CH2)nCCH=CH 13 H2NNHPh AcOH/H2SO4 EtOH/KOH NNHPh (CH2)nCCH=CH 6ac
1, 4a, 6a n = 0, R = H; 2, 4b, 6b n = 1, R = H; 3, 4c, 6c n = 0, R = NO2
NNH2 CCH C H NO2
(CH2)n
The kinetics and mechanism of formation of pyrazolines from ,-unsaturated ketones and phenylhydrazine was studied previously with the aid of polarography [8-10]. The following reaction scheme was proposed as a result, probably also valid in our case. At the first step addition of the more nucleophilic -nitrogen atom occurs at the carbon atom of the carbonyl group of the ,-unsaturated ketones. At the second step conversion of the addition products into hydrazones occurs. According to literature data this is the limiting stage. In the third and subsequent stages cyclization of the hydrazones into pyrazolines occurs. In a continuation of studies on the interaction of ,-unsaturated ketones of the adamantane series with N,N'-binucleophiles we carried out the reaction of ketones 1-3 with semicarbazide and thiosemicarbazide in alcohol in the presence of catalytic quantities of HCl. As is known, the interaction of ,-unsaturated ketones with semicarbazide and thiosemicarbazide leads to the synthesis of pyrazolines [1,2]. However we obtained derivatives of only the carbonyl group, the new semicarbazones and thiosemicarbazones 7 and 8, which displayed no inclination towards heterocyclization on heating either in alkaline (KOHalcohol, piperidine alcohol, 10% EtONa, 20% MeONa, KOHDMSO) or acidic (AcOHH2SO4, propionic acidH2SO4) media.
X NH2NHCNH2 1, 2, 3 X NNHCNH2 (CH2)nCCH=CH 7ac, 8ac 7, 8 n = 0, R = H, b n = 1, R = H, c n = 0, R = NO2; 7ac X = O; 8ac X = S R
576
TABLE 1. Physicochemical Characteristics of the Synthesized Compounds

Compound 1 4 4b 4c 5 6 6b 6c 7 C19H24N2 20H26N2 19H23N3O2 C19H23N3O2 25H28N2 C26H30N2 C25H27N3O2 20H25N3O Empirical formula 2 Found, % Calculated, % 4 8.70 8.63 9.00 8.90 7.15 7.12 7.00 7.12 8.00 7.92 8.60 8.16 6.90 6.78 8.00 7.79 mp, N 5 10.30 9.99 9.00 9.51 12.54 12.91 13.00 12.91 7.45 7.85 7.30 7.56 10.55 10.47 12.16 12.99 6 177-179 96-98 157-158 >300 146-147 114-116 278-280 202-204 2 Ad 7 2900, 2850 2900, 2850 2900, 2850 2900, 2850 2900, 2850 2900, 2850 2900, 2850 2900, 2850 IR spectrum, , cm-1 others 8 1640 (C=N), 3420 (NH) 1670 (C=N), 3480 (NH) 1335, 1605 (NO2), 1665 (C=N), 3425 (NH) 1610 (C=N), 3260 (NH) 1610 (C=N), 3150 (NH) 1620 (C=N), 3130 (NH) 1305, 1600 (NO2), 1670 (C=N), 3230 (NH) 1690 (C=N), 3340, 3120 (NH, NH2) Yield, % 9 51 42 63 89 92 84 87 98
3 81.00 81.38 82.00 81.59 70.25 70.13 70.50 70.13 84.55 84.23 84.10 84.28 75.10 74.79 74.77 74.27
577
578
TABLE 1 (continued)
1 7b 7c 8 8b 8c 9 9b 10 10b 2 21H27N3O C20H24N4O3 C20H25N3S C21H27N3S C20H24N4O2S C20H26N2O2 C20H26N2OS C21H28N2O2 C21H28N2OS 3 75.00 74.74 65.37 65.20 70.37 70.76 71.75 71.35 62.84 62.48 74.00 73.59 70.00 70.14 75.00 74.08 70.55 70.75 4 8.23 8.06 6.94 6.57 7.80 7.42 8.00 7.70 6.00 6.29 8.00 8.03 8.00 7.65 9.00 8.28 7.90 7.92 5 12.45 12.45 15.79 15.21 12.00 12.38 12.00 11.89 15.12 14.57 9.00 8.58 8.00 8.18 8.00 8.23 7.75 7.86 6 192-193 284-286 185-187 184-186 200-201 192-193 209-211 237-239 160-161 7 2900, 2850 2900, 2850 2900, 2850 2900, 2850 2900, 2850 2900, 2850 2900, 2850 2900, 2850 2900, 2850 8 1605 (C=N), 3480, 3170 (NH, NH2) 1325, 1615 (NO2), 1670 (C=N), 3405, 3210 (NH, NH2) 1630 (C=N), 3475, 3340 (NH, NH2) 1610 (C=N), 3420, 3255 (NH, NH2) 1340, 1600 (NO2), 1610 (C=N), 3420, 3355 (NH, NH2) 1695 (=), 3205, 3300 (NH, NH2) 1670 (=), 3230, 3410 (NH, NH2) 1690 (=), 3220, 3350 (NH, NH2) 1680 (=), 3200, 3390 (NH, NH2) 9 96 97 99 98 95 82 85 86 87
TABLE 2. 1H NMR Spectra of the Synthesized Compounds

Compound Chemical shifts, , ppm (J, Hz) 2 Ad, Ad, 15H, m 1.65-1.80 1.65-1.90 1.65-1.85 1.50-1.95 1.65-1.90 1.65-1.90 1.65-1.95 1.60-1.95 1.55-1.80 1.52-1.83 1.65-1.80 1.54-1.85 1.65-1.80 1.65--.95 1.65-1.95 1.65-1.90 1.65-1.90 Other protons 3.30 (1, br. s, NH); 4.70 (2, d, J = 5.6, 2 pyrazoline); 5.25-5.40 (1, m, pyrazoline); 6.64-7.72 (5, m, 65) 2.15 (2, s, Ad2); 3.50 (1, br. s, NH); 5.20 (2, d, J = 6.0, 2 pyrazoline); 5.45 (1, m, pyrazoline); 7.00-7.42 (5, m, 65) 3.50 (1, br. s, NH); 5.20 (2, d, J = 5.8, 2 pyrazoline); 5.50 (1, m, pyrazoline); 7.40-8.20 (4, m, 64) 3.50 (2, br. s, NH2); 6.58 (1, d, J = 15.2, =); 7.95 (1, d, J = 15.2, =64); 8.00-8.30 (4, m, 64) 5.00 (1, br. s, NH); 6.55 (1, d, J = 14.4, =); 6.88 (1, d, J = 14.4, =65), 7.00-7.70 (10, m, 265) 2.23 (2, s, Ad2); 4.60 (1, br. s, NH); 6.98 (1, d, J = 13.1, =); 7.18 (1, d, J = 13.1, =65); 7.26-7.80 (10, m, 265) 5.00 (1, br. s, NH); 6.55 (1, d, J = 14.4, =); 6.88 (1, d, J = 14.4, =65); 7.00-7.70 (10, m, 265) 3.71-3.88 (3H, br. s, NH, NH2); 5.76 (1, d, J = 13.5, =); 5.95 (1, d, J = 13.5, =); 6.92-7.31 (5, m, 65) 2.10 (2, s, AdCH2); 3.23-3.34 (3H, br. s, NH, NH2); 5.28 (1, d, J = 12.9, =); 5.69 (1, d, J = 12.9, =); 7.12-7.24 (5, m, 65) 3.95-4.09 (3H, br. s, NH, NH2); 5.69 (1, d, J = 13.5, =); 5.82 (1, d, J = 13.5, =); 7.11-7.29 (4, m, 64) 3.24-3.46 (3H, br. s, NH, NH2); 5.69 (1, d, J = 13.7, =); 5.82 (1, d, J = 13.7, =); 7.10-7.25 (5, m, 65) 2.10 (2, s, AdCH2); 3.33-3.54 (3H, br. s, NH, NH2); 5.73 (1, d, J = 12.9, =); 5.85 (1, d, J = 12.9, =); 7.07-7.28 (5, m, 65) 3.57-3.69 (3H, br. s, NH, NH2); 5.81 (1, d, J = 13.7, =); 5.96 (1, d, J = 13.7, =); 7.17-7.28 (4, m, 64) 4.42 (2, d, J = 7.3, 2); 4.90 (1, m, ); 6.95 (1, br. s, NH); 7.20-7.50 (5, m, 65); 7.85 (2, br. s, NH2) 4.70 (2, d, J = 7.0, 2); 4.95 (1, m, ); 7.20-7.50 (5, m, 65); 8.80 (1, br. s, NH); 9.05 (2, br. s, NH2) 2.45 (2, s, 2=); 4.35 (2, d, J = 6.8, 2); 4.95 (1, m, ); 7.00 (1, br. s, NH); 7.80 (2H, br. s, NH2) 2.50 (2, s, 2=); 4.65 (2, d, J = 7.6, 2); 4.95 (1, m, ); 7.20-7.45 (5, m, 65); 8.75 (1, br. s, NH); 9.15 (2, br. s, NH2)
4 4b 4c 5 6 6b 6c 7 7b 7c 8 8b 8c 9 9b 10 10b
The reaction of unsaturated ketones with urea and thiourea under base catalysis conditions usually leads to the preparation of hydrogenated derivatives of pyrimidine [1,2]. The interaction of compounds 1 and 2 with urea and thiourea was carried out in methanol in the presence of sodium methylate. As was shown by data of IR and 1H NMR spectroscopy and elemental analysis, addition products at the double bond were obtained, viz. [3-(1-adamantyl)-3-oxo-1-phenylpropyl]urea (9a), [4-(1adamantyl)-3-oxo-1-phenylbutyl]urea (10a), [3-(1-adamantyl)-3-oxo-1-phenylpropyl]thiourea (9b), and [4-(1adamantyl)-3-oxo-1-phenylbutyl]thiourea (10b).
X 1, 2 NH2CNH2 O X
(CH2)nCCH2CHNHCNH2
9a,b, 10a,b 9 n = 0, 10 n = 1, a X = O, b X = S
579
The mechanism of the interaction of urea and its analogs with aromatic ,-unsaturated ketones was considered in [11-13]. The authors assumed that the first step was always addition to the double bond, irrespective of the type of catalyst used. The sequence of the stages of 1,2- and 1,4-addition was not proved strictly. The conclusions were based only on the assumption that urea and its analogs have a low reactivity in relation to carbonyl compounds. The condensation of products of addition at the carbonyl group in the second stage is an intramolecular process. The experimental data obtained by us prove that the first stage of the interaction of ,-unsaturated ketones with urea and thiourea is addition at the double bond. Steric hindrance from the adamantyl residue makes cyclization at the carbonyl group impossible, which is the distinguishing feature of the adamantylcontaining ,-unsaturated ketones 9 and 10 synthesized by us. In the reaction of ,-unsaturated ketones of the adamantane series with hydrazine and phenylhydrazine the effect has been shown of the structure of the initial ketone, of the hydrazine, and of the reaction conditions on the direction of the reaction. On interacting adamantyl-containing unsaturated ketones with semicarbazide and thiosemicarbazide the derivatives at the carbonyl group, semicarbazones and thiosemicarbazones, were obtained, and with urea and thiourea products of addition at the double bond were synthesized.
EXPERIMENTAL The 1H NMR spectra were recorded on Bruker AC 300 (300 MHz) and Bruker DS 80 (80 MHz) instruments in DMSO and (CD3)2CO, internal standard was HMDS. The IR spectra were obtained on a Specord M 80 instrument in potassium bromide. The physicochemical and spectral characteristics of compounds are given in Tables 1 and 2. 5-(1-Adamantyl)-3-phenylpyrazoline (4a), 5-(1-Adamantylmethyl)-3-phenylpyrazoline (4b), 5-(1-Adamantyl)-3-(4-nitrophenyl)pyrazoline (4c) (General Procedure). A mixture of ketone 1 [6], 2 [7], or 3 [6] (3.8 mmol), 99% hydrazine (0.12 ml, 0.12 g, 3.8 mmol), and acetic acid (10 ml) was heated to boiling, conc. H2SO4 (1 drop) was added, and the mixture refluxed for 8 h. The reaction mixture was then diluted with water (100 ml), the solid was filtered off, and recrystallized from ethanol. Hydrazone of 3-(1-Adamantyl)-3-(4-nitrophenyl)-1-propen-3-one (5). A solution of ketone 3 (0.5 g, 1.6 mmol), 99% hydrazine (0.06 ml, 0.06 g, 1.6 mmol), and KOH (0.1 g, 1.8 mmol) in ethanol (10 ml) was refluxed for 1 h. The precipitated solid was filtered off, and recrystallized from DMF. Phenylhydrazones of 3-(1-Adamantyl)-1-phenyl-1-propen-3-one (6a), 4-(1-Adamantyl-1-phenyl-1buten-3-one (6b), and 3-(1-Adamantyl)-3-(4-nitrophenyl)-1-propen-3-one (6c) (General Procedure). Ketone 1, 2, or 3 (10 mmol) was dissolved with heating in ethanol (8 ml), freshly distilled phenylhydrazine (0.97 ml, 1.06 g, 10 mmol), and 20% KOH in alcohol (5 ml) were added. The mixture was refluxed for 1 h, after which the reaction mixture was cooled, the precipitated solid was filtered off, dried, and recrystallized from ethanol. Semicarbazones (7a-c) and Thiosemicarbazones (8a-c) (General Procedure). A solution of ketone 1, 2, or 3 (7.5 mmol), semicarbazide (or thiosemicarbazide) (7.5 mmol), and conc. hydrochloric acid (3 ml) in alcohol (10 ml) was refluxed for 1 h, and cooled. Water (100 ml) was added, the solid was filtered off, dried, and recrystallized from ethanol. [3(or 4)-(1-Adamantyl)-3-oxo-1-phenylpropyl(or butyl)]ureas (9a, 10a), [3(or 4)-(1-Adamantyl)-3oxo-1-phenylpropyl(or butyl)]thioureas (9b, 10b) (General Procedure). A solution of ketone 1 or 2 (1.9 mmol) and urea (or thiourea) (1.9 mmol) in 10% sodium ethylate (15 ml) was refluxed for 5 h. The reaction mixture was cooled, the precipitated solid was filtered off, and recrystallized from ethanol.
580
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. D. N. Dhar, The Chemistry of Chalcones and Related Compounds, Academic Press, New York (1981). S. M. Decenko and V. D. Orlov, Azaheterocycles from Aromatic Unsaturated Ketones [in Russian], Folio, Kharkov (1998). V. P. Litvinov and M.-G. A. Shvekhgeimer, Zh. Org. Khim., 33, 1447 (1997). M.-G. A. Shvekhgeimer and V. P. Litvinov, Zh. Org. Khim., 35, 183 (1999). V. P. Litvinov and M.-G. A. Shvekhgeimer, Zh. Org. Khim., 36, 329 (2000). N. G. Kozlov, E. D. Skakovskii, and G. P. Korotyshova, Zh. Obshch. Khim., 67, 1704 (1997). I. K. Moiseev, M. N. Zemtsova, N. V. Makarova, and A. A. Pimenov, Zh. Org. Khim., 36, 454 (2000). V. F. Lavrushin, V. D. Bezuglyi, G. G. Belous, and V. G. Tishchenko, Zh. Obshch. Khim., 34, 73 (1964). V. D. Bezuglyi, L. A. Kotok, N. P. Shimanskaya, and V. E. Bondarenko, Zh. Obshch. Khim., 39, 2167 (1969). H. Ferres, M. S. Hamdam, and W. R. Jackson, J. Chem. Soc. (B), 1892 (1971). F. H. Al-Hayyar, Y. A. Al-Farkh, and H. S. Hamoud, Can. J. Chem., 57, 2734 (1979). V. P. Mamaev and A. L. Vais, Khim. Geterotsikl. Soedin., 1108, (1975). A. L. Vais and V. P. Mamaev, Khim. Geterotsikl. Soedin., 674 (1974).
581
STEREODIRECTED CATALYTIC SYNTHESIS OF PERHYDROACRIDINES AND THEIR ISOLOGS FROM DECAHYDROACRIDINE-1,8-DIONES

T. G. Nikolaeva1 and Yu. M. Shchekotikhin2 The catalytic reduction of decahydroacridine-1,8-diones has been studied under hydrogen pressure in the presence of Raney nickel and with nascent hydrogen from alkaline treatment of nickelaluminum alloy. Conditions have been developed for the stereodirected synthesis of 8-hydroxy-cisdodecahydroacridin-1-ones and perhydroacridines of the cis-syn-cis and cis-anti-cis configurations. The structure of the hydroacridines was established by 1H NMR spectroscopy, 13C, and IR spectra, and chromato-mass spectrometry. Keywords: 8-hydroxydodecahydroacridin-1-ones, decahydroacridine-1,8-diones, perhydroacridines, catalytic hydrogenation, stereochemistry. The presence of several reaction centers in decahydroacridine-1,8-diones opens broad synthetic possibilities. Previously we investigated the chemical conversions of decahydroacridine-1,8-diones in phenylhydrazination and oximation reactions, and showed that, depending on the structure of the substrate and the conditions, these processes may occur either selectively at the carbonyl group or with the participation of the latter and other reaction centers [1,2]. The present communication is devoted to a study of the chemical behavior of 1,8-dioxodecahydroacridines in catalytic hydrogenation reactions. It is known that decahydroacridine-1,8-diones are stable to the action of complex metal hydrides [3], and in the presence of sodium thioglycolate only reduction of the keto groups to hydroxyl occurs [4]. Decahydroacridine-1,8-diones have not previously been subjected to hydrogenation under conditions of heterogeneous catalysis. Catalytic hydrogenation of decahydroacridine-1,8-diones was effected under various conditions, under hydrogen pressure in the presence of Raney nickel, and with nascent hydrogen formed on alkaline treatment of nickelaluminum alloy. The latter method was previously used successfully for the reduction of pyridines, quinolines, and other related compounds [5,6]. The substrates selected were 1,8-dioxodecahydroacridines differing in the degree of substitution and the nature of the substituent at positions 3, 6, 9, and 10, which enables the influence of the structure of the initial compounds on the direction of the studied processes to be followed. Reduction of acridines 1 with hydrogen in situ (addition of nickelaluminum alloy to an alkaline aqueous methanolic solution) occurs at 60C for 10-12 h. Under these conditions the direction of the conversion is determined by the structure of the substrate.
__________________________________________________________________________________________ Saratov N. G. Chernyshevskii State University, Saratov 410026, Russia. 2 Nita-Farm ZAO, Saratov 410005, Russia; e-mail: nita-farm@overta.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, Vol. 40, No. 5, pp. 693-705, May, 2004. Original article submitted October 31, 2001. 582 0009-3122/04/4005-05822004 Plenum Publishing Corporation
1
O Me Me
O Ni / Al, 1 M KOH Me Me MeOH, 6065 oC Me

2 3
O
1 4 9a
R
9 10
8a
OH
8 5 7 6
Me Me
N R1 1ak
Me
4a
N R1
10a
2ad
1ae R = H, a R1 = H, b R1 = Me, c R1 = Ph, d R1 = PhCH2, e R1 = PhNH, f R = 2-C4H3O (2-furyl), R1 = Me, g R = R1 = Me, h R = Ph, R1 = H, i R = Ph, R1 = PhCH2, j R = 4-MeOC6H4, R1 = Ph, k R = 4-MeOC6H4, R1 = H; 2ac R = H, a R1 = H, b R1 = Me, c R1 = Ph, d R = 2-C4H3O (2-furyl), R1 = Me
The decahydroacridinediones 1a-e unsubstituted at position 9 undergo selective reduction of one of the oxovinyl fragments, being converted into 8-hydroxy-cis-dodecahydroacridin-1-ones 2a-c in 74-89% yield, while hydrogenation of N-benzyl- and N-phenylaminodecahydroacridinediones 1d,e is accompanied by hydrogenolysis of the NCH2 and NNH bonds and leads to the formation of compound 2a (72-79% yield). Reduction in situ of 9- and 9,10-substituted decahydroacridine-1,8-diones 1f-j proceeds ambiguously and depends on the structure of the substituting group. Thus 9-(2-furyl)-10-methyldecahydroacridine-1,8-dione (1f), like compounds 1a-c, is converted into the corresponding cis-dodecahydroacridinone 2d in 78% yield. On reacting 9-aryl- or 9-alkyl-1,8-dioxoacridines 1g-j neither the heterocycle nor the oxo group is reduced even at significantly increased reaction times (24-30 h). In the case of 9-aryl-10-benzyldecahydroacridine-1,8-diones 1i,j only hydrogenolysis of the NCH2 bond was observed and 9-aryl-10H-1,8-dioxodecahydroacridines 1h,k were formed. The marked stability of 9-aryl- and 9-alkyldecahydroacridinones 1g-j, unlike the 9-furyl-substituted compound, towards catalytic hydrogenation is evidently caused by the steric disposition of the aryl or alkyl substituents at position 9 relative to the 1,4-dihydropyridine ring, as a result of which either adsorption of the substrate onto the surface of the catalyst is hindered or steric hindrance is built up against the approach of the reducing agent. The 1,8-dioxodecahydroacridines were subject to more profound catalytic conversion on carrying out the hydrogenation on Raney Ni under forcing conditions, at a hydrogen pressure of 10 MPa and a temperature of 100-120C (the reaction was carried out in batch autoclaves in alcoholic solution). Depending on the duration of contact and the process temperature a directed conversion was successfully effected both to cis-dodecahydroacridine and also to a substituted perhydroacridine with a cis-cis structure. If the hydrogenation of 1,8-dioxodecahydroacridines 1a-c,l is carried out at 100C (at lower temperatures no reaction occurs) for 8 h then 9-R1-10-R2-8-hydroxy-cis-dodecahydroacridinones 2a-c,e are formed (57-72% yield) irrespective of the structure of the substrate. On raising the temperature to 120C or increasing the time of contact with the catalyst to 24 h at 100C, in addition to hydrogenation of the heterocycle, reduction of the carbonyl groups to methylene occurs, and in the case of compound 1a of a phenyl substituent to cyclohexyl. The resulting reaction products are perhydroacridines of the cis-cis type 3a-c. The cis-syn-cis isomer 3a was isolated on hydrogenation on Raney Ni at 120C for 8 h, and the cis-anti-cis isomers 3b,c at 100C for 24 h. Special experiments on the isomerization of compound 3a into isomer 3b showed that perhydroacridines of the cis-syn-cis configuration arise initially, which are converted subsequently into the thermodynamically more stable cis-anti-cis forms (Scheme 1). By varying the catalytic hydrogenation conditions for 1,8-dioxodecahydroacridines it is therefore possible to effect a stereodirected synthesis of perhydroacridines of a given structure, for the cis-anti-cis isomer Raney Ni at 100C, 24 h and for the cis-syn-cis isomer Raney Ni at 120C, 8 h. It was established that in all cases the intermediate compounds were cis-dodecahydroacridines. On hydrogenation of compounds 2b,c on Raney Ni at 100C for 24 h cis-anti-cis-perhydroacridines 3b,c were isolated in 74-78% yield.
583
Scheme 1
O R R N R2 1ac,l R1 O R R H2 Raney Ni EtOH, 10 MPa
O R R
R1
OH H2, Raney Ni R
100
oC,
8h
100 oC, 24 h
N 2ac,e R2
120 oC, 8 h
Me Me N
Me Me
H2, Raney Ni 100 oC, 24 h
3a
Me 100 oC, 24 h Me N R2 3b,c
Me Me
1, 2 ac R = Me, R1 = H, a R2 = H, b R2 = Me, c R2 = Ph; 1l, 2e R = R2 = H, R1 = Ph; 3b R2 = C6H11 (cyclohexyl), c R2 = Me
It may be concluded on the basis of the data obtained that the reduction of 1,8-dioxodecahydroacridines in the presence of nickel catalysts proceeds in a stereodirected manner with cis addition of hydrogen characteristic of catalytic processes, while more forcing conditions of hydrogenation aid the exhaustive saturation of multiple bonds (Table 1). The structure of compounds 2a-e and 3a-e was established by data of 1H and 13C NMR spectroscopy, IR spectra and chromato-mass spectrometry. Characteristic of the IR spectra of the dodecahydroacridines were the presence of intense absorption bands at 3300-3500 cm-1, confirming the presence of hydroxyl groups, and two absorption bands at 1600 and 1640 cm-1 corresponding to the stretching vibrations of the C=CC=O conjugated bond system. In the spectra of compounds 3a-c there was no absorption in these regions. The enamine NH group in the spectra of compounds 2a,e is characterized by absorption at 3250-3300 cm-1, and the phenyl substituents (compounds 2c,e) by absorption at 3080-3100 cm-1. The chromato-mass spectra of hydroacridines 2a-e and 3a-c indicate their homogeneity and consequently their existence as one of the possible isomers. This is indicated by the presence of a single peak on the chromatogram, and the retention times of compounds 2a-c obtained by various routes coincided (for 2a 25.79 min, for 2b 27.51 min, and for 2c 28.99 min). The molecular ion peaks for compounds 2a-e and 3a-c correspond to their molecular masses (Table 2). 584
TABLE 1. Catalytic Hydrogenation of Compounds 1a-f,l, 2b,c on Nickel Catalysts

Initial compound 1 1b Catalyst NiAl Raney Ni NiAl Raney Ni Raney Ni NiAl Raney Ni Raney Ni Raney Ni NiAl NiAl NiAl Raney Ni Raney Ni Raney Ni Medium 1 M KOH + MeOH EtOH 1 M KOH + MeOH EtOH EtOH 1 M KOH + MeOH EtOH EtOH EtOH 1 M KOH + MeOH 1 M KOH + MeOH 1 M KOH + MeOH EtOH EtOH EtOH Temperature, C 60 100 60 100 100 60 100 120 100 60 60 60 100 100 100 Pressure, MPa Atmospheric 10 Atmospheric 10 10 Atmospheric 10 10 10 Atmospheric Atmospheric Atmospheric 10 10 10 Reaction time, h 10-12 8 10-12 8 24 10-12 8 8 24 10-12 10-12 10-12 8 24 24 Reaction product 2a 2a 2b 2b 3c 2 2c 3a 3b 2a 2a 2d 2e 3c 3b Yield, % 89 70 74 67 67 75 57 56 63 72 79 78 72 74 78
1d 1e 1f 1l 2b 2c
585
TABLE 2. Mass Spectra of Compounds 2a-e and 3a-c

Compound 2 2b 2c 2d 2e 3a 3b 3c m/z (Irel, %) 277 []+ (15), 262 (9), 221 (23), 190 (100), 150 (11.5), 87 (38) 291 []+ (21), 276 (8.5), 235 (29), 204 (100), 164 (14), 87 (34) 353 []+ (16.5), 338 (7.5), 297 (34), 266 (100), 226 (9), 87 (31) 357 []+ (9), 329 (13), 301 (39), 270 (100), 230 (19), 87 (35) 297 []+ (12.5), 295 (5.5), 238 (100), 217 (62), 77 (21) 332 (7), 331 []+ (28), 260 (100), 71 (25) 332 (5), 331 []+ (19), 260 (100), 71 (28) 264 (7), 263 []+ (34), 192 (100), 71 (19)
In the mass spectra of compounds 2a-c, which contain no substituent at position 9, an intense peak was present for ion A1, arising by loss of a C4H8 molecule by a retro-DielsAlder reaction characteristic of derivatives of 5,5-dimethylcyclohex-2-enone [7-9]. The formation of cations A2 and A3 is the result of fission of C5H11 and C5H11 from the M+ and A1 ions (Table 2).
O Me Me [M]+ N R 2ac C4H8 O OH Me N R A1 Me OH Me Me + C5H11O
.
Me Me
+ N A2 R
C5H11
O + N A3 R OH
The presence of intense peaks A3 with m/z 238 and A4 m/z 217 was characteristic of the spectrum of 8-hydroxy-9-phenyldodecahydroacridinone (2e). Ion A4 arises by fission of a phenyl group from the [M]+ ion. The absence of geminal methyl substituents in the alicycle of compound 2e probably excludes breakdown by a retro-DielsAlder reaction.
O Ph OH +
.
C3H7O
Ph
N M+ H 2e
C6H5 H2
+ N
H2
.
O OH + N A4
H A3
586
TABLE 3. 1H NMR Spectra of 8-Hydroxydodecahydroacridin-1-ones 2a-e

Compound 2 2b 2c Chemical shifts, , ppm (coupling constants, J, Hz) (8), (8), (10), (9), m (7), 2 1, m 1, m 1, m 1.8 (dd, J1 = 5.0, J2 = 12.0, ); 2.2 (dd, J1 =5.0, J2 = 12.0, ) 1.8 (dd, J1 = 5.0, J2 = 12.0, ); 2.4 (dd, J1 = 5.0, J2 = 12.0, ) 1.8 (dd, J1= 5.0, J2 = 12.0, ); 2.3 (dd, J1 = 5.0, J2 = 12.0, ) 1.8 (dd, J1 = 5.5, J2 = 12.0, ); 2.3 (dd, J1 = 5.5, J2 = 12.0, ) 4.0 4.0 4.2 1.9 1.9 1.9 2.0 (2) 2.0 (2) 2.0 (2) 3.4 3.4 3.6
C(2), 2H 2.3 (s) 2.3 (s) 2.4 (s)
C(4), 2H 2.1 (s) 2.1 (s) 2.1 (s)
C(5), 2H 1.3 (dd, J1 = 5.0, J2 = 12.0, ); 1.7 (dd, J1 = 5.0, J2 = 12.0, ) 1.3 (dd, J1 = 5.5, J2 = 11.5, ); 1.7 (dd, J1 = 5.5, J2 = 11.5, ) 1.3 (dd, J1 = 5.0, J2 = 11.0, ); 1.7 (dd, J1 =5.0, J2 = 11.0, ) 1.3 (dd, J1 = 6.0, J2 = 11.5, ); 1.7 (dd, J1 = 6.0, J2 = 11.5, )
Other signals 0.8-1.0 (12H, s, 4H3); 4.5 (1H, br. s, ); 6.7 (1, s, NH) 0.8-1.0 (12H, s, 4 H3); 4.6 (1, br. s, ); 3.0 (3H, s, NH3) 0.7-0.9 (12H, s, 4 H3); 4.8 (1H, s, ); 7.1 (3, m, C6H5); 7.3 (2, m, C6H5) 0.9-1.0 (12, s, 4 H3); 3.1 (3, s, NH3); 4.7 (1H, br. s, ); 6.1 (1H, d, J = 3.6, Fur); 6.3 (1H, t, Fur); 7.2 (1H, d, J = 3.6, Fur) 7.3 (1, s, NH); 7.2 (5H, m, C6H5); 4.9 (1, s, ); 0.9-1.4 (4, s, (3) and (6))
2d
2.4 (s)
2.2 (s)
4.3
1.9
3.0 (1)
3.5
2e
2.3 (m)
2.0 (m)
1.1 (m)
1.3 (m)
4.4
1.9
2.9 (1)
3.5
587
588
TABLE 4. 13C NMR Spectra of 8-Hydroxy-cis-dodecahydroacridin-1-ones 2a-e

Compound 2a 2b 2c Chemical shifts, , ppm (1) 190.79 191.40 192.88 (2) 50.05 49.21 49.57 (3) 32.29 31.49 32.04 (4) (4) (5) 41.82 36.49 42.12 (6) 31.17 30.33 31.08 (7) 45.75 39.57 44.78 (8) 68.11 66.31 68.46 (8) 41.33 37.31 41.25 (9) 21.89 14.01 21.92 (9) 102.17 101.69 105.41 (10) 47.16 57.79 54.50 R Me (at (3)) Me (at (6)) 28.92; 28.21 29.17; 25.76 28.53; 7.75 34.40; 28.30 32.97; 27.77 34.19; 27.91 R1 R2 37.10 142.18; 129.74*; 129.39*; 127.78 37.90
45.75 159.92 40.89 45.31 156.84 156.59
2d
191.91
49.48
31.70
41.63
157.02
36.55
29.84
41.05
68.66
40.67
25.51
103.38
58.82
29.62; 27.61
32.60; 28.11
2e
190.41
36.67
21.48
28.51
159.30
29.17
20.49
29.17
69.95
42.58
34.37
106.56
51.95
158.01; 139.15; 111.11; 107.38 145.48*; 126.72*; 125.20*
_______ * Signal corresponds to two carbon atoms.
The mass spectra of perhydroacridines 3a-c were generally poorly informative and contain, besides the [M] peak, an intense [M-C5H11]+ peak with m/z 260 (for compounds 3a,b) and 192 (for compound 3c). The 1H NMR spectra of dodecahydroacridines 2a-e (Table 3) and perhydroacridines 3a-c corresponded completely with their structures. The most characteristic for compounds 2a-e were the signals of the hydroxyl group protons, which are displayed as a broadened singlet at 4.5-4.9 ppm, and the chemical shift of the hydrogen atom at position 8 at 4.0-4.4 ppm, which indicates the equatorial disposition of the hydroxyl functions [10]. The presence of the phenyl substituents in compounds 2c,e is confirmed by the presence of multiplets at 7.1-7.3 ppm, and the chemical shift of the NMe group protons in compounds 2b,d were at 3.0-3.1 ppm. The signals of the angular protons at C(8a) and C(10a) (multiplets) are at 1.8-1.9 and 3.4-3.6 ppm respectively, which permits the conclusion that one type of steric structure exists for dodecahydroacridines 2a-e irrespective of the degree and character of substitution. The disposition of the proton signal for the C(10a) atom at 3.4-3.6 ppm in compounds 2a-e corresponds, according to the data of [11], to a cis linkage of the carbo- and heterocycles, but in the case of the N-phenyl-substituted compound 2c this leads to splitting of the signal of the protons of the phenyl substituent at the nitrogen atom. The 1H NMR spectra of perhydroacridines 3a-c indicate the absence from the structure of these compounds of aromatic substituents or hydroxyl functions. They contain signals for methyl and methylene groups and for methine protons at 0.9-3.7 ppm of which the most characteristic are the chemical shifts of the geminal methyl substituents (0.9-1.1 ppm) and the NMe group in compound 3c (2.2 ppm). In the analysis of the 13C NMR spectra of dodecahydroacridinones 2a-e and perhydroacridines 3a-c offresonance decoupling spectra and the literature data of 13C NMR spectra of the isomeric perhydroacridines [12-14] and 3,3-dimethylhydroxanthenes [15] were used for the assignment of signals. The use of off-resonance spectra for compounds 2a-e enabled the tertiary atoms C(8), C(8a), and C(10a) to be distinguished. At lowest field were the signals for the C(8) atom located at 66.31-69.95 ppm (Table 4). The resonance signals for the junction atoms C(8a) and C(10a), the position of which depends directly on the character of the linkage of the rings, were displayed at 37.31-42.58 and 47.16-58.82 ppm respectively. The chemical shifts of the C(8a) and C(10a) signals in compounds 2b-e correlate well with the data for the corresponding cis type 10- and 9,10-substituted perhydroacridines [12,13]. Displacement of the C(10a) atom signal in compound 2a towards high field (47.16 ppm) may probably be explained by the reduction of the deshielding effect of the nitrogen atom due to the absence of electron-donating substituents on it. The presence in the spectra of compounds 2a-e of a high field signal at 14.01-21.92 ppm indicates that the dodecahydroacridinones mentioned are cis isomers [12-15]. The appearance of this signal is explained by the gauche interaction of the heteroatom with the carbon atom found in the -position. In 3,3,6,6-tetramethyl-8-hydroxydodecahydroacridin-1-ones this effect is only possible with the participation of the C(9) atom. The signals at 14.01-21.29 ppm were therefore assigned to the indicated atom (Table 4). The greatest high field displacement was sustained by the C(9) atom in dodecahydroacridine 2b which is linked with the strengthening of the shielding influence of the heteroatom due to the introduction of a methyl group onto it. An analogous effect may already have been observed in the example of piperidine and methylpiperidine [16]. In the case of dodecahydroacridinone 2e, containing no substituent in position 3 and no gem-dimethyl substituents in position 6, the greatest -gauche effect was sustained by atoms C(3) and C(6), the resonance signals of which are displayed at 21.48 and 20.49 ppm respectively, but the chemical shift of the C(9) atom carrying a phenyl residue was at 34.37 ppm in this case. In the spectra of compounds 2a-e (Table 4) the signals of C(1)C(4), C(4a), C(6), and C(9a) and of the geminal methyl groups correlate well with the spectra of the corresponding cis-dodecahydroxanthenones. Assignment of the other resonance signals was made more precise by comparison with the spectra of 3,3-dimethylperhydroxanthenes and the isomeric perhydroacridines. Dodecahydroacridin-1-ones 2a-e are therefore obtained in the form of cis isomers under conditions of catalytic synthesis. The criterion for the cis junction of the cyclohexane and hydropyridine rings, as in the case
+
589
590
TABLE 5. 13C NMR Spectra of Perhydroacridines 3a-c

Me
2 3 1 4 9a 9 10 8a 8 5 7 6
Me
Me
4a
10a
Me
Compound 3a
C(1), (8) 39.45
(2), (7) 31.37
(3), (6) 31.94
(4), (5) 34.33
Chemical shifts, , ppm (4), (10) (8), (9) 56.89 37.67
(9) 23.22
25.36
33.79
R 50.67 (()); 28.23 (() and (); 26.10 (()); 25.73 (() and ()) 56.89 (()); 27.13 (() and ()); 26.83 (()); 26.42 (() and ()) 40.44
3b
33.80
31.06
31.36
32.64
58.62
37.62
25.34
30.85
31.46
3c
34.29
30.67
31.69
33.30
57.07
37.53
25.87
29.82
32.51
of perhydroacridines [12-14] and hydroxanthenes [15], is the presence of a high field signal, which depending on the presence or absence of substituent groups in positions 3 and 6, may belong either to the C(9) atom (compounds 2a-d) or to the C(3) and C(6) atoms (compound 2e). In the spectra of isomers 3a-c (Table 5) seven resonance signals belong to the perhydroacridine skeleton, one of which is at high field and is located at 25.34-25.87 ppm, which, as already mentioned above, is the criterion for the cis linkage of the hetero- and carbocycles, cis-syn-cis or cis-anti-cis [12-14]. In the first case the reduction in the number of signals is linked with the symmetricality of the structure of the molecule, and in the second with the readiness of inversion of the possible conformers, readily changing from one to another even at room temperature. This leads to a reduction in the number of signals in the 13C NMR spectra and their width, apart from the signals of the C(9) atoms and the carbon atoms of the substituents [14]. A similar picture is observed in the spectra of compounds 3b,c, unlike the spectrum of isomer 3a, where the resonance signals of the carbon atoms were not broadened. The varied character of the spectra of perhydroacridines 3a-c serves as a basis for assigning compound 3a to an isomer with a cis-syn-cis configuration, and compounds 3b,c to an isomer with a cis-anti-cis structure. A special feature of the cis-syn-cis-perhydroacridine is the possibility of existing as two conformers differing in energy A (axial CC bonds are in the position to the heteroatom) and B (axial CC bonds are in the position to the nitrogen atom). As is known [12-14] the position and intensity of the C(9) atom serves as a conformational label in this case For conformer A this signal is displayed at lower field (~35 ppm and more), while for conformer B a displacement of the chemical shift of the C(9) atom of ~11 ppm towards high field is observed. In the spectrum of compound 3a the resonance signal of the C(9) atom is displayed at 23.22 ppm, which points in favor of conformation B of cis-syn-cis-perhydroacridine for 3a. The good correlation between the resonance signals of the angular atoms C(4a)C(10a), C(8a)C(9a) in compounds 3a-c and the corresponding N-R-perhydroacridines [14] is an additional argument in favor of the conclusions on the spatial structure of isomers 3a-c. The assignment of the other carbon atoms (Table 5) was made more precise on comparison with the spectra of the isomeric perhydroacridines and perhydroxanthenes [12-15]. The introduction of two methyl groups into positions C(3) and C(6) is satisfactorily described by the -, -, and -increments for dimethylsubstituted cyclohexanes [17] and 3,3-dimethylperhydroxanthenes [15].

Compound 2a 2b 2c 2d 2e 3 3b 3c Empirical formula C17H27NO2 C18H29NO2 C23H31NO2 C22H31NO3 C19H23NO2 C23H41N C23H41N C18H33N Found, % Calculated, % 9.97 9.75 10.00 9.97 9.02 8.78 8.89 8.68 8.13 7.74 12.30 12.39 12.55 12.39 12.68 12.55 mp, N 5.17 5.05 5.00 4.81 4.11 3.97 3.92 3.92 4.83 4.71 4.81 4.23 4.29 4.23 5.49 5.32 220-222 229-231 237-238 230-232 281-283 86-87 71-73 64-65
73.33 73.65 74.57 74.23 77.83 78.19 74.17 73.95 77.00 76.77 83.86 83.38 83.54 83.38 82.07 82.13
591
We have therefore studied for the first time the catalytic hydrogenation of decahydroacridine-1,8-diones under various conditions and have found conditions for reducing them to cis-dodecahydroacridin-1-ones and perhydroacridines of the cis-syn-cis and cis-anti-cis types.
EXPERIMENTAL The IR spectra were recorded on a Specord M 80 instrument (suspensions in nujol and in hexachlorobutadiene), and the 1H and 13C NMR spectra on a Bruker AC 300 (300 and 75 MHz respectively) spectrometer in CDCl3 and CD3OD, the internal standard was TMS. The chromato-mass spectra were obtained on a Hewlett-Packard HP 5972A gas chromatograph with a HP 5890 mass-selective detector on a capillary column (30 m 0.25 mm) with 5% methylphenylsilicone, carrier gas was nitrogen, energy of ionising electrons was 70 eV. A check on the course of reactions and the homogeneity of the compounds isolated was effected by TLC on Silufol UV 254 plates, eluent was hexaneacetonechloroform, 3:1:1, visualizing with iodine vapor. The decahydroacridine-1,8-diones 1a-l were synthesized by the known procedure of [1,2]. 9-(2-Furyl)-8-hydroxy-3,3,6,6,10-pentamethyl-1,2,3,4,5,6,7,8,8a,9,10,10a-cis-dodecahydroacridin1-one (2d). Acridinedione 1f (5.295 g, 15 mmol), methanol (100 ml), and 1 M KOH solution (100 ml) were placed in a three-necked flask of capacity 0.5 liter fitted with a mechanical stirrer, a reflux condenser, and a thermometer. The mixture was brought to boiling (60C) with stirring, and each 20-30 min finely powdered Ni Al alloy (40% Ni) was carefully added in portions of about 0.5 g. At the end of the reaction (10-12 h) the hot reaction mixture was filtered, and the solid Al(OH)3 + Ni was washed with hot methanol (4 20 ml). The filtrate was evaporated, the residue was refluxed in acetone (50 ml) for 20 min, then without cooling an additional portion of Al(OH)3 was filtered off. The filtrate was evaporated to half volume, cooled, and crystalline solid compound 2d was precipitated. This was separated and recrystallized from methanol. Compounds 2a-c were obtained analogously from acridinediones 1a-e (see Tables 1 and 6. The reduction of acridinediones 1i,j was accompanied by the formation of NH-decahydroacridinediones 1h,l. Compound 1g was not reduced under the conditions indicated. 8-Hydroxy-9-phenyl-1,2,3,4,5,6,7,8,8a,9,10,10a-cis-dodecahydroacridin-1-one (2e). Acridinedione 1l (2.97 g, 10 mmol), ethanol (50 ml), and Raney Ni (~0.5 g) were placed in a steel rotating autoclave of capacity 150 ml. Initial hydrogen pressure was 10 MPa and temperature 100C. The reaction was completed after 8 h after absorption of the calculated amount of hydrogen (20 mmol). After removing the catalyst and solvent, compound 2e was crystallized. Compounds 2a-c were synthesized in the same way from acridinediones 1a-c. Perhydroacridines 3a-c (Tables 1, 6) were obtained by the hydrogenation of decahydroacridines 1b,c and cis-dodecahydroacridinones 2b,c by the procedure described above. 3,3,6,6-Tetramethyl-10-cyclohexyl-cis-anti-cis-perhydroacridine (3b). Isomerization of 3,3,6,6-tetramethyl-10-cyclohexyl-cis-syn-cis-perhydroacridine 3a. Compound 3a (3.31 g, 10 mmol), ethanol (50 ml), and Raney Ni (~0.5 g) were placed in a steel rotating autoclave of capacity 150 ml. The initial hydrogen pressure was 10 MPa, and temperature 100C. After 24 h compound 3a was completely isomerised into 3b (check by TLC). The catalyst was filtered off, and compound 3b was crystallized after removing the solvent.
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E. I. Stankevich and G. Ya. Vanag, Izv. Akad. Nauk LatvSSR, Ser. Khim., 223 (1961). H. Antaki, J. Chem. Soc., 2263 (1965). I. N. Gracheva and A. I. Tochilkin, Khim. Geterotsikl. Soedin., 77 (1988). L. K. Keefer and G. Lunn, Chem. Rev., 89, 459 (1989). J. Baldas and Q. N. Porter, Tetrahedron Lett., 1351 (1968). C. Dagher, R. Hanna, P. B. Terentiev, Y. G. Boundel, N. Kost, and B. I. Maksimov, J. Heterocycl. Chem., 19, 645 (1982). P. Cupka, J. Bella, and A. Martvon, Coll. Czech. Chem. Commun., 52, 742 (1987). C. A. Grob and H. R. Kiefer, Helv. Chim. Acta, 48, 799 (1965). V. I. Alekseev, V. A. Kaminskii, and M. N. Tilichenko, Khim. Geterotsikl. Soedin., 235 (1975). A. P. Kriven'ko, T. G. Nikolaeva, L. M. Yudovich, N. T. Komyagin, A. I. Yanovskii, Yu. T. Struchkov, and V. G. Kharchenko, Khim. Geterotsikl. Soedin., 1645 (1987). T. G. Nikolaeva, L. M. Yudovich, A. A. Pastukhova, and A. P. Kriven'ko, Khim. Geterotsikl. Soedin., 200 (1992). T. G. Nikolaeva, P. V. Reshetov, and A. P. Kriven'ko, Khim. Geterotsikl. Soedin., 867 (1997). V. G. Kharchenko, L. M. Yudovich, N. S. Smirnova, G. I. Rybina, and L. I. Markova, Zh. Org. Khim., 23, 576 (1987). G. C. Levy and G. L. Nelson, Carbon-13 Nuclear Magnetic Resonance for Organic Chemists, WileyInterscience, New York (1972), 240 pp. D. K. Dalling and D. M. Grant, J. Am. Chem. Soc., 94, 5318 (1972).
593
SIMPLE SYNTHESIS OF 6-SUBSTITUTED 4a-METHYL-1,2,3,4,4a,10b-HEXAHYDROPHENANTHRIDINES AND -9,10-BENZOPHENANTHRIDINES

Yu. V. Shklyaev and Yu. V. Nifontov A route has been developed for the synthesis of 6-substituted 4a-methyl-1,2,3,4,4a,10bhexahydrophenanthridines and -9,10-benzophenanthridines. The effect has been shown of the nature of the substituent at position 10 of the ring on the chemical shift of the proton at position 10b. Keywords: 9,10-benzophenanthridines, hexahydrophenanthridines, diastereomers, Ritter reaction. Aromatic phenanthridines have been studied adequately well [1-4]. However there is only one study on the chemistry and biological activity of hydrogenated phenanthridines, which is probably linked with the absence of convenient methods of synthesizing them [3]. The synthesis of 6-R-4a-methyl-1,2,3,4,4a,10b-hexahydrophenanthridines (R = Me, CH2COOEt) from 1-methyl-2-phenylcyclohexanol has been described [5]. In spite of its superficial simplicity it requires the use of the difficultly available 2-phenylcyclohexanone and in addition a mixture of all the possible diastereomers is formed.
HO Me
+ H
+ Me
2 1 3 10
+ Me
RCN
10b
9 8 7
**
4a 6
N5
Me
or
**
Me NH COR2
R1 1, 2
1 1
3, 4
R = Me, SMe, CH2COOEt, CH2CONH2; 1 R = Me, 2 R = SMe, 3 R2 = OEt, 4 R2 = NH2
__________________________________________________________________________________________ Institute of Technical Chemistry, Urals Branch of the Russian Academy of Sciences, Perm 614990; e-mail: cheminst@mpm.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, Vol. 40, No. 5, pp. 706-710, May, 2004. Original article submitted October 23, 2001. 594 0009-3122/04/4005-05942004 Plenum Publishing Corporation
It was discovered by us that identical products are also formed by the Ritter reaction from 2-methyl1-phenylcyclohexanol, obtained from phenyl magnesium bromide and 2-methylcyclohexanone. As was shown in [6], when alkyl substituents are present at the second carbon atom of 1-aryl-2,2-dialkylethanols, transposition of the reaction center is observed, and the tertiary carbocation formed in this way, which is not stabilized by a neighboring aryl residue, is the only one which can interact with a nitrile group. 2-Methyl-1-phenylcyclohexanol reacts with nitriles in a similar manner with the formation of phenanthridines 1-4. The Ritter reaction proceeds similarly and for 2-methyl-1-(1-naphthyl)cyclohexanol, obtained from 1-naphthylmagnesium bromide and 2-methylcyclo-hexanone, leads to the preparation of the previously unknown 6-substituted 4a-methyl-1,2,3,4,4a,10b-hexahydro-9,10-benzophenanthridines 5-8.
** N R1 5, 6 Me
R1CN
HO
Me CN COR2 ** NH Me
7, 8 5 R1 = Me, 6 R1 = SMe, 7 R2 = OEt, 8 R2 = NH2
COR2
A characteristic feature of compounds 1-8 is the presence of a signal for the 10b proton of the phenanthridine ring in the 1H NMR spectrum. For the 6-R-1,2,3,4,4a,10b-derivatives 1-4 this signal is found at 2.70-2.73 ppm. For compounds 5-8 the signal is displaced to substantially lower field (for 5 to 3.52, for 6 to 3.38, for 7 to 3.50, and for 8 to 3.39 ppm), which, in our view, may be explained by the significant deshielding of this proton due to the -electrons of the naphthalene ring. In addition this signal is a doublet of doublets, which in combination with the singlet of the methyl group in position 4a of the ring, indicates the presence of only one pair of enantiomers. Additional confirmation is given by the presence of only one signal for the vinyl proton and the heterocyclic NH for compounds 3, 4, 7, and 8. With the aim of clarifying the role of the substituent in position 10 of the phenanthridine ring we studied the behavior in this reaction of 1-(2,5-dimethylphenyl)-2-methylcyclohexanol, obtained from 2,5-xylylmagnesium bromide and 2-methylcyclohexanone. It turned out that in this case the preparation was observed of only one pair of enantiomers of derivatives of 4a,7,10-trimethyl-1,2,3,4,4a,10b-hexahydrophenanthridines 9-12. However the signal of the proton at position 10b of the ring at 2.52-2.59 ppm was displaced towards high field in comparison with compounds 1-4, which is explained by the shielding of this proton by the methyl group at position 10.
Me ** N Me R1 9, 10 Me Me R1CN OH Me Me 11, 12 9 R1 = Me, 10 R1 = SMe, 11 R2 = OEt, 12 R2 = NH2 COR2 Me CN COR2 Me ** NH Me
595
596

Compound 1-HOC6H4COOH*2 2 3 4 5 6 7 8 9-HOC6H4COOH*2 10 11 IR spectrum, , cm-1 1620, 1580, 1500, 1320 3280, 1735, 1605, 1580 3440, 3360, 3190, 1650, 1610 1620, 1580, 1500 1622, 1585, 1510 3250, 1725, 1610 3310, 3245, 1645, 1610 1620, 1585, 1510 3280, 1735, 1605, 1580 3440, 3355, 3190, 1650, 1605
1
NMR spectrum, , ppm (J, Hz) arom. Other protons 2.47 (3, s, 6-CH3) 2.54 (3, s, 6-SCH3) 1.20 (3, t, CH3 ester); 4.10 (2, q, 2); 5.19 (1, s, ); 8.80 (1, s, N) 5.21 (1, s, ); 6.32 (2, br. s, NH2); 8.60 (1, s, NH) 2.40 (3, s, 6-CH3) 2.47 (3, s, SCH3) 1.22 (3, t, CH3 ester); 4.10 (2, q, 2); 5.23 (1, s, ); 8.90 (1, s, NH) 5.23 (1, s, ); 6.25 (2, br. s, NH2); 9.40 (1, s, NH) 2.43 (3, s, 6-CH3); 2.31 (3H, s, 7-CH3); 2.28 (3H, s, 10-CH3) 2.27 (3, s, 10-CH3); 2.34 (3, s, 7-CH3); 2.60 (3, s, 6-SCH3) 1.22 (3, t, J = 7.4, CH3 ester); 2.27 (3, s, 10-CH3); 2.48 (3, s, 7-CH3); 4.08 (2, q, J = 7.3, 2); 4.73 (1, s, ); 9.03 (1, s, N) 2.26 (3, s, 10-CH3); 2.47 (3, s, 7-CH3); 4.79 (1, s, ); 6.20 (2, br. s, NH2); 9.60 (1, s, NH)
3, s, 4a-Me 0.73 0.80 0.83 0.82 0.75 0.80 0.97 0.95 0.73 0.58 0.86
8H, complex. m, (CH2)4 1.35-2.00 1.12-1.96 1.16-2.01 1.21-2.00 1.00-2.00 0.99-2.10 1.43-1.92 1.20-1.80 1.22-1.99 1.30-2.05 1.30-1.90
1H, dd, 10b-* 2.70 2.72 2.73 2.72 3.52 3.38 3.50 3.39 2.52 2.55 2.53
6.80-7.78 (8, m) 7.10-7.56 (4, m) 7.02-7.49 (4, m) 7.13-7.71 (4, m) 7.50-7.93 (5, m); 8.20 (1, d, 7-) 7.60-7.95 (5); 8.25 (1, d, 7-) 7.60-7.99 (5, m); 8.23 (1, d, 7-) 7.50-7.80 (5, m); 8.15 (1, d, 7-) 6.93-7.66 (6, m) 6.88 (1, d); 6.93 (1, d) 7.05(1, d); 7.12 (1, d) 7.00 (1, d); 7.04 (1, d)
12
0.81
1.20-1.80
2.59
_______ * J = 8.3 Hz. *2 Compounds 1 and 9 were identified as salicylates.
TABLE 2. Physicochemical Properties of Compounds 1-12

Compound Empirical formula C22H25NO3 1519NS 1823N2 1620N2 1921N 1921NS 2225N2 2022N2 C24H29NO3 1723NS 2027N2 1824N2 Found, % Calculated, % 7.03 7.12 7.85 7.76 8.12 8.07 8.01 7.81 8.05 7.98 7.20 7.12 7.55 7.46 7.30 7.19 7.72 7.65 8.37 8.48 8.54 8.63 8.53 8.51 mp, N 4.11 3.99 5.84 5.71 5.00 4.91 10.80 10.94 5.12 5.33 4.84 4.75 4.31 4.18 9.31 9.15 3.79 3.69 5.20 5.13 4.60 4.47 10.00 9.86 123-124 (ethyl acetate) 85-86 (hexane) 64-65 (hexane) 129-130 (benzene) 117-118 (hexane) 69-70 (hexane) 115-116 (hexane) 210-211 (ethanol) 127-128 (ethanol) 102-103 (hexane) 89-90 (hexane) 119-120 (ethyl acetate) 39 50 61 66 49 62 81 83 39 53 59 62 Yield, %
75.33 75.21 73.60 73.47 75.50 75.79 75.31 75.00 86.83 86.69 77.00 77.29 78.61 78.81 78.21 78.43 75.85 75.99 74.83 74.67 76.80 76.68 75.91 76.06
1-HOC6H4COOH* 2 3 4 5 6 7 8 9-HOC6H4COOH* 10 11 12
_______ * Compounds 1 and 9 were identified as salicylates.
EXPERIMENTAL The IR spectra were taken on a UR 20 spectrophotometer in nujol. The 1H NMR spectra were recorded on a Bruker AM 300 spectrophotometer (300 MHz) in DMSO-d6, internal standard was TMS. The progress of reactions and the purity of the compounds obtained were checked by TLC on Silufol UV 254 plates (chloroformacetone, 9:1), visualizer was a 0.5% solution of chloranil in toluene. 2-Methylcyclohexanone (from Lancaster) was used without preliminary purification. Synthesis of the initial carbinols was effected by a standard procedure from 2-methylcyclohexanone and the appropriate arylmagnesium bromide in diethyl ether. After distillation in vacuum the obtained mixture of carbinol and the corresponding styrene (~3 : 1, according to data of 1H NMR and liquid chromatography) was used in the reaction without further purification allowing for the molar content of the components. 6-Substituted 4a-Methyl-1,2,3,4,4a,10b-hexahydrophenanthridines and Ethyl Esters of (4a-Methyl-1,2,3,4,4a,5,6,10b-octahydro-6-phenanthridinylidene)acetic Acid (1-3, 5-7, 9-11) (General Procedure). A mixture of carbinol (0.1 mol) and nitrile (0.1 mol) was added dropwise with stirring and cooling (0-10C) to conc. H2SO4 (50 ml). The mixture was stirred for 30 min, diluted with water (300 ml), and extracted with toluene (50 ml). The organic layer was rejected, and the remainder was made alkaline with aqueous ammonia to pH 8-9. The separated solid (for compounds 2, 3, 5-7, 10, 11) was removed, washed with water, dried in the air, and recrystallized from an appropriate solvent.
597
Compounds 1 and 9 were oils and were identified as salicylates. A solution of salicylic acid (1.38 g, 0.01 mol) in dry ether (20 ml) was added in one portion to a solution of substituted 4a-methyl-1,2,3,4,4a,10bhexahydrophenanthridine 1 or 9 (0.01 mol) in dry diethyl ether. The mixture was stirred for 1 min and left for 30 min. The separated solid was removed, washed on the filter with ether (20 ml), and recrystallized. Amides of (4a-Methyl-1,2,3,4,4a,5,6,10b-octahydro-6-phenanthridinylidene)acetic Acids (4, 8, 12) (General Procedure). Cyanoacetamide (1.68 g, 0.02 mol) was dissolved with stirring in cold conc. H2SO4 (15 ml) and the appropriate carbinol (4.28 g, 0.02 mol) was added rapidly in one portion. The mixture was stirred for 15 min, diluted with water (100 ml), and extracted with benzene (20 ml). The organic layer was rejected, and the aqueous layer made alkaline to pH 8-9. The precipitated solid was filtered off, washed with water, dried in the air, and recrystallized. The work was carried out with the financial support of RFFI (grant No. 01-03-96479).
REFERENCES 1. 2. 3. 4. 5. 6. L. P. Walls in R. C. Elderfield (editor), Heterocyclic Compounds, Vol. 4, Wiley, New York (1952), p. 564. A. G. Mikhailovskii and M. I. Vakhrin, Khim. Geterotsikl. Soedin., 1361 (1991). D. B. Rubinov, A. G. Mikhailovskii, and F. A. Lakhvich, Khim. Geterotsikl. Soedin., 1617 (1992). A. G. Mikhailovskii, T. G. Taranova, B. Ya. Syropyatov, and M. I. Vakhrin, Khim.-farm. Zh., 26, No. 11-12, 53 (1992). A. G. Mikhailovskii, V. S. Shklyaev, G. A. Veikhman, and M. I. Vakhrin, Khim. Geterotsikl. Soedin., 1374 (1993). V. A. Glushkov, O. G. Ausheva, and Yu. V. Shklyaev, Khim. Geterotsikl. Soedin., 693 (2000).
598
SYNTHESIS OF FORMYL DERIVATIVES OF 2-HETARYLIMIDAZOLES ANNELATED WITH NAPHTHALENE AND PHENANTHRENE RINGS
A. A. Pechkin1, M. M. Elchaninov2, B. S. Lukyanov1, and Yu. S. Alekseenko1 The formylation reaction of a series of 2-hetarylimidazoles, annelated by naphthalene and phenanthrene rings, using hexamethylenetetramine in PPA and the Vilsmeier reagent has been studied. The furyl and thienyl derivatives form principally the 5-formyl-substituted and the pyrrolylimidazoles were found to give a mixture of the - and -formyl derivatives. Keywords: hetarylimidazoles, formylation. The introduction into the structure of spiropyrans of heterocyclic fragments having luminophoric properties give the potential for the use of similar compounds in utilizing systems of preserving optical information with separate recording and read out channels. The recording of information can be brought about by the action on the molecule of activating UV irradiation and its read out correlated with the change in the luminescence spectrum of the photoinduced form when compared with the cyclic. In this case the very topical question is the preparation of novel heterocyclic aldehydes which are functionalized at the formyl group and which readily allow the introduction of the corresponding hetarene fragment into the spiropyran structures.
N N Me 1, 2 X
(CH2)6N4 PPA 60100 oC
N N Me 6, 7 X CHO
N N Me 3, 4 X
(CH2)6N4 PPA 60100 oC
N N Me 8, 9 X CHO
1, 3, 6, 8 X = O; 2, 4, 7, 9 X = S
__________________________________________________________________________________________ Physical and Organic Chemistry Science Research Institute, Rostov State University, Rostov-on-Don 344090; e-mail: benzol@newmail.ru. 2 Southern Russia State Technical University (Novocherkassk Polytechnic Institute), Novocherkassk 346400. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 711-714, May, 2004. Original article submitted March 20, 2001; revision submitted February 2, 2004. 0009-3122/04/4005-05992004 Plenum Publishing Corporation 599
1
Up to this time the formylation of five-membered -excessive heterocycles and their derivatives has been successfully carried out by a Vilsmeier reaction. However, according to data in [1], this method does not always prove expedient in most hetarylimidazoles. We have attempted to carry out the direct introduction of an aldehyde group into 2-hetarylimidazoles annelated with the naphthalene and phenanthrene rings using this method. However, the reaction only took place for compound 5 under these conditions. Compounds 1-4 proved inert to the action of the Vilsmeier reagent even under quite forcing conditions and so for these compounds hexamethylenetetramine in PPA at 60-100C was used as the formylation method. The 5-formyl derivatives on the hetaryl ring 6-9 were obtained as the formylation products and were separated in 60-75% yields. A study of the formylation reaction of compound 5 using the Vilsmeier reagent gave unexpected results. In contrast to the similar benzimidazole pyrrolyl derivatives [2], which are characterized by the formation of exclusively the 4'-formyl derivatives on the pyrrole ring under these conditions, we observed the formation of a mixture of - and -substituted products. Separation of the isomers gave a 15-20% yield identified as 1-methyl2-(2'-[5'-formyl-1'-methylpyrrolyl])phenanthro[9,10]imidazole (10), an isomer of compound 11.
N N Me 5 N N Me 10 N Me N Me
DMF, POCl3 4060 oC
CHO N CHO
N Me 11
N Me
This points to a weaker electron acceptor effect of the phenanthro[9,10]imidazole substituent when compared with the corresponding benzimidazole fragment. Concurrent reactions are observed when the 5 position of the hetaryl ring is occupied by a phenyl substituent. Hence, from 1H NMR data, the formylation of compound 12 using hexamethylenetetramine in PPA medium gives a mixture of 1-methyl-2-(3-formyl-2-phenylfuryl)- (13) and 1-methyl-2-(5'-[oformylphenyl]furyl)phenanthro[9,10]imidazoles (14).
N N Me O 12 CHO N N Me 13 O 30%
(CH2)6N4 PPA
N Me 14
O OHC 70%
600
TABLE 1. Parameters for the Formyl 2-Hetarylimidazoles

Compound 6 Empirical formula 17H12N2O2 Found, % Calculated, % C H N 73.83 73.92 4.32 4.34 10.04 10.11 mp,
1
NMR spectrum(CDCl3), , ppm (J, Hz)
Yield, % 62
144-145
17H12N2OS
70.14 69.92
4.13 4.11
9.63 9.66
180-181
21H14N2O2
75.93 75.39 72.66 73.13 76.25 76.91 76.52 76.91 80.04 80.58 80.93 80.58
4.33 4.29 4.03 4.09 4.94 5.01 4.91 5.05 4.39 4.48 4.68 4.51
8.25 8.28 7.83 7.69 12.16 12.18 11.92 12.18 7.22 6.69 6.92 6.69
198-199
21H14N2OS
207-208
10
C22H17N3
227-228
11
C22H17N3
215-216
13
C27H18N2O2
209-210
14
C27H18N2O2
204-205
9.78 (1, s, CO); 8.63 (1, d, J = 8.0, -9); 7.90 (1, d, J = 8.0, -6); 7.77 (1, d, J = 8.8, -4); 7.62 (1, t, J = 16.0, -7); 7.52 (1, d, J = 8.8, -5); 7.48 (1, t, J = 15.8, -8); 7.45 (1, d, J = 3.7, -3'); 7.42 (1H, d, J = 3.7, H-4'); 4.22 (3, NCH3) 9.98 (1, s, CO); 8.68 (1, d, J = 8.2, -9); 7.92 (1, d, J = 8.2, -6); 7.82 (1, d, J = 4.0, -4'); 7.74 (1, d, J = 4.0, -3'); 7.72 (1, d, J = 8.8, H-4); 7.64 (1, t, J = 16.0, -7); 7.50 (1, t, J = 16.0, -8); 7.48 (1H, d, J = 8.8, H-5); 4.12 (3, s, NCH3) 9.76 (1, s, CO); 8.80 (1, d, J = 8.0, -7); 8.78 (1, d, J = 8.1, -8); 8.66 (1, d, J = 7.7, -4); 8.46 (1, d, J = 7.7, -11); 7.70 (4, m, -5, H-6, H-9, H-10); 7.52 (1, d, J = 3.3, H-3'); 7.44 (1H, d, J = 3.3, H-4'); 4.60 (3H, s, NCH3) 9.96 (1, s, CO); 8.80 (1, d, J = 8.0, -7); 8.75 (1, d, J = 8.0, -8); 8.68 (1, d, J = 7.7, -4); 8.44 (1, d, J = 7.7, H-11); 7.88 (1, d, J = 3.9, -4'); 7.68 (4, m, -5, H-6, H-9, H-10); 7.60 (1H, d, J = 3.9, H-3'); 4.45 (3, s, NCH3) 9.83 (1, s, CO); 8.82 (1, d, J = 7.7, -4); 8.72 (1, d, J = 8.8, -7); 8.68 (1, d, J = 7.7, -11); 8.50 (1H, d, J = 8.1, H-8); 7.65 (4H, m, H-5, H-6, H-9, H-10); 7.51 (1, d, J = 4.2, -4'); 7.00 (1, d, J = 4.2, H-3'); 4.32 (3H, s, NCH3); 4.05 (3, s, NCH3) 9.70 (1, d, CO); 8.82 (1, d, J = 7.7, -4); 8.72 (1, d, J = 8.8, -7); 8.55 (1, d, J = 7.7, -8); 8.68 (1H, d, J = 7.7, H-11); 7.68 (4, m, H-5, H-6, H-9, H-10); 7.08 (1H, s, H-4'); 6.62 (1, s, -3'); 4.30 (3, s, NCH3); 4.16 (3, s, NCH3) 10.05 (1, s, CO); 8.74 (1, d, J = 8.0, -8); 8.68 (1, d, J = 7.7, -4); 8.47 (1, d, J = 7.7, H-11); 7.93 (1H, s, H-3'); 7.65 (4H, m, H-5, H-6, H-9, H-10); 7.56 (4, m, arom); 4.62 (3, s, NCH3) 10.22 (1, s, CO); 8.72 (1, d, J = 8.0, H-8); 8.68 (1, d, J = 7.7, H-4); 8.48 (2, d, J = 6.3, arom); 8.47 (1, d, J = 7.7, -11); 7.65 (4, m, H-5, H-6, H-9, H-10); 7.26 (1, d, J = 3.0, -3'); 7.05 (1, d, J = 3.0, -4'); 4.50 (3, s, NCH3)
60
52
60
65
17
15
40
601
EXPERIMENTAL H NMR spectra were recorded on a Varian Unity-300 (300 MHz) spectrometer using HMDS internal standard. The course of the reaction was monitored chromatographically on Brockmann activity grade II alumina plates (revealed using iodine vapor) in chloroform or on Silufol-250 plates in chloroform. Synthesis of 1-Methyl-2-(5-formyl-2-furyl)naphtho[1,2-d]imidazole (6). 1-Methyl(2-furyl)naphtho[1,2-d]imidazole 1 (2.98 g, 10 mmol) and hexamethylenetetramine (5.6 g, 40 mmol) were stirred in PPA (40 g) at 90-100C for 4-6 h and the reaction was followed chromatographically. The reaction product was diluted with cold water (150 ml) and carefully neutralized using a 20% solution of ammonia. The product was extracted with chloroform (3 100 ml). The extract was evaporated and the residue was chromatographed on an alumina column with chloroform eluent. The product was recrystallized from heptane. Compounds, 7, 8, 13, 14 were prepared similarly. Formyl Derivatives 10, 11 were prepared under classic Vilsmeier conditions. The isomer mixture was separated by column chromatography on alumina with chloroform eluent. The physicochemical and spectroscopic parameters for the compounds obtained are given in Table 1. The work was carried out with the financial support of the RFFI (grant No. 02-03-81011 Bel 2002) and the CRDF Ministry of Education (grant REC-004).
1
REFERENCES 1. 2. M. M. El'chaninov, L. Ya. Oleinikova, and A. M. Simonov, Khim. Geterotsikl. Soedin., 1047 (1979). M. M. El'chaninov, A. M. Simonov, and L. Ya. Oleinikova, Khim. Geterotsikl. Soedin., 71 (1980).
602
CONDENSED ISOQUINOLINES. 16*. ENAMINE PROPERTIES OF BENZO[4,5]IMIDAZO[1,2-b]ISOQUINOLIN-11(5H)-ONE IN TERMS OF ITS ACYLATION REACTIONS
L. M. Potikha, N. V. Shkilna, V. M. Kisil, and V. O. Kovtunenko A study has shown that the acylation of benzo[4,5]imidazol[1,2-b]isoquinolin-11(5H)-one occurs at N(5) or at C(6) depending on the nature of the acylating reagent and the reaction conditions. It was found that principally C-acylation takes place in the absence of base. The reaction with -halo-substituted carboxylic acid chlorides leads to the formation of C-acylated products which are converted to derivatives of the novel heterocyclic system 7H-2a,6b-diazabenzo[b]cyclopenta[l,m]fluorene-1,7(2H)dione in the presence of base. Keywords: heterocyclic enamines, enamines with a secondary nitrogen atom, benzo[4,5]imidazo[1,2-b]isoquinolin-11(5H)-one and 7H-2a,6b-diazabenzo[b]cyclopenta[l,m]fluorene-1,7(2H)-dione derivatives, acylation. A study of the properties and chemical reactions of heterocyclic enamines is an interesting area of organic chemistry. A synthesis of complex heterocyclic systems on this basis is a vigorously evolving area of organic synthesis [2]. Enamines with a secondary nitrogen atom occupy a special place [3] since, in principle, they may have an enamine or a tautomeric imine structure. The behavior of such heterocyclic enamines is most typified by their acylation and alkylation reactions but others are difficult to predict a priori because of the complexity of calculating the nature of the heterocycle, the effect of functional groups, and other factors [4]. An investigation of the properties of the 7,12-dihydro-5H-isoquino[2,3-a]quinazolin-5-one (1) has shown that it reacts with electrophiles as the enamine 1B and is alkylated at the C(7) atom [5]. According to the 1 H NMR spectroscopic data, compound 1 exists in solution in the imine form 1A, hence the formation of derivatives substituted at the atom C(7) is interpreted by us as due to the presence of modest amounts of the enamine form 1B in equilibrium with 1A.
12
N
7
N
6
1A imine
N H 1B enamine
_______ * For Communication 15 see [1]. __________________________________________________________________________________________ Taras Shevchenko National University, Kiev 01033, Ukraine; e-mail: vkovtunenko@hotmail.com. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 715-728, May, 2004. Original article submitted April 2, 2002. 0009-3122/04/4005-06032004 Plenum Publishing Corporation 603
With the aim of widening our knowledge of the chemical behavior of secondary heterocyclic enamines we have turned in this investigation to the benzo[4,5]imidazo[1,2-b]isoquinolin-11(5H)-one (2). Judging by the 1 H NMR spectroscopic data, compound 2 exists in DMSO-d6 solution in the cross conjugated enamine form 2B which anticipates the possible involvement of the triad of atoms C=CNH in novel heterocyclizations.
O
11
O N N
5
N N H 2B enamine
2A imine
The reaction of compound 2 with electrophiles has been mentioned in the studies [6-8]. However, the quoted results are incomplete and sometimes contradictory. Hence, although the author of the study [6] obtained exclusively the N-acylated derivatives independently of the conditions, the report [8] indicates the formation of a mixture of the N- and C-acylated compounds in the ratio 1:5. It is also known [3] that, for a compound with a stable enamine structure, typical acylation occurs at the -position (in our case at the C(6) atom of system 2). In this work the conditions in the quoted studies were followed and the scope of the type 3 reagents was broadened for different variants of the most typical reaction of enamines that of acylation. We have found that the outcome of the acylation depends on the reaction conditions and on the nature of the acylating reagent. For the acylation of compound 2 with acid chlorides, systems containing dioxane (method A), dioxane and AcONa (method B), and pyridine (method C) were investigated. It was noted that the yield of the N-acylation products when the reaction was carried out in the presence of base increased by an average of 10 (method B) and 15% (method C) in the case of the acylation with the acid chlorides 3a-e.
O N N H 2 + RCOX 3an
O N N5 R 4ae O
+
6
N N H
O 5am
3al X = Cl, n, m X = OCOR; 35 a R = Me, b R = Ph, c R = 2-MeC6H4, d R = 2-FC6H4, e R = 2-BrCH2C6H4; 3, 5 f R = 4-MeC6H4, g R = 4-ClC6H4, h R = 4-C5H4N, i R = 3-C5H4N, j R = CH2Cl, k R = CH(Br)Me, l R = CHCl2, m R = CH2Me; 3 n R = Me
When treating compound 2 with acetyl chloride (3a, methods B, C), benzoyl chloride (3B, method B), and (independently of reaction conditions) with the ortho-substituted benzoic acid chlorides (3c-e) a mixture of the N- (4a-e) and C-acylation products (5a-e) was obtained. At the same time, the reaction of compound 2 with acetyl chloride and benzoyl chloride in dioxane and with the acid chlorides 3f-l independently of the conditions gave exclusively the C-acylated derivatives 5a,b,f-l*. It should be noted that the low overall yield (20%) of _______ * The spectroscopic parameters and melting points of compounds 5a,b agreed with those reported [8]. 604
products when treating compound 2 with o-bromomethylbenzoyl chloride is accompanied by a significant amount of tarring. Compounds 4c-e and 5c-e proved to be extremely close in their solubility and their chromatographic mobility and this, unfortunately, did not allow a complete separation of the mixture. The highest yields (75-89%) of the 6-acetylbenzo[4,5]imidazo[1,2-b]isoquinolin-11(5H)-ones 5a,b,f-l with minimal time consumption (15-20 min) and high product purity was achieved when carrying out the reaction with the corresponding acid chloride 3 in dioxane (method A). A more significant influence on the direction of the acylation is the structure of the acylating agent. With a decrease in the electron accepting properties of the radical R there is an increase in the N-acyl derivative component 4 in the reaction products. Thus under identical conditions (method B) compound 3a with R = Me gives a mixture of the C- and N-acyl derivatives while R = CH2Cl, CH(Br)Me, and CHCl2 give exclusively the C-acylation products. At the same time, the fraction of the N-acyl component in the mixture increases (0 16 67 75%) respectively along the series of aroyl substituents R = 4-Cl-C6H4, Ph, 2-F-C6H4, 2-Me-C6H4) (3g,b,d,c, method C). Acylation with propionic and acetic acid anhydrides 3m,n in the presence of base (AcONa and Na2CO3 respectively, method D) gave the C-acyl derivatives 5m,n in high yield (60 and 70%). The 6-acyl- (5) and 5-acylbenzo[4,5]imidazo[1,2-b]isoquinolin-11(5H)-ones (4) were identified from their spectroscopic parameters (Table 1). The criteria for assignment as the C-acyl derivatives 5 are the characteristic stretching vibrations for the N(5)H group in the IR spectrum (3120-3300 cm-1) plus the N(5)H singlet at 12.6-13.1 ppm and absence of the absorption for the C(6)H methine proton (seen at 6.33 ppm in the starting compound 2) in the 1H NMR spectrum. An assignment of the signal for the C(6)H methine proton in the spectra of the N-acyl derivatives 4a-e is problematic since it falls in the region of aromatic proton absorption while a one proton doublet (J = 8.0 Hz) is observed at 6.4-6.7 ppm for compounds 4b-e and this is assigned as the C(4)H signal (which falls in the region of shielding by the benzene ring of the N-aroyl group). The authors of [8] observed a one proton doublet (J = 8.0 Hz) in the spectrum of 4b at 6.57 ppm and assigned it to the C(6)H resonance. Our assignment is based on the observed one proton C(6)H methine singlet at 7.03 ppm in the recorded 1H NMR spectrum of the mixture of 4e and 5e at 80C. The integrated intensities of the indicated signals were used by us to determine the composition of the mixtures of compounds 4a,c-e and 5a,c-e. There are also differences in the IR spectra of compounds 4 and 5 in the carbonyl stretching band region. The spectra of the 5-acyl derivatives show two C=O bands (1690-1700, 1620-1625 cm-1) but for the 6-acyl derivatives only one broadened band is seen at 1660-1690 cm-1. This result is probably due to the different degree of conjugation in the isoquinoline fragment of the molecule. We have found that the chemical shift of the aromatic protons in the 1H NMR spectra of the C-acyl derivatives 5a,b,f-m change with the structure of the radical R. Whereas in the derivatives with a benzoyl substituent where R = Ar (5b-i) the C(7)H signal is found in the same region as in the starting 2 (7.05-7.19 ppm), in compounds with R = alkyl (5a,j-m) it is found at a markedly lower field in the region 7.50-8.00 ppm. We associate this with a difference in the population of the synplanar 5sp and antiperiplanar 5ap conformations of the C-acyl derivatives. For the compound with alkyl substituents the antiperiplanar conformation 5ap in which the C(7)H proton falls in the area of deshielding by the carbonyl proves to be the more populated.
O N N H R 5sp O
7
O N N H O R 5ap
605
A feature of the spectrum of the -bromopropionyl substituted compound 5k is the double set of signals for the methyl group with the absence of any kind of additional signals in the aromatic region. We also associate this with a difference in the population of the conformation of the radical R arising as a result of the steric hindrance to free rotation about the CH3CH(Br)CO bond. Among the features of the chemical behavior of the acyl derivatives one should note their different stability in acidic medium. While the N-acyl derivatives of the benzo[4,5]imidazo[1,2-b]isoquinolin-11(5H)ones 4 are completely stable the C-substituted 5 are partially deacetylated even upon refluxing in acetic acid for 6-8 h and fully in the presence of perchloric acid after 1 h. With regard to the increased reactivity of the N(5) atom of compound 2 in the presence of base it was interesting to follow the activity of this position in the 6-acyl derivatives 5. It was found that compound 5 is stable to the action of acylating and alkylating reagents. Only the 6-isonicotinoyl- and 6-nicotinoylbenzo[4,5]imidazo[1,2-b]isoquinolin-11(5H)-ones (5h,i) form the N-methylpyridinium salts 6a,b with methyl iodide, as indicated by the rather large low field shift of the signals for the pyridine ring protons (0.3-0.4 ppm), the presence of the N(5) signal in the 13 ppm region, and the unchanged position of the C(4) signal (Table 1). The high reactivity of both the 6 and 5 positions of compound 2 suggests a successful cyclization route when using the reagents with two electrophilic centers. With this in mind we investigated oxalyl chloride and -halo-substituted acid chlorides.
O N N H O N+ 6a 6b I O N N H O I
+ N
The reaction with oxalyl chloride (3, X = Cl, R = ClCO) in dioxane occurs with significant tarring and gives a mixture of unidentified products but chloroacetyl chloride (3j), -bromopropionyl chloride (3k), and dichloroacetyl chloride (3l) gives the 6-acylbenzo[4,5]imidazo[1,2-a]isoquinolin-11(5H)-ones 5j-l. Upon heating the compounds 5j and 5k in DMF in the presence of triethylamine there occurs an intramolecular alkylation at the N(5) atom to give derivatives of the novel heterocyclic system 7H-2a,2b-diazabenzo[b]cyclopenta[l,m]fluorene-1,7(2H)-dione 7a,b (Scheme 1). It should be noted that compound 5k is readily converted to the cyclic product 7b, even upon recrystallization from DMF. In the presence of base the dichloroacetyl derivative 5l undergoes tarring. The structure of the cyclopentafluorenes 7a,b is confirmed by their spectroscopic properties, viz. the absence of a signal for the N(5) group in the 1H NMR spectra and the high field shift of the C(2)H or CH2 signals when compared with those in the starting noncyclic products (Table 1). The mass spectroscopic data for compound 7a also agrees with the structure given. With the aim of finding optimum conditions for the synthesis of the cyclopentafluorenes we have tried various conditions for the cyclization of 6-chloroacetylbenzo[4,5]imidazol[1,2-b]isoquinolin-11(5H)-one (5j). In the presence of bases like triethylamine or benzylamine an intramolecular alkylation occurs to give compound 7a with the greater yield in the former case. Heating compound 5j with p-toluidine leads to the formation of the product of nucleophilic substitution of the halogen 8. In the presence of a strong base (i-PrONa) the intramolecular alkylation of 5j is accompanied by fission at the N(6b)C(7) bond to give the isopropyl ester of 2-(2-oxo-2,4-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yl)benzoic acid (9). This is supported by comparison of the IR data (high frequency shift of the C=O band at 1725 cm-1) with the cyclic product 7a and 606
Scheme 1
O N H N 8 N H O 5j,k Et3N i-PrONa O 2N NaOH N N

1 2 6
O O H N i-PrONa O 9
3
N
1
O N N O OH 10 OH O
7a,b
O N N O 11 N
7 a R = H, b R = Me
the presence of the CO at 1240 cm-1 in the area typical of esters. The 1H NMR spectra show signals for the isopropyl group and the CH2, and N(9)H together with changes in the pattern for the aromatic protons which are characteristic of the benzo[4,5]imidazo[1,2-b]isoquinolin-11(5H)-one heterosystem. The signals for the C(1)H and C(10)H protons in the region 8.0-8.8 ppm are also absent supporting the disturbance to the cyclic structure. This result is not unexpected since the instability of the benzimidazo[1,2-b]isoquinoline heterosystem towards strong base has been previously reported [9, 10]. In this connection it should be noted that heating compound 7a in a 2N alcoholic solution of base caused not only fission of the amide N(6b)C(7) bond but also the C(11b)C(1) to give 2-{[1-(carboxymethyl)-1H-benzimidazol-2-yl]methyl}benzoic acid (10). It is likely that the acid 10 exist in the dimeric form in view of the low frequency shift of the absorption of the C=O and OH groups and the presence of a strong, broad band at 1240 cm-1 for the deformational vibrations of the OH bond. In the presence of i-PrONa only the isoquinoline ring is broken to yield the ester 9. The CH2 methylene group proves active in the Ehrlich reaction. Refluxing a solution of 7a in acetic anhydride with p-dimethylaminobenzaldehyde gives 2-[1-(4-dimethylaminophenyl)methylidene]-1,2-dihydro-7H-2a,2b-diazabenzo[b]cyclopenta[l,m]fluorene-1,7dione (11). Refluxing compound 2 with arylisocyanates in dioxane gives the 6-carbamoyl derivatives 12 in good yield (80-85%). The 1H NMR spectra of these compounds is characterized by the presence of two low field NH signals at 11.9 and 10.2 ppm (see Table 1). An attempt to carry out the reaction of compound 2 with phenylisothiocyanate gave an unexpected result. The reaction product has a very close spectroscopic resemblance to the starting compound but differs from it by the absence of a C(6)H signal in the 1H NMR spectrum and a basic difference in the "fingerprint" region of the IR spectrum.
607
608
TABLE 1. Spectroscopic Characteristics for the 6-R-Benzimidazo[1,2-b]isoquinolin-11(5H)-ones

Compound 1 5b IR spectrum, , cm-1 =O 2 1673 NH 3 3280 H-5, s 4 12.69 H-1, d, J = 8.0 5 8.65 H-10, d, J = 8.0 6 8.35 H-4, d, J = 8.0 7 7.70 H-8, t, J = 8.0 8 7.55
1
NMR spectrum, , ppm (J, Hz) H-3, -9 9 7.34 (1H, t, J = 8.0, -9); 7.29 (1H, t, J = 8.0, -3) 7.35-7.30 (2, m) H-2, t, J = 8.0 10 7.22 H-7, d, J = 8.0 11 7.08 Substituent signals 12 7.60 (2H, d, J = 6.8, -2', H-6'); 7.47-7.43 (3H, m, H-3', H-4', H-5') 7.52 (2, d, -2', H-5'); 7.26-7.22 (3, m, H-3', H-5', H-2); 2.43 (3H, s, CH3) 7.64 (2, d, J = 8.0, H-2', H-6'); 7.54 (2H, d, J = 8.0, H-3', H-5') 8.84 (2H, d, J = 6.2, H-3', H-5'); 7.73 (2, d, J = 6.2, H-2', H-6')
5f
1675
3300
12.59
8.66
8.35
7.66
7.45
7.17
5g 5h
1675 1680
3270 3120
12.70 13.02
8.63 8.66
8.36 8.38
7.68 7.78
7.50 7.49
7.44-7.36 (2, m) 7.42-7.34 (2, m)
7.28 7.29
7.11 7.04
TABLE 1 (continued)
1 5i 2 1675 3 3200 4 12.86 5 8.66 6 8.39 7 7.73 8 7.48 9 7.41-7.36 (2, m) 10 7.29 11 7.19 12 8.80 (1, d, Jm = 1.7, H-2'); 8.67 (1H, dd, J = 5.2, Jm = 1.7, H-6'); 8.28 (1, d, Jo = 8.0, H-4'); 7.78 (1H, dd, J = 5.2, Jo = 8.0, H-5') 9.14 (2H, d, J = 6.2, H-3', H-5'); 8.17 (2, d, J = 6.2, H-2', H-6'); 4.45 (3, s, 3) 10.02 (1H, s, H-2'); 9.33 (1, d, J = 6.8, H-6'); 9.24 (1, d, J = 6.0, H-4'); 8.93-8.87 (2H, m, H-5', H-1); 4.60 (3, s, 3) 2.73 (3, s, 3) 4.88 (2, s, H2Cl) 5.55 (1, m, ); 1.89 (d, J = 6.8, 3)*3, 1.70 (d, J = 6.8, 3)*3
6a
1670
3240
13.16
8.67 *2
8.40
7.81
7.52
7.43 (2, t, J = 8.0)
7.34
7.08
6b
1650
3240
8.57
9.65
8.02
7.83-7.72 (4, m)
5a 5j 5k
1670 1680 1670
3180 3160 3300
12.87 13.06 13.02
8.62 8.58 8.59
8.42 8.39 8.42
8.09 7.93 8.07
7.74 (2, m) 7.43 7.44 7.76-7.71 (2, m) 7.84 7.76 7.52
7.38-7.31 (2, m) 7.38-7.32 (2, m) 7.47-7.39 (2, m)
609
610
TABLE 1 (continued)
1 5l 5m 8 2 1690 1663 1660 3 3120 3200 3260 4 13.21 12.93 *2 5 8.60 8.59 8.62 6 8.43 8.39 8.44 7 8 9 7.55 7.49 7.44 10 7.50-7.43 (3, m, -2, -9, Cl2) 7.39-7.34 (2, m) 3.07 (2H, q J = 7.0, CH2); 1.22 (3H, t, J = 7.0, CH3) 7.37 (1, t, J = 8.0, -9); 10.0 (br., -5, NHCH2); 7.33 (1, t, J = 8.0, -2) 6.86 (2H, d, J = 8.0, H-2', H-6'); 6.54 (2H, d, J = 8.0, H-3', H-5'); 4.55 (2H, s, CH2); 2.17 (3H, s, CH3) 7.28 (1, t, J = 8.0, -9); 10.19 (1, s, NH); 7.23 (1, t, J = 8.0, -2) 7.80 (2, d, J = 8.0, H-2', H-6'); 7.33 (2H, t, J = 8.0, H-3', H-5'); 7.06 (1H, t, J = 8.0, H-4') 10.38 (1, s, NH); 7.24 (1, t, J = 8.0, -2, H-9*2) 8.01 (1H, s, H-2'); 7.68-7.63 (2H, m, H-6', H-8); 7.31 (2H, t, J = 8.0, H-5', H-9); 7.06 (1H, d, J = 8.0, H-4')
7.87 (2, m) 7.79 8.12 7.74 (2, m) 8.08 7.78 7.75
12a
1660
3260, 3360 3280, 3360
11.92
8.64
8.39
8.05
7.63
7.49
7.38
12b
1665
11.98
8.64
8.40
8.04
*2
7.50
7.39
_______ * All of the compounds were recrystallized from DMF. *2 For assignment of the proton signals of the benzimidazo[1,2-b]isoquinoline ring and the signals of the 6-substituent see the "substituent signals" column. *3 Overall intensity 3H.
O N N H HN O H N N
O N N H
O 12a,b R 12 a R = H, b R = Cl 13
The 13C spectrum showed a signal for a quaternary carbon at 82.77 ppm in the region which is characteristic of aliphatic carbon atoms. On the basis of this and mass spectroscopic data which shows the presence of a molecular ion corresponding to double the molecular weight of the starting benzimidazoisoquinoline we deduce that this unknown product is the dimer 6-(11-oxo-5,11dihydrobenzimidazo[1,2-b]isoquinolin-6-yl)benzimidazo[1,2-b]isoquinolin-11(5H)-one (13). It should be noted that the stability of the molecular ion is very low (I = 4%). The basic directions for fragmentation (fission of the C(6)C(6') bond and loss of the C=O group) agree fully with data obtained previously for the starting
TABLE 2. Physicochemical Parameters for the Compounds Synthesized

Compound 5b 5f 5g 5h 5i 6a 6b 5a 5j 5k 5l 5m 8 12a 12b Empirical formula C22H14N2O2 C23H16N2O2 C22H13ClN2O2 C21H13N3O2 C21H13N3O2 C22H15IN3O2 C22H15IN3O2 C17H12N2O2 C17H11ClN2O2 C18H13BrN2O2 C17H10Cl2N2O2 C18H14N2O2 C24H19N3O2 C22H15N3O2 C22H14ClN3O2 Found, % Calculated, % H N 4.26 4.17 4.58 4.43 3.51 3.43 3.86 3.73 3.86 3.71 3.14 3.05 3.14 3.10 4.50 4.38 3.57 3.49 3.55 3.46 2.92 2.89 4.90 4.86 5.02 4.93 4.28 4.15 3.64 3.53 8.09 8.28 7.59 8.03 7.51 7.65 12.38 12.51 12.38 12.45 8.73 8.91 8.73 8.85 9.95 10.14 9.02 9.14 7.59 7.68 8.12 8.19 9.70 9.65 11.02 11.19 11.89 11.95 10.84 10.96 mp, * Hal 299 312 9.51 9.50 289 288 240 (dec.) 287 300 (dec.) 295 11.41 11.48 21.64 21.60 20.54 20.59 213 222 260 191 201 337 9.14 9.21 285 84 80 86 70 71 67 65 75 89 83 75 70 58 79 81 Yield, %
C 78.12 78.09 78.39 78.20 70.88 70.69 74.33 74.13 74.33 74.19 54.90 54.79 54.90 54.78 74.05 73.90 65.71 65.64 58.56 58.40 59.15 59.08 74.45 74.47 75.57 75.50 74.78 74.65 68.13 68.01
_______ * All of the compounds were recrystallized from DMF. 611
benzimidazoisoquinoline 2 [8] and 10-alkylimidazo[1,2-b]isoquinolin-5-one [8] a structural analog of compound 2. It appears that compound 2 is extremely prone to dimerization in the presence of different oxidants including sulfur compounds (phenylisothiocyanate, chlorosulfonic acid, p-toluenesulfonyl chloride, DMSO), nitrobenzene, aromatic aldehydes, and ketones. The highest yield of the dimerization product 13 (90%) was obtained by reaction in dioxane dibromide.
EXPERIMENTAL Melting points for the compounds synthesized were determined on a Boetius type heating block and were not corrected. IR spectra (KBr tablets) were recorded on a Pye-Unicam SP3-300 instrument. 1H NMR spectra for compounds 4e,d, 5e,d, 13 were obtained on a Bruker WP-100 SY (100 MHz) instrument and compounds 2, 4c, 5c,f-m, 6-12 on a Varian Mercury 400 (400 MHz) in DMSO-d6. 13C NMR spectra were taken on the Varian Mercury 400 (100 MHz) in DMSO-d6. For all of these, TMS was used as internal standard. Mass spectra were taken on a Waters Integrity System instrument with a Thermabeam detector (mobile phase CH3CN). Monitoring of the course of the reaction and the purity of the compounds prepared was carried out using TLC on Silufol UV-254 plates. 5,11-Dihydrobenzo[4,5]imidazo[1,2-b]isoquinolin-11-one (2) was prepared by method [6]. 1H NMR spectrum, , ppm (J, Hz): 11.61 (1H, s, NH); 8.62 (1H, d, J = 8.0, C(1)H); 8.28 (1H, d, J = 8.0, C(10)H); 7.51 (2H, m, C(3)H + C(8)H); 7.32 (1H, t, J = 8.0, C(9)H); 7.27 (1H, d, J = 8.0, C(7)H); 7.19-7.12 (2H, m, C(2)H + C(4)H); 6.25 (1H, s, C(6)H). The starting acid chlorides 3 were prepared by treating the corresponding acids with an excess of SOCl2. The physical parameters corresponded with those reported [11, 12]. Acylation of 5,11-dihydrobenzo[4,5]imidazo[1,2-b]isoquinolin-11-one (2). A. The corresponding carboxylic acid chloride 3 (12 mmol) was added to a refluxing suspension of benzimidazoisoquinoline 2 (2.34 g, 10 mmol) in dry dioxane (10 ml) and refluxed for 20 min. After cooling, the precipitate formed was filtered and thoroughly washed with water and alcohol. Recrystallization from DMF gave the 6-acyl substituted 5,11-dihydrobenzo[4,5]imidazo[1,2-b]isoquinoline-11-ones 5a,b,f-l. The reaction with the o-substituted benzoic acid chlorides was carried out similarly. Recrystallization from DMF gave a mixture of compounds 4c-e and 5c-e in the ratio 3:1, 2.5:1, and 3:1.5 respectively. The overall yield of the mixture was 75 (4c + 5c), 80 (4d + 5d), and 20% (4e + 5e). Mixture of 5-(2'-Methylbenzoyl)- and 6-(2'-Methylbenzoyl)-5,11-dihydrobenzo[4,5]imidazo[1,2-b]isoquinolin-11-ones (4c, 5c). IR spectrum, , cm-1: 1670, 1620 (C=O). 1H NMR spectrum, , ppm (J, Hz): 13.18 (s, NH, 5c); 8.76 (d, J = 8.0, C(1)H); 8.35 (d, J = 8.0, C(10)H); 7.19-7.80 (m, Ar); 6.41 (d, J = 8.0, C(4)H, 4c); 2.33 (s, 2'-CH3, 5c); 2.30 (s, 2'-CH3, 4c). Mixture of 5-(2-Fluorobenzoyl)- and 6-(2-Fluorobenzoyl)-5,11-dihydrobenzo[4,5]imidazo[1,2-b]isoquinolin-11-ones (4d, 5d). IR spectrum, , cm-1: 1670, 1625 (C=O). 1H NMR spectrum, , ppm (J, Hz): 12.96 (s, NH, 5d); 8.78 (d, J = 8.0, C(1)H); 8.38 (d, J = 8.0, C(10)H); 7.09-7.98 (m, Ar); 6.76 (d, J = 8.0, C(4)H, 4d). Mixture of 5-(2'-Bromomethylbenzoyl)- and 6-(2'-Bromomethylbenzoyl)-5,11-dihydrobenzo[4,5]imidazo[1,2-b]isoquinolin-11-ones (4e, 5e). IR spectrum, , cm-1: 1670, 1625 (C=O). 1H NMR spectrum, , ppm (J, Hz): 13.00 (s, NH, 5e), 8.79 (d, J = 8.0, C(1)H); 8.35 (d, J = 8.0, C(10)H); 7.12-8.18 (m, Ar); 6.55 (d, J = 8.0, C(4)H, 4e); 4.84 (s, 2'-CH2, 5e); 4.91 (s, 2'-CH2, 4e). B. The corresponding carboxylic acid chloride 3 (12 mmol) was added to a refluxing suspension of benzimidazoisoquinoline 2 (2.34 g, 10 mmol) and NaOAc (1.23 g, 15 mmol) in dry dioxane and refluxed for 20 min. After cooling, the precipitate formed was filtered and thoroughly washed with water and alcohol. Recrystallization from DMF gave the 6-acyl substituted 5,11-dihydrobenzo[4,5]imidazo[1,2-b]isoquinolin-11ones 5b,f-l. 612
The reaction with the acid chloride and chlorides of the o-substituted benzoic acids was carried out similarly. Recrystallization from DMF gave a mixture of the compounds 4a,c-e and 5a,c-e in the ratios 1:4.5, 4.5:1, 3:1, and 3:1 respectively. The overall yield of the mixture was 63 (4a + 5a), 75 (4c + 5c), 80 (4d + 5d), and 20% (4e + 5e). C. (method from study [7]). Recrystallization from DMF of the products of acylation using the acid chlorides 3a-d,f-i gave the 6-acyl-substituted 5,11-dihydrobenzo[4,5]imidazo[1,2-b]isoquinolin-11-ones 5f-i and a mixture of compounds 4a-d and 5a-d in the ratio 1:4 ( 4a + 5a, overall yield of the mixture 43%), 1:5 (4b + 5b, 60%), 5:1 (4c + 5c, 72%), 4:1 (4d + 5d, 71%). D. (method from study [5]). Recrystallization from DMF of the products of acylation using the acetic (3n) and propionic (3m) acid anhydrides gave the 6-acyl-substituted 5,11-dihydrobenzo[4,5]imidazo[1,2-b]isoquinolin-11-ones 5n,m. 1-Methyl-4-(11-oxo-5,11-dihydrobenzimidazo[1,2-b]isoquinolin-6-ylcarbonyl)pyridinium Iodide (6a). A mixture of 6-isonicotinoylbenzimidazo[1,2-b]isoquinoline (5h, 0.34 g, 1 mmol) and methyl iodide (0.19 ml, 3 mmol) in DMF (5 ml) was heated on a water bath at 40-45C for 2 h until the complete solution of the starting 5h. The solvent and excess methyl iodide were evaporated off under reduced pressure and alcohol (3 ml) was added to the residual oil. The precipitate formed was filtered off and washed with alcohol. It was recrystallized from DMF. 1-Methyl-3-(11-oxo-5,11-dihydrobenzimidazo[1,2-b]isoquinolin-6-ylcarbonyl)pyridinium iodide (6b) was prepared similarly using 6-nicotinoylbenzimidazo[1,2-b]isoquinoline 5i. 7H-2a,6b-Diazabenzo[b]cyclopenta[l,m]fluorene-1,7-dione (7a). A mixture of 6-chloroacetylbenzimidazo[1,2-b]isoquinoline 5j (3.1 g, 10 mmol) and triethylamine (0.5 ml) in DMF (5 ml) was refluxed for 1 h. The precipitated solid was filtered off and washed with alcohol. Recrystallization from DMF gave 2.19 g (80%); mp 271-273C (DMF). IR spectrum, , cm-1: 1650 (C=O). 1H NMR spectrum, , ppm (J, Hz): 8.34 (2H, t, J = 8.0, C(6)H, C(8)H); 8.05 (1H, d, J = 8.0, C(11)H); 7.80 (1H, t, J = 8.0, C(10)H); 7.61 (1H, d, J = 8.0, C(3)H); 7.54 (1H, t, J = 8.0, C(4)H); 7.43-7.37 (2H, m, C(5)H, C(9)H); 4.75 (2H, s, CH2). Mass spectrum, m/z, (I, %): 274 [M]+ (100), 246 (29), 190 (6). Found, %: C 74.29; H 3.58; N 10.35. C17H10N2O2. Calculated, %: C 74.44; H 3.67; N 10.21. 2-Methyl-7H-2a,6b-diazabenzo[b]cyclopenta[l,m]fluorene-1,7(2H)-dione (7b) was prepared similarly using the derivative 5k (3.7 g, 10 mmol). Yield 2.50 g (87%); mp 274-277C (DMF). IR spectrum, , cm-1: 1670 (C=O). 1H NMR spectrum, , ppm (J, Hz): 8.35 (2H, d, J = 8.0, C(6)H, C(8)H); 8.08 (1H, d, J = 8.0, C(11)H); 7.75 (1H, t, J = 8.0, C(10)H); 7.63 (1H, d, J = 8.0, C(3)H); 7.49 (1H, t, J = 8.0, C(4)H); 7.10-7.34 (2H, m, C(5)H, C(9)H); 4.81 (1H, q, J = 6.8, C(2)H); 1.71 (3H, d, J = 6.8, CH3). Found, %: C 74.80; H 4.18; N 9.90. C18H12N2O2. Calculated, %: C 74.99; H 4.20; N 9.72. 6-[2-(4-Toluidino)acetyl]benzimidazo[1,2-b]isoquinolin-11(5H)-one (8). A mixture of compound 5j (0.31 g, 1 mmol) and p-toluidine (0.16 g, 1.5 mmol) in DMF (3 ml) was refluxed for 4 h. The solid precipitated after cooling was filtered off, washed with alcohol, and recrystallized from DMF. Isopropyl Ester of 2-(2-Oxo-2,4-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazo-3-yl)benzoic Acid (9). A. A mixture of compound 5j (0.31 g, 1 mmol) and i-PrONa (0.12 g, 1.5 mmol) in i-PrOH (5 ml) was refluxed for 30 min. The solid precipitated after cooling was washed with alcohol and recrystallized from DMF to give 0.22 g (67%). B. The reaction was carried out similarly to method A using 7a (1 mmol). Yield 0.13 g (40%); mp 202-207C (DMF). IR spectrum, , cm-1: 1240 (CO), 1725 (C=O), 3100 (NH). 1H NMR spectrum, , ppm (J, Hz): 12.21 (1H, s, C(4)H); 7.70 (1H, d, J = 8.0, C(3')H); 7.50-7.46 (2H, m, C(5')H, C(6')H); 7.24-7.21 (2H, m, C(4')H, C(8)H); 7.18 (1H, d, J = 8.0, C(5)H); 7.10 (1H, t, J = 8.0, C(6)H); 7.03 (1H, t, J = 8.0, C(7)H); 5.02 (1H, q, J = 6.0, CH(CH3)2); 4.19 (2H, s, C(2)H); 1.40 (6H, d, J = 6.0, CH3). Found, %: C 71.69; H 5.31; N 8.45. C20H18N2O3. Calculated, %: C 71.84, H 5.43; N 8.38. 613
2-{[1-(Carboxymethyl)-1-benzimidazol-2-yl]methyl}benzoic Acid (10). The cyclopentafluorene 7a (0.27 g, 1 mmol) was refluxed in 2N NaOH in methanol (4 ml) for 1 h. The solvent was evaporated in vacuo. The remaining oil was dissolved in water (5 ml) and a dilute solution of hydrochloric acid added to pH 5. After 2 h the precipitated solid was filtered off, washed with alcohol, and recrystallized from methanol. Yield 0.20 g (63.5%); mp 235-238C (methanol). IR spectrum, , cm-1: OH 1240, C=O 1685, OH 2600 cm-1. 1H NMR spectrum, , ppm (J, Hz): 13.01 (2H, br. s, OH); 7.89 (1H, d, J = 8.0, C(3')H); 7.50-7.46 (3H, m, C(4)H, C(7)H, C(5')H); 7.37 (1H, t, J = 8.0, C(4)H); 7.29 (1H, d, J = 8.0, C(6')H); 7.18-7.10 (2H, m, C(5)H, C(6)H); 5.09 (2H, s, 1-CH2); 4.55 (2H, s, 2-CH2). Found, %: C 65.70; H 4.39; N 9.19. C17H14N2O4. Calculated, %: C 65.80; H 4.55; N 9.03. 2-{[4-(Dimethylamino)phenyl]methylidene}-7H-2a,6b-diazabenzo[b]cyclopenta[l,m]fluorene-1,7(2H)-dione (11). A mixture of the cyclopentafluorene 7a (0.27 g, 1 mmol) and p-dimethylaminobenzaldehyde (0.22 g, 1.5 mmol) in Ac2O (4 ml) was refluxed for 30 min. The solvent was evaporated and the remaining oil treated with 2-propanol (3 ml). The precipitated solid was filtered off, washed with i-PrOH, and recrystallized from DMF. Yield 0.27 g (68%); mp 264-266C (DMF). IR spectrum, , cm-1: 1645 (C=O). 1H NMR spectrum, , ppm (J, Hz): 8.45-8.30 (3H, m, C(6)H, C(8)H, =CH); 8.16 (2H, d, J = 8.0, C(3)H, C(11)H); 7.78 (1H, t, J = 8.0, C(10)H); 7.58 (1H, t, J = 8.0, C(4)H); 7.50-7.32 (4H, m, C(5)H, C(9)H, C(2')H, C(5')H); 6.73 (2H, d, J = 8.0, C(3')H, C(4')H); 3.05 (6H, s, CH3). Found, %: C 76.89; H 4.61; N 10.44. C26H19N3O2. Calculated, %: C 77.02; H 4.72; N 10.36. 11-Oxo-N-aryl-5,11-dihydrobenzimidazo[1,2-b]isoquinoline-6-carboxamides (12a,b). The corresponding aryl isocyanate (12 mmol) was added to a refluxing suspension of the benzimidazoisoquinoline 2 (2.34 g, 10 mmol) in dry dioxane (10 ml) and refluxed for 2 h. After cooling, the solid formed was filtered off, throughly washed with water and alcohol, and recrystallized from DMF. 6-(11-Oxo-5,11-dihydrobenzimidazo[1,2-b]isoquinolin-6-yl)-5,11-dihydrobenzimidazo[1,2-b]isoquinolin-11(5H)-one (13). A solution of bromine (0.5 ml, 10 mmol) in dioxane (5 ml) was added dropwise with stirring to a suspension of the benzimidazoisoquinoline 2 (2.34 g, 10 mmol) in dry dioxane (10 ml) which was heated on a water bath. It was heated with stirring for a further 15 min and cooled. The precipitate formed was filtered off and throughly washed with alcohol. Yield 2.1 g (90%); mp > 360C (DMF). IR spectrum, , cm-1: 1645 (C=O), 3140 (NH). 1H NMR spectrum, , ppm (J, Hz): 11.34 (2H, s, C(5,5')H); 8.72 (2H, d, J = 2.0, C(1,1')H); 8.47 (2H, d, J = 2.0, C(10,10')H); 7.49 (2H, t, J = 2.0, C(8,8')H); 7.37 (2H, t, J = 2.0, C(3,3')H); 7.29 (2H, t, J = 2.0, C(9,9')H); 7.24 (2H, t, J = 2.0, C(2,2')H); 7.14 (4H, d, J = 2.0, C(7'7')H, C(4,4')H). 13C NMR spectrum: 160.00 (C-11,11'); 142.04 (C-5a,5a'); 139.51 (C-11b,11b'); 134.04 (C-4a,4a'); 132.78 (C-10,10'); 129.23 (C-10a,10a'); 128.10, 126.64, 123.10, 122.15, 120.82 (C-2,2', C-3,3', C-7 to 9,7' to 9'); 119.13 (C-6a,6a'); 116.52 (C-4,4'); 109.86 (C-1,1'); 82.77 (C-6,6'). Mass spectrum, m/z (I, %): 466 [M]+, 234 (33), 222(12), 205 (11), 149 (49), 125 (35), 98 (100). Found, %: C 77.09; H 4.05; N 12.20. C30H18N4O2. Calculated, %: C 77.24; H 3.89; N 12.01. Parameters for the compounds 5, 6, 8 and 12 are given in Tables 1 and 2.
REFERENCES 1. 2. 3. 4. 5. 614 V. M. Kisel, E. O. Kostyrko, O. V. Shishkin, S. V. Shishkina, and V. A. Kovtunenko, Khim. Geterotsikl. Soedin., 1421 (2002). V. G. Granik, V. A. Makarov, and C. Parkanyi, Adv. Heterocycl. Chem, 72, 283 (1999). K. Blaha and O. Chervinka, Adv. Heterocycl. Chem., 6, 147 (1966). K. Nagarajan, V. R. Rao, R. K. Shah, S. J. Shenoy, H. Fritz, W. J. Richter, and D. Muller, Helv. Chim. Acta, 71, 77 (1988). V. M. Kisel, L. M. Potikha, and V. A. Kovtunenko, Khim. Geterotsikl. Soedin., 131 (2001).
6. 7. 8. 9. 10. 11. 12.
E. Schefczik, Liebigs Ann. Chem., 729, 97 (1969). E. Schefczik. Liebigs Ann. Chem., 729, 83 (1969). K. -Q. Ling, X. -Y. Chen, H. -K. Fun, X. -Y. Huang, and J. -H. Xu, J. Chem. Soc., Perkin Trans.1, 4147 (1998). A. L. Johnson, J. Org. Chem., 41, 836 (1976). F. S. Babichev, Yu. M. Volovenko, E. F. Gavrilova, L. L. Kolomiets, F. G. Nemazannyi, L. A. Pilipenko, and T. A. Silaeva, Russian Patent 1659413; Chem. Abstr., 116, 151763 (1992). I. Heilbron and H. M. Bunbury (editors), Dictionary of Organic Compounds [Russian translation], Inostr. Lit. Publishing House, Moscow (1949). G. Pifferi and E. Testa, Tetrahedron, 22, 2107 (1966).
615
SYNTHESIS OF 2-SUBSTITUTED AND 2,3-DISUBSTITUTED QUINAZOLIN-4-ONES CONTAINING A STERICALLY HINDERED PHENOL RESIDUE
V. I. Kelarev, M. A. Silin, V. N. Koshelev, and O. A. Borisova A series of 2-substituted and 2,3-disubstituted quinazolin-4-ones containing a 3,5-di(tert-butyl)-4hydroxyphenyl group has been synthesized. They were prepared by the condensation of carboxylic acid imino ester hydrochlorides containing the indicated fragment with ethyl anthranilate and also by the reaction of azomethines, N-acylhydrazones, or the 4-phenylthiosemicarbazone of 3,5-di(tert-butyl)-4hydroxybenzaldehyde with 2-methyl-4H-2,1-benzoxazin-4-one. Keywords: azomethines, N-acylhydrazones, carboxylic acid imino esters, sterically hindered phenols, thiosemicarbazones, quinazolin-4-ones, condensation. In this continuation of our study of the synthesis of five- and six-membered nitrogen containing heterocycles which include a shielded phenol residue [1-6] we report the preparation of 2-substituted and 2,3-disubstituted quinazolin-4-ones containing a 3,5-di(tert-butyl)-4-hydroxyphenyl group. There is no information regarding the synthesis and properties of quinazolin-4-one derivatives which contain the indicated substituent. Compounds of this type are currently promising as potentially biologically active materials and also as stabilizers and additives to polymeric materials, hydrocarbon fuel, and lubricating oil. Carboxylic acid imino esters hydrochlorides can be used as convenient synthons for the preparation of quinazolin-4-ones [7, 8]. In this work we have used as starting materials the ethyl imino ester hydrochlorides of 3,5-di(tert-butyl)-4-hydroxybenzoic (1a), 3,5-di(tert-butyl)-4-hydroxyphenylacetic (1b), -[3,5-di(tert-butyl)-4hydroxyphenyl]propionic (1c), 3,5-di(tert-butyl)-4-hydroxyphenylthioacetic (1d), or -[3,5-di(tert-butyl)-4hydroxyphenylthio]propionic acid (1e). Condensation of the imino ester hydrochlorides 1a-e with ethyl anthranilate gives the 2-substituted (3H)-quinazolin-4-ones 2a-e containing the sterically hindered group.
O NH . HCl R(CH2)n C OEt 1ae COOEt N 2ae NH (CH2)nR
NH2
1, 2 R = 3,5-(t-Bu)24-HOC6H2; d, e R = 3,5-(t-Bu)24-HOC6H2S; a n = 0; b, d n = 1; c, e n = 2
__________________________________________________________________________________________ I. M. Gubkin Russian State Oil and Gas University, Moscow 117917; e-mail: himeko@dol.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 729-735, May, 2004. Original article submitted October 23, 2000; revision submitted May 15, 2001. 616 0009-3122/04/4005-06162004 Plenum Publishing Corporation
Improved yields of compounds 2a-e (see Table 1) can be achieved by refluxing equimolar amounts of the reagents in ethanol or dioxane. It should be noted that the duration of the process depends on the reactivity of the starting imino ester hydrochlorides 1a-e. Hence the formation of compounds 2b-e is complete after refluxing the reagents in ethanol for 2.5-3 h whereas the preparation of the quinazolin-4-one 2a from the imino ester hydrochloride 1a needs refluxing in dioxane for 10 h, due to the effect of the electron-donor hydroxyaryl substituent [9] which is bonded to the imino ester group. Thin layer Al2O3 chromatography of the reaction products has shown that, in all of the examples except the quinazolin-4-ones 2a-e, small amounts of the corresponding acid amides or nitriles were present in the reaction mixtures. There is evidence that 2-methyl-4H-benzoxazin-4-one reacting with the aromatic aldehyde derivative azomethines in acetic acid in the presence of sodium acetate gives 3-substituted 2-styrylquinazolin-4-ones [7, 10-12]. In our work we decided to use this method for synthesizing quinazolin-4-ones containing the shielded phenol residue. With this in view we examined the reaction of 2-methyl-4H-3,1-benzoxazin-4-one with the N-alkyl(aryl, hetaryl)-3,5-di(tert-butyl)-4-hydroxybenzylideneamines 3a-d and also with the N-acylhydrazones 3e,f and 3,5-di(tert-butyl)-4-hydroxybenzaldehyde 4-phenylthiosemicarbazone (3g).
O O N Me t-Bu
HO t-Bu 3ag
CH=NR
AcOH, AcONa O N N 4ag Bu-t R
Bu-t OH
3, 4 a R = C8H17, b R = 4-MeC6H4, c R = 2-pyridyl, d R = 2-thiazolyl, g R = PhNHCSNH,

N S SCH2CONH
eR=
CONH ,
fR=
It was found that refluxing equimolar amounts of the reagents and sodium acetate in acetic acid for 4-5 h gave 52-67% yields of the 2-[-(3,5-di(tert-butyl)-4-hydroxyphenyl)vinyl]-3-R-quinazolin-4-ones 4a-g. It should be noted that the azomethines and N-acylhydrazones which are derivatives of 3,5-di(tert-butyl)-4hydroxyacetophenone do not react with 2-methyl-4H-3,1-benzoxazine under these conditions, the starting compounds being recovered unchanged from the reaction mixture even after heating in acetic acid in the presence of sodium acetate for 10 h. The composition and structure of the synthesized quinazolin-4-ones 2a-e and 4a-g were confirmed by elemental analytical data and by IR and 1H NMR spectroscopy. Hence the IR spectra of all of the compounds show a strong absorption in the region 1705-1680 cm-1 assigned to stretching vibrations of the carbonyl group ("amide 1" band) [7]. The C=N stretching vibration of the oxoquinazoline ring corresponds to the absorption band at 1625-1605 cm-1 whose intensity is almost as great as the C=O group absorption [7, 13]. Broad absorption bands are seen in the high frequency region of the spectra of the 2-substituted quinazolin-4-ones 2a-e at 33603220 cm-1 and are assigned to the stretching vibrations of the NH group in the ring [7, 14]. The absorption bands of varying intensity in the range 1545-1525 cm-1 are associated with the planar deformation vibrations of the secondary amino NH groups. 617
618
TABLE 1. Parameters of the Quinazolin-4-one Derivatives 2a-e and 4a-g

Compound 1 2a 2b 2c 2d 2e Empirical formula 2 22H26N2O2 23H28N2O2 24H30N2O2 23H28N2O2S 24H30N2O2S Found, % Calculated, % H N 3 4 5 75.57 75.43 76.01 75.82 76.06 76.19 69.57 69.70 70.37 70.24 78.87 78.65 7.34 7.43 7.55 7.69 8.07 7.94 7.01 7.07 7.24 7.32 8.96 9.17 8.12 8.00 7.78 7.69 7.58 7.40 7.21 7.07 7.02 6.83 5.60 5.73 mp, * 6 177-178 168-169 128-129 184.0-184.5 165-166 Rf *2 7 0.62 0.74 0.82 0.70 0.81
1
NMR spectrum, , ppm (J, Hz)*3 8
Yield, % 9 67 76 74 81 72
4a
32H44N2O2
89-91
0.70
1.56 (18H, br. s, 2 t-C4H9); 4.97 (1H, s, HO); 7.25 (2H, s, HAr); 7.58-7.64 (4H, m, Ar); 9.37 (1H, br. s NH) 1.50 (18H, s, 2 t-C4H9); 3.34 (2H, s, RCH2); 4.92 (1H, s, HO); 7.20 (2H, s, HAr); 7.60-7.67 (4H, m, Ar); 9.28 (1H, br. s NH) 1.52 (18H, s, 2 t-C4H9); 3.68-3.82 (4H, m, RCH2CH2); 5.05 (1H, s, HO), 7.24 (2H, s, HAr); 7.60-7.65 (4H, m, Ar); 9.35 (1H, br. s NH) 1.54 (18H, s, 2 t-C4H9), 3.48 (2H, s, CH2S), 5.12 (1H, s, HO), 7.30 (2H, s, Harom.), 7.74-7.82 (4H, m, arom.), 9.48 (1H, br.s, NH) 1.56 (18H, s, 2 t-C4H9); 2.98 (2H, br. s, CH2S); 3.28 (2H, m, CH2); 5.08 (1H, s, HO); 7.28 (2H, s, HAr); 7.58-7.64 (4H, m, Ar); 9.24 (1H, br. s NH) 1.12 (3H, t, 3); 2.52 (18H, s, 2 t-C4H9); 1.60-1.92 (12H, m, 6CH2); 3.64 (2H, m, CH2N); 5.06 (1H, s, HO); 6.60 (1H, d, CH=CH, J = 16.0); 7.22 (2H, s, HAr); 7.30 (1H, d, J = 16.0, CH=CH); 7.72-7.80 (4H, m, Ar)
52
TABLE 1 (continued)
1 4b 2 31H34N2O2 3 80.02 79.83 76.95 76.82 70.71 70.59 72.70 72.58 66.10 66.22 70.63 70.72 4 7.37 7.30 6.76 6.84 6.24 6.32 6.33 6.45 5.76 5.68 6.75 6.46 5 5.83 6.01 9.08 9.27 9.03 9.15 11.41 11.29 9.51 9.36 10.77 10.63 6 111-113 7 0.54 8 1.58 (18H, br. s, 2 t-C4H9); 2.24 (3H, s, 3); 5.14 (1H, s, HO); 6.68 (1H, d, J = 16.8 CH=CH); 7.18-7.25 (6H, m, 2HAr, 4HHet); 7.37 (1H, d, J = 16.8 CH=CH); 7.62-7.70 (4H, m, Ar) 1.62 (18H, br. s, 2 t-C4H9); 4.96 (1H, s, HO); 6.72 (1H, d, J = 17.2, CH=CH); 7.20 (2H, s, HAr); 7.36 (1H, d, J = 17.2, CH=CH); 7.69-8.04 (8H, m, Het) 1.60 (18H, br. s, 2 t-C4H9); 5.18 (1H, s, HO); 6.65 (1H, d, J = 16.5, CH=CH); 6.94 (1H, d, J45 = 3.2, 5-HHet); 7.20 (2H, s, HAr); 7.39 (1H, d, J = 16.5, CH=CH); 7.45 (1H, d, J45 = 3.2, 4-HHet); 7.65-7.73 (4H, m, Het) 1.54 (18H, br. s, 2 t-C4H9); 4.98 (1H, s, HO); 6.70 (1H, d, J = 17.0, CH=CH); 7.27 (2H, s, HAr); 7.36 (1H, d, J = 17.0, CH=CH); 7.58-7.82 (8H, m, Het); 8.78 (1H, br. s, NH) 1.58 (18H, br. s, 2 t-C4H9); 3.84 (2H, s, CH2S); 5.05 (1H, s, HO); 6.70 (1H, d, J = 16.8, CH=CH); 7.22 (2H, s, HAr); 7.34 (1H, d, J = 16.8, CH=CH); 7.58-7.74 (8H, m, Het); 9.08 (1H, br. s, NH) 1.62 (18H, br. s, 2 t-C4H9); 5.04 (1H, s, HO); 6.36 (1H, br. s, NH); 6.60 (1H, d, J = 17.0, CH=CH); 6.76 (1H, br. s, NH); 6.92-7.02 (5H, m, HPh); 7.24 (2H, s, HAr); 7.35 (1H, d, J = 17.0, CH=CH); 7.70-7.87 (4H, m, Het) 9 64
4c 4d
29H31N3O2 27H29N3O2S
135-136 144-145
0.47 0.48
58 65
4e
30H32N4O3
128-129
0.32
60
4f
33H34N4O3S2
155-156
0.48
62
4g
31H34N4O2S
150.0-151.5
0.37
54
_______ * Compounds 2a,b,4g were recrystallized from 2-propanol; 2s,4d,f from ethanolwater (1:1); 2d,e from dioxanetoluene (1:1); 4b from benzene; 4s,e from ethanolwater (2:1). *2 Solvent system: chloroformacetone, 50:1 (compounds 2a-s, 4e-g); benzenemethanol, 30:1 (compounds 2d,e); CCl4 methanol, 15:1 (compounds 4a-d). *3 Spectra of compounds 2a-e, 4e-g were recorded in DMSO-d6; compounds 4a-d in CDCl3.
619
The spectra of compounds 2a-e taken in chloroform and dichloromethane show an absorption band shift for the C=O bond and the stretching vibrations of the NH group to higher frequency by 15-20 and 185-225 cm-1 respectively and the absorption band for the deformation of the NH group by 15-25 cm-1 to lower frequency and this may be connected with break up of intermolecular hydrogen bonds. The spectra of the 2,3-disubstituted quinazolin-4-ones 4a-g show two absorption bands of moderate intensity in the range 3125-3070 and 1670-1665 cm-1 and the intense absorption band at 980-975 cm-1 is characteristic of an ,-disubstituted vinyl group with a trans configuration [15]. In all of the compounds discussed there is also observed an absorption which is due to the components of the sterically hindered phenol, viz. a rather narrow band at 3655-3635 (characteristic of a shielded phenolic hydroxyl [16]), two bands of medium intensity in the range 1260-1220 due to vibrations of the ArOH group in shielded phenols [17], and two groups of bands at 885-870 and 835-820 cm-1(out of plane deformation vibrations of a tetra substituted benzene ring). In the 1H NMR spectra of the compounds synthesized (Table 1) the signal for the hydroxyl group appears as a singlet in the range 4.92-5.18 ppm, as seen in sterically hindered phenols [16, 18]. The signals for the tert-butyl protons are seen as a broadened singlet at 1.50-1.62 ppm The two magnetically equivalent protons in the hydroxyaryl component correspond to the singlet signal at 7.20-7.32 ppm [3, 4, 18]. In the spectra of the quinazolin-4-ones 2a-e the signals for the NH group protons are found at 9.24-9.48 ppm, which is typical of such heterocycles [7, 13]. The spectra of the quinazolin-4-ones 4a-g show the signals for the vinyl group protons as two doublets at 6.60-6.72 and 7.28-7.39 ppm with a spin-spin coupling of 16.0-17.2 Hz and this confirms the trans relationship of these protons [15]. The oxoquinazoline ring aromatic protons in the spectra of compounds 2a-e and 4a-g are seen as multiplet signals in the range 7.58-7.87 ppm.
EXPERIMENTAL IR spectra were recorded on a Bruker IFS-48 instrument as KBr tablets, in vaseline oil, or in chloroform or dichloromethane. 1H NMR spectra were taken on a Bruker WP-250 spectrometer (250 MHz) with TMS as internal standard. Monitoring of the course of the reaction and the purity of the compounds obtained was performed by TLC on Brockmann activity grade III Al2O3 and revealed using iodine vapor. Parameters for the compounds synthesized are given in Table 1. The starting ethylimino ester hydrochlorides 1a-e [1], N-octyl- (3a) [19], N-(p-tolyl)- (3b) [20], N-(2-pyridyl)- (3c) and N-(2-thiazolyl)-3,5-di(tert-butyl)-4-hydroxybenzylideneamine (3d) [21] as well as N-(pyridyl-4-carbonyl)hydrazone (3e) [19], N-(benzothiazolyl-2-thioacetyl)hydrazone )3f) [22], and 3,5-di(tertbutyl)-4-hydroxybenzaldehyde 4-phenylthiosemicarbazone (3g) [21] were prepared by the known methods quoted individually above. 2-Substituted (3H)-quinazolin-4-ones (2a-e). A mixture of the ethylimino ester hydrochloride 1a-e (15 mmol) and ethyl anthranilate (2.47 g, 15 mmol) was refluxed with stirring for 10 h in 40 ml of anhydrous dioxane (for the preparation of compound 2a) or for 3 h in absolute ethanol (for compounds 2b-e). The reaction mixture was evaporated to dryness at reduced pressure and the residue was crystallized from the appropriate solvent. 2-[-(3,5-Di-tert-butyl-4-hydroxyphenyl)vinyl]-3-R-(3H)-quinazolin-4-ones (4a-g). A mixture of 10 mmol of the azomethine 3a-d, N-acylhydrazone 3e,f, or 4-phenylthiosemicarbazone 3g with 2-methyl-4H2,1-benzoxazin-4-one (1.49 g, 10 mmol), and sodium acetate (0.82 g, 10 mmol) in acetic acid (45 ml) was refluxed with stirring for 5 h, cooled to 20C, and poured into iced water (200 ml). The precipitated solid was filtered off, washed on the filter with water, dried, and either crystallized from the appropriate solvent (see Table 1) or chromatographed on an L 100/160 micron silica gel column (h = 50 cm, d = 4.5 cm) (for the preparation of compound 4a) using chloroform as eluent. 620
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. V. I. Kelarev, F. Laauad Yakh'ya, R. A. Karakhanov, A. F. Lunin, and O. V. Malova, Khim. Geterotsikl. Soedin., 107 (1986). V. I. Kelarev, V. N. Koshelev, R. A. Karakhanov, V. G. Kartsev, S. Yu. Zasedatelev, A. M. Kuatbekov, and G. V. Morozova, Khim. Geterotsikl. Soedin., 514 (1995). V. I. Kelarev, V. N. Koshelev, N. V. Belov, O. V. Malova, and R. A. Karakhanov, Khim. Geterotsikl. Soedin., 240 (1994). V. I. Kelarev, V. N. Koshelev, N. V. Belov, O. V. Malova, and R. A. Karakhanov, Khim. Geterotsikl. Soedin., 224 (1995). V. I. Kelarev, V. N. Koshelev, and M. A. Silin, Khim. Geterotsikl. Soedin., 822 (1997). M. A. Silin, V. I. Kelarev, and V. Abu-Ammar, Khim. Geterotsikl. Soedin., 256 (2000). Kh. M. Shakhidoyatov, 4-Quinazolones and their Biological Activity [in Russian], Fan, Tashkent (1988). V. I. Kelarev and V. N. Koshelev, Usp. Khim., 64, 339 (1995). V. I. Kelarev, S. G. Shvekhgeimer, V. N. Koshelev, G. A. Shvekhgeimer, and A. F. Lunin, Khim. Geterotsikl. Soedin., 889 (1984). J. P. Pauchard and A. E Siegrist, Helv. Chim. Acta, 61, 129 (1978) A. K. Mukerjee and P. Kumar, Chem. and Ind., 936 (1980). K. D. Deodkar, S. D. Samant, S. R. Pednekar, D. S. Kanekar, A. A. Inamdar, and P. Y. Patkar, Indian J. Chem., 21B, 67 (1982). D. J. Brown, in: A. R. Katritzky (editor), Comprehensive Heterocyclic Chemistry, Pergamon Press, Vol. 3, Oxford (1984), p. 57. A. R. Katritzky (editor), Physical Methods in the Chemistry of Heterocyclic Compounds [Russian translation], Khimiya, Moscow, Leningrad (1966), p. 569. R. M. Silverberg, G. C. Bassler, and T. C. Morrill, Spectroscopic Identification of Organic Compounds [Russian translation], Mir, Moscow (1977). V. V. Ershov, G. A. Nikiforov, and A. A. Volod'kin, Sterically Hindered Phenols [in Russian], Khimiya, Moscow (1972). T. N. Pliev, Dokl. Akad. Nauk, SSSR, 176, 113 (1967). T. N. Pliev, Zh. Prikl. Spektrosk., 13, 124 (1970). F. Yu. Rachinskii, G. D. Bol'shakov, Yu. A. Bruk, M. Z. Kremen, L. V. Pavlova, T. G. Potapenko, and N. M. Slachevskaya, in: The Chemistry of Sulfo Organic Compounds Contained in Oils and Oil Products, Khimiya, Vol. 7, Moscow (1964), p. 45. Yu. A. Bruk, F. Yu. Rachinskii, L. V. Zolotova, M. Z. Borodulina, Zh. Obshch. Khim., 42, 1603 (1972). I. A. Golubeva, E. V. Klinaeva, V. N. Koshelev, V. I. Kelarev, and I. A. Gol'dsher, Khim. Tekhnol. Topliv Masel., No. 1, 30 (1997). V. I. Kelarev, M. A. Silin, I. G. Kotova, K. N. Kobrakov, I. A. Rybina, and V. K. Korolev, Khim. Geterotsikl. Soedin., 243 (2003).
20. 21. 22.
621
SOME CHEMICAL TRANSFORMATIONS OF 4,5-DIHYDRO-5-METHYL-3H-SPIRO[BENZ2-AZEPINE-3,1'-CYCLOHEXANE] N-OXIDE

A. V. Varlamov, D. G. Grudinin, and A. I. Chernyshev The oxidation and reduction of 4,5-dihydro-5-methyl-3H-spiro[benz-2-azepine-3,1'-cyclohexane] N-oxide, the reactions of this N-oxide with methylmagnesium iodide, the sodium salt of diethyl malonate, phenyl isocyanate, and its rearrangement by the action of acetic anhydride lead to N-hydroxy-1,2,3,4tetrahydrobenz-2-azepines, benz-2-azepine-1-one, and its N-acetoxy derivative as well as isoxazolidinoand oxadiazolidino[3,2-a]benz-2-azepines spirofused with a cyclohexane ring. Keywords: benz-2-azepines, isoxazolidino- and oxadiazolidino[3,2-a]benz-2-azepines, cyclic nitrones, reduction, nucleophilic addition, oxidation. The properties and reactivity of acyclic nitrones have been studied rather extensively [1]. Cycloaddition is the best studied reaction of cyclic nitrones [2], while reactions with nucleophilic reagents have been studied less extensively [3]. Possessing a method for the synthesis of a benz-2-azepine nitrone, namely, 4,5-dihydro-5methyl-3H-spiro[benz-2-azepine-3,1'-cyclohexane] N-oxide (1) [4], we carried out a systematic study of this compound. We have already studied the [3+2] cycloaddition of alkenes and diethylacetylenedicarboxylate [5-7] and the reaction of 1 with alkylmagnesium and arylmagnesium halides, nitromethane, and cyanide anion [8]. In the present work, we studied the reaction of nitrone 1 with nucleophiles, isocyanates, isothiocyanates, and acetic anhydride. In contrast to benzylmagnesium and phenylmagnesium halides, isopropylmagnesium bromide reacts with nitrone 1 to give 1-isopropyl-5-methyl-4,5-dihydro-3H-spiro[benz-2-azepine-3,1'-cyclohexane], which is a benzazepine imine [8]. In an attempt to determine whether this reaction is common for alkylmagnesium halides and obtain a synthone [9] for use in the synthesis of 1-substituted and fused benzazepines, we carried out the reaction of nitrone 1 with methylmagnesium iodide. This reaction proceeds readily to give a 0.7:1 mixture of hydroxylamine 2 and imine 3 in 65% yield. This mixture was oxidized with hydrogen peroxide in the presence of sodium tungstenate to give the corresponding nitrone 4. Nitrone 1 is reduced by the action of lithium aluminum hydride to the corresponding hydroxylamine 5, which was characterized as O-carbamoyl derivative 6 [10].
__________________________________________________________________________________________ Russian People's Friendship University, 117198 Moscow, Russia; e-mail: avarlamov@sci.pfu.edu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 736-744, May, 2004. Original article submitted March 2, 2001. 622 0009-3122/04/4005-06222004 Plenum Publishing Corporation
Me MeMgI N 1 O LiAlH4 Me
Me
Me
+
N Me 2 [O] OH Me 3 N
Me
N 5 OH
PhNCO
Me
N Me 4 N O 6 O H N Ph O
The reaction of the sodium derivative of diethyl malonate with nitrone 1 does not stop after addition [11], but rather proceeds with intramolecular nucleophilic substitution to give spiro[isoxazolidinobenz-2azepine-5-cyclohexane] (7) formed as a mixture of diastereomers 7a and 7b differing in the arrangement of H11b and the methyl group at C-7. 1H NMR spectroscopy indicated a 1:0.8 ratio of 7a and 7b. A cis arrangement is found for H-11b and H-1 in both diastereomers.
Me 1 NaCH(COOEt)2 N _ O _ EtO
EtOOC O Me
7 11b
CH
OEt Me
7 11b
+
N O H H EtOOC
N O
H H EtOOC
O 7a
O 7b
The [3+2] cycloaddition of alkyl and aryl isocyanates and isothiocyanates to nitrones leads to 1,2,4-oxadiazolin-5-ones and 5-thiones [2]. The addition of phenyl isocyanate and phenyl isothiocyanate to nitrone 1 proceeds regiospecifically and stereoselectively to give mixtures of diastereomers of spiro[1,2,4oxadiazolidinobenz-1-azepinecyclohexanes] 8 and 9 relative to the position of H-11b and the methyl group at C-7. 1H NMR spectroscopy indicated that the ratio of isomers 8a and 9a with trans relationship of these groups 623
624
TABLE 1. 1H NMR Spectra of Spiro[benzazepinecyclohexanes] 2-5, 10 and 11 in CDCl3

Compound 2 3 -4a 1.96 (dd, J4a,4e = 13.7, J4a,5 = 12.5) 1.97 (dd, J4a,4e = 13.7, J4a,5 = 12.2) -4e 2.40 (dd, J4a,4e = 13.7, J4e,5 = 5.8) 2.40 (dd, J4a,4e = 13.7, J4e,5 = 5.8) -5 3.24 (m) 3.10 (m, J5,M = 7.0, J4e,5 = 5.8, J4a,5 = 12.5) 3.11 (m, J5,M = 7.0, J4e,5 = 5.8, J4a,5 = 12.2) 3.18 (m) 3-5, d Chemical shifts, , ppm (SSCC, J, Hz) -cyclohex. 0.9-2.45 (m, cyclohex. + 2-4) 0.9-2.45 7.05-7.50 7.05-7.50 -6-9 other signals 1.60 (d, 3J = 6.7, CH3-1); 4.67 (q, 3J = 6.7, H-1) 2.48 (s, 3-1)
1.36 (J5,M = 7.0) 1.30 (J5,M = 7.0)
1.30 (J5,M = 7.0)
1.02.4
7.1-7.45
2.48 (s, 3-1)
5 10 1.65 (dd, J4a,4e = 13.7, J4a,5 = 11.6) 2.05 (dd, J4a,4e = 13.7, J4e,5 = 5.8)
1.37 (J5,M = 7.0) 1.36 (J5,M = 7.0)
1.2-2.0 (m, cyclohex. + 2-4)
7.35-7.05
3.32 (m, J5,M = 7.0, J4e,5 = 5.8, J4a,5 = 11.6) 3.81 (br. m)
0.8-1.65
11
1.64 (br. m)
2.22 (br. m)
1.38 (J5,M = 7.0)
0.85-1.95
7.24 (dt, J6,7 = 7.6, J6,8 = 1.5, H-6); 7.30 (td, J7,8 = J8,9 = 7.6, J6,8 = 1.5, H-8); 7.44 (td, J6,7 = J7,8 = 7.6, J7,9=1.5, H-7); 7.67 (dd, J8,9 = 7.6, J7,9 = 1.5, H-9) 7.70-7.20
4.47 (br. s, ); 4.06 (d, J, = 14.7, 1A); 4.60 (d, J, = 14.7, 1B) 5.95 (br. s, NH)
2.28 (3, s, 3)
TABLE 2. 1H NMR Spectra of Spiro[isoxazolidino- and Spiro[oxadiazolidinobenzazepinecyclohexanes] 7-9 in CDCl3

Compound 7a -1, dd 4.53 (3J = 12.8) -6a, dd 2.29 (J6a,6e = 15.0) -6e -7, m 3.23 Chemical shifts, , ppm (SSCC, J, Hz) 3-7 -cyclohex., m 1.42 (m) 1.0-2.1 (cyclohex. + -6e) -arom. 6.8-7.4(-6-9) -11b 5.54 (dd, 3 J = 12.8) Other signals 1.40 (t, 3J = 7.0, CH3CH2); 4.41 (q, 3J = 7.0, CH2O) 1.32 (t, 3J = 7.0, CH3CH2); 4.28 (q, 3J = 7.0, CH2O) 6.57 (s) 7.96 (s) 6.91 (s)
7b
4.11 (3J = 11.3)
2.25 (J6a,6e = 15.0)
3.33 2.33 (d, J6a,6e = 14.3) 2.17 (dd, J6a,6e = 14.3, J6e,7 = 5.2) 2.45 (dd, J6a,6e = 15.3, J6e,7 = 2.8) 2.33 (dd, J6a,6e = 14.7, J6e,7 ~0) 3.43 (J7,M = 7.0, J6a,7 = 13.4) 3.50 (J7,M = 7.0, J6e,7 = 5.2) 3.14 (J7,M = 6.7, J6a,7 = 10.7, J6e,7 = 2.8) 3.34 (J7,M = 6.7, J6e,7 ~0)
1.41 (m)
1.0-2.1 (cyclohex. + -6e)
6.8-7.4 (-6-9)
5.62 (dd, 3 J = 11.3)
8a 8b 9a 9b
1.35 (J6a,6e = 14.3, J6a,7 = 13.4) 1.90 (J6a,6e = 15.3, J6a,7 = 10.7)
1.47 (d, J7,M = 7.0)
1.2-2.5
6.9-7.4 (-6-9 +Ph) 6.9-7.4 (-6-9 +Ph) 7.0-7.55 (-6-9 +Ph) 7.0-7.55 (-6-9 +Ph)
6.73 (s)
1.45 (d, J7,M = 7.0)
1.2-2.5 (cyclohex.+ -6a)
1.43 (d, J7,M = 6.7)
1.3-2.6
1.43 (d, J7,M = 6.7)
1.3-2.6 (cyclohex. + -6a)
625
in the adducts with phenyl isocyanate (8) and phenyl isothiocyanate (9) to isomers 8b and 9b was 1.6:1 (8a:8b) and 7.1:1 (9a:9b). The arrangement of H-7 and H-11b in adducts 8a, 8b, 9a, and 9b was established using the homonuclear Overhauser effect. A pure sample of diastereomer 8a was isolated in 57% yield upon crystallization of the reaction mixture from acetone.
Me PhNCX H Ph
7 11b
Me
7
+
N
2
11b
O3
H Ph
N
2
O3
X 8a, 9a 8 X = O; 9 X = S
X 8b, 9b
The action of acid anhydrides, acid chlorides, PCl3, PCl5, POCl3, and sodium ethylate on nitrones leads to their rearrangement to give amides [12]. Similarly, nitrone 1 is converted upon heating at reflux in acetic anhydride into benz-2-azepine-1-one (10) in 82% yield.
Me Ac2O N O H 10 O 1 Pb(OAc)4 N OAc 11 Me
The lead tetraacetate oxidation of nitrone 1 gives the O-acetyl derivative of hydroxamic acid 11 in 90% yield. Manganese dioxide in benzene and potassium periodate in chloroform in the presence of crown ether do not oxidize nitrone 1. The permanganate oxidation under phase-transfer conditions using TBAI and water chloroform leads to the formation of a complex mixture. The mass spectra of all these products show molecular ion peaks of different intensity, corresponding to their chemical formulas. The IR spectra of these compounds show stretching vibration bands of the corresponding functional groups. The OH group stretching bands for hydroxylamines 2 and 5 are found at 3321 and 3222 cm-1, respectively. The NO stretching band in the spectrum of nitrone 4 is found at 1238 cm-1, while the C=N stretching band is found at 1562 cm-1. Three CO stretching bands are found in the mixture of isoxazolidinobenzazepines 7a and 7b (1788, 1768, and 1741 cm-1), while only one CO stretching band is found in the spectrum of oxadiazolidinobenzazepine at 1738 cm-1. The spectra of lactams 10 and 11 have NC=O bands at 1641 and 1654 cm-1, respectively, and also stretching bands for the NH group at 3270 and 3185 cm-1 (10) and ester group at 1754 cm-1 (11). The thione group in the spectrum of 9 is seen at 1221 cm-1. The 1H NMR spectra of fused benzazepinecyclohexanes 2-5, 10, and 11 have signals for all the protons with chemical shifts and coupling constants corresponding to their position in the molecule. The methylene group signals for CH2-4 in hydroxylamines 2 and 5 are overlapped by the cyclohexane ring signals. The CH2-1 protons in the spectrum of 5 are not equivalent and appear as two doublets (4.06 and 4.60 ppm). The broadening of the signals in the spectrum of N-acetoxylactam 11 may be a consequence of conformational transitions of the hydrogenated azepine ring.
626
TABLE 3. Physical Data of the Products

Compound 2 3 4 5 6 7 8 9 10 11 Empirical formula C17H25NO C17H23N C17H23NO C16H23NO C23H28N2O2 C21H27NO4 C23H26N2O2 C23H26N2OS C16H21NO C18H23NO3 79.60 79.38 78.41 78.37 75.73 75.82 70.31 70.59 76.11 76.24 73.18 73.02 79.25 79.01 71.88 71.76 9.03 8.95 9.30 9.39 7.82 7.69 7.33 7.56 7.02 7.18 6.74 6.88 9.00 8.64 7.53 7.64 5.30 5.45 5.98 5.71 7.85 7.69 4.01 3.92 7.91 7.73 7.57 7.41 5.46 5.76 4.49 4.65 Found, % Calculated, % N []+ mp, *2 Rf Yield, % 65
259 241 257 245 364 362 362 378 243 301 125.5-128 141-142.5 107-110 199.5-204 125-127 150-152 88-90
0.51 (1:2)
0.12 (1:1) 0.38 (1:1) 0.73 (1:1) 0.68 (1:1) 0.70 (1:1) 0.56 (1:2) 0.26 (1:1) 0.57 (1:1)
52 84 77 20 96 96 82 90
_______ * Elemental analysis not performed for compounds 2 and 3. *2 Products 2-4 are oils. The 1H NMR spectra of spiro[isoxazolidino- and spiro[oxadiazolidinobenzazepinecyclohexanes] 7-9 given in Table 2 have two signals for H-1, H-6a, H-7, CH3-7, and H-11b, which unequivocally indicates the formation of these compounds as two diastereomers. The J7,6 coupling constant suggests that CH3-7 in all the diastereomers occupies a pseudoequatorial position. Thus, benzazepine nitrone 1 undergoes all the reactions characteristic for cyclic and acyclic nitrones to give 1-substituted and condensed spiro[benz-2-azepine-3-cyclohexanes]. EXPERIMENTAL The IR spectra were taken on UR-20 and IR-75 spectrometers. The mass spectra were obtained on a Finnigan MAT Incos 50 mass spectrometer with direct inlet into the ion source. The ionizing voltage was 70 eV. The 1H NMR spectra of ~2% solutions of the products in CHCl3 were taken on a Bruker WP-200 spectrometer at 200 MHz and 30C with TMS as the internal standard. Thin-layer chromatography was carried out on Silufol UV-254 plates with 1:1, 1:2, and 1:3 ethyl acetatehexane as the eluent and detection with iodine vapor. Column chromatography was carried out using Woelm 32/64 silica gel and L 5/40 silica gel. The melting points were determined in glass capillaries and not corrected. The physicochemical data of the products are given in Table 3. 2-Hydroxy-1,5-dimethyl-1,2,4,5-tetrahydro-3H-spiro[benz-2-azepine-3,1'-cyclohexane] (2) and 4,5Dihydro-1,5-dimethyl-3H-spiro[benz-2-azepine-3,1'-cyclohexane] (3). A sample of nitrone 1 (1.00 g, 4 mmol) was added to a water-cooled solution of methylmagnesium iodide obtained from methyl iodide (0.5 ml, 8 mmol) and magnesium (0.28 g, 12 mmol) in absolute ether (30 ml) and heated at reflux for 1.5 h. The solution was monitored by thin-layer chromatography. Then, the solution was decomposed by adding saturated aqueous ammonium chloride and extracted with three 50-ml ether portions. The combined extracts were dried over MgSO4. The residue after distilling off the solvent was passed through a silica gel layer with 1:5 hexaneethyl 627
acetate as the eluent to give 0.68 g (65%) mixture of 2 and 3. Product 2. IR spectrum in vaseline oil, , cm-1: 3321 (OH), 1041 (NO). Mass spectrum, m/z (Irel, %): 259 [M]+ (12), 244 (9), 243 (18), 242 (100), 226 (1), 216 (10), 211 (5), 200 (4), 188 (5), 172 (4), 157 (4), 148 (11), 147 (12), 146 (13), 145 (18), 131 (70), 130 (13), 129 (4), 128 (14), 117 (42), 116 (17), 115 (36), 114 (16), 105 (13), 103 (12), 98 (9), 91 (48), 77 (18), 55 (17), 41 (43). Product 3: IR spectrum in vaseline oil, , cm-1: 1641 (C=N). Mass spectrum, m/z (Irel, %): 241 [M]+ (20), 240 (100), 226 (6), 225 (14), 224 (11), 215 (18), 206 (6), 199 (12), 198 (42), 183 (13), 176 (5), 174 (8), 162 (25), 161 (11), 160 (14), 158 (19), 157 (17), 155 (11), 147 (12), 146 (99), 145 (49), 144 (73), 143 (30), 142 (13), 131 (11), 130 (25), 129 (37), 128 (56), 117 (16), 116 (16), 115 (58), 103 (38), 98 (1), 91 (46), 81 (17), 77 (55), 67 (20), 55 (26), 53 (29), 51 (23), 41 (35). 4,5-Dihydro-1,5-dimethyl-3H-spiro[benz-2-azepine-3,1'-cyclohexane] N-Oxide (4). A solution of mixture of 2 and 3 (0.86 g, 3.3 mmol), Na2WO42H2O (0.11 g, 0.33 mmol), and 30% H2O2 (1 ml, 33 mmol) in acetone (20 ml) was heated at reflux for 8 h, poured into water (50 ml), and extracted with ether. The extract was washed with water and dried over MgSO4. The residue after distilling off the solvent was subjected to chromatography on silica gel using 1:1 ethyl acetatehexane as the eluent to give 0.44 g (52%) 4 as a thick yellow oil. IR spectrum in vaseline oil, , cm-1: 1562 (C=N), 1238 (NO). Mass spectrum, m/z (Irel, %): 257 [M]+ (13), 243 (11), 241 (6), 240 (48), 228 (10), 226 (12), 225 (14), 224 (8), 215 (10), 214 (6), 200 (23), 198 (18), 195 (5), 184 (13), 172 (8), 163 (33), 162 (20), 161 (31), 160 (16), 159 (17), 147 (44), 146 (100), 145 (70), 144 (43), 143 (30), 132 (14), 131 (34), 130 (34), 129 (40), 128 (37), 117 (18), 116 (13), 115 (38), 104 (14), 103 (30), 98 (13), 91 (39), 81 (22), 77 (34), 67 (22), 55 (26), 43 (53), 41 (47), 39 (27). 2-Hydroxy-5-methyl-1,2,4,5-tetrahydro-3H-spiro[benz-2-azepine-3,1'-cyclohexane] (5). A sample of lithium aluminum hydride (0.8 g, 2 mmol) was added to a suspension of nitrone 1 (0.50 g, 2 mmol) in absolute ether (20 ml) and heated at reflux for 1 h. A sample of 20% aqueous NaOH (0.5 ml) was added with water cooling and stirred until a precipitate formed. The ethereal layer was decanted and the precipitate was washed with two 20-ml ether portions. The combined ethereal extracts were dried over MgSO4. The residue after distilling off ether was crystallized from hexane to give 0.42 g (84%) hydroxylamine 5 as white crystals. IR spectrum (KBr), , cm-1: 3222 (OH), 1022 (NO). Mass spectrum, m/z (Irel, %): 245 [M]+ (25), 229 (29), 228 (100), 226 (5), 214 (7), 202 (43), 200 (4), 186 (25), 172 (10), 158 (6), 156 (6), 143 (8), 141 (3), 132 (67), 131 (59), 130 (19), 129 (18), 118 (31), 117 (77), 115 (39), 105 (13), 103 (8), 98 (20), 91 (42), 77 (15), 55 (13), 41 (24). 5-Methyl-2-(N-phenylcarbamoyloxy)-1,2,4,5-tetrahydro-3H-spiro[benz-2-azepine-3,1'-cyclohexane] (6). A sample of phenyl isocyanate (0.26 ml, 2.4 mmol) was added to a solution of hydroxylamine 5 (0.30 g, 1.2 mmol) in absolute heptane (15 ml) and maintained for 0.5 h at 0C. The crystalline precipitate was filtered off and washed on the filter with absolute heptane to give 0.34 g (77%) 6 as white crystals. IR spectrum (KBr), , cm-1: 3388, 3281 (NH), 1741, 1708 (C=O), 1214 (CON). Mass spectrum, m/z (Irel, %): 364 [M]+ (1), 245 [M+ - PhNCO] (56), 228 (100), 212 (7), 202 (22), 186 (10), 172 (5), 158 (3), 143 (4), 132 (39), 119 [PhNCO] (17), 117 (34), 98 (9), 93 (15), 91 (30), 77 (12), 65 (11), 51 (3), 41 (12). 1-Ethoxycarbonyl-7-methyl-2-oxo-6,7-dihydro-5H-spiro{1,2-isoxazolidino[3,2-a]benz-2-azepine-5,1'cyclohexane} (7). A sample of nitrone 1 (0.5 g, 2 mmol) was added to the sodium derivative of diethyl malonate obtained from sodium amide (0.31 g, 8 mmol) and diethyl malonate (1.21 ml, 8 mmol) in absolute benzene (25 ml). The mixture was heated at reflux for 12 h with monitoring by thin-layer chromatography. Then, ethanol (2 ml) and water (30 ml) were added. The mixture was extracted with benzene and the extract was dried over MgSO4. Benzene was distilled off and the residue was purified by passing through alumina using 1:10 hexane ethyl acetate as the eluent and then crystallization from hexane to give 0.14 g (20%) of a white crystalline mixture of diastereomers of 7. IR spectrum (KBr), , cm-1: 1788, 1768 (CO2Et), 1741 (CO2N). Mass spectrum, m/z (Irel, %): 357 [M]+ (5), 314 (24), 313 (10), 298 (4), 270 (6), 240 (7), 226 (32), 218 (13), 196 (4), 183 (5), 172 (10), 170 (9), 157 (8), 144 (48), 143 (100), 142 (47), 132 (17), 131 (22), 130 (36), 129 (52), 128 (50), 117 (26), 115 (36), 103 (12), 98 (75), 91 (140, 89 (16), 77 (18), 67 (20), 55 (39), 41 (60). 628
7-Methyl-2-oxo-1-phenyl-4,6,7,11b-tetrahydro-5H-spiro{1,2,4-oxadiazolidino[3,2-a]benz-2-azepine5,1'-cyclohexane} (8). A sample of phenyl isocyanate (0.65 ml, 6 mmol) was added to a solution of nitrone 1 (0.5 g, 2 mmol) in absolute benzene (10 ml) and stirred for 2 h at 20C with monitoring by thin-layer chromatography. Benzene was distilled off and the residue was crystallized from acetone to give 0.41 g (57%) 8a as white crystals; mp 202-204C (dec.). Crystallization from hexane gave 0.69 g (96%) mixture of isomers 8a and 8b as white crystals; mp 199.5-204C (dec.). IR spectrum (KBr), , cm-1: 362 [M]+ (2), 318 (3), 243 (23), 227 (24), 226 (100), 201 (5), 172 (9), 156 (3), 144 (11), 132 (25), 131 (45), 130 (31), 129 (15), 119 (59), 115 (16), 103 (7), 98 (8), 91 (39), 77 (32), 64 (17), 55 (12), 44 (23), 41 (21). 7-Methyl-1-phenyl-2-thioxo-4,6,7,11b-tetrahydro-5H-spiro{1,2,4-oxadiazolidino[3,2-a]benz-2-azepine5,1'-cyclohexane} (9). A sample of phenyl isothiocyanate (0.36 ml, 3 mmol) was added to a solution of nitrone 1 (0.5 g, 2 mmol) in absolute benzene (15 ml) and stirred for 3 h at 20C with monitoring by thin-layer chromatography. Benzene was distilled off and the residue was crystallized from 1:10 hexaneethyl acetate to give 0.73 g (96%) mixture of isomers 9a and 9b as yellowish crystals. IR spectrum (KBr), , cm-1: 1221 (C=S), 1048 (NO). Mass spectrum, m/z (Irel, %): 243 [M+ - PhNCS] (5), 226 (30), 184 (4), 148 (4), 148 (4), 144 (3), 137 (11), 135 [PhNCS] (100), 132 (22), 131 (21), 130 (12), 117 (4), 116 (4), 115 (10), 104 (5), 103 (5), 91 (9), 77 (63), 63 (4), 55 (3), 51 (20), 41 (5), 39 (6). 5-Methyl-1-oxo-1,2,4,5-tetrahydro-3H-spiro[benz-2-azepine-3,1'-cyclohexane] (10). A sample of nitrone 1 (3.00 g, 12.3 mmol) in acetic anhydride (20 ml) was heated at reflux for 1 h. Excess acetic anhydride was distilled off in vacuum. The residue was made basic by adding ammonium hydroxide. The precipitate formed was filtered off, washed with water, and dried. Recrystallization from 1:10 hexaneethyl acetate gave 2.45 g (82%) 10 as white crystals. IR spectrum (KBr), , cm-1: 3270, 3185 (NH), 1641 (C=O), 1394 (NH). Mass spectrum, m/z (Irel, %): 243 [M]+ (50), 228 (18), 214 (7), 201 (12), 200 (100), 187 (10), 186 (8), 172 (22), 160 (8), 159 (17), 158 (9), 147 (74), 145 (13), 132 (10), 131 (57), 128 (13), 117 (15), 116 (8), 115 (20), 103 (44), 98 (27), 91 (20), 77 (43), 65 (10), 54 (19), 41 (53), 39 (30). 2-Acetoxy-5-methyl-1-oxo-1,2,4,5-tetrahydro-3H-spiro[benz-2-azepine-3,1'-cyclohexane] (11). A mixture of nitrone 1 (0.17 g, 0.7 mmol) and lead tetraacetate (0.31 g, 0.7 mmol) in absolute benzene (20 ml) was stirred for 4 h at room temperature. The reaction was monitored by thin-layer chromatography. The mixture was filtered and washed on the filter with absolute benzene. Benzene was distilled off and the residue was purified by passing through alumina using 1:1 hexaneethyl acetate as the eluent to give 0.21 g of a light yellow oil. The crude product was crystallized from hexane to give 0.19 g (90%) 11 as white crystals. IR spectrum (KBr), , cm-1: 1754 (CH3CO2), 1654 (CON). Mass spectrum, m/z (Irel, %): 301 [M]+ (2), 260 (18), 259 (100), 143 (15), 242 (79), 241 (18), 228 (17), 227 (80), 126 (11), 216 (38), 200 (8), 186 (5), 176 (15), 171 (9), 160 (20), 148 (26), 147 (86), 146 (90), 144 (5), 133 (28), 132 (29), 131 (50), 130 (11), 129 (15), 128 (19), 117 (24), 116 (11), 115 (28), 105 (16), 104 (45), 103 (43), 98 (7), 91 (27), 81 (35), 77 (38), 67 (13), 55 (26), 43 (95), 41 (41).
REFERENCES 1. 2. 3. 4. 5. 6. J. Hamer and A. Macaluso, Chem. Rev., 64, 473 (1964). D. St. C. Black, R. F. Crozier, and V. C. Davis, Synthesis, 205 (1975). R. C. Bernotas, G. Adams, and A. Carr, Tetrahedron, 52, 6519 (1996). V. Kouznetsov, A. R. Palma, S. Salas, L. Y. Vargas, F. Zubkov, A. Varlamov, and J. R. Martinez, J. Heterocycl. Chem., 34, 1591 (1997). A. V. Varlamov, F. I. Zubkov, K. F. Turchin, A. I. Chernyshev, and R. S. Borisov, Khim. Geterotsikl. Soedin., 1360 (2001). A. V. Varlamov, F. I. Zubkov, A. I. Chernyshev, and N. M. Mikhailov, Abstracts of the Third AllRussian Congress on Man and Pharmaceuticals [in Russian], Farmmedinfo, Moscow (1996), p. 13. 629
7. 8. 9. 10. 11. 12.
A. V. Varlamov, K. F. Turchin, A. I. Chernyshev, F. I. Zubkov, and T. N. Borisova, Khim. Geterotsikl. Soedin., 703 (2000). A. V. Varlamov, D. G. Grudinin, A. I. Chernyshev, A. N. Levov, N. I. Golovtsov, and R. S. Borisov, Khim. Geterotsikl. Soedin., 376 (2001). V. S. Shklyaev, B. B. Aleksandrov, M. S. Gavrilov, and A. G. Mikhailovskii, in: Enamines in Organic Synthesis [in Russian], Urals Branch, Academy of Sciences of the USSR, Sverdlovsk (1989), p. 80. S. Ozaki, Chem. Rev., 72, 457 (1972). H. Stamm and J. Hoenicke, Liebigs Ann. Chem., 478, 143 (1971). M. Lamchen, in: B. S. Thyagarajan (editor), Mechanisms of Molecular Migrations, Vol. 1, Interscience, New York, (1968), p. 36.
630
A FACILE SYNTHESIS OF SUBSTITUTED BENZODIAZEPINES USING SOLID SUPPORT

M. Kidwai, Ruby, and R. Venkataramanan An easy and convenient synthetic procedure for the preparation of benzodiazepines by coupling microwaves with the solvent technique have been elaborated. Keywords: benzodiazepines, o-phenylenediamine, microwave irradiation, solid support. 1,5-Benzodiazepines and their derivatives have been investigated extensively by organic chemists due to their medicinal properties [1] such as analgesic and anti-inflammatory activities [2]. The seven-membered rings are generally synthesized via the [4+3] condensation reaction, most commonly by condensing 1,2-diamines with carbonyl compounds. This procedure involves the use of carcinogenic solvents like xylene [3], which often afforded imidazole [4] as a by-product or as a major component along with benzodiazepines. The use of microwave irradiation (MWI) is well known for the synthesis of a variety of compounds [5, 6] where the chemical reactions are accelerated because of selective absorption of microwaves by polar molecules. The coupling of MWI together with solid-supported reagents under solvent-free conditions [7-9] provides unique chemical processes with special attributes such as enhanced reaction rate, higher yield, greater selectivity, and ease of manipulation [10]. The limitations of microwave-assisted reactions in solution, namely the development of high pressure and the need for specialized vessels, are circumvented via this solid state strategy which enables organic reactions to occur rapidly in open vessels at atmospheric pressure [11]. In view of the reported limitations [12, 13] in the synthesis of 1,5-benzodiazepine and our continued interest in the development of environmentally benign protocols [14-16], we describe herein a microwaveassisted solid state approach for the rapid synthesis of 3H-1,5-benzodiazepines and 3H-1,5-benzodiazepin-2ones (Scheme 1). o-Phenylenediamine (1) and ethyl acetoacetate (2) were condensed according to the literature [3, 4] to yield 4-methyl-3H-1,5-benzodiazepin-2-one (3) in 3-6 h of conventional heating (method A) or 10 min of MWI in solution (method B). The same reaction when carried out using neutral alumina as solid support was completed within 40-60 s of MWI (method C) with yield improved from about 60 to 90%. Moreover, the desired product was obtained exclusively, which was characterized by literature mp and spectral data. The encouraging result in the synthesis of benzodiazepinone prompted us to attempt a similar modification (method C) in the condensation reaction of diamine 1 with other conjugated carbonyl compounds. The reaction of diamine 1 with ,-unsaturated ketones 4a,b over acidic alumina as energy-transfer medium under MWI afforded 3H-1,5-benzodiazepines 5 in 90-94% yield. IR bands in the region of 3430-3440 (NH), 1628-1630 (C=N) and 1300-1450 cm-1 (CN) and 1H NMR signals at 4.0-4.5 (2H, s, CH2) and 5.0-6.0 ppm (1H, s, CH) confirm the formation of the required products.
__________________________________________________________________________________________ Department of Chemistry University of Delhi, Delhi-110007, India; e-mail: mkidwai@mantraonline.com. Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 745-748, May, 2004. Original article submitted August 20, 2002; revision submitted July 30, 2003. 0009-3122/04/4005-06312004 Plenum Publishing Corporation 631
Scheme 1
O NH2 NH2 1 (4) R1CCH=CHR2 MWI, acidic alumina R4 (6) R3CH=CCOOH MWI, acidic alumina O (2) MeCCH2OOEt MWI, neutral alumina O O N 7 H N O Me N 5 H H N R2 R1 R4 N R1
N 3 H N
O Me
(8) MeCCH2CMe MWI, acidic alumina O 4, 5 a R1 = O 6, 7 a R3 , R2 = Me; b R1 = O 9
Me
, R2 = C6H4Br-m , R4 = H O
= Me, R4 = H; b R3 = H, R4 = CH2COOH; c R3 =
Condensation with ,-unsaturated acids 6a-c over acidic alumina afforded 3,4-dihydro-1,5benzodiazepin-2-ones 7 within seconds of irradiation. The products were characterized by the appearance of bands in the IR spectra at 3500-3200 (NH) and 1700-1670 cm-1 (C=O) and signals in the 1H NMR spectra at 2.6-4.6 ppm (1H, s, CH). Similarly using acidic alumina the condensation of acetylacetone (8) with o-phenylenediamine 1 yielded 2,4-dimethyl-3H-1,5-benzodiazepine (9), which was confirmed by literature mp and spectral data. All the above reactions were also pursued under MWI in solution (me-thod B) as well as the conventional method (method A) for a comparative study. Solid-supported reactions gave improved yield and were completed within seconds of MWI in comparison to hours and minutes in conventional and microwaveassisted syntheses in solution, respectively. In conclusion, we have developed an easy and convenient synthetic procedure for the preparation of benzodiazepines by coupling microwaves with the solvent-free technique. Through modernization and simplification of the classical procedure, and avoidance of volatile and toxic solvents and external bases, we have discovered an efficient protocol for organic chemists.
EXPERIMENTAL Melting points were determined by an Electrothermal melting point apparatus and are un-corrected. IR spectra (in KBr) were recorded on a 1710 PerkinElmer FT infrared spectro-photometer. 1H NMR spectra were recorded on a FT NMR Hitachi R-600 (60 MHz) spectrometer in CDCl3 + DMSO-d6 taking TMS as reference. Elemental analysis were performed on a Heraeus CHN-Rapid Analyser. For MWI a Kenstar microwave oven, 632
TABLE 1. Characteristics of compounds synthesized

Compound 3 5a 5b 7a 7b 7c 9 mp, C Lit. mp, C [Ref.] 121 [14] 185 [18] 202 [17] Emprical formula C10H9N2O C14H13N2O C22H17BrN2O2 C10H12N2O C11H11N2O3 C13H12N2O2 C11H12N2 Found, % Calculated, % H 5.79 5.77 4.02 4.03 5.03 5.02 5.28 5.26 Yield, % (method, reaction period) N 12.43 12.44 6.64 6.65 12.79 12.78 12.29 12.28 A (h) 58 (2) 57 (5) 68 (5) 47 (4) 48 (6) 59 (4) 67 (3) B (min) 73 (10) 78 (6) 74 (7) 65 (8) 72 (5) 75 (9) 79 (5) C (s) 95 (50) 93 (50) 90 (40) 92 (40) 93 (60) 94 (60) 97 (40)
C 74.67 74.66 62.71 62.72 60.26 60.27 68.43 68.42
121 245 246 184 255 185 201
633
Model OM9925E (2450 MHz, 800 W), was used. The purity of the compounds was checked on silica gel coated Al plates (Merck). Preparation of Benzodiazepine Derivatives (Table 1). A. Solutions of compounds 2/4a,b/6a-c/8 (0.01 mol) and o-phenylenediamine 1 (0.01 mol) in xylene (10 ml)/glacial acetic acid + ethanol (1:2)/hydrochloric acid (5.5 N)/glacial acetic acid + ethanol (1:2), respectively, were refluxed under constant stirring for 4-6 h. The progress of the reaction was monitored on TLC. The reaction mixtures were cooled and the products that separated were filtered off, dried and recrystallized from ethanol. B. Diamine 1 (0.01 mol) was added to solutions of compounds 2/4a,b/6a-c/8 (0.01 mol) in xylene (5-10 ml) taken in an Erlenmeyer flask, and the contents were subjected to MW1 for an appropriate time and worked up as described in method A. C. Alumina was added to a solution of diamine 1 and compound 2/4a,b/6a-c/8 in ethanol. The reaction mixture was dried and placed in the alumina bath inside the microwave oven at 560 W for 40-60 s. The progress of reaction was monitored by TLC at intervals of 10 s. On completion of the reaction, the reaction mixture was cooled to room temperature, the product was extracted with ethanol (3 10 ml), and the solvent was removed under reduced pressure to yield the corresponding title compounds. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. S. J. Childress and M. I. Gluckman, J. Pharm. Sci., 53, 5 (1964). G. Roma, G. C. Grossi, M. Ghai, and F. Maltriot, Eur. J. Med. Chem., 26, 489 (1991). K. Bougrin, A. K. Bermani, S. Fkihtetouani, and M. Soufiaoui, Tetrahedron Lett., 35, 8373 (1994). J. Davoll, J. Chem. Soc., 308 (1960). G. Kobayashi and Y. Matsuda, Jpn. Pat., 6803385; Chem. Abstr., 69, 96716 (1968). G. Kobayashi, S. Furukawa, and Y. Matsuda, Yakugaku Zasshi, 86, 1156 (1966); Chem. Abstr., 67, 108594 (1967). R. S. Varma and R. K. Saini, Tetrahedron Lett., 38, 2623 (1997). M. Kidwai, Pure Appl. Chem., 73, 147 (2001). M. Kidwai, R. Venkataramanan, and B. Dave, J. Heterocycl. Chem., 39, 1045 (2002). M. Kidwai and R. Venkataramanan, Synthesis, 10, 1509 (2001). R. S. Varma and R. Dahiya, Tetrahedron, 54, 6293 (1998). M. Kidwai, P. Sapra, K. R. Bhusan, R. K. Saxena, and M. Singh, Monatsh. Chem., 131, 85 (2000). A. Loupy, A. Petit, J. Hamelin, F. Texier-Boullet, P. Jacquault, and D. Mathe, Synthesis, 1213 (1998). M. Kidwai, S. Saxena, R. Mohan, and R. Venkataramanan, J. Chem. Soc., Perkin Trans. 1, 1845 (2002). M. Kidwai, R. Venkataramanan, and B. Dave, Green Chem., 3, 278 (2001). M. Kidwai, R. Venkataramanan, and B. Dave, Synth. Commun., 32, 2162 (2002). D. Lloyd, R. M. McDougall, and D. R. Marshall, J. Chem. Soc., 3785 (1965). W. A. Sexton, J. Chem. Soc., 303 (1942).
634
SYNTHESIS OF 3-(3-ALKYL-5-THIOXO1H-4,5-DIHYDRO-1,2,4-TRIAZOL-4-YL)AMINOCARBONYLCHROMONES
Linghua Cao1,2, Lin Zhang1, and Pengyuan Cui1 A series of 3-(3-alkyl-5-thioxo-1H-4,5-dihydro-1,2,4-triazol-4-yl)aminocarbonylchromones has been prepared by oxidation of 3-formylchromone with Jones' reagent followed by reaction with 3-alkyl-4amino-4,5-dihydro-1,2,4-triazole-5(1H)-thione in the presence of POCl3. The structures of the compounds were confirmed by IR, LC-MS, and 1H NMR spectra and elemental analyses. Keywords: 3-(3-alkyl-5-thioxo-1H-4,5-dihydro-1,2,4-triazol-4-yl)aminocarbonylchromones, 3-formylchromone, synthesis. Compounds of chromone series have received considerable attention in the life sciences owing to their specific framework and their versatile and significant biological activities. In the study of modified chromones, compounds with antitumor, antibacterial, antiviral, hypolipidemic, and hypoglycemic activities have been discovered among 3-heterylsubstituted chromones [1]. 1,2,4-Triazoles are also reported to exhibit a broad spectrum of biological activity [2-4]. A series of investigations on combining these components together showed that the triazole-chromone systems formed display novel biological activities and could expand the scope of antibiotics. It stimulated us to introduce the 3-alkyl-4-amino-5-thioxo-1H-4,5-dihydro-1,2,4-triazole (1) fragment [5] into the parent chromone. The bioactivities of these compounds are under investigation. Starting from o-hydroxyacetophenones 2 we obtained 3-formylchromones 3; the latter, through oxidation with Jones' reagent [6], were transformed to 3-carboxychromones 4, which then reacted with 3-alkyl4-amino-5-thioxo-1H-4,5-dihydro-1,2,4-triazoles in the presence of POCl3 to give the target compounds 5-28. The structures of the compounds were characterized by elemental analyses, IR, LC-MS, and 1H NMR spectra. The synthetic route is shown in Scheme 1. In the synthesis of 3-formyl-substituted chromones reported by Nohara et al. [7], there were no variations in the molar ratio of substituted o-hydroxyacetophenonePOCl3DMF. We studied several ratios of the basic material to the reagents, such as 1:1:1, 1:3:3, 1:3:6, and 1:6:12. In the ratio 1:6:12, the yield of the product was 80-90%, which is higher than the reported yields. In the IR spectra, the absorption band of C=O of the carboxyl group of 3-carboxychromone appeared at 1750, which is higher than 1734 cm-1 of 2-carboxychromone. It was identical with that reported in [8]. In 1H NMR spectra, the signal of 2-H in chromones appears at 6-8 ppm [9]. The electron-acceptor substituent at position 3 shifts this signal to a lower field. Therefore the H-2 signals in compounds 5-28 were consequently obtained at 9.10.1 ppm. __________________________________________________________________________________________ College of Chemistry and Chemical Engineering, Xinjiang University, Urumqi 830046, P. R. China; e-mail: clhxj@xju.edu.cn. 2 State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, P. R. China. Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 749-754, May, 2004. Original article submitted July 16, 2002. 0009-3122/04/4005-06352004 Plenum Publishing Corporation 635
1
Scheme 1
S R3CO2H + NH2NHCNHNH2 reflux R3 N NH N S NH2 1af
R1 OH R2 2ad R1 Jones' reagent R2 O 4ad O COMe 1) DMFPOCl3 2) H2O R2
R1 O CHO 3ad O
CO2H
N R1 O R2 O 4ad CO2H R3
H N S NH2 POCl3 R2 O 528 R1 O O S NH N
CNHN R3
1 a R3 = Me, b R3 = Ph, c R3 = n-C3H7, d R3 = n-C4H9, e R3 = n-C5H11, f R3 = CF3; 2-4 a R1 = R2 = H, b R1 = H, R2 = Me, c R1 = H, R2 = Br, d R1 = R2 = Cl; 5-22 R1 = H, 23-28 R1 = Cl; 5-10 R2 = H, 11-16 R2 = Me, 17-22 R2 = Br, 23-28 R2 = Cl; 5, 11, 17, 23 R3 = Me, 6, 12, 18, 24 R3 = Et, 7, 13, 19, 25 R3 = n-Pr, 8, 14, 20, 26 R3 = n-Bu, 9, 15, 21, 27 R3 = n-C5H11, 10, 16, 22, 28 R3 = CF3
The proton signals of the CONH group in compounds 5-28 appeared at 10.2-11.5 ppm as broad singlets. In the thiolactam group they were shifted to 13.6-14.5 ppm. In the IR spectra of the products, the characteristic absorption band of C=O in pyrone appeared at 16201670 cm-1, and the IR spectra of compounds 5-28 displayed a broad band at 3000 (CONH, CSNH), and a band at 1700 (C=O of CONH) or 1310 cm-1 (C=S). All the compounds 5-28 had strong molecular-ion peaks in the LC-MS spectra (the relative abundance was >60% or even the base peak). The LC-MS spectra exhibited the peaks of retro-DielsAlder cracking and the [M+Na-H]+ peak.
EXPERIMENTAL Melting points were recorded on a Yanaco MP-S3 microscopic melting point apparatus and are corrected. IR spectra were recorded on a Bruker FT-IR ERUINOX-55; FTS-40 (KBr pellets). 1H NMR spectra were recorded on a Bruker AC-80 (80 MHz) spectrometer (TMS as internal standard, solvent CDCl3 or DMSO). 636
TABLE 1. Physical Constants of Compounds 5-28

Compound 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Empirical formula C13H10N4O3S C14H12N4O3S C15H14N4O3S C16H16N4O3S C17H18N4O3S C13H7F3N4O3S C14H12N4O3S C15H14N4O3S C16H16N4O3S C17H18N4O3S C18H20N4O3S C14H19F3N4O3S C13H9BrN4O3S C14H11BrN4O3S C15H13BrN4O3S C16H15BrN4O3S C17H17BrN4O3S C13H6BrF3N4O3S C13H8Cl2N4O3S C14H10Cl2N4O3S C15H12Cl2N4O3S C16H14Cl2N4O3S C17H16Cl2N4O3S C13H5Cl2F3N4O3S Found, % Calculated, % H 3.39 3.33 3.89 3.82 4.20 4.27 4.60 4.68 1.86 1.98 4.86 4.89 3.89 3.82 4.31 4.27 4.70 4.68 5.03 5.06 5.44 5.41 2.43 2.45 2.35 2.38 2.79 2.81 3.22 3.20 3.54 3.57 3.94 3.92 1.41 1.39 2.20 2.17 2.69 2.62 3.06 3.03 3.37 3.41 3.74 3.77 1.21 1.19 mp, C N 18.62 18.53 17.80 17.71 16.92 6.96 16.31 16.27 15.79 15.73 16.02 15.99 17.76 17.71 16.89 16.96 16.31 16.27 16.67 15.63 15.09 15.04 15.18 15.13 14.77 14.70 14.07 14.18 13.73 13.69 13.33 13.24 12.85 12.81 12.94 12.87 15.15 15.09 14.62 14.54 14.08 14.03 13.64 13.56 13.20 13.11 13.23 13.18 >300 >300 >300 289-291 247-248 241-243 >300 >300 276-278 >300 278-280 217-219 >300 >300 251-252 247-248 241-243 233-234 284-285 248-249 237-239 230-231 218-219 197-199 Yield, % 51 49 41 40 38 32 53 50 42 39 33 29 51 48 32 30 30 35 48 47 43 40 36 31
C 51.52 51.65 53.10 53.16 54.50 54.53 55.89 55.80 43.86 43.83 44.61 44.57 53.12 53.16 54.56 54.53 55.89 55.80 56.93 56.97 57.96 58.05 45.38 45.41 40.90 40.96 42.51 42.55 43.99 44.02 45.44 45.40 46.73 46.69 35.83 35.88 42.13 42.06 43.72 43.65 45.21 45.13 46.60 46.50 47.84 47.78 36.81 36.72
Elemental analysis were taken on a PerkinElmer 2400 CHN analyzer. TLC was carried out on precoated glass plates of silica gel GF 254. The spots were visualized by exposure under UV light or by the coloration of iodine vapor. All reagents are analytically pure. General Procedure for the Synthesis of 3-Alkyl-4-amino-4,5-dihydro-1,2,4-triazole-5(1H)-thione [5] 1a-f. Thiocarbohydrazide (3.18 g, 0.03 mol) and 0.04 mol of fatty acid were refluxed for 4 h. After that the reaction mixture was distilled in vacuum and the nonreacted fatty acid was taken off. The crude product obtained was recrystallized from EtOH or EtOHH2O; mean yield 76% with this reaction. 637
TABLE 2. Spectral data of compounds 5-28

IR Comspectrum, pound cm-1 1 2 5 1700, 1616, 1312 1701, 1621, 1310 1702, 1620, 1311 1700, 1624, 1309 1703, 1617, 1310 1701, 1618, 1311 1701, 1621, 1319 1705, 1620, 1317 1700, 1623, 1315 1701, 1624, 1310 1702, 1621, 1310 1701, 1617, 1313 1699, 1637, 1310 1695, 1637, 1303 1701, 1625, 1303 1702, 1617, 1315 1700, 1623, 1313
1
H NMR spectrum, , ppm 3
Mass spectrum, m/z (I, %) 4 325 [M+Na]+ (55), 302 [M]+ (98), 173 (100), 145 (35), 121 (52) 355 [M+K]+ (60), 316 [M]+ (90), 173 (100), 145 (50), 121 (46) 353 [M+Na]+ (58), 330 [M]+ (92), 173 (100), 145 (35), 121 (42) 367 [M+Na]+ (58), 344 [M]+ (90), 173 (100), 145 (41), 121 (53) 397 [M+K]+ (60), 358 [M]+ (97), 173 (100), 145 (52), 121 (48) 395 [M+K]+ (60), 356 [M]+ (100), 173 (90), 145 (57), 121 (32) 339 [M+Na]+ (64), 316 [M]+ (98), 187 (100), 159 (35), 135 (42) 369 [M+K]+ (59), 330 [M]+, (100), 187 (91), 159 (43), 135 (38) 383 [M+K]+ (60), 344 [M]+ (100), 187 (93), 159 (41), 135 (32) 381 [M+Na]+ (57), 358 [M]+ (94), 187 (100), 159 (36), 135 (40) 411 [M+K]+ (60), 372 [M]+ (100), 187 (90), 159 (42), 135 (50) 409 [M+K]+ (60), 370 [M]+ (100), 187 (83), 159 (37), 135 (50) 405 [M+2+Na]+ (60), 403 [M+ Na]+ (57), 382 [M+2]+ (100), 380 [M]+ (100) 419 [M+2+Na]+ (60), 417 [M+ Na]+ (58), 396 [M+2]+ (100), 394 [M]+ (100) 419 [M+2+Na]+ (63), 417 [M+ Na]+ (58), 397 [M+2+H]+ (100), 395 [M+H]+ (80) 433 [M+2+Na]+ (60), 431 [M+ Na]+ (60), 411 [M+2+H]+ (100), 409 [M+H]+ (100) 447 [M+2+Na]+ (60), 445 [M+ Na]+ (60), 425 [M+2+H]+ (100), 423 [M+H]+ (100)
10
11
12
2.20 (s, 3H, CH3); 7.57-8.29 (m, 4H, H-5, H-6, H-7, H-8); 9.17 (s, 1H, H-2); 11.44 (s, 1H, CONH); 13.89 (br. s, 1H, CSNH) 1.07-2.37 (m, 5H, C2H5); 7.58-8.22 (m, 4H, H-5, H-6, H-7, H-8); 9.12 (s, H-2); 11.44 (s, 1H, CONH); 13.84 (br. s, 1H, CSNH) 1.06-2.50 (m, 7H, C3H7); 7.54-8.17 (m, 4H, H-5, H-6, H-7, H-8); 9.15 (s, 1H, H-2); 11.42 (s, 1H, CONH); 13.86 (br. s, 1H, CSNH) 1.09-2.56 (m, 9H, C4H9); 7.58-8.25 (m, 4H, H-5, H-6, H-7, H-8); 9.11 (s, 1H, H-2); 11.38 (s, 1H, CONH); 13.79 (br. s, 1H, CSNH) 1.12-2.64 (m, 11H, C5H11); 7.54-8.17 (m, 4H, H-5, H-6, H-7, H-8); 9.15 (s,1H, H-2); 11.42 (s, 1H, CONH); 13.86 (br. s, 1H, CSNH) 2.30 (s, 3H, CH3); 7.43-8.04 (m, 4H, H-5, H-6, H-7, H-8); 9.06 (s, 1H, H-2); 10.63 (s, 1H, CONH); 14.02 (br. s, 1H, CSNH) 2.19 (s, 3H, CH3); 2.48 (s, 3H, CH3); 7.73-8.02 (m, 3H, H-5, H-7, H-8); 9.09 (s, 1H, H-2); 11.45 (s, 1H, CONH); 13.61 (br. s, 1H, CSNH) 1.08-2.40 (m, 8H, CH3, C2H5); 7.68-8.04 (m, 3H, H-5, H-7, H-8); 9.10 (s, 1H, H-2); 11.46 (s, 1H, CONH); 13.64 (br. s, 1H, CSNH) 1.03-2.35 (m, 10H, CH3, C3H7); 7.58-8.05 (m, 3H, H-5, H-7, H-8); 9.11 (s, 1H, H-2); 11.50 (s, 1H, CONH); 13.64 (br. s, 1H, CSNH) 1.01-2.35 (m, 12H, CH3, C3H7); 7.49-8.03 (m, 3H, H-5, H-7, H-8); 9.11 (s, 1H, H-2); 11.56 (s, 1H, CONH); 13.62 (br. s, 1H, CSNH) 1.03-2.30 (m, 10H, CH3, C3H7); 7.51-8.09 (m, 3H, H-5, H-7, H-8); 9.13 (s, 1H, H-2); 11.49 (s, 1H, CONH); 13.65 (br. s, 1H, CSNH) 2.33 (s, 3H, CH3); 7.45-8.05 (m, 3H, H-5, H-7, H-8); 9.07 (s, 1H, H-2); 10.67 (s, 1H, CONH); 14.01 (br. s, 1H, CSNH) 2.23 (s, 3H, CH3); 7.70-8.35 (m, 3H, H-5, H-7, H-8); 9.13 (s, 1H, H-2); 11.33 (s, 1H, CONH); 13.63 (br. s, 1H, CSNH) 0.96-2.67 (m, 5H, C2H5); 7.75-8.30 (m, 3H, H-5, H-7, H-8); 9.17 (s, 1H, H-2); 11.34 (s, 1H, CONH); 13.62 (br. s, 1H, CSNH) 0.99-2.68 (m, 7H, C3H7); 7.73-8.31 (m, 3H, H-5, H-7, H-8); 9.15 (s, 1H, H-2); 11.30 (s, 1H, CONH); 13.66 (br. s, 1H, CSNH) 0.98-2.66 (m, 9H, C4H9); 7.75-8.30 (m, 3H, H-5, H-7, H-8); 9.19 (s, 1H, H-2); 11.31 (s, 1H, CONH); 13.64 (br. s, 1H, CSNH) 0.95-2.63 (m, 11H, C5H11); 7.75-8.30 (m, 3H, H-5, H-7, H-8); 9.17 (s, 1H, H-2); 11.34 (s, 1H, CONH); 13.62 (br. s, 1H, CSNH)
13
14
15
16
17
18
19
20
21
638
TABLE 2 (continued)
1 22 2 1701, 1622, 1311 1723, 1641, 1357 1722, 1641, 1356 1721, 1643, 1357 1721, 1647, 1355 1723, 1646, 1356 1724, 1645, 1353 3 7.57-8.29 (m, 3H, H-5, H-7, H-8); 9.14 (s, 1H, H-2); 11.36 (s, 1H, CONH); 13.69 (br. s, 1H, CSNH) 2.31 (s, 3H, CH3); 7.51-8.01 (m, 2H, H-5, H-7); 9.06 (s, 1H, H-2);11.12 (s, 1H, CONH); 13.93 (br. s, 1H, CSNH) 1.01-2.59 (m, 5H, C2H5); 7.78-8.31 (m, 2H, H-5, H-7); 9.07 (s, 1H, H-2); 11.14 (s, 1H, CONH); 13.95 (br. s, 1H, CSNH) 0.99-2.55 (m, 7H, C3H7); 7.80-8.32 (m, 2H, H-5, H-7); 9.04 (s, 1H, H-2); 11.17 (s, 1H, CONH); 13.91 (br. s, 1H, CSNH) 1.00-2.58 (m, 5H, C2H5); 7.81-8.33 (m, 2H, H-5, H-7); 9.09 (s, 1H, H-2); 11.19 (s, 1H, CONH); 13.90 (br. s, 1H, CSNH) 0.97-2.49 (m, 11H, C5H11); 7.78-8.31 (m, 2H, H-5, H-7); 9.07 (s, 1H, H-2); 11.14 (s, 1H, CONH); 13.95 (br. s, 1H, CSNH) 7.57-8.29 (m, 2H, H-5, H-7); 9.17 (s, 1H, H-2); 11.44 (s, 1H, CONH); 13.89 (br. s, 1H, CSNH) 4 459 [M+2+Na]+ (60), 457 [M+ Na]+ (62), 437 [M+2+H]+ (100), 435 [M+H]+ (100) 413 [M+4+K]+ (100), 411 [M+2+K]+ (70), 409 [M+K]+ (12), 370 [M]+ (75) 427 [M+4+K]+ (100), 425 [M+2+K]+ (68), 423 [M+K]+ (11), 384 [M+ (67) 441 [M+4+K]+ (100), 439 [M+2+K]+ (70), 437 [M+K]+ (15), 398 [M]+ (56) 455 [M+4+K]+ (100), 453 [M+2+K]+ (66), 451 [M+K]+ (13), 412 [M]+ (54) 469 [M+4+K]+ (100), 467 [M+2+K]+ (72), 465 [M+K]+ (16), 426 [M]+ (47) 467 [M+4+K]+ (100), 465 [M+2+K]+ (71), 463 [M+K]+ (18), 424 [M]+ (37)
23
24
25
26
27
28
Synthesis of 3-Formylchromones 3a-d. Phenol or substituted phenol (1 mol) was heated to melting, and an equimolar quantity of acetyl chloride was slowly added under vigorously stirring. Light heating was continued until HCl completely evolved. Then anhydrous AlCl3 (2 mol) was added in separate batches in an icewater bath. Then it was kept about 6-10 h in an oil bath (with phenol or 4-methylphenol the temperature was maintained at 120 2C; with 4-bromophenol and 2,4-dichlorophenol at 125-130C). Then the material was hydrolyzed by crushed ice. It was distilled with water vapor; the oil layer was extracted with CH2Cl2 and dried with anhydrous Na2SO4, and the solvent was removed under reduced pressure. The substituted o-hydroxyacetophenone 2 was obtained. A solution of substituted o-hydroxyacetophenon 2 (0.1 mol) in anhydrous DMF (93 ml) was placed in a flask, and freshly distilled POCl3 (0.6 mol) was added dropwise with mechanical stirring in an ice-water bath; the color of the solution changed from yellow to orange. After that, it was stirred for 12 h at room temperature. The reaction was monitored by TLC [ethyl acetatepetroleum ether (60-90C)acetic acid 50:50:3] to completion, and the mixture was decomposed by ice-water after the reaction was completed. The resulting residue was collected by filtration, washed with water, and recrystallized from ethanolwater. The 3-formyl-substituted chromones are listed below: 3-formylchromone (3a), yield 80%, Rf 0.83, mp 151-152C; 3-formyl-6-methylchromone (3b), yield 85%, Rf 0.74, mp 173-174C (lit. [7]: 174-175C); 6-bromo-3-formylchromone (3c), yield 90%, Rf 0.73, mp 189-192C; 6,8-dichloro-3formylchromone (3d), yield 82%, Rf 0.80, mp 170-171C. General Procedure for the Synthesis of 3-Carboxychromones 4a-d. A solution of 3-formylsubstituted chromone (17.2 mmol) in acetone (240 ml) was added dropwise to 8.5 ml of Jones' reagent in 30 min. The temperature should be maintained at 10-15C. The color of the solution turned into green, and the resinous precipitate was separated. The solution was poured into the other flask and concentrated by reduced pressure to 1/3 of initial volume. It was poured into water (500 ml) with stirring and allowed to stand for ~2 h. 639
The light yellow precipitate was filtered off, washed with water, then dried. The residue was recrystallized from acetone (3-carboxy-6-methylchromone was recrystallized from benzene). General Procedure for the Synthesis of 3-(3-Alkyl-5-thioxo-1H-4,5-dihydro-1,2,4-triazole-4yl)aminocarbonylchromones 5-28. Freshly distilled POCl3 (20 ml) was added with stirring to a mixture of 3-carboxychromone 4a-d (2 mmol) and compounds 1a-f (2 mmol); the reaction was monitored by TLC [ethyl acetatepetroleum ether (60-90C)acetic acid 50:50:3] to completion. It was poured into crushed ice, filtered, washed with water, dried, and recrystallized from DMFEtOH to yield compounds 5-28 (Tables 1 and 2). This work was supported by the Natural Science Foundation (29962002) and the Nankai University State Key Laboratory of Elemento-Organic Chemistry.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. N. V. Gorbulenko, S. A. Kirpa, and V. P. Khilya, Khim. Geterotsikl. Soedin., 29 (1993). Z. Y. Wang, H. X. Shi, and H. J. Shi, J. Heterocycl. Chem., 38, 355 (2001). I. Chaaban and O. O. Oji, J. Indian Chem. Soc., 61, 523 (1984). A. Omar, M. E. Mohsen, and O. M. Aboulwafa (A.-Mohsen M. E. Omar, Omaiama M. Aboulwafa), J. Heterocycl. Chem., 21, 1415 (1984). K. S. Dhaka, J. Mohani, V. K. Chadha, and H. K. Pujari, Indian J. Chem., 12, 287 (1974). A. Nohara, T. Umetani, K. Ukawa, and Y. Sanno, Chem. Pharm. Bull., 22, 2959 (1974). A. Nohara, T. Umetani, and Y. Sanno, Tetraherdron Lett., 1995 (1973). A. Nohara, H. Kuriki, T. Saijo, H. Sugihara, M. Kanno, and Y. Sanno, J. Med. Chem., 20, 141 (1977). P. Khilya, S. V. Kobalev, N. S. Miroshnichenko, and A. V. Turov, Chem. Nat. Compd., 34, 32 (1998).
640
OXIDATIVE REACTIONS OF AZINES. 11*. THE INFLUENCE OF MANGANESE DIOXIDE ON THE REACTION OF TETRAHYDROPYRIDINES WITH FORMALDEHYDE: SYNTHESIS AND MOLECULAR STRUCTURES OF 3-OXA-7-AZABICYCLO[3.3.1]AND 6-OXA-2-AZABICYCLO[3.2.1]OCTANES
A. T. Soldatenkov1, K. B. Polyanskii1, A. V. Temesgen1, N. D. Sergeeva1, V. V. Vysotskaya1, B. B. Averkiev2, M. Yu. Antipin2, and N. N. Lobanov1 New derivatives of piperidino[4,5-d]dioxane and 3-oxa-7-bicyclo[3.3.1]nonane were obtained by the oxidatively catalysed condensation of 4-aryl-1,2,3,6-tetrahydropyridines with formaldehyde. The direction of this reaction is sharply altered in the presence of manganese dioxide to give 6-oxa-2azabicylo[3.2.1]octan-4-one the product of the oxidative condensation of a new type. Keywords: manganese dioxide, oxabicycloalkanes, tetrahydropyridines, formaldehyde, Prins reaction. As the result of oxidatively catalysed condensation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (1a) with formaldehyde (the Prins reaction) with a small excess of the latter 3-hydroxymethyl-1-methyl-6phenyltetrahydropyridine is formed [2], while with a ten-fold excess the product is a substituted piperidino[4,5d]dioxane 2 [3]. There have been no reports so far on the influence of oxidants on the Prins reaction. In a continuation of our studies to discover new reactions of hydropyridines initiated by manganese compounds with different oxidation states [4-6] we have studied in this work the condensation of 4-aryl-substituted 1-methyl-1,2,3,6tetrahydropyridines 1a,b with formaldehyde under conditions of the modified Prins reaction (in the presence of manganese dioxide. In the first place, to study the composition of the reaction mixture formed in the classical Prins reaction in greater detail, we carried out the condensation of tetrahydropyridine 1 with a four-fold excess of formaldehyde which has been described previously [3]. By the use of crystallization and chromatography we succeeded in isolating from the reaction mixture not only the known 1,3-dioxane 3, but also a series of new condensation products: 8-hydroxymethyl derivatives of the piperidinodioxane 3 and also cis- and trans-9-hydroxy-7-methyl-9-phenyl-3-oxa-7-azabicyclo[3.3.1]nonanes (4), which are isomers with respect to the _______ * Paper 10, see [1]. __________________________________________________________________________________________ Russian People's Friendship University, Moscow 117198; e-mail: asoldatenkov@sci.pfu.edu.ru. 2 A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Moscow 117813. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 755-764, May 2004. Original article submitted April 13, 2001. 0009-3122/04/4005-06412004 Plenum Publishing Corporation 641
1
position of the 9-hydroxy groups relative to the nitrogen atom. In the 1H NMR spectra of compounds 2 and 3 the protons in position 4 take the form of a broad doublet (at 3.5-3.6 ppm) with geminal coupling of 1.5 Hz and a doublet of doublets (at 3.6-3.8 ppm) with a vicinal coupling of 2.5-2. Hz which indicates the stereoselectivity of the cis-coupling of the heterocyclic fragments [3].
Ph CH2O N Me 1a HO
9
Ph O Me N 2 Ph O
HO
Ph
+
Me
7 6
O N
5
O3 3 Ph
4
OH
+
N Me
7
5 1
4 2
+
3
N Me trans-4
cis-4
The individual isomers were isolated by crystallization from the mixture of cis- and transbicyclononanes 4 (2:1 according to the 1H NMR spectrum). They were identified on the basis of the magnetoanisotropic influence of the phenyl substituent on the chemical shifts of the protons of the methylene group. Thus in the cis isomer of 4 the protons on the C(2) and C(4) atoms of the tetrahydropyran ring fall within the region of shielding and their signals occur at 3.64 and 2.75 ppm. In the trans isomer of 4 the analogous signals appear at weaker field at 4.02 and 4.54 ppm respectively. Similarly the protons in trans-4 at positions 6 and 8 (the piperidine ring) are screened and their signals occur at 2.42 and 3.0 ppm, whereas the analogous signals for cis-4 occur at 2.84 and 3.25 ppm. In CDCl3 solution, according to the 1H NMR spectrum, the piperidine ring of cis-4 has the boat conformation, fixed by an intramolecular hydrogen bond. In order to refine the spatial structure of the isomers under discussion the X-ray structure of the cis isomer of 4 was determined. The overall structure of the molecule is shown in Fig. 1, the atomic coordinates are given in Tables 1 and 2, and the bond lengths and bond angles in Table 3. The basic geometric parameters of the molecule are normal [7]. The piperidine and tetrahydropyran rings have the chair conformation. The hydroxy group forms an intermolecular hydrogen bond OHN with the nitrogen atom of neighboring molecules, forming a chain along the c axis (Fig. 2). The parameters of the hydrogen bond are O(11)N(1) 2.869(1), H(11)N(1) 2.06(2) A, and the angle O(11)H(11)N(1) 150(1). The hydroxy group is positioned axially to the piperidine ring, while the phenyl group is equatorial ( the deviation of atoms O(11) and C(12) from the mean squared plane of the ring is 1.731(1) and 0.057(1) respectively). The situation is reversed with respect to the tetrahydropyran ring: the OH group takes an equatorial position , while the phenyl group is axial ( the respective deviations of O(11) and C(12) are -0.221(2) and 1.830(2) ). The angle of rotation of the phenyl ring relative to the piperidine ring is 13.55(7) and relative to the tetrahydropyran ring is 81.83(5), while the torsion angle C(4)C(5)C(12)C(13) is 45.1(1).
642
Fig. 1. General view of the molecule of the cis isomer of 4.
Fig. 2. Formation of a chain of molecules of the cis isomer of 4 in the crystal.
643
TABLE 1. Coordinates of the Non-hydrogen Atoms (104) and Equivalent Isotropic Thermal Parameters Ueq (103) in the Structure of the cis Isomer of 4
Atom N(1) C(2) C(3) C(4) C(5) C(6) C(7) C(8) O(9) C(10) O(11) C(12) C(13) C(14) C(15) C(16) C(17) x 6633(1) 6035(1) 7526(1) 8099(1) 7154(1) 6384(1) 5787(1) 7123(1) 8111(1) 8810(1) 6413(1) 7677(1) 8612(1) 9053(1) 8579(2) 7648(2) 7196(1) y 3638(1) 4963(1) 3743(1) 2362(1) 1316(1) 1154(1) 2536(1) 621(1) 1464(1) 1758(2) 1883(1) -27(1) 49(2) -1129(2) -2401(2) -2495(2) -1317(1) z 3753(1) 3499(1) 4861(1) 5277(1) 5478(1) 4220(1) 3833(1) 3333(1) 3255(1) 4401(1) 6227(1) 6068(1) 7049(1) 7674(2) 7335(2) 6383(2) 5753(1) Ueq, 2 36(1) 53(1) 41(1) 37(1) 32(1) 35(1) 38(1) 45(1) 48(1) 48(1) 40(1) 39(1) 51(1) 69(1) 76(1) 74(1) 55(1)
When the condensation of the tetrahydropyridines 1a,b with formaldehyde analogous to that described above but in the presence of manganese dioxide was carried out quite different products were obtained the structures of which did not correspond to any of the possible products of the classical Prins reaction (see [2, 3, TABLE 2. Coordinates of the Hydrogen Atoms (104) and Equivalent Isotropic Thermal Parameters Ueq (103) in the Structure of the cis Isomer of 4
Atom H(2C) H(2B) H(2A) H(3B) H(3A) H(4) H(6) H(7B) H(7A) H(8B) H(8A) H(10B) H(10A) H(11) H(13) H(14) H(15) H(16) H(17) x 5457(14) 6609(16) 5604(14) 8126(13) 7190(11) 8634(11) 5737(11) 5262(11) 5253(12) 7391(12) 6636(12) 9368(14) 9207(12) 6752(13) 8948(13) 9673(18) 8855(17) 7326(16) 6550(15) y 4870(17) 5740(20) 5211(17) 4412(16) 4151(15) 2545(14) 499(14) 2780(13) 2484(13) -292(17) 656(16) 2437(17) 953(16) 1750(17) 928(18) -988(21) -3203(22) -3361(24) -1450(18) z 2706(16) 3424(16) 4155(16) 4702(13) 5562(12) 6038(12) 4234(11) 4389(11) 3022(12) 3560(13) 2492(14) 4280(14) 4741(12) 6988(14) 7287(14) 8329(20) 7729(18) 6128(17) 5071(16) Ueq 2 66(5) 78(5) 72(5) 53(4) 44(3) 44(3) 40(3) 40(3) 44(3) 52(4) 55(4) 60(4) 49(4) 60(4) 62(4) 94(6) 92(6) 91(6) 72(5)
644
TABLE 3. Bond Lengths (d) in The Compound cis-4

Bond N(1)C(2) N(1)C(7) N(1)C(3) C(3)C(4) C(4)C(10) C(4)C(5) C(5)O(11) d, 1.460(2) 1.464(2) 1.468(1) 1.526(2) 1.524(2) 1.542(2) 1.429(1) Bond C(5)C(12) C(5)C(6) C(6)C(8) C(6)C(7) C(8)O(9) O(9)C(10) C(12)C(17) d, 1.532(2) 1.536(1) 1.531(2) 1.531(2) 1.424(2) 1.421(2) 1.387(2) Bond C(12)C(13) C(13)C(14) C(14)C(15) C(15)C(16) C(16)C(17) d, 1.397(2) 1.386(2) 1.373(3) 1.374(3) 1.393(2)
8] and this paper). For example, after standard treatment of the reaction mixture by chromatography compounds 5a,b were isolated which, according to 1H and 13C NMR, had the structure of 6-oxa-2-azabicyclo[3.2.1]octan-4ones, which indicates the unexpected addition of formaldehyde to one of the -positions of the piperidine ring (for a preliminary report see [9]).
Ar N 6a,b MnO2 N Me 1a,b a Ar = Ph; b Ar = p- MeC6H4 Ar H +, CH2O MnO2
6 7
Ar
5
O
8
O
4 3
N2 1 Me 5a,b
The structures of compounds 5a and 5b were established on the basis of the complete assignment of the signals in the 1H and 13C NMR spectra using H,H COSY, C,H COSY and 13C DEPT. In the 1H NMR spectra of both compounds signals of two methylene groups attached to heteroatoms appear at weak field (protons at position 3 at 4.10-4.42 ppm and at position 7 at 3.73-4.23 ppm). The signals of protons at C(8), bonded only to carbon are found at stronger field (2.98-3.16 ppm). The chemical shift of the methyne proton (at 4.00-4.07 ppm)
TABLE 4. Bond Angles () in Compound cis-4

Angle C(2)N(1)C(7) C(2)N(1)C(3) C(7)N(1)C(3) N(1)C(3)C(4) C(10)C(4)C(3) C(10)C(4)C(5) C(3)C(4)C(5) O(11)C(5)C(12) O(11)C(5)C(6) C(12)C(5)C(6) O(11)C(5)C(4) C(12)C(5)C(4) C(6)C(5)C(4) C(8)C(6)C(7) , deg. 110.76(10) 109.65(10) 111.56(8) 113.33(9) 113.16(10) 109.51(10) 109.95(9) 107.47(8) 106.40(8) 115.32(9) 111.24(9) 112.87(9) 103.40(8) 112.70(9) Angle C(8)C(6)C(5) C(7)C(6)C(5) N(1)C(7)C(6) O(9)C(8)C(6) C(10)O(9)C(8) O(9)C(10)C(4) C(17)C(12)C(13) C(17)C(12)C(5) C(13)C(12)C(5) C(14)C(13)C(12) C(15)C(14)C(13) C(14)C(15)C(16) C(15)C(16)C(17) C(12)C(17)C(16) , deg. 110.22(9) 108.99(9) 112.53(9) 114.06(10) 112.39(9) 112.82(9) 117.64(12) 123.13(11) 118.92(11) 121.05(15) 120.5(2) 119.34(14) 120.6(2) 120.9(2)
645
indicates that the CH group is bonded to a nitrogen atom. The presence of similar groups bonded in the OCH2 CHCH2 system is also confirmed by the 13C NMR spectrum of compound 5b (see experimental section). In this spectrum there are also signals assigned to the C=O group (at 200.0 ppm) and of a quaternary aliphatic carbon atom, the chemical shift of which (at 129.7 ppm) confirms the presence of the grouping OCquatC=O. These results indicate the addition of one molecule of formaldehyde at the -position of the piperidine ring with subsequent cyclization of the hydroxymethyl group at the -position (with formation of the tetrahydrofuran unit) and oxidation to structures 5a,b. Analysis of the parameters of the 1H and 13C NMR spectra, Dreiding models, and calculation of the energies of the conformers by molecular mechanics methods, showed that there is some preference for a compressed boat conformation for the piperidine, cis-1,3-diaxially coupled to the tetrahydropyran ring, which has a firmly fixed envelope conformation. The key stage in the probable route to the formation of compounds 5a,b is evidently the oxidative dehydrogenation of the initial tetrahydropyridines, the products of which can then be attacked by formaldehyde. An indirect confirmation of such a dehydration was obtained by separate experiments on the aromatization of substrates 1a,b by boiling their solutions in toluene in the presence of manganese dioxide. Evidently the arylpyridines 6a,b (isolated in 42-45% yield) should be formed via dihydropyridine intermediates. The results discussed permit the suggestion of the following sequence for the formation of the bicyclooctanes 5a,b in the oxidative condensation of tetrahydropyridines with formaldehyde:
Ar 1a,b [O] N Me I HO +
Ar
Ar + HO N Me III
N Me II
Ar O N Me IV + + H2O + H O
Ar OH N Me V [O] 5a,b
The dihydropyridines I, formed in the initial (oxidative) stage, add a protonated formaldehyde at the -position, which leads to the carbocation II, stabilized by form III. An intramolecular cycloaddition then follows to give the bicyclic cation IV which is hydroxylated to the alcohol V by the addition of a molecule of water. The final stage is the oxidation of the alcohols V to the ketones 5a,b (the conversion of alcohols to ketones is well documented [10]). Thus it is established using piperidines as an example that the direction of the Prins reaction can be controlled by manganese dioxide to give the unusual oxidative condensation of tetrahydropyridines with formaldehyde with "one-step" formation of a new group of 6-oxa-2-azabicyclo[3.2.1]octan-4-ones. We note that the structure of the end products in the method we have developed differs principally from the structure of the products of the Prins reaction in the formation of a tetrahydrofuan ring and a -piperidine unit.
646
EXPERIMENTAL IR spectra were recorded on a UR-20 instrument. Mass spectra were obtained with an MX-1303 machine. NMR spectra of CDCl3 solutions with TMS as internal standard were recorded with Bruker W-80, Bruker WM-250, and DPX-500 spectrometers (80, 250, and 500 MHz respectively). The course of reactions and the purity of individual compounds were monitored by TLC on Silufol UV-254 strips with development by iodine vapor. Separation and purification of compounds was carried out by column chromatography on silicagel L-60 (40/100). X-ray Crystallographic Analysis of Compound cis-4. Crystals of the bicyclononane cis-4, with composition C14H19NO2, grown from ether, were monoclinic and had the following crystallographic parameters: P21/c, a = 11.599(3), b = 9.681(3), c = 11.324(3) ; = 101.18(2); V = 1248.4(6) 3; Z = 4; dcalc = 1.241 g/cm3; M = 233.3. The parameters of the unit cell and the intensities of 2869 reflexions were measured on a Siemens P3/PC automatic four-circle diffractometer (T = 20C, MoK radiation, graphite monochromator, /2 scanning, max = 27). The structure was solved by direct methods and refined by full matrix least squares analysis in the anisotropic approximation for non-hydrogen atoms. The hydrogen atoms were localized in difference Fourier maps and refined isotropically. The final residual factors were R1 = 0.0402 from 2217 independent reflexions with I > 2 and wR2 = 0.1262 with all 2731 reflexions. All calculations were carried out using the SHELXTL PLUS (PC version 5.0) family of programs [11].The numbering of the atoms is shown in Fig. 1. Condensation of 4-Phenyltetrahydropyridine 1a with Formaldehyde (the Prins Peaction). A mixture of tetrahydropyridine 1a (3 g, 17.3 mmol) and formaldehyde (as paraformaldehyde) (2 g, 67 mmol) in 60% sulfuric acid (10.5 ml) was boiled for 7 h and then stood at room temperature for 18 h. The reaction mixture was diluted with water (10 ml), 20% potassium hydroxide solution was added to a pH of 10, and the mixture was then extracted with benzene (3 20 ml). The extract was washed with water and dried over magnesium sulfate. The solvent was removed in vacuum and the reside was dissolved in ether. The precipitate which separated on cooling the ether solution was washed with ether and dried to give 9-hydroxy-7-methyl-9-phenyl-3-oxa-7azabicyclo[3.3.1]nonane (4) (0.85 g, 21%) (as a 2:1 mixture of the cis- and trans-isomers according to the NMR spectrum) as a coarse white powder (mp ~160C), containing some clear monocrystals of the cis-isomer, mp 176C (from crystallographic data and the NMR spectrum). The cis-isomer was also isolated by crystallization from methylene chloride in a yield of 8% (0.32 g). Rf 0.40 (acetone). IR spectrum (KBr), , cm-1: 3220, 3100 br. (OH). 1H NMR spectrum, , ppm (J, Hz): 2.38 (3H, s, CH3); 2.68 (2H, m, H-1 and H-5); 2.84 (2H, dd, 2J = 11.1, 3 J = 2.5, H-6 and H-8); 3.25 (2H, dd, 2J = 11.1, 3J =7.3, H-6 and H-8); 3.64 (2H, d, 2J = 11.4, H-2 and H-4); 3.75 (2H, d, 2J = 11.4, H-2 and H-4); 7.30-7.50 (5H, m, Ph). 13C NMR spectrum, , ppm: 37.9 (C(1) and C(5)), 45.11 (CH3), 55.9 (C(6) and C(8)), 69.8 (C(2) and C(4)), 71.8 (C(9)), 126.1, 127.8, 128.9, and 141.6 (C(Ph)). Mass spectrum, m/z (Irel, %): 233 (M+ (100), 232 (38), 216 (27), 190 (20), 184 (8), 170 (10), 133 (34), 128 (35), 105 (38), 91 (15), 77 (16). Found, %: C 72.20; H 8.23; N 5.91. C14H19NO2. Calculated, %: C 72.10; H 8.16; N 6.01. The mother liquor, after removing the cis isomer of 4, was evaporated, and the residue was crystallized from ether to give the trans-isomer of 4 (0.12 g, 3%); mp 180C. Rf 0.42 (acetone). IR spectrum (KBr, , cm-1): 3410 and 3220 br. (OH). Mass spectrum, m/z (Irel, %): 233 [M+] (100). 1H NMR spectrum, , ppm (J, Hz): 2.12 (3H, s, CH3); 2.37 (2H, m, H-1 and H-5); 2.42 (2H, d, 2J =11.4, H-6 and H-8); 3.00 (2H, d, 2J =11.4, H-6 and H-8); 4.02 (2H, dd, 2J = 10.9, 3J = 2.3, H-2 and H-4); 4.54 (2H, dd, 2J = 10.9, 3J = 2.3, H-2 and H-4); 7.30-7.50 (5H, m, C6H5). 13C NMR spectrum, , ppm: 38.3 (C(1) and C(5)), 46.5 (CH3), 58.3 (C(6) and C(8)), 67.4 (C(2) and C(4)), 71.3 (C(9)), 125.4, 128.0, 129.1, 142.4 (C(Ph)). Found, %: C 71.92; H 8.27; N 5.85. C14H19NO2. Calculated, %: C 72.10; H 8.27; N 6.01.
647
The ether mother liquor after separation of the crystalline mixture of the cis- and trans-isomers of 4 was evaporated to give an amber yellow sticky oil (2.0 g) which was separated by chromatography on a silica gel column (d = 3, h =17 cm, eluant acetone) to give consecutively product 3 (0.28 g, 6%) and product 2 (0.6 g, 15%). 8-Hydroxymethyl-6-methyl-8a-phenylpiperidino[4,5-d]dioxane (3), colorless crystals; mp 88-90C, Rf 0.84 (acetone). IR spectrum (KBr, , cm-1): 3210 (OH). Mass spectrum, m/z (Irel, %): 263 [M+]. 1H NMR spectrum, , ppm (J, Hz): 1.57 (1H, br. s, H-8); 2.34 (3H, s, CH3); 2.83-3.05 (6H, m, H2-5,5, H2-7,7, and CH2OH); 3.53 (1H, br. d, 2J = 11.6, H2-4); 3.61 (1H, dd, 2J = 11.6, 3J = 2.6, H-4); 3.90 (1H, m, H-8a); 4.75 and 4.83 (2H, two d, 2J = 6.1, H2-2,2); 7.28-7.50 (5H, m, C6H5). 13C NMR spectrum, , ppm: 35.1 (C(8)), 46.1 (CH3), 47.1 (C(4a)). 55.2 (C(5)), 57.2 (C(7)), 65.8 (C-OH), 66.2 (C(4)), 77.7 (Cquat)-O), 89.4 (C(2)), 126.5, 127.5, 128.4, 129.3, and 140.7 (C(Ph)). Found, %: 68.21; H 8.16; N 5.28. C15H21NO3. Calculated, %: C 68.44; H 7.99; N 5.32. 6-Methyl-8a-phenylpiperidino[4,5-d]dioxane (2); mp 60-62C (in [3] the mp of the hydrochloride only is given, 323C (dec.)), Rf 0.76 (acetone). Mass spectrum, m/z (Irel, %): 233 [M+] (7), 174 (38), 128 (5), 105 (11), 77 (12), 57 (13), 44 (100). 1H NMR spectrum, , ppm (J, Hz): 1.80 (2H, m, H2-8,8); 2.37 (3H, s CH3); 2.50-3.20 (5H, m, H2-5,5 and H2-7,7 and H-4a); 3.60 (1H, br. d, 2J = 11.5, H2-4,4); 3.80 (1H, dd, 2J = 11.5, 3J = 2.5, H-4); 4.77 and 4.83 (2H, two d, 2J = 6.5, H2-2,2); 7.30 (5H, m, Ph). Oxidative Condensation of the Tetrahydropyridines 1a,b with Formaldehyde in the Presence of MnO2 (Modified Prins Reaction). A mixture of 4-aryltetrahydropyridine 1a,b (10 mmol), manganese dioxide (5 g, 50 mmol), formaldehyde (as a 37% aqueous solution) (3 ml, 30 mmol), and conc. H2SO4 (3 ml) was boliled for 7 h. 20% Sodium hydroxide was added to the cold reaction mass to pH 9, and the mixture was extracted with benzene. The solvent was evaporated in vacuum and the residue was chromatographed on a silica column with acetone as eluant. Product 5a (0.84 g, 31%) was obtained from phenyltetrahydropyridine and product 5b (1.0 g, 35%) was obtained from 4-tolyltetrahydropyridine. 2-Methyl-5-phenyl-6-oxa-2-azabicyclo[3.2.1]octan-4-one (5a). A thick, colorless oil, Rf 0.7 (acetone). IR spectrum (nujol mull), , cm-1: 1680 (C=O). 1H NMR spectrum, , ppm (J, Hz): 2.51 (3H, s, CH3); 3.00 (1H, t, 2J = 12.6, Ha-8); 3.16 (1H, br. d, 2J = 12.6, He-8); 3.73 (1H, t, 2J = 10.7, Ha-7); 4.00 (1H, m, He-1); 4.12 (1H, d, 2 J = 9.5, Ha-3); 4.23 (1H, br. d, 2J = 10.7, He-7); 4.42 (1H, br. d, 2J =9.5, He-3); 7.30-7.50 (5H, m, C6H5). Mass spectrum, m/z (Irel, %): 217 [M+] (16), 202 (43), 187 (15), 131 (12), 105 (100), 77 (37). Found, %: C 71.7; H 7.03; N 6.52. C13H15NO2. Calculated, %: C 71.89; H 6.91; N 6.45. 2-Methyl-5-(4-tolyl)-6-oxa-2-azabicyclo[3.2.1]octan-4-one (5b). A thick, colorless oil, Rf 0.7 (acetone). IR spectrum (nujol mull), , cm-1: 1675 (C=O). Mass spectrum, m/z (Irel, %): 231 [ M+] (7), 216 (36), 203 (6), 188 (28), 172 (34), 160 (38), 145 (12), 119 (100), 91 (45). 1H NMR spectrum, , ppm (J, Hz): 2.39 (3H, s, CH3); 2.51 (3H, s, CH3); 2.98 (1H, t, 2J = 12.9, Ha-8); 3.16 (1H, br. d, 2J =12.9, Ha-8); 3.76 (1H, t, 2J =10.9, Ha-7); 4.07 (1H, m, He-1); 4.10 (1H, d, 2J = 9.4, Ha-3); 4.20 (1H, br. d, 2J = 10.9, He-7); 4.40 (1H, br. d, 2J = 9.4, He-3); 7.27 and 7.86 (4H, AX'BX' system, 3J = 7.2, 4J = 1.1, Ar). 13C NMR spectrum, , ppm: 22.6 (CH3 in Ar), 40.3 (C(1)), 40.8 (N-CH3), 55.8 (C(8)), 70.2 (C(7)), 86.7 (C(3)), 129.7 (C(5)), 129.3, 130.5, 144.3, 145.4 (Carom). Found, %: C 73.01; H 7.49; N 5.90. C14H17NO2. Calculated, %: C 72.72; H 7.36; N 6.06. Oxidative Aromatization of the Tetrahydropyridines 1a,b. A mixture of 4-phenyltetrahydropyridine 1a (0.5 g, 2.9 mmol) and manganese dioxide (2.5 g, 29 mmol) in toluene (100 ml) was boiled for 3 h. The manganese dioxide was filtered off and washed on the filter with chloroform (50 ml). The combined filtrates were evaporated in vacuum and the residue was separated by column chromatography on silicagel with 1:1 ether: hexane as eluant to give 4-phenylpyridine, 6a, (0.2 g, 45%), Rf = 0.5 (ether); mp 76-78C [12]. The mass spectrum and 1H NMR spectra were identical to those cited in [5]. Analogously from the tetrahydropyridine 1b (0.5 g, 2.7 mmol) 4-(p-tolyl)pyridine 6b was obtained (0.19 g, 42%), Rf 0.5 (ether); mp 43-45C. 1 H NMR spectrum, , ppm, (J, Hz): 2.40 (3H, s, Me); 7.25 and 7.50 (4H, AA'XX' system, 3J =7.1, 4 J = 1.1, Ar); 7.61 and 8.63 (AA'BB' system, 3J =7.1, 4J = 1.1, Hhet). Mass spectrum, m/z (Irel, %): 169 [M+] (100), 168 (43), 155 (95), 91 (20). Found, %: C 84.98; H 6.67; N 8.01. C12H11N. Calculated, %: 85.21; H 6.51; N 8.28. 648
We thank the Russian Fund for Fundamental Research for financial support of this work (grants nos. 9903-32940a and 00-15-97359).
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. A. T. Soldatenkov, A. V. Temesgen, K. B. Polyanskii, S. A. Soldatova, N. M. Kolyadina, N. I. Golovtsov, and N. D. Sergeeva, Khim. Geterotsikl. Soed., 552 (2003). C. J. Schmidle and R.C. Mansfield, US Pat. 2748140; Chem. Abstr., 51, 2880 (1957). A. F. Casy, A. V. Simmonds, and D. Staniforth, J. Org. Chem., 37, 3189 (1972). A. T. Soldatenkov, A. W. Temesgen, I. A. Bekro, T. P. Khristoforova, S. A. Soldatova, and B. N. Anissimov, Mendeleev Commun., 243 (1997). A. T. Soldatenkov, A. W. Temesgen, L. N. Kuleshova, and V. N. Khrustalev, Mendeleev Commun., 193 (1998). A. T. Soldatenkov, A. W. Temesgen, I. A. Bekro, S. A. Soldatova, and B. N. Anissimov, Mendeleev Commun.,137 (1998). F. H. Allen and O. Kennard, Chem. Des. Autom. News, 31 (1993). A. F. Casy and F. Ogungbamila, Heterocycles, 16, 1913 (1981). A. T. Soldatenkov, K. B. Polyanskii, A. W. Temesgen, S. A. Soldatova, N. D. Sergeeva, N. D. Kolyadina, and N. N. Lobanov, Mendeleev Commun., 27 (2001). S. P. Korshunov and L. I. Vereshchagin, Uspekhi Khimii,35, 2255 (1966). L. M. Sheldrick, SHELXTL, Version 5. Software Reference Manual. Siemens Industrial Automation, Inc. Madison (1994). A. E. Chichibabin and D. I. Rochko, Zh. RFKhO, 62, 1201 (1930).
649
A NEW ROUTE TO PARTIALLY HYDROGENATED THIAZOLO[3,2-a]PYRIDINE

A. D. Dyachenko1, S. M. Desenko2, V. D. Dyachenko1, and A. N. Chernega3 Partially hydrogenated thiazolo[3,2-a]pyridines have been synthesized by the interaction of functionally substituted ammonium di- and tetrahydropyridine-2-thiolates with bromocyclohexanone. The structure of 6,8-dicyano-3-hydroxy-5-oxo-1,3-tetramethylene-2,3,4,5,6,7-hexahydrospiro[thiazolo[3,2-a]pyridine-7,1'-(4'-methylcyclohexane)] has been determined by X-ray crystallography. Keywords: 2-bromocyclohexanone, ammonium pyridin-2-thiolates, thiazolo[3,2-a]pyridines, alkylation, dehydration, dehydrogenation, X-ray crystallography, cyclization. Partially hydrogenated thiazolo[3,2-a]pyridines are a known class of biologically active compounds [1]. They are obtained by the condensation of acyclic 1,5-dicarbonyl compounds with -amino--mercaptopropionic acid [2, 3] and by building on the thiazole ring to pyridin-2-thione. The latter is based on the following method: interaction of 1,4-dihydropyridine-2-thiolates with 1,2-dibromoethane [4] and also by the intramolecular condensation of 2-carbamoylmethylthio-1,4-dihydropyridines [5], 2-allylthiopyridines [6], and 2-cyclohex-2enylthiopyridines [7]. We have proposed a method for the synthesis of 6,8-dicyano-3-hydroxy-5-oxo(amino)-2,3tetramethylene-2,3,4,5,6,7-hexahydrospiro[thiazolo[3,2-a]pyridine-7,1'-(4'-R-cyclohexanones)] 1a, 1b and 2 by alkylating the corresponding salts 3a, 3b, and 4 with 2-bromocyclohexanone. The first step in the reaction is the alkylation of the anions of salts 3a, 3b, and 4 at the sulfur atom with the formation of the sulfide 5. Evidently stereospecific nucleophilic attack by the unshared pair of electrons of the nitrogen atom at the carbonyl carbon then occurs with formation of the partially hydrogenated thiazolopyridines 1a, 1b, and 2:
R Br NC O N H CN S H N 3a,b O O NC O Me N H O 5 1, 3 a R = Me; b R = H CN S NC O HO 1 a,b N CN S R R
__________________________________________________________________________________________ Taras Schevchenko Lugansk State Pedagogical University, Lugansk 91011, Ukraine; e-mail: dvd_lug@online.lg.ua. 2 V. N. Karazin Kharkov State University, Kharkov 61070, Ukraine. b Institute of Organic Chemistry, Ukraine National Academy of Sciences, Kiev 02094, Ukraine; e-mail: iochkiev@ukrpack.net. Translated from Khimiya Geterotsiklicheskikh Soedinenii, pp. 765-775, May, 2004. Original article submitted June 13, 2001; revision submitted February 14, 2002. 650 0009-3122/04/4005-06502004 Plenum Publishing Corporation
1
Br NC H2N N H CN S H N O 4 2 Me O NC H2N HO N CN S
When compound 1b is boiled in ethanol in the presence of conc. H2SO4 water is eliminated to give 6,8-dicyano-5-oxo-2,3-tetramethylene-4,5,6,7-tetrahydrospiro[thiazolo[3,2-a]pyridine-7-cyclohexane] (6) (method A). The same product was obtained when acetic anhydride was used as the dehydrating agent (method B). Using as an example the reaction of compound 1b with -bromoacetophenone in DMF in the presence of KOH it was shown that regioselective alkylation of the partially thiazolopyridines at C(6) was possible to give compound 7, with a structure corresponding to that of the initial heterocycle.
NC O N
CN S
H2SO4 (method A) or Ac2O (method B) 1b
O BrCH2COPh Ph CN NC O HO N S
Alkylation of morpholinium 4-methyl-6-oxo-1,6-dihydropyridine-2-thiolate (8) with 2-bromocyclohexanone also gave a compound containing an OH group, 8-cyano-3-hydroxy-7-methyl-5-oxo2,3-tetramethylene-2,3,4,5-tetrahydrothiazolo[3,2-a]pyridine (9).
Me CN O O N H S H N 8 O 9 H O HO N Br Me CN S
At the same time alkylation under the same conditions of 3-cyano-6-methyl-5-phenylcarbamoyl-4spirocyclohexane-1,4-dihydropyridin-2-thiol (10) with 2-bromocyclohexanone gave the dehydration product of the initial cyclization 11.
651
Br O PhHN Me N H 10 11 CN SH O PhHN Me N O CN S
It should also be noted that alkylation of the aryl-substituted 1,4-dihydropyridinethiolates 12 with 2-bromocyclohexanone led to aromatization, probably caused by aerial oxygen, to give 4-aryl-substituted 2-(2-oxocyclohexylthio)pyridines 13.
Br O PhHN Me 12a,b O
12, 13 a R = 2-thienyl; b R = 4-pyridyl
R CN N H S O PhHN
R CN
H N
Me
Me
S O
13a,b
2-Mercaptopyridines 14a-c react with 2-bromocyclohexanone in basic media to give the sulfides 15a-c only.
Br R NC CN N SH O NC R CN N S O 14ac 15ac
14, 15 a R = 4-HOC6H4; b R = 2-furyl; c R = Me2CHC6H4
H2N
H2N
The physicochemical and spectroscopic characteristics confirmed the structures of the synthesized compounds. A peculiarity of the 1H NMR spectra (DMSO-d6) of the partially hydrogenated thiazolopyridines 1a and 1b is the presence of paired equally intense signals for the SCH-, HO- and C(6)H protons which is evidently explained by the presence of equal amounts of two diastereomers in solution (Table 2). However in the 1H NMR spectrum of compound 1b in CDCl3 the doubled signals are not observed. This fact requires additional study which will be forthcoming shortly. The molecular and crystal structures of 6,8-dicyano-3-hydroxy-5-oxo-2,3-tetramethylene-2,3,4,5,6,7hexahydrospiro[thiazolo[3,2-a]pyridin-7,1'-(4'-methylcyclohexane)] 1a were determined by X-ray crystallography (Fig. 1 and Table 3). Both the six-membered heterocycle N(1)C(1-5) and the five-membered heterocycle S(1)C(1)N(1)C(14)C(15) are considerably non-planar, the displacement of atoms from the least squared plane reached 652
Fig. 1. General view of the molecule (1a) with numbering of the atoms (the only hydrogen atom numbered is H(1). 0.33 and 0.24 respectively. The interfacial angle between the rings is 13.4. The five-membered heterocycle has an envelope conformation: atoms S(1), C(1), N(1), and C(14) are coplanar within limits of 0.05 , while atom C(15) is 0.06 out of the plane. The interfacial angle between the planes S(1)C(1)N(1)C(14) and S(1)C(14)C(15) is 36.6. TABLE 1. Characteristics of the Compounds Synthesized
Found, % Calculated, % 6.30 6.48 5.92 6.16 6.35 6.48 5.72 5.88 5.81 5.90 5.17 5.38 6.47 6.52 4.57 4.73 4.86 5.01 4.51 4.43 3.98 4.17 5.51 5.68
Compound 1a 1b 2 6 7 9 11 13a 13b 15a 15b 15c
Empirical formula C19H23N3O2S C18H21N3O2S C18H22N4OS C18H19N3OS C26H27N3O3S C13H14N2O2S C25H27N3OS C24H21N3O2S2 C25H22N4O2S C19H16N4O2S C17H14N4O2S C22H22N4OS
mp, * N 11.93 11.76 12.41 12.23 16.41 16.36 13.04 12.91 8.96 9.10 10.59 10.68 9.89 10.06 9.43 9.39 12.73 12.66 15.44 15.38 16.69 16.56 14.48 14.35 223-225 174-176 197-199 150-152 230-232 193-195 137-139 207-209 209-211 230-231 222-224 267-268
Yield, %
63.89 63.84 63.11 62.95 62.98 63.13 66.39 66.43 67.50 67.65 59.65 59.52 72.02 71.91 64.25 64.40 67.71 67.85 62.79 62.62 60.47 60.34 67.81 67.66
59 64 73 55 58 81 76 53 51 53 60 57
_______ * Compounds 1a,b, 2, 6, 11, 13a, b were crystallized from ethanol, compounds 7, 9, 15a-c from acetic acid. 653
654
TABLE 2. 1H NMR, IR, and Mass Spectra of Compounds 1a, b, 2, 6, 7, 9, 11, 13a, b, 15a-c
Compound 1 1a Mass spectrum, m/z (Irel,%) M+ 2 * Other fragments 3 * OH 4 3330 IR spectrum, , cm -1 NH CN (NH2) 5 6 2197, 2252 2195, 2250 2160, 2188 2200, 2249 2190, 2268 2205
1
C=O 7 1710
H NMR spectrum, , ppm (J, Hz) 8
1b 2 6 7
343 (59) 342 (62) 325 (20) 461 (32)
310 (23), 300 (27), 246 (47), 216 (23), 128 (25), 97 (100), 69 (47) 324 (10), 299 (41), 245 (83), 203 (25), 147 (10), 41 (100) 300 (38), 246 (33), 179 (15), 97 (35) 356 (43), 260 (58), 179 (29), 105 (100), 77 (91) 244 (29), 219 (55), 97 (54), 96 (52), 55 (54), 41 (100), 39 (45)
3450 3420 3430
3330
1690 1700 1710, 1740 1680
262 (66)
3380
7.23 and 7.13 (1H, two s, OH); 4.82 and 4.48 (1H, two s, C(6)H); 3.67-3.39 (1H, m, SCH); 2.12-1.17 (17H, m, CH and (CH2)8); 0.93 (3H, d, J = 5.8, CH3) 7.10 and 7.01 (1H, two s, OH); 4.49 and 4.36 (1H, two s, C(6)H); 3.50 and 3.60 (1H, two t, J = 4.4, SCH); 2.17-1.23 (18H, m, (CH2)9) 7.92 (1H, s, OH); 6.13 (2H, br. s, NH2); 3.89 (1H, m, SCH); 2.21-1.43 (18H, m, (CH2)9) 4.82 (1H, s, C(6)H); 2.73 (2H, m, CH2); 2.38 (2, m, 2); 1.85-1.15 (14, m, (2)7) 8.05-8.01 (2H, m, C(2)H and C(6)H, C6H5); 7.63-7.47 (3H, m, 65); 7.03 (1H, s, OH); 3.98-3.59 (3H, m, SCH and 2); 2.07-1.23 (18H, m, (CH2)9) 7.10 (1H, s, OH); 6.02 (1H, s, CH); 3.88 (1H, t, J = 4.4, SCH); 2.33 (2H, m, CH2); 2.23 (3H, s, CH3); 2.14-1.79 (2H, m, CH2); 1.59-1.47 (4H, m, (CH2)2)
TABLE 2 (continued)
1 11 2 417 (38) 3 374 (100), 297 (21), 259 (10), 198 (5), 77 (15) 4 5 3360 6 2170 7 1670 8 10.03 (1H, br. s, NH); 7.61 (2H, d, C(2)H and C(6)H, C6H5); 7.37 (2H, dd, J = 7.7 and J = 8.4, C(3)H and C(5)H, C6H5); 7.02 (1H, dd, (4), C6H5); 2.65 (2H, m, CH2); 2.12 (3H, s, CH3); 1.29-1.92 (16H, m, (CH2)8) 10.36 (1H, br. s, NH); 7.69-7.06 (8H, m, 3H, C4H3S +5H, C6H5); 4.86 (1H, m, SCH); 2.59 (3H, s, CH3); 2.13-1.81 (8H, m, (CH2)4) 10.28 (1H, br. s, NH); 9.23 (2H, d, J = 6.0, C(3)H and C(5)H, C5H4N); 7.43 (2H, d, C(2)H and C(6)H, C5H4N); 7.35 (2H, d, C6H5); 7.21 (2H, dd, J = 7.6 and J = 8.2, C(3)H and (5), 65); 7.03 (1H, dd, (4), 65); 4.87 (1H, m, SCH); 2.62 (3H, s, CH3); 2.15-1.82 (8H, m, (CH2)4) 9.82 (1H, br. s, OH); 7.68 (2H, br. s, NH2); 7.30 (2H, d, J = 10.8, C(3)H and C(5)H, 64); 6.91 (2H, d, C(2)H and C(6)H, 64); 4.81 (1H, dd, J = 5.1 and J = 8.5, SCH); 2.63 (2H, m, CH2); 2.12-1.76 (6H, m, (CH2)3) 7.96 (1H, d, J = 2.2, C(5)H, 43); 7.72 (2H, br. s, NH2); 7.39 (1H, dd, C(4)H, 43); 6.75 (1H, d, J = 3.0, C(3)H, 43); 4.79 (1H, dd, J = 4.8 and J = 8.3, SCH); 2.65 (2H, m, CH2); 2.23-1.78 (6H, m, (CH2)3) 7.78 (2H, br. s, NH2); 7.43 (4H, s, Ar); 5.01 (1H, dd, J = 5.9 and J = 8.9, SCH); 3.02 (1H, m, CH); 2.67 (2H, m, CH2); 2.23-1.92 (6H, m, (CH2)3); 1.31 (6H, d, J = 8.1, (CH3)2)
13a 13b
* 442 (100)
* 413 (42), 350 (61), 315 (84), 254 (69), 238 (46), 194 (21), 93 (20)
3320 3330
2215 2220
1680, 1710 1670, 1710
15a * 15b * 15c 390 (65) * 347 (100), 319 (36), 279 (31), 263 (81) *
3450
3330, 3250
2215
1710
3330 3314, 3330, 3472
2205
1690
2196
1711
_______ * Mass spectrum not taken.
655
Fig. 2. Crystal packing of compound 1a.
TABLE 3. Basic Bond Lengths (d) and Bond Angles () in the Molecule of Compound 1a
Bond S(1)C(1) S(1)C(15) O(1)C(14) O(2)C(5) N(1)C(1) N(1)C(5) N(1)C(14) C(1)C(2) C(2)C(3) C(3)C(4) C(4)C(5) C(14)C(15) d, 1.745(3) 1.820(3) 1.391(4) 1.202(4) 1.381(4) 1.379(4) 1.508(4) 1.344(4) 1.529(4) 1.555(4) 1.529(5) 1.533(4) Angle C(1)S(1)C(15) C(1)N(1)C(5) C(1)N(1)C(14) C(5)N(1)C(14) S(1)C(1)N(1) N(1)C(1)C(2) C(1)C(2)C(3) C(2)C(3)C(4) C(3)C(4)C(5) N(1)C(5)C(4) N(1)C(14)C(15) S(1)C(15)C(14) , deg. 91.90(14 121.4(3) 115.4(2) 122.8(2) 110.6(2) 123.8(3) 121.3(3) 103.9(2) 113.8(3) 112.6(3) 102.8(2) 105.1(2)
Calculations on the six-membered ring N(1)C(1-5) using modified CremerPople parameters [8] (S = 0.69, = 41.71, = 13.61) showed that this ring has a conformation intermediate between half-chair and half-boat. Atom N(1) has a trigonal planar configuration of bonds (the sum of the bond angles is 359.6 (7)). The N(1)C(1) (1.381(4) and N(1)C(5) (1.379(4) ) bonds are notably shorter than the average range of 1.43-1.45 characteristic of N(sp2)-C(sp3) single bonds [9, 10] indicating effective n(N(1))*(C(1)=C(2)) and n(N(1)) *(O(2)=C(5)) conjugation. Note that the conformation of the molecule 1a is very suitable for such an interaction: the torsion angles C(5)N(1)C(1)C(2) and C(14)N(1)C(1)C(2) are 6.2 and -167.2, while the torsion angles C(1) N(1)C(5)O(2) and C(14)N(1)C(5)O(2) are -164.3 and 8.6. A characteristic of the structure of compound 1a is the intramolecular hydrogen bond O(1)H(1)O(2) (O(1)O(2) 2.809(4), H(1)O(2) 2.18(6) A, O(1)H(1)O(2) 127(3)). 656
TABLE 4. Atomic Coordinates and Equivalent Isotropic Thermal Parameters, Ueq, in the Structure of 1a
Atom S(1) O(1) O(2) N(1) N(2) N(3) C(1) C(2) C(3) C(4) C(5) C(6) C(7) C(8) C(9) C(10) C(11) C(12) C(13) C(14) C(15) C(16) C(17) C(18) C(19) H(1) x 0.09236(8) 0.5206(3) 0.5890(2) 0.3502(3) -0.1603(3) 0.5899(4) 0.1946(3) 0.1332(3) 0.2344(3) 0.3806(3) 0.4546(3) -0.0302(4) 0.4997(4) 0.2717(4) 0.1339(5) 0.0667(5) 0.0306(4) 0.1640(4) -0.0742(6) 0.3973(3) 0.2609(3) 0.2544(4) 0.2807(5) 0.4300(5) 0.4263(4) 0.591(6) y 0.04485(9) 0.0417(3) 0.2610(3) 0.1552(3) 0.1474(4) 0.3832(5) 0.1422(3) 0.2037(3) 0.3008(3) 0.2406(4) 0.2230(3) 0.1747(3) 0.4997(4) 0.4507(4) 0.5174(4) 0.5172(4) 0.3705(4) 0.2973(4) 0.5790(6) 0.1053(3) -0.0139(3) -0.0506(4) 0.0741(5) 0.1756(5) 0.2251(4) 0.118(6) z 0.25959(8) 0.3392(3) 0.5921(3) 0.4490(2) 0.4496(3) 0.9229(4) 0.4303(3) 0.5297(3) 0.6719(3) 0.6938(3) 0.5769(3) 0.4902(3) 0.8224(4) 0.6757(4) 0.6734(4) 0.7924(4) 0.7941(4) 0.7894(3) 0.7840(6) 0.3190(3) 0.2231(3) 0.0716(4) 0.0285(4) 0.1196(4) 0.2690(4) 0.394(6) Ueq, 2 0.0484 0.0534 0.0675 0.0415 0.0711 0.1011 0.0382 0.0394 0.0384 0.0439 0.0460 0.0471 0.0662 0.0510 0.0662 0.0694 0.0597 0.0475 0.0997 0.0421 0.0454 0.0616 0.0716 0.0732 0.0554 0.11(2)
The short intermolecular contacts O(1)N(2) 2.818(4) (H(1)N(2) 2.18(6) A, O(1)H(1)N(2) 129(3)) shows the possibility of the formation O(1)H(1)N(2) hydrogen bonds (Fig. 2).
EXPERIMENTAL IR spectra of nujol mulls were recorded on an IRS-29 spectrophotometer. 1H NMR spectra of DMSO-d6 solutions with TMS as internal standard were recorded with Bruker WP-100 (100 MHz) (compound 1a), Gemini-200 (199 MHz) (compounds 6 and 7), Bruker WM-250 (250 MHz) (compound 15c), and Bruker AM-300 (300 MHz) spectrometers (compounds 1b, 2, 9, 11, 13a,b, 15a,b). Mass spectra were recorded with a Kratos MS-890 machine (70 eV). Melting points were recorded with a Kofler block. The course of reactions and the purity of synthesized compounds were monitored by TLC (Silufol UV-254, acetonehexane 3:5, spots revealed with iodine vapor). The X-ray Diffraction Study of a Monocrystal of Compound 1a with linear dimensions 0.16 0.22 0.34 mm was carried out at room temperature with an Enraf-Nonius CAD-4 automatic four-circle diffractometer (CuK radiation, ratio of rates of scanning /2 = 1.2, max = 60, segment of the sphere 0 h 11, -12 k 12, -11 k 11). A total of 2896 reflexions were collected of which 2700 were symmetrically independent R factor averaged 0.020). Crystals of compound 1a are triclinic, a = 9.199(2), b = 10.286(2), c = 10.651(2) ; = 107.62(2), = 103.37(2), = 97.83(2); V = 896.6 3; M = 357.47; Z = 2; dcalc 1.32 g/cm3; = 17.009 cm-1; space group P(1)(N2). Calculation of absorption in the crystal was carried out 657
by azimuthal scanning [11]. The structure was solved by direct methods and refined by least squares analysis using the CRYSTALS suite of programs [12]. In the refinement 1977 reflexions with I > 3(I) were used (230 parameters refined, reflexions per parameter 8.6). All hydrogen atoms were revealed from electron density difference synthesis and were included in the calculations with fixed positions and thermal parameters, only atom H(1) was refined isotropically. The Chebyshev weighting scheme [13] with parameters 1.56, -1.21, 0.80, and -0.74 was used in the refinement. The final residual factors were R = 0.055, Rw = 0.054, and GoF = 1.088. The residual electron densities in the difference Fourier series were 0.24 and -0.36 e/3. Atom coordinates are given in Table 4. 6,8-Dicyano-3-hydroxy-5-oxo-2,3-tetramethylene-2,3,4,5,6,7-hexahydrospiro[thiazolo[3,2-a]pyridine-7,1'-(4'-methylcyclohexane)] (1a), 6,8-Dicyano-3-hydroxy-5-oxo-2,3-tetramethylene-2,3,4,5,6,7hexahydrospiro[thiazolo[3,2-a]pyridine-7-cyclohexane] (1b), 5-Amino-6,8-dicyano-3-hydroxy-2,3tetramethylene-2,3,4,7-tetrahydrospiro[thiazolo[3,2-a]pyridine-7-cyclohexane] (2), 8-Cyano-3-hydroxy7-methyl-5-oxo-6-phenylcarbamoyl-2,3-tetramethylene-4,7-dihydrospiro[thiazolo[3,2-a]pyridine] (9), 8-Cyano-5-methyl-6-phenylcarbamoyl-2,3-tetramethylene-4,7-dihydrospiro[thiazolo[3,2-a]pyridine-7cyclohexane] (11), 3-Cyano-6-methy-2-(2'-oxocyclohexylthio)-5-phenylcarbamoyl-4-(2'-thienyl)pyridine (13a), 3-Cyano-6-methyl-2-(2'-oxocyclohexylthio)-5-phenylcartbamoyl-4-(4'-pyridyl)pyridine (13b), 6-Amino-3,5-dicyano-4-(4'-hydroxyphenyl)-2-(2'oxocyclohexylthio)pyridine (15a), 6-Amino-3,5-dicyano-4(2'-furyl)-2-(2'-oxocyclohexylthio)pyridine (15b), and 6-Amino-3,5-dicyano-4-(4'-isopropylphenyl)-2(2'oxocyclohexylthio)pyridine (15c) (General Method). A mixture of the corresponding thione or its salt (10 mmol) and 2-bromocyclohexanone (1.77 g, 10 mmol) in DMF (10 ml) was stirred at 20C for 4 h and then kept for a day. The precipitate was filtered off, washed with 40% aqueous ethanol and hexane to give compounds 1a,b, 2, 9, 11, 13a,b, 15a-c (Table 1). 1 NMR spectrum (CDCl3) of compound 1a, , ppm (J, Hz): 4.58 (1H, s, OH); 3.82 (1H, t, J = 4.1, C(2)H); 3.66 (1H, s, C(6)H); 2.27-1.22 (17H, m, (CH2)4 and (CH2)2CH(CH2)2); 0.96 (3H, d, J = 5.7, CH3). 6,8-Dicyano-5-oxo-2,3-tetramethylene-4,5,6,7-tetrahydrospiro[thiazolo[3,2-a]pyridine-7-cyclohexane] (6). A. A mixture of compound 1b (1.7 g, 5 mmol) and conc. H2SO4 (0.49 ml, 5 mmol) in ethanol (15 ml) was boiled for 2 h. The precipitate which formed over one day was filtered off and washed with ethanol and hexane to give compound 6 (Tables 1-2). B. Compound 1b (1.7 g, 5 mmol) was boiled in Ac2O (5 ml) for one hour. The precipitate which formed over one day was filtered off and washed with ethanol and hexane to give compound 6 (71% yield), identical by TLC and 1H NMR spectrum with the product from method A. 6-Benzoylmethylene-6,8-dicyano-5-oxo-2,3-tetramethylene-2,3,4,5,6,7-hexahydrospiro[thiazolo[3,2-a]pyridine-7-cyclohexane] (7). 10% Aqueous KOH (2.8 ml, 5 mmol) was added with stirring to a suspension of compound 1b (1.7 g, 5 mmol) in DMF (10 ml). -Bromoacetophenone (1 g, 5 mmol) was then added with stirring over 5 minutes and the mixture was stirred for four hours. The precipitate which formed over one day was filtered off and washed with ethanol and hexane to give compound (Tables 1-2). The methods of synthesis and the characteristics of the starting materials 3a,b, 4, 8, 10, 12a,b, and 14a-c are cited in [14].
REFERENCES 1. 2. 3. 4. 658 V. P. Litvinov, L. A. Rodinovskaya, Y. A. Sharanin, A. M. Shestopalov, and A. Senning, Sulfur Reports, 13, 1 (1992). A. Roth and K. Goerlitzer, Arch. Pharm., 326, 642 (1993). K. Goerlitzer and A. Roth, Pharmazie, 50, 729 (1995). A. D. Dyachenko, S. M. Desenko, V. D. Dyachenko, and V. P. Litvinov, Khim. Geterotsikl. Soed., 554 (2000).
5. 6. 7. 8. 9. 10. 11. 12. 13. 14.
A Krauze and G. Duburs, Khim. Geterotsikl. Soed., 1134 (1996). A. M. Shestopalov, L. A. Rodinovskaya, Yu. A. Sharanin, and V. I. Litvinov, Zhur. Org. Khim., 58, 840 (1988). V. I. Litvinov, A. M. Shestopalov, Yu . A Sharanin, V. Yu. Mortikov, and V. N. Nesterov, Doklad. Akad. Nauk., 299, 135 (1988). N. S. Zefirov and V. A. Palyuyulin, Doklad. Akad. Nauk, 252, 111 (1980). M. Burke-Laing and M. Laing, Acta Crystallogr., B32, 3216 (1976). F. H. Allen, O. Kennard, D. G. Watson, L. Brammer, A. G. Orpen, and R. Taylor, J. Chem. Soc., Perkin Trans. 2, P S1 (1987). A. C. T. North, D. C. Phillips, F. Scott, and F. S. Mathews, Acta Crystallogr., A24, 351 (1968). D. J. Watkin, C. K. Prout, J. R. Carruthers, and P. W. Betteridge, CRYSTALS Issue 10, Chemical Crstallograhy Laboratory, Univ. of Oxford (1966). J. R. Carruthers and D. J. Watkin, Acta Crystallogr., A35, 698 (1979). V. D. Dyachenko, Diss. Doctor Khim. Nauk, Moscow (1998).
659
HALOCYCLIZATION OF SUBSTITUTED 2-(ALKENYLTHIO)PYRIMIDIN-6-ONES

N. Yu. Slivka1, Yu. I. Gevaza2, and V. I. Staninets2 Bromination and iodation of 2-(alkenylthio)pyrimidin-6-ones occur selectively and lead to formation of the corresponding 7-oxo-2,3-dihydrothiazolopyrimidinium or 8-oxo-3,4-dihydro-2H-pyrimidothiazinium salts. The selectivity of the reaction is controlled by the nature of the alkenyl substituent on the sulfur atom and the basicity of the N(1) and N(3) atoms of the pyrimidine ring. The iodation reaction rate increases as the basicity of the N(3) atom increases. Keywords: (allylthio)pyrimidines, heterocyclization, iodation. pyrimidothiazines, thiazolidine pyrimidines, bromination,
Iodation of 2-allylthio-1H-pyrimidin-6-ones leads to formation of 3-iodomethyl-7-oxo-2,3-dihydro-8Hthiazolo[3,2-a]pyrimidinium iodides and triiodides [1]. An analogous conversion is also observed in the case of halogenation of 2-(allylthio)thienopyrimidin-6-ones [2, 3]. This work was devoted to determining the selectivity of halocyclization of substituted 2-(alkenylthio)-4R-pyrimidin-6-ones 1a-g and studying the effect of the nature of the substituent R on the rate of the indicated reaction. The starting compounds 1a-d were synthesized from the sodium salt of 6-methylthiouracil and the corresponding alkenyl halide by the procedure in [3]. Compounds 1e-g were obtained from 6-amino-4-hydroxy2-mercaptopyrimidine and the corresponding alkenyl halide by the procedure in [1]. When compounds 1a-g were reacted with bromine or iodine in chloroform or acetic acid, after treatment of the initially formed trihalo derivatives (see [1]) with acetone we selectively obtained substituted 7-oxo-2,3dihydrothiazolopyrimidinium salts 2a-d, 3a-d or 8-oxo-3,4-dihydropyrimidothiazinium salts 4a-c, 5a-c (Scheme 1). Obviously the selectivity of cyclization is determined by the nature and position of the substituents on the allyl moiety bonded to the sulfur atom. Thus from compounds 1a,b,e,f, which have allyl and methallyl substituents, only the salts 2a-d, 3a-d are formed, while only the salts 4a-c, 5a-c are formed from compounds 1c,d,g with a thiocinnamyl or thio-2-methylbutenyl group. The composition and structure of all the synthesized compounds were confirmed by elemental analysis (Table 1), IR spectra, and 1H NMR (Table 2). The 1H NMR spectra indicate that the products 2, 3, and 4, 5 belong to different series of compounds. The signal common to both series, for the SCH2 moiety, in the case of salts 2, 3 has the shape of two doublets of doublets (for R = Me) or two doublets (for R = NH2) in the 3.44-3.46 ppm and 3.70-3.89 ppm region. The multiplet signal for the CH2Hal group is typical of the spectra for compounds 2, 3, which is found in the __________________________________________________________________________________________ Lesya Ukrainka Volyn State University, Lutsk 43025, Ukraine. 2 Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev 02094; e-mail: iochkiev@ukrpack.net. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 776-783, May, 2004. Original article submitted February 15, 2002; revised March 9, 2004. 660 0009-3122/04/4005-06602004 Plenum Publishing Corporation
1
Scheme 1
O NH R R1 R2 Hal 4ac, 5ac O 2a,b AcONa DMSO Me R3 N N 4a,b S AcONa DMSO Me R1 R2 O 1a H2SO4 Me N N 8 S Me 7a,b Br N + N S _ Hal Hal2 1c,d,g R N 1ag O NH S R3 C R1 R2 Hal2 1a,b,e,f R R3 HalH2C 2ad, 3ad O N S + N O NH S _ Hal
BrH2C 6a,b
2, 4 Hal = Br, 3, 5 Hal = I; 1ad R = Me, eg R = NH2; a, e R1 = R2 = R3 = H, b, f R1 = R2 = H, R3 = Me, c, g R1 = R2 = Me, R3 = H, d R1 = R3 = H, R3 = Ph; 2, 3 a, b R = Me, c, d R = NH2; a, c R3 = H, b, d R3 = Me; 4, 5 a, b R = Me, c R = NH2; a, c R1 = R2 = Me, b R1 = H, R2 = Ph; 6 a R3 = H, b R3 = Me; 7 a R1 = R2 = Me, b R1 = H, R2 = Ph
4.15-4.18 ppm region for R = Me and in the 3.76-3.89 ppm region for R = NH2 (compare compounds 2a, 3a and 2c, 3c, 2b, 3b, and 2d, 3d). This difference, and also the different shapes of the signals for the SCH2 group, may be connected with the effect of the steric factor (closely surrounded by solvent molecules, the basic NH2 group creates different steric conditions than the neutral methyl substituent). The appearance of the latter is more likely when the substituents R and CH2Hal are close to each other, i.e., when cyclization occurs at the N(3) atom. Such a direction of the reaction is also confirmed by the conversion of the salts 2a,b to the bases 6a,b when treated with AcONa in DMSO. In the IR spectra of the latter, the absorption band for the carbonyl group is found at 1620 cm1 , which indicates they have a p-quinoid structure (see [1]). The spectra of compounds 4, 5 are considerably different from the spectra considered above. The signal from the SCH2 group of these compounds has the form of two multiplets, which are found 3.56-3.90 ppm and 3.82-3.89 ppm upfield from the signals of the analogous group of compounds 2,3. A typical feature of the considered spectra is the presence of signals from the CHHal and C(4)R1R2 groups. The multiplet signal from the CHHal moiety, compared with the signal from the CH2Hal moiety of compounds 2,3, is found downfield in the narrow interval 4.65-4.70 ppm for all salts 4, 5, which indicates the absence of any appreciable change in its position when the 6-Me substituent is replaced by 6-NH2. On the other hand, such a replacement causes a 0.19-0.28 ppm upfield shift of the signal from the protons of the methyl group in the 4 position (compare 4a and 4c, 5a and 5c). As in the case of compounds 2,3, this is possibly connected with the effect of the steric factor, i.e., it is support for the idea that the R and C(4)R1R2 and R groups are close and consequently that cyclization occurs at the N(3) atom. When the salts 4a,b are treated with AcONa in DMSO, the corresponding bases 7a,b are formed, and the absorption band for the C=O of those compounds is found at 1630-1620 cm-1, supporting the idea that they have a p-quinoid structure and that the direction of cyclization is at the N(3) atom. 661
O NH Me N 9 S Hal2 Me HalHC
O NH + N S Hal _
10, 11 O 10 AcONa DMSO Me BrHC 10 Hal = Br, 11 Hal = I N N S
12
The structure of compounds 2c-5c is supported by the presence in the IR spectra of a signal from the NH group in the 10.01-10.60 ppm region, which however is missing in the spectra of the rest of the salts 2-5 (also see [3]). Formation of products 2-5 suggests that halocyclization of compounds 1a-g occurs, as we might expect [4], with participation of the more basic N(3) atom. However, when the pyrimidinone 1a is treated with sulfuric acid, cyclization occurs at the N(1) atom to form 3,7-dimethyl-5-oxo-2,3-dihydro-8H-thiazolo[3,2-a]pyrimidine (8), the structure of which is supported by the 1H NMR data (Table 2) and the IR spectrum (the absorption band for the C=O group is found at 1680 cm-1, which suggests an o-quinoid structure for compound 8 (see [1])). In this case, the change in the direction of the reaction is probably connected with the high degree of protonation of the more basic N(3) atom in compound 1a.

Compound 1 1b 1c 1d 1e 1f 1g 2 2b 2c 2d Empirical formula 2 C912N2OS C10H14N2OS C14H14N2OS C7H9N3OS C8H11N3OS 9H13N3OS C8H10Br2N2OS C9H12Br2N2OS C7H9Br2N3OS C8H11Br2N3OS 47.11 46.70 45.26 44.90 46.83 46.59 45.01 44.77 Found, % Calculated, % Hal N 3 4 14.03 14.28 13.19 13.33 9.97 10.55 22.18 22.96 21.11 21.33 20.14 19.91 mp, S 5 16.30 16.34 15.07 15.25 11.65 12.41 17.74 17.50 16.34 16.26 15.29 15.18 9.12 9.37 8.98 9.11 9.18 9.34 8.62 8.98 6 146-147 166-167 160-161 Oil Oil Oil 155-156 161-162 (dec.) 148-149 153-155 Rf * 7 0.84 0.79 0.74 0.89 0.88 0.87 0.46 0.47 0.54 0.53 Yield, % 8 81 89 86 67 60 64 73 76 63 60
662
TABLE 1 (continued)
1 3a 3b 3c 3d 4a 4b 4c 5a 5b 5c 6a 6b 7a 7b 8 9 10 11 12 2 C8H10I2N2OS C9H12I2N2OS C7H9I2N3OS C8H11I2N3OS C10H14Br2N2OS C14H14Br2N2OS C9H13Br2N3OS C10H14I2N2OS C14H14I2N2OS C9H13I2N3OS C8H9Br2N2OS C9H11BrN2OS C10H13BrN2OS C14H13BrN2OS C8H10N2OS C8H8N2OS C8H8Br2N2OS C8H8I2N2OS C8H7BrN2OS 47.37 47.00 58.83 58.53 31.11 30.84 3 58.50 58.21 56.82 56.41 58.43 58.10 56.61 56.30 43.47 43.19 37.98 38.20 43.28 43.08 55.03 54.71 49.83 49.58 54.78 54.62 30.62 30.59 29.32 29.04 27.51 27.63 24.02 23.69 4 5 7.13 7.35 7.01 7.12 9.31 9.62 9.20 9.32 8.34 8.66 7.51 7.67 8.34 8.16 6.88 6.90 5.21 5.47 9.16 9.04 12.04 12.27 11.83 11.65 9.83 9.69 8.56 8.31 15.65 15.38 15.65 15.55 6.28 6.46 12.58 12.31 6 184 (dec.) 189-190 (dec.) 177-178 182-183 182-183 (dec.) 169-176* 158-159 222 (dec.) 200-209*2 (dec.) 185-186 139-140 148-149 165-166 148-160*2 17.82 17.60 17.81 17.79 9.28 9.43 101-103 162-163 177-178 212-213 (dec.) 157-158
2
7 0.43 0.45 0.56 0.54 0.44 0.44, 0.62 0.55 0.42 0.43, 0.60 0.57 0.81 0.80 0.85 0.83, 0.92 0.90 0.70 0.48 0.46 0.81
8 79 63 61 57 78 77 69 61 64 58 80 75 78 79 62 81 73 82 72
_______ * Eluent for TLC: chloroformacetonediethylamine, 10:2:1 (compounds 1b-d, 6a,b, 7a,b, 8, 9, and 12), ethyl acetatemethanolacetone, 15:4:2 (compounds 2a,b-5a,b, 10, 11), methanolacetonediethylamine, 10:10:2 (compounds 1e-g, 2c,d, 3c,d, 4c, 5c). *2 mp of the mixture of diastereomers.
Halocyclization also occurs selectively in the case of 6-methyl-2-(propynylthio)pyrimidin-6-one (9): when it is halogenated with bromine or iodine in chloroform, only substituted thiazolidinopyrimidinium salts 10, 11 are formed (Scheme 2). The structure of the latter is supported by 1H NMR spectra (the presence of singlet signals from the SCH2 and CHHal groups in the 4.25-4.34 ppm and 7.07-7.18 ppm respectively), and also by the conversion of product 10 to base 12 when treated with AcONa in DMSO. In the IR spectrum of compound 12, the absorption band for the C=O group is found at 1640 cm-1, which indicates that it has a p-quinoid structure. The starting compound 9 was obtained by the procedure in [3]. In order to determine the effect of the nature of the substituent R on the C(4) atom of (alkenylthio)pyrimidin-6-ones 1a-g, we estimated the relative rate of iodation of compounds 1a,d,e. We found that under identical conditions, after 5 h this reaction proceeds to 57.6% (1a), 51.0% d (1d), 81.6% (1e) 663
TABLE 2. 1H NMR and IR Spectra of Synthesized Compounds

Compound 1b 1c 1d Chemical shifts, , ppm (J, Hz) 1.76 (3, s, H3); 2.12 (3H, s, 4-CH3); 3.81 (2, s, S2); 5.02 (2, m, =2); 5.97 (1, s, H-5); 12.50 (1, s, N) 1.69 (6, s, two CH3); 2.16 (3, s, 4-CH3); 3.77 (2, d, 3J = 6.9, S2); 5.38 (1, m, =); 5.96 (1, s, H-5); 12.46 (1, s, N) 2.21 (3, s, 4-CH3); 3.97 (2, d, 3J = 7.2, S2); 6.39 (1, m, =); 6.66 (1, d, 3J = 10.5, =C6H5,); 7.23-7.39 (5, m, C6H5); 12.52 (1, s, N) 2.31 (3, s, 5-CH3); 3.51 and 3.70 (2, two dd, 2J1 = 2J2 = 12.0, 3J = 5.9, S2); 4.12 (2, m, 2Br); 5.18 (1, m, H-3); 6.20 (1, s, H-6) 1.83 (3, s, 3-CH3); 2.16 (3, s, 5-CH3); 3.58 and 3.75 (2, two dd, 2 J1 = 2J2 = 12.3, 4J = 2.2, S2); 4.15 (2, m, 2Br); 6.22 (1, s, H-6) 3.46 and 3.76 (2, two d, 2J1 = 2J2 = 12.4, S2); 3.81 (2, m, 2Br); 5.17 (1, m, H-3); 6.97 (1, s, H-6); 9.17 (2, br. s, N2); 10.59 (1, s, N) 1.88 (3, s, 3-CH3); 3.46 and 3.72 (2, two d, 2J1 = 2J2 = 12.1, S2); 3.89 (2, m, 2Br); 6.09 (1, s, H-6); 8.73 (2, br. s, N2) 2.31 (3, s, 5-CH3); 3.53 and 3.78 (2, two dd, 2J1 = 2J2 = 12.3, 3J = 5.8, S2,); 4.13 (2, m, 2I); 5.21 (1, m, H-3); 6.23 (1, s, H-6) 1.84 (3, s, 3-CH3); 2.15 (3, s, 5-CH3); 3.66 and 3.76 (2, two dd, 2 J1 = 2J2 = 12.3, 4J = 1.8, S2); 4.18 (2, m, 2); 6.11 (1, s, H-6) 3.48 and 3.77 (2, two d, 2J1 = 2J2 = 12.0, S2); 3.85 (2, m, 2); 5.03 (1, m, H-3); 6.99 (1, s, H-6); 9.14 (2, br. s, N2); 10.60 (1, s, N) 1.83 (3, s, 3-CH3); 3.44 and 3.78 (2, two d, 2J1 = J2 = 12.3, S2); 3.88 (2, m, 2); 6.16 (1, s, H-6); 8.82 (2, br. s, N2) 2.06 (3, s, 4-CH3); 2.15 (3, s, 4-CH3); 2.65 (3, s, 6-CH3); 3.56 and 3.82 (2, two m, S2); 4.66 (1, m, H-3); 6.21 (1, s, H-7) 2.34 (3, s, 6-CH3); 3.90 and 4.02 (2, two m, S2); 4.65 (1, m, H-3); 5.76 (1, d, 3J = 10.2, H-4); 6.21 (1, s, H-7); 6.427.67 (5, m, C6H5) 1.87 (3, s, 4-CH3); 1.94 (3, s, 4-CH3); 3.67 and 4.09 (2, two m, S2); 4.65 (1, m, H-3); 6.19 (1, s, H-7); 9.13 (2, br. s, N2); 10.01 (1, s, N) 2.11 (3, s, 4-CH3); 2.23 (3, s, 4-CH3); 2.49 (3, s, 6-CH3); 3.60 and 3.87 (2, two m, S2); 4.67 (1, m, H-3); 6.15 (1, s, H-7) 2.31 (3, s, 6-CH3); 3.85 and 4.00 (2, two m, S2); 4.70 (1, m, H-3); 5.79 (1, d, 3J = 10.1, H-4); 6.22 (1, s, H-7); 7.547.72 (5, m, C6H5) 1.89 (3, s, 4-CH3); 1.95 (3, s, 4-CH3); 3.70, 4.12 (2, two m, S2); 4.67 (1, m, H-3); 6.17 (1, s, H-7); 9.12 (2, br. s, N2); 10.08 (1, s, N) 2.11 (3, s, 5-CH3); 3.48 and 3.66 (2, two d, 2J1 = 2J2 = 6.6, S2); 3.99 (2, m, 2Br); 5.06 (1, m, H-3); 6.01 (1, s, H-6) 2.19 (3H, d, 3J = 6.9, 3-CH3); 2.21 (3, s, 7-CH3); 3.83 (2H, d, 3J = 6.9, S2); 5.11 (1H, m, H-3); 6.21 (1H, s, H-6) 2.11 (3, s, 4-CH3); 3.19 (1, t, 4J = 2.2, ,); 3.99 (2, d, 4J = 2.2, SCH2); 6.07 (1, s, H-5); 12.49 (1, s, N) 2.31 (3, s, 5-CH3); 4.25 (2, s, S2); 6.26 (1, s, H-6); 7.18 (1, s, =Br) 2.21 (3, s, 5-CH3); 4.34 (2, s, S2); 6.06 (1, s, H-6); 7.07 (1, s, =I) (=), m-1 1670 1670 1670
2 2b 2 2d 3 3b 3 3d 4 4b 4c 5 5b 5 6 8 9 10 11
1680 1700 1690 1695 1685 1700 1700 1700 1700 1690 1685 1680 1700 1690 1620 1680 1670 1700 1700
conversion. The high percentage conversion of compound 1e is probably connected with the presence in that compound of an NH2 group, the electronic effect of which on the N(3) atom increases the basicity of the latter and consequently increases the reactivity. Thus the direction of halocyclization of 2-alkyenylthiopyrimidin-6-ones is substantially affected by the structure of the S-alkeynyl substituent, which leads to regioselective formation of thiazolidinopyrimidinium or pyrimidothiazinium derivatives. An electron-donor substituent on the heterocycle (R = NH2) accelerates the heterocyclization of 2-(alkyenylthio)pyrimidin-6-ones.
664
EXPERIMENTAL The IR spectra were recorded on a UR-20 in KBr disks. The 1H NMR spectra of solutions of the substances in DMSO-d6 were obtained on a Varian VXR-300 spectrometer (300 MHz), internal standard TMS. The course of the reaction was monitored by TLC on Silufol UV-254 plates. 2-Allylthio- (1a), 2-Methallylthio- (1b), and 2-Propargylthio-4-methyl-1H-pyrimidin-6-one (9) (General Procedure). A solution of allyl bromide, methallyl chloride, or propargyl chloride (45 mmol) in alcohol (20 ml) was added with heating (~90C) to sodium salt of 6-methyl-2-thiouracil (5.0 g, 30 mmol) in water (150 ml). The mixture was vigorously shaken and held for 4-5 h at 18-20C. The precipitate of product 1a,b or 1c formed was filtered out and washed with alcohol, then crystallized from a 1:2 alcoholwater mixture and dried at 80-90C. For compound 1a: mp 134C (mp 133C [1]). According to the data in [5], the mp of compound 9 is 162C. 4-Methyl-2-(3-methyl-2-butenylthio)- (1c) and 4-Methyl-2-cinnamylthio-1H-pyrimidin-6-one (1d) (General Procedure). 1-Chloro-3-methyl-2-butene or cinnamyl chloride (45 mmol) was added with stirring to a solution of sodium salt of 6-methyl-2-thiouracil (5 g, 30 mmol) in DMF (70 ml). The mixture was held for 2 h at 50-60C and then cooled down and diluted with water (100 ml). The colorless precipitate of product 1c or 1d formed was filtered out and washed with ether, then crystallized from an alcoholwater mixture and dried at 80-90C. 2-Allylthio- (1e), 2-Methallylthio- (1f), and 2-(3-Methyl-2-butenylthio)-4-amino-1H-pyrimidin-6one (1g) (General Procedure). 6-Amino-4-hydroxy-2-mercaptopyrimidine (5.0 g, 35 mmol) and allyl bromide, methallyl chloride, or 1-chloro-3-methyl-2-butene (35 mmol) were added to a solution of KOH (1.95 g, 35 mmol) in alcohol (90 ml). The mixture was boiled for 2 h under reflux and then cooled down; the colorless precipitate was filtered out and then the filtrate was evaporated down. The product 1e,f or 1g was obtained as a dark yellow oil that dissolved well in water. 3-Bromomethyl-5-methyl(2a) and 3-Bromomethyl-3,5-dimethyl-7-oxo-2,3-dihydro-8Hthiazolo[3,2-a]pyrimidinium (2b), 3-Bromo-4,4,6-trimethyl- (4a), and 3-Bromo-6-methyl-8-oxo-4-phenyl3,4-dihydro-9H-pyrimido[3,2-a]thiazinium (4b), 3-Bromomethylidene-5-methyl-7-oxo-2,3-dihydro-8Hthiazolo[3,2-a]pyrimidinium (10) Bromides (General Procedure). A solution of bromine (1.44 g, 9.0 mmol) in glacial acetic acid (15 ml) was added with stirring to a solution of compound 1a-d (4.5 mmol) or 9 in glacial acetic acid (40 ml). After 2 h, the yellow precipitate of the corresponding tribromide (see [1]) was filtered out and then washed with hot glacial acetic acid. The tribromide obtained (3.0 mmol) was added in several portions to acetone (15 ml); the reaction mixture was stirred for 30 min at 25C. The precipitate was filtered out, washed with acetone, crystallized from alcohol, and dried at 90-100C. The product 2a,b, 4a,b, or 10 was obtained respectively. 3-Iodomethyl-5-methyl- (3a) and 3-Iodomethyl-3,5-dimethyl-7-oxo-2,3-dihydro-8H-thiazolo[3,2-a]pyrimidinium (3b), 3-Iodo-4,4,5-trimethyl- (5a), and 3-Iodo-6-methyl-8-oxo-4-phenyl-3,4-dihydro9H-pyrimido[3,2-a]thiazinium (5b), and 3-Iodomethylidene-5-methyl-7-oxo-2,3-dihydro-8H-thiazolo[3,2-a]pyrimidinium (11) Iodides (General Procedure). A solution of iodine (1.01 g, 4.0 mmol) in alcohol or chloroform (30 ml) was added to a suspension of compound 1a-d or 9 (0.4 g, 2.0 mmol) in alcohol or chloroform (30 ml). The mixture was stirred for 3 h, and then it was held at room temperature for 10-12 h. The brown precipitate of the corresponding triiodide formed (see [1]) was filtered out and washed with alcohol. A solution of NaI2H2O (0.74 g, 4.0 mmol) in acetone (10 ml) was added with stirring to a solution of the triiodide obtained (1.66 g, 2.0 mmol) in acetone (5 ml). After 1 h, the yellow precipitate was filtered out, washed with acetone, crystallized from alcohol, and dried at 90C; the product 3a,b, 5a,b, or 11 was obtained respectively. For compound 3a, the literature mp was 182C [1]. 5-Amino-3-bromomethyl- (2c) and 5-Amino-3-bromomethyl-3-methyl-7-oxo-2,3-dihydro-8Hthiazolo[3,2-a]pyrimidinium (2d), 6-Amino-3-bromo-4,4-dimethyl-8-oxo-3,4-dihydro-9H-pyrimido[3,2-a]thiazinium (4c) Bromides (General Procedure). A solution of bromine (0.79 g, 5.0 mmol) in acetic acid 665
(15 ml) was added dropwise with stirring over a 20 min period to a solution of compound 1e-g (2.5 mmol) in glacial acetic acid (15 ml). The reaction mixture was held for 4 h at 20C and then held for 4 h at -4C. The yellow precipitate of the corresponding tribromide was filtered out and washed with ether. The products 2c,d, 4c were isolated as for compound 2a. 5-Amino-3-iodomethyl- (3c) and 5-Amino-3-iodomethyl-3-methyl-7-oxo-2,3-dihydro[3,2-a]pyrimidinium (3d), 6-Amino-3-iodo-4,4-dimethyl-8-oxo-3,4-dihydro-9H-pyrimido[3,2-a]thiazinium (5c) Iodides (General Procedure). A solution of iodine (1.01 g, 4.0 mmol) in ethanol (40 ml) was added over a 30 min period to a suspension of compound 1e-g (2.0 mmol) in ethanol (30 ml). The alcoholic solution was decanted from the oil formed, the oil was dissolved in acetone (10 ml), and a solution of NaI2H2O (0.74 g, 4.0 mmol) in acetone (10 ml) was added with stirring to the solution obtained. The precipitate was filtered out and washed with acetone, dried at 100C and crystallized from alcohol. The product 3c,d or 5c respectively was obtained. 3-Bromomethyl-5-methyl- (6a) and 3-Bromomethyl-3,5-dimethyl-7-oxo-2,3-dihydrothiazolo[3,2-a]pyrimidine (6b), 3-Bromo-4,4,6-trimethyl- (7a), and 3-Bromo-6-methyl-8-oxo-4-phenyl-3,4dihydropyrimido[3,2-a]thiazine (7b), 3-Bromomethylidene-5-methyl-7-oxo-2,3-dihydrothiazolo[3,2-a]pyrimidine (12) (General Procedure). A 15% solution of AcONa (30 ml) in water was added with stirring to a solution of bromide 2a,b, 4a,b, or 10 (2.0 mmol) in DMSO (50 ml) and the mixture was held at room temperature for 2 h. The white precipitate of the corresponding product 6a,b, 7a,b, 12 was filtered out and dried at 80C. 3,7-Dimethyl-5-oxo-2,3-dihydrothiazolo[3,2-a]pyrimidine (8). A solution of compound 1a (0.18 g, 1.0 mmol) in conc. H2SO4 (2 ml) was held for 10 min in a water bath at 50C, and then was held for 25 h at 15-25C. The reaction mixture was poured into ice water (10 ml) and held for 24 h at 0C. The precipitate of product 8 was filtered out and recrystallized from chloroform.
REFERENCES 1. 2. 3. 4. 5. D. G. Kim and V. I. Shmygarev, Khim. Geterotsikl. Soedin., 211 (1995). P. Wippich, H. Guetschow, and S. Leistner, Synthesis, 714 (2000). R. I. Vas'kevich, S. M. Kripak, V. I. Staninets, Yu. L. Zborovskii, and A. N. Chernega, Zh. Org. Khim., 36, 1091 (2000). V. I. Staninets and E. A. Shilov, Usp. Khim., 40, 491 (1971). M. M. Heravi, K. Aghapoor, and M. A. Nooshabadi, Synth. Commun., 28, 233 (1998).
666
REACTION OF 2-AMINOTHIAZOLES AND THEIR BENZO- AND NAPHTHO DERIVATIVES WITH -SULFONYLTRIFLUOROMETHYLVINYLDIOLS
A. L. Krasovsky, A. M. Moiseev, V. G. Nenajdenko, and E. S. Balenkova By cyclocondensation of 2-aminothiazoles and their benzo and naphtho analogs with -sulfonyltrifluoromethylvinyldiols, we have obtained a series of novel CF3-containing 6,7-dihydro-5H[1,3]thiazolo[3,2-a]pyrimidines. In the case of the sterically hindered 2-aminothiazoles, heterocyclization does not occur and the corresponding enamino ketones are formed. Keywords: 2-aminothiazoles, 6,7-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidines, methylvinyldiols, cyclocondensation. -sulfonyltrifluoro-
Several methods are known for synthesis of thiazolo[3,2-a]pyrimidine derivatives. Thus their keto derivatives are obtained by condensation of 2-aminothiazoles with -keto acid derivatives [1, 2]. Compounds of the second type (onium salts) are synthesized by two alternative schemes: from 2-mercaptopyrimidines and -halo ketones [3], and by cyclocondensation of -aminothiazoles with -diketones, -keto aldehydes, and their acetals [4], -chlorovinyl ketones and aldehydes [5-7]. However, so far studies of the method for synthesis of fluorine-containing derivatives of thiazolo[3,2-a]pyrimidine have been virtually unknown. In this work, we have studied the reaction of 2-aminothiazoles and their benzo and naphtho derivatives with -sulfonyltrifluoromethylvinyldiols 1, 2. Sulfones 1, 2 have been obtained previously by oxidation of the corresponding readily accessible sulfides [8]. We have shown that sulfones 1, 2 readily react with various nucleophiles [9, 10], and also enter into the cyclocondensation reaction with 1,3-binucleophiles [11]. We found that when sulfones 1, 2 react with 2-aminothiazoles in acetonitrile, along with the expected cycloadducts 6,7-dihydro-5H-[1,3,4]thiadiazolo]3,2-a]pyrimidin-7-ols 3-6, the enamino ketones 7 are formed (Table 1). For R' = H, the reaction occurs regiospecifically and stereoselectively: the cycloadducts 3-6 are formed as a mixture of stereoisomers with predominance of the isomer with axial sulfonyl and hydroxy groups, probably due to the presence of a hydrogen bond between these groups. We observed similar stereochemistry earlier in cycloadducts obtained when 2-aminothiadiazoles react with sulfones 1, 2, as is unambiguously supported by the X-ray diffraction data [12]. The presence of a methyl group in the 4 position of the starting 2-aminothiazole creates significant steric hindrance for the sulfonyl group, and accordingly we see stereospecific formation of isomers 3c or 4c with an axial sulfonyl group.
__________________________________________________________________________________________ M. V. Lomonosov Moscow State University, Moscow 119899, Russia; e-mail: Nen@acylium.chem.msu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 784-792, May, 2004. Original article submitted September 25, 2001. 0009-3122/04/4005-06672004 Plenum Publishing Corporation 667
R'' F 3C SO2R 1 E/Z 7/2 2 E R' = H, Me R' R'' S N N SO2R OH R' SO2R N S OH N CF3 5ac, 6ac R'' OH OH R'
S NH2
R' = Ar F 3C R' O N S 7df N H
R''
CF3 3ac, 4ac
1, 3ac, 5ac R = Ph; 2, 4ac, 6ac R = Me
Study of the spinspin coupling constants for the protons of the CHCH2 moiety of the pyrimidine ring of compounds 3-6 and 8 makes it possible to determine the position of the sulfonyl group in those compounds. Thus in the 1H NMR spectrum of compounds 3, 4, 8, we observe spinspin coupling between the equatorial H-5 atom and the hydrogen atoms of the methylene group H-6a and H-6b, with constants J = 0.9-1.9 and J = 7.5-7.9 Hz; in the spectra of compounds 5, 6, we see a large spinspin coupling constant (J = 11.7-12.6 Hz), corresponding to axax coupling, which is possible only when the H-5 atom is in an axial position. With a further increase in the steric bulk of the substituent R' as it goes to an aryl group, the cycloadducts 3-6 are generally not formed. Instead, we obtained products with a linear structure in high yields: the trifluoromethyl-containing enamino ketones 7d-f.
R' N R'' R''' S NH2 R' SO2R N R''' S N OH CF3 N F 3C O N H 1, 2
R' R''
R'' R'''
S 10fh
8af, 9af
8af,i R = Ph; 9af,i R = Me
When various 2-amino-1,3-benzothiazoles and 2-aminonaphtho[2,1-d][1,3]thiazole react with sulfones 1, 2, we also observe formation of both cycloadducts 8, 9 and the products with linear structure 10 (Table 2). However, if the 2-amino-1,3-benzothiazoles contain strong electron-acceptor substituents, for example, 2-amino6-nitro-1,3-benzothiazole, then the reaction does not occur at room temperature and heating leads to tar formation in the reaction mixture.
668
TABLE 1. Reaction Conditions and Reaction Products for the Reaction of 2Aminothiazoles with Sulfones 1, 2
R Ph Me Ph Me Ph Me Ph Me Ph Me Ph Me R' H H Me Ph 4-MeOC6H4 4-ClC6H4 R'' H Me H H H H 36 3a / 5a 4a / 6a 3b / 5b 4b / 6b 3c / 5c 4c / 6c 3(4) / 5(6)* 80 / 20 83 / 17 83 / 17 84 / 16 100 / 0 100 / 0 7 d e f mp, 120 176 Oil 156 Oil 170 174 180 185 Yield, % 86 90 84 88 91 92 85 90 82 87 80 85
_______ * The isomer ratio was determined based on the 1H NMR spectra. In the case of aminobenzothiazoles, we can more rigorously describe the steric requirements imposed on the starting amino heterocycle for the occurrence of the cycloaddition reaction. Probably when the steric bulk of the substituent in the 4 position of the starting 2-amino-1,3-benzothiazole is greater than or equal to the volume of the chlorine atom, the enamine 10 is formed exclusively. On further decrease in the steric bulk of the substituent R' as it goes down to a fluorine atom, we obtained a mixture of the cyclic (8, 9) and linear (10) compounds. Derivatives of 3,4-dihydro-2H-pyrimido[2,1-b][1,3]benzothiazole are formed as the sole reaction TABLE 2. Reaction Conditions and Reaction Products for the Reaction of 2Amino-1,3-benzothiazoles with Sulfones 1, 2
R Ph Me Ph Me Ph Me Ph Me Ph Me Ph Me Ph Me Ph Me Ph Me R' H H H H H F Me Cl H R'' MeO HO Cl Br Me F Me Cl Benzo R''' H H H H H H H H 9f 8i 9i g h 8, 9 8a 9a 8b 9b 8c 9c 8d 9d 8e 9e 8f 10 f 8(9) / Z-10 / E-10 100 / 0 / 0 100 / 0 / 0 100 / 0 / 0 100 / 0 / 0 100 / 0 / 0 100 / 0 / 0 100 / 0 / 0 100 / 0 / 0 100 / 0 / 0 100 / 0 / 0 81 / 14 / 5 100/ 0*2 0 / 70 / 30 0 / 74 / 26 100 / 0 / 0 100 / 0 / 0 mp, 190 192 189 185 192 194 202 198 196 194 184 (131)* 187 131-133 140-142 195 215 Yield 8(9)+10, % 85 86 91 94 90 92 93 95 80 85 73 78 79 82 85 88 90 92
_______ * Melting point of 8f (10f). *2 Product 10 was detected by chromatography. 669
670
TABLE 3. Characteristics of Synthesized Compounds*

Compound 1 3a Empirical formula 2 C13H11F3N2O3S2 Found, % Calculated, % C H 3 4 42.74 42.85 3.00 3.04 NMR spectrum (CD3CN/CF3COOH), , ppm (J, Hz)*2
1
H 5
13
C 6
5a
4a
C8H9F3N2O3S2
31.66 31.79
2.94 3.00
6a
3b
C14H13F3N2O3S2
44.30 44.44
3.32 3.46
5b
2.32 (1, dd, J = 7.5, J = 15.6, H-6); 2.74 (1, d, J = 15.6, H-6); 5.45 (1, dd, J = 1.2, J = 7.5, H-5); 6.18 (1, d, J = 5.1, C-Thiaz); 6.33 (1, d, J = 5.1, C-Thiaz); 7.64 (2, t, Ph); 7.79 (1, t, Ph); 7.85 (2, d, Ph) 1.75 (1, dd, J = 12.1, J = 13.4, H-6); 2.25 (1, dd, J = 6.0, J = 13.4, H-6); 5.33 (1, dd, J = 6.0, J = 12.1, H-5); 6.31 (1, d, J = 5.1, C-Thiaz); 7.48 (1, d, J = 5.1, C-Thiaz); 7.68 (2, t, Ph); 7.80 (1, t, Ph); 7.89 (2, d, Ph) 2.22 (1, dd, J = 7.6, J = 15.7, H-6); 2.64 (1, d, J = 15.7, H-6); 3.34 (3, s, CH3); 5.50 (1, d, J = 7.6, H-5); 6.50 (1, d, J = 5.0, C-Thiaz); 6.91 (1, d, J = 5.0, C-Thiaz) 1.75 (1, br. t, J = 13.3, H-6); 2.28 (1, dd, J = 5.9, J = 13.3, H-6); 3.33 (3, s, CH3); 5.32 (1, dd, J = 5.9, J = 12.3, H-5); 6.46 (1, d, J = 5.1, C-Thiaz); 7.28 (1, d, J = 5.1, C-Thiaz) 2.06 (3, d, J = 1.6, CH3); 2.32 (1, dd, J = 7.6, J = 15.6, H-6); 2.72 (1, d, J = 15.6, H-6); 5.37 (1, dd, J = 1.1, J = 7.6, H-5); 6.07 (1, d, J = 1.6, C-Thiaz); 7.62 (2, t, Ph); 7.79 (1, t, Ph); 7.86 (2, d, Ph) 1.75 (1, dd, J = 12.2, J = 13.3, H-6); 2.16 (3, s, J = 1.6, CH3); 2.25 (1, dd, J = 6.0, J = 13.3, H-6); 5.27 (1, dd, J = 6.0, J = 12.1, H-5); 7.23 (1, d, J = 1.6, C-Thiaz); 7.68 (2, t, Ph); 7.80 (1, t, Ph); 7.90 (2, d, Ph)
25.4, 73.0, 80.6 (q, J = 29.8, OH); 102.2, 125.0 (q, J = 284.8, F3); 127.1, 130.4, 130.6, 130.8, 135.9, 164.6 27.7, 70.6, 81.6 (q, J = 29.9, OH); 102.5, 125.3 (q, J = 285.0, F3); 126.2, 130.4, 130.6, 130.8, 136.4, 165.0 24.2, 38.0, 71.5, 79.4 (q, J = 40.0, OH); 101.2, 125.2 (q, J = 285.2, F3); 126.4, 162.5 26.2, 37.0, 68.5, 80.4 (q, J = 40.1, OH); 100.9, 124.5, 125.5 (q, J = 285.2, F3); 164.6 12.7, 25.9 73.5, 80.6 (q, J = 30.0, OH); 123.4, 125.8 (q, J = 284.8, F3); 131.2, 131.2, 131.4, 131.5, 136.7, 165.7 13.0, 28.2, 71.0, 82.4 (q, J = 31.1, OH); 115.8, 126.1 (q, J = 285.0, F3); 131.2, 131.2, 131.4, 131.6, 137.2, 165.8
TABLE 3 (continued)
1 4b 2 C9H11F3N2O3S2 3 34.22 34.17 4 3.40 3.51 5 2.10 (3, d, J = 1.6, CH3); 2.34 (1, dd, J = 7.5, J = 15.5, H-6); 2.72 (1, d, J = 15.5, H-6); 3.35 (3, s, CH3); 5.44 (1, dd, J = 1.2, J = 7.5, H-5); 6.04 (1, d, J = 1.6, C-Thiaz); 1.81 (1, dd, J = 12.3, J = 13.5, H-6); 2.19 (3, s, J = 1.6, CH3); 2.20 (1, dd, J = 6.0, J = 13.5, H-6); 3.33 (3, s, CH3); 5.27 (1, dd, J = 6.0, J = 12.3, H-5); 7.26 (1, d, J = 1.6, C-Thiaz) 2.12 (3, s, CH3); 2.23 (1, dd, J = 7.6, J = 15.5, H-6); 2.71 (1, d, J = 15.5, H-6); 5.42 (1, d, J = 7.6, H-5); 6.15 (1, s, OH); 6.40 (1, C-Thiaz); 7.59 (2, t, Ph); 7.77 (1, t, Ph); 7.84 (2, d, Ph) 2.20 (3, d, J = 1.6, CH3); 2.26 (1, dd, J = 7.6, J = 15.5, H-6); 2.73 (1, d, J = 15.5, H-6); 3.11 (3, s, CH3); 5.57 (1, d, J = 7.6, H-5); 6.12 (1, s, OH); 6.97 (1, s, C-Thiaz) 6.28 (1, d, J = 14.0, =); 7.53 (3, m, C-Ph); 7.59 (2, m, CH-Ph); 7.94 (1, d, J = 14.0, =); 8.50 (1, s, CH-Thiaz) 3.83 (3H, s, CH3); 6.21 (1, d, J = 14.2, =); 7.08 (2, d, CPh); 7.55 (2, d, CH-Ph); 7.93 (1, d, J = 14.2, =); 8.64 (1, s, CH-Thiaz) 6.30 (1, d, J = 14.3, =); 7.60 (4H, m, C-Ph); 7.86 (1, d, J = 14.3, =); 8.68 (1, s, CH-Thiaz) 3.05 (1, dd, J = 6.1, J = 16.2, H-6); 3.49 (1, d, J = 16.2, H-6); 3.73 (3, s, CH3); 6.23 (1, d, J = 6.1, H-5); 6.47 (1, d, Ar); 6.65 (1, d, C-Ar); 7.21 (1H, s, H-Ar); 7.43 (2, t, Ph); 7.67 (2, d, Ph); 7.68 (1, t, Ph) 3.01 (1, dd, J = 6.0, J = 16.2, H-6); 3.24 (3, s, CH3); 3.37 (1, d, J = 16.2, H-6); 3.82 (3, s, CH3); 6.28 (1, d, J = 6.0, H-5); 7.19 (1, d, Ar); 7.33 (1, s, Ar); 7.69 (1, d, Ar) 6 12.8, 24.3, 38.2, 71.7, 79.6 (q, J = 39.8, OH); 123.0, 125.6 (q, J = 285.1, F3); 126.5, 162.4 13.1, 26.2, 37.5, 68.4, 80.3 (q, J = 40.0, OH); 116.0, 125.8 (q, J = 285.2, F3); 128.4, 164.0
6b
3c
C14H13F3N2O3S2
44.28 44.44
3.30 3.46
13.3, 25.9, 73.7, 80.0 (q, J = 31.1, OH); 98.4, 125.6 (q, J = 285.0, F3); 131.2, 131.3, 131.4, 131.6, 134.6, 164.1 13.2, 26.1, 38.3, 70.5, 78.9 (q, J = 40.6, OH); 95.8, 125.4 (q, J = 285.3, F3); 134.1, 163.1 109.4, 118.3, 124.4 (q, J = 280.1, F3); 128.6, 129.3, 129.8, 133.5, 141.6, 164.8, 171.7, 184.3 (q, J = 36.1, F3) 55.3, 108.4, 114.2, 117.3, 125.1 (q, J = 280.0, F3); 125.7, 130.9, 141.9, 160.7, 165.2, 171.6, 184.2 (q, J = 36.2, F3) 109.0, 116.4, 120.1, 124.8 (q, J = 278.8, F3); 127.1, 130.5, 141.8, 162.4, 164.9, 171.6, 184.3 (q, J = 36.0, F3) 28.5, 57.5, 71.7 81.1 (q, J = 32.5, OH); 109.3, 116.1, 118.6, 123.3 (q, J = 285.5, F3); 124.9, 131.6, 131.9, 132.7, 136.8, 139.2, 161.6, 168.9 28.5, 42.3, 57.5, 71.4, 80.8 (q, J = 32.6, OH); 109.5, 117.5, 119.0, 124.2 (q, J = 285.5, F3); 125.4, 132.1, 160.6, 169.0
4c
C9H11F3N2O3S2
34.03 34.17 52.20 52.35 51.07 51.22 46.85 46.93 48.48 48.64
3.42 3.51 2.94 3.04 3.15 3.38 2.56 2.42 3.30 3.40
7d 7e
C13H9F3N2OS C14H11F3N2O2S
7f 8a
C13H8ClF3N2OS C18H15F3N2O4S2
9a
C13H13F3N2O4S2
40.90 40.83
3.29 3.43
671
672
TABLE 3 (continued)
1 8b 2 C17H13F3N2O4S2 3 47.31 47.44 39.01 39.13 4 3.10 3.04 2.93 3.01 2.51 2.69 2.49 2.61 2.52 2.44 2.15 2.34 3.39 3.53 5 3.04 (1, dd, J = 6.0, J = 16.2, H-6); 3.51 (1, d, J = 16.2, H-6); 6.22 (1, d, J = 6.0, H-5); 6.41 (1, d, Ar); 6.63 (1, d, Ar); 7.22 (1H, s, Ar); 7.45 (2, t, Ar); 7.68 (2, m, Ar) 2.99 (1, dd, J = 6.1, J = 16.1, H-6); 3.22 (3, s, CH3); 3.37 (1, d, J = 16.1, H-6); 6.25 (1, d, J = 6.1, H-5); 7.15 (1, d, Ar); 7.30 (1, s, Ar); 7.60 (1, d, Ar) 3.07 (1, dd, J = 6.1, J = 16.0, H-6); 3.47 (1, d, J = 16.0, H-6); 6.25 (1, d, J = 6.1, H-5); 6.57 (1, d, Ar); 7.04 (1, d, Ar); 7.43 (2, t, Ar); 7.68 (3, m, Ar) 3.02 (1, dd, J = 6.2, J = 16.1, H-6); 3.23 (3, s, CH3); 3.35 (1, d, J = 16.2, H-6); 6.30 (1, d, J = 6.2, H-5); 7.53 (1, d, Ar); 7.68 (1, s, C-Ar); 7.74 (1, d, H-Ar) 3.04 (1, dd, J = 6.0, J = 16.0, H-6); 3.38 (1, d, J = 16.0, H-6); 6.33 (1, d, J = 6.0, H-5); 6.63 (1, d, Ar); 7.29 (1, d, Ar); 7.49 (2, t, Ar); 7.71 (3, m, Ar); 7.96 (1, s, Ar) 2.99 (1, dd, J = 6.1, J = 16.1, H-6); 3.23 (3, s, CH3); 3.33 (1, d, J = 16.1, H-6); 6.27 (1, d, J = 6.1, H-5); 7.70 (1, d, Ar); 7.71 (1, d, Ar); 7.97 (1H, s, Ar) 2.27 (3, s, CH3); 3.08 (1, dd, J = 6.1, J = 16.1, H-6); 3.52 (1, d, J = 16.1, H-6); 6.24 (1, d, J = 6.1, H-5); 6.41 (1, d, Ar); 6.87 (1, d, Ar); 7.39 (2, t, Ar); 7.45 (1, s, Ar); 7.64 (3, m) 2.40 (3, s, CH3); 3.02 (1, dd, J = 6.0, J = 16.1, H-6); 3.23 (3, s, CH3); 3.38 (1, d, J = 16.1, H-6); 6.32 (1, d, J = 6.0, H-5); 7.45 (1, d, Ar); 7.60 (1, s, Ar); 7.65 (1, d, Ar) 6 28.6, 71.5, 81.2 (q, J = 32.6, OH); 102.8, 111.3, 115.7, 123.5 (q, J = 285.9, F3); 124.2, 131.2, 132.2, 136.0, 138.8, 139.2, 156.9, 168.2 28.5, 42.2, 71.1, 80.6 (q, J = 32.6, OH); 112.0, 117.6, 120.0, 124.2 (q, J = 285.5, F3); 125.4, 132.2, 158.3, 169.2 29.2, 72.2, 82.0 (q, J = 33.5, OH); 117.0, 123.6, 125.0 (q, J = 285.4, F3); 125.6, 126.2, 132.4, 132.8, 133.7, 137.0, 137.5, 140.4, 170.9 28.8, 42.2, 71.4, 81.2 (q, J = 32.8, OH); 117.4, 124.3 (q, J = 285.4, F3); 125.0, 125.1, 131.7, 136.3, 136.8, 169.6 28.1, 71.2, 80.8 (q, J = 32.7, OH); 116.5, 121.4, 123.9 (q, J = 285.5, F3); 124.8, 127.7, 131.4, 131.9, 133.1, 136.5, 136.8, 138.1, 168.8 27.5, 41.2, 70.2, 79.7 (q, J = 32.5, OH); 116.9, 121.2, 124.1 (q, J = 285.5, F3); 124.3, 126.8, 133.0, 136.3, 168.1 21.2, 28.5, 71.5, 81.3 (q, J = 32.6, OH); 114.7, 123.2, 124.4 (q, J = 285.5, F3); 125.2, 131.8, 131.9, 132.6, 135.6, 136.6, 139.2, 141.6, 169.4 21.3, 28.4, 42.4, 71.1, 80.6 (q, J = 32.4, OH); 116.1, 123.7, 124.1 (q, J = 286.2, F3); 125.4, 132.4, 136.1, 141.9, 169.5
9b
C12H11F3N2O4S2
8c
C17H12ClF3N2O3S2 45.29 45.49 C12H10ClF3N2O3S2 37.11 37.26 C17H12BrF3N2O3S2 41.32 41.39 C12H10BrF3N2O3S2 33.26 33.42 C18H15F3N2O3S2 50.31 50.46
9c
8d
9d
8e
9e
C13H13F3N2O3S2
42.49 42.62
3.41 3.58
TABLE 1 (continued)
1 8f 2 C17H11F5N2O3S2 3 45.15 45.33 37.23 37.11 42.69 42.86 4 2.33 2.46 2.52 2.34 1.51 1.64 5 3.21 (1, dd, J = 6.4, J = 16.5, H-6); 3.36 (1, d, J = 16.5, H-6); 6.37 (1, br. s, H-5); 6.75 (1, t, Ar); 7.33 (1, d, Ar); 7.48 (2, t, Ar); 7.73 (3, m, Ar) 3.10 (1, dd, J = 6.1, J = 16.2, H-6); 3.24 (3, s, CH3); 3.27 (1, d, J = 16.2, H-6); 6.41 (1, d, J = 6.1, H-5); 6.79 (1, t, Ar); 7.35 (1, d, Ar) 5.85 (1, d, J = 8.3, =); 7.08 (1, m, Ph); 7.44 (1, m, Ph); 8.08 (1, dd, J = 8.3, J = 11.0, =) 6.35 (1H, br. s, =); 7.08 (1, m, Ph); 7.44 (1, m, Ph); 8.27 (1, d, J = 13.9, =) 2.39 (3H, s, CH3); 2.56 (3H, s, CH3); 5.84 (1, d, J = 8.0, =); 7.10 (1, s, Ph); 7.46 (1, s, Ph); 8.10 (1, d, J = 8.0, =) 2.39 (3H, s, CH3); 2.56 (3H, s, CH3); 6.46 (1, br. s, =); 7.09 (1, s, Ph); 7.43 (1, s, Ph); 8.31 (1, d, J = 13.6, =) C11H5Cl2F3N2OS 38.64 38.73 1.30 1.48 5.85 (1, d, J = 8.1, =); 7.10 (1, s, Ph); 7.47 (1, s, Ph); 8.09 (1, dd, J = 8.1, =) 6.33 (1, br. s, =); 7.09 (1, m, Ph); 7.45 (1, m, Ph); 8.30 (1, d, J = 13.7, =) 3.04 (1, dd, J = 6.0, J = 16.0, H-6); 3.38 (1, d, J = 16.0, H-6); 6.33 (1, d, J = 6.0, H-5); 6.63 (1, d, Ar); 7.29 (1, d, Ar); 7.49 (2, t, Ar); 7.71 (3, m, Ar); 7.96 (1, s, Ar) 2.99 (1, dd, J = 6.1, J = 16.1, H-6); 3.23 (3, s, CH3); 3.33 (1, d, J = 16.1, H-6); 6.27 (1, d, J = 6.1, H-5); 7.70 (1, d, Ar); 7.71 (1, d, Ar); 7.97 (1H, s, Ar) 6 29.6, 73.9, 82.2 (q, J = 32.5, OH); 113.2, 116.1, 121.7, 124.9 (q, J = 285.5, F3); 132.5, 133.2, 133.6, 135.5, 137.6, 140.1, 141.5, 169.4 29.4, 42.6, 73.1, 81.8 (q, J = 32.4, OH); 113.5, 116.0, 124.0, 124.3 (q, J = 286.4, F3); 132.4, 136.1, 141.6, 169.6 94.8, 103.8, 105.9, 117.9 (q, J = 280.0, F3); 130.8, 133.3, 138.0, 149.3, 156.9, 162.1, 182.1 (q, J = 35.3, F3) 99.4, 103.8, 105.9, 118.4 (q, J = 278.2, F3); 130.0, 131.2, 135.8, 146.9, 154.4, 159.7, 183.3 (q, J = 35.4, F3) 18.3, 21.7, 94.2, 118.1 (q, J = 280.1, F3); 120.5, 123.5, 126.4, 130.7, 136.9, 150.8, 156.8, 162.0, 182.2 (q, J = 35.4, F3) 18.3, 21.7, 99.1, 118.5 (q, J = 278.8, F3); 120.7, 123.8, 126.4, 130.6, 136.4, 147.8, 154.5, 159.3, 183.5 (q, J = 35.2, F3) 94.5, 103.9, 112.6, 118.1 (q, J = 279.8, F3); 126.8, 132.4, 137.6, 149.5, 156.8, 162.3, 182.2 (q, J = 35.4, F3) 99.6, 104.0, 115.3, 118.6 (q, J = 278.6, F3); 130.1, 131.8, 136.8, 146.9, 154.3, 159.9, 183.5 (q, J = 35.3, F3) 28.1, 71.2, 80.8 (q, J = 32.7, -OH); 116.5, 121.4, 123.9 (q, J = 285.5, F3); 124.8, 127.7, 131.4, 131.9, 133.1, 136.5, 136.8, 138.1, 168.8 27.5, 41.2, 70.2, 79.7 (q, J = 32.5, -OH); 116.9, 121.2, 124.1 (q, J = 285.5, F3); 124.3, 126.8, 133.0, 136.3, 168.1
9f
C12H9F5N2O3S2
cis-10f trans-10f cis-10g
C11H15F5N2OS
C13H11F3N2OS
51.80 51.99
3.54 3.69
trans-10g
cis-10h trans-10h 8i
C21H15F3N2O3S2
54.22 54.30 47.60 47.75
3.31 3.26 3.12 3.26
9i
C16H13F3N2O3S2
_______ IR spectrum, , cm-1: 1100-1300 (CF3), 1370-1385 (SO2), 1590-1610 (=), 1655-1670 (C=O), 3100-3400 (OH). *2 The spectra of compounds 3a,b, 4a,b, and cis-10f-h were taken in CD3CN; the spectra of compounds 3s, 4s, 7d-f were taken in DMSO-d6.
673
product only in the absence of a substituent in the 4 position of the starting 2-amino-1,3-benzothiazole. These data agree well with the values for the effective van der Waals radii of the atoms CH3 (2.00 ) > Cl (1.80 ) > F (1.35 ) > H (1.2 ) [13]. We must note that the reaction of cyclization of sulfones 1, 2 with 2-amino-1,3-benzothiazoles occurs with regiospecific and stereospecific formation of the isomer with axial sulfonyl and hydroxy groups. In this case, the isomer 8, 9 is more favorable both from the standpoint of hydrogen bond formation and for steric reasons. Thus we have studied the reaction of 2-aminothiazoles and their benzo and naphtho derivatives with -sulfonyltrifluoromethylvinyldiols 1, 2. We have found that the direction of the reaction is substantially affected by the steric bulk of the substituents in the starting aminothiazoles. The reaction of the sterically unhindered 2-aminothiazoles and their benzo and naphtho analogs with sulfones 1, 2 in acetonitrile leads to regiospecific formation of CF3-containing 6,7-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidines 3, 6 and stereospecific 3,4-dihydro-2H-pyrimido[2,1-b][1,3]benzothiazoles 8, 9 respectively. In the case of 2-aminothiazoles and 2-amino-1,3-benzothiazoles containing bulky substituents, the reaction occurs with formation of the corresponding enamino ketones 7, 10. We must note that the advantages of the synthesis are the simplicity of the reaction, the ease of separating the end products of the reaction, and the high yields.
EXPERIMENTAL The 1H and 13C spectra were recorded on a Varian VXR-400 spectrometer (400 MHz and 100 MHz respectively) in a 95:5 CD3CNtrifluoroacetic acid mixture, internal standard TMS. The IR spectra were obtained on a UR-20 spectrometer in vaseline oil. The TLC analysis was carried out on Silufol UV-254 plates with visualization in an acidified KMnO4 solution and iodine vapors. Synthesis of Compounds 3-10 (General Procedure). The corresponding 2-aminothiazole (1 mmol), dissolved in a minimal amount of acetonitrile, was added to a solution of sulfone 1, 2 (1 mmol) in acetonitrile (5 ml) at room temperature. The reaction was monitored by TLC. In the case of the heterocyclization reaction, the cycloadducts 3-6, 8, 9 formed were filtered out and washed with acetonitrile (3 1 ml). The oily cycloadducts 3b/5b and 3c were separated chromatographically. When enaminoketones 7, 10 were formed, the solvent was evaporated under vacuum. The enamino ketones were separated by column chromatography on silica gel. This work was done with the financial support of the Russian Foundation for Basic Research (project No. 00-03-32760a and No. 00-03-32763a).
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 674 W. L. Mosby, Heterocyclic Systems with Bridgehead Nitrogen Atoms, New York/London (1961), p. 779. G. Doria, C. Passarotti, R. Sala, R. Magrini, P. Sberze, M. Tibolla, R. Ceserani, G. Arcari, R. Castello, and D. Toti, Il Farmaco, 12, 885 (1985). C. K. Bradsher and D. F. Lohr, J. Heterocycl. Chem., 4, 74 (1967). S. I. Shul'ga and V. A. Chuiguk, Ukr. Khim. Zh., 36, 483 (1968). S. I. Shul'ga and V. A. Chuiguk, Ukr. Khim. Zh., 37, 257 (1971). S. I. Shul'ga and V. A. Chuiguk, Ukr. Khim. Zh., 37, 350 (1971). S. I. Shul'ga and V. A. Chuiguk, Ukr. Khim. Zh., 38, 169 (1972). A. L. Krasovsky, V. G. Nenajdenko, and E. S. Balenkova, Tetrahedron, 57, 201 (2001).
9. 10. 11. 12. 13.
V. G. Nenajdenko, A. L. Krasovsky, M. L. Lebedev, and E. S. Balenkova, Synlett., 12, 1349 (1997). A. L. Krasovsky, V. G. Nenajdenko, and E. S. Balenkova, Izv. Akad. Nauk, Ser. Khim., 1324 (2001). A. L. Krasovsky, V. G. Nenajdenko, and E. S. Balenkova, Synthesis, 1379 (2002). A. L. Krasovsky, A. M. Moiseev, V. G. Nenajdenko, and E. S. Balenkova, Khim. Geterotsikl. Soedin., 253 (2002). L. C. Pauling, The Nature of the Chemical Bond and the Structure of Molecules and Crystals. An Introduction to Modern Structural Chemistry, 3rd Ed., Cornell Univ. Press, Ithaca, New York (1960), p. 644; Chem. Abstr., 54, 6292 (1960).
675
QUANTUM-CHEMICAL STUDY OF THE STRUCTURE OF 1,2,2,3,4,4-HEXACHLORO1,3-DIPHOSPHETANE ISOMERS

G. B. Soifer1 and V. P. Feshin2 We have used the RHF/6-31G* method to optimize the geometric parameters of three isomers of the (ClPCCl2)2 molecule. We have established that the trans isomer is the most stable, and that it is energetically more favorable than the two cis isomers by 7.8 and 14.2 kJ/mole respectively. Keywords: 1,2,2,3,4,4-hexachloro-1,3-diphosphetane, cis and trans isomers, the RHF/6-31G* method, nonempirical calculations, molecular structure. The structural features of molecules with four-membered phosphorus-carbon heterocycles have attracted the attention of researchers for a rather long time; see, for example, [1]. In [2], X-ray diffraction was used to study the molecular structure of crystalline 1,2,2,3,4,4-hexachloro-1,3-diphosphetane (ClPCCl2)2, as a result of which it was established that its molecules in the solid state exist as the trans isomer, contrary to the opinion that the cis isomer is preferred (see the discussion in [2]). So it seemed to be of interest to use quantum-chemical calculations to determine which of the isomers of the given diphosphetane is energetically more favorable, and also the structural features of its possible isomers.
Cl(1) P(1) C(1) Cl(3) Cl(5) Cl(1) P(2) Cl(2) P(1) C(1) Cl(3) Cl(5) Cl(2) P(2)
Cl(4)
C(2) Cl(6)
Cl(4)
C(2) Cl(6)
1
Cl(3) Cl(5)
P(1) C(1)
P(2)
C(2) Cl(1) Cl(4) Cl(6)
Cl(2)
3 __________________________________________________________________________________________ Perm State University, Perm 614600, Russia; e-mail: info@psu.ru. 2 Institute of Technical Chemistry, Urals Branch, Russian Academy of Sciences, Perm 614600; e-mail: cheminst@mpm.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 793-797, May, 2004. Original article submitted May 25, 2001. 676 0009-3122/04/4005-06762004 Plenum Publishing Corporation
1
With this objective, we carried out a nonempirical quantum-chemical calculation for the indicated molecule with full optimization of its geometry by the restricted HartreeFock method (RHF) in the split-valence basis 6-31G* using the program Gaussian 94W [3], and we established that the four-membered heterocycle PCPC is nonplanar with a bend along the CC line (the same nonplanarity of the ring was observed by X-ray diffraction in [2]). Consequently, the existence of three isomers is possible: one trans isomer (1) and two cis isomers (2 and 3). In the trans isomer 1, the PCl bonds are on different sides of the nonplanar P2C2 ring, while in the other two isomers these bonds are located either on the concave side of the ring (cis isomer 2) or on the convex side of the ring (cis isomer 3). According to the calculation, the bending angle of the P2C2 ring along the C(1)C(2) line in the trans form 1 is equal to 21.2, while in the cis forms 2 and 3 it is 8.6 and 27.8 respectively. For comparison, we note that in the trans isomer, in the crystal this bending angle is as large as 29.9 [2]. As we see from the calculated energies of the E-isomers (see Table 1), for the free molecule the trans isomer is the most stable, i.e., just as was experimentally established in the case of the crystal for the studied compound in [2]. In this case, the differences between the total energies of the isomeric forms suggest that the trans isomer 1 is more stable than the cis isomers 2 and 3 by 7.8 and 14.2 kJ/mole respectively. These data are consistent with the conclusion in [2] that as a result of dimerization of the phosphaalkene Cl2C=PCl, the trans isomer 1 is mainly formed. They allow us to also hypothesize that the other dimerization product, the yield of which is ~2% [4], may be the cis isomer 2. Comparison of the calculated bond lengths and bond angles with those found by X-ray diffraction (see Tables 1-3) indicates that their agreement is satisfactory, considering that the calculation was carried out for the free molecule while the experimental structure refers to the crystal. Note the appreciable difference between the lengths of the two PCl bonds in the trans isomer: the P(1) Cl(1) bond is longer than the P(2)Cl(2) bond. This difference is also shown in the experiment, with a somewhat different value. We see differences between the calculated and experimental PC bond lengths of the other two portions of the dimer ring for the trans isomer that are also qualitatively the same. Such a pattern is also observed for the ClPC and CPC angles in different halves of the given isomer (see Table 1). All these structural features of the trans isomer are due to the different directions of the two PCl bonds in the molecule relative to the line of bend for the ring of the four-membered P2C2, which leads to nonequivalence of not only the PCl bonds themselves but also bond angles at the two phosphorus atoms. TABLE 1. Bond Lengths (d) of trans-(1) and cis (2 and 3) Isomers of the (ClPCCl2)2 Molecule, Calculated by the RHF/6-31G* Method, and Bond Lengths of the trans Isomer According to X-ray Diffraction Data [2], and the Molecular Energies (-E)*
d, Bond X-ray diffraction (1) 2.032 2.013 1.911, 1.890 1.876, 1.879 ~1.761 ~1.770 1 2.048 2.033 1.915 1.889 1.767 1.774 2 2.042 2.042 1.912 1.912 1.755 1.790 3 2.027 2.027 1.906 1.906 1.779 1.761
P(1)Cl(1) P(2)Cl(2) P(1)C(1), P(1)C(2) P(2)C(1), P(2)C(2) C(1)Cl(3), C(2)Cl(5) C(1)Cl(4), C(2)Cl(6)
_______ * Molecular energy, -E, au: 3514.03628 (1); 3514.029672 (2); 3514.027235 (3). 677
We note that in the trans isomer 1 the dihedral angle Cl(1)P(1)P(2)Cl(2) according to X-ray diffraction is -179.85 [2], while the calculation gives -179.97 (in the cis isomers 2 and 3, this angle is equal to 0 after full optimization of their geometry). In this case, in the trans isomer 1, according to the calculation the P2C2 ring (and the entire molecule along with it in the free state) has a symmetry plane passing through the Cl(1), P(1), P(2), Cl(2) atoms. As we see from X-ray diffraction data in [2], such symmetry (Cs) is absent in the crystal. The crystal effects lead to distortion of the P2C2 ring, as a result of which the pairwise equality of the PC bond lengths and ClPC angles in each half of the dimer structure 1 breaks down (Tables 1 and 2). While there is a clear difference between the lengths of the two PCl bonds in the trans isomer and this causes nonequivalence of the two halves of the four-membered ring, in the cis isomers we observe that the two parts of the dimer are completely identical. The latter means that the molecule has C2v symmetry, i.e., in addition to the symmetry plane characteristic of the free trans isomer, the cis isomer has another symmetry plane and a two-fold symmetry axis of rotation. TABLE 2. Bond Angles () of trans (1) and cis (2 and 3) Isomers of the (ClPCCl2)2 Molecule, Calculated by the RHF/6-31G* Method, and Bond Angles of the trans Isomer 1 According to X-ray Diffraction Data [2]
, deg. Angle X-ray diffraction (1) 100.1 100.6 105.3 105.5 1 102.2 102.2 107.4 107.4 117.2 112.1 107.0 117.5 109.2 117.2 112.1 107.0 117.5 109.2 82.0 83.4 93.3 93.3 2 102.7 102.7 102.7 102.7 117.8 117.8 106.7 106.7 109.2 117.8 117.8 106.7 106.7 109.2 81.9 81.9 97.5 97.5 3 106.8 106.8 106.9 106.9 111.1 111.1 116.9 116.9 109.4 111.1 111.1 116.9 116.9 109.4 82.7 82.7 90.3 90.3
Cl(1)P(1)C(1) Cl(1)P(1)C(2) Cl(2)P(2)C(1) Cl(2)P(2)C(2) Cl(3)C(1)P(1) Cl(3)C(1)P(2) Cl(4)C(1)P(1) Cl(4)C(1)P(2) Cl(3)C(1)Cl(4) Cl(5)C(2)P(1) Cl(5)C(2)P(2) Cl(6)C(2)P(1) Cl(6)C(2)P(2) Cl(5)C(2)Cl(6) C(1)P(1)C(2) C(1)P(2)C(2) P(1)C(1)P(2) P(1)C(2)P(2)
81.3 82.5 93.4 94.0
TABLE 3. Charges on the Atoms (q) of trans (1) and cis (2 and 3) Isomers of the (ClPCCl2)2 Molecule, Calculated by the RHF/6-31G* Method
Atom P(1) P(2) Cl(1) Cl(2) C(1), C(2) Cl(3), Cl(5) Cl(4), Cl(6) 1 +0.760 +0.763 -0.226 -0.213 -0.658 +0.055 +0.061 q, e 2 +0.777 +0.777 -0.224 -0.224 -0.664 +0.075 +0.037 3 +0.742 +0.742 -0.199 -0.199 -0.653 +0.033 +0.077
678
The charges q on the atoms are distributed accordingly: in the trans isomer, the charges on the chlorine atoms of the two PCl are different (as on the phosphorus atoms, although to a significantly lesser degree), while in each of the cis isomers these charges are identical (Table 3). Of course, in both the trans and the cis isomers, the CCl bonds located on different sides of the nonplanar P2C2 ring remain nonequivalent, which is apparent in the differences between their lengths and the charges on the corresponding chlorine atoms (Tables 1 and 3). As we see, the ratios of the charges on the chlorine atoms of the CCl bonds and the lengths of the latter bonds on different sides of the ring in cis isomers 2 and 3 depend on the position of the PCl bonds relative to the bend of the P2C2 ring: the shorter CCl bonds are located on the same side of the ring as the PCl bonds. In the trans isomer, the differences between the CCl bond lengths are significantly smaller. On the whole, as a result of the quantum chemical study of the conformations of the free (ClPCCl2)2 molecule, we have established that its trans isomer has the highest stability, which according to the data in [2] is also apparent in the solid state. The secondary product of dimerization of the phosphaalkene Cl2C=PCl [4] is probably the cis isomer 2.
REFERENCES 1. 2. 3. A. N. Chernega, M. Yu. Antipin, Yu. T. Struchkov, E. A. Mel'nichuk, and N. G. Feshchenko, Zh. Strukt. Khim., 31, No. 1, 177 (1990). A. N. Chernega, G. N. Koidan, and A. P. Marchenko, Zh. Strukt. Khim., 33, No. 5, 155 (1992). M. J. Frisch, G. W. Trucks, H. B. Schlegel, P. M. W. Gill, B. G. Johnson, M. A. Robb, J. R. Cheeseman, T. Keith, G. A. Petersson, J. A. Montgomery, K. Raghavachari, M. A. Al-Laham, V. G. Zakrzewski, J. V. Ortiz, J. B. Foresman, J. Cioslowski, B. B. Stefanov, A. Nanayakkara, M. Challacombe, C. Y. Peng, Y. P. Ayala, W. Chen, M. W. Wong, J. L. Andres, E. S. Replogle, R. Gomperts, R. L. Martin, D. J. Fox, J. S. Binkley, D. J. Defrees, J. Baker, J. P. Stewart, M. Head-Gordon, C. Gonzalez, and J. A. Pople, Gaussian 94, Revision E.3, Gaussian, Inc., Pittsburgh PA (1995). I. F. Lutsenko, Z. S. Novikova, A. A. Prishchenko, A. A. Borisenko, and A. V. Gromov, The Chemistry and Application of Organophosphorus Compounds [in Russian], Nauka, Leningrad (1987), p. 223.
4.
679
THIRD "BALTICUM ORGANICUM SYNTHETICUM" CONFERENCE IN RIGA

E. Lukevics The first Baltic International Conference on organic synthesis "Balticum Organicum Syntheticum" (BOS-2000) was held in Vilnius (Lithuania) in June, 2000 [1, 2]. In the view of its main organizer V. Snieckus (Queen's University, Canada) the conference would acquaint the chemists of the West with the achievements of Baltic chemists, create conditions for discussion, and strengthen scientific links between them. All this was realized magnificently and formed the basis for the organization of the next conference BOS-2002, which was held in Vilnius in June, 2002 [3, 4]. Now, two years later, the BOS-2004 conference is being held in Riga (Latvia) from June 27 to July 1, 2004. This is the beginning of a new tradition of regular Baltic international conferences on organic synthesis. The third conference has been organized on the basis of the principles that proved so successful at previous conferences. First, there is the distinguished reputation of the invited participants. Plenary and invited speakers are professors from universities and research centers of six nations. They include D. Evans, M. F. Lipton, D. W. C. MacMillan, K. C. Nicolaou, E. Reichmanis, G. Stork, and R. Waltermire representing the USA, R. W. Friesen from Canada, D. Enders and P. Knochel from Germany, J. Cossy from France, S. V. Ley from Great Britain, and T. Fukuyama from Japan. Second, there is the blend of academic science and the interests of the chemical and pharmaceutical industry. The speakers represent not only universities (Harvard, Columbia, Aachen, Cambridge, Tokyo, and a series of others) but also the world's leading pharmaceutical companies, such as Pfizer, Merck, and BristolMyers Squibb. Third, there is extensive participation from students and young scientists. To each of the Balticum Organicum Syntheticum conferences the publisher of "Chemistry of Heterocyclic Compounds" has devoted special issues containing papers on researches into the chemistry of heterocyclic compounds by chemists in the nations of the Baltic Coast [5, 6]. We are also marking the third conference with the publication of special issues (Nos. 6 and 7) containing papers by scientists from Poland, Lithuania, Latvia, and St. Petersburg. The papers in the present issue present the results of researches into heterocalixarenes and also on the development of methods for the synthesis of new derivatives of azetidinone, pyrrolidinones, pyridinones, 3-acylpyridines, pyrimidinediones, imidazopyrimidine, triazolodiazepine, oxazolidine, and oxadiazole, study of the hydroxylation of heteroaromatic aldimines, the transesterification of 2-aziridinecarboxylic esters, the electrochemical oxidation of dihydropyridines, and the transformations of pyrimidinylacetyl azide, determination of the relationships governing screening in the 14N NMR spectra, and determination of the cytotoxicity of derivatives of pyranone, di(3-indolyl) selenide, and the complexes of 8-quinolineselenol with metals.
__________________________________________________________________________________________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 803-804, June, 2004. 0009-3122/04/4006-06812004 Plenum Publishing Corporation 681
In addition, simultaneously with the conference we mark the seventieth anniversaries of outstanding Latvian chemists G. Duburs, Professor of organic chemistry and medicinal chemistry of the A. Strakov Riga Technical University (papers about them and their work will be published in No. 7 of the journal) and habilitation Dr. L. Leite [7], specialist on catalysis, one of whose papers is published in this issue. In the seventh issue of the journal there will also be an article about the anniversary of Prof. O. N. Chupakhin (Russia), Full Member of the Russian Academy of Sciences, who has long collaborated with Latvian chemists. The Editorial Board of "Chemistry of Heteroorganic Compounds" wishes success to the participants of the BOS-2004 conference and thanks all the authors who have sent articles for these special issues.
REFERENCES 1. 2. 3. 4. 5. 6. 7. "Balticum Organicum Syntheticum" International Conference on Organic Synthesis, Program and Abstracts, Vilnius (2000). P. Trapencieris and S. Tumkevicius, Khim. Geterotsikl. Soedin., 1433 (2000). "Balticum Organicum Syntheticum" International Conference on Organic Synthesis, Program and Abstracts, Vilnius (2002). P. Trapencieris, Khim. Geterotsikl. Soedin., 1313 (2002). Khim. Geterotsikl. Soedin., No. 6, No. 7 (2000). Khim. Geterotsikl. Soedin., No. 6, No. 7 (2002). Bibliografija (2003), Latvijas Organiskas Sintezes Instituts (2004).
682
HETEROCALIXARENES. (REVIEW)
W. Sliwa Heterocalixarenes, i.e. heterocycle-based calixarenes, are interesting as receptors of a variety of molecules and ions. These compounds are described with regard to their syntheses, reactivity, and inclusion properties. In the presentation of benzoxazine-based calixarenes attention is paid to their chirality. Keywords: benzoxazine, furan, inclusion properties, pyridine, resorcarenes. Heterocalixarenes or calixhetarenes belong to the family of calixarenes [1-8], compounds intensively studied due to their interesting chemical and physicochemical properties as well as their application possibilities. Calixarenes contain phenol units, while heterocalixarenes are built from heterocyclic moieties, i.e. they are heterocycle-based. Another class are heteracalixarenes, i. e. aza- [9, 10], oxa- [11, 12] and thiacalixarenes [13, 14], in which bridges between phenol units contain heteroatoms N, O, or S. Also known are calixarenes with appended heterocyclic moieties; they do not build the receptor cavities [15]. One should mention here also resorcarenes, built from resorcinol units [16, 17], and cavitands [18-20] resulting from the bridging of resorcinol hydroxyl groups of neighboring aromatic rings. In this review, heterocalixarenes built from pyridine moieties and from other heterocycles are described in the first and second parts, and in the third part those built from benzoxazine units are presented, with special attention paid to their chirality. Calixpyrroles are a large class of heterocalixarenes for which many works are reported [21-23]; therefore, these compounds are reviewed elsewhere [24].
1. HETEROCALIXARENES WITH PYRIDINE UNITS In order to obtain calixarenes 1 built from pyridine moieties, bridged at the 3 and 5 positions, the reactions of 2,6-dihydroxypyridine with aldehydes in acidic medium were performed [25]. The increased temperature and time of reactions allow one to avoid the formation of configurational isomers (Scheme 1). The reaction of calix[4]pyrrole 2 with dichlorocarbene, generated from sodium trichloroacetate, involving pyrrole ring expansion, leads via mono-, di-, and trichloropyridine species 3, 4 and 5 to chloropyridine-based calix[4]arenes 6, bridged at the 2 and 6 positions [26, 27] (Scheme 2). The chlorine atoms are present in positions a or b. One should mention here also macrocycle 7, a specific receptor of tricarboxylate anions, obtained in a simple, one-step procedure from 3-bromomethylpyridinium bromide by neutralization with NaHCO3 and subsequent extraction with dichloromethane [28]. Anions of tricarboxylic acids 8-12 have been used as guests (Scheme 3). __________________________________________________________________________________________ Institute of Chemistry and Environmental Protection, Pedagogical University, 42-201 Czestochowa, Poland; e-mail: w.sliwa@wsp.czest.pl. Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 805-824, June, 2004. Original article submitted January 20, 2003. 0009-3122/04/4006-06832004 Plenum Publishing Corporation 683
Scheme 1
HO R HO RCHO [H+] N HO N OH R OH N OH R N 1 OH
HO
OH
R HO
R = Me, n-Bu, 2-methylpropyl, n-C11H23, Ph, 4-C6H4NO2
Scheme 2
Cl N H NH H N 2 Cla Clb Cla HN N NH H N 3 Clb HN
: CCl2
HCl
: CCl2
HCl
N NH N Clb Cla Cla Clb HN or NH
N
N
Cla
: CCl2
Clb HCl
H N 4b Cla
4a
Clb
N NH N Clb Cla
N
Cla
Clb
N
N
Cla
N
: CCl2
HCl Clb Cla
N Clb Cla
Clb
684
Scheme 3
HOOC N+ + N N + +N 7 4 Br HOOC HOOC 11 12 COOH HOOC COOH COOH COOH COOH 9
COOH COOH 8
HOOC
HOOC
COOH COOH 10
2. HETEROCALIXARENES WITH OTHER HETEROCYCLES The furan-based calixarene 13 was obtained by condensation of furan with acetone. This compound (as a diene) was subjected to a DielsAlder reaction with benzyne (as a dienophile), generated by the pyrolysis of benzenediazonium-2-carboxylate. The formed cycloadduct 14 was catalytically hydrogenated to give monoadduct 15 which was aromatized by acid-promoted dehydration with TsOH in toluene affording 16 [29]. The bis-adducts of 13 with benzyne 17 and 18 hydrogenated in a similar way afforded 19 and 20, aromatized into 21 and 22, respectively [29]. It was established that the bis-adduct 17 has a more opened-up cavity than 18. Also the tris-adduct 23 is known (Scheme 4). The DielsAlder reaction of 13 with DMAD gave the mono-adduct 24 and four isomeric bis-adducts 2528 [29]. The selective hydrogenation of the olefinic units which do not bear the ester functions gives compounds 29-33. They have been subjected to the thermally promoted retro DielsAlder reaction resulting in furan-based calixarenes in which the furan rings involved in cycloadditions contain carboxylate groups in the 3 and 4 positions. The retro DielsAlder reaction was performed by pyrolysis at 220C; in these processes from 29 the furan-based calixarene 34 was obtained, 30 and 31 afforded compound 35, while 32 and 33 gave 36. The carboxylate groups of the synthesized derivatives may be modified, for example, hydrolyzed or transesterified. It should be pointed out that furan-based calixarenes in which the furan units contain dicarboxylate functions at the 3 and 4 positions cannot be obtained by the condensation of 3,4-furandicarboxylate due to the electron-withdrawing deactivating effect of these groups (Scheme 5). In order to obtain calixfuranopyrrole 37, the condensation of its precursors 38 and 39 has been performed [30] (Scheme 6). The reaction of pyrimidine 40 with bis(bromomethyl)benzenes 41 leads to compounds 42 which undergo subsequent cyclization with 41 to give calix[2]arenes 43a-f; selected examples of 43 are presented (Scheme 7, ref. [31]). The titration of calixarene 43f, possessing the chromogenic nitrophenol unit serving as one of the binding sites against metal acetates, results in the formation of 1:1 43fmetal acetate complexes, with preference for alkaline earth metal cations over alkali metal cations. It was observed that 43e weakly binds acetonitrile and malonitrile. Heterocalix[3]arenes containing cyclic ureido systems and linked by carbonyl groups in place of methylene spacers, 44-46, have been synthesized as shown in Scheme 8, ref [32].
685
Scheme 4
686
Scheme 5
O O H2 / MeOH Pd / CaCO3
O O 200oC O
O
O
O
O
O E 29 E
E 24
34
O E E 25 E E O
O
H2 / MeOH Pd / CaCO3 E E O
O O 30 E E 220oC E E
O
O O
O
O E
O E E 26 O
O
H2 / MeOH Pd / CaCO3 E E E E O
E 35
O E 31
687
688 Scheme 5 (continued)

E E E E O O O O E E
O
O H2 / MeOH Pd / CaCO3
O O
E E
E
O
O 220oC
27
32
O O
O
O E E O H2 / MeOH Pd / CaCO3
O E E E O E
E
O
E
O
36 O
28
33
Scheme 6
O NH OH O 38 +
O HN acid HO O O O H N n N H O O
39 37 n = 1, 3
Scheme 7
O OSiMe3 N N 40 Br R1 Br H N O N R1 O H N N O
+
OSiMe3 R2 41 R1 = H, OH, OMe R2 = H, Me R2 42
R4 R4 R1 N O N O R3 R1 O N N 43 a b c d e f R2 43 OMe H OMe OMe OH OH R2 Me H Me Me Me Me R3 H OMe OMe OAc OH OH R4 H OMe Me Me Me NO2
O Br R3 Br
R3 = H, OH, OMe, OAc R4 = H, Me, OMe, N2O
689
Scheme 8
Me Me Me OMe AlCl3 / CHCl3 Me OMe NBS
+
COCl
O Br Br OMe
O HN O N H R HN O
R R
H N N H R
N H R
O N O N
R N OMe O N
O N OMe O N OMe
O 44a,b a R = H, b R = Me
O 45
O 46a,b a R = H, b R = NO2
Similar calix[4]arenes bearing benzene or pyridine units have been obtained and their X-ray crystal structure and conformational analyses performed [33]. The synthesis begins with the FriedelCrafts reaction of isophthaloyl dichloride 47a or 2,6-bis(chlorocarbonyl)pyridine 47b with 2-methylanisole 48, followed by bromination with NBS. The cyclocondensation of the formed dibromide 49a,b with uracil 50, quinazolinedione 51, and benzimidazolone 52 under solid-liquid phase-transfer catalytic conditions gave heterocalixarenes 53-55. Analogous reactions of 47a with 4-methylanisole 56 afforded compounds 57 and 58 (Scheme 9, ref. [33]). Heterocalix[4]arenes 59a,b and heterocalix[8]arenes 60a-d containing benzimidazol-2-one moieties have been synthesized [34]; these latter form crystalline inclusion compounds with solvents: 60atoluene (1:3); 60bCH2Cl2 (1:1); 60ctoluenewater (1:2:1); and 60dacetoneCH2Cl2 (1:1:1). It was observed that these hosts have higher complexing properties than conventional calix[8]arene 61.
690
Scheme 9
Cl O Y Cl O 48 R = Me, n-C8H17 Me OR 1. AiCl3 / CHCl3 2. NBS
47a,b a Y = CH, b Y = N
Br RO
Br OR
Y O 49a,b O
a Y = CH, b Y = N
O HN O N H HN O 50
H N O N H 51 52
N H
O RO N O Y O 53 O RO N O Y O 54 O N OR O O 55 N OR RO N O Y O N OR
691
Scheme 9 (continued)
Me Cl O 47a Cl O OMe 56 Br Br HN O N H MeO O 57 H N MeO O O OMe 52 O N H N O MeO O 58 O OMe N O O N O OMe N O
It was established that heterocalix[9]arene 62 forms with acetone and CH2Cl2 (1:2:2) inclusion complex (Scheme 10, ref. [35]). Scheme 10
R2
N O
R2
N R2 R1 N O O
N N R1 N R2 R2 O N
R1
R1 N O N
R1 O N N
R1 R2
59a,b a R1 = OMe, R2 = H; b R1 = OMe, R2 = t-Bu;
60ad a R1 = OMe, R2 = H; b R1 = OMe, R2 = t-Bu c R1 = OMe, R2 = Ph; d R1 = OH, R2 = t-Bu
692
N Me OH OH HO N OH HO N OH OH HO N O N O OMe O
N O
N Me MeO N O N O N
OMe
Me
61
62
3. HETEROCALIXARENES WITH BENZOXAZINE UNITS Numerous works concern chiral benzoxazine-based calixarenes [36-39], an example being the enantioselective synthesis of axially chiral enantiomerically pure 63 [37].
Me N MeO R O Me N N Me MeO R O N Me 63 R = n-C11H23 R OMe O O R OMe
The reaction of all-cis isomers of resorcarenes 64a,b with primary amines and formaldehyde affords regioselectively C4-symmetrical benzoxazine-based calixarenes 65a,b, which are chiral host molecules with extended cavities [40].
693
The enantiomerization of 65a,b catalyzed by traces of acid proceeds via immonium intermediates 66 [41]. It was observed that the reaction of 65a,b with acetic anhydride results in the opening of the oxazine ring with the elimination of formaldehyde which leads to tetramides 67a,b; the attempted acylation of the hydroxyl groups was not achieved (Scheme 11, ref. [41]). Scheme 11
R1 N HO OH R1NH2 CH2O 4 HO O
R a n-C5H11 64 b n-C6H13
R1 R a n-C5H11 cyclohexyl 65 b n-C6H13 n-C4H9
R1 N HO O + H+ R 4 - H+ HO
R1 + CH2 N CH2 OH - H+ R 4 + H+ O
R1 N OH
66
R1 N HO O Ac2O / Et3N / DMAP R

4
CH3 R1 N CH2 HO OH O
- CH2O
4
65a,b
67a,b
It should be mentioned that the tetrakis(O-methylation) of 65a,b can be performed by treatment with n-butyllithium to deprotonate the hydroxyl group and using methyltriflate as a methylating reagent [37]. 694
The condensation of resorcarenes 68 with amino alcohols and formaldehyde affords benzoxazine-based calixarenes 69 (Scheme 12, ref. [42]). Scheme 12
R1 N HO R HO OH R OH H2N ( ) OH / CH2O n n = 2, 4, 6 HO R HO 68 R = Me, n-C5H11, n-C11H23 OH R OH HO R O N R1 69 R1 = HO(CH2)n OH R O O R1 N N R1 HO R O R OH
It was observed that the chiral benzoxazine-based calixarene (-)-70 undergoes the removal of formaldehyde molecule by treatment with hydrochloric acid in the n-propanol-water system to give resorcarene (-)-71 [43]. This compound exists in the solid phase in a crown conformation; its crystallographic structure data are reported. The HPLC enantiomeric resolution of inherently chiral benzoxazine-based calixarenes 72a-d has been achieved, this experiment being proof of their chirality in solution (Scheme 13, ref. [40]). It was established that chiral, lipophilic benzoxazine-based calixarene 73 forms Langmuir monolayers on water surfaces [44]. The Langmuir isotherm technique is a fast method for the estimation of enantioselection by chiral macrocyclic ligands forming Langmuir films on the water surface; this qualitative test gives information on the magnitude of enantioselection.
R1 N HO R O R1 N N HO R O N R1 73 R = C11H23 R1 = PhCHMe OH R O R1 O R OH
695
Scheme 13
Ph Me NH . HCl
O Me H O Ph N O H Me O N Me (-)-70 Ph O Me H O Me HCl n-PrOH / H2O
Ph N H Me Me N Ph O O
Me
H Me Ph O HCl . NH O
H Me
Me H O Ph NH . HCl Me H
Me H O O
Me H
HCl . NH Me Ph (-)-71
Ph N HO R Ph N N HO R O N Ph R OH a b 72 c d R Me n-C5H11 n-C11H23 Ph-CH2-CH2 O Ph O O R OH
The condensation of resorcarene 64a with ethylenediamine and formaldehyde under high dilution conditions affords the "dimer" 74 [45]. Two possible isomers, the chiral D4-symmetrical 74a and C4h-symmetrical 74b, could not be distinguished by NMR spectroscopy. It was observed that the cavities of both isomers collapse after some picoseconds because two resorcarene units adopt pinched cone conformations with C2 symmetry. Due to this behavior, no inclusion compounds are formed [46]. The acid-catalyzed hydrolysis of 74 leads to oxazine ring opening resulting in the formation of secondary amine 75 (Scheme 14, ref. [45]). In the review only selected examples of heterocalixarenes have been presented. One should mention here also polyazacompounds 76-79 with tetrahedrally situated nitrogen lone pair orbitals and high conformational flexibility [46], as well as the dione 80 [46] and annulenoid tetrathiafulvalenes 81 [47] (Scheme 15). Since many works dealing with calixarenes are reported [48-51] due to their application possibilities as receptors, especially in nuclear waste management, attention should also be paid to heterocalixarenes, as their analogues, which are not yet so much investigated. This topic is concerned with supramolecular chemistry [52-55], a rapidly developing research area of promising perspectives. 696
Scheme 14
Scheme 15
N N N N
N N N N N N
N N N
76
77
697
N N N N N N N 78 N N N N N N N N N N N N N 79 N N N N N N N N
O O O
S O S
NC NC
S S
S S
CN CN
80
81 Y = O, S
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700
HYDROSILYLATION OF (HETERO)AROMATIC ALDIMINES IN THE PRESENCE OF A Pd(I) COMPLEX

I. Iovel, L. Golomba, M. Fleisher, J. Popelis, S. Grinberga, and E. Lukevics The reaction of triethylsilane with heterocyclic and aromatic azomethines, catalyzed by the [Pd(allyl)Cl]2 complex, was studied. It was found that the reaction is affected by the nature of the functional groups in the aza and methine parts of the aldimine molecules, which were produced by the condensation of furan, thiophene, and benzene aldehydes with aniline and its derivatives. The reactivity of a series of imines is compared with their electronic and structural characteristics, determined by quantum-chemical methods. The corresponding furan, thiophene, and aromatic amines and also certain silylamines were synthesized. Keywords: transition metal complexes, Schiff bases, hydrosilylation, catalysis. Investigations into catalytic hydrosilylation of the C=N bond are of both practical significance (for the production of useful items) and theoretical interest (to determine the relationships governing the processes). As known (see the reviews [1-3] and also the papers [4-6]), hydrosilylation of the CH=N double bond leads mainly to the formation of products silylated at the nitrogen atom. Recently, we found for the first time [7] in the reaction of alkylhydrosilanes with furan, thiophene, and pyridine aldimines containing a trifluoromethyl group at the ortho position of the aza part of the molecules that addition of the silyl group at the carbon atom of the imine CH=N bond takes place alongside N-silylation. It is possible that the last process takes place by a carbene mechanism [8]. In this connection it seemed of interest to determine the dependence of the direction of hydrosilylation on the structure of the initial amines and also the effect of electron-donating and accepting functional groups in the aza and methine parts of the molecules on this process. In the present work the method that we developed previously [9-14] with molecular sieves as effective agents for the condensation of aromatic and heterocyclic aldehydes with various amines was used for the production of the aldimines. A series of syntheses were realized, and the corresponding N-(hetarylmethylidene)and N-(arylmethylidene)anilines were obtained. As we discovered earlier [5, 7], one of the most active catalysts for the hydrosilylation of imines is the dimeric complex of monovalent palladium bis{[-chloroallyl]palladium} [Pd(allyl)Cl]2. In the present work we studied the reaction of the above-mentioned previously synthesized aldimines with trimethylsilane in the presence of this complex. The reactions were conducted in benzene at 65C with the substrate and silane in a molar ratio of 1:1.2 and a catalyst concentration of 2 mol %. The reactions were monitored by TLC and GLC-MS. At the end of silylation (the reaction times are given in Table 2) the reaction mixture was treated (as indicated in the experimental section) and was analyzed by 1H NMR. The spectra of the reaction mixture
__________________________________________________________________________________________ Latvian Institute of Organic Synthesis, Riga LV-1006; e-mail: iovel@osi.lv. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 825-838, June, 2004. Original article submitted February 16, 2004. 0009-3122/04/4006-07012004 Plenum Publishing Corporation 701
Scheme 1
R' R' MS 4A H2N R'' PhH, 2080 oC R X 1al C H N R''
CHO
X = O, S; R = H, Me; R' = Me, Br; R'' = H, Me R' R"' CHO R' MS 4A R'' PhH, 2080 oC R"' 1my C N H R''
+ H2N
R' = H, Me, CF3, Br, F, NO2; R'' = H, Me; R"' = H, Me, OMe, Br, NO2
contain three sets of signals, indicating the formation of three types of products structures 2, 3, and 4 (Scheme 2) containing Et3SiCHNH, CH2NSiEt3, and CH2NH groups. These compounds are characterized respectively by two doublets for the protons of the CHNH group (1H1H), a singlet for CH2 (2H), and for the amines 4 by a signal for CH2 and a broad singlet for NH (2H and 1H) (Table 2). The mass spectra of the obtained compounds (Table 3) also correspond to the three indicated types of products. Scheme 2
R' (Het)Ar C H N R'' 1aw HSiEt3, PhH
[Pd(allyl)Cl]2, 65 oC
R' (Het)Ar H C NH SiEt3 R'' 3 OH (Het)Ar C NH H2 R'' 4 _ R' OH (Het)Ar C H2 _ N
R'
SiEt3 R''
By preparative column chromatography it was possible to isolate nearly all the synthesized amines with structure 4 and also certain other silyl derivatives with structures 2 and 3 (Table 2). The signals of the ring protons in all the obtained compounds were in the characteristic regions of the spectrum. In the 1H NMR spectra of the synthesized silyl compounds the SiEt3 group appears in the form of two groups of signals for the CH2 (6H, q) and CH3 (9H, m) in the region of 0.5-1.6 ppm. 702
TABLE 1. The Characteristics of the Synthesized Aldimines

, 7 20 20 20 20 20 80 20 80 20 20 20 80 20 80 20 20 80 Empirical formula 9 C12H11NO C13H13NO C11H8BrNO C12H10BrNO C13H13NO C14H15NO C12H11NS C13H13NS C11H8BrNS C12H10BrNS C13H13NS C14H15NS 72.23 72.52 49.70 49.64 51.14 51.44 5.98 6.09 2.84 3.03 3.43 3.60 6.41 6.50 4.98 5.26 4.82 4.99 14.75 14.89 12.02 12.05 11.55 11.44 46-47 49-50 45-46 C 10 Found, % Calculated, % H N 11 12 mp, *2 Yield, % S 13 14 15 76 76 64 64 60 66 76 56 52 50 74 77
Imine* 1 1a 1b 1c 1d 1e 1f 1g 1h 1i 1j 1k 1l
X 2 O O O O O O S S S S S S
R 3 H Me H Me H Me H Me H Me H Me
R' 4 Me Me Br Br Me Me Me Me Br Br Me Me
R'' 5 H H H H Me Me H H H H Me Me
R''' 6
Time, h 8 22 24 21 26 24 1 24 1 24 24 24 2 24 2 24 24 8
703
704
TABLE 1 (continued)
1 1m 1n 1o 1p 1q 1r 1s 1t 1u 1v 1w 1x 1y 2 3 4 Me CF3 Br F NO2 Me H H H H CF3 CF3 NO2 5 H H H H H Me H H H H H H H 6 H H H H H H Me OMe Br NO2 OMe Br Br 7 20 20 20 20 20 80 20 80 20 20 20 20 20 80 20 20 80 8 23 22 23 22 19 8 20 2 24 21 21 24 22 3 20 24 6 9 C14H13N C14H10F3N C13H10BrN C13H10FN C13H10N2O2 C15H15N C14H13N C14H13NO C13H10BrN C13H10N2O2 C15H12F3NO C14H9BrF3N C13H9BrN2O2 51.40 51.25 51.21 51.17 2.72 2.76 2.85 2.97 4.17 4.27 9.08 9.18 59-60 96-97 79.47 79.59 60.06 60.02 69.03 69.02 6.16 6.20 3.82 3.87 4.44 4.46 6.61 6.63 5.28 5.38 12.28 12.38 49-50 71-72 86-87 77.68 78.37 68.36 69.02 4.81 5.06 4.36 4.46 6.77 7.03 12.69 12.38 28-29 71-72 10 11 12 13 14 15 76 56 74 64 72 83 65 66 69 74 64 87 64
_______ * The imines 1a-g,k-o,r,s,w were oily substances, 1p was not recrystallized. *2 Solvent for recrystallization: hexane (1h,i,t,u,x) or 1:1 hexaneethyl acetate (1j,q,v,y).
TABLE 2. The Characteristics of the Hydrosilylation Reactions and Their Products

Product Initial imine Reaction time, h ( 65) 2 6 6 4 Conversion of imine, % (GLC) 3 68 86 53 after isolation*2 5 4 4b 3c 4c 3d 4d 2e 2.20 2.22 2.00 (6H) 2.15 (6H) 2.11 2.07, 2.36 2.40 2.40 2.11 (6H) 2.9 (6H) 4.31 4.27 ~3.0 4.44 J = 5.0 4j MeC4H2SCH2NHPh (21%) 2k 4j 2k 4k 4.40 3.9 4.6 4.07 4.07 4.51 4.38 4.51 4.0 3.8 3.8 4.0 4.27 J = 5.0 4d MeC4H2OCH2NHPh (18%) 2e 4e 4g 4h 4i 3j 4.20 3.9 4.6 H3 (3, s)
1
NMR (in CDCl3), , ppm, (J, Hz) SiHNH (structure 3) CH (d) 8 NH (d) 9 CH2NH (structure 4) CH2 (s) 10 4.29 4.22 4.33 J = 5.0 4.6 4.29 4.0 NH br. s) 11 3.8 3.8
in reaction mixture*
CH2NSi (structure 2) CH2 (2H, s) 7
1 1a 1b 1c
4 4 4b 3c 4c C4H3OCH2NHPh (9%) 3d
6 2.09 2.04, 2.20
1d
68
1e 1f 1g 1h 1i 1j
24 24 15 20 4 20
86 0 41 100 51 90
4g 4h 4i 3j
1k
35
42
705
706
TABLE 2 (continued)
1 1l 2 35 3 60 4 2l 4l 1m 1n 1o 4 20 11 100 59 72 4m 2n 4n 2o 4o PhCH2NHPh (31%) 4p 4q, q*4 2r 4r 2s 4s 2t 4t 4u, PhCH2NHPh (82%), u*4 4u, PhCHNPh (12%) H2NC6H4CHNPh 2w 4w 5 2l 4l 4m*3 4n 2o 6 2.04 (6H), 2.33 (3H) 2.27 (6H), 2.38 (3H) 2.11 7 4.22 4.18 4.33 4.38 4.36 4.31 4.24 4q 4r 2.18 (6H) 2.27 2.33 3.73 (OCH3) 3.73 (OCH3) 4.55 4.04 4.51 4.27 4.22 4.18 4.0 3.9 ~ 4.8 4.1 2.9 3.2 4.8 8 9 10 11
1p 1q 1r 1s 1t 1u 1u*5 1v 1w
8 20 8 7 15 8 26 17 21
100 100 86 100 81 100 24 25 63
2t 4t
2w
3.47 (OCH3)
4.31
_______ * According to the data from the 1H NMR spectra and GLC-MS of the mixture of products. *2 The products were isolated by column chromatography. Eluants: 10:0.05 benzeneethyl acetate (4a-d,g,h,j,t, 3c,d,j, 2t), 3:1 hexaneethyl acetate (2e, 4i), 9:1 benzeneethyl acetate (2k,l, 4k,l,q,r), benzene (4n), 9:1 hexaneethyl acetate (2o). *3 The product was isolated by recrystallization from hexane (mp 54C). *4 Unidentified side products were formed. *5 Catalyst: RhCl(PPh3)3.
TABLE 3. The Mass Spectra of the Hydrosilylation Products

Compound* 1 4a 4b 3c m/z (Irel, %)*2 2 187 [M]+ (34), 186 [M H]+ (25), 118 (7), 106 [M C4H3OH2]+ (6), 91 (11), 81 [C4H3OCH2]+ (100), 77 (15), 65 (11), 53 (37) 201 [ M]+ (18), 216 (2), 118 (2), 107 (12), 95 [H3CC4H2OCH2]+ (100), 91 (8), 77 (8), 65 (11), 57 (7), 43 (13) 252/250 [M SiEt3]+ (100/100), 184/182 (7/8), 171 (11), 170 [M HSiEt3 Br]+ (9), 157/155 [C6H4Br]+ (5/9), 143 (8), 131 (6), 115 [SiEt3]+ (25), 103 (9), 91 (5), 87 (18), 75 (9), 59 (14), 39 (7) 253/251 [M]+ (100/100), 184 (2), 172 (4), 157/155 [C6H4Br]+ (2/3), 143 (4), 117/115 (3/5), 104 (3), 91 (10), 81 [C4H3OCH2]+ (100), 63 (10), 53 (30), 39 (10), 32 (25) 173 [M]+ (42), 172 [M H]+ (32), 144 [M HCO]+ (10), 115 (12), 106 [M C4H3OH2]+ (5), 91 (5), 81 [C4H3OCH2]+ (100), 77 [Ph]+ (26), 65 (15), 53 (31), 51 (21), 39 (23), 32 (89) 267/265 [M]+ (8/8), 186 [M Br]+ (4), 173/171 (4/4), 157 [C6H4Br]+ (2), 143 (2), 130 (1), 115 (2), 104 (2), 95 [H3CC4H2OCH2]+ (100), 91 (7), 77 (6), 65 (7), 51 (7), 43 (14) 187 [M]+ (16), 172 [M H]+ (2), 95 [H3CC4H2OCH2]+ (100), 77 [Ph]+ (10), 65 (12), 51 (11), 43 (15), 32 (39) 315 [ M]+ (15), 287 (24), 286 [M Et]+ (100), 205 (22), 184 (18), 176 (17), 153 (35), 148 (35), 146 (29), 125 (13), 115 (5), 105 (13), 91 (8), 87 (14), 81 [C4H3OCH2]+ (38), 77 (7), 59 (29), 53 (24) 201 [M]+ (38), 200 [M H]+ (32), 184 (3), 172 (2), 158 (4), 144 (3), 132 (8), 120 (12), 103 (5), 91 (20), 81 [C4H3OCH2]+ (100), 77 (24), 65 (10), 53 (42), 39 (15) 203 [M]+ (28), 106 (3), 97 [C4H3SCH2]+ (100), 91 (10), 77 (11), 65 (11), 53 (37), 45 (13), 39 (15) 217 [M]+ (18), 182 (2), 118 (3), 111 [H3CC4H2SCH2]+ (100), 91 (11), 77 (21), 65 (14), 51 (12), 45 (10), 39 (13) 269/267 [M]+ (13/12), 186 (3), 172 (1), 157/155 [C6H4Br]+ (2/3),143 (2), 115 (2), 105 (2), 97 [C4H3SCH2]+ (100), 91 (11), 63 (10), 77 (8), 63 (10), 53 (11), 45 (15), 39 (11) 283/281 [M]+ (9/9), 200 (1), 184 (2), 168 (2), 155 [C6H4Br]+ (2), 143 (2), 104 (2), 111 [H3CC4H2SCH2]+ (100), 91 (12), 77 (18), 63 (9), 51 (11), 45 (11), 39 (10) 203 [M]+ (21), 111 [H3CC4H2SCH2]+ (100), 77 [Ph]+ (31), 65 (15), 51 (20), 45 (9), 39 (19) 331 [M]+ (23), 300 (13), 301 (27), 302 [M Et]+ (100), 274 (2), 234 (4), 216 [M SiEt]+ (3), 205 (19), 184 (2), 176 (21), 169 (34), 148 (40), 146 (35), 141 (24), 132 (13), 119 (7), 115 (17), 97 [C4H3SCH2]+ (38), 87 (21), 77 (8), 59 (38), 53 (14), 45 (16) 345 [M]+ (22), 314 (6), 315 (14), 316 [M Et]+ (100), 288 (2), 234 (2), 205 (9), 183 (43), 176 (12), 159 (17), 148 (27), 146 (25), 132 (10), 115 (12), 111 [H3CC4H2SCH2]+ (100), 105 (7), 87 (18), 77 (15), 59 (38), 45 (10) 231 [M]+ (14), 134 [M H3CC4H2SCH2]+ (2), 121 (8), 111 [H3CC4H2SCH2]+ (100), 105 (7), 87 (18), 77 (15), 59 (38), 45 (10) 197 [M]+ (40), 196 [M H]+ (13), 120 [M Ph]+ (11), 118 (7), 106 [PhCH2NH]+ (13), 91 [PhCH2]+ (100), 77 [Ph]+ (13), 65 (26), 51 (11), 39 (13) 365 [M]+ (2), 230 (3), 213 (15), 214 [M SiEt3 2F]+ (100), 192 [M SiEt3 2F HF]+ (7), 165 (7), 145 [C6H4CF3]+ (2), 134 (6), 109 (11), 91 [PhCH2]+ (81), 77 [Ph]+ (23), 65 (10), 59 (9), 49 (6) 251 [M]+ (27), 230 (4), 212 (3), 165 (1), 154 (3), 145 [C6H4CF3]+ (2), 91 [PhCH2]+ (100), 77 (4), 69 (12), 51 (5), 39 (4), 32 (7) 263/261 [M]+ (18/19), 180 [M Br]+ (9), 152 (3), 143 (1), 104 (4), 91 [PhCH2]+ (100), 77 [Ph]+ (9), 65 (14), 51 (7), 39 (6) 183 [M]+ (55), 182 [M H]+ (22), 106 [PhH2NH]+ (20), 91 [PhCH2]+ (100), 77 [Ph]+ (26), 65 (22), 51 (15), 39 (10) 201 [M]+ (35), 200 [M H]+ (8), 124 [M Ph+] (8), 122 (7), 91 [PhCH2]+ (100), 77 [Ph]+ (9), 65 (15), 51 (8), 39 (7)
4c
4d
B 2e
4e 4g 4h 4i
4j
C 2k
2l
4l 4m 2n
4n 4o D 4p
707
TABLE 3 (continued)
1 4q 2r 2 228 [M]+ (11), 210 (3), 195 (5), 181 (13), 190 (17), 168 (3), 152 (4), 105 (61), 91 [PhCH2]+ (100), 77 [Ph]+ (14), 65 (24), 51 (11), 39 (10) 325 [M]+ (10), 297 (25), 296 [M Et]+ (100), 281 (6), 266 (3), 234 (2), 207 (16), 205 (10), 176 (13), 163 (8), 148 (29), 146 (14), 135 (10), 115 (4), 105 (8), 91 [PhCH2]+ (30), 87 (14), 73 (6), 59 (21) 211 [M]+ (40), 210 [M H]+ (8), 196 [M Me]+ (2), 134 [M Ph]+ (6), 120 [M PhCH2]+ (42), 103 (3), 91 [PhCH2]+ (100), 77 [Ph]+ (14), 65 (15), 51 (6), 39 (8) 311 [M]+ (15), 283 (26), 282 [M Et]+ (100), 254 (4), 194 (6), 177 (34), 149 (63), 121 (41), 120 (40), 115 (5), 105 [C6H4CH3]+ (56), 87 (23), 77 [ Ph]+ (35), 59 (47) 197 [M]+ (26), 182 (2), 105 [C6H4CH3]+ (100), 91 (4), 79 (10), 77 [ Ph]+ (26), 65 (7), 51 (8) 327 [M]+ (23), 299 (11), 298 [M Et]+ (100), 254 (2), 193 (19), 165 (29), 149 (4), 137 (13), 121 [M SiEt3 PhN]+ (100), 120 (14), 104 (4), 87 (13), 78 (15), 77 [Ph]+ (20), 59 (23) 213 [M]+ (15), 196 (2), 168 (2), 121 [M PhNH]+ (100), 91 (6), 78 (12), 77 [Ph]+ (18), 65 (8), 51 (8) 263/261 [M]+ (40/41), 262/260 [M H]+ (15/9), 182 [M Br]+ (18), 171/169 [CH2C6H4Br]+ (98/100), 106 [PhNHH2]+ (20), 104 (12), 90 [M Br PhNH]+ (54), 91 (46), 77 [Ph]+(41), 65 (15), 63 (21), 51 (24), 39 (15) 181 [M]+ (82), 180 [M H]+ (100), 104 [M Ph]+ (17), 77 [ Ph]+ (85), 63 (7), 51 (37), 39 (8) 196 [M]+ (52), 195 [M H]+ (63), 178 (3), 167 (2), 118 (3), 104 [PhNCH]+ (4), 98 (5), 92 [M PhNCH]+ (9), 77 [ Ph]+ (29), 65 (9), 51 (13), 40 (9), 32 (100) 395 [M]+ (3), 280 [M SiEt3]+ (2), 242 [M SiEt3 2F]+ (100), 222 (7), 172 (2), 134 (5), 121 [CH3OC6H4CH2]+ (56), 109 (3), 91 (9), 77 (23), 59 (9) 281 [M]+ (10), 242 (2), 145 [C6H4CF3]+ (2), 121 [CH3OC6H4CH2]+ (100), 106 (1), 91 (6), 78 (9), 77 (10), 63 (4), 51 (5), 39 (3)
4r
2s 4s 2t
4t 4u
E F 2w 4w
_______ * -C4H3OCH2NHPh, B-H3CC4H2OCH2NHPh, C-H3CC4H2SCH2NHPh, D-PhCH2NHPh, E-PhCHNPh, F-H2NC6H4CHNPh *2 The signals of the characteristic ions are given.
The hydrosilylation of many of the investigated substrates (1a-e,g-p,r-t) mostly leads to the formation of the desired products having structures 2-4. In most cases the respective amines were isolated. Of the initial heterocyclic compounds only the imine 1f did not react with triethylsilane under the investigated conditions. Nearly all the bromine derivatives undergo debromination with the formation of the corresponding saturated compounds or the debromoimine (Tables 2 and 3). This applies particularly to the imine 1u. An attempt to silylate the latter in the presence of the complex RhCl(PPh3)3 did not give positive results. N-Silylation products are hardly formed at all during the hydrosilylation of the two investigated nitro compounds 1q and 1v. Thus, the imine 1q reacts with the formation mainly of unidentified side products, while in the reaction of the aldimine 1v its nitro group is reduced to an NH2 group. The last imine does not react with triethylsilane in the presence of RhCl(PPh3)3 (65C, 26 h) or with dimethylphenylsilane in the presence of [Pd(allyl)Cl]2 and RhCl(PPh3)3 (65C, 13-14 h). Since the nitro- and bromine-containing aromatic imines 1q and 1u hardly gave the desired products at all, we did not investigate their analogs 1x,y. Of all the investigated compounds only the bromine-substituted heterocyclic imines are transformed into the C-silylation products 3c,d,j, which were successfully isolated by column chromatography, demonstrating their adequate stability. The N-silylation products were recorded in the reactions of many imines: 1e,k,l,n,o,r-t,w). Nearly all were isolated by chromatography (with the exception of the products 2n,r that are probably hydrolyzed in the column to the corresponding amines 4n,r, which were isolated (Table 2)).
708
Thus, the unusual direction of transformation leading to the formation of the C-silylated products is only observed in the reactions of the O- and S-heterocyclic imines. Here the presence of the bromine atom at the ortho position of the aza part of the molecules of the reacting imines promotes C-silylation. The obtained data agree with our previous results [7, 8]. Probably, the presence of the heterocycles in the molecules of the reacting imines leads to the appearance of intermediate carbene structures (type I, scheme 3), which are formed during complexation of the substrates with the catalyst (by analogy with the mechanism proposed in [15]) and lead to C-silylation. In addition, the bulky bromine atom at the ortho position to the carbon atom of the aromatic ring attached to the nitrogen atom of the reacting imine group N=C prevents N-silylation sterically (like the CF3 group in [7]). Scheme 3
Pd Het N H Ar Het
H Pd Ar N I Pd Het N H Pd Ar HSiEt3
Het
H N
Ar H
Pd
Het
H N
Ar H
Et3Si
Et3Si
The structure and electronic characteristics of the aldimines 1m-r, containing various substituents at the ortho position of the aza part of the molecule, were calculated by the quantum-chemical AM1 method in order to determine the effect of the functional groups on the characteristics of the molecules (Table 4 and Fig. 1). By comparing the obtaining data it can be seen that the greatest differences in all the values of the parameters (Table 4) are, as expected, characteristic of the molecules 1q,r, which contain the most electronegative NO2 group and two donating CH3 groups respectively. However, the molecules containing CF3 and Br substituents, which have a special effect on hydrosilylation, are characterized by average values of all the calculated electronic parameters. It can, consequently, be supposed that steric and not electronic factors play the major role in the investigated reaction. In fact, as seen from the molecular structures of 1m and 1n (Fig. 1), the CF3 group creates steric hindrances for the addition of the reagent to the nitrogen atom of the imine group, whereas the methyl substituent does not prevent such a reaction.
TABLE 4. The Characteristics of the Compounds, Obtained by the AM1 Quantum-chemical Method
Compound 1m 1n 1o 1p 1q 1r qN -0.148 -0.163 -0.158 -0.157 -0.194 -0.145 qC -0.001 -0.020 -0.019 -0.004 -0.064 -0.004 HOMO, eV -8.91 -9.27 -9.09 -8.95 -9.51 -8.84 LUMO, eV -0.28 -0.85 -0.42 -0.61 -0.91 -0.26
709
Fig. 1. The optimized structures of the molecules of the imines 1m (a) and 1n (b) obtained by the quantum-chemical AM1 method.
EXPERIMENTAL The 1H NMR spectra were recorded on Varian Mercury-200 (200 MHz) and Bruker WH-90/DS (90 MHz) spectrometers for solutions in deuterochloroform with TMS as internal standard. The mass spectra were obtained on an HP6890 GC/MS chromato-mass spectrometer with an HP-5 MS capillary column (30.0 m 250 m 0.25 m) at programmed temperature from 70 to 260C (10 deg/min). Before use the benzene was distilled over calcium hydride. Aldehydes, amines, hydrosilanes, and Pd complex produced by Acros, Aldrich, and Fluka were used. The molecular sieves were 4A (VEB Laborchemie Apolda). General Procedure for the Synthesis of the Aldimines. In a round-bottom flask with a reflux condenser we placed 10 ml of dry benzene and 5 mmol each of the initial aldehyde and amine and then 5 g of the freshly baked molecular sieves. The reaction was conducted at room temperature or with heating on a water bath at 80C in an atmosphere of argon. Samples were taken periodically and analyzed by TLC and GLC-MS. After a specific time interval, depending on the substrates (Table 1), they were almost completely converted into the respective products. At the end of the reaction the sieves were filtered off and washed with benzene. The filtrate was evaporated at reduced pressure (40C/15 mm Hg), and the small residues of the initial substances 710
were removed under vacuum (45-50C/0.1 mm Hg). The products were yellow oily or crystalline substances. The solid compounds were purified by recrystallization from hexane or its mixture with ethyl acetate, and the 1 H NMR spectra were recorded. General Procedure for Hydrosilylation. A 5-cm3 Pierce reaction tube was blown with argon, and 2 ml of dry benzene, 0.01 mmol of the catalyst, and 0.5 mmol of the initial imine were placed in it, after which the mixture was stirred at room temperature for 30 min. The solution was then cooled to 0C with ice, and 0.6 mmol of hydrosilane was added with a syringe. The reaction was carried out at 65C, and samples were taken periodically and analyzed by TLC and GLC-MS. At the end of silylation the reaction mixture was evaporated at reduced pressure (30C/15 mm Hg), and the 1H NMR spectra were recorded. The mixture was then separated by liquid chromatography on a column of silica gel (Kieselgel 60, 0.063-0.200 mesh, Merck) with various eluants. All the obtained products were yellow oily substances, Quantum-chemical Calculations. All the calculations were carried out by the semiempirical AM1 method [16], included in the MOPAC 6 software package [17]. The equilibrium geometric structures of the molecules were calculated with full optimization of the parameters using the PRECISE enhanced accuracy criterion [18]. Analysis of the obtained frequencies of the molecular vibrations showed that all the optimized structures correspond to minima on the potential energy surface of the system. Computer design was realized by means of the JMol software [19]. N-(2-Furylmethylidene)-2-methylaniline (1a). Mass spectrum, m/z (Irel, %): 186 [M + H]+ (9), 185 + [M] (69), 184 [M - H]+ (29), 168 (14), 157 (14), 156 [M - HCO]+ (100), 154 (16), 130 (53), 129 (24), 128 (26), 117 (20), 91 [C6H4CH3]+ (35), 90 (9), 89 (20), 77 (18), 65 (54), 63 (24), 52 (29), 51 (45), 50 (21), 39 (53). 1 H NMR spectrum, , ppm: 2.33 (3H, s, CH3); 6.3-7.8 (7H, m, Ar, Fur); 8.13 (1H, s, CH=N). N-(5-Methyl-2-furylmethylidene)-2-methylaniline (1b). Mass spectrum, m/z, (Irel, %): 200 [M + H]+ (10), 199 [M]+ (68), 198 [M - H]+ (22), 184 [M - M]+ (25), 170 (8), 157 (14), 156 [M - MCO]+ (100), 154 (14), 130 (21), 129 (24), 128 (20), 117 (30), 91 [C6H4CH3]+ (32), 90 (8), 89 (15), 79 (13), 77 [Ph]+ (12), 65 (52), 63 (17), 53 (19), 52 (16), 51 (34), 50 (14), 43 (30), 39 (32). 1H NMR spectrum, , ppm: 2.27 (3H, s, CH3); 2.33 (3H, s, CH3); 6.0-7.3 (6H, m, Ar, Fur); 7.98 (1H, s, CH=N). N-(2-Furylmethylidene)-2-bromoaniline (1c). Mass spectrum, m/z (Irel, %): 251/249 [M]+ (96/100), 250/248 [M - H]+ (57/45), 222 [M - HCO]+ (4), 195 (5), 184/182 (5/6), 171 (11), 170 [M - Br]+ (91), 157/155 [C6H4Br]+ (38/39), 142 (29), 141 (15), 140 (16), 115 (78), 102 (9), 89 (18), 77 (26), 76 (55), 75 (59), 74 (23), 64 (21), 63 (32), 52 (42), 51 (69), 50 (71), 39 (77). 1H NMR spectrum, , ppm: 6.4-7.8 (7H, m, Ar, Fur); 8.09 (1H, s, CH=N). N-(5-Methyl-2-furylmethylidene)-2-bromoaniline (1d). Mass spectrum, m/z (Irel, %): 265/263 [M]+ (99/100) , 264/262 [M - H]+ (48/32), 222 [M - MeCO]+ (7), 195 (3), 184 [M - Br]+ (92), 169 (14), 157/155 [C6H4Br]+ (29/34), 141 (9), 140 (8), 129 (12), 128 (15), 114 (6), 79 (14), 77 (14), 76 (24), 75 (25), 74 (8), 64 (7), 63 (9), 53 (21), 52 (12), 51 (25), 50 (23), 43 (19), 39 (14). 1H NMR spectrum, , ppm: 2.38 (3H, s, CH3); 6.0-7.7 (6H, m, Ar, Fur); 7.98 (1H, s, CH=N). N-(2-Furylmethylidene)-2,6-dimethylaniline (1e). Mass spectrum, m/z (Irel, %): 200 [M + H]+ (10), 199 [M]+ (71), 198 [M - H]+ (33), 183 [M - H- Me]+ (12), 171 (14), 170 [M - HCO]+ (100), 168 (15), 156 (14), 155 (14), 154 (21), 144 (43), 143 (16), 142 (13), 130 (25), 129 (8), 128 (16), 117 (11), 115 (13), 103 (19), 91 (14), 89 (9), 79 (19), 78 (19), 77 (55), 65 (19), 63 (17), 52 (33), 51 (46), 50 (18), 39 (54). 1H NMR spectrum, , ppm: 2.09 (6H, s, CH3); 6.4-7.6 (6H, m, Ar, Fur); 7.91 (1H, s, CH=N). N-(5-Methyl-2-furylmethylidene)-2,6-dimethylaniline (1f). Mass spectrum, m/z (Irel, %): 214 [M + H]+ (10), 213 [M]+ (77), 212 [M - H]+ (22), 198 [M - Me]+ (8), 183 (6), 170 [M - MeCO]+ (100), 168 (9), 155 (14), 154 (15), 144 (15), 143 (9), 142 (7), 130 (14), 128 (8), 117 (7), 115 (7), 103 (13), 91 (10), 79 (24), 78 (13), 77 (36), 65 (15), 53 (14), 51 (29), 50 (18), 43 (28), 39 (26). 1H NMR spectrum, , ppm: 2.11 (6H, s, CH3); 2.38 (3H, s, CH3); 6.0-7.3 (6H, m, Ar, Fur); 7.82 (1H, s, CH=N).
711
N-(2-Thienylmethylidene)-2-methylaniline (1g). Mass spectrum, m/z (Irel, %): 202 [M + H]+ (15), 201 [M]+ (100), 200 [M - H]+ (64), 186 [M - Me]+ (12), 169 (11), 168 [M - HS]+ (78), 167 (41), 156 [M - HCS]+ (12), 154 (6), 129 (7), 118 [M - Th]+ (22), 117 [M - H - Th]+ (28), 110 (6), 91 [C6H4CH3]+ (42), 90 (9), 89 (14), 77 (9), 70 (10), 65 (51), 63 (18), 58 (8), 52 (9), 51 (20), 50 (10), 45 (19), 39 (41). 1H NMR spectrum, , ppm: 2.29 (3H, s, CH3); 6.8-7.6 (7H, m, Ar, Th); 8.38 (1H, s, CH=N). N-(5-Methyl-2-thienylmethylidene)-2-methylaniline (1h). Mass spectrum, m/z (Irel, %): 216 [M + H]+ (5), 215 [M]+ (100), 214 [M - H]+ (33), 200 [M - Me]+ (28), 199 (22), 183 (11), 182 [M - HS]+ (68), 181 (16), 180 (17), 167 (51), 156 [M - MeCS]+ (15), 154 (11), 129 (8), 118 (19), 117 [M - H - MeTh]+ (43), 109 (8), 97 [MeTh]+ (29), 91 [C6H4CH3]+ (52), 90 (13), 89 (21), 77 (15), 69 (9), 65 (65), 63 (24), 59 (12), 53 (20), 52 (13), 51 (37), 50 (17), 45 (24), 39 (48). 1H NMR spectrum, , ppm: 2.27 (3H, s, CH3); 2.47 (3H, s, CH3); 6.6-7.3 (6H, m, Ar, Th); 8.29 (1H, s, CH=N). N-(2-Thienylmethylidene)-2-bromoaniline (1i). Mass spectrum, m/z (Irel, %): 267/265 [M]+ (76/78), 266/264 [M - H]+ (57/45), 187 (14), 186 [M - Br]+(100), 157/155 [C6H4Br]+ (38/39), 140 (7), 115 (16), 93 (15), 84 (13), 77 (14), 76 (32), 75 (35), 74 (10), 63 (14), 52 (7), 51 (99), 50 (30), 45 (25), 39 (32). 1H NMR spectrum, , ppm: 6.8-7.7 (7H, m, Ar, Th); 8.39 (1H, s, CH=N). N-(5-Methyl-2-thienylmethylidene)-2-bromoaniline (1j). Mass spectrum, m/z (Irel, %): 281/279 [M]+ (62/63), 280/278 [M - H]+ (51/43), 201 (14), 200 [M - Br]+ (100), 157/155 [C6H4Br]+ (23/24), 140 (3), 122 (12), 97 (29), 95 (12), 77 (19), 76 (33), 75 (33), 74 (11), 63 (14), 53 (15), 51 (24), 50 (29), 45 (25), 39 (21). 1H NMR spectrum, , ppm: 2.51 (3H, s, CH3); 6.6-7.7 (6H, m, Ar, Th); 8.29 (1H, s, CH=N). N-(2-Thienylmethylidene)-2,6-dimethylaniline (1k). Mass spectrum, m/z (Irel, %): 216 [M + H]+ (18), 215 [M]+ (100), 214 [M - H]+ (59), 199 [M - H - Me]+ (12 ), 182 [M - HS]+ (55), 181 (16), 170 [M - HCS]+ (13), 167 [M - HS - Me]+ (39), 132 (24), 131 (24), 130 (32), 117 (13), 110 (5), 103 (22), 91 (13), 79 (23), 78 (19), 77 (60), 70 (6), 65 (18), 63 (19), 58 (9), 53 (13), 52 (15), 51 (30), 50 (12), 45 (25), 39 (36). 1H NMR spectrum, , ppm: 2.04 (6H, s, CH3); 6.8-7.6 (6H, m, Ar, Th); 8.20 (1H, s, CH=N). N-(5-Methyl-2-thienylmethylidene)-2,6-dimethylaniline (1l). Mass spectrum, m/z (Irel, %): 230 [M + H]+ (18), 229 [M]+ (100), 214 (17), 213 [M - H - Me]+ (23), 196 [M - HS]+ (51), 181 (37), 170 [M - MeCS]+ (16), 132 (16), 131 (25), 130 (27), 117 (9), 105 (8), 103 (16), 97 (18), 79 (18), 78 (12), 77 (44), 65 (15), 63 (10), 53 (16), 52 (7), 51 (18), 50 (6), 45 (13), 39 (26). 1H NMR spectrum, , ppm: 2.04 (6H, s, CH3); 2.44 (3H, s, CH3); 6.6-7.2 (5H, m, Ar, Th); 8.09 (1H, s, CH=N). N-(Benzylidene)-2-methylaniline (1m). Mass spectrum, m/z (Irel, %): 196 [M + H]+ (10), 195 [M]+ (73), 194 [M - H]+ (66), 180 (4), 167 (6), 152 (5), 119 (9), 118 [M - Ph]+ (100), 117 (24), 91 [C6H4CH3]+ (47), 90 (10), 89 (23), 77 [Ph]+ (13), 65 (44), 63 (19), 51 (24), 50 (11). 1H NMR spectrum, , ppm: 2.31 (3H, s, CH3); 6.7-8.0 (9H, m, Ar); 8.33 (1H, s, CH=N). N-(Benzylidene)-2-trifluoromethylaniline (1n). Mass spectrum, m/z (Irel, %): 250 [M + H]+ (11), 249 + [M] (79), 248 [M - H]+ (100), 230 [M - F]+ (6), 208 (4), 180 (5), 172 (10), 152 (6), 145 [PhCF3 - H]+ (53), 125 (11), 95 (16), 89 (7), 76 (14), 77 [Ph]+ (16), 63 (9), 51 (18), 50 (11). 1H NMR spectrum, , ppm: 6.9-8.0 (9H, m, Ar); 8.33 (1H, s, CH=N). N-(Benzylidene)-2-bromoaniline (1o). Mass spectrum, m/z (Irel, %): 261/259 [M]+ (96/100), 260/258 [M - H]+ (96/87), 180 [M - Br]+ (60), 157/155 [C6H4Br]+ (41/42), 152 (24), 102 (9), 90 (25), 89 (32), 76 (26), 77 [Ph]+ (51), 76 (66), 75 (32), 74 (17), 64 (13), 63 (34), 52 (12), 51 (55) 50 (50). 1H NMR spectrum, , ppm: 6.88.0 (9H, m, Ar); 8.31 (1H, s, CH=N). N-(Benzylidene)-2-fluoroaniline (1p). Mass spectrum, m/z (Irel, %): 200 [M + H]+ (11), 199 [M]+ (84), 198 [M - H]+ (100), 122 [M - Ph]+ (12), 95 (15), 78 (8), 77 [Ph]+ (16), 74 (13), 51 (8). 1H NMR spectrum, , ppm: 7.0-8.0 (9H, m, Ar); 8.49 (1H, s, CH=N). N-(Benzylidene)-2-nitroaniline (1q). Mass spectrum, m/z (Irel, %): 226 [M]+ (13), 178 (7), 152 (12), 105 [PhCHNH]+ (100), 89 (10), 78 (5), 77 [Ph]+ (32), 76 (12), 63 (11), 51 (14). 1H NMR spectrum, , ppm: 6.9-8.1 (9H, m, Ar); 8.38 (1H, s, CH=N).
712
N-(Benzylidene)-2,6-dimethylaniline (1r). Mass spectrum, m/z (Irel, %): 210 [M + H]+ (13), 209 [M]+ (82), 208 [M - H]+ (33), 193 [M - H- Me]+ (23), 165 (6), 132 [M - Ph]+ (100), 131 (14), 130 (15), 117 (21), 103 (18), 91 (9), 89 (15), 79 (17), 78 (13), 77 [Ph]+ (39), 65 (10), 63 (12), 51 (19), 39 (15). 1H NMR spectrum, , ppm: 2.09 (6H, s, CH3); 6.9-8.0 (6H, m, Ar); 8.18 (1H, s, CH=N). N-(4-Methylbenzylidene)aniline (1s). Mass spectrum, m/z (Irel, %): 196 [M + H]+ (11), 195 [M]+ (81), 194 [M - H]+ (100), 180 (5), 165 (3), 152 (3), 104 (7), 91 [C6H4CH3]+ (15), 77 [Ph]+ (13), 65 (9), 51 (25). 1 H NMR spectrum, , ppm: 2.36 (3H, s, CH3); 6.9-7.9 (9H, m, Ar); 8.39 (1H, s, CH=N). N-(4-Methoxybenzylidene)aniline (1t). Mass spectrum, m/z (Irel, %): 212 [M + H]+ (13), 211 [M]+ (88), 210 [M - H]+ (100), 196 (6), 167 (22), 104 (6), 91 (5), 77 [Ph]+ (69), 65 (13), 51 (38), 39 (12). 1H NMR spectrum, , ppm: 3.76 (3H, s, OCH3); 6.9-8.0 (9H, m, Ar); 8.36 (1H, s, CH=N). N-(4-Bromobenzylidene)aniline (1u). Mass spectrum, m/z (Irel, %): 261/259 [M]+ (50/54), 260/258 [M H]+ (49/44), 179 [M - Br]+ (13), 152 (8), 104 [PhNCH]+ (19), 89 (11), 78 (9), 77 [Ph]+ (100), 76 (20), 63 (14), 51 (47), 50 (24), 39 (13). 1H NMR spectrum, , ppm: 7.1-7.9 (9H, m, Ar); 8.40 (1H, s, CH=N). N-(4-Nitrobenzylidene)aniline (1v). Mass spectrum, m/z (Irel, %): 227 [M + H]+ (14), 226 [M]+ (100), 225 [M - H]+ (45), 179 (53), 167 (11), 152 (18), ), 104 [PhNCH]+ (30), 89 (3), 78 (9), 77 [Ph]+ (96), 76 (16), 63 (13), 51 (45), 50 (20). 1H NMR spectrum, , ppm: 7.1-8.4 (9H, m, Ar); 8.51 (1H, s, CH=N). N-(4-Methoxybenzylidene)-2-trifluoromethylaniline (1w). Mass spectrum, m/z (Irel, %): 280 [M + H]+ (13), 279 [M]+ (85), 278 [M - H]+ (100), 260 [M - F]+ (5), 235 (11), 145 [PhCF3 - H]+ (34), 134 (5), 125 (8), 108 (5), 95 (10), 77 (13), 65 (11), 51 (10), 39 (5). 1H NMR spectrum, , ppm: 3.87 (3H, s, OCH3); 6.9-8.0 (8H, m, Ar); 8.28 (1H, s, CH=N). N-(4-Bromobenzylidene)-2-trifluoromethylaniline (1x). Mass spectrum, m/z (Irel, %): 329/327 [M]+ (79/85), 328/326 [M - H]+ (89/78), 308 [M - F]+ (5), 247 [M - Br]+ (5), 227 (6), 201 (5), 179 (13), 172 (19), 145 [PhCF3 - H]+ (34), 125 (20), 102 (15), 95 (30), 89 (13), 77 (18), 76 (28), 75 (44), 63 (18), 51 (20), 50 (31), 39 (10). 1H NMR spectrum, , ppm: 7.0-7.9 (8H, m, Ar); 8.32 (1H, s, CH=N). N-(4-Bromobenzylidene)-2-nitroaniline (1y). Mass spectrum, m/z (Irel, %): 306/304 [M]+ (10/10), 259 [M - NO2]+ (2), 208 (7), 185/183 [BrC6H4CHNH]+ (96/100), 178 (17), 167 (5), 157/155 [C6H4Br]+ (15/16), 102 (10), 89 (26), 77 (23), 76 (30), 75 (19), 63 (31), 51 (26) 50 (30), 39 (20). 1H NMR spectrum, , ppm: 7.0-8.1 (8H, m, Ar), 8.33 (1H, s, CH=N). The authors thank the Latvian Council of Science for financing the work (Grant No. 181).
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. B. Marciniec (editor), Comprehensive Handbook of Hydrosilylation, Pergamon, Oxford (1992). V. B. Pukhnarevich, E. Lukevics, L. I. Kopylova, and M. G. Voronkov, Prospects of Hydrosilylation [in Russian], Inst. Organ. Sinteza Latv. Akad. Nauk, Riga (1992). K. A. Horn, Chem. Rev., 95, 1317 (1995). J.-F. Carpentier and V. Bette, Current Org. Chem., 6, 913 (2002). I. Iovel, L. Golomba, J. Popelis, and E. Lukevics, Khim. Geterotsikl. Soedin., 51 (2002). V. V. Zuev, O. P. Kovaleva, and N. K. Skvortsov, Phosphorus, Sulfur, and Silicon and the Related Elements, 179, 83 (2004). I. Iovel, L. Golomba, J. Popelis, S. Grinberga, and E. Lukevics, Khim. Geterotsikl. Soedin., 52 (2003). E. Lukevics, I. Jovel, and L. Golomba, in: Abstracts of XVth FECHEM Conference on Organometallic Chemistry, Zurich, Switzerland (2003], PO104. I. Iovel, L. Golomba, J. Popelis, A. Gaukhman, and E. Lukevics, Khim. Geterotsikl. Soedin., 324 (2000). I. Iovel, L. Golomba, S. Belyakov, and E. Lukevics, Khim. Geterotsikl. Soedin., 778 (2000). I. Iovel, L. Golomba, J. Popelis, S. Grinberga, and E. Lukevics, Khim. Geterotsikl. Soedin., 890 (2000). 713
12. 13. 14. 15. 16. 17. 18. 19.
I. Iovel, L. Golomba, S. Belyakov, A. Kemme, and E. Lukevics, Appl. Organometal. Chem., 15, 733 (2001). I. Iovel, L. Golomba, J. Popelis, S. Grinberga, and E. Lukevics, Khim. Geterotsikl. Soedin., 1375 (2002). I. Iovel, L. Golomba, S. Belyakov, J. Popelis, A. Gaukhman, and E. Lukevits, Khim. Geterotsikl. Soedin., 361 (2003). Ch. M. Standfest-Hauser, K. Mereiter, R. Schmid, and K. Kirchner, Organometallics, 21, 4891 (2002). M. J. S. Dewar, E. G. Zoebisch, E. F. Healy, and J. J. P. Stewart, J. Am. Chem. Soc., 107, 3902 (1985). J. J. P. Stewart, MOPAC, Version 6.0, Quantum Chemical Program Exchange (QCPE), Program No. 455, Bloomington, IN (1984). J. J. P. Stewart, MOPAC, Version 6.0, Manual Program No. 455, Bloomington, IN (1984). JMol: http://www.chem.columbia.edu/~gezelter.
714
SYNTHESIS AND CYTOTOXIC ACTIVITY OF 4-SUBSTITUTED 3-CYANO6,6-DIMETHYL-5,6-DIHYDRO-2-PYRANONES

L. Leite, D. Jansone, M. Fleisher, H. Kazhoka, J. Popelis, N. Veretennikova, I. Shestakova, I. Domracheva, and E. Lukevics The respective 4-(arylvinyl)lactones and compounds of the Michael adduct type were synthesized by the condensation of substituted benzaldehydes with 3-cyano-4,6,6-trimethyl-5,6-dihydro-2-pyranone in the presence of catalytic amounts of sodium hydroxide. It was shown by the semiempirical AM1 method that the indicated products can be formed through one and the same intermediate compound. Some of the synthesized phenylvinyl-5,6-dihydro-2-pyranones have a cytotoxic effect, and this corresponds to the prognosis of the OREX expert system. Keywords: benzaldehyde, substituted -lactones, crotonic condensation mechanism, semiempirical AM1 method, cytotoxic activity, OREX expert system. We have shown that the reaction of methyl-substituted - and -lactones with pyridinecarbaldehydes takes place by a nontraditional mechanism, in which the products from the reaction of one molecule of the aldehyde with two molecules of the pyranone are formed in addition to the products from crotonic condensation [1]. At the same time no departures from the classical mechanism of crotonic condensation were found in [2, 3], devoted to the condensation of benzaldehyde with the above-mentioned lactones, The aim of the present work was to investigate the condensation of 3-cyano-4,6,6-trimethyl-5,6-dihydro2-pyranone (1) with substituted benzaldehydes 2-10 in greater detail and to determine the effect of the electronic structure of the aldehyde on the ratio of the two paths of condensation with the CH acid. Earlier we showed that 3-cyano-6,6-dimethyl-4-[2-(4-nitrophenyl)vinyl]-5,6-dihydro-2-pyranone, like its analogs with pyridyl-containing substituents, have clearly defined cardiovascular activity [1]. The second aim of the work was therefore to analyze the potential biological activity of the synthesized compounds using the OREX system (optimized recognizing expert system), developed at the Latvian Institute of Organic Synthesis, and also to verify experimentally the established structureactivity relation. The reaction of the aldehydes 2-10 with the pyranone 1 was carried out in ethanol in the presence of catalytic amounts of sodium hydroxide with the pyranone, aldehyde, and sodium hydroxide in molar ratios of (0.7-2):1:(0.06-0.13). The initial concentration was 1.87 M for the pyranone and 0.93 M for the aldehydes. According to the data in Table 1, two types of compounds (the products of crotonic condensation 11-19 and compounds of the Michael adduct type 20-28) are formed as a result of the reaction of all the aldehydes with the pyranone 1, and the times at which they appear and the yields depend on the nature of the substituent of the aldehyde and on the temperature. __________________________________________________________________________________________ Latvian Institute of Organic Synthesis, Riga LV-1006, Latvia; e-mail: leite@osi.lv. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 839-849, June, 2004. Original article submitted December 17, 2003. 0009-3122/04/4006-07152004 Plenum Publishing Corporation 715
To compare the reactivity of the benzaldehydes with various substituents the yields of the reaction products were determined by HPLC without isolation from the reaction mixture. The dynamics of the process were monitored by TLC. As seen from Table 1, in the reaction of the unsubstituted aldehyde 2 with pyranone a product of the Michael adduct type 20 is formed preferentially irrespective of the reaction temperature and the molar ratio of the reagents. The yield of this compound increases with increase in the amount of the catalyst and the reaction time. The appearance of the crotonic condensation product 11 was only observed after 4 h.
R1 R O + R O O 1 H 2 _ 10 R R1 R2 CH CH2 O 11 _19 N O O
2
R2
N O
R1
R2
_ 20 28 1 2 1 2 2, 11, 20 R = R = R = H; 3, 12, 21 R = NO2, R = R = H; 4, 13, 22 R = Cl, R1=R2 = H; 5, 14, 23 R = Cl, R1 = H, R2 = Cl; 6, 15, 24 R = NMe2, R1 = R2 = H; 7, 16, 25 R = Me, R1 = R2 = H; 8, 17, 26 R = OH, R1 = R2 = H; 9, 18, 27 R = OMe, R1 = R2 = H; 10, 19, 28 R = OH, R1 = OMe, R2 = H
It was not possible to isolate the products from the reaction of the pyranone 1 and the aldehyde 8. However, to judge from the data from chromatography and from the 1H NMR spectrum two compounds 17 and 26 are formed. With the pyranone and aldehyde 3 in a ratio of 2:1 compound 21 is mainly formed. However, on account of the effect of the electron-withdrawing substituent NO2 the yield is lower than in the case of the unsubstituted aldehyde. Only if the molar ratio of the aldehyde and pyranone is 1.5:1 can the product of the Michael adduct type no longer be detected in the reaction products. In the case of the electron-donating substituent NMe2 (aldehyde 6), as expected, the reaction rate is greatly reduced, and more than 76% of the pyranone remains unreacted even after keeping the reaction mixture for 4 h. The yield of the product 24 in this case is only 1.7%. The structure of the obtained lactones was proved on the basis of the 1H NMR spectra (Tables 2 and 3). According to the 1H NMR spectra, the vinyl fragment of compounds 11-16, 18, and 19 has the trans configuration (3J = 15.9-16.2 Hz). Comparison of the changes in the chemical shifts of the two vinyl protons with replacement of the substituent in the phenyl ring provides grounds for assigning the downfield doublet to the absorption of the proton at the C atom attached to the phenyl group (range of variation of the chemical shifts = 0.42 ppm), while the upfield doublet is assigned to the absorption of the proton at the C atom attached to the pyranone residue ( = 0.26 ppm). Attention is drawn to the fact in the spectra of the lactones 11-16, 18, and 19 the protons the of CH2 and the protons of the two methyl groups in the pyranone ring are magnetically equivalent, whereas in the lactones 20-28 the chemical shifts of the same protons differ (0.04-0.16 and 0.02-0.17 ppm respectively). Dreiding models show that the pyranone ring has the form of a distorted half-chair and the rate of the conformational transitions changes with replacement of the substituent at position 2 of the pyranone. Magnetic nonequivalence is also observed for the CH2 protons of the CH(CH2)2 fragments of compounds 20-28 (2J = 12.4-13.2 Hz). This may be due to the considerable size of the substituted pyranones, which prevents free rotation about the CH2pyranone bond. 716
TABLE 1. Reaction of the Pyranone 1 with Benzaldehydes 2-10 at 78C

Aldehyde pyranoneNaOH molar ratio 1 : 1 : 0.06 1 : 2 : 0.06 1 : 2 : 0.06 1 : 2 : 0.13 1 : 2 : 0.06 1 : 0.7 : 0.06 1 : 2 : 0.06 1 : 2 : 0.06 1 : 2 : 0.06 1 : 2 : 0.06 1 : 2 : 0.06 1 : 2 : 0.06 1 : 2 : 0.06 Time, h Yield of reaction products, % Crotonic Adduct of Michael reaction type condensation 3.1*2 22.6*4 60.0 15.2 33.3 11.7*6 10.9 24.6 14.8 37.9 63.5 41.5 57.6*3 81.4 75.3*5 52.7 52.0 1.7*7 22.7 21.7 39.8 13.2
Aldehyde
2 2 2 2 3 3 4 5 6 7 8 9 10
2.5* 1 4 4 4 4 4 4 4 0.1 0.5 1 0.5
_______ * Reaction temperature 20C. *2 Formed after 4 h. *3 Formed 15 min after mixing of the reagents. *4 Formed at moment the reagents were mixed. *5 Formed after 5 min. *6 Formed after 1 h. *7 Formed after 3 h.
According to our views about the mechanism of the crotonic condensation of pyridinecarbaldehydes with furanone, the two products from the reaction of benzaldehydes with pyranone 1 can be formed through one and the same intermediate product of aldol condensation type A, and the probable source of the protons is hydrated sodium cations [3]. In the present the model condensation of the pyranone 1 with the aldehyde 3 was studied by the semiempirical quantum-chemical AM1 method [4]. The JMol software [5] was used for visualization and animation of the obtained results, and the ChemCraft 1.3 software package [6] was used to create a design of the reaction system. It was assumed that by analogy with the reaction of pyridinecarbaldehydes the reaction of pyranone and the aldehyde 3 will take place in two directions depending on the nature of the attacking nucleophile:
+ HOH OH ArCH CHHet 12 I H A
NO2 N ; Het = O O
H C Het HetC (3) H 2 II H1
Ar
(1)
(2)
ArCH(CH2Het)2 21
Ar =
Me Me
717
718
TABLE 2. The 1H NMR Spectra of the Lactones 11-16, 18, and 19

Compound Empirical formula Found, % Calculated, % H 5.97 5.97 4.67 4.73 4.84 4.90 4.06 4.07 6.75 6.80 6.40 6.41 6.06 6.05 5.72 5.72
mp, C N 5.54 5.53 9.35 9.39 4.88 4.87 4.29 4.35 9.40 9.45 5.26 5.24 4.93 4.94 4.66 4.68 144-146 224-226 180-182 212-214
NMR (CDCl3), , ppm (J, Hz)
C 75.87 75.87 64.40 64.42 66.74 66.79 59.69 59.65 72.88 72.95 76.36 76.38 72.06 72.07 68.19 68.22
11 12 13 14
C16H15NO2 C16H14N2O4 C16H14ClNO2 C16H13Cl2NO2
15 16
C18H20N2O2 C17H17NO2
192-194 143-145
18
C17H17NO3
139-141
19
C17H17NO4
233-236 (dec.)
1.52 (6H, s, CH3 pyranone); 2.87 (2H, s, CH2 pyranone); 7.29 and 7.45 (2H, d and d, J = 16.2, CH=CH); 7.3-7.7 (5H, m, 65) 1.55 (6H, s, CH 3 pyranone); 2.88 (2H, s, CH 2 pyranone); 7.31 and 7.54 (2H, d and d, J = 16.2, CH=CH); 7.76 (2H, m, J = 9.0, 64 H2, H6); 8.3 (2H, m, J = 9.0, 64 H3, H5) 1.53 (6H, s, CH 3 pyranone); 2.86 (2H, s, CH 2 pyranone); 7.25 and 7.46 (2H, d and d, J = 16.1, CH=CH); 7.42 (2H, m, J = 8.9, 63 H2, H6); 7.55 (2H, m, J = 8.9, 64 H3, H5) 1.55 (6H, s, CH3 pyranone); 2.88 2H, s, CH2 pyranone); 7.34 1H, dd, J = 8.6 and 2.0, 63 H5) 7.38 and 7.63 (2H, d and d, J = 16.2, CH=CH); 7.47 (1H, d, J = 2.0, 63 H3); 7.74 (1H, d, J = 8.6, 63 H6) 1.50 (6H, s, CH3 pyranone); 2.81 (2H, s, CH2 pyranone); 3.08 (6H, s, N(CH3)2; 6.68 (2H, m, J = 9.0, 64 H2, H6); 7.22 (2H, s, CH=CH); 7.51 (2H, m, J = 9.0, 64 H3, H5) 1.52 (6H, s, CH3 pyranone); 2.40 (3H, s, CH364); 2.85 (2H, s, CH2 pyranone); 7.24 (2H, m, J = 8.2, 64 H3, H5), 7.26 and 7.39 (2H, d and d, J = 15.6, CH=CH); 7.51 (2H, m, J = 8.2, 64 H2, H6) 1.51 (6H, s, CH3 pyranone); 2.84 (2H, s, CH2 pyranone); 3.87 (3H, s, OCH3); 6.95 (2H, m, J = 8.9, 64 H2, H6); 7.25 and 7.31 (2H, d and d, J = 15.9, CH=CH); 7.58 (2H, m, J = 8.9, 64 H3, H5) 1.42 (6H, s, CH3 pyranone); 3.09 (2H, s, CH2 pyranone); 3.84 (3H, s, OCH3); 6.89 (1H, d, J = 7.8, 63 H5); 7.12 and 7.64 (2H, d and d, J = 15.9, CH=CH); 7.2-7.4 (2H, m, 63 H2, H6); 10.0 (1H, s, OH)
TABLE 3. The Characteristics of the Lactones

Compound 20 21 Empirical formula C25H26N2O4 C25H25N3O6 Found, % Calculated, % C H N 71.72 71.75 64.65 64.79 66.27 66.30 6.26 6.26 5.42 5.44 5.57 5.56 4.87 4.96 6.52 6.53 6.18 6.14 6.24 6.29 6.31 6.50 6.70 6.69 9.03 9.07 6.14 6.18 5.69 5.75 6.47 6.48 6.26 6.32 6.30 6.25 5.63 5.64
1
mp, C
NMR (DMSO-d6), , ppm (J, Hz)
188-192 204-207 (dec.) 183-185 (dec.) 212-214 185-187
22 23 25
C25H25ClN2O4
C25H24Cl2N2O4 61.63 61.61 C26H28N2O4 72.16 72.20 67.76 67.71 69.54 69.63 65.55 65.31
26
C25H26N2O5 0.5 H2O C26H28N2O5
157-160 (dec.) 193-196 (dec.) 158-160 (dec.)
27
28
C26H28N2O6 0.5 C2H5OH 0.5 H2O
1.23 and 1.25 (12H, s and s, CH3 of pyranone); 2.33 and 2.49 (4H, d and d, J = 18.9, CH2 of pyranone); 3.00 (2H, dd, J = 12.4 and 10.4 CH(CH2)2; 3.09 (2H, dd, J = 12.4 and 5.6 CH(CH2)2; 3.49 (1H, m, CH); 7.2-7.5 (5H, m, C6H5) 1.22 and 1.35 (12H, s and s, CH3 of pyranone); 2.75 and 2.80 (4H, d and d, CH2 of pyranone); 3.02 and 3.08 (4H, m and m, CH(CH2)2; 3.71 (1H, m, CH); 7.68 2H, m, J = 9.6, C6H4 H2 and H6); 8.18 (2H, m, J = 9.6, C6H4 H3, H5) 1.18 and 1.32 (12H, s and s, CH3 of pyranone); 2.75 and 2.81 (4H, d and d, CH2 of pyranone); 3.00 and 3.04 (4H, m and m, CH(CH2)2; 3.51 (1H, m, CH); 7.40 (4H, s, C6H4) 1.23 and 1.30 (12H, s and s, CH3 of pyranone); 2.73 and 2.77 (4H, d and d, CH2 of pyranone); 3.05 and 3.11 (4H, m and m, CH (CH2)2; 3.97 (1H, m, CH); 7.4-7.8 (3H, m, C6H3) 1.16 and 1.33 (12H, s and s, CH3 of pyranone); 2.25 (3H, s, CH3C6H4); 2.73 and 2.82 (4H, d and d, J = 19.1, CH2 of pyranone); 2.95 and 3.04 (4H, m and m, CH(CH2)2; 3.50 1H C6H4 (1H, m, CH); 7.12 (2H, m, J = 7.8, C6H4 H2, H6); 7.22 (2H, m, J = 7.8, C6H4 H3, H5) 1.16 and 1.31 (12H, s and s, CH3 of pyranone); 2.72 and 2.79 (4H, d and d, CH2 of pyranone); 2.8-3.1 (4H, m, CH(CH2)2; 3.35 (1H, m, CH); 6.68 (2H, m, J = 8.5, C6H4 H2, H6); 7.14 (2H, m, J = 8.5, C6H4 H3, H5); 9.37 (1H, s, OH) 1.16 and 1.32 (12H, s and s, CH3 of pyranone); 2.72 and 2.83 (2H, d and d, J = 19.2, CH2 of pyranone); 2.95 and 3.03 (4H, m and m, CH(CH2)2; 3.50 (1H, m, CH); 3.71 (3H, s, OCH3); 6.87 (2H, m, J = 8.6, C6H4 H2, H6); 7.26 (2H, m, J = 8.6, C6H4 H3, H5) 1.23 and 1.33 (12H, s and s, CH3 of pyranone); 2.70 and 2.86 (4H, d and d, J = 19.1, CH2 of pyranone); 3.10 (2H, dd, J = 13.2 and 5.6, CH(CH2)2; 3.23 (2H, dd, J = 13.2 and 10.0, CH(CH2)2; 3.57 (1H, m, CH); 3.90 (3H, s, OCH3); 6.72 (1H, d, J = 8.0, C6H3 H5); 6.78 (1H, dd, J = 8.0 and 1.8, C6H3 H6); 7.10 (1H, d, J = 1.8, C6H3 H2); 7.71 (1H, s, OH)
719
Fig. 1. Reaction of the intermediate compound A with the OH- ion: a) the starting position; b) elimination of the H2O molecule; c) the reaction products. Thus, the reaction of the intermediate A with the OH- ion can lead to the product from crotonic condensation 12. At the starting position the OH- ion is on an extension of the C(2)H(1) bond at a distance of 3.10 from the H(1) atom (Fig. 1a). If this distance is reduced to 2.86 a molecule of water is eliminated from the C(1) atom. Subsequently, the H(1) atom is removed from the C(2) atom by the action of the OH- ion, and this leads to the formation of another molecule of water and the product 12 (Fig. 1c). Thus, this reaction path is realized by an E2 mechanism. The length of the double bond in compound 12 of 1.35 corresponds to data in [7]. The calculations show that the reaction takes place spontaneously without an energy barrier. The enthalpy of this reaction is -1011.7 kJ/mol. Figure 2a shows the selected starting position during calculation of the reaction system containing the intermediate compound A and the ion HetC(3)H2-. The C(3)C(1) and C(3)H(1) distances are 5.14 and 3.30 respectively. The HetC(3)H2- ion, in which the C(3) atom is negatively charged (-0.386), attacks the positively
b
Fig. 2. Reaction of the intermediate product A and the ion HetCH2-: a) the initial state; b) the reaction products (compound 21 and a water molecule). 720
charged C(1) atom (0.146) of the intermediate compound A. When the C(3)C(1) distance decreases to 4.89 , a molecule of water is eliminated from the C(1) atom. Further decrease of the distance between the C(3) and C(1) atoms to 1.523 leads to the formation of compound (21) (Fig. 2b). At this moment the distance between the water molecule and the C(1) atom amounts to 4.09 . During visualization of the process it is possible to see how gradual Walden inversion of the configuration at the C(1) atom occurs in the course of the reaction. The calculations show that the reaction of the HetC(3)H2- ion with the intermediate A takes place spontaneously without the need to overcome an energy barrier. The heat of this reaction amounts to -697.1 kJ/mol. Earlier it was shown by calculation that reaction of deprotonated at methyl group furanone with an intermediate compound takes place regioselectively during the condensation of 3-cyano-4,5,5-trimethyl-2(5H)furanone with 3-pyridinecarbaldehyde [3]. Thus, if attack by the indicated anion was directed at the C(1) atom of the intermediate compound (having a structure similar to compound A in the present work), bimolecular nucleophilic substitution (SN2) occurred, resulting in the formation of a product of the Michael adduct type. At the same time the ethenyl derivative of furanone and the initial furanone are formed as a result of attack at the H(1) atom, i.e., an E2 bimolecular elimination reaction occurs. As follows from the results of the quantum-chemical analysis, in the case of the reaction of the pyranone 1 with the aldehyde 3 in the reaction of the intermediate compound A with the deprotonated pyranone only the product of the Michael adduct type is formed, irrespective of the direction of attack by the anion. This may explain the fact that the yield of the product 21 under similar conditions is higher that the yield of the compound of the same type produced by the reaction of 3-cyano-4,5,5-trimethyl-2(5H)-furanone with 3-pyridinecarbaldehyde (81.5 and 59.5% respectively). Thus, the results of the present work indicate that the reactions of - and -methyllactones with aryl and hetaryl aldehydes are fairly general in nature and involve the formation not only of the crotonic condensation product but also a product of the Michael adduct type. The OREX expert system [8, 9] was used to predict the biological activity of the synthesized compounds. OREX is a system of programs for the creation and analysis of a data base and knowledge base and also for predicting biological activity. The algorithms of the logic-structural approach are based on the selection and subsequent incorporation of reliable indicators of biological activity, i.e., the structural fragments that determine the type of biological activity. The description of the chemical structure was based on descriptor centers and graphs representing the topology of the molecule. The program codes the structure of the compounds on the basis of the descriptor centers, singling out descriptors that are in the final count an abstract representation of the structure. The activity indicators are selected from the set of descriptors according to the working rules of a system of the following type:
if the compound has indicator f, it will then exhibit activity A with probability P. The indicators are selected according to their statistical value, determined in the data base employed as statistical sample. During screening of the compounds that we synthesized in the OREX program it was shown that the phenylvinyl derivative of the -lactone may have anticancer activity. It is possible to state with some degree of probability that the mechanism of their action involves the inhibition of RNA synthesis and also necrosis of the tumor in the respective systems (Fig. 3). The cytotoxic activity of the synthesized compounds on a monolayer strain of tumor cells MG-22A (mouse hepatoma) and their ability to stimulate the biosynthesis of nitric oxide radicals (NO), one of the possible components of the cytotoxic effect, were tested on the basis of the prediction results (Table 4). The strongest cytotoxic effect is exhibited by the nitrophenylvinyl and chlorophenyl derivatives of pyranone (compounds 12 and 13), which at low concentrations (5 and 6 g/ml) secure the destruction of cells of the MG-22A line. The pyranone 13 is characterized by a high level of generation of NO in the cells (800%, coloration CV), which may explain its high cardiovascular activity [1]. 721
. Fig. 3. Prediction of the activity in OREX. Total is the total amount of the compounds containing the given descriptor in the data base; Active is the number of active compounds containing the given descriptor in the data base; Conf. is the confidence coefficient, indicating the lowest level of probability with which the compound possessing the given activity indicator actually exhibits this activity; Effic. is the coefficient of efficiency, indicating by how many times the compound possessing this indicator has a higher probability of exhibiting the given activity than any compound taken at random; Covering is the covering coefficient and shows what part of the active compounds possesses a given indicator.
722
TABLE 4. The Biological Effect of Phenyllactones (in vitro) on a Monolayer Culture of MG-22A
Compound 11 12 13 14 15 16 18 19 20 22 23 25 26 27 28 Cytotoxicity, g/ml* TD50 (MTT) TD50 (CV) 26 5 6 58 *2 28 34 *2 *2 52 *2 55 *2 *2 *2 48 33 17 75 *2 42 32 *2 *2 58 *2 74 *2 *2 *2 Generation of NO (100% CV) 67 21 800 17 5 50 50 6 9 300 15 53 11 9 7
_______ * TD50 is the concentration securing 50% destruction of cells, g/ml; CV is coloration with crystal violet; MTT is coloration with 3-(4,5-dimethyl-2thiazolyl)-2,5-diphenyltetrazolium bromide [10, 11]; the nitric oxide was determined by Grace's method in the culture medium a over cells and converted to 100% live cells with coloration by CV [10]. *2 There was no cytotoxic effect.
EXPERIMENTAL The yield of the reaction products was determined by HPLC on a Nova-Pak Silica column (3.9 150 mm). The delivery rate of the eluant (1:1 ethyl acetatehexane) was 1.5 ml/min, UV detector, 254 nm. The 1H NMR spectra were recorded on a Mercury 200B instrument (200 MHz) in deuterochloroform and DMSO-d6 with TMS as internal standard. TLC was conducted on Silufol UV-254 plates with 1:1 ethyl acetate hexane as eluant. The quantum-chemical calculations were carried out by the semiempirical AM1 method using MOPAC 6 software with full optimization of the geometry of the reagents, reaction system, and reaction products in the EF regime at the PRECISE level. Condensation of 3-Cyano-4,6,6-trimethyl-5,6-dihydro-2-pyranone with Benzaldehyde (General Procedure). A mixture of pyranone 1, aldehyde 2-10, and sodium hydroxide in ethanol was heated with stirring to boiling and boiled for 4 h or kept at room temperature. The product of the Michael adduct type that separated was filtered off without cooling the mixture. After cooling to room temperature the ethenyl derivative of the lactone was filtered off. Both products were purified by recrystallization from ethanol. The enthalpy of reaction was calculated as the difference between the total energy of the final state of the system and the sum of the total energies of the isolated reagents the anion (OH- or HetC(3)H2-) and the intermediate. Additional information on the changes in geometry during the reaction can be obtained on request from the authors (e-mail: misha@osi.lv).
723
The work was carried out with financial support from the Latvian Council on Science (Program "Development of Modern Methods of Organic Chemistry with the Aim of Establishing the Industrial Production of New Medicinal Preparations in Latvia").
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. L. Leite, D. Jansone, M. Veveris, H. Cirule, Y. Popelis, G. Melikyan, A. Avetisyan, and E. Lukevics, Eur. J. Med. Chem., 34, 859 (1999). A. Perjessy, A. Avetisyan, A. Aknazaryan, and G. Melikyan, Coll. Czech. Chem. Commun., 54, 1666 (1989). M. Fleisher, D. Jansone, G. Andreeva, L. Leite, and E. Lukevics, Khim. Geterotsikl. Soedin., 748 (2001). J. J. P. Stewart, MOPAC Program Package (QCPE N 455) version 6. JMol: http://www.chem.columbia.edu/~gezelter. ChemCraft: http://chemcraft.boom.ru. F. A. Alien, O. Kennard, and D. G. Watson, J. Chem. Soc., Perkin Trans 2, No. 12, S1 (1987). A. Rozenblit and V. Golender, Logic-Combinatorial Methods in Design of Drugs [in Russian], Zinatne, Riga (1983). N. Veretennikova, A. Skorova, V. Kudryashova, A. Rozenblit, A. Barkans, Ya. Betinsh, V. Drboglav, L. Gitlina, Ya. Grinfelds, P. Mellis, D. Petersone, and V. Shatokhin, in: Fei Chen and Gerrit Schuurmann (editors), QSAR in Environmental Sciences - VII, Setac/Setac Foundation (1997), p. 115. D. J. Fast, R. C. Lynch, and R. W. Leu, J. Leucocyt. Biol., 52, 255 (1992). P. J. Freshney, Culture of Animal Cells (A Manual of Basic Technique), Wiley-Liss, New York (1994), p. 296.
10. 11.
724
UNNATURAL AMINO ACIDS. 2*. SIMPLE METHOD OF OBTAINING ESTERS OF AZIRIDINE-2-CARBOXYLIC ACIDS BY A TRANSESTERIFICATION REACTION
B. Shtrumfs, D. Chernyak, I. Kums, I. Kalvins, and P. Trapencieris A series of N-unsubstituted esters of aziridine-2-carboxylic acid has been obtained by transesterification in basic medium using primary, secondary, and tertiary alcohols. Methods of transesterification using various bases (K2CO3, ROLi, t-BuOK) have been compared. Transesterification with lithium alcoholates also affords the possibility of obtaining esters of N-substituted aziridine-2-carboxylic acids. Transesterification of chiral esters proceeds with retention of the configuration of the chiral center. Keywords: diastereomers, esters of aziridine-2-carboxylic acid, enantiomers, transesterification. Esters of aziridine-2-carboxylic acid are a convenient source of various derivatives of - and -amino acids, due to the high reactivity of the aziridine ring [2,3]. In difference to esters of other amino acids, aziridine2-carboxylates have no tendency to dimerize, consequently the direct transesterification method may be used in the aziridine-2-carboxylate series. The transesterification of aziridine-2-carboxylates has not been described in the literature, although good results have been obtained for compounds of other classes [4] on using acid or base catalysis, catalysis by alcoholates [4-7], organotin [8] and organotitanium compounds [9], and also indium triiodide [10]. To obtain aziridine-2-carboxylates we chose the base catalysis method [4,5] since aziridines are unstable under acid conditions and in the presence of strong Lewis acids. Lithium alcoholates, used in [5], are readily obtained from the corresponding alcohols by reaction with butyllithium. As starting materials we used aziridine-2-carboxylic acid methyl ester 1, for which a convenient method of synthesis has been developed [1], and its 1-alkyl and 1-acyl derivatives obtained by known methods used for the protection of the amino group of amino acids [11]. We have obtained a series of N-unsubstituted aziridine-2-carboxylates 2a-h, using primary, secondary, and tertiary alcohols, and have compared two methods (A and B) of transesterification. The transesterification products were obtained in high or moderate yields (Table 1).
O OMe N H 1 O A: ROH, 20 mol %> K2CO3, 90-120C B: ROH, n-BuLi, THF, -20Croom temp N H 2ah OR
_______ * For Part 1 see [1]. __________________________________________________________________________________________ Latvian Institute of Organic Synthesis, Riga LV-1006; e-mail: boriss@osi.lv. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 850-859, June, 2004. Original article submitted March 23, 2004. 0009-3122/04/4006-07252004 Plenum Publishing Corporation 725
TABLE 1. Yields of Esters 2a-h Synthesized by Methods A and B

Method A Reaction Yield, time, h %* 24 41 Method B Reaction Yield, time, h %* 1 30
Ester
2a
O O N H
2b
O O N H NO2
32
48
<1
2c
O O N H O
O N H
40
2d
24
78*
45
2e
240
67
O O N H
2f
O O N H
100
80
2g
O
100
39
N H HO
2h
O
100
57
N H O
_______ * According to data of gas chromatography.
726
Method A is based on catalysis by K2CO3 base and by the shift in chemical equilibrium in the direction of forming reaction products by distilling out the more volatile alcohol MeOH. Reaction was carried out without solvent. In method B [5] the appropriate lithium alcoholate was used as reagent, generated with butyllithium in situ from the corresponding alcohol. Comparison of methods A and B showed that catalysis by a weak base (K2CO3) gives satisfactory yields of esters only with primary alcohols of the benzyl and allyl types (esters 2a-d). In the case of perillyl alcohol (ester 2d) the reaction proceeds by method A (according to data of gas chromatography the yield was 78%), but the ester was not isolated successfully due to side product formation. The 4-nitrobenzyl ester 2b was successfully obtained only by method A. This is not unexpected since the incompatibility of organolithium bases with nitro compounds is known. In the case of the more sterically hindered alcohols (esters 2e-h) the transesterification proceeds only by method B, since the alcoholates of secondary and tertiary alcohols are more strongly basic than K2CO3. This method enables acylation of alcoholic groups of complex molecules such as steroids, particularly of estradiol derivatives (esters 2g,h). Acylation in the case of estradiol (ester 2g) occurs regioselectively only at the alicyclic and not at the phenolic hydroxyl, although for deprotonation both alcoholic groups use 2 equivalents of BuLi. Attempts to carry out the transesterification reaction with polyhydric alcohols (glycerol, pentaerythritol, diacetonylglucose) did not give the expected reaction products. When using these alcohols in method A a mixture of aziridine ring fission products was obtained, on using the corresponding lithium alcoholates (method B), only starting materials were obtained. Transesterification with lithium alcoholates also enables esters of the N-substituted aziridine-2carboxylic acids 4a-j to be obtained from the corresponding methyl esters (Table 2).
O OMe N X 3ai ROH, n-BuLi, THF, -20Croom temp. N X
O OR
4ai
The reaction of lithium alcoholates with N-alkyl derivatives of aziridine-2-carboxylic acid methyl ester 3a-d proceeds smoothly with yields of esters 4a-d of 41-88%. The steric effects of the substituent at the nitrogen atom proved to have no significant effect on the course of the reaction. Transesterification of methyl esters is the most convenient route to obtain esters 4c,d, since alkylation of esters 2e,f with benzyl and trityl chlorides proceeds slowly and with the formation of side products. The use in this reaction of the corresponding bromides is undesirable due to the higher nucleophilicity of bromide ion, which leads to fission of the aziridine ring even at room temperature. It was shown that the diastereomers of the (-)-menthyl ester of N-benzylaziridine-2-carboxylic acid 4c and 4'c may be separated chromatographically. In the case of the N-unsubstituted compounds 2e the diastereomers are not separable. It was also established that the asymmetric center C(2) of the aziridine ring is not racemized on transesterification. The optically pure ester R-1 [1], obtained from the methyl ester of L-serine by the Mitsunobu reaction [12], on transesterification with lithium tert-butylate by method B gives ester R-2f. Comparison of the N-benzyloxycarbonyl derivative of this ester R-4f, obtained by the standard method [11], with the racemic ester R,S-4f by HPLC on a chiral column (enantiomer retention times 9.3 and 10.5 min) showed that ester R-4f (retention time 9.3 min) is enantiomerically pure.
727
TABLE 2. Yields of Esters 4a-j

Ester 4
N O O O
Reaction time, h 1
Yield, % 88
4b
N
O O
79
4c
O O N
48
4d
N
O
O
41
4e
N O O
O O
65
4f
N
O
O
1
O
15
4g
N
O
O
1
O
21
4h
N O O
O O
71
4i
N O O
O O
76
4j
N
O
O
56
728
O O N H R-1 H 80% t-BuOH, n-BuLi, THF, -20Crom temp. N H
O O H R-2f O O N O O R-4f H
CBzCl, Et3N, CH2Cl2, -5C room temp, 1 h 96%
Transesterification of the corresponding methyl esters of N-acylaziridine-2-carboxylic acid 3e-j also enables the preparation of the series of esters of N-acyl aziridine-2-carboxylic acid 4e-j. Satisfactory yields were observed when the substituent at the nitrogen atom was identical to the ester group (esters 4e,h). On transesterification of the methyl ester of N-benzyloxycarbonylaziridine-2-carboxylic acid 3f with lithium tert-butylate a 1:1 mixture of esters 4f and 4h was formed. Ester 4h is formed by transacylation at the nitrogen atom of the aziridine ring, consequently esters 4f and 4g are conveniently obtained by the N-acylation of esters 2f and 2a respectively. In the case of the carbamoyl derivative 4j the transesterification reaction proceeds smoothly (56%). The tert-butyl carbamate group of ester 3i is also not subject to a transacylation side reaction, and also provides a good yield of ester 4i.
TABLE 3. 1H NMR Spectra of Aziridine-2-carboxylic Acid Esters 2a-h and 4a-n

O OR N X
Compound 1 2a
X 2 H
R 3 Bn
H NMR spectrum (CDCl3), , ppm (J, Hz) 4
2b
4-NO2 64CH2
2c
Allyl
1.09 (1H, br. s, NH); 1.74-1.93 (1H, m, H-3); 1.93-2.08 (1H, m, H-3); 2.47-2.63 (1H, m, H-2); 5.18 (2H, s, 2Ph); 7.30-7.41 (5H, m, arom.) 1.11 (1H, br. s, NH); 1.71-2.06 (2H, m, H-3); 2.40-2.64 (1H, m, H-2); 5.22 (2H, s, CH2Ph); 7.76 (2H, d, J = 9.0, o-H arom.); 8.22 (2H, d, J = 9.0, m-H arom.) 1.08 (1H, br. s, NH); 1.78-2.12 (2H, m, H-3); 2.48-2.65 (1H, m, H-2); 4.63-4.71 (2H, m, CH2C=CH2); 5.245.43 (2H, m, CH2C=CH2); 5.84-6.06 (1H, m, CH2C=CH2)
729
TABLE 3 (continued)
1 2d 2 H 3 Perillyl 4 1.07 (1H, br. s, NH); 1.35-2.26 (9H, m, aliph.); 1.74 (3H, s, CH3); 2.50-2.60 (1H, unresolved dd, H-2); 4.47-4.64 (2H, m, OCH2); 4.68-4.80 (2H, m, C=CH2); 5.75-5.86 (1H, m, aliph.) 0.76 and 0.77 (3H, d and d, J = 7.0 and J = 7.0, menthyl CH3); 0.79-1.16 (4H, m, aliph.); 0.91 (6H, d, J = 6.5, i-Pr); 1.31-2.07 (9H, m, aliph.); 4.73 (1H, ddt, 3J = 2.2, 3J = 4.5, 3J = 10.8, OCH) 0.96 (1H, br. s, NH); 1.48 (9H, s, t-Bu); 1.70-1.84 (1H, m, H-3); 1.86-1.98 (1H, m, H-3); 2.33-2.47 (1H, m, H-2) 0.85 (3H, s, CH3); 1.08-2.38 (15H, m, aliph., NH); 2.55 (1H, dd, 2J = 3.0, 3J = 5.4, H-2); 2.71-2.88 (3H, m, aliph.); 4.68-4.82 (1H, m, OCH); 4.535.52 (1H, br. s, H); 6.55 (1H, d, J = 2.4, o-H arom.); 6.61 (1H, dd, J = 2.4, J = 8.3, o-H arom.); 7.14 (1H, d, J = 8.3, m-H arom.) 0.86 (3H, s, CH3); 1.05 (1H, br. s, NH); 1.17-2.08 (12H, m, aliph.); 2.12-2.38 (3H, m, aliph.); 2.47-2.59 (1H, m, aliph.); 2.79-2.93 (2H, m, aliph.); 3.78 (3H, s, OCH3); 4.69-4.84 (1H, m, OCH); 6.63 (1H, d, J = 2.8, o-H arom.); 6.71 (1H, dd, J = 2.8, J = 8.6, o-H arom.); 7.20 (1H, d, J = 8.6, m-H arom.) 1.47 (9H, s, t-Bu); 1.81 (1H, dd, 2J = 1.2, 3Jcis = 6.8, cis-H-3); 2.07 (1H, dd, 2J = 1.2, 3Jtrans = 3.0, trans-H-3); 2.27 (1H, dd, 3Jtrans = 3.0, 3Jcis = 6.8, H-2); 3.43 (3H, s, OCH3); 3.93 and 3.97 (1H and 1H, B system, J = 7.9, NCH2O) 1.46 (9H, s, t-Bu); 1.64 (1H, unresolved dd, 3 Jcis = 6.3, cis-H-3); 2.07 (1H, dd, 3Jtrans = 3.2, 3 Jcis = 6.3, H-2); 2.19 (1H, dd, 2J = 1.3, 3Jtrans = 3.2, trans-H-3); 3.54 and 3.57 (1H and 1H, B system, J = 13.7, CH2Ph); 7.19-7.38 (5H, m, arom.) 0.60-2.27 (21H, m, aliph.); 3.37 and 3.73 (1H and 1H, M system, J = 13.8, CH2Ph); 4.73 (1H, dt, 3J = 4.4, 3J = 10.7, OCH); 7.11-7.40 (5H, m, arom.) 0.46-2.33 (21H, m, aliph.); 3.26 and 3.85 (1H and 1H, M system, J = 13.7, CH2Ph); 4.75 (1H, dt, 3J = 4.4, 3J = 10.9, OCH); 7.04-7.48 (5H, m, arom.) 1.31 (1H, dd, 2J = 1.6, 3Jcis = 6.1, cis-H-3); 1.49 (9H, s, t-Bu); 1.77 (1H, dd, 3Jtrans = 2.6, 3 Jcis = 6.1, H-2); 2.20 (1H, dd, 2J = 1.6, 3 Jtrans = 2.6, trans-H-3); 7.16-7.34 (9H, m, arom.); 7.46-7.56 (6H, m, arom.) 2.47 (1H, dd, 2J = 1.2, 3Jcis = 5.6, cis-H-3); 2.62 (1H, dd, 2J = 1.2, 3Jtrans = 3.1, trans-H-3); 3.14 (1H, d.d, 3Jtrans = 3.1, 3Jcis = 5.6, H-2); 5.02-5.21 (4H, m, CH2Ph); 7.32-7.38 (10H, m, arom.) 1.45 (9H, s, t-Bu); 2.40 (1H, dd, 2J = 1.3, 3Jcis = 5.0, cis-H-3); 2.55 (1H, dd, 2J = 1.3, 3Jtrans = 3.1, trans-H-3); 3.00 (1H, dd, 3Jtrans = 3.1, 3Jcis = 5.0, H-2); 5.11 and 5.17 (1H and 1H, B system, J = 12.1, CH2Ph); 7.32-7.40 (5H, m, arom.) 1.45 (9H, s, t-Bu); 2.40 (1H, dd, 2J = 1.3, 3Jcis = 5.0, cis-H-3); 2.55 (1H, dd, 2J = 1.3, 3Jtrans = 3.1, trans-H-3); 3.00 (1H, dd, 3Jtrans = 3.1, 3Jcis = 5.0, H-2); 5.11 and 5.17 (1H and 1H, B system, J = 12.1, CH2Ph); 7.32-7.40 (5H, m, arom.)
2e
Menthyl
2f
t-Bu
2g
Estradiolyl
2h
3-Methoxyestradiolyl
4a
2M
t-Bu
4b
Bn
t-Bu
4c
Bn
Menthyl
4'c
Bn
Menthyl
4d
CPh3
t-Bu
4e
CO2Bn
Bn
R,S-4f
CO2Bn
t-Bu
R-4f
CO2Bn
t-Bu
730
TABLE 3 (continued)
1 4g 2 COOBu-t 3 Bn 4 1.43 (9H, s, t-Bu); 2.40 (1H, dd, 2J = 1.4, 3Jcis = 5.2, cis-H-3); 2.55 (1H, dd, 2J = 1.2, 3Jtrans = 3.3, trans-H-3); 3.00 (1H, dd, 3Jtrans = 3.2, 3Jcis = 5.1, H-2); 5.18 and 5.25 (1H and 1H, B system, J = 12.4, CH2Ph); 7.30-7.42 (5H, m, arom.) 1.47 (9H, s, t-Bu); 1.50 (9H, s, t-Bu); 2.32 (1H, dd, 2 J = 1.6, 3Jcis = 5.2, cis-H-3); 2.47 (1H, dd, 2J = 1.6, 3 Jtrans = 3.1, trans-H-3); 2.93 (1H, dd, 3Jtrans = 3.1, 3 Jcis = 5.2, H-2) 0.86 (3H, t, J = 6.7, nonyl CH3); 1.16-1.49 (21H, m, nonyl, t-Bu); 1.55-1.73 (2H, m, aliph.); 2.38 (1H, dd, 2J = 1.5, 3 Jcis = 5.5, cis-H-3); 2.50 (1H, dd, 2J = 1.5, 3 Jtrans = 3.2, trans-H-3); 3.00 (1H, dd, 3Jtrans = 3.2, 3 Jcis = 5.5, H-2); 4.02-4.26 (2H, m, OCH2) 2.48 (1H, dd, 2J = 1.2, 3Jtrans = 3.2, trans-H-3); 2.55 (1H, dd, 2J = 1.2, 3Jcis = 6.3, cis-H-3); 2.92 (3H, s, CH3); 3.02-3.08 (1H, unresolved dd, H-2); 3.05 (3H, s, CH3); 5.14-5.28 (2H, m, CH2Ph); 7.34-7.39 (5H, m, arom.) 1.42 (1H, dd, 2J = 1.0, 3Jcis = 6.3, cis-H-3); 1.50 (9H, s, t-Bu ); 2.01 (1H, dd, 2J = 1.0, 3 Jtrans = 3.4, trans-H-3); 2.38 (1H, dd, 3Jtrans = 3.4, 3 Jcis = 6.3, H-2); 2.69 (1H, dd, J = 4.8, J = 7.7, NCH); 3.37 (3H, s, OCH3); 3.61 (1H, dd, J = 4.8, J = 9.8, OCH); 3.70 (1H, dd, J = 7.7, J = 9.8, OCH); 7.25-7.45 (5H, m, arom.) 1.40 (9H, s, t-Bu), 1.87 (1H, dd, 3Jtrans = 3.3, 3 Jcis = 6.4, H-2); 1.98 (1H, dd, 2J = 1.0, 3 Jcis = 6.3, cis-H-3); 2.39 (1H, dd, 2J = 1.0, 3 Jtrans = 3.3, trans-H-3); 2.75 (1H, dd, J = 4.5, J = 7.9, NCH); 3.34 (3H, s, OCH3); 3.54 (1H, dd, J = 4.8, J = 9.8, OCH); 3.72 (1H, dd, J = 7.9, J = 9.8, OCH); 7.23-7.42 (5H, m, arom.)
4h
COOBu-t
t-Bu
4i
COOBu-t
Nonyl
4j
CONMe2
Bn
4m
CH(Ph)CH2OMe
t-Bu
4n
CH(Ph)CH2OMe
t-Bu
We have shown by two different methods B and C (using potassium tert-butylate as base) that transesterification of the diastereomeric esters 4k and 4l proceeds with retention of the configuration of the substituent at the aziridine nitrogen atom and have obtained the corresponding diastereomeric esters 4m and 4n.
O OMe N Ph H 4k O OMe N Ph H 4l OMe B: t-BuOH, n-BuLi, THF, -20C room temp. C: t-BuOK, THF, -20C room temp. 29% (B) 74% (C) Ph H 4n (R) OBu-t N OMe OMe B: t-BuOH, n-BuLi, THF, -20C room temp. C: t-BuOK, THF, -20C room temp. 70% (B) 82% (C) Ph H 4m O (S) OBu-t N OMe O
731
TABLE 4. Physicochemical Characteristics of Esters of Aziridine-2carboxylic Acids 2 and 4

Compound 2b 2d 2e 2g 2h 4c 4'c 4d 4f 4h 4m 4n Empirical formula C C10H10N2O4 C13H19NO2 C13H23NO2 C21H27NO3 C22H29NO3 C20H29NO2 C20H29NO2 C26H27NO2 C15H19NO4 C12H21NO4 C16H23NO3 C16H23NO3 52.69 54.06 69.30 70.56 68.38 69.29 73.63 73.87 74.14 74.33 75.44 76.15 76.00 76.15 80.89 81.01 64.94 64.97 59.05 59.24 69.30 69.29 69.11 69.29 Found, % Calculated, % H 4.64 4.54 8.59 8.65 10.13 10.29 8.24 7.97 8.28 8.22 9.60 9.27 9.23 9.27 7.05 7.06 6.89 6.91 8.79 8.70 8.40 8.36 8.51 8.36
Rf * N 12.16 12.61 6.28 6.33 5.65 6.22 3.50 4.10 3.92 3.94 3.97 4.44 4.36 4.44 3.65 3.63 5.11 5.05 5.57 5.76 4.99 5.05 5.03 5.05 0.13 0.58 0.62 0.26 0.15 0.63 0.57 0.36 0.57 0.77 0.59 0.46
mp,
115-117
129-130 135-136 107-109 111-112 146-147 137.5-138.5
128
_______ * Mobile phase in TLC: ethyl acetatepetroleum ether, 1:1 (compounds 2b,d,e,g, 4c, 4'c, 4m,n), 1:3 (compounds 2h, 4f), 1:9 (compounds 4d,h).
EXPERIMENTAL The 1H NMR spectra were recorded on a Varian Mercury 200 (200 MHz) spectrometer, internal standard was TMS. Elemental analyses were carried out on a Carlo Erba EA 1108 apparatus. Melting points were determined on a Gallenkamp heating stage and are not corrected. TLC was carried out on DC Alufolien plates of Kieselgel 60. Chiral HPLC of compounds 4f and 4f-l was carried out on a Gilson chromatographic system and a column of Chiralcel OD (Daicel), in hexaneethanol, 95 : 5 (flow rate 1.0 ml/min and UV detector at 254 nm). Dry THF was prepared by double distillation over sodium (second time in the presence of benzoquinone). Transesterification of Aziridine-2-carboxylic Acid Methyl Ester and Its Derivatives (General Procedure). A. Compounds 2a-h (Tables 1,3,4). Potassium carbonate (41.4 g, 300 mmol) was added with stirring to a solution of aziridine-2-carboxylic acid methyl ester [1] (10.1 g, 100 mmol) in the alcohol (100 mmol) at ~20C. The mixture obtained was stirred and heated at 150C in a stream of argon while distilling off the methanol. The reaction mixture was then cooled to room temperature, poured into water (50 ml), and extracted with ether (3 20 ml). The combined ether extracts were washed with water (2 20 ml), and with saturated NaCl solution (20 ml), then dried over Na2SO4, the solution filtered, and the solvent evaporated in vacuum. The obtained esters were purified by chromatography on silica gel with petroleum etherethyl acetate, or by distillation in vacuum.
732
B. Compounds 2a-h and 4a-j (Tables 1-4). A round-bottomed flask (100 ml) was placed in a heater for 5 h at 150C and cooled in a stream of argon to room temperature. The alcohol (100 mmol) was placed in the flask and absolute THF (10 ml) was added. The obtained solution was cooled to -20C in a stream of argon and BuLi (40 ml, 100 mmol) was added dropwise as a 2.5 M solution in hexane. The solution of alcoholate obtained was stirred at -20C for 15 min, a solution of aziridine-2-carboxylic acid methyl ester (100 mmol) in absolute THF (15 ml) was added, the mixture was stirred for 1-5 h at -20C, heated to room temperature, poured into ice water (20 ml), and extracted with ether (3 20 ml). The ether extracts were combined, washed with water (2 20 ml), and with saturated NaCl solution (20 ml), dried over Na2SO4, and the solvent evaporated in vacuum. The esters obtained were purified by chromatography on silica gel in the system petroleum etherethyl acetate, or by distillation in vacuum. C. Compounds 4m and 4n (Tables 3, 4). A round-bottomed flask (100 ml) was placed in a heater at 150C for 5 h and cooled in a current of argon to room temperature. Potassium tert-butylate (100 mmol) was placed in the flask and absolute THF (15 ml) was added. The solution obtained was cooled in a current of argon to -20C and a solution of aziridine-2-carboxylic acid methyl ester (100 mmol) in absolute THF (15 ml) was added dropwise. The mixture was stirred at -20C for 1.5 h, heated to room temperature, poured into ice water (25 ml), and extracted with ether (3 25 ml). The ether extracts were combined, washed with water (2 25 ml), and with saturated NaCl solution (25 ml), dried over Na2SO4, and evaporated. The esters obtained were purified by chromatography on silica gel in the system petroleum etherethyl acetate, 4:1. The work was carried out with the financial support of the Latvian Council for Science (grant LZP 01.192).
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. P. Trapencieris, I. Kalvins, L. Kaulina, and V. Kauss, Organic Process Research & Development, 1, 259 (1997). A. Hassner (editor), Small Ring Molecules, John Wiley and Sons, New York (1983), p. 105. T. Satoh, Chem. Rev., 96, 3303 (1996). J. Otera, Chem. Rev., 93, 1449 (1993). O. Meth-Cohn, J. Chem. Soc., Chem. Commun., 695 (1986). V. A. Vasin and V. V. Razin, Synlett., 658 (2001). M. G. Stanton and M. R. Gagne, J. Am. Chem. Soc., 119, 5075 (1997). R. L. E. Furlan, E. G. Matta, and O. A. Mascaretti, Tetrahedron Lett., 39, 2257 (1998). P. Krasik, Tetrahedron Lett., 39, 4223 (1998). B. C. Ranu, P. Dutta, and A. Sarkar, J. Org. Chem., 63, 6027 (1998). J. P. Greenstein and M. Winitz, Chemistry of the Amino Acids, Vol. 2, John Wiley & Sons, New York (1961). R. G. Kostyanovsky, P. E. Dormov, P. Trapencieris, B. Strumfs, G. Kadorkina, I. Chervin, and I. Kalvins, Mendeleev Commun., 26 (1999).
733
INTERACTION OF HYDROXYLAMINE WITH ESTERS OF 2-OXOBUTENOIC ACIDS. SYNTHESIS OF 3-HYDROXIMINO1-HYDROXY-2-PYRROLIDINONES

M. Katkevics, E. Korchagova, T. Ivanova, V. Slavinska, and E. Lukevics New 3-hydroximino-1-hydroxy-2-pyrrolidinones have been synthesized by the interaction of NH2OH and NH2OBn with the methyl esters of 2-oxo-3-butenoic acid derivatives. Some intermediate compounds have been isolated and identified and the reaction mechanism is discussed. Keywords: hydroxylamine, 3-hydroximino-1-hydroxy-2-pyrrolidinone, cyclic hydroxamic acids, 2-oxo3-butenoic acid esters. Hydroxamic acids display a broad spectrum of biological activity, such as antibacterial [1,2], antitumor [3-5], antitubercular, and fungicidal [6], and are inhibitors of metalloenzymes [7,8]. The unique activity of hydroxamic acids is caused by their chelate-forming properties [6,9,10] and by the ability to generate NO in cells [11]. Various methods have been proposed for obtaining hydroxamic acids [12-15]. One of the known methods of obtaining them is the acylation of hydroxylamine with esters [16]. On interacting hydroxylamine with esters of saturated -keto acids isoxazolin-5-one (the oxime of the corresponding ester was detected spectroscopically in the reaction mixture as an intermediate) and/or isoxazolin-3-one are formed [17]. The intermediate compounds for the latter, 5-hydroxy-3-isoxazolidinone and the linear hydroxamic acid, are found in equilibrium, however the sequence of their formation was not clarified. Unsaturated -keto esters interact with hydroxylamine with the formation of oximes, which, depending on the presence of a substituent, are converted into oxazolines or 1-hydroxy-2-pyridones [18]. It was shown that in reactions with ,-unsaturated esters the first step is a Michael type addition at the double bond, and not acylation of hydroxylamine by the ester group [19]. The reaction of hydroxylamine with esters of 2-oxo-3-butenoic acids has not been studied up to the present time. The latter are valuable starting materials for the synthesis of biologically active compounds. In continuing investigations on the use of the esters mentioned as synthons [20], we have studied the interaction of them with hydroxylamine. 2-Oxo-3-butenoic acid ester has three centers for nucleophilic attack. The use of an excess of hydroxylamine in the investigated reaction, interacting with all the functional groups of the ester, theoretically suggests the formation of 3-hydroximino-1-hydroxy-2-pyrrolidinone 1, two oxazinone isomers 2 and 3, and the linear hydroxamic acid 4 (X = H).
__________________________________________________________________________________________ Latvian Institute of Organic Synthesis, Riga LV-1006; e-mail: martins@osi.lv. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 860-867, June, 2004. Original article submitted January 23, 2004. 734 0009-3122/04/4006-07342004 Plenum Publishing Corporation
N R
OX O
R HN O 2
N O
OX
R O N H 3
N O
XO OX R 4 NH N
OX H N OX O
N OX 1
The interaction of NH2OH with 2-oxo-4-(2-thienyl)-3-butenoic acid ester (5b) was studied at ~20C and pH 8. In the 1H NMR spectrum (DMSO-d6) of the isolated substance three double doublet signals were observed at 5.12 (1H, dd, J = 8.2, 3.8 Hz), 3.35 (1H, dd, J = 18.6, 8.2 Hz), and 2.66 ppm (1H, dd, J = 18.6, 3.8 Hz), which may correspond to compounds 1, 2, and 4 (X = H), but according to elemental composition (the presence of three hydroxylamine fragments) this substance corresponds to structure 4. Additional confirmation of the structure of this compound is the reaction of 5b with NH2OBn, since on interaction with an O-substituted hydroxylamine the formation is possible of only compounds 1 and 4. The 1 H NMR spectrum and elemental composition of the product isolated from the reaction of ester 5b with NH2OBn at pH 7 and ~20C showed the presence of only two NH2OBn fragments in the molecule. The compound was identified as the derivative of 5-(2-thienyl)-2-pyrrolidinone 1b (X = Bn). To define more precisely the structure of the compound obtained on interaction of the initial ester with NH2OH it was alkylated with benzyl bromide. The compound isolated was identical to compound 1b (X = Bn) in all analytical characteristics. This confirms unequivocally that in reactions with NH2OH 3-hydroxyiminopyrrolidinone derivatives 1 are also formed. It has been established that compound 6 crystallizes from the reaction mixture as the 3-hydroximino-1-hydroxy-2-pyrrolidinone and hydroxylamine salt (Scheme 1). After acidification with 1N HCl to pH 2 the monohydrate 7 was isolated. The characteristics of the 3-hydroximinopyrrolidinones 7a-f synthesized are given in Tables 1-3. Scheme 1
N
O
R
OH
O
OH
+ H2N Me
O N OH 6
. NH2OH
OH
.HO O 2 N OH 7 a R = Ph, b R = 2-thienyl, c R = 2-furyl, d R = 3,4-(MeO)2C6H3, e R = 4-ClC6H4, f R = 4-O2NC6H4

R
1N HCl
The intermediate compounds, isolated and identified by us for certain derivatives (5d and 5f), enabled the sequence of reactions of NH2OBn with the functional groups of the initial ester to be determined. The interaction of NH2OBn with 2-oxobutenoic acid occurs in three stages (Scheme 2). It is apparent that at pH 7-8 NH2OBn reacts initially with the -keto group with the formation of oxime 8. Addition of a second molecule of NH2OBn to the double bond then follows (compound 9). The last stage is a 5-exo-trig cyclization with the formation of derivatives of 3-benzyloximinopyrrolidinone 10.
735
Scheme 2
O
O
R
H2N
Me
Bn R
Bn
O
H2N
Me
Bn
8
O
NH
N
N
Bn O Me
Bn
O
Bn
R
N O
Bn
10
a R = Ph, b R = 2-thienyl, c R = 2-furyl, d R = 3,4-(MeO)2C6H3, e R = 4-ClC6H4, f R = 4-O2NC6H4
The rate of cyclization varies significantly depending on the character of the substituent in the initial ester. In the case of phenyl and thienyl derivatives we did not succeed in isolating the intermediate compounds 9a and 9b. After chromatographic purification ester 9c is cyclized both in methanol solution at 0C and without a solvent. However the cyclization of derivatives with a substituted phenyl group 9d-f occurs only on extended heating of a methanolic solution at 60C. The reaction conditions and the characteristics of some isolated intermediate compounds 9c,d, 8f, and 9f are given in Experimental.

Compound 7a 7b 7c 7d 7e 7f 10a 10b 10c 10d 10e 10f Empirical formula C C10H12N2O4 C8H10N2O4S C8H10N2O5 C12H16N2O6 C10H11ClN2O4 C10H11N3O6 C24H22N2O3 C22H20N2O3S C22H20N2O4 C26H26N2O5 C24H21ClN2O3 C24H21N3O5 53.61 53.57 41.74 41.73 44.65 44.86 50.54 50.70 46.67 46.43 44.48 44.62 74.42 74.59 67.06 67.33 69.94 70.20 69.92 69.94 68.43 68.49 66.50 66.81 Found, % Calculated, % H 5.34 5.39 4.15 4.38 4.64 4.71 5.61 5.67 4.13 4.29 3.92 4.12 5.76 5.74 5.08 5.14 5.28 5.36 5.81 5.87 4.93 5.03 4.85 4.91
mp, N 12.45 12.49 12.11 12.17 12.78 13.08 9.60 9.85 10.60 10.83 15.20 15.61 7.23 7.25 7.02 7.14 7.37 7.44 6.22 6.27 6.58 6.66 9.68 9.74 232 (dec.) 245 (dec.) 236 (dec.) 116 (dec.) 235 (dec.) 212 (dec.) 122-123 140-142 124-126 115-117 111-112 178-179
Yield, %*
54 66 46 98 63 49 87 58 76 44 31 42
_______ * Compounds 10d-f were obtained by heating the corresponding compounds 9 at 60C in MeOH for 72 h (10d,f) and 4 h (10e).
736
TABLE 2. 1H NMR Spectra of Compounds 7a-f and 10a-f

Compound 7a Chemical shifts, , ppm. (J, Hz)* -5 (1, dd) R 4.83 (J = 8.1 and 3.7) 5.12 (J = 8.1 and 3.9 ) 7.22-7.41 (5H, m)
-4 (1, dd) 2.44 (J = 18.8 and 3.7), 3.29 (J = 18.8 and 8.1) 2.66 (J = 18.7 and 3.9), 3.35 (J = 18.7 and 8.1)
NOBn or NOH 12.00 (1H, s), 10.20 (1H, s) 12.10 (1H, s), 10.28 (1H, s)
7b
7c
2.73 (J = 18.8 and 3.8), 3.18 (J = 18.8 and 8.2) 2.46 (J = 18.8 and 4.0), 3.26 (J = 18.8 and 7.9) 2.43 (J = 19.0 and 3.7), 3.27 (J = 19.0 and 8.0) 2.49 (J = 18.7 and 3.9), 3.37 (J = 18.7 and 8.3) 2.67 (J = 18.9 and 3.7), 3.36 (J = 18.9 and 8.0) 2.82 (J = 19.0 and 4.0), 3.42 (J = 19.0 and 7.9) 2.87 (J = 18.9 and 3.9), 3.26 (J = 18.9 and 8.2) 2.70 (J = 19.0 and 4.1), 3.30 (J =19.0 and 8.0)
4.90 (J = 8.2 and 3.8)
7d
4.76 (J = 7.9 and 4.0)
7e
4.86 (J = 8.0 and 3.7) 5.04 (J = 8.3 and 3.9) 4.96 (J = 8.0 and 3.7)
7.01 (1H, dd, J = 5.0 and 3.4); 7.13 (1H, dd, J = 3.4 and 1.0), 7.53 (1H, dd, J = 5.0 and 1.0) 6.43 (1H, dd, J = 3.6 and 1.8), 6.50 (1H, d, J = 3.6), 7.65 (1H, d, J = 1.8) 3.74 (6H, s), 6.78 (1H, d, J = 8.3), 6.83 (1H), 6.93 (1H, d, J = 8.3) 7.43-7.47 (2H, m), 7.27-7.21 (2H, m) 8.23-8.28 (2H, m), 7.55-7.60 (2H, m) 7.18-7.42 (5H, m)
12.04 (1H, s), 10.19 (1H, s)
11.97 (1H, s), 10.11 (1H, s)
12.03 (1H, s), 10.23 (1H, s) 12.01 (1H, s), 10.38 (1H, s) 4.71 (1H, d, J = 10.1), 4.99 (1H, d, J = 10.1), 5.25 (2H, s), 7.18-7.42 (10H, m) 4.67 (1H, d, J = 9.7), 4.99 (1H, d, J = 9.7), 5.25 (2H, s), 7.25-7.40 (10H, m) 4.54 (1H, d, J = 10.1), 4.93 (1H, d, J = 10.1); 5.25 (2H, s); 7.26-7.49 (10H, m) 4.67 (1H, d, J = 10.2), 4.97 (1H, d, J = 10.2); 5.24 (2H, s); 7.17-7.38 (10H, m)
7f
10a
10b
5.29 (J = 7.9 and 4.0)
10c
5.08 (J = 8.2 and 3.9)
10d
4.87 (J = 8.0 and 4.1)
10e
2.64 (J = 19.0 and 3.8), 3.35 (J = 19.0 and 8.0)
4.98 (J = 8.0 and 3.8)
7.03 (1H, dd, J = 5.0 and 3.5), 7.22 (1H, d, J = 3.5), 7.57 (1H, d, J = 5.0) 6.47 (1H, dd, J = 3.2 and 1.8); 6.61 (1H, d, J = 3.2 ); 7.69 (1H, d, J = 1.8) 3.71 (3H, s); 3.73 (3H, s); 6.83 (1H, dd, J = 8.2 and 1.7); 6.92 (1H, d, J = 1.7); 6.93 (1H, d, J = 8.2) 7.31-7.45 (4H, m)
10f
2.67 (J=19.1 and 3.8), 3.41 (J = 19.1 and 8.3)
5.02 (J = 8.3 and 3.8)
7.55-7.63 (2H, m); 8.17-8.24 (2H, m);
4.74 (1H, d, J = 10.3), 4.98 (1H, d, J = 10.3); 5.24 (2H, s); 7.18-7.37 (10H, m) 4.82 (1H, d, J = 10.3), 5.02 (1H, d, J = 10.3); 5.25 (2H, s); 7.20-7.41 (10H, m)
_______ * Compounds 7a-f were taken in DMSO-d6, compounds 10a-f in CDCl3.
Derivatives of 3-hydroximino-1-hydroxypyrrolidinone are therefore formed on interaction of esters of 2-oxo-3-butenoic acids with NH2OH. It is apparent that the reaction proceeds by the sequential interaction of NH2OH with the -keto group and the double bond with subsequent intramolecular acylation of the hydroxylamine nitrogen by the ester group. 737
TABLE 3. 13C NMR Spectra of Compounds 7a-f and 10a-f

Compound 7a 7b 7c 7d 7e 7f 10a Chemical shifts, , ppm R 126.4; 128.0; 128.7; 140.2 126.1; 126.4; 126.9; 143.1 109.3; 110.6; 143.4; 151.0 55.5; 55.6; 109.9; 111.8; 118.9; 132.3; 148.6; 149.0 128.5; 128.7; 132.6; 139.1 123.9; 127.9; 147.70; 147.3 126.9; 127.9; 128.7; 138.9
(2) 148.4 147.9 148.1 148.7 148.2 147.74 149.1
(3) 159.1 158.6 158.6 159.3 159.2 159.4 158.2
(4) 30.4 30.5 26.5 30.5 30.2 29.9 30.7
(5)
Bn
59.5 55.3 53.2 59.4 58.9 58.9 57.7
10b
148.6
157.9
31.1
53.4
126.8; 127.2; 127.5; 141.8
10c
148.7
157.8
27.1
51.2
110.2; 110.8; 143.7; 149.8
10d
149.5
158.3
30.7
57.8
55.5; 55.5; 110.6; 111.7; 119.6; 130.9; 148.96; 149.0 128.3; 128.7; 137.9; 132.9
10e
148.2
159.2
30.6
57.1
10f
148.5
158.6
30.5
57.1
123.8; 127.96; 146.5; 147.3;
76.35; 76.43; 128.0; 128.26; 128.29; 128.4; 128.6; 129.1; 134.5; 137.1 76.5; 76.6; 128.0; 128.05; 128.4; 128.4; 128.7; 129.2; 134.4; 137.1 76.5; 76.6; 127.95; 128.0; 128.3; 128.3; 128.7; 129.1; 134.3; 137.0 76.5; 76.5; 127.9; 128.0; 128.2; 128.6; 129.1; 134.6; 137.1 76.4; 76.5; 127.9; 128.0; 128.3; 128.6; 128.9; 129.0; 134.5; 137.0 76.4; 76.6; 127.95; 128.0; 128.2; 128.3; 128.7; 129.1; 134.4; 137.0
EXPERIMENTAL The 1H and 13C NMR spectra were recorded on a Varian 200 Mercury spectrometer (200 and 50 MHz respectively) in CDCl3 (NH2OBn derivatives) and DMSO-d6 (NH2OH derivatives), internal standard was TMS. Column chromatography was carried out on Acros silica gel (0.035-0.07 mm), using gradient elution with petroleum etherethyl acetate 10:1 to 2:1 (for compounds 5a-f and 10a-f). Reaction products 7a-f were isolated by crystallization from water at pH 2. All the synthesized compounds 7a-f gave a characteristic lilac coloration with FeCl3 solution. The reactions were checked by TLC, using Merck silica gel (F254) plates. Systems were petroleum etherethyl acetate 2:1 (for compounds 5-10), and CHCl3MeOHAcOH 85:10:5 (for compounds 7a-f). The initial methyl esters of 2-oxo-3-butenoic acids 5 were obtained by alkylation with methyl iodide of the potassium salts of the appropriate acids, obtained by the procedure of [21] [MeI (3 equiv.), 18-crown-6 (2 mol %), solvent DMF, 22C, 3 h]. Solutions of NH2OH and NH2OBn in methanol were prepared by the standard procedure of [16]. Hydroxylamine Salt of 3-Hydroximino-1-hydroxy-2-oxo-5-(2-thienyl)pyrrolidine (6b). A solution of NH2OH (4.31 g, 0.13 mol) in MeOH (pH 8) (50 ml) was added dropwise to a solution of 2-oxo-4-(2-thienyl)-3butenoic acid methyl ester (5b) (3 g, 15.3 mmol) in MeOH (10 ml) at 0-5C. The reaction mixture was stirred for 1 day at 20-22C. The precipitated solid was filtered off, washed with water, and dried in vacuum. Compound 6b (3.2 g, 85%) was obtained as colorless crystals of mp 235C (decomp.). 1H NMR spectrum 738
(DMSO-d6), , ppm (J, Hz): 7.53 (1H, d, J = 4.8, -Th); 7.13 (1H, d, J = 3.0, -Th); 7.01 (1H, dd, J = 4.8, 3.0, -Th); 5.12 (1H, dd, J = 8.2, 3.8, Th-CH); 3.35 (1H, dd, J = 18.6, 8.2, CH2); 2.66 (1H, dd, 18.6, 3.8, CH2). Found, %: C 39.05; H 4.44; N 16.92; S 12.90. C8H11N3O4S. Calculated, %: C 39.18; H 4.52; N 17.13; S 13.07. 3-Hydroximino-1-hydroxy-2-oxo-5-phenylpyrrolidine Monohydrate (7a) (typical procedure A). A solution of NH2OH (0.189 g, 5.71 mmol) in methanol (pH 8) (1 ml) was added dropwise to a 1.5 M solution (1.1 ml) in methanol of 2-oxo-4-phenylbutenoic acid methyl ester 5a (0.32 g, 1.68 mmol) at 0-5C. The reaction mixture was stirred at 20-22C for 1 day. The precipitated solid was filtered off, and to it was added water (30 ml), the mixture was acidified with 1 N HCl to pH 2, the solid was filtered off, washed with water, and dried. Compound 7a (0.205 g, 54%) was obtained as colorless crystals. 3-Hydroximino-1-hydroxy-2-oxo-5-(2-thienyl)pyrrolidine (7b) Monohydrate was obtained by the general procedure A from compound 5b (0.192 g, 0.98 mmol) in methanol (0.64 ml) and NH2OH (0.27 g, 8.1 mmol) in methanol (pH 8) (3.4 ml) as colorless crystals in a yield of 0.15 g (66%). 5-(2-Furyl)-3-hydroximino-1-hydroxy-2-oxopyrrolidine Monohydrate (7c) was obtained by general procedure A from compound 5c (0.22 g, 1.22 mmol) in methanol (0.8 ml) and NH2OH (0.13 g, 4 mmol) in methanol (pH 8) (1.7 ml) as colorless crystals in a yield of 0.12 g (46%). 5-(3,4-Dimethoxyphenyl)-3-hydroximino-1-hydroxy-2-oxopyrrolidine Monohydrate (7d) was obtained by general procedure A from compound 5d (0.18 g, 0.72 mmol) in methanol (0.8 ml) and NH2OH (0.071 g, 2.158 mmol) in methanol (pH 7) (1.7 ml) as colorless crystals in a yield of 0.20 g (98%). 5-(4-Chlorophenyl)-3-hydroximino-1-hydroxy-2-oxopyrrolidine Monohydrate (7e) was obtained by general procedure A from compound 5e (0.18 g, 0.80 mmol) in methanol (0.8 ml) and NH2OH (0.093 g, 2.804 mmol) in methanol (pH 7) (1.7 ml) as colorless crystals in a yield of 0.13 g (63%). 3-Hydroximino-1-hydroxy-5-(4-nitrophenyl)-2-oxopyrrolidine Monohydrate (7f) was obtained by general procedure A from compound 5f (0.19 g, 0.807 mmol) in methanol (0.8 ml) and NH2OH (0.093 g, 2.827 mmol) in methanol (pH 7) (1.7 ml) as colorless crystals in a yield of 0.108 g (49%). 3-Benzyloximino-1-benzyloxy-2-oxo-5-phenylpyrrolidine (10a) (Typical Procedure B). A solution (~24%) of NH2OBn (0.97 g, 7.87 mmol) in MeOH (pH 7) (4 ml) was added dropwise to a 1.5 M solution of 2-oxo-4-phenylbutenoic acid methyl ester (5a) (0.49 g, 2.58 mmol) in MeOH (1.7 ml) at 0-5C. The reaction mixture was stirred at 20-22C for 1 day. The precipitated solid was filtered off and recrystallized from ethyl acetatepetroleum ether. Compound 10a (0.87 g, 87%) was obtained as colorless crystals. 3-Benzyloximino-1-benzyloxy-2-oxo-5-(2-thienyl)pyrrolidine (10b) was obtained by general procedure B from compound 5b (0.57 g, 2.9 mmol) in methanol (1.9 ml) and NH2OBn (1.07 g, 8.7 mmol) in methanol (pH 7) (4.5 ml) as colorless crystals in a yield of 0.66 g (58%). 3-Benzyloximino-1-benzyloxy-5-(2-furyl)-2-oxopyrrolidine (10c). B. Compound 5c (0.49 g, 2.72 mmol) in methanol (1.6 ml) and NH2OBn (1.90 g, 15.45 mmol) in methanol (pH 7) (7.8 ml) were stirred for 1 day. The methanol was evaporated, and the obtained mixture was chromatographed. A mixture of colorless crystals of compound 10c (0.35 g, 34%) Rf 0.38 (Merck silica gel F254, petroleum etherethyl acetate, 2:1), and compound 9c (0.42 g, 38 %), Rf 0.62 was obtained. A colorless oil, which crystallized during several hours at 22C into compound 10c (overall yield 72%) was also obtained. 1H NMR spectrum (CDCl3), , ppm (J, Hz) of compound 9c: 7.19-7.36 (11H, m, Ph, Fur); 6.26 (1H, dd, J = 3.2, 1.9, -Fur); 6.18 (1H, d, J = 3.2, -Fur); 5.4-5.9 (1H, br. s, NH); 5.26 (2H, s, O-CH2-Ph); 4.55 (2H, d, J = 1.6, O-CH2-Ph); 4.40-4.53 (1H, m, Fur-CH); 3.77 (3H, s, O-CH3); 3.17 (1H, dd, J = 13.2, 8.0, CH2); 3.02 (1H, dd, J = 13.2, 6.9, CH2). 3-Benzyloximino-1-benzyloxy-5-(3,4-dimethoxyphenyl)-2-oxopyrrolidine (10d) (General Procedure B). A mixture of compound 5d (0.18 g, 0.719 mmol) in methanol (0.8 ml) and NH2OBn (0.217 g, 1.758 mmol) in methanol (pH 7) (1.8 ml) was stirred for 1 day, the methanol was evaporated, and the obtained mixture was chromatographed. Compound 10d (0.094 g, 28%), Rf 0.43 (Merck silica gel F254, petroleum etherethyl acetate, 2:1) was isolated as colorless crystals and also compound 9d (0.17 g, 67%), Rf 0.56 as a colorless oil. The latter was partially converted on heating in methanol at 60C for 3 days into compound 10d (overall yield of 10d was 44%. Chromato-mass spectrum of compound 9d, m/z (Irel, %): 355 (6) [M]+, 296 (2) [M-COOCH3]+, 248 (11) 739
[M-OCH2C6H5]+, 234 (6) [M-OCH2C6H5-N]+, 188 (14) [M-OCH2C6H5-COOCH3-H]+, 165 (2) [(CH3O)2C6H3CH=CH+2H]+, 151 (9) [(CH3O)2C6H3CH+H]+, 91 (100), [CH2C6H5]+, 77 (14) [C6H5]+, 59 (15). 3-Benzyloximino-1-benzyloxy-5-(4-chlorophenyl)-2-oxopyrrolidine (10e). B. A mixture of compound 5e (0.178 g, 0.792 mmol) in methanol (1 ml) and NH2OBn (0.244 g, 2.226 mmol) in methanol (pH 8) (1.8 ml) was stirred for 1 day, the methanol was evaporated, and the residue obtained was chromatographed. A mixture of compounds 9e and 10e was obtained, which was not separated. After heating the mixture at 60C for 4 h crystalline compound 10e (0.104 g, 31%) was obtained, Rf 0.37 (Merck silica gel F254, petroleum etherethyl acetate, 2 : 1). 3-Benzyloximino-1-benzyloxy-5-(4-nitrophenyl)-2-oxopyrrolidine (10f). B. A mixture of compound 5f (0.19 g, 0.808 mmol) in methanol (1 ml) and NH2OBn (0.219 g, 1.777 mmol) in methanol (pH 7) (1.8 ml) was stirred for 1 day, the methanol was evaporated, and the resulting residue was chromatographed. Compound 8f (0.018 g, 12%) was obtained with Rf 0.5 (Merck silica gel F254, petroleum etherethyl acetate, 2:1), also compound 9f (0.16 g, 43%) with Rf 0.43, and compound 10f (0.034 g, 9.8%), Rf 0.23, all as cream-colored crystals. On heating a methanolic solution of compound 9f for 72 h at 60C the compound partially cyclized into 10f. The overall yield of compound 10f was 42%. Compound 8f; mp 118-120C. 1H NMR spectrum (CDCl3), , ppm (J, Hz): 8.16-8.24 (2H, m, Ph-NO2); 7.72 (1H, d, J = 16.8, =CH); 7.58-7.67 (2H, m, Ph-NO2); 7.38-7.44 (5H, m, C6H5); 7.34 (1H, d, J = 16.8, CH=); 5.40 (2H, s, O-CH2-Ph); 3.93 (3H, s, O-CH3). Fouind, %: C 63.46; H 4.65; N 8.00. C18H16N2O5. Calculated, %: C 63.53; H 4.74; N 8.23. Compound 9f; mp 148-150C. 1H NMR spectrum (CDCl3), , ppm (J, Hz): 8.04-8.09 (2H, m, Ph-NO2); 7.15-7.42 (12H, m, Ph, Ph-NO2); 5.7 (1H, br. s, NH); 5.21 (2H, s, O-CH2-Ph); 4.53 (2H, d, J = 2.8, O-CH2-Ph); 4.29-4.50 (1H, m, O2N-Ph-CH); 3.78 (3H, s, OCH3); 2.82-3.03 (2H, m, CH2). Alkylation of Compound 6b. Benzyl bromide (0.855 g, 0.59 ml, 5.0 mmol) and K2CO3 (0.76 g, 5.5 mmol) were added to a solution of compound 6b (0.245 g, 1.0 mmol) in DMF (11ml) and the mixture heated at 80C for 6 h. The mixture was filtered, and the solvent distilled off in vacuum. The reaction product was isolated by chromatography in the system petroleum etherethyl acetate, 3:1. The 1H NMR spectrum, elemental analysis, and melting point of the obtained compound were identical with those of compound 10b, yield was 0.19 g (50%) of colorless crystals. The work was financed by the Latvian Council for Science, grant No. 01.0176.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 740 S. M. Paune, CRC Crit. Rev. Microbiol., 16, 81 (1988). K. Tanaka, K. Matsuo, A. Nakanishi, Y. Kataoka, K. Takase, and S. Otsuki, Chem. Pharm. Bull., 36, 2323 (1988). R. Breslow, S. Belvedere, and L. Gershell, Helv. Chim. Acta, 83, 1685 (2000). Y. Tamura, F. Watanabe, T. Nakatani, K. Yasui, M. Fuji, T. Komurasaki, H. Tsuzuki, R. Maekawa, T. Yoshioka, K. Kawada, K. Sugita, and M. Ohtani, J. Med. Chem., 41, 640 (1998). D.-K. Kim, J. Y. Lee, J.-S. Kim, J.-H. Ryu, J.-Y. Choi, J. W. Lee, G.-J. Im, T.-K. Kim, I. W. Seo, H.-J. Park, J. Yoo, J. H. Park, T.-Y. Kim, and Y.-J. Bang, J. Med. Chem., 46, 5745 (2003). M. J. Miller, Chem. Rev., 89, 1563 (1989). E. W. Petrillo and M. A. Ondetti, Med. Res. Rev., 2, 1 (1982). J. C. Powers and J. W. Harper in A. J. Barret and G. Salvesan (editors), Protease Inhibitors, Elsevier, New York (1986), p. 219. J. B. Neilands, Science, 156, 3781 (1967). B. Kurzak, H. Kozlowski, and E. Farkas, Coord. Chem. Rev., 114, 169 (1992).
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C. J. Marmion, T. Murphy, J. R. Docherty, and K. B. Nolan, J. Chem. Soc., Chem. Commun., 1153 (2000). A. Thomas and S. Rajappa, Tetrahedron, 51, 10571 (1995). P. Chittari, V. R. Jahav, K. N. Ganesh, and S. Rajappa, J. Chem. Soc., Perkin Trans. 1, 1319 (1998). A. S. Reddy, M. S. Kumar, and G. R. Reddy, Tetrahedron Lett., 41, 6285 (2000). L. De Luca, G. Giacomelli, and M. Taddei, J. Org. Chem., 66, 2534 (2001). G. I. Zhungietu and A. I. Artemenko, Hydroxamic Acids and Their Derivatives [in Russian], Shtiintsa, Kishinev (1986). A. R. Katritzky, P. Barczynski, D. L. Ostercamp, and T. I. Yousaf, J. Org. Chem., 51, 4037 (1986). G. Lohaus and W. Dittmar, Arzneim.-Forsch., 31, 1311 (1981). F. Becke and G. Mutz, Chem. Ber., 98, 1322 (1965). V. A. Slavinska, Dz. Sile, G. Chipens, Yu. Balodis, G. Rozenthal, K. Venteris, and E. Lukevics, Khim. Geterotsikl. Soedin., 1794 (2003). V. A. Slavinska, Dz. Sile, E. Korchagova, N. Panchenko, M. Katkevich, and E. Lukevics, Latv. J. Chem., No. 1, 87 (1998).
741
SYNTHESIS AND CYTOTOXICITY OF DERIVATIVES OF DI(3-INDOLYL) SELENIDE

E. Abele, J. Popelis, I. Shestakova, I. Domracheva, P. Arsenyan, and E. Lukevics A method has been developed for the synthesis of di(3-indolyl) selenides. From indole and SeO2. N-Alkyl derivatives of di(3-indolyl) selenide have been obtained in the two-phase system alkyl halidesolid K2CO3 (or KOH)18-crown-6toluene. It was discovered that N-unsubstituted di(3-indolyl) selenides possess high cytotoxicity on HT-1080 and MG-22A tumor cell lines. Keywords: indole, selenides, phase-transfer catalysis, cytotoxicity. Selenium-containing indoles are used in organic synthesis as intermediates for radical cyclization [1,2]. These indoles are used as biologically active compounds. It was shown recently that amides of 2,2'-diselenobis(1H-indoles) actively inhibit tyrosine kinase [3,4]. On the other hand, derivatives of benzoseleno[4,3-b]indole [5] are carcinogens [6]. Among recent studies it is necessary to note investigations on routes of synthesis and properties of 1,2,5-selenadiazolo[3,4-e]indoles and their [3,4-f] and [3,4-g] isomers [7]. The classical method of synthesizing 3,3'-diindolyl diselenides is based on the selenocyanation of indole with bis-seleno cyanide with subsequent treatment of the reaction mixture with KOH solution in methanol [8-11]. Some work has been devoted to the synthesis of indole selenides. Previously -(3-indolyl)ethylselenoacetic acid was obtained from -(3-indolyl)ethyl bromide and (HO2CCH2Se)2 [12]. In addition 3,3'-diindolyl selenides were successfully synthesized by the reaction of indoles with SeO2 in benzene [13]. Bisharmine selenides were obtained analogously [14]. The mass spectrometric investigation of indole selenides has been described in detail in [15]. It has also been shown that di(1-methyl-3-indolyl) selenide in the presence of Raney nickel gives biindolyl and indole. Investigation of the cytotoxicity of derivatives of di(3-indolyl) selenides has not been carried out previously and is the aim of the present work. Di(3-indolyl) selenides 3, 4 were obtained from indole 1 and 2-methylindole 2 by the procedure reported in [13]. In the reaction of 2-methylindole with SeO2 in boiling benzene after 2 h the author of [13] obtained di(2methyl-3-indolyl) triselenide (16%) and di(2-methyl-3-indolyl) diselenide (22%). Under similar conditions (4 h in boiling benzene) we obtained di(2-methyl-3-indolyl) selenide (4) as the sole product, but in only 7% yield. The structure of selenide 4 was confirmed by data of elemental analysis, and 1H, 13C, and 77Se NMR spectra. The 77 Se chemical shift for selenide 4 has a characteristic value (1287.29 ppm) for this class of compound. Di(3-indolyl) selenide (3) in the system alkyl halide (R'X)solid K2CO3 (or KOH)18-crown-6toluene forms the N-substituted selenides 5-8 in 28-38% yield (Tables 1-3). In the reaction of selenide 3 with Br(CH2)5Br in the system solid K2CO318-crown-6toluene the mono N-alkylated product 9 was obtained in 30% yield. The cyclic product is not formed under these conditions.
__________________________________________________________________________________________ Latvian Institute of Organic Synthesis, Riga LV-1006; e-mail: abele@osi.lv. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 868-872, June, 2004. Original article submitted December 6, 2002. 742 0009-3122/04/4006-07422004 Plenum Publishing Corporation
R N H 1, 2
SeO2 N H
Se N H
R R
3, 4 R'X, 18-crown-6 Se N R' Br(CH2)5Br, 18-crown-6 K2CO3 Se N H 9 In the synthesis of 6, 7 X = Br; 5, 8 X = I N CH2(CH2)4Br 58 N R'
K2CO3 / PhMe
1, 3 R = H; 2, 4 R = Me; 5 R' = Me; 6 R' = PhCH2; 7 R' = 2-MeC6H4CH2; 8 R' = Me3Si(CH2)3.
The biological activity of the obtained compounds was investigated on two tumor cell lines, viz. HT-1080 (human fibrosarcoma) and MG-22A (mouse hepatoma) (Table 4). Di(3-indolyl) selenide (3) possesses the greatest cytotoxic effect. This compound shows an IC50 of 1 g/ml (CV test) for the fibrosarcoma and 2 g/ml (CV and MTT tests) for the mouse hepatoma. The methyl-substituted selenide 4 also showed a similar activity. The N-alkyl derivatives of selenide 3 showed low cytotoxicity. The high level of NO generation by selenide 3 should be noted (450% in the HT-1080 line and 400% in the MG-22A line).
EXPERIMENTAL The 1H, 13C, and 77Se NMR spectra were recorded on a Varian 200 Mercury spectrometer (200, 50, and 39 MHz respectively) in CDCl3 (in DMSO-d6 for compounds 3 and 4), internal standard was HMDS. For the 77 Se NMR spectra the internal standard was SeO2 ( 1275.5 ppm). Indole, 2-methylindole, selenium dioxide, methyl iodide, benzyl bromide, 2-methylbenzyl bromide, and 18-crown-6 (Acros) were used without further purification. 3-Iodopropyl(trimethyl)silane was obtained by the Grignard reaction [16,17]. Di(3-indolyl) selenide (3) was obtained from indole and SeO2 in benzene as described in [13].
TABLE 1. Interphase Catalyzed Alkylation of Di(3-indolyl) Selenide 3

Reaction time, h 7 8 14 10 Product 5 6 7 8 Empirical formula C18H16N2Se C30H24N2Se C32H28N2Se C28H40N2SeSi2 Found, % Calculated, % C H N 63.46 3.71 73.22 73.31 73.71 73.97 61.04 62.30 4.74 4.75 4.81 4.92 5.44 5.43 7.38 7.46 8.10 8.25 5.65 5.70 5.26 5.39 4.84 5.18 Yield, % 38 28 33 28
R'X
mp, C
MeI PhCH2Br 2-MeC6H4CH2Br Me3Si(CH2)3Br
160-162 >300 (dec.) 168-169 69-70
743
TABLE 2. Data of 1H and 13C NMR Spectra for Selenides 3-8

Selenide 3
1
NMR, , ppm (J, Hz)
NMR spectra, , ppm Indole R'

13
7.04, 7.33 and 7.66 (10H, all m, ring protons); 11.28 (2H, br. s, NH) 2.59 (6H, s, CH3); 6.96, 7.21 and 7.54 (8H, all m, ring protons); 11.24 (2H, br. s, NH) 3.66 (6H, s, CH3); 7.13-7.22 and 7.81 (10, m, ring protons) 5.20 (4H, s, CH2); 7.0-7.3 and 7.77 (20, m and m, ring protons) 2.22 (6H, s, CH3); 5.18 (4H, s, CH2); 7.13-7.24 and 7.75 (18, m and m, ring protons)
98.94, 111.75, 119.36, 19.44, 121.52, 129.40, 130.52, 136.19 18.26 (CH3), 102.74, 115.88, 123.90, 124.37, 125.88, 135.76, 140.56, 144.47 99.55, 109.26, 119.79, 120.36, 121.91, 130.28, 133.64, 137.03 99.98, 109.81, 120.02, 120.53, 122.12, 130.49, 132.98, 137.03
32.77 (CH3)
50.10 (CH2), 126.79, 127.65, 128.76, 136.75 (all Ph)
-0.05 (18H, s, Si(CH3)3); 0.44 (4H, m, SiCH2); 1.75 (4H, m, CH2CH2CH2); 3.99 (4H, t, J = 7.2, NCH2); 7.09-7.28 and 7.84 (10, m and m, ring protons)
99.82, 109.64, 119.98, 19.02 (CH3), 48.15 120.51, 122.04, 130.20, (CH2), 109.73, 126.64, 127.51, 132.68, 136.82 127.89, 130.27, 135.74 (all Ph) 99.19, 109.45, 119.64, -1.81 (SiMe3), 13.91 120.45, 121.72, 130.36, (SiCH2), 24.89 (CH2CH2CH2), 132.64, 136.40 49.65 (NCH2)
Di(2-methyl-3-indolyl) Selenide (4). A suspension of 2-methylindole 2 (7.86 g, 30 mmol) and SeO2 (4.40 g, 39.6 mmol) in benzene (90 ml) was refluxed for 5 h. The reaction mixture was filtered, and the filtrate was evaporated to 20 ml on a rotary evaporator. Hexane was added to turbidity of the reaction mixture. The product was twice recrystallized at 4C from benzenehexane. The yield of compound 4 was 0.70 g (7%). 77 Se NMR spectrum, , ppm: 1287.29.
TABLE 3. Mass Spectra of Selenides 4-8

Selenide 4 m/z (Irel, %)* 340 [M]+ (37), 338 (17), 260 (95), 245 (16), 243 (17), 217 (13), 209 (29), 207 (13), 131 (95), 130 (100), 122 (16), 117 (9), 115 (14), 103 (60), 102 (35), 89 (25), 78 (50), 77 (70), 65 (32), 63 (37) 340 [M]+ (13), 338 (7), 260 (100), 245 (30), 130 (38), 122 (10), 89 (15), 77 (15), 71 (15), 69 (15), 63 (10), 61 (14) 492 [M]+ (20), 412 (100), 321 (95), 204 (25), 177 (8), 130 (11), 102 (11), 97 (12), 91 (95), 89 (35), 77 (24), 71 (17), 69 (25), 65 (72) 520 [M]+ (19), 440 (100), 414 (3), 367 (10), 335 (92), 231 (19), 221 (52), 218 (20), 117 (12), 106 (77), 105 (90), 103 (68), 91 (12), 89 (15), 79 (75), 77 (70), 69 (11), 65 (14), 63 (13) 540 [M]+ (8), 462 (16), 461 (45), 460 (100), 359 (17), 231 (17), 157 (20), 130 (54), 97 (12), 95 (19), 83 (15), 75 (15), 73 (75), 71 (16), 69 (19)
5 6 7
_______ * Ions having m/z >60 and Irel >10% are shown. For selenium-containing fragments ions with the 80Se isotope are given.
744
TABLE 4. Cytotoxic Activity of Selenides 3-8 in vitro

Cell lines Compound IC50* CV*2 3 4 5 6 7 8 1 4 23 *5 *5 *5 HT-1080 IC50, MTT*3 2 12 26 *5 *5 *5 MG-22A NO100% CV*4 450 300 53 6 12 18 IC50* CV 2 2 *5 *5 *5 *5 IC50* MTT 2 3 *5 *5 *5 *5 NO 100% CV 400 250 10 218 13 20
_______ * Concentration g/ml causing death of 50% cells. *2 Staining with Crystal Violet. *3 Staining with 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide. *4 NO concentration (%) (CV staining). *5 No cytotoxic activity.
General Procedure for Interphase Catalysed Alkylation of Di(3-indolyl) Selenide (3)*. The appropriate alkyl halide (2.2 mmol) was added to a suspension of compound 3 (0.311 g, 1 mmol), 18-crown-6 (0.026 g, 0.1 mmol), and powdered KOH (0.224 g, 4 mmol) [in the synthesis of compound 8 powdered K2CO3 (0.552 g, 4 mmol) was used] in toluene (10 ml). The reaction mixture was stirred at room temperature (100C for compound 8) for 8-14 h, filtered, and the filtrate was evaporated on a rotary evaporator. The residue was purified by column chromatography (eluent was hexaneethyl acetate in various concentrations), and compounds 5-8 were obtained (Tables 1-3). 1-(5-Bromopentyl)-3-[(3-indolyl)seleno]indole (9). 1,5-Dibromopentane (0.14 ml, 1 mmol) was added to a suspension of compound 3 (0.311 g, 1 mmol), 18-crown-6 (0.026 g, 0.1 mmol), and powdered K2CO3 (0.414 g, 4 mmol) in toluene (10 ml). The reaction mixture was stirred at 100C for 40 h, filtered, and the filtrate evaporated on a rotary evaporator. The residue was purified by column chromatography (eluent hexaneethyl acetate, 1:0.3), and compound 9 (0.14 g, 30%) was obtained having mp 138-142C. 1H NMR spectrum, , ppm (J, Hz): 1.2-1.8 [8H, m, Br(CH2)4]; 3.99 (2H, t, J = 5.6, NCH2); 6.18 (1H, s, NH); 7.20-7.33 and 7.95 (10H, m, ring protons).
REFERENCES 1. 2. 3. 4. M. Lluisa Bennasar, T. Roca, R. Griera, and J. Bosch, J. Org. Chem., 66, 7547 (2001). M. Lluisa Bennasar, T. Roca, R. Griera, M. Bassa, and J. Bosch, J. Org. Chem., 67, 6268 (2002). L. Sun, J. R. Rubin, A. J. Kraker, and H. D. Hollis Showalter, J. Heterocycl. Chem., 34, 1399 (1997). H. D. Hollis Showalter, A. D. Sercel, B. M. Leja, C. D. Wolfangel, L. A. Ambroso, W. J. Elliott, D. W. Fry, A. J. Kraker, C. T. Howard, G. H. Lu, C. W. Moore, J. M. Nelson, B. J. Roberts, P. W. Vincent, W. A. Denny, and A. M. Thompson, J. Med. Chem., 40, 413 (1997). F. Boberg and R. Wiedermann, Liebigs Ann. Chem., 734, 164 (1970). N. P. Buu-Hoi, A. Groisy, P. Jacquignon, M. Renson, and A. Ruwet, J. Chem. Soc. (C), 1058 (1970).
5. 6.
_______ * With the participation of O. Dzenitis (student). 745
7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.
M. Edin and S. Grivas, ARKIVOC [online computer file], 2, 1036 (2001). Avail. URL: http://www.arkat.org/arkat/journal/Issue7/ms0096.pdf; Chem. Abstr., 137, 154886c (2002). L.-B. Agenas, Acta Chem. Scand., 17, 268 (1963). L.-B. Agenas, Arkiv. Kem., 23, 155 (1964). L.-B. Agenas, Acta Chem. Scand., 22, 1773 (1968). L.-B. Agenas, Arkiv. Kem., 31, 159 (1969). L.-B. Agenas, Arkiv. Kem., 23, 145 (1964). J. F. K. Wilshire, Aust. J. Chem., 20, 359 (1967). M. A. Khan and H. Raees, Z. Naturforsch. B, 51, 1779 (1996). J. Bergman, Acta Chem. Scand., 22, 1883 (1968). N. S. Nametkin, K. S. Vdovin, K. S. Pushchevaya, and V. I. Zav'yalov, Izv. Akad. Nauk SSSR, Ser. Khim., 1453 (1965). J. W. Wilt and C. F. Dockus, J. Am. Chem. Soc., 92, 5813 (1970).
746
NITROGEN NMR SHIELDINGS OF SOME NITRO DERIVATIVES OF 2-AMINO4-METHYLPYRIDINE SYSTEMS

M. Wandas1, A. Puszko1, Z. Biedrzycka2, and M. Witanowski2 High precision 14N NMR shieldings (chemical shifts), bulk susceptibility corrected, are reported for dilute solutions in pure, dry acetone for a group of nitro derivatives of (N-substituted) 2-amino-4methylpyridines, with nitro substituents in either positions 5 or 3 or both, where at least some of these should reveal serious steric hindrance between the substituents involved. The nitrogen shieldings as well as the corresponding PM3 optimized geometries show quite clearly that the 5-nitro derivatives are planar or nearly planar, without any significant hindrance to the -conjugation throughout the molecular system concerned, while the 3-nitro derivatives experience deviations from coplanarity of the pyridine ring and the nitro and amino substituents, with concomitant impairment of -conjugation between these moieties. The nitrogen shieldings of the pyridine nitrogen atoms in N-nitramino-2-alkyl-4methyl 3 (or 5)-nitropyridines indicate that the N-nitramino group acts as a modest donor of -electrons, much weaker with respect to the donor strength of amino, alkylamino, or phenylamino substituents. Keywords: aminonitromethylpyridines, nitramines, nitrogen chemical shifts, nitrogen shieldings, N NMR, PM3 calculations, substituent effects, steric effects.
14
In recent years attention has been attracted by N-substituted derivatives of 2-amino-5-nitropyridine, owing to their promising nonlinear optical properties in the crystalline state [1-3]. These molecules possess high molecular hyperpolarizability and a highly delocalized -electron system bearing an electron donor, the amino group, as well as an electron acceptor, the nitro group. Substituents in such positions provide a pathway to intramolecular charge transfer. The molecules studied in the present work, derivatives of 2-amino-4-methyl-3nitropyridine and 2-amino-4-methyl-5-nitropyridine, are interesting from the point of view of new substitution at the amino moiety, where the substituents include alkyl and aryl groups as well as the N-nitro group. Although 2-amino-substituted 3- and 5-nitropyridines have already been investigated by means of UV, IR, 1H NMR, and interaction dipole moments [4-10], there are only fragmentary data in the literature about the nitrogen NMR of alkylamino- and alkylnitraminonitropyridines [11, 12]. Additionally, compounds of this type have been employed as new nucleophilic substitution or transacylation catalysts [13-16]; as intermediate compounds for herbicides [17, 18], insecticides [19] and antibacterials [20]. Elucidation of the structural and electronic properties of the compounds studied is an important step toward understanding the mechanism of their biological activity. For this purpose, 14N NMR shieldings have been measured here for a set of compounds __________________________________________________________________________________________ Department of Bioorganic Chemistry, University of Economics, 53-432 Wroclaw, Poland. 2 Institute of Organic Chemistry, Polish Academy of Sciences, 01-224 Warsaw, Poland; e-mail: mmw@icho.edu.pl. Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 873-879, June, 2004. Original article submitted October 16, 2003. 0009-3122/04/4006-07472004 Plenum Publishing Corporation 747
1
CH3 O2N N R
CH3 NO2 N R O2N
CH3 NO2 N R
R NH2 NHCH3 NHCH2CH3 N O
Cpd. 1 2 3 4
Cpd. 8 9
Cpd.
14 15
10
HN N(CH3)NO2 N(CH2CH3)NO2
5 6 7
11 12 13
Fig. 1. which included N-substituted derivatives of 2-amino-4-methylpyridine with nitro substituents at positions 3 or 5, or both. The aim of this study was to employ 14N NMR shieldings as a probe for electronic interactions between the substituents and the aromatic ring with due attention paid to steric effects. Steric crowding can disturb the coplanarity of the nitro group or the amino substituent with the aromatic ring (especially in 2-amino-3-nitro- and 2-amino-4-methyl-3,5-dinitropyridines), thus rendering the -electron conjugation less effective.
RESULTS AND DISCUSSION The structures of compounds 1-15 are presented in Fig. 1, and their 14N NMR spectral data are collected in Table 1. The 14N NMR of the compounds studied will be discussed with a view to probing the ground state electronic distribution in these molecular frameworks. Inspecting the 14N NMR shielding ranges (Table 1) shows specific regions for each type of nitrogen in these molecules: aromatic C-nitro groups, from +4 to +12 ppm, nitramino N-nitro groups, from +29 to +34 ppm, pyridine nitrogen atoms, from +76 to +122 ppm, amino groups, from + 271 to +307 ppm, and nitramine amino moieties, from +178 to +199 ppm. Attention is drawn to the sign convention employed in the present work, as was done before [11, 21]; a plus sign corresponds to an increase in nuclear magnetic shielding. Thus we use the term nitrogen shielding rather than chemical shift. The two terms are equivalent in magnitude but are of opposite sign. The pyridine ring nitrogen NMR shielding reflects the nature of the substituents involved. In 2-aminosubstituted derivatives 1-5, 8-11, and 14, 15 the shielding of the aromatic nitrogen is within +114 to +122 ppm, but when the substituent is changed to an alkyl-N-nitramino group (compounds 6, 7, 12, and 13), the aromatic ring nitrogen shieldings decrease to about +75 through +86 ppm. This large change, by about 35 ppm, is accompanied by changes in the nitrogen shielding of the 2-amino and the nitro groups. Upon passing from alkylamino to alkylnitramino-substituted pyridines, the shielding of the amino group decreases by about 110 ppm, but the shielding of the 3- and 5-nitro groups increases, on the average, by 3 ppm. For nitrobenzene in acetone, the NO2 shielding amounts to +9.23 ppm (bulk susceptibility corrected) [22], but in the compounds studied the shielding of the nitro group varies from +3.93 to +11.98 ppm, and depends on the substituents involved. 748
TABLE 1. Nitrogen NMR Shielding of the Compounds Studied, Referenced to Neat Liquid Nitromethane, Bulk Susceptibility Corrected, 32C
Compound (0.1 M solution in acetone) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Nitrogen NMR shielding (ppm) Pyridine nitrogen +117.49 +122.22 +121.83 +117.38 +116.05 +86.37 +85.97 +106.16 +117.76 +97.37 +108.85 +76.27 +75.91 +114.16 +115.68 Nitro nitrogen +8.60 +8.39 +8.51 +9.02 +9.26 +11.34 +11.18 +6.79 +7.22 +3.93 +8.06 +11.98 +12.05 +10.12 (3-NO2) +11.59 (5-NO2) +10.13 (3-NO2) +11.65 (5-NO2) Amino substituent nitrogen (s) +298.57 +299.62 +282.28 +288.28 +270.65 +190.61 (amino) +32.60 (N-nitro) +177.93 (amino) +34.04 (N-nitro) +304.16 +306.49 +306.72 +280.72 +199.29 (amino) +29.26 (N-nitro) +188.09 (amino) +30.64 (N-nitro) +298.03 +281.61
For a given substituent in position 2, there is a striking difference in the nitrogen shieldings between the corresponding 5-nitro and 3-nitro derivatives of N-substituted 2-amino-4-methylpyridines, and this concerns all of the nitrogen atoms. This is clearly seen for the atoms involving the following pairs of compounds: 18, 29, and 511. In these sequences, the pyridine nitrogen nucleus invariably experiences a deshielding effect of about -8 ppm, that of the nitro groups becomes slightly deshielded by about -1.5 ppm, while the amino nitrogen shielding is significantly augmented, by about +8 ppm (Table 2). Analogous, albeit much stronger, effects are observed for the pair 410, where the bulky N-morpholino substituent is likely to force the 3-nitro group of 10 out of the plane of the pyridine ring. The fact that in the foregoing pairs of derivatives of pyridine the nitrogen shielding of the 5-nitro group is higher that of the 3-nitro group enables one to assign the more shielded nitro nitrogen nucleus to the 5-nitro group in the corresponding 3,5-dinitro derivatives 14 and 15 (Table 1). These effects show clearly that the steric interactions in the 3-nitro isomers are responsible for the systematic changes in the nitrogen NMR shieldings upon passing from a given 5-nitro isomer to the corresponding 3-nitro derivative. In order to verify this we carried out semiempirical geometry optimizations using the PM3 method which is likely to provide geometries similar to those obtained by low-level ab initio methods. In all of the cases considered (see footnotes to Table 2), 3-nitro isomers show medium to high distortions from coplanarity of the ring system and the substitutuents involved, by about 10 (compounds 8, 9, 11) to 80 (compound 10), and this concerns the 3-nitro groups as well as the amino substituents. The largest distortion predicted by the calculations for compound 10 is in a perfect agreement with the largest perturbations of the nitrogen shieldings observed. The largest distortion, about 80, is predicted by the calculations for the N-morpholino substituent and the 3-nitro group in 10. On the other hand, in analogous computations, the 5-nitro isomers reveal planar or nearly planar geometries.
749
TABLE 2. Differences in Nitrogen NMR Shieldings Between 3-Nitro and 5-Nitro derivatives of 2-Amino-4-methylpyridines
Pairs of isomers concerned 18 29 511 410 Nitrogen NMR shielding increment (ppm) Pyridine nitrogen Nitro nitrogen Amino nitrogen -11.3 -1.8* +5.6 -4.5 -1.2* +6.9 -7.2 -1.2* +10.8 -20.0 -5.1*2 +19.4
_______ * In these cases the PM3 optimized geometries show twisting of the 3-NO2 plane, by about 10, with respect to the pyridine ring, while the corresponding 5-NO2 group is coplanar with the latter. The same applies to the 2-amino moieties involved. *2 The twist angle amounts to about 80 for the 3-NO2 group and the amino moiety of the N-morpholyl substituent.
The directions of changes induced in the nitrogen shieldings upon passing from the 5-nitro to the 3-nitro isomers (Table 2) suggest, as can be inferred from some general rules that govern nitrogen shielding [21], that the -electron conjugation between the pyridine ring and the substituents involved is significantly impaired, particularly in compound 10, and all of this is in accord with the foregoing computations. The computations for the 3-nitro isomers 8, 9, and 11, where the 2-amino-substituents contain NH moieties, show that the distance between the hydrogen atom and the nearest oxygen atom of the 3-nitro group, in spite of the non-planar structure, amounts to about 1.8 , which is still within the range of weak hydrogen bonds. The existence of such intramolecular hydrogen bonding has already been suggested for some of the present compounds as well as for some analogous derivatives of pyridine, on the basis of various spectroscopic results and dipole moment measurements [4-10]. As far as the nitrogen shieldings of the nitro groups are concerned, especially interesting is that of compound 10, where the nitro group is flanked by a methyl group and a bulky substituent, the N-morpholyl moiety. This arrangement of substituents should force the NO2 group out of the plane of the pyridine ring. Actually, the NO2 nitrogen shielding is much weaker (about +4 ppm) in comparison with those of the NO2 groups in other compounds (about +7 to +12 ppm). The direction of the shift indicates that the conjugation is impaired between the -electron systems of the pyridine ring and the NO2 group in 10, in accord with the foregoing. If we compare the nitrogen shielding of pyridine in acetone, +62.5 ppm [11], with those obtained in the present work as well as those reported in the literature on 2-aminopyridines [21], it is obvious that the 2-amino substituent significantly enhances the pyridine nitrogen shielding, by roughly +50 ppm. The amino substituent at this position acts as a strong donor of -electrons to the delocalized -electron system concerned, provided that the amino substituent is coplanar or nearly coplanar with the aromatic ring system. On the other hand the amino nitrogen shielding decreases with increasing conjugation of its lone pair electrons with the -electrons of the ring [21]. This is exactly what we observe here when steric effects force the amino lone pair into a position where the conjugation is less effective (Table 2). Now we turn to the role of N-nitramino substituents at position 2, those in compounds 6, 7, 12, and 13. Generally, the pertinent nitrogen shieldings of the pyridine nitrogen are higher than that of unsubstituted pyridine but much lower than those of 2-amino-substituted derivatives. This suggests that the nitramino substituent acts as a donor of -electrons, but its donor strength is much lower than those of amino substituents.
750
For the 2-nitramino derivatives, there is also a striking difference between the shieldings of the pyridine nitrogen if we compare the corresponding 5-nitro and 3-nitro isomers. The latter show pyridine nitrogen shielding of about +75 ppm, while those of about +85 ppm are observed for the former. Evidently, steric effects induce severe distortions from coplanarity in the case of the 3-nitro-substituted isomers, in accord with the foregoing observations and computations relating to the 2-amino derivatives. The properties of the 2-nitramino substituent as a modest donor of -electrons have already been observed in the nitrogen shieldings of 6-methyl2-nitramino-5-nitropyridines [11]. We also performed PM3 optimizations of the geometries of the nitramino derivatives 6, 7, 12, and 13. The results were similar to those for the 2-amino derivatives as far as coplanarity distortions were concerned. The nitramino moiety as such is generally planar, particularly in polar solvents and when its -electron system is conjugated with some other -electrons. However, it can also attain a slightly pyramidal arrangement of the bonds of the nitrogen atom [23]. The PM3 computations in the present work revealed slightly pyramidal nitramino moieties in cases of serious steric hindrance (compounds 12 and 13) and twisting of the whole of the moiety, by about 80, from the optimal arrangement for -electron conjugation. A word of comment is necessary here about some significant differences in the amino nitrogen shieldings upon passing from an N(R)CH3 moiety to the corresponding N(R)CH2CH3, i. e., in the following pairs of compounds: 23, 67, 1213, and 1415. The result is invariably a deshielding effect on the amino nitrogen, by about -15 ppm. This is a manifestation of the so-called -effects of alkyl groups. It has already been demonstrated [21] that nitrogen magnetic shielding decreases significantly in the following sequence of alkyl substitution at a nitrogen atom for a given X residue: CH3N(X)RCH2N(X)R2CHN(X)R3CN(X), where R is an alkyl group and X represents any atom or group of atoms. The name of the effects comes from the fact that in each of the foregoing steps a saturated carbon atom is introduced to the -position with respect to the nitrogen atom involved. Each step results in a deshielding effect on the nitrogen, and the nature of this seems to stem from the increasing migration of the electron charge, in the direction of the nitrogen atom, across the CN single bond [24]. In the present case, the differences between the methyl and ethyl derivatives represent a single -effect, that involving the CH3N(X)RCH2N(X) step. Nitrogen NMR shieldings (chemical shifts) seem to provide an effective probe for monitoring electron redistribution within heavily substituted pyridine systems, with due attention paid to steric hindrance induced obstructions to coplanarity and the concomitant impairment of -electron delocalization troughout such molecular systems. The shieldings of the pyridine nitrogen atoms provide a measure of -electron donor strength of substituents, indicating that N-nitramino groups act as weak donors while amino groups are strong donors of -electrons.
EXPERIMENTAL Compounds 1-15 were prepared according to published procedures [25, 26]. The nitrogen magnetic shieldings (chemical shifts) of the systems studied were measured using high-precision 14N NMR spectra; these were taken on a Bruker Avance DRX-500 spectrometer (11.7 T) at 35.00.2C, as maintained by a VT unit, at a frequency of 36.14 MHz (90 pulse, 40 s; acquisition 0.111 s; 4.521 Hz/pt). Efforts were made in order to reduce random and systematic errors in the shieldings to below 0.1 ppm. External liquid nitromethane was employed as reference by means of 10 mm/4mm o.d. coaxial tubes, where the inner tube contained 0.3M nitromethane in acetone-d6 as a direct reference and a source of deuterium lock; the nitrogen shielding of this solution is +0.77 ppm from that of neat liquid nitromethane [21]. This value is obtained from measurements using concentric spherical sample/reference containers in order to eliminate magnetic bulk susceptibility effects. 751
The value of +0.77 ppm is used as a conversion constant, and since the measurements were taken for dilute solutions in pure acetone, the values of the shieldings thus obtained, with respect to that in neat liguid nitromethane, are bulk-susceptibility corrected. The exact resonance frequency of the 14N signal of neat nitromethane was 36.141524 MHz, from which a value of 36.136826 MHz was obtained for the bare nitrogen nucleus [21]. The latter value was used in conjunction with the relevant resonance frequency differences to calculate the nitrogen shieldings relative to that of neat nitromethane. Lorentzian lineshape fitting of the 14N resonance signals was employed to produce values for the precise resonance frequencies of both the samples and reference used. A very pure and dry acetone solvent was used as reported previously [22], and the solutions were prepared and handled under a dry argon atmosphere. The semiempirical quantum-mechanical optimizations were carried out using the PM3 method implemented in the TMHyperChem-5 software package (Hypercube, Inc).
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. R. W. Munn and S. P. B. Smith, Adv. Mat. Opt. Electron., 1, 65 (1992). T. Kondo, F. Akase, M. Kumagai, and R. Ito, Opt. Rev., 2, 128 (1995). Ch. Bosshard, K. Sutter, and P. Gunter, J. Opt. Soc. Am., B6, 721 (1989). M. Wandas, B. Palasek, A. Puszko, and H. Ban-Oganowska, Khim. Geterotsikl. Soedin., 637 (1997). H. Ban-Oganowska, A. Puszko, B. Palasek, and M. Wandas, Spectrochim. Acta, A51, 549 (1996). B. Palasek, Z. Pawelka, and A. Puszko, Polish J. Chem., 71, 353 (1997). M. Wandas and A. Puszko, Khim. Geterotsikl. Soedin., 7, 908, (2000). M. Wandas, Z. Pawelka, and A. Puszko, J. Heterocycl. Chem., 37, 335 (2000). Z. Pawelka, J. Lorenc, and A. Puszko, J. Struct. Chem., 11, 307 (2000). Z. Pawelka, A. Puszko, and B. Palasek, J. Phys. Org. Chem., 10, 835 (1997). B. Palasek, A. Puszko, Z. Biedrzycka, W. Sicinska, and M. Witanowski, Spectroscopy, 13, 251 (1997). K. Laihia, E. Kolehmainen, R. Kauppinen, J. Lorenc, and A. Puszko, Spectrochim. Acta, A58, 1425 (2002). S. Rubinsztajn and M. Zeldin, Macromolecules, 23, 4026 (1990). S. Rubinsztajn and M. Zeldin, Macromolecules, 24, 2682 (1991). A. Deratoni and G. D. Darling, Macromolecules, 24, 767 (1987). E. Delaney, L. E. Wood, and J. M. Klotz , J. Am. Chem. Soc., 104, 1799 (1982). R. L. Robery, Ch. A. Alt, and C. V. DeAminis, US Pat. 5 245 036; Chem. Abstr., 120, 30682 (1994). K. Hagita and T. Hojo, Jpn. Pat. 9124096; Chem. Abstr., 115, 71902 (1991). G. V. Kulkarni, A. Ray, and C. C. Pated, J. Mol. Struct., 71, 253 (1981). M. Edrisi and A. Massouni, Microchem. J., 16, 353 (1971). M. Witanowski, L. Stefaniak, and G. A. Webb, in: Annual Reports in NMR Spectroscopy, 25, Acad. Press, 1993 (and references therein). M. Witanowski, W. Sicinska, Z. Biedrzycka, and G. A. Webb, Magn. Reson. Chem., 31, 916 (1993). M. Witanowski, Z. Biedrzycka, W. Sicinska, and Z. Grabowski, J. Mol. Struct., 602, 199 (2002). M. Witanowski, Z. Biedrzycka, K. Grela, and K. Wejroch, Magn. Reson. Chem., 36, S-85 (1998). M. Pupin and T. Talik, Pr. Nauk. AE, Wroclaw, 291, 111 (1985). M. Wandas and T.Talik, Pr. Nauk. AE, Wroclaw, 435, 129 (1988).
752
ELECTROCHEMICAL OXIDATION OF COMPOUNDS CONTAINING 1,4-DIHYDROPYRIDINE AND PYRIDINIUM RINGS ANALOGS OF GENE TRANSFECTION AGENTS
B. Turovska, J. Stradins, I. Turovskis, A. Plotniece, A. Shmidlers, and G. Duburs A study was carried out on the electrochemical oxidation of 1,4-dihydropyridines, found as substituents in pyridinium salts, which are strong electron acceptors. The potentials for their oxidation in acetonitrile were determined. NMR spectroscopy was used to find the relative acidity of the NH and C H protons and the oxidation potentials were determined for the anionic products of the ionization of the NH bond in dihydropyridine. The only product of the preparative electrolysis, in contrast to chemical oxidation, is the corresponding pyridine, namely, the oxidized dihydropyridine form. Keywords: dihydropyridine electrochemical oxidation. anions, dipyridines, 1,4-dihydropyridines, oxidation mechanism,
Dihydropyridines, which have a broad spectrum of biological activity [1], including acting as gene transfection agents [2], have been the subject of extensive investigation [3, 4]. In an electrochemical study of the individual steps involving transfer of electrons (E) and protons (C) in the dihydropyridinepyridine transformation, all possible mechanisms, namely, EC, EECC, and ECEC, have been examined. Such a variety of results can be explained only if we assume the strong dependence of the oxidation mechanism on the structure of the dihydropyridines studied as well as the experimental conditions. In the present work, we studied the electrochemical oxidation of the 1,4-dihydropyridine ring at C(2) (1), C(3) (2), and C(4) (3) of a pyridinium salt by cyclic voltammetry and preparative electrolysis at constant potential.
ClO4 + N Me EtOOC Me N H 1 H COOEt Me EtOOC Me N H 2 H COOEt Me EtOOC Me N H 3 H COOEt Me ClO4 + N Me Me N+ ClO4
__________________________________________________________________________________________ Latvian Institute of Organic Synthesis, Riga LV-1006, Latvia; e-mail: turovska@osi.lv. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 880-886, June, 2004. Original article submitted April 14, 2004. 0009-3122/04/4006-07532004 Plenum Publishing Corporation 753
Fig. 1. Electrochemical oxidation of 1 (c = 510-4 M) in 0.1 M NaClO4 in acetonitrile on a platinum electrode.
The oxidation of 1-3 in acetonitrile proceeds in one irreversible step (Fig. 1) at the potentials indicated in Table 1. As expected. the oxidation of the dihydropyridine ring is most difficult when it is located at C(2) in the pyridinium ring. Dihydropyridines found at C(3) and C(4) of the pyridinium ring are more readily oxidized by 200 mV. Coulometric measurements taken during preparative oxidation (Table 1) indicate the two-electron nature of the anodic process. The presence of traces of oxygen in the solution reduces the number of electrons participating in the electrode process to a value close to 1e due to the parallel oxidation of the formed radical cations by oxygen. In the chemical oxidation of 1,2',6'-trimethyl-3',5'-bis(ethoxycarbonyl)-1',4'-dihydro-3,4'bipyridinium iodide [1] by sodium nitrite or hydrogen peroxide tar formation occurs. Thus, the corresponding oxidation product was synthesized independently by the oxidation of a derivative of 1',4'-dihydro-3,4'-bipyridine with subsequent alkylation of the dipyridine obtained [1]. In contrast to the chemical oxidation, 1a-3a are the only products of the preparative electrolysis.
_ ClO4 EtOOC Me + Py H + Py COOEt Me 2e 2H + EtOOC Me N 1a3a COOEt Me _ ClO4
N H 13
TABLE 1. Oxidation Potentials (Eox) of 1-4 and 6, Their Anions (Eoxan) and Number of Electrons (n) Participating in Preparative Oxidation
Compound 1 2 3 4 6 Eox, V 1.50 1.27 1.27 1.55 0.90 Eoxan, V 0.30 0.24 0.29 0.50 n 1.70 2.00 1.75 1.71 1.80
754
The anodic oxidation of the 1,4-dihydropyridine fragment in bispyridinium salt 4 process more anodicaly than the analogous oxidation in 1-3. The potential of the peak reaches 1.55 V and the process is irreversible (Fig. 2).
OCHF2 MeOOC +N ClO4 H 2C N H 4 H COOMe CH2 N + ClO4
The preparative electrolysis at 1.6 V is a two-electron process in the absence of oxygen. The structure of the only oxidation product 4a was indicated by 1H NMR spectroscopy.
OCHF2 MeOOC +N ClO4 4a H2C N COOMe CH2 N + ClO4
As the electrochemical oxidation of 1-4 is a two-electron process, it may thereby correspond to the ECEC or EECC mechanism only. Since both the NH and CH protons in the dihydropyridine fragment are involved in the oxidation, we should clarify which of these protons is more acidic. For this purpose, various
Fig. 2. Electrochemical oxidation of 4 (c = 510-4 M) in 0.1 M NaClO4 in acetonitrile on a platinum electrode (1) and in the presence of Na2CO3 (2). 755
bases were added to solutions of the compounds studied. Thus, the addition of Na2CO3 to a solution of 4 in DMSO-d6 leads to formation of dark red anion 5, while the NH signal disappears from the 1H NMR spectrum. According to our previous study [2], for analogs of 4 containing decyl, dodecyl, tetradecyl, and hexadecyl residues the values of pKa is close to 7. A stronger base such as potassium tert-butoxide is required to obtain the anions of 1-3. Despite the geminal arrangement of a strong electron acceptor and a proton at C-4', the loss of the NH signal is the only change in the 1H NMR spectrum in the presence of potassium tert-butoxide. Thus, the NH proton is the most acidic in all 1-4, regardless of the position of the pyridinium residue or residues. The acidity of the NH bond and pKa value for the series of Hantzch 1,4-dihydropyridines were determined by Vigante et al. [5]. Upon oxidation, the acidity of the primary products (radicalcations) are several orders of magnitude greater than the acidity of the starting compounds [6, 7]. Thus, the rapid loss of the NH proton must follow the removal of the first electron from the nitrogen atom in the dihydropyridine. Hence, 1-4 are oxidized according to the ECEC mechanism. In the presence of Na2CO3, an additional peak appears on the cyclic voltammograms of 4 at +0.5 V, corresponding to oxidation of the dihydropyridine anion. Anions 1-3 are oxidized at 0.30, 0.24, and 0.29 V, respectively. The potentials of the electrochemical oxidation peaks of several 4-substituted Hantzch 1,4-dihydropyridines were determined by LopezAlarcon et al. [8], who found that these anions are oxidized at about 0 V more readily by 500 mV than the starting molecules. The preparative electrolysis at the oxidation potentials of the anions of 1-4 could not be carried out to completion due to the rapid blockage of either the platinum or glassy carbon electrode by oxidation intermediates. The electrochemical oxidation of dihydropyridine 6, which has substituents capable of protonation at both C(2) and C(6), proceeds by the same ECEC mechanism. The only product of the two-electron irreversible oxidation at 0.9 V is pyridine 6a.
OCHF2 H MeOOC H2C H2C HNH2C COOEt N H 6 COOMe 2e CH2NH EtOOC CH2 CH2 + 2H ClO4 H2C H2C + H2NH2C COOEt N 6a MeOOC
OCHF2 COOMe + CH2NH2 EtOOC ClO4 CH2 CH2
5% NaHCO3
OCHF2 MeOOC H2C H2C HNH2C COOEt 6b N COOMe CH2NH EtOOC CH2 CH2
756
A pyridine derivative with protonated substituents at C(2) and C(6) is obtained in the oxidation of dihydropyridine 6, which is also a two-electron process. Therefore, 1-4 and 6 are oxidized through an ECEC mechanism, which is most frequently encountered in the literature for 1,4-dihydropyridines [8-10].
EXPERIMENTAL The cyclic voltammetry and preparative electrolysis were carried out in a PAR-170 electrochemical system. The oxidation potentials were found on a stationary platinum electrode (d = 2 mm). All the potentials were measured relative to the saturated calomel electrode. A platinum wire served as the auxiliary electrode. The solvent was purified by adding KMnO4 (2-3 g) to acetonitrile (2.5 l) and distill. Then, P2O5 (5 g) was added to the distillate, which was then redistilled. The acetonitrile sample was stored over CaH2 (10 g) and distilled immediately prior to use. Anhydrous NaClO4 dried in vacuum at 40C was used as the supporting electrolyte. The preparative oxidation was carried out in an H-shaped cell, bubbling argon through both the anodic and cathodic compartments during the entire electrolysis. The anode and cathode were both 42.8-cm platinum mesh screens. The electrolysis was carried out in 0.1 M NaClO4 in acetonitrile (100 ml) at the oxidation potential of each compound. The cell was filled with a solution of the supporting electrolyte. The anodic section was loaded with 1-3 (1.00 g, 2.26 mmol), 4 (1.00 g, 1.39 mmol), or 5 (0.50 g, 0.84 mmol). After completion of the electrolysis, the reaction mixture was evaporated. In order to remove NaClO4, the residue was subjected twice to chromatography on a 270-cm column packed with Acros 0.035-0.070-mm silica gel using 9:1 methylene chloridemethanol as the eluent. The 1H NMR spectra were taken on a Bruker WH-90 spectrometer at 90 MHz in DMSO-d6 for 1-4 and chloroform-d for 5a and 5b with HMDS ( 0.055 ppm) as the internal standard. The perchlorates of 1-4 were obtained from the corresponding bromides [11, 12]. 1,1'-{[3,5-Bis(methoxycarbonyl)-4-(2-difluoromethoxyphenyl)-1,4-dihydropyridine-2,6-diyl]dimethylene}bispyridinium Diperchlorate (4). A sample of 1,1'-{[3,5-bis(methoxycarbonyl)-4-(2difluoromethoxyphenyl)-1,4-dihydropyridine-2,6-diyl]dimethylene}bispyridinium dibromide (1.74 g, 2.55 mmol) [12] was dissolved in ethanol (60 ml) and, then, concentrated (57%) HClO4 (8.7 ml) was added to the solution heated to reflux. The mixture was cooled to -10C. The precipitate formed was filtered off and washed with two 5-ml ethanol portions and, then, two 5-ml ether portions to give 1.60 g of crystalline product. The crude product was redissolved in ethanol (300 ml) at reflux and 7.6 ml conc. HClO4 was added to give 1.42 g (77%) colorless 4 as fine crystals; mp 199-208C, Rf 0.15 (Silufol UV-254, 1:1 acetic acidwater). 1H NMR spectrum, , ppm (J, Hz): 9.85 (1H, br. s, NH); 8.95 (4H, d, J = 6.0, H-2, H-2', H-6, H-6'); 8.60 (2H, t, J = H-4, H-4'); 8.10 (4H, dd, J = 7.0, J = 6.0, H-3, H-3', H-5, H-5'); 6.85-7.50 (4H, m, Ar); 7.13 (1H, t, J = 73.5, CHF2); 5.70 (4H, AB q, J = 14.2, CH2); 5.38 (1H, s, CH dihydropyridine); 3.55 (6H, s, CH3). Found, %: C 46.59; H 3.66; N 5.67. C28H27Cl2F2N3O13. Calculated, %: C 46.55; H 3.77; N 5.82. N-Deprotonated 5. 1H NMR spectrum, , ppm, (J, Hz): 8.65 (4H, d, J = 6.0, H-2, H-2', H-6, H-6'); 8.51 (2H, t, J = 7.0, H-4,H-4'); 7.95 (4H, dd, J = 6.0, H-3, H-3', H-5, H-5'); 6.75-7.40 (4H, m, Ar); 7.03 (1H, t, J = 73.5, CHF2); 5.65 (4H, AB q, J = 14.2, CH2); 5.30 (1H, s, CH dihydropyridine); 3.46 (6H, s, CH3). Products 1-3 were obtained from the corresponding bromides [11, 12] by treating these bromides with equimolar amounts of conc. (57%) HClO4 and then isolating perchlorates 1-3 according to the procedure for 4. Dimethyl Ester of 2,6-Bis{[(2-ethoxycarbonylethyl)amino]methyl}-4-(2-difluoromethoxyphenyl1,4-dihydropyridine-3,5-dicarboxylic Acid (6) was prepared according to our previous reports [12, 13]. 3',5'-Bis(ethoxycarbonyl)-1,2',6'-trimethyl-2,4'-bipyridinium perchlorate (1a). 1H NMR spectrum, , ppm, (J, Hz): 9.25 (dd, J = 6.0, J = 1.0, H-3); 8.65 (1H, td, J = 7.4, J = 1.0, H-5); 8.22 (1H, ddd, J = 7.4, J = 6.0, J = 1.0, H-4); 8.08 (1H, dd, J = 7.4, J = 1.0, H-6); 4.05 (3H, s, NCH3); 4.01 (4H, q, J = 7.0, CH2CH3); 2.71 (6H, s, CH3); 0.94 (6H, t, J = 7.0, CH2CH3).
757
3',5'-Bis(ethoxycarbonyl)-1,2',6'-trimethyl-3,4'-bipyridinium Perchlorate (2a). 1H NMR spectrum, , ppm, (J, Hz): 9.18 (1H, s, H-2); 9.08 (1H, d, J = 6.0, H-4); 8.59 (1H, d, J = 8.0, H-6); 8.23 (1H, dd, J = 8.0, J = 6.0, H-5); 4.40 (3H, s, NCH3); 4.06 (4H, q, J = 7.0, CH2CH3); 2.61 (6H, s, CH3); 0.97 (6H, t, CH2CH3). 3',5'-Bis(ethoxycarbonyl)-1,2',6'-trimethyl-4,4'-bipyridinium perchlorate (3a). 1H NMR spectrum, , ppm, (J, Hz): 9.01 (2H, d, J = 6.0, H-3, H-5); 8.01 (2H, d, J = 6.0, H-2, H-6); 4.41 (3H, s, NCH3); 4.05 (4H, q, J = 7.0, CH2CH3); 2.58 (6H, s, CH3); 1.01 (6H, t, J = 7.0, CH2CH3). 1,1'-{[3,5-Bis(methoxycarbonyl)-4-(2-difluoromethoxyphenyl)pyridine-2,6-diyl]dimethylene}bispyridinium Diperchlorate (4a). 1H NMR spectrum, , ppm, (J, Hz): 8.71 (4H, d, J = 6.0, H-2, H-2', H-6'); 8.60 (2H, t, J = 7.5, H-4, H-4'); 8.00 (4H, dd, J = 7.5, J = 6.0, H-3, H-3', H-5, H-5'); 7.0-7.7 (4H, m, Ar); 7.27 (1H, t, 73.5, CHF2); 6.15 (4H, s, CH2); 3.57 (6H, s, CH3). N,N'-{[3,5-Bis(methoxycarbonyl)-4-(2-difluoromethoxyphenyl)pyridine-2,6-diyl]dimethylene}N,N'-bis(2-ethoxycarbonylethyl)diammonium Diperchlorate (6a). 1H NMR spectrum, , ppm, (J, Hz): 7.25 (4H, m, Ar); 6.81 (4H, br. s, N+H2); 6.37 (1H, t, J = 73.0, CHF2); 4.72 (4H, s, CH2); 4.19 (4H, q, J = CH2CH3); 3.59 (4H, t, J = 6.0, NCH2); 3.52 (6H, s, CH3); 2.97 (4H, t, J = 6.0, COCH2); 1.27 (6H, t, J = 7.0, CH2CH3). Dimethyl Ester of 2,6-Bis{[(2-ethoxycarbonyl)amino]methyl}-4-(2-difluromethoxyphenyl)pyridine-3,5-dicarboxylic Acid (6b). 1H NMR spectrum, , ppm, (J, Hz): 7.12 (4H, m, Ar); 6.36 (1H, t, J = 74.0, CHF2); 4.10 (4H, q, J = 7.01, CH2CH3); 3.97 (4H, s, CH2); 3.49 (6H, s, CH3); 2.87 (4H, t, J = 7.0, NCH2); 2.48 (4H, t, J = COCH2); 2.20 (2H, br. s, NH); 1.22 (6H, t, J = 7.0, CH2CH3). This work was carried out with the support of the Latvian Science Council (Grants Nos. 193 and 173).
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. N. V. Makarova, Chemical Sciences Doctoral Dissertation, Riga (1993). Z. Hyvonen, A. Plotniece, I. Reine, B. Chekavichus, G. Duburs, and A. Urtti, Biochim. Biophys. Acta, 1509, 451 (2000). W. W. Ellis, W. Raebiger, C. J. Curtis, J. W. Bruno, and D. L. DuBois, J. Am. Chem. Soc., 126, 2738 (2004). D. Zhang, L.-Z. Wu, L. Zhou, X. Han, Q.-Z. Yang, L.-P. Zhang, and C.-H. Tung, J. Am. Chem. Soc., 126, 3440 (2004). B. A. Vigante, M. I. Terekhova, Ya. Ya. Ozols, E. S. Petrov, and G. Ya. Dubur, Khim. Geterotsikl. Soedin., 1228 (1989). A. Anne, P. Hapiot, J. Moiroux, P. Neta, and J.-M. Seveant, J. Am. Chem. Soc., 114, 4694 (1992). J.-P. Cheng, Y. Lu, X.-Q. Zhu, Y. Sun, F. Bi, and J. He, J. Org. Chem., 65, 3853 (2003). C. LopezAlarcon, L. J. NuezVergara, and J. A. Squella, Electrochim. Acta, 48, 2505 (2003). J. Ludvik, J. Volke, and J. Klima, Electrochim. Acta, 32, 1063 (1987). J. Stradins, L. Baumane, A. Kalninsh, Ya. Uldrikis, E. Bisenieks, Ya. Poikans, and G. Duburs, Khim. Geterotsikl. Soedin., 1360 (2000). N. V. Makarova, Zh. V. Koronova, A. V. Plotniece, D. Ya. Tirzite, and G. Ya. Duburs, Khim. Geterotsikl. Soedin., 1112 (1995). A. Urtti, Z. Hyvnen, A. Plotniece, N. Makarova, I. Reine, G. Tirzitis, B. Vigante, B. Chekavicus, A. Shmidlers, A. Krauze, R. Zhalubovskis, G. Duburs, M. Turunen, S. YlHerttuala, I. Jskelinen, M.-R. Toppinen, PCT Int. Appl. WO 01/62946; Chem. Abstr., 135, 206419 (2001). V. V. Kastrone, I. S. Reine, and G. Ya. Duburs, Khim. Geterotsikl. Soedin., 1701 (1995).
13.
758
ACTIVATION OF PYRIDINIUM SALTS FOR ELECTROPHILIC ACYLATION: A METHOD FOR CONVERSION OF PYRIDINES INTO 3-ACYLPYRIDINES
A. Klapars1 and E. Vedejs2 Cyanide adducts of N-MOM pyridinium salts react with strong acylating reagents to provide 3-acyl-4cyano-1,4-dihydropyridines that can be aromatized to 3-acylpyridines using ZnCl2 in refluxing ethanol. Keywords: dihydropyridines, pyridine acylation. Electrophilic aromatic substitution reactions of pyridines are extraordinarily challenging. Instead of C-substitution at the pyridine ring, the electrophile typically forms an adduct with the pyridine nitrogen, which even further deactivates the already electron deficient pyridine ring toward electrophilic substitution. For example, the direct nitration of pyridine may require a reaction temperature of 330C to provide only a 15% yield of 3-nitropyridine [1]. To the best of our knowledge, no direct, intermolecular C-acylations of pyridines have been reported [2]. This seriously limits the choice of methods for the preparation of the ubiquitous 3-substituted pyridines [3, 4]. In a limited number of cases, the lack of reactivity of pyridines toward electrophiles has been addressed by converting the recalcitrant pyridine into a temporarily activated 1,4-dihydropyridine [5-9]. In contrast to the electron poor parent pyridine, the electron rich 1,4-dihydropyridine features strongly enhanced reactivity toward electrophiles at the 3-position. Several steps are typically required including formation of the dihydropyridine, the subsequent reaction with an electrophile, and rearomatization to the desired 3-substituted pyridine. A similar concept has been ingeniously employed in a one pot nitration of pyridines in the presence of sulfite as the nucleophile that temporarily activates the pyridine, and then acts as a leaving group in an aromatization step [10, 11]. In principle, mechanistically analogous nucleophilic activation-aromatization sequences may also be possible with other combinations of nucleophiles and electrophiles, but other applications of this principle have not been reported. During our studies on indoloquinone synthesis involving the activation of oxazolium salts with cyanide ion [12], we fortuitously encountered the conversion from pyridinium salts to Reissert-type 4-cyano-1,4dihydropyridines having the general structure 1. We decided to explore their reactivity with electrophiles in anticipation that this might provide an indirect means for the introduction of a substituent into the 3-position of the pyridine ring. The results of this work are presented here.
__________________________________________________________________________________________ Department of Process Research, Merck Research Laboratories, NJ 07065, USA; e-mail: artis_klapars@merck.com. 2 Department of Chemistry, University of Michigan, Ann Arbor, MI 48109, USA; e-mail: edved@umich.edu. Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 887-894, June, 2004. Original article submitted June 01, 2004. 0009-3122/04/4006-07592004 Plenum Publishing Corporation 759
1
The cyanide ion and pyridinium salts form equilibrium mixtures containing labile 1,4-dihydropyridine adducts 1 (Scheme 1) [13, 14]. We found that the treatment of these equilibrium mixtures with strong acylating agents such as trifluoroacetic anhydride, trichloroacetyl chloride, or ethyl oxalyl chloride produces 3-acyl-1,4dihydropyridines 2. Due to stabilization by the electron withdrawing substituent in the 3-position, these acylated dihydropyridines 2 are significantly more robust than the parent dihydropyridines 1 and can be purified by aqueous extraction or even flash chromatography on silica gel. The deactivating effect of the 3-acyl group also prevents the introduction of a second acyl group in the 5-position. However, treatment of 1 with weaker acylating agents (AcCl, Ac2O, Ac2ODMAP, EtOCOCl, PhCOCl, PhCOBr) or various other electrophiles (TMSOTf, BnBr, MeOTf, TsCl) did not provide the desired dihydropyridines 2. Instead, products resulting from the reaction with the cyanide ion, present in the equilibrium mixture, were observed. Sheme 1
H CN _ CN + N+ R Undesired process observed with most electrophiles E+ E+ H CN E CN N R E E N+ R 3 N 4 E N R 1 Desired process observed only with strong acylating agents
The extent of conversion from pyridinium salts to cyanide adducts is strongly affected by the pyridine ring substituents (Scheme 2). For example, treatment of the 1,4-dimethylpyridinium salt 5 with benzyltrimethylammonium cyanide gave an equilibrium mixture of 5 and the cyanide adduct 6 in a 95:5 ratio according to NMR analysis, favoring the starting pyridinium salt 5. On the other hand, the presence of a moderately electron withdrawing N-methoxymethyl (MOM) group in 7 reversed the ratio to favor the dihydropyridine 8 over 7 (85:15). Neither of the dihydropyridines 6 nor 8 was reactive enough for acylation by trichloroacetyl chloride. When the same experiments were repeated with the 3-methylpyridinium salts 10 and 11, conversion to the cyanide adducts 12 and 13 was strongly favored in both cases. Clearly, the diminished steric effect compared to the 4-methyl analogues is responsible for this difference. More importantly, the reactivity of 12 and 13 with strong electrophiles was also improved. Thus, treatment with trichloroacetyl chloride in the presence of a hindered tertiary amine (Hnig's base) as HCl scavenger resulted in conversion to the acylated dihydropyridines 14 and 15. Initially, we regarded the N-allyl pyridinium salt 10 as the more desirable starting material compared to the N-MOM analogue 11 in terms of the toxicity and cost issues. However, the N-allyl intermediate 12 consistently gave lower yields of the 3-acylated product 14 compared to the corresponding reaction from 13. Therefore, the N-MOM pyridinium salts were chosen for further development. The optimized procedure was applied to the acylation of several pyridine substrates (Scheme 3) using the same sequence of N-alkylation with MeOCH2Cl (MOMCl), addition of the soluble cyanide source BnMe3N+CN- to generate the activated dihydropyridine, and C-acylation in the presence of Hnig's base. Ethyl oxalyl chloride gave generally good results with several pyridine substrates, so this reagent was used for comparison studies with unsubstituted pyridine as well as with the 3-methyl and 2-methyl derivatives. In the
760
Sheme 2
Me BnMe3N CN N+ R 5 R = Me 7 R = CH2OMe CDCl3 95 15 : : 5 85
+
Me CN
Cl3CCOCl NEtPr2-i
Me CN O CCl3
N R 6 R = Me 8 R = CH2OMe H CN Cl3CCOCl NEtPr2-i Me
N R 9
H CN O CCl3 N R
Me N+ R
BnMe3N CN CDCl3
Me N R
10 R = Allyl 11 R = CH2OMe
15 1
: :
85 99
12 R = Allyl 13 R = CH2OMe
14 R = Allyl 15 R = MOM
(39%) (80%)
case of the 3-methylpyridine, a single regioisomeric dihydropyridine intermediate 16b was observed, as also seen in the trichloroacetylation experiments to give 12. However, the 2-methyl pyridine example afforded a 1:7 mixture of two separable regioisomers 18:19. The aromatization of the dihydropyridines 16 and 19 to the desired 3-acyl pyridines 17 and 20 was accomplished with the help of ZnCl2 as a mild cyanophile (Scheme 1). Upon addition of anhydrous ZnCl2 to 16a or 19, a rapid decyanation to the pyridinium salt 3 (R = MOM) could be detected by NMR analysis of the reaction mixture. Importantly, the formation of the pyridinium salt activated the MOM group toward deprotection via nucleophilic displacement. This was accomplished by refluxing the crude pyridinium salt mixture in ethanol, resulting in the formation of 17 and 20 in 67-70% overall yield from the starting pyridine. When the same aromatization procedure was used with the trichloroacetylated dihydropyridine 15, aromatization occurred as usual, but the refluxing ethanol deprotection step also cleaved the trichloroacetyl group in a haloform-type reaction to give the corresponding picolinate ester 21 (54% overall). This transformation proved quite useful because the alternative of preparing the picolinate via direct carboxylation of the dihydropyridine adduct 13 with chloroformate esters was unsuccessful due to competing cyanide transfer to the relatively unreactive electrophile. Trifluoroacetylation of pyridine via the dihydropyridine 1 (R = MOM) salt was also possible, and gave an isolable dihydropyridine 22. The aromatization of 22 using the zinc chloride procedure was viable according to NMR assay of the reaction mixture. However, attempts to recover 3-trifluoroacetylpyridine 23 from the crude product were not successful. The product proved to be highly polar, suggesting the formation of hydrates that could not be purified by chromatography. Another unusual example was encountered in the quinoline series. Quinoline activation and C-acylation with oxalyl chloride proceeded normally and gave the dihydroquinoline 24 in a typical 71% yield. However, 24 proved to be relatively stable, and the cyanide group resisted the usual zinc chloride aromatization conditions. Aromatization did take place with the stronger cyanophile AgOTf, but the quinoline product 25 was obtained in low (35%) yield. In summary, an indirect method for the 3-acylation of pyridines is described via the intermediate N-MOM pyridinium salts. This method utilizes the cyanide ion as a temporary nucleophile to form an activated, electron rich dihydropyridine intermediate that is susceptible to acylation at the 3-position, and subsequent aromatization. The cyanide can be permanently introduced in the pyridine ring if a pyridine N-oxide is treated with TMSCN [15, 16]. Although the method is applicable only to highly reactive acylating agents and requires the use of the toxic cyanide and MeOCH2Cl, no better alternatives for the 3-acylation of pyridines in a one-pot procedure are currently available. 761
Sheme 3
1. MeOCH2Cl 2. BnMe3N+CN N 3. EtO2CCOCl NEtPr2-i H CN O Me O N CH2OMe 16a R = H 16b R = Me 1. MeOCH2Cl 2. BnMe3N+CN Me N 3. EtO2CCOCl NEtPr2-i H CN O OEt N Me O CH2OME 18 O OEt 1: 7 18 : 19 Me N CH2OMe 19 H CN O Me N 1. MeOCH2Cl 2. BnMe3N+CN 3. EtO2CCOCl NEtPr2-i Me CCl3 N CH2OMe 15 1. ZnCl2 MeCN, rt 2. EtOH, reflux Me OEt N 21 (54%) O 1. ZnCl2 MeCN, rt 2. EtOH, reflux Me N 20 (55%) O OEt OEt O 1. ZnCl2 MeCN, rt 2. EtOH, reflux R N O OEt
17a R = H (70%), 16b R = Me (67%)
H CN O
H CN O 1. MeOCH2Cl 2. BnMe3N+CN N 3. (F3CCO)2O NEtPr2-i CF3 N CH2OMe 22 (90%) N 23
O CF3
1. MeOCH2Cl 2. BnMe3N+CN N 3. EtO2CCOCl NEtPr2-i
H CN O O OEt AgOTf EtOH, reflux N
O OEt O
N CH2OMe 24 (71%)
25 (36%)
EXPERIMENTAL General procedures. Solvents and reagents were purified as follows: acetonitrile was distilled from P2O5; diisopropylethylamine was distilled from CaH2; methoxymethyl chloride (Aldrich, technical grade) was distilled and sparged with nitrogen gas to remove the HCl impurity (CAUTION: methoxymethyl chloride and particularly an impurity present in the reagent are strong carcinogens); the purified reagents and solvents were 762
stored under nitrogen. Chloroform (anhydrous, stabilized with amylenes) was obtained from Aldrich and used immediately after opening of the bottle. Zinc chloride (Mallinckrodt, anhydrous) was used without further purification. All reactions were performed under an atmosphere of nitrogen in glassware dried in an oven (150C) and cooled with a stream of nitrogen. All reaction mixtures were stirred magnetically. Flash chromatography was performed with 230-400 mesh EM silica gel 60. Analytical TLC was performed on EM glass plates coated with a 250 m layer of silica gel 60 F254. Melting points were obtained on a Lab Devices MelTemp apparatus and are uncorrected. Benzyltrimethylammonium Cyanide (BnMe3N+CN) was prepared according to a procedure reported by Vedejs and Monahan [17] with some modifications (CAUTION: cyanide is a strong poison; sodium hypochlorite bleach solution can be used to detoxify the cyanide residues). Benzyltrimethylammonium chloride (Aldrich, 39.8 g, 0.214 mol) was dried at 0.5 mm Hg vacuum and dissolved in 50 ml of anhydrous MeOH. The resulting solution was transferred via cannula into a stirred solution of NaCN (15.8 g, 0.322 mol) in 300 ml of anhydrous MeOH. After stirring for 30 min at room temperature, the white suspension was carefully concentrated (rotary evaporation followed by 0.5 mm Hg vacuum) with minimal exposure to the atmospheric moisture. The residue was treated with 200 ml of hot anhydrous acetonitrile, and the resulting suspension was filtered hot through a fritted glass filter under nitrogen. The filtrate was carefully concentrated by rotary evaporation at room temperature to ca. 50 ml volume with minimal exposure to atmospheric moisture. The resulting suspension was filtered under nitrogen, and the crystals were dried at 0.5 mm Hg vacuum to give 23.7 g (63%) of the product as white hygroscopic crystals. The product was stable at room temperature for several years if it was stored and handled in a dry box under nitrogen. Ethyl 4-cyano-1-methoxymethyl-1,4-dihydro-3-pyridineglyoxylate (16a). To a solution of pyridine (0.33 ml, 4.08 mmol) in 10 ml of CHCl3 at room temperature was added methoxymethyl chloride (0.34 ml, 4.48 mmol). After stirring at room temperature for 1 h, the colorless solution was transferred via cannula into a 50 ml round bottom flask charged with benzyltrimethylammonium cyanide (660 mg, 3.74 mmol). The resulting clear solution was cooled to 0C (ice bath), and diisopropylethylamine (0.80 ml, 4.59 mmol) was added followed by ethyl oxalyl chloride (0.48 ml, 4.30 mmol). After stirring at 0C for 1 h, the orange solution was poured into 50 ml of ether and washed with 2 20 ml of water. The bright yellow organic layer was dried (Na2SO4) and concentrated by rotary evaporation to give the crude dihydropyridine 16a, which was used in the next step without further purification. Analytical TLC on silica gel 60 F254, hexaneacetone (1:1), Rf 0.47. Molecular ion calculated for C12H14N2O4 250.09530; found m/e 250.0943, error = 4 ppm. IR spectrum (neat) , cm-1: 2231 (CN), 1726 (C=O), 1678 (C=O). NMR spectrum (300 MHz, CDCl3), , ppm (J, Hz): 7.97 (1H, d, J = 1.4); 6.27 (1H, dt, J = 7.9, 1.4); 5.20 (1H, dd, J = 7.9, 4.6); 4.65 (2H, s); 4.60 (1H, dd, J = 4.6, 1.4); 4.35 (2H, q, J = 7.2); 3.36 (3H, s); 1.39 (3H, t, J = 7.2). 13C NMR spectrum (76 MHz, CDCl3), , ppm: 180.1, 162.2, 146.6, 128.7, 118.4, 103.2, 102.3, 85.4, 62.2, 56.0, 24.0, 13.9. Ethyl 3-Pyridineglyoxylate (17a). The crude dihydropyridine 16a prepared above was dissolved in anhydrous acetonitrile (5 ml, including cannula washings), and the solution was transferred via cannula into a 25 ml round bottom flask charged with ZnCl2 (1.05 g, 7.70 mmol). After stirring at room temperature for 5 h, the yellow suspension was filtered through Celite eluting with 2 2 ml of anhydrous acetonitrile. Anhydrous ethanol (10 ml) was added to the filtrate, the resulting tan solution was refluxed for 15 h, cooled to room temperature, and then poured into 10% aqueous solution of NaHCO3 (20 ml) at 0C (ice bath). The resulting suspension was filtered through Celite eluting with 2 10 ml of ethanol. The tan filtrate was extracted with 3 30 ml of CH2Cl2. The combined organic phase was dried (Na2SO4), concentrated by rotary evaporation, and the residue was purified by flash chromatography on silica gel (2.5 20 cm, hexaneacetone (4:1) eluent, 15 ml fractions). Fraction 9-15 gave 467 mg (70%) of the pyridine 17a as a light yellow liquid [18]. Ethyl 5-Methyl-3-pyridineglyoxylate (16b). To a solution of 3-methylpyridine (0.40 ml, 4.11 mmol) in 10 ml of CHCl3 at room temperature was added methoxymethyl chloride (0.34 ml, 4.48 mmol). After stirring at room temperature for 1 h, the colorless solution was transferred via cannula into a 50 ml round bottom flask charged with benzyltrimethylammonium cyanide (670 mg, 3.80 mmol). The resulting clear solution was cooled 763
to 0C (ice bath), and diisopropylethylamine (0.80 ml, 4.59 mmol) was added followed by ethyl oxalyl chloride (0.48 ml, 4.30 mmol). After stirring at 0C for 1 h, the orange solution was poured into 50 ml of ether and washed with 2 20 ml of water. The yellow organic layer was dried (Na2SO4) and concentrated by rotary evaporation to give the crude dihydropyridine 16b, which was used in the next step without further purification. The crude dihydropyridine 16b prepared above was dissolved in anhydrous acetonitrile (5 ml, including cannula washings), and the solution was transferred via cannula into a 25 ml round bottom flask charged with ZnCl2 (1.06 g, 7.78 mmol). After stirring at room temperature for 4 h, the orange suspension was filtered through Celite eluting with 2 2 ml of anhydrous acetonitrile. Anhydrous ethanol (10 ml) was added to the filtrate, the resulting tan solution was refluxed for 12 h, cooled to room temperature, and then poured into 10% aqueous solution of NaHCO3 (20 ml) at 0C (ice bath). The resulting suspension was filtered through Celite eluting with 3 5 ml of ethanol. The tan filtrate was extracted with 3 30 ml of CH2Cl2. The combined organic phase was dried (Na2SO4), concentrated by rotary evaporation, and the residue was purified by flash chromatography on silica gel (2.5 20 cm, hexaneacetone (4:1) eluent, 15 ml fractions). Fractions 8-12 gave 492 mg (67%) of the pyridine 17b as a pale yellow liquid. Analytical TLC on silica gel 60 F254, hexaneacetone (2:1), Rf 0.43. Molecular ion calculated for C10H11NO3 193.07390; found m/e 193.0744, error = 3 ppm. IR spectrum (neat), , cm-1: 1734 (C=O), 1693 (C=O). NMR spectrum (300 MHz, CDCl3), , ppm (J, Hz): 9.05 (1H, d, J = 2.0); 8.69 (1H, d, J = 2.0); 8.14 (1H, t, J = 2.0); 4.48 (2H, q, J = 7.1); 2.44 (3H, s); 1.44 (3H, t, J = 7.1). 13C NMR spectrum (76 MHz, CDCl3), , ppm: 184.8, 162.3, 155.2, 148.6, 136.9, 133.5, 127.9, 62.5, 18.1, 13.9. Ethyl 2-Methyl-3-pyridineglyoxylate (20). To a solution of 2-methylpyridine (0.42 ml, 4.25 mmol) in 10 ml of CHCl3 at room temperature was added methoxymethyl chloride (0.34 ml, 4.48 mmol). After stirring at room temperature for 1 h, the colorless solution was transferred via cannula into a 50 ml round bottom flask charged with benzyltrimethylammonium cyanide (670 mg, 3.80 mmol). The resulting colorless solution was cooled to -40C (dry ice-acetonitrile bath), and diisopropylethylamine (0.80 ml, 4.59 mmol) was added followed by ethyl oxalyl chloride (0.48 ml, 4.30 mmol). After stirring at -40C for 3 h, the cooling bath was removed. The reaction mixture was allowed to warm to room temperature for 1 h, poured into 50 ml of ether and washed with 2 20 ml of water. The tan organic layer was dried (Na2SO4), concentrated by rotary evaporation to give a 7:1 ratio of the dihydropyridine isomers, and the residue was purified by flash chromatography on silica gel (4 20 cm, hexaneacetone (3:1) eluent, 15 ml fractions). Fractions 45-70 gave the desired dihydropyridine regioisomer 19, which was used in the next step without further purification. The dihydropyridine 19 prepared above was dissolved in anhydrous acetonitrile (5 ml, including cannula washings), and the solution was transferred via cannula into a 25 ml round bottom flask charged with ZnCl2 (970 mg, 7.12 mmol). After stirring at room temperature for 4 h, the orange suspension was filtered through Celite eluting with 2 1 ml of anhydrous acetonitrile. Anhydrous ethanol (10 ml) was added to the filtrate, the resulting tan solution was refluxed for 12 h, cooled to room temperature, and then poured into 10% aqueous solution of NaHCO3 (20 ml) at 0C (ice bath). The resulting suspension was filtered through Celite eluting with 3 10 ml of ethanol. The tan filtrate was extracted with 3 30 ml of CH2Cl2. The combined organic phase was dried (Na2SO4), concentrated by rotary evaporation, and the residue was purified by flash chromatography on silica gel (2.5 20 cm, hexaneacetone (3:1) eluent, 15 ml fractions). Fractions 8-14 gave 406 mg (55%) of the pyridine 20 as a colorless liquid. Analytical TLC on silica gel 60 F254, hexaneacetone (2:1), Rf = 0.40. Molecular ion calculated for C10H11NO3 193.07390; found m/e 193.0742, error = 2 ppm. IR spectrum (neat), , cm-1: 1734 (C=O), 1697 (C=O). NMR spectrum (300 MHz, CDCl3), , ppm (J, Hz): 8.69 (1H, dd, J = 1.8, 4.9); 8.04 (1H, dd, J = 1.8, 8.0); 7.30 (1H, dd, J = 4.9, 8.0); 4.45 (2H, q, J = 7.2); 2.80 (3H, s); 1.42 (3H, t, J = 7.2. 13C NMR spectrum (76 MHz, CDCl3), , ppm: 187.4, 163.3, 160.1, 152.7, 139.0, 127.3, 120.8, 62.6, 24.4, 13.9. 4-Cyano-1-methoxymethyl-5-methyl-3-trichloroacetyl-1,4-dihydropyridine (15). To a solution of 3-methylpyridine (0.40 ml, 4.11 mmol) in 10 ml of CHCl3 at room temperature was added methoxymethyl chloride (0.34 ml, 4.48 mmol). After stirring at room temperature for 1 h, the colorless solution was transferred 764
via cannula into a 50 ml round bottom flask charged with benzyltrimethylammonium cyanide (670 mg, 3.80 mmol). The resulting colorless solution was cooled to 0C (ice bath), and diisopropylethylamine (0.80 ml, 4.59 mmol) was added followed by trichloroacetyl chloride (0.48 ml, 4.30 mmol). The cooling bath was removed, and the reaction mixture was stirred at room temperature for 1 h. The yellow solution was poured into 100 ml of ethyl acetate and washed with 2 20 ml of water. The tan organic layer was dried (Na2SO4) and concentrated by rotary evaporation to give the crude dihydropyridine 15, which was used in the next step without further purification. Analytical TLC on silica gel 60 F254, hexaneacetone (2:1), Rf = 0.35. Pure material was obtained by crystallization from chloroform, mp 160-161C, decomposition, yellow plates. Molecular ion calculated for C11H11Cl3N2O2 307.98861; found m/e 307.9857, error = 9 ppm. IR spectrum (KBr), , cm-1: 2225 (CN), 1695 (C=O). NMR spectrum (300 MHz, CDCl3), , ppm (J, Hz): 7.98 (1H, s); 6.08 (1H, s); 4.70 (1H, AB q, J = 10.5); 4.63 (1H, AB q, J = 10.5); 4.45 (1H, s); 3.34 (3H, s); 1.93 (3H, s); 7.98 (1H, s); 6.08 (1H, s); 4.70 (1H, AB q, J = 10.5); 4.63 (1H, AB q, J = 10.5); 4.45 (1H, s); 3.34 (3H, s); 1.93 (3H, s). 13C NMR spectrum (76 MHz, DMSO-d6), , ppm: 177.9, 145.9, 124.1, 118.4, 111.5, 95.2, 92.6, 84.6, 55.1, 30.5, 17.9. Ethyl 5-Methyl-3-pyridinecarboxylate (21). A solution of the crude dihydropyridine 15 prepared above and ZnCl2 (2.04 g, 15.0 mmol) in 10 ml of anhydrous ethanol was refluxed for 24 h. After cooling to room temperature, the reaction mixture was poured into 10% aqueous solution of NaHCO3 (40 ml) at 0C (ice bath). The resulting suspension was filtered through Celite eluting with 3 5 ml of ethanol, and the brown filtrate was extracted with 2 60 ml of CH2Cl2. The combined organic phase was dried (Na2SO4), concentrated by rotary evaporation, and the residue was purified by flash chromatography on silica gel (2.5 20 cm, hexaneacetone (4:1) eluent, 7 ml fractions). Fractions 14-22 were concentrated by rotary evaporation and purified by another flash chromatography on silica gel (2.5 20 cm, hexaneethyl acetate (2:1) eluent, 7 ml fractions). Fractions 2027 gave 340 mg (54%) of the pyridine 21 as a pale tan liquid, identical with the literature report according to NMR assay [19]. 4-Cyano-1-methoxymethyl-3-trifluoroacetyl-1,4-dihydropyridine (22). To a solution of pyridine (0.34 ml, 4.20 mmol) in 10 ml of CHCl3 at room temperature was added methoxymethyl chloride (0.34 ml, 4.48 mmol). After stirring at room temperature for 1 h, the colorless solution was transferred via cannula into a 50 ml round bottom flask charged with benzyltrimethylammonium cyanide (675 mg, 3.82 mmol). The resulting colorless solution was cooled to 0C (ice bath), and diisopropylethylamine (0.80 ml, 4.59 mmol) was added followed by trifluoroacetic anhydride (0.60 ml, 4.25 mmol). The yellow solution was stirred at 0C for 1 h, poured into 50 ml of ether, and washed with 2 20 ml of water. The tan organic layer was dried (Na2SO4), concentrated by rotary evaporation, and the residue was purified by flash chromatography on silica gel (2.5 20 cm, dichloromethaneether (20:1) eluent, 15 ml fractions). Fractions 9-12 gave 852 mg (90%) of the dihydropyridine 22 as yellow crystals. Analytical TLC on silica gel 60 F254, hexaneacetone (2:1), Rf 0.34. Pure material was obtained by crystallization from etherhexane, mp 49-50 oC, yellow crystals. Molecular ion calculated for C10H9F3N2O2 246.06160; found m/e 246.0609, error = 3 ppm. IR spectrum (neat), , cm-1: 2235 (CN), 1662 (C=O). NMR spectrum (300 MHz, CDCl3), , ppm (J, Hz): 7.49 (1H, t, J = 1.2); 6.31 (1H, dt, J = 7.9, 1.2); 5.24 (1H, dd, J = 7.9, 4.5); 4.69 (2H, s); 4.58 (1H, dt, J = 4.5, 1.2); 3.37 (3H, s). 13C NMR spectrum (76 MHz, CDCl3), , ppm (J, Hz): 176.5 (q, J = 34.8); 145.5 (q, J = 4.7); 128.6, 118.1, 116.7 (q, J = 290.4); 102.5; 99.6; 85.5; 56.0; 24.2. 19F NMR spectrum (282 MHz, CDCl3), , ppm: 69.9. Ethyl 4-Cyano-1-methoxymethyl-1,4-dihydro-3-quinolineglyoxylate (24). To a solution of quinoline (0.50 ml, 4.23 mmol) in 10 ml of CHCl3 at room temperature was added methoxymethyl chloride (0.34 ml, 4.48 mmol). After stirring at room temperature for 1 h, the light green solution was transferred via cannula into a 50 ml round bottom flask charged with benzyltrimethylammonium cyanide (680 mg, 3.86 mmol). After stirring at room temperature for 4 h, the tan solution was cooled to 0C (ice bath), and diisopropylethylamine (0.80 ml, 4.59 mmol) was added followed by ethyl oxalyl chloride (0.48 ml, 4.30 mmol). The cooling bath was removed, the reaction mixture was stirred at room temperature for 1 h, the resulting brown solution was poured into 50 ml of ether, and washed with 2 20 ml of water. The organic layer was dried (Na2SO4), concentrated by 765
rotary evaporation, and the residue was purified by flash chromatography on silica gel (2.5 20 cm, hexane ethyl acetate (1:1) eluent, 15 ml fractions). Fractions 13-21 gave 822 mg (71%) of the dihydroquinoline 24 as a yellow solid. Analytical TLC on silica gel 60 F254, hexaneacetone (1:1), Rf 0.60. Pure material was obtained by crystallization from ethanol, mp 118-119 oC, yellow needles. Molecular ion calculatedd for C16H16N2O4 300.1110; found m/e 300.1116, error = 2 ppm. IR spectrum (KBr), , cm-1: 2233 (C N), 1736 (C=O), 1722 (C=O). NMR spectrum (300 MHz, CDCl3), , ppm (J, Hz): 8.27 (1H, s); 7.46-7.21 (4H, m); 5.24 (1H, s); 5.12 (2H, s); 4.36 (2H, q, J = 7.3); 3.41 (3H, s); 1.40 (3H, t, J = 7.3). 13C NMR spectrum (76 MHz, CDCl3), , ppm: 179.1, 162.3, 148.1, 134.7, 130.3, 129.8, 126.3, 118.9, 117.8, 115.8, 102.6, 84.1, 62.3, 55.9, 27.5, 13.9. The research reported in this paper was performed at the Department of Chemistry, University of Wisconsin, Madison, WI 53706, USA. Funding was provided by the National Institutes of Health (CA17918).
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. F. Friedl, Ber., 428 (1912). M. A. Brodney and A. Padwa, Tetrahedron Lett., 38, 6153 (1997). P. Baumgarten and A. Dornow, Ber., 72, 563 (1939). Y. Satoh, M. Ichihashi, and K. Okumura, Chem. Pharm. Bull., 40, 912 (1992). R. M. Acheson, N. D. Wright, and P. A. Tasker, J. Chem. Soc., Perkin Trans. 1, 2918 (1972). D. L. Comins and N. B. Mantlo, Tetrahedron Lett., 24, 3683 (1983). O. Tsuge, T. Kanemasa, T. Naritomi, and T. Tanaka, J. Chem. Lett., 1255 (1984). M. Haase, H. Goerls, and E. Anders, Synthesis, 195 (1998). M.-L. Bennasar, C. Juan, and J. Bosch, Tetrahedron Lett., 39, 9275 (1998). J. M. Bakke and I. Hegbom, Acta Chem. Scand., 48, 181 (1994). H. Suzuki, M. Iwaya, and T. Mori, Tetrahedron Lett., 38, 5647 (1997). E. Vedejs, A. Klapars, B. N. Naidu, D. W. Piotrowski, and F. C. Tucci, J. Am. Chem. Soc., 122, 5401 (2000). R. Foster and C. A. Fyfe, Tetrahedron, 25, 1489 (1969). R. E. Lyle and G. J. Gauthier, Tetrahedron Lett., 4615 (1965). W. K. Fife, J. Org. Chem., 48, 1375 (1983). H. Vorbrggen, and K. Krolikiewicz, Synthesis, 316 (1983). E. Vedejs and S. D. Monahan, J. Org. Chem., 62, 4763 (1997). M. K. Nurullaeva, U. M. Azizov, E. E. Mikhlina, K. F. Turchin, V. A. Silin, and L. Yakhontov, Chem. Abstr., 106, 32790 (1987). D. S. Noyce and J. A. Virgilio, J. Org. Chem., 38, 2660 (1973).
766
CONDENSATION PRODUCTS OF 1-ARYL3-ETHOXYCARBONYL-2-METHYL1,4,5,6-TETRAHYDRO-4(1H)PYRIDONES WITH HYDRAZINE, PHENYLHYDRAZINE, AND HYDROXYLAMINE

R. Vaickelioniene1, V. Mickevicius1, and G. Mikulskiene2 We have studied condensation of 1-(4-bromophenyl- and 2,5-dimethylphenyl)-3-ethoxycarbonyl-2methyl-1,4,5,6-tetrahydro-4(1H)pyridones with hydrazine, phenylhydrazine, and hydroxylamine, as a result of which we obtained nucleophilic substitution and intramolecular cyclization products: 5-(4-bromophenyl- and 2,5-dimethylphenyl)-4-methyl-2,5,6,7-tetrahydro-3H-pyrazole[4,3-c]pyridin-3ones, 5-(4-bromophenyl- and 2,5-dimethylphenyl)-4-methyl-6,7-dihydroisoxazole[4,3-c]pyridin-3(5H)ones. We used computer modeling of the molecules of the studied compounds to obtain additional information on the structural features of the reaction products. Keywords: 1-aryl-3-ethoxycarbonyl-2-methyl-1,4,5,6-tetrahydro-4(1H)pyridones, hydrazides of pyridine-3-carboxylic acids, ketoenol tautomerism, condensation, exchange processes, 1H and 13 C NMR spectroscopy, cyclization. Pyridone derivatives include compounds known to have pharmaceutical [1, 2] and agrochemical [1-3] activity. In this paper, we have studied the reactions of 1-aryl-3-ethoxycarbonyltetrahydro-2-methyl-4(1H)pyridones with some nucleophiles. When tetrahydropyridones 1a,b are refluxed with hydrazine hydrate in methanol, the hydrazides of 1-(4-bromophenyl)-4-hydroxy-2-methyl-1,6-dihydropyridine-3-carboxylic acid (2a) and 1-(2,5-dimethylphenyl)-4-hydroxy-2-methyl-1,6-dihydropyridine-3-carboxylic acid (2b) are formed, which separate out from the reaction mixture even during the reaction. According to the 1H NMR spectra, the enol form is observed not only in the synthesized hydrazides 2a,b but also in their condensation products with aromatic aldehydes: 2-(4-methoxyphenyl)methylidene hydrazide of (1-(4-bromophenyl)-4-hydroxy-2-methyl-1,6-dihydro-3-pyridinecarboxylic acid (3a), 2-(3,4-dimethoxyphenyl)methylidene hydrazide of 1-(4-bromophenyl)-4-hydroxy-2-methyl-1,6-dihydropyridine-3-carboxylic acid (4a), 2-(4-dimethylaminophenyl)methylidene hydrazide of 1-(2,5-dimethylphenyl)-4-hydroxy-2-methyl-1,6dihydropyridine-3-carboxylic acid (5b), apparently due to the strong intramolecular hydrogen bond between the oxygen atom of the 4-OH group of the heterocycle and the hydrazine moiety. When compound 1a is heated with phenylhydrazine in methanol, the carbonyl group in the 4 position of the heterocycle undergoes nucleophilic __________________________________________________________________________________________
2
Kaunas University of Technology, Kaunas 50299, Lithuania; e-mail: Vytautas.Mickevicius@ktu.lt. Institute of Biochemistry, Vilnius LT-08622, Lithuania; e-mail: gemam@bchi.lt. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 895-904, June, 2004. Original article submitted July 1, 2003; revision submitted March 15, 2004. 0009-3122/04/4006-07672004 Plenum Publishing Corporation 767
attack first of all. In fact, in the 1H NMR spectrum of compound 8a, we observe signals from the ester group OEt as a quartet at 4.24 ppm and a triplet at 1.28 ppm, and new signals also appear from the monosubstituted phenyl. The reaction of 1-(4-bromophenyl)-3-ethoxycarbonyl-2-methyl-1,4,5,6-tetrahydro-4(1H)pyridone (1a) with hydrazine hydrate or phenylhydrazine in glacial acetic acid at the boiling point of the mixture leads to formation of condensed bicyclic compounds: 5-(4-bromophenyl)-4-methyl-2,5,6,7-tetrahydro-3H-pyrazolo-[4,3-c]pyridin3-one (6a) and 5-(4-bromophenyl)-4-methyl-2-phenyl-2,5,6,7-tetrahydro-3H-pyrazolo[4,3-c]-pyridin-3-one (7a). By the same method, from compound 1b we also obtained 5-(2,5-dimethylphenyl)-4-methyl-2,5,6,7-tetrahydro3H-pyrazolo[4,3-c]pyridin-3-one (6b). Upon condensation of tetrahydropyridones 1a,b with hydroxylamine hydrochloride in a boiling mixture of 2-propanol and pyridine, the corresponding 5-aryl-4-methyl-6,7dihydroisoxazolo[4,3-c]pyridin-3(5H)-ones 9a,b are formed.
O Me O NH2OH Me R N 1a,b 4 N2H4, H+ PhNHNH2 5 PhNHNH2, H+ R N 2a,b H+ O Me R N 8a CO2Et N N H Ph 6a,b, 7a O Me R N N H OH 3a, 4a, 5b N Ar H+ R N Me N N R1 ArCHO CO2Et O R N 9a,b N2H4 O Me N H OH NH2 N
R = 4-BrC6H4; b R = 2,5-Me263; 3 Ar = 4-MeOC6H4; 4a Ar = 3,4-(MeO)2C6H3; 5b Ar = 4-Me2NC6H4; 6,b R1 = H; 7 R1 = Ph
The structures of the synthesized compounds were confirmed by 1H and 13C NMR spectroscopy, with assignment of the signals based on the general substituent additivity rules [4]. The appearance of new characteristic signals in the NMR spectra of compounds 6a,b, 7a, 9b confirms the formation of new cyclic structures. The NMR spectra of the compounds 2a,b, 3a, 4a, and 5b proved to be unexpectedly complex: the 1 H NMR spectra were complicated by the presence of a large number of signals and some broadening of those signals; the 13C NMR spectra were complicated by the absence of the required number of signals. Apparently 768
TABLE 1. 1H NMR Spectra (DMSO-d6) for Compounds 2-9

Compound 2a Chemical shifts, , ppm (J, Hz) 2.34 (3H, br. s, 2-CH3); 2.82 (2H, m*, CH2CO); 3.25 (2H, m*, CH2N); 5.30 (2H, br. s, NH2); 5.87 (1H, br. s*, CH=); 6.53 (2H, d, J = 8.9, H-2', H-6' arom.); 7.19 (2H, d, J = 8.9, H-3', H-5' arom.); 10.84 (1H, br. s, NH) 2.0 (3H, s, 2'-CH3); 2.20 (3H, s, 5'-CH3); 2.36 (3H, br. s, 2-CH3); 2.91 (2H, m*, CH2CO); 3.32 (2H, m*, CH2N); 4.76 (1H, br. s*, H=); 5.33 (2H, br. s, NH2); 6.32 (1H, d, J = 7.4, H-3' arom.); 6.37 (1H, s, H-6' arom.); 6.82 (1H, d, J = 7.4, H-4' arom.); 10.87 (1H, br. s, NH) 2.62 (3H, br. s, 2-CH3); 2.92 (2H, m*, CH2CO); 3.33 (2H, m*, CH2N); 3.82 (3H, s, OCH3); 5.90 (1H, br. s*, CH=); 6.56 (2H, d, J = 8.8, H-2', H-6' arom.); 7.02 (2H, d, J = 8.8, H-2'', H-6'' arom.); 7.19 (2H, d, J = 8.8, H-3', H-5' arom.); 7.60 (2H, d, J = 8.8, 3''-, 5''-H); 8.39 (1H, s, CH=); 11.21 (1H, br. s, NH); 14.20 (1H, br. s, OH) 2.64 (3H, br. s, 2-CH3); 2.89 (2H, m*, CH2CO); 3.40 (2H, m*, CH2N); 3.82 (6H, s, OCH3); 5.89 (1H, br. s*, CH=); 6.56 (2H, d, J = 8.8, H-2', H-6' arom.); 7.05 (1H, d, J = 8.4, H-5'' arom.); 7.20 (2H, d, H-3', H-5' arom.); 7.35 (1H, d. d, H-6'' arom.); 7.41 (1H, s, H-2'' arom.); 8.38 (1H, s, CH=); 11.21, 12.20 (1H, br. s, NH); 14.20 (1H, br. s, OH) 2.01 (3H, s, 2'-CH3); 2.20 (3H, s, 5'-CH3); 2.65 (3H, br. s, 2-CH3); 2.96 (2H, m*, CH2CO); 3.00 (6H, s, N(CH3)2); 3.37 (2H, m*, H2N); 4.80 (1H, m*, CH=); 6.32 (1H, d, J = 7.4, H-3' arom.); 6.41 (1H, s, H-6' arom.); 6.76 (2H, d, J = 8.9, H-3'', H-5'' arom.); 6.84 (1H, d, J = 7.4, H-4' arom.); 7.63 (2H, d, J = 8.9, H-2'', H-6'' arom.); 8.28 (1H, s, H=); 11.17, 12.01 (1H, br. s, NH); 14.03, 14.26 (1H, br. s, OH) 2.18 (3H, s, 2-CH3); 2.78 (2H, t, J = 6.7, CH2C=N); 3.90 (2H, t, J = 6.7, CH2N); 7.42 (2H, d, J = 8.6, H-2', H-6' arom.); 7.70 (2H, d, J = 8.6, H-3', H-5' arom.); 10.50 (1H, s, NH) 2.06 (3H, s, 2'-CH3); 2.18 (3H, s, 5'-CH3); 2.30 (3H, s, 2-CH3); 2.81 (2H, m , CH2C=N); 3.78 (2H, m , CH2N); 7.10-7.32 (3H, m , H-3', H-4', H-6' arom.); 10.50 (1H, s, NH) 2.36 (3H, s, 2-CH3); 2.99 (2H, t, J = 7.2, CH2C=N); 3.91 (2H, t, J = 7.2, CH2N); 7.08 (2H, d, J = 8.8, H-2', H-6' arom.); 7.12 (1H, t, J = 7.4, H-4" arom.); 7.38 (2H, t, J = 7.4, H-3'', H-5" arom.); 7.59 (2H, d, J = 8.8, H-3', H-5' arom.); 8.02 (2H, d, J = 7.4, H-2", H-6" arom.) 1.28 (3H, t, CH2CH3); 1.76 (3H, s, 2-CH3); 2.93 (2H, t, CH2C=N); 3.93 (2H, t, CH2N); 4.24 (2H, q, CH2CH3); 6.60-8.20 (9H, m , H arom.); 8.86 (1H, s, NH) 2.15 (3, s, 3); 2.94 (2H, t, CH2C=N); 3.98 (2H, t, CH2N); 7.43 and 7.74 (4, 2d, J = 8.8, H arom.) 2.18 (3H, s, 2'-CH3); 2.21 (3H, s, 5'-CH3); 2.37 (3H, s, 2-CH3); 3.83 (2H, t, J = 6.6, CH2C=N); 3.77-3.91 (2H, m , CH2N); 6.96 (1H, s, H-6' arom.); 7.15-7.27 (2H, m , H-3', H-4' arom.)
2b
3a
4a
5b
6b 7
8 9 9b
_______ * Signals for exchange multiplets of the ketoenol form.
ketoenol tautomerism is typical of compounds 2a,b, 3a, 4a, and 5b [5-8]. Detailed study of the 1H NMR spectra of compounds 2a,b, 3a, 4a, and 5b showed that in solution the compounds exist simultaneously in both the ketone and enol forms. The process of ketoenol tautomerism explains the broadening of the multiplets and the intensity distribution among them. We know that depending on the proton exchange rate between the keto enol forms, in the 1H NMR spectra [4] we observe either individual multiplets or broadened exchange signals. Computer modeling of the molecules, based on the concepts of molecular mechanics (MM2 method) and semiempirical molecular orbital methods (MOPAC program), is quite useful in studying ketoenol forms [9]. By minimization of the total energy of the model molecules, we established that the enol form is typically lower in energy (2a enol form, -6.79 kcal/mol) than the keto form (-3.43 kcal/mol). In the 1H NMR spectra of compounds 2a,b, 3a, 4a, and 5b, we observe individual multiplet signals for the protons of the NCH2 moiety (~3.3 ppm) and the CH2CO moiety (~2.9 ppm) and broad singlets for the CH=COH moiety (~5.9 ppm and 4.8 ppm). The integrated intensity of the multiplet signal from the protons of 769
TABLE 2. 13C NMR Spectra (DMSO-d6) for Compounds 6a, 6b, 71, 9b
O C XR N
4 5
R1
3' 2' 1' 4' 2
CH3
3
6 R2 = Br, X = N, R, R1, R3 = H 6b R = H, X = N, R1, R3 = CH3 R2 = Br, X = N, R1, R3 = H,

2'' 3'' 4''
2
5' 6'
N
6
7 R =
1''
R3
9b X = O, R1, R3 = CH3
Carbon atoms C(2) C(3) C(4) C(5) C(6) C=O 2-CH3 C(1') C(2') C(3') C(4') C(5') C(6') 2'-CH3 5'-CH3 C(1") C(2") C(3") C(4")
6 160.92 100.40 144.82 23.30 52.96 166.76 14.97 141.92 128.79 132.50 120.90 132.50 128.79
Chemical chifts, , ppm 6b 7 161.37 99.45 144.83 23.35 52.02 166.77 14.52 141.02 131.13 131.34 129.46 136.90 127.62 16.66 20.32 163.89 102.40 145.28 23.88 53.38 162.56 15.40 141.40 128.66 133.33 122.58 133.33 128.66
9b 164.98 91.45 156.30 22.38 51.87 172.05 15.40 140.43 131.02 131.77 130.50 138.22 127.13 17.05 20.81
139.17 118.89 127.95 123.93
the NCH2 group is equal to the sum of the intensities of the signals from the CH2CO and CH=COH moieties. The multiplet from the NCH2 moiety is broadened and quartet-shaped, probably due to overlap of a doublet (for the enol form) and a triplet (for the ketone form). The multiplet from the CH2CO moiety (the ketone form) is broadened and triplet-shaped. In the spectra of compounds 2a,b, 3a, 4a, and 5b, we observed significant broadening and a signal from the protons of the 2-CH3 group, although this group is not involved in the direct process of ketoenol exchange. Detailed study of the data obtained by computer modeling (Table 3) indicated the presence of charge transfer (the appearance of a partial double bond NC(2)) between the benzene ring and the heterocycle in the studied structures. In this case, an extended double bond system is formed. Since the CH=CH group has a greater -I effect [10] than the phenyl moiety, the shielding of the 2-CH3 group will change. A change in the electron density in the heterocycle is also indicated by the appearance of conjugation between C(2)=C(3) and C(4)=C(5) upon formation of the enol form, and also formation and breaking of the intramolecular hydrogen bond [4, 6, 11-13] between the 4-OH and 3-CC=O groups. The change in the electron density in the heterocycle affects the chemical shift of the signals from the protons of the 2-CH3 group and thus is responsible for broadening of such signals.
770
The presence of a NHN=CHAr moiety in compounds 3a, 4a, and 5b is why Z/E-isomerism is possible, In the H NMR spectra of compounds 4a and 5b, there are rather intense signals from protons of the NH group at 11.21 ppm and 11.17 ppm respectively, and there are low-intensity broadened signals at 12.0 ppm. Based on
1
TABLE 3. Models of Synthesized Compounds (Total Energy Optimized to a Global Minimum)

2 (keto form) 2 (enol form)
-3.43 kcal/mol
-6.79 kcal/mol
3 (E)
3 (Z)
-4.06 kcal/mol
-16.51 kcal/mol
4 (E)
4a (Z)
-5.75 kcal/mol
-16.41 kcal/mol
771
TABLE 3 (continued)
5b (E) 5b (Z)
-10.51 kcal/mol
-18.71 kcal/mol
6b
15.40 kcal/mol
15.35 kcal/mol
9b
15.33 kcal/mol
18.62 kcal/mol
8 (Z-isomer relative to the C(5) atom in the heterocycle)
8 (E-isomer relative to the C(5) atom in the heterocycle)
1.53 kcal/mol
2.61 kcal/mol
772
this, we can conclude that the studied compounds 4a and 5b exist predominantly in the form of Z-isomers, but with a fairly small E-isomer impurity. We do not observe Z/E-isomerism for compound 3a. The computer modeling data for 3a, 4a, and 5b showed that the existence of Z-isomers is most favorable, since their energy is about 10 kcal/mol lower than the energy of the E-isomer. According to computer modeling data, compound 8a more likely exists in the form of the Z-isomer (relative to the C(5) atom of the heterocycle), having lower total energy than the corresponding E isomer. The bulky substituent at the C(3) atom probably hinders formation of the E-isomer [13]. The signals for the carbon atoms in the 13C NMR spectra of compounds 6a,b, 7a, 9b were fully assigned. In these compounds, exchange processes are stopped by formation of cyclic structures. In the 13C NMR spectra of compounds 2a,b, 3a, 4a, 5b, due to a dynamic equilibrium between the interconverting ketoenol isomers, formation of a system of double bonds between the benzene and heterocyclic moieties, and formation of intramolecular hydrogen bonds, the shielding effect for the carbon atoms becomes somewhat indeterminate. So some signals in the compounds with a change in electron density may not be detected by the instrument. The problem of assigning the lines in the 13C NMR spectra of such compounds is complicated by the averaged nature of the effect of the substituents due to the ketoenol forms of the compounds formed, and also the possibility of recording individuals signals for atoms of the ketoenol forms.
EXPERIMENTAL The 1H and 13C NMR spectra were obtained on a Varian Unity Inova (300 MHz) and a Bruker AC 250-P (250 MHz), internal standard TMS. The IR spectra in KBr disks were recorded on a Perkin-Elmer Spectrum BX FT-IR system. The course of the reactions and the purity of the compounds obtained were monitored by TLC on Silufol UV-254 plates, visualization in UV light or iodine vapors. Hydrazide of 1-(4-Bromophenyl)-4-hydroxy-2-methyl-1,6-dihydropyridine-3-carboxylic Acid (2a). 1-(4-Bromophenyl)-3-ethoxycarbonyl-2-methyl-1,4,5,6-tetrahydro-4(1H)-pyridone (1a) (0.5 g, 1.5 mmol) and hydrazine hydrate (0.15 g, 3.0 mmol) in methanol (10 ml) were refluxed for 2 h. The reaction mixture was cooled down, the precipitated crystals were filtered out and washed with methanol and then ether, and then dried. Yield 0.38 g (78%); mp 200-202C (dioxane). IR spectrum, , cm-1: 3383.83, 3317.19, 3148.66; 1640.36. Found, %: C 48.29; H 4.22; N 12.87. C13H14BrN3O2. Calculated, %: C 48.17; H 4.35; N 12.96. Hydrazide of 1-(2,5-Dimethylphenyl)-4-hydroxy-2-methyl-1,6-dihydro-3-pyridinecarboxylic Acid (2b) was obtained as for compound 2a, from 1-(2,5-dimethylphenyl)-3-ethoxycarbonyl-2-methyl-1,4,5,6tetrahydro-4(1H)-pyridone (1b) (1.0 g, 3.5 mmol), hydrazine hydrate (0.4 g, 8.0 mmol) and methanol (10 ml). Yield 0.75 g (78%); mp 195-196C (dioxane). Found, %: C 65.76; H 6.82; N 15.18. C15H19N3O2. Calculated, %: C 65.91; H 7.01; N 15.37. 2-(4-Methoxyphenyl)methylidene Hydrazide of 1-(4-Bromophenyl)-4-hydroxy-2-methyl-1,6dihydropyridine-3-carboxylic Acid (3a). A mixture of hydrazide 2a (0.33 g, 1.0 mmol) and 4-methoxybenzaldehyde (0.27 g, 2.0 mmol) in 2-propanol (10 ml) was boiled for 2 h and cooled down; the precipitate was filtered out and washed with propanol and then ether, and then dried. Yield 0.37 g (84%); mp 219-221C (2-propanol). IR spectrum, , cm-1: 3320.48, 3148.92; 1632.12, 1605.66. Found, %: C 57.17; H 4.47; N 9.58. C21H20BrN3O3. Calculated, %: C 57.02; H 4.56; N 9.50. 2-(3,4-Dimethoxyphenyl)methylidene Hydrazide of 1-(4-Bromophenyl)-4-hydroxy-2-methyl-1,6dihydropyridine-3-carboxylic Acid (4a) was obtained as for methylidene hydrazide 3a from hydrazide 2a (0.33 g, 1.0 mmol), 3,4-dimethoxybenzaldehyde (0.25 g, 1.5 mmol) in 2-propanol (10 ml). Yield 0.40 g (85%); mp 217-219C (2-propanol). Found, %: C 55.49; H 4.40; N 9.18. C22H22BrN3O4. Calculated, %: C 55.94; H 4.69; N 8.90.
773
2-[4-(N,N-Dimethylamino)phenyl]methylidene Hydrazide of 1-(2,5-Dimethylphenyl)-4-hydroxy-2methyl-1,6-dihydropyridine-3-carboxylic Acid (5b) was obtained similarly, from hydrazide 2b (0.5 g, 1.8 mmol), 4-dimethylaminobenzaldehyde (0.3 g, 1.8 mmol) in 2-propanol (10 ml). Yield 0.34 g (47%); mp 245-246C (2-propanol). Found, %: C 71.44; H 6.75; N 13.98. C24H28N4O2. Calculated, %: C 71.26; H 6.98; N 13.85. 5-(4-Bromophenyl)-4-methyl-2,5,6,7-tetrahydro-3H-pyrazolo[4,3-c]pyridin-3-one (6a). A. Compound 1a (0.5 g, 1.5 mmol), hydrazine hydrate (0.15 g, 3.0 mmol), and glacial acetic acid (5 ml) were refluxed for 3 h. The mixture was diluted with water (15 ml) and cooled down; the precipitated crystals of compound 6a were filtered out and washed with water and then ethanol, and then dried. Yield 0.38 g (82%); mp 277-278.5C (dioxane). IR spectrum, , cm-1: 3258.10, 3142.43; 1644.53. Found, %: C 51.16; H 4.07; N 13.65. C13H12BrN3O. Calculated, %: C 51.00; H 3.95; N 13.73. B. Obtained by boiling hydrazide 2a (0.49 g, 1.5 mmol) and glacial acetic acid (5 ml) for 1.5 h. Isolated as in method A. Yield 0.39 g (85%). 5-(2,5-Dimethylphenyl)-4-methyl-2,5,6,7-tetrahydro-3H-pyrazolo[4,3-c]pyridin-3-one (6b). A. Synthesized and isolated as for pyrazolepyridinone 6a, from tetrahydropyridone 1b (1.0 g, 3.5 mmol), hydrazine hydrate (0.3 g, 6.0 mmol), and glacial acetic acid (5 ml). Yield 0.62 g (70%); mp 300-301C (dioxane). Found, %: C 70.72; H 6.52; N 16.67. C15H17N3O. Calculated, %: C 70.56; H 6.71; N 16.46. B. Obtained by boiling hydrazide 2b (0.5 g, 1.8 mmol) and glacial acetic acid (5 ml) for 1.5 h. Isolated as in method A. Yield 0.65 g (73%). 5-(4-Bromophenyl)-4-methyl-2-phenyl-2,5,6,7-tetrahydro-3H-pyrazolo[4,3-c]pyridin-3-one (7a). A. A mixture of compound 1a (0.5 g, 1.5 mmol), phenylhydrazine (0.32 g, 3.0 mmol) and glacial acetic acid (5 ml) was boiled for 3 h. The reaction mixture was diluted with water (15 ml) and cooled down; the precipitated crystals were filtered out and washed with methanol and then ether, and then dried. Yield 0.40 g (75%); mp 262263.5C (dioxane). IR spectrum, , cm-1: 1649.42; 1592.23; 1571.49; 1498.90; 1482.46; 1330.71. Found, %: C 59.83; H 4.12; N 10.87. C19H16BrN3O. Calculated, %: C 59.70; H 4.22; N 10.99. B. Compound 7a was obtained by boiling hydrazone 8a (0.43 g, 1.0 mmol) in glacial acetic acid (9 ml). Isolated as in method A. Yield 0.42 g (80%). Ethyl Ester of 1-(4-Bromophenyl)-2-methyl-4-(2-phenylhydrazono)-1,4,5,6-tetrahydropyridine-3carboxylic Acid (8a). A mixture of compound 1a (0.5 g, 1.5 mmol), phenylhydrazine (0.32 g, 3.0 mmol) in methanol (10 ml) was boiled for 2 h. The reaction mixture was cooled down; the precipitated crystals were filtered out and washed with methanol and then ether, and then dried. Yield 0.47 g (73%); mp 267-268.5C (2-propanol). IR spectra, , cm-1: 3275.83; 1649.96; 1591.96; 1571.21; 1482.75; 1330.82. Found, %: C 58.70; H 5.26; N 9.97. C21H22BrN3O2. Calculated, %: C 58.89; H 5.18; N 9.81. 5-(4-Bromophenyl)-4-methyl-6,7-dihydroisoxazolo[4,3-c]pyridin-3(5H)-one (9a). A mixture of tetrahydropyridone 1a (0.5 g, 1.5 mmol), hydroxylamine hydrochloride (0.16 g, 2.25 mmol), 2-propanol (5 ml), and pyridine (1 ml) was boiled for 2 h and then diluted with water (10 ml). The precipitate was filtered out and washed with propanol and then ether, and then dried. Yield 0.36 g (78%); mp 262-264C (2-propanol). IR spectrum, , cm-1: 3419.26, 3363.66, 3044.95, 2980.17, 1720.85, 1601.97. Found, %: C 50.98; H 3.52; N 9.20. C13H11BrN2O2. Calculated, %: C 50.84; H 3.61; N 9.12. 5-(2,5-Dimethylphenyl)-4-methyl-6,7-dihydroisoxazolo[4,3-c]pyridin-3-(5H)-one (9b) was obtained from pyridone 1b (0.43 g, 1.5 mmol), hydroxylamine hydrochloride (0.16 g, 2.25 mmol), 2-propanol (5 ml), and pyridine (1 ml) by the method for synthesis and isolation of compound 7a. Yield 0.31 g (81%); mp 228-229C (2-propanol). Found, %: C 70.41; H 6.11; N 11.09. C15H16N2O2. Calculated, %: C 70.29; H 6.29; N 10.93.
774
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. G. Yukihisa and M. Kazuhisa, Jpn. Pat. 6242970; Chem. Abstr., 107, 134204 (1987). M. Theophyle and P. Heinrich, Eur. Pat. Appl. EP 316279 (1989); Chem. Abstr., 112, 7378 (1990). C. R. Glenn, Can. Pat. 1115238; Chem. Abstr., 97, 92147 (1982). H. O. Kalinowski, S. Berger, and S. Braun, 13C NMR Spectroscopy [in German], Georg Thieme Verlag, Stuttgart/New York (1984). J. March, Organic Chemistry [Russian translation; I. P. Beletskii, ed.], Mir, Moscow (1987), 1. E. Liepins, M. V. Petrova, E. Gudriniece, J. Paulins, and S. L. Kuznetsov, Magn. Reson. Chem., 27, 907 (1989). J. L. Jios and H. Duddeck, Z. Naturforsch., 55b, 193 (2000). J. T. Pulkkinen, R. Laatikainen, J. J. Vepsalainen, and M. J. Ahlgren, Magn. Reson. Chem., 37, 119 (1999). B. Ya. Simkin and I. I. Sheikhet, Quantum Chemical and Statistical Theory of Solutions. Computational Methods and Their Application [in Russian], Nauka, Moscow (1987). A. N. Vereshchagin, The Inductive Effect [in Russian], Nauka, Moscow (1987). K. Kishore, D. N. Sathyanarayana, and V. F. Bhanu, Magn. Reson. Chem., 25, 471 (1987). L. Belvisi, C. Gennari, A. Madder, A. Mielgo, D. Potenza, and C. Scolastico, Eur. J. Org. Chem., 695 (2000). R. S. Baltrusis, V. J. Mickevicius, I. Bilinskaite, R. M. Zolotoyabko, and E. E. Liepins, Khim. Geterotiskl. Soedin., 1096 (1990).
775
SYNTHESIS OF QUINOLINE-8-SELENOL, ITS COMPLEX COMPOUNDS WITH METALS AND THEIR CYTOTOXIC ACTIVITY
J. Ashaks1, Yu. Bankovsky1, D. Zaruma1, I. Shestakova2, I. Domracheva2, A. Nesterova2, and E. Lukevics2 We have developed a novel method for synthesis of quinoline-8-selenol using selenourea instead of the previously used potassium selenocyanate. We have synthesized a series of metal quinoline-8-selenolates. We have studied the cytotoxic activity of the synthesized compounds against HT-1080, MG-22A, B16, Neuro 2A tumor cells. Mercury quinoline-8-selenolate is distinguished by high cytotoxicity for the three cell lines; the cadmium complex is most effective against B16 melanoma cells. Keywords: quinoline-8-selenol, metal quinoline-8-selenolates, cytotoxicity. Organic and inorganic derivatives of selenium effectively inhibit growth of a number of tumors [1-6]. One of the mechanisms proposed to explain this effect is based on the cytotoxic effect of selenium on tumor cells [1, 7, 8]. In continuing our studies on the cytotoxicity of organoselenium compounds, we have synthesized metal complexes of quinoline-8-selenol and have studied their cytotoxicity against 4 lines of tumor cells. Synthesis of quinoline-8-selenol from 8-aminoquinoline is described in the literature [9]. According to this method, 8-aminoquinoline undergoes diazotization and the diazonium salt is treated with potassium selenocyanate. The quinoline-8-selenolate obtained is hydrolyzed by hydrochloric acid in the presence of hypophosphorous acid, and quinoline-8-selenol is obtained in 12% yield. We have developed a novel method for synthesis of quinoline-8-selenol, using selenourea instead of potassium selenocyanate, which made it possible to increase the yield of the target product up to 32%. The synthesis was carried out according to the Scheme 1. 8-Aminoquinoline (1) undergoes diazotization, and by treatment of the diazonium salt 2 with selenourea we obtain the quinoline-8-isoselenouronium derivative 3, and by base hydrolysis of the latter in the presence of oxygen in the air 8,8'-diquinolyl diselenide (4) is formed, which is reduced by hypophosphorous acid in hydrochloric acid medium to form quinoline-8-selenol (5). In order to obtain pure 8,8'-diquinolyl diselenide, the quinoline-8-selenol is oxidized in alkaline medium by hydrogen peroxide. By treatment of quinoline-8-selenol with methyl iodide in alkaline medium, we obtain 8-methylselenoquinoline (6). We obtained complex compounds (Table 1) by reaction of quinoline-8-selenol with metal salts. We studied the cytotoxic activity of quinoline, 8-methylselenoquinoline (6), and compound 4. Quinoline itself does not have cytotoxic activity; compound 6 exhibits weak cytotoxicity, while 8,8'-diquinolyl diselenide is significantly more active, especially with respect to HT-1080 cells (Table 2). __________________________________________________________________________________________ Institute of Inorganic Chemistry, Riga Technical University, Salaspils LV-2169, Latvia; e-mail: nki@nki.lv. 2 Latvian Institute of Organic Synthesis, Riga LV-1006; e-mail: sinta@osi.lv. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 905-910, June, 2004. Original article submitted December 18, 2002. 776 0009-3122/04/4006-07762004 Plenum Publishing Corporation
1
Scheme 1
HNO2, HBr SeC(NH2)2
N NH2 1 N2Br
N 2 HN Se C
N 3 NH2
NaOH, O2
H3PO2, HCl
N Se 4 Se
H2O2, NaOH
MeI, NaOH
N SeH 5 SeMe
N 6
TABLE 1. Results of Elemental Analysis and Yields of Metal Quinoline-8Selenolates

Composition of complex 1 Zn(C9H6NSe)2 Cd(C9H6NSe)2 Hg(C9H6NSe)2 Ga(C9H6NSe)3 In(C9H6NSe)3 Sn(C9H6NSe)2 Pb(C9H6NSe)2 As(C9H6NSe)3 Sb(C9H6NSe)3 Bi(C9H6NSe)3 VO(C9H6NSe)2 MoO2(C9H6NSe)2 Cr(C9H6NSe)3 AgC9H6NSe Found, % Calculated, % 3 2.68 2.52 2.15 2.30 2.07 1.97 2.56 2.62 2.57 2.46 2.14 2.27 1.84 1.95 2.43 2.61 2.62 2.44 2.25 2.18 2.33 2.51 2.23 2.23 2.48 2.69 2.12 1.92
Yield, % N 4 5.72 5.84 5.58 5.32 4.37 4.56 6.19 6.08 5.83 5.71 5.23 5.26 4.63 4.51 5.87 6.03 5.78 5.65 5.17 5.06 6.03 5.82 5.35 5.17 6.20 6.24 4.58 4.45 5 86 84 87 75 85 83 83 74 83 75 86 89 76 93
2 45.73 45.08 41.36 41.05 34.98 35.16 47.37 46.93 44.03 44.05 41.62 40.57 35.52 34.79 46.12 46.58 44.11 43.64 39.12 39.06 44.13 44.93 40.27 39.88 48.44 48.17 34.67 34.32
777
TABLE 1 (continued)
1 Pd(C9H6NSe)2 Pt(C9H6NSe)2 Rh(C9H6NSe)3 Ir(C9H6NSe)3 Ru(C9H6NSe)3 Os(C9H6NSe)3 2 41.07 41.53 35.72 35.48 44.30 44.78 40.25 39.86 44.23 44.89 40.53 39.96 3 2.42 2.32 1.87 1.98 2.63 2.50 2.37 2.23 2.57 2.51 2.05 2.23 4 5.41 5.38 4.48 4.60 5.93 5.80 5.28 5.17 6.08 5.82 5.34 5.18 5 80 95 75 91 73 89
TABLE 2. Cytotoxicity of Quinoline-8-Selenol Complexes, IC50 (g/ml)

Nr. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. Formula Quinoline C10H9Nse (VI) C18H12N2Se2 (IV) AgC9H6NSe Pd(C9H6NSe)2 Pt(C9H6NSe)2 Zn(C9H6NSe)2 VO(C9H6NSe)2 MoO2(C9H6NSe)2 Cd(C9H6NSe)2 Hg(C9H6NSe)2 Sn(C9H6NSe)2 Pb(C9H6NSe)2 Cr(C9H6NSe)3 Sb(C9H6NSe)3 In(C9H6NSe)3 Ga(C9H6NSe)3 As(C9H6NSe)3 Bi(C9H6NSe)3 Rh(C9H6NSe)3 Ir(C9H6NSe)3 Ru(C9H6NSe)3 Os(C9H6NSe)3 HT-1080 CV MTT * 38 0.8 100 2 68 1 2 3 3 << 1 3 2 * 3 0.4 3 1 3 15 16 5 2 * 53 2 32 4 100 3 2 3 3 << 1 2 3 34 2 0.6 1 2 3 46 6 2 2 MG-22A CV MTT 28 20 3 53 6 * 3 3 3 3 0.011 2 2 * 1 3 3 3 3 36 28 8 2 65 26 2 59 12 * 2 4 3 3 0.029 3 3 * 3 3 1 3 4 23 11 8 2 Neuro 2A CV MTT nt nt 5 26 nt nt 12 3 3 3 << 1 3 2 nt 6 3 3 3 3 13 16 4 3 nt nt 1 12 nt nt 22 2 2 2 << 1 2 1 nt 11 6 2 1 2 14 14 2 1 B16 MTT nt nt 24 nt nt nt 34 1 1 << 1 10 1 3 nt 7 3 3 1 1 12 nt 1 11
CV nt nt 7 nt nt nt 33 1 3 << 1 3 1 1 nt 4 8 1 1 1 13 nt 1 *
_______ * No cytotoxic effect; nt = not tested.
Among the quinoline-selenol complexes, the mercury(II) complex has high cytotoxicity against all the studied tumor cell lines. Its IC50 against MG-22A mouse hepatoma cells was 0.011 (CV) and 0.029 g/ml (MTT). The cadmium(II) complex proved to be the most active with respect to B16 melanoma cells, while the indium(III) complex exhibited the greatest cytotoxicity against HT-1080 human lung fibrosarcoma cells. The arsenic(III), zinc(II), gallium(III), and osmium(III) complexes also were active against these cells. It is interesting that the osmium derivative is not effective against B16 melanoma, but is highly toxic for normal
778
cells. The gallium(III) complex is active against MG-22A cells. Antimony(III) and osmium(III) complexes also exhibited high cytotoxicity against these cells. The lead(II), tin(II), and bismuth(III) complexes are effective against both Neuro 2A and B16 melanoma. The data obtained allow us to assess the effect of the nature of the metal in the quinoline-8-selenol complexes on their cytotoxicity and selectivity of action, which is necessary in order to search further for compounds that are the most cytotoxic for tumor cells and the least harmful for normal cells.
EXPERIMENTAL Elemental analyses were done using an Analyser CHN analyzer (Czechoslovakia). The UV spectra were recorded on a Specord UV-vis spectrophotometer (Carl Zeiss, Jena). 8,8'-Diquinolyl Diselenide (4). 8-Aminoquinoline (5.0 g) was dissolved in a mixture of 40% hydrobromic acid (25 ml) and water (80 ml). The mixture was cooled down in an ice bath to +2C, and a solution of sodium nitrite (2.4 g) in water (20 ml) was poured in. The solution was stirred for 5 min and then a solution of selenourea (5 g) in water (100 ml) was added, and the mixture was heated for 1 h on a water bath at 70C. Water (200 ml) was added to the red solution of the quinoline-8-isoselenouronium derivative, the mixture was cooled down to room temperature, and a 30% NaOH solution was added until it tested alkaline. The mixture was allowed to stand for 1 h in air, occasionally transferring it from one beaker to another to promote oxidation of the quinoline-8-selenol by the oxygen in the air. Then the solution was filtered and the precipitate was dissolved in a mixture of hydrochloric acid (1:1) (15 ml) and a 50% solution of hypophosphorous acid (H3PO2) (5 ml), and heated for 5 min on a water bath. Then the solution was diluted with argon-saturated water (400 ml), a 30% NaOH solution was added until it tested alkaline, and it was filtered. A 10% hydrogen peroxide solution was added to the filtrate until precipitation was complete. The colorless precipitate was filtered out, washed with water, and dried in air. The reduction and oxidation procedure was repeated to purify compound 4. Yield of diselenide 4 2.3 g (32%); mp 205C. UV spectrum in chloroform: 1 = 251 nm, 2 = 335 nm, 1 = 38 000, 2 = 9600. Found, %: C 52.63; H 2.72; N 6.91. C18H12N2Se2. Calculated, %: C 52.19; H 2.92; N 6.77. Quinoline-8-selenol (5). Compound 4 (0.5 g) was dissolved in hydrochloric acid (1:1) (2 ml), a 50% H3PO2 solution (2 ml) and water (5 ml) were added, and it was allowed to stand for 10 min. Then water (20 ml) and a saturated sodium acetate solution (10 ml) were added. The precipitated dark-red material was filtered out, washed with water, saturated with argon, and dried above KOH in a desiccator filled with argon. Yield of compound 5 0.35 g (70%). Compound 5 is oxidized in air over the course of a few days to form the colorless compound 4, but is rapidly oxidized upon heating; so we could not determine its melting point. Found, %: C 52.43; H 3.47; N 6.58. C9H7NSe. Calculated, %: C 51.94; H 3.39; N 6.73. 8-Methylselenoquinoline (6). Compound 4 (0.5 g) was dissolved in hydrochloric acid (1:1) (2 ml), then a 50% H3PO2 (2 ml) solution and water (5 ml) were added and it was allowed to stand for 10 min. Then ethanol (20 ml) and methyl iodide (0.2 ml) were added along with a 30% NaOH solution until the color of the solution changed from dark-red to light-yellow. Then the solution was gradually diluted with water up to 100 ml. The precipitated light-yellow crystalline precipitate was filtered out, washed with water, and dried in air. Yield of compound 6 0.39 g (73%); mp 60C. UV spectrum in chloroform: 1 = 259 nm, 2 = 345 nm, 1 = 16 800, 2 = 4600. Found, %: C 53.12; H 3.87; N 6.52. C10H9NSe. Calculated, %: C 54.07; H 4.08; N 6.31. Synthesis of Metal Quinoline-8-selenolates (Table 1). Compound 4 (0.5 g) was dissolved in 3M hydrochloric acid (4 ml), then ethanol (10 ml) and a 50% H3PO2 solution (2 ml) were added and the mixture was allowed to stand for 10 min. Then a saturated sodium acetate solution (7 ml) was added to the solution of quinoline-8-selenol obtained, and then a solution of the metal salt in water (5 ml) was immediately added with stirring: 0.25 g Zn(CH3COO)2H2O; 0.3 g Cd(CH3COO)22H2O; 0.3 g HgCl2; 0.16 g Ga2(SO4)3; 0.25 g In2(SO4)37H2O; 0.25 g SnCl22H2O; 0.35 g Pb(NO3)2; 0.12 g Na2HAsO3; 0.25 g K(SbO)C4H4O60.5H2O; 779
0.35 g Bi(C4H4O6)36H2O; 0.24 g VOSO43H2O; 0.27 g Na2MoO42H2O; 0.37 g KCr(SO4)212H2O; 0.39 g AgNO3; 0.2 g PdCl2; 0.5 g K2[PtCl4]2; 0.15 g RhCl3; 0.39 g (NH4)3[IrCl6]; 0.27 g K2[Ru(H2O)Cl5]; 0.56 g K2[OsBr6]. In the case of Pt, Rh, Ir, Ru, Os, and Cr salts, the reaction mixture was heated for 5 min on a water bath. The precipitate of metal quinoline-8-selenolates obtained was filtered out, washed with water, dried in air, and recrystallized from chloroform. Determination of cytotoxicity. The cytotoxic effect of the compounds was tested on monolayer cultures of HT-1080 (human fibrosarcoma), MG-22A (mouse hepatoma), B16 (mouse melanoma), Neuro 2A (mouse neuroblastoma). The cells were cultured in Sigma DMEM medium without phenol red or antibiotics and with 5% Sigma fetal serum. After thawing, ampules were used with only 1-4 passages of the cell cultures, 2-5 104 cells/ml depending on the cell culture used; they were added to a 96-well plate to which the drug had already been added. The control cells without the drug were cultured on a separate plate. The cells were cultured for 72 h at 37C in 5% CO2. The number of live cells was determined by staining with crystal violet (CV), from the integrity of the cell membranes and from staining with MTT [3-(4,5-dimethylthiazole-2,5-diphenyltetrazolium bromide)], from the activity of mitochondrial enzymes in the cell. The number of cells on the control plate was taken as 100% [10]. The median inhibitory concentration (IC50) of the quinoline-8-selenol complexes is given in Table 2.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. M. P. Rayman, Lancet, 356, 233 (2000). W. Wu, K. Murakami, M. Koketsu, Y. Yomada, and I. Saiki, Anticancer Res., 19, 5375 (1999). P. B. Caffrey and G. D. Frenkel, Cancer Lett., 52, 4812 (1992). P. B. Caffrey and G. D. Frenkel, Cancer Lett., 81, 59 (1994). P. B. Caffrey and G. D. Frenkel, Cancer Lett., 121, 177 (1997). H. M. Shen, C. F. Yang, and C. N. Ong, Int. J. Cancer, 81, 820 (1999). E. Lukevics, P. Arsenyan, I. Shestakova, I. Domracheva, I. Kanepe, S. Belyakov, J. Popelis, and O. Pudova, Appl. Organomet. Chem., 16, 228 (2000). E. Lukevics, P. Arsenyan, K. Rubina, I. Shestakova, I. Domracheva, A. Nesterova, J. Popelis, and O. Pudova, Appl. Organomet. Chem., 16, 235 (2000). E. Sekido, Q. Fernando, and H. Freiser, Anal. Chem., 36, 1768 (1964). P. J. Freshney, Culture of Animal Cells (A Manual of Basic Technique), Wiley-Liss, New York (1994), p. 296.
780
SYNTHESIS AND CYCLIZATION OF N-(4-PHENOXYPHENYL)--ALANINES

V. Mickevicius, M. Mickevicius, and R. Vaickelioniene We have used the reaction of 4-aminodiphenyl ester with acrylic, methacrylic, crotonic, and itaconic acids to synthesize N-substituted -alanines, which undergo ring closure to form derivatives of dihydropyrimidinedione and 4-carboxy-2-pyrrolidinone. We have studied the reactions of acylation and recyclization of the dihydropyrimidinedione ring, and we have synthesized derivatives of 4-carboxy-1-(4phenoxyphenyl)-2-pyrrolidinone: arylidene hydrazides, 2[(2-oxo-4-pyrrolidinyl-1-(4-phenoxyphenyl)]benzimidazole. Keywords: arylidene hydrazides, dihydropyrimidinediones, N-substituted -alanines, 4-carboxy-2pyrrolidinones. Continuing studies in the area of synthesis and cyclization of N-substituted amino acids [1-4], we have developed a method for synthesis of N-(4-phenoxyphenyl)--alanines and we have studied their heterocyclization to form five-membered and six-membered heterocycles. We obtained N-(4-phenoxyphenyl)--alanine (2) and its - and -derivatives 3, 4 by addition of 4-aminodiphenyl ester (1) to ,-unsaturated acids (acrylic, methacrylic, crotonic) in 50% acetic acid. We did not isolate -alanine 2 separately in pure form, and for synthesis of the heterocyclic systems we used the reaction mixture of the amine 1 with acrylic acid, since in this reaction a mixture is formed of two compounds that are complicated to separate: N-(4-phenoxyphenyl)--alanine (2) and N-carboxyethyl-N-(4-phenoxyphenyl)-alanine. When the synthesized N-(4-phenoxyphenyl)--alanines 2-4 are boiled with urea in glacial acetic acid, the corresponding N-carbamoyl-N-(4-phenoxyphenyl)--alanines 6, 11, 15 are formed, which without isolation were treated with conc. HCl to undergo ring closure to form 2,4-(1H,3H)-dihydropyrimidinediones 8, 13, 17. When potassium thiocyanate is used instead of urea, the corresponding 4-(1H,3H)-dihydropyrimidinone-2thiones 9, 14, 18 are formed. The dihydropyrimidinedione ring is rather unstable in alkaline medium. Thus compounds 8, 9 are readily cleaved to form N-carbamoyl(or thiocarbamoyl)-N-(4-phenoxyphenyl)--alanines 6, 7 in 10% NaOH solution. In the 1H NMR spectra of dihydropyrimidinedione 8 and its 2-thio analog 9, in addition to signals from the proton of the NH group and the aromatic protons, upfield we observe signals from the 5-CH2 and 6-CH2 protons as characteristic triplets. The protons of the CH and CH2 groups of the heterocyclic moiety of the molecules for the 5- and 6-methyldihydropyrimidinediones 13, 17 and their 2-thio analogs 14, 18 form a typical AMX system, where the signals from protons of the CH2 group appear as two doublets.
__________________________________________________________________________________________ Kaunas University of Technology, Kaunas LT-3028, Lithuania; e-mail: Vytautas.Mickevicius@ctf.ktu.lt. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 911-917, June, 2004. Original article submitted June 18, 2002. 0009-3122/04/4006-07812004 Plenum Publishing Corporation 781
X O R N H [2] OH HO [6], [7] a R N O O N 1. (NH2)2CO; 2. KSCN R N NH2 R HCl 10% NaOH N
X NH 8, 9 PhCOCl O Ph O 10 X X N NH O Me 13, 14 O
O NH2 1 c b R N H Me 3 OH
1. (NH2)2CO; R N 2. KSCN
R NH2 Me HCl
HO O [11], [12] X 1. (NH2)2CO; 2. KSCN OH R Me HO O [15], [16] N NH2 HCl R Me
Me d R N H
X N NH O 17, 18
. HCl
4 O
N H HO [5] O
OH O R N O 19 NH2 NH2 O O R N N H 22, 23 O O c OH Me C H O d OH HO CH2 O OH N R

1
MeOH, H+
O R N
NH2NH2 . H2O O 20 O Me
O R N O 21 HN NH2 ArCHO
HO
O R N
170220 N 24 N H
oC
a H2C
O OH
Me b H2C
R = 4-PhOC6H4; 22 R1 = H; 23 R1 = OMe; 6, 8, 11, 13, 15, 17 X = O, 7, 9, 12, 14, 16, 18 X = S
782
TABLE 1. Characteristics and Elemental Analysis Data for the Synthesized Compounds
Compound 1 3 4 6 7 8 9 10 Empirical formula 2 C16H17NO3 C16H17NO3 HCl C16H16N2O4 C16H16N2O3S C16H14N2O3 C16H14N2O2S C23H18N2O4 C 3 71.01 70.83 62.71 62.35 64.15 63.99 61.06 60.74 68.31 68.08 64.21 64.41 71.88 71.49 Found, % Calculated, % H 4 5.97 6.32 5.36 5.52 4.98 5.37 4.85 5.10 5.39 5.00 4.93 4.73 5.01 4.70 mp, (solvent) 6 100.5-102 (ethanol) 195.5-197.5 (acetic acid) 152.5-154.5 (ethanol) 136.5-138.5 (ethanol) 189-191 (ethanol) 190-192 (ethanol) 172.5-174 (ethanol)
1
NMR spectrum, , ppm (J, Hz)* 7
Yield, % 8 54 48 85 91 44 55 90
N 5 5.03 5.16 4.38 4.55 9.12 9.33 8.68 8.85 9.77 9.92 9.55 9.39 7.11 7.25
1.15 (3H, d, J = 8.2, 3); 2.4-2.8 (1, m, ); 2.9-3.5 (2, m, 2); 6.5-7.5 (9, m, arom. ) 1.33 (3H, d, J = 8.3, 3); 2.4-3.1 (2, m, 2); 3.6-4.1 (1, m, ); 6.9-7.8 (9, m, arom. ); 9.65 (2, br. s, N2+) 2.45 (2H, t, J = 7.0, 2); 3.75 (2, t, J = 7.0, N2); 5.62 (2, s, N2); 6.9-7.8 (9, m, arom. ); 11.812.6 (1, br. s, ) 2.55 (2H, t, J = 7.0, 2); 4.25 (2, t, J = 7.0, N2); 5.60 (1, s, N2); 6.9-7.6 (9, m, arom. ) 2.68 (2H, t, J = 6.9, 5-); 3.72 (2, t, J = 6.9, 6-); 6.8-7.6 (9, m, arom. ); 10.39 (1, s, N) 2.80 (2H, t, J = 7.0, 5-); 3.88 (2, t, J = 7.0, 6-); 6.9-7.7 (9, m, arom. ); 11.21 (1, s, N) 3.10 (2H, t, J = 7.0, 5-); 4.11 (2, t, J = 7.0, 6-); 6.9-8.2 (14, m, arom. )
783
784
TABLE 1 (continued)
1 13 2 C17H16N2O3 3 68.75 68.91 65.62 65.36 69.10 68.91 65.49 65.36 68.84 68.68 69.18 69.44 65.76 65.58 71.95 72.17 70.31 69.92 74.69 74.78 4 5.57 5.44 4.98 5.16 5.31 5.44 5.48 5.16 4.85 5.09 5.67 5.50 5.41 5.50 5.51 5.30 5.29 5.40 5.12 5.18 5 9.28 9.45 8.76 8.97 9.22 9.45 8.76 8.97 4.59 4.71 4.38 4.50 13.66 13.50 10.34 10.52 9.91 9.78 11.31 11.37 6 201.5-203 (ethanol) 158.5-160.5 (ethanol) 169.5-171.5 (ethanol) 156-157.5 (ethanol) 181-183 (ethanol) 76.5-77.5 (ethanol) 169-171 (dioxane) 126.5-128 (dioxane) 180-182 (dioxane) 171-173 (toluene) 7 1.12 (3H, d, J = 8.2, 3); 2.7-3.1 (1, m, X-portion of M, 5-); 3.5-3.9 (2, m, AM-portion of M, 6-); 6.9-7.6 (9, m, arom. ); 10.31 (1, s, N) 1.12 (3H, d, J = 8.2, 3); 2.8-3.2 (1, m, X-portion of M, 5-); 3.5-4.1 (2, m, AM-portion of M, 6-); 6.9-7.6 (9, m, arom. ); 11.22 (1, s, N) 1.14 (3H, d, J = 8.3, 3); 2.3-3.3 (2, m, AM-portion of M, 5-); 3.9-4.2 (1, m, X-portion of M, 6-); 6.8-7.6 (9, m, arom. ); 10.38 (1, s, N) 1.21 (3H, d, J = 8.0, 3); 2.3-3.5 (2, m, AM-portion of M, 5-); 3.9-4.3 (1, m, X-portion of M, 6-); 6.9-7.6 (9, m, arom. ); 11.28 (1, s, N) 2.6-3.0 (2, m, 3-); 3.2-3.5 (1, m, ); 3.9-4.2 (2, m, 5-); 6.9-7.8 (9, m, arom. ) 2.6-2.9 (2, m, 3-); 3.2-3.6 (1, m, ); 3.72 (3, s, 3); 3.8-4.2 (2, m, 5-); 6.9-7.8 (9, m, arom. ) 2.6-2.8 (2, m, 3-); 2.9-3.4 (1, m, ); 3.6-4.1 (2, m, 5-); 4.33 (2, br. s, N2); 6.8-7.9 (9, m, arom. ); 9.26 (1, s, N) Mixture of Z/E-isomers (60/40); 2.6-3.0 (2, m, 3-); 3.2-3.5 (1, m, ); 3.8-4.3 (2, m, 5-); 6.9-8.4 (14, m, arom. ); 11.50 and 11.59 (1, 2s, N) Mixture of Z/E-isomers (60/40); 2.6-3.0 (2, m, 3-); 3.1-3.5 (1, m, ); 3.83 (3, s, 3); 3.9-4.3 (2, m, 5-); 6.8-8.3 (14, m, arom. ); 11.45 and 11.59 (1, 2s, N) 2.8-3.2 (2, m, 3-); 3.8-4.1 (1, m, 4-); 4.1-4.4 (2, m, 5-); 6.8-8.3 (13, m, arom. ); 12.93 (1, s, N) 8 53
14
C17H16N2O2S
67
17
C17H16N2O3
55
18
C17H16N2O2S
56
19 20 21 22
C17H15NO4 C18H17NO4 C17H17N3O3 C24H21N3O3
79 74 91 84
23
C25H23N3O4
87
24
C23H19N3O2
44
_______ * 1H NMR spectra were obtained in DMSO-d6 solutions.
1-Substituted dihydropyrimidinediones are not acylated by acid anhydrides, but are readily acylated by acid chlorides. When 1-(4-phenoxyphenyl)-2,4-(1H,3H)-dihydropyrimidinedione (8) is heated with benzoyl chloride in pyridine, the corresponding 3-benzoyl derivative 10 is isolated and in its 1H NMR spectrum we do not see any signal from an amide proton. In the 1H NMR spectrum of the starting compound 8, the amide proton gives a signal at 10.39 ppm. In studying the reaction of 4-aminodiphenyl ester (1) with itaconic acid, as in [3, 5, 6], we could not isolate the addition product 3-carboxy-N-(4-phenoxyphenylamino)butanoic acid (5), since the addition product 5 already formed during the reaction undergoes ring closure to form the derivative of 4-carboxy-2-pyrrolidinone 19. We studied some chemical conversions of 4-carboxy-1-(4-phenoxyphenyl)-2-pyrrolidinone (19). By treatment with methanol in the presence of sulfuric acid, we obtained the corresponding methyl ester 20, which then was converted to hydrazide 21 by hydrazinolysis. The carboxylic acid hydrazide 21 is readily condensed with aromatic aldehydes, forming arylidene hydrazides 22, 23. We obtained the benzimidazole derivative 24 by fusion of compound 19 with o-phenylenediamine at 170-220C. From the 1H NMR spectra, we see that the arylidene hydrazides 22, 23 in DMSO-d6 solution exist in the form of two isomers, and give two sets of signals of different intensities. The ratio of Z/E-isomers is calculated based on splitting of the signal from the proton of the amide group and is approximately 60/40 for both compounds.
EXPERIMENTAL The 1H NMR spectra were obtained on a Joel FX 100 (100 MHz) spectrometer, internal standard HMDS. The course of the reactions and the purity of the compounds obtained were monitored by TLC on Silufol UV-254 plates, visualization was carried out in UV light or with iodine vapors. N-(4-Benzoxyphenyl)--methyl--alanine (3). 4-Aminodiphenyl ester (1) (37.0 g, 0.2 mol), methacrylic acid (25.8 g, 0.3 mol), hydroquinone (1 g), and 50% acetic acid (70 ml) were heated for 15 h at 70C, then water (150 ml) was added and the precipitated mass was separated by decanting the solvent and washed three times with water. The residue was dissolved in a 10% NaOH solution (200 ml); the unreacted amine was filtered out and the filtrate was acidified with acetic acid down to pH 6. The precipitated oily mass was crystallized out on standing at 5C. The crystals of compound 3 were filtered out, washed with water, and crystallized from ethanol. N-(4-Benzoxyphenyl)--methyl--alanine Hydrochloride (4) was obtained from 4-aminodiphenyl ester (1) (37.0 g, 0.2 mol) and crotonic acid (25.8 g, 0.3 mol) by the procedure for synthesis of compound 3, except the reaction was carried out with boiling. The precipitated oily material, -alanine 4, was dissolved in ethyl ether (200 ml), the ether solution was dried by freezing at -20C and then filtered, and a stream of dry HCl was passed through the ether solution to the saturation point. The precipitated -alanine hydrochloride 4 was filtered out and washed with acetone and then ether. N-Carbamoyl-N-(4-phenoxyphenyl)--alanine (6). Dihydropyrimidinedione 8 (2.82 g, 0.01 mol) was heated in 10% NaOH (40 ml) to boiling. The mixture was allowed to stand for 30 min at 20C and filtered. The filtrate was acidified with 20% acetic acid to pH 6. The precipitated crystals of compound 6 were filtered out and washed with water. N-Thiocarbamoyl-N-(4-phenoxyphenyl)--alanine (7) was obtained from the corresponding dihydropyrimidinone-2-thione 9 (2.98 g, 0.01 mol), as for compound 6. 1-(4-Phenoxyphenyl)dihydro-2,4-(1H,3H)-pyrimidinedione (8). Compound 1 (37.5 g, 0.2 mol), acrylic acid (21.6 g, 0.3 mol), and 50% acetic acid (70 ml) were boiled for 5 h, then water (150 ml) was added and the precipitated mass was separated by decanting the solvent and then was washed three times with water. The residue was dissolved in a 10% NaOH solution (200 ml), the unreacted amine was filtered out, and the filtrate was acidified with acetic acid to pH 6. The precipitated oily mass was dissolved in glacial acetic acid 785
(100 ml), urea (24 g, 0.4 mol) was added, and the mixture was boiled for 14 h. Conc. HCl (50 ml) was carefully added to the boiling mixture and it was boiled for another 20 min, then water (150 ml) was added. The crystals that precipitated upon cooling were filtered out and washed with water. In order to remove N-substituted ureas, the crystals were dissolved with heating in a 10% sodium hydroxide solution (150 ml), cooled down, and filtered. The filtrate was heated to boiling, acetic acid (35 ml) was carefully poured in, and then conc. HCl was added to pH 0-1 and it was boiled for 10 min. The crystals of dihydropyrimidinedione 8 that precipitated upon cooling were filtered out and washed with water. 1-(4-(Phenoxyphenyl)dihydro-4-(1H,3H)-pyrimidinone-2-thione (9) was obtained as for compound 8, except that potassium thiocyanate (29.1 g, 0.3 mol) was used instead of urea. 3-Benzoyl-1-(4-phenoxyphenyl)dihydro-2,4-(1H,3H)-pyrimidinone (10). Dihydropyrimidinedione 8 (2.82 g, 0.01 mol), benzoyl chloride (2.08 g, 0.02 mol) in pyrimidine (10 ml) were boiled for 2 h, the mixture was diluted with water (1:10), the precipitated mass was removed, washed three times with water, and crystallized from ethanol. 5-Methyl(or 6-methyl)-1-(4-phenoxyphenyl)dihydro-2,4-(1H,3H)-pyrimidinediones (13, 17). The corresponding -alanine or its hydrochloride 3, 4 (0.05 mol), urea (6.0 g, 0.01 mol), and acetic acid (25 ml) were boiled for 14 h; conc. HCl (15 ml) was added, and it was boiled for another 15 min. Then the mixture was diluted with water (50 ml) and cooled down; the precipitated crystals of dihydropyrimidinediones 13, 17 were filtered out and washed with water. In order to remove the N-substituted ureas, the crystals were dissolved with heating in a 10% sodium hydroxide solution (30 ml), cooled down, and filtered. The filtrate was heated to boiling, acetic acid (15 ml) was carefully poured in, and then conc. HCl (15 ml) was added and it was boiled for 5-10 min. The crystals of dihydropyrimidinediones 13, 17 that precipitated upon cooling were filtered out and washed with water. 5-Methyl(or 6-methyl)-1-(4-phenoxyphenyl)-4-(1H,3H)-dihydropyrimidinedione-2-thiones (14, 18) were obtained from the corresponding -alanine or its hydrochloride 3, 4 (0.05 mol) and potassium thiocyanate (5.8 g, 0.06 mol), as for compounds 13, 17. 4-Carboxy-1-(4-phenoxyphenyl)-2-pyrrolidinone (19). Compound 1 (37.0 g, 0.2 mol) and itaconic acid (32.5 g, 0.25 mol) in 50% acetic acid (250 ml) were boiled for 5 h, the mixture was diluted with water (250 ml) and cooled down, the precipitated crystals were filtered out and washed with water. They were purified twice by dissolving the crystals obtained in 50% NaOH (250 ml), filtering out the unreacted amine, and acidifying the filtrate with 10% HCl to pH 1. 4-Methoxycarbonyl-1-(4-phenoxyphenyl)-2-pyrrolidinone (20). A mixture of 4-carboxy-2pyrrolidinone 19 (8.91 g, 0.03 mol), methanol (150 ml), and conc. H2SO4 (1 ml) was boiled for 8 h. The liquid fractions were distilled off under vacuum. A 5% Na2CO3 solution (150 ml) was added to the residue and the mixture was heated to boiling. The crystals of compound 20 that precipitated after cooling were filtered out, washed with water, and crystallized from ethanol. Hydrazide of 4-Carboxy-1-(4-phenoxyphenyl)-2-pyrrolidinone (21). The methyl ester 20 (6.22 g, 0.02 mol) in a mixture of hydrazine hydrate (4.0 g, 0.08 mol) and 2-propanol (50 ml) was boiled for 30 min. The crystals of hydrazide 21 that precipitated upon cooling were filtered out and washed with 2-propanol and then ether. Arylidene Hydrazides of 4-Carboxy-1-(4-phenoxyphenyl)-2-pyrrolidinone (22, 23). Hydrazide 21 (1.55 g, 0.005 mol) and the corresponding aldehyde (0.01 mol) were boiled for 2 h in 2-propanol (30 ml) and then cooled down. The precipitated crystals were filtered out and washed with 2-propanol and then ether. 2-{[2-Oxo-4-pyrrolidinyl-1-(4-phenoxyphenyl)]}benzimidazole (24). A mixture of 4-carboxy-2pyrrolidinone 19 (1.94 g, 0.05 mol) and o-phenylenediamine (0.76 g, 0.07 mol) was heated for 3 h at 170C. Then the temperature was raised to 210-220C, and heating was continued for another 30 min. A 5% NaOH solution (50 ml) was added to the remaining reaction mass; this was boiled for 5 min and allowed to stand at 20C for 30 min. The dark-brown crystals formed were filtered out, washed with water, dried, and crystallized from toluene. 786
REFERENCES 1. 2. 3. 4. 5. 6. V. Mickevicius, R. Baltrusis, I. Bilinskaite, E. Liepins, and R. Zolotoyabko, Khim. Geterotsikl. Soedin., 1096 (1990). V. Mickevicius, R. Baltrusis, I. Bilinskaite, E. Liepins, and R. Zolotoyabko, Khim. Geterotsikl. Soedin., 1240 (1991). V. Mickevicius and A. Patupaite, Khim. Geterotsikl. Soedin., 951 (2000). V. Mickevicius and Z. I. Beresnevicius, Khim. Geterotsikl. Soedin., 629 (1997). Z. I. Beresnevicius and V. Viliunas, Khim. Geterotsikl. Soedin., 932 (2000). P. L. Paytash, E. Sparrow, and J. C. Gathe, J. Am. Chem. Soc., 72, 1415 (1950).
787
SYNTHESIS AND REACTIONS OF (6-METHYL-2-METHYLSULFANYL-4-OXO3,4-DIHYDRO-3-PYRIMIDINYL)ACETYL AZIDE

V. Jakubkene, A. Stura, and P. Vainilavicius Nitrosation of (6-methyl-2-methylsulfanyl-4-oxo-3,4-dihydro-3-pyrimidinyl)acetic acid hydrazide using sodium nitrite in acid medium gave the corresponding azide. Reaction of the latter with alcohols or phenols gave carbamates and with amines gave carbamides. Keywords: acyl azides, hydrazides, carbamates, carbamides, pyrimidines. We have previously prepared the (6-methyl-2-methylsulfanyl-4-oxo-3,4-dihydro-3-pyrimidinyl)acetic acid hydrazide (1) [1] and studied its intramolecular cyclization [2] and reaction with C-electrophiles [3,4] in order to synthesize compounds which show cardiotonic [3] and anti-inflammatory [4] activity. However, this investigation has far from exhausted the synthetic potential of the given compound. Since the nitrosation of acylhydrazines using sodium or potassium nitrite in acid medium is one method for preparing acyl azides [5-10] (which are of interest as reactive intermediates in the synthesis of various compounds) we considered this method suitable for the synthesis of (6-methyl-2-methylsulfanyl-4-oxo-3,4-dihydro-3-pyrimidinyl)acetyl azide (2a) and the study of some of its reactions.
O N Me N 1 CH2CONHNH2 HNO2 SMe Me N 2a O ROH Me O N Me N CH2NHCOOR N SMe Me N A N CH2NCO RR'NH SMe R1 O CH2NHCON R SMe O N CH2CON3 O N Me N H CH2CON3 O 2b
3ad
N SMe 4ad 3 a R = Me, b R = Et, c R = Ph, d R = C6H4Cl-4, 4a R = Bu, R1 = H; b R = Bz, R1 = H; c R = R1 = Pr; d R + R1 = (CH2)4O
__________________________________________________________________________________________ Vilnius University, Vilnius LT-2006, Lithuania; e-mail: povilas.vainilavicius@chf.vu.lt. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 918-922, June, 2004. Original article submitted January 27, 2003. 788 0009-3122/04/4006-07882004 Plenum Publishing Corporation
Azide 2a was prepared by the nitrosation of the hydrazide 1 using sodium nitrite at 0-5C in 50% acetic acid (method A) or in dilute hydrochloric acid (method B). The use of hydrochloric acid in method B led to a small amount of the azide 2b in addition to the target compound 2a. In this case the greater strength of the hydrochloric compared with acetic acid can evidently cause fission of the CS bond, as noted by us before [1]. A Curtius rearrangement was carried out by refluxing the azide 2a in absolute benzene. However the isocyanate A could not be isolated in the pure state, apparently due to its tendency to polymerize. The Curtius rearrangement of the azide 2a was used to prepare the carbamate 3 and carbamide 4 derivatives of the isocyanate A. Refluxing the azide 2a with absolute methanol or ethanol gave the carbamates 3a,b and phenol and 4-chlorophenol in absolute benzene the carbamates 3c,d. The carbamides 4a-d were separated after refluxing the azide 2a for 4 h in absolute benzene and the addition of the corresponding amine to the solution of the isocyanate A formed in situ. It should be noted that, in reverse order to their nucleophilicity, butyl- and benzylamine form the carbamides 4a,b straight after addition of the amine but dipropylamine and morpholine form the carbamides 4c,d after refluxing the reaction mixture for 2 h. The IR spectrum of azide 2b contains bands for the lactam C(4)=O group at 1634 cm-1 and C(2)=O at 1741 cm-1 which is typical of uracils [11, 12] and the IR spectra of compounds 2a, 3 and 4 show a band for the lactam C(4)=O group at 1625-1678 cm-1 which is characteristic of N(3)-substituted 2-alkylthiopyrimidin-4-ones [13, 14]. In the IR spectra of the azides 2a,b the absorption band of the azide group is found at 2150-2154 cm-1 and the acetyl C=O group in the region of 1716 cm-1. For the carbamates 3 and carbamides 4, the IR absorption bands of the C=O groups are in the region 1720-1747 and 1685-1695 cm-1 and for the NH groups at 3205-3299 and 33233364 cm-1 respectively. The 1H NMR spectra of the carbamates 3 and carbamides 4 show, along with the signals for the remaining protons, the presence of doublets for the protons of the NCH2 groups at 5.38-5.51 ppm and multiplets for the NH group protons at 5.80-6.83 ppm. A study of the anti-inflammatory activity by E. Udrenaite (Medical Faculty, Vilnius University) has shown that the carbamides 4 suppress the anti-inflammatory process to a similar degree as acetylsalicylic acid.
TABLE 1. Characteristics for the Synthesized Compound 3, 4

Compound 3a 3b 3c 3d 4a 4b 4c 4d Empirical formula C9H13N3O3S C10H15N3O3S C14H15N3O3S C14H14ClN3O3S C12H20N4O2S C15H18N4O2S C14H24N4O2S C12H18N4O3S Found, % Calculated, % H 5.26 5.35 5.97 6.26 4.67 4.95 3.86 4.15 6.74 7.09 5.52 5.70 7.75 7.74 6.28 6.08 Yield, % 69 55 84 84 52 49 76 44
mp, N 17.25 17.27 17.57 17.41 13.87 13.76 12.51 12.36 19.78 19.73 17.61 17.60 17.99 17.93 18.86 18.78 124-126 96-97 132-134 141-142 154-157 161-163 97-98 190-192
C 44.62 44.43 50.01 49.72 55.35 55.07 49.74 49.49 50.86 50.68 56.77 56.59 54.12 53.82 48.10 48.31
789
TABLE 2. IR and 1H NMR Spectroscopic Data for Compounds 3, 4

Compound 3 IR spectrum, , cm-1 3284 (NH); 1733 (C=O); 1678 (C(4)=O) 3299 (NH); 1720 (C=O); 1649 (C(4)=O) 3205 (NH); 1745 (C=O); 1657 (C(4)=O) 3267 (NH); 1747 (C=O); 1674 (C(4)=O) 3329 (NH); 1695 (C=O); 1627 (C(4)=O) 3323 (NH); 1695 (C=O); 1625 (C(4)=O) 3364 (NH); 1687 (C=O); 1638 (C(4)=O) 1685 (C=O); 1645 (C(4)=O)
1
NMR spectrum(CDCl3), , ppm (J, Hz)
3b
3c
2.23 (3H, s, CH3); 2.58 (3H, s, SCH3); 3.71 (3H, s, OCH3); 5.40 (2H, d, J = 7, NCH2); 6.03 (1H, s, CH); 5.94-6.28 (1H, m, NH)* 1.24 (3H, t, J = 7, CH3); 2.23 (3H, s, CH3); 2.58 (3H, s, SCH3); 4.15 (2H, q, J = 7, OCH2); 5.38 (2H, d, J = 8, NCH2); 6.05 (1H, s, CH); 5.92-6.23 (1H, m, NH)* 2.25 (3H, s, CH3); 2.57 (3H, s, SCH3); 5.51 (2H, d, J = 8, NCH2); 6.08 (1H, s, CH); 6.29-6.77 (1H, m, NH); 7.00-7.46 (5H, m, arom) 2.25 (3H, s, CH3); 2.57 (3H, s, SCH3); 5.49 (2H, d, J = 8, NCH2); 6.07 (1H, s, CH); 6.44-6.77 (1H, m, NH); 7.08 (2H, d, J = 10, arom); 7.31 (2H, d, J = 10, arom) 0.77-1.06 (3H, m, CH3); 1.15-1.67 (4, m, CH2); 2.22 (3H, s, CH3); 2.57 (3H, s, SCH3); 3.17 (2, q, J = 7, NCH2); 5.4 (2H, d, J = 8, NCH2); 6.02 (1H, s, CH); 6.12-6.49 (2H, m, NH) 2.14 (3H, s, CH3); 2.56 (3H, s, SCH3); 4.38 (2H, d, J = 7, NCH2); 5.43 (2H, d, J = 8, NCH2); 5.65 (1H, s, CH); 6.46-6.83 (2H, m, NH); 7.12-7.42 (5H, m, arom) 0.86 (6H, t, J = 8, CH3); 1.50 (4, q, J = 8, CH2); 2.21 (3H, s, CH3); 2.54 (3H, s, SCH3); 3.13 (4, q, J = 8, NCH2); 5.45 (2H, d, J = 8, NCH2); 6.01 (1H, s, CH); 5.80-6.17 (2H, m, NH)* 2.23 (3H, s, CH3); 2.58 (3H, s, SCH3); 3.18-3.47 (4, m, N(CH2)2); 3.53-3.78 (4, m, (CH2)2); 5.49 (2H, d, J = 8, NCH2); 6.02 (1H, s, CH); 5.92-6.38 (1H, m, NH)*
3d
4a
4b
4c
4d
_______ * Signal obscured by the singlet for the CH group proton.
EXPERIMENTAL Monitoring of the course of the reaction and the purity of the compounds was carried out on Silufol UV-254 plates. 1H NMR spectra were recorded on a Tesla BS-587A instrument (80 MHz) using CDCl3 solvent and TMS internal standard. IR spectra were taken on a Perkin-Elmer Bx FT-IR spectrometer in vaseline oil. Basic characteristics for the compounds 3, 4 are given in Tables 1 and 2. The synthesis of compound 1 has been reported in [1]. (6-Methyl-2-methylsulfanyl-4-oxo-3,4-dihydro-3-pyrimidinyl)- and (6-Methyl-2,4-dioxo-1,2,3,4tetrahydro-3-pyrimidinyl)acetyl Azides (2a,b). A. A solution of the hydrazide 1 (1.14 g, 5 mmol) in 50% CH3COOH (40 ml) was cooled to 0-5C and a solution of NaNO2 (0.4 g, 5.8 mmol) in water (1 ml) was added dropwise with vigorous stirring at such a rate that the reaction temperature did not exceed 5C. The reaction mixture was stirred at the same temperature for 1.5 h, the precipitate was filtered off, and the filtrate was extracted with ether. The extract was washed with water, dried over Na2SO4, and the solvent was evaporated to give compound 2a (0.64 g, 53.6%); mp 83-84C (hexane). IR spectrum (KBr), , cm-1: 1690 (C(4)=O), 1716 (C=O), 2154 (N3). 1H NMR spectrum (CDCl3), , ppm: 2.25 (3H, s, CH3); 2.58 (3H, s, SCH3); 4.82 (2H, s, NCH2); 6.09 (1H, s, CH). Found, %: C 40.43; H 3.64; N 29.12. C8H9N5O2S. Calculated, %: C 40.16; H 3.79; N 29.27. B. Concentrated HCl (4 ml) was added to a suspension of the hydrazide 1 (1.14 g, 5 mmol) in water (15 ml) and a solution of NaNO2 (1.04 g, 15 mmol) in water (1.3 ml) was added with vigorous stirring and at such a rate that the temperature of the reaction mixture did not exceed 5C. The product was stirred at the same 790
temperature for 15 min and the precipitate formed was filtered off, washed with water, and dried in a vacuum desiccator over Na2SO4 to give compound 2a (0.72 g, 60%). The filtrate was allowed to stand for 2 h at 5C and the precipitate formed was filtered off, washed with water, and dried in a vacuum desiccator over Na2SO4 to give compound 2b (0.05 g, 5%); mp 135-137C. IR spectrum, , cm-1: 1634 (C(4)=O), 1716 (C=O), 1741 (C(2)=O), 2150 (N3). 1H NMR spectrum (CDCl3), , ppm: 2.18 (3H, s, CH3); 4.65 (2H, s, NCH2); 5.64 (1H, s, CH); 10.17 (1H, s, NH). Found, %: C 40.53; H 3.57; N 33.62. C7H7N5O3. Calculated, %: C 40.19; H 3.37; N 33.48. Methyl and Ethyl (6-Methyl-2-methylsulfanyl-4-oxo-3,4-dihydro-3-pyrimidinyl)methylcarbamates (3a,b). A solution of the azide 2a (1.2 g, 5 mmol) in absolute methanol (for 3a) of ethanol (for 3b) was refluxed for 7 h. Excess solvent was distilled off and the residue was recrystallized from water. Phenyl and 4-Chlorophenyl (6-Methyl-2-methylsulfanyl-4-oxo-3,4-dihydro-3-pyrimidinyl)methylcarbamates (3c,d). The corresponding phenol (5 mmol) was added to a solution of the azide 2a (1.2 g, 5 mmol) in absolute benzene (10 ml) and refluxed for 5 h. Solvent was evaporated, the residue was triturated with octane, and the precipitate was filtered off and recrystallized from a mixture of octane and 2-propanol (5:1) (compound 3c) or from octane (compound 3d). 3-Butylamino- and 3-Benzylamino-1-(6-methyl-2-methylsulfanyl-4-oxo-3,4-dihydro-3-pyrimidinyl)methylcarbamides (4a,b). A solution of the azide 2a (1.2 g, 5 mmol) in absolute benzene (20 ml) was refluxed for 4 h and the corresponding amine (5.2 mmol) was added. A precipitate was formed immediately which, after the reaction mixture had been cooled, was filtered off and recrystallized from benzene. 3-Dipropylamino- and 3-Morpholinoamino-1-(6-methyl-2-methylsulfanyl-4-oxo-3,4-dihydro-3pyrimidinyl)methylcarbamides (4c,d). A solution of the azide 2a (1.2 g, 5 mmol) in absolute benzene (20 ml) was refluxed for 4 h, the corresponding amine (5.2 mmol) was added, and refluxing was continued for a further 2 h. The solution was evaporated to half volume, cooled, and the precipitate formed was filtered off and recrystallized from hexane (compound 4c) or methanol (compound 4d).
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. P. Vainilavichius, V. Syadyaryavichiute, and S. Mocishkite, Khim. Geterotsikl. Soedin., 1655 (1992). V. Syadyaryavichiute and P. Vainilavichius, Khim. Geterotsikl. Soedin., 967 (1994). V. Sedereviciute, V. Garaliene, P. Vainilavicius, and A. Hetzheim, Pharmazie, 53, 233 (1998). V. Yakubkene and P. Vainilavichius, Khim. Geterotsikl. Soedin., 1125 (1998). C. G. Overberger, J.-P. Anselm, and J. G. Lombardino, Organic Compounds with Nitrogen-Nitrogen Bonds, Khimiya, Leningrad (1970), p. 118. N. N. Suvorov, V. S. Velezheva, A. V. Yarosh, Yu. V. Erofeev, and T. N. Kozik, Khim. Geterotsikl. Soedin., 1099 (1975). S. E. Poritere, R. A. Paegle, and M. Yu. Lidak, Khim. Geterotsikl. Soedin. 126 (1985). M. S. South, J. Heterocycl. Chem., 28, 1003 (1991). S. Ryng and T. Glowiak, Synth. Commun., 27, 1359 (1997). H. S. Kim, T. E. Kim, S. U. Lee, D. I. Kim, and S. W. Han, J. Heterocycl. Chem., 35, 1515 (1998). C. L. Angell, J. Chem. Soc., 504 (1961). E. Wittenburg, Chem. Ber., 99, 2380 (1966). P. I. Vainilavichyus and V. Yu. Syadyaryavichyute, Khim. Geterotsikl. Soedin., 1520 (1987). P. I. Vainilavichyus and V. Yu. Syadyaryavichyute, Khim. Geterotsikl. Soedin., 1655 (1987).
791
CYCLIZATION OF THE REACTION PRODUCTS OF p-PHENYLENEDIAMINE WITH MALEIC ACID

K. Rutkauskas and Z.-I. Beresnevicius Treatment of p-phenylenediamine with maleic acid and its diethyl ester gave di- and tetracarboxylic amino acids and their esters. A benzene derivative having an -alanine and an aspartic acid residue has been prepared. The cyclization of aminocarboxylic acids to imidazole and pyrimidine derivatives has been carried out. Keywords: acrylic acid, hydropyrimidinedione, carboxymethylimidazolidinedione, carboxymethylimidazolidinethione, maleic acid, p-phenylenediamine. N-Substituted amino acids are convenient compounds for the preparation of heterocyclic systems. The action of urea, cyanates, or thiocyanates on N-aryl--alanine gives substituted hydropyrimidinediones or their thio analogs [1] but N-arylaspartic acids give imidazolidinedione derivatives under these conditions [2]. In this work we have carried out the reaction of p-phenylenediamine with maleic acid and its ester and studied the cyclization reactions of the aminocarboxylic acids obtained with urea and potassium thiocyanate. Depending on reaction time, heating p-phenylenediamine with diethyl maleate gives the products of mono- or diaddition. The sole product obtained in modest yield (33%) after heating for 6 h was diethyl N-(4-aminophenyl)aspartate (2), but after 16 h the tetraethyl ester 3 could also be obtained via column chromatography along with compound 2. The 1H NMR spectra of compounds 2 and 3 show singlets at 1.07 and 2.7 ppm corresponding to the methyl and methylene fragments of the ester groups. The overlapping signals for the aliphatic CHCH2 part of the aspartic acids were observed at 3.9-4.3 ppm. Basic hydrolysis of the esters 2 and 3 and subsequent acidification of the hydrolysate with acetic acid gave the di- (4) and tetracarboxylic (5) acids. The N-(4-aminophenyl)aspartic acid (4) was also prepared by the reduction of N-(4-nitrophenyl)aspartic acid which was synthesized by treating p-nitroaniline with maleic acid and by a direct synthesis from p-phenylenediamine and maleic acid. The patent [3] reports that p-phenylenediamine forms the corresponding amide with maleic acid and undergoes hydrolysis to give the acid 4. When the amine 1 was heated with maleic acid in water for 6 h we were unable to observe formation of the amide but the acid 4 was separated from the reaction mixture upon cooling. N-[4-(2-Carboxyethylamino)phenyl]aspartic acid (6) was synthesized from the amino acid 4 by heating with acrylic acid in dilute acetic acid. The 1H NMR spectrum of the tricarboxylic acid 6, when compared with the spectrum of compound 4, shows additional signals for the methylene groups of the aliphatic part of
__________________________________________________________________________________________ Kaunas Technological University, Kaunas 3028, Lithuania; e-mail: zigmuntas.beresnevicius@ktu.lt. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 923-927, June, 2004. Original article submitted December 4, 2002; revision submitted April 14, 2003. 792 0009-3122/04/4006-07922004 Plenum Publishing Corporation
-alanine. Heating of the tricarboxylic acid 6 with urea in acetic acid and subsequent addition of HCl gives the 1,4-bis[2,4-(1H,3H))-dioxohexahydropyrimidin-1-yl]benzene (7), i.e. the -alanine and the aspartic acid residues form the same heterocyclic system. This is explained by the fact that N-substituted -alanine with urea in acid medium forms N-carbamoyl -alanine which is cyclized to the dihydropyrimidinedione. Under the same conditions, N-substituted aspartic acid forms a ureidosuccinic acid derivative [4] which cyclises to the corresponding 5-carboxymethylhydantoin derivative or an orotic acid derivative which undergoes decarboxylation in these conditions to give the dihydropyrimidinedione.
Scheme 1
O O O O N H 3
O O O N H O H2N 2 NH2
O O O N H O
HO O OH
NH2 OH O HO O N H 5 N H HO O OH O O HO 1
H2N 4
N H
HO O OH N H 6 N H O
Compound 7 was also obtained along with compound 10 from the aspartic acid dimer 5 by heating the latter with urea. The bisdihydrouracil derivative is difficultly soluble whereas the 1,4-bis(2,4-dioxo-5carboxymethylimidazolidin-1-yl)benzene (10) is soluble in water. Heating the tricarboxylic acid 6 with potassium thiocyanate in acetic acid and subsequent addition of hydrochloric acid gave compound 8 which has thiohydantoin and thiodihydrouracil residues in its structure. Under analogous conditions, the tetracarboxylic acid 5 and thiocyanate give the derivative 9 which has two carboxymethylthiohydantoin substituents (Scheme 2). The 1H NMR spectrum of compound 7 shows triplets at 2.7 and 3.6 ppm characteristic of dihydropyrimidinediones, corresponding to the two methylene groups. The spectra of the imidazole derivatives 9 and 10 show multiplets for the methylene groups at 3.1-3.6 and triplets for the methine groups near 5 ppm.
793
Scheme 2
S HN O O OH 9 HO N S N NH O O HN O O OH 8 S N S N H N O
H N 5 O
O N 7
O N
H N O 6
O HN O O OH 10 N
O N NH O O HO HN O O
O N
O N
H N O
OH
11
EXPERIMENTAL H NMR spectra were recorded on Bruker AW-80 (80 MHz) and JEOL FX-100 (100 MHz) instruments with HMDS as internal standard. Monitoring of the reaction course and the purity of the compounds obtained was carried out by TLC on Silufol 254 and Silufol UV-254 plates. Diethyl N-(4-Aminophenyl)aspartate (2) and Diethyl N-[4-(1,2-Bisethoxycarbonylethylamino)phenyl]aspartate (3). A mixture of amine 1 (10.8 g, 100 mmol), diethyl maleate (34.4 g, 200 mmol), and acetic acid (50 ml) was refluxed for 16 h. The liquid fractions were distilled in vacuo to give an oily mass (21.2 g). Passage of 1 g of this mass through a 100/250 grade silica gel column, eluting with acetone and hexane (1:1), gave fractions with Rf 0.64 and 0.47. The solvent was distilled off and the fraction with Rf 0.64 was crystallized from hexane to give the diethyl ester 2 (0.4 g, 30%); mp 47-48C. Found, %: C 59.62; H 7.20; N 9.83. C14H20N2O4. Calculated, %: C 60.01; H 7.14; N 10.00. The fraction with Rf 0.47 gave 0.4 g (20%) of the tetraethyl ester 3 as a viscous oil. 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 1.04 (6H, t, J = 7, 2CH3); 1.06 (6H, t, J = 7, 2CH3); 2.73 (4H, d, J = 4.2, 2CHCH2); 3.7-4.2 (10H, m, 2CH, 4CH2); 6.3 (4H, s, ArH). Found, %: C 58.51; H 7.32; N 6.39. C22H32N2O8. Calculated, %: C 58.40; H 7.07; N 6.19. N-(4-Aminophenyl)aspartic Acid (4). A. A mixture of p-phenylenediamine (10.8 g, 100 mmol), maleic acid (5.8 g, 50 mmol), and water (200 ml) was refluxed for 20 h, NaOH (45%, 50 ml) was added, and the heating was continued for a further 6 h. The cooled reaction mixture was neutralized with acetic acid to pH 6. The crystals formed were filtered off and washed with water, alcohol, and ether. Yield of 17.66 g (79%); mp 230231.5C.
1
794
B. A mixture of ester 2 (28.0 g, 100 mmol), water (100 ml), ethanol (20 ml), and NaOH (25 g, 625 mmol) was refluxed for 2 h. After cooling, the reaction mixture was treated with acetic acid to pH 6 and the precipitated compound was filtered, washed with water, alcohol, and ether to give a yield of 20.16 g (90%). C. N-(4-Nitrophenyl)aspartic acid (25.4 g, 100 mmol) was dissolved in 10% ammonia (180 ml) and Na2S2O4 was added to the disappearance of the yellow color in the solution. The reaction mixture was then filtered and the filtrate was diluted with water (200 ml) and neutralized with acetic acid to pH 6. The crystals formed were filtered off and washed with water, alcohol and ether to give a yield of 9.5 g (42%). D. A solution of the amine 1 (5.4 g, 50 mmol) and maleic acid (5.8 g, 50 mmol) in water (100 ml) was refluxed for 6 h. After cooling, the crystals formed were filtered off and washed with water, alcohol, and ether. Yield 10.0 g (89%). 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 2.55 (2H, d, J = 5, CH2); 3.9 (1H, t, J = 5, CH); 6.4 (4H, dd, J = 7.3; J = 2, ArH); 6.6-7.2 (2H, br. s, NH2). Found, %: C 53.18; H 5.62; N 12.44. C10H12N2O4. Calculated, %: C 53.57; H 5.36; N 12.28. A mixed sample of the substance 4 prepared by the methods A-D did not show a depression of melting point. N-[4-(1,2-Dicarboxyethyl)amino]phenylaspartic Acid (5). Compound 1 (5.04 g, 50 mmol) and maleic acid (11.6 g, 100 mmol) in water (100 ml) was refluxed for 6 h. The mixture was cooled and the precipitate was filtered off and washed with water and acetone. Yield 5.52 g (53%); mp 203-204C (ethanol). 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 2.54 (4H, d, J = 5, 2CH2); 3.9 (2H, t, J = 5, 2CH); 6.47 (4H, s, ArH); 6.6-7.38 (4H, br. s, 4OH). Found, %: C 49.81; H 4.98; N 8.38. C14H16N2O8. Calculated, %: C 49.41; H 4.70; N 8.23. N-[4-(2-Carboxyethyl)amino]phenylaspartic Acid (6). A mixture of the aspartic acid 4 (2.24 g, 10 mmol), acrylic acid (0.75 ml, 11 mmol), and 60% acetic acid (50 ml) was refluxed for 4 h. The liquid fractions were distilled in vacuo and the remaining viscous mass was treated with acetone, whereupon it crystallized. The crystals were filtered off, crystallized from a mixture of acetic acid and acetone (1:5), and washed with alcohol. Yield 2 g (67%); mp 97-98.5C. 1H NMR spectrum (CF3COOH), , ppm (J, Hz); 2.55 (2H, t, J = 6, COCH2); 2.87-3.25 (2H, m, CH2); 3.42-3.85 (2H, m, NCH2); 4.45-4.75 (1H, m, CH); 6.0-7.75 (4H, ArH). Found, %; C 52.48; H 5.08; N 9.45. C13H16N2O6. Calculated, %: C 52.70; H 5.40; N 9.46. 1,4-Bis[2,4-(1H,3H)-dioxohexahydropyrimidin-1-yl]benzene (7). A mixture of the tricarboxylic acid 6 (14.8 g, 50 mmol) and urea (12 g, 200 mmol) in acetic acid (100 ml) was refluxed for 8 h, HCl (30 ml) was added, and refluxing was continued for a further 2 h. The reaction mixture was cooled and the crystals were filtered off and washed with refluxing acetic acid and acetone. Yield 6.75 g (45%); mp 320C. According to the study [5] the mp is 320C. 1H NMR spectrum (CF3COOH), , ppm (J, Hz): 2.7 (4H, t, J = 5, COCH2); 3.67 (4H, t, J = 5, NCH2); 7.07 (4H, s, ArH). Found, %: C 55.36; H 4.82; N 18.58. C14H14N4O4. Calculated, %: C 55.63; H 4.63; N 18.54. 1-[4-(Hexahydro-4-oxo-2-thioxopyrimidin-1-yl)phenyl]-4-oxo-2-thioxo-5-imidazolidineacetic Acid (8). A mixture of the acid 6 (19.8 g, 50 mmol), acetic acid (70 ml), and potassium thiocyanate (20 g, 200 mmol) was refluxed for 10 h, conc. HCl (15 ml) was added, and the refluxing was continued for a further 2 h. The reaction mixture was cooled, diluted with water (200 ml), and the crystals formed were filtered off. Yield 12.5 g (66%); mp 210-211C (ethanol). 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 2.55 (2H, d, J = 4, CHCH2); 2.8 (2H, t, J = 5, COCH2); 3.93 (2H, t, J = 5, NCH2); 5.02 (1H, t, J = 4, CH); 7.47 (4H, s, ArH); 11.23 (1H, s, NH); 12.1-12.5 (1H, br. s, NH). Found, %: C 47.92; H 4.07; N 14.71. C15H14N4O4S2. Calculated, %: C 47.62; H 3.70; N 14.81. 1-[-4-(5-Carboxymethyl)-4-oxo-2-thioxoimidazolidin-1-yl]phenyl-4-oxo-2-thioxo-5-imidazolidineacetic Acid (9). A mixture of the acid 5 (6.8 g, 20 mmol), potassium thiocyanate (3.84 g, 60 mmol) and 70% acetic acid (70 ml) was refluxed for 8 h, hydrochloric acid (20 ml) was added, and heating was continued for a further 2 h. The reaction mixture was cooled, neutralized with sodium carbonate, and the crystals formed were filtered off and washed with water and acetone. Yield 5.1 g (60%); mp 221-222.5C (ethanolwater). 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 3.21 (4H, d, J = 5, 2CH2); 4.92 (2H, t, J = 5, 2CH); 6.91 (4H, s, ArH); 9.81 (2H, s, 2NH). Found, %: C 45.72; H 3.41; N 13.49. C16H14N4O6S2. Calculated, %: C 47.62; H 3.70; N 14.81. 795
1,4-Bis[2,4-(1H,3H)-dioxohexahydropyrimidin-1-yl]benzene (7) and 1,4-Bis(5-carboxymethyl-2,4dioxoimidazolidin-1-yl)benzene (10). A mixture of the acid 5, (3.4 g, 10 mmol), urea (5 g, 88 mmol), and acetic acid (50 ml) was refluxed for 16 h. HCl (15 ml) was added to the reaction mixture and refluxing was continued for a further 30 min. The mixture was cooled and poured into water (200 ml). The precipitated crystalline compound 7 was filtered off. Yield 1.55 g (45%); mp 320C. A mixed sample of compound 7 with that prepared from the tricarboxylic acid 6 did not give a depression of melting point. The filtrate obtained after the removal of compound 7 was evaporated in vacuo and the residue was refluxed in acetone, filtered, and the acetone evaporated to give the acid 10 (0.92 g, 27%); mp 254-255.5C (water). 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 2.67 (4H, d, J = 5, 2CH2); 4.21 (2H, d, J = 5, 2CH); 6.9 (4H, s, ArH); 11.3 (2H, s, NH). Found, %: C 50.04; H 3.71; N 14.53. C16H14N4O8. Calculated, %: C 49.23; H 3.59; N 14.36. 1-[4-(5-Carboxymethyl-2,4-dioxoimidazolidin-1-yl)phenyl]dihydropyrimidin-2,4-(1H,3H)-dione (11). A mixture of the tricarboxylic acid 6 (5.92 g, 20 mmol), sodium isocyanate (5.2 g, 80 mmol), and acetic acid (40 ml) was refluxed for 4 h. The reaction mixture was cooled and poured into acetone (200 ml). The precipitated NaCl was separated and the filtrate was evaporated to dryness in vacuo. The oily mass was treated with water (20 ml) and allowed to stand for 20 h at 6C. The crystals formed were filtered off. Yield 4.4 g (64%); mp 291-292.5C (ethanolwater). 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 2.51 (2H, d, J = 5, CHCH2); 2.82 (2H, t, J = 7, COCH2); 3.94 (2H, t, J = 7, NCH2); 5.13 (1H, t, J = 5, CH); 7.43 (1H, s, NH); 7.48 (4H, s, ArH); 11.5 (1H, br. s, NH). Found, %: C 55.62; H 4.42. C15H14N4O6. Calculated, %: C 52.02; H 4.05.
REFERENCES 1. 2. 3. 4. 5. R. S. Baltrushis, Z.-I. G. Beresnevichyus, I. M. Vizgaitis, and Yu. V. Gatilov, Khim. Geterotsikl. Soedin., 1267 (1983). R. S. Baltrushis, Z.-I. G. Beresnevichyus, I. M. Vizgaitis, and Yu. V. Gatilov, Khim. Geterotsikl. Soedin., 1669 (1981). W. Reppe and H. Uffer, US Patent 2200220; Chem. Abstr., 34, 5859 (1940). Z.-I. G. Beresnevicius, Doctorial Dissertation in Chemical Sciences, Kaunas (1989). G. A. Makhteeva, Dissertation of Candidates in Chemical Sciences, Kaunas (1977).
796
ADDITION OF NITRILE OXIDES TO ARYL ALLYL ETHERS

E. Alksnis, V. Muravenko, V. Dirnens, and E. Lukevics 3,5-Disubstituted isoxazolines with an aryloxymethyl group in position 5 have been synthesized. The [2+3] cycloaddition reaction of benzonitrile oxide to a 5-chlorosalicylic acid derivative containing two allyl groups occurs to give a compound with an oxazolinylmethyl fragment both in the ester and the ether parts of the molecule. The addition of nitrile oxides to the aryl allyl ethers occurs regiospecifically to give the 5-substituted isomer. Keywords: aryl allyl ethers, isoxazolines, nitrile oxides, hydroxamic acid chlorides. An isoxazoline heterocycle is a valuable synthon in organic chemistry for the preparation of -hydroxy ketones [1-7], -amino alcohols [8,9], ,-unsaturated oximes [10, 11], and -hydroxy nitriles [12, 13]. Amongst isoxazolines there are found compounds with such pharmacological properties as analgesic [14], antiinflammatory [15], antibacterial [16], and GPIIb/IIIa inhibiting [17, 18] activity. In biogenic amines an isoxazoline ring is an important part of the molecule for interaction with different receptors [19]. One of the basic methods for the synthesis of these heterocycles is the [2+3] cycloaddition of nitrile oxides, generated from hydroxamic acid chlorides in the presence of triethylamine, or of silylnitronates to alkenes [20-23]. 3-Acetyl(benzoyl)-5-phenoxymethylisoxazolines were prepared by the addition of nitrile oxides, generated from acetone and acetophenone in the presence of ammonium cerium(IV) sulfate, to phenyl allyl ether [24]. The 3-aryl-5-aryloxymethylisoxazolines 12-19 were synthesized by the addition of the arylnitrile oxides 9-11 to the substituted aryl allyl ethers 1-8. The "one-pot" reactions were carried out in the sequence: 1) reaction of an aryloxime with N-chlorosuccinimide in chloroform to give the corresponding arylhydroxamic acid chloride, 2) addition of the unsaturated compound, and 3) addition of triethylamine as dehydrohalogenating agent for generation of the nitrile oxide. The [2+3] cycloaddition occurs regiospecifically and always forms the single 5-substituted isoxazoline regioisomer. Addition of benzonitrile to compound 8 occurs at both allyl groups to give compound 19 which contains isoxazolinomethyl fragments in both the ester and the ether parts of the molecule (Scheme 1). The starting ethers 1-8 were prepared by the alkylation of substituted phenols by allyl bromide under phase-transfer catalysis conditions (PTC) [25]. In the case of 5-chlorosalicylic acid, compound 8 was obtained and this contained allyl groups in both the ester and in the ether fragments of the molecule.
__________________________________________________________________________________________ Latvian Institute of Organic Synthesis, Riga LV 1006; e-mail: dirnens@osi.lv. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 928-931, June, 2004. Original article submitted April 14, 2004. 0009-3122/04/4006-07972004 Plenum Publishing Corporation 797
Scheme 1
R2 C
911
N+ O
_ R1 O CH2 CH O N
1219
CH 2 R2
R1
O
18
CH2CH=CH2
Compound 12 13 14 15
R1 4,6-Br2C6H3 4-ClC6H4 2-Me-4-ClC6H3 2,4,5-Cl3C6H2

O CO CH2 CH O N CH 2 C6H5
R2 C6H5 4-BrC6H4 4-ClC6H4 C6H5
Compound 16 17 18 19
R1 2,4,6-Cl3C6H2 4-O2NC6H4 4-EtOOCC6H4 *
R2 4-BrC6H4 C6H5 4-ClC6H4 C6H5
_______ * Cl
EXPERIMENTAL H NMR spectra for compounds 13, 14, 16-19 were recorded on a Bruker WP-90 instrument (90 MHz) and for compound 12, 15 on a Varian Mercury-200BB (200 MHz) instrument using CDCl3 solvent and with TMS as internal standard. The general method for preparing the isoxazolines 12-19 is given in the study [26]. Characteristics for the compounds synthesized are given in Tables 1 and 2.
1
TABLE 1. Characteristics of the Isoxazoline Derivatives 12-19

Compound 12 13 14 15 16 17 18 19 Empirical formula C16H13Br2NO2 C16H13BrClNO2 C17H15Cl2NO2 C16H12Cl3NO2 C16H11BrCl3NO2 C16H14N2O4 C19H18ClNO4 C27H23ClN2O5 Molecular weight C 411.10 366.64 336.22 356.64 435.53 298.30 359.81 490.95 46.90 46.75 52.41 52.42 60.88 60.73 54.01 53.89 44.01 44.13 64.19 64.42 63.30 63.43 65.81 66.06 Found, % Calculated, % H 3.20 3.19 3.55 3.57 4.52 4.50 3.37 3.39 2.58 2.55 4.71 4.73 5.02 5.04 4.74 4.72
mp, C N 3.40 3.41 3.83 3.82 4.20 4.17 3.92 3.93 3.25 3.22 9.42 9.39 3.91 3.89 5.73 5.71 90 134 119 140 113 142 96 154
Yield, %
45 61 48 41 47 65 57 51
798
TABLE 2. 1H NMR Spectra of the Isoxazolines 12-19

Compound 12 Chemical shifts, , ppm (SSCC, J, Hz) 3.56 (1H, dd, J = 8.3, J = 17.1, CH); 3.60 (1H, dd, J = 9.3, J = 17.1, CH); 4.17 (1H, dd, J = 5.1, J = 10.0, CH); 4.21 (1H, dd, J = 4.4, J = 10.0, CH); 5.05-5.21 (1, m, ); 6.84 (1, d, J = 8.8, arom.); 7.37 (1H, dd, J = 2.4, J = 8.8, arom.); 7.42-7.47 (3, m, arom.); 7.68 (1, d, J = 2.4, arom.); 7.74-7.80 (2, m, arom.) 3.28 (1H, dd, J = 7.4, J = 15.2, CH); 3.49 (1H, dd, J = 9.2, J = 15.2, CH); 4.01(1H, dd, J = 5.6, J = 10.1, CH); 4.16 (1H, dd, J = 4.2, J = 10.1, CH); 4.94-5.25 (1, m, ); 6.81 (2, d, J = 8.6, arom.); 7.18 (2, d, J = 8.6, arom.); 7.52 (4, s, arom.) 2.03 (3H, s, CH3); 3.32 (1H, dd, J = 7.4, J = 16.6, CH); 3.52 (1H, dd, J = 9.2, J = 16.6, CH); 4.03 (2H, m, CH2); 4.96-5.27 (1, m, ); 6.69 (1, d, J = 8.8, arom.); 6.98-7.14 (2, m, arom.); 7.36 (2, d, J = 8.4, arom.); 7.61 (2, d, J = 8.4, arom.) 3.51 (1H, dd, J = 7.3, J = 17.0, CH); 3.61 (1H, dd, J = 10.2, J = 17.0, CH); 4.16 (1H, dd, J = 5.1, J = 9.9, CH); 4.22 (1H, dd, J = 4.2, J = 9.9, CH); 5.02-5.21 (1, m, ); 7.08 (1, s, arom.); 7.45-7.47 (4, m, arom.); 7.72-7.77 (2, m, arom.) 3.43 (1H, dd, J = 9.8, J = 16.3, CH); 3.58 (1H, dd, J = 10.3, J = 16.3, CH); 4.09 (1H, dd, J = 5.9, J = 9.9, CH); 4.21 (1H, dd, J = 4.8, J = 9.9, CH); 4.55-5.29 (1, m, ); 7.25 (2, s, arom.); 7.52 (4, s, arom.) 3.32 (1H, dd, J = 7.2, J = 14.2, CH); 3.58 (1H, dd, J = 9.6, J = 14.2, CH); 4.14 (1H, dd, J = 5.2, J = 8.4, CH); 4.25 (1H, dd, J = 4.2, J = 8.4, CH); 4.98-5.29 (1, m, ); 6.94 (2, d, J = 9.2, arom.); 7.32-7.45 (3, m, arom.); 7.54-7.69 (2, m, arom.); 8.14 (2, d, J = 9.2, arom.) 1.34 (3H, t, J = 7.0, CH3); 3.29 (1H, dd, J = 7.6, J = 15.4, CH); 3.49 (1H, dd, J = 9.4, J = 15.4, CH); 4.07 (1H, dd, J = 5.8, J = 9.2, CH); 4.21 (1H, dd, J = 4.4, J = 9.2, CH); 4.32 (2H, q, J = 7.0, CH2); 4.96-5.27 (1, m, ); 6.85 (2, d, J = 8.0, arom.); 7.34 (2, d, J = 8.4, arom.); 7.58 (2, d, J = 8.4, arom.); 7.94 (2, d, J = 8.0, arom.) 3.12 (1H, dd, J = 7.2, J = 16.3, CH); 3.18 (1H, dd, J = 8.2, J = 16.8, CH); 3.43 (1H, dd, J = 10.3, J =16.3, CH); 3.49 (1H, dd, J = 13.5, J = 16.8, CH); 4.12-4.16 (2, m, 2); 4.29-4.36 (2, m, C2); 4.81-5.29 (2, m, 2C); 6.94 (1, d, J = 8.6, arom.); 7.32-7.40 (6, m, arom.); 7.58-7.72 (6, m, arom.)
13
14
15
16
17
18
19
REFERENCE 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. A. P. Kozikowski and P. D. Stein, J. Amer. Chem. Soc., 104, 4023 (1982). D. P. Curran, J. Amer. Chem. Soc., 105, 5826 (1983). B. H. Kim, Y. J. Chung, and E. J. Ryu, Tetrahedron Lett., 34, 8465 (1993). S. H. Andersen, K. K. Sharma, and K. B. G. Torssell, Tetrahedron, 39, 2241 (1983). P. G. Baraldi, A. Barco, S. Benetti, S. Manfredini, and D. Simoni, Synthesis, 276 (1987). J. W. Bode and E. M. Carreira, Org. Lett., 3, 1587 (2001). A. P. Kozikowski and M. Adamczyk, Tetrahedron Lett., 23, 3123 (1982). A. P. Kozikowski and Y. Y. Chen, J. Org. Chem., 46, 5248 (1981). J. Mller and V. Jger, Tetrahedron Lett., 23, 4777 (1982). V. Jger and H. Grund, Angew. Chem. Int. Ed. Engl., 15, 50 (1976). S. Y. Lee, B. S. Lee, C. W. Lee, and D. Y. Oh, J. Org. Chem., 65, 256 (2000). G. W. Moersch, E. L. Wittle, and W. A. Neuklis, J. Org. Chem., 32, 1387 (1967). A. Yashiro, Y. Nishida, K. Kobayashi, and M. Ohno, Synlett, 361 (2000). A. Mishra, S. K. Jain, and J. G. Asthana, Orient. J. Chem., 14, 151 (1998). D. H. Ko, M. F. Maponja, M. A. Khalil, E. T. Oriaku, Z. You, and J. Lee, J. Med. Chem. Res., 8, 313 (1998).
799
16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26.
Y. Y. Kang, K. J. Shin, K. H. Yoo, K. J. Seo, C. Y. Hong, C. S. Lee, S. Y. Park, D. J. Kim, and S. W. Park, Bioorg. Med. Chem. Lett., 10, 95 (2000). L. H. Zhang, J. C. Chung, T. D. Kostello, J. Valvis, P. Ma, S. Kauffman, and R. Ward, J. Org. Chem., 62, 2466 (1997). P. N. Confalone, F. Jin, and S. A. Mousa, Bioorg. Med. Chem. Lett., 9, 55 (1999). A. A. Patchett and R. P. Nargund, Ann. Rep. Med. Chem., 35, 289 (2000). R. Huisgen, Angew. Chem., 75, 604 (1963). G. Grundmann, Synthesis, 344 (1970). K. Torssell and O. Zenthen, Acta Chem. Scand., B32, 118 (1978). S. C. Sharma and K. Torssell, Acta Chem. Scand., B33, 379 (1979). Ken-ichi Itoh and C. Akira Horiuchi, Tetrahedron, 60, 1671 (2004). A. McKillop, J. C. Fiaud, and R. P. Hug, Tetrahedron, 30, 1379 (1974). V. Dirnens, O. Slyadevskaya, and E. Lukevics, Khim. Geterotsikl. Soedin., 499 (2002).
800
REACTION OF N-PHENYLBENZAMIDINE WITH O-ACETYLBENZENEOXIMOYL CHLORIDE

W. Szczepankiewicz1, J. Suwinski1, and Z. Karczmarzyk2 The reaction of N-phenylbenzamidine with O-acetylbenzeneoximoyl chloride in methanol solution gave unexpectedly 5-methoxy-3,4,5-triphenyl-4,5-dihydro-1,2,4-oxadiazole, which structure was confirmed by X-ray analysis. The last step of this reaction was simulated by the PM3 semiempirical method. Keywords: amidines, nitrile N-oxides, oxadiazoles, oximoyl chlorides, X-ray analysis, semiempirical calculations, synthesis. 4-Arylaminoquinazolines are intensively investigated because of their potent antitumor properities [1, 2]. Recently, we have shown that these compounds can be obtained from 2-amino-N-arylbenzamidines and formic acid or aldehydes by formation of 2,3 and 3,4 bonds of the quinazoline system [3, 4]. Basing on results of semiempirical calculations and experimental data concerning the formation of similar systems, we believe that 4-arylaminoquinazolines can also be synthesized (Scheme 1) from 4-arylamino-1-hydroxy(or acyloxy)-1,3diaza-1,3-butadienes 5. The synthesis should occur as a tandem pericyclic process [5] including the formation of the 1,8a quinazoline bond by thermal disrotatory electrocyclization of the starting material. We tried to obtain the latter compound from N-arylbenzamidines 1 and oximoyl chlorides 2. However, this reaction afforded N-substituted amidoxime benzoates 4 instead of the expected 5 (Scheme 1, Path A, Y = H) [6]. The first step of the reaction is the formation of nitrile N-oxides from an oximoyl chloride in the presence of the basic Scheme 1
O N N Ar Cl NH2 1 Path A H2N N Ar Ar '
H2O, H +
Ar ' O ArNH N O 4
+
Ar' 2
NOY Path B NAr
NHAr N N OY Ar ' HOY 6
NHAr N N Ar '
NH N 5 OY Ar '
__________________________________________________________________________________________ Institute of Organic Chemistry and Technology, Silesian University of Technology, 44-100 Gliwice, Poland; e-mail: wojtex@polsl.gliwice.pl. 2 Department of Chemistry, University of Podlasie, 08-110 Siedlce, Poland. Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 932-938, June, 2004. Original article submitted August 9, 2002. 0009-3122/04/4006-08012004 Plenum Publishing Corporation 801
1
N-arylbenzamidines. Nitrile oxide reacts then with an unconverted amidine to form 5-amino-4,5-dihydro-1,2,4oxadiazole 3 by the 1,3-dipolar cycloaddition reaction. During acidic work-up of the reaction mixture the compound 3 transforms to 4. In this work we attempted to perform nucleophilic substitution of the chlorine atom in O-acetylbenzeneoximoyl chloride by the amino nitrogen atom of an amidine (Scheme 1, Path B, Y = Ac) assuming that O-acetylation of the oxime group would prevent formation of nitrile N-oxide. Indeed, we found that the reaction of N-phenylbenzamidine with O-acetylbenzeneoximoyl chloride in methanol solution, in the presence of Et3N, affords a crystalline precipitate straight from the reaction mixture. 1H NMR spectrum of the precipitate showed the expected signals of aromatic protons and a singlet of the methyl group. Unexpectedly, the latter signal should be referred to protons of methoxy rather than of the acetyl group. X-Ray analysis confirmed this unexpected result, proving that the main reaction product was 5-methoxy-3,4,5triphenyl-4,5-dihydro-1,2,4-oxadiazole (7) (Scheme 2, Fig. 1). Scheme 2
NH2 PhC=NPh Cl Et3N MeOH MeO Ph Ph 7 N Ph O N
Ph
NOCOMe
Oxadiazole 7 probably arises from a preliminary attack of the amidine on the acetyl carbon atom in O-acetylbenzeneoximoyl chloride to produce N-acetylamidine and a free oximoyl chloride. The oximoyl chloride transforms to nitrile N-oxide which undergoes 1,3-dipolar cycloaddition to yet unconverted N-phenylbenzamidine giving 5-amino-3,4,5-triphenyl-4,5-dihydro-1,2,4-oxadiazole (3). Finally, 3 reacts with methanol used as a solvent to yield oxadiazole 7 (Scheme 3).
Fig. 1. Crystal structure of 7 showing 50% probability displacement ellipsoids. Selected bond lengths () and angles (): C1N2 1.366(2), C3N2 1.464(2), C3O4 1.425(2), N5O4 1.435(2), C1N5 1.287(2), C3O6 1.399(2), C31C3O6 106.91(12), N2C3O4 100.76(11), C1N2C3 107.90(11), C21N2C1C11 22.8(2), N5C1C11C12 135.9(2). 802
Scheme 3
NH2 PhC=NPh NH Cl Cl PhCNPh COMe Cl Ph NOH NH2 Et3N + N _ O
Ph
NOCOMe
Ph
NOH
Ph
Ph
+ N
_ O
H2N Ph Ph N
O N Ph 3 MeOH NH3
MeO Ph Ph N
O N Ph 7
PhC=NPh
The use of chloroform instead of methanol in the reaction of N-phenylbenzamidine with O-acetylbenzeneoximoyl chloride led to formation of O-benzoylamidoxime (4, Ar = Ar' = Ph). This result confirms the formation of nitrile N-oxide, followed by its cycloaddition to the amidine. An additional confirmation of this postulate was the reaction of O-acetylbenzeneoximoyl chloride with benzophenone imine which gave the well-known 3,5,5-triphenyl-4,5-dihydro-1,2,4-oxadiazole (8) [7, 8]. The latter result supports the assumption that the first reaction stage is an attack of the imine nitrogen atom on the acetyl group with the formation of oximoyl chloride followed by its transformation in the presence of a base into nitrile N-oxide further reacting as the dipolar reagent with the C=N bond of the imine to form 8 (Scheme 4). Scheme 4
Ph Ph NH Cl Ph Ph NAc + N Cl
Ph
N OAc
+
_ O Ph
Ph
NOH
Cl Ph NOH
Et3N
Ph
O N N H 8 Ph
Ph
+ N
_ O
Ph
Ph NH
Ph
These results show that the amidine rather attacks the C=O carbon atom than the imidoyl one despite their formal similarity. It was interesting to estimate how polar is the CCl bond in O-acetylbenzeneoximoyl chloride. Treating its 1 molar solution in acetonitrile with equimolar amount of silver nitrate (the mixture obtained was left in the dark at room temperature for two weeks) produced only traces of silver chloride. In contrast to that, imidoyl chlorides produced silver chloride precipitate in nearly quantitative amount almost immediately, under similar conditions [9]. A comparison of these results might indicate that the CCl bond in the investigated O-acetylbenzeneoximoyl chloride is much more similar to the chlorovinylic bond than to the chloroacylic one.
803
We had doubts about a pathway of substitution of the amino group by methanol in the transformation of 3 to 7. Results of quantum-chemical semiempirical calculations [10], accomplished by PM3 [11] and a modified [12] COSMO procedure [13], show that the protonation of substrate 3 plays the main role in this transformation. It was necessary to make the assumption that methanol is a donor of protons. Oxadiazoles are not too strong bases but even a slight concentration of the protonated form should initiate the reaction, especially taking into account that the basicity of oxygen and nitrogen organic bases increases in methanol solution [14]. Initially, we have simulated SN1 and SN2 mechanisms of substitution of the protonated amino group by the methoxide anion, but the path with the less energy profile is initiated by the protonation of the cyclic oxygen atom in SS to form oxonium ion SS1 (Scheme 5). This cation is unstable and decomposes spontaneously to acyclic amidineamidoxime SSI1, which is attacked by the methoxide anion and transforms via the transition state TSSNC to the aminoamidoxime TIN. Transprotonation of TIN gives the betaine TINI. The structure TINI would transform directly by an intramolecular cyclization of the SN2 type to the final products, but we have found a path with less energy profile. TINI can decompose through the transition state TSD to betaine IZI with lose of the ammonia moiety. IZI cyclizes to products PP via the transition state TSIZI. Estimated heats of formation of ground and transition states show that the slowest step in this reaction is the decomposition of TINI to IZI and ammonia (Table 1). Finally, the investigated transformation belongs to the ANRORC type mechanism (addition of nucleophile, ring opening, ring closure) promoted by the initial protonation. Scheme 5
H O N N Ph SS H2N _ + NH2 MeO Ph N Ph SS1 # MeO Ph N HO TSSNC + NH3 Ph N N +O TSD MeO Ph Ph PP N Ph Ph Ph HO TIN N N NH2 Ph Ph HO SSI1 MeO Ph Ph N N +O TINI NH3 O N Ph Ph N Ph TSIZI + NH3 Ph N
H2N Ph Ph
MeOH
O+ N N
_ MeO
Ph
Ph Ph
MeO Ph Ph N
NH2 Ph
MeO Ph Ph
# Ph
OMe + N Ph N +O IZI O N
NH3
MeO
NH3
804
TABLE 1. Heats of Formation of Ground and Transition States Calculated by the PM3/COSMO Method for Transformation of 3 to 7 at 25C in Methanol Solution
State SS SSI SSI1 TSSNC TIN Heat of formation, kcal/mol 27.8 41.2 68.7 44.7 State TINI TSD IZI TSIZI PP Heat of formation, kcal/mol 36.9 71.2 53.4 69.1 36.1
The investigated reaction of N-phenylbenzamidine with O-acetylbenzene-oximoyl chloride in methanol solution leads to 5-methoxy-3,4,5-triphenyl-4,5-dihydro-1,2,4-oxadiazole. Unfortunately, the facts rule out this approach to the synthesis of 1-acetoxy-4-arylamino-4-phenyl-1,3-diaza-1,3-butadienes 5. However, the results do not exclude our assumption that blocking of the hydroxy group of oximoyl chloride by its alkylation or arylation would be a convenient route to formation of the desired diazabutadienes, promising potential starting materials in the thermal synthesis of quinazolines. The latter hypothesis is under investigation.
EXPERIMENTAL Melting points were measured on Boetius HMK apparatus. EI-MS spectra were recorded on Shimadzu QP-2000 apparatus. 1H NMR was scanned on Varian XL-300 (300 MHz) with TMS as an internal reference. Crystallographic data have been deposited with Cambridge Crystallographic Data Centre as a supplementary publication number CCDC 157269. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, fax: +44(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk. Quantum-chemical calculation were performed using MOPAC 2000 package [10], on a PC computer (Intel Pentium III, 767 MHz). The eigenvector following (EF) optimization procedure (GNORM = 0.5) was applied to estimation of ground states and transition states (as TS variant of EF). The solvation effect of methanol was calculated with the COSMO model (EPS = 32.63, NSPA = 90, DISEX = 4) [12]. Synthesis of 5-Methoxy-3,4,5-triphenyl-4,5-dihydro-1,2,4-oxadiazole (7). To a freshly prepared benzeneoximoyl chloride [16] solution in chloroform an equimolar amount of acetic anhydride was added at 0C. The reaction mixture was stirred overnight at ambient temperature. The solvent was removed under reduced pressure and the resulting amber oil was left for crystallization at 0C. The colorless crystals were filtered off, washed with hexane, air-dried, and used in the next step without additional purification. To a solution of N-phenylbenzamidine (1.96 g, 10 mmol) and O-acetylbenzeneoximoyl chloride (1.98 g, 10 mmol) in methanol (20 ml) triethylamine (1.01 g, 10 mmol) was added and the resulting solution was stirred for 2 h at ambient temperature. The white crystalline precipitate formed upon stirring was filtered off, washed with cold methanol, air-dried, and recrystallized from methanol. Crystals suitable for X-ray diffraction analysis were grown by slow evaporation of hexane solution. Yield of 7 as colorless prisms was 1.39 g (42%); mp 125-127C. 1H NMR (DMSO-d6): 3.6 (3H, s, OCH3); 6.8-7.5 (15H, m, H-aromatics). m/z 330 [M]+ (2), 299 (2), 288 (1), 297 (2), 210 (1), 195 (15), 194 (100), 193 (12), 105 (36), 103 (10), 91 (14), 77(45), 52 (22). Crystallographic Data for 7. C21H18N2O2, M = 330.37, orthorhombic, space group Pbca; a = 8.1642(6), b = 12.3137(9), c = 34.292(3) ; V = 3447(4) 3; Z = 8; dcalc = 1.273 g cm-3; F(000) = 1392; = 0.662 mm-1; crystal size 0.40 0.20 0.15 mm. X-Ray data were collected on a KUMA KM4 four-circle diffractometer at room temperature. Lattice parameters were obtained from least-squares refinement of setting angles of 64 reflections ( range 14.46-16.92) using the KM4 program system [17]. Intensity data were collected 805
using graphite-filtered CuK ( = 1.54178 ) radiation and applying the 2 scan technique; number of measured reflections 4167 ( range 2.58-80.15, index ranges -1 h 10, -15 k 1, -43 l 1), number of independent reflection 3234 (Rint = 0.262), data reduction was performed with the DATAPROC program package [18]. The structure was solved by direct methods using SHELXS86 [19] and refined by full-matrix least squares with anisotropic temperature factors for non-hydrogen atoms with SHELXL93 [20]. All hydrogen atoms were placed in calculated positions and their coordinates were refined using a riding model with isotropic displacement parameters taken as 1.5 times those of the respective parent atoms. The programs supplied atomic scattering factors. The final R = 0.0438, wR = 0.1195 {w = [2(Fo)2 + 0.0704P2 + 0.7554P]-1, where P = (Fo2 + 2Fc2)/3} for 3232 reflections [I >2(I)] and 227 parameters, goodness of fit on F2S = 1.045, (/)max = 0.000, ()max = 0.258 and ()min = -0.215 e-3. Empirical isotropic extinction parameter x = 0.0025(2) were also applied with Fc' = kFc[1 + 0.001Fc23/sin(2)]-1/4.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. D. W. Fry, A. J. Kraker, A. McMichael, L. A. Ambroso, J. M. Nelson, W. R. Leopold, R. W. Connors, and A. J. Bridges, Science, 265, 1093 (1994). S. W. Wright, D. L. Hageman, L. D. McClure, A. A. Carlo, J. L. Treadway, A. M. Mathiowetz, J. M. Withka, and P. H. Bauer, Bioorg. Med. Chem. Lett., 11, 17 (2001). W. Szczepankiewicz and J. Suwinski, Tetrahedron Lett., 39, 1785 (1998). W. Szczepankiewicz and J. Suwinski, R. Bujok, Tetrahedron, 56, 9343 (2000). J. Suwinski and M. A. A. Mohamed, Polish J. Chem., 75, 965 (2001). W. Szczepankiewicz, J. Suwinski, T. Borowiak, M. Kubicki, and P. Wagner, Polish J. Chem., 76, 1137 (2002). C. De Micheli, R. Gandolfi, and P. Grunanger, Tetrahedron, 30, 3765 (1974). W. Szczepankiewicz, J. Suwinski, and J. Slowikowska, Acta Crystallogr., C55, 2158 (1999). E. Carvalfo, J. Iley, and E. Rosa, J. Chem. Soc., Chem. Commun., 1249 (1988). J. P. P. Stewart, Mopac 2000.00 Manual, Fujitsu Limited, Tokyo, 1999. M. J. S. Dewar and W. Thiel, J. Am. Chem. Soc., 99, 4899 (1977). D. M. Dolney, G. D. Hawkins, P. Wignet, D. A. Liotard, C. J. Cramer, and D. G. Truhlar, J. Comput. Chem., 21, 340 (2000). A. Klamt and G. Schrmann, J. Chem. Soc., Perkin Trans. 2, 799 (1993). F. Rived, M. Roses, and E. Bosch, Anal. Chim. Acta, 374, 309 (1998). M. J. S. Dewar, E. G. Zoebish, E. F. Helay, and J. P. P. Stewart, J. Am. Chem. Soc., 107, 3902 (1985). Y. H. Chiang, J. Org. Chem., 36, 2146 (1971). KUMA Diffraction. KM4 User's Guide. Version 3.2. KUMA Diffraction, Wrocaw, Poland, 1991. Z. Galdecki, A. Kowalski, and L. Uszynski, DATAPROC the Data Processing Program. Version 9.0. KUMA Diffraction, Wroclaw, Poland, 1995. G. M. Sheldrick, Acta Crystallogr., A46, 467 (1990). G. M. Sheldrick, Program for the Refinement of Crystal Structures, University of Gttingen, Germany, Gttingen, 1993.
806
OXIDATIVE RECYCLIZATION OF 4,6,7-TRICHLORO-5-HYDROXY-2-(2-PYRIMIDYLAMINO)-2,3-DIHYDROBENZO[b]FURAN

G. Karlivans and R. Valters When 4,6,7-trichloro-5-hydroxy-2-(2-pyrimidylamino)- 2,3-dihydrobenzo[b]furan reacted with phenyliodoso diacetate, an unexpected oxidative recyclization was observed to give 3-(3,5,6-trichloro1,4-benzoquinon-2-yl)imidazo[1,2-a]pyrimidine. 2-[N-2-(3,5,6-Trichloro-1,4-benzoquinon-2-yl)ethenylamino]pyrimidine is the intermediate product in the conversion. Keywords: 4,6,7-trichloro-5-hydroxy-2-(2-pyrimidylamino)-2,3-dihydrobenzo[b]furan, 3-(3,5,6-trichloro1,4-benzoquinon-2-yl)imidazo[1,2-a]pyrimidine, phenyliodoso diacetate. The structural units of imidazo[1,2-a]pyridine, imidazo[1,2-a]pyrazine, and imidazo[1,2-a]pyrimidine are encountered in many pharmacologically active substances, such as antagonists of benzodiazepine and bradykinin receptors, inhibitors of gastric acid secretion, anti-inflammatories, cytoprotective agents, antibacterials, antifungal agents, cardiostimulators, etc. (see [1,2] and literature cited therein). The classical method for the synthesis of imidazo[1,2-a]pyridines, imidazo[1,2-a]pyrazines, and imidazo[1,2-a]pyrimidines is the condensation of -halo ketones with the corresponding 2-aminoazines [3-5]. A one step synthesis of imidazo[1,2-a]azines via a three component condensation of a 2-aminoazine, an aldehyde, and an isonitrile has been described [1,2] recently. In this paper the design of the ring of trichloro-1,4-benzoquinolyl-substituted imidazo[1,2-a]pyrimidine in an unexpected oxidative recyclization reaction of 4,6,7-trichloro-5-hydroxy-2-(2-pyrimidylamino)-2,3dihydrobenzo[b]furan (1) is proposed. We have shown recently [6] that the benzo[b]furan 1 is formed in the reaction of 4,6,7-trichloro-2,5-dihydroxy-2,3-dihydrobenzo[b]furan with 2-aminopyrimidine. When the benzo[b]furan 1 reacts with phenyliodoso diacetate in DMSO solution at 20C oxidation scission of the dihydrobenzofuran ring occurs with the formation of the intermediate 2-[N-2-(3,5,6-trichloro-1,4benzoquinon-2-yl)ethenylamino]pyrimidine (2), which then itself undergoes original oxidative cyclization to give 3-(3,5,6-trichloro-1,4-benzoquinon-2-yl)imidazo[1,2-a]pyrimidine (3). The benzoquinone 3 is easily reduced to 3-(3,4,6-trichloro-2,5-dihydroxyphenyl)imidazo[1,2-a]pyrimidine (4), so that the 1H NMR spectrum (in DMSO-d6) of compound 3 corresponds to the structure of the hydroquinone 4. Reduction of 3 to 4 was carried out by boiling in ethanol. Acylation of compound 4 with acetyl anhydride in pyridine in the presence of 4-dimethylaminopyridine (DMAP) [7] gave 3-(5-acetoxy-3,4,6trichloro-2-hydroxyphenyl)imidazo[1,2-a]pyrimidine (5). The phenolic hydroxy group in position 2 is not acylated under these conditions, possibly because of an intramolecular hydrogen bond between the OH group and the nitrogen atom of the heterocycle.
__________________________________________________________________________________________ Riga Technical University, Riga LV-1048, Latvia; e-mail: rvalters@latnet.lv. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, 939-942, June, 2004. Original article submitted March 25, 2004. 0009-3122/04/4006-08072004 Plenum Publishing Corporation 807
Cl HO
N NH O
Cl
Cl
1 2H N CH=CH NH N 2H
Cl O
1
PhI(OAc)2
O Cl
O Cl
N Cl 3
N
N + 2EtOH
Cl O
Cl 2
OH
3 2
N
4
OH
Cl
N
6
8 7
Ac2O Py / DMAP
Cl
N
Cl OAc
Cl OH
Cl
Cl 5 N
4
OAc
Ac2O / H3PO4 1
Cl
CH=CH
NH N
Cl OAc
Cl 6
Formation of the intermediate compound 2 is confirmed by the 1H NMR spectrum of a sample taken 5 min after the beginning of the reaction. This spectrum contains, apart from the proton signals of the starting material and reaction product, signals corresponding to the CH=CHNH unit (E-configuration). This unit occurs in the structure of 2-[N-2-(2,5-diacetoxy-3,4,6-trichlorophenyl)ethenylamino]pyrimidine (6), obtained by acetylation of compound 1 with acetic anhydride in the presence of orthophosphoric acid. The coupling constant (3J = 15 Hz) between the protons of the ethenyl fragment in the 1H NMR spectrum of compound 6 confirms its E-configuration. In the IR spectrum of the benzoquinone 3 bands for the C=O and C=C groups of the quinone are observed, but bands for the OH group are absent. The benzoquinone 3 is intensely colored and the presence in its UV spectrum of a band at 576 nm indicates the intramolecular charge transfer between the electron-donating heterocycle and the electron-accepting 1,4-benzoquinone fragment (cf [8]). In the 1H NMR spectra of compounds 4 and 5 the signals of the protons in positions 5, 6, and 7 of the imidazo[1,2-a]pyrimidine ring appear as a doublet of doublets. The chemical shifts and the coupling constants of these signals (see Experimental) agree well with the spectrum of 2-(4-methoxyphenyl)-3benzylaminoimidazo[1,2-a]pyrimidine [1] in which there are doublets of doublets: H-5 8.49 (3J = 6.8, 4J = 2.0), H-6 6.89 ( 3J = 4.1, 4J = 6.8), H-7 8.37 ppm (3J = 4.1, 4J = 2.0 Hz). A singlet is also observed for the proton in position 2 of the imidazo[1,2-a]pyrimidone ring, the chemical shift of which agrees with the data in [9, 10].
808
EXPERIMENTAL IR spectra of nujol mulls were recorded on a Specord M-80 (1900-1500 cm-1, NaCl prism) and of hexachlorobutadiene mulls (3800-2000 cm-1, LiF prism). Electronic spectra of chloroform solutions (c = 2.510-5 mol/l). 1H NMR spectra were recorded on a Bruker WH-90 (90 MHz) instrument with TMS as internal standard. 3-(3,5,6-Trichloro-1,4-benzoquinon-2-yl)imidazo[1,2-a]pyrimidine (3). Phenyliodoso diacetate (0.80 g, 2.5 mmol) in DMSO (5 ml) was added dropwise over 3 min to a solution of benzofuran 1 (0.33 g, 1 mmol) (prepared according to [6]) in DMSO (5 ml) with stirring (magnetic stirrer) at 20C. The mixture was stirred for 1 h at 20C and water (100 ml) was then added. The precipitate of 3 was separated, washed , and dried. The product was treated with methylene chloride (5 ml), the undissolved residue was separated, washed with petroleum ether, and dried. Yield 0.25 g (77%). Deep-blue crystals; mp >250C (dec.). IR spectrum (thin layer), , cm-1: 1686 (C=O), 1624, 1582 (C=C), 1538, 1502. UV spectrum (CHCl3, c = 2.510-1mol/l): max, nm (log ): 302 (4.24), 576 (3.70). 1H NMR spectrum, see compound 4. Found, %: C 43.34; H 1.78; Cl 31.98; N 12.32. C12H4Cl3N3O2. Calculated, %: C 43.87; H 1.23; Cl 32.38; N 12.79. 3-(3,4,6-Trichloro-2,5-dihydroxyphenyl)imidazo[1,2-a]pyrimidine (4). A solution of benzoquinone 3 (0.33 g, 1 mmol) in ethanol (10 ml) was boiled until the reaction mixture was colorless (~30 min). The solvent was evaporated in vacuum to 2 ml and the solution was kept at 0C for 20 h. The precipitate of the product 4 was separated, washed with ethanol, and dried . Yield 0.28 g (85%). Gray crystals; mp >200C (dec). IR spectrum (thin layer), , cm-1: 3120 (OH), 2927 (OH), 1622, 1562, 1530, 1494. 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 7.07 (1H, dd, 3J = 4, 4J = 6, H-6); 7.83 (1H, s, H-2); 8.42 (1H, dd, 3J = 6, 4J = 2, H-5); 8.60 (1H, dd, 3J = 4, 4J = 2, H-7); 9.70 (1H, br. s, OH); 10.00 (1H, br. s, OH). Found, %: C 43.55; H 2.03; Cl 31.78; N 12.80. C12H6Cl3N3O2. Calculated, %: C 43.60; H 1.83; Cl 32.18; N 12.71. 3-(5-Acetoxy-3,4,6-trichloro-2-hydroxyphenyl)imidazo[1,2-a]pyrimidine (5). A mixture of compound 4 (0.33 g, 1 mmol), anhydrous pyridine (4 ml), acetic anhydride (2 ml, 20 mmol), and 4-dimethylaminopyridine (0.025 g, 0.2 mmol) was stirred at 20C for 1 h, then at 50-60C for 2 h, and was finally boiled for 1 h. After cooling, water (50 ml) was added, the precipitate was separated, washed with water, and dried. After crystallization from ethanol plus activated charcoal, colorless crystals of compound 5 were obtained. Yield 0.25 g (68%); mp ~260C (dec). IR spectrum (thin layer), , cm-1: 2560 (br, OHN), 1778 (C=O). 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 1.92 (3H, s, CH3); 7.11 (1H, dd, 3J = 4, 4J = 6, H-6); 7.73 (1H, s, H-2); 8.49 (1H, dd, 3J = 6, 4J = 2, H-5); 8.64 (1H, dd, 3J = 4, 4J = 2, H-7); 10.95 (1H, br. s, OH). Found, %: C 44.94; H 2.14; Cl 28.72; N 11.15. C14H8Cl3N3O3. Calculated, %: C 45.13; H 2.16; Cl 28.55; N 11.28. 2-[N-2-(2,5-Diacetoxy-3,4,6-trichlorophenyl)ethenylamino]pyrimidine (6). Benzofuran 1 (0.33 g, 1 mmol), acetyl anhydride (5ml), and orthophosphoric acid (3 drops) were heated at 100C for 1 h. The mixture was cooled and water (50 ml) was added. After 12 h, the precipitate was filtered off, washed with water and dried to give colorless crystals of 6 (0.36 g, 86%). After recrystallization from benzene and then from 1:3 benzenecarbon tetrachloride; mp 184-185C (dec). IR spectrum (thin layer), , cm-1: 3210 (NH), 1775 (C=O), 1638 (C=C), 1517. 1H NMR spectrum (CDCl3 + DMSO-d6), , ppm (J, Hz): 2.33 (3H, s CH3); 2.39 (3H, s, CH3); 6.02 (1H, d, 3J = 15, CH); 6.70 (1H, t, 3J = 5, H-5 Het); 8.13 (1H, dd, 3J =15, 4J = 12, CH); 8.34 (2H, d, 3J = 5, H-4 Het, H-6 Het); 8.60 (1H, br. d, 3J = 12, NH). Found, %: C 46.10; H 2.86; Cl 25.50; N 9.94. C16H12Cl3N3O4. Calculated, %: C 46.12; H 2.90; Cl 25.53; N 10.09.
809
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. K. Groebke, L. Weber, and F. Mehlin, Synlett., 661 (1998). C. Blackburn, Tetrahedron Lett., 39, 5469 (1998). W. L. Mosby, in: Heterocyclic Systems with Bridgehead Nitrogen Atom. W. L. Mosby (ed.), Wiley, New York (1961). Pt. 1, p. 460, Pt.2, p. 802. C. Sablayrolles, G. H. Cros, J. C. Milhavet, E. Recheng, J.-P. Chapat, M. Boucard, J. J. Serrano, and J. H. McNeill, J. Med. Chem., 27, 206 (1984). W. A. Spitzer, F. Victor, G. D. Pollock, and J. S. Hayes, J. Med. Chem., 31, 1590 (1988). G. Karlivans and R. Valters, Khim. Geterotsikl. Soed., 1837 (2003). A. Orita, C. Tanahashi, A. Kakuda, and J. Otera, J. Org. Chem., 66, 8926 (2001). R. Valters, G. Karlivans, J. Gulbis, M. Utinans, and A. Bace, Phosph., Sulfur, and Silicon. 95 & 96, 457 (1994). S. Laneri, A. Sacchi, and E. Abignente, J. Heterocyclic Chem., 37, 1265 (2000). T. Kappe, J. Heterocyclic Chem., 32, 1003 (1995).
810
SYNTHESIS OF SUBSTITUTED 5,6-DIHYDRO-4H-[1,2,4]TRIAZOLO[4,3-a][1,5]BENZODIAZEPINES

L. Kosychova, Z. Stumbreviciute, L. Pleckaitiene, R. Janciene, and B. D. Puodziunaite A one-pot synthetic approach to the novel 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepines by thermal cyclization of 4-acylhydrazino-2,3-dihydro-1H-1,5-benzodiazepines is described. Keywords: 4-acylhydrazino-2,3-dihydro-1H-1,5-benzodiazepines, 4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepines, cyclization. Benzodiazepines and their polycyclic derivatives are important medicinal agents for the treatment of CNS disturbances [1-4]. Moreover, some annulated benzodiazepines, e.g., naturally occurring pyrrolo[2,1-c][1,4]benzodiazepines such as anthramycin [5], thiazolo[4,3-c][1,4]benzodiazepines [6] and substituted chromeno[4,3-b][1,5]benzodiazepine stereoisomers [7] have been found to exhibit antitumor and antineoplastic activities. The majority of these compounds have common general structures, comprising a tri- or tetracyclic almost planar chromophore [8]. In view of these benefits and our interest in the study of novel compounds bearing potential biological activity, our research group became interested in triazolo[4,3-a][1,5]benzodiazepine derivatives. We report here the synthesis and the physicochemical properties of new compounds. The preparation of some analogous target compounds was first reported by E. Szarvasi [9, 10] through the one-step cyclocondensation procedure starting from the corresponding tetrahydro-1,5-benzodiazepine-2(1H)thiones and arylhydrazides. This procedure involved heating the reactants at 200C or refluxing them in higher boiling solvents (e.g., trimethylbenzene). However, this approach can be restricted by the lack of reactivity of the thiolactams towards weak nucleophiles [11]. Besides, it was proved that the formation of the triazole ring in the 1,4-benzodiazepine series occurred through the intermediates obtained by phosphorylation with the moisture sensitive di(4-morpholinyl)phosphinic chloride (commercially not available) of lactams and subsequent reaction of an intermediate imine with hydrazides [2]. In the present work we used a procedure based on the thermal cyclization of 4-acylhydrazino-2,3dihydro-1H-1,5-benzodiazepines (1a-m) for the synthesis of the desired tricyclic compounds of the general formula 2. The procedure herein reported was chosen after a number of experiments in order to obtain the highest yields of the tricyclic derivatives. As a rule, the cyclization of 1 was achieved in refluxing anhydrous ethanol or butanol. Dehydration of 4-methyl-substituted derivatives 1l,m was performed only at a higher temperature by refluxing in xylene and removing the formed water. Generally, it was demonstrated that cyclization of the starting materials proceeded within a separate time limit for each compound and depended on its structure, as well as on the solubility in an appropriate solvent. An attempt to prepare triazole 2e from the corresponding thiolactam [12] and an excess of the acetylhydrazine in refluxing tetrahydrofuran in the presence of mercuric chloride [13] led to the mercury-benzodiazepine compound. The formation of a metal complex in __________________________________________________________________________________________ Institute of Biochemistry, LT-2600 Vilnius, Lithuania; e-mail: apalaima@bchi.lt. Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 6, 943-948, June, 2004. Original article submitted May 27, 2002. 0009-3122/04/4006-08112004 Plenum Publishing Corporation 811
the nucleophilic substitution reaction of tetrahydro-1,5-benzodiazepinethiones with amines was also observed [14]. The key starting materials 1a-m were prepared from the corresponding 4-methylthio-2,3-dihydro-1H-1,5benzodiazepines and acetyl- or benzoylhydrazines, as previously described [15]. According to this procedure compounds 1b,d,f,g,k,l have been obtained for the first time.
R3 NHNHCOR N R N R2 1am R1 N R2 2am R1
3
N N N R
1, 2 a b c d e f g h i j k l m
R H H H H Me Me Me Me Me H H H H
R1 H H H H H H H H H Me Me Me Me
R2 H H CH2Ph CH2Ph H H Me CH2Ph CH2Ph H H CH2Ph CH2Ph
R3 Me Ph Me Ph Me Ph Ph Me Ph Me Ph Me Ph
The structures of new compounds 1 and 2 were assigned by analytical and spectral data. For triazolobenzodiazepines 2a-m, the IR spectra are characterized by C=N stretching absorption bands at 1600-1520 cm-1. The 1H NMR spectra of these compounds, registered in CDCl3, exhibit signals corresponding to the diazepine skeleton protons. It can be noted that the C(1)CH3 signals of 2a,c,e,h,j,l (R3 = CH3) appear as sharp singlets at 2.45-2.51 ppm, thus indicating the formation of the triazole ring. The in vitro anticancer activity of some newly synthesized tricyclic compounds has been tested at the National Cancer Institute (NCI, USA). According to the NCI's Developmental Therapeutics Program the compounds 2c,e,h,j,k have been evaluated in the 3-cell line, one dose primary anticancer assay. Only the compound 2c which passed criteria for activity in this assay has been scheduled for testing against the full panel of 60 human tumor cell lines. The compound 2c, bearing a lipophilic benzyl substituent at the N(6) atom of the tricyclic heterosystem, exhibited noteworthy activity and remarkable selectivity for leukemia and breast cancer cell lines.
EXPERIMENTAL Melting points were determined in open glass capillaries and are not corrected. IR spectra were recorded on a Specord IR-75 spectrometer. 1H NMR spectra were measured at 80 MHz on a Tesla BS-587A spectrometer with TMS as an internal reference. TLC analyses were carried out on Silufol UV-254 silica gel plates in the butanolacetic acidwater, 4:2:1, system. Compounds 1a,c,e,h-j,m were synthesized following the reported method [15]. 812
TABLE 1. Physical and Analytical Data of the Newly Synthesized Compounds

Compound 1b 1d 1f 1g 1k 1l 2a 2b 2c 2d 2e 2f 2g 2h 2i 2j 2k 2l 2m Reaction time, h 7 10 20 8 5 8 8 28 15 25 18 6 16 Empirical formula (MW) C16H16N4O (280.33) C23H22N4O (370.45) C17H18N4O (294.36) C18H20N4O (308.38) C17H18N4O (294.36) C24H24N4O (384.48) C11H12N4 (200.24) C16H14N4 (262.32) C18H18N4 (290.37) C23H20N4 (352.44) C12H14N4 (214.27) C17H16N4 (276.34) C18H18N4 (290.37) C19H20N4 (304.40) C24H22N4 (366.47) C12H14N4 (214.27) C17H16N4 (276.34) C19H20N4 (304.40) C24H22N4 (366.47) Found, % Calculated, % H 5.59 5.75 5.81 5.99 6.26 6.16 6.36 6.54 6.02 6.16 6.17 6.29 5.91 6.04 5.43 5.38 6.51 6.25 6.02 6.14 6.91 6.59 6.01 5.84 6.53 6.25 6.93 6.62 6.17 6.05 6.79 6.59 6.12 5.84 6.47 6.62 6.00 6.05 mp, C (solvent) 199-200 (EtOH) 206-208 (EtOH) 166-168 (EtOH) 192-195 (EtOH) 174-176 (EtOH) 178-181 (EtOH) 174-176 (EtOAc) 183-185*2 (EtOAc) 138-139 (EtOAc) 146-147 (EtOAc) 186-188 (EtOAc) 240-242*3 (EtOH) 162-165 (Et2O) 120-122 (EtOAc) 174-176 (EtOAc) 194-196 (EtOH) 134-136 (EtOH) 128-130 (EtOAc) 190-193 (EtOAc)
Yield*, %
C 68.34 68.55 74.69 74.57 69.51 69.37 70.18 70.11 69.66 69.37 75.12 74.98 65.77 65.98 73.39 73.26 74.29 74.46 76.66 76.80 67.38 67.27 74.12 73.89 74.67 74.46 74.95 74.97 78.74 78.66 67.49 67.27 73.61 73.89 75.11 74.97 78.53 78.66
N 20.23 19.98 15.22 15.12 19.23 19.03 18.21 18.17 19.15 19.03 14.42 14.57 28.02 27.98 21.31 21.36 19.27 19.29 16.91 17.06 26.30 26.15 20.39 20.27 19.20 19.29 18.59 18.40 15.42 15.29 26.26 26.15 19.93 20.27 18.32 18.40 15.20 15.29
57 87 48 70 74 75 41 49 82 70 65 71 74 58 69 62 65 84 86
_______ * Yields are based on purified products. *2 Lit. [9] 183-185C. *3 Lit. [9] 239-240C.
5,6-Dihydro-4-R-5-R'-6-R"-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepines (2a-m) (General Procedure). A suspension of the appropriate acylhydrazinobenzodiazepine 1a-m (5.0 mmol) in 60 ml of anhydrous EtOH (for compounds 1a,b,h in 50 ml of anhydrous BuOH and for compounds 1l,m in 50 ml of o-xylene employing DeanStark trap) was heated at reflux. After a while the reaction mixture became clear and refluxing was continued. The reaction was monitored by TLC analysis. When the starting material was no 813
TABLE 2. IR and 1H NMR Spectral Data for the Newly Synthesized Compounds
Compound 1b 1d IR (nujol), , cm-1 3350, 3180, 3135 (NH), 1660 (CO) 3280, 3185 (NH), 1665 (CO) 3325, 3220 (NH), 1655 (CO) 3300, 3220 (NH), 1660 (CO) 3270, 3175 (NH), 1660 (CO) 3280, 3180, 3150 (NH), 1645 (CO)
1
H NMR, , ppm (J, Hz)*
1f
1g
1k
1l
2a 2b 2c 2d 2e
3260 (NH), 1600, 1585, 1550 3300 (NH), 1600, 1580, 1525 1600, 1535 1600, 1575, 1535 3255 (NH), 1605, 1535 3250, 3175 (NH), 1660, 1520 1600, 1535, 1525 1600, 1535, 1525
2f 2g 2h
2i
1595, 1520
2j
3270 (NH), 1600, 1535 3240 (NH), 1600, 1640 1600, 1545, 1530
2k
2l
2m
1595, 1535
2.55 (2H, m, CH2); 3.50 (2H, m, CH2N); 5.40 (1H, s, NHCH2); 6.80-8.10 (9H, m, HAr); 8.35 (1H, br. s, NH); 9.98 (1H, br. s, NH) 2.43 (2H, m, CH2); 3.34 (2H, m, CH2N); 4.32 (2H, s, CH2Ph); 6.85-8.10 (14H, m, HAr); 8.71 (1H, br. s, NH); 10.21 (1H, br. s, NH) 1.12 (3H, d, CH3); 2.30-3.80 (3H, m, CH2CH); 5.44 (1H, br. s, NHCH2); 6.80-8.05 (9H, m, HAr); 8.27 (1H, br. s, NH); 10.01 (1H, br. s, NH) 1.10 (3H, d, CH3CH); 2.30-3.80 (3H, m, CH2CH); 2.72 (2H, s, CH3); 6.85-8.05 (9H, m, HAr); 8.60 (1H, br. s, NH); 10.10 (1H, s, NH) 1.20 (3H, d, CH3); 2.00-2.60 (2H, m, CH2); 3.82 (1H, m, CH); 5.04 (1H, br. s, NHCH); 6.85-8.05 (9H, m, HAr); 10.21 (2H, br. s, NHNH) 1.01 (3H, d, CH3CH); 1.93 and 2.03 (3H, two s, CH3); 2.00-2.80 (2H, m, CH2); 3.67 (1H, m, CH); 4.26 (1H, AB-q, J = 15.2, CH2Ph); 4.37 (1H, AB-q, J = 15.2, CH2Ph); 6.80-7.40 (9H, m, HAr); 8.34, 8.43, 9.58, 9.72 (2H, four br. s, NHNH) 2.51 (3H, s, CH3); 3.04 (2H, m, CH2); 3.49 (1H, br. s, NH); 3.72 (2H, m, CH2N); 6.85-7.50 (4H, m, HAr) 3.11 (2H, m, CH2); 3.50 (1H, br. s, NH); 3.78 (2H, m, CH2N); 6.65-7.55 (9H, m, HAr) 2.46 (3H, s, CH3); 2.88 (2H, m, CH2); 3.35 (2H, m, CH2N); 4.21 (2H, s, CH2Ph); 6.85-7.40 (9H, m, HAr) 3.03 (2H, m, CH2); 3.52 (2H, m, CH2N); 4.36 (2H, s, CH2Ph); 6.65-7.55 (14H, m, HAr) 1.49 (3H, d, CH3CH); 2.50 (3H, s, CH3); 3.00 (1H, br. s, NH); 3.06 (1H, m, CH); 3.15-3.85 (2H, m, CH2); 6.90-7.40 (4H, m, HAr) 1.52 (3H, d, CH3CH); 2.95-3.90 (3H, m, CH2CH); 3.81 (1H, br. s, NH); 6.65-7.50 (9H, m, HAr) 1.53 (3H, d, CH3); 2.70-3.80 (3H, m, CH2CH); 2.86 (3H, s, CH3N); 6.60-7.45 (9H, m, HAr) 1.38 (3H, d, CH3CH); 2.51 (3H, s, CH3); 2.70-3.31 (3H, m, CH2CH); 4.07 (1H, AB-q, J = 14.8, CH2); 4.36 (1H, AB-q, J = 14.8, CH2); 6.95-7.30 (9H, m, HAr) 1.49 (3H, d, CH3); 2.70-3.80 (3H, m, CH2CH); 4.18 (1H, AB-q, J = 14.8, CH2); 4.47 (1H, AB-q, J = 14.8, CH2); 6.60-7.50 (14H, m, HAr) 1.26 (3H, d, CH3CH); 2.48 (3H, s, CH3); 2.72 (1H, dd, J = 6.3, 14.5, CH2); 3.07 (1H, dd, J = 5.4, 14.5, CH2); 3.37 (1H, br. s, NH); 3.98 (1H, m, CH); 6.90-7.35 (4H, m, HAr) 1.27 (3H, d, CH3CH); 2.70 (1H, dd, J = 6.6, 14.6, CH2); 3.07 (1H, dd, J = 5.2, 14.6, CH2); 3.74 (1H, br. s, NH); 4.03 (1H, m, CH); 6.60-7.50 (9H, m, HAr) 1.14 (3H, d, CH3CH); 2.28 (1H, dd, J = 10.4, 14.3, CH2C=); 2.45 (3H, s, CH3); 3.24 (1H, dd, J = 6.8, 14.8, CH2C=); 3.87 (1H, m, CH); 4.17 (1H, AB-q, J = 15.2, CH2Ph); 4.35 (1H, AB-q, J = 15.2, CH2Ph); 6.70-7.40 (9H, m, HAr) 1.24 (3H, d, CH3CH); 2.40 (1H, dd, J = 11.2, 14.4, CH2C=); 3.38 (1H, dd, J = 6.0, 14.4, CH2C=); 3.98 (1H, m, CH); 4.24 (1H, AB-q, J = 14.4, CH2Ph); 4.54 (1H, AB-q, J = 14.4, CH2Ph); 6.70-7.40 (14H, m, HAr)
_______ * Solvents: compounds 1b,d,f,g,k,l recorded in DMSO-d6, 2a-m in CDCl3.
814
longer detectable (reaction time for each material is presented in Table 1) the work up of the reaction mixture for the separate compound was performed differently. The mixture was concentrated by evaporation under reduced pressure to 20 ml and left to cool. The precipitated product (2d,f,j) was filtered. In the case of compounds 2a,b,g-i,k the solvent was evaporated to dryness. The thick residue was triturated with diethyl ether and the resultant product was filtered. After the reaction solvent was evaporated to dryness, the compounds 2l,m were obtained as solids. The dark reaction mixture (compound 2c,e) after being cooled to room temperature was filtered through a short plug of silica gel (Chemapol L 40/100, 8 g). After the column was eluted with ethanol (20 ml), the combined organic fractions were evaporated to give a solid residue. Compounds 2a-m were obtained as white or light yellow crystals by recrystallization from the proper solvent.
REFERENCES 1. 2. 3. 4. 5. A. R. Katritzky, R. Abonia, B. Yang, M. Qi, and B. Insuasty, Synthesis, 1487 (1998) and references cited therein. G. Stefancich, M. Artico, and R. Silvestri, J. Heterocycl. Chem., 29, 1005 (1992). G. Roma, G. C. Grossi, M. Di Braccio, M. Chia, and F. Mattioli, Eur. J. Med. Chem., 26, 489 (1991). O. A. Phillips, K. S. Keshava Murthy, C. Y. Fiakpui, and E. E. Knaus, Can. J. Chem., 77, 216 (1999). D. E. Thurston, in: S. Neidle and M. J. Waring (editors), Advances in the Study of Pyrrolo[2,1-c][1,4]benzodiazepine (PBD) Antitumour Antibiotics. Molecular Aspects of Anticancer Drug-DNA Interactions, Macmillan Press Ltd., London, 1993, 1, 54. A. C. Gillard, S. Rault, M. Boulouard, and M. Robba, J. Heterocycl. Chem., 32, 1741 (1995). W. Werner, J. Baumgart, G. Burckhardt, W. F. Fleck, K. Geller, W. Gutsche, H. Hanschmann, A. Messerschmidt, W. Rmer, D. Tresselt, and G. Lber, Biophys. Chem., 35, 271 (1990). A. Da Settimo, G. Primofiore, A. M. Marini, F. Da Settimo, C. La Motta, and S. Salerno, J. Heterocycl. Chem., 36, 639 (1999). E. Szarvasi, M. Grand, J. C. Depin, and A. Betbeder-Matibet, Eur. J. Med. Chem., 13, 113 (1978). E. Szarvasi, Ger. Offen. Pat. 2409308; Chem. Abstr., 82, 4328 (1975). M. P. Foloppe, I. Rault, S. Rault, and M. Robba, Heterocycles, 36, 63 (1993). B. Puodziunaite, L. Kosychova, R. Janciene, and Z. Stumbreviciute, Monatsh. Chem., 128, 1275 (1997). K. Grlitzer, C. Wilpert, H. Rbsamen-Waigmann, H. Suhartono, L. Wang, and A. Immelmann, Arch. Pharm. (Weinheim), 328, 247 (1995). R. Janciene, L. Kosychova, V. Bukelskiene, V. Domkus, Z. Stumbreviciute, V. Ragaleviciene, and B. D. Puodziunaite, Arzneim.-Forsch., 52, 475 (2002). B. Puodziunaite, L. Kosychova, R. Janciene, and Z. Stumbreviciute, Chem. Heterocycl. Comp., 34, 334 (1998).
6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
815
SYNTHESIS OF CYTOTOXIC 4-SULFONYL-, 4-SULFONYLTHIOAND 4-SULFOTHIOAZETIDINONES-2*

G. Veinberg, M. Vorona, D. Musel, R. Bokaldere, I. Shestakova, I. Kanepe, and E. Lukevics 4-Sulfonylazetidinones-2 were synthesized by the reaction of DBU and organic halides with the esters of penicillin sulfones. 4-Sulfonylthio- and 4-sulfothioazetidinones-2 were synthesized by nucleophilic substitution of the 2-benzothiazolylthio groups in 4-(benzothiazolylthio)azetidinones-2 using sodium sulfinates or sodium hydrogen sulfite. A study of their cytotoxic activities revealed the anticancer effect of compounds containing methylsulfonylthio-, 4-tolylsulfonylthio-, and 4-methoxycarbonylaminophenylsulfonylthio-substituents at position 4 of the -lactam ring relative to a wide range of monolayer cultures of cancer cells in vitro. Keywords: 2-[4-sulfonyl-2-oxoazetidinyl-1]-2-(isopropyliden)acetic acid esters, 2-[4-sulfonylthio-2oxoazetidinyl-1]-, and 2-[4-sulfothio-2-oxoazetidinyl-1]-2-(isopropenyl)acetic acid esters, cytotoxic activity. In a continuation of a study connected with the synthesis of 1,3,4-trisubstituted -lactams and the analysis of the relationship between their structure and cytotoxic activities [1, 2], we have chosen as new objects azetidinones-2 formed as result of scission of the S(1)C(2) bond in the thiazolidine ring of penicillin sulfones.
R
6 7
R N
5 1 2 4 3
SO2
DBU O N
SO2 _ COOR 2a
1
R N
_ SO2
R Hal 3ad
1
R
3 4 2 1
SO2R2 N COOR1 4af
COOR 1 1a,b
COOR 2b
1 a R = H; R1 = CHPh2; b R = Cl, R1 = CH2Ph; 3 a R2 = Me, Hal = I; b R2 = CH2Ph, Hal = Br; c R2 = CH2CH=CH2, Hal = Br; d R2 = CH2SiMe3, Hal = I; 4 a R = H; R1 = CHPh2, R2 = Me; b R = H; R1 = CHPh2, R2 = CH2Ph; c R = Cl, R1= CH2Ph, R2 = Me; d R = Cl, R2 = CH2Ph; e R = Cl, R1 = CH2Ph, R2 = CH2CH=CH2; f R = Cl, R1 = CH2Ph, R2 = CH=CHMe-trans
_______ * Dedicated to Academician A. Strakovs on his jubilee. __________________________________________________________________________________________ Latvian Institute of Organic Synthesis, Riga LV-1006; e-mail: veinberg@osi.lv. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, 949-956, June 2004. Original article submitted December 7, 2002. 816 0009-3122/04/4006-08162004 Plenum Publishing Corporation
The synthesis of the target 4-sulfonyl-substituted azetidinones 4a-i was carried out using the reactions, studied in [3,4], which includes: deprotonation of atom C(3) in the penicillin sulfone 1 with the help of DBU, leading to an equilibrium mixture of anions in which the thiazolidine ring is retained (2a) and the product of its opening (2b); and alkylation of the anion 2b with organic halides 3. In contrast to the alternative method , based on the desulfuration of 4-dithiosubstituted azetidinones-2 by triphenylphosphine with subsequent oxidation of the 4-thioazetidinone-2 to the corresponding sulfone [5], the reaction with the use of DBU and organic halides occurs with retention of configuration at C(4), which is indicated by the characteristic coupling constant J = 1-2 Hz of the trans-orientated vicinal protons on C(3) and C(4) in compounds 4a-f. When iodomethyltrimethylsilane (3d) was used as the alkylating agent, in place of the expected 4-trimethylsilylmethylsulfonylazetidinones-2 (5a,b), 4-methylsulfonylazetidinones-2 (4a,c) were isolated which indicates that the trimethylsilyl groups in the intermediate 4-trimethylsilylmethylsulfonylazetidinones-2 (5a,b) underwent electrophilic displacement by a proton.
DBU Me3SiCH2I 3d HI R N 5a,b COOCH2Ph
SO2CH2SiMe3
HI 4a,c Me3SiI
1a,b
5 a R = H; b R = Me
The formation of the mixture of isomers 4e and 4f from the reaction of penicillin 1b with allyl bromide 3c indicates the deprotonation of the methylene group in the 4-alkylsulfonyl substituent under the influence of DBU with subsequent migration of the double bond.
CH SO2 CH N O COOCH2Ph 4e Cl N O COOCH2Ph 4f
SO2CH=CHMe -trans
Cl N O
SO2CH2CH=CH2
Cl
CH2
DBU +
COOCH2Ph
Interaction of DBU with the sulfone of 6-(tert-butoxycarbonyl)aminopenicillanate 1c gives deprotonation at C(3) and opening of the thiazolidine ring but also reversal of the configuration at C(6) with formation of a mixture of 3R- and 3S-isomers of azetidinones-2 (4g). The isomeric 3-amino-4methylsulfonylazetidinones 4h and 4i, formed by treatment of compound 4g with trifluoroacetic acid were successfully isolated by preparative column chromatography.
817
Me3COOCHN
SO2 N
DBU 3a
Me3COOCHN
SO2Me N
O 1c H2N CF3COOH O 4h COOCH2Ph COOCH2Ph
O 4g H2N COOCH2Ph
SO2Me
SO2Me N
+
N O 4i COOCH2Ph
Nucleophilic substitution of the 2-thiobenzothiazolyl groups in the 4-dithio-substituted azetidinones-2 6 with sodium sulfinates 7 or sodium hydrogen sulfite according the patented methods [6, 7] led to the previously unknown 4-sulfonylthio- and 4-sulfothioazetidinones-2 , 8a-d and 9a,b.
S S R N O 6a,b COOCHPh2 NaHSO3 R N O 9a,b COOCHPh2 SSO3Na S N 1. AgNO3 2. R1SO2Na 7a-d N O 8a-d COOCHPh2
SSO2R
6, 9 a R = H, b R = Cl; 7, 8 a R1 = Me, b R1 = 4-MeC6H4, c R1 = 4-MeOCONHC6H4, d R1= 2-naphthyl
The biological part of the study in vitro included the determination of the cytotoxic properties of the compounds synthesized in monolayer cancer cells and the ability to initiate the biosynthesis of the nitric oxide radical (TG100), the high reactivity of which is an important ingredient of the cytotoxic effect [8, 9]. The TD50 concentrations of the substrates were determined by the standard method on four lines of cancer cells: HT-1080 (human fibrosarcoma), MG-22A (mouse hepatoma), B 16 (mouse melanoma) and Neuro 2A (mouse neuroblastoma) [9]. The compounds synthesized can be divided into three groups according to their biological effects. In the first group are compounds which possess no cytotoxic effects at concentrations up to 100 g/ml. This group includes esters of the sulfones of penicillanic acids 1a-c, 4-sulfonyl-3,3-dihydroazetidinones-2 4a,b, and 4-methylsulfonyl-3-aminoazetidinones-2 with free and substituted amino groups, 4g-i (Table 1, No:1-5, 10-12).
818
TABLE 1. Biological Properties of Derivatives of 1,3,4-Trisubstituted Azetidinones-2

Cytotoxic effect (g/ml) and specific NO generating effect with respect to tumour cells * HT-1080 MG-22A TD50 (CV) >100 >100 >100 >100 >100 57 43 6 >100 >100 >100 2.8 8.7 4 26.8 53 56 TD50 (MTT) 100 >100 >100 >100 >100 54 93 4.9 >100 >100 >100 30 10 35.7 39.2 52 60 TG100 36 8 6 3 2 200 67 250 20 15 21 400 500 200 150 500 286 TD50 (CV) >100 >100 >100 >100 >100 24 13 8.2 22 27 37 0.8 6.8 5.6 34.3 52 48 TD50 (MTT) 100 >100 >100 >100 >100 28 16 9.5 21.3 10 >100 9.0 4.5 5 46.4 48 50 TG100 43 7 9 5 6 200 44 250 40 50 59 450 450 250 100 600 750
No.
Compound
1 2 3 4 5 6 7 8 10 11 12 13 14 15 16 17 18
1a 1b 1c 4a 4b 4c 4d 4e, 4f 4g 4h 4i 8a 8b 8c 8d 9a 9b
_______ * TD50 concentration causing 50% death of the cells; CV crystal violet; MTT staining 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; TG100 specific NO generating ability [9]. The second group, characterized by small cytotoxic effects, includes 3-chloro-4-sulfonylazetidinones-2 4c,d and the sodium salts of 4-sulfothioazetidinones-2 9a,b (Table 1, No: 6, 7, 17, 18). The third group includes the most active substances with cytotoxic effects over a wide range of cancer cells: the isomeric mixture of 4-(prop-2-enylsulfonyl)- and 4-(trans-prop-1-enylsulfonyl)azetidinones-2 4e,f and the whole group of 4-sulfonylthioazetidinones-2 8a-c (Tables 1 and 2). As in previous papers [1, 2], for all three groups there is an excellent correlation between cytotoxic concentrations and the intensity of intracellular generation of the nitric oxide radicals, which indicates the interrelation of these two biological effects. TABLE 2. Biological Properties of Derivatives of 1,3,4-Trisubstituted Azetidinones-2
Cytotoxic effect (g/ml) and specific NO generating ability with respect to cancer cells B 16 Neuro 2A TD50 (CV) 6.2 3.0 7.8 <1 TD50 (MTT) 8.8 38 10.4 <1 TG100 200 450 450 200 TD50 (CV) 4.1 5.3 47 59 TD50 (MTT) 4.5 58 58 53 TG100 150 400 400 100
No.
Compound
1 2 3 4
4e, 4f 8a 8b 8c
819
EXPERIMENTAL H NMR spectra of DMSO-d6 solutions with TMS as internal standard were recorded on a Bruker WH-90/DS (90 MHz) machine. Microanalytical data were determined using a Carlo Erba 1108 analyzer. The course of reactions was monitored by TLC on Merck Kieselgel plates with spots revealed by UV radiation. Merck Kieselgel (0.063-0.230 mm) was used for preparative column chromatography. Reagents and materials from Aldrich, Acros, and Sigma were used in the experiments. Benzyl Ester of the Sulfone of 6-(tert-Butoxycarbonyl)aminopenicillanic Acid (1c). 3-Chloroperbenzoic acid (75%) (3.30 g, 14.28 mmol) was added to a solution of the benzyl ester of 6-(tertbutoxycarbonyl)aminopenicillanic acid ( 2.0 g, 4.92 mmol) in dichloromethane (40 ml) at 0C. The mixture was stirred at room temperature for 1 h, diluted with dichloromethane (20 ml), washed with 5% Na2SO3 solution (50 ml), 5% Na2CO3 solution (2 50 ml), and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was fractionated by column chromatography with 1:3 ethyl acetate-hexane as eluent. The fraction with Rf 0.30 was collected and evaporated to give compound 1c (1.5 g, 69%); mp 70-73C. 1 H NMR spectrum (CDCl3), , ppm (J, Hz): 1.44 (12H, br. s, t -Bu, CH3); 1.51 (3H, s, CH3); 4.44 (1H, s, 3-H); 4.71 (1H, d, J = 4, 5-H); 5.11 and 5.26 (2H, AB-system, J = 12, CH2); 5.71-5.93 (2H, m, 6-H, NH); 7.33 (5H, s, C6H5). Found, %: C 59.29; H 6.49; N 6.92. C20H26N2O5S. Calculated, %: C 59.09; H 6.45; N 6.89. 4-Sulfonyl-substituted Azetidinones-2, 4a-g. DBU (0.6 mmol) was added to a sulfone ester of penicillanic acid 1a-c (0.5 mmol) in dichloromethane (7 ml) at 0C. The mixture was kept at room temperature for 5 min and then an organic halide 3a-d (0.5 mmol) was added. The mixture was stirred at room temperature for 1 h, then dichloromethane (15 ml) was added, and the mixture was washed with 0.5 N HCl (10 ml), 5% NaCl solution (2 10 ml), and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the residue was fractionated by silicagel column chromatography with 1:3 ethyl acetatehexane as eluent. The fraction containing the desired product was collected and evaporated. Benzhydryl 2-[4(R)-Methylsulfonyl-2-oxoazetidinyl-1]-2-(isopropyliden)acetate (4a). A. The compound was obtained as an amorphous substance from the reaction of penicillin 1a with 3a in a yield of 72%. 1 H NMR spectrum (CDCl3), , ppm (J, Hz): 2.11 (3H, s, CH3); 2.28 (3H, s, CH3); 2.53 (3H, s, SO2CH3); 3.17 (1H, dd, J = 16, J = 6, 3-H cis); 3.41(1H, dd, J = 16, J = 3, 3,3-H trans); 4.88 (1H, dd, J = 6, J = 3, 4-H); 6.93 (1H, s, CHPh2); 7.31 (10H, s, C6H5). Found, %: 64.12; H 5.75; N 3.48. C22H23NO5S. Calculated, %: C 63.90; H 5.61; N 3.39. B. The identical compound was obtained from the interaction of penicillin 1a and iodide 3d. Yield 52%. Benzhydryl 2-[4(R)-Benzylsulfonyl-2-oxoazetidinyl-1]-2-(isopropyliden)acetate (4b) was obtained as an oil from the reaction of penicillin 1a and 3b. Yield 15%. 1H NMR spectrum (CDCl3), , ppm (J, Hz): 2.13 (3H, s, CH3); 2.31 (3H, s, CH3); 2.98 (1H, dd, J = 16, J =5, 3-H cis); 3.19 (1H, dd, J = 16, J =5, 3-H trans); 3.86 and 4.11 (2H, AB-system, J = 15, SO2CH2); 4.80 (1H, dd, J = 2, J = 5, 4-H); 6.91 (1H, s, CHPh2); 7.22-7.56 (15H, m, 3C6H5). Found, %: C 68.74; H 5.66; N 2.73. C28H27NO5S. Calculated, %: 68.69; H 5.56; N 2.86. Benzyl 2-[3(S)-Chloro-4(R)-methylsulfonyl-2-oxoazetidinyl-1]-2-(isopropyliden)acetate (4c). A. The compound was obtained as an amorphous solid from the reaction of 1b and 3a in 23% yield. 1H NMR spectrum (CDCl3), , ppm (J, Hz): 2.07 (3H, s, CH3); 2.31 (3H, s , CH3); 2.71 (3H, s, SO2CH3); 5.02 (1H, br. s, 4-H); 5.09 (1H, br. s, 3-H); 5.15 and 5.40 (2H, AB-system, J = 12, CH2Ph); 7.40 (5H, s, C6H5). Found %: C 51.76; H 4.97; N 3.86. C16H18ClNO5S. Calculated, %: C 51.68; H 4.88; N 3.77. B. The identical compound was obtained from the reaction of 1b and 3d in 19% yield. Benzyl 2-[4(R)-Benzylsulfonyl-3(S)-chloro-2-oxoazetidinyl-1]-2-(isopropyliden)acetate (4d) was obtained as an amorphous solid from the reaction of 1b and 3b in 32% yield. 1H NMR spectrum (CDCl3), , ppm (J, Hz): 2.09 (3H, s, CH3); 2.31 (3H, s, CH3); 4.06 and 4.26 (2H, AB-system, J = 15, SO2CH2); 4.82 (1H, d, J = 1, 4-H); 4.93 (1H, d, J = 1, 3-H); 5.06 and 5.24 (2H, AB-system, J = 12, CH2Ph); 7.40 (10H, s, 2C6H5). Found, %: C 59.13; H 5.07; N 3.26. C22H22ClNO5S. Calculated, %: C 58.99; H 4.95; N 3.13. 820
1
Benzyl 2-[4(R)-(Prop-2-enylsulfonyl-3(S)-chloro-2-oxoazetidinyl-1]-2(isopropyliden)acetate (4e) and Benzyl 2-[4(R)-(trans-Prop-1-enylsulfonyl-3(S)-chloro-2-oxoazetidinyl-1]-2(isopropyliden)acetate (4f). The mixture of isomers was obtained by the interaction of 1b and 3c in 23% yield. According to HPLC (Ultrasphere Si, 20:80 chloroformhexane) the ratio of 4e to 4f is 1:3, their overall content in the substance isolated was >97%. Found, %: C 54.54; H 4.99; N 3.76. C18H20NO5S. Calculated, %: C 54.34; H 5.07; N 3.52. 1 H NMR spectrum (CDCl3), , ppm (J, Hz): 4e: 2.09 (3H, s, CH3); 2.31 (3H, s, CH3); 3.42-3.74 (2H, m, CH2-allyl); 4.88 (1H, d, J = 2, 4-H); 5.01 (1H, d, J = 2, 3-H); 5.24-5.44 (4H, m, CH2Ph, =CH2); 5.44-5.80 (1H, m, CH-allyl); 7.33 (5H, s, C6H5). 4f: 1.84 (3H, dd, J = 7, J = 1.6, CH3 propenyl); 2.06 (3H, s, CH3); 2.27 (3H, s, CH3); 4.88 (1H, d, J = 2, 4-H); 5.01 (1H, d, J = 2, 3-H); 5.11 and 5.33 (2H, AB-system, J = 12, CH2Ph); 5.90 (1H, dd, J = 14, J = 1.6, 1-H propenyl); 6.82 (1H, dd, J = 14, J = 7, 2-H propenyl); 7.33 (5H, s, C6H5). Benzyl 2-[3-tert-Butoxycarbonylamino-4(R)-(methylsulfonyl)-2-oxoazetidinyl-1]-2-(isopropyliden)acetate (4g) was obtained as an amorphous substance from the reaction of 1b and 3a in 40% yield. 1H NMR spectrum (CDCl3), , ppm (J, Hz): 1.46 (9H, s, t -Bu); 2.07 (3H, s, CH3); 2.31 (3H, s, CH3); 2.71 (3H, s, SO2CH3); 5.02 (1H, br. s, 4-H); 5.09 (1H, br. s, 3-H); 5.15 and 5.40 (2H, AB-system, J = 12, CH2Ph); 5.65-5.75 (1H, m, NH); 7.40 (5H, s, C6H5). Found, %: C 55.87; H 6.32; N 6.30. C28H20N2O7S. Calculated, %: C 55.74; H 6.24; N 6.19. Benzyl 2-[3(R)-Amino-4(R)-methylsulfonyl-2-oxazetidinyl-1]-2-(isopropyliden)acetate (4h) and Benzyl 2-[3(S)-Amino-4(R)-methylsulfonyl-2-oxazetidinyl-1]-2-(isopropyliden)acetate (4i). Compound 4g (650 mg, 1.43 mmol) was dissolved at 0C in dichloromethane (2 ml) and trifluoroacetic acid (3 ml). The solution was stirred for 2 h at 0C and for 1 h at room temperature, diluted with dichloromethane (70 ml), washed with 5% potassium carbonate (50 ml) until neutral, with water, and then dried over anhydrous Na2SO4. The solvent was removed at reduced pressure and the residue was fractionated by column chromatography with ethyl acetate as eluent. The fraction with Rf 0.48 contained ester 4h (100 mg, 20%); mp 90-92C. 1H NMR spectrum (CDCl3), , ppm (J, Hz): 2.06 (2H, br. s, NH2); 2.15 (3H, s, CH3); 2.26 (3H, s, CH3); 2.88 (3H, s, SO2CH3); 4.53 (1H, d, J = 5, 4-H); 4.95 (1H, d, J = 5, 3-H); 5.11, 5.31 (2H, AB-system, J = 13, CH2Ph); 7.37 (5H, s, C6H5). Found, %: C 54.81; H 5.62; N 7.60. C16H20N2O5S. Calculated, %: C 54.53; H 5.72; N 7.95. The fractions with Rf 0.31 contained ester 4i (51 mg, 10%) as an oily substance, 98% pure according to HPLC (Zorbax RxC18, mobile phase 45:55 acetonitrile-water). 1H NMR spectrum (CDCl3), , ppm (J, Hz): 1.69 (2H, br. s, NH2); 2.04 (3H, s, CH3); 2.26 (3H, s, CH3); 2.66 (3H, s, SO2CH3); 4.57 (1H, d, J = 2, 4-H); 4.66 (1H, d, J = 2, 3-H); 5.11 and 5.33 (2H, AB-system, J = 13, CH2Ph); 7.37 (5H, s, C6H5). 4-Sulfonylthio-substituted Azetidinones-2 8a-d. Silver nitrate (105 mg, 0.5 mmol) was added to benzhydryl 2-[4-(2-benzothiazolyldithio)-2-oxoazetidinyl-1]-2-(isopropenyl)acetate (0.5 mmol) (6a) in 9:1 acetonewater (5 ml), the mixture was stirred for 30 min at room temperature and then a sodium sulfinate 7a-d (0.5 mmol) in 9:1 acetonewater (5 ml) was added. The mixture was stirred for 2 h at room temperature and then filtered through of Celite. The filtrate was dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure and the residue was fractionated on a silica gel column with 3:2 ethyl acetatehexane as eluent. The fractions containing the desired product were collected and evaporated. Benzhydryl 2-(4-Methylsulfonylthio-2-oxoazetidinyl-1]-2-(isopropenyl)acetate (8a) was obtained as an amorphous substance from the interaction of compounds 6a and 7a in 21% yield. 1H NMR spectrum (CDCl3), , ppm (J, Hz): 1.88 (3H, s, CH3); 3.24 (1H, dd, J = 16, J = 2, 3-H, trans); 3.31 (3H, s, SO2CH3); 3.71 (1H, dd, J = 16, J = 5, 3-H cis); 4.93 (2H, d, J = 7, =CH2); 5.11 (1H, d, J = 1, NCHCOO); 5.68 (1H, dd, J = 5, J = 2, 4-H); 7.00 (1H, s, CHPh2); 7.35 (10H, s, 2C6H5). Found, %: C 59.46; H 5.37; N 3.16. C22H23NO5S2. Calculated, %: C 59.30; H 5.20; N 3.14. Benzhydryl 2-[4-(4-Tolylsulfonylthio-2-oxoazetidinyl-1]-2-(isopropenyl)acetate (8b) was obtained as an amorphous substance from the interaction of compounds 6a and 7b in 35% yield. 1H NMR spectrum (CDCl3), , ppm (J, Hz): 1.62 (3H, s, CH3); 2.31 (3H, s, CH3Ph); 2.91 (1H, dd, J = 2, J = 16, 3-H trans); 3.53 (1H, dd, J =16, J = 5, 3-H cis); 4.66 (2H, d, J = 7, =CH2); 4.89 (1H, d, J = 1, NCHCOO); 5.37 (1H, dd, J = 5, 821
J = 2, 4-H); 7.04 (1H, s,CHPh2); 7.17 and 7.67 (4H, two d, J = 8, C6H4); 7.42 (10H, s, 2C6H5). Found, %: C 63.91; H 5.26; N 2.66. C28H27NO5S20.25H2O. Calculated, %: C 63.85; H 5.35; N 2.62. Benzhydryl 2-[4-(4-Methoxycarbonylaminophenyl)sulfonylthio-2-oxoazetidinyl-1]-2-(isopropenyl)acetate (8c) was obtained from the interaction of compounds 6a and 7c in 31% yield; mp 60-63C. 1H NMR spectrum (CDCl3), , ppm (J, Hz): 1.77 (3H, s, CH3); 2.99 (1H, dd, J = 17, J = 2, 3-H trans); 3.52 (1H, dd, J = 17, J = 6, 3-H cis); 3.80 (3H, s, OCH3); 4.75 (2H, d, J = 7, =CH2); 4.97 (1H, d, J = 1, NCHCOO); 5.46 (1H, dd, J = 6, J = 2, 4-H); 6.82 (1H, br. s, NH); 6.91 (1H, br. s, CHPh2); 7.35 (10H, s, 2C6H5); 7.79 and 7.82 (4H, two d, C6H4). Found, %: C 59.99; H 4.86; N 4.82. C29H28N2O7S2. Calculated, %: C 60.29; H 4.89; N 4.64. Benzhydryl 2-[4-(2-Naphthyl)sulfonylthio-2-oxoazetidinyl-1]-2-(isopropenyl)acetate (8d) was obtained as an amorphous substance from the interaction of compounds 6a and 7d in 36% yield; mp 45-48C. 1H NMR spectrum (CDCl3), , ppm (J, Hz): 1.73 (3H, s, CH3); 2.97 (1H, dd, J =15, J = 3, 3-H trans); 3.50 (1H, dd, J = 15, J = 6, 3-H cis); 4.71 (2H, d, J = 12, =CH2); 4.89 (1H, d, J = 1, NCHCOO); 5.53 (1H, dd, J = 6, J = 3, 4H); 6.82 (1H, s, CHPh2); 7.26 (10H, s, 2C6H5); 7.57-8.04 (6H, m, 3-H-8-H naphthyl); 8.42 (1H, s, 1-H naphthyl). Found, %: C 66.7; H 4.88; N 2.51. C31H27NO5S2. Calculated, %: C 66.15; H 4.82; N 2.57. Sodium 2-[Sulfothio-2-oxoazetidinyl-1]-2-(isopropenyl)acetate (9a). NaHSO3 (40 mg, 0.38 mmol) was added to compound 6a (209 mg, 0.37 mmol) in a mixture of THF (10 ml) and water (3ml). The mixture was stirred at room temperature for 30 min and evaporated. The residue was dissolved in water and filtered. The filtrate was evaporated, the residue was dissolved in absolute ethanol, filtered, and evaporated to give compound 9a (150 mg, 80%); mp 86-88C. 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 1.75 (3H, s, CH3), , 2.86 (1H, dd, J = 16, J = 3, 3-H trans); 3.53 (1H, dd, J =16, J = 6, 3-H cis); 5.00 (2H, br. s, =CH2); 5.15 (1H, s, NCHCOO); 5.24 (1H, q, J = 6, J = 3, 4-H); 6.82 (1H, s, CHPh2); 7.42 (10H, s, C6H5). Found, %: C 50.86; H 4.33; N 2.82. C21H20NNaO6S21.5H2O. Calculated, %: C 50.80; H 4.66; N 2.96. Sodium 2-[4(R)-Sulfothio-3(S)-chloro-2-oxazetidinyl-1]-2-(isopropenyl)acetate (9b) was obtained in 75% yield as an amorphous substance analogously to 9a, starting from compound 6b. 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 1.77 (3H, s, CH3); 5.02 (2H, br. s, =CH2); 5.11 (1H, s, NCHCOO); 5.20 (1H, d, J = 1, 4-H); 5.26 (1H, d, J =1, 3-H); 6.89 (1H, s, CHPh2); 7.40 (10H, s, 2C6H5). Found, %: C 48.34; H 3.90; N 2.71. C21H19ClNNaO6S2H2O. Calculated, %: C 48.32; H 4.05; N 2.68.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. G. Veinberg, R. Bokaldere, K. Dikovskaya. M. Vorona, D. Musel, H. Kazhoka, I. Turovsky, I. Shestakova, I. Kanepe, I. Domrachova, and E. Lukevics, Chem. Heterocycl. Comp., 34, 1266 (1998). G. Veinberg, R. Bokaldere, K. Dikovskaya. M. Vorona, I. Kanepe, I. Shestakova, and E. Lukevics, Khim. Geterotsikl. Soed., 680 (2003). C. M. Pant and R. J. Stoodley, J. Chem. Soc., Perkin Trans. 1, 1366 (1978). I. Lukic, Org. Prep. Proc. Int. Briefs, 31, 352 (1999). K. Prasad, G. Schulz, H. Hamberger, and P. Stutz, Heterocycles, 19, 291 (1982). S. Torii, H. Tanaka, M. Sasaoka, S. Nagao, S. Uto, S. Hayase, and T. Shiroi, Ger. Offen. DE 3443225; Chem. Abstr., 103, 123265 (1985). Fujisawa Pharmaceutical Co. Ltd., Jpn. Pat., 57 57474; Chem. Abstr., 98, 197890 (1983). J. F. Kerwin Jr., F. R. J. Lancaster Jr., and P. L. Feldman, J. Med. Chem., 38, 4343 (1995). G. A. Veinberg, I. Shestakova, N. Grigan, D. Musel, I. Kanepe, I. Domrachova, V. Grigoryeva, O. Zharkova, I. Turovskis, I. Kalvinsh, A. Strakovs, and E. Lukevics, Eur. J. Med. Chem., 33, 755 (1998).
822
The Seventieth Birthday of Professor ANDRIS STRAKOVS

In June, 2004, Prof. Andris Strakov, prominent Latvian chemist working in the field of the chemistry of heterocyclic compounds, celebrates his seventieth birthday. Andris Strakovs was born on June 27, 1934 at Valmiera in Latvia. In 1957 he finished at the Chemical Faculty of Latvian State University, and in 1957-1959 he worked on assignment as tutor at the Daugavpils Pedagogical Institute. Researches on the sulfonic acids of 1,3-indanediones, already started in his student years under the guidance of Prof. E. Gudriniece and continued in Daugavpils and in post-graduate studies at Riga Polytechnical Institute (1959-1961), were added together to form his Candidate's Thesis (1962). Strakov worked as assistant and senior teacher in the Department of Organic Chemistry at the Chemical Faculty of Riga Polytechnical Institute led by Prof. G. Vanags, and in 1964 he was transferred to the newly formed Department of Fine Organic Synthesis, where he has worked up to the present time; in 1989-2000 he was the leader of this department. From 1974 to 1985 Strakov was prorector for research at Riga Polytechnical Institute (since 1990 Riga Technical University), and in 1977 he was given the title of professor. In 1972 Strakovs and Gudriniece were awarded the G. Vanags prize of the Academy of Sciences of the Latvian SSR for a cycle of papers on "Derivatives of the heterocyclic series based on dicarbonyl compounds," and in 1975 he defended a doctor's thesis on "Heterocycles based on 1,3-cyclohexanediones." In 1992 Strakov was elected Corresponding Member of the Academy of Sciences of Latvia, and in 1995 he was elected Full Member. In 1965-1985 Strakovs interests were concentrated on the synthesis of -oxocyclohexene heterocycles in the reactions of 2-acyl-1,3-cyclohexanediones mainly with bifunctional N- and N,O-nucleophiles and investigation of their properties. The modification of 4-oxo-4,5,6,7-tetrahydroindazoles and 5-oxo-5,6,7,8____________________________________________________________________________________________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 969-970, July, 2004. 0009-3122/04/4007-08292004 Springer Science+Business Media, Inc. 829
tetrahydroquinazolines both in the heterocyclic and in the carbocyclic parts of the molecules was investigated. The derivatives obtained during oxidation, formylation, bromination, and other reactions proved extremely promising for the synthesis of complex polycondensed systems and, in particular, derivatives of imidazolo[4,5-c]pyrazoles, imidazolo[4,5-d]pyrimidines, indazolo[4,5-d]imidazoles, imidazolo[4,5-d]thiazoles, imidazolo[4,5-b]diazepines, pyrazolo[4,3-a]phenazines, pyrazolo[4,3-a]acridines, pyrazolo[4,5-d]quinazolines, isoxazolo[5,4-c]imidazoles, etc.. During these researches close links were formed with the N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences (A. A. Akhrem, A. M. Moiseenkov) and, later, with the Institute of Bioorganic Chemistry, Academy of Sciences of Belarus. In the last decade prof. Strakovs has conducted researches into the synthesis of histaminergic substances in various classes of compounds. Much effort was directed at researches into the synthesis of 2-, 3-, and 2,3-substituted 4(3H)-quinazolinones. Of the researches in this direction it is necessary to mention in particular the introduction of cyclobutane-containing groups and various heterocyclic substituting groups. Investigations are being carried out into the synthesis of pyridodiazepines in the reactions of 2,3-diaminopyridine with 1,3-cyclohexanediones and aromatic aldehydes, 4-hydroxycoumarin, and 4-hydroxy4-pyrones. The synthesis of a series of polycondensed heterocyclic systems based on 4-hydroxycoumarin has been realized. In conjunction with coworkers Andris Strakovs has published more than 200 papers in scientific journals and 100 reports in conferences, and 10 dissertations have been defended under his guidance. The colleagues of Andris Strakov warmly congratulate him and wish him health, long years of fruitful work, and new successes in his scientific activity.
830
BENZO[b]TELLUROPHENE, DIBENZO[b,d]TELLUROPHENE, AND THEIR DERIVATIVES. (REVIEW)

I. D. Sadekov and V. I. Minkin Data on the synthesis, reactions, crystal structure, and spectral characteristics of benzo[b]tellurophene, dibenzo[b,d]tellurophene, and their derivatives are reviewed and analyzed. Keywords: benzo[b]tellurophene, dibenzo[b,d]tellurophene, cyclization. Tellurophene and its derivatives have unique reactivity in comparison with other five-membered heteroaromatic compounds and have therefore attracted considerable attention. Detailed reviews have been devoted to their synthesis and transformations [1, 2]. At the same time the benzannelated derivatives (benzo[b]tellurophenes and dibenzo[b,d]tellurophenes), methods for the production of which are examined in the present review, have been studied to a significantly lesser degree. Of the five-membered heterocycles containing one tellurium atom dibenzotellurophene was synthesized first [3], while the first representatives of tellurophenes and benzotellurophenes, i.e., tetraphenyltellurophene [4] and 3-chloro-2-phenylbenzo-[b]tellurophene [5] respectively, were obtained much later.
1. BENZO[b]TELLUROPHENE In contrast to its chalcogen analogs benzo[b]selenophene and particularly benzo[b]thiophene, benzo[b]tellurophene (1) and its derivatives have been studied insufficiently [1, 2, 6]. Although a paper on the synthesis of one member of this series, i.e., 3-oxo-2,3-dihydrobenzo[b]tellurophene (telluroindoxyl) appeared in 1928 [7], it proved erroneous [8, 9]. The first reliably described representative of benzo[b]tellurophenes is probably 3-chloro-2-phenylbenzo[b]tellurophene, which was obtained in 1971 [5].
1.1. Synthesis of Benzo[b]tellurophene and Its Derivatives Methods for the synthesis of benzo[b]tellurophene (1) and its derivatives from noncyclic organotellurium compounds can be divided into two main groups according to the method of closure of the tellurophene ring and the structure of the initial substances. The first group includes the cyclization of C(2)C(3) and C(2)Te of carbonyl(vinyl)-substituted benzenes, containing a TeR group (R = CH2Y, where Y is an electron-withdrawing substituent) or TeMeBr2 group at the ortho position. 2-Substituted benzo[b]tellurophenes __________________________________________________________________________________________ Scientific-Research Institute of Physical and Organic Chemistry, Rostov State University, Rostov-onDon, Russia. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 974-996, July, 2004. Original article submitted October 9, 2002. 834 0009-3122/04/4007-08342004 Springer Science+Business Media, Inc.
are mainly formed as a result of these reactions. The second group of methods involving TeCarom cyclization, which lead to 3-halobenzo[b]tellurophenes, are based on the use of the comparatively readily obtainable (2-phenylvinyl)tellurium trichlorides PhCR2CR1TeCl3. These reactions are specific to the chemistry of benzo[b]tellurophenes, in so far as the selenium and sulfur analogs of the above-mentioned -telluranes are unstable. The first benzo[b]tellurophene (1) was obtained by a four-stage synthesis [9] from o-(methyltelluro)benzaldehyde [10] and bromoacetic acid. The overall yield of the product 1 amounted to 54% (calculated on the initial aldehyde).
CHO + BrCH2COOH TeMe CHO + Te Me CH2COOH _ Br MeBr
CHO Te CH2COOH
Py, H2O Te COOH
quinoline, Cu, CO2 Te 1
2-Acetylbenzo[b]tellurophene was synthesized from the same aldehyde and bromoacetone in a similar way with an extremely low yield [11]. Low yields of 2-substituted 3-methylbenzo[b]tellurophenes were obtained in the reaction of o-(methyltelluro)acetophenone [12] and bromides BrCH2R [11, 13]. Thus, the yield of 2-carboxy-3methylbenzo[b]tellurophene amounted to 10% [13]. Another approach to the production of 2-R-benzo[b]tellurophenes 2 was based on the intramolecular cyclization of substituted styrenes 3 by boiling in pyridine [11]. The initial o-(methyltelluro)styrenes 4 for the synthesis of compounds 3 were obtained with high yields by the Wittig reaction of o-(methyltelluro)benzaldehyde with stabilized phosphoranes. Oxidation of the tellurides 4 with bromine leads to the products 3 with almost quantitative yields. However, it was not possible to obtain 2-formylbenzo[b]tellurophene by this method.
CHO CH=CHR Br2
+
TeMe
Ph3P CHR TeMe 4
CH=CHR Me Te Br 3 Br
Py, MeBr, HBr 2 Te R
835
Derivatives of lithioacetylenes are promising for use in the synthesis of benzo[b]tellurophene 1 and its substituted derivatives 2. Thus, compound 1 was obtained with a yield of 85% by the reaction of the lithium derivative 5 with Te powder in THF followed by treatment of the obtained lithium tellurolate with a mixture of tbutyl alcohol and HMPTA [14].
C CLi
+ Te 5 THF
C CLi
TeLi
t-BuOH, HMPTA 1
Li
o-Bromoethynylbenzenes 6, synthesized with yields of 78-93% by the coupling of o-bromoiodobenzene with substituted acetylenes RCCH catalyzed by PdCl2(PPh3)2, were used for the production of 2-R-benzo[b]tellurophenes 2. The required products 2 were obtained with yields of 45-74% by treating compounds 6 with t-butyllithium and with tellurium and then adding ethanol to the reaction mixture [15].
C CR
C CR
1. t-BuLi 2. Te
EtOH
Br
TeLi
R = Me, t-Bu, Ph, Me3Si
3-Chlorobenzo[b]tellurophenes 7 were synthesized by the intramolecular electrophilic cyclization of -chlorostyryltellurium trichlorides. The first representative of the series 3-chloro-2-phenylbenzo[b]tellurophene (7a) was obtained with an almost quantitative yield by the reduction of 1,1,3-trichloro-2phenylbenzo[b]tellurophene (8a) [5]. The latter was in turn obtained with a yield of more than 50% by heating -phenyl--chlorostyryltellurium trichloride (9a) [16].
Cl PhC CPh + TeCl4 9a Cl Te Cl 8a Cl Ph Cl3Te Ph 1,2,4-Cl3C6H3, HCl
K2S2O5 2Cl _ Te 7a
Cl Ph
It should be noted that attempts at thermal cyclization of the trichloride 9b were unsuccessful. However, when this compound was boiled in acetic acid in the presence of lithium chloride the 3-chlorobenzo[b]tellurophene 7b was obtained with a yield of 38% together with bis(-chlorostyryl) telluride 10 [17].
Cl Cl AcOH, LiCl, Te 7b
[PhC(Cl)=CH]2Te 10
Cl3Te 9b
836
An extremely convenient preparative method for the production of 3-halobenzo[b]tellurophenes, not requiring the prior synthesis of vinyltellurium trichlorides of type 9, was developed by Bergman [17, 18]. Compounds 7c-f were obtained with yields of 21-92% by the reaction of arylacetylenes with TeO2 in acetic acid in the presence of an excess of LiX (X = Cl, Br, I). The products were purified by conversion into the corresponding 1,1-dichlorobenzotellurophenes 8, crystallization of the latter, and reduction.
C CH + TeO2 R X R 7cf Te X R Cl 8cf Te Cl AcOH, LiX,
Cl2 Na2S2O5
7, 8 c R = H, X = Br; d R = H, X = I; e R = Me, X = Cl; f R = Br, X = Cl
Certain disubstituted acetylenes enter into a similar reaction. Thus, the benzo[b]tellurophenes 7g,h were synthesized with yields of 28 and 49% respectively from 1-phenyl-1-propyne under conditions similar to those described above [17]. However, heterocycles of type 7 were not obtained from diphenylacetylene and 1,4-diphenyl-1,3-butadiyne.
X Te 7g,h Me R 11ac Cl Te CH=C(Cl)Ph R 11df Te Cl C(Ph)=CHCl
7 g X = Cl, h X = Br; 11 a, d R = H, b, e R = Me, c, f R = Br
It should be noted that compounds 11a-c or 11d-f are also formed in addition to the products 7 if lithium chloride is used as source of halogen [17]. A possible mechanism for the reaction includes electrophilic addition of the intermediate tellurium halide acetates 12 (the structure of which was not accurately established) at the triple bond of the acetylenes followed by ring opening and reductive elimination of the -telluranes 13 [17, 18].
C CH + Te(OAc)nX4-n R 12 R Te(OAc)nX3-n X AcOH
X R 13
reductive elimination R
3-n
X Te 7
Te(OAc)n-1X
837
To judge from the behavior of various derivatives of the R2TeX2 type spontaneous elimination of electronegative substituents from -telluranes 13 is unlikely. Such a process obviously takes place under the influence of compounds present in the reaction mixture. In fact, when the tellurium dichloride 8b is boiled with phenylacetylene in acetic acid 3-chlorobenzo[b]tellurophene 7b, a mixture (95:5) of the Z- and E-isomers of 1,2-dichloro-1-phenylethylene, and a certain amount of compound 11a or 11d are formed [17].
Cl AcOH,
+
Te Cl 8b Cl
PhC CH
Ph 7b
Ph
Cl + 11a (11d) H
+
Cl Cl
+
Cl
It should be noted that compound 7c was also obtained by boiling acetophenone semicarbazone with TeO2 in acetic acid in the presence of lithium bromide [17]. It is clear that the TeO2, like SeO2 [19], oxidizes the semicarbazone to phenylacetylene, which reacts as described above. However, the yield of 3-bromobenzotellurophene (7c) amounts to only 9%, while the semicarbazones of other ketones do not react at all [17]. Benzo[b]thiophene and benzo[b]selenophene (yields 85 and 40% respectively) were synthesized by high-temperature reaction of diphenyl dichalcogenides with acetylene [20]. However, in the case of diphenyl ditelluride under the same conditions the yield of benzo[b]tellurophene (1) amounted to only 1-2%. Benzo[b]tellurophene 1 and a series of its derivatives were synthesized from compounds containing fivemembered tellurium-containing cyclic fragments. In particular, the product 1 was obtained with a 20% yield from the telluroindoxyl 14 (see section 1.3) by reduction with sodium borohydride [21]. Treatment of compound 14 with tetrahalides CX4 (X = Cl, Br) in the presence of triphenylphosphine gave 3-halobenzo[b]tellurophenes 7b,c with yields of 25 and 30% respectively [13]. The 3-substituted compounds 15a-c were obtained from telluroindoxyl 14 by the Wittig or WitterHorner reaction [13]. Here the isomeric compounds 16a-c were formed in addition to the products 15a-c. The ratio of the isomers depended on the nature of the employed phosphorane and on the reaction conditions. The reaction probably takes place through the intermediate 17, which undergoes either a sigmatropic 1,3-hydrogen shift, leading to the products 15, or a 1,3-sigmatropic tellurium shift with the formation of the product 16 [13].
O Te 14 CX4, Ph3P 7b,c Te 15ac 1517 a R = CN, b R = COMe, c R = CO2Et 16ac CH2R Me Te R
NaBH4 1
Ph3P=CHR Te 17ac
CHR
838
Such rearrangement is specific to telluroindoxyl and does not occur in the case of its sulfur and selenium analogs. With the use of telluroindoxyl in the WittigHorner reaction it is possible to employ lower temperatures and to reduce the amount of isomerization products 16 [13]. Thus, compounds 15a,c were synthesized with yields of 80 and 55% respectively. Aromatization by the action of dichlorodicyanobenzoquinone (DDQ) was used for the production of certain benzo[b]tellurophenes of type 2 and naphtho[1,2-b]tellurophene 18 [22].
DDQ Te R
2 Te
DDQ Te 18
R = NO2, COMe, CO2Et
Tellurochromenes were used for the synthesis of 2-formylbenzo[b]tellurophenes 19a-d. Oxidation of the tellurochromenes by selenium dioxide is accompanied by ring contraction, leading to the aldehydes 19a-d with yields of 25-60% [23, 24].
R1 SeO2, Py R2 R3 Te R2 Te R3 19ad R1 CHO
a R1 = R2 = R3 = H; b R1 = Me, R2 = R3 = H; c R1 = R3 = H, R2 = Me; d R1 = R2 = H, R3 = Me
The aldehyde 19a was also obtained when K2Cr2O7 was used as oxidizing agent [25]. The initial compounds 21 for the synthesis of telluro[2,3-b]quinolines 20 were oxidized to the diiodides 22, but the latter were not isolated but were used in situ. When 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was used as base the yields of the heterocycles 20 were relatively low (18-35%) [26].
R2 R3 I2, CCl4 N R4 21 R2 R3 N R4 20 Te R1 Te R4 22 N I Te I R1 R3 R2 R1 DBU, CHCl3 HI
R1 = R2 = R3 = R4 = H; further indicated R H: R4 = Me; R2 = R4 = Me; R3 = Cl; R1 = Ph
839
1.2. Reactions of Benzo[b]tellurophene and Its Derivatives Like other derivatives of dicoordinated tellurium, benzo[b]tellurophene is oxidized by halogens or SO2Cl2 under mild conditions to the 1,1-dihalides 23 with yields close to quantitative [9, 11, 17]. Treatment of benzo[b]tellurophene 1 with methyl bromide leads to the telluronium salt 24 [9]. Electrophilic substitution reactions, typical of benzannelated five-membered heterocycles, are complicated in the case of compound 1 by the ability of the dicoordinated tellurium atom to change to the tetracoordinated state and form complexes with various Lewis acids. Thus, 2-acetylbenzo[b]tellurophene was obtained with a yield of 10% during treatment of the benzotellurophene 1 with acetic anhydride in the presence of TiCl4 [13]. If TiCl4 is replaced by trifluoroacetic acid a mixture (76:24) of 2- and 3-acetylbenzo[b]tellurophenes is formed. The 2-acetyl-3-methyl-, 2-acetyl-3-bromo-, and 3-acetyl-2-methylbenzo[b]tellurophenes were synthesized from 3-methyl, 3-bromo-, and 2-methyl-substituted derivatives of compound 1 under the same conditions with yields of 80, 40, and 25% respectively [13]. The treatment of benzotellurophene 1 with hexamethylenetetramine in the presence of trifluoroacetic acid gave its 2-formyl derivative with a yield of 10% [13]. In contrast to benzo[b]thiophene, where halogenation takes place at positions 2 and 3 of the heterocycle, in the case of benzo[b]tellurophene 1 and also of its 3-substituted and 3,6-disubstituted derivatives the process takes place at position 2. Its first stage is the formation of -telluranes of type 23. When compounds 23 (with R1 = H) are boiled with halogens or SO2Cl2 in o-dichlorobenzene, 1,1,2-trihalobenzo[b]tellurophenes 25 are formed with yields of 50-80%. Reduction of the latter with hydrazine hydrate gave 2-halobenzo[b]tellurophenes. The 1,1,2-tribromide 25 does not undergo further bromination. However, the bromination of 1,1,3-tribromobenzo[b]tellurophene gave 1,1,2,3-tetrabromobenzo[b]tellurophene, which was reduced by the action of hydrazine hydrate to the 2,3-dibromo derivative [13].
R2 R3 Te R1 X2 / SO2Cl2 R3 23 X 1 MeBr
+ _ Te Br Me
R2 Te X R1
1 Ac2O/CF3COOH Te
COMe
24 X2, o-Cl2C6H4, 23 R1 = H R3
R2 Te X 25 X X
N2 H4 _ 2X
R2 R3 Te X
23 R1 = COCl, R2 = R3 = H, X = Cl; R1 = COOH, R2 = R3 = H, X = Br [11]; 23, 25 R1 = H, R2 = R3 = H, X = Cl, Br [9]; R2 = Cl, Br, R3 = H, X = Cl [17]; R2 = Cl, R3 = Me, Br, X = Cl [1]
2-Lithiobenzo[b]tellurophene was obtained by the reaction of compound (1) with butyllithium (THF, 0C) [11, 27]. Its carbonization led to benzo[b]tellurophene-2-carboxylic acid [11], reaction with DMF led to 2-formylbenzo[b]tellurophene (yield 60%), and reaction with methyl iodide and D2O led to 2-methylbenzo[b]tellurophene (yield 88%) and 2-deuterobenzo[b]tellurophene (yield 98%) respectively [27]. If the reaction with butyllithium is conducted in hexane at 20C, the CTe bonds are cleaved with the formation of Bu2Te and the dilithium derivative 26 [27]. Treatment of compound 26 with Bu2SnCl2 gave 1,1-dibutylbenzostannole with an 80% yield [27]. 840
BuLi, THF, 0C Te CH=CHLi Bu2SnCl2 Li 26 LiCl Bu Sn Bu Li
BuLi, C6H14, 20 oC Bu2Te
Attempts at the synthesis of 3-lithiobenzo[b]tellurophene by double decomposition of 3-bromobenzo[b]tellurophene with butyllithium were unsuccessful. Even at low temperatures the only product was 2-butyltellurophenylacetylene [17, 18].
Br
BuLi
C CH
LiBr
Te
TeBu
Benzo[b]tellurophenes containing the substituents COOH, COCl, CHO, COMe, and CN enter into the usual reactions for these groups [11, 13], and this made it possible to synthesize new representatives of the series.
1.3. 3-Oxo-2,3-dihydrobenzo[b]tellurophene and Its Derivatives Telluroindoxyl 14 was first obtained by Renson [21] with a fairly low yield starting from (2-carboxyphenyl)telluroacetic acid.
COOH Te/2
1. NaBH4 2. ClCH2COOH
COOH Te OCOMe KOH 14 Te CH2COOH
Ac2O,
A preparative method for the production of compound 14 with a yield of 80% involves reaction of an alcohol solution of potassium hydroxide with 2-(bromotellurenyl)acetophenone [21]. Ammonia [28] or potassium acetate [29] can be used in place of potassium hydroxide. Another approach to the synthesis of the telluroindoxyl 14 (with a yield of 36%) was based on the intramolecular cyclization of 2-butyltellurodiazoacetophenone [30].
841
COMe
TeBr
B: HBr
14
CuO, C6H6,
COMe
TeBu
1. HCO2Me, Na, Et2O 2. TosN3, EtOH
COCHN2
TeBu
Compound 14 was obtained with a yield of 84% by boiling a solution of 3-chlorobenzo[b]tellurophene 7b in trifluoroacetic acid [17]. It should be noted that 3-bromobenzo[b]tellurophene 7c does not enter into such a reaction.
Cl H Te H Te
+
7b
CF3COOH,
Cl H H
H2O
14
The telluroindoxyl 14 exists exclusively in the keto form in all solvents and does not form a 3-methoxy derivative when treated with dimethyl sulfate or methyl iodide in an alkaline medium. It enters readily into reactions characteristic of ketones, forming an oxime, a semicarbazone, and a 2,4-dinitrophenylhydrazone [21]. If it is boiled with phenylhydrazine in acetic acid, the tetracyclic product 27 is formed [21].
NR Te PhNHNH2, AcOH, Te 27 H N
RNH2 H2O
14
R = OH, NHCONH2, 2,4-(O2N)2C6H3NH
Like other derivatives of dicoordinated tellurium, compound 14 is oxidized by halogens to the corresponding -telluranes, while in reaction with methyl iodide it forms a telluronium salt [21].
O MeI
+ Te
O 14 X2 X Te X
Me
_ I
X = Cl, Br, I
When a solution of telluroindoxyl in DMF is heated for a long time [21] or during oxidation with K3Fe(CN)6 in an alkaline medium [29] telluroindigo 28 is formed as a violet crystalline compound with = 637 nm (for selenoindigo = 564 nm). Telluroindoxyl condenses readily with nitrosobenzene and DMF dimethyl acetal [21]. In reaction with aromatic aldehydes it forms 2-arylidene-3-oxo-2,3dihydrobenzo[b]tellurophenes (telluroaurones) 29 [21]. These same compounds were obtained with yields of >80% by the condensation of 2-bromotellurenylacetophenone with aromatic aldehydes in the presence of piperidine [31]
842
O O Te Te
28
O2 or K3Fe(CN)6 O Te CHNMe2 Me2NCH(OMe)2 MeOH ArCHO H2O O Te 29 O COMe + ArCHO TeBr Te Br 29 Ar = Ph, 2-MeC6H4, 3-O2NC6H4 [21]; 2-ClC6H4, 4-ClC6H4, 4-IC6H4, 4-MeC6H4, 4-MeOC6H4, 4-Me2NC6H4, 1-C10H7 [31] piperidine CH CHAr AcOH, CHAr PhNO 14 H2O Te NPh
Telluroindoxyl is unstable in an acidic medium. During the action of acids under mild conditions the CH2Te bond is cleaved, leading to 2-acetylphenyltellurenyl halides or tellurocyanate [21]. Reducing agents (NaHSO3 and H3PO2) transform telluroindoxyl into bis(2-acetyl) ditelluride [32].
COMe Te/2 NaHSO3 14 or H3PO4 X = Cl, Br, I, CN TeX HX COMe
1.4. Physicochemical Characteristics of Benzo[b]tellurophene and Its Derivatives For benzo[b]tellurophene 1 and its derivatives the photoelectronic [33], mass [34], and IR [35] spectra and also the 1H [36, 37] and 125Te [38, 39] NMR spectra have been investigated. As follows from analysis of the photoelectronic spectrum, the HOMO of compound 1 is mainly localized at the heteroatom, and this explains its ability to enter into oxidative addition. Table 1 presents data from the 1H NMR spectra of benzo[b]tellurophene, benzo[b]furan, benzo[b]thiophene, and benzo[b]selenophene. It was shown that the chemical shifts of the protons at position 3 correlate with the electronegativity of the heteroatom [36, 40, 41].
843
TABLE 1. The 1H NMR Spectra of Benzofuran, Benzothiophene, and Benzotellurophene

4 5 6 7 3 2
Position of protons 2 3 4 5 6 7
Chemical shifts, , ppm. E=O E=Se E=Te [40] E=S [41] [37] [37] 7.52 6.66 7.49 7.13 7.19 7.42 7.27 7.19 7.70 7.25 7.22 7.77 7.79 7.42 7.69 7.24 7.14 7.77 8.55 7.84 7.71 7.26 7.03 7.82
SSCC, J, Hz J E=O [40] 2.19 0.87 7.89 1.28 0.80 7.27 0.92 8.43 E=S [41] E=Se [37] E=Te [37] 5.57 0.86 8.09 1.16 0.73 7.22 1.17 8.06 5.57 0.65 7.97 1.02 0.48 7.22 1.17 8.27 6.95 0.43 7.97 1.07 0.51 7.24 1.08 8.00
J2,3 J3,5 J4,5 J4,6 J4,7 J5,6 J5,7 J6,7
The 125Te chemical shifts of a series of monosubstituted benzotellurophenes are given in [38, 39]. They are more sensitive to the nature of the substituents than the 77Se chemical shifts in the corresponding benzo[b]selenophenes. A good linear correlation was obtained between the 125Te chemical shifts of benzo[b]tellurophenes and of tellurophenes containing the same substituents, which demonstrates the similarity in the mechanism of transmission of the electronic effects of the latter in both heterocycles. The ionization constants (pKa) of benzo[b]tellurophene-2-carboxylic acid and its hetero analogs are given in Table 2. In the transition from benzofuran-2-carboxylic acid to benzo[b]tellurophene-2-carboxylic acid the pKa value increases by approximately 1.0 [42]. Comparison of these pKa values with the pKa values of TABLE 2. The Ionization Constants (pKa)* and CO Values of the Hetero Analogs
E
COOH
[42]. The Solvolysis Characteristics (30% EtOH, [43]

kE/kS*3 1.5 1.0 1.7 5.2 kB/kM103 *4 4.8 9.7 9.5 8.9
60C) of the Hetero Analogs

E O S Se Te pKa 4.20 (4.54) 4.67 (5.05) 4.79 (5.14) 5.13 (5.48) CO*2 1758 (1755) 1733 (1734) 1731 (1728) 1716 (1721)
CH2CO2Et
k105 *3 (s-1) 0.95 0.63 1.04 3.26
_______ * The pKa value was determined by potentiometry in a 1:1 mixture of water and ethanol [42]; the pKa values of the corresponding nonannelated hetero analogs are given in parentheses. *2 The CO values of the nonannelated heterocycles are given in parentheses [42]. *3 kE is the solvolysis rate constant of the respective heterocycle, kS is the solvolysis rate constant of 1-(2-benzo[b]thienyl)ethyl acetate [43]. *4 kB is the solvolysis rate constant of the benzannelated derivatives, kM is the same for the monocyclic derivatives [43]. 844
tellurophene-2-carboxylic acid and its hetero analogs [42] shows that benzannelation reduces the pKa value by approximately 0.35 irrespective of the nature of the heteroatom. It should be noted that in contrast to the 2-carboxy derivatives the pKa values of benzo[b]tellurophene-3-carboxylic acid and its benzo[b]furan, benzo[b]thiophene, and benzo[b]selenophene analogs are close to each other (5.79, 5.54, 5.67, and 5.65 respectively) [13]. Table 2 also gives data on the kinetics of the solvolysis of 1-(2-hetaryl)ethyl acetates [43], which show that the solvolysis rate decreases in the series of derivatives in the following order: Benzotellurophene > benzoselenophene > benzofuran > benzothiophene.
2. DIBENZO[b,d]TELLUROPHENE Some data on dibenzo[b,d]tellurophene and its derivatives, published after 1985, were reviewed in [4-6].
2.1. Synthesis of Dibenzo[b,d]tellurophene and Its Derivatives The first representative of dibenzotellurophenes, 5,5-dibromobenzotellurophene (30a), was obtained with a low yield by the reaction of biphenyl with TeBr4 at 240-250C [3]. Reaction with TeCl4 leads to the 5,5-dichloride 30b with a higher yield. Both dihalides are easily reduced to dibenzotellurophene 31a by the action of K2S2O5 [3]. A possible mechanism for the production of the dihalides 30 involves the initial formation of 4-biphenylyltellurium trihalides 32 and their rearrangement to the 2-isomers 33, which undergo cyclization with the elimination of HX (X = Cl, Br). A similar mechanism was proposed for the reaction of diphenyl ether with TeCl4, leading to 10,10-dichlorophenoxatellurin [44].
+ TeX4 HX
X3Te TeX3 33a,b K2S2O5 2X Te X 30a,b 30, 32, 33 a X = Br, b X = Cl X 31a Te
32a,b
HX
If the reaction between biphenyl and TeCl4 is carried out at a lower temperature (140-160C), it stops at the formation of the trichloride 32b and does not lead to the product 30b, as stated in [45]. In fact, reduction of the reaction product with sodium sulfide gives red-orange crystals melting at 175.5C [clearly, bis(2-biphenylyl) ditelluride], whereas the dibenzotellurophene 31a is a light-yellow compound with a melting point of 92.0-94.5C.
845
The 5,5-dichloride 30b was obtained with an almost quantitative yield by boiling 2-diphenyltellurium trichloride 33b (synthesized from biphenylylmercury chloride and TeCl4 with a yield of 76% or from 2-lithiobiphenyl and TeCl4 with a yield of 16%) in nitrobenzene [46].
PhNO2, 33b 30b HCl
It is clear that the most general method for the synthesis of dibenzotellurophenes is the reaction of 2,2'-diiodobiphenyls with a "tellurizing" agent in N-methylpyrrolidone (NMP) [47]. This agent, denoted as Te Cu, is produced by the reaction of Na2Te with CuI (ratio 1:2) in N-MP. Its structure was not determined precisely; it was assumed that it was a mixture of Te-containing compounds, elemental tellurium, and metallic copper [47]. The yields of the dibenzotellurophenes 31a-e amounted to 40-52%.
R2 R3 I I R2 TeCu, NMP, R1 R2 R2 R1 Te 31ae 31 b R1 = R3 = H, R2 = NO2; c R1 = NO2, R2 = H, R3 = Cl; d R1 = R3 = NO2, R2 = H; e R1 = NO2, R2 = H, R3 = NH2
R3
In other methods for the synthesis of compounds of type 31 2,2'-dilithiobiphenyls and mercuriobiphenyls were used as starting compounds [48-51]. Thus, dibenzotellurophenes 31a,f were obtained with yields of 5254% in the reaction of the dilithium derivatives 34a,b with TeCl2 [48, 49, 51]. If the synthetic equivalent 1,1dichloro-2,5-dihydrotellurophene was used in place of TeCl2 [52] the yield of the heterocycle 30a was increased to 78% [53].
R Li Li 34a,b
R +
TeCl2
R LiCl Te 31a,f
31 f, 34 b R = Me; 34 a R = H
However, in the reaction of the dilithium derivative 34c with 1,1-dichloro-2,5-dihydrotellurophene the product 31g was obtained with a yield of 13% [53].
MeO MeO Li 34c Li OMe THF, 20C OMe MeO OMe OMe Te 31g
+
Te Cl Cl
MeO CH2=CHCH=CH2 LiCl
846
By analogy with the reactions of aryllithiums with tellurium, which leads after oxidation of the formed lithium tellurophenolates ArTeLi to diaryl tellurides, it could be expected that treatment of the dilithium derivative 34c with tellurium followed by oxidation with atmospheric oxygen would lead to the product 35 with a six-membered ring containing two Te atoms. However, the only reaction product is the dibenzotellurophene 31g, which is probably formed by elimination of the tellurium atom from compound 35.
MeO 1. Te 34c 2. O2 Te Te 35 MeO OMe Te 31g OMe
It should be noted that the selenium analog of the latter was isolated with a yield of only 4% [53] and the yield of the dibenzotellurophene 31h was extremely low [54].
NMe2 NMe2 NMe2 NMe2
Li Li
Te 31h
The dibenzotellurophenes 31b,f were obtained with fairly high yields (79-82%) by heating tellurium with the tetrameric 2-mercurio-2,2'-biphenylenes [48, 49, 51]. However, the poor accessibility of the latter makes this reaction unsuitable for preparation of the products.
R
Hg
+ Te Hg Te R R
31b,f
The same can be said of the production of the dibenzotellurophene 31a by thermal decomposition of bis(2,2'-biphenylene)tellurium 36 [48, 49, 51, 55]. Since the precursor of the spiran 36 is 2,2'-dilithiobiphenyl, which can be converted directly into compound 31a, this reaction does not have significant synthetic value.
Te
31a
higher polyphenylenes
36
847
A specific method for the synthesis of the dibenzotellurophene 31a, which can clearly be used for the production of other tellurium-containing heterocycles, involves heating dibenzothiophene S,S-oxide with powdered tellurium [56]. However, the yield of the product 31a was only 10%. Compound 31a was also obtained with a small yield by heating 5,5,10,10-thianthrene tetroxide with amorphous tellurium [57].
+ Te
SO2
31a
S O2
O2 S
+ Te
SO2
S O2
The synthesis of octafluorodibenzotellurophene 31i was realized by the high-temperature reaction of tellurium with 2,2-diiodooctafluorobiphenyl (yield 66%) [58], 1,2-diiodotetrafluorobenzene (yield 17%) [59, 60], and bis(2-nonafluorobiphenylyl)mercury (yield 10%) [59]. The same product was obtained with a yield of 17% from 2,2'-dilithiooctafluorobiphenyl and TeCl4 [58]. It should be noted that the corresponding dibenzotellurophene 5,5-dichlorides are formed in the reaction of 2,2'-dilithiobiphenyls 34a [48, 49] and 34c [53] with TeCl4.
F I I
Te, 325 oC Te, 300 oC F /2 Hg F F Te 31i Te, 450 oC I F I F TeCl4
F Li Li
Te-(Trifluoromethyl)dibenzotellurophenium triflate 37 was obtained with a yield of 84% by the reaction of 2-biphenylyl trifluoromethyl telluride with DMSO and Tf2O [61, 62]. The intermediate in this reaction is probably the salt 38, formed by attack of the sulfonium salt 39 at the tellurium atom.
848
OTf
+
TeCF3
Me SMe + TfO 39
+ Me Te CF3
TfO Me2SO + Tf2O
Me 38
_ TfO
Me2S TfOH
_ CF3 TfO 37
+ Te
The salt 37 was also obtained from 2-biphenylyl trifluoromethyl telluride and bromine in methylene chloride followed by the addition of TfOH to the reaction mixture [62]. Some reactions of the salt 37 [62, 63] are shown below.
O2N
+ Te
NO2 _ TfO
TfONO2
37
+ _ Bu4N Br
+ Te
CF3 (76%)
SO3, H2SO4, 40 oC, 1 x _ SO3

+ Te
CF3
Br-
CF3 40
The salt 37 and its sulfur and selenium analogs are electrophilic trifluoromethylating compounds, the reactivity of which increases in the order Te < Se <S [62]. From the practical stand point it is more convenient to use salts of type 40 [63], since they have strong trifluoromethylating ability, while the side products of the reaction dibenzotellurophene-3-sulfonic acid and its analogs are soluble in water and are easily separated from the trifluoromethylation products.
2.2. Reactions of Dibenzo[b,d]tellurophene and Its Derivatives Like other tellurium-containing compounds, dibenzo[b,d]tellurophene 31a enters readily into oxidative addition of halogens, forming dibenzotellurophene 5,5-dihalides with high yields [46, 48, 49]. Since the latter are easily reduced to the initial compound by the action of K2S2O5, the transformations are used for the purification of dibenzotellurophene [48, 49]. Reaction with methyl iodide leads to Te-methyldibenzotellurophenium iodide, which is unstable and decomposes when heated in ethanol. Treatment of dibenzo[b,d]tellurophene with chloramine-T gave 2,2'-biphenylenetelluriotosylamine [49, 51]. Hydrolysis of this compound leads to dibenzotellurophene oxide [49]. Synthesis of the latter was also achieved by hydrolysis of dibenzotellurophene 5,5-dichloride [3]. 849
+ Te I Me
MeI X2 31a K2S2O5 NaCl 4-MeC6H4SO2NNaCl
30
H2O, H
+ Te _ N SO2C6H4Me-4
Te O
Treatment of dibenzotellurophene 31a with an excess of butyllithium led to cleavage of both CTe bonds, resulting in the formation of 2,2'-dilithiobiphenyl and dibutyl telluride [50]. When compound 31a is heated with powdered sulfur the tellurium atom is substituted by a sulfur atom [3]. The action of concentrated nitric acid leads to 3-nitrodibenzotellurophene 5,5-dinitrate, which on reduction gives 3-nitrobenzotellurophene [57].
S, Te S HNO3 K2S2O5 _ 2NO3 NO2 ONO2 NO2 Te 31a Bu2Te Li Li BuLi
Te O2NO
Dibenzotellurophene forms stable 1:1 adducts with HgCl2, 1,3,5-trinitrobenzene [49], picric acid [49, 64], and tetracyanoquinodimethane (TCQDM) [65]. It is detellurized by triiron dodecacarbonyl, where the main products are the dibenzoferrole 41, isolated with a yield of 28%, and FeTe [66].
31a
Fe(CO)12 Fe(CO)3 Fe(CO)3 41
+ FeTe
850
Like the noncyclic diaryltellurium dichlorides, which form aryltellurium trichlorides in reaction with TeCl4 [67], the dibenzotellurophene 5,5-dichloride 30b is converted into 2,2-bis(trichlorotelluro)biphenyl 42 (yield 87%) when boiled with TeCl4 in o-dichlorobenzene [68]. Reduction of this product with an aqueous solution of Na2S2O5 gives the poly(o-phenyleneditelluride) 43, contaminated with metallic tellurium impurity; a side product of the reaction is dibenzotellurophene 31a, isolated with a yield of 8%.
30b + TeCl4 o-Cl2C6H4, Na2S2O5
TeCl3 TeCl3 42
Te 31a + Te n 43
2.3. Molecular and Crystal Structure of Dibenzotellurophene and Its Derivatives* The molecular and crystal structures of dibenzotellurophene 31a [69], its complex with TCQDM [65], and dibenzotellurophene 5,5-diiodide [70] were studied by X-ray crystallographic analysis. The dibenzotellurophene molecule is practically planar; the dihedral angles between the benzene rings and the heterocycle amount to 1.4 and 0.6. The length of the TeC bond (2.087 ) is within the normal limits for such bonds [71]. The CTeC bond angle (81.7) is the smallest in the series of related heterocyclic systems containing elements of group VIA as heteroatoms. Dibenzotellurophene 5,5-diiodide has the structure of a trigonal bipyramid [70]. The dibenzotellurophene fragment of this compound shows a greater departure from planarity compared with dibenzotellurophene: The dihedral angles are 3.3. The TeC bond length (2.12 ) and the CTeC bond angle (81.8) are almost the same as in dibenzotellurophene. The iodine atoms occupy the apical positions. The TeI bond length is 2.936 , and the ITeI angle is 178.5. The Te atom forms weak intermolecular bonds with the I atoms of two neighboring molecules; the TeI bond lengths are 3.717 and 3.696 . (The sum of van der Waals radii of Te and I is 4.35 [72].) Thus, with allowance for the secondary bonds the coordination polyhedron at the Te atom represents an octahedron. The TeI interactions link the individual molecules of the diiodide in the crystal into polymeric chains. In the 125Te NMR spectrum the chemical shift for dibenzotellurophene amounts to 486.3 ppm [73]. The mass spectra of octafluorodibenzotellurophene were studied in [74]. The work was carried out with financial support from the Russian Fundamental Research Fund (project 00-15-97320) and INTAS (project 884-01).
_______ * See also: E. Lukevics, P. Arsenyan, S. Belyakov, and O. Pudova, Khim. Geterotsikl. Soedin., 867 (2002) or Chem. Heterocyclic Compds, 763 (2002). Editor's comment. 851
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853
ACYLATION OF AMINES WITH 5-PHENYLTETRAZOL-2-YLACETYL CHLORIDE

S. M. Putis, V. Yu. Zubarev, V. S. Poplavskii, and V. A. Ostrovskii The acylation of primary and secondary amines by 5-phenyltetrazol-2-ylacetyl chloride leads to the corresponding tetrazolylacetamides irrespective of the nature of the substituent in the structure of the amine. Keywords: 5-phenyltetrazol-2-ylacetamide, 5-phenyltetrazol-2-ylacetyl chloride, acylation. Tetrazolylacetic acids and their derivatives are regarded as potential biologically active compounds. A special position is occupied by the amides of tetrazolylacetic acids, which are intermediate products for the synthesis of biologically active compounds. For example, antibiotics of the cephalosporin series (kefzol, ceftezol), which contain a tetrazolylacetic acid fragment in their chemical structure, have found widespread use in clinical practise [1]. These drugs form a group of semisynthetic cephalosporin antibiotics that are highly effective and have extended therapeutic activity. The search for analogous compounds having improved characteristics and also investigation of the reactivity of the key reagents in the synthesis of compounds of diverse practical significance present an urgent task in modern medical chemistry [2, 3]. The esters of tetrazolylacetic acids play a special role in the synthesis of antibiotics containing a tetrazole fragment [4]. In previous work we showed for the case of ethyl 5-phenyltetrazol-2-ylacetate that such esters can be regarded as key reagents in the synthesis of certain tetrazolylacetamides [5]. However, the aminolysis of tetrazolylacetic esters does not make it possible to obtain the corresponding amides from amines with branched structures and aromatic or heterocyclic substituents [5]. An alternative to aminolysis of the esters may be acylation of the amines by carboxylic acid chlorides. Unfortunately, there are no published data that would characterize the ability of tetrazolylacetyl chlorides to enter into the acylation of nitrogen compounds. Exceptions are the reactions with 7-aminocephalosporanic acid and its derivatives and also the transacylation of tetrazoles [4, 6, 7]. In the present work we studied the acylation of various amines by 5-phenyltetrazol-2-ylacetyl chloride. In order to produce the respective acetamides we used amines with low basicity (aniline and its derivatives) and with branched aliphatic and bulky substituents containing several reactive amino groups and also some weakly nucleophilic heterocyclic amines. The acylation was conducted in ether, chloroform, or THF depending on the solubility of the amine [7]. Triethylamine was used as base to combine with the released hydrogen chloride. The amides of 5-phenyltetrazol2-ylacetamides were synthesized from the respective acid chlorides according to the following scheme:
__________________________________________________________________________________________ St. Petersburg State Technological Institute (Technical University), St. Petersburg, Russia; e-mail: ostrovskii@mail.convey.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 997-1005, July, 2004. Original article submitted April 8, 2004. 854 0009-3122/04/4007-08542004 Springer Science+Business Media, Inc.
Ph N N N 1
1
+
Cl
Et3N R1R2NH Et3N . HCl
Ph N N N N 214
O NR1R2
2 R1 = R2 = Et; 3 R1 = R2 = CH2CH2CN; 4 R1R2 = (CH2)5; 5 R1R2 = (CH2)2O(CH2)2; 6 R R2 = (CH2)2N(CO2Et)(CH2)2; 7-14 R1 = H; R2 = Ph, 8 R2 = 4-O2NC6H4, 9 R2 = 3-NO2C6H4, 10 R2 = 2-O2NC6H4, 11 R2 = 3,5-(NO2)2C6H3, 12 R2 = MeCHPh, 13 R2 = (1,2,4-triazol-4-yl), 14 R2 = (4-methylfurazan-3-yl)
By the effective acylation of sterically blocked and low-basicity amines with 5-phenyltetrazol-2-ylacetyl chloride it was possible the extend this strategy to the synthesis of the amides from bifunctional amines. As model bifunctional amines we used diazo-18-crown-6 (having sterically blocked amino groups) and 3,4-diaminofurazan, which contains amino groups with reduced nucleophilicity [8]. The above-mentioned amines were acylated with a twofold molar excess of the acid chloride 1. In both cases we obtained the products from exhaustive substitution, i.e., N,N'-bis(5-phenyltetrazol-2-ylacetyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecane (15) and N,N'-bis(5-phenyltetrazol-2-ylmethylcarbonyl)-3,4-diaminofurazan (16).
Ph N N diazo-18-crown-6 Ph N 2 N N N Cl N N 3,4-diaminofurazan 16 HN N O NH N O Ph N N O O O O 15 N N N N O Ph N N N O O N O N N N N Ph
While continuing this direction of investigation, we attempted the exhaustive acylation of hydrazine. However, during the reaction in THF we only isolated the monosubstitution product. For this reason it was necessary to use more rigorous conditions and to use boiling toluene, in which the monosubstitution product formed at the first stage of acylation is readily soluble. Under these conditions exhaustive acylation is complete in 10 h (monitored by TLC) with the formation of N,N'-bis(5-phenyltetrazol-2-ylmethylcarbonyl)-1,2-hydrazine (17).
Ph 2 1 Ph N N N N O N H 17 N H O N N N N Et3N NH2NH2 toluene
Unfortunately, we were unable to obtain the amide 13 by this method. Analysis of the published data showed that quaternary 1,2,4-triazolium salts are formed during the acylation of 4-amino-1,2,4-triazole with carboxylic acid chlorides used in equimolar amounts. With the addition of a base (such as triethylamine) these salts undergo cleavage of the triazole ring [9]. 855
O O R Cl N N + N N N NH2 Et3N O R NH2NH2 + HCO2H O R NHNH2 N NH CHO N NH2 R _ Cl
N NH2
H2O
We used 4-amino-1,2,4-triazole itself as base for the acylation of 4-amino-1,2,4-triazole at the amino group. N-(1,2,4-Triazol-2-yl)-5-phenyltriazol-2-ylacetamide (13) was isolated as a result of the reaction.
N
2 H2N
Ph
N N N N
O
N H
13
N N N
Thus, acylation with 5-phenyltetrazol-2-ylacetyl chloride takes place readily both with highly basic amines containing branched substituents and with low-basicity amines. At the same time it was not possible to acylate N,N-diphenylamine with the acid chloride (1). Steric hindrances probably play a significant role in this case [10]. The tetrazolylacetamides, which have become accessible as a result of the present investigation, in turn open up the way to further functionalization with the production of polynuclear tetrazoles. Thus, the corresponding tritetrazole 18 was obtained from the amide 3 containing two cyanoethyl groups.
Ph N N O N N N NH N
N N
N 18
NH
N N
It is interesting that an attempt at the production of the tritetrazole 18 using the cycloaddition [11] of dimethylammonium azide to the dinitrile 3 in DMF did not lead to the desired result. We therefore used the recently proposed conditions [12] (azidization with triethylammonium azide in toluene) for the preparation of the tritetrazole 18. By optimizing these conditions it was possible to reduce the temperature of the process from 110 to 95C and to shorten the reaction time from 24 to 6 h (monitored by TLC). 856
TABLE 1. The 1H NMR Spectra of the Amides 2-18

Compound 2 3 4 5 6 7 Chemical shifts of signals, , ppm (J, Hz) N(2)CH2 (s) Other signals [NH (s)] 5.91 6.10 5.95 5.99 6.01 5.77 [10.64] 5.87 [11.25] 5.84 [11.11] 5.90 [10.92] 5.92 [11.57] 5.57 [9.01] 5.86 [12.30] 5.95 [10.40] 5.95 (4) 5.89 (4) [11.24 (2H)] 5.68 (4) [10.92 (2)] 5.99 3.43 (2, q, J = 7.0, 2); 3.31 (2, q, J = 7.0, 2); 1.20 (3, t, J = 6.9, 3); 1.05 (3, t, J = 6.9, 3) 3.83 (2, t, J = 6.9, 2); 3.63 (2, t, J = 6.9, 2); 3.03 (2, t, J = 6.9, 2); 2.78 (2, t, J = 6.9, 2) 3.48-3.43 (4, m, 2); 1.61 (4, s, 2); 1.48 (2, s, 2) 3.69 (2, t, J = 4.4, 2); 3.61 (2, t, J = 4.4, 2); 3.54 (2, t, J = 4.4, 2); 3.47 (2, t, J = 4.4, 2) 4.08 (2, q, J = 7.2, 2); 3.54-3.47 (6, m, 2); 3.42-3.40 (2, m, 2); 1.20 (3, t, J =7.0, 3) 7.61-7.55 (2, m, CONH-C6H5); 7.35 (2, t, J = 7.1 Hz, CONH-C6H5); 7.11 (1, t, J = 7.0 Hz, CONH-C6H5) 8.25 (2, d, J = 9.5, ); 7.84 (2, d, J = 8.7, ) 8.58 (1, s, CH); 7.98-7.90 (2, m, CH); 7.65 (1, t, J = 8.4, CH) 8.01 (1, d, J = 7.0, ); 7.76 (2, d, J = 7.0, ); 7.45 (1, J = 5, ) 8.82 (2, d, J = 2.2, CH); 8.56 (1, t, J = 2.0, CH) 7.40-7.31 (4H, m, CH-C6H5); 7.30-7.22 (1H, m, CH-C6H5); 4.94 (1H, q, J = 7.2, CH); 1.41 (3, d, J = 7.2, CH3) 8.76 (2, s, in triazole) 2.39 (3, s, 3) 3.80-3.54 (24, m, CH2) 17.1-12.8 (2, br. s, CN4H); 3.87 (2, t, J = 6.9, 2); 3.69 (2, t, J=6.9, 2); 3.37 (2, t, J = 6.9, 2); 3.16 (2, t, J = 6.9, 2)
C(5)C6H5 (m) 8.09-8.07 (2), 7.60-7.54 (3) 8.09-8.07 (2), 7.60-7.55 (3) 8.09-8.06 (2), 7.60-7.56 (3) 8.09-8.06 (2), 7.61-7.53 (3) 8.08-8.06 (2), 7.60-7.55 (3) 8.10-8.08 (2), 7.61-7.55 (3) 8.11-8.07 (2), 7.60-7.52 (3) 8.11-8.07 (2), 7.60-7.53 (3) 8.11-8.09 (2), 7.60-7.55 (3) 8.11-8.08 (2), 7.61-7.55 (3) 8.10-8.01 (2), 7.61-7.51 (3) 8.13-8.03 (2), 7.63-7.52 (3) 8.18-8.11 (2), 7.59-7.50 (3) 8.09-8.04 (4), 7.58-7.52 (6) 8.16-8.03 (4), 7.65-7.49 (6) 8.12-8.03 (4), 7.61-7.51 (6) 8.12-8.03 (2), 7.60 7.53 (3)
8 9 10 11 12
13 14* 15 16 17 18
_______ * The 1H NMR spectrum of compound 14 was recorded in acetone-d6, and the spectra of the other compounds were recorded in DMSO-d6.
EXPERIMENTAL The 1H and 13C NMR spectra of the synthesized amides were recorded on a Bruker DPX-300 instrument (300 MHz for 1H and 75 MHz for 13C) with DMSO-d6 as internal standard. The IR spectra were obtained on a Perkin-Elmer Spectrum 1000 instrument for tablets with potassium bromide. Elemental analysis was performed on a semiautomatic Hewlett-Packard 185 C,H,N analyzer. The melting points were determined on a PTP instrument at 1 deg/min in the melting range. The reaction was monitored by TLC on Merck Kieselgel 60F245 plates with development in UV light.
857
858
TABLE 2. The 13C NMR Spectra of the Amides 2-18

Compound 2 3 4 5 6 7 8 9 10 11 12 13 14* 15 16 17 18 Chemical shifts, , ppm N(2)CH2 53.9 53.9 54.0 53.9 54.0 55.3 55.5 55.3 55.0 55.4 54.8 53.4 55.6 54.1 54.8 54.2 54.0
CH2=O 163.9 165.2 163.9 164.0 164.0 164.2 164.3 164.3 164.3 164.5 164.1 164.6 165.9 164.9 164.3 165.1 164.8
CN4 163.4 164.1 162.6 163.3 163.4 162.9 164.1 163.8 163.7 163.7 163.2 164.4 164.9 163.9 164.1 163.9 164.1
C6H5 130.5, 129.3, 126.9, 126.3 130.6, 129.3, 126.8, 126.3 130.5, 129.3, 126.9, 126.2 130.5, 129.3, 126.9, 126.2 130.6, 129.3, 126.9, 127.3 130.6, 139.3, 126.8, 126.3 130.7, 129.3, 126.7, 126.4 130.6, 129.3, 126.7, 126.3 130.6, 129.3, 126.7, 126.4 130.7, 130.2, 126.7, 126.4 130.6, 129.3, 126.9, 126.3 130.8, 129.4, 126.6, 126.4 131.3, 129.9, 128.3, 127.4 130.5, 129.2, 126.9, 126.3 130.7, 129.4, 126.7, 126.4 131.6, 130.2, 127.6, 127.2 130.6, 129.3, 126.9, 126.3
Other signals
13.9 (2), 12.7 (3) 118.8 (N), 42.4 (ON2), 41.5 (ON2), 16.6 (2CN), 15.2 (2CN) 45.3, 42.5, 25.7, 25.1, 23.7 (2) 65.8 (2O2), 44.8, 41.9 (2) 154.6 (), 61.0 (2), 44.1, 43.1, 42.9, 41.3 (2), 14.5 (3) 138.2, 128.9, 124.0, 119.3 (NHC6H5) 144.2 (NO2), 142.8 (ONC), 125.1 (CHCNO2), 119.2 (ONCCH) 139.2, 130.2, 125.3, 118.5, 113.5 (C in the substituent) 142.5, 134.1, 130.1, 126.1, 125.7, 125.1 (C in the substituent) 155.8, 151.5, 148.3, 140.1, 118.8, 113.2 (C in the substituent) 143.9, 128.3, 126.0 (CHC6H5), 48.5 (CH), 22.4 (CH3) 143.4 (C(3) and (5 in tetrazole) 151.2, 149.2 (C(3) and (4) in furazan), 8.9 (CH3) 70.1, 70.0, 69.4, 69.3, 68.4, 68.3, 49.5, 48.1 (C in the substituent) 152.2 (C(3) and (4) and furazan) 153.7 ((5) in tetrazole), 43.6 (ON2), 42.4 (ON2), 22.4 (2C(5)), 21.2 (2C(5))
_______ *The NMR spectra of compound 14 were recorded in acetone-d6, and the others in DMSO- d6.
5-Phenyltetrazol-2-ylacetyl Chloride (1). A mixture of 5-phenyltetrazol-2-ylacetic acid (6 g, 30 mmol) and phosphorus pentachloride (6.75 g, 32 mmol) was heated at 100C until homogeneous with the formation of a colorless solution. To the hot solution we added 75 ml of boiling hexane. As the solution cooled colorless crystals were formed. The suspension was filtered, and the acid chloride was crystallized from hexane. We obtained 6.43 g (96%) of compound 1; mp 103-104C. 1H NMR spectrum, , ppm: 8.17-8.14 (2H, m, C6H5); 7.53-7.49 (3H, m, C6H5); 5.84 (2H, s, N(2)CH2). 13C NMR spectrum, , ppm: 166.5 (=), 166.2 (CN4), 131.0, 129.2, 127.2, 126.6 (65), 60.7 (N(2)CH2). IR spectrum, , cm-1: 1777 (C=O), 2985, 2945 (), 1450, 1278, 1148, 1073, 1022, 933 (vibration of the tetrazole ring), 729, 688 (C6H5). Found, %: C 48.31; H 3.20; N 25.60. C9H7lN4O. Calculated, %: C 48.55; H 3.17; N 25.17. Preparation of Tetrazolylacetamides 2-12. (General Procedure). To a solution of the substrate 1 (10 mmol) in ether (chloroform or THF) (50 ml) at 0-2C with stirring we added the amine (10 mmol) in ether (chloroform or THF) (20 ml) and triethylamine (10 mmol) in the same solvent (10 ml). An exothermic effect was observed during the reaction. After 1-2 h at room temperature the solvent was evaporated under vacuum, and the residue was washed with distilled water (320 ml) and crystallized from the respective solvent or solvent system. Diethylamide of 5-Phenyltetrazol-2-ylacetic Acid (2). By crystallization from 50% ethanol we obtained 1.25 g (48%) of the amide 2; mp 98-99C. Rf 0.74 (9:1 chloroformmethanol). IR spectrum, , cm-1: 1658 (C=O), 2982, 2936 (), 1425, 1269, 1205, 1144, 1100, 1073, 1023 (vibration of the tetrazole ring), 730, 690 (C6H5). Found, %: C 60.57; H 6.97; N 27.34. C13H17N5O. Calculated, %: C 60.21; H 6.61; N 27.01. Bis(2-cyanoethyl)amide of 5-Phenyltetrazol-2-ylacetic Acid (3). By crystallization from 2-propanol we obtained 2.25 g (73%) of the amide 3; mp 162-163C. Rf 0.54 (95:5 chloroformmethanol). IR spectrum, , cm-1: 1672 (C=O), 2999 (), 1435, 1261, 1203, 1177, 1072, 1027 (vibration of the tetrazole ring), 729, 692 (C6H5), 2252 (CN). Found, %: C 58.28; H 4.59; N 32.03. C15H15N7O. Calculated, %: C 58.24; H 4.89; N 31.70. Piperidide of 5-Phenyltetrazol-2-ylacetic Acid (4). By crystallization from ethanol we obtained 1.32 g (42%) of the amide 4; mp 178-179C. Rf 0.76 (95:5 chloroformmethanol). IR spectrum, , cm-1: 1662, 1649 (C=O), 2987, 2939, 2857 (), 1425, 1254, 1230, 1138, 1097, 1030 (vibration of the tetrazole ring), 728, 691 (C6H5). Found, %: C 62.25; H 5.67; N 25.47. C14H17N5O. Calculated, %: C 61.98; H 6.32; N 25.81. Morpholide of 5-Phenyltetrazol-2-ylacetic Acid (5). By crystallization from 25% ethanol we obtained 0.71 g (26%) of the amide 5; mp 178-179C. Rf 0.62 (9:1 chloroformmethanol). IR spectrum, , cm-1: 1667, 1651 (C=O), 2986, 2944, 2851 (), 1426, 1241, 1200, 1157, 1120, 1072, 1020 (vibration of the tetrazole ring),729, 691 (C6H5), 1273 (COC). Found, %: C 57.27; H 5.23; N 25.93. C13H15N5O2. Calculated, %: C 57.13; H 5.53; N 25.63. N'-Ethoxycarbonylpiperazide of 5-Phenyltetrazol-2-ylacetic Acid (6). By crystallization from 50% 2propanol we obtained 1.24 g (40%) of the amide 6; mp 132-133C. Rf 0.72 (9:1 chloroformmethanol). IR spectrum, , cm-1: 1672, 1665 (NC=O), 1730 (OC=O), 2993, 2932, 2874 (), 1421, 1254, 1210, 1154, 1090, 1071, 1027 (vibration of the tetrazole ring), 732, 694 (C6H5). Found, %: C 56.70; H 5.41; N 25.03. C16H20N6O3. Calculated, %: C 55.80; H 5.85; N 24.40 Anilide of 5-Phenyltetrazol-2-ylacetic Acid (7). By crystallization from 60% 2-propanol we obtained 2.95 g (70%) of the amide 7; mp 189-190C. Rf 0.28 (chloroform). IR spectrum, , cm-1: 1672 (C=O), 2998, 2954, 2851 (), 3440, 3275 (NH), 1447, 1255, 1204, 1140, 1072, 1027 (vibration of the tetrazole ring), 730, 692 (C6H5). Found, %: C 65.03; H 5.18; N 25.17. C15H13N5O. Calculated, %: C 64.51; H 4.61; N 25.07. p-Nitroanilide of 5-phenyltetrazol-2-ylacetic Acid (8). By crystallization from 50% ethanol we obtained 2.14 g (66%) of the amide 8; mp 211-212C. Rf 0.8 (95:5 chloroformmethanol). IR spectrum, , cm-1: 1694 (C=O), 3336 (NH), 2990, 2930, 2845 (), 1555, 1512, 1345 (NO2), 1448, 1252, 1192, 1150, 1109, 1069, 1023 (vibration of the tetrazole ring), 729, 688 (C6H5), 844 (1,4-disubstituted benzene). Found, %: C 55.77; H 3.58; N 26.10. C15H12N6O3. Calculated, %: C 55.56; H 3.73; N 25.91. 859
m-Nitroanilide of 5-Phenyltetrazol-2-ylacetic Acid (9). By crystallization from 50% ethanol we obtained 2.53 g (78%) of the amide 9; mp 217-218C. Rf 0.70 (95:5 chloroformmethanol). IR spectrum, , cm-1: 1686 (C=O), 3330 (NH), 3000, 2943, 2840 (), 1551, 1529, 1355 (NO2), 1450, 1255, 1207, 1150, 1104, 1072, 1021 (vibration of the tetrazole ring), 729, 689 (C6H5), 801 (1,3-disubstituted benzene). Found, %: C 55.32; H 4.00; N 26.28. C15H12N6O3. Calculated, %: C 55.56; H 3.73; N 25.91. o-Nitroanilide of 5-Phenyltetrazol-2-ylacetic Acid (10). By crystallization from 50% ethanol we obtained 2.31 g (71%) of the amide 10; mp 196-197C. Rf 0.85 (95:5 chloroformmethanol). IR spectrum, , cm-1: 1718 (C=O), 3293 (NH), 2995, 2950, 2860 (), 1560, 1520, 1353 (NO2), 1450, 1269, 1203, 1149, 1098, 1073, 1020 (vibration of the tetrazole ring), 730, 689 (C6H5), 743 (1,2-disubstituted benzene). Found, %: C 55.21; H 4.06; N 25.80. C15H12N6O3. Calculated, %: C 55.56; H 3.73; N 25.91. 3,4-Dinitroanilide of 5-Phenylthiazol-2-ylacetic Acid (11). By crystallization from 50% ethanol we obtained 2.52 g (68%) of the amide 11; mp 218-219C. Rf 0.40 (95:5 chloroformethanol). IR spectrum, , cm-1: 1713 (C=O), 3361 (NH), 2994, 2948, 2843 (), 1550, 1536, 1346 (NO2), 1452, 1261, 1199, 1147, 1109, 1076, 1025 (vibration of the tetrazole ring), 727, 685 (C6H5), 828, 787 (1,3,5-trisubstituted benzene). Found, %: C 48.27; H 2.91; N 26.34. C15H11N7O5. Calculated, %: C 48.79; H 3.00; N 26.55. N-(1-Phenylethyl)amide of 5-Phenyltetrazol-2-ylacetic Acid (12). By crystallization from 70% 2-propanol we obtained 2.0 g (65%) of the amide 12; mp 169-170C. Rf 0.63 (9:1 chloroformmethanol). IR spectrum, , cm-1: 1657 (C=O), 3270 (NH), 2990, 2947 (), 1448, 1247, 1205, 1100, 1043, 1026 (vibration of the tetrazole ring), 1385 (CN), 731, 692 (C6H5). Found, %: C 66.64; H 5.73; N 22.55. C17H17N5O. Calculated, %: C 66.43; H 5.57; N 22.79. N-(1,2,4-Triazol-4-yl)amide of 5-Phenyltetrazol-2-ylacetic Acid (13). During the synthesis of this amide 4-amino-1,2,4-triazole, taken in a 2:1 molar ratio in relation to the acid chloride 1, was used instead of triethylamine. By crystallization from 50% ethanol we obtained 1.83 g (68%) of the amide 13; mp 216-217C. IR spectrum, , cm-1: 1722 (C=O), 3120 (NH), 2994, 2950 (), 1451, 1260, 1200, 1173, 1071, 1044 (vibration of the tetrazole ring), 1359 (CN), 734, 694 (C6H5). Found, %: C 48.93; H 4.09; N 41.46. C11H10N8O. Calculated, %: C 48.89; H 3.73; N 41.46. N-(4-Methylfurazan-3-yl)amide of 5-Phenyltetrazol-2-ylacetic Acid (14). By crystallization from 50% 2-propanol we obtained 2.02 g (71%) of the amide 14; mp 190-191C. Rf 0.36 (9:1 chloroformmethanol). IR spectrum, , cm-1: 1704 (C=O), 3273 (NH), 2996, 2953 (), 1448, 1252, 1200, 1155, 1100, 1043, 1024 (vibration of the tetrazole ring), 1388 (CN), 727, 686 (C6H5). Found, %: C 50.27; H 3.64; N 34.64. C12H11N7O2. Calculated, %: C 50.53; H 3.89; N 34.37. N,N'-Bis(5-phenyltetrazol-2-ylacetyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadodecane (15). During the synthesis of this amide we used compound 1 (20 mmol) in chloroform (100 ml) and triethylamine (20 mmol) in chloroform (20 ml). By crystallization from ethanol we obtained 3.0 g (47%) of the diamide 15; mp 183-184C. Rf 0.68 (9:1 chloroformmethanol). IR spectrum, , cm-1: 1665 (C=O), 3004, 2959, 2856 (), 1450, 1249, 1203, 1140, 1110 1090, 1029 (vibration of the tetrazole ring), 1296, 1050 (COC), 1336, 1029 (CN), 730, 696 (C6H5). Found, %: C 57.42; H 6.01; N 22.27. C30H38N10O6. Calculated, %: C 56.77; H 6.03; N 22.07. N,N'-Bis(5-phenyltetrazol-2-ylmethylcarbonyl)-3,4-diaminofurazan (16). During the synthesis of this amide we used compound 1 (20 mmol) in THF (100 ml) and triethylamine (20 mmol) in THF (20 ml). By crystallization from 50% ethanol we obtained 5.34 g (62%) of the amide 16; mp 196C (decomp.). Rf 0.46 (9:1 chloroformmethanol). IR spectrum, , cm-1: 1698 (C=O), 3000, 2948 (), 1449, 1246, 1200, 1142, 1104, 1046, 1026 (vibration of the tetrazole ring), 1353 (CN), 730, 690 (C6H5). Found, %: C 50.21; H 3.83; N 36.06. C20H16N12O3. Calculated, %: C 50.85; H 3.41; N 35.58. N,N'-Bis(5-phenyltetrazol-2-ylmethylcarbonyl)-1,2-hydrazine (17). To a solution of the acid chloride 1 (4.7 g, 21 mmol) in toluene (100 ml) at 0-2C with stirring we added hydrazine hydrate (0.5 g, 10 mmol) in toluene (10 ml) and triethylamine (2.02 g, 20 mmol) in toluene (10 ml). The reaction mixture was boiled for 10 h on a salt bath, the solvent was evaporated under vacuum, and the residue was washed with 860
distilled water (320 ml) and crystallized from aqueous DMF. We obtained 1.66 g (41%) of the hydrazine 17; mp 246-248C. IR spectrum, , cm-1: 1629 (C=O), 3217 (NH), 3001, 2994 (), 1449, 1232, 1140, 1060, 1029 (vibration of the tetrazole ring), 1399 (CN), 729, 689 (C6H5). Found, %: C 52.83; H 4.48; N 34.24. C18H16N10O2. Calculated, %: C 53.46; H 3.99; N 34.64. N,N'-Bis[2-(tetrazol-5-yl)ethyl]amide of 5-Phenyltetrazol-2-ylacetic Acid (18). To a suspension of compound 3 (1 g, 3.2 mmol) in toluene (100 ml) we added triethylamine hydrochloride (2.67 g, 19.2 mmol) and sodium azide (1.26 g, 19.2 mmol). The mixture was stirred at 98-100C for 5 h, cooled to room temperature, and washed with water (370 ml). The aqueous layer was separated and acidified to pH 1-2 with concentrated hydrochloric acid. The precipitate was filtered off and crystallized from ethanol. We obtained 0.9 g (70%) of the tetrazole 18; mp 124-126C. IR spectrum, , cm-1: 1631 (C=O), 1453, 1238, 1100, 1066 (vibration of the tetrazole ring), 3428 (NH-tetrazole), 1379 (CN), 731, 693 (C6H5). Found, %: C 45.12; H 4.65; N 45.65. C15H17N13O. Calculated, %: C 45.57; H 4.33; N 46.05. The work was carried out with financial support from the Ministry of Education of the Russian Federation (grant T02-09.3-3222) and the Federal Special-Purpose Program of State Support and Integration of Education and Fundamental Science (grant No. I0667).
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. A. Kleeman and J. Engel, Pharmaceutical Substances, Thieme, Stuttgard (1999). S. J. Wittenberger, Org. Prep. Proced. Int., 26, 499 (1994). V. A. Ostrovskii and A. O. Koren, Heterocycles, 53, 1421 (2000). S. Yayao and W. G. Strycker, Ger. Patent 1907545; Chem. Abs., 72, 43683 (1970). S. M. Putis, V. Yu. Zubarev, V. S. Poplavskii, and V. A. Ostrovskii, Khim. Geterotsikl. Soedin., 759 (2001). V. A. Ostrovskii, V. S. Poplavskii, V. Yu. Zubarev, and G. B. Erussalimsky, Mendeleev Commun., 24 (1996). G. I. Koldobskii and V. A. Ostrovskii, Usp. Khim., 63, 847 (1994). V. G. Andrianov and A. V. Eremeev, Khim. Geterotsikl. Soedin., 1157 (1984). H. G. O. Becker, K. Heimburger, and H. J. Timpe, Wissenschaftl. Zeitschr., 8, 118 (1966). D. Barton and W. D. Ollis, General Organic Chemistry [Russian translation], Khimiya, Vol. 3, Moscow (1982), p. 191. V. Yu. Zubarev and V. A. Ostrovskii, Khim. Geterotsikl. Soedin., 1133 (1996). K. Koguro, T. Oga, S. Mitsui, and R. Orita, Synthesis, 6, 910 (1998).
861
SYNTHESIS OF 6-BROMOMETHYL-SUBSTITUTED DERIVATIVES OF PYRIDIN-2(1H)-ONES AND THEIR REACTION WITH NUCLEOPHILES

Z. A. Kalme, R. A. Zhalubovskis, A. Shmidlers, J. Celmins, and G. Duburs 6-Bromomethyl-substituted derivatives of pyridin-2(1H)-ones were obtained by the bromination of 6-methyl-3,4-dihydropyridin-2(1H)-ones, and are the basis for the synthesis of thieno- and furo[3,4-b]pyridin-2(1H)-ones and also for obtaining new amino derivatives in the pyridin-2(1H)-one series. Keywords: amino derivatives of pyridin-2(1H)-ones, pyridin-2(1H)-ones, thieno- and furo[3,4-b]pyridin-2(1H)ones, bromination. Derivatives of pyridin-2(1H)-ones are of interest as compounds, depending on the structure, of significant biological activity. In this series cardiovascular preparations (amrinone, milrinone) [1,2], and compounds inhibiting HIV [3,4] were found and developed. 3,4-Dihydropyridin-2(1H)-ones 3a-c are synthesized by the condensation of -aminocrotonic acid methyl ester 1 with benzylidenecyanoacetamides 2 in a mixture of ethanolacetic acid, 1:2. Judging by data of 1 H NMR spectra pyridones 3 are a mixture of cis and trans isomers. According to the data of [5], the signals with the greatest coupling constants (J34 = 7 Hz) correspond to the cis-isomer and with the least (J34 = 3 Hz) to the trans-isomer. The ratio of cis and trans isomers was 1:9. Bromination of the synthesized pyridin-2(1H)-ones 3 has been carried out with the aim of obtaining furo- and thieno[3,4-b]pyridin-2(1H)-ones. The use of N-bromosuccinimide as brominating agent (a specific reagent for brominating CH3 groups in the allyl position) did not give the expected result. Bromo derivatives 5 were obtained by the interaction of pyridones 3 with bromine in acetic acid. According to the data of [6], the formation of the oxidized form 5 occurs as a result of fission of a molecule of HBr from the proposed intermediate dibromo compound 4. In a less polar solvent (CHCl3) and on irradiation with a lamp (500 watt), it is evident that the radical mechanism dominates and bromination proceeds only at the methyl group. Unlike 6-bromomethylpyridin-2(1H)ones 5, the 6-bromomethyl-3,4-dihydropyridin-2(1H)-one 7 was difficult to obtain in the pure state, since on crystallizing lactonization occurs with the formation of 2,5-dioxo-4-phenyl-1,2,3,4,5,7-hexahydrofuro[3,4-b]pyridine-3-carbonitrile (8). In the case of pyridin-2(1H)-ones 5 even after extended boiling in ethanol no lactonization with the formation of furo[3,4-b]pyridin-2(1H)-ones 6 was observed (Scheme 1). A band is observed in the IR spectra of dihydropyridones 3 for the stretching vibrations of the nitrile group at 2260-2275 cm-1, but in the case of pyridones 5 it is displaced in the direction of lower frequencies by 25-35 cm-1, which indicates the presence of a more conjugated system.
__________________________________________________________________________________________ Latvian Institute of Organic Synthesis, Riga LV 1006; e-mail: kalme@osi.lv. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1006-1013, July, 2004. Original article submitted March 1, 2004. 862 0009-3122/04/4007-08622004 Springer Science+Business Media, Inc.
Scheme 1
Ar MeOOC CH + Me C 1 NH2 H2N 2 O CN MeOOC Me N H 3 3a Ar CN O
Br2
Ar MeOOC BrCH2 N H 4 Br CN O
MeCOOH
Br2 CHCl3, h Ph
MeOOC BrCH2 N H 7
CN O
_ HBr Ar MeOOC BrCH2 N H 5 CN O O O O N H 6 O Ph CN O
EtOH Ph CN N H 8 O
2, 3, 5 a Ar = Ph, b Ar = m-NO2C6H4, c Ar = p-NO2C6H4
Doublet signals are displayed in the 1H NMR spectra of the dihydro derivatives 3 for the H-3 and H-4 protons, which disappear from the spectra of pyridones 5. On interacting pyridone 5a with thiourea initially thiouronium salt 9 is formed, which in strongly alkaline medium is cyclized into 2,5-dioxo-4-phenyl-1,2,5,7tetrahydrothieno[3,4-b]pyridine-3-carbonitrile (10). The signals of the 5-methoxycarbonyl and amino groups present in the spectrum of bromide 9 disappear 1 in the H NMR spectra of thiolactone 10. Since the electronegativity of the sulfur atom is less than that of oxygen then in the IR spectra of the thiolactones the carbonyl group vibrations are displaced from 1731 (for lactone 8) to 1670 cm-1. On using hydrazine hydrate as the nucleophilic reagent not only is the bromine atom replaced by hydrazine but the hydrazine hydrate also reacts with the 5-methoxycarbonyl group with the formation of 5-carbazoyl-3-cyano-6-hydrazinomethyl-4-phenylpyridin-2(1H)-one (11). Signals are observed in the 1H NMR spectra for the methylene protons at 4.10 ppm, signals for the OMe group protons are absent and there is a broadened singlet at 6.10 ppm which corresponds to 6 protons (2H2N-NH). The results of the interaction of the bromomethyl derivatives 5 depend on the character of the amine used.
863
Ph MeNHOC MeNHCH2 N H 12 Ph MeOOC H2 N + H2N Br SCH2 N H 9

3
Ph CN O MeNH2 NH2 N MeOOC CN N H 13 Ph H2NNH2 H2NNHOC H2NNHCH2 HNR1R2 N H 11 Ph CN O O
+ N CH2 Br
CN S=C O
NH2 5a
NaOH
H2NR
MeOOC N H 14
CN O
O S
Ph CN NC N H 10 O O N H C H2 N R3 15 C H2 N H Ph COOMe MeOOC Ph
R1R2NCH2 CN
14 a R1 + R2 = (CH2)5; b R1 = H, R2 = CH2CH2Ph; c R1 = H, R2 = Ph; d R1 = H, R2 = CH2COOEt; 15 a R3 = (CH2)3COOEt; b R3 = (CH2)3Me
The amino derivatives 14 are obtained by the reaction of pyridin-2(1H)-one 5a with piperidine, 2-phenylethylamine, aniline, and glycine ethyl ester hydrochloride. In the 1H NMR spectra of amines 14a-d the signals for the 6-CH2 group protons are retained at 3.55-4.37 ppm.
TABLE 1. Characteristics of Compounds 3, 5, and 8-15

Compound 1 3a 3b 3c 5a 5b 5c 8 9 Empirical formula 2 C15H14N2O3 C15H13N3O5 C15H13N3O5 C15H11BrN2O3 C15H10BrN3O5 C15H10BrN3O5 C14H10N2O3 C16H15BrN4O3S C 3 66.72 66.65 57.35 57.14 57.37 57.14 51.40 51.89 45.69 45.94 46.01 45.94 65.60 66.14 45.05 45.40 Found, % Calculated, % H N Br 4 5 6 5.03 5.22 3.95 4.16 4.01 4.16 2.90 3.19 2.32 2.57 2.22 2.57 4.05 3.96 3.53 3.57 10.29 10.36 13.28 13.33 13.39 13.33 7.80 8.07 10.47 10.71 10.55 10.71 10.73 11.02 13.16 13.24
mp, C S 7 8 174-176 187-189 190-193
Yield, % 9 57 60 52 42 43 45 52 85
23.20 23.02 20.92 20.37 19.74 20.37
182-184 168-170 170-172 222-224 7.54 7.57 172-174
864
TABLE 1 (continued)
1 10 11 12 13 14a 14b 14c 14d 15a 15b 2 C14H8N2O2S 1/2H2O C14H14N6O2 C16H16N4O2 C20H16BrN3O3 C20H21N3O3 H2O C23H21N3O3 C21H17N3O3 C19H19N3O5 C36H33N5O8 C34H31N5O6 3 60.74 60.64 56.37 56.17 64.67 64.85 56.45 56.35 64.85 65.05 70.92 71.30 70.13 70.18 61.10 61.78 64.15 65.15 67.47 67.42 4 2.96 3.27 4.73 4.72 5.33 5.24 3.85 3.78 6.29 6.27 5.09 5.46 4.76 4.77 4.93 5.18 4.95 5.01 5.00 5.16 5 10.33 10.10 28.11 28.12 18.88 18.91 9.68 9.86 11.28 11.37 10.55 10.84 11.67 11.69 10.97 11.38 10.49 10.55 11.47 11.56 6 7 11.79 11.56 8 152-154 180-182 275-277 182-184 88-90 193-195 188-190 238-240 214-216 205-208 9 40 71 78 65 57 34 81 17 12 42
TABLE 2. Spectral Characteristics of Compounds 3, 5, and 8-15

Compound 1 3 IR spectrum, , cm-1 C=O CN NH 2 3 4 1640, 1710 2260 3170, 3280
1
NMR spectrum (DMSO-d6), , ppm (J, Hz)* 5
3b
1645, 1715
2270
3180, 3280
3c
1645, 1715
2275
3185, 3270
5a 5b 5c
1650, 1750 1650, 1735 1658, 1735 1678, 1731 1652, 1713
2240 2240 2240
3160, 3220 3160, 3310 3160, 3310 3180, 3220, 3280 3240, 3330
2245
2222
2.40 (0.3H, s, 6-CH3, cis); 2.45 (2.7H, s, 6-CH3, trans); 3.35 (3H, s, CH3); 4.45 (0.1H, d, J = 7, 3-H, cis); 4.22 (0.9H, d, J = 3.2, 3-H, trans); 4.95 (0.1H, d, J = 7.4, 4-H, cis); 4.58 (0.9H, d, J = 3.2, 4-H, trans); 7.26 (5, m, C 6H5 ); 10.48 (0.1H, s, NH, cis); 10.80 (0.9H, s, NH, trans) 2.35 (0.3H, s, 6-CH3, cis); 2.37 (2.7H, s, 6-CH3, trans); 3.53 (0.3H, s, CH3, cis); 3.55 (2.7H, s, CH3, trans); 4.28 (0.9H, d, J = 4, 3-H, trans); 4.60 (0.1H, d, J = 7.4, 3-H, cis); 4.72 (0.9H, d, J = 4.0, 4-H, trans); 4.95 (0.1H, d, J = 7.4, 4-H, cis); 7.40 (2, d, C 6 H4 ); 8.10 (2, d, C6 H4); 10.50 (0.1H, s, NH, cis); 10.82 (0.9H, s, NH, trans) 2.32 (0.3H, s, 6-CH3, cis); 2.34 (2.7H, s, 6-CH3, trans); 3.44 (3H, s, CH3); 4.24 (0.9H, d, J = 3.0, 3-H, trans); 4.48 (0.1H, d, J = 7.0, 3-H, cis); 4.55 (0.9H, d, J = 3.0, 4-H, trans); 4.85 (0.1H, d, J = 7.0, 4-H, cis); 7.33 (2, m , C 6H4 ); 8.33 (2, m , C 6H4 ); 10.44 (0.9H, s, NH, cis); 10.77 (0.1H, s, NH, trans) 3.38 (3H, s, OCH3); 4.6 (2H, s, CH2); 7.38 (5H, m, C6 H5); 13.10 (1H, br. s, NH) 3.44 (3H, s, OCH3); 4.25 (2H, s, CH2); 7.97 (4H, m, C6 H4); 13.42 (1H, br. s, NH) 3.45 (3H, s, OCH3); 4.60 (2H, s, CH2); 7.68 (2H, d, J = 8, C 6 H2 ); 8.32 (2H, d, J = 8, C 6H2 ); 13.49 (1H, br. s, NH) 4.3 (1H, d, J = 8, CH); 5.1 (1H, d, J = 8, CH); 4.95 (2H, s, CH2); 7.35 (5H, s, C6 H5 ); 11.37 (1H, s, NH) 3.35 (3H, s, OCH3); 4.44 (2H, s, CH2); 7.19-7.63 (5H, m, C6 H5 ); 9.29 (4H, br. s, H2 NC=N+H2)
865
TABLE 2 (continued)
1 10 11 12 13 2 1655, 1670 1647, 1693 1660, 1672 1670, 1728 1645, 1693 1640, 1730 1650, 1730 1650, 1720, 1745 1645, 1735 3 2230 2210 2218 2210 4 3140 3215, 3310 3160 3360 5 4.5 (2H, s, CH2); 7.23-7.60 (5H, m, C6 H5 ); 11.7 (1H, br. s, NH) 4.10 (2H, s, CH2); 5.60-6.70 (6H, br. s, 2NHNH2); 7.35 (5H, s, C6 H5) 2.35 (3H, s, CH2NHCH3); 2.82 (3H, s, CONHCH3); 4.02 (2H, s, CH2); 7.35 (5H, s, C 6 H5 ) 3.45 (3H, s, CH3); 6.12 (2H, s, CH2); 7.3-7.7 (5H, m, C6 H5 ); 8.17-9.25 (5H, m, pyridinium) 1.40 (6H, br. s, (CH2)3); 2.38 (4H, m, CH2NCH2); 3.37 (3H, s, OCH3); 3.55 (2H, s, CH2 ); 7.20-7.58 (5H, m, C 6 H5 ) 2.733.40 (4H, m, CH2CH2); 3.44 (4H, s, CH3+NH); 4.10 (2H, s, CH2 ); 7.15-7.73 (10H, m, 2C6 H5 ) 3.37 (4H, s, CH3+NH amine); 4.37 (2H, s, CH2 ); 6.47-7.60 (10H, m, 2C6 H5 ) 1.26 (3H, m, CH2CH3); 3.40 (4H, s, CH3+NH amine); 3.60 (2H, s, CH2); 4.22 (2H, q, CH2 3); 4.3 (2H, s, CH2 ); 7.40 (5H, s, C6 H5 ) 1.26 (3H, m, CH2CH3); 2.00 (2H, m, 3-CH2); 2.28 (4H, m, 2CH2); 2.84 (2H, m, CH2 ); 3.45 (6H, s, 2OCH3); 3.96 (4H, s, CH2 ); 4.06 (2H, q, CH2 3); 7.36 (10H, m, 2C6 H5 ) 0.78 (3H, t, CH2CH3); 1.32 (4, m, CH2CH2CH3); 2.4 (2, t, CH2CH2CH2CH3); 3.45 (6H, s, 2OCH3); 3.75 (4H, s, N(CH2 )2 ); 7.25-7.62 (10H, m, 2C 6H5 ); 12.85 (2H, br. s, 2NH)
14a
2218
3260, 3370 3100, 3330 3170, 3320, 3380 3150, 3210 3140, 3210
14b
2230
14c
2220
14d
2230
15a
2230
15b
1685, 1730, 1745
2230
3150, 3260
_______ * The 1H NMR spectra of compounds 14a and 15a were taken in CDCl3.
On using aqueous methylamine solution under mild conditions (room temperature), besides replacement of bromine by a methylamino group, amidation of the ester group at position 5 also occurs with the formation of 5-cyano-2-methylaminomethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-(N-methyl)carboxamide (12). In their turn the application of -aminobutyric acid ethyl ester and n-butylamine as nucleophiles leads to the formation of dimers 15, in which one molecule of amine is linked to two molecules of pyridone. The integrated intensities of the proton signals of the pyridone ring substituents in the dimers 15 in the 1H NMR spectra were doubled in comparison with the proton signals of the amine residue (R3). It is known that quaternized derivatives of pyridine are potential agents for gene transfection [7]. We have shown the possibility of synthesizing quaternized derivatives in the pyridone series, using pyridine as an example. Pyridinium bromide 13 was obtained by the interaction of pyridone 3a with pyridine. It is seen from the 1H NMR spectra that compared with bromine the pyridinium cation displaces the signal of the methylene protons towards low field from 4.50 to 6.10 ppm.
EXPERIMENTAL The IR spectra were recorded on a Perkin-Elmer 580B instrument in Nujol, the 1H NMR spectra on a WH 90/DC (90 MHz) instrument, internal standard was TMS. A check on the progress of reactions and the homogeneity of substances was carried out by TLC on Silufol plates in acetonehexane, 1:1. 866
The characteristics of the synthesized compounds are given in Tables 1 and 2. 5-Cyano-2-methyl-6-oxo-4-phenyl-1,4,5,6-tetrahydropyridine-3-carboxylic Acid Methyl Ester (3a). -Aminocrotonic acid methyl ester 1 (1.15 g, 10 mmol) and benzylidenecyanoacetamide 2 (1.72 g, 10 mmol) were dissolved in a mixture (20 ml) of acetic acidethanol, 1:2. The solution obtained was boiled for 3 h and then maintained at 5-8C for 24 h. The solid formed was filtered off, washed with ethanol, and crystallized from ethanol. Compound 3a (1.6 g) was obtained. Compounds 3b,c were obtained analogously. 2-Bromomethyl-5-cyano-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic Acid Methyl Ester (5a). Dihydropyridone 3a (5 g, 18.5 mmol) was suspended in acetic acid (20 ml). Bromine (2 ml, 37 mmol) in acetic acid (10 ml) was added dropwise with vigorous stirring during 50 min to the obtained suspension. The clear solution obtained was left for 24 h at 20C, and was then poured into water (800 ml) with vigorous stirring. The resulting solid was filtered off, washed with a large amount of water, and recrystallized from ethanol. Compound 5a (2.7 g) was obtained Compounds 5b,c were obtained analogously. 2-Bromomethyl-5-cyano-6-oxo-4-phenyl-1,4,5,6-tetrahydropyridine-3-carboxylic Acid Methyl Ester (7) and 2,5-Dioxo-4-phenyl-1,2,3,4,5,7-hexahydro-furo[3,4-b]pyridine-3-carbonitrile (8). Compound 3a (1.35 g, 5 mmol) was suspended in dry chloroform (12 ml) and a solution of bromine (0.88 g, 5.5 mmol) in dry chloroform (3 ml) was added dropwise while boiling and irradiating with a lamp (500 watt). After the addition of all the bromine, stirring and irradiation was continued for a further 10 min. The reaction mixture was then poured into water (100 ml) and unpurified compound 7 (0.73 g) was filtered off. Furopyridone 8 (0.66 g) was obtained after crystallization of compound 7 from ethanol. S-[(5-Cyano-3-methoxycarbonyl-6-oxo-4-phenyl-1,6-dihydro-2-pyridyl)methyl]thiouronium Bromide (9). Compound 5a (0.5 g, 1.44 mmol) was suspended in acetonitrile (7 ml), and thiourea (0.11 g, 1.44 mmol) was added. The mixture obtained was stirred at room temperature for 3 h. The solid formed was filtered off, and washed with acetonitrile (2 x 5 ml). Compound 9 (0.52 g) was obtained. 2,5-Dioxo-4-phenyl-1,2,5,7-tetrahydrothieno[3,4-b]pyridine-3-carbonitrile (10). Compound 9 (0.4 g, 0.93 mmol) was added to a solution of NaOH (0.15 g, 3.7 mmol) in water (20 ml). The mixture was stirred for 24 h, acidified to pH ~4-5 with hydrochloric acid, and stirring continued for a further 30 min. The resulting solid was filtered off, washed with water to a neutral reaction, and recrystallized from ethanol. Compound 10 (0.1 g) was obtained. 3-Carbazoyl-5-cyano-2-hydrazinomethyl-6-oxo-4-phenyl-1,6-dihydropyridine (11). Hydrazine hydrate (55%) (2 ml) was added to a suspension of pyridone 5a (0.5 g, 1.44 mmol) in ethanol (7 ml), and the mixture boiled for 40 min. The resulting solid was filtered off, and recrystallized from ethanol. Compound 11 (0.3 g) was obtained. 5-Cyano-2-methylaminomethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-(N-methyl)carboxamide (12). Aqueous 30% methylamine solution (1 ml, 8.6 mmol) was added to a suspension of pyridone 5a (0.3 g, 0.86 mmol) in ethanol (10 ml). The clear solution obtained was stirred at room temperature, and after 10 min a precipitate formed, which was filtered off next day, and washed with ethanol (10 ml). Compound 12 (0.2 g) was obtained. 1-[(5-Cyano-3-methoxycarbonyl-6-oxo-4-phenyl-1,6-dihydro-2-pyridyl)-methyl]pyridinium Bromide (13). Pyridone 5a (0.94 g, 2.71 mmol) was dissolved with heating in acetone (75 ml) and pyridine (0.24 g, 2.71 mmol) was added. The solution obtained was stirred for 2 h at ~20C, and the solvent evaporated in vacuum. The residue was dissolved in methanol and left for 24 h at ~20C. The solid was filtered off and recrystallized from 2-propanol. Pyridinium bromide 13 (0.75 g) was obtained. 5-Cyano-6-oxo-4-phenyl-2-piperidinomethyl-1,6-dihydropyridine-3-carboxylic Acid Methyl Ester (14a). Piperidine (1.5 ml, 15.3 mmol) was added to a solution of pyridone 5a (0.5 g, 1.44 mmol) in DMF (8 ml). The reaction mixture was stirred at 80C for 1 h, cooled, and poured into water (15 ml). After a day the solid was filtered off, and crystallized from ethanolether, 1:3. Compound 14a (0.3 g) was obtained. 867
5-Cyano-6-oxo-4-phenyl-2-[(2-phenylethyl)aminomethyl]-1,6-dihydropyridine-3-carboxylic Acid Methyl Ester (14b). 2-Phenylethylamine (0.35 g, 2.88 mmol) was added to a solution of pyridone 5a (0.5 g, 1.44 mmol) in methanol (20 ml) . The solution obtained was boiled for 10 min, cooled, and poured into water (50 ml). The solid was filtered off, and crystallized from ethanolether, 1:1. Compound 14b (0.19 g) was obtained. 2-Anilinomethyl-5-cyano-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic Acid Methyl Ester (14c). A solution of pyridone 5a (0.5 g, 1.44 mmol) and aniline (0.27 g, 2.88 mmol) in DMF (5 ml) was stirred for 2 h at ~20C, then poured into water (50 ml) acidified with hydrochloric acid (pH 4-5). The solid was filtered off, and crystallized from ethanol. Compound 14c (0.42 g) was obtained. 5-Cyano-2-[(ethoxycarbonylmethyl)aminomethyl]-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic Acid Methyl Ester (14d). A solution of pyridone 5a (0.5 g, 1.44 mmol) and glycine ethyl ester hydrochloride (0.41 g, 2.94 mmol) in DMF (5 ml) was stirred for 1 h 30 min at ~20C, then poured into water (50 ml). The solid was filtered off and crystallized from ethanolether, 1:1. Compound 14d (0.09 g) was obtained. 4-[Bis(5-cyano-3-methoxycarbonyl-6-oxo-4-phenyl-1,6-dihydro-2-pyridylmethyl)]aminobutyric Acid Ethyl Ester (15a). A solution of pyridone 5a (0.5 g, 1.44 mmol), -aminobutyric acid ethyl ester hydrochloride (0.48 g, 2.86 mmol), and triethylamine (0.4 ml, 2.86 mmol) in methanol (5 ml) was stirred at ~20C for 6 h, and left for a day. The reaction mixture was poured into acidified (pH ~2) water (50 ml). The solid was filtered off, and crystallized from ethanolchloroform, 10:1. Compound 15a (0.09 g) was obtained. Bis(5-cyano-3-methoxycarbonyl-6-oxo-4-phenyl-1,6-dihydro-2-pyridyl-methyl)butylamine (15b). A mixture of pyridone 5a (0.55 g, 1.58 mmol) and n-butylamine (0.31 ml, 3.14 mmol) in ethanol (35 ml) was boiled for 2 h, cooled, and poured into acidified (pH ~4-5) water (150 ml). The solid was filtered off, and crystallized from ethanol. Compound 15b (0.4 g) was obtained.
REFERENCES 1. 2. 3. 4. 5. 6. 7. B. Wetzel and N. Havel, Trends Pharmacol. Sci., 91, 166 (1988). C. Q. Earl, J. Linden, and J. Weglicki, J. Cardiovasc. Pharmacol., 8, 864 (1986). R. Garg and S. P. Gupta, J. Enzyme Inhib., 12, 1 (1997). V. Dolle, E. Fan, C. H. Nguyr, and A. M. Aubertin, J. Med. Chem., 28, 4679 (1995). A. A. Krauze, E. E. Liepin'sh, Z. A. Kalme, Yu. E. Pelcher, and G. Ya. Dubur, Khim. Geterotsikl. Soedin., 1504 (1984). Z. A. Bomika, Yu. E. Pelcher, A. A. Krauze, Yu. Sh. Gol'dberg, and G. Ya. Dubur, Khim. Geterotsikl. Soedin., 783 (1981). Z. Hyvonen, A. Plotniece, I. Reine, B. Chekavichus, G. Duburs and A. Urtti, Biochim. Biophys. Acta, 1509, 451 (2000).
868
REACTION OF 3,5-CARBONYLSUBSTITUTED 1,4-DIHYDROPYRIDINES WITH HYDRAZINE HYDRATE

E. Bisenieks, J. Uldrikis, and G. Duburs The interaction of 3,5-carbonyl-substituted derivatives of 1,4-dihydropyridine and some analogs of it with hydrazine hydrate occurs with fission of the heterocycle. In the case of alkoxycarbonyl-substituted compounds a reverse Michael reaction predominates leading to fragmentation of the molecules. Keywords: 3-acyl- and 3-alkoxycarbonyl-5-oxo-1,4-dihydroindeno[1,2-b]pyridines, 3,5-acyl- and 3,5-alkoxycarbonyl-1,4-dihydropyridines, pyrazole derivatives, fission of heterocycle with hydrazine. The majority of the known derivatives of 1,4-dihydropyridine have electron-withdrawing substituents, which usually contain a carbonyl group, in positions 3 and 5. Conjugation of the carbonyl substituents with the NH group of the 1,4-dihydropyridine ring reduces the tendency of these compounds towards oxidation, and simultaneously reduces the carbonyl reactivity and imparts weakly acidic properties to the ring NH group [1]. Consequently there is little information on the reactions of these compounds with hydrazines. For example, the preparation of the 2,4-dinitrophenylhydrazone of 3,5-diacetyl-1,4-dihydropyridine is known [2], as is the reaction of hydrazine with 2,3,5,6-tetraethoxycarbonyl-1,4-dihydropyridine, where the initial addition of hydrazine to the substituents in positions 2 and 6 facilitates intramolecular cyclization with the substituents in positions 3 and 5 [3]. This principle is also used in other syntheses of condensed heterocycles [4, 5]. The report on the preparation of the dihydrazide of 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid [6] proved to be erroneous. It was later established that bis(5-methyl-3-oxo-4-pyrazolyl)methane is formed [7]. In the reactions of 3,5-diethoxycarbonyl-2,6-dimethyl-1,4-dihydropyridine [7] and its 4-methyl, 4-ethyl, 4-phenyl, and 4-(2-chlorophenyl) derivatives, and also of 3,5-diacetyl-2,6-dimethyl-1,4-dihydropyridine and its 4-methyl and 4-phenyl derivatives [8], with a small excess of hydrazine hydrate without solvent, decomposition of the heterocycle was observed and derivatives of bispyrazolylmethane were obtained. A large proportion of the reactions required extended (up to 65 h) heating. We have studied this reaction with a wider circle of related compounds, with tricyclic and pentacyclic compounds containing the 1,4-dihydropyridine ring, and also with a tetrahydropyrimidine derivative. With the aim of accelerating the process we carried out the reaction of the compounds being studied with an excess of hydrazine hydrate in an autoclave at 100-150C and in a solvent in order to avoid heterogeneous reactions. Under these conditions the reaction of 3,5-acyl derivatives of 1,4-dihydropyridine 1a-f with hydrazine hydrate proceeds more readily and pure bispyrazolylmethanes 2a-f are formed in high yield. Compound 2b [8] was obtained previously on cyclization of methylene-3,3'-bisacetylacetone with hydrazine.
__________________________________________________________________________________________ Latvian Institute of Organic Synthesis, Riga LV 1006; e-mail: gduburs@osi.lv. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1014-1021. July, 2004. Original article submitted February 17, 2004. 0009-3122/04/4007-08692004 Springer Science+Business Media, Inc. 869
O
R2 R1
R3
O
R2
H2NNH2
R2
R3
R2
N
N H
R1
2af
N
R1
N H 1af
R1
N H
1, 2 a R1 = H, R2 = Me, R3 = H; b R1 = R2 = Me; R3 = H; c R1 = R2 = Me, R3 = 3-Py; d R1 = R2 = Me, R3 = 2-6H4OCHF2; e R1 = R2 = Me, R3 = 3,4,5-(MeO)3C6H2; f R1 = Me, R2 = Ph, R3 = H
The reaction occurs even with compounds 1d and 1e, which have bulky substituents in position 4, and also with the 3,5-dibenzoyl-substituted 1,4-dihydropyridine 1f. In difference to the data of [8] the solvent (ethanol) does not change the process. Esters of 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3a-d react with hydrazine hydrate readily and unambiguously. The conversion of compound 3b was also successful on boiling in ethanolic solution.
O R2O Me N R1 Me O OR2 H2N NH2 HN N H Me Me O O NH N H
3ae
3 a R1 = H, R2 = Me; b R1 = H, R2 = Et; c R1 = H, R2 = menthyl; d R1 = H, R2 = (CH2)13Me; R1 = Me; R2 = Et
Compound 4 was previously obtained on cyclization of methylene-2,2'-bisacetoacetic ester with hydrazine. The size of the ester radical R2 has comparatively little influence on the reaction rate. Reaction with the N-methyl-substituted compound 3e occurs more slowly. The formation of the second pyrazole ring requires elimination of methylamine. The reaction may be used for obtaining unsymmetrical bispyrazolylmethanes. Compound 6 is formed from 3-acetyl-5-ethoxycarbonyl-2,6-dimethyl-4-phenyl-1,4-dihydropyridine (5) by reaction with hydrazine hydrate.
O Me Me N H 5 Me Ph O OEt Me Ph O NH Me Me 6 N H
+ H2N
NH2
N N H
140C, 4 h
The structure of compound 6 was confirmed by the 1H NMR spectrum, but the IR spectrum is similar to the spectra of bispyrazolylmethanes 2 and methylenebispyrazolone 4. In the IR spectrum of the latter the stretching vibrations of the associated NH groups are displayed as bands in the 2400-3200 cm-1 region due to strengthening of the hydrogen bonds caused by resonance effects (of possible tautomeric bipolar structures). The presence of NH and C=O (or COH) groups are thereby masked [9]. 870
The reaction of hydrazine hydrate with compounds 1b and 3a-d unsubstituted at position 4 proceeds significantly more rapidly than with their analogs substituted at position 4. This probably indicates the addition of hydrazine to the carbonyl group as the first stage of the process with subsequent intramolecular addition of the NH group at the C(5)=C(6) double bond, with fission of the 1,4-dihydropyridine ring and the formation of a pyrazole. 4-Aryl-3,5-diethoxycarbonyl-2,6-dimethyl-1,4-dihydropyridines react poorly with hydrazine hydrate [8]. We carried out these reactions with an excess of hydrazine hydrate in alcohol solution at 130-150C. In the case of the bulky 5-norbornen-2-yl substituent at position 4 the initial dihydropyridine remains unchanged. The 1,4-dihydropyridine ring is retained also in the case of the 4-phenyl-substituted compound, but its 4-(3-pyridyl) analog 10 reacted with ring fission and the formation of bispyrazolylmethane 11. Reactions occurred readily with methyl esters but frequently in addition to the expected bispyrazolonylmethane derivative such products as 5-methyl-3-pyrazolone (8), and the hydrazone or azine of the aldehyde used for the synthesis of the corresponding dihydropyridine were formed. Consequently, the so-called reverse Michael reaction is observed.
O 7 R2 Me O OR1 H2N NH2 N H 7, 10 Me 150C, 2 h NH N H 8 (47%) N 10 HN N H Me Me 11 (~30%) O O NH N H
+
OCHF2 H N 9 O N H
O R1O Me
F2HCO
Me
NH N H 8
7 R1 = Me, R2 = 2-C6H4OCHF2; 10 R1 = Et, R2 = 3-Py
The yield of these side products in the reaction with dihydropyridine 7 exceeds the yield of the expected bispyrazolonylmethane. The 1,4-dihydropyridine ring is also broken on treatment of derivatives of 1,4-dihydroindeno[1,2-b]pyridine with hydrazine hydrate. It was possible to isolate compound 15 in the reaction with the 3-acetylsubstituted compound 12. The reverse Michael reaction predominates in the reactions with the 3-alkoxycarbonyl derivatives 13 and 14 under these conditions. It was possible to isolate 1,3-indanedione dihydrazone (16) in up to 60% yield from the reaction mixture, and products of the recombination of fragments of the molecule, such as 3-pyridylbis(5-methyl-3-oxo-4-pyrazolyl)methane (11). Compound 13, unsubstituted at position 4, forms a mixture of compounds even under less rigid conditions (Scheme 1). In the case of 10,12-dioxo-11-phenyl-5,10,11,12-tetrahydrodiindeno[1,2-b:2',1'-e]pyridine (18), a polycyclic derivative of 1,4-dihydropyridine, heating with hydrazine hydrate takes place without fission of the heterocycle (Scheme 2). Under the reaction conditions probably addition of hydrazine to a carbonyl group occurs, which is accompanied by spontaneous aromatization of the heterocycle. Simultaneously a WolffKishner reaction occurs and 11-phenyl-10H,12H-diindeno[1,2-b:2',1'-e]pyridine (19) is formed. Compound 19 was obtained previously from the product of oxidation of compound 18 [10].
871
Scheme 1
O R2 O R1 N 1214 H Me
+ H2N NH2
12
150C, 5 h
13
100C, 2 h NNH2
14
125C, 5 h
NNH2 Ph
Me N NH
O N NH NH O O NH Me + Me N H
NNH2 Me 15 (23%) + NNH2
NNH2 Me 17 + 16 HN N H
11 (24%) 16 (60%)
16
NNH2
12 R1 = Me, R2 = Ph; 13 R1 = OEt, R2 = H; 14 R1= OEt, R2 = 3-Py
Scheme 2
O Ph O H2N NH2 140C, 5 h N H N Ph
18
19
Fission of the heterocycle and the formation of a pyrazole derivative also occurs on treatment of other related system with hydrazine hydrate.
Ph HN S N H Me O Me H2N NH2 130C, 5 h H2N S N H Me N H Ph Me N
20
21
3,5-Dimethyl-4-(-thioureidobenzyl)pyrazole (21) is formed on interacting 5-acetyl-6-methyl-2-thioxo4-phenyl-1,2,3,4-tetrahydropyrimidine (20) with hydrazine hydrate. 872
TABLE 1. Reactions with Hydrazine Hydrate

Compound investigated g mmol 0.10 0.33 10.0 15.0 0.33 10.0 0.33 30 0.33 0.66 0.34 0.33 10.0 10.0 0.33 0.33 10.0 0.06 10.0 0.55 1.71 37.0 45.0 0.92 31.5 1.47 120 0.70 1.12 1.27 1.10 27.2 30.3 1.05 1.23 30.1 0.17 40.6 Hydrazine hydrate mmol 10.3 24.7 510 306 24.7 410 24.7 1240 24.7 10.4 24.7 24.7 410 410 24.7 24.7 204 10.3 510 Ethanol, ml 2.5 2.5 55 60 2.5 60 2.5 200 2.5 2.2 2.5 2.5 60 60 2.5 2.5 60 2.5 55 Reaction conditions t, C time, h 140 140 150 150 140 140 140 ~80 140 140 140 140 150 150 140 100 125 140 130 6 2 5 3 4 6 0.5 6 1 1 6 4 5 5 6 2 5 5 5 Product obtained amount, g yield, % 0.05 52 0.28 80 7.69 74 14.10 91 0.20 59 8.80 85 0.25 82 21.73 88* 0.12 83 0.19 82 0.12 45 0.23 74 2.50 47 0.91 11*2 0.10 27*3 Not isolated 3.16 60 1.04 24 0.02 36 9.90 37
No. 1a 1b 1c 1d 1e 1f 3a 3b 3c 3d 3e 5 7 10 12 13 14 18 20
ml 0.5 1.2 25 15 1.2 20 1.2 60 1.2 0.52 1.2 1.2 20 20 1.2 1.2 10 0.5 25
No. 2a 2b 2c 2d 2e 2f 4 4 4 4 4 6 8 11 15 16+17 16 11 19 21
_______ * Boiling in a flask under reflux. *2 A mixture (2.28 g) of compounds 11 and 8 was isolated in addition. *3 A mixture (0.23 g) of compounds 15 and 16 was obtained on evaporation.
873
EXPERIMENTAL
The 1H NMR spectra were taken on a Bruker WH-90 (90 MHz) spectrometer in DMSO-d6, internal standard was HMDS ( 0.055 ppm). The IR spectra were recorded in the region 1500-3600 cm-1 on a PerkinElmer 580B instrument as nujol suspensions. The compounds being studied were synthesized by known methods. Reactions were carried out in thickwalled glass vessels of volume 5 ml or in a 100 ml autoclave, in ethanol with an excess quantity of hydrazine hydrate. The reaction conditions and results are collated in Table 1. Bis(3-methyl-4-pyrazolyl)methane (2a). A mixture of 3,5-diacetyl-1,4-dihydropyridine monohydrate (1a), hydrazine hydrate, and ethanol (see Table 1) was heated for 6 h at 140C. The reaction mixture was evaporated, the colorless compound 2a obtained was recrystallized from ethyl acetatehexane. Yield 0.05 g (52%); mp 165-167C. 1H NMR spectrum, , ppm: 2.07 (6H, s, 3,3'-CH3); 3.39 (2H, s, CH2); 7.16 (2H, s, H-5,5'); 11.55-12.65 (2H, br. s, 1,1'-NH). Found, %: C 61.21; H 6.84; N 31.60. C9H12N4. Calculated, %: C 61.34; H 6.86; N 31.79. Bis(3,5-dimethyl-4-pyrazolyl)methane (2b) was obtained from 3,5-diacetyl-2,6-dimethyl-1,4dihydropyridine 1b and was isolated after cooling the reaction mixture. The reaction also went well in dioxane (1 h at 140C or 3 h on boiling). Bis(3,5-dimethyl-4-pyrazolyl)-3-pyridylmethane (2c) was obtained from 3,5-diacetyl-2,6-dimethyl-4(3-pyridyl)-1,4-dihydropyridine (1c) on cooling the reaction mixture. The colorless compound had mp 320C (sublimes). 1H NMR spectrum, , ppm: 1.70 (12H, s, 4CH3); 5.26 (1H, s, CH); 7.20-7.50 (2H, m, H-4, H-5 Py); 8.25-8.45 (2H, m, H-2, H-6 Py); 11.92 (2H, br. s, NH). Found, %: C 68.26; H 6.82; N 24.86. C16H19N5. Calculated, %: C 68.30; H 6.81; N 24.89. 2-Difluoromethoxyphenylbis(3,5-dimethyl-4-pyrazolyl)methane (2d) was obtained from 3,5-diacetyl2,6-dimethyl-4-(2-difluoromethoxyphenyl)-1,4-dihydropyridine (1d). Colorless substance with mp 297-300C. IR spectrum, , cm-1: 3170, 3120, 3060, 3040 (NH), 1587, 1510. 1H NMR spectrum, , ppm, (J, Hz): 1.67 (12H, s, 4CH3); 5.35 (1H, s, CH); 7.02 (1H, t, J = 75, OCHF2); 6.90-7.45 (4H, m, C6H4); 11.90 (2H, br. s, 2NH). Found, %: C 62.44; H 5.85; N 16.27. C18H20F2N4O. Calculated, %: C 62.42; H 5.82; N 16.17. Bis(3,5-dimethyl-4-pyrazolyl)-3,4,5-trimethoxyphenylmethane (2e) was obtained from 3,5-diacetyl2,6-dimethyl-4-(3,4,5-trimethoxyphenyl)-1,4-dihydropyridine (1e). The colorless substance had mp 279-281C (DMFwater). A portion of the substance was isolated from the cooled reaction mixture, and the remainder on evaporation. 1H NMR spectrum, , ppm: 1.72 (12H, s, 3,5,3',5'-CH3); 3.61 (9H, s, 3-CH3O); 5.15 (1H, s, CH); 6.33 (2H, s, C6H2); 11.87 (2H, br. s, 2NH). Found, %: C 64.84; H 7.01; N 15.09. C20H26N4O3. Calculated, %: C 64.85; H 7.07; N 15.12. Bis(5-methyl-3-phenyl-4-pyrazolyl)methane (2f) was obtained from 3,5-dibenzoyl-2,6-dimethyl-1,4dihydropyridine 1f after evaporation of the reaction mixture as a colorless substance of mp 146-148C (ethyl acetatehexane). 1H NMR spectrum, , ppm: 1.84 (6H, s, 2CH3); 3.80 (2H, s, CH2); 7.10-7.60 (10H, m, 2C6H5); 10.5-12.5 (2H, br. s, NH). Found, %: C 76.45; H 6.15; N 17.13. C21H20N4. Calculated, %: C 76.80; H 6.14; N 17.06. Phenyl(3,5-dimethyl-4-pyrazolyl)(5'-methyl-3'-oxo-4'-pyrazolyl)methane (6) was obtained from 3-acetyl-5-ethoxycarbonyl-2,6-dimethyl-4-phenyl-1,4-dihydropyridine 5. After evaporating the reaction mixture the residue was washed with acetone, mp 281-282C (decomp.). IR spectrum, , cm-1: 3310, 3160 (NH pyrazole), 2500-3120 (band with weakly expressed maxima at 3020-3120 and 2600-2700, NH pyrazolone), 1600, 1590, 1530, 1510. 1H NMR spectrum, , ppm: 1.68 (3H, s, CH3 pyrazolone); 1.73 (6H, s, 2CH3 pyrazole); 5.13 (1H, s, CH); 6.95-7.50 (5H, m, C6H5); 10.00-11.50 (3H, br. s, 3NH). Found, %: C 67.96; H 6.50; N 19.62. C16H18N4O. Calculated, %: C 68.06; H 6.43; N 19.84. Bis(5-methyl-3-oxo-4-pyrazolyl)(3-pyridyl)methane (11) was obtained from 3,5-diethoxycarbonyl2,6-dimethyl-4-(3-pyridyl)-1,4-dihydropyridine (10). Colorless substance with mp >300C (decomp.). 5-Methyl3-oxo-4-pyrazole 8 is formed as a side product. Compound 11 was isolated in 24% yield from the reaction 874
mixture in the reaction of 3-ethoxycarbonyl-2-methyl-5-oxo-4-(3-pyridyl)-1,4-dihydroindeno[1,2-b]pyridine (14) with hydrazine hydrate, together with the dihydrazone of 1,3-indanedione (16) (60% yield). 1H NMR spectrum, , ppm (J, Hz): 2.08 (6H, s, 2CH3); 4.88 (1H, s, CH); 7.24 (1H, dd, J1 = 8, J2 = 4.5, H-5 Py); 7.54 (1H, dt, J1 = 8, J2 = 4.5, H-4 Py); 8.30-8.40 (2H, m, H-2, H-6 Py); 9.50-11.70 (4H, br. s, 4NH). Found, %: C 58.60; H 5.39; N 24.72. C14H15N5O2. Calculated, %: C 58.94; H 5.30; N 24.55. 3,5-Dimethyl-4-[-(1,3-dihydrazono-2-indanyl)benzyl]pyrazole (15) was obtained from 5-oxo-4phenyl-1,4-dihydroindeno[1,3-b]pyridine 12 on cooling the reaction mixture. Yellow crystalline substance of mp 165C (decomp.). 1H NMR spectrum, , ppm (J, Hz): 1.70 (6H, s, 2CH3); 4.67 (1H, d, J = 2, 2-H indanyl); 4.92 (1H, br. s, CHC6H5); 6.40 (4H, s, 2NNH2); 7.00-7.80 (9H, m, C6H5 and 4,5,6,7-H indanyl); 10.90-11.55 (1H, br. s, NH pyrazole). After crystallization from ethanol: 1.05 (3H, m, J = 7, CH3); 3.45 (2H, m, CH2); 4.32 (1H, t, J = 5, OH). Found, %: C 68.49; H 6.82; N 21.05. C21H22N6C2H5OH. Calculated, %: C 68.29; H 6.92; N 20.79. An additional amount of compound 15 was obtained mixed with 1,3-indanedione dihydrazone (16) on evaporating the filtrate from the reaction mixture. 11-Phenyl-10H,12H-diindeno[1,2-b:2',1'-e]pyridine (19) was obtained from 10,12-dioxo-11-phenyl5,10,11,12-tetrahydrodiindeno[1,2-b:2',1'-e]pyridine (18) after cooling the reaction mixture. Bright-yellow substance with mp 293-295C. Found, %: C 90.41; H 5.20; N 4.15. C25H17N. Calculated, %: C 90.60; H 5.17; N 4.23. 3,5-Dimethyl-4-[-thioureidobenzyl)pyrazole (21) was obtained from 5-acetyl-6-methyl-2-thioxo-4phenyl-1,2,3,4-tetrahydropyrimidine (20). After evaporating, the reaction mixture was stirred with ethyl acetate. Colorless crystalline solid 21 was precipitated; mp 189-191C (acetoneethyl acetate). 1H NMR spectrum, , ppm (J, Hz): 1.95 (6H, s, 3,5-CH3); 6.60 (1H, d, J = 9, 4-CH); 6.90-7.45 (7H, m, C6H5 and NH2); 8.05 (1H, d, J = 9, 4--NH); 10.05 (1H, br. s, 1-NH). Found, %: C 59.68; H 6.11; N 21.76. C13H16N4S. Calculated, %: C 59.97; H 6.19; N 21.52.
REFERENCES
1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
U. Eisner and J. Kuthan, Chem. Rev., 72, 1 (1972). F. Michael and H. Dralle, Liebigs Ann. Chem., 670, 57 (1963). R. Balicki, L. Kaczmarek, and P. Nantka-Namirski, Pol. J. Chem., 53, 893 (1979). I. Meyers, P. D. Edwards, T. R. Balley, and G. E. Jr. Jagdman, J. Org. Chem., 50, 1019 (1998). Y. Sato, BRD Patent 2629892; Chem. Abstr., 86, 189726 (1977). Z. V. Esayan, S. G. Chshmarityan, N. A. Apoyan, and G. L. Papayan, Arm. Khim. Zh., 35, 178 (1982). M. S. Mohamed, M. M. Ismail, and K. M. Ghoneim, J. Serb. Chem. Soc., 51, 405 (1986). M. S. Mohamed, Egypt. J. Pharm. Sci., 34, 99 (1993). L. Bellamy, New Data on the IR Spectra of Complex Molecules [Russian translation], Mir, Moscow (1971), p. 303. J. N. Chatterjea, S. C. Shaw, and S. N. Singh, J. Indian Chem. Soc., 55, 149 (1978).
875
SYNTHESIS, CARDIOVASCULAR ACTIVITY, AND ELECTROCHEMICAL OXIDATION OF NITRILES OF 5-ETHOXYCARBONYL-2-METHYLTHIO-1,4-DIHYDROPYRIDINE-3-CARBOXYLIC ACID

A. Krauze, L. Baumane, L. Sile, L. Chernova, M. Vilums, R. Vitolina, G. Duburs, and J. Stradins Nitriles of 4-aryl-5-ethoxycarbonyl-2-methylthio-1,4-dihydropyridine-3-carboxylic acid have been obtained by the methylation of 1,4-dihydropyridine-2-thiolates; of 1,4-dihydropyridine-2(3H)-thiones in the presence of a stoichiometric amount of piperidine, and of a mixture of 1,4,5,6-tetrahydro- and 1,4-dihydropyridine-2-thiolates with methyl iodide. One-pot multicomponent synthesis has also been used in the condensation of ethyl 2-arylmethyleneacetoacetate, 2-cyanothioacetamide, piperidine, and methyl iodide; of ethyl acetoacetate, 3-aryl-2-cyanothioacrylamide, piperidine, and methyl iodide; and of ethyl acetoacetate, an aromatic aldehyde, 2-cyanothioacetamide, piperidine, and methyl iodide. The latter, a five-component method, takes place rapidly and under mild conditions, it is efficient (yields of 75-96%, economy of time, labour, and resources) and "green" (there is no need to synthesize lachrymators, such as 3-aryl-2-cyanothioacrylamides).The cardiovascular activity and the electrochemical oxidation of the synthesized 2-methylthio-1,4-dihydropyridines have been investigated. A comparative analysis has been carried out of the ability towards electrochemical oxidation as a function of the electronic properties of the substituent at position 4 of the heterocycle. Keywords: 1,4-dihydropyridines, electrochemical oxidation. cardiovascular activity, one-pot multicomponent synthesis,
Many of the widely studied esters of 4-substituted 1,4-dihydropyridine-3,5-dicarboxylic acids possess marked cardiovascular activity and many preparations for the treatment of cardiovascular diseases have been created from them [1-4]. An important role, determining the activity of these compounds, is played by the presence of alkoxycarbonyl groups at positions 3 or 5, a methyl group at positions 2 or 6, and an aryl group at position 4. Nitrophenyl, alkoxyphenyl, and halogen-substituted phenyl groups are characterized as effective pharmacophores [1]. 2-Alkylthio-1,4-dihydropyridines display cardiovascular [5], hepatoprotective [6], antioxidant (AOA) [7], and antiradical (ARA) [8] activity, however these compounds are still insufficiently studied pharmacologically.
__________________________________________________________________________________________ Latvian Institute of Organic Synthesis, Riga LV-1006; e-mail: lbaumane@osi.lv. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1022-1035, July. 2004. Original article submitted April 2, 2004. 876 0009-3122/04/4007-08762004 Springer Science+Business Media, Inc.
R O CN O _ HO N H S + NH2 O
O N H
CN _ S + NH2
4am
R O O a C MeI O c
2am
R CN
+
O H2N
CN
+
S
N H
O O
+
O
+
H2N S
+
N H
R MeI D O O CN F MeI
[1+5]
HO
N H
[1+5]
5
H + H + H +
R O CN O O N H CN MeI B
N H
R O
N H
+
S
1 a m
+ H
3 am
A H + MeI
[1+5] 2
E MeI
2+4
2+4
b R O O CN
+
O H2N S
+
N H
R = H, b R = 4-OH; c R = 4-OMe; d R = 2-OMe; e R = 4-NMe2; f R = 4-Cl; g R = 3-Cl; h R = 2-Cl; i R = 2,4-Cl2; j R = 4-NO2; k R = 3-NO2; l R = 4-CN; m R = 3-CN
877
In a continuation of investigations on the synthesis and study of the properties of 2-alkylthio-1,4dihydropyridines [9] and to improve the methods of obtaining them [10-11], we have synthesized a series of new nitriles of 4-aryl-5-ethoxycarbonyl-6-methyl-2-methylthio-1,4-dihydropyridine-3-carboxylic acid 1, in which the substituents on the 4-phenyl residue are varied widely, and have investigated their cardiovascular activity. A comparative analysis has been carried out of the ability of 1,4-dihydropyridines 1 towards electrochemical oxidation as a function of the electronic properties of the substituents at position 4 of the heterocycle. Such data enable the search for biologically active substances to be carried out in a more purpose directed manner. In principle the important problem, the construction of 1,4-dihydropyridine-2(3H)-thione ring, is extremely complex, since these compounds are subject to oxidation in dilute solutions. Three of the main methods were already described in 1983 [12] and have been widely used since [13-23]. For a comparative analysis of the methods 2-chlorophenyl and 2,4-dichlorophenyl-substituted 1,4-dihydropyridine-2(3H)-thiones 3h and 3i were obtained by the condensation of a) ethyl 2-arylmethyleneacetoacetate, 2-cyanothioacetamide, and piperidine, b) ethyl acetoacetate, 3-aryl-2-cyanothioacrylamide, and piperidine, and c) ethyl acetoacetate, aromatic aldehyde, 2-cyanothioacetamide, and piperidine. On acidification of the resulting mixture of salts 2 and 4 the 1,4-dihydropyridine-2(3H)-thiones 3h and 3i were obtained in overall yields of 36-60%. The overall yields, calculated on the initial aldehyde, were 31-50% (Table 1). It should also be noted that the ethyl esters of 2arylmethyleneacetoacetic acid are formed as a mixture of cis and trans isomers [24] and their isolation is extended in time and laborious, since products of a further Michael reaction are formed on heating with the participation of ethyl acetoacetate as a methylene component. 3-Aryl-2-cyanothioacrylamides are lachrymators and in the presence of bases are inclined to dimerize [25]. The mentioned reactions using 2-cyanothioacetamide must be carried out under mild conditions. The use of stronger bases or boiling leads to a complex mixture (dimerization of 2-cyanothioacetamide, reaction of ethyl acetoacetate with 2-cyanothioacetamide [26]) and a reduction in yield. The use in these syntheses of a stoichiometric amount of piperidine [13-21] or N-methylmorpholine [22-23] was a fortunate finding. The intermediate piperidinium thiolates 4 or 2 are poorly soluble in ethanol, which provides their rapid separation from the reaction medium. Depending on the structure of the substituent in positions 5 and 6 and on the reaction temperature thiolates 4 or 2 are separated [15,16]. If under the reaction conditions a mixture of compounds 4 and 2 at a ratio of approximately 1:1 is formed then the products crystallize out with more difficulty. Too much dilution of the reaction mixture also hinders separation of the desired products and aids their oxidation to pyridine-2(3H)-thiones and bispyridyl disulfides [14]. TABLE 1. Characteristics of the Synthesized Compounds 2-4
Compound 4h + 2h Empirical formula Found, % Calculated, % H N
mp, S
Method
Yield, %*
4i + 2i
3h
C16H15ClN2O2S C16H14Cl2N2O2S 0.5 H2O
57.33 57.40 51.18 50.80
4.24 4.52 3.88 4.00
8.26 8.37 7.15 7.41
9.58 9.58 8.12 8.48
129-131
3i
99-101
A B C A B C A B C B C
55 (40) 63 (48) 45 (45) 73 (40) 65 (60) 57 (57) 43(31) 50 (38) 36 (36) 60 (33) 53 (50) 47 (47)
_______ * The overall yield calculated on the aldehyde is given in parentheses. 878
In the case of thiones 3h and 3i the salts corresponding to them are also separated as mixtures 4h + 2h (~3:1) and 4i + 2i (~6:1), according to the 1H NMR spectra. 6-Hydroxy-1,4,5,6-tetrahydropyridine-2-thiolates 4 on thermal treatment (at times a recrystallization is sufficient) may be converted into dihydropyridine-2-thiolates 2, but to obtain the desired products 1 the mixture of salts 4 and 2 is practicable. A longer but productive method of obtaining pure thiolates 2 is the conversion of thiolates 4 into thiones 3, and then back into 2-thiolates 2 by the action of piperidine. 1,4-Dihydropyridine2(3H)-thiones 3 are also unstable in dilute solution and are readily oxidized [7,8], however pure thiolates 2 and thiones 3 are preserved for years under argon. It should be noted that it is difficult to obtain thiones 3 containing electron-donating substituents in the 4-aryl group. Due to ready oxidation it was not possible to isolate thione 3d containing a 4-(2-methoxyphenyl) substituent, and in the case of thiones 3a-c,e reaction yields were low for the same reason. Nitriles of 4-aryl-5-ethoxycarbonyl-2-methylthio-1,4-dihydropyridine-3-carboxylic acids 1 were obtained by six methods, A) by the methylation of 1,4-dihydropyridine-2-thiolates 2, B) by the methylation of 1,4-dihydropyridine-2(3H)-thiones 3 in the presence of a stoichiometric amount of piperidine, C) by the methylation of mixtures of 1,4,5,6-tetrahydro- and 1,4-dihydropyridine-2-thiolates 4 and 2, D) by the condensation of ethyl 2-arylmethyleneacetoacetate, 2-cyanothioacetamide, piperidine, and methyl iodide, E) by the condensation of ethyl acetoacetate, 3-aryl-2-cyanothioacrylamide, piperidine, and methyl iodide, and F) by the condensation of ethyl acetoacetate, an aromatic aldehyde, 2-cyanothioacetamide, piperidine, and methyl iodide. In the case of methods C-F it is necessary to acidify the reaction mixture to complete the reaction. Allowing for the above, the target 2-methylthio-1,4-dihydropyridines 1 were obtained by the six methods, including the methylation of thiolates 2 and of thiones 3. Methods of four-component synthesis (D, E) have insignificant advantages since the overall yields calculated on the initial aldehyde were higher. In the case of methods A-C yields were 24-50% and in the case of methods D and E 33-80%. Method F, the condensation of ethyl acetoacetate with aromatic aldehydes and 2-cyanothioacetamide in the presence of piperidine and subsequent action of methyl iodide, was the most productive, as indicated by the yields of reaction products (75-96%) and also by economy of labour and resources. The use of methods of multicomponent synthesis enables the preparation of 2-methylthio-1,4-dihydropyridine 1d, which is not successful by the stepwise synthesis. It should be noted that in the case of methods C, D, E, and F 1,4-dihydropyridines 1 are formed with 6-hydroxy-1,4,5,6-tetrahydropyridines 5 as contaminant. On acidifying the reaction mixture of compounds 1 + 5 the final dehydration of 5 occurs with the formation of 1,4-dihydropyridines 1 exclusively. It has therefore been shown that, on obtaining 1,4-dihydropyridines 1 by the stepwise methods A-E, significant reductions of product yields arise both in the synthesis of the initial ethyl esters of 2-arylmethyleneacetoacetic acids and 3-aryl-2-cyanothioacrylamides and also on isolating the unstable 1,4-dihydropyridine-2(3H)-thiones 3. The five-component synthesis of 2-methylthio-1,4-dihydropyridines (method F), proceeding rapidly and under mild conditions, is efficient and "green", since the need to synthesize 3-aryl-2-cyanothioacrylamides, which are lachrymators, becomes superfluous. The structures of compounds 1-5 were proved spectroscopically. In the IR spectra the most characteristic absorption bands were for the stretching vibrations of the cyano group, which are observed at 2156 cm-1 for mixtures of salts 2 and 4, at 2190-2204 cm-1 for nitriles of 1,4-dihydropyridine-3-carboxylic acids 1, and at 2248-2250 cm-1 for 1,4-dihydropyridine-2(3H)-thiones 3. In the 1H NMR spectra of compounds 4 the most characteristic signals were for the H-4 and H-5 protons at 2.68-2.72 and 4.64-4.72 ppm as doublets with coupling constants ~12 Hz, which indicates the trans-diaxial disposition of these protons [18]. In the case of salts 2 and 1,4-dihydropyridines 1 the signals of the H-4 protons were at 4.53-5.30 ppm. In the 1H NMR spectra of thiones 3 the signals of the most characteristic protons H-3 and H-4 were strongly broadened and overlapped due to the thioneenethiol tautomeric equilibrium and cistrans isomerism. The characteristics of the synthesized compounds and the data of 1H NMR and IR spectra are given in Tables 1-4.
879
TABLE 2. Characteristics of the Synthesized Compounds 1

Compound 1a 1b 1c 1d 1e 1f 1g 1h Empirical formula C17H18N2O2S C17H18N2O3S H2O C18H20N2O3S C18H20N2O3S C19H23N3O2S 0.5 H2O C17H17ClN2O2S C17H17ClN2O2S C17H17ClN2O2S Found, % Calculated, % H N 5.72 5.77 5.63 5.78 5.77 5.86 5.84 5.86 6.48 6.60 4.79 4.91 4.86 4.91 4.80 4.91 8.91 8.91 8.08 8.04 8.06 8.13 8.04 8.13 11.31 11.46 7.84 8.03 7.96 8.03 7.93 8.10
mp, S 10.20 10.20 8.89 9.12 9.25 9.31 9.06 9.31 8.57 8.75 8.95 9.19 9.09 9.19 9.12 9.19 123-125 [3] 146-148 [27] 150-152 163-165 140-142 116-118 [3] 127-128 174-176
Method Yield, %*
C 64.94 64.94 58.64 58.61 62.78 62.77 62.53 62.77 61.93 62.28 62.28 58.53 58.49 58.53 58.50 58.53
A D E E E B A D F B C D E F C D E F B D B B F
90 (50) 53 (52) 81 (46) 97 (33) 77 (55) 67 (28) 82 (36) 74 (56) 81 (81) 76 (24) 96 (46) 80 (58) 91 (69) 96 (96) 79 (47) 86 (47) 86 (80) 78 (78) 67 (37) 57 (38) 83 (41) 48 (24) 75 (75)
1i
C17H16Cl2N2O2S
53.31 53.27
4.10 4.21
7.21 7.31
8.32 8.37
186-188
1j 1k 1l 1m
C17H17N3O4S C17H17N3O4S C18H17N3O3S C18H17N3O2S
56.76 56.81 56.54 56.81 63.84 63.70 63.22 63.70
4.77 4.77 4.77 4.77 4.95 5.05 4.84 5.05
11.52 11.69 11.69 11.69 12.22 12.38 12.33 12.38
8.90 8.92 8.69 8.92 9.27 9.45 9.40 9.45
161-162 102-104 107-109 135-137
_______ * Yields calculated on the aldehyde are given in parentheses.
The electrochemical oxidation of compounds 1 was carried out in anhydrous acetonitrile at the stationary glass-graphite electrode. Compounds were adsorbed onto the surface of the electrode since the electrolysis was carried out in the presence of surface-active camphor at 0.1% concentration. For all the 1,4-dihydropyridine derivatives 1 (except for 1e) one irreversible oxidation peak was recorded in the potential range Ep = 1.28-1.44 V relative to the saturated calomel electrode (Table 5). Polarograms were also recorded for compounds 1a and 1f at the rotating disk electrode with a ring, and their characteristics were compared with results obtained previously for compounds close in structure [11]. The electrochemical oxidation of compounds 1 proceeds along the previously established route. At the disk electrode one oxidation wave arises at a half-wave potential E1/2 = 1.03 (for 1a) or E1/2 = 1.08 V (for 1f), but at the ring electrode waves were recorded for the electroreduction products: E1/2 = -1.08, 1.80 (for 1a) and E1/2 = -1.01, -1.73 V (for 1f), indicating the formation of the corresponding pyridinium cation and pyridine as the oxidation products [11, 28-33]. The molecules of compounds 1a-m have unsymmetrical substituents on the heterocycle, consequently it seemed of interest to clarify how the electronic properties of the cyano group in position 3 and the thiomethyl group in position 2 of the heterocycle influence electrooxidizability in comparison with the symmetrical 3,5-diethoxycarbonyl-2,6-dimethyl-4-phenyl derivative of 1,4-dihydropyridine. Cyclic voltammerric curves were recorded under the same experimental conditions for the model compounds 3,5-diethoxycarbonyl-2,6-dimethyl880
4-phenyl-1,4-dihydropyridine (6) and 3-cyano-5-ethoxycarbonyl-2,6-dimethyl-4-phenyl-1,4-dihydropyridine (7). It was shown that replacement of the ethoxycarbonyl group by cyano hinders the removal of the first electron by 90 mV (Ep = 1.13 for 6 and Ep = 1.22 V for 7). Further replacement of a methyl group by thiomethyl (compound 1a) in position 2 of the heterocycle hinders electrooxidation still more by 90 mV (Ep = 1.22 for 7 and Ep = 1.32 V for 1a). When considering the influence of substituents in the phenyl ring at position 4 of a 1,4-dihydropyridine, it was established that meta and para nitro groups hinder the electrooxidation by 120 and 140 mV respectively (compounds 1k and 1j). Compounds substituted in the ortho position (1d and 1h) were oxidized more readily than the corresponding para- and meta-substituted compounds, due to intramolecular interactions. 4-(p-Dimethylaminophenyl)-1,4-dihydropyridine 1e is oxidized stepwise with the formation of several oxidation
TABLE 3. Spectral Characteristics of Compounds 1

Compound 1a IR spectrum, , cm-1 1702 (C=O); 2198 (CN); 3278 (NH) 1654, 1680 sh (C=O); 2202 (CN); 3190 (NH) 1676, 1698 (C=O); 2192, 2200 (CN); 3224, 3266 (NH) 1700 (C=O); 2190(CN); 3280 (NH) 1680 (C=O); 2194 (CN); 3226, 3278 (NH) 1688 (C=O); 2202 (CN); 3280 (NH) 1686 (C=O); 2196(CN); 3284 (NH) 1688 (C=O); 2194 (CN); 3290 (NH) 1708 (C=O); 2194 (CN); 3304 (NH) 1640 (C=O); 2204(CN); 3195, 3260 (NH) 1646, 1670 (C=O); 2202(CN); 3316 (NH) 1634 (C=O); 2198, 2222 (CN); 3192, 3250 (NH) 1700 (C=O); 2198, 2218 (CN); 3320 (NH)
1
NMR spectrum (CDCl3), , ppm
1b
1.13 and 4.03 (5H, t and q, C2H5); 2.36 (3H, s, 6-CH3); 2.44 (3, s, SCH3); 4.68 (1H, s, H-4); 6.34 (1H, br. s, NH); 7.22 (4, m, C6H5) 1.16* and 4.03 (5H, t and q, C2H5); 2.32 (3H, s, 6-CH3); 2.42 (3, s, SCH3); 4.53 (1H, s, 4-H); 6.74 and 7.00 (4, d and d, C6H4); 8.14 (1H, br. s, NH) 1.16 and 4.03 (5H, t and q, C2H5); 2.37 (3H, s, 6-CH3); 2.47 (3, s, SCH3); 3.77 (3, s, CH3); 4.63 (1H, s, H-4); 6.13 (1H, br. s, NH); 6.83 and 7.18 (4, d and d, C6H4) 1.00 and 3.98 (5H, t and q, C2H5); 2.37 (3H, s, 6-CH3); 2.42 (3, s, SCH3); 3.86 (3, s, CH3); 5.15 (1H, s, H-4); 6.18 (1H, s, NH); 6.8-7.3 (4, m, C6H4) 1.17 and 4.04 (5H, t and q, C2H5); 2.35 (3H, s, 6-CH3); 2.44 (3, s, SCH3); 2.90 [4, s, N(CH3)2]; 4.57 (1H, s, H-4); 6.22 (1H, br. s, NH); 6.17 and 7.08 (4, d and d, C6H4) 1.13 and 4.04 (5H, t and q, C2H5); 2.35 (3H, s, 6-CH3); 2.42 (3, s, SCH3); 4.66 (1H, s, H-4); 6.52 (1H, br. s, NH); 7.1-7.4 (4, m, C6H4) 1.13 and 4.04 (5H, t and q, C2H5); 2.35 (3H, s, 6-CH3); 2.43 (3, s, SCH3); 4.65 (1H, s, H-4); 6.30 (1H, br. s, NH); 7.0-7.3 (4, m, C6H4) 1.08 and 3.98 (5H, t and q, C2H5); 2.37 (3H, s, 6-CH3); 2.42 (3, s, SCH3); 5.30 (1H, s, H-4); 6.40 (1H, br. s, NH); 7.0-7.4 (4, m, C6H4) 1.12 and 3.98 (5H, t and q, C2H5); 2.38 (3H, s, 6-CH3); 2.45 (3, s, SCH3); 5.27 (1H, s, H-4); 6.18 (1H, br. s, NH); 7.22 and 7.38 (4, m, C6H4) 1.15 and 4.08 (5H, t and q, C2H5); 2.43 (3H, s, 6-CH3); 2.51 (3, s, SCH3); 4.83 (1H, s, H-4); 6.14 (1H, br. s, NH); 7.44 and 8.20 (4, d and d, C6H4) 1.14 and 4.06 (5H, t and q, C2H5); 2.37 (3H, s, 6-CH3); 2.47 (3, s, SCH3); 4.82 (1H, s, H-4); 6.58 (1H, br. s, NH); 7.4-8.2 (4, m, C6H4) 1.12 and 4.06 (5H, t and q, C2H5); 2.38 (3H, s, 6-CH3); 2.48 (3, s, SCH3); 4.77 (1H, s, H-4); 6.18 (1H, s, NH); 7.37 and 7.64 (4, d and d, C6H4) 1.14 and 4.03 (5H, t and q, C2H5); 2.38 (3H, s, 6-CH3); 2.47 (3, s, SCH3); 4.72 (1H, s, H-4); 6.43 (1H, br. s, NH); 7.40-7.65 (4, m, C6H4)
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
_______ * CDCl3 + DMSO. 881

Compound 2h + 4h IR spectrum, , m-1 1720 (C=O); 2156 (CN); 3170 (NH); 3400 (OH)
1
NMR spectrum (CDCl3), , ppm (J, Hz)
2i + 4i
1720 (C=O); 2156 (CN); 3206 (NH); 3406 (OH)
3h
3i
1702 (C=O); 2248 (CN); 3280 (NH) 1698 (C=O); 2250 (CN); 3230 (NH)
0.91 and 3.96 (5H, t and q, 25); 1.48 (3H, s, 6-3); 1.6-.8 [6H, m, (CH2)3]; 2.68 and 4.72 (2H, d and d, J = 12, H-5 and -4); 2.9-.1 [4H, m, N(CH2)2]; 5.82 (1H, br. s, H); 6.58 (1H, br. s, NH); 7.0-.5 (4, m, C6H4); 1.07 and 3.96 (5H, t and q, 25); 1.6-.8 [6H, m, (CH2)3]; 2.35 (3H, s, 6-3); 2.9-.1 [4H, m, N(CH2)2]; 5.18 (1H, s, H-4); 7.0-.5 (4, m, C6H4) 0.97 and 3.98 (5H, t and q, 25); 1.48 (3H, s, 6-3); 1.6-.8 [6H, m, (CH2)3]; 2.72 and 4.64 (2H, d and d, J = 12.2, H-5 and -4); 2.9-3.1 [4H, m, N(CH2)2]; 5.84 (1H, br. s, H); ~ 6.6 (1H, br. s, NH); 7.1-7.5 (4, m, C6H4); 1.08 and 3.98 (5H, t and q, 25); 1.6-1.8 [6H, m, (CH2)3]; 2.34 (3H, s, 6-3); 2.9-3.1 [4H, m, N(CH2)2]; 5.12 (1H, s, H-4); 7.1-7.5 (4, m, C6H4) 1.16, 4.10 and 4.20 (5H, t and q, 25 ); 2.50 and 2.62 (3H, s and s, 6-3); 4.9-5.3 (2H, m, -3 and H-4); 6.9-7.6 (4, m, C6H4); 8.42 (1H, br. s, NH) 1.20, 4.14 and 4.20 (5H, t and q, 25 ); 2.54 and 2.63 (3H, s and s, 6-3); 4.9-5.3 (2H, m, H-3 and -4); 6.98, 7.22, 7.52 (3, d, J = 10, dd, J = 2 and 10, d, J = 2, C6H3); 8.98 (1, br. s, NH).
peaks at extremely positive potentials. A similar phenomenon was observed previously when oxidizing the corresponding symmetrical 1,4-dihydropyridines [34]. Facilitation of the oxidation of compound 1e is explained by the prior electrooxidation of the dimethylamino group. To check this hypothesis oxidation of compound 1e was carried out at the rotating disk electrode and at the ring electrode were recorded waves for the reduction of the oxidized products. It turned out that in the process of the electrooxidation of 1e four waves were formed with half-wave potentials E1/2 = 0.42, 0.80, 1.12, and 2.00 V relative to the Ag/AgNO3 reference electrode (it is probable that at the stationary electrode the fourth wave is hidden by separation of the background). At the ring electrode, depending on the degree of oxidation of 1e, two oxidized products are detected capable of being reduced at potentials E1/2 = -1.29 V (oxidation was carried out at the potential of the limiting current of the third wave) and E1/2 = -0.80 V (oxidation proceeds at the potential of the stationary current of the fourth wave), which corresponds to the pyridinium cation with various substituents at position 4 of the heterocycle. From the values of the reduction potentials it may be proposed that in the first stage the substituent partially retained electrondonating properties, and in the second the product contains a markedly electron-withdrawing substituent.
TABLE 5. Values of the Potentials of Oxidation Peaks on Cyclic Scanning of the Potential of the Stationary Electrode (Ep) for Compounds 1a-m in Acetonitrile on a Base of 0.1 M (C4H9)4PF6 with Added 0.1% Camphor
No 1 2 3 4 5 6 7 Compound 1a 1b 1c 1d 1e 1f 1g p, V 1.32 1.32 1.33 1.28 0.79; 0.99; 1.50 1.42 1.42 No 8 9 10 11 12 13 Compound 1h 1i 1j 1k 1l 1m p, V 1.36 1.40 1.44 1.42 1.42 1.39
882
The characteristics of the influence of substituents in the phenyl ring are mainly in agreement with the data given previously for symmetrical 3,5-dicarbethoxy-2,6-dimethyl-4-phenyl-substituted 1,4-dihydropyridines in [34,35]. However the introduction of a chlorine atom into the para or meta position of the phenyl ring (compounds 1f and 1g), in difference to the symmetrical 1,4-dihydropyridines, hinders oxidation like a nitro group in the meta position. Attempts were undertaken by the method of correlation-statistical analysis to trace quantitatively the influence of substituents in the phenyl ring on the electrooxidation potentials Ep. A linear correlation is observed with the Taft * constants. Nine representatives of the series (except for 1d-g) fit onto a correlation straight line with parameters * = 0.120 V (r = 0.977, S = 0.011), and if 1c and 1m are also excluded from the equation then the remaining representatives of the series practically lie on the straight line with * = 0.133 (r = 0.992, S = 0.006). It is possible that the noted deviations from the straight line are caused by the specific properties of certain substituents, since the electro-oxidation potentials of 1,4-dihydropyridines at solid electrodes depends not only on electronic and steric effects but also on adsorbability, coplanarity, and the orientation of electroactive molecules on the electrode surface [36-38]. The sensitivity constant * for the influence of substituents in the phenyl ring for compounds of the type of 1 differs little in size from that for symmetrical 4-phenyl-substituted 3,5-diethoxycarbonyl-2,6-dimethyl-1,4-dihydropyridines (* = 0.15 [34]). Consequently replacement of a methyl group by a thiomethyl in position 2 and an ethoxycarbonyl group by cyano in position 3 of the heterocycle has no significant influence on the effect of the substituents in the phenyl ring. The cardiovascular activity of nitriles of 2-methylthio-1,4-dihydropyridine-3-carboxylic acid 4 was studied in experimental animals, in cats, dogs, and spontaneously hypertensive rats (SHR), and the acute toxicity was studied in mice. As is seen from Table 6 compounds 1f and 1k in high doses cause an increase in coronary bloodflow by 25-40% for 3-10 min, simultaneously reducing systemic arterial pressure by 29-53%. In experiments in dogs 1,4-dihydropyridine 1a at low doses displays a more marked coronary dilatating action (30-58%) with a duration of 10-20 min, while not changing the systemic arterial pressure and pulse rate. Compound 1k, containing the pharmacophoric 3-nitrophenyl group, gives an insignificant hypotensive effect in experiments in SHR. The investigated compounds had low toxicity. The lethal dose was greater than 1000 mg/kg.
TABLE 6. Effect of 2-Methylthio-1,4-dihydropyridines 1 on Parameters of the Cardiovascular System and Their Acute Toxicity
Increase Duration in coronary of effect, blood flow, min % 30* 58* 40 25 25 n. i. 30 36 10 20 3 6 10 5 10 Change in pulse rate, % Hypotensive activity, % Hypotensive activity in SHR (10mg/kg), mm Hg
Compound
Dose, mg/kg
LD50, mg/kg ip
1 1f
0.01 0.1 0.1 1.0 5.0 0.1 1.0 5.0
1k
n. i. n. i. 8 25 34 14 31 27
n. i. n. i. 41 36 41 14 29 53
>1000 >5000
13 6 h
>2000
_______ *Coronary blood (intravenously).
flow
was
measured
fluorometrically
in
dogs
883
EXPERIMENTAL Chemical Section. The IR spectra of the initial compounds were taken on a Perkin-Elmer 580B spectrometer in nujol. The 1H NMR spectra were recorded on a Bruker WH 90/DC (90 MHz) spectrometer in CDCl3, internal standard was HMDS ( 0.05 ppm). A check on the progress of reactions and the homogeneity of substances was effected by TLC on Silufol UV 254 plates, eluent was chloroformhexaneacetone, 2:1:1. Compounds were recrystallized from ethanol. The initial ethyl esters of 2-arylmethyleneacetoacetic acid were synthesized according to [39], and the 3-aryl-2-cyanothioacrylamides according to [25]. Yields of products were: ethyl 2-phenylmethyleneacetoacetate 80%, ethyl 2-(4-chlorophenyl)methyleneacetoacetate 75%, ethyl 2-(2chlorophenyl)methyleneacetoacetate 72%, ethyl 2-(2,4-dichlorophenyl)methyleneacetoacetate 55%, ethyl 2-(4nitrophenyl)methyleneacetoacetate 66%, ethyl 2-(3-nitrophenyl)methyleneacetoacetate 80%, 2-cyano-3-(4hydroxyphenyl)thioacrylamide 57%, 2-cyano-3-(4-methoxyphenyl)thioacrylamide 81%, 2-cyano-3-(2-methoxyphenyl)thioacrylamide 72%, 2-cyano-3-(4-dimethylaminophenyl)thioacrylamide 88%, 3-(2-chlorophenyl)-2cyanothioacrylamide 76%, and 3-(2,4-dichlorophenyl)-2-cyanothioacrylamide 93%. Yields of thiolates were 2a 69% [14], 2f 59% [14], and thiones 3e 48% [14], 3k 61% [15], and 3l 24% [21]. Cyclic voltammetric curves were recorded on a PAR 170 (USA) electrochemical system using a threeelectrode cell with a stationary glass-graphite electrode. The reference electrode was an aqueous saturated calomel electrode, fitted with a transfer bridge for working in nonaqueous solvents. Electrochemical investigations by the method of a rotating disk electrode with a ring were carried out in equipment consisting of a PAR (USA) Ring-Disk-Electrode System Model 636 and a Bruker E 350 twin potentiostat. The disk and ring electrodes were prepared from glass-graphite. The calculated efficiency coefficient of the electrodes [40] was 0.39 and the rate of rotation of electrodes was 2000 rpm. All potentials were measured relative to a 0.1 N silver reference electrode (Ag/AgNO3). All investigations were carried out in nonaqueous acetonitrile, purified by the procedure of [41], with the addition of 0.1% camphor. Depolarizer concentration was 5.10-4 M. Base electrolyte was 110-1 M tetrabutylammonium hexafluorophosphate. General Methods for the Synthesis of Nitriles of 4-Aryl-3-cyano-5-ethoxycarbonyl-6-methyl-2thioxo-1,4-dihydropyridine-3-carboxylic Acids (3). a) A mixture of ethyl 2-arylmethyleneacetoacetate (5 mmol) and 2-cyanothioacetamide (5 mmol) in ethanol (15-20 ml) was heated briefly to dissolve the starting materials, piperidine (6 mmol) was added, and the mixture stirred for 10-30 min. The solid formed was filtered off and washed with ethanol (5-10 ml) cooled to 0C. A mixture of compounds 4h and 2h, and 4i and 2i was obtained by this method (see Table 2 for 1H NMR spectra). The mixture of salts 2 and 4 (5 mmol) and 1 M HCl in ethanol (10 ml) was heated briefly and stirred for 10-20 min at room temperature. The resulting solid was filtered off, washed with ethanol (5-10 ml) cooled to 0C, and with water (10 ml). Compounds 3h and 3i were obtained by this method. b) A mixture of ethyl acetoacetate (5 mmol) and 3-aryl-2-cyanothioacrylamide (5 mmol) in ethanol (15-20 ml) was heated briefly to dissolve the starting materials. Piperidine (6 mmol) was added, and the mixture stirred for 10-30 min. The resulting solid was filtered off, and washed with ethanol (5-10 ml) cooled to 0C. Mixtures of compounds 2d and 4d, 2h and 4h, and 2i and 4i were obtained by this method (see Table 4 for 1 H NMR spectra). The mixture of salts 2 and 4 (5 mmol) and 1M HCl in ethanol (10 ml) was heated briefly and stirred for 10-20 min at room temperature. The resulting solid was filtered off, washed with ethanol (5-10 ml) cooled to 0C, and with water (10 ml). Compounds 3h and 3i were obtained by this method. c) A mixture of aromatic aldehyde (5 mmol), 2-cyanothioacetamide (5 mmol), and piperidine (1 mmol) in ethanol (15-20 ml) was heated briefly to effect solution. Then ethyl acetoacetate (5 mmol) and piperidine (5 mmol) were added with stirring at room temperature. The resulting solid was filtered off, and washed with ethanol (5-10 ml) cooled to 0C. Mixtures of compounds 2d and 4d, 2h and 4h, and 2i and 4i were obtained by this method (see Table 4 for 1H NMR spectra ). Mixtures of salts 4 and 2 (5 mmol) and 1 M HCl in ethanol (10 ml) were heated briefly and stirred for 10-20 min at room temperature. The resulting solid was filtered off, washed with ethanol (5-10 ml) cooled to 0C, and with water (10 ml). Compounds 3h and 3i were obtained by this method. 884
General Method for the Synthesis of Nitriles of 4-Aryl-3-cyano-5-ethoxycarbonyl-6-methyl-2methylthio-1,4-dihydropyridine-3-carboxylic Acids (1). A. A mixture of 1,4-dihydropyridine-2(3H)-thiolate (10 mmol) and methyl iodide (15 mmol) or dimethyl sulfate (12 mmol) in ethanol (20-40 ml) was boiled for 2-5 min on a water bath, then stirred for 1 h at room temperature. The solid which had formed was filtered off, washed with ethanol (5-10 ml) cooled to 0C, and with water (10 ml). Compounds 1a,f were obtained by this method. B. A mixture of 1,4-dihydropyridine-2(3H)-thione 3 (10 mmol), piperidine (11 mmol), and methyl iodide (15 mmol) or dimethyl sulfate (12 mmol) in ethanol (20-40 ml) was boiled on a water bath, then stirred for 1 h at room temperature. The resulting solid was filtered off, washed with ethanol (5-10 ml) cooled to 0C, and with water (10 ml). Compounds 1e,h,j,k,l were obtained by this method. C. A mixture of 1,4,5,6-tetrahydropyridin-2(3H)-thiolate 4 (with admixture of thiolate 2) (10 mmol) and methyl iodide (15 mmol) in ethanol (20-40 ml) was boiled on a water bath, 3 M HCl in ethanol (2 ml) was added, and the mixture was then stirred for 1 h at room temperature. The precipitate which formed was filtered off, washed with ethanol (5-10 ml) cooled to 0C, and with water (10 ml). Compounds 1h,i were obtained by this method. D. A mixture of ethyl 2-arylmethyleneacetoacetate (5 mmol), 2-cyanothioacetamide (5 mmol), and piperidine (6 mmol) in ethanol (15-20 ml) was boiled briefly to effect solution, and after 10 min methyl iodide (10 mmol) was added. The mixture was boiled for 5 min on a water bath and 3 M HCl (2 ml) was added. The resulting solid was filtered off, washed with ethanol (5-10 ml) cooled to 0C, and with water (10 ml). Compounds 1a,f,h,i,j were obtained by this method. E. A mixture of ethyl acetoacetate (5 mmol), 3-aryl-2-cyanothioacrylamide, and piperidine (6 mmol) in ethanol (15-20 ml) was boiled briefly to effect solution and after 10 min methyl iodide (10 mmol) was added. The mixture was boiled for 5 min on a water bath and 3 M HCl in ethanol (2 ml) was added. The solid formed was filtered off, washed with ethanol (5-10 ml) cooled to 0C, and with water (10 ml). Compounds 1b-d,h,i were obtained by this method. F. A mixture of aromatic aldehyde (5 mmol), 2-cyanothioacetamide (5 mmol), and piperidine (1 mmol) in ethanol (15-20 ml) was boiled briefly to effect solution. While stirring at room temperature, ethyl acetoacetate (5 mmol) and piperidine (5 mmol) were added and then after 10 min methyl iodide (30 mmol) was added. The mixture was boiled for 5 min on a water bath, and 3 M HCl in ethanol (2 ml) was added. The solid formed was filtered off, washed with ethanol (5-10 ml) cooled to 0C, and with water (10 ml). Compounds 1g-i,m were obtained by this method. Pharmacological Section. Experiments were carried out in cats of both sexes of weight 2.3-3.6 kg, anesthetized with chloralose (90 mg/kg, ip). Systemic arterial pressure was recorded by an electromanometric method from the common carotid artery. The dp/dt was calculated with the aid of a pressure processor (Nihon Kohden). ECG were drawn in standard I mode. The volume rate of coronary blood flow was determined by the method of N. V. Kaverina [42], and blood flow in the femoral artery with the aid of a MFV 1200 flowmeter (Nihon Kohden). All records were produced on a RM 6000 (Nihon Kohden) polygraph. In experiments on mongrel dogs of both sexes of weight 13-24 kg, anesthetized with pentobarbital sodium (50 mg/kg, ip), systemic arterial pressure and ECG were recorded as in the experiments on cats. Substances were dissolved in 50% dimethylacetamide and injected intra-venously through a cannula introduced into the femoral vein. Each substance was investigated in 3-4 animals and mean data calculated. In the experiments on awake, spontaneously hypertensive rats of the Okamoto-Aoki line [43] the systemic arterial pressure was determined by plethysmography [44] before administering the substance and 0.5, 1, 3, 6, and 24 h afterwards. Each dose of substance was investigated in 3-6 rats using aqueous suspensions prepared in Tween 80, which were introduced into the stomach through a probe.
885
Acute toxicity was investigated in white random-bred mice of weight 18-24 g. A suspension of the substance in water with added Tween 80 (0.05 ml 6% Tween per 5 mg substance) was administered intraperitoneally. Each dose was investigated in 3-6 mice, animals were observed for 10 d. The mean lethal dose (LD50) was determined by the method of Litchfield and Wilcoxon.
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887
CYCLOCONDENSATION OF 2-FLUORO5-NITROBENZALDEHYDE WITH AMIDINES. NEW SYNTHESIS OF ISOQUINOLINES*

D. V. Dar'in, S. I. Selivanov, P. S. Lobanov, and A. A. Potekhin The direction of the cyclocondensation of 2-fluoro-5-nitrobenzaldehyde with five amidines having -hydrogen atoms has been studied. It was established that depending on the structure of the amidine the main products of the reaction may be not only quinazolines but also 3-aminoisoquinolines. A new convenient route has been found for the synthesis of 3-aminoisoquinolines consisting of the cyclocondensation of -acylacetamidines with 2-fluoro-5-nitrobenzaldehyde. Keywords: amidines as N,N- and C,N-dinucleophiles, isoquinolines, 2-fluoro-5-nitrobenzaldehyde, cyclocondensation. The cyclocondensation of amidines with activated ortho-fluorobenzaldehydes was discovered recently, and is a simple and convenient method for synthesizing 4-unsubstituted quinazolines. Amidines, the behavior of which was studied in this reaction, react as N,N'-dinucleophiles [2]. In addition it is known that amidines having a hydrogen atom in the -position to the amidine fragment may also act as N,C-dinucleophiles in reactions with 1,3-dielectrophiles [3]. In reactions with activated orthofluorobenzaldehydes such amidines might form 2-aminoquinolines 4 or 3-aminoisoquinolines 5, together with quinazolines 3 isomeric with them.
O2N CHO NH
+
F 1
H2N 2
O2N N 3
N R
O2N
O2N
+
N 4 NH2
+
5 R
N NH2
a R = H; b R = Ph; c R = CONH2; d R = COPh; e R = CO2Et
We have investigated the reaction of substituted acetamidines 2a-e, differing in the nature of the substituent at the -carbon atom and consequently in the reactivity of the carbon nucleophilic center, with aldehyde 1. _______ * For the preliminary communication see [1]. __________________________________________________________________________________________ St. Petersburg State University, Saint Petersburg 198504, Russia; e-mail: psl@pisem.net. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1036-1042. July, 2004. Original article submitted June 27, 2003. 888 0009-3122/04/4007-08882004 Springer Science+Business Media, Inc.
Amidines 2a-c were reacted as the hydrochlorides as we used the conditions described in [2]. Potassium carbonate was used as base. Amidines 2d and 2e were reacted as the free bases. Judging by the 1H NMR spectra they exist in the enediamine form (NH2)2C=CHR (R = COPh and CO2Et). In the reaction of aldehyde 1 with acetamidine 2a, with the least ability to display C-nucleophilic properties, the main product, as expected, proved to be 2-methyl-6-nitroquinazoline (3a), isolated in 58% yield. 2-Amino-6-nitroquinoline (4a), resulting from participation of the carbon nucleophilic center of acetamidine, was also successfully isolated from the reaction mixture in ~1.5% yield. The structures of quinazoline 3a and aminoquinoline 4a were confirmed by their 1H NMR spectra. Compound 4a may be assigned a quinoline structure and not the isomeric isoquinoline, since in its 1H NMR spectrum a spin-spin interaction is observed between the protons at positions 3 and 4 with a coupling constant of 9.0 Hz (doublets at 6.89 and 8.13 ppm), which corresponds to their ortho disposition. Aminoquinoline 4a has been repeatedly described in the literature [4-6]. Various authors give its melting point in the range 255-265C. The sample obtained by us decomposed at ~250C. Two isomeric compounds were isolated in the reaction with phenylacetamidine (2b). These were 2-benzyl-6-nitroquinazoline (3b) in 18% yield and 2-amino-6-nitro-3-phenylquinoline (4b), purified through the picrate and isolated in 6% yield. The structures of quinazoline 3b and aminoquinoline 4b were confirmed by their 1H NMR spectra. To prove the structure of aminoquinoline 4b a NOESY spectrum was taken in which a cross peak was observed between the signals of the 4-H proton of the heterocycle and the ortho-protons of the benzene ring, which indicates the relatively close disposition of them both, which occurs only in the quinoline structure. In the reaction with carbamoylacetamidine (2c) we isolated only 3-amino-4-carbamoyl-7nitroisoquinoline (5c) in 63% yield. It is not possible to draw an unequivocal conclusion between the quinoline 4c and isoquinoline 5c structures on the basis of the 1H NMR spectrum of this compound, since the expected difference of chemical shifts of the protons for these structures is small, and the character of the spin-spin interactions is the same. Consequently to demonstrate the structure of this compound the spin-spin interactions between the 1H and 13C nuclei were studied. A complete assignment of the signals in the 13C NMR spectrum was carried out on the basis of unidimensional 13C NMR spectra without proton decoupling and DEPT-135 and of two-dimensional COLOC correlation spectra (with optimization of sensitivity at J = 8 Hz) and HSQC without broadband decoupling from the 13C nuclei [7]. The chemical shift (156.1 ppm) detected for the signal of the C(1) atom (or C(4) for quinoline) served to indicate the isoquinoline structure, since the values of the chemical shifts for unsubstituted structures were 152.0 ppm for C(1) in isoquinoline and 136.1 for C(4) in quinoline [8]. In addition, from the 13C spectrum without proton decoupling we obtained a value for the direct coupling constant 1 J(C(1)H) = 181.5 Hz, at corresponding values for the unsubstituted compounds 1J(C(1)-H) = 178 Hz (isoquinoline), and 1J(C(4)H) = 162 Hz (quinoline) [8]. The chemical shift of the C(1) atom signal and the value of its direct coupling constant are adequately weighty, but indirect arguments in favor of the fact that the compound obtained is an isoquinoline. For a direct demonstration, a so-called relay INEPT-INADEQUATE experiment [9] was carried out, designed to clarify spin systems of the form 1H13C13C and including the sequential transfer of polarization from the proton to the geminal carbon atom through the 1JH-C and 1JC-C coupling constants. In the INEPT-INADEQUATE spectrum (Fig. 1) signals of the quaternary carbon atoms linked in both structures with methine carbon atoms (C(4a), C(7), and C(8a) for isoquinoline and C(4a), C(6), and C(8a) for quinoline), were observed, as might have been expected, in the form of antiphase doublets with coupling constants 1 JC-C ~65 Hz. In the structure of the C(4) atom signal (C(3) for quinoline) at 104.3 ppm the indicated doublet splitting was absent. In the structure of quinoline 4c the C(3) atom has a vicinal proton (4-H) and the signal of this atom should be represented as an antiphase doublet. In the structure of isoquinoline 5c the C(4) atom does not have vicinal protons. On the basis of the shape of the signal at 104 ppm we may confidently assign the structure of isoquinoline 5c to the compound being investigated.
889
Fig. 1. INEPT-INADEQUATE spectrum of compound 5c.
In addition to the signals of the main substance, a group of low intensity signals was observed in the H NMR spectrum of isoquinoline 5c, which may belong to the isomeric aminoquinoline 4c, the content of which in the reaction product was less than 1%. On carrying out the reaction of benzoylacetamidine (2d) with aldehyde 1 under the conditions used for amidines 2a-c, we isolated a reaction mixture with a low content of the main substance strongly contaminated with side products. On carrying out this reaction without base (method A) the main reaction product was 3-amino-4-benzoyl-7-nitroisoquinoline (5d), isolated in 47% yield. The structure of aminoisoquinoline 5d was confirmed by its 1H and 13C NMR spectra. In the 1H NMR spectrum the signals of the 1-H, 6-H, and 8-H protons and the protons of the amino group have chemical shifts close to the signals of the analogous protons of isoquinoline 5c. The exception was the signal for the proton at position 5 (doublet with coupling constant 9.3 Hz), the displacement of which into the low frequency region by 0.64 ppm in comparison with the signal for 5-H of isoquinoline 5c may be explained by the shielding action of the benzene ring. Assignment of the signals of the methine carbon atoms in the 13C spectrum was carried out using DEPT and HSQC spectra and the
1
TABLE 1. Yield of Products from the Reaction of Aldehyde 1 with Amidines 2a-e
Amidine 2 2b 2c 2d 2e Yield, % 3 58 18 0 0 0 4 1.5 6 0.5* 2.5* 2* 5 0 0 63 47 37
_______ * Not isolated.
890
quaternary atoms were assigned by comparison with the position of the signals of the analogous atoms in the spectrum of aminoisoquinoline 5c. The signal of the C(1) atom was located at 157.8 ppm and the coupling constant 1J(C(1)H) = 186.8 Hz, which corresponds to the value expected for an isoquinoline. On carrying out the same reaction in the presence of triethylamine (method B) aminoisoquinoline 5d is formed in somewhat lower yield. Signals were detected in the 1H NMR spectrum of the main product which may be assigned to the isomeric 2-amino-3-benzoyl-6-nitroquinoline (4d), present at 5%. In the HSQC spectrum, without decoupling from the 13C nuclei, appropriate cross peaks are also observed belonging to monomeric aminoquinoline 4d, among which may be isolated a cross peak between the signal of the 4-H proton (8.60 ppm) and the signal of the C(4) atom at 147.5 ppm. The value 1J(C(4)H) = 166.2 Hz observed at this cross peak corresponds to that expected for quinoline. On carrying out the reaction of aldehyde 1 with amidine 2e under the same conditions as in the case of amidines 2a-c, the main product proved to be dihydropyridine 6e, containing as contaminants 3-amino-4ethoxycarbonyl-7-nitroisoquinoline (5e) and 2-amino-3-ethoxycarbonyl-6-nitroquinoline (4e).
NH2
EtO2C
2e . HCl
5e
4e
NH
NH2
F
CO2Et
O2N
6e
A satisfactory yield of isoquinoline 5e was achieved by gradually adding a solution of amidine 2e as the free base to the solution of aldehyde 1 (method A). In this way isoquinoline 5e was isolated in 40% yield, containing, judging by the 1H NMR spectrum, quinoline 4e (6%). The structure of isoquinoline 5e was demonstrated by a chemical method. Acid 5f (R = CO2H) was obtained by the hydrolysis of ester 5e, the decarboxylation of which led to isoquinoline 5a. Pure dihydropyridine 6e was obtained in 74% yield by method B. The direction of the process as a function of amidine structure may therefore be demonstrated by the summary Table 1. The reaction discovered by us represents a new scheme for assembling the isoquinoline ring and broadens the possibility of synthesizing substituted isoquinolines.
EXPERIMENTAL The NMR spectra were obtained on a Bruker DPX-300 (300 MHz) instrument in DMSO-d6. Reaction of Aldehyde 1 with Acetamidine (2a). A mixture of aldehyde 1 [10] (0.84 g, 5 mmol), acetamidine hydrochloride (0.77 g, 7.5 mmol), potassium carbonate (1.03 g, 7.5 mmol), and molecular sieves 4E (1.5 g) in dry acetonitrile (40 ml) was boiled with stirring for 4 h. The solid was filtered off and washed with ethyl acetate. The filtrate was evaporated, and the residue chromatographed on a column. Initially as eluent hexaneether was used, gradually increasing the proportion of ether from 20 to 75%. 2-Methyl-6nitroquinazoline (3a) (0.55 g, 58%) of mp 150-154C was isolated. A sample pure for analysis was obtained by recrystallization from methanolacetonitrile, 3:1. 1H NMR spectrum, , ppm (J, Hz): 2.84 (3H, s, CH3); 8.05 (1H, d, J = 9.1, 8-H); 8.61 (1H, m, J = 9.1, J = 2.5, 7-H); 9.12 (1H, d, J = 2.5, 5-H); 9.78 (1H, s, 4-H). Found, %: C 57.21; H 3.72; N 22.10. C9H7N3O2. Calculated, %: C 57.14; H 3.73; N 22.21. The column was then eluted with hexaneetherethyl acetate, 1:3:1, as a result of which the second reaction product, 2-amino-6nitroquinoline (4a), was isolated in a yield of 0.011 g (1.5%) having mp 250C (decomp.). (Lit. mp 261C [4], 891
265C [5], 256C [6]). A sample pure for analysis was obtained by sublimation at 150C (1 mm Hg). 1H NMR spectrum, , ppm (J, Hz): 6.89 (1H, d, J = 9.0, 3-H); 7.23 (2H, NH2); 7.50 (1H, d, J = 9.3, 8-H); 8.13 (1H, d, J = 9.0, 4-H); 8.22 (1H, m, J = 9.3, J = 2.5, 7-H); 8.68 (1H, d, J = 2.5, 5-H). Reaction of Aldehyde 1 with Phenylacetamidine (2b). A mixture of aldehyde 1 (0.68 g, 4 mmol), phenylacetamidine hydrochloride [11] (1.1 g, 6.6 mmol), K2CO3 (0.92 g, 6.6 mmol), and molecular sieves 4E (1.3 g) in dry acetonitrile (40 ml) was boiled with stirring for 5 h. The solid was filtered off, washed with ethyl acetate, and the solvent evaporated. The residue was chromatographed on a column, which was eluted with hexaneether gradually increasing the proportion of ether (5:1, 4:1, 3:1, 2:1, 1:1). 2-Benzyl-6-nitroquinazoline (3b) was isolated in a yield of 0.19 g (18%) having mp 128-130C. A sample pure for analysis was obtained by recrystallization from methanol. 1H NMR spectrum, , ppm (J, Hz): 4.43 (2H, s, CH2); 7.20-7.40 (5H, m, C6H5); 8.15 (1H, d, J = 9.2, 8-H); 8.64 (1H, d, J = 9.2, 7-H); 9.27 (1H, s, 5-H); 9.86 (1H, s, 4-H). Found, %: C 67.93; H 4.26; N 15.70. C15H11N3O2. Calculated, %: C 67.92; H 4.18; N 15.84. 2-Amino-6-nitro-3-phenyl-quinoline (4b) (0.18 g) was isolated heavily contaminated and after recrystallization from methanolacetonitrile 3:1, it contained impurities. The preparation was purified through the picrate. Yield (calculated on aldehyde 1) 6%; mp 270C (acetonitrile). Found, %: C 50.45; H 2.87; N 16.52. C15H11N3C6H3N3O7. Calculated, %: C 51.02; H 2.85; N 16.99. Pure aminoquinoline 4b of mp 184-188C was obtained by treating aminoquinoline 4b picrate with an excess of aqueous KOH solution. 1H NMR spectrum, , ppm (J, Hz): 6.83 (2H, NH2); 7.44-7.53 (5H, m, C6H5); 7.57 (1H, d, J = 9.3, 8-H); 8.10 (1H, s, 4-H); 8.23 (1H, m, J = 9.3, J = 3.0, 7-H); 8.73 (1H, d, J = 3.0, 5-H). Reaction of Aldehyde 1 with Carbamoylacetamidine (2c). A mixture of aldehyde 1 (0.57 g, 3.4 mmol), amidine hydrochloride 2c (0.7 g, 5.1 mmol), K2CO3 (0.7 g, 5.1 mmol), and molecular sieves 4E (0.8 g) in dry acetonitrile (40 ml) was boiled for 45 min, then cooled to ~10C, the solid was filtered off, washed with ethanol, and with hot water, after which it was stirred with hot DMF (10 ml), the sieves filtered off, and the reaction product reprecipitated from the filtrate with ethanolether, 1:1. 3-Amino-4-carbamoyl-7nitroisoquinoline (5c) (0.5 g, 63%) was obtained with mp >300C. A sample pure for analysis was obtained by recrystallization from DMF, sequentially boiling in water, ethanol, and acetonitrile, then subliming at 220C (1 mm Hg). 1H NMR spectrum, , ppm (J, Hz): 6.86 (2H, 3-NH2); 7.83 (1H, d, J = 9.3, 5-H); 7.85 (1H, CONH); 8.06 (1H, CONH); 8.24 (1H, m, J = 9.3, J = 2.5, 6-H); 8.93 (1H, d, J = 2.5, 8-H); 9.19 (1H, s, 1-H). 13C NMR spectrum, , ppm: 104.4 (C(4)), 119.8 (C(8a)); 123.83 (C(5)); 123.85 (C(6)); 126.1 (C(8)); 137.4 (C(4a)); 141.0 (C(7)); 156.0 (C(3)); 156.1(C(1), 1J(C-H) = 182 Hz); 168.1 (CO). Found, %: C 51.66; H 3.52; N 24.19. C10H8N4O3. Calculated, %: C 51.73; H 3.47; N 24.13. Reaction of Aldehyde 1 with Benzoylacetamidine (2d). Amidine 2d was obtained by the procedure of [13], 1H NMR spectrum, , ppm: 5.15 (1H, s, =CH); 6.3 (2H, NH2); 6.6 (1H, NH); 7.30-7.70 (5H, C6H5); 10.0 (1H, NH). A. A mixture of aldehyde 1 (0.61 g, 3.6 mmol), amidine 2d (0.48 g, 3.0 mmol), and molecular sieves 4E (0.8 g) in dry acetonitrile (20 ml) was boiled with stirring for 3 h. The sieves were filtered off, the solvent evaporated, and the residue crystallized from methanolacetonitrile, 1:1. Yield of compound 5d was 0.41 g (47%) of mp 192-194C. 1H NMR spectrum, , ppm (J, Hz): 7.13 (2H, NH2); 7.19 (1H, d, J = 9.3, 5-H); 7.53 (2H, t, m-H); 7.68 (1H, t, p-H); 7.76 (2H, d, o-H); 8.07 (1H, m, J = 9.3, J = 2.5, 6-H); 8.95 (1H, d, J = 2.5, 8-H); 9.33 (1H, s, 1-H). 13C NMR spectrum, , ppm: 104.8 (C(4)); 119.9 (C(8a)); 123.4 (C(5)); 124.2 (C(6)); 126.3 (C(8)); 129.0 (m-C6H5); 129.4 (o-C6H5); 133.7 (p-C6H5); 137.72, 138.6 (C(4a), ipso-C6H5); 141.2 (C(7)); 156.6 (C(3)); 157.9 (C(1), 1J(CH) = 186.8 Hz); 195.8 (CO). Found, %: C 65.36; H 3.79; N 14.29. C16H11N3O3. Calculated, %: C 65.53; H 3.78; N 14,33. B. A mixture of aldehyde 1 (0.34 g, 2 mmol), amidine 2d (0.27 g, 1.7 mmol), and triethylamine (0.22 g, 2.2 mmol) in dry acetonitrile (30 ml) was boiled for 2 h. The solvent was evaporated, and the residue resolved on a chromatographic column. This was eluted with a hexaneether mixture, gradually increasing the proportion of ether (4:1, 3:1, 2:1, 1:1, 1:2). 3-Amino-4-benzoyl-7-nitroisoquinoline (5d) was isolated in this way, and
892
after recrystallization from methanolacetonitrile, 3:1, contained the isomeric reaction product 2-amino-3benzoyl-6-nitroquinoline (4d) (5%). The yield of compound 5d was 0.185 g (37%); mp 192-194C. Reaction of Aldehyde 1 with Ethyl Amidinoacetate (2e). Amidine 2e was obtained as the free base by extracting an aqueous solution of amidine hydrochloride 2e [12] and a 50% excess of potassium carbonate with ethyl acetate. 1H NMR spectrum, , ppm: 1.09 (3H, t, CH3); 3.78 (1H, s, =CH); 3.86 (2H, q, CH2); 5.79 (2H, s, NH2); 6.9 (2H, NH2). A. A solution of amidine 2e (0.27 g, 2.1 mmol) in DMF (8 ml) was added dropwise with heating (50C) and stirring during 1 h to a mixture of aldehyde 1 (0.39 g, 2.3 mmol), molecular sieves 4E (0.5 g), and acetonitrile (6 ml). After a further 1 h at 50C the reaction mixture was poured into water (50 ml), and the resulting crystals recrystallized from methanolacetonitrile, 4:1. The yield of 3-amino-4-ethoxycarbonyl-7nitroisoquinoline (5e) (containing ~5% 2-amino-3-ethoxycarbonyl-6-nitroquinoline (4e)) was 0.22 g (40%); mp 174-177C. 1H NMR spectrum, , ppm (J, Hz): 1.39 (3H, t, CH3); 4.42 (2H, q, CH2); 7.92 (2H, NH2); 8.28 (1H, m, J = 9.3, J = 2.5, 6-H); 8.51 (1H, d, J = 9.3, 5-H); 8.89 (1H, d, J = 2.5, 8-H); 9.30 (1H, s, 1-H). Found, %: C 55.19; H 4.17; N 16.03. C12H11N3O4. Calculated, %: C 55.17; H 4.24; N 16.08. B. Potassium carbonate (0.61 g, 4.4 mmol) was added to a solution of aldehyde 1 (0.37 g, 2.2 mmol) and amidine hydrochloride 2e (0.73 g, 4.4 mmol) in DMF (10 ml) and the mixture stirred for 1 h 30 min at ~20C. The reaction mixture was then poured into water (40 ml) and the resulting crystals of diethyl 2,6-diamino-4-(2fluoro-5-nitrophenyl)-4,5-dihydropyridine-3,5-dicarboxylate (6e) were filtered off, dried, and recrystallized from dichloromethane. Yield was 0.64 g (74%); mp 178-182C. 1H NMR spectrum, , ppm: 1.02 (6H, t, CH3); 3.84 (4H, m, CH2); 4.91 (1H, s, 4-CH); 7.12 (4H, NH2); 7.27 (1H, t, 3-Har); 7.99 (2H, m, 4-Har and 6-Har); 8.62 (1H, s, NH). The picrate of 6e was isolated analytically pure, mp 205-207C. Found, %: C 44.29; H 3.57; N 15.75. C17H19FN4O6C6H3N3O7. Calculated, %: C 44.31; H 3.56; N 15.73. 3-Amino-7-nitroisoquinoline (5a). Solutions of isoquinoline 5e (0.2 g, 0.77 mmol) and KOH (0.14 g, 2.5 mmol) in ethanol were mixed and boiled for 2 h 30 min, the solution was cooled, and the precipitated darkred crystals filtered off. The potassium salt of 3-amino-7-nitroisoquinoline-3-carboxylic acid (0.12 g, 57%) was obtained. A solution of the salt (0.1 g) in water (3 ml) was acidified with dilute hydrochloric acid, the precipitated yellow crystals were filtered off, and dried. Acid 5f (0.06 g, 70%) was obtained; mp >250C. 1 H NMR spectrum, , ppm (J, Hz): 8.10 (2H, br. s, NH2); 8.33 (1H, m, J = 9.3, J = 2.5, 6-H); 8.72 (1H, d, J = 9.3, 5-H); 8.91 (1H, d, J = 2.5, 8-H); 9.29 (1H, s, 1-H); 13.6 (1H, COOH). The obtained acid (0.03 g) was triturated thoroughly with CaO (0.05 g) and heated at 220C and 1 mm Hg in a sublimation apparatus. 3-Amino7-nitroisoquinoline (5a) (0.01 g, 42%) was isolated with mp 236-238C (decomp.). 1H NMR spectrum (CDCl3), , ppm (J, Hz): 4.86 (2H, NH2); 6.78 (1H, s, 4-H); 7.61 (1H, d, J = 9.3, 5-H); 8.27 (1H, m, J = 9.3, J = 2.5, 6-H); 8.78 (1H, d, J = 2.5, 8-H); 9.05 (1H, s, 1-H).
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. D. V. Dar'in, S. I. Selivanov, P. S. Lobanov, and A. A. Potekhin, Khim. Geterotsikl. Soedin., 1155 (2002). H. Kotsuki, H. Sakai, H. Morimoto, and H. Suenaga, Synlett, 1993 (1999). D. G. Batt and G. C. Hoghton, J. Heterocycl. Chem., 32, 963 (1995). A. E. Tschitschibabin, D. P. Witkovsky, and M. I. Lapschin, Chem. Ber., 58, 803 (1925). O. Fischer and U. Guthmann, J. Prakt. Chem., 93, 378 (1916). J. C. E. Simpson and P. H. Wright, J. Chem. Soc., 1707 (1948). E. Deroum, Contemporary Methods of NMR for Chemical Investigations [Russian translation], Mir, Moscow (1992). H.-O. Kalinowsky, S. Berger, and S. Braun, 13C-NMR Spektroskopie, Georg Thieme Verlag, StuttgartNew York (1984). 893
9. 10. 11. 12. 13.
H. Kessler, W. Bermel, and C. Griesinger, J. Magn. Reson., 62, 573 (1985). D. J. Gale and J. F. K. Wilshire, Aust. J. Chem., 23, 1063 (1970). P. E. Fanta and E. H. Hedman, J. Am. Chem. Soc., 78, 1434 (1956). S. M. McElvain and B. E. Tate, J. Am. Chem. Soc., 73, 2760 (1951). B. Roth and J. M. Smith, Jr., J. Am. Chem. Soc., 71, 616 (1949).
894
OXIDATIVE ADDITION OF N-AMINOPHTHALIMIDE AND 3-AMINO-2-METHYLQUINAZOLIN-4(3H)-ONE TO CONJUGATED AZOCYCLOPENTENES AND AZOCYCLOHEXENES

S. M. Buchaka1, M. A. Kuznetsov1, and J. G. Schantl2 The oxidation of N-aminophthalimide and 3-amino-2-methylquinazolin-4(3H)-one in the presence of conjugated azocyclopentenes, azocyclohexenes, and 3-arylazocyclohexen-2-ones gives adducts at the carbon-carbon double bond corresponding to C-azoaziridines and/or bicyclic 2H-1,2,3-triazoles. Keywords: C-azoaziridines, 1-azocycloalkenes, 3-azocycloalken-2-ones, 3-amino-2-methylquinazolin4(3H)-one, N-aminophthalimide, 2H-1,2,3-triazoles, oxidative aminoaziridination. The oxidation of a series of N-amino heterocycles related to N-aminophthalimide using lead tetraacetate in the presence of a compound with a carbon-carbon double bond gives N-aminoaziridine derivatives or the aminoazimine valence isomers of triaziridines [1, 2] with azo compounds. Non-conjugated ,-unsaturated alkylazoalkenes react with the system N-aminophthalimide Pb(OAc)4 at the azo group only [3] but with conjugated phenylazoalkenes and 1-isopropylazocycloalkenes to give adducts at the C=C bond (the corresponding C-azoaziridines) and also, quite unexpectedly, 2H-1,2,3-triazoles and 1,2-dicarbonyl compound dihydrazones [3-5]. The formation of the two latter types of compound has not previously been reported in the reactions with olefines or in reactions with azo compounds and is clearly due to the specific conjugated azoalkene system. In this case the composition of the products of the oxidative addition of N-aminophthalimide to conjugated azocycloalkenes strongly depends, at first glance, on small changes in the structure of the substrate. Whereas in the reaction of the systems N-aminophthalimide Pb(OAc)4 with 1-isopropylazocyclopentene, 1-isopropylazocyclohexene, and 1-phenylazocyclohexene we have separated only the bicyclic C-azoaziridines, the single product of the reaction with 1-phenylazocyclopentene is 2-phenyl-2,4,5,6-tetrahydrocyclopenta[d][1,2,3]triazole [3-5] in 70% yield. In order to reveal the factors which determine the course of the oxidative addition of N-amino heterocycles to conjugated azocycloalkenes we have carried out the oxidation of N-aminophthalimide (PiNNH2) and the related 3-amino-2-methylquinazolin-4(3H)-one (MeQNNH2) using lead tetraacetate in the presence of a series of conjugated azocyclopentenes 1a,b and azocyclohexenes 1c-j, in which we have varied the nature of the substituent on the azo group and the C=C bond.
__________________________________________________________________________________________
2
St. Petersburg State University, St. Petersburg 198504, Russia; e-mail: mak@org.chem.lgu.spb.su. Institute for Organic Chemistry, Innsbruck University, Innsbruck A-6020, Austria; e-mail: Joachim.Schantl@uibk.ac.at. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1043-1051, July, 2004. Original article submitted May 27, 2004. 0009-3122/04/4007-08952004 Springer Science+Business Media, Inc. 895
R N N N R HetNNH2 Pb(OAc)4 Pb(OAc)2 2AcOH HetNH N N HetNNH2 Pb(OAc)4 ( )n 1ag Pb(OAc)2 2AcOH R NHet N N N
( )n 4ac,e
( )n 2c,d,f,g HetN = PiN 3c,d,f,g HetN = MeQN

O
PiN
N
O
MeQN
N
N Me
14 a, b n = 1; cg n = 2; a, c R = Ph, b, d R = p-O2NC6H4; e R = p-MeOC6H4; f R = i-Pr, g R=

OAc
In addition to the compounds 1a,c,f already introduced into the reaction with N-aminophthalimide we have taken arylazocycloalkenes with acceptor 1b,d and donor 1e substituents in the aromatic ring. The 1-cyclohexylazocyclohexanol acetate 1g was selected as a sterically hindered azoalkene. In addition, we considered it useful to introduce an acceptor group at the C=C bond (substrates 1h-j) since, in the case of the oxidative aminoaziridination of olefines, such a structural modification generally increases the yield of the adduct [1].
R N N O R' R' 1hj PiNNH2 Pb(OAc)4 Pb(OAc)2 2AcOH R PiN N N N O R' R' 2hj
1, 2 h R = Ph, R' = H; i R = p-O2NC6H4, R' = H; j R = Ph, R' = Me
The reactions were carried out with an equimolar ratio of reagents with the addition, in turn, of small portions of the corresponding N-amino heterocycle and Pb(OAc)4 to a cooled solution (-20 to -30C) of the azocycloalkene 1 in methylene chloride with a small excess of potassium carbonate. Separation of the reaction mixture was carried out by column chromatography on silica gel. As a result, for both N-amino heterocycles with the majority of 1-azocyclohexenes 1c,d,f,g and all of the 3-azocyclohexen-2-ones 1h-j, the bicyclic aziridine adducts 2 and 3 at the carbon-carbon double bond were obtained in yields from 10 to 57%. The separation of the mixture of products with the azocyclopentenes 1a,b and 4-(cyclohexen-1-ylazo)anisole (1e) gave the bicyclic 1,2,3-triazoles 4a,b,e. In none of the given reactions were there recorded adducts at the azo group or dihydrazones of the 1,2-dicarbonyl compounds. In addition to the azoaziridines 2, 3 or triazoles 4 there are always present in the reaction mixtures phthalimide or 2-methylquinazolin-4(3H)-one (the desamination products of the starting N-amino heterocycles). Their formation is typical of the oxidative reactions of N-aminophthalimide and related compounds [6, 7] and always accompanies the oxidative addition at the multiple bond or the unsaturated pair of electrons. Hence the yield of these desamination products can serve as a measure of the "inertness" of the substrate. However, the
896
formation of the 2H-triazoles 4 are considered as an exception since with either mechanism the phthalimide or 2methylquinazolin-4(3H)-one must separate only after the reaction with the azoalkene and here it is a main and not a side product of the reaction. The composition of the bicyclic 1,2,3-triazoles 4 and the majority of the azoaziridines 2, 3 were confirmed from elemental analytical data, their structure from 1H and 13C NMR spectroscopy, and in the case of the azoaziridines their mass spectra (in which the molecular ion peaks could be detected). The assignment of signals in the NMR spectra was made on the basis of a spectroscopic comparison of the entire series of compounds prepared and also from literature data with the use of additive schemes [3-5, 8, 9]. Certain azo-7-azabicyclo[4.1.0]heptanes proved to be quite unstable in CDCl3 solution hence to monitor the state of the samples we recorded their 1H NMR spectra both before and after the recording of the 13C NMR spectra. The low stability of the azoaziridines complicates carrying out their elemental analysis and also recording their mass spectra. Hence in the EI mass spectrum of the 6-(4-nitrophenyl)azo-7-phthalimido-7azabicyclo[4.1.0]heptan-2-one (2i) recorded under standard conditions with direct introduction of the sample the molecular ion peak is absent. This is related to the fact that, with a comparatively slow heating of the sample, it decomposes well before its vaporization. The molecular ion peak for the azoaziridine 2i could be recorded only with rapid heating of the sample above 400C, however the intensity is low in this case. In both mass spectra the base peaks are signals for the decomposition products of the azoaziridine. A typical feature of N-aminoaziridine derivatives is the inversion (slow on the NMR time scale) of the endocyclic nitrogen atom [8], which often leads to the appearance of signals for two invertomers in their spectra. In the NMR spectra of the N-phthalimidoaziridines 2 only one set of signals is seen and signs of slow dynamic processes are absent and thus point to their existence in a single, more stable form. The position of the signals of the aziridine protons of the syn and anti invertomers are usually markedly different [8], but for all of the azo-7azabicyclo[4.1.0]heptanes 2 they lie in quite a narrow range (3.70-4.25 ppm) hence it can be assumed that all these azoaziridines can be assigned to a single series of stereoisomers. Since the effective bulk of the azo group is less than the tetramethylene chain of the bicyclic system these are more likely the invertomers with a syn positioning of the azo group and the phthalimide substitutent (Z-invertomers) (cf. [4, 5]). Confirmation of this comes from the anomalously high field signal for the CH3COO proton group (1.63 ppm) in the 1H NMR spectrum of the adduct 2g which lies far from the usual limits for its chemical shift range (1.9-2.2 ppm; in the starting azo compound 1g it is at 2.11 ppm). Its position can only be explained by the acetoxy group falling in the area of magnetic shielding by the phthalimide group. Optimization of the geometry of the different conformers of the E- and Z-invertomers of the adduct 2g by the method of molecular mechanics (AMBER force field) and the semi-empirical methods AM1 and PM3 have shown that this is only possible for a syn positioning of the phthalimide substituent and the azo group. It might be expected that when crossing from the phthalimidoaziridines 2 to the compounds of series 3 with the more sterically demanding 2-methyl-4-oxoquinazolinyl substituent the Z-invertomer would also be more thermodynamically stable. However, in the 1H NMR spectra of the adducts 3c,d,f with 3-amino-2methylquinazolin-4(3H)-one, there are clear signs of a slowing of the dynamic processes on the NMR time scale and even the appearance of a second form, clearly seen in the spectra of the isopropylazoaziridine 3f. Thus the signals of the aziridine proton, the methyl group, and the aromatic H-5 proton signal of the heterocyclic fragment are markedly broadened. Moreover, the intensity of the signal for the aziridine proton at 4 ppm is slightly reduced and along with this there is present an additional broad signal in the range 3.0-3.4 ppm. The observed picture can be explained by the appearance in the NMR spectra of the aminoaziridines 3 of hindered rotation about the NN bond. Since the van der Waals radius of the methyl group is significantly larger than the oxygen atom and substituents in the six-membered ring of the oxoquinazolinyl radical is placed markedly closer to the aziridine fragment than the carbonyl groups of the five membered phthalimide ring, the barrier to rotation about the NN bond of the asymmetric oxoquinazolinyl substituent can be so high that evidence for hindered rotation and even signals for the separate rotamers might be observed.
897
A notable feature of the 1H NMR spectra of the azoaziridines 2f [3] and 3f is the diastereotopism of the methyl groups of the isopropyl fragment and, in the 1H NMR spectra of the phthalimidoaziridine 2g, a pairwise diastereotopism of the oppositely placed C(2',6') and C(3',5') cyclic substituents is observed. The number of signals in the NMR spectra of the bicyclic 2H-triazoles 4 and also the nature of the multiplets in the proton spectra point to the magnetic equivalence of the oppositely placed atoms in the molecule. This agrees with the structure 4 proposed by us (local symmetry C2v) and fully excludes their structure as the isomeric 1H-triazoles. With the exception of the adduct of 1-isopropylazocyclohexene with 3-amino-2-methylquinazolin4(3H)-one 3f (which is a pale, greenish oil) the remaining azoaziridines are colored (orange, yellow, or greenish), crystalline materials which are readily soluble in polar organic solvents. Their stability depends strongly on the nature of the substituent on the azo group. Hence the azoaziridines with an acceptor substituent on the azo group decompose slowly, even when they are stored at room temperature. The compounds 2d and 2i with a p-nitrophenyl substituent are particular unstable and rapidly decompose in CDCl3 solution to a mixture of phthalimide and the bicyclic triazole 4d or 4i respectively. At the same time, the C-isopropylazoaziridines 2f, 3f are unchanged in chloroform solution, even when gently heated over several days. In this connection, it should be noted that in the 1H NMR spectrum of the mixture of reaction products of 3-amino-2-methylquinazolin-4(3H)-one with 4-(cyclopenten-1-ylazo)-1-nitrobenzene 1b before its separation on a silica gel column there is seen a broadened triplet at 3.93 ppm which is absent in the spectra of all of the compounds separated on the column. It cannot be ruled out that this signal corresponds to a proton of the azoaziridine 3b which decomposes on silica gel to the 1,2,3-triazole 4b. The low stability of the proposed azo-6azabicyclo[3.1.0]hexane 3b with a 4-nitrophenyl substituent on the azo group is in good agreement with the dependence noted above. Also in agreement we had previously been able to separate and characterize the corresponding 1-isopropylazo-6-azabicyclo[3.1.0[hexane [3] from the reaction of N-aminophthalimide with 1-isopropylazocyclopentene. By studying the effect of the structure of the reagents on the course of the oxidative addition of N-aminophthalimide and 3-amino-2-methylquinazolin-4(3H)-one to the conjugated azocycloalkenes 1a-j it can immediately be seen that both N-amino heterocycles react very similarly, although the yields of the adducts with the N-aminophthalimide are usually a little higher. This is possibly due simply to the greater steric bulk of the 3-amino-2-methylquinazolin-4(3H)-one. The change from the arylazocyclohexenes 1c,d to the corresponding arylazocyclohexenones 1h-j has comparatively little effect on the preparative yields of the C-azoaziridines 2. At the same time, the yield and composition of the reaction products depends on the substituent on the azo group and the size of the carbocycle in the azocycloalkene. The addition to 4-(cyclohexen-1-ylazo)anisole 1e clearly occurs poorly since almost all is recovered from the reaction with N-aminophthalimide and with both N-amino heterocycles the 2-(4-methoxyphenyl)triazole 4e is produced in low yield. A similar low yield of the adduct 2g occurs with the acetate 1g, in which a bulky tertiary substituent is found on the azo group. The reason for this seems purely steric. In the reactions with azocyclopentenes we more often separate the 2H-triazoles and with the azocyclohexenes the corresponding C-azoaziridines. In summary, we have shown that the formation not only of azoaziridines but also of 1,2,3-triazoles occurs generally in the series of conjugated azocyclohexenes and azocyclopentenes. We consider that, independently of the size of the ring olefine fragment, the oxidative addition of the N-amino heterocyclic compound to the conjugated azocycloalkene occurs at the carbon-carbon double bond to give azoaziridines. Formation of the bicyclic 2H-1,2,3-triazoles is the result of secondary reactions. A study of the possible preparation of bicyclic 1,2,3-triazoles by the decomposition of azoaziridines will be the subject of our next paper.
898
EXPERIMENTAL H and 13C NMR spectra were recorded on Varian Gemini 2000 (200 and 50 MHz) and Bruker DPX-300 (300 and 75 MHz) instruments using CDCl3 solvent. The internal standard was the residual proton signal for the solvent at 7.25 ppm or carbon signal at 77.0 ppm. DEPT Spectra were used for assignment of the carbon atom signals. Mass spectra were obtained on Finnigan MAT 95 and MX-1303 mass spectrometers. Electron impact ionization was used with an ionization energy of 70 eV and FAB (Cs source, 20 kV 0.2 A) in a 3-nitrobenzyl alcohol matrix. Elemental analysis was carried out on a Hewlett-Packard HP-185B C,H,N automatic analyzer. Melting points were measured on a Boetius type heating stage with a VEB Analytik PHMK 05 direct reading device at an accuracy of 0.2C. The composition of the reaction mixtures and their separated fractions together with the purity of the individual components were monitored by TLC on Macherey-Nagel Polygram sil G/UV254 and Alugram sil G/UV254 plates. The conjugated azocycloalkenes used in this work were synthesized by known methods or on their basis [10-15]. Oxidative Addition of N-Amino Heterocycles to Azocycloalkenes. (General Method). N-Aminophthalimide (162 mg, 1 mmol) [16] (or 175 mg of 3-amino-2-methylquinazolin-4(3H)-one [17]) and lead tetraacetate (520 mg, 1 mmol) (containing 15% acetic acid) were added alternately and in small portions over 30 min to a suspension of potassium carbonate (966 mg, 7 mmol (690 mg, 5 mmol)) in anhydrous methylene chloride (50 ml) containing the azo compound (1 mmol) with vigorous stirring and cooling to -20 to -30C. The reaction mixture was held for a further 20 min at -20 to -30C, then heated to 12-16C, and filtered through a 1.5-20 cm layer of silica gel. The viscous precipitate of inorganic salts was washed with methylene chloride to a colorless filtrate. Solvent was removed at reduced temperature in vacuo using a water pump and the oily residue was separated on a silica gel column (40-63 m) using hexane (or petroleum ether)ether (5:1) as eluent with a gradual increase in the fraction of the latter. Addition of N-Aminophthalimide to 1-Nitro-4-(cyclohexen-1-ylazo)benzene (1d) (0.5 mmol) to give the starting azo compound 1d (44 mg, 38%), phthalimide (24 mg, 33%), and 112 mg (57%, 93% based on recovered starting azo compound) of 1-(4-nitrophenyl)azo-7-phthalimido-7-azabicyclo[4.1.0]heptane (2d) as bright yellow crystals; mp 109.8-110.3C, Rf 0.15 (petroleum etherether, 5:1). Using TLC and NMR spectroscopy, the aziridine was found to decompose rapidly in CDCl3 solution. 1H NMR spectrum, , ppm (J, Hz): 1.30-1.75 (4H, m, H-3,4); 2.04-2.28 (2H, m, H-5); 2.49 (1H, m, H-2); 2.93 (1H, m, H-2); 3.91 (1H, dd, J = 5.3, J = 1.3, H-6); 7.53 (2H, d, J = 9.2, Ar); 7.65-7.77 (4H, m, PiN); 8.18 (2H, d, J = 9.2, Ar). 13C NMR spectrum, , ppm: 19.9 and 20.2 (C(3,4)); 23.3 and 23.5 (C(2,5)); 52.0 (C(6)); 74.1 (C(1)); 122.8, 123.0 (PiN, C(3,6) and Ar, C(2,6)); 124.6 (Ar, C(3,5)); 130.5 (PiN, C(1,2)); 134.1 (PiN, C(4,5)); 148.5 (Ar, C(1)); 155.0 (Ar, C(4)); 165.0 (PiN, C=O). Mass spectrum (FAB), m/z (I, %): 393 (22), 392 (M++ 1) (54), 391 (M+) (33), 327 (30), 308 (25), 307 (100), 289 (60), 281 (42), 267 (25), 245 (85), 244 (40), 221 (27), 207 (43). Addition of N-Aminophthalimide to 4-(Cyclohexen-1-ylazo)anisole (1e) (1.6 mmol) to give the starting azo compound 1e (191 mg, 55%), phthalimide (206 mg, 89%), and 192 mg of an oily residue which, from NMR spectroscopic data, is a mixture of the starting azo compounds 1e and 2-(4-methoxyphenyl)-4,5,6,7tetrahydro-2H-benzo-1,2,3-triazole (4e) in the molar ratio 5.4: 1. 1H NMR spectrum, , ppm (J, Hz): signals for the 4-(cyclohexen-1-ylazo)anisole 1e: 1.70-1.78 (4H, m, H-4,5); 2.40-2.50 (4H, m, H-3,6); 3.85 (3H, s, CH3O); 6.88 (1H, t, H-2); 6.95 (2H, d, J = 9, Ar, H-3,5); 7.72 (2H, d, J = 9, Ar, H-2,6); triazole signals: 1.90-1.95 (4H, m, H-5,6); 2.84-2.88 (4H, m, H-4,7); 3.84 (3H, s, CH3O); 6.95 (2H, d, J = 9, Ar, H-3,5); 7.92 (2H, d, J = 9, Ar, H-2,6). 13C NMR spectrum, , ppm: azo compound 1e signals: 22.1 and 22.4 (C(4,5)); 22.8 (C(3)); 26.3 (C(6)); 55.5 (MeO); 114.1 (Ar, C(3,5)); 123.9 (Ar, C(2,6)); 139.9 (C(2)); 147.1 (Ar, C(1)); 155.0 (Ar, C(4)), 161.1 (C(1)): triazole 4a signals: 21.9 (C(5,6)); 23.1 (C(4,7)); 55.5 (CH3O); 114.3 (Ar, C(3,5)); 119.7 (Ar, C(2,6)); 145.1 (C(3a,7a) and Ar, C(1)); 158.7 (Ar, C(4)).
1
899
Addition of N-Aminophthalimide to 1-(1-Cyclohexenylazo)cyclohexanol Acetate (1g) (3.5 mmol) to give the starting azo compound 1g (356 mg, 41%) and 1-(1-acetoxycyclohexyl)azo-7-phthalimido-7azabicyclo[4.1.0]heptane 2g (146 mg, 10%) as yellow crystals; mp 114-117C. 1H NMR spectrum, , ppm (J, Hz): 1.19-1.82 (m, H-2',3,3',4,4'5',6'); 1.63 (s, MeCOO) and 1.99-2.13 (m, H-2,5) overall 19H; 2.33 (1H, m, H-5); 2.60 (1H, m, H-2); 3.73 (1H, d, J = 4.9, H-6); 7.63-7.75 (4H, m, PiN). 13C NMR spectrum, , ppm: 19.9 and 20.1 (C(3,4)); 21.2 (AcO); 22.9 and 23.3 (C(2,5)); 21.8, 21.9, 24.9, 32.6, and 32.8 (C(2',3',4',5',6')); 49.5 (C(6)); 71.7 (C(1)); 102.4 (C(1')); 122.6 (PiN, C(3,6)); 130.7 (PiN, C(1,2)); 133.7 (PiN, C(4,5)); 164.9 (PiN, C=O); 168.9 (AcO, C=O). Mass spectrum (EI), m/z (I, %); 410 [M+] (12), 368 (16), 350 (4), 325 (35), 299 (17), 267 (17), 264 (14), 248 (100), 222 (99), 207 (39), 179 (33), 167 (31), 154 (96), 10 (89 ), 109 (86), 104 (20), Found, %: C 64.67; H 6.35; N 13.43. C22H26N4O4. Calculated, %: C 64.38; H 6.39; N 13.65. Later fractions contained phthalimide (145 mg, 28%). Addition of N-Aminophthalimide to 3-Phenylazocyclohexen-2-one (1h) (2.4 mmol) to give the starting compound 1h (311 mg, 65%), phthalimide (198 mg, 56%), and 268 mg (31%, 88% based on recovered starting material) of 6-phenylazo-7-phthalimido-7-azabicyclo[4.1.0]heptan-2-one (2h) as yellow crystals with mp 172C. 1H NMR spectrum, , ppm (J, Hz): 1.86-1.95 (1H, m, H-4); 2.09-2.30 (2H, m, H-3,4); 2.61-2.76 (3H, m, H-3,5); 4.23 (1H, s, H-1); 7.34-7.40 (3H, m, Ph, H-3,4,5); 7.47-7.50 (2H, m, Ph, H-2,6); 7.67-7.79 (4H, m, PiN). 13C NMR spectrum , ppm: 17.6 (C(4)); 23.2 (C(3)); 36.8 (C(5)); 54.3 (C(1)); 74.5 (C(6)); 122.4 and 123.2 (PiN, C(3,6) and Ph, C(2,6)); 129.0 (Ph, C(3,5)); 130.3 (PiN, C(1,2)); 131.4 (Ph, C(4)); 134.1 (PiN, C(4,5)); 151.6 (Ph, C(1)); 164.2 (PiN, C=O); 201.1 (C(2)). Addition of N-Aminophthalimide to 3-(4-Nitrophenyl)azocyclohexen-2-one (1i) (2.3 mmol). Several fractions of the filtrate with change in intensity of the solution color were collected when filtering through a layer of silica gel. The latter colorless fraction contained only phthalimide (77 mg). The remaining fractions were combined and the solvent was distilled off in vacuo. The oily residue (849 mg) was triturated with a minimum amount of ether until a precipitate appeared and this was filtered off (phthalimide 27 mg). The filtrate was evaporated. Repeat of this procedure gave a further 56 mg of phthalimide (overall yield of phthalimide 160 mg (47%)). According to 1H NMR spectroscopic analysis, the oily residue after evaporation of the filtrate (671 mg) was a mixture of the starting azo compound 1i and the aziridine 2i in the molar ratio of 1.8:1 (346 mg (62%) of 1i and 317 mg (34%, 88% based on the recovered starting azo compound) of 2i and also contained traces of phthalimide. It was dissolved in a minimum amount of methylene chloride, hexane was added to solution turbidity, and the mixture was left in the cold for several hours. The precipitate was filtered off (starting azo compound 1i) and the filtrate was evaporated (206 mg, a mixture of the starting azo compounds 1i and the aziridine 2i in the molar ratio 1: 4 according to 1H NMR spectroscopy). Repeat of this procedure gave 6-(4-nitrophenyl)azo-7-phthalimido-7-azabicyclo[4.1.0]heptan-2-one 2i (141 mg, 15%) as orange crystals. 1 H NMR spectrum, , ppm (J, Hz): 1.88-1.93 (1H, m, H-4); 2.14-2.31 (3H, m, H-3,4); 2.64-2.65 (2H, m, H-5); 4.24 (1H, s, H-1); 7.61 (2H, d, J = 8.2, Ar, H-2,6); 7.70-7.80 (4H, m, PiN); 8.22 (2H, d, J = 9.2, Ar, H-3,5). 13 C NMR spectrum, , ppm: 17.3 (C(4)); 23.1 (C(3)); 36.7 (C(5)); 54.9 (C(1)); 75.3 (C(6)); 123.0 and 123.3 (PiN, C(3,6) and Ar, C(2,6)); 124.7 (Ar, C(3,5)); 130.1 (PiN, C(1,2)); 134.4 (PiN, C(4,5)); 148.9 (Ar, C(1)); 154.6 (Ar, C(4)); 164.2 (PiN, C=O); 200.3 (C(2)). Mass spectrum (EI) obtained with rapid heating above 400C, m/z (I, %): 405 [M+] (3), 366 (37), 349 (35), 319 (28), 276 (39), 259 (43), 258 (60), 216 (100), 162 (83), 148 (52), 147 (83), 130 (44), 122 (79), 104 (78), 93 (78), 92 (79). In the mass spectrum obtained under the standard conditions of plotting the main peaks were m/z 258 and 147 corresponding to the molecular ion peaks of the triazole 4i and phthalimide. The molecular ion peak of the azoaziridine 2i is located only with rapid sample heating above 400C. Addition of N-Aminophthalimide to 5,5-Dimethyl-3-phenylazocyclohex-2-enone(1j) (3.5 mmol) to give compound 1j (437 mg, 55%), phthalimide (167 mg, 33%), and 595 mg (44%, 97% based on recovered starting azo compound) of 4,4-dimethyl-6-phenylazo-7-phthalimido-7-azabicyclo[4.1.0]heptan-2-one (2j) as yellow crystals with mp 113C (decomp.). 1H NMR spectrum, , ppm (J, Hz): 0.90 (3H, s, CH3); 1.16 (H, s, CH3); 2.07 (1H, d, J = 13.3, H-3); 2.21 (1H, d, J = 14.8, H-5); 2.70 (1H, d, J = 13.8, H-3); 3.22 (1H, d, 900
J = 14.3, H-5); 4.13 (1H, s, H-1); 7.33-7.35 (3H, m, Ph, H-3,4,5); 7.46-7.48 (2H, d, J = 7.2, Ph, H-2,6); 7.67-7.79 (4H, m, PiN). 13C NMR spectrum, , ppm: 26.9 (CH3); 30.4 (CH3); 35.2 (C(4)); 35.9 (C(3)); 50.0 (C(5)); 54.0 (C(1)); 76.1 (C(6)); 122.5 and 123.2 (PiN, C(3,6) and Ph, C(2,6)); 129.0 (Ph, C(3,5)); 130.2 (PiN, C(1,2)); 131.4 (Ph, C(4)); 134.1 (PiN, C(4,5)); 151.3 (Ph, C(1)); 164.2 (PiN, C=O); 202.4 (C(2)). Found, %: C 67.94; H 4.71; N 13.04. C22H20N4O3. Calculated, %: C 68.03; H 5.19; N 14.42. Addition of 3-Amino-2-methylquinazolin-4(3H)-one to Cyclopenten-1-ylazobenzene (1a) (5 mmol). The oily residue (692 mg) was dissolved in a minimum amount of ether and the precipitate formed was filtered off (336 mg (42%) of the quinazolinone). The filtrate was evaporated on a rotary evaporator to give 2-phenyl2,4,5,6-tetrahydrocyclopenta-1,2,3-triazole 4a (344 mg, 37%) as white crystals with mp 62C (lit. mp 62-64C [4, 5]). The 1H and 13C NMR spectra for the compound obtained agreed with data in [4, 5]. Addition of 3-Amino-2-methylquinazolin-4(3H)-one to 1-Nitro-4-(cyclopenten-1-ylazo)benzene (1b) (0.6 mmol). Several fractions of the filtrate with change in intensity of the solution color were collected when filtering through a layer of silica gel. The latter colorless fraction contained only 2-methylquinazolin4(3H)-one (53 mg). The remaining fractions were combined and the solvent distilled off in vacuo. The 1H NMR spectrum of the mixture obtained showed a characteristic triplet for the aziridine proton at 3.93 ppm. The oily residue (183 mg) was chromatographed of a silica gel column (20 g) using petroleum ethermethylene chloride (4:1), gradually increasing its polarity to 1: 1 to give the starting azo compound 1b (20 mg, 15%) and 2-(4-nitrophenyl)-2,4,5,6-tetrahydrocyclopenta-1,2,3-triazole 4b (120 mg, 87%) as yellowish crystals with mp 227-229C (decomp.) and Rf 0.63 (ether). 1H NMR spectrum, , ppm (J, Hz): 2.58 (2H, q, J = 7.6, H-5); 2.87 (4H, t, J = 7.6, H-4,6); 8.09 (2H, d, J = 9.3, Ar, H-2,6); 8.28 (2H, d, J = 9.3, Ar, H-3,5). 13C NMR spectrum, , ppm: 22.1 (C(4,6)); 28.7 (C(5)); 117.9 (Ar, C(2,6)); 125.2 (Ar, C(3,5)); 144.6 and 145.3 (Ar, C(1,4)), 159.0 (C(3a,6a)). Found, %: C 57.61; H 4.48; N 23.39. C11H10N4O2. Calculated, %: C 57.39; H 4.35; N 24.35. Later fractions contained 2-methylquinazolin-4(3H)-one (27 mg) (overall yield 80 mg (82%)). Addition of 3-Amino-2-methylquinazolin-4(3H)-one to Cyclohexen-1-ylazobenzene (1c) (5 mmol) to give the starting azo compound 1c (200 mg, 22%), 2-phenyl-4,5,6,7-tetrahydro-2H-benzotriazole 4c (12 mg, 1%) as white crystals with mp 70C. 1H NMR spectrum, , ppm (J, Hz): 1.85-1.90 (4H, m, H-5,6); 2.78-2.82 (4H, m, H-4,7); 7.25 (1H, t, Ph, H-4); 7.42 (2H, t, Ph,, H-3,5); 7.96 (2H, d, Ph, H-2,6). 13C NMR spectrum, , ppm: 21.9 (C5,6); 23.1 (C4,7); 118.3 (Ph, C2,6); 126.5 (Ph, C4); 129.2 (Ph, C3,5); 140.1 (Ph, C1); 145.7 (C3a,7a)] together with 1.209 g of a mixture of the aziridine 3c and 2-methylquinazolin-4(3H)-one. The last fraction was triturated with a small amount of a low polarity mixture of cold petroleum ether and ether. The crystals formed were filtered off, the filtrate was evaporated on a rotary evaporator, and the residue was recrystallized from methanol. The yield of 2-methyl-3-(1-phenylazo-7-azabicyclo[4.1.0]hept-7-yl)quinazolin-4(3H)-one (3c) was 653 mg (37%, 47% based on recovered starting azo compound) as yellow needles with mp 98-101C. 1H NMR spectrum, , ppm (J, Hz): 1.50-1.76 (4H, m, H-3,4); 1.97-2.21 (2H, m, H-5); 2.38 (3H, s, CH3); 2.62-2.70 (1H, m, H-2); 2.94-3.01 (1H, m, H-2); 3.20 broad signal and 3.98 (d, J = 4.1) overall 1H, H-6; 7.26-7.46 (6H, m, Ph and MeQN, H-6); 7.57-7.72 (2H, m, MeQN, H-7,8); 8.24 (1H, d, J = 8, MeQN, H-5). 13C NMR spectrum, , ppm: 19.8, 20.5, 23.2, 23.6 (C(2,3,4,5)); 22.6 (MeQN, Me); 53.0 (C(6)); 76.6 (C(1)); 121.4 (C(4a)); 122.1 (Ph, C(2,6)); 126.0, 126.1, 126.4 (MeQN, C(5,6,8)); 128.8 (Ph, C(3,5)); 131.2 (Ph, C(4)); 133.5 (MeQN, C(7)); 145.9 (C(8a)); 151.4 (Ph, C(1)); 154.0 (MeQN, C(2)); 160.1 (MeQN, C(4)). Found, %: C 70.24; H 5.96; N 19.91. C21H21N5O. Calculated, %: C 70.20; H 5.85; N 19.50. The yield of the 2-methylquinazolin-4(3H)-one was 365 mg (45%). Addition of 3-Amino-2-methylquinazolin-4(3H)-one to 1-Nitro-4-(cyclohexen-1-ylazo)benzene (1d) (2 mmol) to give the starting azo compound 1d (54 mg, 12%) and 2-methyl-3-(1-(4-nitrophenyl)azo-7azabicyclo[4.1.0]hept-7-yl)quinazolin-4(3H)-one 3d (364 mg, 45%, 51% based on recovered starting azo compound) as yellow crystals with mp 180.4-181.1C. 1H NMR spectrum, , ppm (J, Hz): 1.47-1.82 (4H, m, H-3,4); 2.04-2.24 (2H, m, H-5); 2.35 (3H, br. s, MeQN, CH3); 2.62-2.74 (1H, m, H-2); 3.00 (1H, ddd, J = 14.6, J = 8, J = 6, H-2); 3.39 br. s and 4.15 br. s (1H, H-6); 7.40-7.48 (3H, m, Ar, H-2,6 and MeQN, H-6); 7.60 (1H,
901
d, J = 8, MeQN, H-8); 7.72 (1H, t, J = 7.8, MeQN, H-7); 8.15-8.18 (3H, m, Ar, H-3,5 and MeQN, H-5). 13 C NMR spectrum, , ppm: 19.7 and 20.4 (C(3,4)); 22.7 (MeQN, CH3); 23.2 and 23.5 (C(2,5)); 54.2 (C(6)); 76.0 (C(1)); 122.9 (C(4a), Ar, C(2,6)); 124.7 br. signal, 126.3 br. signal, 126.4 and 126.7 (Ar, C(3,5) and MeQN, C(5,6,8)); 133.9 (MeQN, C(7)); 146.0 (C(8a)); 148.1 (Ar, C(1)); 154.3 and 155.2 (Ar, C(4) and MeQN, C(2)); 160.1 (MeQN, C(4)). Mass spectrum (FAB), m/z (I, %): 405 [M+] (84), 369 (74), 338 (48), 307 (65), 289 (52), 282 (32), 245 (100). Found, %: C 62.47; H 5.20; N 19.86. C21H20N6O3. Calculated, %: C 62.37; H 4.99; N 20.78. Later fractions contained 2-methylquinazolin-4(3H)-one (99 mg, 31%). Addition of 3-Amino-2-methylquinazolin-4(3H)-one to 4-(Cyclohexen-1-ylazo)benzene (1e) (2 mmol) to give the starting azo compound 1e (42 mg, 10%), 2-(4-methoxyphenyl)-4,5,6,7-tetrahydro-2H1,2,3-triazole 4e (30 mg, 7%), 110 mg of a mixture of several compounds with similar retention times using a mixture of petroleum etherether (5: 1) (for which the 1H NMR spectrum showed no signals in the range 3-5 ppm), and the quinazolinone (100 mg, 31%). Compound 4e. 1H NMR spectrum, , ppm (J, Hz): 1.89 (4H, m, H-5,6); 2.80 (4H, m, H-4,7); 3.84 (3H, s, MeO); 6.95 (2H, d, J = 9, Ar, H=3,5); 7.89 (2H, m J = 9, Ar, H-2,6). 13C NMR spectrum: 21.8 (C(5,6)); 23.1 (C(4,7)); 55.5 (MeO); 114.3 (Ar, C(3,5)); 119.8 (Ar, C(2,6)); 145.1 (C(3a,7a) and Ar, C(1)); 158.4 (Ar, C(4)). Addition of 3-Amino-2-methylquinazolin-4(3H)-one to 1-Isopropylazocyclohexene (1f) (4 mmol) to give the starting azo compound 1f (46 mg, 7%) and 3-(1-isopropylazo-7-azabicyclo[4.1.0]hept-7-yl)-2methylquinazolin-4(3H)-one 3f (628 mg, 48%, 52% based on recovered starting azo compound) as a greenish oil. 1H NMR spectrum, , ppm (J, Hz): 1.05 (d, J = 6.8) and 1.06 (d, J = 6.6), 6H, i-Pr, 2CH3; 1.30-1.60 (4H, m, H-3,4); 1.92-2.09 (2H, m, H-5); 2.34 s and 2.40 s (3H, MeQN, CH3); 2.43-2.67 (2H, m, H-2); 3.59 (1H, sept, J = 6.6, i-Pr, CH); 3.05 br. s and 3.85 (1H, d, J = 4.2, H-6); 7.23 (1H, t, J = 7.2, MeQN, H-6); 7.40-7.55 (2H, m, MeQN, H-7,8); 8.10 (d, J = 7.2) and 8.01-8.06 m (1H, MeQN, H-5). 13C NMR spectrum, , ppm: signals for the main rotamer: 19.7 (i-Pr, 2CH3); 19.6 and 20.2 (C(3,4)); 22.6 (MeQN, CH3); 22.8 (C(5)); 23.2 (C(2)); 50.9 (C(6)); 67.9 (i-Pr, CH); 74.5 (C(1)); 121.3 (C(4a)); 125.7, 125.9, 126.2 (MeQN, C(5,6,8)); 133.2 (MeQN, C(7)); 145.8 (C(8a)); 153.9 (MeQN, C(2)); 159.8 (MeQN, C(4)): signals for the minor rotamer: 20.9 (MeQN, Me); 126.1, 127.8, 128.1 (MeQN, C(5,6,8)); 136.0 (MeQN, C(7)); 146.0 (C(8a)).
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 902 M. A. Kuznetsov and B. V. Ioffe, Usp. Khim., 58, 1271 (1989). A. A. Suvorov and M. A. Kuznetsov, Usp. Khim., 56, 1324 (1987). M. A. Kuznetsov, V. N. Belov, and S. M. Buchaka, Zh, Org. Khim, in press. M. A. Kuznetsov, L. M. Kuznetsova, and J. G. Schantl, Zh. Org. Khim., 36, 836 (2000). M. A. Kuznetsov, L. M. Kuznetsova, J. G. Schantl, and K. Wurst, Eur. J. Org. Chem., 1309 (2001). L. Hoesch and A. S. Dreiding, Helv. Chim. Acta, 58, 980 (1975). R. S. Atkinson, Tetrahedron, 55, 1519 (1999). R. S. Atkinson and J. R. Malpass, J. Chem. Soc., Perkin Trans. 1, 2242 (1977). H.-O. Kalinowski, S. Berger, and S. Braun, 13C NMR Spectroscopy, Georg Thieme Verlag, Stuttgart (1984). J. G. Schantl and P. Hebeisen, Tetrahedron, 46, 395 (1990). J. Schantl, Monatsh. Chem., 103, 1705, 1718 (1972). J. Schantl, Monatsh. Chem., 105, 220 (1974). S. Brodka and H. Simon, Chem. Ber., 102, 3647 (1969). B. T. Gillis and M. P. La Montagne, J. Org. Chem., 33, 762 (1968). H. J. Teuber, E. Worbs, and D. Cornelius, Chem. Ber., 101, 3918 (1968). H. D. K. Drew and H. H. Hatt, J. Chem. Soc., 16 (1937). D. J. Anderson, T. L. Gilchrist, D. C. Horwell, and C. W. Rees, J. Chem. Soc. (C), 576 (1970).
RING-CHAIN TAUTOMERISM OF 1,2,3,4-TETRAHYDROQUINAZOLINES. THE PRODUCTS OF REACTION OF 1,3-DICARBONYL COMPOUNDS WITH 2-AMINOMETHYLANILINE
K. N. Zelenin, A. A. Potapov, V. V. Alekseyev, and I. V. Lagoda The reaction of 2-aminomethylaniline with 1,3-dicarbonyl compounds gives a series of 1,2,3,4-tetrahydroquinazoline derivatives. A ring-chain tautomeric equilibrium of the type enamine1,2,3,4-tetrahydroquinazoline is observed in solutions of these compounds and its position depends of the structure of the starting dicarbonyl component and the solvent polarity. Keywords: 1,2,3,4-tetrahydroquinazolines, ring-chain tautomerism. The condensation products of 2-aminomethylaniline 1 with aliphatic aldehydes and ketones exist in solvents of different polarity totally in the cyclic 1,2,3,4-tetrahydroquinazoline form [1-4]. However, a change to the N-(2-aminobenzyl)imines of substituted aromatic aldehydes leads to the appearance of a 1,2,3,4-tetrahydroquinazoline-imine ring-chain type tautomeric equilibrium [5]. In this tautomeric equilibrium the cyclic form generally predominates. With this in mind we have found a single example (the derivative of 2-aminomethylaniline 1 with acetoacetic acid morpholide) in which the linear imine form A can be stabilized via a prototropic transition to the enamine A' [6]. On the basis of reported data [7-9] there might be expected here the appearance of a three component tautomeric equilibrium which includes the cyclic form B and the two geometric isomers of the enamine form A'E,Z. However, only the two tautomers A'Z and B were in fact discovered. In our work we have turned to other derivatives of 1,3-dicarbonyl compounds. Assuming that the imineenamine equilibrium will be characterized by similar dependencies as for the keto-enol equilibrium in the starting 1,3-dioxo compounds [7-9] we have selected three groups of 1,3-dicarbonyl compounds, viz. 1,3-dioxo compounds 2a-c, 1,3-keto esters 2d,e, and the 1,3-keto amides 2f-h, since the fraction of the enol form decreases systematically in this series of starting 1,3-dioxo compounds [7-9]. The series of the condensation products 3a-h (yields 35-75%, Table 1) of 2-aminomethylaniline 1 with the selected 1,3-dicarbonyl compounds were obtained by us and their structure investigated using the 1H NMR method (Tables 2 and 3). Proof of the presence of the 1,2,3,4-tetrahydroquinazoline tautomer B was based on the presence in the 13 C NMR spectra of C(2) atom signals of the tetrahydropyrimidine ring which appeared in the region 63-65 ppm and are typical of an sp3-hybridized carbon atom in an NCN environment [5, 6]. __________________________________________________________________________________________ Russian Military-Medical Academy, St. Petersburg 194044; e-mail: zelenin@infopro.spb.su. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1052-1059, July, 2004. Original article submitted February 12, 2004. 0009-3122/04/4007-09032004 Springer Science+Business Media, Inc. 903
R NH R N H 3-B R' O R N 1 R' R O 2 O R'' NH2 O 3-A NH2 N H 3-A'Z O R R' R'' R'' N H NH2 3-A'E R'
O R"
R' R''
2, 3 a R = H, b-d, f-h R = Me; a-d, f-h R' = H; e RR' = (CH2)5; a, c R" = Ph, b R" = Me, d, e R" = OEt, f R" = NEt2, g R'' = NHC6H3(OMe)2-2,4; h R'' = N(22)2
The enamine form A' in the NMR spectra presents as the "olefine" proton signals in the region 4.45-5.76 ppm and the NH signal at 9.21-11.52 ppm as well as the sp2-hybridized "olefine" carbon atoms at 82-96 and 154-167 ppm respectively (Tables 2 and 3). These data agree with the spectra of many enamines, as referred to in the reviews [7, 8].
TABLE 1. Parameters for Compounds 3a-h

Compound 3a Empirical formula C16H16N2O Found, % Calculated, % H 6.50 6.39 7.71 7.90 6.94 6.81 7.88 7.74 8.51 8.39 8.68 8.87 6.77 6.79 7.45 7.69
mp, * N 11.03 11.10 13.53 13.71 10.37 10.52 11.79 11.96 9.59 9.71 16.22 16.08 12.53 12.31 15.03 15.26 133-134
Rf (eluent)
Yield, %
C 76.22 76.16 70.50 70.56 76.75 76.66 66.46 66.64 70.73 70.80 68.77 68.93 66.55 66.84 65.14 65.43
3b 3c
C12H16N2O C17H18N2O
72-74 170-171
3d
C13H18N2O2
63-65
3e
C17H24N2O2
80-81
3f 3g
C15H23N3O C19H23N3O3
Oil 64-65
3h
C15H21N3O2
146-148
0.43 (heptaneether, 1:1) 0.71 (ethyl acetate) 0.61 (ethanol benzene, 1:1) 0.53 (ethyl acetate benzene, 1:1) 0.71 (ethyl acetate benzene, 1:1) 0.53 (methanol) 0.51 (ethyl acetate benzene, 1:1) 0.37 (methanol)
67
74 75
45
53
35 47
50
_______ * Solvent hexanebenzene, 1:1. 904
TABLE 2. 1H NMR Spectra of Compounds 3a-h

Chemical shift (CDCl3), , ppm (J, Hz) 1-NH CH2NH CH2 or C=CH br. s (1) 5 6 7 4.45 (1, s) 5.76 (1, d, J = 7.36) 5.76 (1, s) 4.53 (1, s) 2.63 (1, d, J = 5.14); 2.67 (1, d, J = 5.14) 3.76 3.66 3.75 3.72 4.68 3.78 10.89 10.47 11.52 8.61 * 9.33
Compound 1 3a 3b 3c 3d
Form (%) 2 'Z 'Z 'Z 'Z (45) B (55)
CH3 (3, s) 3 1.97 2.11 1.95 1.41
CH2NH 4 4.22 (2, d, J = 4.85) 4.33 (2, d, J = 4.73) 4.38 (2, d, J = 4.88) 4.28 (2, d, J = 5.04) 3.97 (2, s) 4.29 (2, d, J = 4.93)
Other group 8 1.99 (3, s, CH3); 6.60-7.00 (4, m, arom.) 6.70-8.00 (9, m, arom.) 6.70-8.00 (9, m, arom.) 1.24 (3, t, J = 7.40, 23); 4.12 (2, q, J = 7.40, CH2CH3); 6.60-7.10 (4, m, arom.) 1.21 (3, t, J = 7.40, 23); 4.03 (2, q, J = 7.40, CH2CH3); 6.60-7.10 (4, m, arom.) 1.13 (3, t, J = 7.33, 23); 1.18-1.23 (4, m, 22); 1.52-1.59 (2, m, 2); 2.03-2.20 (4, m, 22); 4.10 (2, q, J = 7.33, CH2CH3); 6.60-7.00 (4, m, arom.) 1.24 (3, t, J = 7.33, 23); 1.41-1.52 (4, m, 22); 1.65-1.75 (2, m, 2); 2.46-2.57 (4, m, 22); 4.13 (2, q, J = 7.33, CH2CH3); 6.40-7.10 (4, m, arom.)
3e
'Z (89)
B (11)
3.86 (1, d, J = 7.36); 3.92 (1, d, J = 7.36)
4.47
905
906
TABLE 2 (continued)
1 3f 2 'Z (10) 3 2.03 4 4.22 (2, d, J = 4.83) 4.58 (1, s) 5 6 3.78 7 9.52 8 1.02, 1.27 (6, t, J = 7.48, N(CH2CH3)2); 2.91-3.24 (4, m, J = 7.48, N(CH2CH3)2); 6.50-8.10 (4, m, arom.) 1.08, 1.12 (6, t, J = 7.48, N(CH2CH3)2); 3.25-3.45 (4, m, J = 7.48, N(CH2CH3)2); 6.50-8.00 (4, m, arom.) 3.72 (3H, s, OCH3); 3.79 (3H, s, OCH3); 6.40-8.20 (7, m, arom.) 3.75 (3H, s, OCH3); 3.77 (3H, s, OCH3); 6.40-8.20 (7, m, arom.) 3.42-3.49 (8, m, [N(CH2CH2)2O]); 6.60-7.10 (4, m, arom.) 3.59-3.69 (8, m, N(CH2CH2)2O]); 6.50-7.00 (4, m, arom.)
B (90)
1.40
3.91 (1, d, J = 7.01); 3.98 (1, d, J = 7.01) 4.25 (2, d, J = 6.28) 4.02 (1, d, J = 7.14); 4.05 (1, d, J = 7.14) 4.29 (2, d, J = 4.87) 3.96 (1, d, J = 7.09); 4.03 (1, d, J = 7.09)
2.50 (1, d, J = 5.89); 2.65 (1, d, J = 5.89) 4.55 (1, s) 2.50 (1, d, J = 15.74); 2.83 (1, d, J = 15.74) 4.64 (1, s) 2.59 (1, d, J = 5.68); 2.65 (1, d, J = 5.68)
4.59
3g
'Z (9) B (91)
1.93 1.44 1.99 1.46
3.77 4.44 5.37 *
9.86 * 9.21 *
3h
'Z (32) B (68)
_______ * Signal not observed.
TABLE 3. 13C NMR Spectra of Compound 3a-h

Compound 3a 3b 3c 3d Chemical shift (CDCl3), , ppm (8) = 144.70 144.33 144.44 144.50 142.17 144.45 142.57 115.79-132.67 (10 signals) 144.70 142.50 98.52-156.48 (22 signals) 115.82-128.62 (10 signals) 144.64 141.83 144.58 142.54 190.19 195.22 188.09 170.47 171.24 170.66 174.08 170.31 169.82 168.74 168.02 170.01 169.34 153.30 (=) 21.50 (CH3), 28.72 (CH3), 163.46 (=) 19.62 (CH3), 165.13 (=) 14.57 (CH2CH3), 19.55 (CH3), 58.39 (CH2CH3), 161.88 (=) 14.15 (CH2CH3), 26.10 (CH3), 60.56 (CH2CH3), 65.16 ((2)) 14.25 (CH2CH3), 25.02, 25.82, 28.28, 28.80, 31.79 ((CH2)5), 60.37 (CH2CH3), 167.32 (=) 14.15 (CH2CH3), 24.48, 25.22, 26.49, 26.96, 27.11 ((CH2)5), 60.50 (CH2CH3), 70.57 ((2)) 12.99, 13.97 (NCH2CH3)2, 20.15 (CH3), 40.14, 41.98 (NCH2CH3)2, 154.88 (=) 12.63, 14.23 (NCH2CH3)2, 24.78 (CH3), 40.30, 42.24 (NCH2CH3)2, 65.75 ((2)) 19.58 (CH3), 55.57 (OCH3), 55.61 (OCH3), 159.67 (=) 26.06 (CH3), 55.48 (OCH3), 55.73 (OCH3), 65.30 ((2)) 25.63 (CH3), 46.13 (N(CH2CH2)2O), 66.90 (N(CH2CH2)2O), 160.38 (=) 20.18 (CH3), 41.54 (N(CH2CH2)2O), 66.19 (N(CH2CH2)2O), 65.73 ((2))
Form (%) 'Z 'Z 'Z 'Z (45) B (55) 'Z (89) B (11)
CH2N 49.48 44.21 44.44 44.46 44.00 44.60 41.72 49.89 42.17 44.36 46.59 44.51 42.17
= or 2 91.24 96.02 92.82 83.66 42.01 95.93 41.60 83.16 41.39 86.92 41.77 82.01 41.74
C arom. 116.41-139.53 (11 signals) 116.29-140.16 (5 signals) 116.54-140.17 (11 signals) 115.44-128.82 (10 signals) 114.83-128.91 (10 signals)
other groups
3e
3f
'Z (10) B (90)
3g 3h
'Z (9) B (91) 'Z (32) B (68)
907
In addition to this, the presence of these forms in solution is unambiguously indicated by the 13C NMR spectroscopic signals for the C8a atoms at 141-142 corresponding to the cyclic form B and 144-145 ppm for the linear form A' [5]. With regard to the specifics, the condensation products with benzoylacetaldehyde (3a), acetylacetone (3b), and benzoylacetone (3c) exist in solutions of different polarity* in the single enamine form. We consider this to be the Z-isomer form since it is known [7-11] to be stabilized by intramolecular hydrogen bonding. Important support for this structure is, in fact, found in the anomalously high field position of the signals of the NH protons involved in this bond and this is, moreover, weakly sensitive to temperature and concentration effects. Further evidence for this structure is the spin spin coupling between the CH=CH protons in the 1H NMR spectrum of the derivative 3a. Its value of J = 7.36 Hz corresponds to a cis relationship of these protons in the multiple bond. The condensation product 3d of the 2-aminomethylaniline 1 with acetoacetic ester (2d) exists in solutions as a 1:1 mixture of the cyclic B and enamine A'Z forms. In compound 3e, prepared from the cyclic -keto ester 2e, the fraction of the enamine form is 89%. This agrees with data [7, 8], according to which the conjugated enamine tautomer A'Z is favored by the introduction of a cyclic element into a series of nitrogen containing 1,3-keto ester derivatives. In the tautomeric equilibrium for the condensation products 3f-h of 2-aminomethylaniline 1 with the 1,3keto amides 2f-h the cyclic form B predominates. The content of the linear form in solution does not exceed 32%. The linear form consists of the cis- isomer and this is confirmed by the NOE spectra of compound 3h. The Overhauser effect is observed for the C=CH proton signal when the methyl protons are irradiated thus pointing to this cis orientation. The effect of the solvent on the position of the tautomeric equilibrium is very marked. Changing from solution in CDCl3 to DMSO-d6 causes an increase in the fraction of the enamine tautomer A', which increases consecutively in the series of derivatives of 1,3-diketones, 1,3-keto esters, and 1,3-keto amides. It can be seen that our results agree with known literature data regarding the tendency for the fraction of the enamine tautomer to increase within the series of nitrogenous derivatives of -diketones, -keto esters, and -keto amides [7-11]. It was of interest that the ring-chain tautomer effect in the series of functionally substituted imines of 1,3-dicarbonyl compounds has remained virtually unreported [10]. It was only known that the - and -hydroxyalkylimines of -dicarbonyl compounds demonstrate such a property; however its dependence has not been investigated [7]. Hence the data obtained by us for the series chosen can help reveal the mechanism of the ring-chain tautomerism in the series of nitrogenous derivatives of 1,3-dicarbonyl compounds as a whole.
EXPERIMENTAL The NMR spectra of solutions in DMSO-d6 and CDCl3 were taken on JEOL JNM-A-500 (500 and 125 MHz for 1H and 13C respectively) and Bruker AM-300 (300 and 75 MHz for 1H and 13C respectively) under conditions of complete suppression of spin spin coupling with the carbon atoms and with HMDS internal standard. Elemental analysis was carried out for the first time using a Carlo Erba Strumentazione analyzer (model 1106). Monitoring of the course of the reaction and the purity of the compounds obtained was carried out by TLC on Silufol UV-254 plates. Chromatographic separation was carried out on column and using flash chromatography with Merck Silicagel 60 with a specific choice of solvent system.
_______ * The spectra recorded in DMSO solutions are similar and therefore not reported here. 908
Parameters for the synthesized compounds 3 are given in Table 1. 3-[(2-Aminobenzyl)amino]-1-phenylprop-2-en-1-one (3a). A solution of the 2-aminomethylaniline 1 (0.33 g, 2.7 mmol) in methanol (20 ml) was stirred with a solution of freshly prepared benzoylacetaldehyde (2a) (0.39 g, 2.7 mmol) in methanol (10 ml). The mixture was allowed to stand at room temperature for 1 day. At the end of the reaction (monitoring by TLC) the solvent was removed in vacuo and the residue was purified by flash chromatography using diethyl ether as eluent. 3-[(2-Aminobenzyl)amino]-1-phenylbut-2-en-1-one (3c) was prepared under the same conditions from freshly prepared benzoylacetone (2c) and 2-aminomethylaniline 1. 4-[(2-Aminobenzyl)amino]pent-3-en-2-one (3b). 2-Aminomethylaniline 1 (0.33 g, 2.7 mmol) was dissolved in anhydrous benzene (20 ml). A solution of acetylacetone (2b) (0.28 g, 2.7 mmol) in anhydrous benzene (5 ml) and a catalytic amount of trifluoroacetic acid were added. The reaction mixture was held for 1 day at 20C while the reaction was followed by the TLC method. At the end of the reaction the mixture was dried over anhydrous sodium sulfate, the mother liquor decanted, and the solvent was evaporated in vacuo. The residue was recrystallized from hexane, filtered, washed with pentane, and dried in vacuo using an oil pump. Ethyl 3-[(2-Aminobenzyl)amino]but-2-enoate (3d). A solution of ethyl acetoacetate (2d) (0.35 g, 2.7 mmol) in benzene (5 ml) and a catalytic amount of trifluoroacetic acid were added to a solution of the 2-aminomethylaniline 1 (0.33 g, 2.7 mmol) in benzene (20 ml). The reaction mixture was held for 1 day at 20C while the reaction was followed by the TLC method. At the end of the reaction the solvent was evaporated in vacuo and the remaining oil was crystallized from a mixture of pentane and ether (1:1). The crystalline precipitate was separated by filtration, washed with pentane, and dried in vacuo using an oil pump. Ethyl 2-[(-2-Aminobenzyl)amino]cyclopent-1-en-1-carboxylate (3e) was prepared similarly to compound 3d from the 2-aminomethylaniline 1 and ethyl 2-oxocycloheptanoate (2e). N,N-Diethyl-2-(2-methyl-1,2,3,4-tetrahydroquinazolin-2-yl)acetamide (3f). A solution of acetoacetic acid N,N-diethylamide (2f) (0.45 g, 2.7 mmol) in methanol (10 ml) was added to a solution of the 2-aminomethylaniline 1 (0.33 g, 2.7 mmol) in methanol (10 ml). The mixture was held for 1 day at 20C. At the end of the reaction (TLC monitoring) the solvent was evaporated in vacuo. The remaining viscous oil could not be crystallized but appeared to be spectroscopically pure N,N-diethyl-2-(2-methyl-1,2,3,4tetrahydroquinazolin-2-yl)acetamide (3f). N-(2,4-Dimethoxyphenyl)-2-(2-methyl-1,2,3,4-tetrahydroquinazolin-2-yl)acetamide (3g) and 2-Methyl-2-(2-morpholin-4-yl-2-oxoethyl)-1,2,3,4-tetrahydroquinazoline (3h) were prepared similarly to compound 3f from the 2-aminomethylaniline 1 and N-(2,4-dimethoxyphenyl)-3-oxobutanamide (2g) and 4-morpholin-4-yl-4-oxobutan-2-one (2h) respectively.
REFERENCES 1. 2. 3. 4. 5. 6. 7. G. Kempter, H. -J. Ziegner, G. Moser, and W. Natho, Wiss. Z. Pdagog. Hochsch. Karl Liebknecht, Potsdam, 21, 5 (1977). J. J. van den Eynde, J. Godin, A. Mayence, A. Maquestiau, and E. Anders, Synthesis, 9, 867 (1993). J. Lessel, Arch. Pharm. (Weinheim), 327, 329 (1994). L. Lazar and F. Flp, Eur. J. Org. Chem., 3025 (2003). J. Sinkkonen, K. N. Zelenin, A. A. Potapov, I. V. Lagoda, V. V. Alekseyev, and K. Pihlaja, Tetrahedron, 59, 1939 (2003). K. N. Zelenin, A. A. Potapov, I. V. Lagoda, V. V. Alekseyev, Ya. Sinkkonen, and K. Pihlaja, Khim. Geterotsikl. Soedin., 1305 (2002). S. I. Yakimovich and K. N. Zelenin, Zh. Obshch. Khim., 65, 705 (1995).
909
8. 9. 10. 11.
S. I. Yakimovich and I. V. Zerova, Enamines in Organic Synthesis, Sverdlovsk, (1989), p. 90. Ya. F. Freimanis, The Chemistry of Enamino Ketones, Enamino Imines, and Enamino Thiones, Zinatne, Riga, (1974), 274 p. S. I. Yakimovich, V. N. Nikolaev, and N. V. Koshmina, Zh. Org. Khim., 18, 1173 (1982). S. I. Yakimovich, I. V. Zerova, and K. N. Zelenin, Ross. Khim. Zh., 43, 115 (1999).
910
REGIOSELECTIVITY OF NUCLEOPHILIC ATTACK IN THE REACTIONS OF 1,2,4-TRIAZINE 4-OXIDES WITH CERTAIN C-NUCLEOPHILES
D. N. Kozhevnikov1, A. M. Prokhorov1, V. L. Rusinov1, and O. N. Chupakhin2 The addition of CH-active compounds to 6-aryl-1,2,4-triazine 4-oxide is reversible and occurs under conditions of kinetic control at position 5 of the heterocycle to form cyclic C(5)-H adducts. Under conditions of thermodynamic control the nucleophilic attack is directed to position 3 of the heterocycle and is accompanied by its opening to form the more stable open chain addition products. Attack of ethylmagnesium bromide is directed exclusively to the 5 position of the 6-aryl-1,2,4-triazine 4-oxides as a result of the irreversibility of the given reaction. Keywords: 1,3-diketones, organomagnesium compounds, 1,2,4-triazine, nucleophilic substitution of hydrogen. A study of the regioselectivity of the reaction of polydentate substrates is an important area in the chemistry of heterocycles and makes it possible to predict the ratio of regioisomers or, in preference, to direct the reaction [1]. This also applies to the reactions of 6-aryl-1,2,4-triazine 4-oxides which have proved themselves to be highly electrophilic substrates in the nucleophilic substitution reactions of hydrogen (SNH) with N-, S-, O-, and C-nucleophiles [2, 3]. Previously carried out investigations have shown that nucleophilic attack is directed to the 3 or 5 position of the 1,2,4-triazine ring, as determined by the nature of the reagents and the reaction conditions. Thus the reaction of 1,2,4-triazine 4-oxides with cyanamide [4], cyanide anion [5], water in the presence of benzoyl chloride [6], or indoles and phenols with trifluoroacetic acid [7, 8] occurs exclusively via addition of the nucleophile at the 5 position of the heterocycle. On the other hand, the reaction of individual CH-active compounds with 1,2,4-triazine 4-oxides occurs by the addition of the nucleophile at position 3 of the heterocycle and with subsequent opening [9, 10]. By aminating 1,2,4-triazine 4-oxides with ammonia or with primary and secondary aliphatic amines it has been shown that the addition of the amine at position 5 of the heterocycle is a kinetically controlled process whereas the addition at position 3 with ring opening is thermodynamically controlled [11]. In this connection we have studied the regioselectivity of the addition of C-nucleophiles to the 6-aryl1,2,4-triazine 4-oxides 1 since the CC bond formed in this way is more stable than the CO, CN, or CS bonds and the reversible reactions of the regioisomers can occur more slowly, making their investigation easier. We chose cyclic 1,3-diketones as the C-nucleophiles. It has previously been reported that the reaction of 1,2,4-triazine 4-oxides 1 with 1,3-dimethylbarbituric acid and indane-1,3-dione at room temperature occurs with addition of these C-nucleophiles at position 5 of the heterocycle to form the C(5)-H adducts 2 and 3 [12]. In __________________________________________________________________________________________ Ural State Technical University, Yekaterinburg 620002, Russia; e-mail: rusinov@htf.ustu.ru. I. Ya. Postovsky Institute of Organic Synthesis, Ural Section, Russian Academy of Sciences, Yekaterinburg 620219; e-mail: chupakhin@ios.uran.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1060-1064, July, 2004. Original article submitted July 15, 2002.
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continuing our study of this reaction we have found that an increase in the temperature or the time changes the course of the nucleophilic attack. When the reaction is carried out in refluxing acetic acid the dimethylbarbituric acid addition occurs at position 3 of the triazine system with the formation of the opened products 1-hydroxy-6(1,3-dimethyl-2,4,6(1H,3H,5H)-trioxopyrimid-5-ylidene)-1,4,5-triazahexa-1,3-dienes 4a,b in 50-60% yields. The similar product 1-hydroxy-6-(1,3-dioxoindan-2-ylidene)-3-phenyl-1,4,5-triazahexa-1,3-diene (5a) was prepared in 55% yield by treating the 1,2,4-triazine 4-oxide 1a with indanedione in the presence of trifluoroacetic acid over 14 days at room temperature.
Ar O Me O N N Me OH 2a,b 117 oC MeCOOH Ar N N OH O N Me Ar N OH
Ph O Ph N + N O 1a 14 days N OH O 5a 2 days HO N N OH F3CCOOH Ph 3a N NH O OH O N
N N
O CF3COOH 20 oC Ar N + N O 1a,b 117 oC MeCOOH Ar N OH N Me O N OH O 4a,b N Me O N N H O N Me N Me O N N Me N N Me OH
OH
+
O
NH
O N Me O
a Ar = Ph , b Ar = 4-Tol
The change in reaction course with change in temperature and time is consistent with the proposal of kinetic control of nucleophilic attack at position 5 and thermodynamic at position 3 of the heterocycle. In the latter case a gain factor in energy is evidently achieved upon ring opening. For confirmation we have carried out the following experiment. The C(5)-adducts 2 were heated in acetic acid over 30 min. As a result, a complete conversion of the cyclic C(5)-H adducts 2 to the open chain triazahexadienes 4 was observed, these being obtained through the addition of the nucleophile at position 3 of the 1,2,4-triazine 4-oxide 1a. 912
Such reactions can theoretically be accompanied by the formation of the starting substrate and nucleophile via the reversibility of the addition stage or by an intramolecular sigmatropic shift in the pyrimidine fragment. The latter variant seems less likely but, in order to exclude it completely, we carried out the transformation of the adduct 2a reported above in the presence of an equimolar amount of 1,2,4-triazine 4-oxide as an external entrainment trap. A small difference in the aryl substituent at position 6 of the 1,2,4-triazine ring (phenyl and p-tolyl) did not prove to have a significant effect on the reaction course because of the remoteness of the latter from the reaction centers. After refluxing in acetic acid for 30 min the reaction mixture in this case consists of practically equal amounts of the open chain products 4a and 4b and also the 1,2,4-triazine 4-oxides 1a and 1b (according to 1H NMR spectroscopic data). This points to an intermolecular transfer of the nucleophilic fragment and hence to the reversibility of the formation of the C(5)-H adducts 2.
Ph O Me O N N Me 2a AcOH 117 oC Ph N N OH O 4a N Me Tol N Me O N N OH O 4b N Me 1b (2a : 1b = 1 : 1) OH N OH N N Tol N + N O N
NH
NH
O N Me O
1a
1b
(4a : 4b = 1 : 1)
To confirm the proposal of kinetic control of the nucleophilic attack at position 5 of the heterocycle the reaction of the 6-aryl-1,2,4-triazine 4-oxides 1 with such C- nucleophiles as organomagnesium compounds was investigated. It should be noted that the addition of the latter is an irreversible process [1, 13, 14] which, in turn, excludes the equilibria of interconverting regioisomers. It was found that the 1,2,4-triazine 4-oxides 1 react with ethylmagnesium bromide to give only the 6-aryl-5-ethyl-4-hydroxy-4,5-dihydro-1,2,4-triazine 6a-c C(5) adducts. We point out that this is the first example of the reaction of 1,2,4-triazine 4-oxides with Grignard reagents. The 1H NMR spectroscopic data for compounds 6a-c agrees with the proposed structure and differs markedly from the spectra of the 5-aryl-3-ethyl-4-hydroxy-3,4-dihydro-1,2,4-triazine 7 C(3)-H adducts prepared by a counter synthesis [15].
Ar Et H N N N Ar EtMgBr THF EtMgBr 1ac THF N OH 7 N N Et H
OH 6ac
a Ar = Ph, b Ar = 4-MeC6H4, c Ar = 4-MeOC6H4
Hence it follows that, in the reactions of 1,2,4-triazine 4-oxides with nucleophiles, there are observed kinetic selectivity of addition of the nucleophile at position 5 of the heterocycle and thermodynamic selectivity at position 3 of the heterocycle with opening of the latter. 913
EXPERIMENTAL H NMR spectra were recorded on a Bruker WM-250 (250 MHz) spectrometer with TMS as internal standard. Monitoring of the course of the reaction and the purity of the products was carried out by TLC on Silufol UV-254 plates with ethyl acetate eluent and revealed using UV light. The 1,2,4-triazine 4-oxides 1 were synthesized according to the method [16]. Reaction of 1,2,4-Triazine 4-Oxides 1a,b with 1,3-Dimethylbarbituric Acid. (General Method). A solution of the 6-aryl-1,2,4-triazine 4-oxide 1 (4 mmol) and 1,3-dimethylbarbituric acid (624 mg, 4 mmol) in acetic acid (30 ml) was refluxed for 30 min. The precipitate formed on cooling was filtered off and recrystallized from ethanol. 1-Hydroxy-6-(1,3-dimethyl-2,4,6(1H,3H,5H)-trioxopyrimidyl-5-idene)-3-phenyl-1,4,5-triazahexa1,3-diene (4a). Yield 1120 mg (85%); mp 255-257C. 1H NMR spectrum, , ppm (J, Hz): 3.16 (3H, s, NCH3); 3.20 (3H, s, NCH3); 7.4 (3H, m); 7.8 (2H, m); 8.38 (1H, s); 8.44 (1H, d, J = 11.6); 12.80 (1H, s, OH); 14.13 (1H, d, J = 11.6, NH). Found, %: C 54.89; H 4.49; N 21.34. C15H15N5O4. Calculated, %: C 54.71; H 4.59; N 21.27. 1-Hydroxy-6-(1,3-dimethyl-2,4,6(1H,3H,5H)-trioxopyrimidyl-5-idene)-3-(4-tolyl)-1,4,5-triazahexa1,3-diene (4b). Yield 1100 mg (80%); mp >270C. 1H NMR spectrum, , ppm (J, Hz): 2.38 (3H, s, CH3); 3.20 (3H, s, NCH3); 3.23 (3H, s, NCH3); 7.22 (3H, m); 7.67 (2H, m); 8.32 (1H, s); 8.46 (1H, d, J = 11.1); 12.68 (1H, s, OH); 14.15 (1H, d, J = 11.1, NH). Found, %: C 55.80; H 5.18; N 20.56. C16H18N5O4. Calculated, %: C 55.97; H 4.99; N 20.40. 1-Hydroxy-6-(1,3-dioxoindan-2-ylidene)-3-phenyl-1,4,5-triazahexa-1,3-diene (5a). A solution of the 6-phenyl-1,2,4-triazine 4-oxide 1a (4 mmol) and indanedione (584 mg, 4 mmol) in trifluoroacetic acid was allowed to stand at room temperature for 14 days, after which it was diluted with water and the residue was recrystallized from ethanol. Yield 700 mg (55%); mp 180-181C. 1H NMR spectrum, , ppm (J, Hz): 7.4 (3H, m); 7.76 (s, 4H, indane); 7.8 (2H, m); 8.15 (1H, d, J = 11.0); 8.46 (1H, s); 12.9 (1H, s, OH); 14.0 (1H, d, J = 11.0, NH). Found, %: C 67.55; H 4.26; N 13.02. C18H13N3O3. Calculated, %: C 67.71; H 4.10; N 13.16. Reaction of the 1,2,4-Triazine 4-Oxides 1a,b with Ethylmagnesium Bromide. (General Method). A solution of ethylmagnesium bromide in THF (obtained from 2 mmol of Mg and 2.5 mmol of bromoethane) was added to the triazine 4-oxide 1 (1 mmol) with vigorous stirring. The solution formed was evaporated, water (20 ml) was added, and the mixture was refluxed for 5-10 min, cooled to room temperature, and the precipitate was filtered off. 5-Ethyl-4-hydroxy-6-phenyl-4,5-dihydro-1,2,4-triazine(6a). Yield 70 mg (35%); mp 195-197C. 1 H NMR spectrum, , ppm (J, Hz): 0.97 (3H, t, CH3CH2); 1.65 and 2.05 (both 1H, m, CH3CH2); 5.23 (1H, t, H-5); 7.43 (3H, m); 7.79 (2H, m); 8.35 (1H, s, H-3). Found, %: C 64.89; H 6.49; N 20.54. C11H13N3O. Calculated, %: C 65.01; H 6.45; N 20.67. 5-Ethyl-4-hydroxy-6-tolyl-4,5-dihydro-1,2,4-triazine(6b). Yield 140 mg (65%); mp 250-253C (decomp.). 1H NMR spectrum, , ppm (J, Hz): 0.85 (3H, t, CH3CH2); 1.65 and 2.00 (both 1H, m, CH3CH2); 2.36 (3H, s, CH3); 5.41 (1H, t, H-5); 7.32 (2H, d); 7.78 (2H, d); 9.14 (1H, s, H-3). Found, %: C 66.21; H 7.09; N 19.18. C12H15N3O. Calculated, %: C 66.34; H 6.96; N 19.34. 5-Ethyl-4-hydroxy-6-(4-methoxyphenyl)-4,5-dihydro-1,2,4-triazine (6c). Yield 120 mg (50%); mp 213-215C. 1H NMR spectrum, , ppm (J, Hz): 0.88 (3H, t, CH3CH2); 1.65 and 2.05 (both 1H, m, CH3CH2); 3.80 (3H, s, CH3); 4.98 (1H, t, H-5); 6.93 (2H, d); 7.70 (2H, d); 8.12 (1H, s, H-3). Found, %: C 61.88; H 6.34; N 17.82. C12H15N3O2. Calculated, %: C 61.79; H 6.48; N 18.01. This work was carried out with financial support of the RFFI (grant No. 02-03-32627) and the Ural Science Research Center (grant CRDF REC-005).
1
914
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. I. S. Poddubnyi, Khim. Geterotsikl. Soedin., 774 (1995). O. N. Chupakhin, V.N. Charushin, and H. C. van der Plas, Nucleophilic Aromatic Substitution of Hydrogen, Academic Press, New York, San Diego (1994), p. 367. D. N. Kozhevnikov, V. L. Rusinov, and O. N. Chupakhin, Adv. Heterocycl. Chem., 82, 261 (2002). V. N. Kozhevnikov, A. M. Prokhorov, D. N. Kozhevnikov, V. L. Rusinov, and O. N. Chupakhin, Izv. Akad. Nauk, Ser. Khim., 1128 (2000). O. N. Chupakhin, V. L. Rusinov, E. N. Ulomsky, D. N. Kozhevnikov, and H. Neunhoeffer, Mendeleev Commun., 66 (1997). H. Neunhoeffer and V. Bhnisch, Liebigs Ann. Chem., 153 (1976). V. L. Rusinov, D. N. Kozhevnikov, E. N. Ulomsky, O. N. Chupakhin, G. G. Aleksandrov, and H. Neunhoeffer, Zh. Org. Khim., 34, 429 (1998). D. N. Kozhevnikov, E. N. Ulomsky, V. L. Rusinov, O. N. Chupakhin, and H. Neunhoeffer, Mendeleev Commun., 116 (1997). Yu. A. Azev, H. Neunhoeffer, S. Foro, H. J. Lindner, and S. V. Shorshnev, Mendeleev Commun., 229 (1995). Yu. A. Azev, O. V. Gryazeva, and S. V. Shorshnev, Khim. Geterotsikl. Soedin., 564 (2001). A. Rykowski, O. N. Chupakhin, D. N. Kozhevnikov, V. N. Kozhevnikov, V. L. Rusinov, and H. C. van der Plas, Heterocycles, 55, 127 (2001). D. N. Kozhevnikov, I. S. Kovalev, V. L. Rusinov, and O. N. Chupakhin, Khim. Geterotsikl. Soedin., 1239 (2001). D. Doddi, G. Ercolani, and P. Mencarelli, J. Org. Chem., 57, 789 (1992). T. -L. Ho, Tetrahedron, 41, 3 (1985). D. N. Kozhevnikov, V. N. Kozhevnikov, V. L. Rusinov, O. N. Chupakhin, E. O. Sidorov, and N. A. Klyuev, Zh. Org. Khim., 34, 423 (1998). H. Neunhoeffer, F. Weischedel and V. Bhnisch, Liebigs Ann. Chem., 750, 12 (1971).
915
SYNTHESIS OF DERIVATIVES OF 1,3,4-OXADIAZOLES BASED ON MONOHYDRAZIDES OF 2-ARYL-4-METHYL4-CYCLOHEXEN-1,2-DICARBOXYLIC ACIDS

D. Zicane, Z. Tetere, I. Ravina, and M. Petrova The corresponding derivatives of 1,3,4-oxadiazoles have been synthesized by the reaction of monohydrazides of 2-aryl-4-methyl-4-cyclohexen-1,1-dicarboxylic acids with triethyl orthoformate or triethyl orthoacetate. Keywords: 2-(2-aryl)-4-methycyclohexen-4-yl)-[1,3,4]oxadiazoles, 1,3,4-oxadiazoles, monohydrazides of 2-aryl-4-methyl-4-cyclohexen-1,1-dicarboxylic acids, triethyl orthoformate, triethyl orthoacetate. Some derivatives of 1,3,4-oxadiazoles possess anti-inflammatory, analgesic, antiviral, and antibacterial activity [1-3]. These compounds are also used in the dyestuffs industry [4], in thermostable polymeric materials [5], and in scintillation techniques [6]. Information on methods of synthesis of compounds containing the 1,3,4-oxadiazole ring and on starting materials for their synthesis is very limited in the literature [7]. Therefore we have studied more deeply the possibility of synthesizing derivatives of 1,3,4-oxadiazole from monohydrazides of 2-aryl-4-methyl-4cyclohexen-1,1-dicarboxylic acid 1a-e which we synthesized previously [8]. One of the methods to prepare 1,3,4-oxadiazoles is the interaction of hydrazides of carboxylic acids with an excess of triethyl orthoformate (2) [9, 10]. The preparation of 2-aryl-substituted 1,3,4-oxadiazoles by boiling the corresponding hydrazides for 15-20 h with ester 2 [11].
R R
(EtO)3CR1 NH2 2, 3 N N O Me R1
N H COOH Me 1ae 4ae, 5ae
1, 4, 5 a R = H; b R = F; c R = Cl; d R = Br; e R = NO2; 2, 4 R1 = H; 3, 5 R1 = Me
__________________________________________________________________________________________ Riga Technical Institute, Riga LV-1048, Latvia; e-mail: daina_zi@ktf.rtu.lv. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, 1065-1067, July, 2004. Original article submitted April 9, 2002. 916 0009-3122/04/4007-09162004 Springer Science+Business Media, Inc.
TABLE 1. Characteristics of Compounds 4a-e and 5a-e

Compound Empirical formula Found, % Calculated, % H N 6.90 6.71 5.93 5.85 5.61 5.50 4.61 4.74 4.27 5.30 7.20 7.13 6.38 6.29 6.01 5.93 5.06 5.14 5.81 5.72 11.73 11.66 10.72 10.85 10.31 10.20 8.65 8.78 14.68 14.73 10.97 11.01 10.34 10.29 9.80 9.70 8.48 8.41 9.28 9.36
mp, Hal 93-95 95-97 13.01 12.90 25.16 25.03 92-94 69-72 97-99 61-62 44-46 12.36 12.28 24.02 23.98 94-95 71-73 107-109
Yield, %
75.04 74.97 69.61 69.75 65.69 65.57 56.62 56.44 63.38 63.15 75.48 75.56 70.42 70.57 66.69 66.55 57.58 57.67 64.31 64.20
4 4b 4c 4d 4e 5a 5b 5c 5d 5e
1516N2O 1515FN2O 1515ClN2O 1515BrN2O 1515N3O3 1618N2O 1617FN2O 1617ClN2O 1617BrN2O 1617N3O3
66 73 74 67 64 70 53 60 56 52
We have found that monohydrazides of aryl-substituted cyclohexendicarboxylic acids 1a-e react with triethyl orthoformate 2 considerably faster. The corresponding 1,3,4-oxadiazoles 4a-e were isolated from the reaction mixture after boiling the components for 3 h. Under analogous conditions we also obtained derivatives of 5-methyl-substituted 1,3,4-oxadiazoles 5a-e, the formation of which occurred still more rapidly on boiling the hydrazide starting materials 1a-e with triethyl orthoacetate (3) for 1 h.
TABLE 2. 1H NMR Spectra of Compounds 4a-e and 5a-e

Compound 4 4b 4c 4d 4e 5a 5b 5c 5d 5e Chemical shifts, , ppm. (J, Hz) 1.73 (3, s, 3); 2.45 (4, m, 22); 3.51 (2, m, 2); 5.48 (1, m, =); 6.78-7.24 (5, m, 65); 8.18 (1, s, N=) 1.74 (3, s, 3); 2.42 (4, m, 22); 3.45 (2, m, 2); 5.43 (1, m, =); 6.73 (4, m, 64); 8.05 (1, s, N=) 1.75 (3, s, 3); 2.42 (4, m, 22); 3.53 (2, m, 2); 5.55 (1, m, =); 6.93 (2, m, 3J = 8, 64); 7.22 (2, m, 3J = 8, 64); 8.26 (1, s, N=) 1.74 (3, s, 3); 2.42 (4, m, 22); 3.43 (2, m, 2); 5.37 (1, m, =); 6.67 (2, m, 3J = 8, 64); 7.26 (2, m, 3J = 8, 64); 8.05 (1, s, N=) 1.77 (3, s, 3); 2.48 (4, m, 22); 3.57 (2, m, 2); 5.61 (1, m, =); 7.22 (2, m, 3J = 9, 64); 8.01 (2, m, 3J = 9, 64); 8.26 (1, s, N=) 1.71 (3, s, 3); 2.29 (3, s, 3); 2.44 (4, m, 22); 3.42 (2, m, 2); 5.48 (1, m, =); 6.89-7.29 (5, m, C6H5) 1.68 (3, s, 3); 2.33 (3, s, 3); 2.38 (4, m, 22); 3.42 (2, m, 2); 5.49 (1, m, =); 6.91 (4, m, C6H4) 1.71 (3, s, 3); 2.32 (4, m, 22); 2.36 (3, s, 3); 3.44 (2, m, 2); 5.48 (1, m, =); 6.91 (2, m, 3J = 8, C6H4); 7.11 (2H, m, 3J = 8, C6H4) 1.73 (3, s, 3); 2.33 (3, s, 3); 2.38 (4, m, 22); 3.42 (2, m, 2); 5.49 (1, m, =); 6.84 (2, m, 3J = 8, C6H4); 7.29 (2, m, 3J = 8, C6H4) 1.75 (3, s, 3); 2.31 (3, s, 3); 2.48 (4, m, 22); 3.31 (2, m, 2); 5.55 (1, m, =); 7.20 (2, m, 3J = 9, C6H4); 8.10 (2, m, 3J = 9, C6H4)
917
The synthesized 2-hexenyl derivatives of 1,3,4-oxadiazole are colorless crystalline substances with comparatively low melting points. The structures and composition of the compounds obtained were confirmed 1H NMR data and elemental analyses.
EXPERIMENTAL H NMR spectra of CDCl3 solutions with HMDS internal standard ( 0.055) were recorded on a Bruker WH 90/DS (90 MHz) spectrometer. The purity of the compounds synthesized was confirmed by TLC on Silufol strips with solvent systems ethyl acetatebenzene (1:2) for 4a,e and 5a, chloroformmethanol (9:1) for 4c,d and 5d,e, and chloroformmethanolacetic acid (95:5:3) for 4b and 5b,c. Characteristics of the compounds synthesized are given in Tables 1 and 2. 2-[4-Methyl-2-(4-R-phenyl)-4-cyclohexen-1-yl][1,3,4-]oxadiazoles 4a-e. Hydrazides 1a-e (1 mmol) and triethyl orthoformate (2 ml) were refluxed for 3 h. The excess ester 2 was evaporated, the residue was cooled and triturated with hexane (4a-d) or methanol (4e). The solid was filtered off and recrystallized from 1:1 methanolwater (4a,c,e) or 1:1 ethanolwater (4b,d). 2-[4-Methyl-2-(4-R-phenyl)-4-cyclohexen-1-yl]-5-methyl[1,3,4-]oxadiazoles 5a-e. Hydrazides 1a-e (1 mmol) and triethyl orthoacetate (2 ml) were refluxed for 1 h. The excess ester 2 was evaporated, the residue was cooled and triturated with hexane (5a,c), petroleum ether (5d), or methanol (5e). The solid was filtered off and recrystallized from 1:1 methanolwater. Compound 5b was isolated by addition of water to the residue after evaporation of the excess ester 3, extraction with ethyl acetate, drying of the extract with anhydrous magnesium sulfate and evaporation of the solvent. The authors thank the "BAPEKS" company for a gift of triethyl orthoacetate.
1
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. S. M. Golovleva, Yu. A. Moskvichev, D. B. Kobylinskii, and V. V. Ermolaeva, Khim. Geterotsikl. Soed., 1201 (2001). E. P. Nesynov and A. G. Grekov, Uspekhi Khimii, 33, 1184 (1964). H. Knig, W. Seifken, and H. Offe, Chem. Ber., 87, 825 (1954). B. M. Krasovitskii, R. M. Matskevich, N. S. Dokunikhin, and N. A. Trubitsina, Zhur. Obshch. Khim., 30, 2608 (1960). J. Sauer, R. Huisgen, and H. Sturm, Tetrahedron, 11, 241 (1960). A. P. Grekov and O. P. Shvaika, in: Scintillators and Scintillating Materials [in Russian], Moscow (1960), 105. T. Gilchrist, Chemistry of Heterocyclic Compounds [Russian translation], Mir, Moscow (1966). D. R. Zicane, I. T. Ravina, I. A. Rijkure, Z. F. Tetere, E. Yu. Gudriniece, and U. O. Kalei, Zhur. Org. Khim., 36, 521 (2000). C. Ainsworth, J. Am. Chem. Soc., 77, 1148 (1955). M. Vincent, J. Maillard, and M. Benard, Bull. Soc. Chim. France, 1580 (1962). A. P. Grekov, O. P. Shvaika, and L. M. Erupova, Zhur. Obshch. Chim., 6, 2027 (1959).
918
SYNTHESIS OF 2-ARYL AND 2-HETARYL DERIVATIVES OF 2'-AMINOSPIRO[(1,3-DIOXANE)5,5'-THIAZOLIN]-4'-ONE AND SPIRO[(1,3-DIOXANE)5,5'-THIAZOLIDINE]-2',4'-DIONE

S. M. Ramsh1, A. G. Ivanenko2, V. A. Shpilyovy1, N. L. Medvedskiy1, and P. M. Kushakova1 2-(Het)aryl derivatives of 2'-aminospiro[(1,3-dioxane)-5,5'-thiazolin]-4'-one or spiro[(1,3-dioxane)5,5'-thiazolidine]-2',4'-dione are formed by the acid catalyzed interaction of 2-amino-5,5bis(hydroxymethyl)-4-thiazolinone or its oxo analog 5,5-bis(hydroxymethyl)thiazolidine-2,4-dione with (hetero)aromatic aldehydes. Keywords: 2-amino-5,5-bis(hydroxymethyl)-4-thiazolinone, 2-(het)aryl derivatives of 2'-aminospiro[(1,3-dioxane)-5,5'-thiazolin]-4'-one and spiro[(1,3-dioxane)-5,5'-thiazolidine]-2',4'-dione, reactions with aldehydes. It is known that polyatomic alcohols are able to react with aldehydes and ketones under the influence of acid catalysts to form cyclic acetals and ketals [1]. In particular derivatives of 1,3-dioxane are formed from 1,3-diols [2]. It seemed of interest to discover whether the compounds 2-amino-5,5-bis(hydroxymethyl)-4thiazolinone (1) and its oxo analog 5,5-bis(hydroxymethyl)-2,4-thiazolidinone (2), which we synthesized previously [3], would undergo similar reactions. It seemed that they did not differ in their structures from other 1,3-diols and formed with aromatic and heteroaromatic aldehydes in the presence of acid 2-(het)aryl-2'aminospiro[(1,3-dioxane)-5,5'-thiazolin]-4'-ones 3a-l or 2-(het)aryl-2'-aminospiro[(1,3-dioxane)-5,5'-thiazolidine]2',4'-diones 4a-l respectively (Table 1).
N H2N S 1 HN O S 2 O CH2OH CH2OH RCHO O S O 4al O CH2OH CH2OH RCHO H2N S 3al HN O O O R N O O R
3,4 a R = Ph; b R = o-64Cl; c R = m-64Br; d R = p-64NO2; e R = m-64NO2; f R = 3-Py; g R = 4-Py; h R = p-64NMe2; i R = p-64NEt2; j R = p-64OMe; k R = m,p-63(OMe)2; l R = p-64Me
__________________________________________________________________________________________ St. Petersburg State Technological Institute (Technical University), St. Petersburg 198013, Russia; e-mail: gsramsh@mail.wplus.net. 2 Institute of Toxicology, Ministry of Public Health of the Russian Federation, St. Petersburg 193019, Russia; e-mail: drugs@mail.lanck.net. Translated from Khimii Geterotsiklicheskikh Soedinenii, No. 7, 1068-1075, July 2004. Original article submitted October 12, 2003. 0009-3122/04/4007-09192004 Springer Science+Business Media, Inc. 919
1
TABLE 1. 2-Aryl(hetaryl)-2'-aminospiro[(1,3-dioxane)-5,5'-thiazolin]-4'-ones 3a-l and 2-aryl(hetaryl)[spiro(1,3-dioxane)-5,5'-thiazolidine]-2',4'-diones 4a-l

Compound 3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l Empirical formula C C12H12N2O3S C12H11ClN2O3S C12H11BrN2O3S C12H11N3O5S C12H11N3O5S C11H11N3O3S C11H11N3O3S C14H17N3O3S C16H21N3O3S C13H14N2O4S C14H16N2O5S C13H14N2O3S C12H11NO4S C12H10ClNO4S C12H10BrNO4S C12H10N2O6S C12H10N2O6S C11H10N2O4S C11H10N2O4S C14H16N2O4S C16H20N2O4S C13H13NO5S C14H15NO6S C13H13NO4S 54.40 54.53 48.31 48.24 41.88 42.00 46.64 46.60 46.74 46.60 49.86 49.80 49.89 49.80 54.79 54.71 57.27 57.29 53.18 53.05 51.85 51.84 56.05 56.10 54.39 54.33 48.11 48.09 42.00 41.88 46.53 46.45 46.45 46.45 49.60 49.62 49.43 49.62 54.68 54.53 57.17 57.12 52.81 52.87 51.65 51.68 55.97 55.90 Found, % Calculated, % H 4.49 4.58 3.64 3.71 3.21 3.23 3.67 3.58 3.64 3.58 3.95 4.18 4.14 4.18 5.66 5.57 6.30 6.31 4.71 4.79 5.01 4.97 5.11 5.07 4.14 4.18 3.30 3.36 2.82 2.93 3.17 3.25 3.21 3.25 3.90 3.79 3.58 3.79 5.22 5.23 5.92 5.99 4.35 4.44 4.60 4.65 4.73 4.69
mp, N 10.70 10.60 9.43 9.38 8.28 8.16 13.58 13.59 13.65 13.59 15.86 15.84 15.89 15.84 13.67 13.67 12.48 12.53 9.59 9.52 8.59 8.64 10.01 10.06 5.36 5.28 4.59 4.67 4.08 4.07 9.05 9.03 9.15 9.03 10.50 10.52 10.47 10.52 9.20 9.08 8.29 8.33 4.73 4.74 4.35 4.31 4.97 5.01 273-275 257-259 269-270 350-353 295-298 (dec.) 295-300 (dec.) 302-305 (dec.) 238-240 (dec.) 232-234 (dec.) 260-262 258-260 263-265 (dec.) 203-205 214-216 173-175 263-265 (dec.) 235-238 (dec.) 254-258 (dec.) 272-275 (dec.) 200-203 (dec.) 206-208 (dec.) 198-201 239-241 (dec.) 212-215
Yield, %
50 52 46 57 78 81 81 70 35 72 38 61 60 51 71 90 82 83 80 30 82 60 47 68
All reactions were carried out in sulfuric acid or boron trifluoride etherate, i.e., the acid and etherate were used as both catalysts and as reaction media. In the case of the basic aldehydes (R = p-C6H4NMe2, p-C6H4NEt2, 3-Py, 4-Py) this facilitated the appearance of the catalytic effect by neutralization of their basicity. The syntheses were carried out at room temperature by simple mixing of the reagents in the following order: the aldehyde was added to a mixture of compound 1 or 2 in sulfuric acid or boron trifluoride etherate. When the reaction mixture was heterogeneous it was subjected to intense stirring. As a rule a precipitate of the 920
product appeared after 4h to 10 d, it was filtered off and was treated with NaHCO3 solution. If a precipitate did not occur after prolonged standing or appeared in only small amounts, it was either precipitated with diglyme or absolute ether or it was isolated after neutralization with excess NaHCO3. In sulfuric acid the reaction proceeded sufficiently for isolation of the reaction products only with pyridinealdehydes, nitro- and amino-substituted benzaldehydes, i.e. in those cases in which the aryl substituent in the aldehyde itself possessed strong acceptor properties (p-C6H4NO2, m-C6H4NO2), or acquired them by protonation of the substituent (p-C6H4NMe2, m-C6H4NEt2), or of the hetaryl ring (3-Py, 4-Py). With the remaining benzaldehydes the electrophilicity of carbonyl carbon with respect to the protonic acid is evidently insufficient for condensation with the alcohol, however when a Lewis acid was used boron trifluoride etherate the reaction proceeded with acceptable yields. The acid-base properties of the heterocyclic fragment of the diol (for compound 1 pKa of the conjugate acid is probably close to the pKa of 2-amino-2-thiazolinone, ~2.1[4]; the estimated value of the pKa of the acid ionization for compound 2, based on potentiometric titration with aqueous base, is ~6.0) probably do not affect the reaction under the reaction conditions, and the other diols can condense with aromatic and heteroaromatic aldehydes in any case. Because of the high acidity of compound 2 the amino-substituted benzaldehydes form salts with it which are difficult to dissolve and make it difficult to separate the reaction products. We observed a similar difficulty for these aldehydes in carrying out the reaction with boron trifluoride etherate, evidently because of formation of poorly soluble complexes with the etherate. In all these cases sulfolan was added to homogenize the reaction mixture. A similar method was used to obtain derivatives of veratraldehyde (3,4-dimethoxybenzaldehyde) which apparently also forms a poorly soluble complex with boron trifluoride etherate. Compounds 3a-l and 4a-l are high melting crystalline compounds, which im most cases decompose on melting (Table 1), the composition and structure of which were determined via spectroscopic data (Table 2). The characteristic signals in the 1H NMR spectra of compounds 3a-l and 4a-l are found in narrow ranges of chemical shifts. Thus the proton signals for the NH2 groups in compounds 3 fall in the range 9.1-8.9, while those for the NH groups in compounds 4 fall in the range 12.4-12.1 ppm. The signals for proton H-2 of the 1,3dioxane rings are found in the range 6.0-5.5, and those of H-4 and H-6 in the range 4.5-4.2 ppm for all of the compounds 3 and 4. As a rule the signals of the protons H-4 and H-6 are split into a geminal AB quartet, but in the spectra of compounds 4b,d, and l these signal are singlets. In the 1H NMR spectra of compounds 3g and 4g two sets of proton signals were observed. On the basis of the pattern of the spectrum, the integrated intensities of the observed signals, and the elemental analyses, it can be concluded that these are individual compounds, nut which exist under the conditions of recording the spectra as a mixture of two geometric isomers in the ratios of 2.9:1 and 9:1 respectively, which probably differ in the conformation of the dioxane rings.
EXPERIMENTAL IR spectra of KBr disks were recorded on UR-20 spectrometer. 1H NMR spectra of DMSO-d6 solutions with TMS internal standard were recorded on Bruker AC-200 (200 MHz) (compound 4b), Bruker AM-300 (300 MHz) (compounds 3a,c-h,j-l, 4a,c-g,k,l), and Bruker AM-500 (500 MHz) (3b,i, 4h-j) instruments. TLC was carried out on Silufol UV-254 strips with 5:1 benzene2-propanol as eluent. 2-Amino-5,5-bis(hydroxymethyl)-4-thiazolinone (1) and 5,5-bis(hydroxymethyl)thiazolidine-2,4dione (2) were prepared by a previousl described method [3].
921
922
TABLE 2. Spectroscopic Characteristics of Compounds 3a-l and 4a-l

Compound 1 3a 3b 3c 3d 3e 3f 3g*3 3h 3i 3j 3k 3l 4a IR spectrum, , cm-1 = =N 2 3 1680 1675 1675 1690 1700 1690 1660 1700 1700 1665 1670 1690 1770, 1690 1650 1640 1650 1650 1670 1650 1620 1650 1625 1620 1640 1650 1640 NMR spectrum, , ppm C(2)H, s C(4(6))HA* 6 7
1
NH 4 9.2, 9.0 9.2, 9.0 9.0 9.1, 9.0 9.2, 8.9 9.2, 8.9 9.2 (1+2), 8.9 (1), 8.8 (2) 9.1, 8.9 9.0, 8.8 9.1, 8.9 9.1, 8.9 9.1, 8.9 12.2
Ph(Py), m 5 7.4*2 7.8-7.2 8.1-7.0 8.3, 7.7 8.3-7.6 8.6, 7.8, 7.4 8.64 (2), 8.57 (1), 7.43 (2), 7.39 (1) 7.2, 6.6 7.2, 6.6 7.3, 6.9 7.0-6.8 7.3, 7.2 7.4*2
C(4(6))HB* 8 4.2 4.2 4.2 4.2 4.2 4.2 4.2 (1), 4.0 (2) 4.1 4.1 4.2 4.1 4.1 4.4
R 9 2.9, s 3.4, q*4; 1.2, t*5 3.8, s 3.8, s 2.3, s
5.8 6.0 5.8 6.0 5.9 5.9 5.9 (2), 5.8 (1) 5.6 5.5 5.7 5.6 5.7 5.7
4.4 4.4 4.4 4.5 4.5 4.5 4.5 (1), 4.2 (2) 4.4 4.4 4.4 4.4 4.4 4.5
TABLE 2 (continued)
1 4b 4c 4d 4e 4f 4g*3 4h 4i 4j 4k 4l 2 1760, 1715 1760, 1710 1750, 1700 1750, 1700 1790, 1710 1750, 1710 1750, 1710 1760, 1700 1775, 1700 1755, 1710 1750, 1700 3 1610 1615 1620 1630 1610 1620 1625 1630 1630 1615 1620 4 12.4 12.2 12.2 12.2 12.2 (1+2) 12.2 (1), 12.0 (2) 12.2 12.1 12.3 12.2 12.2 5 7.4-7.6 7.3-7.7 8.2, 7.7 8.2, 7.8, 7.7 8.8-7.3 8.59 (1+2), 7.44 (2), 7.37 (1) 7.2, 6.6 7.2, 6.6 7.3, 6.9 7.0-6.8 7.3, 7.2 6 6.0 5.7 6.0 5.9 5.8 5.8 (1), 5.7 (2) 5.5 5.5 5.7 5.6 5.7 7 4.5*2 4.4 4.5*2 4.6 4.5 4.5 (1), 4.4 (2) 4.4 4.4 4.5 4.5 4.4*2 4.4 4.4 4.4 (1), 4.2 (2) 4.4 4.3 4.4 4.4 4.3 8 9 3.0, s 3.4, q*4; 1.1, t*5 3.8, s 3.8, s 2.3, s
_______ * Protons H-4, H-6 absorb as a geminal AB quartet. From the chemical shifts of HA and HB, JgemAB = 11 Hz. *2 Singlet signal. *3 In the 1H NMR spectra there are two sets of signals, corresponding to two conformers, a major (1) and a minor (2). *4 Signal of methylene protons. *5 Signal of methyl protons.
923
2'-Amino-2-phenylspiro[(1,3-dioxane)-5,5'-thiazolin]-4'-one (3a). Benzaldehyde (0.69 g, 0.66 ml, 6.5 mmol) was added with stirring to a mixture of the monohydrate of compound 1 (1.0 g, 5.1 mmol) and boron trifluoride etherate (2 ml). The initial compound 1 dissolved partially and then a new precipitate appeared and the reaction mixture thickened by degrees. After dilution with an equal volume of absolute ether, stirring was continued for 10 h, the solid was then filtered off, washed with absolute ether, treated with 10% aqueous NaHCO3, and washed with water. Compounds 3b, c, j, and l were obtained analogously from compound 1 and o-chlorobenzaldehyde, m-bromobenzaldehyde, p-methoxybenzaldehyde, and p-methylbenzaldehyde respectively. 2'-Amino-2-(3-nitrophenyl)spiro[(1,3-dioxane)-5,5'-thiazolin]-4'-one (3e). m-Nitrobenzaldehyde (3.2 g, 21.2 mmol) was added to a solution of compound 1 (4.0 g, 20.6 mmol) in sulfuric acid (12 ml). The reaction mixture was diluted over 2 d with 1.5 volumes of absolute ether and then kept in a refrigerator for a week. The precipitate was filtered off, washed with diglyme, treated with 10% aqueous NaHCO3, and washed with water. Compound 3d was obtained analogously from compound 1 and p-nitrobenzaldehyde. 2'-Amino-2-(3-pyridyl)spiro[(1,3-dioxane)-5,5'-thiazolin]-4'-one (3f). 3-Pyridinecarbaldehyde (3.7 g, 3.3 ml, 34.5 mmol) was added to a mixture of compound 1 (6.8 g, 35.0 mmol) and sulfuric acid (12 ml). After 4 d the reaction mixture was poured into 10% aqueous NaHCO3 (350 ml). After evolution of CO2 had ceased, the precipitate which formed was filtered off and washed with water. Compounds 3g (from compound 1 and the hydrate of 4-pyridinecarbaldehyde), 4f (from compound 2 and 3-pyridinealdehyde), and 4g (from compound 2 and the hydrate of 4-pyridinecarbaldehyde) were prepared analogously. 2'-Amino-2-(4-dimethylaminophenyl)spiro[(1,3-dioxane)-5,5'-thiazolin]-4'-one (3h). p-Dimethylaminobenzaldehyde (1.4 g, 9.4 mmol) was added to a solution of compound 1 (2.0 g, 10.3 mmol) in sulfuric acid (3 ml). After 4-5 d a precipitate formed an additional amount of which was formed by diluting the reaction mixture with diglyme. After standing for 4 d in the refrigerator, the precipitate was filtered off, washed with diglyme, treated with 10% aqueous NaHCO3 until evolution of CO2 ceased, filtered again, boiled with a mixture of 10% aqueous NaHCO3 (10 ml) and i-PrOH (10 ml) for 30 min, filtered hot and washed with water. 2'-Amino-2-(4-diethylaminophenyl)spiro[(1,3-dioxane)-5,5'-thiazolin]-4'-one (3i). p-Diethylaminobenzaldehyde (1.5 g, 8.5 mmol) was added to a solution of compound 1 (2.0 g, 10.3 mmol) in sulfuric acid (3 ml). After 3 days the reaction mixture was poured into 10% aqueous NaHCO3 (100 ml), the precipitate was filtered off and recrystallized from ethanol. 2-Phenylspiro[(1,3-dioxane)-5,5'-thiazolidine]-2',4'-dione (4a). Benzaldehyde (0.69 g, 0.66 ml, 6.5 mmol) was added to an intensely stirred mixture of compound 2 (1.0 g, 5.6 mmol) and boron trifluoride etherate (2 ml). Along with the dissolution of compound 2, the gradual formation of a new precipitate was observed. After 2h stirring the reaction mixture was diluted with an equal volume of absolute ether, stirring was continued for a further 10 h, the precipitate formed was filtered off, washed with absolute ether, treated with 10% aqueous NaHCO3, and washed with water. Compounds 4b,c,j, and l were obtained analogously to compound 4a from compound 2 and o-chlorobenzaldehyde, m-bromobenzaldehyde, p-methoxybenzaldehyde, and p-methylbenzaldehyde respectively. 2-(4-Nitrophenyl)spiro[(1,3-dioxane)-5,5'-thiazolidine]-2',4'-dione (4d). p-Nitrobenzaldehyde (3.2 g, 21.2 mmol) was added to a mixture of compound 2 (4.0 g, 22.6 mmol) and sulfuric acid (12 ml). After 2 d the reaction mixture was diluted with 1.5 volumes of diglyme and kept in the refrigerator for a week. The precipitate was filtered off, washed with diglyme, treated with 10% aqueous NHCO3, and washed with water. Compound 4e was prepared analogously from compound 2 and m-nitrobenzaldehyde. 2-(4-Diethylaminophenyl)spiro[(1,3-dioxane)-5,5'-thiazolidine]-2',4'-dione (4i). Boron trifluoride etherate (8 ml) and compound 2 (1.7 g, 9.6 mmol) were added to a solution of p-dimethylaminobenzaldehyde in sulfolane (10 ml). The reaction mixture was shaken periodically and compound 2 dissolved progressively. After 924
10 d the reaction mixture was poured into 10% aqueous NaHCO3 (100 ml), the precipitate was filtered off and washed successively with water and ethanol. Compound 4h was obtained from compound 2 and p-dimethylaminobenzaldehyde analogously. 2-(3,4-Dimethoxyphenyl)spiro[(1,3-dioxane)-5,5'-thiazolidine]-2',4'-dione (4k). Boron trifluoride etherate (6 ml) and compound 2 (3.0g, 16.9 mmol) were added successively with stirring to a solution of 3,4-dimethoxybenzaldehyde (2.8 g, 16.8 mmol) in sulfolane (30 ml). Stirring was continued until compound 2 had dissolved. After 4 h the reaction mixture was poured into 10% aqueous NaHCO3 (100 ml). The precipitate was filtered off and washed successively with water and ethanol. Compound 3k was obtained analogously from compound 1 and 3,4-dimethoxybenzaldehyde. All of the precipitated compounds were dried initially in air and then in vacuum to constant weight. The authors thank D. B. Lazarev for help in preparing this paper.
REFERENCES 1. 2. 3. K. Buler and D. Pearson. Organic Syntheses [Russian translation], Mir, Moscow (1973), 1, p. 582. S. M. Ramsh and A. G. Ivanenko. Khim. Geterotsikl. Soed., 1743 (2003). S. M. Ramsh, N. A. Smorygo, and A. I. Ginak. Khim. Geterotsikl. Soed., 1066 (1984).
925
TAUTOMERIC AND CONFORMATIONAL ISOMERISM OF MERCAPTOACETYLHYDRAZONES OF METHYL ALKYL KETONES

A. Yu. Ershov and N. V. Koshmina Mercaptoacetylhydrazones of methyl alkyl ketones (Alk = Me, Et, Pr, i-Pr, i-Bu, s-Bu, t-Bu) exist in solutions as a tautomeric mixture of linear and cyclic 1,3,4-thiadiazine forms.The linear hydrazone form exists as a set of conformers caused by restricted rotation of the amide group relative to the CN bond. It is shown that tautomeric equilibrium constants correlate with the steric constants of the alkyl substituents, ES. Keywords: mercaptoacetylhydrazones, 1,3,4-thiadiazin-5(4H)-ones, ring-chain tautomerism, the Taft equation. The results of studies of frequently encountered ring-chain tautomeric conversions, linked with intramolecular reversible addition of the nucleophilic groups OH, NH, and SH to the C=N group are reflected in the monographs [1, 2]. It is known that the hydrazones of lactic and -aminopropionic acids have linear structures [3, 4], whereas the mercaptoacetylhydrazone of acetone, which we prepared recently, is inclined to ring-chain tautomerism in solutions with participation of the 1,3,4-thiadiazin-5-one ring [5]. The objective of the present work was to study the tendency to tautomeric conversion of the mercaptoacetylhydrazones 1a-g derived from methyl alkyl ketones, and also the effect of steric parameters of alkyl substituents on the position of tautomeric equilibrium.
R N Me NH O SH R N O SH SH Me NH Me N R NH O Me N O SH R NH O H N S NH Me R
E,E '-A
E,Z '-A
Z,E '-A 1ag
Z,Z '-A
1 a R = Me, b R = Et, c R = Pr, d R = i-Pr, e R = i-Bu, f R = s-Bu, g R = t-Bu
Compounds 1a-g were obtained in 50-75% yield by the brief expsure of equimolar quantities of the hydrazide of thioglycolic acid and the corresponding methyl alkyl ketone in water or aqueous alcoholic solution at room temperature (see Table 1 and Experimental). __________________________________________________________________________________________ Institute of High Molecular Compounds, Russian Academy of Sciences, St. Petersburg 199004; e-mail: ershov@hg.macro.ru. St. Petersburg State University, St. Petersburg 198904, Russia. Translated from Khimii Geterotsiklicheskikh Soedinenii, No. 7, 1076-1080, July, 2004. Original article submitted February 24, 2003. 926 0009-3122/04/4007-09262004 Springer Science+Business Media, Inc.
TABLE 1. Physicochemical Characteristics of Compounds 1b-g

Compound 1b 1c 1d 1e 1f 1g Empirical formula C C6H12N2OS 714N2OS 714N2OS 816N2OS 816N2OS 816N2OS 45.04 44.97 48.31 48.25 48.20 48.25 50.97 51.03 51.08 51.03 50.96 51.03 Found, % Calculated, % H 7.49 7.55 8.06 8.10 8.14 8.10 8.50 8.56 8.61 8.56 8.63 8.56
mp, N 17.53 17.48 16.14 16.08 16.11 16.08 14.94 14.88 14.95 14.88 14.82 14.88 Oil Oil 108-110 92-95 83-85 94-96
Yield, %
65 60 75 70 75 50
It was shown previously [5] that in solution in pyridine-d5 compound 1a , along with ring-chain tautomerism of the type A B, shows a doubling of signals for the hydrazone form A in its 1H NMR spectrum, caused by restricted amide rotation of the mercaptoacetyl group relative to the CN bond and the existence of the forms E,E'-A and E,Z'-A. In the case of compounds 1b-g it is to be expected that there is the possibility of spatial Z,E-isomers of the mercaptoacetylhydrazone unit relative to the C=N bond and consequently the appearance of four possible linear forms in solution: E,E'-A, E,Z'-A, Z,E'-A, and Z,Z'-A. Assignment of the signals to the geometric isomers Z,E'-A and Z,Z'-A can be carried out on the basis of the appearance for the hydrazones of the deshielding effect of the hydrazone unit on the methylene or methyl protons in the cis-positions in the 1H NMR spectrum [6]. As a result these signals should appear at weaker field than the analogous signals for the isomeric forms E,E'-A and E,Z'-A. It should be noted that we did not observe any signals in the 1H NMR spectra of compounds 1b-g which could be assigned to the configurational isomers Z,E'-A, and Z,Z'-A, arising from spatial isomerization. Compounds 1a-g have a considerable tendency to chain-ring tautomerism in solution and the introduction of alkyl substituents favors the linear form A. The logarithms of the tautomeric equilibrium constants for 1a-g show a linear correlation with the steric constants ES according to the equation: lg KT = -0.16 + 0.67ES , where the correlation coefficient r = 0.993. A similar dependence is characteristic for chain-ring equilbria where the cyclic isomer arises as a result of reversible addition to the double bond carrying the bulky alkyl substituent [7, 8] (see Fig. 1). Conformational equilibria are less sensitive to a change in volume of the substituent at the C=N bond and are strongly shifted to the form E,E'-A in which steric interactions are considerably less than for the alternative form E,Z'-A. Assignments of signals in the 1H NMR spectrum to a particular conformational isomer of the linear forms A does not present a difficulty if established criteria and rules presented earlier in monographs [9, 10] are followed, together with recent work [11] on the steric structure of cyanacetylhydrazones of carbonyl compounds which are close structural analogs of the A forms of compounds 1a-g. We note that one of the typical signs of forms E,E'-A in the 1H NMR spectrum is the presence of spin-spin interaction of the protons of the methylene groups of the mercaptoacetyl group and the proton of the SH group (J = 7.0 Hz, Table 2) as a result of which the signals of these groups appear as a doublet and a triplet respectively. Indications of the cyclic form B in solution are the strong field shift of the signals of the protons of the methyl group, diasterotopy of the protons at position 6 (which in separate cases form a typical AB system with J = 14 Hz), and also the signal of the sp3-hybridized C(2) at 70.0 ppm in the 13C NMR spectra (Table 3). 927
928
TABLE 2. Tautomeric Composition, 1H NMR Spectra, and Tautomeric Equilibrium Constants for Compounds 1a-g in Pyridine-d5
Compound
1a
Tautomeric composition (%)

,E '- (44) E,Z '- (15) B (41) ,E '- (54) E,Z '- (10) B (36) ,E '- (57) E,Z '- (10) B (33) ,E '- (68) E,Z '- (7) B (25) ,E '- (77) E,Z '- (7) B (16) ,E '- (83) E,Z '- (6) B (11) ,E '- (88) E,Z '- (6) B (6)
=CMe (A) or C(2)Me (B), s or two s

1.90; 1.92 1.92; 1.97 1.68 1.90 1.96 1.61 1.93 1.94 1.64 1.90 1.92 1.55 1.93 1.96 1.69 1.90 1.92 1.58 1.91 1.97 1.66
1 H NMR spectra, , ppm (J, Hz)*2 SS2 (A) or SH C(6)2 (B)
[B]
H, br. s or two br. s
10.83 10.95 6.55; 10.36 10.85 10.95 6.42; 10.29 10.80 10.87 6.34; 10.20 10.93 10.97 6.42; 10.37 10.91 10.95 6.35; 10.32 10.86 10.94 6.32; 10.25 10.80 10.88 6.13; 10.15
KT =
[A]*2
1b
1c
1d
1e
1f
1g
3.84, s 3.61, s 3.70, s 3.85, s 3.57, s 3.60; 3.69 (dd, J = 14.0) 3.84, s 3.56, s 3.59; 3.70 (dd, J = 14.0) 3.84 (d, J = 7.0) 3.58, s 3.54; 3.71 (dd, J = 14.0) 3.86 (d, J = 7.0) 3.58, s 3.48; 3.67 (dd, J = 14.0) 3.85 (d, J = 7.0) 3.57, s 3.46; 3.75 (dd, J = 14.0) 3.83 (d, J = 7.0) 3.58, s 3.41; 3.73 (dd, J = 14.0)
2.92, s 2.50, s 2.92, s 2.49, s 2.88, s 2.48, s 2.95 (t, J = 7.0) 2.58, s 2.93 (t, J = 7.0) 2.49, s 2.89 (t, J = 7.0) 2.47, s 2.87 (t, J = 7.0) 2.48, s
0.69
0.56
0.49
0.33
0.19
0.12
0.06
_______ * 1H NMR spectra were recorded 72 h after dissolution of compound 1; signals of the protons of the substituents R are not cited. *2 [A] is the sum of the content of forms E,E'-A and E,Z'-A.
Fig. 1. Correlation of the logarithm of the tautomeric equilibrium constant with the steric constants ES of the alkyl substituents.
TABLE 3. 13C NMR Spectra of Compounds 1a and 1e

Compound 1 Solvent DMSO-d6 Form ,E '- E,Z '- B ,E '- E,Z '- B Chemical shifts, , ppm C=N / (2) = / C(5) 152.2 157.2 69.1 153.5 158.3 73.2 167.2 172.4 173.9 166.8 172.2 173.5
MeC= / Me(2) 18.2 17.8 30.5 16.1 16.2 29.4
2 / (6) 25.5 26.8 29.4 26.4 26.9 27.5
DMF-d7
Determination of the conformational state of the six-membered thiadiazine forms requires further work.
EXPERIMENTAL H and 13C NMR spectra were recorded with Bruker AC 200 and Bruker AM 500 instruments (200 and 125 MHz respectively). The quantitaive ratios of the tautomeric forms were determined from the intensities of the signals of the methyl groups in the 1H NMR spectra. The measurement error was 1%. The course of reactions and the purity of the compounds synthesized were monitore by TLC on Silufol UV-254 strips with 2:1 benzeneacetone as eluent. Compound 1a was described previously [5]. 2-Alkyl-2-methyl-2,3,56-tetrahydro-1,3,4-thiadiazin-5(4H)-ones (1b-g) (general method). A mixture of a carbonyl compound (0.015 mol) and the hydrazide of thioglycolic acid (1.06 g, 0.01 mol) in water (25 ml) (for compounds 1d-g in 4:1 water ethanol (30 ml) was kept at 25C for 2 h. The crystals of product 1 which formed were filtered off , dried, and recrystallized from hexane.
1
929
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. R. E. Valter, Ring-chain Isomerization in Organic Chemistry [in Russian], Zinatne, Riga (1978), 238. B. V. Ioffe, M. A. Kuznetsov, and A. A. Potekhin, Chemistry of Organic Derivatives of Hydrazine [in Russian], Khimiya, Leningrad (1979), 188 p. A. A. Potekhin and V. M. Karel'skii, Zhur. Org. Khim., 7, 2100 (1971). P. S. Lobanov, A. N. Poltorak, and A. A. Potekhin, Zhur. Org. Khim., 14, 1086 (1978). A. Yu. Ershov and N. V. Koshmina, Khim. Geterotsikl. Soed., 1431 (2001). G. J. Karabatsos, J. D. Graham, and F. M. Vane, J. Am. Chem. Soc., 84, 753 (1962). A. S. Dneprovskii and T. I. Temnikova, Theoretical Basis of Organic Chemistry [in Russian], Khimiya, Leningrad (1979), 580 p. V. A. Pal'm, Basis of the Quantitative Theory of Organic Reactions [in Russian], Khimiya, Leningrad (1977), 359. N. A. Parpiev, V. G. Yuspov, S. I. Yakimovich, and Kh. T. Sharipov, Acylhydrazones and Their Complexes with Transition Metals [in Russian], Fen, Tashkent (1988), 163 p. Yu. P. Kitaev and B. I. Buzykin, Hydrazones [in Russian], Nauka, Moscow (1974), 381 p. K. N. Zelenin, S. V. Oleinik, V. V. Alekseev, and A. A. Potekhin, Zhur. Obshch. Khim., 71, 1182 (2001).
930
Candida rugosa LIPASE-CATALYZED KINETIC RESOLUTION OF 3-(ISOBUTYRYLOXY)METHYL 4-[2-(DIFLUOROMETHOXY)PHENYL]-2-METHYL5,5-DIOXO-1,4-DIHYDROBENZOTHIENO[3,2-b]PYRIDINE-3-CARBOXYLATE

A. Sobolev1, R. Zhalubovskis1, M. C. R. Franssen2, B. Vigante1, B. Chekavichus1, G. Duburs1, and Ae. de Groot2 The lipase-catalyzed kinetic resolution of 3-(isobutyryloxy)methyl 4-[2-(difluoromethoxy)phenyl]-2methyl-5,5-dioxo-1,4-dihydrobenzothieno[3,2-b]pyridine-3-carboxylate has been performed. The most enantioselective reaction (E = 28) was transesterification with n-butanol in water-saturated toluene at 45C. Keywords: enantiopure transesterification. 1,4-dihydropyridines, enzyme-catalyzed reaction, kinetic resolution,
The pharmacological activities of drugs depend on their interaction with biological matrices (so-called drug targets). These drug targets, such as proteins (receptors, enzymes), nucleic acids, and biomembranes (phospholipids and glycolipids), have complex three-dimensional structures, which are capable of recognizing and binding specifically the ligand (drug) molecule in only one of the many possible arrangements in threedimensional space [1, 2]. As a result of this direct correlation between drug stereochemistry and biological activity, the governing bodies that regulate the approval of new medicines in the USA [3, 4] and Europe [5] have issued specific rules pertaining to the development of stereoisomeric drugs [2, 6, 7]. Chirality plays an important role in the activity of 1,4-dihydropyridines (1,4-DHPs) and both quantitative and qualitative differences have been reported [8, 9]. The preferred method for the resolution of monocyclic 1,4-DHPs is enzymatic kinetic resolution, often assisted by the incorporation of an enzymatically labile group. This approach has been pioneered by the group of Sih [10] and Achiwa [11] and has been successfully used also by our research group [12-14]. Polycyclic 1,4-DHPs in enantiopure form are desired for extended pharmacological studies, since racemic 1,4-dihydrobenzothieno[3,2-b]pyridine 5,5-dioxides 1 [15] and 5-oxo-4,5-dihydro-1,4-indeno[1,2-b]pyridines 2 [16] have exhibited various biological activities. Many representatives of both classes of compounds (e.g., 1 [R = phenyl, 4-bromophenyl, 4-nitrophenyl] and 2b) show coronary dilating activities [17-19]. 1,4-DHPs 2a and 2c have exhibited anticancer activities [20]. Herein, we report the Candida rugosa lipase-catalyzed kinetic resolution of 3-(isobutyryloxy)methyl 4-[2-(difluoromethoxy)phenyl]-2-methyl-5,5-dioxo-1,4-dihydrobenzothieno[3,2-b]pyridine-3-carboxylate as a model compound for the resolution of these polycyclic 1,4-DHP derivatives. __________________________________________________________________________________________ Latvian Institute of Organic Synthesis, Riga LV-1006, Latvia; e-mail: Arkady@osi.lv. 2 Laboratory of Organic Chemistry, Wageningen University, 6703 HB Wageningen, The Netherlands; e-mail: Maurice.Franssen@wur.nl. Published in Khimii Geterotsiklicheskikh Soedinenii, No. 7, 1076-1080, July, 2004. Original article submitted February 24, 2003. 0009-3122/04/4007-09312004 Springer Science+Business Media, Inc. 931
1
O O S
R R1 N H 1 Me R = H, Me, Ph, C6H4Cl-4, C6H4OMe-4, C6H4OH-4, C6H4Br-4, C6H3(OMe)2-2,3, C6H4NO2-4, PhCH=CH R1 = COOAlk, COMe, CN, C(O)SEt, C(S)OEt, C(S)SEt
R R1 N H 2 2a R = Me Ph N N H , R1 = COOMe
2b R = Ph, C6H4OH-2, C6H4NO2-2 and -4; R1 = C(O)SEt, C(O)SCH2Ph
COO 2c R = N , R1 =
The synthesis of enantiopure polycyclic 1,4-DHPs has been performed via lipase-catalyzed kinetic resolution of the corresponding acyloxymethyl derivative 8. The racemic acyloxymethyl ester 8 has been prepared in a four-step sequence as depicted in scheme 1. Thus, condensation of benzo[b]thiophen-3(2H)-one 1,1-dioxide (3) [21] with 2-(difluoromethoxy)benzaldehyde, followed by Hantzsch cyclization of the intermediate 4 with 2-cyanoethyl 3-aminocrotonate (5), furnished the polycyclic 1,4-DHP 6 framework according to the earlier reported method [15]. The hydrolysis of cyanoethyl ester 6 with KOH gave carboxylic acid 7. The last step consists of the esterification of 7 with isobutyryloxymethyl chloride [13]. The choice of enzymes for primary screening was based on the previous work of our group [12-14, 22] and literature data [11, 23]. The primary screening was carried out in water-saturated diisopropyl ether (IPE) at 45C. Of these tested hydrolases (Lipase PS and AH, Candida antarctica lipase B [Novozym 435 and Chirazyme L-2, c.-f., C3, lyo. (CAL-B)], Rhizomucor miehei lipase, Burkholderia cepacia lipase, and Candida rugosa lipase [CRL]), only CRL showed significant hydrolytic activity towards substrate 8. CRL-Mediated hydrolysis of 8 in water-saturated IPE at 45C (Table 1, entry 1) occurred with moderate enantioselectivity (E = 12 [24]). The very low solubility of the substrate in IPE and the moderate enantioselectivity of CRL led us to investigate other reaction conditions. The influence of the solvent on the enantioselectivity of CRL was studied in more detail and some examples are given in Table 1. It was found that the use of toluene as the solvent increased the solubility of substrate 8. CRL-Catalyzed hydrolysis in toluene that was saturated with water at the reaction temperature occurred with moderate selectivity (Table 1, entry 2). CRL was found to be not active when toluene was used with n-butanol as nucleophile in the absence of water (Table 1, entry 3). Better results were obtained when 5-50 mmol/l n-butanol in water-saturated toluene was used as the reaction
932
Scheme 1
O O S O 3 O a 42% O 4 O S OCHF2 O OCH2CH2CN Me 5 b 49%
+
H2N
OCHF2 O O S N H 7 e 46% Me H O OH c, d 66% O O S N H 6
OCHF2 H COOCH2CH2CN Me
OCHF2 O O S N H 8
Reagents and conditions: a 2-(difluoromethoxy)benzaldehyde, AcOH, piperidine, , 3 h; b EtOH : AcOH (20 : 1), , 3 h; c EtOH, KOH, room temperature, 3 h; d H2O, HCl; e ClCH2OC(O)Pr-i, K2CO3, DMF, room temperature, 3 h
O O Me O
medium (Table 1, entries 4-7). Using less n-butanol at higher temperatures appeared to give the most enantioselective reaction (E = 28) (Table 1, entry 6). The amount of water in the reaction mixture seems to be important for the enantioselectivity of CRL, as E = 22 for the reaction where the toluene was water-saturated at room temperature, whereas an E = 28 was obtained in the case where the toluene was water-saturated at 45C (Table 1, entry 6). The experimentally determined water content in toluene was around 0.045 and 0.10% at 25 and 45C, respectively. The monoacid 7 and the remaining ester 8 were isolated after 2 h of reaction with CRL when the conversion reached ~30%, in order to have a good enantiomeric excess of the reaction product (eep). The enantiomerically pure monoacid 7 appeared to have an optical rotation of -61.4 (c 0.5, acetone) whereas the enantiomerically enriched remaining ester had an optical rotation of +29.1 (c 1.0, acetone). The remaining substrate (+)-8 preferentially crystallises as a single enantiomer. After purification of (+)-8 via crystallization from diluted methanol, the eep of the product was much higher than expected (94%).
933
TABLE 1. CRL-Catalyzed Kinetic Resolution of 8

Entry 1 2 3 4 5 6 7 T, C 45 25 45 45 25 45 45 Reaction medium IPE/H2Ob Toluene/H2Oc 50 mmol/l n-butanol in toluened 50 mmol/l n-butanol in toluene/H2Oe 5 mmol/l n-butanol in toluene/H2Oe 5 mmol/l n-butanol in toluene/H2Oe 5 mmol/l n-butanol in toluene/H2Of Conversion Time, h % eep, % 6 20 4 5.5 6.0 2.0 4.5 49 25 42 41 31 25 69 82 77 83 90 89 Ea 12.01.0 14.00.8 16.01.4 23.01.6 28.02.8 22.02.7
_______ a The enantiomeric ratio (E) was calculated using the computer program EIVFIT [25]. b A solution of 5 mg of 8 in 20 ml IPE that was water-saturated at room temperature with 5 mg of CRL was shaken at 250 revolutions per minute (rpm). c A solution of 5 mg of 8 in 5 ml of toluene that was water-saturated at the reaction temperature with 5 mg of CRL was shaken at 250 rpm. d A solution of 5 mg of 8 in 5 ml of 50 mmol/l n-butanol in toluene with 5 mg of CRL was shaken at 250 rpm. e A solution of 5 mg of 8 in 5 ml of 5-50 mmol/l n-butanol in toluene that was water-saturated at the reaction temperature with 5 mg of CRL was shaken at 250 rpm. f A solution of 5 mg of 8 in 5 ml of 5 mmol/l n-butanol in toluene that was water-saturated at room temperature with 5 mg of CRL was shaken at 250 rpm.
Scheme 2
O O S N
OCHF2 O H O Me O
O O S
OCHF2 H O * N H (-)-7 31% 91% ee Me OH
OCHF2 H O * N H (+)-8 34% 94% ee Me O O
O S
H rac-8
Reagents and conditions: a Candida rugosa lipase, 5 mmol/l n-butanol solution in toluene that was water-saturated at the reaction temperature, 2 h at 45C
In conclusion, the Candida rugosa lipase-catalyzed kinetic resolution of 3-(isobutyryloxy)methyl 4-[2-(difluoromethoxy)phenyl]-2-methyl-5,5-dioxo-1,4-dihydrobenzothieno[3,2-b]pyridine-3-carboxylate has been developed. The enantioselectivity of Candida rugosa lipase can be improved by changing the reaction medium and the temperature. The change of the reaction medium from water-saturated diisopropyl ether to 934
5 mmol/l solution of n-butanol in toluene resulted in a higher enantiomeric ratio (E = 28). This method shows that these tricyclic compounds are accepted by CRL and that enantiomeric recognition is feasible. This opens new avenues for the preparation of enantiopure fused 1,4-DHPs.
EXPERIMENTAL All reagents were purchased from Aldrich, Acros or Merck and used without further purification. HPLC grade solvents were from Labscan (Dublin, Ireland). Candida rugosa lipase, (lipase (EC 3.1.1.3) Type VII from Candida rugosa, 875 U/mg) was purchased from Sigma. Lipase AH, and Lipase PS were gifts from Amano Pharmaceutical Co., Ltd. (Japan). Immobilized Candida antarctica lipase B (Novozym 435) was a gift from Novo Nordisk A/S (Bagsvaerd, Denmark). Rhizomucor miehei lipase (Chirazyme L-9, c.-f, lyo.), Candida antarctica lipase B (Boehringer Mannheim, Chirazyme L-2, c.-f., C3, lyo.), and Burkholderia cepacia lipase (Chirazyme L-1, c.-f., lyo.) were gifts from Boehringer-Mannheim (Mannheim, Germany). Enzymatic reactions were carried out in a New Brunswick Scientific Innova 4080 incubatory orbital shaker at 250 rpm. Flash column chromatography was performed on Merck silica gel 60 (230-400 mesh or 70-230 mesh). TLC was performed on 20 20 cm Silica gel TLC-PET F254 foils (Fluka). 1H NMR spectra were recorded on a Bruker WH 90/DC (90 MHz) or a Bruker AC-E 200 (200 MHz) spectrometer. 13C NMR spectra were recorded on a Bruker AC-E 200 (50 MHz). Mass spectral data were determined on a AEI MS-905 mass spectrometer. Melting points were determined on a Boetius apparatus and are uncorrected. Optical rotation values were measured with a Perkin Elmer 241 digital polarimeter. Elemental analyses were determined on a Carlo-Erba elemental analyzer. The conversions and enantiomeric excesses of all enzymatic reactions were analyzed by HPLC on an enantioselective column Chirex 3011, 4.6 250 mm, 5 m (Phenomenex) using a Ginkotek 580A pump (Germering, Germany) and an Applied Biosystems 759A absorbance detector at 254 nm or a LC-1110 pump and a LC-1200 UV/Vis detector at 254 nm, GBC (Dandenong, Australia). The eluent was 0.05 M ammonium acetate in MeOH at a flow rate of 1 ml/min. Peak areas were determined electronically with the Chromeleon chromatography data system, Dionex Softron GmbH (Germering, Germany) or DP-800, GBC (Dandenong, Australia). Water content in toluene was determined by gas chromatography, using a Hewlett Packard 5890 gas chromatograph equipped with a thermal conductivity detector (TCD) and a Porapak QS column. 2-[2-(Difluoromethoxy)benzylidene]benzo[b]thiophen-3(2H)-one 1,1-Dioxide (4). Benzo[b]thiophen-3(2H)-one 1,1-dioxide 3 (1.64 g, 9 mmol), 2-(difluoromethoxy)benzaldehyde (1.55 g, 9 mmol), and piperidine (0.06 ml) in acetic acid (20 ml) were stirred under reflux for 3 h. After storing in the refrigerator the precipitated product was filtered to give 1.38 g of crude 4. The precipitate was crystallized from methanol to give white crystals of 4 (1.27 g, 42%); mp 195-198C. 1H NMR spectrum (DMSO-d6, 90 MHz), , ppm (J, Hz): 7.108.40 (m, 9H, ArH and =CH); 7.40 (t, 1H, JHF = 74.0, OCHF2). MS: 336 [M]+. Found, %: C 56.20; H 2.94. C16H10F2O4S. Calculated, %: C 57.14; H 3.00. 3-(2-Cyanoethyl) 4-[2-(Difluoromethoxy)phenyl]-2-methyl-5,5-dioxo-1,4-dihydrobenzothieno[3,2-b]pyridine-3-carboxylate (6). To a solution of 4 (1.34 g, 4 mmol) in a mixture of ethanol (20 ml) and acetic acid (4 ml), 2-cyanoethyl 3-aminocrotonate 5 (0.62 g, 4 mmol) was added. The reaction mixture was stirred under reflux for 3 h. After refrigeration of the mixture, the orange precipitate was filtered off. The crude product was crystallized from methanolacetic acid to give a yellow powder of 6 (0.92 g, 49%); mp 230-234C. 1 H NMR spectrum (DMSO-d6, 90 MHz), , ppm (J, Hz): 2.40 (s, 3H, CH3, overlap with DMSO-d6); 2.70 (t, 2H, J = 6.5, CH2CH2CN); 4.05 (t, 2H, J = 6.5, CH2CH2CN); 5.30 (s, 1H, CH); 6.90-8.10 (m, 8H, Ar-H); 6.97 (t, 1H, JH-F = 76.0, OCHF2); 9.80 (s, 1H, NH). MS: 472 [M]+. Found, %: C 57.79; H 3.74; N 5.59; S 6.57. C23H18F2N2O5S. Calculated, %: C 58.47; H 3.84; N 5.93; S 6.79. 4-[2-(Difluoromethoxy)phenyl]-2-methyl-5,5-dioxo-1,4-dihydrobenzothieno[3,2-b]pyridine-3carboxylic Acid (7). Compound 6 (1.89 g, 4 mmol) in ethanol (20 ml) was heated under reflux until dissolution was complete, after which it was cooled down. Crushed KOH (0.28 g, 5 mmol) was added to the reaction 935
mixture at room temperature and this mixture was then stirred for 3 h at the same temperature before being evaporated. The residue was diluted with water. The ice-cooled solution was acidified with diluted aqueous HCl to pH 4.0-5.0. The precipitated product was filtered off, washed with water, and crystallized from methanol to give a yellow powder of 7 (1.11 g, 66%); mp 223-225C. 1H NMR spectrum (DMSO-d6, 90 MHz), , ppm (J, Hz): 2.40 (s, 3H, CH3, overlap with DMSO-d6); 5.30 (s, 1H, CH); 6.98 (1H, t, JHF = 76.0, OCHF2); 7.04-8.10 (m, 8H, ArH); 9.55 (br. s, 1H, NH); 10.90 (br. s, 1H, COOH). Found, %: C 56.95; H 3.52; N 3.39; S 7.71. C20H15F2NO5S. Calculated, %: C 57.28; H 3.60; N 3.34; S 7.65. 3-(Isobutyryloxy)methyl 4-[2-(Difluoromethoxy)phenyl]-2-methyl-5,5-dioxo-1,4-dihydrobenzothieno[3,2-b]pyridine-3-carboxylate (8). To a solution of 7 (0.53 g, 1.3 mmol) in dry DMF (7 ml), K2CO3 (0.21 g, 1.5 mmol) was added at room temperature and the reaction mixture was stirred for 2 h, after which isobutyryloxymethyl chloride (0.22 g, 1.6 mmol) was added. The mixture was stirred for 3 h, poured into ice cold water, and extracted with CHCl3. The organic layer was washed with water (three times) and brine, dried over MgSO4, and evaporated. The remaining residue was crystallized from methanol to give 0.30 g (46%) of 8 as a yellow powder; mp 185-187C. 1H NMR spectrum (CDCl3, 200 MHz), , ppm (J, Hz): 1.05 (d, 3H, J = 6.9, CHCH3); 1.07 (d, 3H, J = 6.9, CHCH3); 2.40 (septet, 1H, J = 6.9, CH(CH3)2); 2.44 (s, 3H, CH3); 5.43 (s, 1H, CH); 5.69 (ABq, 2H, OCH2O); 6.54 (t, 1H, JHF = 74.4, OCHF2); 6.59 (br. s, 1H, NH); 7.00-7.64 (m, 8H, ArH). MS: 519 [M]+. Found, %: C 57.64; H 4.35; N 2.64; S 6.26. C25H23F2NO7S. Calculated, %: C 57.80; H 4.46; N 2.70; S 6.17. Candida Rugosa Lipase-catalyzed Kinetic Resolution of Racemic 8. To a solution of 8 (85 mg, 0.16 mmol) in 5 mmol/l n-butanol in toluene (85 ml) that was water-saturated at 45C was added Candida rugosa lipase (85 mg) and the resulting mixture was shaken for 2 h at 45C. The reaction mixture was diluted with acetonitrile (200 ml), evaporated and directly flash chromatographed on silica gel with chloroform petroleum ether (bp 40-60C)acetoneethanol (9:7:2:2) to give ()-7 and (+)-8. The ees of both compounds were determined after crystallisation. ()-4-[2-(Difluoromethoxy)phenyl]-2-methyl-5,5-dioxo-1,4-dihydrobenzothieno[3,2-b]pyridine-3carboxylic Acid (()-7). Yield 21 mg (31%) as a yellow powder from methanolwater; mp 166-167C; 91% ee; []D20 -61.4 (c 0.5, acetone). 1H NMR spectrum (DMSO-d6, 200 MHz), , ppm (J, Hz): 2.46 (s, 3H, CH3); 5.36 (s, 1H, CH); 6.98 (t, 1H, JHF = 74.3, OCHF2); 7.03-7.34 (m, 4H, ArH); 7.58-8.08 (m, 4H, ArH); 9.71 (br. s, 1H, NH). 13C NMR spectrum (DMSO-d6, 50 MHz), , ppm (J, Hz): 18.35 (CH3); 30.12 (CH); 102.07 (C); 110.16 (C); 116.82 (CH, t, JCF = 250.0, OCHF2); 116.83 (CH); 120.27 (CH); 121.20 (CH); 125.19 (CH); 126.04 (C); 128.07 (CH); 130.00 (CH); 130.65 (CH); 132.93 (CH); 135.36 (C); 135.75 (C); 137.86 (C); 146.22 (C); 148.31 (C); 167.75 (C). Found, %: C 56.72; H 3.40; N 3.37; S 7.75. C20H15F2NO5S. Calculated, %: C 57.28; H 3.60; N 3.34; S 7.65. (+)-3-(Isobutyryloxy)methyl 4-[2-(Difluoromethoxy)phenyl]-2-methyl-5,5-dioxo-1,4-dihydrobenzothieno[3,2-b]pyridine-3-carboxylate ((+)-8). Yield 29 mg (34%) as a yellow powder from methanol water; mp 85-86C; 94% ee; []D20 +29.1 (c 1.0, acetone). 1H NMR (DMSO-d6, 200 MHz), , ppm (J, Hz): 0.92 (d, 3H, J = 6.9, CHCH3); 0.97 (d, 3H, J = 6.9, CHCH3); 2.39 (septet, 1H, J = 6.9, CH(CH3)2); 2.48 (s, 3H, CH3); 5.34 (s, 1H, CH); 5.62 (ABq, 2H, J = 5.8, OCH2O); 7.02 (t, 1H, JHF = 74.2, OCHF2); 7.07-7.32 (m, 4H, ArH); 7.60-8.09 (m, 4H, ArH); 9.99 (br. s, 1H, NH). 13C NMR spectrum (DMSO-d6, 50 MHz), , ppm (J, Hz): 18.00 (CH3); 18.04 (CH3); 18.69 (CH3); 29.90 (CH); 32.61(CH); 78.26 (CH2); 99.63 (C); 110.94 (C); 116.56 (CH); 116.75 (CH, t, JCF = 255.1 Hz, OCHF2); 120.38 (CH); 121.27 (CH); 125.02 (CH); 125.76 (C); 128.25 (CH); 129.87 (CH); 130.77 (CH); 133.03 (CH); 134.88 (C); 135.02 (C); 137.71 (C); 148.47 (C); 149.61(C); 164.50 (C); 174.58 (C). MS: 519 [M]+. Found, %: C 57.50; H 4.31; N 2.62; S 6.29. C25H23F2NO7S. Calculated, %: C 57.80; H 4.46; N 2.70; S 6.17. Financial support by NATO (Linkage grant LST.CLG 974948) and Programme 04.12 of the Latvian Council of Science is gratefully acknowledged.
936
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. H. Y. Aboul-Enein and I. W. Wainer, The Impact of Stereochemistry on Drug Development and Use, John Wiley & Sons, 1997, 728 pp. M. C. Hillier and P. J. Reider, Drug Discovery Today, 7, 303 (2002). M. Strong, Food Drug Law J., 54, 463 (1999). FDA, Chirality, 4, 338 (1992). CPMP, Note for Guidance: Investigation of Chiral Active Substances, III/3501/91 (1993). J. M. D. Daniels, E. R. Nestmann, and A. Kerr, Drug Inf. J., 31, 639 (1997). P. Baldrick, Drug Inf. J., 35, 99 (2001). S. Goldmann and J. Stoltefuss, Angew. Chem., Int. Ed. Engl., 30, 1559 (1991). Y. Tokuma and H. Noguchi, J. Chromatogr. A., 694, 181 (1995). X. K. Holdgrun and C. J. Sih, Tetrahedron Lett., 32, 3465 (1991). K. Achiwa and T. Kato, Curr. Org. Chem., 3, 77 (1999). A. Sobolev, M. C. R. Franssen, B. Vigante, B. Cekavicus, N. Makarova, G. Duburs, and Ae. de Groot, Tetrahedron Asymmetry, 12, 3251 (2001). A. Sobolev, M. C. R. Franssen, B. Vigante, B. Cekavicus, R. Zhalubovskis, H. Kooijman, A. L. Spek, G. Duburs, and Ae. de Groot, J. Org. Chem., 67, 401 (2002). A. Sobolev, M. C. R. Franssen, J. Poikans, G. Duburs, and Ae. de Groot, Tetrahedron Asymmetry, 13, 2389 (2002). R. R. Dubure, B. A. Vigante, J. J. Ozols, G. J. Dubur, and G. I. Rozentale, Khim. Geterotsikl. Soed., 1563 (1986). V. Petrow, J. Saper, and B. Sturgeon, J. Chem. Soc., 2134 (1949). R. R. Dubure, R. O. Vitolina, J. J. Ozols, G. J. Duburs, A. A. Kimenis, and G. V. Zarins, USSR Inventor's certificate 1018396; Chem. Abstr., 105, 191950 (1986). B. A. Vigante, J. J. Ozol, G. O. Sileniece, A. A. Kimenis, and G. J. Dubur, USSR Inventor's certificate 794006; Chem. Abstr., 95, 704 (1981). B. A. Vigante, J. J. Ozol, R. O. Vitolina, G. O. Sileniece, A. A. Kimenis, and G. J. Dubur, Ger. Offen. 2909852; Chem. Abstr., 94, 15579 (1981). E. A. Bisenieks, J. R. Uldrikis, G. J. Dubur, G. D. Tirzit, A. Z. Dauvarte, A. A. Zidermane, E. V. Ivanov, and T. V. Ponomareva, USSR Inventor's certificate 1050261; Chem. Abstr., 124, 333068 (1996). M. A. Mackanova and G. J. Vanag, Dokl. Akad. Nauk SSSR, 132, 615 (1960). A. Sobolev, M. C. R. Franssen, N. Makarova, G. Duburs, and Ae. de Groot, Tetrahedron Asymmetry, 11, 4559 (2000). M. Chudik, V. Mastihuba, and B. Decroix, Heterocycles, 48, 1943 (1998). C. S. Chen, Y. Fujimoto, G. Girdaukas, and C. J. Sih, J. Am. Chem. Soc., 104, 7294 (1982). J. A. Jongejan, J. B. A. van Tol, A. Geerlof, and J. A. Duine, Recl. Trav. Chim. Pays-Bas, 110, 247 (1991).
937
REACTIONS OF 2-AMINO-4-METHYL6-(2-PYRIDYL)- AND 2-AMINO-4-METHYL6-PHENYL-7,8-DIHYDROINDAZOLO[4,5-d]THIAZOLES WITH ALDEHYDES

I. Strakova, M. Petrova, and A. Strakovs The reaction of 2-amino-4-methyl-6-(2-pyridyl)-7,8-dihydroindazolo[4,5-d]thiazole, obtained by treating 3-methyl-4-oxo-1-(2-pyridyl)-4,5,6,7-tetrahydroindazole with pyridinium bromide perbromide and then with thiourea, and 2-amino-4-methyl-6-phenyl-7,8-dihydroindazolo[4,5-d]thiazole with 4-bromo-, 4-fluoro-, 4-dimethylamino-, 4-methoxy-, 3,4-dimethoxy-, and 3,4-methylenedioxybenzaldehydes, furfural, pyridinecarbaldehyde, and thiophenecarbaldehyde gave the corresponding Schiff bases. The products of the condensation of these aminothiazoles with cinnamaldehyde, 1-(2-pyridyl)- and 4-chloro-1-(2,4-difluorophenyl)-5-formyl-3-methyl-6,7-dihydroindazoles, 2-formyldimedone, and 2-formyl-1,3-indanedione were also obtained. Keywords: 2-amino-4-methyl-6-(2-pyridyl)- and 2-amino-4-methyl-6-phenyl-7,8-dihydroindazolo[4,5-d]thiazoles, aromatic aldehydes, 2-formyl-1,3-cyclanediones, Schiff bases. According to our previous work [1], we synthesized 2-amino-4-methyl-6-(2-pyridyl)-7,8dihydroindazolo[4,5-d]thiazole (3a) by means of the bromination of 3-methyl-4-oxo-1-(2-pyridyl)-4,5,6,7tetrahydroindazole (1a) using pyridinium bromide perbromide followed by the reaction of the 5-bromo derivative obtained (2a) with thiourea. Indazoles and benzthiazoles with hydrogenated carbocyclic systems as well as tricyclic condensed systems containing a hydrogenated indazole or benzthiazole fragment have recently been the subject of extensive study due to their biological activity [3-6]. In order to modify aminothiazoles 3, we carried out condensation with various types of aldehydes, including substituted benzaldehydes, pyridinecarbaldehyde, thiophenecarbaldehyde, furfural, and cinnamaldehyde. We also carried out condensation with 1-(2-pyridyl)- and 4-chloro-1-(2,4-difluorophenyl)-5-formyl-3-methyl-6,7-dihydroindazoles, 2-formyldimedone, and 2-formyl-1,3indanedione. 1 H NMR spectroscopy shows a signal for the primary amino group in 3a at 4.98 ppm, signals for the azomethine protons of Schiff bases 4 at 8.71-9.13 ppm, and for the azomethine proton in 5 at 9.16 ppm. The 1 H NMR spectra of the products of the condensation of amines 3 with 2-formyl-1,3-cyclanediones clearly show signals for protons of a trans-arranged aminomethylene structural fragment (=CH 8.42-8.52 ppm, 3J = 12 Hz, NH 11.36-11.39 ppm, 3J = 12 Hz). The chemical shifts of the protons of the other structural elements of 4-6 support the proposed structures. The carbonyl stretching band for -bromo ketone 2a is found in the IR spectrum at 1680 cm-1, while the primary amino group stretching bands for 3a are found at 3320 and 3410 cm-1. __________________________________________________________________________________________ Riga Technical University, Riga LV-1048, Latvia; e-mail: marina@osi.lv Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1089-1094, July, 2004. Original article submitted October 8, 2002. 938 0009-3122/04/4007-09382004 Springer Science+Business Media, Inc.
R N N O Me 1a,b Py, HBr . Br2 N Br O 2a,b Me N
H2NCSNH2 R N N S N N CH R1 4ar Me H2N 3a,b O R1 H S N Me N N R
R N N S N N Cl Me N N R1 5ac 6a,b CH Me O S N Me N N
R N N S N O Me
..
.H N
H O
..
.H N
H O
1-3, 6 a R = 2-Py; b R = Ph; 4 a-g R = 2-Py, h-r R = Ph; a R1 = Ph; b R1 = p-BrC6H4; c R1 = p-FC6H4; d R1 = 3-Py; e R1 = 2-furyl; f R1 = 2-thienyl; g R1 = PhCH=CH; h R1 = p-BrC6H4; i R1 = p-FC6H4; j R1 = p-Me2NC6H4; k R1 = p-MeOC6H4; l R1 = 3,4-(MeO)2C6H4; m R1 = 3,4-O(CH2)C6H3; n R1 = 3-Py; o R1 = 4-Py; p R1 = 2-furyl; q R1 = 2-thienyl; r R1 = PhCH=CH; 5 a, b R = Ph, c R = 2-Py, a R1 = 2,4-F2C6H3; b, c R1 = 2-Py
TABLE 1. Characteristics of Compounds 4-7

Compound 1 4a 4b 4c 4d Empirical formula 2 C21H17N5S C21H16BrN5S C21H16FN5S C20H16N6S Found, % Calculated, % N 4 5 4.60 4.61 3.52 3.58 4.20 4.14 4.30 4.33 18.92 18.86 17.61 17.74 17.83 17.98 22.44 22.57
mp, S 6 8.40 8.63 7 177-179 250-251 239-240 8.80 8.61 185-186
Yield, % 8 81 66 77 27
3 67.77 67.90 55.81 56.00 64.59 64.76 64.61 64.50
939
TABLE 1 (continued)
1 4e 4f 4g 4h 4i 4j 4k 4l 4m 4n 4o 4p 4q 4r 5a 5b 5c 6 6b 7 2 C19H15N5OS C19H15N5S2 C23H19N5S C22H17BrN4S C22H17FN4S2 C24H23N5S C23H20N4OS C24H22N4O2S C23H18N4O2S C21H17N5S C21H17N5S C20H16N4OS C20H16N4S2 C24H20N4S C30H23ClF2N6S C29H24ClN7S C28H23ClN8S C24H17N52S C25H18N42S C23H23N52S 3 63.01 63.14 60.33 60.45 69.40 69.50 58.61 58.80 67.90 68.02 69.61 69.70 68.84 68.97 66.80 66.95 66.52 66.65 67.71 67.90 67.77 67.90 66.73 66.64 63.70 63.80 72.77 72.70 62.68 62.88 64.80 64.73 62.31 62.39 65.42 65.59 68.36 68.48 63.60 63.72 4 4.14 4.18 3.95 4.01 4.77 4.82 3.76 3.81 4.38 4.41 5.64 5.61 4.89 5.03 5.08 5.15 4.30 4.38 4.48 4.61 4.55 4.61 4.42 4.48 4.35 4.28 4.95 5.08 4.00 4.03 4.45 4.50 4.34 4.30 3.79 3.90 4.09 3.14 5.30 5.35 5 19.30 19.38 18.50 18.56 17.75 17.62 12.32 12.47 14.31 14.42 16.80 16.94 14.06 13.99 13.03 13.01 13.40 13.52 18.66 18.86 18.69 18.86 15.65 15.55 14.80 14.88 14.02 14.13 14.55 14.67 18.10 18.22 20.71 20.79 15.82 15.94 12.62 12.78 16.11 16.16 6 8.90 8.87 17.20 16.99 8.20 8.07 7 184-185 211-212 187-188 192-193 198-200 7.60 7.75 8.10 8.01 7.50 7.45 7.60 7.74 8.50 8.63 8.70 8.63 8.80 8.90 16.80 17.03 7.90 8.09 216-217 174-175 163-164 183-185 176-177 202-205 164-165 168-169 176-178 213-215 173-176 261-263 7.20 7.29 7.20 7.31 7.50 7.40 300-305 272-273 224-225 8 94 56 75 44 51 29 25 47 24 41 27 84 66 50 53 74 83 74 81 93
TABLE 2. 1H NMR Spectra of Products

Compound 1 2 3 Chemical shifts, , ppm (SSCC, J, Hz)* 2 2.47 (2, m, 2); 2.53 (2, s, 3); 3.53 (2, m, 2); 4.46 (1, t, 3J = 3, ); 7.21 (1, m, Ar); 7.78-7.89 (2H, m, Ar); 7.91 (1H, dd, 3J = 5, 4J = 1.5, Ar) 2.51 (3, m, 3); 2.91 (2, t, 3J = 7, 2); 3.58 (2, t, 3J = 7, 2); 4.98 (2, br. s, N2); 7.02 (1, m, Ar); 7.71-7.91 (2H, m, Ar); 8.33 (1H, dd, 3J = 5, 4J = 1, Ar) 2.62 (3, s, 3); 3.09 (2, t, 3J = 7, 2); 3.64 (2, t, 3J = 7, 2); 7.07 (1, dd. d, 3J = 5, 3J = 6, 4J = 1, Ar); 7.02 (1, m, Ar); 7.38-7.91 (7H, m, Ar); 8.31 (1H, dd, 3J = 5, 4J = 1, Ar); 8.91 (1H, s, =CH) 2.62 (3, s, 3); 3.13 (2, t, 3J = 7, 2); 3.64 (2, t, 3J = 7, 2); 7.13 (1, m, Ar); 7.49-7.96 (6H, m, Ar); 8.36 (1H, dd, 3J = 5, 4J = 1.5, Ar); 8.93 (1H, s, =CH) 2.62 (3, s, 3); 3.09 (2, t, 3J = 7, 2); 3.64 (2, t, 3J = 7, 2); 7.09-7.85 (7H, m, Ar); 8.33 (1H, dd, 3J = 5, 4J = 1, Ar); 8.96 (1H, s, =CH) 2.58 (3, s, 3); 3.13 (2, t, 3J = 7, 2); 3.58 (2, t, 3J = 7, 2); 7.07-8.31 (7H, m, Ar); 8.64 (1H, d, 3J = 5, Ar); 9.02 (2H, s, =CH)
4b 4 4d
940
TABLE 2 (continued)
1 4e
3
2 2.61 (3, s, 3); 3.09 (2, m, 3J = 7, 2); 3.64 (2, m, 3J = 7, 2); 6.53 (1H, dd, J = 5, 4J = 1.5, Ar); 7.07 (2H, m, Ar); 7.60 (1H, d, 4J = 1.5, Ar); 7.71 (1H, dd, 3J = 7, 4 J = 1.5, Ar); 7.89 (1H, d, 3J = 8, Ar); 8.33 (1H, dd, 3J = 5, 4J = 1.5, Ar); 8.87 (1H, s, =CH) 2.61 (3, s, 3); 3.07 (2, t, 3J = 7, 2); 3.58 (2, t, 3J = 7, 2); 7.11-7.93 (6H, m, Ar); 8.33 (1H, dd, 3J = 5, 4J = 1.5, Ar); 9.08 (1H, s, =CH) 2.65 (3, s, 3); 3.09 (2, t, 3J = 7, 2); 3.64 (2, t, 3J = 7, 2); 7.13-7.86 (10H, m, Ar); 8.38 (1H, dd, 3J = 5, 4J = 1, Ar); 8.71 (1H, d, 3J = 8, =CH) 2.61 (3, s, 3); 3.02 (4, s, 22); 7.36 (5H, m, Ar); 7.51 (2H, m, 3J = 8, Ar); 7.82 (2H, m, 3J = 8, Ar); 8.89 (1H, s, =CH) 2.64 (3, s, 3); 3.09 (4, s, 22); 7.11-7.47 (7H, m, Ar); 7.91 (2H, m, Ar); 8.93 (1H, s, =CH) 2.62 (3, s, 3); 3.02 (4, s, 22); 3.06 (6, s, N(3)2); 6.62 (2H, m, 3J = 8, Ar); 7.38 (5H, m, Ar); 7.78 (2H, m, 3J = 8, Ar); 8.71 (1, s, =CH) 2.62 (3, s, 3); 3.02 (4, s, 22); 3.82 (3, s, 3); 6.89 (2H, m, 3J = 8, Ar); 7.38 (5H, m, Ar); 7.89 (2H, m, 3J = 8, Ar); 8.78 (1, s, =CH) 2.62 (3, s, 3); 3.04 (4, s, 22); 3.89 (3, s, O3); 3.94 (3, s, O3); 6.86 (1H, d, 3J = 8, Ar); 7.41 (6H, m, Ar); 7.62 (1H, d, 4J = 2, Ar); 8.81 (1, s, =CH) 2.58 (3, s, 3); 3.01 (4, s, 22); 5.96 (2, s, 2); 6.82 (2H, m, 3J = 8, Ar); 7.36-7.51 (6H, m, Ar); 8.78 (1, s, =CH) 2.62 (3, s, 3); 3.09 (4, s, 22); 7.38 (6, m, Ar); 8.29 (1H, d. t, 3J = 8, 4J = 1.5, Ar); 8.69 (1H, dd, 3J = 5, 4J = 1.5, Ar); 9.01 (1H, d, 4J = 1.5, Ar); 9.04 (1, s, =CH) 2.62 (3, s, 3); 3.13 (4, s, 22); 7.42 (5, m, Ar); 7.81 (2H, m, 3J = 5, Ar); 8.69 (2H, m, 3J = 5, Ar); 9.06 (1H, s, =CH) 2.58 (3, s, 3); 3.04 (4, s, 22); 6.56 (1, dd, 3J = 4, 4J = 2, Ar); 7.07 (1H, d, 3 J = 4, Ar); 7.12-7.47 (5H, m, Ar); 7.61 (1H, d, 4J = 2, Ar); 8.91 (1H, s, =CH) 2.58 (3, s, 3); 3.02 (4, s, 22); 7.07-7.58 (8H, m, Ar); 9.07 (1H, s, =CH) 2.42 (3, s, 3); 3.04 (4, s, 22); 7.16-7.53 (12H, m, Ar, 2=CH); 8.71 (1H, d, 3J = 9, =CH) 2.51 (3, s, 3); 2.62 (4, s, 22); 2.63-3.02 (4, m, 22); 3.04 (3, s, 3); 6.91-7.49 (8H, m, Ar); 9.16 (1H, s, =CH) 2.49 (3, s, 3); 2.58 (3, s, 3); 2.96 (4, s, 22); 2.98-3.38 (4, m, 22); 7.13-7.91 (8H, m, Ar); 8.36 (1H, dd, 3J = 5, 4J = 1.5, Ar); 9.16 (1, s,=CH) 2.53 (3, s, 3); 2.62 (3, s, 3); 3.01-3.71 (8, m, 42); 7.13 (3H, m, Ar); 7.82 (4H, m, Ar); 8.36 (2H, m, Ar); 9.16 (1H, s, =CH) 2.61 (3, s, 3); 3.04 (2, t, 3J = 7, CH2); 3.64 (2, t, 3J = 7, 2); 7.11 (1H, m, Ar); 7.82 (6H, m, Ar); 8.35 (1H, m, Ar); 8.42 (1, d, 3J = 12, =CH); 11.36 (1H, d, 3J = 12, NH) 2.63 (3, s, 3); 3.08 (4, s, 2CH2); 7.43-7.78 (9H, m, Ar); 8.52 (1H, d, 3J = 12, =CH); 11.39 (1H, d, 3J = 12, NH) 1.02 (6, s, 23); 2.36 (2, s, 2); 2.38 (2, s, 2); 2.51 (3, s, 3); 3.04 (2, t, 3J = 7, CH2); 3.62 (2, t, 3J = 7, 2); 7.04 (1, dd. d, 2J = 5, 3J = 7, 4J = 1.5, Ar); 7.69 (1, d. t, 3J = 7, 4J = 1.5, Ar); 7.89 (1, dd, 3J = 7, 4J = 1.5, Ar); 8.31 (1, dd, 3J = 5, 4J = 1.5, Ar); 8.67 (1H, d, 3J = 13, =H); 12.16 (1H, d, 3J = 13, NH)
4f 4g 4h 4i 4j 4k 4l 4m 4n 4 4p 4q 4r 5 5b 5 6
6b 7
_______ * The 1H NMR spectra of 4e, 4i, 4l, 4p, and 4q were taken in DMSO-d6, the spectra of the other compounds were taken in CDCl3.
EXPERIMENTAL The 1H NMR spectra were taken on a Bruker WH-90/DS at 90 MHz using TMS as the internal standard. The IR spectra were taken on a Specord IR-75 spectrometer for suspensions in vaseline oil at 1800-1500 cm-1 and in hexachlorobutadiene at 3600-2000 cm-1. The aldehyde samples used were supplied by Acros. The characteristics of 4-7 are given in Tables 1 and 2. 941
Our previous procedure [2] was used to prepare 1a, while 2-amino-6-phenyl-7,8-dihydroindazolo[4,5-d]thiazole was prepared by a procedure described in our earlier work [1]. 5-Bromo-3-methyl-4-oxo-1-(2-pyridyl)-4,5,6,7-tetrahydroindazole (2a). A solution of pyridinium bromide perbromide (3.20 g, 10 mmol) in acetic acid (50 ml) was added to a solution of indazole 1a (2.27 g, 10 mmol) in acetic acid (30 ml) and heated at reflux for 20 min. Then, water (100 ml) was added to the hot reaction mixture. The tarry product, which rapidly solidifies, was filtered off and recrystallized from 2:1 ethanolwater to give 1.71 g (56%) of 2a; mp 121-122C. IR spectrum, , cm-1: 1680 (C=O). Found, %: C 51.11; H 4.02; Br 25.90; N 13.55. C13H12BrN3O. Calculated, %: C 51.00; H 3.95; Br 26.10; N 13.73. 2-Amino-4-methyl-6-(2-pyridyl)-7,8-dihydroindazolo[4,5-d]thiazole (3a). A mixture of bromoketone 2a (1.54 g, 5 mmol) and thiourea (0.38 g, 5 mmol) in ethanol (40 ml) was heated at reflux for 14 h and then cooled. Water (80 ml) and concentrated ammonium hydroxide (2 ml) was added. The precipitate formed was filtered off and recrystallized from 2:1 ethanolwater to give 1.02 g (72%) of 3a; mp 106-108C. IR spectrum, , cm-1: 3320, 3410 (NH). Found, %: C 59.22; H 4.50; N 24.60; S 11.20. C14H13N5S. Calculated, %: C 59.34; H 4.62; N 24.72; S 11.32. 2-Benzalamino(4a), 2-(4-Bromobenzal)amino(4b), 2-(4-Fluorobenzal)amino(4c), 2-(3-Pyridylmethylene)amino- (4d), 2-(2-Furylmethylene)amino- (4e), 2-(2-Thienylmethylene)amino- (4f), 2-(3-Phenyl-2-propen-1-ylidene)amino- (4g) 4-methyl-6-(2-pyridyl)-7,8-dihydroindazolo[4,5-d]thiazoles, 2-(4-Bromobenzal)amino- (4h), 2-(4-Fluorobenzal)amino- (4i), 2-(4-Dimethylaminobenzal)amino- (4j), 2-(4-Methoxybenzal)amino- (4k), 2-(3,4-Dimethoxybenzal)amino- (4l), 2-(3,4-Methylenedioxybenzal)amino- (4m), 2-(3-Pyridylmethylene)amino- (4n), 2-(4-Pyridylmethylene)amino- (4o), 2-(2-Furylmethylene)amino- (4p), 2-(2-Thienylmethylene)amino- (4q), and 2-(3-Phenyl-2-propen-1-ylidene)amino(4r) 4-methyl-6-phenyl-7,8-dihydroindazolo[4,5-d]thiazoles. Hot solutions of the corresponding aminothiazole (3a or 3b) (2 mmol) in ethanol (20 ml) and an equimolar amount of aldehyde in ethanol (10 ml) were combined and heated at reflux for 4 h. The reaction mixture was left for 24 h in a refrigerator. The precipitate of 4 was filtered off and recrystallized, 4a,d,k-r from ethanol, 4b,c,h-j from DMF,and 4e-g from ethanolDMF. 2-[4-Chloro-1-(2,4-difluorophenyl)-3-methyl-6,7-dihydroindazol-5-yl]methyleneamino-4-methyl-6phenyl- (5a), 2-[4-Chloro-3-methyl-1-(2-pyridyl)-6,7-dihydroindazol-5-yl]methyleneamino-4-methyl-6phenyl- (5b), and 2-[4-Chloro-3-methyl-1-(2-pyridyl)-6,7-dihydroindazol-5-yl]methylenamino-4-methyl-6(2-pyridyl)- (5c) 7,8-dihydroindazolo[4,5-d]thiazoles. Hot solutions of the corresponding amine 3 and 1-substituted 4-chloro-5-formyl-3-methyl-6,7-dihydroindazole [7] were combined and heated at reflux for 1 h. The reaction mixtures were left stand in a refrigerator for 24 h, filtered off and recrystallized, 5b,c from DMF and 5a from ethanolDMF. 2-[4-Methyl-6-(2-pyridyl)- (6a) and 2-[4-Methyl-6-phenyl- (6b) indazolo[4,5-d]thiazol-2-yl]aminomethylene-1,3-indanediones, 2-[4-Methyl-6-(2-pyridyl)indazolo[4,5-d]thiazol-2-yl]aminomethylene-5,5dimethyl-1,3-cyclohexanedione (7). Hot solutions of corresponding amine 3 and 2-formyl-1,3cyclohexanedione were combined and heated at reflux for 10-15 min. The reaction mixtures were cooled and filtered. Diones 6a,b were obtained by recrystallization from DMF, while dione 7 was obtained by recrystallization from ethanolDMF.
REFERENCES 1. 2. 3. I. A. Strakova, A. Ya. Strakov, and M. V. Petrova, Khim. Geterotsikl. Soedin., 497 (1996). I. A. Strakova, A. Ya. Strakov, and M. V. Petrova, Latv. J. Chem., 733 (1994). G. A. Nishiguchi, A. L. Rodriguez, and J. A. Katzenellenbogen, Bioorg. Med. Chem. Lett., 12, 947 (2002).
942
4. 5. 6. 7.
M. D. Chordia, L. J. Murphree, T. L. Macdonald, J. Linden, and R. A. Olsson, Bioorg. Med. Chem. Lett., 12, 1563 (2002). R. Faure, A. Frideling, J.-P. Galy, J. Alkorta, and J. Elguero, Heterocycles, 57, 307 (2002). V. Colotta, D. Catarzi, F. Varano, L. Cecchi, G. Filacchioni, C. Martini, L. Trincavelli, and A. Lucacchini, J. Med. Chem., 43, 3118 (2000). I. A. Strakova, L. G. Delyatitskaya, M. V. Petrova, and A. Ya. Strakov, Khim. Geterotsikl. Soedin., 768 (1998).
943
10-ARYL-7,7-DIMETHYL-5,6,7,8,9,10-HEXAHYDRO11H-PYRIDO[3,2-b][1,4]BENZODIAZEPIN-9-ONES
N. N. Tonkikh, A. Strakovs, and M. V. Petrova In reactions of 3-(2-amino-3-pyridyl)amino-5,5-dimethylcyclohex-2-en-1-one with aromatic aldehydes (2- and 4-hydroxy-, 2-hydroxy-3-methoxy-, 4-dimethylamino-, 4-methoxy-, 2,4- and 3,4-dimethoxy-, 3,4-methylenedioxy-, 4-bromo-, 4-fluoro-, 4-chloro-, 2-nitro- and 3-nitrobenzaldehydes, furfural, and 2-thiophenecarbaldehyde), we have obtained the corresponding 10-aryl-7,7-dimethyl-5,6,7,8,9,10hexahydro-11H-pyrido[3,2-b][1,4]benzodiazepin-9-ones. Keywords: aromatic aldehydes, 2,3-diaminopyridine, dimedone, pyrido[3,2-b][1,4]benzodiazepine derivatives. Our attempts to synthesize derivatives of hydrogenated pyrido[3,2-b][1,4]- or pyrido[2,3-b][1,4]benzodiazepines by reactions of 2,3-diaminopyridine (1) with 2-formyldimedone [1] and 2-carbamidodimedone [2] did not lead to the indicated type of compounds. In this paper, we describe the reactions of 3-(2-amino-3-pyridyl)amino-5,5-dimethylcyclohex-2-en-1one with aromatic aldehydes, which lead to synthesis of 10-aryl-7,7-dimethyl-5,6,7,8,9,10-hexahydro-11Hpyrido[3,2-b][1,4]benzodiazepin-9-ones. Such a general scheme (reaction of enamines, obtained from 1,3-cyclohexanediones, and aromatic o-diamines with aldehydes) has been widely used for synthesis of derivatives of dibenzodiazepine [3-7] and also pyridobenzodiazepine [8], among which the pyrido[2,3-b][1,4]benzodiazepine derivatives have the most valuable pharmacological properties [9-11].
O NH2 N 1 H N N NH2 4 O NH2 HO NH2 N O 2 ArCHO 5ao N N H H N N H 3
O Ar 6ao
5, 6 a Ar = 2-HOC6H4; b Ar = 4-C6H4; c Ar = 2--3-MeOC6H3; d Ar = 4-Me2NC6H4; e Ar = 4-MeOC6H4; f Ar = 2,4-(MeO)2C6H3; g Ar = 3,4-(MeO)2C6H3; h Ar = 3,4-CH2O2C6H3; i Ar = 4-BrC6H4; j Ar = 4-ClC6H4; k Ar = 4-FC6H4; l Ar = 2-O2NC6H4; m Ar = 3-O2NC6H4; n Ar = 2-C4H3O; o Ar = 2-C4H3S
__________________________________________________________________________________________ Riga Technical University, Riga LV-1048, Latvia; e-mail: marina@osi.lv. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1095-1100, July, 2004. Original article submitted March 13, 2001; revision submitted September 29, 2003. 944 0009-3122/04/4007-09442004 Springer Science+Business Media, Inc.
In the reaction of 2,3-diaminopyridine (1) with dimedone 2, two isomeric enamines 3 and 4 can be formed. We know [8] that when diamine 1 reacts with 1,3-cyclohexanedione, the product of reaction at the 3-amino group is obtained. In the reaction under discussion of diamine 1 with dimedone, carried out under conditions for azeotropic distillation of water, only one compound is isolated from the reaction mixture and identified. Based on 1H NMR spectra, we have assigned this compound the structure of 3-(2-amino-3-pyridyl)amino-5,5-dimethylcyclohex-2-en-1-one (4). We identified enamine 4 by comparing its spectra with the 1 H NMR spectra of 3-(2-amino-3-pyridyl)aminocyclohex-2-en-1-one [8]. The chemical shifts and spinspin coupling constants in the spectra of both these compounds virtually coincide: the differences between their chemical shifts () are 0.07 ppm for the NH2 group and 0.06 ppm for the =CH group. The maximum chemical shift difference is observed for the C(3)H protons of the pyridine moiety of the molecule ( = 0.12 ppm), where the chemical shift values for the C(2)H protons ( = 0.05 ppm) and C(3)H protons ( = 0.03 ppm) are virtually the same in both compounds, while the spinspin coupling constants (3JH,H = 5 Hz, 3JH,H = 7.5 Hz) match within the experimental accuracy limits. In the spectra of both of the compared compounds, we observe a strongly broadened signal from the NH proton relatively upfield at ~7.3 ppm. Chromatographic data for the reaction mixture after isolation of enamine 4 suggest the presence of four more compounds in the mixture, probably also including enamine 3, which unfortunately we could not isolate. We carried out the reaction of enamine 4 with aldehydes 5a-d, containing the functional groups [OH, N(CH3)2], by boiling equimolar amounts of the reagents in ethanol in the presence of piperidine acetate. We used the same conditions in the reactions of enamine 4 with furfural 5n and 2-thiophenecarbaldehyde 5o. In the

Compound 4 6a 6b 6 6d 6e 6f 6g 6h 6i 6j 6k 6l 6m 6n 6o Empirical formula C13H17N3O C20H21N3O2 C20H21N3O2 C21H23N3O3 C22H26N4O C21H23N3O2 C22H25N3O3 C22H25N3O3 C21H21N3O3 C20H20BrN3O C20H20ClN3O C20H20FN3O C20H20N4O3 C20H20N4O3 C18H19N3O2 C18H19N3OS Found, % Calculated, % H N 7.49 7.41 6.16 6.31 6.33 6.31 6.16 6.34 6.49 6.64 6.69 6.63 6.60 6.64 6.73 6.64 5.70 5.83 5.01 5.06 5.56 5.70 6.04 5.98 5.50 5.53 5.39 5.53 6.03 6.19 5.80 5.88 18.10 18.17 12.60 12.53 12.42 12.53 11.42 11.50 14.14 14.20 11.91 12.03 11.11 11.07 10.93 11.07 11.60 11.56 10.66 10.55 11.72 11.88 12.33 12.45 15.27 15.38 15.19 15.38 13.42 13.58 12.73 12.91
mp, Hal (S) 223-224 252-253 291-292 243-244 252-253 197-198 213-215 126-127 233-234 19.90 20.06 9.80 10.02 237-239 249-251 237-238 196-197 179-181 244-245 (9.60) (9.85) 271-272
Yield, %
67.30 67.50 71.44 71.62 71.50 71.62 69.19 69.02 66.81 66.98 72.01 72.18 69.42 69.63 69.50 69.63 69.21 69.40 60.11 60.31 67.71 67.89 71.01 71.20 65.70 65.92 65.77 65.92 69.65 69.88 66.26 66.43
26 82 70 47 70 38 43 60 66 62 38 73 73 77 74 83
945
TABLE 2. IR and 1H NMR Spectra of Synthesized Compounds

Compound 1 4 IR spectrum, , cm-1 2 1666, 1595, 1570, 550-1530; 3400, 3350, 3250-3100 1645; 3350-3250; 3200-3080
1
NMR spectrum, , ppm. (SSCC, J, Hz)* 3
6a
6b
1642; 3450-3200; 3150-3050 1645; 3300-3200; 3150-3050
6c
6d
1638; 3300, 3200; 3150-3050
6e
1640; 3300, 3200-3100
6f
1645;3350, 3250-3100
6g
1644; 3350, 3260, 3200-3100
6h
1638; 3300, 3200-3050
6i
1638; 3300, 3200-3050
6j
1638; 3300, 3240-3080
6k
1645; 3300, 3250-3100
1.03 (6H, s, 2CH3); 2.18 (2H, s, CH2); 2.36 (2H, s, CH2); 4.71 (2H, br. s, NH2); 5.09 (1H, s, =CH-); 6.64 (1H, dd, 3J = 7.5, 4 J = 5, 53N); 7.30 (1H, br. s, NH); 7.38 (1H, dd, 3J = 7.5, 4J = 2, 53N); 7.87 (1H, dd, 3J = 5, 4J = 2, 53N) 1.03 (3H, s, CH3); 1.14 (3H, s, CH3); 2.11 and 2.17 (2H, two d, 2 J = 14, CH2); 2.69 (2H, s, CH2); 5.81 (1H, d, 3J = 6, CH); 6.00 (1H, d, 3J = 6, NH); 6.41-6.96 (6H, m, 64, 53N); 7.25 (1H, dd, 3J =7, 4J = 2, 53N); 7.56 (1, dd, 3J = 5, 4J = 2, C5H3N); 8.94 (1H, br. s, ); 9.76 (1, br. s, NH) 0.95 (3H, s, CH3); 1.14 (3H, s, CH3); 2.12 and 2.20 (2H, two d, 2 J = 14, CH2); 2.55 (2H, s, CH2); 5.74 (1H, d, 3J = 6, CH); 6.49-7.72 (8H, m, 64, 53N, NH); 7.77 (1H, br. s, N); 9.14 (1H, br. s, ) 1.05 (3H, s, CH3); 1.12 (3H, s, CH3); 2.12 and 2.20 (2H, two d, 2 J = 14, CH2); 2.67 (2H, s, CH2); 3.76 (3H, s, OCH3); 5.77 (1H, d, 3 J = 6, NH); 6.05 (1, d, 3J = 6, ); 6.25-6.81 (4H, m, 63, 53N); 7.34 (1H, dd, 3J = 7, 4J = 1.5, 53N); 7.58 (1H, dd, 3J = 7, 4 J = 1.5, 53N); 8.96 (1, br. s, NH); 9.03 (1H, br. s, OH) 1.01 (3H, s, CH3); 1.12 (3H, s, CH3); 2.15 and 2.21 (2H, two d, 2 J = 16, CH2); 2.54 (2H, s, CH2); 2.81 (6H, s, NCH3); 5.77 (1H, d, 3 J = 6, H); 6.46-6.78 (4H, m, 64, 53N, NH); 7.03 (2H, m, 3 J = 8, 64); 7.27 (1, dd, 3J = 7, 4J = 1.5, 53N); 7.65 (1H, dd, 3 J = 5, 4J = 1.5, 53N); 7.78 (1, br. s, NH) 1.01 (3H, s, CH3); 1.12 (3H, s, CH3); 2.13 and 2.21 (2H, two d, 2 J = 14, CH2); 2.58 (2H, s, CH2); 3.67 (3H, s, OCH3); 5.76 (1H, d, 3 J = 6, H); 6.58-7.27 (6H, m, 64, 53N, NH); 7.27 (1, dd, 3 J = 7, 4J = 1.5, 53N); 7.63 (1H, dd, 3J = 5, 4J = 1.5, 53N); 7.87 (1, br. s, NH) 1.01 (3H, s, CH3); 1.09 (3H, s, CH3); 2.14 and 2.22 (2H, two d, 2 J = 15, CH2); 2.56 (2H, s, CH2); 3.58 (3H, s, OCH3); 3.65 (3, s, 3); 5.76 (1H, d, 3J = 6, =H-); 6.54 (5H, m, 63, 53N, NH); 7.25 (1, dd, 3J = 7, 4J = 1.5, 53N); 7.63 (1H, dd, 3J = 5, 4J = 1.5, 53N); 8.81 (1, br. s, NH) 1.03 (3H, s, CH3); 1.12 (3H, s, CH3); 2.12 and 2.20 (2H, two d, 2 J = 15, CH2); 2.63 (2H, s, CH2); 3.67 (3H, s, OCH3); 3.91 (3, s, O3); 5.72 (1H, d, 3J = 6, NH); 5.83 (1H, d, 3J = 6, ); 6.21-6.75 (4H, m, 63, 53N); 7.27 (1H, m, 3J = 8, 63); 7.58 (1, dd, 3J = 5, 4J = 1, 53N); 8.92 (1, br. s, NH) 1.01 (3H, s, CH3); 1.12 (3H, s, CH3); 2.15 and 2.21 (2H, two d, 2 J = 16, CH2); 2.58 (2H, s, CH2); 5.74 (1H, d, 3J = 6, H); 5.94 (2, s, 2); 6.58-6.82 (5H, m, 63, 53N, NH); 7.27 (1H, dd, 3J = 7, 4J = 1.5, 53N); 7.67 (1, dd, 3J = 5, 4J = 1.5, 53N); 8.85 (1, br. s, NH) 0.98 (3H, s, CH3); 1.09 (3H, s, CH3); 2.12 and 2.20 (2H, two d, 2 J = 14, CH2); 2.56 (2H, s, CH2); 5.78 (1H, d, 3J = 6, H); 6.67 (1, dd, 3J = 7, 3J = 5, 53N); 6.87 (1H, d, 3J = 6, NH); 7.04-7.45 (5H, m, 64, 53N, NH); 7.67 (1H, dd, 3J = 5, 4J = 2, 53N); 8.89 (1, br. s, NH) 1.03 (3H, s, CH3); 1.09 (3H, s, CH3); 2.14 and 2.22 (2H, two d, 2 J = 15, CH2); 2.65 (2H, s, CH2); 5.83 (1H, d, 3J = 6, H); 6.62 (1, dd, 3J = 7, 3J = 5, 53N); 6.85 (1H, d, 3J = 6, NH); 7.18-7.34 (5H, m, 64, 53N); 7.69 (1H, dd, 3J = 5, 4J = 1.5, 53N); 8.92 (1, br. s, NH) 1.01 (3H, s, CH3); 1.11 (3H, s, CH3); 2.14 and 2.22 (2H, two d, 2 J = 14, CH2); 2.55 (2H, s, CH2); 5.83 (1H, d, 3J = 6, H); 6.58-7.33 (7, m, 64, 53N, NH); 7.67 (1, dd, 3J = 5, 4J = 1.5, 53N); 8.89 (1, br. s, NH)
946
TABLE 2 (continued)
1 6l 2 1640; 3350, 3250-3100 1643; 3300, 3240-3080
2 3
3 0.98 (3H, s, CH3); 1.09 (3H, s, CH3); 2.06 and 2.14 (2H, two d, J = 14, CH2); 2.67 (2H, s, CH2); 5.78 (1H, d, 3J = 6, NH); 6.07 (1H, d, J = 6, ); 6.78-8.06 (7, m, 64, 53N); 8.89 (1, br. s, NH) 1.01 (3H, s, CH3); 1.14 (3H, s, CH3); 2.21 and 2.29 (2H, two d, 2 J = 15, CH2); 2.63 (2H, s, CH2); 6.09 (1H, br. s, ); 6.89 (1, dd, 3 J = 7, 3J = 5, 53N); 7.49-8.12 (7, m, 64, 53N, NH); 9.25 (1, br. s, NH) 0.96 (3H, s, CH3); 1.07 (3H, s, CH3); 2.11 and 2.17 (2H, two d, 2 J = 16, CH2); 2.51 (2H, s, CH2); 5.81 (1H, d, J = 6, CH); 5.82 (1, m, 43O); 6.14 (1H, m, 43O); 6.67 (2H, m, C5H3N, NH); 7.29-7.42 (2H, m, 4H3O, C5H3N); 7.72 (1, dd, 3J = 5, 4 J = 1, C5H3N); 8.88 (1, br. s, NH) 0.99 (3H, s, CH3); 1.05 (3H, s, CH3); 2.12 and 2.20 (2H, two d, 2 J = 14, CH2); 2.55 (2H, s, CH2); 6.03 (1H, d, 3J = 6, CH); 6.58-6.92 (4, m, 53N, C4H3S); 7.14-7.34 (2H, m, 5H3N, C4H3S); 7.69 (1H, dd, 3J = 5, 4J = 1.5, C5H3N); 8.89 (1, br. s, NH)
6m
6n
1635; 3320, 3200-3050
6o
1637; 3350, 3220-3080
_______ * The 1H NMR spectrum of compound 4 was recorded in CDCl3; the spectra for the rest of the compounds were recorded in DMSO-d6.
reactions with the aldehydes 5e-m, the best results were achieved by boiling in ethanol in the presence of sulfuric acid. In the 1H NMR spectra of the derivatives of pyridodiazepine 6, the proton at the C(10) atom is characterized by a doublet 5.74-6.09 ppm (J = 6 Hz), and the proton at the adjacent N(11) atom gives a doublet 5.72-6.87 ppm (J = 6 Hz). The protons of the methylene group at C(8) are magnetically nonequivalent and coupled (geminal spinspin coupling constant 14-16 Hz), representing an AB spin system. In the IR spectra, the carbonyl group of compounds 6 is characterized by absorption bands in the interval 1645-1635 cm-1, while the stretching vibrations of the NH bonds are intense bands in the 3350-3100 cm-1 region.
EXPERIMENTAL The IR spectra were taken on a Specord IR-75 for suspensions of the compounds in vaseline oil (1800-1500 cm-1, only the absorption bands for the carbonyl group are given) and in hexachlorobutadiene (36002000 cm-1, the stretching vibration bands for the CH bonds in the 3050-2800 cm-1 region are not given). The 1 H NMR spectra were measured on Bruker WH-90/DS (90 MHz) and Varian-BB Mercury (200 MHz) spectrometers, internal standard HMDS ( 0.055 ppm) We used Fluka 2,3-diaminopyridine for synthesis of enamine 4. 3-(2-Amino-3-pyridyl)amino-5,5-dimethylcyclohex-2-en-1-one (4). A solution of dimedone (2.80 g, 20 mmol) and 2,3-diaminopyridine (2.18 g, 20 mmol) in toluene (100 ml) in the presence of a catalytic amount of p-toluenesulfonic acid was boiled for 3 h with a DeanStark attachment. Then the toluene was distilled off under vacuum and dry THF (30 ml) was added to the residue. The solution obtained was held for 24 hours in a refrigerator; the precipitate was filtered out and recrystallized one more time from THF. Enamine 4 (1.20 g, 26%) was obtained. 10-(2-Hydroxyphenyl)- (6a), 10-(4-Hydroxyphenyl)- (6b), 10-(2-Hydroxy-3-methoxyphenyl)- (6c), 10-(4-Dimethylaminophenyl)- (6d), 10-(2-Furyl)- (6n), and 10-(2-Thiophenyl)- (6o) 7,7-dimethyl5,6,7,8,9,10-hexahydro-11H-pyrido[3,2-b][1,4]benzodiazepin-9-ones. A solution of enamine 4 (1.5 mmol), 947
the corresponding aldehyde 5 (1.5 mmol), glacial CH3COOH (0.15 ml), and piperidine (0.20 ml) in ethanol (15 ml) was boiled for 3 h. The reaction mixture was poured into crushed ice to cool down. When a tarry residue was formed, it was triturated until it solidified; the precipitate formed was filtered out, and the compounds 6a,c,d,n,o were recrystallized from ethanol and the diazepinone 6b was recrystallized from 2-propanol. 10-(4-Methoxyphenyl)- (6e), 10-(2,4-Dimethoxyphenyl)- (6f), 10-(3,4-Dimethoxyphenyl)- (6g), 10-(3,4-Methylenedioxyphenyl)(6h), 10-(4-Bromophenyl)(6i), 10-(4-Chlorophenyl)(6j), 10-(4-Fluorophenyl)- (6k), 10-(2-Nitrophenyl)- (6l), and 10-(3-Nitrophenyl)- (6m) 7,7-dimethyl5,6,7,8,9,10-hexahydro-11H-pyrido[3,2-b][1,4]benzodiazepin-9-ones. A solution of enamine 4 (1.5 mmol), the corresponding aldehyde 5 (1.5 mmol), and conc. H2SO4 (0.15 ml) in ethanol (15 ml) was boiled for 3 h. Then the solvent (7-10 ml) was distilled off under vacuum. The residue was poured into crushed ice and an aqueous KOH solution was added until pH 7 was achieved; after 24 hours, the precipitate was filtered out and compounds 6e-g,j-m were recrystallized from 2-propanol, the diazepinone 6h was recrystallized from ethanol, and the diazepinone 6i was recrystallized from dioxane.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. A. Strakovs, M. V. Petrova, N. N. Tonkikh, E. E. Brooks, S. J. Biehle, and G. P. Kreishman, J. Org. Chem., 64, 1462 (1999). N. N. Tonkikh, A. Strakovs, M. V. Petrova, V. V. Chernyshev, and H. Schenk, Khim. Geterotsikl. Soedin., 822 (2002). R. Martinez, E. Angeles, and F. Martinez, Heterocycl. Commun., 2, 47 (1996). N. Rashed, M. Sayed, and E. S. H. El-Ashry, J. Chin. Chem. Soc., 40, 189 (1993); Chem. Abstr. 119, 139194 (1993). E. J. J. Vanden, A. Mayence, A. Magnestian, and E. Andrs, Bull. Soc. Chim. Belg., 101, 801 (1992). M. A. Lukhate and P. S. Fernandes, J. Indian Chem. Soc., 67, 609 (1990). S. Miyano and N. Abe, Chem. Pharm. Bull., 20, 1588 (1972). Y. Blache, M. Hichour, G. Di Blasi, J.-M. Chezal, H. Viols, O. Chavignon, J.-C. Taulade, and J.-P. Chapat, Heterocycles, 51, 1003 (1999). T. Watanabe, I. Kinoyama, K. Takizawa, S. Hirano, and T. Shibanuma, Chem. Pharm. Bull., 47, 672 (1999). T. Watanabe, I. Kinoyama, A. Kakefuda, T. Okazaki, K. Takizawa, S. Hirano, H. Shibata, and I. Yanagisawa, Chem. Pharm. Bull., 45, 996 (1997). F. X. Woolard, J. Paetsch, and J. A. Ellman, J. Org. Chem., 62, 6102 (1997).
948
11-ARYL-3,3-DIMETHYL-7- AND 7,8-SUBSTITUTED 1,2,3,4,10,11-HEXAHYDRO5H-DIBENZO[b,e]-1,4-DIAZEPIN-1-ONES

N. N. Tonkikh, A. Strakovs, K. V. Rizhanova, and M. V. Petrova In reactions of 3-(5- and 5,6-substituted 2-aminophenylamino)-5,5-dimethylcyclohex-2-en-ones with carbaldehydes of pyridine, thiophene, and furan and substituted benzaldehydes, we have obtained 21 novel 7H-7-methoxycarbonyl-, 7-benzoyl-, 7-trifluoromethyl-, 7-nitro- and 7,8-dichloro-11-aryl-3,3dimethyl-1,2,3,4,10,11-hexahydro-5H-dibenzo[b,e]-1,4-diazepin-1-one. Keywords: dimedone, substituted 1,2-phenylenediamines, pyridine-, thiophene-, furancarbaldehydes, dibenzo[b,e]-1,4-diazepine derivatives. Modification of dibenzo[b,e]-1,4-diazepines is part of extensive research on synthesis of derivatives of tricyclic systems including a 1,4-diazepine moiety, among which pyrido[2,3-b]benzo[e]-1,4-diazepines and dipyrido[3,2-b:2,3-e]-1,4-diazepines are key derivatives according to the criterion of pharmacological value [1-11]. In an extension of [12], in this study we obtained dibenzo[e]-1,4-diazepines by the method used in [13-16]: reaction of 3-(2-aminophenylamino)-5,5-dimethylcyclohex-2-en-1-ones with pyridine-, thiophene-, furancarbaldehydes and substituted benzaldehydes. By boiling 1,2-phenylenediamines 1a-f with dimedone 2 in toluene in the presence of catalytic amounts of p-toluenesulfonic acid under conditions for azeotropic distillation of water, we obtained (2-aminophenyl)aminocyclohexenes 3a-f. When using 5-substituted 1,2-phenylenediamines 1b-e, two isomeric enaminones could be formed. In the 1H NMR spectra of the latter, we observe a broadened two-proton signal from the primary amino group in the 3.76-5.81 ppm region, one six-proton singlet from the methyl groups and two two-proton singlets from the CH2 groups of the dimedone moiety. The proton at the C(2) atom absorbs in the interval 4.65-5.07 ppm, while the enamine NH proton absorbs downfield at 7.56-8.23 ppm. The spatial proximity of the enamine NH and aromatic C(6)H protons is proven based on 1H NMR difference spectroscopy (NOE), which made it possible to choose in favor of the structures 3b-e. The reaction of enamines 3a-f with substituted benzaldehydes, 2-, 3-, 4-pyridinecarbaldehydes, 2-thiophenecarbaldehyde (4a-j) was carried out by boiling in ethanol in the presence of catalytic amounts of H2SO4, while the reaction with furfural 4k was carried out in the presence of piperidine acetate. The structure of the dibenzodiazepines in 5a-u was confirmed by IR and 1H NMR spectra. In the 1 H NMR spectra, the methyl groups of the dimedone moiety are magnetically nonequivalent, and are detected as two three-proton singlets in the 0.98-1.05 ppm range. The protons from one of the methylene groups are also magnetically nonequivalent in some diazepines 5, and their absorption is represented by an AB spin system with geminal constant 16-18 Hz. __________________________________________________________________________________________ Riga Technical University, Riga LV-1048, Latvia; e-mail: marina@osi.lv. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1101-1107, July, 2004. Original article submitted March 19, 2002; revision submitted September 29, 2003. 0009-3122/04/4007-09492004 Springer Science+Business Media, Inc. 949
R R' 1af
NH2
HO
R R' O 2 ArCHO 4ak
H N NH2 3af O
+
NH2
R R' N H
H N
Ar
5au
1, 3 a R = R' = H; b R = COOMe, R' = H; c R = COPh, R' = H; d R = CF3, R' = H; e R = NO2, R' = H; f R = R' = Cl; 4 a Ar = C6H3F2-3,5; b Ar = C6H3O2CH2-3,4; c Ar = C6H4NO2-3; d Ar = C6H4Cl-4; e Ar = C6H4F-4; f Ar = C6H3(OMe)2-3,4; g Ar = 2-pyridyl, h Ar = 3-pyridyl, i Ar = 4-pyridyl, j Ar = 2-thienyl, k Ar = 2-furyl; 5 a-r R' = H, s-u R' = Cl; a R = H, Ar = C6H3F2-3,5; b R = H, Ar = 2-pyridyl; c R = , Ar = 3-pyridyl; d R = , Ar = 4-pyridyl; e R = COOMe, Ar = C6H3O2CH2-3,4; f R = COOMe, Ar = C6H3F2-3,5; g R = COOMe, Ar = 3-pyridyl; h R = COOMe, Ar = 4-pyridyl; i R = COPh, Ar = C6H4NO2-3; j R = COPh, Ar = 4-pyridyl; k R = COPh, Ar = 2-thienyl; l R = COPh, Ar = 2-furyl; m R = CF3, Ar = C6H4Cl-4; n R = CF3, Ar = C6H4F-4; o R = CF3, Ar = 2-thienyl; p R = CF3, Ar = 2-furyl; q R = NO2, Ar = 2-thienyl; r R = NO2, Ar = 2-furyl; s R = Cl, Ar = C6H3(OMe)2-3,4; t R = Cl, Ar = C6H3F2-3,5; u R = Cl, Ar = 4-pyridyl
The signals from the protons at the tertiary C(11) atom are detected as doublets in the interval 5.68-6.82 ppm with vicinal spinspin coupling constant 5 Hz. The N(10)H proton is represented by such a doublet ( 6.58-5.53) in most of the diazepines 5, except in cases when it is overlapped by aromatic signals. The N(5)H signals resonate downfield: 8.93-9.12 ppm.
EXPERIMENTAL The IR spectra were recorded on a Specord IR-75 for suspensions of the compounds in vaseline oil (1800-1500 cm-1 region) and in hexachlorobutadiene (3600-2000 cm-1 region). In the 1800-1500 cm-1 region, only the carbonyl frequencies are given. The frequencies of the stretching vibrations of the CH bond in the 3050-2800 cm-1 region are not given. The 1H NMR spectra were recorded on a Bruker WH/90DS (90 MHz), internal standard TMS. In this work, we used diamines and aldehydes from Lancaster, Acros, and Fluka. To monitor the course of the reactions, we used Merck Silica Gel 60 F254 plates, with the systems 7:3 ethyl acetatetoluene (A), 4:3 ethyl acetatetoluene (B); visualization by heating and exposure to UV light. 3-(2-Aminophenylamino)-5,5-dimethylcyclohex-2-en-1-one (3a) was obtained by the procedure in [13]. 3-(2-Amino-5-methoxycarbonylphenylamino)- (3b), 3-(2-Amino-5-benzoylphenylamino)- (3c), 3-(2Amino-5-trifluoromethylphenylamino)- (3d), 3-(2-Amino-5-nitrophenylamino)- (3e), 3-(2-Amino-4,5dichlorophenylamino)- (3f) 5,5-dimethylcyclohex-2-en-1-ones. Dimedone 2 (5 mmol) and the corresponding diamine 1b-f (5 mmol) were boiled in toluene (100 ml) in the presence of catalytic amounts of p-toluenesulfonic acid under conditions for azeotropic distillation of water for 3 h. The enamine 3e that precipitated upon cooling
950

Compound 3b 3c 3d 3e 3f 5a 5b 5c 5d 5e 5f 5g 5h 5i 5j 5k 5l 5m 5n 5o 5p 5q 5r 5s 5t 5u Empirical formula C16H20N2O3 C21H22N2O2 C15H17F3N2O C14H17N3O3 C14H16Cl2N2O C21H20F2N2O C20H21N3O C20H21N3O C20H21N3O C24H24N2O5 C23H22F2N2O3 C22H23N3O3 C22H23N3O3 C28H25N3O4 C27H25N3O2 C26H24N2O2S C26H24N2O3 C22H20 ClF3N2O C22H20F4N2O C20H19F3N2OS C20H19F3N2O2 C19H19N3O3S C19H19N3O4 C23H24Cl2N2O3 C21H18Cl2F2N2O C20H19Cl2N3O Found, % Calculated, % N 6.77 6.99 6.60 6.63 5.71 5.75 6.15 6.23 5.50 5.39 5.60 5.69 6.48 6.63 6.60 6.63 6.66 6.63 5.70 5.75 5.30 5.38 6.09 6.14 6.02 6.14 5.30 5.39 5.82 5.95 5.60 5.65 5.81 5.86 4.80 4.79 4.91 4.99 4.97 4.88 5.01 5.09 5.13 5.18 5.30 5.42 5.32 5.41 4.25 4.29 4.90 4.93 9.84 9.72 8.31 8.38 9.18 9.39 15.11 15.26 9.29 9.36 7.79 7.90 13.13 13.16 13.97 13.16 13.11 13.16 6.52 6.66 6.68 6.79 11.10 11.13 11.18 11.13 8.79 8.99 10.01 9.92 6.43 6.54 6.65 6.79 6.55 6.66 6.81 6.93 7.00 7.14 7.28 7.44 11.21 11.37 11.70 11.89 6.12 6.26 6.49 6.62 10.75 10.82
mp, l (S) 213-214 145-146 211-211 204-206 23.50 23.70 218-219 247-248 230-233 216-218 260-263 235-236 181-182 261-263 280-281 263-265 266-269 (7.30) (7.48) 284-285 269-271 220-222 206-207 (8.40) (8.17) 258-260 269-271 (8.70) (8.68) 289-290 278-280 15.60 15.85 16.60 16.75 18.10 18.26 188-189 149-151 266-268
Yield, %
66.65 66.65 75.25 75.42 60.50 60.39 60.89 61.08 56.16 56.20 71.02 71.17 75.01 75.20 75.14 75.20 75.05 75.20 68.73 68.56 67.11 66.98 70.17 70.01 69.84 70.01 71.79 71.93 76.66 76.57 72.67 72.87 75.80 75.71 62.61 62.78 65.15 65.34 61.11 61.21 63.65 63.82 61.60 61.77 64.43 64.58 61.54 61.75 59.40 59.59 61.66 61.86
35 66 81 55 54 46 53 94 88 36 60 54 53 87 51 42 87 86 74 80 78 68 77 45 83 51
was recrystallized from toluene. In the rest of the cases, the toluene was completely driven off on a rotary evaporator, the dry residue (with addition of activated carbon) was recrystallized from THF (compounds 3c,d), toluene (compound 3b), or ethanol (compound 3f).
951
TABLE 2. Spectral Characteristics of Synthesized Compounds

Compound 1 3b IR spectrum , cm-1 2 1706, 1630; 3460, 3330, 3220 1645, 1625; 3480, 3280, 3200 1630; 3450, 3300, 3180
1
NMR spectrum (DMSO-d6), , ppm (SSCC, J, Hz) 3
3d
1635; 3480, 3340, 3240 1635; 3400, 3300, 3220 1630; 3300, 3220, 3100 1633; 3300, 3200, 3100 1628; 33320, 3210, 100
3f
5b
5c
5d
1630; 3300, 3190, 3100
1710, 1630; 3320, 3180, 3080
5f
1710, 1635; 3300, 3200
5g
1705,1638; 3330, 3100-3050
5h
1706, 1640; 3300, 3080
1.03 (6, s, 23); 2.03 (2, s, 2); 2.43 (2, s, 2); 3.78 (3, s, O3); 4.65 (1, d, =); 5.81 (2H, br. s, NH2); 6.74 (1H, d, 3J = 8, C6H3); 7.44 (1H, d, 4J = 2, C6H3); 7.56 (1, dd, 3J = 8, 4J = 2, C6H3); 8.09 (1H, br. s, NH) 0.95 (6, s, 23); 1.96 (2, s, 2); 2.33 (2, s, 2); 4.62 (1, s, =); 5.93 (2H, br. s, NH2); 6.77 (1H, d, 3J = 8, C6H3); 7.36-7.64 (7H, m, 65, C6H3); 8.16 (1H, br. s, NH) 0.97 (6, s, 23); 1.96 (2, s, 2); 2.33 (2, s, 2); 4.56 (1, s, =); 5.58 (2H, br. s, NH2); 6.82 (1H, d, 3J = 8, C6H3); 7.11 (1H, d, 4J = 2, 63); 7.29 (1H, dd, 3J = 8, 4J = 2, 63); 8.17 (1H, br. s, NH) 1.01 (6, s, 23); 2.02 (2, s, 2); 2.41 (2, s, 2); 4.61 (1, s, =); 6.41 (2H, br. s, NH2); 6.82 (1H, d, 3J = 8, C6H3); 7.81 (1H, d, 4J = 2, 63); 7.91 (1H, dd, 3J = 8, 4J = 2, 63); 8.24 (1H, br. s, NH) 1.01 (6, s, 23); 2.16 (2, s, 2); 2.36 (2, s, 2); 3.76 (2, br. s, NH2); 5.07 (1, s, =); 6.92 (1H, s, C6H2); 7.14 (1H, s, 62); 7.56 (1H, br. s, NH) 0.98 (3, s, 3); 1.07 (3, s, 3); 2.11 (2, s, 2); 2.56 (2, s, 2); 5.93 (1, s, ); 6.16 (1H, br. s, NH); 6.53-6.97 (7, m, 64, C6H3); 8.78 (1H, br. s, NH) 0.93 (3, s, 3); 0.98 (3, s, 3); 1.96 (1, d, 2J = 16, ); 2.13 (1, d, 2J = 16, ); 2.51 (2, s, 2); 5.73 (1, d, 3J = 5, ); 6.04 (1, d, 3J = 5, N); 6.53-7.02 (6, m, 64, C5H4N); 7.41 (1H, m, 5H4N); 8.33 (1H, m, 5H4N); 8.71 (1H, br. s, NH) 1.01 (3, s, 3); 1.08 (3, s, 3); 2.12 (1, d, 2J = 18, ); 2.26 (1, d, 2J = 18, ); 2.61 (2, s, 2); 5.76 (1, d, 3J = 5, ); 6.26 (1, d, 3J = 5, N); 6.56-7.47 (6, m, 64, C5H3N); 8.21 (1H, dd, 3J = 5, 4J = 1.5, 5H4N); 8.37 (1H, d, 4J = 1.5, 5H4N); 8.92 (1H, br. s, NH) 0.95 (3, s, 3); 1.03 (3, s, 3); 2.07 (1, d, 2J = 16, ); 2.19 (1, d, 2J = 16, ); 2.58 (2H, s, CH2); 5.64 (1, d, 3J = 5, ); 6.27 (1, d, 3J = 5, N); 6.47-6.98 (6, m, 64, C5H4N); 8.27 (2H, m, 5H4N); 8.78 (1H, br. s, NH) 1.01 (3, s, 3); 1.12 (3, s, 3); 2.12 (1, d, 2J = 17, ); 2.23 (1, d, 2J = 17, ); 2.65 (2, m, 2); 3.81 (3, s, O3); 5.67 (1, d, 3J = 5, ); 5.92 (2, s, -2-); 6.56 (4, m, 263); 6.92 (1H, d, 3J = 5, N); 7.24 (1, dd, 3J = 8, 4J = 2, C6H3); 7.74 (1, d, 3J = 2, C6H3); 9.05 (1H, br. s, NH) 1.01 (3, s, 3); 1.11 (3, s, 3); 2.18 (2, s, 2); 2.63 (2, s, 2); 3.78 (3, s, O3); 5.76 (1, d, 3J = 5, ); 6.47 (1H, d, 3J = 5, NH); 6.66-7.02 (4H, m, 263); 7.34 (1H, dd, 3J = 8, 4J = 1.5, 63); 7.69 (1, d, 4J = 1.5, C6H3); 9.09 (1H, br. s, NH) 0.99 (3, s, 3); 1.07 (3, s, 3); 2.02 (1, d, 2J = 18, ); 2.18 (1, d, 2J = 18, ); 2.59 (2, s, 2); 3.78 (3, s, O3); 5.83 (1, d, 3J = 5, ); 6.65 (1H, d, 3J = 8, C6H3); 6.96 (1H, d, 3J = 5, NH); 7.03-7.53 (3, m, C5H4N, C6H3); 7.77 (1, d, 4J = 2, C6H3); 8.26-8.41 (2, m, C5H4N); 9.12 (1H, br. s, NH) 1.01 (3, s, 3); 1.12 (3, s, 3); 2.14 (1, d, 2J = 16, ); 2.21 (1, d, 2J = 16, ); 2.55 (2, m, 2); 3.76 (3, s, O3); 5.76 (1, d, 3J = 5, ); 6.68 (1H, d, 3J = 8, C6H3); 6.96 (3H, m, 3J = 5, C5H4N, NH); 7.32 (1H, dd, 3J = 8, 4J = 2, C6H3); 7.41 (1H, d, 4J = 2, C6H3); 8.41 (2, m, 3J = 5, C5H4N); 9.12 (1H, br. s, NH)
952
TABLE 2 (continued)
1 5i 2 1640, 1630; 3350, 3200, 3080 3 0.94 (3, s, 3); 1.08 (3, s, 3); 2.07 (1, d, 2J = 18, ); 2.18 (1, d, 2J = 18, ); 2.61 (2, s, 2); 5.88 (1, d, 3J = 5, ); 6.72 (1H, d, 3J = 8, C6H3); 7.18 (3H, m, 6H3, NH); 7.57 (6, m, C6H5, C6H4); 7.97-8.07 (3, m, C6H4); 9.08 (1H, br. s, NH) 0.99 (3, s, 3); 1.02 (3, s, 3); 2.03 (1, d, 2J = 16, ); 2.15 (1, d, 2J = 16, ); 2.53 (2, s, 2); 5.71 (1, br. s, ); 6.66 (1H, d, 3J = 8, C6H3); 7.07-7.56 (9, m, C5H4N, C6H4, NH); 8.31 (3, m, C6H4, C6H3); 8.98 (1H, br. s, NH) 1.01 (3, s, 3); 1.03 (3, s, 3); 2.06 (1, d, 2J = 17, ); 2.18 (1, d, 2J = 17, ); 2.53 (2, s, 2); 5.96 (1, d, 3J = 2, ); 6.74-7.08 (5, m, C6H3, C4H3S); 7.04 (1H, d, 3J = 5, NH); 7.59 (6, m, C6H5, C6H3); 8.99 (1H, br. s, NH) 0.93 (3, s, 3); 1.03 (3, s, 3); 2.11 (1, d, 2J = 17, ); 2.26 (1, d, 2J = 17, ); 2.53 (2, s, 2); 5.77 (3, m, C4H3O); 6.14 (1, m, C6H3); 6.71 (1, d, 3J = 5, ); 7.08 (2H, m, C6H3, NH); 7.36-7.69 (6, m, C6H5, C6H3); 8.98 (1H, br. s, NH) 0.93 (3, s, 3); 1.08 (3, s, 3); 2.04 (1, d, 2J = 18, ); 2.17 (1, d, 2J = 18, ); 2.61 (2, s, 2); 5.71 (1, d, 3J = 5, ); 6.58-7.27 (8, m, C6H4, C6H3, NH); 8.99 (1H, br. s, NH) 0.96 (3, s, 3); 1.07 (3, s, 3); 2.05 (1, d, 2J = 16, ); 2.17 (1, d, 2J = 16, ); 2.61 (2, s, 2); 5.72 (1, d, 3J = 5, ); 6.64-7.29 (8, m, C6H4, C6H3, NH); 9.04 (1H, d, 3J = 5, NH) 1.01 (3, s, 3); 1.05 (3, s, 3); 2.04 (1, d, 2J = 16, ); 2.19 (1, d, 2J = 16, ); 2.24 (2, s, 2); 5.90 (1, d, 3J = 5, ); 6.73-7.30 (7, m, C6H3, C4H3S, NH); 9.00 (1H, br. s, NH) 0.96 (3, s, 3); 1.08 (3, s, 3); 2.04 (1, d, 2J = 16, ); 2.16 (1, d, 2J = 16, ); 2.53 (2, s, 2); 5.73 (2, m, C4H3O, ); 6.12 (1H, m, C4H3O); 6.71-7.38 (5, m, C6H3, C4H3O, NH); 8.93 (1H, br. s, NH) 1.01 (3, s, 3); 1.06 (3, s, 3); 2.05 (1, d, 2J = 18, ); 2.18 (1, d, 2J = 18, ); 2.52 (2, s, 2); 5.99 (1, d, 3J = 6, ); 6.79-7.58 (6, m, C6H3, C4H3S, NH); 7.97 (1H, d, 4J = 2, C6H3); 9.17 (1H, br. s, NH) 0.92 (3, s, 3); 1.03 (3, s, 3); 2.02 (1, d, 2J = 18, ); 2.16 (1, d, 2J = 18, ); 2.52 (2, s, 2); 5.81 (2, m, C4H3N, ); 6.12 (1H, m, C4H3O); 6.82 (1, d, 3J = 8, C6H3); 7.43-7.58 (2, m, C4H3O, NH); 7.62 (1, dd, 3J = 8, 4J = 2, C6H3); 7.97 (1, d, 4J = 2, C6H3); 9.12 (1H, br. s, NH) 1.05 (3, s, 3); 1.12 (3, s, 3); 2.23 (2, s, 2); 2.52 (2, s, 2); 3.67 (3, s, OCH3); 3.81 (3, s, OCH3); 4.96 (1H, br. s, NH); 5.72 (1H, br. s, ); 6.62 (3H, m, C6H3); 7.18 (1H, s, C6H2); 7.43 (1H, s, C6H2); 8.43 (1H, br. s, NH) 1.12 (3, s, 3); 1.15 (3, s, 3); 2.25 (2, s, 2); 2.61 (2, s, 2); 5.87 (1, s, CH); 6.47-6.83 (4, m, C6H3, NH); 6.85 (1H, s, C6H2); 7.47 (1H, s, C6H2); 8.61 (1H, br. s, NH) 1.06 (3, s, 3); 1.07 (3, s, 3); 2.21 (2, s, 2); 2.61 (2, s, 2); 5.78 (1, d, 3J = 5, CH); 6.66 (1, d, 3J = 5, NH); 6.84 (1H, s, C6H2); 7.27 (1H, s, C6H2); 7.28-7.45 (2, m, C5H4N); 8.36 (2H, m, C5H4N); 9.06 (1H, br. s, NH)
5j
1645, 1630; 3320, 3180, 3070 1645, 1635; 3300, 3200, 3090 1640, 1630; 3320, 3200, 3100 1630; 3350, 3220 1632; 3320, 3200, 3090 1630, 3300, 3210, 3100 1630; 3330, 3200, 3100-3050 1635; 3350, 3240, 3100-3050 1631; 3330, 3200, 3100-3050
5k
5l
5m
5n
5o
5p
5q
5r
5s
1630; 3300, 3210, 3100 1632; 3340, 3200, 3100 1630; 3320, 3220, 3100
5t
5u
11-(2-Pyridyl)- (5b), 11-(3-Pyridyl)- (5c), 11-(4-Pyridyl)- (5d), 7-Methoxycarbonyl-11-(3-pyridyl)(5g), 7-Methoxycarbonyl-11-(4-pyridyl)- (5h), 7-Benzoyl-11-(4-pyridyl)- (5j), 7,8-Dichloro-11-(4-pyridyl)(5u) 3,3-dimethyl-1,2,3,4,10,11-hexahydro-5H-dibenzo[b,e][1,4]diazepin-1-ones. The corresponding enaminone 3 (3 mmol) and pyridine carbaldehyde (3 mmol) were boiled in ethanol (40 ml) in the presence of conc. H2SO4 (0.15 ml) for 3 h. Ethanol (25-30 ml) was distilled off on a rotary evaporator, water (40 ml) was added, and the mixture was neutralized with a concentrated aqueous solution of NaHCO3. The precipitate was filtered out and recrystallized from 2-propanol. 953
11-(3,5-Difluorophenyl)(5a), 7-Methoxycarbonyl-11-(3,4-methylenedioxyphenyl)(5e), 7-Methoxycarbonyl-11-(3,5-difluorophenyl)(5f), 7,8-Dichloro-11-(3,4-dimethoxyphenyl)(5s), 7,8-Dichloro-11-(3,5-difluoro)- (5t) 3,3-dimethyl-1,2,3,4,10,11-hexahydro-5H-dibenzo[b,e][1,4]diazepin-1ones. Enaminone 3 (3 mmol) and the corresponding aldehyde 4 (2.5 mmol) were boiled in ethanol (30 ml) in the presence of 2 drops of conc. H2SO4 for 2.5 h; half the volume of the ethanol was driven off on a rotary evaporator and the mixture was placed in a refrigerator for 24 hours. Water (1-2 ml) was added as needed. The precipitate was filtered out and recrystallized from ethanol (compounds 5a,s), 2-propanol (compounds 5e,f), or THF (compound 5t). 3,3-Dimethyl-7-nitro-11-(2-thienyl)-1,2,3,4,10,11-hexahydro-5H-dibenzo[b,e][1,4]diazepin-1-one (5q). Enaminone 3e (3 mmol) and thiophene-2-carbaldehyde 4j (3 mmol) were boiled in ethanol (30 ml) in the presence of conc. H2SO4 (0.15 ml) for 4 h. The mixture was poured into crushed ice and then the precipitate of dibenzodiazepine was filtered out and recrystallized from 2-propanol. 7-Benzoyl- (5l), 7-Trifluoromethyl- (5p), 7-Nitro- (5r) 3,3-dimethyl-11-(2-furyl)-1,2,3,4,10,11hexahydro-5H-dibenzo[b,e][1,4]diazepin-1-ones. A mixture of enaminone 3 (2 mmol), furfural (2 mmol), glacial CH3COOH (0.3 ml), and piperidine (0.4 ml) were boiled for 3 h in ethanol (30 ml). The mixture was cooled and poured into crushed ice. The precipitate was filtered out and recrystallized from toluene. 7-Benzoyl-11-(3-nitrophenyl)- (5i), 7-Benzoyl-11-(2-thienyl)- (5k), 11-(4-Chlorophenyl)-7trifluoromethyl- (5m), 7-Trifluoromethyl-11-(4-fluorophenyl)- (5n), 11-(2-Thienyl)-7-trifluoromethyl- (5o) 3,3-dimethyl-1,2,3,4,10,11-hexahydro-5H-dibenzo[b,e][1,4]diazepin-1-ones. A mixture of enaminone 3c,d (2 mmol) and the corresponding aldehyde 4 (2 mmol) were boiled for 3 h in ethanol (30 ml) in the presence of conc. H2SO4 (0.15 ml). The mixture was cooled and poured into crushed ice. The precipitate of dibenzodiazepine was filtered out and recrystallized from toluene.
REFERENCES 1. 2. 3. 4. Y. Blache, M. Hichour, G. Di Blasi, J.-M. Chezal, H. Viols, O. Chavingnon, J. C. Taulade, and J. P. Chapat, Heterocycles, 51, 1003 (1999). T. Watanabe, I. Kinoyama, K. Takizawa, S. Hirano, and T. Shibanuma, Chem. Pharm. Bull., 47, 672 (1999). T. Watanabe, A. Kakefuda, A. Tanaka, K. Takizawa, S. Hirano, H. Shibata, Y. Yamaguva, and I. Yanagisava, Chem. Pharm. Bull., 46, 53 (1998). C. L. Cywin, J. M. Klunder, M. A. Hoermann, J. R. Brickwood, E. David, R. Schwartz, D. Pauletti, K. J. Barringer, Ch. L. Sorge, D. A. Erickson, D. P. Joseph, and S. E. Hattox, J. Med. Chem., 41, 2972 (1998). T. A. Kelly, D. W. McNeil, J. M. Rose, E. David, Cheng-Kon Shin, and P. M. Grob, J. Med. Chem., 40, 2430 (1997). G. Heinisch and B. Matuszak, J. Heterocycl. Chem., 34, 1421 (1997). T. Watanabe, A. Kakefuda, I. Kinoyama, K. Takizawa, S. Hirano, H. Shibata, and I. Yanagisava, Chem. Pharm. Bull., 45, 1458 (1997). T. Watanabe, I. Kinoyama, A. Kakefuda, T. Okazaki, K. Takizawa, S. Hirano, H. Shibata, and I. Yanagisava, Chem. Pharm. Bull., 45, 996 (1997). J. R. Proudfoot, U. R. Patel, S. R. Kapadia, and K. Hargrave, J. Med. Chem., 38, 1406 (1995). T. A. Kelly, D. W. McNeil, U. R. Patel, E. David, K. D. Hargrave, P. M. Grob, M. Cardozo, A. Agarwal, and J. Adams, J. Med. Chem., 38, 4839 (1995). A. Minarini, M. L. Bolognesi, R. Budriesi, M. Canossa, A. Chiarini, S. Spampinato, and C. Melchiorre, J. Med. Chem., 37, 3363 (1994).
5. 6. 7. 8. 9. 10. 11.
954
12. 13. 14. 15. 16.
N. N. Tonkikh, A. Strakovs, and M. V. Petrova, Khim. Geterotsikl. Soedin., 1095 (2004). T. Kametani, M. Ihara, and K. Takahashi, Chem. Pharm. Bull., 20, 1588 (1972). K. Matsuo, M. Ohta, and K. Tanaka, Chem. Pharm. Bull., 33, 4063 (1985). M. A. Likhate and P. S. Fernandes, J. Indian Chem. Soc., 67, No. 7, 609 (1990). N. Rashed, M. Sayed, and E. S. H. El Ashry, J. Chin. Chem. Soc., 40, 189 (1993); Chem. Abstr., 119, 139194 (1993).
955
SELECTIVE CYCLOPROPANATION OF CHROMENES WITH A PHENYLACRYLOYL SUBSTITUENT BY BROMINECONTAINING ZINC ENOLATES

V. V. Shchepin, M. M. Kalyugnii, and N. Yu. Russkikh Keywords: 1-aryl-2,2-dibromoalkanones, cyclopropanation products, chromenones with a phenylacryloyl substituent, zinc enolates. Halogen-containing metal enolates react with ,-unsaturated carbonyl compounds to form a cyclopropane ring [1-4]. As the systems to be cyclopropanated, in this work we studied 3-(3-phenylacryloyl)chromen-2-ones and benzo[f]chromen-3-ones, which formally contain two C=CC=O moieties in their molecules. Our studies have shown that nucleophilic bromine-containing zinc enolates 2a-c, obtained from 1-aryl-2,2-dibromoalkanones 1a-c and zinc, react exclusively with the double bond of the heterocycle, forming intermediate addition products 3a,b and 4, which in turn are converted to the cyclopropanation products: 1-alkyl-1-aroyl-1a-(3-phenylacryloyl)-1a,7b-dihydro-1H-cyclopropa[c]chromen-2ones 4a,b and 1-benzoyl-1-methyl-1a-(3-phenylacryloyl)-1a,9c-dihydro-1H-3-oxacyclopropa[c]phenanthren-2one (5). 1-(4-Bromobenzoyl)-1-methyl-1a-(3-phenylacryloyl)-1a,7b-dihydro-1H-cyclopropa[c]chromen-2one (4a). Yield 33%; mp 197-200C. IR spectrum (vaseline oil), , cm-1: 1590, 1685, 1740. 1H NMR spectrum (300 MHz, DMSO-d6), , ppm (J, Hz): 1.12 (3H, s, Me); 3.75 (1H, s, CH); 7.30, 7.55 (2H, d, J = 15, CH=CH); 7.17-7.80 (13H, m, C6H4, Ph, 4-BrC6H4). Found, %: C 66.90; H 4.03. C27H19O4Br. Calculated, %: C 66.54; H 3.93. 1-Ethyl-1a-(3-phenylacryloyl)-1-(4-toluoyl)-1a,7b-dihydro-1H-cyclopropa[c]chromen-2-one (4b). Yield 29%; mp 144-145C. IR spectrum (vaseline oil), , cm-1: 1605, 1675, 1745. 1H NMR spectrum (60 MHz, CDCl3), , ppm (J, Hz): 0.57 (3H, t, J = 7, CH2CH3); 0.90-1.50, 1.60-2.20 (2H, two m, CH2CH3); 2.26 (3H, s, CH3C6H4); 3.72 (1H, s, CH); 6.90-8.00 (15H, m, C6H4, Ph, 4-MeC6H4, CH=CH). Found, %: C 79.61; H 5.69, C29H24O4. Calculated, %; C 79.80; H 5.54. 1-Benzoyl-1-methyl-1a-(3-phenylacryloyl)-1a,9c-dihydro-1H-3-oxacyclopropa[c]phenanthren-2one (5). Yield 21%; mp 240-250C. IR spectrum (vaseline oil), , cm-1: 1600, 1675, 1745. 1H NMR spectrum (60 MHz, DMSO-d6 + CDCl3, 1:1), , ppm: 1.17 (3H, s, CH3); 4.13 (1H, s, CH); 6.90-8.00 (18H, m, C10H6, Ph, Ph, CH=CH). Found, %: C 81.00; H 5.01. C31H22O4. Calculated, %: C 81.21; H 4.84.
__________________________________________________________________________________________ Perm State University, Perm 614000, Russia; e-mail: info@psu.ru, shchepin@imail.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1108-1109, July, 2004. Original article submitted October 21, 2003. 956 0009-3122/04/4007-09562004 Springer Science+Business Media, Inc.
RCBr2COAr 1ac
Zn
R Br 2ac
OZnBr Ar
COCH=CHPh O O
COCH=CHPh O 2ac O
Br
COAr COCH=CHPh ZnBr
Br
Me
COPh COCH=CHPh ZnBr
O 3a,b
O 4
ZnBr2
COAr COCH=CHPh H
Me
COPh COCH=CHPh
O O 4a,b
O 5
1-4 R = Me, Ar = 4-BrC6H4, b R = Et, Ar = 4-MeC6H4; 1, 2 c R = Me, Ar = Ph
REFERENCES 1. 2. 3. 4. M. Causse-Zoller and R. Fraisse-Jullien, Bull. Soc. Chim., 430 (1966). N. Kawabata and M. Tanimoto, Tetrahedron, 36, 3517 (1980). C. Chen, J. Huang, and Y. Shen, Tetrahedron, 45, 3010 (1989). J. C. Je Menn and A. T. J. Sarrasin, Can. J. Chem., 69, 761 (1991).
957
UNEXPECTED O-METHYLATION OF N-(2-HYDROXYETHYL)-1,2,3,4-TETRAHYDROQUINOLINE AND -1,2,3,4-TETRAHYDROISOQUINOLINE IN SILYLALKYLATION BY TRIMETHYLCHLOROMETHYLSILANE UNDER PHASETRANSFER CATALYSIS CONDITIONS
A. E. Zablotskaya, I. D. Segal, and E. Lukevics Keywords: tetrahydroisoquinoline, tetrahydroquinoline, alkylation, silylation, phase-transfer catalysis. In continuing a study of the biological activity of organosilicon derivatives of tetrahydroquinoline and tetrahydroisoquinoline [1-3], we have attempted to obtain trialkylsilylalkyl derivatives of hydroxyethyltetrahydro(iso)quinolines under phase-transfer catalysis conditions.
N CH2CH2OH
C6H6 /KOH/KI/ Aliquat R 336 Me3SiCH2Cl
N CH2CH2OMe
NCH2CH2OH PhMe /K2CO3 /KI/18-crown -6
NCH2CH2OMe MeOCH2CH2Cl
NH
We have established that as a result of silylalkylation of primary alcohol groups in N-(2-hydroxyethyl)1,2,3,4-tetrahydroisoquinoline and -tetrahydroquinoline by trimethylchloromethylsilane under phase-transfer catalysis conditions, the major reaction products are N-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinoline and N-(2-methoxyethyl)-1,2,3,4-tetrahydroquinoline respectively; i.e., instead of the target O-trimethylsilylmethylation, we see that O-methylation of the primary alcohol groups occurs. The reaction was conducted in the system C6H6/KOH/KI/Aliquat 336 for 10 h at a temperature of 80C and an equivalent reagent ratio of 1:1.05 tetrahydroquinoline:silane. The yield of methylation products is greater than 40%. The structure of the __________________________________________________________________________________________ Latvian Institute of Organic Synthesis, Riga LV-1006; e-mail: aez@osi.lv. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1110-1111, July, 2004. Original article submitted April 27, 2004. 958 0009-3122/04/4007-09582004 Springer Science+Business Media, Inc.
N-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinoline obtained was confirmed by an alternate synthesis: N-alkylation of tetrahydroisoquinoline by 2-chloroethylmethyl ether under phase-transfer catalysis conditions using the system toluene/K2CO3/KI/18-crown-6. General O-Silylalkylation Method. A mixture of the heterocyclic 2-amino alcohol (6.3 g, 35.5 mmol), potassium hydroxide (9.97 g, 178 mmol), potassium iodide (11.79 g, 71 mmol), trimethylchloromethylsilane (4.42 g, 36 mmol), and Aliquat 336 (0.72 g, 1.78 mmol) in dry benzene (25 ml) was stirred at 80C for 10 h. Then the precipitate was filtered out, the solvent was distilled off from the filtrate, and the product was isolated by distillation under vacuum. N-Alkylation. A mixture of tetrahydroisoquinoline (0.49 g, 3.7 mmol), potassium carbonate (1.53 g, 11.1 mmol), potassium iodide (1.24 g, 7.5 mmol), 2-chloroethylmethyl ether (0.42 g, 4.4 mmol), and 18-crown-6 (0.049 mg, 0.2 mmol) in dry toluene (2.3 ml) was stirred at 100C for 14 h. Then the precipitate was filtered out, the solvent was distilled off from the filtrate, and the product was isolated as a results of chromatographic separation of the reaction products on a column with eluent 52:48 ethyl acetatehexane. Yield 0.28 g (40%). N-(2-Methoxyethyl)-1,2,3,4-tetrahydroisoquinoline. Yield 3.25 g (48%); bp 126-128C (3 mm Hg). Mass spectrum, m/z (Irel, %): 191 [M]+, 146 [M+ CH2OCH3]. 1H NMR spectrum (90 MHz, CDCl3), , ppm (J, Hz): 2.77 (2H, t, J = 6, NCH2); 2.83 (4H, m, 3,4-CH2); 3.37 (3H, s, OCH3); 3.47 (2H, t, J = 6, OCH2); 3.72 (2H, s, 1-CH2); 6.92-7.12 (4H, m, arom.). Found, %: C 75.10; H 9.07; N 7.52. C12H17NO. Calculated, %: C 75.35; H 8.96; N 7.32. N-(2-Methoxyethyl)-1,2,3,4-tetrahydroquinoline. Yield 2.78 g (41%); bp 135-137C (4 mm Hg). Content of the major compound, 98.2%, according to HPLC data (Symmetry C18, 4.6 150 mm, system: 70% acetonitrile + 30% [0.1% H3PO4 + H2O], pH 2.5). UV detector ( = 220 nm). Mass spectrum, m/z (Irel, %): 191 [M]+, 146 [M+ CH2OCH3]. 1H NMR spectrum (90 MHz, CDCl3), , ppm: 1.92 (2H, m, 3-CH2); 2.75 (2H, t, 4-CH2); 3.23-3.66 (9H, m, OCH3 + OCH2 + 2-CH2 + NCH2); 6.47-7.31 (4H, m, arom.). Found, %: C 75.43; H 9.04; N 7.25.C12H17NO. Calculated, %: C 75.35; H 8.96; N 7.32.
REFERENCES 1. 2. 3. E. Lukevics, I. Segal, A. Zablotskaya, and S. Germane, Khim. Geterotsikl. Soedin., 793 (1996). E. Lukevics, S. Germane, I. Segal, and A. Zablotskaya, Khim. Geterotsikl. Soedin., 270 (1997). E. Lukevics, I. Segal, A. Zablotskaya, and S. Germane, Molecules, 2, 180 (1997).
959
CYCLIZATION OF N,N-BIS(2-CHLOROETHYL)METHYLAMINE IN AQUEOUS HYDRAZINE

P. M. Kushakova1, V. A. Kuznetsov1, A. N. Chernobroviy2, and A. V. Garabadgiu1 Keywords: 1-amino-4-methylpiperazine, haloalkylamines, N-(2-chloroethyl)-N-(2-hydrazinoethyl)methylamine. 1-Amino-4-methylpiperazine (1) is widely used as an intermediate in synthesis of medicinal drugs [1]. Several methods for obtaining it are known. A method based on a two-step scheme has been used industrially, starting from piperazine and followed by its nitrosation and reduction [2, 3]. We have obtained compound 1 for the first time by reaction of N,N-bis(2-chloroethyl)methylamine (2) with an aqueous solution of hydrazine, and we have also developed an efficient method for its isolation. Analysis of the literature [3, 4] allowed us to determine the optimum ratio of the reagents when the dihalo derivative is used as the substrate. In the temperature range 40-50C, the ratio of the reagents is substrate 1:N2H4 (50%) 1:10. Analysis of the reaction mass using GLC data, chromatography/mass spectrometry, and 13C NMR showed that along with the target product 1, a number of impurities are formed which we identified.
CH2CH2Cl CH2CH2Cl 2 Me N 1 CH2CH2Cl 4 MeN(CH2CH2NHNH2)2 3 N NH2 50% aqueous NH2NH2 + Me N CH2CH2Cl
Me
Me
CH2CH2NHNH2
In particular, using chromatography/mass spectrometry, we observed formation of up to 2% N,N-bis(2hydrazinoethyl)methylamine (3). For less than 80% conversion of substrate 2, we identified N-(2-chloroethyl)N-(2-hydrazinoethyl)methylamine (4) in the reaction mass. Along with the identified compounds 1, 3, 4, the compounds remaining in the vat after distillation of the target product 1 evidently can be assigned as quaternary ammonium bases [3, 4].
__________________________________________________________________________________________ St. Petersburg State Institute of Technology (Technical University), St. Petersburg 190013, Russia; e-mail: gar@sitecs.spb.ru. 2 Olainfarm AO, Riga LV-2114, Latvia; e-mail: alchern@olainfarm.lv. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1111-1112, July, 2004. Original article submitted May 7, 2004. 960 0009-3122/04/4007-09602004 Springer Science+Business Media, Inc.
1
1-Amino-4-methylpiperazine (1). N,N-bis(2-chloroethyl)methylamine hydrochloride (51.0 g, 0.265 mol) was added to a 50% aqueous solution of hydrazine (132 ml, 2.65 mol). The mixture was held for 2 h at 50C. The reaction mass was evaporated under vacuum to dryness. A 1 M sodium hydroxide solution (100 ml) was added to the dry residue, and the mixture was stirred for 40 min. The precipitate was filtered out. The filtrate was distilled under vacuum. Yield 26.5 g (87%); bp 128-131C (13 mm Hg). 13C NMR spectrum (D2O), , ppm: 57.51 (C(2), NCH2); 54.15 (C(3), CH2N); 45.01 (C(1), CH3). Mass spectrum (electron impact, 70 eV), m/z (Irel, %): 116 [M+1]+ (5.5), 115 [M]+ (79.5), 99 [MNH2]+ (73.9), 98 [MNH3]+ (21.3), 58 [M CH3N(CH2)2]+ (20.6), 57 [MNH2N(CH2)2]+ (24.5). Found, %: C 52.58; H 11.21; N 36.39. C5H13N3. Calculated, %: C 52.14; H 11.38; N 36.48.
REFERENCES 1. 2. 3. 4. B. T. Golding and M. J. Kebbell, J. Chem. Soc., Perkin Trans. 2, 1859 (1988). P. D. Barleff, S. D. Ross, and C. C. Swain, J. Am. Chem. Soc., 69, 2971 (1947). V. S. Borisenko, V. A. Bobylev, and G. F. Tereshchenko, Zh. Obshch. Khim., 55, 1141 (1985). V. A. Surkin, I. G. Zenkevich, P. S. Lobanov, and A. A. Potekhin, Zh. Org. Khim., 19, 2288 (1983).
961
KISHNER REDUCTION OF 3,3-DIMETHYL6-TRIFLUOROMETHYL-1,2,3,4-TETRAHYDROINDOLO[2,3-c]QUINOLIN-1-ONE

A. V. Kibal'ny and A. A. Afonin Keywords: 3,3-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydroindolo[2,3-c]quinolin-1-one, hydrazinolysis. reduction,
In connection with a study of the biological activity of tetracyclic derivatives of -carboline, we have carried out reduction of the carbonyl group for several tetracyclic ketones of this series that we obtained in [1, 2], which led to synthesis of compounds with pronounced nootropic properties [2, 3]. We isolated the Kishner reduction products in close to quantitative yield. Reduction of 3,3-dimethyl-6-trifluoromethyl-1,2,3,4tetrahydroindolo[2,3-c]quinolin-1-one (1) under these conditions unexpectedly led to a mixture of indoloquinoline derivatives not containing a trifluoromethyl group. Based on spectral characteristics (IR spectroscopy, mass spectroscopy, and 1H NMR spectroscopy) and analytical characteristics of the three identified products, we established that along with reduction of the carbonyl group, hydrazinolysis of the trifluoromethyl group occurs with formation of substituted hydrazine 2, 6-unsubstituted indoloquinoline 3, and the hydrazide of the corresponding carboxylic acid 4.
O N2H4 N N H 1 CF3 KOH
N N H 2 HNNH2
+
N H 3
+
N H O 4
HNNH2
__________________________________________________________________________________________ L. M. Litvinenko Institute of Physical Organic Chemistry and Coal Chemistry, National Academy of Sciences of Ukraine, Donetsk 83114; e-mail: kibalny@infou.donetsk.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1113-1114, July, 2004. Original article submitted September 16, 2003. 962 0009-3122/04/4007-09622004 Springer Science+Business Media, Inc.
There are not many examples of reactions of the trifluoromethyl group in heterocycles [4]. Usually stable relative to treatment with various reagents, the trifluoromethyl group is probably activated in a heterocyclic system with -rich and -deficient properties, which determines its ambiguous behavior in the reaction with hydrazine. We have observed such a transformation for the first time in a series of tetracyclic derivatives of -carboline. 6-Hydrazino-3,3-dimethyl-1,2,3,4-tetrahydroindolo[2,3-c]quinoline (2). Yield 35%; mp 208-210C (benzene). Rf 0.25 (Silufol UV-254, chloroformpyridine, 10:1). IR spectrum (KBr), , cm-1: 3425-3230, 1620, 1565. 1H NMR spectrum (Bruker AM-300 (300 MHz), DMSO-d6, TMS), , ppm (J, Hz): 1.03 (6H, s, 3,3-(CH3)2); 1.78 (2H, t, J ~ 6, 2-CH2); 2.75 (2H, s, 4-CH2); 3.32 (2H, t, J ~ 6, 1-CH2); 4.91 (2H, s, 6-NNH2); 5.21 (1H, br. s, 6-NH); 7.16 (1H, t, J ~ 8, H-10); 7.44 (1H, t, J ~ 8, H-9; 7.61 (1H, d, J ~ 8, H-8); 8.12 (1H, d, J ~ 8, H-11); 11.0 (1H, s, H-7). Mass spectrum (Finnigan MAT.INCOS 50, 70 eV), m/z (I, %): 280 (100), 262 (30), 251 (19), 233 (4), 224 (22), 206 (33), 195 (17), 179 (9), 166 (13), 154 (7), 140 (12), 124 (32), 116 (14), 89 (9), 78 (31), 63 (8), 51 (12), 41 (25). Calculated: M = 280.38. Found, %: C 72.6; H 7.4; N 20.1. C17H20N4. Calculated, %: C 72.83; H 7.19; N 19.98. 3,3-Dimethyl-1,2,3,4-tetrahydroindolo[2,3-c]quinoline (3). Yield 34%, mp 212-213C (toluene). Rf 0.45 (Silufol UV-254, chloroformpyridine, 10:1). IR spectrum (KBr), , cm-1: 3230, 1625, 1610, 1565. 1 H NMR spectrum, , ppm (J, Hz): 1.02 (6H, s, 3,3-(CH3)2); 1.73 (2H, t, J ~ 6, 2-CH2); 2.67 (2H, s, 4-CH2); 3.42 (2H, t, J ~ 6, 1-CH2); 7.31 (1H, t, J ~ 8, H-10); 7.65 (1H, t, J ~ 8, H-9); 7.82 (1H, d, J ~ 8, H-8); 8.17 (1H, d, J ~ 8, H-11); 8.98 (1H, s, H-6); 12.2 (1H, s, H-7). Found, %: C 81.3; H 7.3; N 11.3. C17H18N2. Calculated, %: C 81.56; H 7.25; N 11.19. 6-Hydrazinocarbonyl-3,3-dimethyl-1,2,3,4-tetrahydroindolo[2,3-c]quinoline (4). Yield 6%; mp 265-267C (chloroform), Rf 0.15 (Silufol UV-254, chloroformpyridine, 10:1). IR spectrum (KBr), , cm-1: 3380-3200, 1655, 1630, 1600, 1575, 1555, 1525. 1H NMR spectrum, , ppm (J, Hz): 1.07 (6H, s, 3,3-(CH3)2); 1.62 (2H, t, J ~ 6, 2-CH2); 2.78 (2H, s, 4-CH2); 3.22 (2H, t, J ~ 6, 1-CH2); 6.97 (2H, br. s, 6-NH2); 7.18 (1H, t, J ~ 8, H-10); 7.24 (1H, t, J ~ 8, H-9); 7.41 (1H, d, J ~ 8, H-8); 8.06 (1H, d, J ~ 8, H-11); 8.39 (2H, br. s, 6-NH); 11.8 (1H, s, H-7). Found, %: C 69.9; H 6.6; N 18.4. C18H20N4O. Calculated, %: C 70.11; H 6.54; N 18.17.
REFERENCES 1. 2. 3. 4. V. I. Dulenko, V. I. Luk'yanenko, A. V. Kibal'ny, A. A. Malienko, and Yu. A. Nikolyukin, Khim. Geterotsikl. Soedin., 363 (1985). O. V. Kibal'ny, A. Nikolyukin, and V. I. Dulenko, Fiziologichno Aktivni Rechovini, No. 2(34), 23 (2002). V. I. Dulenko, I. V. Komissarov, Yu. A. Nikolyukin, O. V. Kibal'ny, O. V. Titievs'kii, and O. Ya. Leshchinsk'ka, Ukr. Pat. 24393A; B. I., No. 5 (1998). N. Isikawa and E. Kobayashi, Fluorine. Chemistry and Applications [Russian translation from Japanese], Mir, Moscow (1982), p. 280.
963
TRANSFORMATIONS OF 5-AMINO4-(3,4-DIMETHOXYPHENYL)PYRAZOLES IN THE DIAZOTIZATION REACTION

I. V. Pavlov, K. I. Kobrakov, and S. L. Bogza Keywords: azo dye, 5-aminopyrazole, cinnoline, azo coupling, diazotization. Diazotization reactions of 5-aminopyrazoles, leading to pyrazolyl-5-diazonium salts, are described in the literature [1, 2]. In the case of aminopyrazoles having a 3,4-dimethyloxyphenyl substituent in the position 4 that readily undergoes electrophilic attack, the reaction does not stop at the diazotization step. Upon nitrosation by sodium nitrite in acetic acid, the diazo compound formed as an intermediate undergoes intramolecular azo coupling to form 1,3-disubstituted 7,8-dimethoxypyrazolo[3,4-c]cinnolines [3].
MeO OMe Cl MeO OMe Cl
NaNO2 H2 N N N N Cl AcOH
N N N N
N Cl
Cl 1 MeO OMe Cl
Cl 2
1) NaNO2, H2SO4 2) ArH Ar N N N N Cl N
3, 4
Cl
3 Ar = 2-hydroxynaphthyl, 4 Ar = p-Me2NC6H4
__________________________________________________________________________________________ A. N. Kosygin Moscow State Technical University, Moscow 119991, Russia; e-mail: office@mstu.ac.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1115-1116, July, 2004. Original article submitted May 6, 2004. 964 0009-3122/04/4007-09642004 Springer Science+Business Media, Inc.
We have established that aminopyrazoles containing the indicated substituent in the position 4, depending on the diazotization reaction conditions, can be converted to either the corresponding cinnoline 2 or to the stable azo compounds 3, 4. The azo compounds obtained are used for synthesis of hetaryl-substituted azo dyes capable of dying textiles made from natural and synthetic fibers under standard conditions, thereby ensuring high stability parameters of the dyed material relative to washing, dry and wet friction. 1-(4-Chlorophenyl)-3-(3,5-dichloropyridin-2-yl)-7,8-dimethoxy-3H-pyrazolo[3,4-c]cinnoline (2). Yield 31%; mp 245-247C. 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 3.90 (3H, s, OMe); 4.07 (3H, s, OMe); 7.52 (1H, s); 7.75 (2H, d, J = 9.6); 8.03 (2H, d, J = 9.6); 8.10 (1H, s); 8.75 (1H, d, J = 2.8); 8.85 (1H, d, J = 2.8). Found, %: C 54.22; H 2.95; N 14.36. C22H14Cl3N5O2. Calculated, %: C 54.29; H 2.90; N 14.39. (E)-1-{[3-(4-Chlorophenyl)-1-(3,5-dichloropyridin-2-yl)-4-(3,4-dimethoxyphenyl)]-1H-pyrazol-5yldiazenyl}naphth-2-ol (3). Yield 70%; mp 170-172C. UV spectrum (EtOH), max, nm (log ): 349 (3.96), 387 (4.0), 438 (4.0), 456 (4.0), 494 (4.0). Found, %: C 54.22; H 2.95; N 14.36. C22H14C3N5O2. Calculated, %: C 54.29; H 2.90; N 14.39. (E)-4-{[3-(4-Chlorophenyl)-1-(3,5-dichloropyridin-2-yl)-4-(3,4-dimethoxyphenyl)]-1H-pyrazol-5yldiazenyl}-N,N-dimethylaniline (4). Yield 62%; mp 185-186C (decomp.). UV spectrum (EtOH), max, nm (log ): 237 (4.79), 316 (3.64), 363 (3.78), 443 (3.92), 482 (3.88). Found, %: C 59.22; H 4.22; N 13.76. C30H25Cl3N6O2. Calculated, %: C 59.27; H 4.15; N 13.82.
REFERENCES 1. 2. 3. H. Reimlinger and A. Van Overstaeten, Chem. Ber., 99, 3350 (1966). M. H. Elnagdi, D.. Fleita, E. A. Hafiz, and S. M. Fahmi, J. Org. Chem., 41, 3781 (1976). S. L. Bogza, Dissertation in competition for the academic degree of Doctor of Chemical Sciences, Moscow (2003).
965
SYNTHESIS AND CHARACTERISTICS OF TETRACYCLIC SYSTEMS OF BENZO[b]FUROINDOLES AND THEIR DERIVATIVES. (REVIEW)
T. E. Khoshtariya Published data on the nomenclature, structure, synthesis, and chemical characteristics of benzo[b]furoindoles with a pyrrole ring fused at various positions in relation to initial tricyclic system of dibenzofuran are reviewed. Keywords: benzofurans, benzo[b]furoindoles, dioxobenzo[b]furoindoles, indoles, nomenclature, Japp Klingemann reaction, FriedelCrafts, VilsmeierHaack, Mannich, Fischer synthesis. Data on unsubstituted benzo[b]furoindoles first appeared in 1984 [1, 2]. Substances with antibacterial activity, including high tuberculostatic activity, were found among their derivatives [3].
1. NOMENCLATURE AND STRUCTURE OF BENZO[b]FUROINDOLES Over the course of time the nomenclature of the tetracyclic systems benzo[b]furoindoles has undergone considerable change. In [1, 2] names of type A were used: Indolo[7,6-d]benzo[b]furan (A1), indolo[4,5-d]benzo[b]furan (A2), indolo[6,5-d]benzo[b]furan (A3), indolo[5,6-d]benzo[b]furan (A4), indolo[5,4-d]benzo[b]furan (A5), and indolo[6,7-d]benzo[b]furan (A6).
1 2 3 4 4 6 5 3 2
HN
7
NH
1
H1 N
2 3
O 1
O 2
O 3
4 5 3 1 2 5 6
5 4
O 4
N H
O 5
1 NH 2 3
O 6
HN
1 3 2
__________________________________________________________________________________________ Georgian Technical University, Tbilisi 380075; e-mail: ibsge@hotmail.com. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1123-1136, August, 2004. Original article submitted July 10, 2000. 0009-3122/04/4008-09672004 Springer Science+Business Media, Inc. 967
In contemporary literature new names of type B, which conform to the IUPAC nomenclature rules and the Ring Index, are used: 1H-benzo[b]furo[2,3-g]indole (B1), 1H-benzo[b]furo[3,2-e]indole (B2), 1H-benzo[b]furo[2,3-f]indole (B3), 1H-benzo[b]furo[3,2-f]indole (B4), 1H-benzo[b]furo[2,3-e]indole (B5), and 1H-benzo[b]furo[3,2-g]indole (B6) [4-7].
1 2 a
HN
10 9 g 8 7 6
b c
1 3 10 9 d e c
b 2 a
NH
3 4 5
d 5 e 4 8 7 6
O 1
O 2
e f
9 8 7 6 5 f
10
H1 N
d
5 2 3 6 7 8 9
c b 1
O 3
a b
3 a 2
O 4
10
N H
6 7 e 8 9 10
5 4 7
6 g
e 4 d c
O 5
d c 1
NH
a 2 b
8 9
10
O HN
1 a 2
3 b
2. METHODS OF SYNTHESIS OF UNSUBSTITUTED BENZO[b]FUROINDOLES The methods for the synthesis of benzo[b]furoindoles can be divided into two main groups: Syntheses based on the amino derivatives of dibenzofurans using the classical E. Fischer reaction [1, 2] and based on the reduction of dioxodihydrobenzo[b]furoindoles (obtained by the Sandmeyer method) with diborane in THF at -78C [4-7].
2.1. Syntheses Based on Amino Derivatives of Dibenzofurans 2.1.1. Synthesis of Dibenzofuranylhydrazones of Ethyl Pyruvate. Of all the methods widely used for the annelation of a pyrrole ring to various types of aromatic and heterocyclic systems (the Reissert, Madelung, Bischler, Fischer, Nenitzescu, JappKlingemann, and a series of other reactions [8-15]) the most suitable in the synthesis of benzo[b]furoindoles was the classical Fischer reaction and its modification based on the Japp Klingemann reaction [1, 2] (Scheme 1). The starting compounds were 1-, 2-, 3-, and 4-aminodibenzofurans 1-4, which were transformed successively into the respective diazonium salts 5-8 and then into the hydrazine hydrochlorides 9-12. The reaction of these hydrazines with ethyl pyruvate leads to the hydrazones 13-16. These hydrazones exist as mixtures of syn (Z) and anti (E) forms with a preference for the latter.
O H N O Z N OEt Me H N O E N Me O OEt
968
Scheme 1
NH2 NaNO2/HCl O 14 N2Cl NHNH2. HCl MeCOCO2Et O 58 O 912 CO2Et NHN Me O 1316 SnCl2
R HN R NH O 1719 O 2022 O 2325 H N R
O 2628
NH R
O 2931
N H
O HN 3234 R
17, 20, 23, 26, 29, 32 R = CO2Et; 18, 21, 24, 27, 30, 33 R = CO2H; 19, 22, 25, 28, 31, 34 R = H
If the JappKlingemann reaction (azo coupling of the respective diazonium salt with acetoacetic ester) is used for the production of the hydrazones 13-16, the so-called azo esters [the ethyl esters of -(dibenzofuranylazo)--acetylpropionic acids] are formed in addition to the mixture of isomeric hydrazones [3, 16-19]. They readily isomerize during the reaction to the respective hydrazones, but sometimes they can nevertheless be isolated and characterized [20, 21]:
O Me N N O CO2Et
969
2.1.2. Conditions for Indolization of the Dibenzylfurylhydrazones of Ethyl Pyruvate. Among the numerous catalysts for the Fischer cyclization [Lewis acids, sulfuric acid in glacial acetic acid, polyphosphoric acid (PPA), alcohol solution of hydrogen chloride] ethyl polyphosphate (EPP) has proved most effective for the production of benzo[b]furoindoles [1, 2]. On the basis of spectral investigations it was established [3] that the anti form of the hydrazones undergoes cyclization. 2.1.3. Synthesis of Isomeric Benzo[b]furoindoles. The cyclization of the 1- and 4-dibenzofuranylhydrazones (13 and 16) of ethyl pyruvate by the action of EPP leads to the formation of the corresponding angular ethyl benzo[b]furo[2,3-g]- and benzo[b]furo[3,2-g]indole-2-carboxylates (17) and (32):
CO2Et HNN Me EPP O 13 O 17 HN CO2Et
EPP O HNN 16 Me 32 CO2Et O HN CO2Et
Indolization of the 2- and 3-dibenzofuranylhydrazones of ethyl pyruvate (compounds 14 and 15) gives a mixture of the corresponding linear and angular ethyl benzo[b]furo[3,2-e]- and benzo(b)furo[2,3-f]-, benzo[b]furo[2,3-e]-, and benzo[b]furo[3,2-f]-2-carboxylates 20 and 23, 26 and 29 in equal proportions [3]:
CO2Et NH CO2Et EPP Me O 14 O 23 O 20 H N CO2Et
H N N
O CO2Et Me O 29 EPP 26
NH CO2Et
O 15
N N H
N H
CO2Et
970
The carboxylic acids 18, 21, 24, 27, 30, and 33 were obtained with quantitative yields by saponification of the respective esters 17, 20, 23, 26, 29, and 32 with a wateralcohol solution of alkali, while the unsubstituted 1H-benzo[b]furoindoles 19, 22, 25, 28, 31, and 32 were obtained by thermal decarboxylation of the acids in an inert gas atmosphere:
N H
CO2Et
O CO2
N H
CO2H
N H
The criteria for the assignment of the synthesized structures to the angular and linear isomers on the basis of the 1H NMR spectra are given in [1, 2].
2.2. Syntheses Based on Dioxodihydrobenzo[b]furoindoles Another original method, based on the use of dioxodihydro-1H-benzo[b]furoindoles (easily obtained by the Sandmeyer reaction) as starting compounds, was described for the construction of the tetracyclic system of benzo[b]furoindoles [4-7]. Reaction of the amino derivatives of dibenzofuran 1-4 with chloral hydrate and hydroxylamine hydrochloride in an acidic medium gave the corresponding isonitrosoacetamidodibenzofurans 35-38, the cyclization of which in sulfuric acid led to the required compounds 39-44:
NOH Cl3CCHO . H2O + NH2OH . HCl O 3538 O N H
14
O HN O
O O NH H N O 41 O NH O O 43 N H O O HN 44 O O O O
O 39
O 40
O 42
971
The heterocyclic systems synthesized in this way are easily reduced to the corresponding indole systems, and the yields and the direction of the process depend on the choice of reducing agent. Thus, the action of lithium aluminum hydride in absolute pyridine gives a mixture of hydroxybenzo[b]furoindoles 45-48 (~40-50%), a small amount of unsubstituted benzo[b]furoindoles 19, 28, 31, and 34, and the unreacted original compounds 39, 42-44. The use of diborane in THF at -78C as reducing agent gave acceptable yields of the corresponding unsubstituted benzo[b]furoindoles 19, 28, 31, and 34 [4-7, 22].
OH O 46 HO NH O 47 O 48 HN OH N H
HN
OH
LiAlH4, NaBH4
O N H O
O 45
O 39, 4244 B2H6
O 34 HN
HN
O 19
O 28
NH
O 31
N H
The results agree fully with published data indicating that isatins are reduced readily and with quantitative yields to indoles [23], while indole itself is fairly resistant to diborane even at room temperature [24].
3. CHEMICAL PROPERTIES OF BENZO[b]FUROINDOLES The behavior of the heterocyclic systems 19, 22, 25, 28, and 31 in some electrophilic substitution reactions typical of the indole system (acetylation, the Vilsmeier reaction, the Mannich reaction, and azo coupling) was described in [25, 26]. In view of the specific affinity of the heterocycles to indole and benzofuran, the obtained results were assessed in comparison with indole and dibenzofuran.
972
3.1. Acetylation It was found that the behavior of the investigated heterocyclic systems during acetylation with acetic anhydride [25, 26] differs substantially from the behavior of indole under analogous conditions [27]. Thus, whereas indole forms a mixture of insignificant amounts of 1-acetyl- and 3-acetylindoles during treatment with pure acetic anhydride while the main product is 1,3-diacetylindole [27], under such conditions the benzo[b]furoindoles 22, 25, 28, and 31 only form the N-acetyl derivatives [25, 26], and the reaction only takes place with prolonged boiling (20-30 h) in acetic anhydride.
COMe N COMe O 49 22, 25, 28, 31 O 50 N
COMe O 51 N O 52 N COMe
The use of a mixture of acetic acid and acetic anhydride for the acetylation of benzo[b]furoindoles does not change the direction of the reaction. Data from the NMR, IR, and UV spectra fully support the structure of the synthesized acetyl derivatives [25, 26]. The nature of the initial fragmentation of the molecular ions of these compounds under electron impact does not depend on the type of fusion of the rings and involves the successive elimination COMe, COCH2, HCN, CS, CO, Me, and other groups (depending on the structure of the compounds), and in some cases this is confirmed convincibly by the corresponding metastable transitions [25, 26]. It is convenient to discuss the acylation of benzo[b]furoindoles in the FriedelCrafts reaction, like all the other chemical characteristics, in comparison with the behavior of indole and dibenzofuran under analogous conditions. It is generally known that unsubstituted indole is resinified in the presence of Lewis acids, 1,3-diacetylindole does not react at all with acetyl chloride in the presence of aluminum chloride [28, 29], while the acetylation of 1-acetyl-2,3-dimethylindole takes place in the benzene ring with the formation of the 6-acetyl derivative [30]. It is also known that in a sufficiently acidic medium indole forms dimers and trimers depending on the acidity of the medium [30, 31]. In the literature there data indicating that it is the substituted benzene ring in the tricyclic system of dibenzofuran that undergoes acetylation by acetyl chloride in the presence of aluminum chloride [32, 33]. In contrast to the behavior of unsubstituted indole and dibenzofuran, under FriedelCrafts conditions the investigated compounds mainly form "dimerization products" with a small amount of the products from acetylation of the indolenine nitrogen atom of the dimer as impurity [34]. As in the case of the indoles [30, 31], this is determined by the ease of protonation of the system. It is interesting that the dimerization of linear benzo[b]furoindoles 25 and 31 takes place considerably more readily than that of the compounds with angular structure 22 and 28 [34]. The authors explain this fact by the different ease of protonation of the linear and angular structures, as was confirmed by kinetic investigations of azo coupling and by data from the 1H NMR spectra (the chemical shifts of the protons at the -position of the pyrrole ring) [34]. In addition a substantial
973
role is probably also played by steric factors: The isomers with linear structures are sterically more accessible for the formation of dimers than the angular structures. The dimers are formed according to the following general scheme:
O 28, 31 O
N H
H N H
1
O H H
1 2
NH
N O 53a, 54
H R
H NH
55a 53a R = H, 54 R = COMe
Depending on the reaction conditions [34], compounds 53b and 55b are also formed in addition to the isomers 53a and 55a, and the ratios of the obtained dimers 53a-53b and 55a-55b are 60:40 and 50:50 respectively:
O O HN 2 H H
3 3
NH H
1
H HN
NH O
53b
55b
It was established experimentally that change in the reaction time substantially affects the ratio of the geometric forms in the case of the linear heterocycles 53a,b and does not affect the ratio of the isomeric dimers with angular structure 55a,b [34]. Thus, if the duration of the reaction of benzo[b]furoindole 31 with acetyl chloride in the presence of aluminum chloride is increased to 2.5-3 h the stereoisomer 53b is fully converted into the stereoisomer 53a. The formation of a small amount of the N-acetyl derivative 54 as impurity is also observed under these conditions.
974
In the case of compound 31 it was shown that the dimer is not formed if the weaker Lewis acid SnCl4 is used in the FriedelCrafts reaction, but the product from acetylation at the -position of the pyrrole ring in the tetracyclic system 56 is formed smoothly [35]:
SnCl4 31 + MeCOCl O 56 N H COMe
3.2. The Vilsmeier Reaction One of the reactions most widely used for the synthesis of the carbonyl derivatives of indole is the VilsmeierHaack reaction [36]. The indole derivatives produced by this reaction are of interest both from the biological standpoint and as intermediate compounds for the synthesis of a whole series of physiologically active substances [37-45]. This was the process that was used for the production of formyl and acetyl derivatives of 1H-benzo[b]furoindoles [25, 26, 46]. The standard Vilsmeier complex N,N-DMFPOCl3 was used as formylating agent. In the given case, as also for the indole derivatives [45], formylation takes place smoothly at the position of the pyrrole ring of the 1H-benzo[b]furoindoles [25, 26]:
O H DMF / POCl3 O N H O 5760 N H
N,N-Dimethylacetamide and N,N-diethylchloroacetamide with phosphorus oxychloride were used as reagents for Vilsmeier acetylation. It was found that in reaction with the N,N-diethylacetamide complex the tetracyclic systems with linear structure 25 and 31 give chlorine-substituted dimers, and as in the case of the FriedelCrafts reaction substitution takes place at the nitrogen atom of the hydrogenated pyrrole ring [34]. The heterocycles with angular structure 22 and 28, like pyrrolocarbazole [47], lead mainly to the product from chloroacetylation at the -carbon atom of the pyrrole ring.
O O H N H
1
N H 25, 31
22, 28
O H
3
NH
N O 61
COCH2Cl
ClCH2OC 62
975
3.3. The Mannich Reaction The N,N-dimethylaminomethyl derivatives of benzo[b]furoindoles are formed readily and with almost quantitative yields in the reaction of compounds 22, 25, 28, and 31 with formaldehyde and an aqueous solution of dimethylamine under the conditions described for indole [48]. It was shown that the reaction takes place unambiguously at the -position of the pyrrole ring both for the linear and for the angular isomers of benzo[b]furoindoles [25, 26].
Me N 22, 25, 28, 31 CH2O, Me2NH O 6366 N H Me
3.4. The Azo Coupling Reaction The effect of weak electrophiles on the course of electrophilic substitution in the benzo[b]furoindole series was investigated for the case of the most selective reagents benzene- and 4-chloro- and 4-nitrobenzenediazonium chlorides [26]. In view of some structural similarity between the indicated heterocyclic systems and indole the reaction was conducted under the usual conditions for indole [49-52]. As for indole, the most suitable reaction medium was a neutral medium, in which the azo coupling process took place without any significant problems. True, the azo coupling with the above-mentioned diazo components takes place readily and fairly smoothly, but the reaction rate and the yields of the azo coupling products bear a distinct relationship to the nature of annelation of the pyrrole ring and the nature of the electrophile. Thus, for example, benzo[b]furoindoles with linear structure 25 and 31 enter into azo coupling considerably more readily than the corresponding isomers with angular structure 22 and 28.
H N NH R O 6769 22, 25, 28, 31 7072 O N N
N N
R O R N N 7375 O 7678 NH
N N
N H
67, 70, 73, 76 R = H, 68, 71, 74, 77 R = p-Cl, 69, 72, 75, 78 R = p-NO2
976
As expected, the largest yields were obtained in the reaction of the heterocyclic systems with p-nitrobenzenediazonium chloride, and the smallest yields were obtained with benzenediazonium chloride [25, 26]. A more detailed analysis of the behavior of isomeric benzo[b]furoindoles was made in [53], which gives a quantitative assessment of the role of annelation of the pyrrole ring in relation to the dibenzofuran system based on kinetic data on the reaction of the isomeric structures with weak and, consequently, selective electrophilic reagents, i.e., arenediazonium fluoroborates. Thus, the published data examined above demonstrate that the synthesis route: tricyclic dibenzofuran system nitro derivative amine hydrazine hydrazone cyclic ester cyclic acid unsubstituted tetracyclic benzo[b]furoindole system [1,2], together with the use of dihydroxy-1H-benzo[b]furoindoles as starting compounds [4-7] make it possible to obtain not only new heterocyclic systems but also to synthesize from them a series of derivatives that are of practical interest.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. T. E. Khoshtariya, M. L. Kakhabrishvili, L. N. Kurkovskaya, and N. N. Suvorov, Khim. Geterotsikl. Soedin., 1366 (1984). T. E. Khoshtariya, M. L. Kakhabrishvili, M. I. Sikharulidze, L. N. Kurkovskaya, and N. N. Suvorov, Khim. Geterotsikl. Soedin., 631 (1985). T. E. Khoshtariya, Thesis for Doctor of Chemical Sciences [in Russian], Moscow (1985). T. O. Dzhashi, T. E. Khoshtariya, L. N. Kurkovskaya, N. T. Mirziashvili, and M. I. Sikharulidze, Khim. Geterotsikl. Soedin., 1419 (1999). T. E. Khoshtariya, T. O. Dzhashi, and L. N. Kurkovskaya, Khim. Geterotsikl. Soedin., 627 (1999). T. E. Khoshtariya, T. O. Dzhashi, T. G. Tsintsadze, M. G. Maisuradze, and N. Z. Chinchinadze, in: Abstracts of International Congress of Pharmacists of Ukraine [in Russian], Kharkov (1999), p. 463. T. E. Khoshtariya, T. O. Dzhashi, T. G. Tsintsadze, and L. M. Tevzadze, in: Abstracts of International Congress of Pharmacists of Ukraine [in Russian], Kharkov (1999), p. 463. A. Reissert, Berichte, 30, 1030 (1897). W. O. Kermack, W. H. Perkin, and R. Robinson, J. Chem. Soc., 1602 (1921). W. Madelung, Berichte, 45, 1128 (1912). A. Bischler, Berichte, 25, 2860 (1892). A. Bischler and P. Fireman, Berichte, 26, 1336 (1893). Z. Phillips, in: Organic Reactions [Russian translation], Inostr. Lit. (1963), Vol. 10, p. 148. B. Robinson, Usp. Khim., 40, 1434 (1971). N. N. Suvorov, V. P. Mamaev, and V. M. Rodionov, in: Reactions and Methods of Investigation of Organic Compounds [in Russian], Goskhimizdat, Moscow (1959), Vol. 9, p. 9. H. C. Iao and P. Resnick, J. Am. Chem. Soc., 84, 3514 (1962). M. N. Popova, V. I. Shishkina, and L. P. Kislitsa, Izv. Vuzov, Khimiya Khim. Tekhnol., 1054 (1973). O. Dimroth and M. Hartman, Berichte, 41, 4012 (1908). H. Henecka, H. Timmler, L. Rudolf, and W. Geiger, Chem. Ber., 90, 1060 (1957). B. Heath-Brown and P. G. Phillott, J. Chem. Soc., 7185 (1965). G. S. Chandler, R. H. Jones, and W. H. F. Sasse, Austr. J. Chem., 18, 108 (1965). T. O. Dzhashi, Thesis for Candidate of Chemical Sciences [in Russian], Tbilisi, 1999. S. A. Monti and R. R. Schmidt, Tetrahedron Lett., 3331 (1971). H. Sirowey, S. A. Khan, and H. Plieninger, Synthesis, 84 (1972). T. E. Khoshtariya, M. L. Kakhabrishvili, M. I. Sikharylidze, L. N. Kurkovskaya, and N. N. Suvorov, Khim. Geterotsikl. Soedin., 355 (1985).
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T. E. Khoshtariya, M. I. Sikharulidze, M. L. Kakhabrishvili, L. N. Kurkovskaya, and N. N. Suvorov, Soobshch. Akad. Nauk GSSR, 117, 325 (1985). J. Joule and E. Smit, in: Fundamentals of the Chemistry of Heterocyclic Compounds [Russian translation], Mir, Moscow (1975), p. 290. G. S. Mosina, Thesis for Candidate of Chemical Sciences [in Russian], Moscow (1970). W. J. Caudion, W. H. Hook, and S. G. P. Plant, J. Chem. Soc., 1631 (1947). H. F. Hibson and G. F. Smith, J. Chem. Soc., 3544 (1957). G. F. Smith, Adv. Heterocycl. Chem., 2, 287 (1963). S. G. P. Plant, K. M. Rogers, and S. B. C. Williams, J. Chem. Soc., 741 (1935). S. G. P. Plant and S. B. C. Williams, J. Chem. Soc., 1142 (1934). T. E. Khoshtariya, L. N. Kurkovskaya, and N. N. Suvorov, Khim. Geterotsikl. Soedin., 986 (1995). T. E. Khoshtariya and L. N. Kurkovskaya, Khim. Geterotsikl. Soedin., 1078 (1995). A. Vilsmeier and A. Haack, Berichte, 60, 119 (1927). G. F. Smith, J. Chem. Soc., 3842 (1954). S. Clementi, P. Linda, and G. Marino, J. Chem. Soc., Chem. Commun., 427 (1972). W. C. Anthony, J. Org. Chem., 25, 2019 (1960). L. M. Preobrazhenskaya, L. M. Orlova, S. S. Liberman, G. S. Mosina, V. G. Avramenko, N. P. Sorokina, and N. N. Suvorov, Khim.-Farm. Zh., No. 1, 32 (1972). L. M. Preobrazhenskaya, L. M. Orlova, Z. G. Starostina, S. S. Liberman, G. P. Sukhlina, and N. N. Suvorov, Khim.-Farm. Zh., No. 10, 5 (1970). B. Paolo, Ann. Chim. Ital., 57, 376 (1967). A. Chattejee and K. M. Bismass, J. Org. Chem., 38, 4002 (1973). H. P. Young, J. Chem. Soc., 3493 (1958). F. N. James and H. P. Saunders, in: Syntheses of Organic Preparations [Russian translation], Inostr. Lit., Moscow (1961), Chap. 11, p. 30. T. E. Khoshtariya, L. N. Kurkovskaya, and N. N. Suvorov, Khim. Geterotsikl. Soedin., 1331 (1996). M. I. Sikharulidze, T. E. Khoshtariya, L. N. Kurkovskaya, and N. N. Suvorov, Khim. Geterotsikl. Soedin., 497 (1981). I. Kuhn and O. Stein, Berichte, 70, 567 (1937). J. H. Binks and J. H. Ridd, J. Chem. Soc., 2398 (1957). R. D. Brown, H. C. Diffin, I. G. Maynard, and J. H. Ridd, J. Chem. Soc., 3937 (1953). V. G. Avramenko, V. D. Nazina, and N. N. Suvorov, Khim. Geterotsikl. Soedin., 1071 (1970). V. D. Nazina, Thesis for Candidate of Chemical Sciences [in Russian], Moscow (1970). N. K. Genkina, L. N. Kurkovskaya, T. E. Khoshtariya, and N. N. Suvorov, Zh. Org. Khim., 21, 1552 (1985).
978
INVESTIGATION IN THE AREA OF FURAN ACETAL COMPOUNDS. 13*. SYNTHESIS AND STRUCTURE OF 1,3-DIOXACYCLANES BASED ON FURFURAL AND GLYCEROL
E. V. Gromachevskaya, F. V. Kvitkovsky, E. B. Usova, and V. G. Kulnevich The optimum conditions were found for the condensation of glycerol with furfural. It was shown that the reaction of glycerol with furfural gives a mixture of the cis and trans isomers of five- and six-membered furan 1,3-dioxacyclanes. The cis- and trans-5-hydroxy-2-furyl-1,3-dioxanes were isolated by column chromatography, and their stereochemical structure was established by IR and NMR spectroscopy. Keywords: glycerol, 1,3-dioxane, 1,3-dioxolane, stereoisomers, conformation. Owing to the wide range of useful characteristics found among the numerous derivatives of furan one of the most promising and vigorously developing branches of the chemistry of heterocycles is the chemistry of furan compounds. Intensive study of cyclic furan acetals has made a substantial contribution to the development of stereochemistry and has opened up new wide-ranging possibilities for the production of practically valuable substances. The high biological activity of furan 1,3-dioxacyclanes is well known [2-5]. Acetalization of furan aldehydes by various diols is usually employed for the production of cyclic furan acetals [6-10]. By kinetic investigation of this process it was possible to formulate theories concerning the mechanism of the reaction and to perfect a synthesis procedure ensuring minimal resin formation [1, 11-13]. The use of glycerol in this reaction is interesting in respect of both the development of the chemistry of heterocyclic compounds and the production of substances that are structurally similar to natural compounds. It is known [14-26] that glycerol enters into condensation with carbonyl compounds under the conditions of acid catalysis in an inert medium, forming 1,3-dioxacyclanes. The condensation of glycerol with ketones leads to 2,2disubstituted 4-hydroxymethyl-1,3-dioxolanes [14, 17-21], while condensation with aldehydes leads to the formation of a complex mixture of isomers, i.e., the cis and trans forms of 2-substituted 4-hydroxymethyl-1,3dioxolanes and 5-hydroxy-1,3-dioxanes [22, 23, 26-29]. There are data on the separation of the isomers, i.e., the products from the reaction of benzaldehyde and acetaldehyde with glycerol, and their identification by spectral methods [22, 26-32]. There are few publications on the synthesis of 1,3-dioxacyclanes by the reaction of furan aldehydes with glycerol [33, 34], and they do not report on the isomeric composition, the fine structure, or the characteristics of the compounds that are formed. We realized the reaction of glycerol with furfural [35] and as a result obtained a product in the form of a thick viscous liquid (Table 1), which will subsequently be called furfurylideneglycerol. _______ * For Communication 12, see [1]. __________________________________________________________________________________________ Kuban State Technological University, Krasnodar 350072, Russia; e-mail: Chem_Elena@mail.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1137-1144, August, 2004. Original article submitted October 8, 2001; revision submitted February 6, 2003. 0009-3122/04/4008-09792004 Springer Science+Business Media, Inc. 979
The 1H NMR spectrum of furfurylideneglycerol contains signals for the protons of the furan ring, the respective multiplet bands of the methylene and methine protons of the dioxacycle and the hydroxyl proton in the region of 4.3-3.4 ppm, and four singlet signals at 5.9, 5.8, 5.6, and 5.4 ppm, which we assigned to the H-2 proton of the 1,3-dioxacyclane (Table 2). A spectrum of such a type makes it possible to suppose that the product from the reaction of furfural and glycerol represents a mixture of four isomers of five- and sixmembered 1,3-dioxacyclanes having two substituents. By column chromatography of the condensation product we isolated three fractions, i.e., two crystalline fractions and one liquid.
H OH O O + HO OH O 1 O H O Hb O Ha Ha Hb Hx
O O O O O 4 OH 3 O HO O O O 2
OH
In the region of 5.4-5.6 ppm the 1H NMR spectra of the substances contain a single singlet, which corresponds to the resonance of the H-2 proton and demonstrates the individuality of the compounds. Analysis of the 1H NMR spectra of the crystalline compounds makes it possible to assign them the structure of 1,3-dioxane derivatives 1 and 2; the presence of a multiplet with intensity of 1H at 3.2 and 3.6 ppm, corresponding to the H-5 proton of the dioxane ring, and the splitting of the signal for the proton of the OH group into a doublet with J = 7.7 Hz indicate a vicinal arrangement for the Hx proton and the OH group [36]. In the 1H NMR spectrum of the isomer 1 the two multiplets at 3.9 and 4.1 ppm correspond to the H-4 and H-6 protons. The axial and equatorial protons are not equivalent. The difference in the chemical shifts of their signals ( = 0.2 ppm) confirms the chair conformation of the 1,3-dioxane ring in compound 1 [37]. The spinspin coupling constant of the Ha, Hb, and Hx protons, forming an ABX system, is J = 3.5 Hz. According to the Karplus rule [36] this indicates that they have a mutually skewed orientation, which is only possible with the equatorial arrangement of the H-5 proton and, consequently, the axial arrangement of the OH group. In the light of the foregoing and of the fact that the furan fragment as a "heavy substituent" occupies the equatorial position [38] it can be assumed that the 1,3-dioxane 1 has the cis configuration. The 1H NMR spectrum of the isomer 2 contains multiplet bands at 3.5 and 4.0 ppm, corresponding to the axial (Ha) and equatorial (Hb) protons at the C(4) and C(6) atoms and indicates that the isomer has the chair conformation. The bands at 4.4 ppm were assigned to the hydroxyl proton and that at 3.2 ppm to the Hx proton at the C(5) atom. On the basis of the 1H NMR spectrum and data in [27] it is possible to give the isomer 2 the structure of trans-2-(2-furyl)-5-hydroxy-1,3-dioxane in the chair conformation with an axial Hx proton and the trans arrangement of the furan ring and the hydroxyl group. In the 1H NMR spectrum of the liquid fraction there are two signals of almost equal intensity at 5.9 and 5.8 ppm, belonging to the protons at the C(2) atom of the five-membered heterocycle [27]. Consequently, the liquid fraction represents a mixture of isomers, i.e., cis- and trans-2-(2-furyl)-4-hydroxymethyl-1,3-dioxolanes 3 and 4 in approximately equal proportions. Multiplet bands at 3.9-4.4 ppm correspond to the resonance of the protons at the C(4) and C(6) atoms of the 1,3-dioxolane ring and the protons of the hydroxymethyl group. 980
TABLE 1. The Physicochemical and Spectral Characteristics of 2-Furyl-1,3-dioxacyclanes

IR spectrum (vaseline oil), , cm-1 Compound bp, C/mm, mp, C Density d17 Refractive index nD17 Rf (hexaneether 1:1) OH Furfurylideneglycerol 150157/9 1.2673 1.5037 3400 (3645 3604)* 3230 (3604)* C=CH ar 3140, 3110, 1600, 1570 3140, 3110, 1600, 1570 3140, 3110, 1610, 1380 3140, 3110, 1600 OCO 1150, 1080, 1010 1150, 1080, 1000 1140, 1090, 1025 1150, 1100, 1080, 1020 212.8 (3.93)
UV spectrum (water), max (log ), nm
6364
0.16
214.6 (3.89)
5758
0.26
3250
3, 4
1.2484
1.5013
0.22
3400
_______ * In CCl4.
981
982
TABLE 2. The 1H NMR Spectra of 2-Furyl-1,3-dioxacyclanes

Chemical shifts, , ppm (J, Hz) Compound* Furan protons -5 -3, -4 7.5 (1, m) 7.5 (1, dd, J35 = 0.8, J45 = 1.8) 6.3 (2, m) 6.4 (2, m) -2 5.9, 5.8, 5.6, 5.4 (1, s, s, s, s) 5.6 (1, s) -4, -6 (22) 4.3-3.4 (6, m) 3.9 (2,dddd, Ha -4, a -6); 4.1 (2,dddd, b -4, b -6, 2 J44 = 2J66 = 11.5, 3 J = 3J = 3.5, 4 J = 1.5, 4J =0.75) 3.5 (2, m, a -4, a -6); 4.1 (2, m, b-4, b-6) 3.9-4.4 (5, m) 3.6 (1, ddd, J=7.7, 3 J = 3J = 3.5)
3
-5
Furfurylideneglycerol 1
4.2 (1, d, 3 J=7.7)
2 3, 4
6.3 (2, m) 7.4 (1, t, J35 = 0.8, J45 = 1.8) 7.4 (1, m) 6.4 (2, m)
5.4 (1, s) 5.9, 5.8, (1, s, s)
3.2 (1, m)
4.4 (1, br. s) 2.8 (1, br. s)
_______ * The spectra of furfurylideneglycerol, of the compounds 1 and 2 were recorded in (CD3)2CO, of the compounds 3 and 4 in CD2Cl2. The spectrum of compound 1 was obtained on a Bruker AC-200P instrument.
The furan protons of the isomers 1-4 resonate in the usual regions for these protons [39]. Thus, the product from the acid-catalyzed reaction of furfural and glycerol contains all four isomers 1-4. The ratios of the various isomeric forms 1:2:3:4 in the reaction product, determined by means of the 1H NMR spectrum by integration of the bands in the region of 5.3-5.9 ppm corresponding to the resonance of the H-2 protons of each of the four isomers, amount to 15:10:40:35. In the IR spectra of furfurylideneglycerol and compounds 1-4 there is a series of bands characteristic of the absorption of the OCO fragment in the region of 1110-1150 cm-1, the furan ring at 1570-1600 cm-1, and the stretching vibrations of the hydroxyl group at 3110-3140 cm-1. In the IR spectra of dilute solutions of furfurylidene in carbon tetrachloride there are two absorption bands at 3645 and 3604 cm-1, while for compound 1 there is one band at 3604 cm-1 (Table 1). The higherfrequency absorption band was assigned to the vibrations of the free hydroxyl group [40, 41], while the absorption at 3604 cm-1 was assigned to an intramolecular hydrogen bond [41, 42]. The high stability of the configuration of this isomer 1 can be explained by the presence in the molecules of the isomer 1 of an intramolecular hydrogen bond between the hydrogen atoms of the hydroxyl group and the oxygen atoms of the heterocycle. The electronic spectra of furfurylideneglycerol and the 1,3-dioxane 1 contain one absorption maximum in the ultraviolet region at 213 and 215 nm respectively. The synthesis of furan acetals is traditionally conducted in benzene solution in the presence of acidic catalysts KU-2 in the H+ form [34] and p-toluene(benzene)sulfonic acid [34] with the reagents in various ratios [34, 35]. We determined the optimum conditions for the synthesis, making it possible to realize the condensation of furfural with glycerol with yields of 70-75%: Equimolar proportions of the reagents, catalyst p-toluenesulfonic acid (0.03% on the total mass of the initial reagents), solvent benzene. The reaction is conducted in the boiling solvent for 3-3.5 h with azeotropic distillation of the water that forms. The ratios of the products 1:2:3:4 in the product obtained under the above-mentioned conditions amounted to 15:10:40:35 (here and subsequently determined from the 1H NMR spectra). Furfurylideneglycerol, which is a mixture of isomers 1-4 with the composition indicated above, is stable at room temperature for three months, in contrast to the unstable analog benzylideneglycerol [27]. After three months the composition of furfurylideneglycerol changes; the five-membered rings isomerize to the more stable six-membered rings, and the acetals subsequently decompose (furfural appears as impurity). If the temperature is reduced (~2-3C) the furfurylideneglycerol remains for ~6 months. It was established that the various temperature and time factors for the realization of the reaction lead to change in the ratio of the isomers, and this agrees with the theories put forward in [24, 29-31]. If the temperature of the reaction medium is increased to 110C (solvent boiling toluene) and the reaction rate in increased, the five-membered isomers 3 and 4, which are kinetically controlled products [the ratios of the acetals 1:2:3:4 amount to 10:5:45:40], predominate in the reaction product. With decrease in the rate of the process at room temperature (the reaction time amounts to several days) the dioxolane 3 and 4 and dioxane 1 and 2 derivatives are formed in approximately identical amounts. (The ratios of the acetals 1:2:3:4 amount to 30:18:27:25.) Here, however, the overall yield of the product decreases appreciably in the first case as a result of resin formation and in the second as a result of the low reaction rate.
EXPERIMENTAL The IR spectra were recorded on a Specord-71 instrument at room temperature. The 1H NMR spectra were recorded on Tesla BS-467 (60 MHz, internal standard HMDS) and Bruker AC-200-P (200 MHz, internal standard TMS) instruments. The 13C NMR spectrum was recorded on a Bruker AM-300 instrument (75 MHz) in deuterochloroform with TMS as internal standard. The electronic spectra were recorded in ethanol on a Specord UV-Vis spectrophotometer. 983
Conditions for the Reaction of Furfural with Glycerol. In a three-neck flask fitted with a stirrer, a reflux condenser, and a DeanStark tube we placed furfural (19.2 g, 200 mmol), glycerol (18.4 g, 200 mmol), benzene (80 ml), and p-toluenesulfonic acid (0.011 g). The mixture was boiled for 3 h with stirring. The end of the reaction was determined by the cessation of the deposition of water in the trap. After distillation of the solvent the product was isolated by vacuum distillation. We obtained 25.5 g (75%) of the condensation product. Found %: C 56.8; H 5.40. C8H10O4. Calculated %: C 56.5; H 5.90. Distribution of the Isomers of 2-Furyl-1,3-dioxacyclanes. The mixture of isomers weighing 1.2 g was separated on a column (3.5 18 cm) of silica gel L 40/100 with mixtures of hexane and ether in ratios of 7:3 (450 ml) and 1:1 (350 ml) or ether (300 ml) as eluant. With the first mixture of solvents we eluted 0.05 g of the oily compound 2, which gradually crystallized. With the second mixture we eluted 0.75 g of a liquid fraction containing the acetals 3 and 4. With ether we eluted the crystalline compound 1. The separation of the isomers was monitored by TLC on Silufol UV-254 plates with a 1:1 mixture of hexane and ether as eluant. A 2N solution of 2,4-dinitrophenylhydrazine was used as developer. cis-Hydroxy-2-(2-furyl)-1,3-dioxane (1). 13C NMR spectrum, , ppm: 63.2, 67.7, 77.5, 98.5 ((5), (4), (6), (2) (1,3-dioxacycle), 109.6, 113.4, 143.9, 152.0 ((3), (4), (2), (5) (furan ring).
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34. 35.
36. 37. 38. 39. 40. 41. 42.
N. A. Preobrazhenskii and R. P. Evstigneeva (editors), Chemistry of Biologically Active Natural Compounds [in Russian], Khimiya, Moscow (1976), p. 236. M. M. Murza, M. G. Safarov, and G. N. Miftakhova, Zh. Org. Khim., 21, 1550 (1985). D. I. Ismailov, A. V. Gulin, and S. S. Sabirov, Dokl. Akad. Nauk Tadz. SSR, 386 (1984). A. Plasecki, Pol. J. Chem., 58, 1215 (1984). J. Kempe and G. Kiessling, Z. Chem., 26, No. 3, 97 (1986). B. Serdarevich, Can. J. Biochem., 44, 743 (1966). G. T. Teregulova, L. Z. Rol'nik, and S. S. Zlotskii, Zh. Prikl. Khim., 64, 1591 (1991). J.-L. Gras, H. Dulphy, C. Marot, and P. Rollin, Tetrahedron Lett., 34, 4335 (1993). M. Ihara, Y. Takino, M. Tomotake, and K. Fukumoto, J. Chem. Soc., Perkin Trans. 1, 2287 (1990). B. Serdarevich, J. Am. Oil Chem. Soc., 44, No. 4, 38 (1967). J. Gelas, Bull. Soc. Chim. France, 2341 (1970). J. Gelas, Bull. Soc. Chim. France, 4041 (1970). E. L. Eliel, Stereochemistry of Carbon Compounds [Russian translation], Mir, Moscow (1965), p. 195. J. Gelas, Bull. Soc. Chim. France, 566 (1991). J. Gelas, Bull. Soc. Chim. France, 1300 (1969). E. A. Kantor, R. S. Musavirov, and M. A. Khusainov, in: Synthesis Based on Petrochemical Products [in Russian], Novosibirsk (1990), p. 219. Z. I. Zelikman, V. G. Kul'nevich, and V. G. Kalashnikova, in: Chemistry and Chemical Technology. Collection of Scientific Papers of Krasnodar Polytechnical Institute [in Russian], Krasnodar (1973), p. 17. J. Kuleiza and A. Kanulski, Zesryty Nauk. Politech. Lodz. Chem. Sporyweza, No. 8, 27 (1963). E. V. Gromachevskaya, N. I. Nen'ko, E. B. Usova, V. G. Kulnevich, V. P. Smolyakov, F. V. Kvitkovsky, and V. G. Kalashnikova, Russian Federation Pat. 2138164; Byull. Izobr., No. 27, 142 (1999). B. I. Ionin and B. A. Ershov, in: NMR Spectroscopy in Organic Chemistry [in Russian], Khimiya, Leningrad (1967), p. 15. E. A. Kantor, A. N. Syrkin, L. F. Lapuka, R. S. Musavirov, and R. A. Rakhmankulov, NMR Spectroscopy of Oxygen-Containing Heterocycles [in Russian], Ufa (1980). Yu. Yu. Samitov, Atlas of Nuclear Magnetic Resonance Spectra of Stereoisomers [in Russian], Vol. 2, Kazan, (1983), p. 196. E. Ya. Lukevics (editor), Advances in the Chemistry of Furan [in Russian], Zinatne, Riga (1978). H. Buc and J. Necl, Comp. Rend., 252, No. 12, 1786 (1961). A. B. Foster, A. H. Hainls, and M. Stacey, Tetrahedron, 16, 177 (1961). N. Baggett, J. S. Brimacombe, A. B. Foster, and M. Stancey, J. Chem. Soc., 2574 (1960).
985
FEATURES OF THE REACTION OF HETEROCYCLIC ANALOGS OF 2'-ALKOXYCHALCONES WITH LANTHANIDE SHIFT REAGENTS
A. V. Turov, A. A. Tkachuk, and V. P. Khilya The reaction of lanthanide shift reagents with the heterocyclic analogs of substituted 2'-alkoxychalcones was studied. It was shown that the coordination of Eu(fod)3 and Yb(fod)3 with them takes place in different ways. The former forms mainly adducts of the chelate type with participation of the oxygen atoms of the carbonyl and alkoxyl groups in coordination, while from the latter only the adduct at the carbonyl group is obtained. For this reason it was concluded that there are some limitations to the use of the reagents for conformational analysis of organic compounds. It was shown that they can only be used to study the conformational movements of the molecules not affecting the complexation process. Keywords: heterocyclic analogs of chalcones, lanthanide shift reagents, configuration, lanthanideinduced shifts. Lanthanide shift reagents (LSR) make it possible to obtain extremely useful information on features of the structure of a molecule in solution [1, 2]. However, individual aspects of the reaction of the LSR with organic donor molecules have so far been insufficiently studied. In particular, this concerns their coordination with bifunctional compounds, which include chalcones and their heterocyclic analogs (physiologically active substances and synthons for the production of various flavonoids and isoflavonoids [3-5]. In view of the importance of the compounds a series of papers have been devoted to determination of details of their structure [6-9]. In spite of the simplicity of the molecule of chalcone or its analogs with general formula 1, on account of the presence of the enone fragment containing three single bonds (a, b, and d) the existence of eight planar conformers is possible. The realization of one or the other conformer can be determining in the biological activity of these substances. Compounds of type 1 can be investigated by means of lanthanide shift reagents.
OR1 R2 O a 1 b c d Het
Het = 2-thiazolyl, 2-benzofuryl, 2-pyridyl; R1 = CH2Ph, H; R2 = alkyl
__________________________________________________________________________________________ Taras Shevchenko Kiev National University, Kiev 01033, Ukraine; e-mail: nmrlab@univ.kiev.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1145-1151, August, 2004. Original article submitted November 27, 2001; revision submitted January 28, 2003. 986 0009-3122/04/4008-09862004 Springer Science+Business Media, Inc.
Significant paramagnetic shifts are observed in the 1H NMR spectra of their solutions containing Eu(fod)3 [4, 10, 11]. Unusual here was the more active interaction of this LSR with the 2'-benzyloxy derivatives compared with the corresponding phenols (R1 = H), although the steric hindrances to complexation at the carbonyl group (the most effective coordination center of the carbonyl of chalcones) are increased during 2'-alkylation. The observed lanthanide-induced shifts (LIS) indicate a specific direction of coordination; the LSR reacts to a significant degree at the oxygen atom of the 2'-OCH2Ph group, which usually has a small capacity for coordination. Since the participation of the ether oxygen atom in complexation with the LSR has not in the course of time obtained a rational explanation, it was studied in greater detail in the present work; the reaction of the analogs of chalcones 2-4 (Table 1) with such lanthanide shift reagents as Eu(fod)3 and Yb(fod)3 was investigated.
Cl R2O
4' 3' 2' 5'
OCH2R
1 7
6 5
R3O
6'
O 2ac Me O
2
O
7 3' 4' 5' 6' 2' 6
Me
5 4
OCH2Ph O O 3
3
Me
Me
4' 5'
3'
OCH2COOMe
2' 7
O
2 3
4
5
6'
2 a R1 = Ph, R2 = Cl, R3 = H; b R1 = Ph, R2 = F, R3 = H; c R1 = OMe, R2 = H, R3 = OCH2OMe
During the coordination of Eu(fod)3 with compounds 2c, 3, and 4 the previously described effect was observed; it takes place to a significant degree at the oxygen atom of the 2'-OCH2R1 fragment. This is demonstrated by the larger lanthanide-induced shifts of the signal for the protons of its CH2 group compared with the LIS of the signals for the olefinic protons and the 6'-H proton in the ArCO fragment of the molecule (see Table 1). The presence of the halogen atom at position 5' (compounds 2a,b) weakens the coordination between the ether oxygen atom and the LSR, which increases substantially with substitution of the substituent R1 = CH2Ph by the less bulky R1 = Me (in compound 2c) or R1 = CH2COOMe (in compound 4). For example, in the case of compound 2c the signal for the protons of the 2'-OCH2 group has a lanthanide-induced shift of 7.8 ppm, whereas the signals of the olefinic protons are shifted by only 3.0 ppm. The reaction of compounds 2-4 with the LSR Yb(fod)3 takes place in a different way. In this case the largest lanthanide-induced shifts are observed for the signal of the 6'-H proton of the ArCO fragment and the signals of the olefinic protons, whereas the shifts of the signals for the protons of the 2'-OCH2 group are significantly smaller. This indicates preferred coordination of the LSR at the carbonyl group of the chalcone. Such a conclusion is confirmed by calculations of the structure of the LSRsubstrate adducts on the assumption that they are purely dipolar in nature and that there is only one coordination center, i.e., the oxygen atom of the carbonyl group.
987
The McConnelRobertson equation:

i
expt
= Ki (3 cos2 i 1) / ri3
where iexpt is the experimental LIS for nucleus i and i and ri are the polar coordinates of the nucleus in the adduct, is widely used to calculate the structure of the adducts. The method proposed in [12] is based on the fact the constant K is the same for all magnetic nuclei of a given type. In this case the calculation amounts to a search for a point close to the coordination center where the equation presented above is fulfilled in the best way. We obtained the degree of spread of the calculated Ki values from the average Kav in the form of the standard deviation , where:
2 = [ (Ki Kav)] / (n 1),

i=1
where n is the number of magnetic nuclei used in the calculation. Thus, if three-dimensional coordinates are placed along the two coordinate axes while the standard deviation is placed along the third axis, we obtain a three-dimensional diagram of the values of the standard deviation at each point of space. For the adducts of Yb(fod)3 with the chalcones 2-4 it was found that the Yb atom in the adduct lies at a distance of 2.5-2.6 from the carbonyl oxygen atom on a continuation of the C=O bond, while the calculated lanthanide-induced shifts agree well with the experimental values (Table 1). The results of one such calculation for the adduct of Yb(fod)3 with compound 4 without allowance for the LIS of the signals for the protons of the heterocyclic fragment are shown in Fig. 1 as an example. The coordinates of the atoms in the molecule were determined by minimizing its energy by molecular mechanics. In the figure the planar ArCOCH=CH fragment lies in the XY plane, the C=O bond is directed parallel to the X axis, and the carbonyl oxygen atom is at point (0, 0). The standard deviation lies along the Z axis. In accordance with [12] the minimum corresponds to a point in space for which with localization of the Yb ion at this point there is a better correlation between the calculated and experimental values. This indicates that the calculation agrees with the selected model of complexation, i.e., that coordination of the LSR takes place exclusively at the carbonyl oxygen atom. Attempts to conduct analogous calculations for the europium adducts of compounds 2-4 were unsuccessful. The observed LIS cannot be interpreted in terms of the existence of the molecule in only one conformation with coordination of the LSR at one coordination center (the carbonyl or ether oxygen atom). We tried to calculate the LIS for these adducts on the assumption that the experimental lanthanide-induced shifts (iexpt) represent the sum of LIS taken with different weight contributions (n) due to coordination of the LSR at the carbonyl group of two conformers with respect to bond a. In one of them the oxygen atom of the substituent 2'-OCH2R1 is at the shortest distance to the carbonyl group (the s-cis conformer), while in the other it is at the longest distance from it (the s-trans conformer): iexpt = ni cis + (1 n)i trans It was found that even the given approximation does not lead to satisfactory correlation of the calculated and experimental LIS. A third possible approach was based on the idea that the molecule exists in the indicated conformations with a different coordination of the LSR in each of them. It is probably such a situation that is realized in practise. For this model of complexation, however, the search for the minimum of the standard deviation must be made for seven unknowns (the three coordinates of the lanthanide in the two adducts and their ratio), which requires the use of too large an amount of independent LIS in the calculations.
988
TABLE 1. The 1H NMR Spectra of the Investigated Compounds

LIS (in CDCl3), , ppm COCH=CH 5'-H 6'-H -H -H 2,2-H2 or 3-Me 1.1 1.4 {-2.47} (1.65) 1.0 1.1 {-2.77} (1.85) 0.1 0.8 {-5.3} (3.1) 0.5 -2.5 {-2.9} 3,3-H2 or 4,4-H2 1.1 1.4 {-0.39} (0.68) 1.0 1.1 {-0.44} (0.75) 0.4 0.8 {-8.4} (1.45) 0.2 -2.5 (-2.9)
Version of spectrum 2'-CH2 3'-H
ArCO 4'-H or 4'-Me 1.5 3.0 {1.3} 1.8 3.0 {1.4} 0.3 1.6 {1.5} 0.9 1.7 {2.5} 0.7 1.4 {2.4}
Het 5-H 6-CH3 or 8-H 7-H
2a+Eu(fod)3 2a+Yb(fod)3
3.1 2.4 {2.3} 3.4 2.4 {2.6} 7.8 7.1 {5.0} 6.9 7.1 {6.7} 6.8 {6.3} 7.8 {6.3}
2.5 3 {2} 2.7 3.0 {2.3} 4.0 6.5 {4.4} 3.4 2.0 {5.7} 4.2 6.6 {5.5}
3.8 10.1 {10.1}
2.9 8.4 {6.0} 3.5 8.8 {6.6}
3.5 10.8 {10.2) 4.4 11.4 {11.4}
0.3 0.5 {0.26} 0.3 0.5 {0.3} 0.4 0.9 {0.6} 0.2 0.7 (0.7) -0.6-0.5 0.2 {-0.7} (2.6)
2b+Eu(fod)3 2b+Yb(fod)3
5.1 11.3 {11.3}
2c+Eu(fod)3 2c+Yb(fod)3
1.1 2.3 {2.0} 4.1 2.0 {2.6} 0.9 2.8 {2.4}
5.0 21.7 {21.7}
3.0 14.6 {12.8} 3.3 19.1 {17.1} 2.2 17.3 {16.1}
2.9 17.4 {22.0} 4.1 26.1 {29.5} 2.2 20.9 {27.7}
0.5 1.4 {2.69} (-0.81) 0.5 1.0 {3.0} (-0.91) 0.3 1.6 {-5.9} (1.7) 0.2 0.7 {0.7}
3+Eu(fod)3 3+Yb(fod)3 4+Eu(fod)3 4+Yb(fod)3
6.3 29.1 {29.1} 4.3 27.4 {27.4}
0.2 1.7 (2.4)
2.4 {7.1} (-0.8)
0.7 {-1.4} (7.3)
_______ * The found and calculated lanthanide-induced shifts of the signals for the protons are given. (The calculated lanthanideinduced shifts for the s-trans conformers in relation to bonds a and d are given in braces, and those for the s-cis conformers in relation to bond d are given in parentheses.)
989
Fig. 1. The results from calculation of the structure of the adduct of Yb(fod)3 with compound 4. The dependence of the standard deviation on the XY coordinates is represented by a three-dimensional surface, the minimum of which corresponds to the position of the Yb ion in the adduct. The coordination center is at the origin of the coordinates. For clarity of definition of the coordinates of the minimum a projection of the three-dimensional surface onto the XY plane is shown.
The participation of the ether oxygen atom in complexation with Eu(fod)3 is an effect related to the interaction of the LSR with certain other bifunctional compounds described recently [1]. This fits well with the concept of chelation of the bidentate ligand with the LSR, since the observed differences in the coordination of the europium and ytterbium LSR are similar to those described recently for other compounds, such as substituted thiones [13]. It can be concluded on the basis of the observed LIS that the molecules of the investigated compounds in the adducts with various lanthanide shift reagents are in different conformations in relation to bond a. In the adducts with Yb(fod)3, in which coordination takes place exclusively at the carbonyl group (without chelation), the s-trans conformation is present (see above). Here the 2'-OCH2R1 group is distant from the coordination center, and small LIS are observed for its protons. In the adducts with Eu(fod)3, for which a chelate structure is realized, the molecule has the s-cis conformation. In this case the 2'-OCH2R1 group is close to the lanthanide ion, and significant (in relation to the other signals) LIS are observed for its protons. Thus, the conformation of a molecule of type 1 in relation to bond a in the adduct, determined by the LSR method, depends on the shift reagent employed. However, this does not necessarily mean that complexation with the LSR affects the conformation of the molecule; with decrease in temperature there is no significant change in the ratios between the observed LIS, and so there is no redistribution of the weight contributions from the individual conformations of the molecule. Thus, when the spectra are measured at 260 K, there is a small increase in all the LIS, which fits fully into Bleaney's theory of pseudocontact interaction [14]. It can be supposed that when several conformations are realized simultaneously for the molecule and the lifetime of each of them significantly exceeds the time for which the LSRsubstrate exists the LSR reacts with the individual conformer almost independently. If coordination of the molecule with the LSR is possible in all its conformations, the resultant LIS will be averaged for all of them, and from their values it is possible in principle to find the conformational composition of the molecule. Such a situation is realized during coordination of the investigated compounds 2-4 with Eu(fod)3. If, however, coordination of the molecule with the LSR does not occur in one of the conformations (as in the case of the reaction of compounds 2-4 with Yb(fod)3) the resultant LIS are determined only by one or the other conformation in which complexation of the molecule with the LSR is possible. Other
990
Standard deviation,
conformations are not revealed by means of the LSR, and starting from analysis of the LIS it is possible to show that they are not realized at all. In this case, however, they can be detected by other methods, e.g., by NOE (see, for example, [15]). The question arises in this connection of the justification for using lanthanide shift reagents in the conformational analysis of compounds of type 1, since the obtained stereochemistry of the molecule in the adduct cannot correspond to the true conformational composition in the solution. The use of lanthanide shift reagents should probably be restricted to cases where change in the conformation of the molecule does not substantially affect the coordination with the LSR. For the analogs of the chalcones, although it is not possible by means of Yb(fod)3 to determine the conformational composition in relation to bond a, it is possible to judge the orientation of the heterocyclic fragment in relation to bond d, since with any degree of its rotation about this bond the interaction of the molecule with the LSR takes place in an identical way. Thus, the appreciable diamagnetic shift of the 3-CH3 group in the adduct of compound 3 with Yb(fod)3 indicates the s-cis orientation for the benzofuran fragment in relation to bond d, in which this group is closer to the lanthanide, agreeing well with the results from calculation of the LIS. In the other investigated adducts with Yb(fod)3 there is an equilibrium between the two conformations of the heterocyclic fragment, since the values of the experimental LIS lie between those that can be calculated for the s-trans and s-cis conformers in relation to bond d.
EXPERIMENTAL The 1H NMR spectra of the investigated compounds were measured on a Bruker WP-100-SY spectrometer (100 MHz). Commercial lanthanide shift reagents were used without further purification. The syntheses of compounds 2-4 and 1H NMR spectra were described in [16, 17].
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. A. V. Turov and V. P. Khilya, Khim. Geterotsikl. Soedin., 723 (1996). U. Bologa, A. Schiketanz, C. Musat, D. Vilicica, C. Draghici, M. D. Gheorghiu, and A. T. Balaban, Rev. Roum. Chim., 34, 1131 (1989). D. R. Dhar and D. Barton, The Chemistry of Chalcones and Related Compounds, John Wiley & Sons, New York (1981), p. 285. L. G. Grishko, A. V. Turov, M. G. Spasenov, and V. P. Khilya, Khim. Geterotsikl. Soedin., 1202 (1981). Gy. Litkei, T. Patonay, R. Bognar, V. Khilya, A. Aitmambetov, A. Turov, and F. Babichev, Pharmazie, 39, 741 (1984). N. G. Furmanova, N. I. Sorokina, V. I. Andrianov, U. Bologa, and T. Balaban, Struct. Chem., 2, 651 (1991). A. V. Turov, V. P. Khilya, and D. Litkei, Khim. Geterotsikl. Soedin., 244 (1994). A. V. Turov and V. P. Khilya, Khim. Geterotsikl. Soedin., 457 (1994). A. V. Turov, A. Aitmanbetov, and V. P. Khilya, Ukr. Khim. Zh., 59, 62 (1993). L. G. Grishko, A. V. Turov, I. A. Potrusaeva, and V. P. Khilya, Ukr. Khim. Zh., 49, 174 (1983). I. G. Marchenko, A. V. Turov, and V. P. Khilya, Dokl. Akad. Nauk UkrSSR, Ser. B, 43 (1979). M. Yu. Kornilov, V. V. Plakhotnik, A. V. Turov, and V. P. Khilya, Ukr. Khim. Zh., 58, 1026 (1992). A. V. Turov and V. P. Khilya, Khim. Geterotsikl. Soedin., 605 (1999). B. Bleaney, J. Magn. Reson., 8, 91 (1972). V. P. Khilya, S. P. Bondarenko, and A. V. Turov, Khim. Geterotsikl. Soedin., 666 (1998). V. P. Khilya, Kh. Al-Budi, A. Aitmambetov, L. G. Grishko, A. V. Turov, D. M. Zakharik, and D. Litkei, Khim. Geterotsikl. Soedin., 879 (1992). L. Grishko, A. Turov, V. Khilya, Gy. Litkei, and T. Patonay, Acta Chim. Hung., 112, 401 (1983). 991
REACTIONS OF AMIDINES WITH 5-METHYLENE-1,3-DIOXOLAN-2-ONES

A. A. Bogolyubov1, N. B. Chernysheva1, V. V. Nesterov2, M. Yu. Antipin2, and V. V. Semenov1 The composition and yields of the products from the reaction of 4,4-dialkyl-5-methylene-1,3-dioxolan-2ones with amidines depend on the structure of the initial amidine and on the reaction conditions. 2-Aminopyridines lead to 3-substituted 4-hydroxy-4-methyloxazolidin-2-ones and 4-methyleneoxazolidin-2-ones and also to sym-carbamides. 2-Amino-4,6-dimethylpyrimidine leads to the corresponding 4-methyleneoxazolidin-2-one. 3-Aminothiazoles give linear oxourethanes and symcarbamides. Keywords: 2-aminopyridines, 2-aminopyrimidines, 2-aminothiazoles, 4-hydroxyoxazolidin-2-ones, 5-methylene-1,3-dioxolan-2-ones, 4-methyleneoxazolidin-2-ones, sym-carbamides, carbamates. The aim of this work was to study the previously undescribed reaction of 5-methylene-1,3-dioxolan-2ones 1 with amidine systems. Unlike the reaction with aliphatic and aromatic amines [1], this reaction takes place in a more complicated manner and requires closer temperature control. 2-Aminopyrimidine 2 reacts with dioxolanone 1a as an ordinary primary amine. The reaction takes place at 150C in 46 h and leads to the oxazolidinone 5a with a yield of 40%. It passes through the consecutive stages of the linear carbamate 3a and the cyclic oxazolidinone 4a.
N O O 1a HO N O O 4a N N _ H2O O O
H2N N
O O 2
CO NH
N N
3a
N N O 5a N
In the 1H NMR spectrum of the oxazolidinone 5a there is a characteristic signal for the methylene group in the form of two doublets (4.24 ppm, 1H, and 4.87 ppm, 1H) with a small geminal spinspin coupling constant J = 1.5 Hz. The IR spectrum contains the vibrations of the C=O group at 1770 cm-1, and the mass spectrum contains a peak for M+. __________________________________________________________________________________________ N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow 119991; e-mail: vs@cacr.ioc.ac.ru. 2 A. N. Nesmeyanov Institute of Heteroorganic Compounds, Russian Academy of Sciences, Moscow 119991; e-mail: mishan@xray.ineos.ac.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1152-1163, August, 2004. Original article submitted April 9, 2001. 992 0009-3122/04/4008-09922004 Springer Science+Business Media, Inc.
1
The reaction of 2-aminopyridines 6a-d with dioxolanes 1a,b takes place in a more complicated way. At 60C its only products are the oxazolidinones 4 and/or 5, and the reaction never goes to completion (TLC). At 110C and above it is complicated appreciably by the formation of sym-carbamides of type 7. In this case intermediate linear carbamates like 3a were also not isolated; they probably undergo total cyclization to the oxazolidinones 4b-f. The oxazolidinone 4b was also not isolated; it is immediately transformed into the unsaturated oxazolidinone 5b. (Some of the oxazolidinones 4 are thermally unstable and readily lose water not only when heated but also at room temperature [1].*)
R2 R1 O O 1a,b O + H2N N 6ad R3 R2 R1 O HO N N O 4[b,c], df R3 R3
+
N 7a
NH CO
2
R2 R1 O O 5b, [ce] N N
R3
1 a R2 = R1 = Me, b R2+R1 = (CH2)5; 4 be R2 = R1 = Me, b R3 = H, c R3 = 3-Me; d R3 = 4-Me; e R3 = 6-Me, f R2+R1 = (CH2)5, R3 = 6-Me; 5 b R2 = R1 = Me, R3 = H, c R2 = R1 = Me, R3 = 3-Me; 6 a R3 = H, b R3 = 3-Me, c R3 = 4-Me, d R3 = 6-Me; 7 a R3 = H
According to the 1H NMR spectra, the oxazolidinone 4c is formed in a mixture with the oxazolidinone 5c (~1:1); we were unable to separate them. When heated for 1 h at 110C the oxazolidinones 4c/5c decomposed to a complex mixture of unidentified products. The oxazolidinones 4d and 4e contain a small amount of the corresponding oxazolidinone of type 5. The impurity was not removed either by crystallization or by chromatographic separation. The yield in the reaction amounted to 31-65%. The dependence of the ratio of the products on temperature and reaction time is illustrated for the case of the reaction of the dioxolanone 1a and 2-aminopyridine 6a (Table 1). According to the data in the table, the process is greatly accelerated with increase in temperature, but the sym-carbamide 7a is formed here as side product, and the yields both of the target product 5b and of the side product 7a decrease. In the 1H NMR spectrum of the oxazolidinone 5b there are two characteristic doublets of the C=CH2 group, while the spectra of the oxazolidinones 4d-f contain the expected signals of the OH-4 (6.20-6.60 ppm, 1H, s) and CH3-4 (1.52-1.68 ppm, 3H, s) groups. In the IR spectra of the oxazolidinones 4 and 5 there are vibrations of the C=O group, and in the spectra of the oxazolidinones 4d-f there are vibrations of the OH group. The IR spectrum of the sym-carbamide 7a contains the quartet of the NH group characteristic of carbamides and also the vibrations of the C=O group. The mass spectra of compounds 5b, 4d-f, and 7a contain M+ peaks (Tables 2-4). _______ * It was found, however, that the oxazolidinone 5b was converted almost quantitatively by the action of atmospheric moisture after three years into the oxazolidinone 4b, according to 1H NMR spectroscopy. We will discuss the transition from 4 to 5 and from 5 to 4 in future publications. 993
TABLE 1. The Dependence of the Yields of Oxazolidinones 5b and symCarbamide 7a on Temperature

Reaction conditions Temperature, C Time, h 15-25 60 110 180 3 months 115 9 0.5 Yield, % 5b 0* 43 26 13 7a 0* 0* 27 13
_______ * Monitored by TLC.
In addition, X-ray investigations were undertaken in order to confirm the structure of the oxazolidinone 4f (Fig. 1). The five-membered heterocycle in the molecule has a distorted envelope conformation; the C(2) atom deviates from the C(3)O(1)C(1)N(2) plane by -0.388 . (The plane is fulfilled with an accuracy of 0.03 .) The cyclohexane ring is in the chair conformation; the C(3) and C(6) atoms project from the plane drawn through the C(4)C(5)C(7)C(8) atoms by -0.621 and 0.665 respectively. (The deviation of the atoms from the average plane does not exceed 0.011 .) The dihedral angle between the two planar fragments mentioned above is 82.5. The six-membered heterocycle is planar. (The plane is fulfilled with an accuracy of 0.009 .) The twisting of the molecule about the C(9)N(2) bond is determined by the dihedral angle between the six-membered heterocycle and the planar part of the five-membered ring, equal to 39.9. The observed mutual orientation of the heterocycles leads to the formation of a strong intramolecular hydrogen bond between the hydrogen atom of the hydroxyl group and the nitrogen atom of the pyridine ring O(3)H(3O)N(1) with parameters: O(3)N(1) 2.828(2), O(3)H(3O) 0.88(3), H(3O)N(1) 2.16(3) , angle O(3)H(3O)N(1) 132(2). In addition, an intramolecular nonbonding contact is observed between the O(2) atom of the carbonyl group and the H(10) atom of the pyridine ring with H(10)O(2) distance 2.48(3) , which is less than the sum of the van der Waals radii of these atoms [2]. (Therefore, according to 1H NMR, the chemical shift of the H-10 proton is 7.38 ppm.) The other geometric parameters of compound 4f (the bond lengths and bond angles) have the usual values [3].
Fig. 1. Oxazolidinone 4f. 994
TABLE 2. The Constants and Yields of the Oxazolidinones 4 and 5, Carbamates 3, and sym-Carbamides 7
Compound 3b mp, C* 132-134 Rf*2 0.63 IR spectrum, , cm-1 1725, 1750 (CO); 3360 (NH) 1745 (CO); 3410 (NH) Mass spectrum, m/z (I, %) 318 [M]+ (13.1), 233 (10.9), 219 (18.0), 217 (100.0), 190 (36.9), 148 (36.9), 147 (42.2), 116 (12.4), 115 (12.6) 348 [M]+ (6.8), 331 (21.1), 287 (26.0), 86 (31.3), 271 (25.3), 248 (11.7), 248 (100.0), 221 (18.0), 203 (12.6), 179 (14.8), 178 (18.1), 163 (26.0), 159 (11.7), 146 (11.6), 135 (21.1), 134 (19.0) 278 [M]+ (10.9), 192 (11.8), 179 (12.9), 178 (58.8), 176 (100.0), 149 (47.2), 148 (33.2), 135 (29.3), 108 (11.2), 96 (11.2), 92 (22.3) 228 [M]+ (16.4), 187 (13.0), 142 (26.7), 127 (100.0), 126 (13.6), 100 (36.7), 85 (22.3), 82 (12.0) 236 [M]+ (1.9), 221 (13.6), 193 (1.5), 178 (2.5), 151 (23.6), 150 (13.5), 135 (100.0), 108 (43.3), 93 (14.5), 92 (51.2) 236 [M]+ (3.6), 221 (34.4), 193 (3.4), 178 (11.0), 150 (12.8), 151 (54.1), 135 (100.0), 108 (39.0), 92 (79.1), 93 (15.9) 276 [M]+ (3.2), 261 (17.7), 149 (34.0), 136 (15.0), 135 (100.0), 134 (34.5), 108 (14.2), 99 (32.6), 92 (38.1), 80 (49.9) 233 [M]+ (1.2), 191 (10.2), 190 (79.2), 189 (100.0), 175 (45.6), 107 (22.4), 93 (10.6), 82 (13.1) 214 [M]+ (21.7), 121 (44.4), 120 (41.8), 94 (100.0), 92 (20.5) Yield, % 56
3c
105-108
0.86
60
3d
97-99
0.68
1735, 1750 (CO); 3360 (NH) 1730, 1750 (CO); 3360 (NH) 1735 (CO); 3430 (OH)*3 1735, 3460*3
68
3e
73-75
0.55
60
4d
76-79
0.4
65
4e
72-75
0.4
53
4f
92-94
0.44
1750, 3400
31
5a
79-81
0.42
1770
40
5b 7a
57-59 175-177
0.5 0.18
7b
260-270 (with dec.) 258-294 (with dec.) 315-320
7c
7d
7e
275 (subl.)
1725*3 1695, 1750, 3000, 3050, 3130, 3220 1660, 1675, 2840, 2950, 3100, 3220 1685, 2860, 2950, 3120, 3200 1680, 2760, 2910, 2970, 3030 1645, 3040, 3110, 3140, 3200
43 27
24
46
42
51
_______ * The melting points of compounds 3b-e, 4d-f, 5a,b, and 7b were measured in a sealed capillary, and those of compounds 7b-e on a thermometer bulb. *2 Obtained in chloroformmethanol, 9:1 (compounds 3b-e), benzeneethyl acetate, 2:1 (compounds 4d,e, 5b, and 7a), benzeneethyl acetate, 9:1 (compound 4f), and benzeneethyl acetate, 1:1 (compound 5a) mixtures; compounds 7b-e do not have mobility. *3 The IR spectra of compounds 4d,e and 5b were recorded on a UR-20 instrument.
995

Compound 3b Chemical shifts, , ppm (J, Hz)* [1.54 (3H, s) and 1.60 (3H, s), OC(CH3)2], 1.90 (3H, s, C(O)CH3), 2.40 (3H, s, 4-CH3 Ph), 5.61 (1H, s, NH), 7.14 (1H, s, HHet-5), [7.25 (2H, d, J = 10.1) and 7.70 (2H, d, J = 10.1), HPh-2, HPh-6; HPh-3, HPh-5] [1.53 (3H, s) and 1.56 (3H, s), OC(CH3)2], 1.86 (3H, s, C(O)CH3), 2.00 (3H, s, 5-CH3 Het), 5.62 (1H, s, NH), 3.88 (3H, s, 4-OCH3 Ph), [7.00 (2H, d, J = 10.4) and 7.55 (2H, d, J = 10.4); HPh-2, HPh-6; HPh-3, HPh-5] [1.56 (3H, s) and 1.58 (3H, s), OC(CH3)2], 1.90 (3H, s, C(O)CH3), 5.75 (1H, s, NH), [7.28-7.50 (2H, m) and 7.70-7.88 (2H, m), HHet-4, HHet-5, HHet-6, HHet-7] [1.50 (3H, s) and 1.52 (3H, s), OC(CH3)2], 1.81 (3H, s, C(O)CH3), 5.40 (1H, s, NH), [7.03 (1H, d, J = 5.6) and 7.43 (1H, d, J = 5.6), HHet-4, HHet-5] [1.44 (3H, s) and 1.49 (3H, s), 2C(5)H3], 1.68 (3H, s, C(4)H3), 6.45 (1H, s, OH), 2.38 (3H, s, 4-CH3 Py), 6.95 (1H, d, J = 7.5, HPy-5), 7.62 (1H, s, HPy-3), 8.15 (1H, d, J = 7.5, HPy-6) [1.44 (3H, s), 1.50 (3H, s, 2C(5)H3), 1.68 (3H, s, C(4)H3), 2.50 (3H, s, 6-CH3 Py), 6.60 (1H, s, OH), 6.95 (1H, d, J = 7.5, HPy-5), 7.55-7.70 (2H, m, HPy-3, HPy-4) [1.56-1.91 (9H, m) and 2.05-2.18 (1H, m), 5,5-(CH2)5], 1.52 (3H, s, C(4)H3), 2.50 (3H, s, 6-CH3 Py), 6.20 (1H, s, OH), 7.08 (1H, d, J = 7.5, HPy-5), 7.38 (1H, d, J = 7.5, HPy-3), 7.71 (1H, t, HPy-4) 1.60 (6H, s, 2 C(5)H3), 2.50 (6H, s, 3,5-CH3 Pirim), [4.24 (1H, d, J = 1.5) and 4.87 (1H, d, J = 1.5, C(4)=CH2], 6.98 (1H, s, HPirim-4) 1.60 (6H, s, 2C(5)H3), [4.38 (1H, d, J = 1.3) and 4.59 (1H, d, J = 1.3), C(4)=CH2], 7.45 (1H, t, HPy-5), 7.61 (1H, d, J = 6.5, HPy-3), 8.00 (1H, t, HPy-4), 8.54 (1H, d, J =1.9, HPy-6) 6.98 (4H, d. d, J = 6.0, J = 7.2, H-4, H-4'), 7.68 (8H, t, H-3, H-3', H-5, H-5'), 8.38 (4H, d, J = 6.0, H-6, H-6'), 11.00 (2H, br. s, 2,2'-NH)
3c
3d 3e 4d
4e 4f
5a 5b
7a
_______ * The spectrum of compound 4f was recorded in DMSO-d6, the others in CDCl3.
TABLE 4. The Data from Elemental Analysis

Compound 3b 3c 3d 3e 5a 5b 7a 7b 7c 7d 7e Empirical formula C C16H18N2O3S C17H20N2O4S C13H14N2O3S C9H12N2O3S C12H15N3O2 C11H12N2O2 C11H10N4O C21H18N4OS2 C23H22N4O3S2 C14H10N4OS2 C7H6N4OS2 60.37 60.38 58.60 58.62 56.10 56.12 47.33 47.35 62.75 61.77 64.70 64.71 61.65 61.68 62.03 62.04 59.18 59.20 53.45 53.48 37.13 37.15 Found, % Calculated, % H N 5.69 5.66 5.78 5.75 5.06 5.04 5.36 5.31 6.53 6.49 5.90 5.88 4.70 4.67 4.50 4.47 4.79 4.76 3.25 3.21 2.71 2.68 8.80 8.81 8.05 8.05 10.06 10.07 12.29 12.27 18.07 18.02 13.73 13.73 26.20 26.17 13.77 13.78 11.99 12.01 17.80 17.82 24.75 24.76
S 10.06 10.06 9.21 9.20 11.52 11.51 14.07 14.05 15.79 15.77 13.75 13.74 20.38 20.39 28.31 28.33
996
Unlike the 2-aminopyrimidine 2 and 2-aminopyridines 6, the 2-aminothiazoles 8 that we investigated in reaction with dioxolanone 1a at 60C give the linear oxourethanes 3b-e with yields of 56-68%.
R1 1a N R S 8ad NH2
R1 N R S NH O 3be O O
R1 N
S 7be
NH CO
2
8a, 3b, 7b R = H, R1 = 4-MePh; 8b, 3c, 7c R = Me, R1 = 4-MeOPh; 8c, 3d, 7d R + R1 = CH=CHCH=CH; 8d, 3e, 7e R = R1 = H
TABLE 5. The Bond Lengths in Oxazolidinone 4f

Bond O(1)C(1) O(1)C(3) O(2)C(1) O(3)C(2) N(1)C(9) N(1)C(13) N(2)C(1) N(2)C(9) d, 1.340 (2) 1.466 (2) 1.203 (2) 1.416 (2) 1.332 (2) 1.348 (2) 1.369 (2) 1.418 (2) Bond N(2)C(2) C(2)C(15) C(2)C(3) C(3)C(8) C(3)C(4) C(4)C(5) C(5)C(6) C(6)C(7) d, 1.466 (2) 1.517 (3) 1.549 (3) 1.516 (3) 1.522 (3) 1.520 (3) 1.519 (3) 1.510 (4) Bond C(7)C(8) C(9)C(10) C(10)C(11) C(11)C(12) C(12)C(13) C(13)C(14) d, 1.530 (3) 1.380 (3) 1.375 (3) 1.371 (4) 1.374 (3) 1.500 (4)
TABLE 6. The Principal Bond Angles in the Oxazolidinone 4f

Angle C(1)O(1)C(3) C(9)N(1)C(13) C(1)N(2)C(9) C(1)N(2)C(2) C(9)N(2)C(2) O(2)C(1)O(1) O(2)C(1)N(2) O(1)C(1)N(2) O(3)C(2)N(2) O(3)C(2)C(15) N(2)C(2)C(15) O(3)C(2)C(3) N(2)C(2)C(3) C(15)C(2)C(3) O(1)C(3)C(8) O(1)C(3)C(4) C(8)C(3)C(4) , deg 110.1 (1) 118.0 (2) 122.8 (2) 110.8 (2) 122.8 (2) 122.6 (2) 127.7 (2) 109.7 (2) 109.9 (2) 110.3 (2) 112.7 (2) 108.8 (2) 100.2 (1) 114.6 (2) 107.6 (2) 106.6 (2) 111.5 (2) Angle O(1)C(3)C(2) C(8)C(3)C(2) C(4)C(3)C(2) C(5)C(4)C(3) C(6)C(5)C(4) C(7)C(6)C(5) C(6)C(7)C(8) C(3)C(8)C(7) N(1)C(9)C(10) N(1)C(9)N(2) C(10)C(9)N(2) C(11)C(10)C(9) C(12)C(11)C(10) C(11)C(12)C(13) N(1)C(13)C(12) N(1)C(13)C(14) C(12)C(13)C(14) , deg 102.8 (1) 113.9 (2) 113.7 (2) 112.5 (2) 110.6 (2) 110.8 (2) 112.1 (2) 112.4 (2) 123.8 (2) 114.6 (2) 121.6 (2) 117.4 (2) 119.6 (2) 119.8 (2) 121.3 (2) 115.9 (2) 122.8 (2)
997
TABLE 7. The Principal Torsion Angles in the Oxazolidinone 4f

Angle C(3)O(1)C(1)O(2) C(3)O(1)C(1)N(2) C(2)N(2)C(1)O(1) C(2)N(2)C(1)O(2) C(9)N(2)C(1)O(1) C(9)N(2)C(1)O(2) C(1)N(2)C(2)O(3) C(1)N(2)C(2)C(3) C(1)N(2)C(2)C(15) C(9)N(2)C(2)O(3) C(9)N(2)C(2)C(3) C(9)N(2)C(2)C(15) C(1)O(1)(3)(2) C(1)O(1)(3)(4) C(1)O(1)(3)(8) O(3)C(2)C(3)O(1) O(3)C(2)C(3)C(4) O(3)C(2)C(3)C(8) N(2)C(2)C(3)O(1) N(2)C(2)C(3)C(4) , deg -172.2 7.5 10.1 -170.2 169.4 -10.9 92.7 -21.7 -143.8 -66.6 179.0 56.8 -20.6 99.2 -141.1 -91.0 154.3 25.1 24.2 -90.6 Angle N(2)C(2)C(3)C(8) C(15)C(2)C(3)O(1) C(15)C(2)C(3)C(4) C(15)C(2)C(3)C(8) O(1)C(3)C(4)C(5) C(2)C(3)C(4)C(5) C(8)C(3)C(4)C(5) C(3)C(4)C(5)C(6) C(4)C(5)C(6)C(7) C(5)C(6)C(7)C(8) O(1)C(3)C(8)C(7) C(2)C(3)C(8)C(7) C(4)C(3)C(8)C(7) C(6)C(7)C(8)C(3) C(13)N(1)C(9)N(2) C(1)N(2)C(9)N(1) C(1)N(2)C(9)C(10) C(2)N(2)C(9)N(1) C(2)N(2)C(9)C(10) , deg 140.3 145.0 30.3 -98.8 64.3 176.8 -52.8 55.9 -56.8 55.5 -65.8 -179.1 50.7 -52.9 -175.9 -139.2 42.3 17.7 -160.9
At 110C and above, as also in the case of 2-aminopyridines 6, the formation of sym-carbamides 7b-e as side products is observed. At 110C the sym-carbamide 7e is the main substance, while the carbamate 3e is present in trace quantities (monitored by TLC). Evidence for the linear structure of compounds 3b-e is provided by the absence in the 1H NMR spectra of signals for the OH and CH3 or C=CH2 groups at position 4, characteristic of the corresponding oxazolidinones of type 4 or 5, and also by the presence of the CH3 group at C=O (1.81-1.90 ppm, 3H, s), whereas the C(4)H3 group of the oxazolidinones 4 has a chemical shift of 1.52-1.68 ppm. The vibrations of the indicated hydroxyl group are also absent in the IR spectra of the carbamates 3b-e. In the IR spectra of the sym-carbamides 7b-e the expected quartet of the NH group and also the vibrations of the C=O group are observed. The mass spectra of compounds 3b-e contain [M]+ peaks. All our attempts to convert the carbamates 3b-e into the corresponding oxazolidinones of type 4 and 5 were unsuccessful; neither boiling in ortho-xylene with molecular sieves as dehydrating medium nor additional acid catalysis with TsOH or base catalysis with triethylamine led to the desired oxazolidinones. In all cases decomposition of the carbamates 3b-e to the sym-carbamides 7b-e and a complex mixture of unknown liquid products was observed. (According to GLC, 14 peaks were recorded for the sym-carbamide 7e.)
EXPERIMENTAL The 1H NMR spectra were recorded on a Bruker WM-250 instrument at 250 MHz with TMS as internal standard. The IR spectra were recorded on a Perkin-Elmer 577 instrument in potassium bromide. The mass spectra were obtained on a Kratos MS-30 spectrometer with direct injection of the sample at 70 eV and 250C. Flash chromatography on a "dry" column [6] was used for separation of the mixtures (Silufol 5/40, gradient elution with benzene and ethyl acetate). Thin-layer chromatography was performed on Silufol UV-254 plates. The cooling bath was acetonedry ice. The physicochemical and spectral characteristics are given in Tables 2-4. 998
TABLE 8. The Coordinates (104) and Isotropic (Equivalent for the Nonhydrogen Atoms) Temperature Factors of the Atoms in Oxazolidinone 4f
Atom O(1) O(2) O(3) N(1) N(2) C(1) C(2) C(3) C(4) C(5) C(6) C(7) C(8) C(9) C(10) C(11) C(12) C(13) C(14) C(15) H(3O) H(4,1) H(4,2) H(5,1) H(5,2) H(6,1) H(6,2) H(7,1) H(7,2) H(8,1) H(8,2) H(10) H(11) H(12) H(14,1) H(14,2) H(14,3) H(15,1) H(15,2) H(15,3) x 695(1) -19(2) 1285(2) 1973(2) 1693(2) 721(2) 2186(2) 1849(2) 3120(2) 2732(3) 2187(3) 891(3) 1233(3) 1790(2) 1731(2) 1916(2) 2156(2) 2167(2) 2392(5) 3781(3) 1361(30) 3416(22) 3895(24) 1986(24) 3610(27) 3009(27) 1943(26) 80(26) 520(28) 2011(24) 364(26) 1564(24) 1856(25) 2316(24) 2707(39) 1615(50) 2986(53) 4031(27) 3875(23) 4419(26) y 2943(1) 4072(1) 708(1) 1675(1) 2646(1) 3294(2) 1663(2) 2097(2) 2729(2) 3203(2) 2259(3) 1654(3) 1189(2) 2686(2) 3705(2) 3665(3) 2636(2) 1652(2) 494(3) 1369(3) 581(24) 3372(20) 2123(20) 3795(21) 3618(21) 1699(23) 2572(21) 2195(21) 1042(23) 548(19) 853(20) 4429(19) 4379(22) 2597(20) 560(31) 88(42) 39(46) 771(23) 1052(19) 2084(23) z 7814(1) 6589(1) 6739(1) 4907(1) 6365(1) 6883(1) 6940(1) 7983(1) 8458(2) 9457(2) 10122(2) 9672(2) 8655(2) 5333(1) 4830(2) 3836(2) 3389(2) 3932(2) 3492(3) 6764(2) 6111(20) 8018(15) 8521(14) 9380(15) 9740(16) 10240(16) 10733(18) 9614(16) 10058(19) 8687(14) 8345(16) 5154(15) 3495(17) 2733(17) 2840(28) 3458(28) 3808(33) 7228(19) 6159(17) 6812(16) U, 2 50(1) 67(1) 61(1) 48(1) 43(1) 46(1) 43(1) 42(1) 53(1) 62(1) 68(1) 66(1) 55(1) 43(1) 52(1) 62(1) 61(1) 54(1) 84(1) 60(1) 96(10) 61(6) 63(7) 67(7) 78(7) 78(8) 80(8) 67(7) 88(8) 62(6) 72(7) 65(7) 79(8) 68(7) 143(13) 177(21) 206(26) 83(8) 65(7) 77(8)
The dioxolanones 1a,b were obtained according to the procedure described in [4] (see also [5]) in the form of colorless crystals. Oxazolidinone (4f). The compound was obtained from acetonitrile by slow crystallization over 3 days. The crystals of 4f (C15H20N2O3) are monoclinic. At 25C: = 9.134(2), b = 11.721(3), = 13.705(3) ; = 90.20(2); V = 1467.2(5) 3; dcalc = 1.251 g/cm3; Z = 4; space group P21/n. The unit cell parameters and the intensities of 3080 reflections were measured on a Siemens P3/PC automatic four-circle diffractometer [(MoK) = 0.71072 , graphite monochromator, /2 scan, max 28]. The structure was interpreted by the direct method and refined by full-matrix least-squares treatment in anisotropic approximation for the nonhydrogen atoms. The hydrogen atoms were localized objectively in a Fourier difference synthesis and 999
refined in isotropic approximation. The final divergence factors were wR2 = 0.1270 in 2881 unique reflections [R1 - 0.052 in 1754 unique reflections with I > 2(I)]. The calculations were performed on an IBM PC/AT-586 computer using SHELXTL PLUS and SHELXL-93 software [7]. The bond lengths, bond and torsion angles, coordinates (104), and isotropic (equivalent for the nonhydrogen atoms) temperature factors of the atoms of oxazolidinone 4f are given in Tables 5-8. Synthesis of Carbamates (3b-e) (General Procedure). The respective thiazole 8a-d (4-50 mmol) and dioxolanone 1a (12-90 mmol) were melted at 60C for 64 h. The mixture was allowed to crystallize at room temperature (1-3 days), and the crystals were washed with 2 1 ml of benzene. The benzene washing liquids were combined, and petroleum ether (5-10 ml, depending on the specific procedure) was added to them. The crystals were washed with this solution on the filter. The crystals were further treated with a mixture of petroleum ether and benzene or with pure petroleum ether (depending on the specific procedure), and the substance was dried under vacuum over phosphorus pentoxide. 1,1-Dimethyl-2-oxopropyl 4-(4-methylphenyl)thiazole-2-carbamate (3b). This compound was obtained with a yield of 2.15 g in the form of yellow crystals from the thiazole 8a (1.90 g, 10 mmol) and the dioxolanone 1a (3.84 g, 30 mmol) by adding petroleum ether (10 ml) and further washing with 2 2 ml of petroleum ether. 1,1-Dimethyl-2-oxopropyl 3-Methyl-4-(4-methoxyphenyl)thiazole-2-carbamate (3c). This compound was obtained with a yield of 0.84 g in the form of yellow crystals from the thiazole 8b (0.88 g, 4 mmol) and dioxolanone 1a (1.53 g, 12 mmol) by adding petroleum ether (5 ml) and then washing once with a further 2 ml of petroleum ether. 1,1-Dimethyl-2-oxopropyl Benzothiazole-2-carbamate (3d). This compound was obtained with a yield of 4.66 g in the form of white crystals from the thiazole 8c (4.51 g, 30 mmol) and the dioxolanone 1a (11.52 g, 90 mmol) by adding petroleum ether (5 ml) and then washing with a further 3 2 ml of a 1:1 mixture of petroleum ether and benzene. 1,1-Dimethyl-2-oxopropyl Thiazole-2-carbamate (3e). A mixture of thiazole 8d (0.86 g, 10 mmol) and the dioxolanone 1a (1.28 g, 10 mmol) was melted. The liquid mixture was separated by chromatography, and the solvent was evaporated. The substance was allowed to crystallize at room temperature (1-3 days). The product was obtained with a yield of 1.79 g in the form of white crystals. 4-Hydroxy-3-(4-methyl-2-pyridyl)-4,4,5-trimethyloxazolidin-2-one (4d) and 4-Hydroxy-3-(6methyl-2-pyridyl)-4,4,5-trimethyloxazolidin-2-one (4e). A mixture of the respective aminopyridine 6 (1.08 g, 10 mmol) and the dioxolanone 1a (1.41 g, 11 mmol) was melted at 60C for 113 h and then at 80C for a further 34 h. We added compound 1a (0.51 g, 4 mmol), benzene (10 ml), and triethylamine (1 ml) and boiled the mixture for 1 h. The solvent was evaporated, and the product was recrystallized from a 1:4 mixture of benzene and petroleum ether (2.5 ml). The crystals that separated were washed on the filter with 2 2.5 ml of 4:1 benzenepetroleum ether mixture, cooled to 7-10C. The product was dried over phosphorus pentoxide under vacuum. We obtained 1.45 g of the oxazolidinone 4d and 1.15 g of the oxazolidinone 4e respectively. 4-Hydroxy-4-methyl-3-(6-methyl-2-pyridyl)-5,5-pentamethyleneoxazolidin-2-one (4f). A mixture of the aminopyridine 6d (3.24 g, 30 mmol) and the dioxolanone 1b (6.08 g, 31 mmol) was melted at 60C for 120 h and left at 15C for 48 h. The crystals that separated were washed on the filter with 2 2 ml of a 3:1 mixture of petroleum ether and benzene, and 2.77 g of colorless crystals was obtained. The washing liquids were combined with the mother solution and evaporated in air. A seed was added to the obtained oil (otherwise the mixture did not crystallize), the mixture was kept at 15C for 1-2 days, and a further 0.10 g of the substance was obtained. 5,5-Dimethyl-4-methylene-3-(4,6-dimethyl-2-pyrimidyl)oxazolidin-2-one (5a). A mixture of 2-aminopyrimidine 2 (2.00 g, 15.21 mmol) with the dioxolanone 1a (2.01 g, 15.71 mmol) was melted at 150C for 46 h. The mixture was separated by column chromatography, and 2.04 g (54%) of the product was obtained. It was dissolved in boiling ether (3 ml) and precipitated with petroleum ether (9 ml) with cooling; we obtained 1.50 g of the pure product. 1000
5,5-Dimethyl-4-methylene-3-(2-pyridyl)oxazolidin-2-one (5b) and sym-Bis(2-pyridyl)carbamide (7a). A mixture of the aminopyridine 6a (13.3-30 mmol) and the dioxolanone 1a (13.0-30 mmol) was melted at the required temperature (see Table 1). The melt was left at room temperature overnight, the partly crystallized reaction mixture was washed on the filter with 2 0.5 ml of cold benzene, and the benzene washing liquids and mother solution were combined. (The volumes of the solvents are given for a load of 30 mmol.) The carbamide 7a that separated was crystallized from benzene (3 ml), and the mother solution from crystallization was discarded. The substance was dried over phosphorus pentoxide under vacuum. The benzene was distilled from the first mother solution, and the mixture was left overnight. The crystals of the oxazolidinone 5b were filtered off from the mother solution, washed with 2 1 ml of cooled triethylamine, dried over phosphorus pentoxide under vacuum, and dissolved by heating in benzene (0.5 ml), and petroleum ether (5 ml) was added. The mixture was rubbed with cooling, and the crystals that separated were washed on the filter with 2 6 ml of a 5:1 mixture of petroleum ether and chloroform that had been cooled to 7-10C and dried over phosphorus pentoxide under vacuum. In this way 2.62 g of the oxazolidinone 5b was obtained from 6a (2.82 g, 30 mmol) and 1a (3.84 g, 30 mmol) after 115 h at 60C. Synthesis of sym-Carbamides (7b-d) and Carbamates (3b-d) (General Procedure). The respective thiazole 8a-c (10-20 mmol) and the dioxolanone 1a (10-20 mmol) were melted at 110C for 5.5 h in the case of 3b/7b and 3c/7d and 13 h in the case of 3d/7d. We added 10 ml of benzene to the same flask and boiled the mixture for 15-20 min. The mixture was cooled, and the carbamide 7b-d was filtered off, washed with 3 3 ml of benzene, and dried. The benzene washing liquids and the mother solution were combined, evaporated to 3-4 ml, and cooled to 7-10C; the crystals of the carbamate 3b-d that separated were transferred to a filter and washed with 2 ml of cold benzene (7-10C) and then with 2 2 ml of a cold 5:1 mixture of petroleum ether and benzene. The substances were dried over phosphorus pentoxide under vacuum. Thus, from thiazole 8a (2.20 g, 10 mmol) and the dioxolanone 1a (1.28 g, 10 mmol) we obtained yellow crystals of compounds 3b (0.56 g) and 7b (0.55 g); from the thiazole 8b (3.08 g, 20 mmol) and the dioxolanone 1a (2.56 g, 20 mmol) we obtained yellow crystals of compounds 3c (1.87 g) and 7c (1.74 g); from the thiazole 8c (3.02 g, 20 mmol) and the dioxolanone 1a (2.56 g, 20 mmol) we obtained white crystals of compounds 3d (1.81 g) and 7d (1.37 g). sym-Bis(2-thiazolyl)carbamide (7e). A mixture of the thiazole 8d (4.30 g, 50 mmol) and the dioxolanone 1a (6.40 g, 50 mmol) was melted at 110C for 3 h. We added benzene (10 ml) to the same flask and boiled the mixture for 15-20 min. The mixture was cooled, and the carbamide 7e was filtered off, washed with 3 3 ml of benzene, and dried: we obtained 2.51 g of light-brown crystals of 7e. sym-Carbamides (7b-e). The compounds were high-melting powders, insoluble in most of the usual solvents, moderately soluble when heated in DMSO, and readily soluble in trifluoroacetic acid.
REFERENCES 1. 2. 3. 4. 5. 6. 7. N. B. Chernysheva, A. A. Bogolyubov, and V. V. Semenov, Khim. Geterotsikl. Soedin., 241 (1999). R. S. Rowland and R. Taylor, J. Phys. Chem., 100, 7384 (1996). F. N. Allen, O. Kennard, D. G. Watson, L. Brammer, A. G. Orpen, and R. Taylor, J. Chem. Soc., Perkin Trans. 2, 12, S1 (1987). P. Dimroth and H. Pasedach, German Patent 1098953; Chem. Abstr., 56, 2453 (1962). www.chemical-block.com J. Sharp, I. Gosney, and A. Rowley, Practical Organic Chemistry [Russian translation], Mir, Moscow (1993), p. 188. G. M. Sheldrick, SHELXTL. Version 5, Software Reference Manual, Siemens Industrial Automation, Madison, WI (1994).
1001
SYNTHESIS OF ARYLIDENE DERIVATIVES OF 1-ARYL-3H-PYRROL-2-ONES

A. Yu. Egorova and V. V. Nesterova The aminolysis of 5-aryl-3-arylidene-3H-furan-2-ones by the action of aromatic amines leads to the formation of substituted amides of 4-oxo acids, the subsequent azacyclization of which in the presence of acetic anhydride leads to the formation of 1,5-diaryl-substituted 3-arylidene-3H-pyrrol-2-ones. The mechanism of the occurring and alternative transformations is discussed. Keywords: 4-oxoalkanamides, 5-aryl(alkyl)-3-arylidene-3H-furan-2-ones, 5-aryl(alkyl)-3-arylidene-3Hpyrrol-2-ones, aromatic amines, ammonolysis. Many examples of the condensation of aromatic aldehydes with 5H- and 3H-furan-2-ones [1-5] are known. At the same time the reaction of aromatic aldehydes with their nitrogen-containing analogs 3H-pyrrol-2ones has only been described for N-unsubstituted 5-aryl(alkyl)-3H-pyrrol-2-ones [6]; the synthesis of 5-aryl(alkyl)-3-arylidene-3H-pyrrol-2-ones was realized either by ammonolysis of their O-hetero analogs (by the action of ammonia) or by the reaction of N-unsubstituted 5-aryl(alkyl)-3H-pyrrol-2-ones with aromatic aldehydes. In the present work we studied the condensation of N-aryl-substituted 3H-pyrrol-2-ones 1 with aromatic aldehydes 2a-c, which requires harsher conditions than in the case of the O,S-hetero analogs. The reaction was conducted in solution in acetic anhydride in the presence of anhydrous sodium acetate with prolonged heating of the reagents.
H R CHAr Ac2O O 2ac AcONa, R N Ar 3ac
1
+
N Ar 1
1
ArC
2 a Ar = 2-HOC6H4, b Ar = Ph, c Ar = 3-O2NC6H4
As we established, this reaction takes place slowly, and the yields of the products 3a-c do not exceed 2530%, which can be explained by the lower mobility of the protons of the methylene unit compared with the thiophen- and furan-2-ones [7]. In order to increase the yield of the arylidene derivatives 3a-c we proposed a different method for their production, more convenient in preparative respects than the method described above and based on aminolysis of the respective furan derivatives followed by cyclization of the obtained 4-oxo acids [8].
__________________________________________________________________________________________ N. G. Chernyshevskii Saratov State University, Saratov 410600, Russia; e-mail: lerchikk2002@mail.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1163-1168, August, 2004. Original article submitted July 27, 2002; revision submitted December 23, 2003. 1002 0009-3122/04/4008-10022004 Springer Science+Business Media, Inc.
CHAr R
CHAr
CHAr O NHAr 1 Ac2O H2O R N Ar 3ag

1
O 4ag
Ar1NH2
RCCH2CC O 5ag
35 a R = Ph, Ar = 2-HOC6H4; b R = Ph, Ar = Ph; c R = Ph, Ar = 3-O2NC6H4; d R = 3-MeC6H4, Ar = 4-MeOC6H4; e R = 4-MeC6H4, Ar = 3-O2NC6H4; f R = 4-MeC6H4, Ar = Ph; g R = C5H11, Ar = 4-Me2NC6H4; 3, 5 ac, e, f Ar1 = 3-MeC6H4, d, g Ar1 = Ph
As starting compounds we used 5-aryl-3-arylidene-3H-furan-2-ones 4a-g, which already contain an arylidene substituent at position 3 of the heterocycle. Compounds 4a-g were obtained by the method in [5], which we developed on the basis of the condensation of aromatic aldehydes with 4-oxoalkanoic acids. The aminolysis of compounds 4a-g was carried out by refluxing in an excess of the aminating agent in ethanol for 1.5-2 h. We showed that it was possible to isolate the intermediate compounds 5a-g. Such intermediates were not isolated earlier [6] during the reaction of 3-arylidene-substituted 3H-furan-2-ones with ammonia. This is probably due to the fact that the nitrogen atom in the aromatic amines that we used (aniline and p-toluidine) has lower nucleophilicity than in ammonia. The formation of the amides 5a-g was proved by the data from elemental analysis and IR spectroscopy. Further intramolecular cyclization of the amides 5a-g was realized in the presence of dehydrating agents and, in particular, acetic anhydride. The possible formation of a series of products was not excluded; attack by the electron pair of the nitrogen atom may be directed at the electron-deficient carbon atom of the oxo group at position 4 with the formation of 5-hydroxypyrrolidones, from which the elimination of water leads to the targeted 3-arylidene-3H-pyrrol-2-ones (path A); other possible reaction paths are attack on the aromatic fragments of the molecule by the electron-deficient carbon atom of the oxo group with the formation of the amides of naphthenic acids (path B) or benzoazepinones (path C).
CHAr HO R A N O H2O R N O CHAr
O CH RCCH2CC=O O B OH R N H H2O R
O N H
: NH
C
R OH CH N H O R
H2O N H O
CH
1003
Path C is probably not realized on account of the difficulty of closure of the seven-membered ring. Reaction by path B is hindered in connection with the reduced electron density in the aromatic ring on account of the presence of the electron-withdrawing substituent. In actual fact, only path A is realized; the targeted compounds 3a-g are obtained with quantitative yields when the amides 5a-g are refluxed in acetic anhydride. The physicochemical characteristics of the amides 5a-g and the derivatives of pyrrol-2-ones 3a-g are given in Table 1. In the IR spectra of the amides 5a-g there are absorption bands in the region of 1685-1665 cm-1 (the carbonyl group of aromatic ketones), in the region of 1660-1630 cm-1 (the amide carbonyl group), and in the region of 3320-3250 cm-1 (the absorption band corresponding to the NH group) (Table 2). The IR spectra of
TABLE 1. The Physicochemical Characteristics of 3-Arylidene-3H-pyrrol-2ones 3a-g and Amides 5a-g

Compound Empirical formula C 3a 3b 3c 3d 3e 3f 3g 5a 5b 5c 5d 5e 5f 5g 2419NO2 2419NO 2420N2O3 2521NO2 2520N2O3 C25H21NO C24H28N2O 2421NO3 2420NO2 2420N24 C25H23NO3 2522N2O4 2523NO2 2430N2O3 82.12 81.59 84.35 85.45 75.35 75.00 82.07 81.74 76.14 75.76 85.70 85.47 80.35 80.00 77.42 77.62 88.12 88.89 72.42 72.00 77.53 77.92 72.75 72.46 81.03 81.30 76.94 76.19 Found, % Calculated, % H 5.23 5.38 5.46 5.63 5.46 5.21 6.23 5.72 5.00 5.06 6.15 5.98 7.86 7.78 6.00 5.66 6.34 6.94 5.12 5.00 5.60 5.98 5.49 5.31 6.09 6.23 7.78 7.94 Yield, % (method)
mp, N 4.10 3.97 3.64 4.15 7.93 7.29 3.83 3.80 7.45 7.07 4.05 3.99 7.93 7.78 3.45 3.77 3.94 4.32 7.10 7.00 3.82 3.64 6.54 6.76 3.05 3.79 7.82 7.41 118-120 134-136 127-130 158-160 145-146 139-141 147-148 162-164 160-162 180-182 128-130 121-123 156-158 128-130
27 (A), 87 (B) 30 (A), 53 (B) 25 (A), 72 (B) 73 (A) 68 A) 77 (A) 73 (A) 67 (A) 96 (A) 87 (A) 56 (A) 68 (A) 92 (A) 66 (A)
TABLE 2. IR Spectroscopic Data of the Amides 5a-g

Compound 5a 5b 5c 5d 5e 5f 5g =, cm-1 1685 1680 1665 1665 1670 1665 1675 CN + NH, cm-1 1660 1655 1650 1630 1630 1635 1650 NH, cm-1 3320-3250 3320-3260 3330-3200 3330-3250 3330-3200 3320-3250 3320-3200
1004
TABLE 3. The Spectral Characteristics of 3-Arylidene-3H-pyrrol-2-ones 3a-g

Compound IR spectrum, , cm-1 =, =(endocycle), H-4 =CHAr =(exocycle), (1H, s) (1H, s) 1590, 1606, 1550, 3044-3080 6.7 6.9
1
NMR spectrum, , ppm Other signals
3a
3b
1600, 1606, 1572, 3044-3090 1580, 1608, 1580, 3050-3080
6.3
6.8
6.7
6.9
3d
1580, 1606, 1560, 3050-3030
6.6
6.9
3e
1590, 1608, 1580, 3044-3080 1600, 1606, 1570, 3044-3080 1580, 1608, 1560, 3050-3080
6.6
6.9
3f
6.6
6.8
3g
6.6
6.9
7.10-7.14 (4, m, HO64); 7.14-7.30 (5, m, 65); 7.30-7.60 (4, m, CH364); 5.20 (1H, s, HOC6H4); 2.2 (3, s, CH364) 7.14-7.30 (10, m, 265); 7.30-7.50 (4, m, CH364); 2.2 (3, s, CH364) 7.14-7.25 (5, m, 65); 7.25-7.50 (4, m, CH364); 7.50-7.70 (4, m, O2N64); 2.2 (3, s, CH364) 7.00-7.20 (4, m, CH364); 7.20-7.40 (4, m, CH3O64); 7.40-7.60 (5, m, 65); 2.2 (3, s, CH364); 2.3 (3, s, CH3O64) 7.00-7.40 (8, m, 2 CH364); 7.40-7.60 (4, m, O2N64); 2.2 (6, s, 2 CH364) 7.00-7.30 (8, m, 2 CH364); 7.30-7.60 (5, m, 65); 2.2 (6, s, 2 CH364) 7.00-7.20 (5, m, 65); 7.20-7.40 (4, m, (CH3)2N64); 2.3 (6, s, (CH3)2N64); 0.90-2.00 (11, m, 511)
compounds 3a-g contain absorption bands for the amide carbonyl at 1600-1580 cm-1, the stretching vibrations CH of the benzene ring in the region of 3080-3044 cm-1, bands belonging to the absorption of the C=C bond of the heterocycle in the region of 1608-1606 cm-1, and bands corresponding to the exocyclic C=C bond in the region of 1572-1525 cm-1. In the 1H NMR spectra of compounds 3a-g there are singlets for the vinyl protons at position 4 of the heterocycle at 6.30-6.70 ppm, and in the more downfield region (6.80-6.90 ppm) there is a signal for the hydrogen atom of the exocyclic ethylene bond (Table 3). The absence of signals for the protons at the nitrogen atoms and also the absence of additional signals for the vinyl protons make it possible to conclude that the reaction products are 3-arylidene-3H-pyrrol-2-ones 3a-g.
EXPERIMENTAL The IR spectra were recorded on an IKS-29 instrument in vaseline oil. The 1H NMR spectra were recorded on a Varian FT-80A instrument (80 MHz) in deuterochloroform with TMS as internal standard. The 5-aryl-3-arylidene-3H-furan-2-ones 4a-g were obtained by the method in [5]. The 1,5-diaryl-3Hpyrrol-2-one 1 was obtained by the method in [8]. N-Aryl-5-aryl-3-arylidene-3H-pyrrol-2-ones (3a-c). A. To a solution of pyrrol-2-one (1) (4 mmol) in acetic anhydride we added the respective aromatic aldehyde (4 mmol) and anhydrous sodium acetate (4 mmol). The reaction mixture was heated for 4.5 h. The hot mixture was poured into cold water, and the crystals that separated were filtered off on a Schott filter and recrystallized from hexane.
1005
N-Arylamides of 4-Alkyl- and 4-Aryl-2-arylidene-4-oxobutyric Acid (5a-g). To a solution of 3-arylidene-3H-furan-2-one 4a-g (3 mmol) in ethanol we added the aromatic amine (9 mmol). The reaction mixture was refluxed for 1.5 h. The crystals that separated were filtered off on a Schott filter and recrystallized from isopropyl alcohol. N-Aryl-5-alkyl- and N-Aryl-5-aryl-3-arylidene-3H-pyrrol-2-ones (3a-g). B. A 1-mmole sample of the N-arylamide of 2-arylidene-4-aryl(alkyl)-4-oxobutyric acid 5a-g was refluxed in acetic anhydride (7 ml) for 1 h. The hot mixture was poured into cold water. The crystals that separated were filtered off on a Schott filter and recrystallized from hexane.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. Y. S. Rao, Chem. Rev., 64, 353 (1964). A. A. Avetisyan and G. G. Tokmadzhyan, Khim. Geterotsikl. Soedin., 723 (1987). A. A. Avetisyan and M. T. Dangyan, Usp. Khim., 46, 1250 (1977). Y. S. Rao, Chem. Rev., 76, 625 (1976). A. Yu. Egorova, P. V. Reshetov, N. A. Morozova, and V. A. Sedavkina, Khim. Geterotsikl. Soedin., 1043 (1977). A. Yu. Egorova, Izv. Akad. Nauk. Ser. Khim., 172 (2002). V. A. Sedavkina, N. A. Morozova, and A. Yu. Egorova, Khim. Geterotsikl. Soedin., 451 (1987). A. Yu. Egorova, V. A. Sedavkina, and Z. Yu. Timofeeva, Khim. Geterotsikl. Soedin., 755 (2001).
1006
SYNTHESIS OF ETHYL cis- AND trans-4-CHLORO-5-OXO-1,2-DIPHENYLPYRROLIDINE-2-CARBOXYLATE

A. O. Martirosyan1, V. E. Hovhanesyan1, S. P. Gasparyan1, A. A. Karapetyan1, G. A. Panosyan2, and V. O. Martirosyan1 Ethyl cis- and trans-4-chloro-5-oxo-1,2-diphenylpyrrolidine-2-carboxylate have been synthesized by the cyclization of ethyl N-(,-dichloropropionyl)-N-phenyl--aminophenylacetate. Keywords: ,-dichloropropionyl chloride, 4-chloro-5-oxo-1,2-diphenylpyrrolidine-2-carboxylic acid, -(phenylamino)phenylacetic acid, phenylacetic acid. We have previously developed a method for the synthesis of 2-phenylproline derivatives involving the cyclization of the corresponding N-(-chloropropionyl)--phenylglycines under phase-transfer catalytic conditions [1]. The 2-phenylproline derivatives prepared using this method can be included in a large group of nonnucleosidic compounds which are inhibitors of the enzyme of the reverse transcriptase virus in immunodeficient individuals (HIV-1) [2].
Cl COOEt HN Cl O Cl Cl Cl 1 O 2 N COOEt
COOEt N Cl O
COOEt
COOEt Cl N O 3
+
Cl 4
N O
__________________________________________________________________________________________ A. L. Mndzhoyan Institute of Fine Chemistry, Armenian Republic National Academy of Sciences, Yerevan 375014. 2 Center for Molecular Study, Armenian Republic National Academy of Sciences, Yerevan 375014; e-mail: west@msrc.am. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1169-1170, August, 2004. Original article submitted April 4, 2002. 0009-3122/04/4008-10072004 Springer Science+Business Media, Inc. 1007
1
With the aim of further functionalizing the pyrrolidine ring we have studied the possible cyclization of ethyl N-phenyl-N-(,-dichloropropionyl)--aminophenylacetate (2), which was prepared by the acylation of ethyl N-phenyl--phenylglycinate (1) [3] using ,-dichloropropionyl chloride. Under phase transfer catalytic conditions the cyclization does not form the -lactam (3) but occurs regioselectively to form a mixture of the two stereoisomers of ethyl cis- and trans-4-chloro-5-oxo-1,2-diphenylpyrrolidine-2-carboxylate (4) in almost equal amounts. This is supported by the 1H NMR spectrum which shows two sets of signals.
EXPERIMENTAL H NMR spectra were recorded on a Varian Mercury-300 instrument (300 MHz) at 31C and mass spectra on an MX-1321A instrument with an ionization energy of 70 eV. TLC was performed on Silufol UV-254 plates in the system acetonehexane (1:1). Ethyl N-(,-Dichloropropionyl)-N-phenyl--phenylglycinate (2). ,-Dichloropropionyl chloride (1.6 g, 10 mmol) was added to a mixture of ester 1 [3] (2.55 g, 10 mmol), triethylamine (1.05 g, 10 mmol) and acetone (30 ml) at 0-5C. Acetone was distilled off and the residue was diluted with ether (100 ml), washed with dilute HCl solution, then water, and dried over sodium sulfate. The ether was distilled off to give the ester 2; mp 85-86C (2-propanol). 1H NMR spectrum (DMSO-d6CCl4, 1:3), , ppm: 7.85-6.35 (10H, m, 2C6H5); 5.99 (1H, s, CHN); 4.31-4.00 (4H, m, OCH2, CH2Cl); 3.74-3.57 (1H, m, CHCl); 1.29 (3H, t, CH3). Found, %: C 59.73; H 5.18; Cl 18.81; N 4.00. C19H19Cl2NO3. Calculated, %: C 60.00; H 5.00; Cl 18.68; N 3.68. M+ 379 (determined by mass spectrometry). Ethyl cis- and trans-4-Chloro-5-oxo-1,2-diphenylpyrrolidine-2-carboxylate (4). A mixture of the ester 2 (3.8 g, 10 mmol), dry potassium carbonate (4.0 g, 30 mmol), triethylbenzylammonium chloride (0.12 g, 5 mmol), and acetonitrile (20 ml) was stirred for 4 h at 45-50C. The reaction product was filtered, the filtrate evaporated, and the residue was dissolved in chloroform, washed with water, and dried over sodium sulfate. Chloroform was distilled off to give the ester 4 (2.9 g, 84%); mp 74-76C (2-propanol), Rf 0.45 and 0.44. 1 H NMR spectrum (DMSO-d6CCl4, 1:3), , ppm (J, Hz): 7.36-7.02 (10H, m, 2C6H5); 4.91 (0.5H, dd, J = 9.5 and 8.1, CHCl); 4.67 (0.5H, dd, J = 7.5 and 4.4 CHCl); 4.36-4.11 (2H, m, OCH2); 3.43 (0.5H, dd, J = 13.5 and 8.3, CH2); 3.32 (0.5H, dd, J = 14.0 and 7.4, CH2); 3.04 (0.5H, dd, J = 14.0 and 4.3, CH2); 2.82 (0.5H, dd, J = 13.5 and 9.6, CH2); 1.19 (1.5H, t, J = 7.1, CH3); 1.10 (1.5H, t, J = 7.1, CH3). Found, %: C 66.12; H 5.38; Cl 10.52; N 4.12. C19H18ClNO3. Calculated, %: C 66.38; H 5.24; Cl 10.33; N 4.08.
1
REFERENCES 1. 2. 3. A. O. Martirosyan, S. P. Gasparyan, V. E. Hovhanesyan, Sh. L. Mndzhoyan, M. V. Aleksanyan, M. N. Nikishchenko, and G. Sh. Babayan, Khim. Geterotsikl. Soedin., 488 (2000). E. De. Clerq, Rev. Medical Virology, 6, 97 (1996). T. A. Martin and W. T. Comer, J. Org. Chem., 35, 3914 (1970).
1008
SYNTHESIS, STRUCTURE, AND SOME PROPERTIES OF SUBSTITUTED 3-CARBETHOXY(METHOXY)-5-CYANO-1,2,3,4-TETRAHYDROSPIROCYCLOHEXANE-4-PYRIDINE-2-THIONES

A. D. Dyachenko1, S. M. Desenko2, V. D. Dyachenko1, and A. N. Chernega3 The condensation of cyclohexylidenemalononitrile or cyclohexylidenecyanoacetic ester with thioamidoethyl(methyl)malonate in the presence of sodium ethylate gave 6-amino-3-carbethoxy-5cyano-4-spirocyclohexane-1,2,3,4-tetrahydropyridine-2-thione and 3-carbethoxy(methoxy)-5-cyano-6oxo-4-spirocyclohexanepiperidine-2-thiones which were used in the synthesis of the corresponding substituted 2-alkylthiotetrahydropyridines. 5-Carbethoxy-3-cyano-3-methyl-6-methylthio-4-spirocyclohexane-3,4-dihydropyridine-2(1H)-one was studied by X-ray crystallography. Keywords: thioamidoethyl(methyl)malonate, 4-cycloalkanespiro-substituted pyridine-2-thiones, cyclohexylidenemalononitrile, cyclohexylidenecyanoacetic ester, alkylation, intramolecular Claisen condensation, Michael reaction, X-ray crystallography. We have previously prepared 3-cyano-4-cycloalkanespiro-substituted, partially hydrogenated pyridine2-thiones [1-3], which are promising intermediates in the search for preparations with medicinal value [4, 5]. In extending our investigation in this direction we have discovered a route for the synthesis of 3-carbethoxy(methoxy)-substituted analogs of the class of compound mentioned above which involves the reaction of the cyclohexylidenemalononitrile (1) with thioamidoethylmalonate (2) in ethanol in the presence of sodium ethylate. During the reaction the formation of the 6-amino-3-carbethoxy-5-cyano-4-spirocyclohexane1,2,3,4-tetrahydropyridine-2-thione (3) is apparently preceded by the generation of the corresponding Michael adduct 4 (Scheme 1). In order to prove the structure of compound 3 (Table 1) we have used the alkylation by the halides 5 in basic medium together with spectroscopic methods (see Experimental section and Table 2). The organic sulfides 6 obtained in this way are in accord with the general trends in the chemistry of pyridinethiones [6]. The use of the cyclohexylidenecyanoacetate ester 7 as Michael acceptor in the reaction with the CH-acids 2 led to the preparation of 3-carbethoxy(methoxy)-5-cyano-6-oxo-4-spirocyclohexanepiperidine-2thiones 8. In this case, the hypothetical Michael adduct 9 could not be isolated. The use of alkylation as a "characteristic reaction" of thiones [6] together with a series of spectroscopic methods (see Experimental section and Table 2) readily prove the structure of compound 8 (Scheme 2). __________________________________________________________________________________________ Taras Shevchenko National Pedagogical University, Lugansk 91011, Ukraine; e-mail: dvd_lug@online.lg.ua. 2 V. N. Karazin National University, Kharkov 61070, Ukraine; e-mail: desenko@univer.kharkov.ua. 3 Organic Chemistry Institute, Ukraine National Academy of Sciences, Kiev 02094; e-mail: iochkiev@ukrpack.net. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1171-1178, August, 2004. Original article submitted December 18, 2001. 0009-3122/04/4008-10092004 Springer Science+Business Media, Inc. 1009
1
Scheme 1
EtO O S NC 1 CN H2N 2 EtONa NC C .. N H N 2
O OEt S 4
O NC H2N N 6a,b S Hal OEt Z 5a,b Z NC H2N N H 3
O OEt S
5 a Hal = Br, b Hal = Cl; 5, 6 a Z = 4-O2NC6H4CO; b Z = thiazol-2-ylcarbamoyl
Scheme 2
RO O OEt NC 7 O 2a,b O NC O N H 10af S OR Z 5 ch NC O N H 8a,b H2N S EtO .. O N H2 EtONa NC
O OR S 9
O OR S
2, 8 a R = Et, b R = Me; 5 c Hal = Cl, Z = PhNHCO, d Hal = Cl, Z = Ph, e Hal = I, Z = H, f Hal = Cl, Z = 4-BrC6H4NHCO, g Hal = I, Z = Me, h Hal = Br, Z = PhCO; 10 a R = Et, Z = PhNHCO, b R = Et, Z = Ph, c R = Et, Z = H, d R = Et, Z = 4-BrC6H4NHCO, e R = Me, Z = Me, f R = Me, Z = PhCO
The sulfides 10 obtained by this means can undergo further reactions. Hence the reaction of compound 10c with MeI in basic medium occurs regioselectively via C-methylation to give 5-carbethoxy-3-cyano-3methyl-6-methylthio-4-spirocyclohexane-3,4-dihydropyridine-2(1H)-one (11) (method A), which can also be synthesized in a single stage from the thione 8a and MeI (method B).
1010
TABLE 1. Parameters for Compounds 3, 6a,b, 8a,b, 10a-f, 11, 12

Compound Empirical formula C 3 6a 6b 8a 8b 10a 10b 10c 10d 10e 10f 11 12 C14H19N3O2S C22H24N4O5S C19H23N5O3S2 C14H18N2O3S C13H16N2O3S C22H25N3O4S C21H24N2O3S C15H20N2O3S C22H24BrN3O4S C15H20N2O3S C21H22N2O4S C16H22N2O3S C20H18N2O3S 57.12 57.31 57.96 57.88 52.51 52.64 56.95 57.12 55.73 55.69 61.90 61.81 65.73 65.60 58.35 58.42 52.02 52.18 58.31 58.42 63.35 63.29 59.67 59.60 65.61 65.55 Found, % Calculated, % H 6.46 6.53 5.19 5.30 5.41 5.35 5.98 6.16 5.69 5.75 5.73 5.89 6.31 6.29 6.39 6.54 4.91 4.78 6.59 6.54 5.50 5.57 6.73 6.88 5.05 4.95 mp, (crystallization solvent) 192-194 (EtOH) 180-182 (EtOHDMF, 1:1) 164-166 (EtOH) 154-156 (EtOH) 139-141 (MeOH) 153-155 (AcOH) 179-181 (EtOH) 135-137 (EtOH) 173-175 (AcOH) 156-158 (MeOH) 178-180 (MeOHDMF, 1:1) 191-193 (EtOH) 268-269 (DMF)
Yield, %
N 14.54 14.32 12.20 12.27 16.00 16.15 9.31 9.52 9.84 10.00 9.92 9.83 7.12 7.29 8.97 9.09 8.13 8.30 8.97 9.09 6.99 7.03 8.79 8.69 7.41 7.65
83 66 76 75 61 79 71 62 57 53 55 58 68
O KOH/MeI 10c A NC Me O N H 11 2KOH/2MeI OEt B SMe 8a
Treatment of compound 10f with an aqueous solution of KOH in refluxing ethanol gives 2-benzoyl-5cyano-3-hydroxy-6-oxo-4,5,6,7-tetrahydrospiro(cyclohexane-4-thieno[2,3-b]pyridine) (12) as a result of an intramolecular Claisen condensation.
OH 10f KOH NC O N H 12 S O Ph
To establish the regioselectivity of the alkylation of functionally substituted tetrahydropyridines which contain several nucleophilic centers unambiguously, we have studied compound 11 using an X-ray structural method (Fig. 1 and Table 3).
1011
TABLE 2. IR and 1H NMR Spectra for Compounds 3, 6a,b, 8a,b, 10a-f, 11, 12
Compound 3 6a IR spectrum, , cm-1 CN, NH C=O 3430, 3330 3510, 3390 3420, 3300, 3150 3180 3210 3320 2170, 1715 2170, 1720, 1700 2165, 1740, 1680 2255, 1710 2245, 1710 2265, 1720, 1700, 1660 2250, 1735, 1710 2250, 1710, 1680 2255, 1700, 1685, 1665 2250, 1720, 1700 2270, 1710, 1670 2250, 1710, 1680 2255, 1710, 1690
1
6b
8a 8b 10a
10b
3270, 3180 3240
10c
11.73 (1H, s, NH); 6.02 (2, br. s, NH2); 4.08 (3, m, OCH2 and H-3); 1.35-1.68 (10, m, (CH2)5); 1.23 (3H, t, J = 7.0, CH3) 8.27 (4, two d, J = 9.0, Ar); 5.97 (2, br. s, NH2); 4.78 (2, q, SCH2); 4.11 (2, q, OCH2); 3.54 (1, s, H-3); 1.33-1.76 (10, m, (CH2)5); 1.22 (3, t, CH3) 12.14 (1, br. s, NH); 7.38 and 7.02 (2, both d, J = 3.3, Het); 6.12 (2, br. s, NH2); 4.07 (4, m, SCH2 and OCH2); 3.50 (1H, s,H-3); 1.27-1.79 (10H, m, (CH2)5); 1.18 (3, t, CH3) 13.42 (1, br. s, NH); 4.75 and 4.51 (2, both s, H-3 and H-5); 4.21 (2, q, OCH2); 1.39-1.73 (10H, m, (CH2)5); 1.22 (3, t, CH3) 13.39 (1, br. s, NH); 4.77 and 4.52 (2, both s, H-3 and H-5); 3.80 (3, s, OCH3); 1.42-1.72 (10, m, (CH2)5) 10.60 (1, s, NH); 10.12 (1, s, C6H5NHCO); 7.54 (2, d, J = 7.6, C6H5); 7.26 (2, dd, C6H5); 7.03 (1, dd, J = 7.3, C6H5); 4.09 (3, m, OCH2 and H-3); 3.67 (2, q, SCH2); 1.38-1.93 (10H, m, (CH2)5); 1.22 (3, t, CH3) 10.48 (1, s, NH); 7.25 (5, m, C6H5); 4.09 (5, m, SCH, OCH2 and H-3); 1.35-1.72 (10H, m, (CH2)5); 1.21 (3, t, CH3) 10.37 (1, s, NH); 4.18 (2, q, OCH2); 4.04 (1, s, H-3); 2.31 (3, s, SCH3); 1.39-1.84 (10H, m, (CH2)5); 1.18 (3, t, CH3) 10.42 (1, s, NH); 10.17 (1H, s,4-BrC6H4NHCO); 7.53 and 7.46 (2H, both d, J = 9.0, Ar); 4.18 (3H, m, OCH2 and H-3); 3.69 (2H, q, SCH2); 1.38-1.84 (10H, m, (CH2)5); 1.21 (3H, t, CH3) 10.36 (1H, s,NH); 4.02 (1H, s,H-3); 3.74 (3H, s,OCH3); 2.86 (2H, q, SCH2); 1.43-1.76 (10H, m, (CH2)5); 1.23 (3H, t, J = 7.2, CH3) 10.41 (1H, s,NH); 7.32-7.47 (5H, m, C6H5); 4.29 (1H, s,H-3); 3.78 (3H, s,OCH3); 3.42 (2H, q, SCH2); 1.25-1.80 (10H, m, (CH2)5) 10.37 (1H, s,NH); 4.19 (2H, q, OCH2); 2.28 (3H, s,SCH3); 1.12-2.19 (10H, m, (CH2)5); 1.47 (3H, s,CH3); 1.30 (3H, t, OCH2CH3) 14.20 (1H, br. s, ); 12.01 (1, s, NH); 7.51-7.87 (5H, m, C6H5); 4.61 (1H, s,H-5); 2.65 (1H, m, CH); 1.93 (1H, m, CH); 1.29-1.67 (8H, m, (CH2)4)
10d
3350
10e
3300
10f
3420
11
32703210 3430
12
TABLE 3. Basic Bond Lengths (d) and Valence Angles () in the Compound 11 Molecule
Bond S(1)C(5) S(1)C(16) O(1)C(1) N(1)C(1) N(1)C(5) N(2)C(7) C(1)C(2) C(2)C(3) C(3)C(4) C(4)C(5) d, 1.747(5) 1.806(7) 1.220(6) 1.368(7) 1.409(6) 1.146(8) 1.519(8) 1.560(7) 1.528(7) 1.339(7) Angle C(5)S(1)C(16) C(1)N(1)C(5) N(1)C(1)C(2) C(1)C(2)C(3) C(2)C(3)C(4) C(3)C(4)C(5) S(1)C(5)N(1) S(1)C(5)C(4) N(1)C(5)C(4) , deg. 100.3(3) 123.2(5) 114.5(4) 110.8(4) 105.4(4) 120.6(4) 115.5(4) 124.2(4) 120.3(5)
1012
Fig. 1. Overall view of the compound 11 molecule with atomic numbering.
TABLE 4. Atomic Coordinates and Equivalent Isotropic Thermal Parameters (Ueq) in the Structure 11
Atom S(1) O(1) O(2) O(3) N(1) N(2) C(1) C(2) C(3) C(4) C(5) C(6) C(7) C(8) C(9) C(10) C(11) C(12) C(13) C(14) C(15) C(16) H(1) x 0.8651(3) 0.3574(7) 0.6745(8) 0.9580(7) 0.5942(7) 0.140(1) 0.4353(8) 0.3622(8) 0.5416(8) 0.6728(8) 0.6983(8) 0.2250(9) 0.2383(9) 0.6636(8) 0.8232(9) 0.7324(12) 0.6236(12) 0.466(1) 0.7682(9) 1.0631(17) 1.205(2) 0.7037(11) 0.644(14) y 0.54250(13) 0.4335(4) 0.3079(4) 0.2828(5) 0.4689(4) 0.1648(7) 0.4061(5) 0.3073(5) 0.2362(4) 0.3285(5) 0.4364(5) 0.3642(6) 0.2284(6) 0.1812(5) 0.0946(5) -0.0038(6) 0.0433(6) 0.1380(5) 0.3052(5) 0.2650(12) 0.1833(13) 0.6707(6) 0.542(8) z 0.36655(18) -0.0136(4) 0.5418(4) 0.4852(4) 0.1632(4) -0.0015(7) 0.0940(5) 0.1643(5) 0.2459(5) 0.3291(4) 0.2849(5) 0.2382(6) 0.0687(6) 0.1595(5) 0.2258(6) 0.2834(7) 0.3745(7) 0.3162(5) 0.4632(5) 0.6163(8) 0.636(1) 0.3478(6) 0.102(9) Ueq, 2 0.0635 0.0696 0.0713 0.0807 0.0503 0.0972 0.0491 0.0468 0.0421 0.0433 0.0476 0.0662 0.0633 0.0479 0.0626 0.0741 0.0742 0.0596 0.0555 0.1438 0.1535 0.0658 0.12(3)
1013
Fig. 2. Crystal packing for compound 11 (the dotted lines show the intermolecular hydrogen bonds).
The central six-membered N(1)C(1-5) heterocycle is markedly non-planar and exists in a half-boat conformation (the modified Kremer-Pople [7] S, , and parameters being 0.69, 47.8, and 25.8 respectively). The ring torsional angles are: N(1)C(1)C(2)C(3) -43.6, C(1)C(2)C(3)C(4) 55.9, C(2)C(3)C(4)C(5) -38.0, C(3)C(4)C(5)N(1) 4.0, C(4)C(5)N(1)C(1) 14.1, and C(5)N(1)C(1)C(2) 7.5. The N(1) atom has a planar trigonal bond configuration with overall valence angles at this atom of 369.3. As a consequence of the conjugation of the unshared electron pair of the N(1) atom with the O(1)=C(1) and C(4)=C(5) double bond -systems, the interatomic distances for N(1)C(1) of 1.368(7) and N(1)C(5) 1.409(6) are markedly shortened when compared with the standard value of 1.45 for a typical N(sp2)C(sp2) bond [8]. The basic geometrical parameters for molecule 11 are typical [9]. In particular, the bond lengths for S(1)C(5) of 1.747(5) and S(1)C(16) 1.806(7) are almost identical to the corresponding parameters in the PhSMe molecule (SC(sp2) 1.749(4) and SC(sp3) 1.803(4) ) [10]. In the crystal of compound 11 the molecules are combined in infinite chains via O(2)H(1)N(1) hydrogen bonding (Fig. 2) (O(2)N(1) 2.973(7), O(2)H(1) 1.90(10) , O(2)H(1)N(1) 164(5)).
EXPERIMENTAL X-ray Structural Investigation of the Monocrystal of Compound 11 with the linear parameters 0.16 0.19 0.68 mm was carried out at room temperature on an Enraf-Nonius CAD-4, automatic, four circle diffractometer (CuK irradiation, relative scanning rate 2/ = 1.2, max = 70, spherical segment 0 h 8, 0 k 13, -13 l 13). In all, 1826 reflections were gathered of which 1598 are symmetrically independent (Rint = 0.028). Crystals of compound 11 are monoclinic with a = 6.923(1), b = 11.265(3), c = 11.117(3) ; = 104.75(2); V = 838.4 3; M = 332.4; Z = 2; dcalc = 1.28 g/cm3; = 17.9 cm-1; F(000) = 345.5, and space group Pc. The structure was solved using a direct method and refined using least squares analysis in a full matrix, anisotropic approximation with the CRYSTALS program package [11]. 1365 Reflections with I > 3(I) were used in the refinement (203 refinement parameters, number of reflections per parameter 6.7). All of the hydrogen atoms were revealed in electron density difference synthesis and included in the calculation with fixed positions and thermal parameters (only atom H(1) was refined isotropically). Calculation of the absorbance in the crystal was carried out using the azimuthal scanning method [12]. The Chebyshev weighting scheme [13] was used in the refinement with the parameters 0.96, 0.95, and -0.20. The final values of the difference factors were R = 0.058 and Rw = 0.062, GOF = 1.103. The absolute configuration was established using the Flack method 1014
[14] (enantiopolar parameter refinement to 0.07(1) for 1486 reflections with non averaged Friedel equivalents). The complete set of X-ray structural information has been deposited in the Cambridge structural data bank (reg. No. CCDC176372). IR Spectra were taken on an IRS-29 spectrometer using vaseline oil. 1H NMR spectra were recorded on Gemini-200 (199 MHz) (compounds 6a,b, 10a,c,e, 12), Bruker AM-300 (300 MHz) (compounds 3, 8a,b), and Bruker DRX500 (500 MHz) (compounds 10b,d,f, 11) equipment using DMSO-d6 solvent and TMS internal standard. Mass spectra were recorded on a Kratos MS-890 (70 eV) spectrometer. Melting points were determined on a Koffler block. Monitoring of the reaction course and the purity of the compounds obtained was carried out using TLC (Silufol UV-254, acetone-hexane, 3: 5) and revealed using iodine vapor. The physicochemical and spectroscopic parameters for compounds 3, 6, 8, 10, 11, 12 are given in Tables 1 and 2. 6-Amino-3-carbethoxy-5-cyano-4-spirocyclohexane-1,2,3,4-tetrahydropyridine-2-thione (3). A solution obtained from sodium (0.23 g, 10 mmol) in ethanol (5 ml) was added to a solution of thioamidoethylmalonate (1.47 g, 10 mmol) in ethanol (20 ml). Cyclohexylidenemalononitrile (1.46 g, 10 mmol) was then added with stirring. The reaction mixture was stirred for 2 h and left for 1 day after which it was acidified with 10% aqueous HCl solution to pH 5. The precipitate formed was filtered off and washed with 40% aqueous ethanol to give compound 3. The mass spectrum of compound 3 (EI, 70 eV), m/z (Irel, %) showed: 293 [M+] (73), 247 (29), 220 (70), 178 (100), 155 (58). 6-Amino-3-carbethoxy-5-cyano-2-(4'-nitrobenzoylmethylthio)-4-spirocyclohexane-3,4-dihydropyridine (6a), 6-Amino-3-carbethoxy-5-cyano-4-spirocyclohexane-2-(thiazol-2'-ylcarbamoylmethylthio)3,4-dihydropyridine (6b), 5-Carbethoxy-3-cyano-2-oxo-6-phenylcarbamoylmethylthio-4-spirocyclohexane1,2,3,4-tetrahydropyridine (10a), 6-Benzylthio-5-carbethoxy-3-cyano-2-oxo-4-spirocyclohexane-1,2,3,4tetrahydropyridine (10b), 5-Carbethoxy-3-cyano-6-methylthio-2-oxo-4-spirocyclohexane-1,2,3,4-tetrahydropyridine (10c), 2-(4'-Bromophenylcarbamoylmethylthio)-5-carbethoxy-3-cyano-2-oxo-4-spirocyclohexane-1,2,3,4-tetrahydropyridine (10d), 5-Carbomethoxy-3-cyano-6-ethylthio-2-oxo-4-spirocyclohexane1,2,3,4-tetrahydropyridine (10e), 6-Benzoylmethylthio-5-carbomethoxy-3-cyano-2-oxo-4-spirocyclohexane-1,2,3,4-tetrahydropyridine (10f). A mixture of the corresponding thione (10 mmol), 10% aqueous KOH (5.6 ml, 10 mmol), and the corresponding alkyl halide (10 mmol) in DMF (20 ml) was stirred at 20C for 4 h and left for one day. The precipitate was filtered off and washed with 40% aqueous ethanol solution and hexane to give compounds 6a,b, 10a-f. Mass spectrum of compound 10e (EI, 70 eV), m/z (Irel, %): 308 [M+] (55), 279 (30), 249 (100), 180 (35). 3-Carbethoxy-5-cyano-6-oxo-4-spirocyclohexanepiperidine-2-thione (8a) and 3-Carbomethoxy-5cyano-6-oxo-4-spirocyclohexanepiperidine-2-thione (8b). A solution obtained from sodium (0.23 g, 10 mmol) in ethanol (5 ml) was added to a solution of the corresponding compound 2 (10 mmol) in ethanol (20 ml). Cyclohexylidenecyanoacetic ester (1.93 g, 10 mmol) was then added with stirring. The reaction mixture was stirred for 2 h and left for one day after which it was acidified with 10% aqueous HCl solution to pH 5. The precipitate formed was filtered off and washed with 40% aqueous ethanol solution to give compounds 8a,b. Mass spectrum (EI, 70 eV), m/z (Irel, %), compound 8a: 294 [M+] (90), 249 (20), 222 (100), 194 (56), 166 (30), 148 (30), 138 (52), 122 (25); compound 8b: 280 [M+] (100), 221 (45), 193 (45), 160 (42), 148 (78), 133 (27). 5-Carbethoxy-3-cyano-3-methyl-6-methylthio-4-spirocyclohexane-3,4-dihydropyridine-2(1H)-one (11). A. A 10% aqueous solution of KOH (5.6 ml, 10 mmol) and then MeI (0.62 ml, 10 mmol) were added with stirring to a solution of compound 10c (3.08 g, 10 mmol) in DMF (10 ml) and stirred was continued for 2 h. After 1 day the precipitate formed was filtered off and washed with ethanol and hexane to give compound 11. B. A 10% aqueous solution of KOH (5.6 ml, 10 mmol) and then MeI (0.62 ml, 10 mmol) were added with stirring to a solution of compound 8a (1.47 g, 5 mmol) in DMF (10 ml) and stirring was continued for 2 h. After 1 day the precipitate formed was filtered off and washed with ethanol and hexane to give compound 11 in 72% yield. The melting point and the chromatographic and spectroscopic date agreed with the analogous data for compound 11 prepared as in method A. Mass spectrum of compound 11 (EI, 70 eV), m/z (Irel, %): 322 [M+] (70), 307 (100), 277 (32), 261 (69), 226 (35), 180 (55), 148 (48). 1015
2-Benzoyl-5-cyano-3-hydroxy-6-oxo-4,5,6,7-tetrahydrospiro(cyclohexane-4-thioeno[2,3-b]pyridine) (12). A 10% aqueous solution of KOH (2.8 ml, 5 mmol) was added to a solution of compound 10f (1.99 g, 5 mmol) in ethanol (25 ml) and refluxed for 1 h. After 1 day the precipitate formed was filtered off and washed with ethanol and hexane to give compound 12.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. V. D. Dyachenko, A. E. Mitroshin, and V. P. Litvinov, Khim. Geterotsikl. Soedin., 1235 (1996). V. D. Dyachenko, S. G. Krivokolysko, V. N. Nesterov, Yu. T. Struchkov, and V. P. Litvinov, Izv. Akad. Nauk, Ser. Khim., 2535 (1996). V. D. Dyachenko and V. P. Litvinov, Khim. Geterotsikl. Soedin. 208 (1998). V. V. Kuznetsov, Khim. -Farm. Zh., 25, No. 7, 61 (1991). V. P. Litvinov, S. G. Krivokolysko, and V. D. Dyachenko, Khim. Geterotsikl. Soedin., 579 (1999). V. P. Litvinov, L. A. Rodinovskaya, Yu. A. Sharanin, A. M. Shestopalov, and A. Senning, Sulfur Reports, 13, 1 (1992). N. S. Zefirov and V. A. Palyudin, Dokl. Akad Nauk, 252, 111 (1980). M. Burke-Laing and M. Laing, Acta Crystallogr., B32, 3216 (1976). F. H. Allen, O. Kennard, D. G. Watson, L. Brammer, A. G. Orpen, and R. Taylor, J. Chem. Soc., Perkin Trans. 2, S1 (1987). S. Sandal, H. M. Seip, and T. Torgrimsen, J. Mol. Struct., 57, 101 (1979). D. J. Watkin, C. K. Prout, J. R. Carruthers, and P. W. Betteridge, CRYSTALS Issue 10, Chemical Crystallography Laboratory, Oxford University (1996). A. C. T. North, D. C. Phillips, F. Scott, and F. S. Matthews, Acta Crystallogr., A24, 351 (1968). J. R. Carruthers and D. J. Watkin, Acta Crystallogr., A35, 698 (1979). H. D. Flack, Acta Crystallogr., A39, 876 (1983).
1016
REGIOSELECTIVE SYNTHESIS AND PROPERTIES OF 6-AMINO-3-CARBAMOYL-5-CYANO3,4-DIHYDROSPIROCYCLOHEXANE-4-PYRIDINE2-THIOL AND 5-CYANO-3-THIOCARBAMOYL4-SPIROCYCLOHEXANEPIPERIDINE-2,6-DIONE

A. D. Dyachenko1, S. M. Desenko2, and V. D. Dyachenko1 Treatment of monothiomalonodiamide with cyclohexylidenemalononitrile or cyclohexylidenecyanoacetic ester in the presence of sodium ethylate gave 6-amino-3-carbamoyl-5-cyano-3,4dihydrospirocyclohexane-4-pyridine-2-thiol and 5-cyano-3-thiocarbamoyl-4-spirocyclohexanepiperidine-2,6-dione. Their alkylation and hydrolysis have been studied. Keywords: 3,4-dihydrospirocyclohexane-4-pyridine-2-thiol, monothiomalonodiamide, spirocyclohexane4-piperidine-2,6-dione, cyclohexylidenemalononitrile, cyclohexylidenecyanoacetic ester, alkylation, hydrolysis, Michael reaction, regioselective synthesis, cyclization, cyclocondensation. By contrast with the quite well studied 4-aryl-substituted 3-cyanopyridine-2(1H)-thiones [1], there have been reported in the literature few of the carbamoyl-substituted analogs [2-6] and the spiro-substituted 3-carbamoylpyridine-2-thiones are unknown. At the same time, spiro-substituted heterocycles are of interest for pharmacological study [7]. In connection with the above we now report the development of regioselective methods of synthesis of 6-amino-3-carbamoyl-5-cyano-3,4-dihydrospirocyclohexane-4-pyridine-2-thiol (1) and 5-cyano-3-thiocarbamoyl-4-spirocyclohexanepiperidine-2,6-dione (2). The thiol 1 was prepared in high yields (78-83%) by two methods. First from monothiomalonodiamide (3) and cyclohexylidenemalononitrile (4) via a Michael reaction and secondly by the cyclocondensation of the CH-acid 3 with cyclohexylidenecyanothioacetamide (5). Both reactions occur at 25C in absolute ethanol with catalysis by EtONa and apparently include the formation of the corresponding intermediate Michael adducts 6 and 7 which, however, could not be separated. The composition and structure of compound 1 was confirmed through elemental analysis, spectroscopic data (Tables 1-3), and some chemical reactions. Hence the treatment of the thiol 1 with an aqueous HCl solution occurred even at room temperature with hydrolysis of the enamine fragment to form 3-carbamoyl-5-cyano-6oxo-4-spirocyclohexanepiperidine-2-thione (8), which is an isomer of compound 2. The reaction of thiol 1 with the alkylating agents 9 in basic medium gave the organic sulfides 10a-f.
__________________________________________________________________________________________ Taras Shevchenko State Pedagogical University, Lugansk 91011, Ukraine; e-mail: dvd_lug@online.lg.ua. 2 V. N. Karazin Kharkov National University, Kharkov 61070, Ukraine. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1179-1185, August, 2004. Original article submitted December 18, 2001. 0009-3122/04/4008-10172004 Springer Science+Business Media, Inc. 1017
1
CN H2N S O H2N 3 4 Method A CN NC N N H2 6 NC NH2 S 5 Method B H2O/H+ NH3 O N H 8 S C S O NH2 O NH2
NC
O NC H2N NC NH2 H2S S N H2 7 S 1 H2N N
O NH2 SH
O X Y 9af NC H2N N 10af S NH2 Y
9 a X = I, b, d, f X = Cl, c, e X = Br; 9, 10 a, Y = H, b Y = CONHPh, c Y = COC6H4Me-4, N d Y = COOEt, e Y = CH=CH2, f Y =
COHN
It should be noted that compound 10 also undergoes acid hydrolysis but it does not stop at the stage of the formation of the corresponding oxo compound of type 8. Hence the treatment of the substituted dihydropiperidine 10a with a 10% aqueous solution of HCl gave 3-carbamoyl-5-cyano-4spirocyclohexanepiperidine-2,6-dione (11).
O 10a H2O/H
+
NC O N H 11 O
NH2
The second target product (dione 2b) was synthesized in 93% yield by the condensation of the monothiomalonodiamide (3) with cyclohexylidenecyanoacetic ester (12) under Michael reaction conditions and probably occurs via the hypothetical adduct 13.
1018
Hydrolysis of compound 2 in acidic medium leads to the thiocarboxylic acid 14 and alkylation with allyl bromide 15 in basic medium to the thioester 16. Compound 16 could also be prepared by an independent route from the substituted glutarimide 14 and allyl bromide 15 in the presence of aqueous KOH solution. The data presented above infers that the formation of 16 involves the basic hydrolysis of the thioamide fragment of compound 2, leading to the thiocarboxylic acid anion which subsequently undergoes alkylation. The alkylation of the thioamide 2 by phenacyl bromide 17 allows the synthesis of the novel heterocyclic system 4-benzoyl-5-imino-10-spirocyclohexane-8-aza-3-thiabicyclo[1,3,4]decane-2,7,9-trione (18).
S NC O
3 12
OEt
NC
NH2
EtO
..
O
N H2
O EtOH
13
Ph Ph S NC O N H 2 O O NH2 Br O 17 HN
6 1
O
4
S O
N H 18
Br
15
H2O/H+
17, H2O/OH
S NC O N H 16 O O
15, H2O/OH
SH NC O N H
14
O O
The production of 18 indicates that the reaction may not stop at the stage of formation of the type 16 thioester but can proceed further via a Thorpe-Ziegler cyclization [8] to the imino derivative 18. The latter compound can also be obtained by the alkylation of the thiocarboxylic acid 14 with compound 17. The structure and composition of compound 18 were confirmed by the results of elemental analysis and from spectroscopic data. Hence the IR spectrum of compound 18 showed characteristic absorption bands for the stretching vibrations of the imide, imine, and carbonyl groups (Table 2). At the same time, the absorption band for the stretching vibrations of the nitrile group are absent in this spectrum. The appearance of the signal for the H-4 proton at quite low field ( 6.71 ppm) is a feature of the 1H NMR spectrum and is explained in terms of the deshielding by three, neighboring C=O, C=NH, and SC=O electron acceptor groups.
1019
TABLE 1. Characteristics of Compounds 1, 2, 8, 10a-f, 11, 14, 16, 18

Compound Empirical formula C 1 2 8 10a 10b 10 10d 10e 10f 11 14 16 18 C12H16N4OS C12H15N3O2S C12H15N3O2S C13H18N4OS C20H23N5O2S C21H24N4O2S C16H22N4O3S C15H20N4OS C17H20N6O2S2 C12H15N3O3 C12H14N2O3S C15H18N2O3S C20H20N2O4S 54.40 54.52 54.23 54.32 54.20 54.32 55.96 56.09 60.63 60.43 63.56 63.61 54.96 54.84 59.33 59.18 50.56 50.48 58.00 57.82 54.39 54.12 58.94 58.80 62.64 62.48 Found, % Calculated, % H 5.97 6.10 5.77 5.70 5.79 5.70 6.62 6.52 5.76 5.83 6.14 6.10 6.45 6.33 6.53 6.62 5.11 4.98 5.91 6.07 5.19 5.30 6.05 5.92 5.10 5.24
mp, N 21.26 21.19 15.91 15.84 15.97 15.84 20.01 20.13 17.79 17.62 14.25 14.13 16.12 15.99 18.22 18.40 20.71 20.76 16.75 16.86 10.49 10.52 9.01 9.14 7.33 7.29 309-311 253-255 230-232 216-218 221-223 192-194 174-176 166-168 213-215 258-260 277-278 199-200 255-257
Yield, %
78 93 85 57 71 64 76 52 81 41 80 54 59
TABLE 2. Spectroscopic Characteristics of Compounds 1, 2, 8, 10a-f, 11, 14, 16, 18

-1 Com- IR spectrum, , cm CN, pound NH, NH2 NHCO 1 2 3 1
3210, 3270, 3330, 3410, 3485 3330
2160, 1680
6.67 and 6.56 (1 and 1H, two br. s, CONH2); 5.38 (2, br. s, NH2); 3.72 (1, s, -3); 1.17-1.58 (10, m, 52)*
2260, 1690 2250, 1690, 1660 2165, 1683 2185, 1670
3310, 3470 3360, 3530 3210, 3315, 3375, 3425
10
10b
11.11 and 9.78 (1 and 1H, two br. s, CSNH2); 9.22 (1, br. s, NH); 4.00 (1, s, -5); 3.63 (1, s, -3), 1.33-1.59 (10, m, 52) 12.86 (1, br. s, NH); 8.18 and 7.45 (1 and 1H, two br. s, CONH2); 5.01 (1, s, -5); 4.55 (1, s, -3); 1.19-1.82 (10, m, 52) 7.35 and 6.97 (1 and 1H, two br. s, CONH2); 5.76 (2, br. s, NH2); 3.46 (1, s, -3); 2.42 (3, s, SCH3); 1.27-1.62 (10, m, 52) 9.89 (1, s, NH); 7.53 (2, d, J = 7.6, C6H5); 7.47 (1H, br. s, CONH2); 7.25 (2, dd, J = 8.0, C6H5); 7.00 (2H, m, C6H5 and CONH2); 5.97 (2, br. s, NH2); 3.91 and 3.88 (1 and 1H, two d, J = 3.9, SCH2); 3.55 (1H, s, H-3); 1.24-1.63 (10H, m, 52)
1020
TABLE 2 (continued)
1 10 2 3300, 3360, 3450 3 2175, 1695, 1680 4 7.91 and 7.34 (2 and 2H, two d, J = 8.2, Ar); 7.47 and 7.02 (1 and 1H, two br. s, CONH2); 5.81 (2, br. s, NH2); 4.78 and 4.60 (1 and 1H, two d, J = 16.8, SCH2); 3.56 (1H, s, H-3); 2.44 (3H, s, CH3); 1.27-1.64 (10H, m, 5CH2) 7.45 and 7.00 (1 and 1H, two s, CONH2); 5.80 (2, br. s, NH2); 4.08 (2H, q, J = 7.2, OCH2); 4.01 and 3.89 (1 and 1H, two d, J = 16.3, SCH2); 3.49 (1H, s, H-3); 1.25-1.58 (10H, m, 52); 1.21 (3, t, J = 7.2, 3) 7.37 and 6.96 (1 and 1H, two s, CONH2); 5.82 (3, m, NH2 and =); 5.33 and 5.14 (1 and 1H, two d, J = 16.8, J = 9.9, CH2); 3.70 (2H, t, J = 7.0, SCH2); 3.43 (1, s, H-3); 1.29-1.60 (10H, m, 52) 12.08 (1, s, NH); 7.43 (2, m, H-4 thiazole and CONH2); 7.16 (1H, d, J = 4.0, H-5 thiazole); 6.94 (1, br. s, CONH2); 5.89 (2H, br. s, NH2); 4.13 and 4.01 (1 and 1H, two d, J = 15.2, SCH2); 3.52 (1H, s, H-3); 1.28-1.63 (10H, m, 5CH2) 11.50 (1, br. s, NH); 8.12 and 7.52 (1 and 1H, two br. s, CONH2); 5.06 (1H, s, H-5); 3.99 (1H, s, H-3); 1.23-1.71 (10H, m, 5CH2) 13.07 (1, br. s, SH); 11.61 (1H, br. s, NH); 4.23 (1H, s, H-3); 3.76 (1H, s, H-5); 1.36-1.51 (10H, m, 5CH2) 11.32 (1, s, NH); 5.87 (1H, m, =); 5.35 and 5.19 (1 and 1H, two d, J = 17.0, J = 10.1, CH2); 3.82 (3H, m, SCH2 and -5); 3.63 (1, s, -3); 1.38-1.57 (10, m, 52) 11.78 (1, s, =NH); 11.46 (1H, s, NH); 8.01 (2H, d, C6H5); 7.63 (1H, m, C6H5); 7.54 (2H, m, C6H5); 6.71 (1, s, SCH); 3.92 (1H, s, H-1); 3.59 (1H, s, H-6); 1.37-1.60 (10H, m, 5CH2)
10d
3210, 3390, 3510
2170, 1740, 1695
10
3340, 3450, 3510
2163, 1680
10f
3350, 3420
2155, 1660, 1650 2250, 1710, 1680 2255, 1730 2265, 1760, 1720, 1710 1745, 1710, 1640
11
3240, 3450 3240 3210
14 16
18
3210, 3364
_______ * The SH signal was not found, evidently because of rapid deuterium exchange.
TABLE 3. Mass Spectra of Compounds 1, 2, 8, 10a,b, 11, 14, 16, 18

Compound 1 2 8 10 10b 14 16 18 m/z (Irel, %) Other fragments 221 (31), 178 (53), 165 (47), 121 (52), 81 (61), 68 (90), 55 (84), 41 (100) 232 (71), 210 (17), 179 (12), 123 (20), 102 (34), 79 (15) 248 (30), 221 (45), 179 (25), 145 (100), 118 (52), 102 (45), 44 (43) 261 (8), 246 (2), 234 (19), 218 (13), 192 (100), 179 (26), 146 (8), 120 (8), 67 (12), 44 (39) 293 (31), 263 (47), 218 (77), 190 (30), 177 (19), 135 (15), 120 (26), 93 (100), 65 (53), 39 (74) 233 (28), 206 (10), 195 (25), 141 (15), 122 (35), 79 (15) 291 (100), 265 (12), 194 (18), 180 (4), 138 (10), 123 (18), 86 (18), 41 (29) 352 (70), 355 (5), 324 (12), 307 (5), 296 (18), 275 (5), 238 (5), 214 (11), 186 (20), 146 (5), 123 (73), 105 (100), 77 (62)
M+ 264 (3) 265 (100) 265 (65) 278 (23) 397 (9) 266 (100) 306 (11)
1021
EXPERIMENTAL The 1H NMR spectra of compounds 1, 2, 8, 10a-e, 11, 14 were recorded on a Gemini-200 instrument (199 MHz) and compounds 10f, 16, 18 on a Bruker DRX500 (500 MHz) using DMSO-d6 solvent and TMS internal standard. Mass spectra were taken on a Kratos MS-890 spectrometer (70 eV). Melting points were determined on a Koffler block. IR spectra were recorded on an IRS-29 instrument using vaseline oil. Monitoring of the course of the reaction and the purity of the materials obtained was carried out using TLC on Silufol UV-254 plates in the system acetone-hexane, 3: 5 and revealed using iodine vapor. 6-Amino-3-carbamoyl-5-cyano-3,4-dihydrospirocyclohexane-4-pyridine-2-thiol (1). A. The monothiomalonodiamide 3 (1.18 g, 10 mmol) was added to a solution of sodium (0.23 g, 10 mmol) in absolute ethanol (20 ml) and the mixture was stirred to the formation of a solution, after which the cyclohexylidenemalononitrile 4 (1.46 g, 10 mmol) was added and the stirring was continued for 15 min. The formed yellow precipitate of 1 was filtered off and washed with ethanol and hexane. B. Using the method described above with the cyclohexylidenecyanothioacetamide 5 (1.8 g, 10 mmol) in place of compound 4 to give the product 1. The melting point, 1H NMR spectrum, and Rf agreed with those for the sample prepared using method A. 5-Cyano-3-thiocarbamoyl-4-spirocyclohexanepiperidine-2,6-dione (2) was prepared similarly to compound 1 from equimolar amounts (both 10 mmol) of compounds 3 and 12. The reaction mixture was held for 1 day at 20C and compound 2 was filtered off. 3-Carbamoyl-5-cyano-6-oxo-4-spirocyclohexanepiperidine-2-thione (8). A solution of 10% aqueous HCl was added dropwise with stirring to a suspension of the thiol 1 (1.32 g, 5 mmol) in ethanol (10 ml) to pH 5. The mixture obtained was held for 1 day at room temperature and the light-yellow crystals of compound 8 were filtered off. 6-Amino-3-carbamoyl-5-cyano-2-methylthio-3,4-dihydrospirocyclohexane-4-piperidine (10a), 6-Amino-3-carbamoyl-5-cyano-2-phenylcarbamoylmethylthio-3,4-dihydrospirocyclohexane-4-pyridine (10b), 6-Amino-3-carbamoyl-5-cyano-2-(4-methylbenzoylmethylthio)-3,4-dihydrospirocyclohexane-4pyridine (10c), 6-Amino-3-carbamoyl-2-carbethoxymethylthio-5-cyano-3,4-dihydrospirocyclohexane-4pyridine (10d), 2-Allylthio-6-amino-3-carbamoyl-5-cyano-3,4-dihydrospirocyclohexane-4-pyridine (10e), and 6-Amino-3-carbamoyl-5-cyano-2-[(thiazol-2-ylcarbamoyl)methylthio]-3,4-dihydrospirocyclohexane-4pyridine (10f). 10% Aqueous KOH (2.8 ml, 5 mmol) and then the halide 9 (5 mmol) were added with stirring to a solution of the thiol 1 (1.32 g, 5 mmol) in DMF (10 ml) at 20C. The reaction mixture was stirred for 2 h. The precipitated product 10 was filtered off and washed with 40% aqueous ethanol and hexane. 3-Carbamoyl-5-cyano-4-spirocyclohexanepiperidine-2,6-dione (11). A mixture of compound 10a (1.39 g, 5 mmol) and 10% aqueous HCl (2.74 ml, 7.5 mmol) was refluxed with a reflux condenser for 1 h and held at room temperature for 12 h. The precipitated product 11 was filtered off and washed with ethanol and hexane. 5-Cyano-3-thiocarboxy-4-spirocyclohexanepiperidine-2,6-dione (14) was prepared from the dione 2 (1.32 g, 5 mmol) similarly to the thione 8. The product 14 was filtered off and washed with ethanol and hexane. 3-Allylthiocarbonyl-5-cyano-4-spirocyclohexanepiperidine-2,6-dione (16). A. A 10% aqueous solution of KOH (2.8 ml, 5 mmol) was added with stirring to a suspension of compound 2 (1.32 g, 5 mmol) in DMF (10 ml). After formation of a homogeneous mixture the allyl bromide 15 (0.42 ml, 5 mmol) was added and the reaction mixture was stirred for 4 h and then held for 1 day at room temperature. The precipitated product 16 was filtered, washed with ethanol and hexane, and recrystallized from ethanol. B. As in method A replacing compound 2 with the thioacid 14 (1.33 g, 5 mmol) to give the product 16 whose chromatographic data, melting point, 1H NMR spectrum, and Rf were identical to those for the sample prepared by method A.
1022
4-Benzoyl-5-imino-10-spirocyclohexane-8-aza-3-thiabicyclo[1,3,4]decane-2,7,9-trione (18). A. A solution of 10% aqueous KOH (2.8 ml, 5 mmol) and then phenacyl bromide 17 (1.0 g, 5 mmol) were added with stirring to a suspension of compound 2 (1.32 g, 5 mmol) in DMF (10 ml). The reaction mixture was stirred for 4 h and held for 1 day at room temperature. The precipitated product 18 was filtered off, washed with ethanol and hexane, and recrystallized from glacial AcOH. B. As in method A replacing compound 2 with the thioacid 14 (1.33 g, 5 mmol) to give the product 18, identical to the sample prepared by method A (mp, 1H NMR spectrum, Rf).
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. V. P. Litvinov, L. A. Rodinovskaya, Yu. A. Sharanin, A. M. Shestopalov, and A. Senning, Sulfur Reports, 13, 1 (1992). W. Schaper, Synthesis, 861 (1985). L. A. Rodinovskaya, A. M. Shestopalov, and V. N. Nesterov, Khim. Geterotsikl. Soedin., 1376 (1996). A. Krauze and G. Duburs, Khim. Geterotsikl. Soedin., 506 (1999). A. Krauze (Krause), J. Popelis, and G. Duburs, Heterocycl. Commun., 3, 515 (1997). A. A. Krauze, A. Rumler, F. Khagen, Kh.-I. En'sh, I. G. Shturm, and G. Ya. Dubur, Khim. Geterotsikl. Soedin., 75 (1992). V. V. Kuznetsov, Khim.-Farm. Zh., 25, 61 (1991). F. S. Babichev (editor), Intramolecular Interaction of Nitriles and CH, OH, and SH Groups [in Russian], Naukova Dumka, Kiev (1985).
1023
REACTION OF POLYFLUORINATED -DIIMINES WITH KETONES. A NOVEL METHOD FOR THE SYNTHESIS OF FLUORINATED PYRIDINES
O. E. Petrova, M. A. Kurykin, and E. I. Mysov Reaction of polyfluorinated -diimines with ketones gave polyfluorinated pyridines. Keywords: ketones, polyfluorinated dihydropyrimidines, polyfluorinated -diimines, polyfluorinated pyridines, condensation. The six-membered azaheterocycles pyridine and pyrimidine occupy a special place amongst heterocyclic compounds. Medicinal compounds based on azaheterocyclic structures are found in almost all areas of pharmacology. Fluorinated pyridines and pyrimidines [1-4] are of interest since the introduction of a fluorine into a molecule generally increases the physiological activity of the compound [5] and also increases the stability of the medicinal compound towards oxidation by the oxygen in the air [6]. 1,3-Bifunctional, fluorinated building units are usually used to synthesize fluorinated pyridines. -Diketones [7-10], -alkoxyvinyl ketones [10, 11], aminovinyl ketones [12], etc. can serve as fluorinated 1,3-bifunctional compounds. We have previously reported the use of 2-amino-4-iminoperfluoroalk-2-enes 1, which are aza analogs of -diketones, as convenient starting materials in the synthesis of fluorinated pyrimidines [13, 14]. In this work we propose for the first time the use of the polyfluorinated -diimines 1 as starting materials for the preparation of fluorinated pyridines. In the literature only one example of the reaction of nonfluorinated -diimines with ketones has been reported. Moreover, the condensation occurs only in the presence of aluminium chloride and ends with the formation of dihydropyrimidines [15]. We have found that the imino enamines 1 react with methyl alkyl ketones and acetophenone at 90-180C in the absence of catalysts to give polyfluorinated pyridines. It was found that the reaction occurs by a scheme which includes the formation of dihydropyrimidines which subsequently eliminate ammonia to give the polyfluorinated pyridines. The course of the reaction was monitored using 19F NMR spectroscopy. The fluorinated -diimine 1a reacts with acetone, evidently, initially to form adduct A which cyclizes, in the conditions selected by us, with the loss of water to give the dihydropyrimidines 2 and 3.
__________________________________________________________________________________________ A. N. Nesmeyanov Institute for Organoelement Compounds, Russian Academy of Sciences, Moscow 119991; e-mail: mak@ineos.ac.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1186-1192, August, 2004. Original article submitted December 28, 2001. 1024 0009-3122/04/4008-10242004 Springer Science+Business Media, Inc.
F F3C NH2 1a NH CF3 F3C
F CF3 NH HO Me A F H F CF3 N Me 2 NH Me F3C CF3 N Me 3 N Me NH3 NH Me H2O
Me2CO
F3C
F F3C N
b CF3 c
Me 4
The presence and the reactions of the 1,2- and 2,5-dihydropyrimidines 2 and 3 were established using 19F NMR spectroscopy. In the course of the reaction, the heptet signal at = 94.0 ppm (J = 15 Hz) for the vinyl fluorine atom of the dihydropyrimidine 2 and the double heptet at 106.0 ppm (J = 46 and 8 Hz) for the CFH group of the dihydropyrimidine 3 are slowly transformed to a multiplet at 57.0 ppm for the pyridine 4. The formation of the dihydropyrimidines 2 and 3 was also confirmed by mass spectroscopic data. After preliminary separation on a capillary chromatographic column the mass spectra of the reaction mixture showed the M+ molecular ions for compounds 2 and 3.
F F3C NH2 1b F F 3C N Me 7 F a F 3C N Me 5 b CF2 CF3 c d eF C 3 F C2F 5 NH Me F3C F C2F 5 N Me 8 f g CF2 CF3h F 3C H F C2F 5 N N NH3 NH C2F5
Me2CO H2O
HN Me
Me Me 9
N Me 6
According to 19F NMR spectroscopic data the condensation of the unsymmetrical -diimine 1b with acetone occurs over a longer time and gives a mixture of the isomeric pyridines 5 and 6 in the ratio 75: 25. As in the preceding case, the pyridines 5 and 6 are formed from the corresponding dihydropyrimidines 7-9. This is
1025
confirmed by the presence in the 19F NMR spectrum of the reaction mixture of signals for the fluorine -atoms of compounds 7, 8 as multiplets at 92.0 and 93.5 ppm and also the appearance of a double multiplet at = 104.0 ppm (J = 47 Hz) for the CFH group of the dihydropyrimidine 9. Subsequently, the fluorine -atom signals of all the dihydropyrimidines are transformed to a multiplet at = 54.1 ppm corresponding to the pyridine 5 and a multiplet at = 53.8 ppm for the corresponding pyridine 6. The synthesized pyridines 5 and 6 were obtained as a mixture and we were unable to separate the individual compounds. We have studied the reaction of the imino enamine 1a with methyl ethyl ketone, in which the reaction can occur both at the methyl and at a methylene group and it was found that both routes are realized.
1a
MeCOEt
H2O
F F 3C N Me 12 b CF3 N Et 10 c d NH Et CF3 F 3C
H F
* N * N Et 13, 14 e
CF3 NH3
Me
F F3C
F F3C N
f CF3 Me
Me 11
The reaction of 1a with methyl ethyl ketone gives a mixture of the 6-ethyl- and 2,3-dimethylpyridines 10 and 11. In the initial cyclization of compound 1a with the ketone the 1,2-dihydropyrimidine (12) and the two diastereomers of the 2,5-dihydropyrimidine 13 and 14 are formed. The 19F NMR spectrum shows pyrimidine signals as a heptet at = 96.0 ppm (J = 15z) for 12 and two doublets of heptets for 13 and 14 at = 103 and 104 ppm (with repeated spin-spin couplings of 46 and 7 Hz). Further reaction of the pyrimidines 12-14 to the pyridines 10, 11 occurs via the elimination of ammonia. The structure of the pyridines obtained was confirmed by the NMR and mass spectroscopic data. Hence the 19F NMR spectrum shows signals for the CF group fluorine of the pyridine 10 as a quartet of quartets of doublets at 53.6 ppm and a quartet of quartets at 52.2 ppm in 11. The 1 H NMR spectrum shows signals for the methyl groups as singlets in the pyridine 11 and two signals assigned to the ethyl group of compound 10 as a triplet and quartet. In addition, after preliminary chromatographic separation on a capillary column the mass spectrum shows the molecular ions for the synthesized pyridines. The pyridines 10 and 11 were obtained as a mixture and separation into the individual components was not achieved. The reaction of the -diimine 1a with acetophenone under analogous conditions gave the pyridine 15, the occurrence of which also infers the formation of the corresponding dihydropyrimidines 16-18. The CF group fluorine atom signals for the latter are seen in the 19F NMR spectrum of the reaction mixture as a multiplet at = 91.0 ppm for the compound 16 and two doublets of multiplets at = 106.0 and 108.0 ppm (J = 46 Hz in each case) for 17 and 18. The unsymmetrical imino enamine 1b reacts with acetophenone to give a mixture of the isomeric pyridines 19 and 20. However the intermediate dihydropyrimidines 21-24 could not be identified by the 19F NMR method. The structure of the obtained pyridines was proved from NMR and mass spectroscopic data. 1026
F F 3C N Me MeCOPh H2O 1b F 3C HN Me 21 a F F3C N Ph b N Ph NH Ph 16 CF3 F 3C
H * N Me
F CF3 NH3 aFC 3 N
b c CF3
1a
* N Ph
17, 18
Ph 15 F * N Me * N Ph C2F5
F C2F5 F 3C
F C2F5 N Me 22 c CF2 CF3d F F3C N Ph f NH Ph F 3C
23, 24
CF2g CF3 h
19
20
1027
TABLE 1. Characteristics of Compounds 4-6, 10, 11, 15, 19, 20

Compound 4 5, 6 10, 11 15 19, 20 Empirical formula C C8H4F7N C9H4F9N C9H6F7N C13H6F7N C14H6F9N 38.69 38.87 36.23 36.36 41.62 41.38 50.56 50.48 47.11 46.80 Found, % Calculated, % H F 1.85 1.62 1.52 1.35 2.43 2.30 1.84 1.94 2.06 1.67 53.64 53.85 57.05 57.58 50.56 50.96 Bp, C (mm Hg) N 4.47 4.53 3.92 3.90 46-48 (13) 48-50 (15) 60-63 (14) * 125-127 (14) Reaction time, h 48 60 25 22 31 Yield, % 47.6 64.0 70.0 62.8 61.0
_______ * Mp 65-67C, sublimation 140-142C (23 mm Hg). TABLE 2. Spectroscopic Characteristics of Compounds 4-6, 10, 11, 15, 19, 20
Compound 4 Mass spectrum, m/z (Irel, %) 247 [M]+ (100), 228 [C8H4F6N] (60), 227 [C8H3F6N] (83), 178 [C7H4F4N] (19), 177 [C7H3F4N] (53), 158 [C7H3F3N] (46), 69 [CF3] (12) 297 [M]+ (68), 278 [C9H4F8N] (22), 277 [C9H3F8N] (18), 228 [C8H4 F6N](100), 208 [C8H3 F5N] (15), 69 [CF3] (20) NMR spectrum, , ppm (J, Hz) 1 F H 2.6 (3H, s, CH3), 7.6 (1H, d, J(F-H) = 4.4)
19
-12 (3F, d, J = 12.5, CF3c), -10 (3F, d, J = 16.5, CF3a), 57.0 (1F, m, Fb)
10
11
15
19
20
261 [M]+ (100), 260 [C9H5F7N] (100), 242 [C9H6F6N] (30), 240 [C9H4F6N] (78), 213 [C7H1F6N] (23), 69 [CF3] (22) 261 [M]+ (100), 242 [C9H6F6N] (37), 241 [C9H5F6N] (90), 69 [CF3] (18) 309 [M]+ (100), 290 [13H6F6N] (27), 240 [12H6F4N] (18), 77 [C6H5] (3), 69 [CF3]+ (6) 359 [M]+ (100), 340 [14H8F8N] (25), 290 [C13H8F6N] (92), 220 [12H7F3N] (15), 77 [C6H5] (8) 359 [M]+ (100), 340 [14H8F8N] (9), 290 [C13H8F6N] (24), 220 [12H7F3N] (8), 77 [C6H5] (4)
-13.0 (3F, d, J = 12.0, CF3), 7.0 (3F, d, J = 6.0, CF3d), 38.8 (2F, d, J = 23.0,CF2c), 53.8 (1F, m, Fb) -10.5 (3F, d, J = 16.0, CF3), 9.0 (3F, d, J = 11.0, CF3h), 38.3 (2F, d, J = 20.0, CF2g), 54.1 (1F, m, Ff) -14.8 (3F, d, J = 13.5, CF3), -12.0 (3F, d, J = 15.5, CF3a), 53.6 (1F, qqd, J = 4.4, Fb)
2.8 (3H, s, CH3), 7.85 (1H, d, J(F-H) = 4.4) 2.8 (3H, s, CH3), 7.8 (1H, d, J(F-H) = 4.4) 1.55 (3, t, J = 7.0, 23), 3.1 (2, q, 23), 7.75 (1, d, J(F-H) = 4.4) 2.65 and 2.75 (6, both s, 2CH3)
-21.0 (3F, d, J = 30.0, F3f), -12.0 (3F, d, J = 15.5, CF3d), 52.2 (1F, qq, F) -15.0 (3F, d, J = 13.5, F3), -12.0 (3F, d, J = 16.0, F3), 52.0 (1F, m, Fb)
7.2-7.95 (5, m, Ar), 8.0 (1H, d, J(F-H) = 4.4)
-13.0 (3F, d, J = 13.0, CF2a), 6.5 (3F, d, J = 4.0, CF3d), 38.0 (2F, d, J = 22.0, CF2c), 53.0 (1F, m, Fb) -11.0 (3F, d, J = 15.5, CF3e), 8.5 (3F, d, J = 11.5, CF3h), 38.5 (2F, d, J = 20.0, CF2g), 52.0 (1F, m, Ff)
6.1-7.65 (12, m, (3) and Ar)
1028
By varying the conditions of the reaction and the ratio of starting reagents we found that the optimum yields of the pyridines 4, 5, 10, 11 could be achieved with the use of a two fold excess of the ketone and the pyridines 15, 19, 20 by carrying out the reaction with the use of dioxane or diglyme solvent. All of the polyfluoropyridines are liquids characterised by their smell, light-yellow color, and insolubility in water. An exception is the pyridine 15 which is a solid material. Hence the proposed, novel method yields polyfluoropyridines from available fluorinated imino enamines [16].
EXPERIMENTAL H NMR and 19F NMR spectra were recorded on a Bruker AC-200F spectrometer (200 and 188 MHz respectively) with TMS and CF3COOH external standard and mass spectra on a VG-7070E spectrometer (ionizing voltage 70 eV). The yields and characteristics of the compounds obtained are given in Tables 1 and 2. 3-Fluoro-6-methyl-2,4-bis(trifluoromethyl)pyridine (4). A mixture of the -diimine 1a (4.0 g, 17.7 mmol) and acetone (2.3 g, 40.3 mmol) was refluxed with a reflux condenser for 48 h. The cooled reaction mixture was poured into CH2Cl2 (20 ml), washed with water (2 30 ml), and the organic layer was separated, dried over CaCl2, and distilled to give the pyridine 4 (2.1 g) 3-Fluoro-6-methyl-2-pentafluoroethyl-4-trifluoromethylpyridine (5) and 3-Fluoro-6-methyl-4pentafluoroethyl-2-trifluoromethylpyridine (6). A mixture of the -diimine 1b (5.3 g, 19.3 mmol) and acetone (2.8 g, 50.0 mmol) was refluxed with a reflux condenser for 60 h. The cooled reaction mixture was poured into CH2Cl2 (30 ml), washed with water (2 30 ml), and the organic layer was separated, dried over CaCl2, and distilled to give a mixture (3.7 g) containing 75% of the pyridine 5 and 25% of pyridine 6 from 19 F NMR data. 6-Ethyl-3-fluoro-2,4-bis(trifluoromethyl)pyridine (10) and 5-Fluoro-2,3-dimethyl-4,6-bis(trifluoromethyl)pyridine (11). A mixture of the -diimine 1a (3.8 g, 17 mmol) and methyl ethyl ketone (2.4 g, 34.0 mmol) was refluxed with a reflux condenser for 25 h. The cooled reaction mixture was poured into CH2Cl2 (30 ml), washed with water (2 30 ml), and the organic layer was separated, dried over CaCl2, and distilled to give a mixture (3.1 g) containing 68% of compound 10 and 32% of compound 11 from 19F NMR data. 3-Fluoro-6-phenyl-2,4-bis(trifluoromethyl)pyridine (15). A solution of the -diimine 1a (8.2 g, 36.6 mmol) and acetophenone (4.4 g, 36.6 mmol) in diglyme (10 ml) was refluxed with a reflux condenser for 22 h. The cooled reaction product was poured into water and the precipitate formed was filtered off, dried in air, and sublimated to give the pyridine 15 (7.1 g, 62.8%). 3-Fluoro-2-pentafluoroethyl-6-phenyl-4-trifluoromethylpyridine (19) and 3-Fluoro-4-pentafluoroethyl-6-phenyl-2-trifluoromethylpyridine (20). A solution of the -diimine 1b (4.0 g, 14.6 mmol) and acetophenone (1.8 g, 15 mmol) in dioxane (10 ml) was refluxed with a reflux condenser for 31 h. The cooled reaction mixture was poured into CH2Cl2 (30 ml), washed with water (2 30 ml), dried over CaCl2, and distilled to give a mixture (3.3 g) which contained 73% of the pyridine 19 and 27% of pyridine 20 from 19F NMR data.
1
REFERENCES 1. 2. 3. 4. 5. K. Burger, U. Wassmuth, F. Hein, and S. Rotlegger, Liebigs Ann. Chem., 991 (1984). T. Ishihara, Y. Okada, M. Kuroboshi, T. Shinozaki, and T. Ando, Chem. Lett., 819 (1988). S. Adam, Tetrahedron, 45, 1409 (1989). A. A. Zidermane, Fluoropyridines in Cancer Chemotherapy, Zinatne, Riga (1982). Y. T. Welch, Tetrahedron, 43, 3123 (1987).
1029
6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
A. L. Jackman, P. R. Marcham, T. J. Thornton, J. A. M. Bishop, B. M. O'Connor, L. R. Hughes, A. H. Calvert, and T. R. Jones, J. Med. Chem., 33, 3067 (1990). R. Balicki and P. Natka-Namirski, Pol. J. Chem., 54, 2175 (1980). V. A. Dorokhov, L. S. Vasil'ev, F. E. Surzhikov, and V. S. Bogdanov, Izv. Akad. Nauk, Ser. Khim., 1329 (1995). I. Katsuyama, S. Ogawa. Y. Yamaguchi, K. Funabiki, M. Matsui, H. Muramatsu, and H. Shibata, Synthesis, 1321 (1997). L. G. Nikishin, V. P. Kislyi, V. N. Nesterov, A. M. Shestopalov, Yu. T. Struchkov, and V. V. Semenov, Izv. Akad. Nauk, Ser. Khim., 482 (1998). N. Zanatta, R. Barichelo, H. G. Bonacarso, and M. A. P. Martins, Synthesis, 765 (1999). V. I. Filyakova, V. G. Ratner, N. S. Karpenko, and K. I. Pashkevich, Izv. Akad. Nauk, Ser. Khim. 2278 (1996). O. E. Petrova, M. A. Kurykin, and D. V. Gorlov, Izv. Akad. Nauk, Ser. Khim., 2195 (1999). O. E. Petrova, M. A. Kurykin, and D. V. Gorlov, 13th European Symposium on Fluorine Chemistry, Bordeaux, France, 2001, 2-P52. J. Barluenga, M. Tomas, S. Fustero, and V. Gotor, Synthesis, 346 (1979). O. E. Petrova, M. A. Kurykin, and D. V. Gorlov, Izv. Akad. Nauk, Ser. Khim., 1710 (1999).
1030
CHARACTERISTICS OF THE DISSOCIATIVE IONIZATION OF 9-ARYL(HETARYL)-3,3,6,6-TETRAMETHYLDECAHYDROACRIDINE-1,8-DIONES UNDER THE INFLUENCE OF ELECTRON IMPACT
Yu. M. Shchekotikhin1 and T. G. Nickolaeva2 The mass spectra of 9-aryl(hetaryl)-3,3,6,6-tetramethyldecahydroacridine-1,8-diones have been studied and the basic directions of their dissociative ionization under the influence of electron impact have been elucidated. It has been shown that the decomposition pathways of decahydroacridine-1,8-diones depend on the nature of the substituents at position 10 and is connected with the preferential formation of a pyridinium structure with subsequent retrodiene decomposition of the molecules. Keywords: 3,3,6,6-tetramethyl-9-R-decahydroacridine-1,8-diones, dissociative ionization, retrodiene decomposition. Beside the wide use of mass spectrometry in contemporary organic chemistry to obtain information on the structure of materials, this method has received relatively limited use for the structural investigation of such classes of organic compounds as decahydroacridine-1,8-diones [1, 2]. In a continuation of the study of the regularities of the synthesis and properties of the latter [3-7] we have undertaken the investigation of the mass spectral behavior of a large series of 9-aryl(hetaryl)-3,3,6,6-tetramethyl-1,2,3,4,5,6,7,8,9,10-decahydroacridine1,8-diones (1a-n). The wide variation in the substances studied allowed the elucidation of the basic rules of the dissociative ionization of compounds 1 under the influence of electron impact depending on their structures. Structural assignments were carried out using literature data on the mass spectrometric investigation of 1,8-dioxo-sym-octahydroxanthenes [8], 6,6-dimethyl-4-oxo-4,5,6,7-tetrahydroindoles [9], 7,7-dimethyl-5-oxo1,4,5,6,7,8-hexahydroquinolines [10], and 3,5-diacyl-1,4-dihydropyridines [11]. The structures of the substituted decahydroacridine-1,8-diones 1a-n were established by IR and 1H NMR spectroscopy [3-5].
O Me Me N R1 1an
1 ,b R1 = H, c-g R1 = Me, h-j R1 = Ph, k-n R1 = PhCH2; a, f, i, m R = 5-O2N-2-C4H2O (5-nitro-2-furyl), b, g, j, n R = 2-C4H3S (2-thienyl), c, k R = Ph, d, h, l R = 4-MeOC6H4, e R = 2-C4H3O (2-furyl)
O Me Me
__________________________________________________________________________________________ "Nita-Farm", Saratov 410005, Russia; e-mail: nita-farm@overta.ru. 2 Saratov State University, Saratov 410026, Russia. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, 1193-1197, August, 2004. Original article submitted November 14, 2001. 0009-3122/04/4008-10312004 Springer Science+Business Media, Inc. 1031
O Me
+ + O Me Me
Me Me N R1 1aj R O M +
Me2C=CH C Me
+ N R1 A2 RH
.
O C4H8 O + N R1 2 C4H8 C4H8 A3 Me Me A1 O
Me Me
+ N R1
Me Me
CO O
O + N Me2C=CHC A8 CO + Me2C=CH A10 + O A4 R

1
O Me Me A5 CO O R1 N A9 CO + N R1 A7 + A6 + N R1 A8 + N R1
C4H8
In the spectra of NH-decahydroacridine-1,8-diones 1a,b, and also of the hydroacridines 1c-j, which contain methyl or phenyl substituents on the nitrogen atom, the molecular ion peaks M+ are quite intense, and this peak is the most intense for 10-phenyl-9-thienyldecahydroacridinedione 1j (Table 1). On the other hand, the N-benzyldecahydroacridine-1,8-diones 1k-n are characterized by M+ peaks of low intensity. The presence of a para-methoxyphenyl radical in position 9 (compounds 1d,h,l) decreased the relative intensity of the molecular ion peak. The presence of the MeO group in these compounds causes the formation of the ion [M+ - CH2O]+ which is characteristic for the dissociative ionization of anisoles [12]. The stability of the M+ ions (WM) changes in dependence of the nature of the substituent groups at positions 9 and 10: the largest value of WM was observed for the acridinediones 1b,g,j which have a thienyl group in position 9, and the smallest value was for the Nbenzyl-substituted 1,8-dioxodecahydroacridines 1k-n. Compounds 1a,f,i have moderate values of WM which is normal for nitroaromatic compounds [13]. In their spectra peaks for the ions [A - NO]+ are present which indicates the elimination of the fragment NO from the species formed by decomposition of the molecular ion. 1032
O Me
+ PhCH2
O Me Me A11 C4H8
Me Me N CH2Ph M 1kn +
Me Me
Me
+ N H
. R
A1 Me Me O R
A8 R O + N H A13 C4H8 C4H8 CO + N H
O Me Me A12
A8 R O + N H A15 CO O + N H A14 R O
CO
A10
In the case of the 1,8-dioxodecahydroacridines 1a-j, decomposition of the molecular ion may follow two different pathways. The dominant direction of dissociative ionization is scission of the radical R from position 9 of the molecular ions leading to the formation of stable pyridinium cations A1, which is in agreement with the fragmentation of 4-R-1,4-dihydropyridnes [10-11, 14]. This process is accompanied by the appearance of intense peaks, which, for compounds 1a-i, are the most intense peaks present. The other pathway is via loss of the ion C5H7O+ (m/z = 83), however the peaks arising in this way (A2) have low intensity. Further fragmentation of the A1 ions occurs via retrodiene decomposition with successive elimination of two C4H8 molecules to form the cations A3 and A4. The mass numbers of fragments A1-A4 indicate that the substituent on the nitrogen atom is retained. In the mass spectra of the decahydroacridin-1,8-diones 1a-j peaks of the ions A5, A6, and A7 are observed which arise from loss of the molecule CO from the cations A3, A4, and A6. Fragment A5 may also be formed directly from A2 and A6 from A5 from a retro-DielsAlder reaction with loss of an alkene molecule, and A7 from A5 by elimination of the ion C5H7O+ (A8). There are also the ions A9, which evidently have a cyclopropenylium structure, and cations A8 and A10 which are characteristic for derivatives of 5,5-dimethyl-2cylohexenone [8, 10, 15]. In contrast to the 9-R-10-R1-decahydroacridine-1,8-diones 1a-j (R1 = H, Me, Ph), the effect of the structure of the substituent on the nitrogen atom in the 10-benzyldecahydroacridine-1,8-diones 1k-n on the direction of decomposition under the influence of electron impact can be traced. A feature of the dissociative ionization of 1,8-dioxodecahydroacridines 1k-n is associated with the appearance in their spectra of very intense fragments A11 which arise from scission of the C-N bond and loss of the radical PhCH2 from M+ ion. This route is confirmed by the presence of the signal for the ion C7H7+ (evidently with the tropylium structure), which is characteristic of the electron impact mass spectra of alkylbenzenes [16]. The peak A1 has low intensity for the acridindiones 1k-n and the peaks for the cations A2-A7 are absent. In the high and medium mass number 1033
TABLE 1. Mass-spectra of Decahydroacridine-1,8-diones 1a-n

Compound 1a 1b 1c 1d 1e 1f 1g 1h 1i 1j 1k 1l 1m 1n m/z (Irel, %) 386 (5), 385 (12), 384 [+] (52), 367 (14), 301 (23), 272 (100), 216 (57), 188 (32), 160 (19), 132 (12), 104 (10), 83 (19), 55 (15), 52 (6) 357 (10), 356 (19.5), 355 [+] (84), 272 (100), 216 (29), 188 (18), 160 (11), 132 (8), 104 (5), 83 (10), 55 (8), 52 (7) 365 (9), 364 (20), 363 [+] (76), 286 (100), 280 (19), 230 (49), 202 (36), 174 (25), 146 (17), 118 (12), 83 (11), 66 (9), 55 (5) 395 (4), 394 (7), 393 [+] (26), 363 (17), 310 (11), 286 (100), 230 (53), 202 (39), 174 (27), 146 (20), 118 (13), 83 (14), 66 (12), 55 (14) 355 (8), 354 (17), 353 [+] (70), 286 (100), 270 (20), 230 (48), 202 (33), 174 (24), 146 (17), 118 (9), 83 (16), 66 (7), 55 (12) 400 (7), 399 (14), 398 [+] (58), 381 (32), 315 (27), 286 (100), 230 (53), 202 (36), 174 (28), 146 (19), 118 (12), 83 (20), 66 (9), 55 (16) 371 (11), 370 (22.5), 369 [+] (92), 286 (100), 230 (31), 202 (21), 174 (14), 146 (9),118 (5), 83 (10), 66 (5), 55 (7) 457 (8), 456 (16), 455 [+] (48), 425 (16), 372 (9), 348 (100), 292 (45), 274 (32), 236 (23), 208 (14), 180 (8), 128 (10), 83 (16), 55 (12) 462 (8), 461 (17), 460 [+] (58), 443 (12), 377 (16), 348 (100), 292 (64), 274 (41), 236 (31), 208 (22), 180 (15), 128 (12), 83 (27), 55 (18) 433 (16), 432 (30), 431 [+] (100), 348 (92), 292 (44), 274 (31), 236 (23), 208 (15), 180 (10), 128 (6), 83 (11), 55 (6) 441 (3), 440 (6), 439 [+] (18), 368 (23), 348 (100), 292 (54), 264 (36), 236 (19), 208 (8), 91 (32), 83 (17), 55 (10) 471 (2), 470 (4), 469 [+] (12), 439 (10), 378 (100), 368 (29), 322 (57), 294 (34), 266 (18), 264 (8), 238 (11), 236 (7), 91 (36), 83 (20), 55 (12) 476 (2), 475 (5), 474 [+] (17), 383 (100), 368 (19), 327 (61), 299 (49), 297 (26), 271 (32), 243 (9), 241 (11), 213 (5), 91 (42), 83 (24), 55 (17) 447 (3), 446 (7), 445 [+] (23), 368 (19), 354 (100), 298 (47), 270 (36), 242 (29), 214 (13), 91 (27), 83 (16), 55 (9) WM 22.5 57.9 37.1 24.7 33.2 22.4 62.1 25.3 23.2 61.3 9.0 5.3 6.1 9.1
_______ * Found, %: S 10.40. Calculated , %: S 10.33 range splintering peaks A12-A15 are most characteristic, which arise from a decomposition scheme similar to the fragmentation of the 1,8-dioxodecahydroacridines 1a,b which are not substituted on the nitrogen atom. The peaks of the cations A8 and A10 observed in the spectra of compounds 1k-n have considerably greater intensity than in their NH-, N-methyl, and N-phenyl analogs 1a-j. It should be noted that in all cases the nature of the substituent at position 9 has no effect on the decomposition pathways for the decahydroacridin-1,8-diones under the influence of electron impact. Thus we have investigated the mass spectra of 9-aryl(hetaryl)-3,3,6,6-tetramethyldecahydroacridine-1,8diones and discovered the basic directions of their dissociative ionization under the influence of electron impact. The factor which determines the decomposition pathways of the decahydroacridine-1,8-diones studied is the structure of the substituent at position 10. Fragmentation of these compounds is predominantly connected with the formation of pyridinium structures and subsequent retrodiene decomposition of the molecules. The results obtained can be used to determine the structures of decahydroacridine-1,8-diones and related compounds.
EXPERIMENTAL Chromato-mass spectra were obtained with a Hewlett-Packard HP-5972A with an HP-5890 mass selective detector, using a capillary column packed with 5% methylphenylsilicone (30 m 0.25 mm). The column temperature was 250C, the carrier gas was nitrogen, and the ionization energy of the electrons was 70 eV. 1034
The decahydroacridine-1,8-diones 1a-n were synthesized by the known methods [3-5].
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. P. Shanmugasundaram, K. J. Prabahar, and V. T. Ramakrishnan, J. Heterocycl. Chem., 30, 1003 (1993). A. A. Bakibaev and V. D. Filimonov, Zh. Org. Khim., 25, 1579 (1989). T. G. Nikolaeva, Yu. M. Shchekotikhin, A. S. Ponomarev, and A. P. Kriven'ko, Khim. Geterotsikl. Soed., 475 (2000). Yu. M. Shchekotikhin, T. G. Nikolaeva, G. M. Shub, and A. P. Kriven'ko, Khim.-farm. Zhur., No. 4, 29 (2001). Yu. M. Shchekotikhin, Yu. A. Getmanenko, T. G. Nikolaeva, and A. P. Kriven'ko, Khim. Geterotsikl. Soed., 1344 (2001). T. G. Nikolaeva, Yu. M. Shchekotikhin, Yu. A. Getmanenko, and A. P. Kriven'ko, Khim. Geterotsikl. Soed., 416 (2000). T. G. Nikolaeva, and Yu. M. Shchekotikhin, Khim. Geterotsikl. Soed., 693 (2004). J. Baldas and Q. N. Porter, Tetrahedron Lett., 1351 (1968). C. Dagher, R. Hanna, P. B. Terentiev, Y. G. Boundel, A. N. Kost, and B. I. Maksimov, J. Heterocycl. Chem., 19, 645 (1982). P. Gupka, J. Bella, and A. Martvon, Coll. Czech. Chem. Commun., 52, 742 (1987). U. Eisner and J. Kuthan, Chem. Rev., 72, 1 (1972). C. S. Barnes and J. H. Occolowitz, Austral. J. Chem., 16, 219 (1963). R. A. Khmel'nitskii, Yu. A. Efremov, and N. V. Fedyainov, Izv TSKhA, No. 3, 199 (1978). J. Kuthan and A. Kurfurst, Ind. Eng. Chem, Prod. Res. Dev., 21, 191 (1982). A. Maquestiau and P. Lejeune, Bull. Soc. Chim. Belg.,76, 133 (1967). F. W. McLafferty, Mass Spectrometry of Organic Ions. Academic Press, New York (1963), p. 10.
1035
SYNTHESIS OF 3,3-DIALKYL-1-(3-COUMARINYL)3,4-DIHYDROISOQUINOLINES
A. G. Mikhailovskii1 and M. I. Vahrin2 The reaction of dialkylbenzylcarbinols with 3-cyanocoumarin in the presence of sulfuric acid gave 3,3-dialkyl-1-(3-coumarinyl)- 3,4-dihydroisoquinoline. Keywords: dialkylbenzylcarbinols, 3,3-dialkyl-1-(3-coumarinyl)isoquinolines, Ritter cyclocondensation. The role and importance of isoquinolines [1-3] and coumarin [4-7] derivatives in organic synthesis, nature and medicine are well known. However substances which have both isoquinoline and coumarins in their structures have not been described in the literature until now. Coupling of these two heterocylic units in one molecule is of undoubted interest since new potential synthons would be formed in this way. Moreover the presence of a nitrogen-containing heterocycle opens the possibility of preparing salts suitable for pharmacological study. We have previously shown the possibility of using the Ritter reaction for the synthesis of the isoquinoline ring [8-10]. In a continuation of studies in this field we have observed that the carbinols 1a-f reacted with 3-cyanocoumarin (2) in the presence of sulfuric acid to form the 3,3-dialkyl-1-(3-coumarinyl)-3,4dihydroisoquinolines 3a-f. Use of 2-methyl-3-(1-naphthyl)propanol-2 as the carbinol gave compound 4. Carbinol 1a reacted with 3-cyanobenzo[f]coumarin in benzene and sulfuric acid to give compound 5. The characteristics of compounds 3-5 are cited in Table 1. The small yield of compound 5 may probably be explained by the steric effect of the nitrile which contains an additional annelated phenyl ring in its structure.
R1 R1 R1 1af R2 R2 R2 N O O R2 N O O OH R2 R2 CN R1 O O 3af N R2 R2
+
O 2 O
H2SO4
__________________________________________________________________________________________ Institute of Technical Chemistry, Ural Division, Russian Academy of Sciences, Perm 61460, Russia; e-mail: cheminst@mpm.ru. 2 Perm State Pharmaceutical Academy, Perm 614990, Russia; e-mail: pfa@degacom.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, 1198-1200, August, 2004. Original article submitted September 20, 2002. 1036 0009-3122/04/4008-10362004 Springer Science+Business Media, Inc.
1

Compound R1 or R1+R1 R2+R2 Empirical formula Found, % Calculated, % C H N 79.1 79.2 79.4 79.5 72.7 72.7 80.1 80.2 80.3 80.4 74.3 74.4 81.5 81.6 81.4 81.6 5.6 5.7 6.0 6.0 5.7 5.8 5.7 5.8 6.1 6.2 5.4 5.5 5.3 5.4 5.3 5.4 4.7 4.6 4.4 4.4 4.0 3.9 4.4 4.3 4.2 4.1 3.6 3.6 3.9 4.0 4.0 4.0 Yield, %
mp,
3a 3b 3c 3d 3e 3f 4 5
H H Me H H O(CH2)O
Me + Me Me + Et Me + Me (CH2)4 (CH2)5 (CH2)5 Me + Me Me + Me
C20H17NO2 C21H19NO2 C22H21NO4 C22H19NO2 C23H21NO2 C24H21NO4 C24H19N2 C24H19NO2
154-155 148-150 140-142 131-132 162-163 233-234 189-191 225-227
77 71 83 43 41 82 67 12
TABLE 2. 1H NMR Spectra of the Compounds Synthesized

Compound 3a 3b Chemical shifts, , ppm 3(1)-CH2, s arom. protons and R1 2.78 2.74 6.90-7.63, m (8H) 6.92-7.58, m (8H)
R2 1.27, s (2CH3) 1.18, s (3); 1.08, t (32); 1.35, q (32) 1.23, s (2CH3)
HC=, s 7.93 7.86
3c
2.90
3d 3e 3f
1.41-1.88, m (4H2) 1.40-1.90, m (5H2) 1.35-1.63, m (5H2)
2.87 2.83 2.70
4 5
1.35, s (2CH3) 1.30, s (2CH3)
3.25 2.85
6.66, s (H-5), 6.68, s (H-8), 3.70, s and 3.83, s (2CH3O), 7.17-7.67, m (4H) 7.08-7.73, m (4H) 7.12-7.75, m (4H) 6.85, s (H-5), 6.86, s (H-8), 6.88-7.45, m (4H), 5.97, s (2) 7.55-8.20, m (6H) 7.72-8.50, m (6H)
7.94
8.03 8.02 8.10
8.05 8.07
All the 1H NMR spectra of compounds 3-5 (Table 2) contain signals of the protons of the substituents R1 and R , the 4-CH2 groups of the dihydroisoquinoline ring, the aromatic protons and the characteristic singlets of the coumarin proton CH= (7.93-8.10 ppm), which completely confirms their structures. The IR spectra of compounds 3-5 contain stretching bands at 1725 (C=O) and 1620 cm-1 (C=N). Compounds 3-5 have azadiene structures [11] so that cycloaddition reactions are possible for them.
2
EXPERIMENTAL H NMR spectra in CDCl3 solutions with HMDS as internal standard were recorded with a Bruker AM-300 (300 MHz) instrument. IR spectra of nujol mulls were recorded on a UR-20 spectrometer. The starting carbinols are known compounds [8-10]. The corresponding nitriles were prepared by a known method [12]. 1037
1
1-(3-Coumarinyl)-6,7-(R1)2-3,3-(R2)2-isoquinolines (3a-e), 4-(3-Coumarinyl)-2,2-dimethylbenzo[f]isoquinoline (4), and 1-(3-Benzo[f]coumarinyl)-3,3-dimethylisoquinoline (5). The corresponding carbinol (10 mmol) and 3-cyanocoumarin (1.88 g, 11 mmol) (compounds 2-4) or 3-cyanobenzo[f]coumarin (2.21 g, 10 mmol) (compound 5) were mixed. Glacial acetic acid (2ml) was added in the case of compounds 3c,f. Concentrated sulfuric acid (5 ml) was added dropwise to the stirred mixture at 0C. The reaction mixture was stirred for 10 min, cooled to room temperature and poured into cold (~5C) water (100 ml). The benzene layer was separated. Any small amount of precipitate was filtered off. The aqueous phase was neutralized with sodium hydrogen carbonate solution. The precipitate formed was filtered off, dried, and recrystallized from isopropanol.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. V. D. Gensler, in: R. Elderfield (editor), Heterocyclic Compounds, [Russian translation], Izd-vo Inostr. Lit., Moscow (1965), Vol. 4, p. 264. T. Kametani and K. Fukumoto, Heterocyclic Compounds, G. Grethe (editor), J. Wiley, New York (1981), 38, 139. Chemistry of Heterocyclic Compounds, G. M. Coppola and H. F. Schuster (editors), J. Wiley, New York (1998), Vol. 3, p. 38. S. Vavzonek, in: R. Elderfield (editor), Heterocyclic Compounds, [Russian translation], Izd-vo Inostr. Lit., Moscow (1954), Vol. 2, p. 134. General Organic Chemistry, D. Barton and U. D. Ollis (editors) [Russian translation], Khimiya, Moscow (1985), Vol. 9, p. 61. V. M. Malikov and A. I. Saidkhodzhaev, Khimiya Prirod. Soedin., 560 (1998). G. Feuer, Progress in Medicinal Chemistry, G. P. Ellis and G. B. West (editors), North-Holland Publ. Co., Amsterdam (1974), p. 85. V. S. Shklyaev, B. B. Aleksandrov, G. I. Legotkina, M. I. Vakhrin, M. S. Gavrilov, and A. G. Mikhailovskii, Khim. Geterotsikl. Soed., 1560 (1983). A. G. Mikhailovskii, V. S. Shklyaev, and E. V. Feshina, Khim. Geterotsikl. Soed., 236 (1998). A. G. Mikhailovskii, Khim. Geterotsikl. Soed., 264 (2000). M. Behforous and M. Ahmadian, Tetrahedron, 56, 5259 (2000). W. Baker and C. S. Homes, J. Chem. Soc., 119 (1953).
1038
STUDIES ON REACTIONS OF CYCLIC OXALYL COMPOUNDS WITH HYDRAZINES OR HYDRAZONES. 2*. SYNTHESIS AND REACTIONS OF 4-BENZOYL1-(4-NITROPHENYL)-5-PHENYL-1HPYRAZOLE-3-CARBOXYLIC ACID
A. Sener1, R. Kasimogullari2, M. K. Sener1, and H. Genc1 4-Benzoyl-1-(4-nitrophenyl)-5-phenyl-1H-pyrazole-3-carboxylic acid, obtained from the corresponding furan-2,3-dione and N-benzylidene-N'-(4-nitrophenyl)hydrazine, was converted via reactions of its acid chloride with various alcohols or N-nucleophiles into the corresponding ester or amide derivatives. The nitrile of the starting acid and 1-(4-aminophenyl)-4-benzoyl-5-phenyl-1H-pyrazole-3-carboxylic acid were also obtained. While cyclocondensation reactions of the two acids and the nitrile mentioned with hydrazines lead to pyrazolo[3,4-d]pyridazine derivatives, the reaction of starting acid with 2-hydrazinopyridine provided the hydrazonopyrazole acid derivative. Keywords: cyclic oxalyl compounds, pyrazole, pyrazolopyridazine, quinoline. In the last thirty years considerable interest has been focused on pyrazole chemistry, due to the versatile biological activities of pyrazole derivatives [2-4]. Our studies related to preparing pyrazole and fused pyrazole derivatives by the functionalization and cyclization reactions of some pyrazolecarboxylic acids, obtained from furandione 1, with various nucleophiles was previously reported [1, 5, 6]. In the present study, we have attempted both to prove the reproducibility of the reaction of furandione 1 with another hydrazone and to extend our investigations related to preparing new pyrazole derivatives.
RESULTS AND DISCUSSION Heating of furandione 1 and benzaldehyde 4-nitrophenylhydrazone (1/1 mol) for 75 min without any solvent led to the formation of the compound 2, in ca. 45% yield. A reasonable pathway different from that discussed with phenylhydrazone [6] for reaction from furandione 1 to pyrazole carboxylic acid 2 is outlined briefly in Scheme 1.
_______ * For Part 1 see [1]. __________________________________________________________________________________________ Yznc Yil niversity, Art and Science Faculty, Chemistry Department, 65080 Van, Turkey; e-mail: asener_2002@jahoo.com. 2 Atatrk niversity, Art and Science Faculty, Chemistry Department, Erzurum, Turkey; e-mail: rahmikasimoglu@hotmail.com Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1201-1208, August, 2004. Original article submitted August 26, 2002. 0009-3122/04/4008-10392004 Springer Science+Business Media, Inc. 1039
1
Scheme 1
O Ph Ph O N(Ar)N=CHPh _ O 1 O H Ph Ph O _
COO
_ N N Ar A
O +
H Ph
O Ph Ph
COO O +
_ Ph
O COO + N N Ar C O Ph COOH N N Ar 2 Ar = C6H4NO2-4 H Ph
_ _ OH H Ph
_ N N Ar H B
Ph
PhCHO
Ph
Ring opening for the formation of the first intermediate A should be initiated by a nucleophilic attack of the NH group adjacent to the phenyl ring of hydrazone at C(5) of the furandione ring similar to the reactions of furandione 1 with various H-active nucleophiles [7, 8]. Ring closure of the intermediate A to oxadiazepine intermediate B via addition of the N=CHPh group to the C=O moiety takes place by the catalytic effect of the carboxylic acid proton similar to the addition of azines to furandiones [9]. Rearrangement of the intermediate B generates the pyrazole carboxylate intermediate C, and finally loss of the benzaldehyde molecule gives compound 2. The acid 2 could be easily converted into the corresponding acid chloride 3, ester 4, amide 5, and nitrile 6 by conventional chemical procedures. Reduction of 2 with sodium polysulfide led to the derivative of aminophenyl-substituted acid 7 (Scheme 2). The structures of the compounds thus obtained were confirmed by analytical and spectral data (see Experimental). The correct structures of the unsymmetrically substituted urea derivatives 5d,e were established by another chemical procedure consisting of the reaction of the primary amide 5a with phenyl isocyanate, which resulted in the formation of the phenylurea derivative 5d, originally prepared from the acid chloride 3 in the usual way. Reactions of pyrazole dicarbonyl derivatives with hydrazines are convenient methods to build the pyrazolo[3,4-d]pyridazine systems [5, 10, 11]. Thus, the pyrazole acids 2, 7 were cyclized with hydrazines to the pyrazolo[3,4-d]-pyridazinones 8a-d, in 40-75% yields. Additionally, 8c was also obtained by the second method consisting of reduction of 8a with sodium polysulfide. In a similar way, pyrazole-3-carbonitrile 6 with
1040
Scheme 2
O Ph Ph COOH SOCl2 N N C6H4NO2-4 2 Na2SX O Ph Ph COOH N N C6H4NH2-4 7 PhNCO Ph Ph O CONu N N C6H4NO2-4 5ae Ph 5d 5a SOCl2, DMF Ph N 6 C6H4NO2-4 O CN N Ph N N C6H4NO2-4 3 NuH HCl Ph O COCl ROH(Py) Ph N N C6H4NO2-4 4 Ph O O OR
4 R = i-Pr; 5 a Nu = NH2, b Nu = NHEt, c Nu = NEt2, d Nu = NHCONHPh, e Nu = NHCONHBu-t
anhydrous hydrazine in boiling methanol containing a catalytic amount of sodium methoxide was also cyclized to the 7-aminopyrazolo[3,4-d]pyridazine derivative 8e. Cyclization reactions of compounds 8c,d with acetaldehyde in strong acidic medium lead to quinoline derivatives 9a,b (Scheme 3). Structure elucidation of compounds 8a-e and 9a,b is based mainly on 13C NMR spectroscopy (see Experimental). Scheme 3
R R1 N N Ph 2, 6, 7 R1NHNH2 _ 2H2O N N R2 8 N Me 8a Na2SX 8c 9a,b X MeCHO(H+) (for 8c,d) N N Ph Ph N N O
Ph
8a,c R1 = Ph, b, d, e R1 = H; a, b, e R2 = C6H4NO2-4, c, d R2 = C6H4NH2-4; a-d X = O, e X = NH; 9 a R = H, b R = Ph
1041
On the other hand, the reaction of 2 with 2-hydrazinopyridine instead of phenylhydrazine or hydrazine hydrate did not give the corresponding pyrazolopyridazine derivative. Surprisingly, however, 2-hydrazinopyridine was added to 2 to yield a new pyrazole acid 10 containing a hydrazone group. The failure or the difficulty in forming the pyridazine nucleus from 2 with 2-hydrazinopyridine can be explained by the low nucleophilicity of the nitrogen atom adjacent to the pyridine ring. Additionally, decarboxylation of 10 on an oil bath at elevated temperatures led to cleavage of the CC bond with loss of CO2, finally yielding the corresponding hydrazonopyrazole derivative 11 (Scheme 4). Scheme 4
N HN N 2-C5H4NNHNH2 Ph Ph N C6H4NO2 -4 10 COOH N CO2 Ph Ph
C5H4N-2 NH N
N N C6H4NO2-4 11
Compounds 10 and 11 show characteristic IR absorption bands at 3450 (NH), 1681 (C=N) and 3438 (NH), 1679 cm-1 (C=N), respectively. The IR spectra of compound 10 showed no absorption bands corresponding to the COOH group such as 3300-2500 (b, OH, COOH) and 1700-1750 cm-1 (C=O, COOH) like that of 4-benzoyl-1,5-diphenylpyrazole-3-carboxylic acid [6]. However, absorption bands at approximately 1620 and 1579 cm-1 corresponding to an ionized carboxylate group [12] were observed. From its IR spectrum, it may be deduced that compound 10 exists as the betaine in the solid state, but the 13C NMR signal for the carboxyl group of 10 appears at nearly equivalent chemical shift values to that observed with carboxylic acid groups of 2 and 7. Obviously in solution the classical acid form is predominant (see Experimental).
EXPERIMENTAL Solvents were dried by refluxing with the appropriate drying agents and distilled before use. Melting points were determined on an Electrothermal Gallenkamp apparatus and are uncorrected. Microanalyses were performed on a Carlo Erba Elemental Analyser Model 1108. The IR spectra were obtained in potassium bromide pellets using a Mattson 1000 FTIR spectrometer. The 1H and 13C NMR spectra were recorded on Varian (200 MHz) and Varian (50 MHz) spectrometers, respectively, using TMS as an internal standard. All experiments were followed by TLC using DC Alufolien Kieselgel 60 F 254 Merck and Camag TLC lamp (254/366 nm). 4-Benzoyl-1-(4-nitrophenyl)-5-phenyl-1H-pyrazole-3-carboxylic Acid (2). An equimolar mixture of furandione 1 (0.278 g, 1 mmol) and (4-nitrophenylhydrazono) (phenyl) methane (0.241 g, 1 mmol) was heated without a solvent at 100-110C for 75 min (up to disappearance of benzaldehyde odor). After cooling to room temperature, the residue was treated with dry toluene and the formed crude product was recrystallized from ethanol to give 0.186 g (45%) of a colorless solid; mp 210C (decomp.). IR spectrum, , cm-1: 3400-2500 (b, OH, COOH), 1717 (C=O, COOH), 1680 (C=O, benzoyl). 1H NMR spectrum (DMSO-d6), , ppm: 8.3-7.2 (m, ArH). 13C NMR spectrum (DMSO-d6), , ppm: 192.26 (C=O, benzoyl); 163.83 (C=O, COOH); 148.50 (CNO2); 1042
145.33 (C(3)); 145.22 (C(5)); 145.09 (C(1) of C6H4NO2); 139.31 (CPh); 135.32, 131.46, 130.90, 130.50, 130.44, 129.13 (CPh); 128.22, 126.34, 125.41 (C(4)). Found, %: C 66.69; H 3.69; N 10.20. C23H15N3O5. Calculated, %: C 66.83; H 3.66; N 10.16. 4-Benzoyl-1-(4-nitrophenyl)-5-phenyl-1H-pyrazole-3-carbonyl Chloride (3). Acid 2 (0.413 g, 1 mmol) and thionyl chloride (1 ml, 13.8 mmol) were refluxed on a steam bath for 5 h. After cooling, the crude precipitate was filtered off and recrystallized from a mixture of cyclohexane and carbon tetrachloride, yield 0.281 g (65%); mp 190C. IR spectrum, , cm-1: 1757 (C=O, acyl), 1676 (C=O, benzoyl). 13C NMR spectrum (CDCl3), , ppm: 190.74 (C=O, benzoyl); 162.88 (C=O, acyl); 148.69 (CNO2); 146.47 (C(3)); 146.40 (C(5)); 144.48 (C(1) of C6H4NO2); 138.30 (CPh); 135.26, 131.72, 130.98, 130.67, 130.49, 130.00, 127.90 (CPh); 127.11, 125.98, 125.72 (C(4)). Found, %: C 64.09; H 3.26; Cl 8.17; N 9.69. C23H14N3O4Cl. Calculated, %: C 63.97; H 3.27; Cl 8.21; N 9.73. Isopropyl 4-Benzoyl-1-(4-nitrophenyl)-5-phenyl-1H-pyrazole-3-carboxylate (4). The acid chloride 3 (0.431 g, 1 mmol) and a moderate excess of isopropyl alcohol were refluxed together with a catalytic amount of pyridine for 2.5 h. After cooling, the solution was acidified by adding diluted hydrochloric acid (12%) to give a crude solid, which was recrystallized from the same alcohol. The yield 0.342 g (75%); mp 156C. IR spectrum, , cm-1: 1741 (C=O, ester), 1676 (C=O, benzoyl). Found, %: C 68.75; H 4.67; N 9.20. C26H21N3O5. Calculated, %: C 68.56; H 4.65; N 9.23. 4-Benzoyl-1-(4-nitrophenyl)-5-phenyl-1H-pyrazole-3-carboxamide (5a). A moderate stream of gaseous ammonia was allowed to bubble through a solution of acid chloride 3 (0.432 g, 1 mmol) in 20 ml of carbon tetrachloride during 0.5 h with ice-cooling. Then the crude precipitate was filtered off and recrystallized from methanol to give 0.289 g (70%) of 5a; mp 210C. IR spectrum, , cm-1: 3438 (NH2), 1674 (C=O, benzoyl), 1625 (C=O, amide). 13C NMR spectrum (CDCl3), , ppm: 192.45 (C=O); 163.34 (C=O, amide); 148.17 (C NO2); 147.28 (C(3)); 145.49 (C(5)); 144.97 (C(1) of C6H4NO2); 139.13 (CPh); 134.59, 131.24, 131.01, 130.74, 130.32, 129.64, 128.78 (CPh); 126.68, 125.82, 124.64 (C(4)). Found, %: C 67.19; H 3.90; N 13.64. C23H16N4O4. Calculated, %: C 66.99; H 3.91; N 13.59. Amides 5b,c and Ureas 5d,e. (General Procedure). An equimolar mixture of the acid chloride 3 (0.431 g, 1 mmol) and the corresponding amine or urea (1 mmol) was refluxed in xylene for 3-6 h. After evaporation, the oily residue was treated with dry ether and the formed crude product was recrystallized. N-Ethyl-4-benzoyl-1-(4-nitrophenyl)-5-phenyl-1H-pyrazole-3-carboxamide (5b). Reflux time 3 h (ethylamine). Yield 0.34 g (77%); mp 177C (aqueous EtOH). IR spectrum, , cm-1 3259 (NH), 1676 (C=O), 1631 (C=O, amide). Found, %: C 67.99; H 4.61; N 12.68. C25H20N4O4. Calculated, %: C 68.17; H 4.58; N 12.72. 4-Benzoyl-N,N-diethyl-1-(4-nitrophenyl)-5-phenyl-1H-pyrazole-3-carboxamide (5c). Reflux time 3.5 h (diethylamine). Yield 0.281 g (60%); mp 176C (EtOH). IR spectrum, , cm-1: 1670 (C=O), 1632 (C=O). Found, %: C 69.05; H 5.19; N 11.89. C27H24N4O4. Calculated, %: C 69.22; H 5.16; N 11.96.7 N-[4-Benzoyl-1-(4-nitrophenyl)-5-phenyl-1H-pyrazole-3-carbonyl]-N'-phenylurea (5d). A. Reflux time 4 h (phenylurea). Yield 0.186 g (35%); mp 223C (EtOH). IR spectrum, , cm-1: 3405, 3320 (NH), 1745 (C=O, urea), 1669 (C=O), 1628 (C=O). 13C NMR spectrum (CDCl3), , ppm: 192.27 (C=O); 163.65 (C=O); 151.05 (C=O, urea); 149.98 (CNO2); 146.17 (C(3)); 145.42 (C(1) of C6H4NO2); 145.28 (C(5)); 140.05 (NPh); 138.77 (CPh); 135.05, 132.75, 132.05, 131.88, 131.57, 131.09, 130.75, 130.43, 127.98 (CPh); 126.05, 125.17, 122.76, 122.35 (C(4)). Found, %: C 67.65; H 4.03; N 13.22. C30H21N5O5. Calculated, %: C 67.79; H 3.98; N 13.18. B. The acid amide 5a (0.412 g, 1 mmol) and phenylisocyanate (0.2 ml, 1.8 mmol) were refluxed in xylene for 6 h. Then the solvent was evaporated and the residue was recrystallized from ethanol to give 0.425 g (80%) of 5d, identical in mp and IR spectrum with the product obtained as described above. N-[4-Benzoyl-1-(4-nitrophenyl)-5-phenyl-1H-pyrazole-3-carbonyl]-N'-(tert-butyl)urea (5e). Reflux time 4 h (tert-butylurea). Yield 0.286 g (56%); mp 244C (n-PrOH). IR spectrum, , cm-1: 3380-3340 (NH), 1727 (C=O, urea), 1668 (C=O), 1627 (C=O). 1H NMR spectrum (DMSO-d6), , ppm: 8.9 (s, 1H, NH); 8.6 (s, 1043
1H, NH); 8.2-7.3 (m, 14H, ArH); 1.3 (s, 9H, CH3). Found, %: C 65.93; H 4.95; N 13.65. C28H25N5O5. Calculated, %: C 65.74; H 4.93; N 13.69. 4-Benzoyl-1-(4-nitrophenyl)-5-phenyl-1H-pyrazole-3-carbonitrile (6). A cold solution of the acid amide 5a (0.412 g, 1 mmol) in a mixture of DMF (0.7 ml) and SOCl2 (0.15 ml) was stirred at 0-5C for 2 h. After heating to room temperature, stirring was continued overnight, then the reaction mixture was poured onto crushed ice and the separated solid filtered off, washed with water, and recrystallized from n-PrOH to give 0.217 g (55%) of 6 mp 214C. IR spectrum, , cm-1: 2265 (CN), 1670 (C=O). 13C NMR spectrum (CDCl3), , ppm: 189.01 (C=O); 148.75 (CNO2); 146.82 (C(1) of C6H4NO2); 144.21 (C(5)); 137.80 (C(3)); 134.95, 131.77, 131.43, 130.89, 130.34, 129.72, 129.17 (CPh); 127.77 (C(4)); 127.15, 126.90 (CPh); 113.17 (CN). Found, %: C 70.19; H 3.61; N 14.18. C23H14N4O3. Calculated, %: C 70.05; H 3.58; N 14.21. 1-(4-Aminophenyl)-4-benzoyl-5-phenyl-1H-pyrazole-3-carboxylic Acid (7). A cold solution of sodium polysulfide (10 mmol), prepared from Na2S9H2O (2.5 g, 10 mmol) with powdered sulfur (0.7 g) in boiling water, was added to a solution of 2 (4.13 g, 10 mmol) in ethanol with stirring. The reaction mixture was refluxed on a steam bath for 60 min. After cooling and acidification with concentrated HCl, it was refluxed again for 30 min to precipitate sulfur, cooled, and the separated solid filtered off. Then, the filtrate was made alkaline by adding concentrated aqueous ammonia (slight excess) and kept in the refrigerator overnight. The crude precipitate was washed with water and recrystallized from a mixture of ethanol and water to give 1.96 g (51%) of 7 mp 228C. IR spectrum, , cm-1: 3438 (NH2), 3300-2500 (b, OH, COOH), 1727 (C=O, COOH), 1672 (C=O, benzoyl). 13C NMR spectrum (CDCl3), , ppm: 192.87 (C=O); 164.22 (COOH); 150.95 (NH2Ph); 144.52 (C(3)); 143.42 (C(5)); 139.56 (C(1) in C6H4NH2-4); 135.10, 131.37, 130.80, 130.71 (CPh); 130.41, 130.10, 129.94, 128.92 (CPh); 128.58, 123.99, 115.08 (C(4)). Found, %: C 72.25; H 4.45; N 10.93. C23H17N3O3. Calculated, %: C 72.05; H 4.47; N 10.96. 2,6-Dihydropyrazolo[3,4-d]pyridazin-7-ones 8a-d. (General Procedure). An equimolar mixture of 2 and the respective hydrazine was refluxed in xylene for 1-4 h. After the solvent was removed by evaporation, the oily residue was treated with ether and the formed crude product was recrystallized. 2-(4-Nitrophenyl)-3,4,6-triphenyl-2,6-dihydropyrazolo[3,4-d]pyridazin-7-one (8a). Reflux time 3 h (phenylhydrazine). Yield 0.364 g (75%); mp 267C (methanol). IR spectrum, , cm-1: 1686 (C=O). 13C NMR spectrum (DMSO-d6), , ppm: 156.60 (C=O); 148.68 (CNO2); 145.48 (C(7a)); 145.17 (C(4)); 145.035 (C(3)); 142.96 (C(1) in C6H4NO2); 141.87 (C(1) in NPh); 135.14, 131.66, 131.07 (CPh); 130.03, 129.97, 129.89, 129.03, 128.92, 128.71 (CPh); 127.87, 127.26, 125.67, 118.59 (C(3a)). Found, %: C 71.55; H 3.97; N 14.38. C29H19N5O3. Calculated, %: C 71.74; H 3.94; N 14.42. 2-(4-Nitrophenyl)-3,4-diphenyl-2,6-dihydropyrazolo[3,4-d]pyridazin-7-one (8b). Reflux time 1 h (hydrazine hydrate). Yield 0.299 g (73%); mp 305C (n-BuOH). IR spectrum, , cm-1: 3300-2800 (b, NH OH), 13 1677 (C=O). C NMR spectrum (DMSO-d6), , ppm: 157.74 (C=O); 148.90 (CNO2); 145.37 (C(7a)); 144.43 (C(4)); 142.51 (C(3)); 141.19 (C(1) in C6H4NO2), 135.88, 132.38, 131.09, 130.06, 129.99 (CPh); 129.81, 129.23, 129.14, 129.05 (CPh); 126.17, 118.76 (C(3a)). Found, %: C 67.31; H 3.71; N, 17.17. C23H15N5O3. Calcula-ted, %: C 67.48; H 3.69; N 17.11. 2-(4-Aminophenyl)-3,4,6-triphenyl-2,6-dihydropyrazolo[3,4-d]pyridazin-7-one (8c). A. Reflux time 4 h (phenylhydrazine). Yield 0.205 g (45%); mp 290C (n-BuOH). IR spectrum, , cm-1: 3489-3387 (NH2), 1667 (C=O). 1H NMR spectrum (CDCl3), , ppm: 7.6-6.6 (m, 19H, ArH); 3.9-2.6 (b, 2H, NH2). 13C NMR spectrum (CDCl3), , ppm: 157.77 (C=O); 148.99 (CNH2); 146.23 (C(7a)); 144.87 (C(4)); 143.93 (C(3)); 141.69 (C(1) in NPh); 136.25 (C(1) in C6H4NH2); 132.53, 131.92 (CPh); 130.80, 130.66, 130.46, 130.23 (CPh); 130.04, 129.61, 129.42, 129.10, 128.11, 118.40 (C(3a)); 116.72. Found, %: C 76.75; H 4.66; N 15.41. C29H21N5O. Calculated, %: C 76.47; H 4.65; N 15.37. B. Pyridazinone 8a (0.485 g, 1 mmol) and Na2SX (1 mmol) were refluxed in a mixture of EtOH and water on a steam bath for about 1 h. The crude product which precipitated in boiling solvents was filtered off and recrystallized from n-BuOH to give 0.273 g (60%) of 8c, identical in mp and IR spectrum with the product obtained as described above. 1044
2-(4-Aminophenyl)-3,4-diphenyl-2,6-dihydropyrazolo[3,4-d]pyridazin-7-one (8d). Reflux time 3 h (hydrazine hydrate). Yield 0.152 g (40 %); mp 342C (EtOH). IR spectrum, , cm-1: 3489-3308 (NH2), 3250-2800 (b, NH OH), 1659 (C=O). 13C NMR spectrum (DMSO-d6), , ppm: 157.98 (C=O); 151.17 (C NH2); 145.37 (C(7a)); 143.18 (C(4)); 141.54 (C(3)); 136.19 (C(1) in C6H4NH2); 132.35, 130.37 (CPh); 130.06, 129.83, 129.75, 129.42, 129.08, 128.97 (CPh); 128.79, 118.01 (C(3a)); 114.86. Found, %: C 72.99; H 4.54; N 18.41. C23H17N5O. Calculated, %: C 72.81; H 4.52; N 18.46. [2-(4-Nitrophenyl)-3,4-diphenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl]amine (8e). Nitrile 6 (0.394 g, 1 mmol) and anhydrous hydrazine (0.032 g, 1 mmol) were refluxed in methanol containing a catalytic amount of sodium methoxide on an oil bath for 15 h. After cooling to room temperature, the crude precipitate was isolated by filtration and recrystallized from n-BuOH. Yield 0.225 g (55%); mp 315C. IR spectrum, , cm-1: 3300-3000 (NH), 1663 (C=NH). 13C NMR spectrum (CDCl3), , ppm: 158.05 (C=NH); 149.11 (CNO2); 146.77 (C(1) in C6H4NO2); 146.40 (C(7a)); 144.31 (C(3)); 140.88 (C(4)); 133.07, 132.03 (CPh); 131.99, 131.04 (CPh); 130.71, 130.23, 129.59, 129.17, 128.75, 127.25, 123.28 (C(3a)). Found, %: C 67.58; H 4.02; N 20.51. C23H16N6O2. Calculated, %: C 67.64; H 3.95; N 20.58. 2-(2-Methylquinolin-6-yl)-3,4-diphenyl-2,6-dihydropyrazolo[3,4-d]pyridazin-7-one (9a). To a cold solution of compound 8d (1 mmol) in concentrated HCl (15-20 ml), acetaldehyde (0.1 ml, 2 mmol) and nitrobenzene (0.123 g, 1 mmol) were added with stirring, and stirring was continued at room temperature for 2 h. Then, the reaction mixture was refluxed on a steam bath for 10 h with stirring and filtered. The filtrate was made alkaline by adding concentrated aqueous ammonia and kept in a refrigerator overnight. The separated solid was filtered off, washed with water, and recrystallized from a mixture of methanol and water. Yield 0.193 g (45%); mp 280C. IR spectrum, , cm-1: 3450-2750 (NH OH), 1663 (C=O). 13C NMR spectrum (DMSO-d6), , ppm: 162.36 (C=O); 157.95 (C(2')); 148.26 (C(8'a)); 145.37 (C(7a)); 143.99 (C(4)); 142.29 (C(3)); 138.20, 137.54, 136.04, 132.33, 130.72, 130.48 (CPh); 130.08, 129.81 (CPh); 129.58, 129.42, 129.15, 128.91, 128.76, 127.34, 125.03, 118.40 (C(3a)); 26.69 (Me). Found, %: C 75.30; H 4.48; N 16.27. C27H19N5O. Calculated, %: C 75.51; H 4.46; N 16.31. 2-(2-Methylquinolin-6-yl)-3,4,6-triphenyl-2,6-dihydropyrazolo[3,4-d]pyridazin-7-one (9b) was obtained similarly to 9a from 8c. Reflux time 8 h, yield 0.237 g (46%); mp 244C (methanol). IR spectrum, , cm-1: 1666 (C=O). 13C NMR spectrum (DMSO-d6), , ppm: 162.48 (C=O); 156.59 (C(2')); 148.35 (C(8'a)); 145.60 (C(7a)); 144.18 (C(4)); 143.46 (C(3)); 142.80, 138.26, 137.47, 135.51, 132.41, 130.93, 130.83, 130.48 (CPh); 130.39, 130.23, 129.69, 129.32, 129.21, 128.91 (CPh); 128.11, 127.40, 127.27, 125.12, 118.14 (C(3a)); 26.71 (Me). Found, %: C 78.17; H 4.54; N 13.82. C33H23N5O. Calculated, %: C 78.41; H 4.55; N 13.86. 1-(4-Nitrophenyl)-5-phenyl-4-[phenyl(pyridin-2-ylhydrazono)methyl]-1H-pyrazole-3-carboxylic Acid (10). Compound 2 (0.413 g, 1 mmol) and 0.109 g (1 mmol) of 2-hydrazinopyridine were refluxed in xylene on an oil bath for 3 h. The solvent was evaporated and the remaining oily residue was treated with ether to give a crude product which was recrystallized from ethanol. Yield 0.434 g (86%); mp 309C (decomp.). IR spectrum, , cm-1: 3450 (NH), 1681 (C=N), 1620, 1579 (COO-). 1H NMR spectrum (DMSO-d6), , ppm: 10.1 (b, acidic proton); 8.9 (b, 1H, NH); 8.3-6.8 (m, 18H, ArH). 13C NMR spectrum (DMSO-d6),, ppm: 163.99 (COO-); 156.82 (C(2'), Py); 149.25 (CNO2); 148.22 (C=N); 145.88 (C(3)); 145.82 (C(6'), Py); 144.97 (C(5)); 139.84 (C(1) in C6H4NO2); 139.76, 138.81, 131.16, 131.08 (CPh); 130.83, 130.43, 129.93, 129.61 (CPh); 128.08, 127.36, 126.20, 126.10, 117.37, 109.08 (C(4)). Found, %: C 66.51; H 4.05; N 16.73. C28H20N6O4. Calculated, %: C 66.66; H 4.00; N 16.66. [1-(4-Nitrophenyl)-5-phenyl-1H-pyrazol-4-yl(phenyl)methanone-N-pyridin-2-ylhydrazone (11). Compound 10 (0.46 g, 1 mmol) was heated to 310-315C on an oil bath for about 0.5 h without a solvent. After cooling to room temperature, the residue was treated with ether to give a crude product which was recrystallized from ethanol. Yield 0.253 g (55%); mp 320C. IR spectrum, , cm-1: 3438 (NH), 1679 (C=N). 13C NMR spectrum (CDCl3), , ppm: 156.65 (C(2'), Py); 155.22 (C=N); 150.84 (C(6'), Py); 149.09 (CNO2); 145.51
1045
(C(3)); 145.24 (C(5)); 144.47 (C(1) in C6H4NO2); 143.24 (CPh); 140.46, 135.18, 132.37, 131.28, 130.39, 129.89, 129.32, 129.24, 128.70 (CPh); 126.77, 125.83, 124.08, 118.70 (C(4)). Found, %: C 70.53; H 4.39; N 18.20. C27H20N6O2. Calculated, %: C 70.42; H 4.38; N 18.25. The authors thank the research fund of Y. Yil University for financial support.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. A. Sener, R. Kasmogullari, M. K. Sener, I. Bildirici, and Y. Akcamur, J. Heterocycl. Chem., 39, 869 (2002). A. M. Farghaly, N. S. Habib, M. A. Khalil, O. A. El-Sayed, and J. Alexandria, Pharm. Sci., 3, 90 (1989). R. N. Mahajan, F. H. Havaldar, and P. S. Fernandes, J. Indian Chem. Soc., 68, 245 (1991). P. G. Baraldi, S. Manfredini, R. Romagnoli, L. Stevanato, A. N. Zaid, and R. Manservigi, Nucleosides and Nucleotides, 17, 2165 (1998). Y. Akcamur, A. Sener, A. M. Ipekoglu, and G. Kollenz, J. Heterocycl. Chem., 34, 221 (1997). Y. Akcamur, G. Penn, E. Ziegler, H. Sterk, G. Kollenz, K. Peters, E. M. Peters, and H. G. von Schnering, Monatsh. Chem., 117, 231 (1986). Y. Akcamur, B. Altural, E. Saripinar, G. Kollenz, O. Kappe, K. Peters, E. M. Peters, and H. G. Schnering, J. Heterocycl. Chem., 25, 1419 (1988). B. Altural, Y. Akcamur, E. Saripinar, I. Yildirim, and G. Kollenz, Monatsh. Chem., 120, 1015 (1989). E. E. Schweizer, J. E. Hayes, K. J. Lee, and A. L. Rheingold, J. Org. Chem., 52, 1324 (1987). J. P. Marquet, J. D. Bourzat, J. Andre-Loisfert, and E. Bisagni, Tetrahedron, 29, 435 (1973). A. S. Shawali, J. Heterocycl. Chem., 14, 375 (1977). G. C. Bassler, T. C. Morrill, and R. M. Silverstein (editors), Spectrometric Identification of Organic Compounds, J. Wiley and Sons, New York, NY (1991), p. 118.
1046
SYNTHESIS OF PYRIDAZINONE DERIVATIVES

S. A. Hovakimyan1, A. V. Babakhanyan1, V. S. Voskanyan2, V. E. Karapetian2, G. A. Panosyan3, and S. T. Kocharian1 The reaction of methyl esters of 3-methyl-2-oxo- and 2-oxo-3-phenyl-3-pentenoic acids with hydrazine hydrate and phenylhydrazine was used to synthesize new pyridazinone derivatives. These products are formed through intermediate hydrazides with subsequent cyclization. 4-Hydroxy-3oxotetrahydropyridazines are mainly formed using equimolar amounts of the starting reagents, while the corresponding hydrazones of 3,4-dioxohexahydropyridazines are formed in the case of a two-fold excess of hydrazine hydrate or phenylhydrazine. Evidence was obtained indicating the existence of a ketoenol tautomerism for 4-hydroxy-3-oxopyridazines. Keywords: hydrazine, methyl esters of 3-methyl-2-oxo- and 2-oxo-3-phenyl-3-pentenoic acids, pyridazinone, phenylhydrazine, ketoenol tautomerism. Pyridazinones hold considerable interest relative to the preparation of organic intermediates and physiologically active compounds [1-4]. Some of the reported methods for the synthesis of these compounds involve the condensation of 3-aroylpropionic or -acetylacrylic acids with alkyl- and arylhydrazines [5, 6]. Various pyridazine derivatives can also be obtained by the reaction of aryldiazonium salts with the ethyl ester of methylenemalonic acid [1]. 3-Pyrrolinone derivatives are obtained in good yield from methyl esters of 3-methyl-2-oxo- (1a) and 2-oxo-3-phenyl-3-pentenoic acids (1b) and primary amines [7]. This finding suggested that pyridazinone derivatives could be obtained by replacing primary amines with hydrazine or hydrazine derivatives. In the present work, we studied the reaction of keto esters 1a,b with hydrazine hydrate (2a) and phenylhydrazine (2b). Pathways I, II, and III are theoretically possible for this reaction. Pathways I and II feature initial hydrazinolysis of the ester group in 1 followed by cyclization to give a six-membered (pathway I) or five-membered heterocycle (pathway II). Competing pathway III entails initial addition of hydrazine 2 at the unsaturated bond in ester 1 with subsequent cyclization. We have found that 1 and 2 react according to pathway I. In the case of equimolar amounts of these reagents, keto enols, namely, substituted 4-hydroxy-3-oxotetrahydropyridazines 3a-d are mainly formed. On the other hand, monohydrazones 4a-d of the ketonic tautomers of 3a-d are mainly formed using a two-fold excess of hydrazine 2 (Scheme 1). We should note that replacing hydrazine hydrate with 64% hydrazine in the synthesis of 4a hardly affects the product yield, which is 62.7% in the former case and 57.5% in the latter.
__________________________________________________________________________________________ Kh. Abovyan Armenian State Pedagogical University, 375010 Yerevan, Republic of Armenia. Institute of Organic Chemistry, National Academy of Sciences of the Republic of Armenia, 375091 Yerevan, Republic of Armenia; e-mail: artan@dolphin.su. 3 Molecular Structure Research Center, National Academy of Sciences of the Republic of Armenia, 375014 Yerevan, Republic of Armenia; e-mail: harkar@msrc.am. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1209-1213, August, 2004. Original article submitted December 26, 2001; revision submitted October 4, 2002.
2 1
0009-3122/04/4008-10472004 Springer Science+Business Media, Inc.
1047
Scheme 1
MeCH=CRCOCOOMe 1a,b I, II [ MeCH=CRCOCONHNHR1 ]
NH2NHR1 2a*,b R III
[ MeCHCHCOCOOMe ] NHNHR1
I R Me R1 N OH N H O Me
5
II R O Me
2
R O N R1 5 O
R1
N H
O R O HN
3ad NH2NHR1 H2O R Me R1 N NNHR1 N H 4ad O
Me
N NHR1
1 a R = Me, b R = Ph; 2 a R1 = H (* hydrate), b R1 = Ph; 3, 4 a R = Me, R1 = H; b R = Me, R1 = Ph; c R = Ph, R1 = H; d R = R1 = Ph
The composition and structure of the products were supported by elemental analysis (Table 1) and IR and NMR spectroscopy (Table 2). Thus, the IR spectra of 3 and 4 have a band for the amide carbonyl group at 1665-1668 cm-1 characteristic for six-membered cyclic amides. The lack of coupling between the NH and CH protons in the 1H NMR spectrum of 3d is evidence for the structure given. When these groups are adjacent as in structure 5 (obtained through pathway III), the usual values of the coupling constant J = 5-6 Hz. The spectral and experimental results indicate that products 3 and 4 are mainly formed in the enol form. In a detailed study of the ketoenol equilibrium of these compounds, we carried out the reaction of 3a,c with hydrazine hydrate to give the corresponding hydrazones 4a,c and the reaction of 3b,d with acetyl chloride to give acetyl derivatives 6a,b (Tables 1 and 2).
3a,c
+ +
NH2NH2 . H2O
4a,c R Me
3b,d
MeCOCl R1N N COMe 6a,b
OCOMe O
6 a R = Me, R1 = Ph; b R = R1 = Ph
1048
TABLE 1. Characteristics of Products

Compound 3a 3b 3c 3d 4a Empirical formula C6H10N2O2 C12H14N2O2 C11H12N2O2 C17H16N2O2 C 6H12N4O Found, % Calculated, % H 7.34 7.04 6.87 6.42 6.23 5.88 6.19 5.71 7.86 7.70 6.84 6.49 6.92 6.42 6.05 5.71 5.67 6.00 6.16 5.49 [M]+, m/z N 20.29 19.72 12.70 12.84 13.66 13.73 9.97 10.00 36.09 35.90 18.64 18.18 26.00 25.69 9.78 10.00 9.53 9.27 8.02 7.69 142 218 204 280 156 134-135 146-168 152-154 205-206 Yield, % (method) 40.3 57.5 56.3 53.5 62.7(A), 57.5 (B), 92.8 (C) 41.8 (A) 92.5 (A), 67 (C) 68.4 (A) 85.7 93.6
mp, *
C 50.80 50.70 66.48 66.06 64.86 64.71 72.20 72.86 46.37 46.15 69.77 70.13 61.13 60.55 72.33 72.86 63.97 63.57 69.53 69.23
4b 4c 4d 6a 6b
C18H20N4O C11H14N4O C17H16N2O2 C16H18N2O4 C21H20N2O4
308 218 280 302 364
165-166 165-167 210-211 121-122 dec.
_______ * Compound 4a - bp 133-136C (5 mm Hg). TABLE 2. Spectral Data of Products

Compound 1 3a IR spectrum, , cm-1 2 1625 (C=C); 1667 (C=O); 3150-3400 (NH, OH)
1
spectrum NMR, , ppm (J, Hz) 3
3b
3c
3d*
4a
4b
4c
1.28 (3H, d, J = 6.6, 6-CH3); 1.98 (3, s, 5-3); 3.97 (1, q, J = 6.6, 6-); 4.56 (1, br. s, 1-); 7.55 (1, br. s, OH); 9.78 (1H, br. s, 2-H) 690, 760, 1590, 1.27 (3, d, J = 6.6, 6-CH3); 1.96 (3, s, 5-CH3); 3040 (arom.); 1620 (C=C); 3.9 (1, q, J = 6.6, 6-H); 6.80-7.20 (5, m, C6H5); 1665 (C=O); 7.85 (1, s, ); 9.80 (1, br. s, 2) 3200-3375 (NH, OH) 690, 755, 1595, 1.28 (3H, d, J = 6.6, 6-CH3); 3.90 (1, q, J = 6.6, 6-); 3035 (arom.); 1620 (C=C); 4.60 (1, br. s, 1-); 6.90-7.20 (5, m, C6H5); 1665 (C=O); 8.02 (1, s, OH); 9.80 (1, br. s, 2-) 3200-3350 (NH, OH) 690, 755, 1590, 1.38 (3H, d, J = 6.6, 6-CH3); 4.62 (1, q, J = 6.6, 6-); 3030 (arom.); 1665 (C=O); 6.68 (2, d, J = 7.8, o-H in 1-C6H5); 6.71 (1, m, 3200-3375 (NH, OH) J = 7.2, p- in 1-C6H5); 7.21 (1, J = 7.2, - in 5-C6H5); 7.12 (2, m, J = 7.5, m- in 5-C6H5); 7.35 (2, m, J = 7.8, m- in 1-C6H5); 7.65 (2H, d, J = 7.8, o-H in 5-C6H5); 8.06 (1H, s, OH); 9.99 (1, s, NH) 1620 (C=N); 1665 (C=O); 0.96-1.28 (6H, m, 5- and 6-C3); 3.00-4.10 (2, m, 2200-3375 (NH) 5- and 6-); 4.58 (1, br. s, 1-); 7.00 (2, br. s, NH2); 9.88 (1, br. s, 2-) 690, 755, 1590, 0.98-1.26 (6H, m, 5- and 6-3); 3.10-4.10 (2, m, 3035 (arom.); 1620 (C=N); 5- and 6-); 7.00-7.20 (10, m, 2C6H5); 1665 (C=O); 8.21 (1, br. s, NHPh); 9.85 (1, br. s, 2- ) 200-3350 (NH) 690, 750, 1590, 1.28 (3H, d, J = 6.6, 6-CH3); 3.90 (1H, m, 6-H); 3035 (arom.); 1625 (C=N); 4.62 (1, br., 1-); 5.06 (1H, br., 5-H); 1665 (C=O); 7.00-7.40 (7H, m, NH2 and C6H5); 9.85 (1, br. s, 2-) 3200-3370 (NH)
1049
TABLE 2 (continued)
1 4d 2 690, 750, 1595, 3035 (arom.); 1620 (C=N), 1668 (C=O); 3200-3350 (NH) 690, 1750, 1590, 3035 (arom.);1665 (C=O); 1170, 1240, 1725 (COO); 1680-1685 (C=O) 690, 1755, 1590, 3030 (arom.); 1625 (C=C); 1170, 1220, 1725 (COO); 1660-1665 (C=O) 3 1.29 (3H, d, J = 6.6, 6-CH3); 3.90 (1, m, 6-); 5.08 (1H, d, J = 6.0, 5-H); 8.19 (1, br. s, NHPh); 7.00-7.20 (15, m, 3C6H5); 9.82 (1, br. s, 2-H) 1.29 (3H, d, J = 6.6, 6-CH3); 1.93; 1.96 and 2.00 (9, three s, 5-CH3 and 2CH3CO); 3.80 (1H, q, J = 6.6, 6-H); 7.20 (5, m, C6H5 1.27 (3H, d, J = 6.5, 6-CH3); 1.98 and 2.10 (6, two s, CH3CO); 3.80 (1H, q, J = 6.5, 6-H); 7.00-7.20 (10, m, 2C6H5)
6a
6b
_______ * 13C NMR spectrum, , ppm: 17.75 (6-CH3), 54.25 (6-C), 111.87 (o-C in 1-C6H5), 118.40 (p-C in 1-C6H5), 126.21 (p-C in 5-C6H5), 126.73 (o-C in 5-C6H5), 127.66 (m-C in 5-C6H5), 128.24 (m-C in 1-C6H5), 162.54 (CO), 121.53, 131.89, 142.04, and 147.53 (double signals for nuclei 4-C and 5-C). The signals were assigned using a two-dimensional heteronuclear correlation spectrum and the HMQC method.
The relatively low yield of hydrazone 4c may be attributed to the presence of a phenyl group at C(5) of the hexahydropyridazinone ring, which favors formation of the enol form giving a more conjugated system and hindering the reaction of this form with hydrazine hydrate. This hypothesis finds support in the results of the reaction of keto esters 1a,b with primary amines, leading to pyrrolinones [7]. Thus, we have developed a convenient one-step synthesis for pyridazinone derivatives, which have not been readily available until now, from keto esters 1a,b.
EXPERIMENTAL The IR spectra were taken for samples in vaseline oil on a UR-20 spectrometer and the 1H NMR spectra were taken on a PerkinElmer R-12B spectrometer at 60 MHz and a Varian Mercury 300 spectrometer at 300 MHz for solutions in 1:3 DMSO-d6CCl4. The 13C NMR spectra were taken on a Varian Mercury spectrometer at 75 MHz with complete suppression of 13C and 1H nuclei in CCl4 using TMS as the internal standard. The mass spectra were taken on an MKh-1320 mass spectrometer with direct sample inlet into the ionization chamber. The ionization voltage was 70 eV. The gas-liquid chromatographic analysis of the starting reagents was carried out on an LKhM-80 chromatograph using a 2-m 3-mm column packed with 10% Apiezon L on Inerton-AW (0.20-0.25 mm). The column temperature was raised from 100 to 220C at 16C/min. The helium gas carrier flow rate was 60 ml/min. 1-R1-5-R-4-Hydroxy-6-methyl-1,6-dihydropyridazin-3(2H)-ones (3a-d). (General Method). A 20% solution of hydrazine hydrate (0.02 mol) in ethanol was added dropwise over 30 min with stirring to a solution of keto ester 1 (0.02 mol) in ethanol (6 ml) maintained at from -12 to -10C. The reaction mixture was stirred at this temperature for 30 min, then for 2 h 30 min at room temperature, maintained under these conditions for about 16 h, and finally heated at reflux for 2 h. The solvent was removed and the residue (product 3) was washed with ether and then hexane and finally recrystallized from ethanol. 1-R1-5-R-4-(R1-Hydrazino)-6-methyl-1,4,5,6-tetrahydro-3(2H)-ones (4a-d). A. Products 4a-d were obtained analogously to 3, using hydrazine hydrate (0.04 mol). 1050
B. Product 4a was obtained according to Method A using 64% hydrazine (0.04 mol). C. Products 4a,c were synthesized analogously to 3 using 3a,c instead of keto esters 1a,c. 1-R1-5-R-4-Acetoxy-2-acetyl-6-methyl-1,6-dihydropyridazin-3(2H)-ones (6a,b). Acetyl chloride (0.015 mol) was added very slowly dropwise to a solution of 3b or 3d (0.006 mol) in pyridine (4 ml) with cooling in an ice bath. A precipitate formed immediately. Cooling was terminated. The reaction mixture was maintained at room temperature for about 16 h and then 2% hydrochloric acid (160 ml) was carefully added with good stirring. The crystalline precipitates of 6a,b were filtered off and recrystallized from ethanol.
REFERENCES 1. 2. 3. 4. 5. 6. 7. R. Elderfield (editor), Heterocyclic Compounds [Russian translation], Vol. 6, Izd. Inostr. Lit., Moscow (1960), Vol. 6, p. 88. K. Kaji, H. Nagashima, Y. Hoirose, and H. Oda, Chem. Pharm. Bull., 33, 982 (1985). R. S. Vartanyan, A. L. Gyul'budagyan, and A. Kh. Khanamiryan, Arm. Khim. Zh., 44, 596 (1987). A. G. Anderson, Jr. and P. K. Roland, J. Org. Chem., 49, 4769 (1984). N. F. Volynets, I. V. Samartseva, I. V. Khramova, and L. A. Pavlova, Zh. Org. Khim., 20, 1760 (1984). N. U. Cromwell, K. E. Cook, and P. L. Cregen, J. Am. Chem. Soc., 78, 4416 (1956). S. T. Kocharyan, N. P. Churkina, T. L. Razina, V. E. Karapetyan, S. M. Ogandzhanyan, V. S. Voskanyan, and A. T. Babayan, Khim. Geterotsikl. Soedin., 1345 (1994).
1051
CONDENSED ISOQUINOLINES. 17*. ENAMINE PROPERTIES OF BENZIMIDAZO[1,2-b]ISOQUINOLIN-11(5H)-ONE IN ALKYLATION REACTIONS

L. M. Potikha, N. V. Shkilna, V. M. Kisil, and V. A. Kovtunenko The alkylation of benzimidazo[1,2-b]isoquinolin-11(5H)-one has been studied. This occurs at N(5) or C(6) depending on the type of alkylating agent and the reaction conditions. It was shown that C(6) alkylation is effected in reactions with reactive alkyl halides. A repeat alkylation occurs preferentially at the same position. Interaction with o-xylylidene dibromide leads to spiro[benzimidazo[1,2-b]-isoquinolin-6,2'indan]-11-one and 1,6-dihydro-11H-6a,11b-diazobenzo[b]benzo[5,6]cyclohepta-[1,2,3-l,m]fluoren-11one, which are derivatives of new heterocyclic systems. Keywords: heterocyclic enamines, derivatives of 1,6-dihydro-11H-6a,11b-diazabenzo[b]benzo[5,6]cyclohepta[1,2,3-l,m]fluoren-11-one and spiro[benzimidazo[1,2-b]isoquinolin-6,2'-indan]-11-one, alkylation. Depending on the nature of the reagent the acylation of benzimidazo[1,2-b]isoquinolin-11(5H)-one (1) leads to the formation of two types of benzimidazoisoquinolines substituted at positions 5 or 6 [1]. These results are in complete agreement with the behavior of secondary enamines [2,3], the structural element of which is present in the compound 1 molecule. However the most characteristic reaction of enamines, alkylation, has not yet been studied among derivatives of 1. Only two examples of this reaction are known, the N(5)-methylation [4,5] and C(6)-diallylation of compound 1 [5]. While continuing the investigations of alkylation in the condensed isoquinoline series [6,7] in the present work, we have studied the alkylation of benzimidazoisoquinoline 1 by various alkylating agents under various conditions. The direction of alkylation in enamines is determined by the nature of the alkylation agent, although on alkylation with phenacyl or benzyl halides attack at the -carbon is more preferred [2]. In reality, interaction of compound 1 with substituted -bromoacetophenones takes place extremely vigorously with the formation of a complex mixture of products. Only in the case of reaction with p-bromophenacyl bromide was the C(6)-alkylation product successfully isolated and characterized, viz. 6-[2-(4-bromophenyl)-2-oxoethyl]benzimidazo[1,2b]isoquinolin-11(5H)-one (2). In the cases of phenacyl and p-methoxyphenacyl bromides only compound 3, the product of oxidative dimerization of compound 1, was successfully identified in the mixture of products. The ease of formation of compound 3 was noted by us previously [1]. _______ * For Part 16 see [1]. __________________________________________________________________________________________ T. Shevchenko National University, Kiev 01033, Ukraine; e-mail: vkovtunenko@hotmail.com. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1214-1225, August, 2004. Original article submitted July 12, 2002. 1052 0009-3122/04/4008-10522004 Springer Science+Business Media, Inc.
O N N 7 O O N N H O 1 N N H H N N O 3 Me O N N H
2 Br O N N H O N N
R1 R1 R3 R2 R3 O N N 5ac R2
R3 R2
R1 4ac
+
R3 R2 R1 6ad R1 R2 R3
4a, 6b R1 = R3 = Me, R2 = H; 4b, 5b, 6c R1 = R3 = H, R2 = NO2; 4c, 5c, 6d R1 = CN, R2 = R3 = H, 5a, 6a R1 = R2 = R3 = H
The main criterion for establishing the direction of alkylation of compound 1 was in all cases the retention or nonappearance of the signals of the N(5)H or C(6)H protons in the 1H NMR spectra. For example, the structure of compound 2 as the product of C(6)-alkylation is confirmed by the presence of the signal of the N(5)H group in the IR and 1H NMR spectra (Table 1), and also by the absence of resonance at 6.3 ppm for the C(6)H observed in the initial compound 1. Three types of alkylation product are formed on carrying out the reaction of heterocycle 1 with benzyl halides in 2-propanol in the presence of i-PrONa, viz. 6-benzylbenzimidoazo[1,2-b]isoquinolin-11(5H)-ones (4a,b), 6,6-dibenzylbenzimidazo[1,2-b]isoquinolin-11(5H)-ones (5a-c), and 5,6-dibenzylbenzimidazo[1,2-b]isoquinolin-11(5H)-ones (6a-d). The amount of alkyl derivatives 4-6 in the mixture formed depends on the 1053
1054
TABLE 1. Spectral Characteristics of 6-R-benzimidazo[1,2-b]isoquinolin-11(5H)-ones

Compound C=O 1 2 2 1660, 1620 IR spectrum, , cm-1 NH 3 3280 Other signals 4 H-5, s 5 11.72 H-1, d, J = 8.0 6 8.65
1 NMR spectrum, , ppm (J, Hz) Signals of benzimidazo[1,2-b]isoquinoline nucleus H-10, d, H-8, t, H-7, d, H-3, t, H-4, d, H-9, t, H-2, t, J = 8.0 J = 8.0 J = 8.0 J = 8.0 J = 8.0 J = 8.0 J = 8.0 7 8 9 10 11 12 13
Signals of substituent 6-CH2, ArH 2, s 14 15 8.12 (2H, d, J = 8.0, H-2', H-6'), 7.84 (2H, d, J = 8.0, H-3', H-5') 7.06 (1H, s, H-3'), 6.70 (1H, d, J = 8.0, H-5'), 6.48 (1H, d, J = 8.0, H-6') 8.16 (1H, s, H-2'), 8.03 (1H, d, J = 8.0, H-4'), 7.67 (1H, d, J = 8.0, H-6'), 7.52 (1H, t, J = 8.0, H-5') 4.76
Other signals 16
8.37
7.60
7.50
7.41
7.31
7.28
7.22
4a
1650
3300
11.74
8.67
8.39
7.56
7.33
7.40
7.30
7.27
7.22
4.14
2.48 (3H, s, 2'-CH3), 2.19 (3H, s, 4'-CH3)
4b
1650
3200
1560, 1340 (s,asNO2)
11.97
8.65
8.37
7.63-7.57 (2H, m)
7.42
7.35
7.27
7.23
4.46
TABLE 1 (continued)
1 4 2 1655 3 3180 4 2200 (CN) 5 11.92 6 8.67 7 8.40 8 7.59 9 * 10 * 11 7.34 12 7.28 13 7.24 14 7.89 (1H, d, J = 8.0, H-3', 7.47-7.37 (4H, m, H-3, H-7, H-4', H-5'), 7.03 (1H, d, J = 8.0, H-6') 6.88 (2H, m, H-3', H-4'), 6.75 (2H, m, H-2', H-6') 7.71 (1H, d, J = 7.2, H-3'), H-4', H-5'*2, 6.98 (1H, d, J = 7.2, H-6') 7.58-7.54 (2H, m, H-8, H-5'), 7.67 (1H, d, J = 8.0, H-3'), H-4'*2, 6.95 (1H, d, J = 7.2, H-6') 7.94 (1H, m, H-3'), 7.37-7.30 (2H, m, H-7, H-5'), H-4'*2, 6.90 (1H, m, H-6') 15 4.52 16
1650
3200
11.69 (2H)
8.71 (2H)
8.45 (2H)
7.63 (2H)
7.59 (2H)
7.37 (2H)
7.34 (2H)
7.29 (2H)
7.19 (2H)
4.54 (4H)
11
1655
3180
3280, 3410 ( NH2)

s,as
12.29
8.63
8.37
7.58
7.47
7.32
7.25-7.12 (5H, m, H-2, H-4, H-9, H-4', H-5')
4.41
8.13 (1H, s, NHAHB), 7.74 (1H, s, NHAHB) 10.12 (1H, s, N'HN''H CONH2), 8.11 (1H, s, N'HN''H CONH2), 5.99 (2H, s, NH2) 3.97 (3H, s, OCH3)
13a
1655
3200
3300, 3410 s,as ( NH2)
11.84
8.64
8.37
*2
7.33
7.27-7.13 (5H, m, H-2, H-4, H-7, H-9, H-4')
4.41
13b
1640, 1710
3050
1230 (CO)
11.63
8.66
8.39
8.49
7.27-7.21 (4H, m, H-3, H-4, H-9, H-4')
7.15
4.62
_______ * Overlap of signals of benzimidazo[1,2-b]isoquinoline nucleus and signals of substituent, see column 14. *2 Overlap of signals of benzimidazo[1,2-b]isoquinoline.
1055
nature of the substituent in the benzyl radical and on the ratio of the reactants used in the reaction. At an equivalent ratio of reactants (method A) only in the case of 2,4-dimethylbenzyl chloride was a single reaction product, the monobenzyl derivative 4a, obtained. In the remaining experiments mixtures were formed either of the initial 1 with dibenzyl derivatives (5a, 6a, and 5c, 6d), or, as in the case of 3-nitrobenzyl chloride, a mixture of mono- and dibenzyl derivatives (4b, 5b). The use of a twofold excess af alkylating agent (method B) leads to an increase in the overall alkylation yield and a growth in the proportion of dibenzylation products. However in this case also the predominant product with 2,4-dimethylbenzyl chloride (mixture of 4a, 6b) remains the 6-benzyl derivative 4a, probably caused by the reduced reactivity of the reactant itself, and also by steric hindrance from the side of the ortho substituent towards a second attack at position 6. The 5,6-dialkyl derivatives 6a-d are formed in low yield (10-25%). Only the 5,6-dibenzyl derivative 6a was isolated and characterized, and in the remaining cases the presence of compounds of the type of 6 were recorded in the mixture with the aid of 1 H NMR spectra of the unpurified reaction products. The benzylation of compound 1 by fusion is complicated in many cases by significant resinification. On fusing 1 with benzyl chloride (180C) the 6,6-dibenzyl derivative 5a is obtained in low yield (20%), but on using o-bromomethylbenzonitrile the monobenzylation product 4c was isolated successfully. Attempts at a repeat alkylation (without base and on fusing) of the mono-6-benzyl derivatives 4a-c to the dibenzyl derivatives led to the formation of mixtures of unidentified products. On carrying out the benzylation of heterocycle 1 without base by heating a mixture of the reactants in DMF or MeCN, the formation of dimer 3, already mentioned above, was observed. The obtained data indicate the participation of nitrogen analogs of enolate ions in the benzylation in the presence of i-PrONa, generated both from the initial benzimidazoisoquinoline 1, and from compounds 4. The impossibility of forming such an anion for 5-methylbenzimidazo[1,2-b]isoquinolin-11(5H)-one (7), obtained previously [4,5], explains the inertness of the latter in this reaction. It may therefore be stated that the main direction of alkylation of compound 1 is at position C(6). The repeat alkylation also takes place predominantly at the same position. The structure of the benzylation products 4-6 was established by spectral methods (Tables 1, 2). For all three types of benzyl derivatives the signal of the C(6)H methine proton observed at 6.3 ppm in the initial compound 1 was absent from the 1H NMR spectra. In the spectra of the monobenzyl derivatives 4a,b there are signals for the N(5)H group (at 11.7-11.9 ppm in the 1H NMR spectrum and at 3100 cm-1 in the IR spectrum), which are absent from the spectra of the dibenzyl derivatives 5a-c, 6a. The observed differences in signal form and the chemical shifts of the methylene protons of the benzyl substituents of dibenzyl derivatives 5 and 6 also enable their structures to be determined unequivocally. The methylene protons of 5,6-dibenzyl derivatives 6a-d are observed as two singlets at 3.8-4.4 (C(6)CH2) and 5.0-5.6 ppm (N(5)CH2), and the signal of the methylene groups in 6,6-dibenzyl derivatives 5a-c at 3.9-4.2 ppm is observed as an AB spin system with geminal coupling constant 13.2 Hz. The nonequivalence of the methylene group protons at C(6) in compounds 5a-c is evidently caused by steric hindrance to rotation about the C(6)CH2Ar single bonds. The data on the benzylation of compound 1 and also the possibility of intramolecular alkylation discovered by us previously [1] using 6-(-halo)acetyl derivatives of 1 as examples enabled us to hope for successful heterocyclization using a reactant with two alkylating functions, o-xylylidene dibromide. On carrying out the reaction in the presence of an equivalent quantity of i-PrONa we obtained the unusual monoalkylation product 6-{2-[11-oxo-5,11-dihydrobenzo[4,5]imidazo[1,2-b]isoquinolin-6-yl)methyl]benzyl}benzo[4,5]imidazo[1,2-b]isoquinolin-11(5H)-one (8). The use of a twofold excess of base leads to a mixture of derivatives of two new heterocyclic systems, spiro(benzimidazo[1,2-b]isoquinolin-6,2'-indan)-11-one (9) and 1,6-dihydro-11H6a,11b-diazabenzo[b]benzo[5,6]cyclohepta[1,2,3-l,m]fluoren-11-one (10) in a 1:5 ratio.
1056
TABLE 2. Spectral Characteristics of 6,6-Dibenzyl Derivatives 5a-c and Spiro-substituted Compounds 9, 12

IR spectrum, , cm-1 C=O 1 5a 2 1700 Other signals 3 H-1, d, J = 8.0 4 8.31 NMR spectrum (DMSO-d6), , ppm (J, Hz) Signals of the benzimidazo[1,2-b]isoquinoline nucleus Signals of substituents H-10, d, H-4, d, H-2, t, H-7, d, H-3, t, H-8, t, H-9, t, 6-CH, ArH J = 8.0 J = 8.0 J = 8.0 J = 8.0 J = 8.0 J = 8.0 J = 8.0 2, d
1
Compound
5 8.09
6 7.92
9 7.48
10 7.46
11 7.35
12 6.86 (2H, t, J = 8.0, H-4'), 6.75 (4H, t, J = 8.0, H-3', H-5'), 6.39 (4H, d, J = 8.0, H-2', H-6') 7.80 (2H, d, J = 8.0, H-4'), 7.29 (2H, s, H-2'), 7.15 (2H, t, J = 8.0, H-5'), 6.86 (2H, d, J = 8.0, H-6') H-3'*, 7.18 (2H, t, J = 8.0, H-5'), 7.08 (2H, t, J = 8.0, H-4'), 6.31 (2H, d, J = 8.0, H-6') 7.30 (4H, m, H-4' H-7') H-5', H-7'*2, 7.58 (1H, t, J = 8.0, H-6'), 7.23 (1H, d, J = 8.0, H-4')
13 4.02 (J = 13.2)
6-CH, 2, d 14 3.79 (J = 13.2)
7.90-7.88 (2H, m)
5b
1700
1510, 1340 ( NO2)

s,as
8.53
8.07-8.00 (3H, m)
7.95
7.59
7.53
7.42
4.14 (J = 13.2)
4.06 (J = 13.2)
5c
1700
2210 (CN)
8.22
8.11
8.07
7.84-7.80 (2H, m)
7.56
7.50-7.42 (4H, m, H-8, H-9, H-3') 7.41-7.38 (2H, m) 7.44 7.39
4.26 (J = 13.2)
4.15 (J = 13.2)
9 12
1695 1710 (br.)
8.38 8.31 (m) 8.43-8.40 (2H, m)
7.64 (2H, m) 7.89 (2H, m, H-4, H-7')
7.34
7.55
7.74-7.61 (4H, m, H-2, H-3, H-7, H-5')
4.11 (J= 16.5) 4.57 (1, J = 18.0)
3.58 (J = 16.5) 4.04 (1, J = 18.0)
_______ * Overlap of signals of benzimidazo[1,2-b]isoquinoline nucleus and signals of a substituent, see columns 10, 11. *2 Overlap of signals of benzimidazo[1,2-b]isoquinoline nucleus and signals of a substituent, see columns 6-9.
1057
O O N N H 9 O H N N O 8 10
1 10
N N
N N
6
The structures of products 8-10 were confirmed by their spectral data (Tables 1, 2) which were extremely similar to the spectra of benzyl and dibenzyl derivatives 4-6. Among their special features may be noted the position of the C(7)H proton signal in the 1H NMR spectrum of spiro product 9 observed at higher field (7.34 ppm) compared with the corresponding signal of 6,6-dibenzyl derivatives 5a-c due to shielding of the spiroindane fragment by the benzene ring. In connection with the ease of acylation of compound 1 it seemed of interest to investigate the problem of the acylation of alkyl-substituted benzimidazoisoquinolines. Experiments on the acylation of compound 7 showed its inertness. The 6-benzyl derivatives 4a,b in dioxane in the absence of base did not interact with acylating agents, and in pyridine gave a mixture of unidentified products. The conversion of 6-(2-cyanobenzyl)benzimidazoisoquinoline 4c described above proved to be extremely interesting. On boiling in acetic acid in the presence of HBr this compound is hydrolyzed to amide 11, but on more extended heating in acetic acid it is possible to obtain the product of intramolecular acylation, spiro(benzimidazo[1,2-b]isoquinolin6(11H),2'-indan)-1',11-dione (12).
O HOAc, HBr N N H HOAc O O N N RH HOAc O N N H
4c
11
CONH2 12 13 a R = NHNHCONH2, b R = OMe
COR 13a,b
We drew a conclusion on the spiro structure of compound 12 on the basis of data of its 1H NMR spectrum. Apart from the absence from the low field region of signals of exchanging protons of the NH type, which corresponds both to the C(6) acylation product and to the N(5) acylation product, attention is attracted primarily by the position and form of the methylene group proton signal. Two one-proton doublets with J = 18.0 Hz were recorded in the region of 4.0 and 4.5 ppm which correspond in position and form to the 1058
TABLE 3. Physicochemical Characteristics of the Synthesized Compounds

Compound 2*2 4a 4b 4c 5a 5b 5c 8 9 11 12 13a 13b Empirical formula C C23H15BrN2O2 C24H20N2O C22H15N3O3 C23H15N3O C29H22N2O C29H20N4O5 C31H20N4O C38H26N4O2 C23H16N2O C23H17N3O2 C23H14N2O2 C24H19N5O3 C24H18N2O3 63.96 64.05 81.69 81.79 71.50 71.54 78.98 79.07 83.92 84.03 68.94 69.04 80.07 80.15 79.88 79.98 82.10 82.12 75.09 75.19 78.74 78.84 67.74 67.76 75.30 75.38 Found, % Calculated, % H 3.45 3.51 5.65 5.72 4.00 4.09 4.30 4.33 5.48 5.35 3.95 4.00 4.26 4.34 4.50 4.59 4.72 4.79 4.61 4.66 3.95 4.03 5.54 5.50 4.68 4.74 Yield, % (method) 65 57 (A), 45 (B) 31 (A) 75 40 (A), 55 (B) 34 (A), 55 (B) 47 (A), 63 (B) 60 18 76 63 57 75
mp, * N 6.58 6.50 8.01 7.95 11.45 11.38 12.10 12.03 6.86 6.76 11.19 11.11 12.10 12.06 9.85 9.82 8.35 8.33 11.47 11.44 8.05 8.00 16.43 16.46 7.37 7.33 248 (dec.) 211 270 201 159 195 134 204 240 294 282 295 215
_______ * Compound 4a was recrystallized from MeCN, 5a from EtOH, and the remainder from DMF. *2 Analytical data for Br: 18.56% (found), 18.53% (calculated).
protons of the methylene groups of spiro compound 9, also observed as an AB spin system with J = 16.5 Hz (Table 2). In the 13C NMR spectrum two signals were observed in the region of absorption of aliphatic carbon atoms assigned by us to the resonance of C(spiro) (56.68 ppm) and C(3')H2 (42.55 ppm) and there was a signal for C(1') (199.94 ppm) characteristic of the absorption of carbonyl carbon atoms [8]. In the IR spectrum a broad band was observed at 1710 cm-1 corresponding to the vibrations of two carbonyl groups. The formation of the intramolecular acylation product was also confirmed by mass spectral data (350 [M]+, 39%). Spiroindanone 12, being fairly stable in acid media, proved to be extremely sensitive to the action of bases. The spiroindanone ring was easily broken with the formation of derivatives of 6-(2-carboxybenzyl)benzimidazo[1,2-b]isoquinolin-11(5H)-one. On attempting to obtain the semicarbazone we isolated the acylated semicarbazide 13a, and on boiling in methanol in the presence of Et3N the methyl ester 13b was obtained.
EXPERIMENTAL The melting points of the synthesized compounds were determined on Boetius type heating equipment and are not corrected. The IR spectra (KBr disks) were recorded on a Pye-Unicam SP 3-300 instrument. The 1 H and 13C NMR spectra were obtained on a Varian Mercury 400 instrument (400 MHz for 1H and 100 MHz for 1059
C) in DMSO-d6, internal standard was TMS. The assignment of signals of the aromatic protons was confirmed by data of COSY HH spectra for compounds 2, 5a, 6a, 10, and 12. The mass spectra were obtained on a Waters Integrity System instrument, with a Thermabeam detector (mobile phase CH3CN). A check on the progress of reactions and the purity of the compounds obtained was effected by TLC on Silufol UV-254 plates. The characteristics of the compounds obtained are given in Tables 1-3. Benzimidazo[1,2-b]isoquinolin-11(5H)-one (1) was obtained by the procedure of [4], and 5-methylbenzimidazo[1,2-b]isoquinolin-11(5H)-one (7) by the procedure of [5]. 6-[2-(4-Bromophenyl)-2-oxoethyl]benzimidazo[1,2-b]isoquinolin-11(5H)-one (2). p-Bromophenacyl bromide (3.61 g, 13 mmol) was added to a solution of benzimidazoisoquinoline 1 (2.34 g, 10 mmol) in DMF (10 ml) and the mixture boiled for 40 min. After cooling, the precipitated solid was filtered off, and washed with acetone. Recrystallization was from DMF. Alkylation of Benzimidazo[1,2-b]isoquinolin-11(5H)-ones with Benzyl Halides in Solution was carried out using various ratios of reactants calculated on heterocycle 1 (10 mmol). A. Sodium (0.25 g, 11 mmol) and benzyl halide (11 mmol). B. Sodium (0.5 g, 22 mmol) and benzyl halide (22 mmol). Compound 1 (2.34 g, 10 mmol) was added to a solution of sodium isopropylate in 2-propanol (10 ml) and dissolved on heating. The appropriate benzyl halide was added to the solution obtained and the mixture boiled for 1.5-2 h. After cooling the reaction mixture, the solid formed was filtered off, washed thoroughly with water, and with alcohol, and recrystallized from DMF. Further isolation of products was carried out separately from the solid and the filtrate. When using benzyl chloride (method A) a solid (0.93 g) was obtained consisting, according to data of 1 the H NMR spectrum*, of compound 6a and initial 1 in a ratio of 1:1. On alkylation by method B the solid (1.03 g) consisted exclusively of 5,6-dibenzylbenzimidazo[1,2-b]isoquinolin-11(5H)-one (6a), the yield of which was 25%; mp 242-244C (DMF). IR spectrum, , cm-1: 1650 (C=O). 1H NMR spectrum, , ppm (J, Hz): 8.79 (1H, d, J = 8.0, C(1)H); 8.42 (1H, d, J = 8.0, C(10)H); 7.56 (1H, t, J = 8.0, C(8)H); 7.46 (1H, d, J = 8.0, C(7)H); 7.23-7.37 (8H, m, C(2)H-C(4)H, C(9)H, C(3')H, C(5')H); 7.19 (2H, m, C(4')H); 7.10 (4H, m, C(2')H, C(6')H; 5.26 (2H, s, 5-CH2); 4.18 (2H, s, 6-CH2). Found, %: C 83.96; H 5.30; N 6.79. C29H22N2O. Calculated, %: C 84.03; H 5.35; N 6.76. When alkylating with 2,4-dimethylbenzyl chloride by method A the solid consisted exclusively of NaCl. On alkylating by method B the solid (0.25 g) contained a mixture of 6-(2,4-dimethylbenzyl)benzimidazo[1,2-b]isoquinolin-11(5H)-one (4a) and 5,6-di(2,4-dimethylbenzyl)benzimidazo[1,2-b]isoquinolin-11(5H)one (6b). According to the data of the 1H NMR spectrum, , ppm (J, Hz): 8.81 (m, ArH); 8.45 (m, ArH); 6.30-7.60 (m, ArH); 5.03 (s, 5-CH2, 6b); 4.15 (s, 6-CH2, 4a); 3.83 (s, 6-CH2, 6b); 2.49 (s, 2'-CH3, 4a); 2.23 (s, 5-[2',4'-(CH3)2C6H4CH2], 6b); 2.19 (s, 4'-CH3, 4a); 1.96 (s, 6-(2'-CH3-4'-CH3-C6H4CH2), 6b); 1.85 [s, 6-(2'-CH34'-CH3-C6H4CH2), 6b], ratio 4a:6b, 5:1. By method A from 3-nitrobenzyl chloride a mixture (0.22 g) was obtained, consisting, according to data 1 of the H NMR spectrum, of 6-(3-nitrobenzyl)-benzimidazo[1,2-b]isoquinolin-11(5H)-one (4b) and initial 1 in a ratio of 3:2. By method B a mixture (0.3 g) was obtained of the 6-benzyl derivative 4b and 5,6-di(3nitrobenzyl)benzimidazo[1,2-b]isoquinolin-11(5H)-one (6c). According to data of the 1H NMR spectrum, , ppm (J, Hz): 11.96 (br. s, NH, 4b); 8.35-8.90 (m, ArH); 7.15-8.19 (m, ArH); 5.65 (s, 5-CH2, 6c); 4.47 (s, 6-CH2, 4b and 6-CH2, 6c), the 4b:6c ratio in the mixture was 5:1. On using 2-cyanobenzyl bromide (method A) a mixture (0.23 g) was obtained consisting, according to data of the 1H NMR spectrum, of 5,6-di(2-cyanobenzyl)-benzimidazo[1,2-b]isoquinolin-11(5H)-one (6d) and initial 1 in a ratio of 1:3. By method B a mixture (0.2 g) was obtained of 6,6-di(2-cyanobenzyl)benzimidazo[1,2-b]isoquinolin-11(5H)-one (5c) and the 5,6-dibenzyl derivative 6d. According to data of the 1H NMR spectrum, , ppm (J, Hz): 8.05-8.85 (m, ArH); 7.10-7.90 (m, ArH); 6.30 (m, ArH); 5.46 (s, 5-CH2, 6d); 4.05-4.28 (m, 6-CH2, 5c and 6-CH2, 6d), the ratio of 5c:6d in the mixture was 1:6. _______ *Data of the 1H NMR spectrum of the initial compound 1 are given in [1]. 1060
13
The filtrate was evaporated in vacuum, water (15 ml) was added to the residual oil, and the mixture left for 1 day. The solid formed was filtered off, and washed with a small amount of 2-propanol. On using benzyl chloride by method A 1.65 g (40%) and by method B 2.26 g (55%) of 6,6-dibenzylbenzimidazo[1,2-b]isoquinolin-11(6H)-one (5a) was obtained. When using 2,4-dimethylbenzyl chloride by method A 2.0 g (57%) or method B 1.58 g (45%) of 6-(2,4-dimethylbenzyl)benzimidazo[1,2-b]isoquinolin-11(5H)-one (4a) was obtained (Tables 1 and 3). When using 3-nitrobenzyl chloride a mixture was obtained (method A) of 6-(3-nitrobenzyl)benzimidazo[1,2-b]isoquinolin-11(5H)-one (4b) and 6,6-di(3-nitrobenzyl)benzimidazo[1,2-b]isoquinolin11(5H)-one (5b), which was separated by recrystallization from DMF (Tables 1-3). The solid precipitated on cooling was filtered off and the monobenzyl derivative 4b (1.14 g, 31%) was obtained. Water was added to the filtrate and the precipitate of dibenzyl derivative 5b was filtered off. Yield 1 g (34%). The 6,6-dibenzyl derivative 5b (1.67 g, 55%) was obtained by method B. Using o-bromomethylbenzonitrile compound 5c (2.18 g by method A or 2.92 g by method B) was obtained (Tables 2 and 3). 6-(2-Cyanobenzyl)benzo[4,5]imidazo[1,2-b]isoquinolin-11(5H)-one (4c) (Tables 1 and 3). A mixture of compound 1 (2.34 g, 10 mmol) and o-bromomethylbenzonitrile (2.94 g, 15 mmol) was fused on an oil bath at 135C for 40 min. The mixture was cooled, and acetone (10 ml) added. The resulting solid was filtered off, washed with acetone, and dissolved with heating in morpholine (5 ml). After cooling, water (20 ml) was added, and the solid formed was filtered off. 6-{2-[(11-Oxo-5,11-dihydrobenzo[4,5]imidazo[1,2-b]isoquinol-6-yl)methyl]-benzyl}benzo[4,5]imidazo[1,2-b]isoquinolin-11(5H)-one (8) (Tables 1 and 3). Compound 1 (2.34 g, 10 mmol) was added to a solution of i-PrONa (0.9 g, 11 mmol) in 2-propanol (10 ml), and dissolved on heating. o-Xylylidene dibromide (3.16 g, 12 mmol) was added and the mixture was boiled for 1.5-2 h. The resulting solid was filtered off, and the filtrate evaporated in vacuum. Water (15 ml) was added to the residual oil, and the mixture was left for 1 day. The solid was filtered off, washed thoroughly with water, and with alcohol, and recrystallized from DMF. 1,6-Dihydro-11H-6a,11b-diazabenzo[b]benzo[5,6]cyclohepta[1,2,3-l,m]fluoren-11-one (10). Benzimidazoisoquinoline 1 (2.34 g, 10 mmol) was added to a solution of sodium (0.5 g, 22 mmol) in 2-propanol (10 ml) and dissolved on heating. o-Xylylidene dibromide (3.16 g, 12 mmol) was added to the solution obtained, and the mixture was boiled for 1.5 h. After cooling the solid formed was filtered off. Further isolation of alkylated products was carried out separately for the solid and the filtrate (see below). The solid formed was filtered off, washed thoroughly with water, and recrystallized from DMF. Yield 2.18 g (65%); mp 246-248C (DMF). IR spectrum, , cm-1: 1645 (C=O). 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 8.64 (1H, d, J = 8.0, C(10)H); 8.36 (1H, d, J = 8.0, C(12)H); 8.04 (1H, d, J = 8.0, C(15)H); 7.70 (2H, m, C(7)H, C(14)H); 7.54 (1H, dd, Jo = 8.0, Jm = 2.0, C(5)H); 7.43 (2H, m, C(2)H, C(8)H); 7.22-7.30 (3H, m, C(3)H, C(4)H, C(13)H); 7.16 (1H, t, J = 8.0, C(9)H); 5.58 (2H, s, 6-CH2); 4.50 (2H, s, 1-CH2). Found, %: C 82.09; H 4.70; N 8.32. C23H16N2O. Calculated, %: C 82.12; H 4.79; N 8.33. Spiro(benzimidazo[1,2-b]isoquinolin-6,2'-indan)-11-one (9) (Tables 2 and 3) was isolated from the filtrate remaining after filtering off cycloheptafluorene 10. The solvent was evaporated in vacuum, water (10 ml) was added to the residual oil, and the mixture left for 1 day. The solid formed was filtered off, washed with water, and with alcohol, and recrystallized from DMF. 6-(Carbamoylbenzyl)benzimidazo[1,2-b]isoquinolin-11(5H)-one (11) (Tables 1 and 3). A mixture of benzimidazoisoquinoline 1 (2.34 g, 10 mmol) and o-bromomethylbenzonitrile (2.94 g, 15 mmol) was melted in an oil bath at 135C for 40 min. The mixture was cooled and acetone (10 ml) was added. The resulting solid was filtered off and washed with acetone. The solid substance obtained was boiled for 3 h in acetic acid (15 ml), during which time the hydrobromide of the 6-(2-cyanobenzyl)-substituted compound 4c gradually dissolved and the solid benzamide 11 was precipitated. After cooling, the solid was filtered off, washed with AcOH, and with alcohol, and recrystallized from AcOH.
1061
Spiro[benzimidazo[1,2-b]isoquinolin-6(11H),2'-indan]-1',11-dione (12) (Tables 2 and 3). A suspension of benzamide 11 (3.67 g, 10 mmol) in AcOH (20 ml) was boiled for 4 h. The initial benzamide gradually dissolved. After cooling, the precipitated solid was filtered off, washed with AcOH, and with alcohol, and recrystallized from DMF. 13C NMR spectrum, , ppm: 199.94 (C-1'); 155.29 (C-3'a); 154.13 (C-5a); 142.73 (C-4a); 139.69 (C-6a); 137.33 (C-5'); 135.70 (C-8); 132.32 (C-7'a); 131.69 (C-11b); 129.41, 129.14, 127.75, 126.36, 126.17, 125.94, 125.85, 125.51 (C-2, C-3, C-7, C-9, C-10, C-10a, C-4', C-6', C-7'); 119.99 (C-4); 115.54 (C-1); 56.68 (C-6); 42.55 (C-3'). Mass spectrum, m/z (I, %): 350 (39) [M]+, 321 (41), 292 (6). 6-(2-Semicarbazidocarbonylbenzyl)benzimidazo[1,2-b]isoquinolin-11(5H)-one (13a) (Tables 1 and 3). A mixture of semicarbazide hydrochloride (2 g) and anhydrous sodium acetate (2 g) in absolute ethanol (20 ml) was boiled and filtered hot. Spiroindanone 12 (0.9 g, 2.6 mmol) was added to the filtrate and the mixture was heated on the water bath for 1.5 h until complete solution of the initial compound. Water (10 ml) was added, and the mixture cooled. The precipitated solid was filtered off, washed with water, and with alcohol, and recrystallized from DMF. 6-(2-Methoxycarbonylbenzyl)benzimidazo[1,2-b]isoquinolin-11(5H)-one (13b) (Tables 1 and 3). Triethylamine (2 ml) was added to a suspension of spiroindanone 12 (1.75 g, 5 mmol) in methanol (20 ml) and the mixture was boiled for 4 h. The initial compound gradually dissolved and solid methyl benzoate 13b was precipitated. After cooling, the solid was filtered off, washed with methanol, and recrystallized from DMF.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. L. M. Potikha, N. V. Shkilna, V. M. Kisil, and V. A. Kovtunenko, Khim. Geterotsikl. Soedin., 715 (2004). K. Blaha and O. Chervinka, Adv. Heterocycl. Chem., 6, 147 (1966). P. W. Hickmott, Tetrahedron, 38, 3363 (1982). E. Schefczik, Liebigs Ann. Chem., 729, 83 (1969). K.-Q. Ling, X.-Y. Chen., H.-K. Fun, X.-Y. Huang, and J.-H. Xu, J. Chem. Soc., Perkin Trans. 1, 4147 (1998). V. M. Kisel', L.M. Potikha, and V. A. Kovtunenko, Khim. Geterotsikl. Soedin., 423 (1995). V. M.Kisel', L.M. Potikha, and V. A. Kovtunenko, Khim. Geterotsikl. Soedin., 131 (2001). A. J. Gordon and R. A. Ford, Chemist's Companion, Handbook of Practical Data, Techniques and References, Wiley-Interscience, New York (1972), 560 pp.
1062
4-OXO-3,4-DIHYDROQUINAZOLINYLAND BENZIMIDAZOLYL-ACETONITRILES IN ANNELATION REACTIONS OF A HALOQUINOLINE RING

O. V. Khilya, T. A. Volovnenko, A. V. Turov, and Yu. M. Volovenko The interaction of 4-oxo-3,4-dihydroquinazolinyl- and benzimidazolyl-acetonitriles with 2,6-dihalobenzaldehydes leads to 3-(2,6-dihalophenyl)-2-(4-oxo-3,4-dihydro-2-quinazolinyl)acrylonitriles and 2-(1H-benzo[d]imidazol-2-yl)-3-(2,6-dihalophenyl)acrylonitriles respectively. As a result of intramolecular cyclization of these nitriles 4-halo-12-oxo-12H-quino[2,1-b]quinazoline-6-carbonitriles and 4-halobenzo[4,5]-imidazo[1,2-a]quinoline-6-carbonitriles respectively are formed. Keywords: benzimidazolylacetonitrile, 2-(1H-benzo[d]imidazol-2-yl)-3-(2,6-dihalophenyl)acrylonitriles, 4-halobenzo[4,5]imidazo[1,2-a]quinoline-6-carbonitriles, 4-halo-12-oxo-12H-quino[2,1-b]quinazoline-6-carbonitriles, 3-(2,6-dihalophenyl)-2-(4-oxo-3,4-dihydro-2-quinazolinyl)acrylonitriles, 4-oxo-3,4-dihydroquinazolinylacetonitrile. The constant attention to derivatives of 3H-quinazolin-4-one is caused both by the broad spectrum of their biological action [1-5], and by the possibility of structural modification [6,7], particularly the synthesis of new heterocyclic systems based on them. Among the styrylquinazolones, the condensation products of 3H-quinazolin-4-one with aromatic aldehydes, preparations are known possessing anticancer properties [8]. Previously we synthesized a series of 3-aryl- and 3-pyridyl-2-(4-oxo-3,4-dihydro-2quinazolinyl)acrylonitriles [7], among which compounds displaying hemostatic activity appeared [9]. In a continuation of our investigations the condensation has been studied in the present work of 2-(4-oxo-3,4-dihydro-2-quinazolinyl)acetonitriles 1a-e with aromatic 2,6-dihalobenzaldehydes 2a,b and the perfluoroaldehyde 2c. On boiling a mixture of the indicated reactants in dioxane for 2-3 h 3-(2,6-dihalophenyl or pentafluorophenyl)-2-(4-oxo-3,4-dihydro-2-quinazolinyl)acrylonitriles 3a-j are formed. Crystallization of the product began even after 20-30 min. On heating compounds 3a-h in DMF for several hours cyclization products were detected by TLC. These were 4-halo-12-oxo-12H-quino[2,1-b]quinazoline-6-carbonitriles 4a-h, which are formed by intramolecular arylation at a nitrogen atom of the quinazolinone system. Cyclization may be accelerated by the addition of an equimolar quantity of base (triethylamine, pyridine). However its use is undesirable in the condensation of nitriles 1 with aldehydes 2 since the desired products 3 contain contamination by the corresponding cyclization product 4. __________________________________________________________________________________________ Kiev Taras Shevchenko National University, Kiev 01033, Ukraine; e-mail: olgakh@mail.univ.kiev.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1226-1232, August, 2004. Original article submitted November 19, 2002; revision submitted March 16, 2004. 0009-3122/04/4008-10632004 Springer Science+Business Media, Inc. 1063
R4 R1 R2 R3 1ae, 5 A N NH CN OHC R5 R6 R7 2ac
, dioxane R7 R1 R2 R3 3aj, 7a,b , DMF R1

10 11
R6 R5 R4 , DMF excess Et3N
A N
F NH
NC R6 R7 A N CN 4ah, 6ac
1 2 3
R5
4
R4
R1 R2 R3 R7 R6 8
2
A N
N CN
R2
R3
R4 R5
1-4 A = C=O; 5-7 A = bond; 1 a R1 = R2 = R3 = H, b R1 = Me, R2 = R3 = H, c R1 = Br, R = R3 = H, d R2 = Cl, R1 = R3= H, e R1 = R3 = Me, R2 = H; 2 a R4 = F, R5 = R6 = R7= H, b R4 = Cl, R5 = R6 = R7= H, c R4 = R5 = R6 = R7 = F; 3, 4 a-h R5 = R6 = R7= H; a-e R4 = F; a R1 = R2 = R3 = H, b R1 = Me, R2 = R3 = H, c R1 = Br, R2 = R3 = H, d R2 = Cl, R1 = R3 = H, e R1 = R3 = Me, R2 = H; f-h R4 = Cl, f R1 = R2 = R3 = H, g R1 = Br, R2 = R3 = H, h R1 = R3 = Me, R2 = H; 3i,j R4 = R5 = R6 = R7 = F; i R1 = R2 = R3 = H, j R1 = Me, R2 = R3 = H; 5, 6a,b, 7a,b R1 = R2 = R3 = H; a R4 = F, R5 = R6 = R7 = H, b R4 = Cl, R5 = R6 = R7 = H; 6c R1 = R2 = R3 = H, R4 = R5 = R6 = R7 = F
The synthesis of model compounds from benzimidazolylacetonitrile 5 was carried out with the aim of clarifying the direction of arylation (at N(1) or N(3) of the quinazolinone ring). These were 4-halobenzo[4,5]imidazo[1,2-a]quinoline-6-carbonitriles 6a-c through the corresponding 2-(1H-benzo[d]imidazol-2-yl)-3-(2,6-dihalophenyl)acrylonitriles 7a,b. It should be noted that stopping the reaction of nitrile 5 with aldehydes 2 at the stage of forming substituted acrylonitrile 7 is not always successful. Frequently a significant amount of the cyclization product 6 is formed, which dominates when using perfluorobenzaldehyde 2c. The derivatives of both the quinazolinone and of the benzimidazole series 4 and 6 respectively may also be obtained in one step (without isolating condensation products 3 and 7) in DMF in the presence of an excess of triethylamine. All the compounds synthesized 3, 4, 6, and 7 are high-melting crystalline substances suitable for further conversions without previous purification. 1064
TABLE 1. Characteristics of 3-(2,6-Dihalophenyl)-2-(4-oxo-3,4-dihydro-2quinazolinyl)acrylonitriles 3 and 2-(1H-Benzo[d]imidazol-2-yl)-3-(2,6dihalophenyl)acrylonitriles 7

Compound 3a 3b 3c 3d 3e 3f 3g Empirical formula C17H9F2N3O C18H11F2N3O C17H8BrF2N3O C17H8ClF2N3O C19H13F2N3O C17H9ClFN3O C17H8BrClFN3O Found, % Calculated, % N Cl (Br) 13.72 13.59 13.21 13.00 10.97 10.83 12.39 12.23 12.60 12.46 13.07 12.90 10.49 10.38 (20.74) (20.57) 10.43 10.31 10.95 10.88 8.85 8.76 (19.90) (19.75) 10.18 10.02 12.11 11.91
mp, *
Yield, %
198-200 252-253 269-270 241-242 261-262 244-245 258
81 82 84 87 86 85 80
3h 3i 3j 7a 7b
C19H13ClFN3O C17H6F5N3O C18H8F5N3O C16H9F2N3 C16H9ClFN3
11.97 11.88 11.70 11.57 11.27 11.14 15.07 14.94 14.27 14.11
256-257 253-254 261-262 171-172 216-217
84 82 80 65 53
_______ * After recrystallization from dioxane (3, 7b) or n-butanol (7a).
The composition and structure of products 3, 4, 6, and 7 were confirmed (Tables 1-4) by the results of elemental analysis and data of IR and NMR spectra. In the 1H NMR spectra of acrylonitriles 3 and 7 there were signals for the aromatic protons at 7.5-8.2 ppm, a signal for the proton of the CH=CCN fragment at 8.2-8.6, and for the NH group at 12.7-13.4 ppm. Absorption bands were present in the IR spectra of these compounds for the CN group at 2230-2250 and for the C=O group at 1660-1670 cm-1, but in the spectra of compounds 7 there were also bands for the NH group at 3330 cm-1. In the spectra of tetracyclic derivatives 4 and 6 the signals for the aromatic protons were found at 7.5-8.8 ppm. The signal for the NH group was absent, but the signal for the proton of the CH=CCN fragment (in the pyridine ring of these compounds) is displaced by 0.1-0.6 ppm towards low field compared with the signal for the analogous fragment in acrylonitriles 3 and 7. In the IR spectra of compounds 4 and 6 the absorption band for the C=O group is found at 1685-1700 cm-1, and for the CN group at 2240-2250 cm-1. The interaction between the spatially adjacent H-1 and H-11 protons was recorded with the aid of the NOE for compound 6b, and its absence was also shown for the quinazolinone derivatives 4. In the spectra of the latter the signal for the H-1 proton is found at lower field (9.2-9.3 ppm) due to the deshielding influence of the carbonyl group spatially adjacent to it. In the case of compounds 6a,b, in which such a group is absent, the signal of the H-1 proton is found at 8.6-8.9 ppm. The facts presented indicate that the intramolecular arylation of compounds 3 occurs at the N(3) atom. The alternative direction of arylation at the N(1) atom, leading to product 8, does not occur. 1065
1066
TABLE 2. Spectral Characteristics of Compounds 3a-j and 7a,b

-1 Com- IR spectrum, , cm pound 1
NMR spectrum (DMSO-d6), , ppm (coupling constants, J, Hz) HAr 7.71 (1H, m, H-4); 7.37 (2H, br. t, 3J = 8.4, H-3, H-5) 7.64 (1H, m, H-4); 7.24 (2H, br. t, 3J = 8.4, H-3, H-5) 7.65 (1H, m, H-4); 7.24 (2H, br. t, 3J = 8.4, H-3, H-5) 7.66 (1H, m, H-4); 7.25 (2H, br. t, 3J = 8.4, H-3, H-5) 7.64 (1H, m, H-4); 7.24 (2H, br. t, 3J = 8.4, H-3, H-5) 7.63 (1H, m, H-5); 7.56 (1H, br. d, 3J = 8.5, H-3); 7.50 (1H, br. t, 3J = 8.5, H-4) 7.66 (1H, m, H-5); 7.57 (1H, br. d, 3J = 8.4, H-3); 7.51 (1H, br. t, 3J = 8.4, H-4) 7.64 (1H, m, H-5); 7.56 (1H, br. d, 3J = 8.5, H-3); 7.51 (1H, br. t, 3J = 8.5, H-4) 7.64 (3H, m, H-3, H-5) 7.64 (1H, m, H-5); 7.56 (1H, br. d, 3J = 8.5, H-3); 7.51 (1H, br. t, 3J = 8.5, H-4) CHCCN (1H, s) 8.48 8.41 8.44 8.46 8.40 8.52 8.53 8.49 8.44 8.40 8.20 8.26 NH (1H, br. s) 12.89 12.76 13.03 13.00 12.73 12.94 13.12 12.85 12.90 12.81 13.15 13.36
HHet 8.18 (1H, br. d, 3J = 8.4, H-5); 7.90 (1H, br. t, 3J = 8.4, H-7); 7.78 (1H, br. d, 3J = 8.4, H-8); 7.62 (1H, br. t, 3J = 8.4, H-6) 7.96 (1H, br. s, H-5); 7.67 (2H, m, H-7, -8); 2.50 (3H, s, C(6)H3) 8.24 (1H, d, 4J = 2.6, H-5); 7.95 (1H, dd, 3J = 8.4, 4 J = 2.6, H-7); 7.72 (1H, d, 3J = 8.4, H-8) 8.15 (1H, d, 3J = 8.4, H-5); 7.79 (1H, d, 4J = 2.0, H-8); 7.55 (1H, dd, 3J = 8.4, J = 2.0, H-6) 7.78 (1H, s, H-5); 7.50 (1H, s, H-7); 2.60 (3H, s, C(8)H3); 2.47 (3H, s, C(6)H3) 8.17 (1H, br. d, 3J = 7.5, H-5); 7.89 (1H, br. t, 3J = 7.5, H-7); 7.77 (1H, br. d, 3J = 7.5, H-8); 7.66 (1H, br. t, 3J = 7.5, H-6) 8.25 (1H, br. s, H-5); 8.03 (1H, br. d, 3J = 8.4, H-7); 7.72 (1H, d, 3J = 8.4, H-8) 7.81 (1H, s, H-5); 7.59 (1H, s, H-7); 2.56 (3H, s, C(8)H3); 2.44 (3H, s, C(6)H3) 8.17 (1H, br. d, 3J = 8.0, H-5); 7.90 (1H, br. t, 3J = 8.0, H-7); 7.80 (1H, br. d, 3J = 8.0, H-8); 7.63 (1H, br. t, 3J = 8.0, H-6) 7.97 (1H, br. s, H-5); 7.70 (2H, m, H-7, H-8); 2.50 (3H, s, C(6)H3) 7.25 (4, m, H-4, -7) 7.64 (2, m, -4, H-7); 7.31 (2, m, -5, H-6)
3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 7a 7b
1670 1665 1670 1670 1665 1660 1670 1650 1680 1670 3360* 3330*
2240 2230 2240 2240 2230 2230 2240 2230 2240 2240 2250 2250
_______ *Absorption band of NH group.
TABLE 3. Characteristics of Compounds 4a-h and 6a-c

Compound 4a 4b 4c 4d 4e 4f 4g Empirical formula C17H8FN3O C18H10FN3O C17H7BrFN3O C17H7ClFN3O C19H12FN3O C17H8ClN3O C17H7BrClN3O Found, % Calculated, % N Cl (Br) 14.71 14.53 13.98 13.86 11.63 11.41 13.23 12.98 13.38 13.24 13.90 13.74 11.20 10.92 (21.87) (21.70) 11.16 10.95 11.64 11.59 9.33 9.22 (20.81) (20.78) 10.70 10.62 12.93 12.77 mp, (from DMF) 205-206 208-210 288-289 220-222 264-265 229-230 308-309
Yield, %
82 91 87 90 92 90 82
4h 6a 6b 6c
C19H12ClN3O C16H8FN3 C16H8ClN3 C16H5F4N3
12.75 12.59 16.29 16.08 15.28 15.13 13.41 13.33
269-270 299-300 312-313 308-309
85 83 78 75
In the case of compounds 3f-h and 7b interaction at position 2 or 6 of the arylating fragment with a Cl or F leaving group respectively is possible. The 19F NMR spectra of compounds 4f-h and 6b indicate the absence of fluorine. Consequently reaction occurs at position 6. The presence of fluorine was confirmed for difluoro and polyfluoro derivatives by 19F NMR spectra. Signals for fluorine atoms were observed at -42.29 (3a), -32.86 (3b), -33.20 (3g), -32.12 (3h), 16.23 (2F), 2.50 (1F), and -9.20 (2F) (3i), 16.14 (2F), 2.39 (1F), and -9.23 (2F), (3j), -42.86 (4e), -40.07 (6a), -65.06, -66.43, -73.65, and -85.78 ppm (6c).
EXPERIMENTAL A check on the progress of reactions and the purity of the compounds synthesized was carried out by TLC on Silufol UV 254 plates in chloroformmethanol, 9:1. The NMR spectra were measured on a Varian Mercury 400 spectrometer (400 MHz for 1H nuclei and 376 MHz for 19F) in DMSO-d6. Internal standard was TMS (1H NMR) or CFCl3 (19F NMR). The IR spectra were recorded on a Pye-Unicam SP 3-300 instrument. Melting points were measured on a miniature heating stage of the Boetius type with a PHMK 05 observing device (VEB Analytik). The initial compounds 1 were synthesized by the known procedure of [7]. 3-(2,6-Dihalophenyl)-2-(4-oxo-3,4-dihydro-2-quinazolinyl)acrylonitriles (3a-j), 2-(1H-Benzo[d]imidazol-2-yl)-3-(2,6-dihalophenyl)acrylonitriles (7a,b) (General Procedure). A mixture of nitrile 1a-e, 5 (5 mmol) and aldehyde 2a-c (5 mmol) in dioxane (40 ml) was boiled for 2-3 h, checking the progress of the reaction by TLC. The reaction mixture was cooled, the solid products 3a-j, 7a,b filtered off, and washed with alcohol. The filtrate was evaporated, and a further quantity of product obtained.
1067
TABLE 4. Spectral Characteristics of Compounds 4a-h and 6a-c

Compound 4a IR spectrum, , cm-1 = 1700 2250
1
NMR spectrum (DMSO-d6), , ppm (J, Hz)
4b
1700
2250
4c
1700
2250
4d
1705
2250
4e
1700
2250
4f
1690
2240
4g* 4h
1685 1700
2240 2250
6a
2240
6b
2240
6b*
2240
6c
2240
9.21 (1H, br. d, 3J = 8.4, H-1); 8.66 (1H, s, H-5); 8.29 (1H, br. d, 3J = 8.0, H-11); 7.92 (1H, br. t, 3J = 8.0, H-9); 7.80 (1H, m, H-3); 7.78 (1H, br. d, 3J = 8.0, H-8); 7.60 (1H, br. t, 3J = 8.0, H-10); 7.42 (1H, 3J = 8.4, H-2) 9.21 (1H, br. d, 3J = 9.0, H-1); 8.62 (1H, s, H-5); 8.08 (1H, br. s, H-11); 7.79 (1H, m, H-3); 7.74 (1H, br. d, 3J = 8.4, H-9); 7.69 (1H, d, 3J = 8.4, H-8); 7.41 (1H, br. t, 3J = 9.0, H-2) 9.19 (1H, br. d, 3J = 8.6, H-1); 8.88 (1H, s, H-5); 8.38 (1H, br. s, H-11); 8.08 (1H, br. d, 3J = 8.4, H-9); 7.78 (1H, m, H-3); 7.75 (1H, d, 3J = 8.4, H-8); 7.56 (1H, br. t, 3J = 8.6, H-2) 9.20 (1H, br. d, 3J = 8.8, H-1); 8.88 (1H, s, H-5); 8.28 (1H, d, 3 J = 8.4, H-11); 7.87 (1H, m, H-3); 7.84 (1H, br. s, H-8); 7.66 (1H, br. d, 3J = 8.4, H-10); 7.55 (1H, br. t, 3J = 8.8, H-2) 9.27 (1H, br. d, 3J = 8.8, H-1); 8.59 (1H, s, H-5); 7.89 (1H, s, H-11); 7.80 (1H, m, H-3); 7.57 (1H, s, H-9) 7.41 (1H, br. t, 3J = 8.8, H-2); 2.62 (3H, s, 8-CH3); 2.48 (3H, s, C(10)H3) 9.28 (1H, br. d, 3J = 7.6, H-1); 8.84 (1H, s, H-5); 8.33 (1H, br. d, 3J = 7.6, H-11); 7.98 (1H, br. t, 3J = 7.6, H-9); 7.82 (3H, m, H-2, H-3, H-8); 7.66 (1H, br. t, 3J = 7.6, H-10) 9.34 (1H, br. d, 3J = 7.6, H-1); 9.66 (1H, s, H-5); 8.75 (1H, br. s, H-11); 8.08-8.28 (4H, m, H-2, H-3, H-8, H-9) 9.25 (1H, br. d, 3J = 7.6, H-1); 8.61 (1H, s, H-5); 7.74 (1H, s, H-11); 7.74 (2H, m, H-3, H-2); 7.55 (1H, s, H-9); 2.53 (3H, s, C(8)H3); 2.39 (3H, s, C(10)H3) 8.72 (1H, s, H-5); 8.61 (1H, m, H-1); 8.57 (1H, m, H-11); 7.98 (1H, m, H-8); 7.98 (1H, m, H-3); 7.58 (2H, m, H-9, H-10); 7.47 (1H, br. t, 3J = 7.6, H-2) 8.91 (1H, s, H-5); 8.90 (1H, br. d, 3J = 8.0, H-1); 8.80 (1H, br. d, 3J = 8.0, H-11); 8.07 (1H, br. d, 3J =8.0, H-3); 8.00 (1H, br. t, 3J = 8.0, H-2); 7.85 (1H, br. d, 3J = 8.0, H-8); 7.65 (2H, m, H-9, H-10) 9.62 (1H, s, H-5); 9.10 (1H, br. d, 3J = 8.0, H-1); 8.87 (1H, br. d, 3 J = 8.0, H-11); 8.37 (1H, br. t, 3J = 8.0, H-2); 8.20 (1H, br. d, 3 J = 8.0, H-3); 8.16 (1H, br. d, 3J = 8.0, H-8); 8.08 (2H, m, H-9, H-10) 8.96 (1H, s, H-5); 8.34 (1H, m, H-11); 8.04 (1H, br. d, 3J = 8.0, H-8); 7.61 (2H, m, H-9, H-10)
_______ * The 1H NMR spectrum was recorded in CF3CO2D.
4-Halo-12-oxo-12H-quino[2,1-b]quinazolinecarbonitriles (4a-h), 4-Halobenzo[4,5]imidazo[1,2-a]quinoline-6-carbonitriles (6a,b) (General Procedure). A solution of compound 3a-h or 7a,b (5 mmol) in DMF (30 ml) was boiled for 5-8 h or for 2-4 h with the addition of triethylamine (5 mmol). After cooling, the solid products 4a-h or 6a,b were filtered off, washed with alcohol, and with water. A small amount of product may be isolated after evaporating the filtrate. 1,2,3,4-Tetrafluorobenzo[4,5]imidazo[1,2-a]quinoline-6-carbonitrile (6c). Triethylamine (10 mmol) was added to a suspension of nitrile 5 (5 mmol) and compound 2c (5 mmol) in DMF (20 ml), and the mixture obtained was boiled for 2-3 h. After cooling, the solid was filtered off, washed with alcohol, with water, and product 6c was obtained. After evaporating the filtrate an additional small quantity of product 6c was obtained and was crystallized from DMF.
1068
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. I. K. Kacker and S. H. Zaheer, J. Indian Chem. Soc., 28, 344 (1951). S. Kobayashi, M. Veno, R. Suzuki, H. Ishitani, H.-S. Kim, and Y. Nataya, J. Org. Chem., 64, 6833 (1999). M. Ishizaki and S. Osada, Jpn. Pat. 06128213; Chem. Abstr., 121, 205215 (1994). M. Ishizaki and S. Osada, Jpn. Pat. 05339224; Chem. Abstr., 122, 31556 (1995). M. Ishizaki, S. Nagata, and T. Kobutani, Eur. Patent 506373; Chem. Abstr., 119, 225824 (1993). J. Fleischer, K. Takacs, and I. Hermecz, J. Heterocycl. Chem., 34, 1251 (1997). Yu. M. Volovenko, O. V. Khilya, T. A. Volovnenko, and T. V. Shokol, Khim. Geterotsikl. Soedin., 350 (2002). J. B. Jiang, D. P. Hesson, B. A. Dusak, D. L. Dexter, G. J. Kang, and E. Hamel, J. Med. Chem., 33, 1721 (1990). Yu. M. Volovenko, O. V. Khilya, and T. A. Volovnenko, in: New Technologies for Obtaining and Applying Biologically Active Substances. Abstracts. International Practical Science Conference, KNTs, Alushta, Krym, Simferopol (2002), p. 15.
1069
INTERACTION OF CYCLIC SCHIFF'S BASES WITH 2-METHYLTHIOPYRIMIDINE-4,6-DIONE ENOL ACETATE. SYNTHESIS OF 5-(2-ACETYL6,7-DIMETHOXY-1,2,3,4-TETRAHYDRO1-ISOQUINOLYL)-6-HYDROXY-2-METHYLTHIO1,4-DIHYDRO-4-PYRIMIDINONES
O. V. Gulyakevich1, K. A. Krasnov2, A. L. Mikhal'chuk1, and A. A. Akhrem1 5-(2-Acetyl-1,2,3,4-tetrahydro-1-isoquinolyl)-6-hydroxy-2-methylthio-1,4-dihydro-4-pyrimidinones have been obtained by the interaction of 3,4-dihydroisoquinolines with 2-methylthio-4-oxo-1,4-dihydro-6pyrimidinyl acetate. It was shown that N,O-methyl derivatives are formed in interaction of the obtained products with diazomethane. Keywords: 3,4-dihydroisoquinolines, pyrimidine-4,6-dione enol acetates, 5-(1-isoquinolyl)pyrimidines, condensation reaction. The derivatives of isoquinoline and pyrimidine are two groups of natural and synthetic regulators of many important processes of the active life of simple and higher organisms [1,2]. Isoquinolines are most widely represented in the plant world by the extremely vast group of isoquinoline alkaloids, the biological functions of which still have not been adequately clarified [3]. Pyrimidines, such as barbituric acid and its derivatives, respond to the transmission of signals along nerve channels and participate in the receptor system of -aminobutyric acid functioning in nerve cells, they display hypotensive, antiatherosclerotic and other important forms of physiological activity [4]. It therefore seemed of interest to develop approaches to the synthesis and study of the properties of compounds combining isoquinoline and pyrimidine fragments in their structure. Only a few examples of constructing such systems have been described in the literature, in particular derivatives of pyrimido[5',4':5,6]pyrido[2,1-a]isoquinoline or 8,15,17-triaza-D-homogonane 1 [5].
O O N R R 1
1
R R1 R O O R1 2 R2 NCOR .
3
N R2
OH
.. .
__________________________________________________________________________________________ Institute of Bioorganic Chemistry, National Academy of Sciences (NAN) of Belarus, Minsk 220141; e-mail: mikchalch@imaph.bas-net.by. 2 Saint-Petersburg I. I. Mechnikov State Medical Academy, SaintPetersburg 195067, Russia; e-mail: veselkoff@mail.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1233-1240, August, 2004. Original article submitted January 10, 2002; revision submitted November 1, 2002. 1070 0009-3122/04/4008-10702004 Springer Science+Business Media, Inc.
It is known [6,7] that on interacting 3,4-dihydroisoquinolines with enol acylates of aliphatic and alicyclic -dicarbonyl compounds N-acyl-1-isoquinolyl derivatives of the corresponding -dicarbonyl compounds (see 2) are formed. These are of theoretical and practical interest, particularly as potential biologically active compounds. The possibility has been shown in the present work of extending this reaction to heterocyclic dicarbonyl compounds, to derivatives of 4,6-dihydroxypyrimidine, with the aim of obtaining products with isoquinoline and pyrimidine fragments in their molecules. Scheme 1
H O H N N S Me A O O 4 Me O N S N Me O O Me O N S B N Me O H O Me
4C
R R H
N 3a,b
R R
5 4 1 8 3 2
R NCOMe OH
5 4 1 8 3 2 NCOMe
R R O H N S Me 5C N Me NCOMe OH H
HO
H
3' N 1' 2' N
O H
H
3' N 1' 2 ' N
OH
S 5A
Me 5a,b 3, 5 a R = H, b R = OMe 5B
The condensation of 3,4-dihydroisoquinolines 3a,b with enol acetate 4 was effected by boiling an equimolar mixture of reactants in ethyl alcohol until their disappearance from the reaction mixture (by TLC). Products for which structures 5a and 5b are proposed were obtained from the reaction in high yield (72-78%). It is important to note that the initial compound 4 is in reality a mixture of tautomers, 2-methylthio-6oxo-1,6-dihydro-4-pyrimidinyl acetate 4A and 6-hydroxy-2-methylthio-4-pyrimidinyl acetate 4B. Theoretically it is possible to suggest also the formation of the tautomeric 2-methylthio-4-oxo-1,4-dihydro-6-pyrimidinyl acetate 4C. However the results of quantum-chemical analysis, particularly H0 values of -78.718 for tautomer 4A, -77.047 for tautomer 4B, and -66.383 kcal/mol for tautomer 4C, indicate that tautomers 4A,B are thermodynamically more preferred. According to quantum-chemical analysis the most preferred derivatives of 4 are the conformers represented in Scheme 1 with the acetoxy group unfolded by ~30 relative to the plane of the pyrimidine ring. In the IR spectrum of enol acetate 4 (the characteristics of all the compounds synthesized are given in Experimental) a characteristic set of absorption bands (AB) is present in the region of the stretching vibrations of the CH, NH, C=O, C=N, and C=C bonds [8,9]. 1071
In the UV spectrum of compound 4 there are two AB in the 200-260 nm region, one as a shoulder on the long-wave slope of the very intense AB with a maximum located at 200 nm, and a broad AB at ~285 nm. Differentiation of the spectral contour enabled refinement of the position of the two primary AB located at 223.6 and 243.3 nm and showed that the long-wave AB is the result of the overlap of three AB with maxima at 274.4, 285, and 299.1 nm. The 1H and 13C NMR spectra of enol acetate 4 (see Experimental) also confirm the structure assigned to it. It should be noted particularly that the formation of no intermediate product was recorded by TLC in this reaction, either on boiling or at room temperature. This observation indicates that the process occurs by a coordinated mechanism through the six-membered transition state (TS) and product 6 and not as sequential Michael CC addition and ON isomerization of the acetyl group of adduct 6 into the desired compound 5. On the other hand, the absence of products of replacement of the acetyl fragment by an appropriate residue of homologous acid on carrying out the reaction in the presence of homologous acids, indicates the intramolecular mechanism for the ON migration of the acyl residue. This also indicates a preference for the mechanism represented in Scheme 2, since in precisely the six-membered transition state (TS) the optimum geometric and steric conditions of forming bonds and redistributing electrons are achieved. Scheme 2
R 3a,b R N. . O H N S TS a R = H, b R = OMe N Me 6a,b O O NCOMe O H N S Me N O H 5a,b
+4
The composition and structure of products 5a,b are confirmed by data of elemental analysis and physicochemical investigations. Specific features of their IR spectra are the broad AB at 2200-3100 cm-1 caused by the vibrations of the NH and OH groups of tautomers 5A and 5B and the absorption of the carbonyl groups characteristic of amides at 1640-1670 cm-1 [8]. The presence of bands assigned to the vibrations of the NH+ group in the spectra at 790-980 cm-1 [8, 9], is also notable. This may be caused by the significant contribution of betaine structures to the resulting mesomeric state. In the electronic absorption spectra of compounds 5a,b approximately three intense broadened and asymmetric AB are observed, and for the dimethoxy-substituted 5b these AB are displaced towards the short-wave region of the spectrum. Differential analysis of the spectral contours showed that the AB observed at 220-240 and ~280 nm are composite and are caused by contributions of bands located at 212.3, 230.8, 259.1, 276.8, and 309.8 nm for compound 5a and 205, 230.4, 267.5, 285, and 311.6 nm for compound 5b. Investigation of compounds 5a,b by NMR spectroscopy has shown that it is possible to observe the development of their tautomers depending on the solvent and temperature used. In the 1H NMR spectra of compounds 5a,b in CDCl3 there was only one set of signals of resonance absorption while in the spectra of DMSO-d6 solutions the signals of separate groups of protons were as a rule duplicated, corresponding to the existence of tautomerism. An analogous picture was also observed for the 13C NMR spectra.
1072
Signals for all the protons of the structures proposed were present in the 1H NMR spectra of compounds 5a,b. A noteworthy special feature of the spectra of compounds in CDCl3 is the fact that the signals of the NH and OH groups are displayed as a two-proton broadened singlet at 12.50-13.00 ppm. This indicates the existence of rapid proton exchange. On reducing the temperature to -20C, and then to -50 and -70C a broadening of this singlet is observed, which is then split, at the minimum, into three broadened signals located at ~15, ~12, and ~10 ppm with different integral intensity and variable position, depending on the temperature. These data correlate with the results of theoretical 1H NMR spectra for tautomers 5A and 5B of compound 5a, assuming the disposition of proton signals for the NH and OH groups at 11 (NH), 12 (OH), and 16 ppm (OH), and as a result confirm the tautomeric multicenter character of compounds 5a,b. It should be noted that together with tautomers 5A and 5B, as in the case of enol acetate 4, it is theoretically possible to assume the existence of tautomer 5C as well. However, judging by the heat of formation (H0) of the indicated tautomers of -41.249 (5A), -39.702 (5B), and -30.781 kcal/mole (5C) it is possible to assert that tautomers 5A and 5B are the most populated. Optimization of the geometry of molecules 5a,b shows that the pyridine ring of the isoquinoline fragment has a boat conformation and the pyrimidine fragment is almost perpendicular (100-105) to the plane of benzene ring of the isoquinoline fragment, and its plane is unfolded to the latter. These data correlate satisfactorily with the results of X-ray structural analysis of cycloalkanedione analogs of compounds 5a,b [10]. In the 13C NMR spectrum (DMSO-d6) of dimethoxy-substituted compound 5b, associated signals were observed for a part of the signals, which, on the strength of that mentioned above, may be explained by the presence of two tautomers 5A and 5B in solution and also by the low (relative to the NMR time scale) rate of their interconversion. Signals which might have been assigned to tautomer 5C were not observed either in the 1H NMR spectra or in the 13C NMR spectra. Scheme 3
S CH2N2 MeO N Me Me N OMe NAc 7 S N O Me S N H OMe NAc H O N Me N OMe NAc 9 11 10 O N 8 S Me N Me OMe NAc 5a N S Me N OMe NAc
Further evidence in favor of the structure assigned to compounds 5a,b was obtained on methylation of the first of them with diazomethane in methanol, as a result of which a mixture of two regiomerically methylated products was obtained. These were isolated in the individual state and characterized. The products were assigned the structures of the O,O- and N,O-dimethyl derivatives 7 and 8 respectively, their ratio in the 1073
mixture was 2:3 (according to 1H NMR spectral data). Strictly speaking, as a result of the interaction with diazomethane, which proceeds analogously to the methylation of barbiturates and pyrimidines studied previously [12], the product of N,O-methylation 9 might theoretically also be formed. The absence of the latter is caused by the thermodynamic unprofitability of N-N proton isomerization of the ortho-quinoid derivative 10, formed as an intermediate, into the para-quinoid derivative 11. Such an explanation is in good agreement with the data of quantum-chemical calculations showing that compounds 7 (H0 -41.249 kcal/mol) and 8 (H0 -39 702 kcal/mol) are energetically preferred to the compound 9 (H0 -30.781 kcal/mol). The studied interaction of dihydroisoquinolines 3a,b with the enol acetate of pyrimidine derivative 4 opens approaches to the synthesis of heterocyclic products combining in their structures the pharmacophoric fragments of tetrahydroisoquinoline and heterocyclic -dicarbonyl compounds.
EXPERIMENTAL The IR spectra were obtained on a Protege 460 instrument (KBr disks), and the UV spectra on a Specord M 400 spectrophotometer (in ethanol). The 1H and 13C NMR spectra were recorded on Bruker AC 200 (200 MHz for 1H and 50 MHz for 13C nuclei) and Bruker AM 500 (500 MHz for 1H and 200 MHz for 13C nuclei) radiospectrometers, internal standard was TMS. Mass spectra were obtained on a HP 5972 MS mass spectrometer, energy of ionizing electrons was 70 eV. Melting points were determined on a Boetius heating block. A check on the progress of reactions and the purity of products 4, 5a,b, 7, and 8 was effected by TLC on Silufol UV 254 plates or silica gel 60 F254 Merck. Eluents were chloroformmethanol, 9:1 (5a,b); chloroform ethyl acetate, 3:1 (7, 8); 2-propanolwater, 4:1 (4). The quantum-chemical calculations were carried out by the AM-1 method within the framework of the program set HyperChem 6.01 (Hypercub Inc., info@hyper.com). 3,4-Dihydroisoquinolines 3a,b were obtained under the conditions of the BischlerNapieralski reaction for the cyclodehydration of the appropriate formamides by the action of polyphosphoric acid (PFK) for compound 3a or phosphorus oxychloride for compound 3b [11]. 2-Methylthio-6-oxo-1,6-dihydro-4-pyrimidinyl Acetate (4). 2-Methylthio-4,6-dihydroxypyrimidine [13] (15.8 g, 0.1 mol) was added to solution of Na2CO3 (10.6 g, 0.1 mol) in water (150 ml), and the mixture was stirred at 40C until complete solution. Acetic anhydride (15.5 g, 0.15 mol) was added in small portions to the obtained solution during 5 min with vigorous stirring at 20C. After the end of CO2 evolution the reaction mixture was stirred for 30 min and maintained at 15C for 4 h. The precipitated solid was filtered off, washed with water, and recrystallized from alcohol. Enol acetate 4 (10.6 g, 53%) was obtained as white finely prismatic crystals of mp 223C. IR spectrum, , cm-1: 3140, 3100, 3020, 2945, 2800-2890, 2730-2780, 2690, 1787, 1670, 1583, 1565, 1479, 1390, 1378, 1250, 1221, 1178, 1031, 991, 932, 894, 841, 760. UV spectrum, max, nm (): 220.3 (14335), 240 (12630), 283.6 (14230); min, nm (): 213.6 (13505), 235 (12170), 256.2 (6560). 1H NMR spectrum (DMSO-d6), , ppm: 2.26 (3H, s, CH3C=O); 2.45 (3H, s, CH3S); 5.92 (1H, s, H-5); 13.04 (1H, br. s, NH). 13C NMR spectrum (DMSO-d6), , ppm: 13.44 (CH3S); 21.42 (CH3C=O); 97.79 (C(5)); 164.05 (C(2)); 166.24 (C(4) + C(6)); 168.85 (OC=O). Found, %: C 41.87; H 3.98; N 13.85; S 15.94; [M]+ 200. C7H8N2O3S. Calculated, %: C 41.99; H 4.03; N 13.99; S 16.01. M 200.21. rac-5-(2-Acetyl-1,2,3,4-tetrahydro-1-isoquinolyl)-4-hydroxy-2-methylthio-1,6-dihydro-6-pyrimidinone (5a). Mixture of compound 3a (0.66 g, 5 mmol) and enol acetate 4 (1 g, 5 mmol) in ethyl alcohol (20 ml) was boiled for 3 h, then evaporated to 2/3 of initial volume and maintained at +5C for ~16 h. The precipitated solid was filtered off, washed on the filter with ether, and recrystallized from alcoholether, 1:3. Product 5a (1.13 g, 72.2%) was obtained as light cream prismatic crystals of mp 245-247C. IR spectrum, , cm-1: 2200-3050, 1636, 1600, 1584, 1550, 1480, 1445, 1430, 1388, 1322, 1280, 1221, 970, 925, 813, 796, 763, 750. UV spectrum, max, nm (log ): 208 (4.37), 242.4 (3.83), 284.3 (4.03); min, nm (log ): 236.6 (3.82), 256.4 (3.65). 1H NMR spectrum (CDCl3), , ppm (J, Hz): 2.18 (3H, s, COCH3); 2.45 (3H, s, SCH3); 2.92 (1H, dd, Ja,e gem = 12.0,
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Ja,a vic = 5.0, Ja,e vic = 5.0, Ha-4); 3.03 (1H, ddd, Je,a gem = 12.0, Je,a vic = 5.0, Je,e vic = 12.0, He-4); 3.88 (1H, dd, Ja,e gem = 14.0, Ja,a vic = 5.0, Ja,e vic = 5.0, Ha3); 4.18 (1H, ddd, Je,a gem = 15.0, Je,e vic = 12.0, Je,a vic = 5.0, He-3); 6.18 (1H, s, H-1); 6.90-6.99 (1H, m, H-6); 7.04 (3H, m, H-5, H-7, H-8); 12.50 (2H, br. s, OH, NH). 1H NMR spectrum (DMSO-d6), , ppm: 2.11 and 2.12 (3H, two s, COCH3); 2.48 (3H, s, SCH3); 2.78 (1H, m, Ha-4); 2.96 (1H, m, He-4); 3.60 and 4.14 (1H, two m, Ha-3); 3.96 and 4.61 (1H, two m, He-3); 6.09 and 6.17 (1H, two s, H-1); 6.99-7.10 (4H, m, HAr); 11.90 (2H, br. s, NH, OH). Found, %: C 57.90; H 5.11; N 12.54; S 9.76. [M]+ 331. C16H17N3O3S. Calculated, %: C 57.99; H 5.17; N 12.68; S 9.67. M 331.40. rac-5-(2-Acetyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolyl)-4-hydroxy-2-methylthio-1,6-dihydro6-pyrimidinone (5b). Mixture of compound 3b (0.96 g, 5 mmol) and enol acetate 4 (1 g, 5 mmol) in ethyl alcohol (30 ml) was boiled for 3 h. The crystals precipitated after cooling were filtered off, washed on the filter with ether, and recrystallized from chloroformetherhexane, 1:1:2. Product 5b (1.53 g, 78.1%) was obtained as pale yellow prismatic crystals of mp 251-252C. IR spectrum, , cm-1: 2830-3100, 2500-2800, 1670, 1640, 1607, 1583, 1554, 1525, 1460-1485, 1339, 1264, 1226, 1215, 1200, 1130, 865, 795. UV spectrum, max, nm (log ): 204.6 (4.74), 224 (4.20), 281.2 (4.07); min, nm, (log ): 253.9 (3.62). 1H NMR spectrum (CDCl3), , ppm (J, Hz): 2.20 (3H, s, COCH3); 2.52 (3H, s, SCH3); 2.86 (1H, dd, Ja,e gem = 12.0, Ja,a vic = 5.0, Ja,e vic = 5.0, Ha-4); 2.98 (1H, ddd, Je,a gem = 12.0, Je,a vic = 5.0, Je,e vic = 12.0, He-4); 3.76 (3H, s, OCH3); 3.85 (3H, s, OCH3); 3.88 (1H, dd, Ja,e gem = 15.0, Ja,a vic = 5.0, Ja,e vic = 5.0, Ha-3); 4.17 (1H, ddd, Je,a gem = 15.0, Je,e vic = 12.0, Je,a vic = 5.0, He-3); 6.16 (1H, s, H-1); 6.42 (1H, s, H-5); 6.60 (1H, s, H-8); 12.80 (2H, br. s, OH, NH). 1H NMR spectrum (DMSO-d6), , ppm: 2.06 and 2.08 (3H, two s, COCH3); 2.47 (3H, s, SCH3); 2.60-2.80 (2H, m, 2H-4); 3.54 and 4.02 (1H, m, Ha-3); 3.58 (3H, s, OCH3); 3.72 (3H, s, OCH3'); 3.86 and 4.52 (1H, two m, He-3); 6.00 and 6.18 (1H, two s, H-1); 6.46 and 6.51 (1H, two s, H-5); 6.70 and 6.71 (1H, two s, H-8); 11.95 (2H, br. s, NH, OH). 13 C NMR spectrum (DMSO-d6), , ppm: 13.01 (SCH3); 22.03 and 22.26 (CH3C=O); 28.39 and 29.97 (C(4)); 37.95 and 43.02 (C(3)); 48.81 and 50.74 (C(1)); 55.95 (CH3O); 56.18 (CH3O); 101.24 and 101.37 (C(5')); 110.39 (C(5)); 112.55 (C(8)); 127.01 and 128.03 (C(8a)); 128.37 (C(4a)); 147.91, 148.14 (C(6), C(7)); 161.15 (CH3C=O); 165.40 (C(4'), C(6')); 170.02 and 170.15 (C(2')). Found, %: C 55.19; H 5.37; N 10.69; S 8.27; [M]+ 391. C18H21N3O5S. Calculated, %: C 55.23; H 5.41; N 10.73; S 8.29. M 391.44. Methylation of the mixture of tautomers of compound 5a, 1-[1-(4,6-dihydroxy-2-methylthio-5pyrimidinyl)-1,2,3,4-tetrahydro-2-isoquinolyl]-1-ethanone (5A) and (2-acetyl-1,2,3,4-tetrahydro-1isoquinolyl)-4-hydroxy-2-methylthio-1,6-dihydro-6-pyrimidinone (5B). Gaseous diazomethane, obtained from hydrazine hydrate, chloroform, and potassium hydroxide by the method of [14], was passed into suspension of compound 5a (0.5 g) in absolute methanol (20 ml) at 10C. After forming a solution with a stable yellow color, the mixture was left for 1 h, brought to room temperature, and then water (7 ml) was added. The precipitate formed was separated and twice recrystallized from heptane. 1-[1-(4,6-Dimethoxy-2-methylthio-5pyrimidinyl)-1,2,3,4-tetrahydro-2-isoquinolyl]-1-ethanone (7) (0.009 g, 1.7%) was obtained as white needlelike crystals of mp 97-98C. Rf 0.45. 1H NMR spectrum (CDCl3), , ppm: 2.12 and 2.13 (3H, two s, COCH3); 2.51 and 2.53 (3H, two s, SCH3); 2.85-3.05 (2H, m, H-4); 3.61 and 4.00 (1H, two m, Ha-3); 3.90 and 3.92 (6H, two s, OCH3, OCH3'); 3.94 and 4.37 (1H, two m, He-9); 6.24 and 6.59 (1H two s, H-1); 6.77-7.16 (4H, m, HAr). The aqueous methanol mother liquor was diluted with water to 60 ml, the precipitated solid was separated and recrystallized from CCl4. 5-(2-Acetyl-1,2,3,4-tetrahydro-1-isoquinolyl)-1-methyl-4-methoxy-2-methylthio-1,6-dihydro-6-pyrimidinone (8) (0.007 g, 1.3%) was obtained as white needle-like crystals of mp 143-144C. Rf 0.25. 1H NMR spectrum (DMSO-d6), , ppm: 2.22 and 2.27 (3H, two s, COCH3); 2.59 (3H, s, SCH3); 2.82-3.04 (2H, m, 2H-4); 3.51 and 3.98 (1H, two m, Ha-3); 3.84 and 4.09 (3H, two s, OCH3, OCH3'); 4.08 and 4.79 (1H, two m, He-3); 6.38 and 6.50 (1H, two m, H-1); 6.81-7.16 (4H, m, HAr).
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REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. R. H. F. Manske and H. L. Holmes (editors), The Alkaloids. Chemistry and Physiology, Vol. 4, Academic Press, New York (1954), p. 357. M. D. Mashkovskii, Drugs, Vol. 1, Torsing, Kharkov (1997), p. 560. T. A. Henry, The Plant Alkaloids, 3rd Edit., Blakiston, Philadelphia (1939), 689 pp. P. V. Sergeev and N. L. Shimanovskii, Receptors of Physiologically Active Substances [in Russian], Meditsina, Moscow (1987), p. 213. A. L. Mikhal'chuk, O. V. Gulyakevich, K. A. Krasnov, V. I. Slesarev, and A. A. Akhrem, Zh. Org. Khim., 29, 1236 (1993). A. A. Akhrem and Yu. G. Chernov, Dokl. Akad. Nauk SSSR, 298, 616 (1988). A. A. Akhrem, E. V. Borisov, and Yu. G. Chernov, Zh. Org. Khim., 26, 1114 (1990). A. Smith, Applied IR Spectroscopy [Russian translation], Mir, Moscow (1982), p. 328. L. J. Bellamy, The Infra-Red Spectra of Complex Molecules, Methuen, London, Wiley, New York (1957), 425 pp. E. V. Borisov, Yu. G. Chernov, L. G. Kuz'mina, V. A. Tereshko, and A. A. Akhrem, Izv. Akad. Nauk, Ser. Khim., 107 (1995). V. M. Whaley and T. R. Govindachari, in Organic Reactions, Vol. 6, Wiley, New York (1951), p. 151. K. A. Krasnov, V. I. Slesarev, A. P. Zakharov, and E. G. Grigor'eva, Khim. Geterotsikl. Soedin., 1523 (1987). G. D. Davies. R. K. Robins, and C. C. Cheng, J. Am Chem. Soc., 84, 1724 (1962). B. Staudinger and O. Kupfer, Ber., 45, 294 (1912).
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STUDY OF THE PRODUCTS OF IODOCYCLIZATION OF 4-ALLYL5-PHENYL-1,2,4-TRIAZOLE-3-THIONE

V. I. Shmygarev and D. G. Kim The interaction of 4-allyl-5-phenyl-1,2,4-triazole-3-thione with iodine proceeds with the formation of a mixture of 6-iodomethyl-3-phenyl-5,6-dihydrothiazolo[2,3-c]-1,2,4-triazole and 6-iodo-3-phenyl-6,7dihydro-5H-1,2,4-triazolo[3,4-b]-1,3-thiazine. The structures of the cyclization products obtained were established on the basis of the 1H NMR spectra of their dehydroiodinated derivatives. 6-Methyl-3phenylthiazolo[2,3-c]-1,2,4-triazole, 3-phenyl-5H-1,2,4-triazolo[3,4-b]-1,3-thiazine, and 3-phenyl-7H1,2,4-triazolo[3,4-b]-1,3-thiazine are formed on eliminating HI from the cyclization products. Keywords: 4-allyl-5-phenyl-1,2,4-triazole-3-thione, 6-iodomethyl-3-phenyl-5,6-dihydrothiazolo[2,3-c]1,2,4-triazole, 6-iodo-3-phenyl-6,7-dihydro-5H-1,2,4-triazolo[3,4-b]-1,3-thiazine, 6-methyl-3-phenylthiazolo[2,3-c]-1,2.4-triazole, 3-phenyl-5H-1,2,4-triazolo[3,4-b]-1,3-thiazine, 3-phenyl-7H-1,2,4triazolo[3,4-b]-1,3-thiazine, iodocyclization. The interaction of 4-alkenyl derivatives of 1,2,4-triazole-3-thiones and analogous systems of the pyrimidine series with electrophilic reagents leads to the 5-endo products of cyclization containing a fivemembered ring [1-6]. In the opinion of the authors of [1] the reaction of 4-allyl-5-phenyl-1,2,4-triazole-3-thione (1) with iodine in ethanol leads to the formation of the hydroiodide of 6-iodomethyl-3-phenyl-5,6-dihydrothiazolo[2,3-c]-1,2,4-triazole (2) (Scheme 1). We have investigated the interaction of thione 1 with iodine in CH2Cl2 at room temperature. In difference to the data of [1] it has been established that iodocyclization leads to a mixture of products, compound 2 and 6-iodo-3-phenyl-6,7-dihydro-5H-1,2,4-triazolo[3,4-b]-1,3-thiazine (3), which were isolated by treating the reaction mixture containing an excess of iodine with a solution of Na2S2O3 and Na2CO3. Compounds 2 and 3 may also be isolated as the hydroiodides by treating the reaction mixture with sodium iodide in acetone. The thiazole compound 2 has melting point 156C and thiazine 3 194C. The ratio of isomers 2 and 3 was 4:1. The 1H NMR spectra of cyclization products 2 and 3 have been studied (Table 1). Both products have, in addition to the signals of the aromatic ring protons, three further groups of signals. These are a multiplet at low field for the H-6 proton, multiplets for the protons of the CH2I and NCH2 groups in thiazole 2, and multiplets for the protons of the SCH2 and NCH2 groups in thiazine 3. The signals lying at lower field in both
__________________________________________________________________________________________ Chelyabinsk State University, Chemical Faculty, Chelyabinsk 454021, Russia; e-mail: bobas@csu.ru, kim@csu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1241-1245, August, 2004. Original article submitted November 20, 2001. 0009-3122/04/4008-10772004 Springer Science+Business Media, Inc. 1077
Scheme 1
O NHNH2 1. 2. NaOH NCS Ph H N N N S 1. I2 2. Na2S2O3, Na2CO3 or NaI, NaHCO3
1
1 N N
3 7a 2 1
N S7
6
N
8a
Ph
N 4
5
+
I
Ph
4N 5 6
S8
7
2 KOH, MeOH N N Ph N 4 S Me Ph N N N S
I KOH, MeOH
N N Ph N S
N N
Ph
N 5b
5a
compounds may be assigned to the NCH2 groups, and the signals at higher field correspond to the protons of the CH2I group in compound 2 and the SCH2 group in compound 3. The values of the chemical shifts and coupling constants were found by the known rules for higher order spectra [7].
HX I HA HA HX I HA HX HB
HB
HB
2a
2b
2c
The coupling constants observed 3JAX = 4.4 and 3JBX = 10.8 Hz for the iodomethyl group protons in thiazole 2 indicate the large contribution of structures 2a and 2b to the conformational equilibrium. Quantumchemical calculations of the heats of formation by the PM3 semiempirical method showed the higher stability of conformers 2a and 2b in comparison with conformer 2c by 26.0 and 14.3 kJ/mol respectively. The values found for the coupling constants in thiazine 3 indicate the more significant contribution of the structure with a pseudoaxial disposition of the iodine atom to the conformational equilibrium. According to the calculations by the PM3 method, the conformer with a pseudoaxial disposition of iodine atom is 126.0 kJ/mol more stable than the conformer with a pseudoequatorial disposition. To confirm the structures of compounds 2 and 3 the 1H NMR spectra of their dehydroiodinated derivatives, formed by treating isomers 2 and 3 with a methanolic solution of potassium hydroxide, were investigated.
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TABLE 1. 1H NMR Spectral Characteristics of 4-Allyl-5-phenyl-1,2,4triazolo-3-thione and Its Cyclic Derivatives

Compound 1 2
3 3
Chemical shifts (CDCl3), , ppm (J, Hz) 12.5 (1H, s, NH); 7.4-7.7 (5H, m, 65); 5.99 (1H, m, CH2CH=CH2); 5.30 (1H, dt, Jcis = 10.2, CH2CH=CHH); 5.08 (1H, dt, 3Jtrans = 17.2, CH2CH=CHH); 4.73 (2H, dt, J = 5.0, 4J = 1.7, CH2CH=CH2) 7.4-7.6 (3H, m, 65); 7.7-7.8 (2H, m, 65); 4.74 (1, m, SCHCH2N); 4.48* (1, 3 JMX = 6.4, 2JMN = 11.2, NCHHM); 4.42* (1, 3JNX = 4.0, 2JNM = 11.2, NCHNH); 3.64* (1H, 3JAX = 4.4, 2JAB = 10.5, CHHAI); 3.51* (1, 3JBX = 10.8, 2JAB = 10.5, CHHBI) 7.57.6 (5H, m, 65); 4.92 (1, m, CH2CHICH2); 4.55* (1, 3JMX = 3.7, 2JMN = 13.0, NCHHM); 4.45* (1, 3JNX = 8.3, 2JNM = 13.0, NCHNH); 3.61* (1H, 3JAX = 2.2, 2 JAB = 12.9, SCHHA); 3.59* (1, 3JBX = 8.3, 2JAB = 12.9, SCHHB) 7.81-7.89 (2H, m, 65); 7.477.59 (3H, m, 65); 7.41 (1, q, 4J = 1.1, H-5); 2.46 (3H, d, 4J = 1.1, CH3) 7.5-7.7 (5H, m, 65); 6.41 (1, dt, 3J = 10.0, 4J = 1.7, SCH=); 5.96 (1, dt, 3J = 3.7, 3 J = 10.0, CH=); 4.79 (2, dd, 3J = 3.7, 4J = 1.7, NCH2) 7.5-7.7 (5H, m, 65); 6.89 (1, dt, 3J = 8.0, 4J = 1.4, NCH=); 5.76 (1, dt, 3J = 8.0, 3 J = 5.4, CH=); 3.61 (2, dd, 3J = 5.4, 4J = 1.4, SCH2)
4 5a*2 5b*2
_______ * In the composition of the multiplet. *2 Mixture of isomers.
It turned out that only 6-methyl-3-phenylthiazolo[2,3-c]-1,2,4-triazole (4) is formed under these conditions from product 2. In the 1H NMR spectrum of compound 4, apart from two groups of signals for the benzene ring protons, two further signals were present with relative intensity 3:1 corresponding to the protons of the methyl group at 2.45 ppm and the H-5 proton of the thiazole ring at 7.42 ppm. This is in agreement with literature data on the chemical shifts of protons of thiazole ring and a methyl group in related systems [8-10]. Thiazine 3 gives a mixture of elimination products, 3-phenyl-5H-1,2,4-triazolo[3,4-b]-1,3-thiazine (5a) and 3-phenyl-7H-1,2,4-triazolo[3,4-b]-1,3-thiazine (5b). In the 1H NMR spectrum of this mixture, apart from the multiplet common to compounds 5a and 5b corresponding to the aromatic ring protons, a further six signals are observed dividing into two groups according to integral intensity. In each group there are two one-proton doublets of triplets at low field, corresponding to the proton at the double bond, and a two-proton doublet of doublets at high field belonging to the two methylene protons. The signal from the H-7 protons in compound 5b is close in chemical shift to the analogous signal in 3-phenyl-5-(2-propynylthio)-4H-1,2,4-triazole [11] (3.61 and 3.83 ppm respectively), but the signal from the H-5 protons in compound 5a is observed at lower field, as for the signal of the analogous methylene protons in thione 1 (4.79 and 4.71 ppm respectively). This is in agreement with the disposition of the signal from the H-5 proton in compound 5b at lower field compared with the signal from the H-7 proton in compound 5a (6.89 and 6.19 ppm respectively). The coupling constant between the proton at the double bond and the methylene group protons is 4J = 1.7 in compound 5a and 4J = 1.4 Hz in compound 5b, which is characteristic of spin-spin interactions in allylic systems [7].
EXPERIMENTAL The 1H NMR spectra were recorded on a Bruker spectrometer (200 MHz) in CDCl3. TLC was carried out on Sorbfil PTSKh-V-UF plates, visualization was in UV light or with iodine vapor.
1079
4-Allyl-5-phenyl-1,2,4-triazole-3(4H)-thione (1). Mixture of KSCN (3.92 g, 40.0 mmol) and allyl bromide (3.90 ml, 45.0 mmol) in dry acetone (20 ml) was boiled in a round-bottomed flask for 2 h. Acetone was distilled off on a rotary evaporator, xylene (30 ml) was added to the residue, KBr was filtered off, and the resulting solution boiled for a further hour. Solution of benzoic acid hydrazide (5.44 g, 40.0 mmol) in hot xylene (20 ml) was added to the obtained solution of allyl isothiocyanate. The precipitated solid was filtered off, washed with pentane, and dried. 1-Allyl-4-benzoylthiosemicarbazide (8.93 g, 95%) was obtained, which was dissolved in 2.5% NaOH solution (80 ml) and heated on a water bath for 3 h. The obtained solution was acidified with glacial acetic acid (7.0 ml) to pH 6. An oil separated, which crystallized. After two recrystallizations of the product from a benzenehexane mixture (50 ml) thione 1 (6.60 g, 70% on benzoic acid hydrazide) was obtained having mp 120C (mp 118C [1]), Rf 0.47 (ethyl acetatehexane, 1:3). 6-Iodomethyl-3-phenyl-5,6-dihydrothiazolo[2,3-c]-1,2,4-triazole (2) and 6-Iodo-3-phenyl-6,7dihydro-5H-1,2,4-triazolo[3,4-b]-1,3-thiazine (3). 4-Allyl-5-phenyl-1,2,4-triazole-3-thione (2.17 g, 10.0 mmol) was dissolved in CH2Cl2 (100 ml) and sublimed iodine (6.34 g, 25.0 mmol) was added. The mixture was left to stand at room temperature in the dark for several days, then CH2Cl2 was evaporated under reduced pressure. Further treatment may be carried out by two procedures. A. The residue was dissolved in acetone (20 ml) and poured with cooling into solution of Na2S2O35H2O (8.69 g, 35.0 mmol) and Na2CO3 (1.27 g, 12.0 mmol) in water (150 ml). The solid which precipitated was a mixture (3.29 g, 96%) of cyclization products. A sample (500 mg) of the mixture was separated chromatographically on a column of silica gel (eluent was ethyl acetate) and thiazole 2 (388 mg, 77.6%) and thiazine 3 (96 mg, 19.2%) were obtained. It is possible to obtain the individual products by fractional extraction of the more soluble isomer 2 from the mixture of isomers with chloroform. From the mixture (3.00 g) of isomers compound 2 (2.04 g, 68%) and product 3 (0.40 g, 13%) were obtained. 6-Iodomethyl-3-phenyl-5,6-dihydrothiazolo[2,3-c]-1,2,4-triazole (2). Mp 156C (acetonitrile), Rf 0.28 (ethyl acetate). Found, %: I 36.6; S 9.40. C11H10IN3S. Calculated, %: I 36.98; S 9.34. 6-Iodo-3-phenyl-6,7-dihydro-5H-1,2,4-triazolo[3,4-b]-1,3-thiazine (3). Mp 194C (70% AcOH), Rf 0.21 (ethyl acetate). Found, %: I 36.50; S 9.30. C11H10IN3S. Calculated, %: I 36.98; S 9.34. B. The reaction mixture was dissolved in acetone and treated with NaI2H2O (3.72 g, 20.0 mmol) in acetone (20 ml). The precipitated hydroiodide was filtered off, washed with acetone, and the solid obtained was dried in the dark. Mixture (4.19 g, 89%) of hydroiodides of compounds 2 and 3 was obtained, which was stirred for 1 h in solution of NaHCO3 (0.84 g, 10 mmol) in water (50.0 ml). The obtained solid was filtered off, washed with water, and dried in the dark. Mixture (2.99 g, 98%) of compounds 2 and 3 was obtained. Separation of the isomers was carried out as in method A. 6-Methyl-3-phenylthiazolo[2,3-c]-1,2,4-triazole (4). Compound 2 (343 mg, 1.0 mmol) was dissolved in 5% solution (15 ml) of KOH in methanol, the solution was heated to boiling, then left for several hours at room temperature. MeOH was evaporated under reduced pressure, the residue was extracted with CHCl3 (3 10 ml), the combined extracts dried over anhydrous Na2SO4, CHCl3 was evaporated, and the residue recrystallized from benzenehexane. Thiazole 4 (185 mg, 86%) was obtained; mp 196C, Rf 0.26 (ethyl acetate). Found, %: S 14.80. C11H9N3S. Calculated, %: S 14.89. Mixture of 3-Phenyl-5H-1,2,4-triazolo[3,4-b]-1,3-thiazine (5a) and 3-Phenyl-7H-1,2,4-triazolo[3,4-b]1,3-thiazine (5b). Elimination of HI from thiazine 3 (100 mg, 0.29 mmol) was carried out analogously to the preparation of compound 4. After evaporation of the solvent the mixture (59 mg, 95%) of isomers 5a and 5b was obtained. Found, %: S 14.71. C11H9N3S. Calculated, %: S 14.89.
REFERENCES 1. 2. 3. 1080 M. N. Tsitsika, S. M. Khripak, and I. V. Smolanka, Ukr. Khim. Zh., 42, 841 (1976). S. Ernst, S. Jelonek, J. Silez, and K. Schulze, Tetrahedron, 52, 791 (1996). L. Strzemecka, Polish J. Chem., 57, 567 (1983).
4. 5. 6. 7. 8. 9. 10. 11.
M. Tamaru and Z. Yoshida, J. Org. Chem., 50, 764 (1985). D. G. Kim and V. I. Shmygarev, Khim. Geterotsikl. Soedin., 211 (1995). P. Wippich, C. Hendreich, M. Gutshow, and S. Leistner, Synthesis, 741 (1996). B. I. Ionin, B. A. Ershov, and A. I. Kol'tsov, NMR Spectroscopy in Organic Chemistry [in Russian], Khimiya, Leningrad (1983). K. T. Potts and S. Husain, J. Org. Chem., 36, 10 (1971). Y. Tamura, H. Hayashy, J. H. Kim, and M. Ikeda, J. Heterocycl. Chem., 10, 947 (1973). Y. Tamura, H. Hayashy, E. Saeki, J. H. Kim, and M. Ikeda, J. Heterocycl. Chem., 11, 459 (1974). V. P. Upadhyaya, T. G. S. Nath, and V. R. Srinivasan, Synthesis, 283 (1978).
1081
REACTIONS OF 1,3-SUBSTITUTED BENZOTHIENO[2,3-c]PYRYLIUM SALTS WITH PRIMARY AMINES

S. V. Tolkunov, M. A. Kryuchkov, V. S. Tolkunov, and V. I. Dulenko We have studied the reactions of benzothieno[2,3-c]pyrylium salts with primary amines. We have shown that recyclization occurs in two directions, and whether benzothieno[2,3-c]pyridinium salts or 1-aminodibenzothiophenes are formed is determined by the nature of the primary amine. Keywords: 1-aminodibenzothiophenes, benzothieno[2,3-c]pyridinium perchlorates, benzothieno[2,3-c]pyrylium perchlorates, recyclization. Recyclization of alkyl-substituted pyrylium salts by primary amines can occur both with participation of the -alkyl substituents (leading to alkylanilines) or without involvement of the substituents (forming N-pyridinium salts). The reaction of monocyclic pyrylium salts and 1,3-dialkyl-substituted benzo[c]pyrylium salts with primary amines leads to pyridinium and isoquinolinium salts [1, 2]. On the other hand, 1-alkyl-3-aryland 1-alkyl-3,4-diaryl-substituted benzo[c]pyrylium salts reacted with primary amines yield only substituted naphthylamines [3]. Reactions between primary amines and pyrylium salts annelated with heterocycles have not been studied. We have studied the reaction of 1,3-disubstituted benzothieno[2,3-c]pyrylium salts 1, 2 with primary amines. It has been hypothesized that recyclization of pyrylium salts by primary amines occurs according to an ANRORC scheme, and includes addition of the nucleophile at the position 1 of the pyrylium ring [4]. Further opening of the pyran ring leads to intermediate formation of ketimines A, which exist in equilibrium with the tautomeric enamine form B. Formation of the end products (benzothieno[2,3-c]pyridinium salts 3-5 and 1-aminodibenzothiophenes 6) obviously is determined by the ratio of forms A and B, and depends on the nature of amine. So reaction of pyrylium salts 1a,b with anilines leads to pyridinium salts 3b,c and 4a,b, while recyclization of pyrylium salts 2a,b by methylamine and monoethanolamine leads exclusively to the 1-R4-aminobenzothiophenes 6b-d. Reactions of the salts 1a and 2c,b with benzylamine and furfurylamine lead to a mixture of pyridinium salts 3a, 5a,b and 1-R4-aminodibenzothiophenes 6a,d,e. The structure of 1-R4-aminobenzothiophenes 6a-e, established from the 1H NMR spectra, confirms that addition of primary amines to pyrylium salts 1, 2 occurs at the position 1. The presence of an arylamino group at the position 3 of the pyrylium ring should signify that the product of ring opening after addition of amine at C(1) occurs to be not able to undergo further recyclizations. In fact, in studying the reaction of 1,6-dimethyl-3-(4'tolylamino)benzothieno[2,3-c]pyrylium perchlorate (7) with benzylamine, we isolated for the first time the
__________________________________________________________________________________________ L. M. Litvinenko Institute of Physical Organic Chemistry and Coal Chemistry, National Academy of Ukraine, Donetsk 83114; e-mail: tolkunov@uvika.dn.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1246-1250, August, 2004. Original article submitted October 11, 2001. 1082 0009-3122/04/4008-10822004 Springer Science+Business Media, Inc.
R3 + S R1 1a,b, 2ac O
R2 R4NH2 _
R3 O S R1 A
R2
R3
R2 O NHR4
ClO4
NR4 B
S R1
R3 +N
R2 S R1 3ac, 4a,b, 5a,b R4 _ ClO4
R3
R2 S R4 6ae NH R1
1 a, b R1 = H, R2 = Me, a R3 = H, b R3 = Cl; 2 a, c R1 = H, b R1 = Me, a-c R2 = Ph, a, b R3 = H, c R3 = Me; 3 a-c R1 = R3 = H, R2 = Me, a R4 = Bn, b R4 = p-MeC6H4, c R4 = p-ClC6H4; 4 a,b R1 = H, R2 = Me, R3 = Cl, a R4 = Ph, b R4 = p-ClC6H4; 5 a R1 = H, b R1 = Me, a, b R2 = Ph, a R3 = Me, b R3 = H, a, b R4 = furfuryl; 6 a-c, e R1 = H, d R1 = Me, a R2 = Me, b-e R2 = Ph, a-d R3 = H, e R3 = Me; a R4 = Bn, b R4 = Me, c R4 = CH2CH2OH, d, e R4 = furfuryl

Compound 3a 3b 3c 4a 4b 5a 5b 6a* 6b 6c 6d* 6e 8 Empirical formula C C20H18ClNO4S C20H18ClNO4S C19H15Cl2NO4S C19H15Cl2NO4S C19H14Cl3NO4S C24H20ClNO5S C24H20ClNO5S C20H18ClNS C19H15NS C20H17NOS C24H20ClNOS C24H19NOS C27H26N2OS 59.61 59.48 59.36 59.48 53.61 53.77 53.95 53.77 49.91 49.73 61.52 61.34 61.52 61.34 70.57 70.69 79.02 78.89 75.17 75.24 71.15 71.02 78.22 78.05 75.87 76.02 Found, % Calculated, % H Cl N 4.33 4.46 4.31 4.46 3.41 3.54 3.41 3.54 3.17 3.05 4.39 4.26 4.18 4.26 5.44 5.30 5.31 5.19 5.47 5.33 4.87 4.93 5.37 5.15 6.25 6.14 8.65 8.80 8.94 8.80 16.88 16.75 16.86 16.75 23.35 23.23 7.34 7.56 7.73 7.56 10.21 10.46 8.61 8.75 3.31 3.47 3.33 3.47 3.45 3.30 3.47 3.30 3.12 3.05 2.73 2.98 2.81 2.98 4.23 4.12 4.71 4.85 4.28 4.39 3.60 3.45 3.65 3.79 6.44 6.57 Yield, % 14 78 74 58 50 12 18 23 86 90 57 78 91
mp, S 7.80 7.93 7.85 7.93 7.61 7.55 7.60 7.55 7.12 6.98 6.69 6.82 6.77 6.82 9.35 9.43 11.16 11.07 10.21 10.03 7.67 7.89 8.82 8.67 7.60 7.52 270 243-244 267-268 283 273-274 248 173 171-172 94-95 148-149 175-177 116 150-152
_______ * Hydrochlorides. 1083
1084
TABLE 2 1H NMR Spectral 1-R4-aminodibenzothiophenes 6a-e

Compound
Characteristics
of
Benzothieno[2,3-c]pyridinium
perchlorates
3-5
and
Chemical shifts, , ppm (J, Hz) 1-CH3 (1-C2H5) [4'-CH3] 3.03 3.70 [2.28] 2.69 2.68 2.70 2.55 (1.00, 2.98, J = 7.1) Aliphatic protons 3-CH3 (6-CH3) [2-CH3] 2.84 2.55 2.50 2.48 2.49 (2.35) 2.31 NR4, NHR4 6.03 (CH2) 4.43 (CH2) 5.05 (CH2) 4.51 (CH2); 6.56 (NH) 3.80 (d, J = 5.4, CH3); 5.65 (q, NH) 3.45 (2H, m, CH2NH); 3.68 (2H, m, CH2OH); 4.95 (t, J = 5.6, OH); 5.49 (t, J = 5.5, NH) 4.55 (2H, d, J = 6.3, CH2); 6.25 (t, NH) 4.57 (2H, d, J = 6.3, CH2); 6.25 (t, NH) Aromatic protons
3a 3b 3c 4a 4b 5a 5b 6a* 6b 6c
7.10 (2H, m, 2'-, 6'-H); 7.40 (3H, m, 3'-, 4'-, 5'-H); 7.78 (1H, t, 7-H); 7.90 (1H, t, 6-H); 8.35 (1H, d, J56 = 8.4, 5-H); 8.65 (1H, d, J78 = 8.4, 8-H); 8.94 (1H, s, 4-H) 7.44 (2H, d, J32 = 8.2, 3'-, 5'-H); 7.69 (2H, d, J23 = 8.2, 2'-, 6'-H,); 7.76 (1H, t, 7-H); 7.88 (1H, t, 6-H); 8.40 (1H, d, J87 = 8.0, 8-H); 8.75 (1H, d, J56 = 8.0, 5-H); 9.05 (1H, s, 4-H) 7.76-8.00 (2H, m, 6-, 7-H); 7.79 (2H, d, J32 = 8.2, 3'-, 5'-H); 7.90 (2H, d, J23 = 8.2, 2'-, 6'-H); 8.40 (1H, d, J87 = 8.0, 8-H); 8.75 (1H, d, J56 = 8.0, 5-H); 9.05 (1H, s, 4-H) 7.69-7.84 (5H, m, 2'-, 3'-, 4'-, 5'-, 6'-H); 7.97 (1H, dd, J78 = 8.8, J75 = 2.1, 7-H); 8.44 (1H, d, J87 = 8.8, 8-H); 8.90 (1H, d, J57 = 2.1, 5-H); 9.05 (1H, s, 4-H) 7.77 (2H, d, J32 = 8.1, 3'-, 5'-H); 7.89 (2H, d, J23 = 8.1, 2'-, 6'-H); 7.97 (1H, d, J78 = 8.7, 7-H); 8.45 (1H, d, J87 = 8.7, 8-H); 8.91 (1H, s, 5-H); 9.09 (1H, s, 4-H) 7.08 (12H, m) 7.50-7.25 (13H) 7.20-7.48 (9H, m); 7.51 (1H, s, 4-H); 8.00 (1H, d, J = 8.4, 8-H); 8.20 (1H, d, J = 8.4, 5-H) 6.85 (1H, s, 2-H); 7.27-7.54 (5H, m); 7.80-7.82 (2H, m, 6-, 7-H); 7.85 (1H, s, 4-H); 8.10 (1H, d, J87 = 8.4, 8-H); 8.36 (1H, d, J56 = 8.4, 5-H) 6.96 (1H, s, 2-H); 7.30-7.60 (5H, m); 7.75-7.86 (2H, m, 6-, 7-H); 7.90 (1H, s, 4-H); 8.10 (1H, d, J87 = 8.4, 8-H); 8.38 (1H, d, J56 = 8.4, 5-H)
6d 6e
[2.15] (2.49)
6.15 (1H, s, 4-Hfuran); 6.25 (1H, s, 3-Hfuran); 7.30-7.59 (7H, m, Hphenyl); 7.59 (1H, s, 5-Hfuran); 7.79 (1H, s, 4-H); 7.90 (1H, d, J87 = 8.4, 8-H); 8.22 (1H, d, J56 = 8.4, 5-H) 6.38 (2H, m, 3-, 4-Hfuran); 7.03 (1H, s, 2-H); 7.31-7.49 (5H, m, Hphenyl); 7.59 (1H, s, 5-Hfuran); 7.74 (1H, s, 4-H); 7.76 (1H, d, J78 = 7.4, 7-H); 7.88 (1H, d, J87 = 7.4, 8-H); 8.22 (1H, s, 5-H)
_______ * Spectra of hydrochlorides.
product of addition of amine at the position 1 of N-(p-tolyl)amide of 2-[(1-benzylimino)ethyl]-5methylbenzothiophene-3-acetic acid (8). Formation of such intermediate ketimines was postulated earlier by Dimroth and other researchers [1, 4-6].
Me + S Me 7 O
H N Me _ ClO4 Me
PhCH2NH2 H N O N Me 8
Me
EXPERIMENTAL The 1H NMR spectra were taken on a Gemini-200 (200 MHz) spectrometer in DMSO-d6, internal standard TMS. The characteristics of the synthesized compounds are given in Tables 1 and 2. 1,3-Disubstituted benzothieno[2,3-c]pyrylium perchlorates 1a,b, 2a-c were obtained by the procedures in [7, 8]. Synthesis of N-Aryl-1,3-dimethylbenzothieno[2,3-c]pyridinium Perchlorates (3) (General Procedure). The corresponding pyrylium perchlorates 1a,b (5 mmol) were added to solution of arylamine (5 mmol) in acetic acid. The mixture was heated on a water bath for 1 h. The mixture was cooled down; the precipitate was filtered off and washed with alcohol and then ether, and then dried. Compounds 3b,c, 4a,b were obtained. They were crystallized from methanol. Reaction of Benzothieno[2,3-c]pyrylium Perchlorates with Aliphatic Amines. The corresponding primary amine (5.1 mmol) was added to suspension of the substituted pyrylium perchlorates (5 mmol) in alcohol and then heated for 1 h and cooled down. The precipitate of pyridinium perchlorates 3a, 5a,b formed was filtered off, washed with acetone and then ether, and then dried. The obtained products were crystallized from methanol. The filtrate was evaporated down and then diluted with water; the precipitate of 1-R4-aminodibenzothiophenes 6a-e was filtered off and then crystallized from isopropyl alcohol. N-(p-Tolyl)amide of 2-[(1-Benzylimino)ethyl]-5-methylbenzothiophene-3-acetic Acid (8). Benzylamine (2.5 ml) was added to suspension of 1,6-dimethyl-3-(4'-tolylamino)benzothieno[2,3-c]pyrylium perchlorate 7 (5 mmol) in isopropyl alcohol (25 ml). The reaction mixture was cooled down and water (25 ml) was added. The precipitate was filtered off and washed with water, and then crystallized from a mixture of benzenehexane, 1:3. 1H NMR spectrum, , ppm (J, Hz): 2.15 (3H, s, 4'-CH3); 2.42 (3H, s, 5-CH3); 2.49 (3H, s, CH3C=N); 4.13 (2H, s, CH2CO); 4.79 (2H, s, CH2N); 6.91 (2H, d, J = 8.0, 3'-, 5'-H); 7.03 (2H, d, J = 8.0, 2'-, 6'-H); 7.24-7.31 (5H, m, H); 7.46 (1H, d, J = 8.2, 6-H); 7.80 (1H, d, J = 8.2, 7-H); 7.86 (1H, s, 4-H); 10.48 (1H, s, NH).
1085
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. K. Dimroth, Angew. Chem., 72, 331 (1960). G. N. Dorofeenko, E. I. Sadekova, and V. V. Goncharova, Khim. Geterotsikl. Soedin., 1308 (1970). E. V. Kuznetsov and G. N. Dorofeenko, Khim. Geterotsikl. Soedin., 1437 (1971). G. P. Safaryan, I. V. Shcherbakova, G. N. Dorofeenko, and E. V. Kuznetsov, Khim. Geterotsikl. Soedin., 1608 (1981). S. V. Verin, D. E. Tosunyan, and E. V. Kuznetsov, Khim. Geterotsikl. Soedin., 1468 (1991). V. I. Terenin, L. G. Yudin, R. S. Sagitullin, V. N. Torocheshnikov, V. I. Dulenko, Yu. A. Nikolyukin, and A. N. Kost, Khim. Geterotsikl. Soedin., 73 (1983). V. I. Dulenko, S. V. Tolkunov, and N. N. Alekseev, Khim. Geterotsikl. Soedin., 1351 (1981). S. V. Tolkunov, Khim. Geterotsikl. Soedin., 1335 (1998).
1086
REACTION OF SUBSTITUTED 2-ALLYLTHIOPYRIMIDIN-4(3H)-ONES WITH SULFENYL CHLORIDES

A. I. Vaskevich, Yu. I. Gevaza, R. I. Vaskevich, and V. I. Staninets Reaction of substituted 2-allyl-thiopyrimidin-4(3H)-ones with p-nitrobenzosulfenyl chloride gives the products of addition at the allyl moiety, while the reaction with 2-benzothiazolyl sulfenyl chloride yields thiazolidinopyrimidines with an angular structure. Keywords: allylthiopyrimidines, 2-benzothiazolyl sulfenyl chloride, p-nitrobenzosulfenyl chloride, thiazolidinopyrimidine, thiazolidinothienopyrimidines, thiazolidinoquinazolone. Among the wide range of reactions of sulfenyl halides [1], their reaction with unsaturated compounds [2, 3] is special because these reactions occur mostly under mild conditions and lead to formation of products which often have practical application [4]. Furthermore, they are convenient models for a detailed study of the mechanism of these conversions [5]. In a series of research projects, we plan to determine: 1) the effect of the nature of the sulfenating reagents on the rate and direction of the reaction with unsaturated bifunctional compounds; 2) the effect of the structure of the unsaturated compounds on the direction of the reaction; 3) the synthetic possibilities for these reactions, with the aim of using them further for obtaining various classes of heterocyclic compounds having physiological activity. As the object of the investigations, we selected 2-allylthiothieno[2,3-d]pyrimidin-4(3H)-ones 1a-c, 2-allylthioquinazolin-4(3H)-one (1d), and 2-allylthio-6-methyl-4(3H)-pyrimidinone (1e), since their derivatives have a broad spectrum of physiological activity [6]. We showed earlier that cyclization of 2-allylthiothieno[2,3-d]pyrimidin-4(3H)-ones when treated with iodine or bromine leads to formation of dihydrothiazolothienopyrimidines with angular structure [7]. In this work, we studied the reaction of compounds 1a-e with p-nitrobenzosulfenyl chloride (2) and with 2-benzothiazolylsulfenyl chloride (3), and we established that in the case of sulfenyl chloride 2, the products of addition at the double bond of the allyl moiety of compounds 4a-e are formed. Using sulfenyl chloride 3 leads to formation of cyclic derivatives 5a-e with participation of the N(1) atom of the pyrimidine system. When compounds 5 are treated with sodium acetate in DMSO, the bases 6 are formed (Scheme 1). From the yields of compounds 5, we can hypothesize that the nature of the substituents on the pyrimidine ring affects the cyclization of compounds 1 with 2-benzothiazolylsulfenyl chloride: acceptor substituents promote cyclization, donor substituents hinder the occurrence of the reaction. The effect of the substituents on the pyrimidine ring seems to be weak in the case of reaction of compounds 1 with p-nitrobenzosulfenyl chloride. __________________________________________________________________________________________ Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev 02094; e-mail: iochkiev@ukrpack.net. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1251-1255, August, 2004. Original article submitted January 18, 2001. 0009-3122/04/4008-10872004 Springer Science+Business Media, Inc. 1087
Scheme 1
O R1 NH R2 N 1ae R1 O
R3SCl 2
NH R2 N 4ae
Cl SCH2CHCH2SR 3
SCH2CH=CH2
R4SCl 3
O R1 NH R2 N HC Cl S. R4 A S CH2 R1
O R1 NH + R2 _N Cl H2C S R4 5ae Me
5 6
O
7
N8
4N
..
MeCOONa DMSO
R2
S1
2
. . CH2
H2C S
R4
6ae
1, 46 a
R1R2
= S
R1R2
= S 2, 4 R3 =
R1R2
= Me NO2 , S
d R1R2 =
e R1 = H, R2 = Me; N
3, 5, 6 R4 = S
In the 1H NMR spectra of compounds 4, we observe signals from the protons of HetSCH2CHCl CH2SAr in the region 3.39-3.81 ppm (CH2), 4.01-4.21 ppm (CH2), and a multiplet from the methine moiety CHCl at 4.22-4.42 ppm. We cannot clearly establish the regiochemistry of addition of sulfenyl chloride 2 to the allyl moiety of compounds 1 based on these data. However, we may hypothesize that the addition occurs according to Markovnikov's rule. The 1H NMR spectroscopy data for compounds 5, 6 support formation of the thiazolidine ring. Thus signals from the protons in the methylene group of the thiazolidine ring and protons in the CH2SHet moiety appear in the spectra as characteristic signals for an ABX system in the 3.50-4.15 ppm region. The methine proton of the thiazolidine ring gives a multiplet in the 5.40-6.02 region (compound 5) and the 5.26-5.72 ppm region (compound 6). Furthermore, we see signals from the benzothiazole ring: two triplets and doublets each in the 7.36-8.04 ppm region. The difference between the chemical shifts for the proton of the CHCl moiety in the addition products 4 (4.22-4.42 ppm) and the methine proton of the thiazolidine ring of the cyclic compounds 5, 6 (5.26-6.02 ppm) allows us to establish the structure of the products for the studied reactions.
1088
In the IR spectra of compounds 4, there are absorption bands for the carbonyl group in the 1675-1670 cm-1 region, while for compounds 5 we see these bands at 1720-1710 cm-1. For compounds 6, the absorption region for the carbonyl group was 1640-1635 cm-1, which proves formation of cyclic products with participation of the N(1) atom of the pyrimidine ring [7, 8]. TABLE 1. Physicochemical Characteristics of Compounds 4-6
Compound 4 4b 4c 4d 4e 5 5b 5c 5d 5e 6 6b 6c 6d 6e Empirical formula C19H18ClN3O3S3 C18H16ClN3O3S3 C17H16ClN3O3S3 C17H14ClN3O3S2 C14H14ClN3O3S2 C20H18ClN3OS4 C19H16ClN3OS4 C18H16ClN3OS4 C18H14ClN3OS3 C15H14ClN3OS3 C20H17N3OS4 C19H15N3OS4 C18H15N3OS4 C18H13N3OS3 C15H13N3OS3 Found, % Calculated, % Cl N 3.76 3.88 3.47 3.55 3.58 3.65 3.39 3.46 3.68 3.79 3.71 3.78 3.43 3.46 3.44 3.55 3.28 3.36 3.57 3.68 3.79 3.86 3.43 3.52 3.54 3.62 3.37 3.42 3.65 3.77 7.64 7.58 7.85 7.81 8.07 8.02 8.65 8.69 9.47 9.53 7.26 7.38 7.57 7.61 7.67 7.81 8.37 8.44 9.14 9.23 8.71 8.98 9.16 9.26 9.46 9.51 10.17 10.30 11.28 11.30 8.63 8.75 8.96 9.02 9.13 9.25 9.96 10.01 10.89 10.94 9.42 9.47 9.74 9.78 9.97 10.06 10.79 10.96 12.04 12.09 Yield, % 61 63 69 68 43 48 42 45 62 8 80 87 98 69 53
mp, * S 20.47 20.55 21.04 21.19 21.61 21.77 15.64 15.72 17.17 17.25 26.68 26.72 27.49 27.52 28.06 28.25 22.84 22.91 25.01 25.05 28.83 28.91 29.73 29.86 30.82 30.71 25.03 25.08 27.59 27.68 215-217 204-207 200-202 196-197 161-164 136-139 148-151 138-140 136-138 194-196 248-250 238-239 211-213 222-223 220-222
48.64 48.76 47.54 47.62 46.14 46.20 49.84 50.06 45.14 45.22 49.84 50.04 48.79 48.96 47.53 47.61 51.37 51.48 46.78 46.92 54.03 54.15 53.02 53.12 51.65 51.77 56.28 56.37 51.77 51.85
_______ * Compounds 4a-e, 6a-e were recrystallized from an alcoholDMSO mixture. TABLE 2. 1H NMR and IR Spectra of Compounds 4-6
Compound 1 4 IR spectrum, (=), cm-1 2 1665
1
4b
1670
4c
1670
4d
1680
1.77 (4, m, 22); 2.71-2.81 (4, m, 22); 3.47-3.74 (2, m, 2); 4.02-4.18 (2, m, 2); 4.27-4.36 (1, m, ); 7.72, 8.17 (4, 2d, J1 = 9.0, J2 = 8.7, 64); 12.66 (1, br. s, NH) 2.30-2.43 (2, m, 2); 2.87-2.89 (4, m, 22); 3.48-3.77 (2, m, 2); 4.02-4.21 (2, m, 2); 4.29-4.39 (1, m, ); 7.73, 8.17 (4, 2d, J1 = 8.8, J2 = 8.7, 64); 12.75 (1, br. s, NH) 2.30 (6H, s, 2CH3); 3.39-3.73 (2, m, 2); 4.00-4.19 (2, m, 2); 4.22-4.36 (1, m, ); 7.70, 8.15 (4, 2d, J1 = 9.0, J2= 8.8, 64); 12.62 (1, br. s, NH) 3.63-3.81 (2, m, 2); 4.04-4.18 (2, m, 2); 4.34-4.42 (1H, m, CH); 7.37-8.17 (8, m, 264); 12.67 (1, br. s, NH)
1089
TABLE 2 (continued)
1 4e 2 1675 3 2.18 (3, s, 3); 3.45-3.72 (2, m, 2); 4.01-4.17 (2, m, 2); 4.29-4.36 (4, m, 22 ); 6.04 (1, s, ); 7.76, 8.17 (4, 2d, J1 = J2 = 8.7, 64) 1.69-1.80 (4, m, 22); 2.63-2.79 (4, m, 22); 3.95-4.13 (4, m, 22); 5.42-5.50 (1, m, ); 7.38, 7.48 (2, 2t, J1 = J2 = 7.2, 2 arom.); 7.72, 7.99 (2, 2d, J1 = 7.8, J2 = 7.5, 2 arom.) 2.33-2.42 (2, m, 2); 2.62-2.97 (4, m, 22); 3.76-4.13 (4, m, 22); 5.49-5.56 (1, m, ); 7.38, 7.49 (2, 2t, J1 = 8.1, J2 = 6.9, 2 arom.); 7.75, 7.99 (2, 2d, J1 = 7.8, J2 = 8.7, 2 arom.) 2.23 (3H, s, CH3); 2.41 (3, s, 3); 3.73-4.12 (4, m, 22); 5.40-5.50 (1, m, ); 7.38, 7.49 (2, 2t, J1 = J2 = 7.2, 2 arom.); 7.75, 8.00 (2, 2d, J1 =J2 = 8.0, 2 arom.) 3.76-4.15 (4, m, 22); 5.93-6.02 (1, m, ); 7.39-8.42 (8, m, 8 arom.) 2.68 (3, s, 3); 3.61-4.14 (4, m, 22); 5.47-5.53 (1, m, ); 6.15 (1, s, ), 7.40, 7.51 (2, 2t, J1 = J2 = 7.5, 2 arom.); 7.80, 8.04 (2, 2d, J1 = J2 = 7.5, 2 arom.) 1.69-1.79 (4, m, 22); 2.71-2.73 (4, m, 22); 3.59-4.01 (4, m, 22); 5.27-5.33 (1, m, ); 7.36, 7.47 (2, 2t, J1 = 7.8, J2 = 8.1, 2 arom.); 7.76, 7.96 (2, 2d, J1 = 7.5, J2 = 8.1, 2 arom.) 2.32-2.41 (2, m, 2); 2.65-2.93 (4, m, 22); 3.61-4.03 (4, m, 22); 5.31-5.38 (1, m, ); 7.37, 7.48 (2, 2t, J1 = 7.8, J2 = 8.0, 2 arom.); 7.79, 7.98 (2, 2d, J1 = 8.1, J2 = 7.8, 2 arom.) 2.24 (3H, s, CH3); 2.37 (3, s, 3); 3.60-4.01 (4, m, 22); 5.28-5.33 (1, m, ); 7.38, 7.49 (2, 2t, J1 = 6.9, J2 = 6.6, 2 arom.); 7.79, 7.99 (2, 2d, J1 = J2 = 7.8, 2 arom.) 3.62-3.97 (4, m, 22); 5.65-5.72 (1, m, ); 7.39-8.24 (8, m, 8) 2.55 (3, s, 3); 3.50-3.91 (4, m, 22); 5.26-5.31 (1, m, ); 5.75 (1, s, ), 7.39, 7.50 (2, 2t, J1 = 7.8, J2 = 8.0, 2 arom.); 7.81, 8.04 (2, 2d, J1 = J2 = 7.8, 2 arom.)
1720
5b
1720
5c
1715
5d 5e
1720 1720
1640
6b
1635
6c
1640
6d 6e
1650 1645
EXPERIMENTAL The IR spectra were recorded on a UR-20 in KBr disks. The 1H NMR spectra were obtained on a Varian VXR-300 spectrometer (300 MHz) in DMSO-d6, internal standard TMS. The procedure for synthesis of 2-allylthiothieno[2,3-d]pyrimidin-4(3H)-ones 1a-c and 2-allylthioquinazolin-4(3H)-one (1d) is described in [9]; the procedure for synthesis of 2-allylthio-6-methyl4(3H)-hydropyrimidinone (1e) is described in [8]; the procedure for synthesis of p-nitrobenzosulfenyl chloride (2) is described in [10]; and the procedure for synthesis of 2-benzothiazolyl sulfenyl chloride (3) is described in [11]. The physicochemical and spectral characteristics of the synthesized compounds are given in Tables 1 and 2. 2-[2-Chloro-3-(p-nitrobenzosulfenyl)propylthio]-5,6-R1,R2-thieno[2,3-d]pyrimidin-4(3H)-ones 4a-c, 2-[2-Chloro-3-(p-nitrobenzosulfenyl)propylthio]quinazolin-4(3H)-one (4d), and 2-[2-Chloro-3-(p-nitrobenzosulfenyl)propylthio]-6-methyl-4(3H)-pyrimidinone (4e). Sulfenyl chloride 2 (0.45 g, 2.4 mmol) was added to a suspension of the corresponding compound 1 (2 mmol) in chloroform (30 ml). The mixture was stirred for 9-18 h at a temperature of 15-25C; the precipitate of compound 4 was filtered out, washed with chloroform and then ether, and recrystallized from DMSO. 1090
3-(2-Benzothiazolylthio)methyl-6,7-R1,R2-8-oxo-2,3-dihydro-9H-thiazolo[3,2-a]thieno[3,2-e]pyrimidinium Chlorides 5a-c, 3-(2-Benzothiazolylthio)methyl-9-oxo-2,3-dihydro-10H-thiazolo[3,2-a]quinazolonium Chloride (5d), and 3-(2-Benzothiazolylthio)methyl-5-methyl-7-oxo-2,3-dihydro-8Hthiazolo[3,2-a]pyrimidinium Chloride (5e) were synthesized as for compounds 4, from 2-benzothiazolyl sulfenyl chloride and the corresponding compounds 1. 3(2-Benzothiazolylthio)methyl-6,7-R1,R2-8-oxo-2,3-dihydrothiazolo[3,2-a]thieno[3,2-e]pyrimidines 6a-c, 3-(2-Benzothiazolylthio)methyl-9-oxo-2,3-dihydrothiazolo[3,2-a]quinazolone (6d), and 3-(2-Benzothiazolylthio)methyl-5-methyl-7-oxo-2,3-dihydrothiazolo[3,2-a]pyrimidine (6e). A 20% aqueous solution of sodium acetate (10 ml) was added with stirring to a solution of salt 5 (2 mmol) in DMSO (10 ml). After 0.5 h, the precipitate formed was filtered out and washed with alcohol and then ether. They were recrystallized from a 1:2 alcoholDMSO mixture.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. Yu. G. Gololobov and N. I. Gusar', Sulfenyl Chlorides [in Russian], Nauka, Moscow (1989). K. S. Nicolaou, S. P. Seitz, W. P. Sipio, and J. F. Blount, J. Am. Chem. Soc., 101, 3884 (1979). T. Ohsawa, M. Ihara, and K. Fukumoto, J. Org. Chem., 48, 3644 (1983). I. V. Koval', Usp. Khim., 64, 781 (1995). N. S. Zefirov and I. V. Bodrikov, Zh. Org. Khim., 19, 2225 (1983). F. Russo, A. Santagati, M. Santagati, A. Caruso, M. G. Leone, A. Felice, and M. Amico-Roxas, Eur. J. Med. Chem., 24, 91 (1989). R. I. Vas'kevich, S. M. Khripak, V. I. Staninets, Yu. L. Zborovskii, and A. N. Chernega, Zh. Org. Khim., 36, 1091 (2000). D. G. Kim and V. I. Shmygarev, Khim. Geterotsikl. Soedin., 211 (1995). P. Wippich, C. Hendreich, M. Gutschow, and S. Leistner, Synthesis, 741 (1996). T. Zincke, Liebigs Ann. Chem., 400 (1913). US Patent Application 2257974 (1942); Chem. Abstr. 36:930 (1942).
1091
2-R-5-AR(HET)-5,6-DIHYDRO-7H-[1,2,4]TRIAZOLO[5,1-b][1,3]-THIAZIN-7-ONES
V. N. Britsun and M. O. Lozinskii A novel method for synthesis of 2-R-5-Ar(Het)-5,6-dihydro-7H-[1,2,4]triazolo[5,1-b][1,3]thiazin-7-ones by condensation of 3-R-4,5-dihydro-1H-1,2,4-triazole-5-thiones with 3-aryl(heteryl)-2-propenoyl chlorides is proposed. Keywords: 2-R-5-aryl(heteryl)-5,6-dihydro-7H-[1,2,4]triazolo[5,1-b][1,3]thiazin-7-ones, 3-aryl-(heteryl)2-propenoyl chlorides, 3-aryl-4,5-dihydro-1H-1,2,4-triazole-5-thiones. 4,5-Dihydro-1H-1,2,4-triazole-5-thione is the starting reagent for synthesis of condensed heterocycles, in particular derivatives of 4H-1,3-thiazin-4-one [1-3]. We know that 1,2,4-triazole-5-thiones are acylated by acid chlorides only at the position 1 [4, 5], while compounds are readily added to the thione group (at 20C) when they contain an activated multiple bond, such as the methyl ester of propiolic acid [3], acrylic acid [6], or acrylonitrile [7]. We established earlier [8] that when unsubstituted 1,2,4-triazole-5-thione 1a reacts with cinnamoyl chloride (2a), it is not the corresponding 1-acyl-1,2,4-triazole-5-thione 3a that is formed but rather its cyclization product: 5-phenyl-5,6-dihydro-7H-[1,2,4]triazolo[5,1-b][1,3]thiazin-7-one (4a). In this work, we have studied such a reaction for novel examples with participation of 3-aryl-4,5-dihydro-1H-1,2,4-triazole-5-thiones 1b-d and 3-aryl(heteryl)-2-propenoyl chlorides 2b-h, where (probably through intermediate acylation products of 3b-k [9]) we obtain 2-R-5-R1-5,6-dihydro-7H-[1,2,4]triazolo[5,1-b][1,3]-thiazin-7-ones 4b-k.
H N N
Cl
+
S
O
Py
R1
N H 1ad
Py HCl
2ah
O
N
O
N
N
N
3ak
N
N
SH
R1
S
4ak
R1
1a, 3, 4 ah R = H; 1b, 3, 4 i R = Ph; 1c, 3, 4 j R = p-MeOC6H4; 1d, 3, 4 k R = p-NO2C6H4; 24 a, 3, 4 ik R1= Ph; 24 b R1 = 3,4-(MeO)2C6H3, c R1 = p-NO2C6H4, d R1 = p-ClC6H4, e R1 = p-FC6H4, f R1 = 1-naphthyl, g R1 = 3,4-methylenedioxyphenyl, h R1 = 2-thienyl
__________________________________________________________________________________________ Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev 02094; e-mail: iochkiev@ukrpack.net. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1256-1260, August, 2004. Original article submitted February 4, 2002. 1092 0009-3122/04/4008-10922004 Springer Science+Business Media, Inc.
The process occurs under mild conditions (boiling in pyridine for 1 h), and compounds 4 are formed in good yields (50%-72%), where when R = H, R1 = Ar the yield is higher (4a-g, 60%-72%) than when R = Ar, R1 = Ph (4i-k, 50%-55%); but when R = H, R1 = 2-thienyl, product 4h is obtained in 51% yield. The composition and structure of the synthesized compounds 4 are confirmed by the elemental analysis results and data from spectral investigation methods (Tables 1 and 2). Meaningful proof for the formation of a heterocycle comes from the 1H NMR spectroscopy data. The double bond of the starting 3-aryl-2-propenoyl chloride 2, the proton signals of which appear in the 1H NMR spectra as two doublets in the 6.80 ppm and 7.50 ppm region, after heterocyclization is converted to the single bond of compounds 4, with proton signals in the 3.30-5.50 ppm region (an ABX system). Analysis of the lineshape in the 13C NMR spectrum for compound 4a, obtained without proton decoupling, also supports formation of a six-membered thiazine ring, since the signal for the carbonyl carbon atom ( 162.92 ppm) appears as a doublet of triplets (2JCH = 7.1, 3JCH = 4.3 Hz) as a result of spinspin coupling with the protons of the CH2CH moiety. In the IR spectra of the products 4a-k, an absorption band for the C=O group is characteristic (1730-1720 cm-1).
TABLE 1. Characteristics of Synthesized Compounds 4a-k, 5a-h

Compound 4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 5a 5b 5c 5d 5e 5f 5g 5h Empirical formula C11H9N3OS C13H13N3O3S C11H8N4O3S C11H8ClN3OS C11H8FN3OS C15H11N3OS C12H9N3O3S C9H7N3OS2 C17H13N3OS C18H15N3O2S C17H12N4O3S C11H11N3O2S C13H15N3O4S C11H10N4O4S C11H10ClN3O2S C11H10FN3O2S C15H13N3O2S C12H11N3O4S C9H9N3O2S2 Found, % Calculated, % H N 57.27 57.14 53.45 53.61 47.70 47.83 49.70 49.72 52.87 53.01 64.27 64.06 52.47 52.36 45.53 45.57 66.64 66.45 64.23 64.09 57.92 57.95 53.12 53.00 50.62 50.48 45.19 44.90 46.48 46.57 49.53 49.43 60.32 60.19 49.31 49.14 42.13 42.34 3.73 3.90 4.59 4.47 3.09 2.90 3.23 3.01 3.29 3.21 3.77 3.91 3.06 3.27 2.80 2.95 4.04 4.23 4.66 4.45 3.66 3.41 4.20 4.45 4.71 4.89 3.21 3.42 3.34 3.55 3.88 3.77 4.23 4.38 3.59 3.78 3.28 3.55 18.33 18.18 14.31 14.43 20.02 20.29 15.71 15.82 16.64 16.87 15.19 14.95 15.38 15.27 17.88 17.72 13.85 13.68 12.59 12.46 15.72 15.91 16.71 16.86 13.73 13.58 18.71 19.04 14.70 14.81 15.61 15.72 14.22 14.04 14.20 14.33 16.54 16.46 mp, C Yield, % [+]
163-165 158-160 200-202 158-160 140-142 213-215 192-193 150-153 170-173 191-193 250-252 143-145 167-169 191-193 170-172 161-163 198-200 181-183 147-149
70 68 72 68 65 67 60 51 55 52 50 83 90 86 94 88 91 71 75
231 291 276 266 249 281 275 237 307 337 352 249 309 294 283 267 299 293 255
1093
We note that 2-Ar-triazolo[5,1-b][1,3]thiazin-7-ones 4i-k are quite stable compounds, while their analogs 4a-h which are unsubstituted at the 2 position slowly undergo hydrolysis due to moisture in the air when stored under normal conditions, forming 3-aryl-3-(1H-1,2,4-triazole-5-thio)propanoic acids 5a-h:
O H2O N N NH S 5ah OH R1
4ah
5 a R1= Ph, b R1 = 3,4-(MeO)2C6H3, c R1 = p-O2NC6H4, d R1 = p-ClC6H4, e R1 = p-FC6H4, f R1 = 1-naphthyl, g R1 = 3,4-methylenedioxyphenyl, h R1 = 2-thienyl
We may assume that the 2-aryl-substituted triazolothiazinones 4i-k are stable compounds because of conjugation of the triazole ring with the aromatic ring at the 2 position. When compounds 4a-h are recrystallized from aqueous acetic acid or when they are heated with hot water, the hydrolysis rate increases considerably. The composition and structure of acids 5 are supported by the results of elemental analysis (Table 1) and data from spectral investigation methods. In the 1H NMR spectra of compounds 5, broadened singlets from protons of the COOH (12.37-12.55 ppm) and NH (14.12-14.23 ppm) groups are characteristic, and in the IR spectra there is a characteristic absorption band for C=O (1680-1720 cm-1). Thus the reaction of 3-aryl-4,5-dihydro-1H-1,2,4-triazole-5-thiones with 3-aryl(heteryl)-2-propenoyl chlorides is of a general nature, and is a novel and convenient one-step method for synthesis of substituted 5,6-dihydro-7H-[1,2,4]triazolo[5,1-b][1,3]thiazin-7-ones, allowing us to vary the substituents (Ar, Het) at the positions 2 and 5.
TABLE 2. Spectral Characteristics of Compounds 4a-k, 5a-h

Compound 1 4a* 4b IR spectrum, , cm-1 2 3100, 1730 (C=O), 1510, 1450, 1410, 1320 3100, 1730 (C=O), 1600, 1500, 1400, 1310 3100, 1730 (C=O), 1540 (N=O), 1500, 1400 3100, 1720 (C=O), 1590, 1490, 1410, 1360 3100, 1730 (C=O), 1590, 1510, 1400, 1310 3000, 1730 (C=O), 1590, 1500, 1390, 1320 3000, 1720 (C=O), 1590, 1510, 1440, 1400, 1310
1
4c
4d 4e
4f
4g
3.42 (1, m, -6); 3.90 (1, m, -6); 5.45 (1, m, -5); 7.42-7.51 (5, m, C6H5); 8.31 (1, s, -2) 3.36 (1, m, -6); 3.77 (6, s, 23); 3.89 (1, m, -6); 5.40 (1, m, -5); 6.99 (2, m, -, m-HAr); 7.10 (1, s, o-HAr); 8.28 (1, s, -2) 3.53 (1, m, -6); 3.94 (1, m, -6); 5.64 (1, m, -5); 7.80 (2, d, J = 9.3, o-HAr); 8.28 (2, d, J = 9.3, m-HAr); 8.32 (1, s, -2) 3.42 (1, m, -6); 3.85 (1, m, -6); 5.48 (1, m, -5); 7.52 (4, m, o-, m-HAr); 8.30 (1, s, -2) 3.50 (1, m, -6); 3.85 (1, m, -6); 5.43 (1, m, -5); 7.25 (2, t, J = 8.1, -HAr); 7.67 (2, m, m-HAr); 8.30 (1, s, -2) 3.50 (1, m, -6); 4.12 (1, m, -6); 6.39 (1, m, -5); 7.60-8.01 (6, m, C10H7); 8.25 (1, m, C10H7); 8.32 (1, s, -2) 3.28 (1, m, -6); 3.88 (1, m, -6); 5.38 (1, m, -5); 6.06 (2, s, 2), 6.95 (2, m, - m-Ar); 7.11 (1, s, o-HAr); 8.29 (1, s, -2)
1094
TABLE 2 (continued)
1 4h 2 3200, 1720 (C=O), 1580, 1500, 1400, 1310 3200-3000, 1720 (C=O), 1600, 1480, 1430 3100-3000, 1720 (C=O), 1600, 1480, 1460, 1410 3100-3000, 1720 (C=O), 1590, 1530 (N=O), 1480, 1400 3300-2800, 1700 (C=O), 1450, 1410, 1360 3300, 2900, 2550, 1700 (C=O), 1610, 1520, 1480 3250, 2900, 2600, 1690 (C=O), 1520, 1500, 1410 3200, 2950, 2500, 1680 (C=O), 1490, 1430, 1370 3200, 2950, 2600, 1700 (C=O), 1660, 1490, 1370 3100-2600, 1720 (C=O), 1500, 1400, 1310 3100-2600, 1700 (C=O), 1600, 1500, 1430, 1350 3200, 2900, 2550, 1710 (C=O), 1530, 1480, 1320 3 3.61 (1, m, -6); 3.78 (1, m, -6); 5.68 (1, m, -5); 7.03 (1, d. d, J1 = 5.1, J2 = 3.0, HHet-4); 7.18 (1, d, J = 3.0, HHet-3); 7.54 (1, d, J = 5.1, HHet-5); 8.27 (1, s, -2) 3.47 (1, m, -6); 3.88 (1, m, -6); 5.49 (1, m, -5); 7.46-8.10 (10, m, 2C6H5) 3.38 (1, m, -6); 3.83 (3, s, 3); 3.90 (1, m, -6); 5.48 (1, m, -5); 7.07 (2, d, J = 8.1, m-Ar); 7.41-7.54 (5, m, C6H5); 8.03 (2, d, J = 8.1, o-Ar) 3.44 (1, m, -6); 3.95 (1, m, -6); 5.56 (1, m, -5); 7.41-7.56 (5, m, 65); 8.32 (2, d, J = 9.1, -HAr); 8.39 (2, d, J = 9.1, m-HAr) 3.14 (2, m, C2CO); 5.01 (1, m, SC); 7.40 (5, m, 65); 8.54 (1, br. s, -3); 12.44 (1, br. s, ); 14.13 (1, br. s, NH) 3.09 (2, m, C2CO); 3.66 (6, s, 2 O3); 4.97 (1, m, SC); 6.83 (2, d, J = 5.1, o-, m-HAr); 7.12 (1, s, o-HAr); 8.58 (1, br. s, -3); 12.38 (1, br. s, ); 14.15 (1, br. s, NH) 3.05 (2, m, C2CO); 5.13 (1, m, SC); 7.11 (2, d, J = 9.1, o-HAr); 8.34 (2, d, J = 9.1, m-HAr); 8.48 (1, br. s, -3); 12.41 (1, br. s, ); 14.17 (1, br. s, NH) 3.04 (2, m, C2CO); 4.98 (1, m, SC); 7.36 (2, d, J = 9.2, -Ar); 7.42 (2, d, J = 9.2, m-Ar); 8.47 (1, br. s, -3); 12.50 (1, br. s, ); 14.20 (1, br. s, NH) 3.09 (2, m, C2CO); 4.99 (1, m, SC); 7.15 (2, t, J = 7.7, o-Ar); 7.46 (2, t, J = 7.7, m-Ar); 8.49 (1, br. s, -3); 12.55 (1, br. s, ); 14.17 (1, br. s, NH) 3.36 (2, m, C2CO); 5.84 (1, m, SC); 7.57-8.33 (7, m, C10H7); 8.53 (1, br. s, -3); 12.40 (1, br. s, ); 14.23 (1, br. s, NH) 3.02 (2, m, C2CO); 4.95 (1, m, SC); 6.02 (2, s, 2), 6.82 (2, m, o- m-Ar); 7.01 (1, s, o-HAr); 8.48 (1, br. s, -3); 12.37 (1, br. s, ); 14.23 (1, br. s, NH) 3.07 (2, m, C2CO); 4.94 (1, m, SC); 6.92 (1, d. d, J1 = 5.4, J2 = 3.2, HHet-4); 7.13 (1, d, J = 3.2, HHet-3); 7.58 (1, d, J = 5.4, HHet-5); 8.44 (1, br. s, -3); 12.41 (1, br. s, ); 14.15 (1, br. s, NH)
4i 4j
4k
5a
5b
5c
5d
5e
5f
5g
5h
_______ * 13C spectrum, , ppm: 40.47 (C-6), 42.64 (C-5), 127.52 (C6H5), 128.80 (C6H5), 129.10 (C6H5), 136.66 (C6H5), 153.16 (C-2), 156.06 (C-3a), 162.93 (C-7).
EXPERIMENTAL The NMR spectra were recorded on a Varian-300 (300 MHz (1H), 75 MHz (13C)) in DMSO-d6, internal standard TMS. The mass spectra were taken on an MKh-1303; the IR spectra were taken on a UR-20 in KBr disks. 2-R-5-Ar(Het)-5,6-Dihydro-7H-[1,2,4]triazolo[5,1-b][1,3]thiazin-7-ones (4a-k) (General Procedure). Acid chloride 2 (10 mmol) in benzene (4 ml) was added to a solution of compound 1 (10 mmol) in pyridine (4 ml) at 20C. The solution was boiled for 1 h under reflux and then cooled, and then water was added. The precipitated product 4 was filtered out, recrystallized from acetic acid, and dried. 1095
3-Ar(Het)-3-(1H-1,2,4-Triazole-5-thio)propanoic Acids (5a-h) (General Procedure). A mixture of water (5 ml) and compound 4a-h (5 mmol) was held for 24 h at 95C and then cooled. Product 5 was filtered out, recrystallized from acetic acid, and dried.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. B. V. Trzhtsinskaya, E. I. Kositsyna, and B. Z. Pertsikov, Khim. Geterotsikl. Soedin., 271 (1987). J. P. Clayton, P. J. O'Hanlon, and T. G. King, J. Chem. Soc., Perkin Trans. 1, 1352 (1980). N. D. Heindel and J. R. Reid, J. Org. Chem., 45, 2479 (1980). S. Kumar, R. Dahiya, and H. K. Pujari, Indian J. Chem., 30, 38 (1991); Chem. Abstr. 114:143278 (1991). M. M. Tsitsika, S. M. Khripak, and I. V. Smolanka, Khim. Geterotsikl. Soedin., 851 (1974). J. W. Gates, A. W. Wise, D. A. Beavers, and P. E. Miller, Ger. Pat. 2016082 (1970); Chem. Abstr. 74:53817 (1971). A. S. Azaryan, N. S. Iradyan, and A. A. Aroyan, Arm. Khim. Zh., 28, 705 (1975). V. N. Britsun and M. O. Lozinskii, Zh. Org. Khim., 37, 1102 (2001). V. N. Britsun and M. O. Lozinskii, Khim. Geterotsikl. Soedin., 1103 (2003).
1096
SUBSTITUTED AND SPIRO-ANNELATED PERHYDRO-1,2,3-OXATHIAZINE 2,2-DIOXIDES AND 1-BENZYL-4-METHYLAZETIDINES

A. V. Varlamov1, N. V. Sidorenko1, F. I. Zubkov1, A. I. Chernyshev1, and K. F. Turchin2 We obtained perhydro-1,2,3-oxathiazine 2,2-dioxides by cyclization of 4-N-benzylamino-4tetramethylene(phenyl-, methylphenyl-, dimethyl)but-1-enes in conc. H2SO4 at 25C. When treated with an alcoholic solution of base, the oxathiazines are converted to 2-substituted and spiro-annelated 1-benzyl-4-methylazetidines. Keywords: azetidines, homoallyl amines, 1,2,3-oxathiazine 2,2-dioxides. The chemistry of completely hydrogenated 1,2,3-oxathiazine 2,2-dioxides has been virtually unstudied [1, 2]. This is because of the lack of simple methods for synthesis of such heterocyclic systems, difficulties encountered in their isolation, and also their high chemical lability. Cyclization of gem-benzylaminoallylcyclohexane and -cyclooctane when treated with conc. H2SO4 in boiling chloroform was used earlier to obtain spiro[1,2,3-oxathiazine-4,1'-cyclohexane(-cyclooctane)], and they were subsequently cleaved to form the corresponding spiro[azetidine-2,1'-cycloalkanes] [3, 4]. With the aim of studying the limits of applicability for the method and the stereochemistry of the process, we studied cyclization of a series of homoallylamines 1a-d when treated with sulfuric acid. The starting allylamines 1a-d are readily formed by reaction of the corresponding Schiff's bases with allyl magnesium bromide [5, 6]. When amines 1a-d are treated with excess conc. H2SO4 at 25C, the 1,2,3-oxathiazine 2,2-dioxides 2a-d are formed in 43%-83% yield. Formation of the oxathiazines 2 probably occurs through a cyclic ammonium salt, the subsequent dehydration of which when treated with excess H2SO4 yields the target compounds. Oxathiazines 2 are finely crystalline white powders that are high-melting and poorly soluble in most organic solvents. Their structure has been proven by the totality of spectral data (Tables 1 and 2). The IR spectra of compounds 2a-d are characterized by the presence of intense stretching vibration bands for the SO2 group at 1370-1190 cm-1. In the mass spectra of compounds 2, there are no molecular ion peaks but we observe peaks for fragmentary ions [M-80]+, corresponding to ejection of an SO3 molecule from M+. As we might expect, the maximum intensity in all cases is observed for ions with m/z 91, due to elimination of a benzyl radical from the nitrogen atom.
__________________________________________________________________________________________ Russian People's Friendship University, Moscow 117198; e-mail: avarlamov@sci.pfu.edu.ru. 2 Center for Drug Chemistry/All-Russian Scientific Research Pharmaceutical Chemistry Institute, Moscow 119815; e-mail: turchin@drug.org.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1261-1269, August, 2004. Original article submitted November 23, 2001. 0009-3122/04/4008-10972004 Springer Science+Business Media, Inc. 1097
1
1098
TABLE 1. Physicochemical and Spectral Characteristics of Oxathiazines 2a-d and Azetidines 3a-d
Compound* 2a 2b 2c 2d 3a 3b 3c 3d Empirical formula 15H21NO3S 17H19NO3S 64.35 18H21NO3S 65.26 13H19NO3S 57.99 15H21N 17H19N 86.08 18H21N 86.06 13H19N 82.54 10.05 8.37 8.02 83.89 83.72 7.06 10.01 9.77 6.34 5.99 Found, % Calculated, % H 7.23 7.09 N 4.98 4.73 4.09 4.42 4.03 4.23 5.12 5.20 6.48 6.51 5.70 5.91 5.55 5.56 7.21 7.41 Found [M]
+
mp, Calculated 295 317 331 296 215 237 251 189 214-215.5 87-100 (with decomp.) 185-190 (with decomp. 225-227
Rf*2
60.89 60.81
IR spectrum, cm-1, SO2 1298, 1190 1282, 1231 1370, 1215 1233, 1187
Yield, %
215 [SO3]+ 237 [SO3]+ 189 [SO3]+ 215 237 251 189
0.50 0.30 0.47 0.55 0.62
43 83 69 51 31 40 30 48
_______ * For compounds 2b,c and 3b,c, data are given for isomer mixtures. *2 The Rf values were obtained in a mixture of ethyl acetatehexane, 1:3 (compounds 3a,d), 1:4 (compound 3b), and 1:5 (compound 3c).
TABLE 2. 1H NMR Spectra of 1,2,3-Oxathiazine 2,2-Dioxides 2a-d

Compound* 2 2b maj 2b min 2c maj 2c min 2d Chemical shifts, , ppm N2 6-H3 6 d 4.59 ddq 4.64 dq 4.93 ddq 4.85 dq 4.70 dq 4.59 m 1.27 1.26 1.31 1.36 0.97 1.24 4.35 3.97 3.98 3.63 3.79 3.64 3.95 3.47 4.04 3.83 4.21 4.04 SSCC, J, Hz Ar m 7.67-7.27 R1 R2 2.00-1.51 m 4, 5 10.4 11.0 7.75-7.15 1.49 s 1.99 s 7.65-7.35 1.46 s 1.39 s 4, 5 3.1 4.0 5, 5 16.2 12.0 15.0 15.8 15.6 15.6 5, 6 10.7 9.5 11.8 10.4 10.1 10.7 5, 6 1.2 0 3.1 0 0 1.2 6, CH3 6.1 6.4 6.1 5.2 5.8 6.4 2N 12.2 13.7 13.1 12.8
4 dd 4.11 4.42
2.20 1.67 dd dd 2.71-2.48 m 2.47 ddd 2.75 dd 2.45 dd 2.11 dd 2.04 ddd 1.75 d 1.84 d 1.65 dd
7.46-7.09 m
_______ * The 1H NMR spectra were taken in DMSO-d6 (compound 2a) and CDCl3 (compound 2b-d).
1099
H N
Bn H2SO4
2
H H 1 R N+ R2 Me H2O
O O
S O
1ad Bn O O S O Me 2ad N R
1
Bn KOH
2
N Me
R1 R
2
EtOH
3ad
1, 2 R1+R2 = (CH2)4; b R1 = H, R2 = Ph; c R1 = Me, R2 = Ph; d R1 = R2 = Me
According to the 1H NMR data (Table 2), the oxathiazines 2a and 2d, symmetrically substituted at C(4), are formed as a single geometric isomer which exists in the chair conformation with an equatorial 6-Me group. The 1H NMR spectra of these compounds are characterized by the presence of a multiplet for the H-6 proton at 4.59 ppm. The spinspin coupling constant J5a6a = 10.7 Hz is clear evidence for an axial position for the H-6 proton.
O O S Bn N
3 1 2
R2
1 6
O R
5
Me
2a,d
Cyclization of the homoallylamines 1b and 1c, which are asymmetrically substituted at the position 4, occurs stereoselectively. Compounds 2b and 2c are formed as mixtures of two isomers with respect to the position of the substituents at C(4) and the methyl group at C(6) of the oxathiazine ring, in a ratio of ~1:1.7 and 1:1.8 respectively. This is indicated by the presence of a double set of signals for each group of protons in their 1 H NMR spectra (see Table 2). Detailed analysis of the spectra for mixtures of the 2b and 2c isomers allowed us to draw a conclusion concerning their structure. The spectrum of the minor 2b isomer is characterized by the presence of large (11.0 and 11.8 Hz) and small (4.0 and 3.1 Hz) vicinal spinspin coupling constants for the H-4 and H-6 protons, with chemical shifts of respectively 4.42 ppm and 4.93 ppm. Consequently, for this isomer we may hypothesize a chair conformation with an axial position for the H-4 and H-6 protons and an equatorial position for the 4-Ph and 6-Me groups. In the 1H NMR spectrum of the major 2b isomer, for the H-6 proton with chemical shift 4.64 ppm we observe only one large spinspin coupling constant J56 = 9.5 Hz; the second constant is equal to zero. For the H-4 proton with chemical shift 4.11 ppm, we observe two spinspin coupling constants J45 = 10.4 Hz and 3.1 Hz. The values of these constants allow us to hypothesize a twist conformation for the major isomer. Thus in analogy with cyclization of 4-N-phenylamino- and 4-N-benzylamino-1-butenes to form 2-substituted 4-methyltetrahydroquinolines and 3-substituted 5-methyltetrahydrobenz-2-azepines [5-8], we may hypothesize that the isomers formed upon cyclization of homoallylamine 1b have an equatorial position for the 6-Me groups and differ only in the orientation of the 4-Ph substituent.
1100
O O Bn N Ph 2b minor O Ph O Bn N e S
4 1 6
a O e a a Bn SO2 N e Ph e Me O a Me
S a
a O e
5
Me
a 2b major
The minor isomer with an equatorial position of the substituents at C(4) and C(6) is energetically favorable, while the major isomer, due to steric 1,3-diaxial interaction, goes to the twist conformation, where these interactions are smaller. Evidence in favor of the indicated hypotheses comes from the results of cyclization of homoallylamine 1c to form oxathiazine 2c. In this case, we might also expect formation of two isomers with an equatorial 6-Me group and accordingly an equatorial and axial phenyl substituent at C(4).
O Me O Bn N Ph S O Me Bn O N Me O Ph S
4 5
Me
a Bn SO2 N Ph Me
2c minor
a e Me Bn SO2 N Me Ph
2c major
e Me O a
O a
In both isomers, the 1,3-diaxial interaction of the substituents at C(4) is responsible for their existence in the twist form. In the 1H NMR spectra of the 2c isomers (Table 2), we observe only one spinspin coupling constant J56 = 10.1 Hz for the minor isomer and 10.4 Hz for the major isomer. The second spinspin coupling constant is J56 = 0. Perhydrooxathiazine 2,2-dioxides 2a-d, when treated with a 15% alcoholic solution of potassium hydroxide, are converted in 30-61% yield to azetidines 3a-d, which are fluid oils. Based on literature data [9], we may suggest that in the first step, as a result of attack on the sulfur atom by the ethoxy dianion, cleavage of the NS bond of the oxathiazine ring occurs. Subsequent nucleophilic attack on the amide anion formed at the carbon atom bearing the sulfo group leads to the final azetidine.
1101
The structure of azetidines 3a-d has been proven by spectral methods. In their IR spectra, we see no absorption bands for the NH and OH bonds. In the mass spectra, there are molecular ion peaks of medium intensity, corresponding to their empirical formulas. The main direction of decomposition of the molecular ion is associated with abstraction of a benzyl radical. In the mass spectra, we also observe ions that are characteristic for fragmentation of azetidines, due to the ring "breaking in half" at the C(1)C(4) and C(2)C(3) bonds. Azetidines 3b and 3c, which are asymmetrically substituted at the 2 position, are formed as a mixture of isomers with respect to the position of the substituents at C(2) and C(4), in a ratio of ~1:1. In the starting oxathiazines 2b and 2c, the isomer ratio was 1:1.7 and 1:1.8; consequently, the reaction is not stereoselective. In contrast to the 3b isomers, the stereoisomers of azetidine 3c have different chromatographic mobilities and were isolated using column chromatography.
Me Ph
4 1 3
HB
Me Me
HB
Bn
HA
2
Bn
N Ph
HA
Me
3cA
3cB
Their stereochemistry was established using the protonproton nuclear Overhauser effect (NOE) (Table 3). The most pronounced NOE appears on protons of the methyl groups at C(2) and C(4). Thus in the spectrum of the chromatographically more mobile isomer 3cA (Rf 0.55), there is no NOE for protons in the methyl groups, while in the spectrum of the less mobile 3cB (Rf 0.47) we observe the NOE. Thus in isomer 3cA, the methyl groups are trans to each other while in 3cB they are cis. The 1H NMR spectra of azetidines 3a-d (Table 4) are characterized by the presence of a doublet signal from the protons of the 4-Me group at 1.1-0.9 ppm (J4Me = 5.8-6.2 Hz), two doublet-of-doublet signals from the methylene protons at C(3) with chemical shift 2.7-1.6 ppm, and a multiplet from the H-4 proton at 3.6-3.2 ppm. The methylene protons of the N-benzyl group are chemically nonequivalent, and are detected at 3.9-3.2 ppm (AB system, JAB = 12.8-14.0 Hz).
TABLE 3. Assessment of the Nuclear Overhauser Effect (NOE) from the 1H NMR Spectra of Compounds 3cA and 3cB
C 3c NOE on protons* 2-Me 3-H 3-H 4-H 4-Me 2-Me 3-H 3-H 4-H 4-Me Irradiated protons {3-H} + + + + + + + + + + + + + + +
{2-Me} + +
{3-H} +
{4-H} +
{4-Me}
+ +
3cB
_______ * The plus sign (+) marks NOE's exceeding 3%. 1102
TABLE 4. 1H and 13C NMR Spectra of Azetidines 3a-d*

Compound 3a 3bA 3bB 3cA 3cB 3d Chemical shifts, , ppm 4-M N2 4 d 3.19 ddk 3.40 m 3.50*2 m 3.37 m 3.56 m 3.22 ddk 0.90 0.85 1.05 0.83 1.09 0.90 3.69 3.46 3.87 3.51 3.48 3.15 3.91 3.53 3.44 3.21 3.70 3.40 SSCC, J, Hz Ar m 7.45-7.10 7.50-7.10 7.50-7.10 7.50-7.10 7.50-7.10 7.45-7.15 R1 R2 1.25-2.00 m 1.60s 1.64s 0.85s 0.89s 2,3 8.2 7.0 2,3 6.9 8.0 3,3 9.8 10.0 10.0 10.1 11.0 9.7 3,4 7.3 8.2 7.2 8.2 7.0 7.0 3,4 8.2 7.3 7.2 7.3 7.6 8.0 4,M 6.1 6.1 6.1 5.8 6.1 6.1 2N 12.8 12.8 12.8 13.1 14.0 13.0
2 dd 3.23 3.00
3 1.96 dd 1.83 m 1.90*2 m 1.81 dd 1.92 dd 1.90 dd
3 1.64 dd 2.21 m 2.80 m 2.23 dd 2.75 dd 2.20 dd
_______ * The chemical shifts in the 13C NMR spectra were measured relative to the signal for the solvent CDCl3, 77.0 ppm. 13 C NMR spectrum, , ppm for 3cA: 150.31 and 140.17 (s, quaternary-Ph), 128.93, 127.89, 127.88, 124.67 (d, m, o-Ph), 126.57 and 125.81 (d, p-Ph), 63.65 (s, C(2)), 57.64 (d, C(4)), 55.49 (t, CH2N), 41.96 (t, C(3)), 20.43 (q, 2-Me), 22.85 (q, 4-Me). For compound 3cB: 144.27 and 140.27 (s, quaternary-Ph), 128.53, 127.85, 127.78, 126.53 (d, m, o-Ph), 126.49 and 126.32 (d, p-Ph), 63.09 (s, C(2)), 55.99 (d, C(4)), 53.44 (t, CH2N), 40.41 (t, C(3)), 29.14 (q, 2-Me), 21.74 (q, 4-Me). *2 An exact determination was difficult due to the mutual overlap of the proton signals.
1103
In the 13C NMR spectra (Table 4) for the 3cA and 3cB isomers, we observe signals from all the carbon atoms in the molecule; their multiplicity and spinspin coupling constants also correlate well with the structure. In particular, at 53.44-65.09 ppm we see signals from the NCH2 carbon atoms, C(2) and C(4), bonded to the electronegative nitrogen atom.
EXPERIMENTAL The IR spectra were recorded on UR-20 or Specord IR-75 spectrometers in KBr disks (for the crystalline compounds) or in a film (for the oils). The mass spectra were recorded on Finnigan MAT 95 XL and HP MS 5988 mass spectrometers with direct injection of the sample into the ion source. Ionizing potential 70 eV. The 1H and 13C NMR spectra were obtained at 20C on a Bruker WP-200 (200 MHz) or a Bruker WH-400 (400 MHz and 100 MHz for 1H and 13C respectively), internal standard TMS. For the TLC, we used Silufol UV-254 plates (visualization by iodine vapor). The physicochemical and spectral characteristics are given in Tables 1, 2, and 4. 3-Benzyl-6-methyl-3,4,5,6-tetrahydrospiro[1,2,3-oxathiazine-2,2-dioxide-4,1'-cyclopentane] (2a), 6Methyl-3,4,5,6-tetrahydro-4-phenyl- (2b), [-4,6-Dimethyl-4-phenyl- (2c), -4,4,6-Trimethyl- (2d)]-3-benzyl1,2,3-oxathiazine-2,2-dioxides (General Procedure). Homoallyl amine 1a-d (0.015 mol) were added carefully to 96% H2SO4 (25 ml) that had been cooled down to ~0C. The reaction mixture was stirred until completely homogenized, and then allowed to stand at room temperature for 24 hours. The next day, the reaction mass was poured over ice (~100 cm3), neutralized with a 25% aqueous solution of ammonia while cooled with ice water, and the pH was brought up to pH ~8-9. The reaction products were extracted with chloroform (5 40 ml), and the extract was dried with Na2SO4. After the solvent was removed, the crystals that precipitated were washed several times with ethyl acetate. Oxathiazines 2 were obtained as finely crystalline white powders. 1-Benzyl-4-methylspiro[azetidine-2,1'-cyclopentane] (3a), 1-Benzyl-4-methyl-2-phenylazetidine (3b), 2,4-Dimethyl-2-phenyl- (3c), 1-Benzyl[2,2,4-trimethyl- (3d)]azetidines (General Procedure). Oxathiazine 3a-d (7.00 mmol) was boiled in a 15% ethanol solution of KOH (25 ml) for 20 h. Then the reaction mass was poured into water (100 mL) and extracted with ether (3 50 ml), and then the extract was dried with MgSO4. After the solvent was driven off, the residue was purified on aluminum oxide (2 2 cm), with ether as the eluent. Azetidines 3a-d were obtained as yellow fluid oils. The mixture of isomers of compound 3c was chromatographed on a column (25 0.7 cm) with aluminum oxide; the eluent was 1:30 ethyl acetatehexane. We individually isolated azetidines 3cA (11%, Rf 0.55) and 3cB (7%, Rf 0.47) The yields, physicochemical characteristics, and elemental analysis data for azetidines 3a-d are given in Table 1; the 1H and 13C NMR spectroscopy data are given in Table 4. This work was done with the financial support of the Russian Foundation for Basic Research (grants No. 99-03-32942a and 01-03-32844).
REFERENCES 1. 2. 3. 4. K. K. Andersen and M. G. Kocioler, J. Org. Chem., 60, 2003 (1995). D. Alker, K. J. Doyle, L. M. Harwood, and A. McGregor, Tetrahedron Asymmetry, 1, 877 (1990). A. V. Varlamov, F. I. Zubkov, A. I. Chernyshev, V. V. Kuznetsov, and A. P. Pal'ma, Khim. Geterotsikl. Soedin., 223 (1999). L. M. Vargas, W. Rozo, and V. V. Kouznetsov, Heterocycles, 53, 785 (2000).
1104
5. 6. 7. 8. 9.
V. V. Kuznetsov, S. V. Lantsetov, A. E. Aliev, A. V. Varlamov, and N. S. Prostakov, Zh. Org. Khim., 28, 74 (1992). A. V. Varlamov, V. V. Kouznetsov, F. I. Zubkov, A. I. Chernyshev, G. G. Alexandrov, A. Palma, L. Vargas, and S. Salas, Synthesis, 849 (2001). V. V. Kuznetsov, A. E. Aliev, and N. S. Prostakov, Khim. Geterotsikl. Soedin., 73 (1994). L. Y. Vargas and V. Kouznetsov, Heterocycl. Commun., 4, 341 (1998). B. J. Littler, T. Gallagher, I. K. Boddy, and P. D. Riordan, Synlett, 22 (1997).
1105
HETARYLCYANAMIDES. (REVIEW)
D. D. Nekrasov The nomenclature and the synthesis of hetarylcyanamides and their reactions that take place at the cyanoamino group are discussed. Keywords: hetarylcyanamides, synthesis, chemical properties. The development of simple methods for the synthesis of stable HetNHCN compounds and the possibility of producing of new heterocyclic systems with useful practical characteristics based on them have recently increased the interest of chemists in compounds with such structures. By analogy with alkyl- and arylcyanamides they have been called hetarylcyanamides.
RNHCN alkylcyanamides ArNHCN arylcyanamides HetNHCN hetarylcyanamides
In the IUPAC rules the cyanamide function (unlike the structurally similar OCN or SCN) does not have a separate name. In this respect hetarylcyanamides can probably be regarded more correctly as nitrile derivatives of carbamic acid and called hetarylcarbamonitriles. Sometimes such compounds are called substituted amines, for example,
NHCN
N-cyano-2-pyridylamine or N-(cyano)-N-(2-pyridyl)amine
During the formulation of names for such compounds some authors give priority to the heterocycle and for this reason place the cyanoamino group in the prefix. If its location in the heterocycle is ambiguous, it is indicated by a locant. For example,
N NCHN N cyanoamino-sym-triazine N S NHCN 2-cyanoaminothiazole N
In order to present the material consistently we will call these compounds hetarylcyanamides.
__________________________________________________________________________________________ Institute of Technical Chemistry, Ural Branch of the Russian Academy of Sciences, Perm; e-mail: bav@psu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1283-1302, September, 2004. Original article submitted January 17, 2001. 0009-3122/04/4009-11072004 Springer Science+Business Media, Inc. 1107
1. METHODS OF SYNTHESIS There are various methods for the synthesis hetarylcyanamides involving the construction of the heterocycle from functionalized N-cyano compounds with retention of the cyanamide function or the introduction of a cyanoamino group into the heterocycle. Thus, the 1,3-dipolar cycloaddition of methyl- or ethyldicyanamide with mesitylnitrile oxide or benzyl azide gives the corresponding oxadiazolyl- and tetrazolylcyanamides 1 and 2 [1].
Mes Mes CN R N CN Bn N3 N N N Bn 2 C N O N O 1 N N CN R
N N CN R
1 R = Me, Et; 2 R = Me
The reaction of o-phenylenediamines with cyanoguanidine leads 2-benzimidazolylguanidines, which are readily converted by the action 2-benzimidazolylcyanamides 3 [2-6].
NH R3NHC NHCN N NH2 R2 NHR1 MeS C MeS NCN/NEt3 R2 N R1 3 N R1 HNO2 N NHC
to of
the formation of nitrous acid into
NH NHR3
NHCN
Analogous cyanamides 3 were obtained from o-phenylenediamines and dimethyl N-cyanodithioimidocarbonate in the presence of triethylamine. Electron-donating substituents in the benzene ring promote the reaction, while electron-withdrawing substituents hinder it. In the absence of the catalyst different reaction products are formed [7]. The reaction of diphenyl cyanocarbamate with o-phenylenediamine at room temperature leads to derivatives of N-cyano-O-phenylisourea, which undergo cyclization to the cyanamides 3 when boiled in 2-propanol. In an analogous reaction o-aminophenol immediately forms 2-benzoxazolylcyanamide [8].
1108
CN
X NH2 NH2
N X N H O
PhO N CN PhO
X = H, Cl
Cyanoguanidine reacts with acetylacetone, forming 4,6-dimethyl-2-pyrimidylcyanamide (4) [9].

Me C O CH2 C O N Me H2N C NH ROCR1 NCOR 2 R2 N N 5 NHCN R1 N NHCN 4 Me Me N NHCN
The 1,3,5-triazinylcyanamides 5 were synthesized by the cyclocondensation of cyanoguanidine with imidic esters [10]. Methods for the production of hetarylcyanamides based on the modification of substituents in the heterocycle to a cyanamide function are more varied. Thus, for example, the hydroxyiminomethyleneamino group is modified by the action of a dehydrating agent in the presence of a base [11, 12].
Het
NHCN 6 Het = 2-pyridyl, 2-pyrimidyl, 2-pyrazinyl, 3-pyridazinyl, 6-chloro-3-pyridazinyl, 2-thiazolyl
NH CH
NOH
POCl3
Het
Oxidative desulfurization of 2-pyridylthiourea by the action of mercuric oxide or cupric hydroxide gives 2-pyridylcyanamide (7) [13].
Hg N NHCNH2 S
2+
or
Cu
2+
N 7
NHCN
Substituted 1,3,5-triazinylcyanamides 8 can be obtained in a similar way [14].

RHN N N N RHN N H C S R = Alk NH2 Hg 2+ N N RHN 8 RHN N NHCN
1109
The reaction of hetarylphosgene imines with ammonia can probably be used as a general method for the production of hetarylcyanamides 9 [15].
Cl Het N C Cl NH3 8090 oC
Het 9
NHCN
Het = 4-R1-6-R2-1,3,5-triazinyl
Substitution of the chlorine in 2-chloro-4,6-dimethylpyrimidine by a cyanamide group gives the corresponding hetarylcyanamide 4 [8].
Me N Cl N Me NaNHCN 4
Monochloro-substituted sym-triazines also undergo cyanoamination with sodium cyanide to form triazinylcyanamides 10 [16-19].
R1 N N N R2 R1 N N N R2 + NMe3 _ Cl Na2NCN bkb Ca(HNCN)2 R2 N N 10 Cl Na2NCN R1 N NHCN
R1R2 = alkyl(aryl)amino; R1 = alkylamino, R2 = MeO, MeS
Trimethyl-sym-triazinylammonium chlorides undergo cyanoamination considerably more readily, and this makes it possible to conduct the reaction not only with sodium cyanide but also with calcium cyanamide [20-24]. The widely used method involving cyanation of alkyl- and arylamines with cyan halides has limited application in the case of hetarylamines. Only in the presence of a strong base such as butyllithium was it possible to realize this reaction with 1,3,5-triazinylamine with the formation of the corresponding cyanamide 11 [25].
R N N N RO RO 11 NH2 ClCN / BuLi R N N N NHCN
If there are two amino groups in the triazine ring, cyanation takes place under milder conditions. In this case cyanogen bromide in the presence of calcium carbonate is used as cyanation agent [26]. 1110
Ph N N N H2 N NH2 BrCN / CaCO3
Ph N N N NCHN 12 NHCN
The reaction takes place at both amino groups with the formation of triazinedicyanamide 12. Some azinylcyanamides, such as 7 [27] or 13 [28], can be obtained by the cleavage of thiazoloazines with alkali.
N
N
N CHO
H2 N
7
NaOH
N
N
NCO2Et
NaOH / H2O
H2 N
NHCN
N
13
Derivatives of 1,3,4-triazoloazines unsubstituted at position 2 are easily cleaved by the action of bases with the formation of the cyanamides 14-17.
R Cl N N O N N liq. NH3 [29] O H2N N R N NH 14 CN
R = -D-ribofuranosyl
CH2R N+ N Me R = H, CN, COOMe Bn BnCl H2N N H2N N SR N N N MeI H2N N SR R = Me, PhCH2 [32] N N SR 16 Me Me _ + N I K2CO3 N H2N N SR 17 N N CN N CN N CH2R _ Br Me Et3N N [30, 31] Me 15 N N CN
Me
1111
2. CHEMICAL PROPERTIES Hetarylcyanamides enter into reaction with a wide range of reagents, since their molecules contain two substantially different reaction centers, i.e., the nucleophilic nitrogen atom of the amino group and the electrophilic carbon atom of the nitrile group. The molecules of such compounds are capable of substitution at the amino group or addition and cycloaddition at the triple bond of the nitrile group. Many of the reactions affecting the amino group are catalyzed by bases or require the participation of an anion. The reactions at the nitrile group take place in the presence both of acids and of bases. The hetaryl substituent has the greatest effect on the amino group. On account of the fact that the amino and cyano groups are linked to each other the effect of the heterocycle extends indirectly to the cyano group. This makes the hetarylcyanamides (in contrast to the aliphatic and aromatic analogs) more resistant to di- and trimerization.
2.1. Reactions of the Amino Group The hetarylcyanamides 6 are easily methylated by treatment with dimethylformamide dimethyl acetal (DMF DMA) with the formation of the corresponding N-methylhetarylcyanamides 18 [11].
Me
DMF DMA
6
Het
N 18
CN
The methylation of 2-pyrazinylcyanamide with diazomethane leads to N-methylation in the side chain (compound 19) and N-methylation at the N(1) atom in the heterocycle (compound 20) [12].
Me N N NHCN CH2N2 N 19 N N CN Me N N CN
+
N 20
The hydrogen atom in the NH group of hetarylcyanamides 10 has acidic character, and this makes it possible to obtain stable potassium salts. These salts react readily with alkyl halides [33-36], arylalkyl halides [37], halohydrins [38], chloroethyl tosylates [39], haloalkyl ethers [40], chloroacetic, propionic, and bromomalonic esters [41-43], haloacetonitriles [41], and others. The reaction products are N-alkylhetarylcyanamides 21-28 (Scheme 1). The hetarylcyanamides 10 are acylated by the SchottenBaumann procedure with the formation of the derivatives 29 [44].
O 10 Hal C R3 R2 R1 N N N 29 NCN C R3 O
1112
Scheme 1
RR1N N N N X 21 R2I N CN R2 N N X 22 ICH2Ar RR1N N N CN CH2Ar N N X 23 RR1N N N CN CH2Y
HalCH2Y RR1N N
RR1N N ClCH2CN N N X _ N CN K+
I(CH2)2OH
N N X RR1N 24
N CN (CH2)2OH
ArSO2O(CH2)2Cl N
N N CN N (CH2)2Cl
RO(CH2)nHal R3OOCHR2Hal RR1N
X 25
N N RR1N N N N X 28 N CN CH2CN N N X 27 RR1N N N CN CHR2COOR3 N X 26 N CN (CH2)nOR2
2.2. Addition at the Cyano Group Hydrolysis of the cyano group of hetarylcyanamides in sulfuric acid (1:1) gives the corresponding N-hetarylureas 30 [11, 12, 45]. The hetarylthioureas 31 are formed when hydrogen sulfide is passed through a solution of the hetarylcyanamide 6 in the presence of triethylamine or ammonia [12, 14, 46-48].
Het + H / H2O Het NH 30 C O NH2 Het NH CN H2S / Et3N NH C S 31 NH2
1113
Aminolysis of the hetarylcyanamide 32 leads to the formation of the hetarylguanidine 33 [46].

Me N Et O N H 32 NHCN NH3 P, 100 oC O Et N H 33 Me N NH C NH NH2
Analogous compounds are formed during addition to the cyano group of substituted amines [47, 48]. Pyrimidylcyanamide 4 reacts with trisubstituted thioureas in a hydrochloric acid medium. The reaction products in this case are thiobisformamidines 34 [46].
R1 N R2 4 C S HCl Me NH Ar Me N NH N C NH 34 S C NAr N R2 R1
. HCl
Alcoholysis of hetarylcyanamides in the presence of gaseous hydrogen chloride leads to the formation of the hydrochlorides of hetaryl-O-alkylisoureas 35 [49].
NH . HCl Het N CN R1 Het = 1,3,5-triazinyl R2 OH / HCl Het N R1 C 35 OR2
Alcoholysis in dilute hydrochloric acid is accompanied by hydrolysis of the intermediately formed O-alkylisoureas to the carbamic esters 36 [50].
N N H 36 NH C O OR
ROH / HCl 10 : 2
3-Methyl-5-(4-phenyl-2-thiazolylamino)-1,2,4-triazole (39) was obtained from thiazolylcyanamide 37 and acetylhydrazine through derivatives of acetylaminoguanidine 38 [51].
Ph MeCONHNH2 S 37 NHCN S 38 Ph N NH NH C NHNHCOMe 10% NaOH N N Me N N H 39 S N Ph
1114
The reaction of o-phenylenediamine and o-aminothiophenol with hetarylcyanamides 6 takes place with the immediate formation of the corresponding derivatives of hetarylaminobenzimidazole 40 and hetarylaminobenzothiazole 41. o-Aminophenol reacts under harsher conditions and with more prolonged reaction time, leading to the formation of hetarylaminobenzoxazoles 42 [52].
NH2
N
NH2
NHHet N
NH2 SH
40 S NHHet N
NH2 OH
41 O N 42 NHHet
The pyrimidylaminotriazole 43 is formed when pyrimidylcyanamide 4 is treated with hydrazine hydrate and formaldehyde. The analogous reaction with benzaldehyde as carbonyl component leads to the formation of compounds 44. The three-component condensation of cyanamide, formaldehyde, and benzylamine or phenylethylamine gives pyrimidylaminotriazole 45 [53].
R Me RCH=O / H2NNH2 Me N N N H 43 Ph Me PhCOHNNH2 / H2O 4 Me N N N H 44 Me Ph(CH2)nNH2 / H2O Me N N N H 45 N N N (CH2)nPh (CH2)nPh N H N N N H N N
2-(2-Benzimidazolylamino)-4-hydroxypyrimidines 47 were synthesized by the cyclization of hetarylcyanamide 46 with substituted o-phenylenediamines [54].
1115
OH N Me N 46 NHCN
OH
R2
NH2 NH R1
R2 N R1
N N H 47
N N Me
The hetarylcyanamide 4 reacts abnormally with -diketones and -keto esters in the presence of catalytic amounts of nickel acetylacetate with the formation of the N,N-acetals of diacyl- and alkoxycarbonyl(acyl)ketenes 48 and 49 [55, 56].
O O Me N N Me 4 O R1 R2 O Me N O R2OC 48 Me N H N NH2 O COR1 H N NH2
R1CCH2CR2
49 R1 = Alk or Ph, R2 = Me or EtO
R1
R2
2.2.1. Cycloaddition at the Cyano Group. Nitrile oxides and nitrile imines react at the cyano group according to a 1,3-dipolar cycloaddition mechanism. In the first case hetarylamino-1,2,4-oxadiazoles (50) are formed, and in the second hetarylamino-1,2,4-triazoles (51) [46].
R C N O HetHN 6 + _ N N N HetHN N Ph 51 Het = pyrimidyl, 1,3,5-triazinyl N R N O 50 Ph Ph N
PhC
The hetarylcyanamides 6 react with azides in two directions, forming 5-amino-1-hetaryltetrazoles 52 or 5-hetarylaminotetrazoles 53. Compounds of the first type are formed under mild conditions, whereas in higherboiling solvents or with azidotrimethylsilane the thermodynamically more stable compounds 53 are formed [52].
1116
NH3 H2N 6 Me3SiN3 HetNH
N N 52 N N H 53
N N
Het N N
2-Isopropylborylaminopyridine adds smoothly to the cyanamide 3 with the formation of the [4+2] cycloadduct 54 [57].
Het
H N C N i-Pr N
Het NH B Pr-i
N HN
N B NH Pr-i 54
+
N NHB(i-Pr)2
i-Pr
The benzimidazolylcyanamide 3 enters into [4+2]-cycloaddition with aroylketenes, generated during thermolysis of 5-aryl-2,3-dihydrofuran-2,3-diones. The products are benzimidazolylaminooxazinones 55 [58].
O Ar O O CO O O 3
+
Ar
C Ar O O
N N H
N N H
55
The pyrimidylcyanamide 4 does not enter into this reaction.
2.3. Reactions with the Simultaneous Participation of the Amino and Cyano Groups As already mentioned above, the hetarylcyanamides 10 can react at both groups simultaneously; at the first stage substitution by the functionalized alkyl halide occurs in the amino group, and at the second intramolecular addition of the introduced function occurs at the multiple bond of the cyano group. This is illustrated by the scheme. 1117
O NCNCHR2CO2R3 HalCHR2COOR3 [4143] R1HN N N N X KOH R3OH R1HN NHCN N RHN N N X NCNCHR2CONHR3 ClCHR2CONHR3 [59, 60] O [40] Hal(CH2)2OCMe R1HN N N N X R3 N O NCN(CH2)2OH N Me2N N N NMe2 RHN HN N N 58 O N N R1HN N X N 57 X N N O KN O N N 56 N N X H R2
In some cases the order of the stages may be reversed [61]

NH NHCN N RHN N N NHR HCl . H2NCH2CO2Et HN HNCNHCH2CO2Et HN N RHN N N N NHR RHN N 59 NHR N N O
On account of the acidic characteristics of the NH group in the hetarylcyanamide 10 2-aminoethylammonium salts are formed in its reaction with ethylenediamine, and on heating they release ammonia to form compounds 60 [62].
HN + NCNNH3(CH2)2NH2 H2NCH2CH2NH2 10 R N N N R1 NH3 R HN N N 60 N N R1
Oxirane and aziridine react with the hetarylcyanamides 10 with the formation of compounds 58 [62] and 60 [63]. 1118
2.4. Reactions with the Participation of the Cyanoamino Group and the Heterocycle As a rule condensed heterocyclic systems are formed in reactions that take place with participation of the cyanoamino group and the heterocycle. Thus, treatment of 2-pyrazinylcyanamide with hydroxylaminesulfonic acid in the presence of polyphosphoric acid gives the triazolopyrazine 61 [52].
N N
NHCN
H2NOSO3H PPA
N N
N N
61
NH2
With acetylacetone in the presence of nickel acetate the benzimidazolylcyanamide 3 undergoes cyclocondensation to form the pyrimido[1,2-a]benzimidazole 62 [64]. Acylacetic esters enter into this reaction with the formation of pyrimido[1,2-a]benzimidazoles 63 [65].
N MeCOCH2COMe Ni(acac)2 N N H NHCN RCOCH2CO2Et Ni(RCOCHCO2Et)2 N Me 62 N N NH2 CO2Et 63 N N NH2
Annelation of the pyrimidine ring to the benzimidazole ring is promoted by activation of the CN group in the hetarylcyanamide by the catalyst. In the absence of the nickel salts it is not possible to synthesize compounds 62 and 63 even if acidic or basic catalysts are used.
2.5. Intramolecular Reaction of the Cyanamide Group with Other Groups in the Heterocycle The cyanation of 1-amino-2-mercaptotriazole 64 with bromocyanogen gives the hetarylcyanamide 65, which undergoes cyclization under the reaction conditions to 6-amino-sym-triazolo[3,4-b]-1,3,4-thiadiazole 66 [66].
N Py N NH2 64 N SH BrCN Py N N N SH Py N N N 66 N S NH2
NHCN 65
The cyanation of 5-amino-4-imidazolecarboxamide 67 takes place in a similar way. The reaction of the amide and cyanamide groups in the intermediate compound 68 leads to the formation of the guanine derivatives 69 [67, 68]. 1119
O C N N R1 67 NH2 BrCN NHR 2 N N
O C NH2 H2N N
O N N R2 69 N R1
NCN
R2 R1 68
The recyclization of imidazo[1,5-b]-s-triazole 70 to the guanine 72 also takes place with the participation of these groups [69].
O H2N C N N N N Me _ OH N _ N 71 NCN Me 70 H2N O C NH2 N N Me 72 N H O N
Amination of the purines 73 with a labeled amine showed that dehalogenation takes place by an SN (ANRORC) mechanism with the intermediate formation of the hetarylcyanamide 74. The final product of such a reaction is the aminopurine 75 [70].
R N X N 73 N H N * _ NH2 N N H R * NH NHCN H2N * N N 75 N H R N
74 R = H, Ph; X = F, Cl, SMe
If there is a nitrile group at position 3 of the hetarylcyanamide 76, cyclization takes place under the influence of hydrogen bromide. The nitrile group is more active at reduced temperature, and the cyanamide group at increased temperature. In the first case compound 77 is formed, and in the second its regioisomer 78 is formed [71, 72].
Me CN O N H 76 NHCN HBr 1015
oC
Me
Br NH
Me
Br N
N H
NHCN
N H 77
N H
NH2
Me CN HBr O N H NCN ~100 oC O
Me CN NH N H N H Br O
Me
NH2 N
N H 78
Br
1120
In the presence of hydrogen chloride only one isomer 78 was isolated irrespective of the reaction conditions [72]. Thus, the published data on the synthesis and properties of hetarylcyanamides that we examined indicate that these compounds can be used as important synthons for the production of various azaheterocycles. In addition, these hetarylcyanamides exhibit specific biological activity. Thus, derivatives of sym-triazinylcyanamides have found use as pesticides [73]. Substances with sedative and tranquillizing activity have been found among the synthesized 1,3-oxazin-4-ones produced from hetarylcyanamides [74]. A series of papers devoted to the problems discussed in this review appeared in 2000-2001 [75-79].
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1123
THE USE OF 4-(BROMOMETHYLENE)5,5-DIMETHYL-1,3-DIOXOLAN-2-ONE AS "MASKED" -BROMO-'-HYDROXY KETONE IN THE SYNTHESIS OF HETEROCYCLIC SYSTEMS
A. A. Bogolyubov, N. B. Chernysheva, and V. V. Semenov 4-(Bromomethylene)-5,5-dimethyl-1,3-dioxolan-2-one was obtained on the basis of the readily obtainable 4-methylene-5,5-dimethyl-1,3-dioxolan-2-one. It forms 2-imidazo[1,2-a]pyridin-2-yl-2propanol with 2-aminopyridine, 11a-hydroxy-1,1-dimethyl-3-oxo-1,5,11,11a-tetrahydro[1,3]oxazolo[3,4-a]pyrido[1,2-d]-10-pyrazinium bromide with 2-(aminomethyl)pyridine, and the corresponding derivative of 4-hydroxyoxazolidin-2-one with 2-(3,4-dimethoxyphenyl)ethylamine. The last product was converted by intramolecular amidoalkylation without isolation into 10b-(bromomethyl)-8,9-dimethoxy1,1-dimethyl-1,5,6,10b-tetrahydro[1,3]oxazolo[3,4-a]isoquinolin-3-one. Keywords: 4-bromo-4-(bromomethyl)-5,5-dimethyl-1,3-dioxolan-2-one, 11a-hydroxy-1,1-dimethyl-3oxo-1,5,11,11a-tetrahydro[1,3]oxazolo[3,4-a]pyrido[1,2-d]-10-pyrazinium bromide, 4-(bromomethylene)5,5-dimethyl-1,3-dioxolan-2-one, 10b-(bromomethyl)-8,9-dimethoxy-1,1-dimethyl-1,5,6,10btetrahydro-[1,3]oxazolo[4,3-a]isoquinolin-3-one, 2-imidazo[1,2-a]pyridin-2-yl-2-propanol, intramolecular amido-alkylation. The dioxolanones 2 and 3 can be regarded as "masked" precursors of the -halo-'-hydroxy ketone HalCH2COC(RR1)OH. In cases where the corresponding -ketones do not exhibit the required regioselectivity it is possible to achieve the required direction of reaction by using compounds 2 and 3. It is known that the readily obtainable 4-methylene-1,3-dioxolan-2-ones (1a-c), prepared from propargyl alcohols and CO2, can add Cl2 [1]. Here the dioxolanones 3 or 4 are obtained. The compositions and yields of the products depend on the reaction conditions. Thus, in methylene chloride the dioxolanone 3a was obtained with a 91% yield after 2 h at -50C, and the dioxolanone 4a was obtained with a 79% yield after 3 h at -30C.
X R R1 O O 1ac O X2 R1 O O O 2ad R X X for 2d NEt3 R R1 O O O 3ad X X2 R1 O O 4ac O R X
1-4 a R + R1 = (CH2)5, X = Cl; b R = R1 = Me, X = Cl; c R = Me, R1 = Et, X = Cl; 2, 3 d R = R1 = Me, X = Br
__________________________________________________________________________________________ N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow; e-mail: vs@cacr.ioc.ac.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1303-1309, September, 2004. Original article submitted January 23, 2002. 1124 0009-3122/04/4009-11242004 Springer Science+Business Media, Inc.
The dioxolanones 2a-c were not characterized by the authors of [1] since these substances are evidently unstable. On the other hand, the dioxolanone 2d that we synthesized with a yield of 57% is completely stable under certain conditions (see the experimental section). By analogy with the dehydrobromination of 4-bromo-4(bromomethyl)oxazolidin-2-ones [2] triethylamine in dry benzene was used to convert 2d into the unsaturated dioxolanone 3d with a yield of 90%. It should be noted that pyridine is not suitable for this purpose. There is no [M]+ peak in the mass spectrum of the dioxolanone 2d, but there is an M - 81 (M - HBr) peak coinciding with [M]+ of the dioxolanone 3d, and in addition there is a peak for M - 81 - 44 (M HBr CO2). The mass spectrum of the dioxolanone 3d is identical with the mass spectrum of the dioxolanone 2d. The structure of all the synthesized substances, including the dioxolanones 2d and 3d, was also confirmed by data from the IR and 1H NMR spectra (Tables 1 and 2). The dioxolanone 2d reacts with 2-aminopyridine in the presence of calcined K2CO3 in anhydrous ethanol with the formation of the imidazolopyridine 7. The yield in this reaction amounts to 74%; the use of 95% ethanol reduces the yield to 6-8%. In our proposed method the yield is no lower on average than during the direct reaction of -bromo ketones with 2-aminopyridines [3].
Br 2d 2-H2NPy
N 2-H2NPy K2CO3 O O 6 N OEt
3d
EtOH 2-H2NPy O O 5
O OEt
K2CO3 HO N
In our opinion the reaction takes place through a stage involving the formation of the dioxolanone 3d and the linear unsymmetrical carbonates 5 and 6. Opening of the dioxolanones 1, related to the dioxolanones 2d and 3d, by alcohols in the presence of bases was described in [4]. It is also known that at 60C in the absence of a solvent the dioxolanones 1 react with 2-aminopyridine and are converted after 115 h into 3-(2-pyridyl)oxazolidinones [5]. The mass spectrum of the imidazopyridine 7 contains [M]+, [M - 15]+ (M - Me), and [M - 15 - 18] (M - Me - H2O) peaks. One of the standard methods for the synthesis of oxazoloisoquinolines of type D is reaction of the corresponding oxazolidine-2,4-dione A with a suitable organolithium compound; the obtained oxazolidinone B is then treated with trifluoroacetic acid [6]. The first stage of the process is complicated by the formation of C as impurity.
O RLi Hv N O A O -78C, THF, 6 h CF3COOH MeO R MeO AD R = Bu, Hv = N O D, 95% O OMe HO Hv N O O B, 58% R O
Hv
NH
OR O C, 16%
OMe
1125
This approach cannot be applied to oxazoloisoquinoline 9 of type D examined below, where R = CH2Br. By analogy with our previous work [7] we used the reaction presented below for the synthesis of compound 9.
Br 2d
OH H+ N O 8 O H2O
MeO MeO Br O 9 N O
HvNH2
K2CO3 MeCN Hv
The intermediate not isolated oxazolidinone 8 is formed during the reaction of 2-(3,4-dimethoxyphenyl)ethylamine (homoveratrylamine, HvNH2) with the dioxolanone 2d.* When treated with 99.8% formic acid the oxazolidinone 8 gives the desired product 9 with a yield of 61%. The concentration of the substance 8 in the reaction mixture amounted to 0.12 g/ml. If the amount of the acid is reduced to a quarter, the yield of 9 decreases to 30%; we have observed this effect before [7]. In this case the process is complicated by side reactions. In the mass spectrum of the oxazoloisoquinoline 9 there are [M]+, [M - 81] (M - HBr), [M - 94] (M - CH2Br), and [M - 94 - 44] (M - CH2Br - CO2) peaks. An example of the use of the dioxolanone 3d is the preparation of the salt 13 a representative of the new heterocyclic system oxazolo[3,4-a]pyrido[1,2-d]-10-pyrazinium.
N H2N
3d
HO O O fast N 10 HBr
Br N
slow +H2O fast H2O O O 12 fast N
Br N
O N O O 11 N slow +HBr O
HO N O 13
+ N _ Br
If a chloroform solution of 2-(aminomethyl)pyridine is added to a chloroform solution of the dioxolanone 3d, the salt 13 separates out. To judge from TLC the mother solution contains several substances, presumably 11 and 12, but no longer contains the initial 2-(aminomethyl)pyridine. The salt 13 begins to separate _______ * The reaction of amines with the related dioxolanones 1 was examined in [8]. 1126
out even at the moment the solutions are mixed, and it can therefore be supposed that the oxazolidinone 10 is unstable and immediately changes into compounds* 11, 12, and 13, its concentration is low, and it cannot be seen on the TLC. We consider that compounds 11 and 12 are slowly transformed into the salt 13, as shown in the scheme. If the salt is periodically removed from the mother solution, it is possible to observe the separation of new portions of the salt 13 from the solution. After 20 h at 50C approximately 25% of the salt 13 has separated from the mother solution (total yield 48%). The best results were obtained with benzene as solvent, and the yield in this case amounted to 83%. From benzene practically all the salt separates immediately. Further
TABLE 1. The Constants and Yields of the Synthesized Compounds

Compound 2d mp, C* Rf (system) IR spectrum, cm-1 1816 Mass spectrum, m/z (I, %) 288 [M]+ absent, 207 (20.0), 163 (30.3), 137 (46.4), 135 (52.3), 123 (58.5), 121 (65.9) 207 [M]+ (20.0), 163 (30.3), 137 (46.4), 135 (52.3), 123 (58.5), 121 (65.9) 176 [M]+ (23.5), 161 (100.0), 143 (13.0), 119 (18.1) 370 [M]+ (0.5), 289 (22.0), 176 (100.0), 232 (70.5) 234 [M+ - 1] (35.0), 216 (14.0), 173 (28.1), 157 (14.0), 148 (13.2) Yield, %
54-55.5
57
3d
105-106.5
1828, 1688 3240 1740 1748, 3424
90
7 9 13
120-121 146-151 129-144 (with dec.)
0.22 (B)*2 0.28 ()
74 61 83
_______ * mp in sealed capillary. *2 Fivefold elution.

Compound 2d 2d 3d 7 9 Chemical shifts (DMSO-d6), , ppm (J, Hz)* [1.64 (3H, s), 1.84 (3H, s)] (5,5-CH3); [3.90 (1H, d, J = 13.3); 4.03 (1H, d, J = 13.3)] (4-CH2Br) [1.62 (3H, s), 1.78 (3H, s)] (5,5-CH3); 4.33 (2H, s, 4-CH2Br) 1.64 (6H, s, 5,5-CH3); 6.13 (1H, s, 4-CHBr) 1.47 (6H, s, 2-C(CH3)2OH); 4.78 (1H, br. s, 2-C(CH3)2OH); 6.78 (1H, t, H-6); 7.18 (1H, t, H-7); 7.43 (1H, d, J = 10.0, H-8); 7.68 (1H, s, H-3); 8.43 (1H, d, J = 8.3, H-5) [0.97 (3H, s), 1.76 (3H, s)] (1,1-CH3); {[2.70 (d, J = 4.9), 2.76 (d, J = 4.9)] (1H); 2.83-3.00 (1H, m)} (H-6,6); {[3.37 (d, J = 4.9), 3.42 (d, J = 4.9), 3.47 (d, J = 4.9)] (1H); [4.12 (d, J = 7.1), 4.17 (d, J = 7.1)] (1H)} (H-5,5); 3.80-3.93 (8H, m, 8,9-OCH3, 10b-CH2Br); [6.47 (1H, s), 6.67 (1H, s)] (H-7,10) [1.48 (3H, s), 1.52 (3H, s)] (1,1-CH3); [4.88 (1H, d, J = 20.1); 5.19 (1H, d, J = 20.1)] (H-11,11); [5.02 (1H, d, J = 15.0), 5.11 (1H, d, J = 15.0)] (H-5,5); 6.97 (1H, br. s, 11a-OH), 8.11 (1H, t, H-8); 8.25 (1H, d, J = 7.8, H-6); 8.64 (1H, t, H-7); 8.97 (1H, d, J = 7.8, H-9)
13
_______ * Compounds 2d and 9 were recorded in deuterochloroform. _______ * The opening of the epoxide ring in oxazolidinones of type 11 was described in [9]. The transformation of the oxazolidinones 10 into the oxazolidinones 12 is reversible [5] (see also [2]). 1127
heating of the mother solution is not advised a highly contaminated salt 13 separates from it. (After 20 h at 50C the chloroform mother solution also contains a certain amount of unreacted substances, but its further use is inadvisable for the same reason.) The order in which the reagents are mixed is very important in this reaction; the 2-(aminomethyl)pyridine is added to the dioxolanone 3d, or otherwise the reaction is complicated by side products. It is also recommended to cool the reaction mixture at the beginning of the reaction. The solvents must be dry, or otherwise the salt 13 separates in the form of a noncrystallizing oil. The mass spectrum of the salt 13 contains [M - 81] (M - HBr), [M - 81 - 18] (M - HBr - H2O), and [M - 81 - 18 - 44] (M - HBr - H2O - CO2) peaks. The signals for the protons of the pyridinium ring in the 1 H NMR spectrum of the salt 13 are shifted downfield by ~0.5 ppm compared with the signals of the protons in the unquaternized pyridine rings. Thus, the dioxolanones 2d and 3d are convenient synthons for the synthesis of heterocyclic compounds. Three of the five synthesized compounds 7, 9, and 13 contain the pharmacophoric oxazolidinone ring and/or a ethanolamine fragment and may therefore be of interest as potential biologically active compounds. EXPERIMENTAL The 1H NMR spectra were recorded on a Bruker WM-500 instrument (500 MHz; for compound 9 250 MHz, for 13 300 MHz) with TMS as internal standard. The IR spectra were obtained on a Perkin-Elmer 577 instrument (potassium bromide). The mass spectra were obtained on a Kratos MS-30 mass spectrometer (direct injection, 70 eV, 250C). Thin-layer chromatography was carried out on Silufol UV-254 plates with 2:1 benzeneethyl acetate (A) and 2:1 ethyl acetatebenzene (B) systems. The cooling bath was acetonedry ice. The extracts were dried by filtration through a layer of cotton wool. The dioxolanone 1b was obtained by the procedure described in [10, 11]. 4-Bromo-4-(bromomethyl)-5,5-dimethyl-dioxolan-2-one (2d). To a solution of dioxolanone 1a (6.54 g, 51.13 mmol) in methylene chloride (10 ml) we added a mixture of calcined potassium carbonate ground to a powder (7.07 g) and Trilon B (0.01-0.03 g). To the suspension with cooling at -3 to +3C and vigorous stirring over 20 min we added dropwise a solution of bromine (8.18 g, 51.13 mmol) in methylene chloride (10 ml). The reaction mixture was allowed to heat up to room temperature. If the pH the mixture was not neutral, the mixture was heated to 30-40C and stirred to a neutral pH (~20-40 min). The mixture was filtered through cotton wool, the solid residue was washed with methylene chloride (3 5 ml), the combined washing liquids and mother solution were evaporated, and the solvent residues were removed under vacuum. The residue was kept at 2-5C for six days. The crystals were filtered off from the syrupy mother solution, washed with heptane (3 5 ml), and dried, 10.33 g (70%) of the technical product was obtained, and benzene (2 ml) was added. The mixture was heated until the crystals had disappeared, and heptane (4 ml) was added to the obtained viscous solution. It was rubbed with a glass spatula on a cooling bath. The crystals were filtered off, washed with heptane (3 5 ml), and dried, and 6.60 g of the dioxolanone 2d was obtained. The combined washing liquids and mother solution were evaporated. The crystals were separated, washed with heptane (3 1 ml), and dried, and an additional 1.72 g of the product was obtained. The total yield was 8.32 g. The pure product was fully stable at room temperature for more than two years, but impurities of Fe, Co, Ni, and possibly other heavy metals promote the release of hydrogen bromide. The decomposition is autocatalytic in nature and is appreciably accelerated in a moist atmosphere. A sign that decomposition has begun is the appearance of orange-colored crystals. In this case it is recommended that the substance be recrystallized. The dioxolanone 2d is best stored at 0-4C without access to moisture over calcined potassium carbonate in a dark glass vessel. 4-(Bromomethylene)-5,5-dimethyl-1,3-dioxolan-2-one (3d). To a solution of the dioxolanone 2d (6.59 g, 22.88 mmol) in dry benzene (8 ml) at room temperature we added dry triethylamine (3.1 ml), and after 15 min we heated the mixture at 70-80C. The mother solution was separated from the NEt3HBr, the salt was washed with benzene (3 3 ml), and the combined wash liquids and mother solution were evaporated. The 1128
solvent residues were removed under vacuum, the crystals were washed with heptane (4 3 ml) and dried, and 4.27 g of the dioxolanone 3d was obtained. When necessary the substance was purified by vacuum sublimation at 10 mm Hg (bath temperature 140C). The product must be stored and handled in the same way as the initial dioxolanone 2d. The dioxolanone 3d is a weak lacrimator and irritant. Found %: C 34.78; H 3.55; Br 38.47. C6H7BrO3. Calculated %: C 34.81; H 3.50; Br 38.50. 2-Imidazo[1,2-a]pyridin-2-yl-2-propanol (7). A mixture of 2-aminopyridine (1.41 g, 15.00 mmol), calcined potassium carbonate ground to a powder (4.14 g, 30.00 mmol), the dioxolanone 3d (4.54 g, 15.76 mmol), and absolute ethanol (20 ml) was kept at 50C for 18 h 30 min with periodic stirring. The solvent was evaporated, and the substance was extracted from the solid residue with 20, 15, and 10 ml of chloroform. The extract was filtered through cotton wool and evaporated. The crystals that separated were treated with 3 ml of heptane and dried, and 2.20 g (83%) of the technical product was obtained. It was dissolved in hot benzene (4 ml) and precipitated with heptane (3 ml) with cooling; the crystals were washed with a 5:1 mixture of heptane and benzene (3 2 ml) and with heptane (3 ml) and dried under vacuum at 90C and 3 mm Hg. A small amount of a transparent liquid with unestablished composition distilled into the trap. (According to the mass spectrum, the liquid contained two substances with molecular weights of 187 and 235.) We obtained 1.95 g of light-brown crystals. Found %: C 75.44; H 7.42; N 8.00. C11H13NO. Calculated %: C 75.40; H 7.50; N 7.98. 10b-(Bromomethyl)-8,9-dimethoxy-1,1-dimethyl-1,5,6,10b-tetrahydro[1,3-a]oxazolo[4,3-a]isoquinolin2-one (9). To a mixture of the dioxolanone 2d (1.87 g, 6.49 mmol) and calcined potassium carbonate ground to a powder (0.91 g, 6.59 mmol) in methylene chloride (10 ml) at room temperature we added homoveratrylamine (1.06 g, 5.86 mmol) in methylene chloride (5 ml); the mixture was stirred until the release of CO2 had stopped (~1 h) and left overnight. The inorganic salts were separated and washed with methylene chloride (3 2 ml). The combined washing liquids and mother solution were evaporated, the obtained dark oil was dissolved in 99.8% formic acid (20 ml), and the mixture was kept at room temperature for 24 h. The formic acid was distilled, and the residue was treated with 10 ml of water and extracted with 35 ml of methylene chloride. The extract was washed with water (3 15 ml) and filtered through cotton wool and evaporated. The substance was precipitated with heptane (30 ml) from a hot solution in methylene chloride (10 ml). The mixture was placed in a cooling bath, and the crystals were separated. They were washed with a 5:1 mixture of heptane and methylene chloride (5 ml) and dried under vacuum, and 1.32 g of light-cream crystals was obtained. Found %: C 51.90; H 5.44; Br 21.58; N 3.79. C16H20BrNO4. Calculated %: C 51.88; H 8.19; Br 21.50; N 4.88. 11a-Hydroxy-1,1-dimethyl-3-oxo-1,5,11,11a-tetrahydro[1,3-a]oxazolo[3,4-a]pyrido[1,2-d]-10pyrazinium Bromide (13). To a solution of the dioxolanone 2d (1.44 g, 5.00 mmol) in dry benzene (11 ml) we added dry triethylamine (1.7 ml). After 15 min the mixture was heated to 70-80C and kept for 30 min. The crystals of NEt3HBr were separated and washed with benzene (3 3 ml). The combined washing liquids and the mother solution were evaporated, and the dioxolanone 3d was obtained in the form of a light-brown oil. A. To a solution of the dioxolanone 3d in chloroform (5 ml), cooled to -20C, we added 2-(aminomethyl)pyridine (0.54 g, 5.00 mmol) in dry chloroform (5 ml). The mixture was allowed to heat to room temperature, and the salt 13 separated out. The mixture was heated at 50C for 20 h. The salt was filtered off, washed with chloroform (3 3 ml), and dried, and 0.75 g of light-brown plates was obtained. B. To a solution of the dioxolanone 3d in dry benzene (1 ml), cooled to 6-8C, we added 2-(aminomethyl)pyridine (0.54 g, 5.00 mmol) in benzene (1 ml). The mixture was allowed to heat to room temperature, and the salt 13 separated out. It was filtered off, washed with benzene (3 1 ml), and dried, and 1.30 g of dark-brown plates was obtained. Thin-layer chromatography of the solutions obtained in systems A and B showed the presence of at least two substances, probably the intermediates 11 and 12, in the form of two spots with Rf 0.60 and 0.85. It was not possible to isolate these compounds.
1129
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. P. Dimroth and H. Pasedach, Ger. Patent 1158079; Chem. Abstr., 38, 6849 (1964). C. C. Browne and N. Punja, J. Chem. Soc., Perkin Trans. 1, 16, 1525 (1975). R. Adams and J. S. Dis, J. Am. Chem. Soc., 80, 4618 (1958). J. Fournier, C. Bruneau, and P. H. Dixneuf, Synlett, 5, 453 (1992). A. A. Bogolyubov, N. B. Chernysheva, V. V. Nesterov, M. Yu. Antipin, and V. V. Semenov, Khim. Geterotsikl. Soedin., 1152 (2004). M. I. Collado, N. Sotomayor, M.-J. Villa, and E. Lette, Tetrahedron Lett., 37, 6193 (1996). N. B. Chernysheva, A. A. Bogolyubov, V. V. Murav'ev, V. V. Elkin, and V. V. Semenov, Khim. Geterotsikl. Soedin., 1409 (2000). N. B. Chernysheva, A. A. Bogolyubov, and V. V. Semenov, Khim. Geterotsikl. Soedin., 241 (1999). V. Nuti and M. F. Saetone, Tetrahedron, 26, 3875 (1970). P. Dimroth and H. Pasedach, Ger. Patent 1098953; Chem. Abstr., 56, 2453 (1962). www.chemical-block.com.
1130
SYNTHESIS AND REACTIONS OF 1-(3-CHLOROPROPYL)-6,7-DIMETHOXY3-METHYLBENZO[c]PYRYLIUM PERCHLORATE

A. V. Kibalny, A. A. Afonin, and V. I. Dulenko Acid-catalyzed acylation of 3,4-dimethoxyphenylacetone with -chlorobutyryl chloride gave 1-(3-chloropropyl)-6,7-dimethoxy-3-methylbenzo[c]pyrylium perchlorate. Recyclization of the product with nitrogen nucleophiles (ammonia, primary amines, hydrazine derivatives, hydroxylamine) led through the corresponding isoquinolinium salts to benzo[f]indolizinium, pyridazino[2,1-b]isoquinolinium, and 1,2-oxazino[2,1-b]isoquinolinium salts. Keywords: 3,4-dimethoxyphenylacetone, 1-(3-chloropropyl)-6,7-dimethoxy-3-methylbenzo[c]pyrylium, -chlorobutyryl chloride, recyclization. The variety of transformations found in pyrylium salts [1, 2] is due both to the presence of the heteroatom and to the nature of the substituents. In our opinion, one important aspect of the development of the chemistry of the pyrylium cation is the introduction of a functional substituent into its molecule. Of particular interest are cases where the substituent participates in recyclization reactions, since here new important transformations for pyrylium salts are observed [3-7]. In the development of this we synthesized pyrylium salts in which the functional group is in the -alkyl substituent by using the chlorides of functionally substituted carboxylic acids in acid-catalyzed heterocyclization [8]. Thus, we have found that the acylation of mesityl oxide, 3,4-dimethoxyphenylacetone, and 3-indolylacetone with -butyryl chloride gives respectively mono-, di-, and tricyclic pyrylium cations, which undergo recyclization with ammonia to dihydroindolizinium derivatives by intramolecular quaternization of the intermediate pyridine base, i.e., the reaction takes place with reconstruction of the ring [9]. It seemed of interest to study the reaction of -(-chloropropyl)pyrylium salts with various nitrogen nucleophiles. In the present work we describe the synthesis and some recyclization reactions of 1-(3-chloropropyl)-6,7-dimethoxy-3-methylbenzo[c]pyrylium perchlorate (1), produced by two procedures for the acylation of 3,4-dimethoxyphenylacetone (2) with -chlorobutyryl chloride, i.e., in the presence of perchloric acid and with the use of Lewis acids. The preferred method was the use of tin tetrachloride in methylene chloride with the intermediate isolation of 1-(3-chloropropyl)-6,7-dimethoxy-3-methylbenzo[c]pyrylium hexachlorostannate (3), the treatment of which with perchloric acid in methanol led to the corresponding perchlorate 1 with an overall yield of 80% (compared with the 63% obtained during acylation of the ketone 2 using perchloric acid). __________________________________________________________________________________________ L. M. Litvinenko Institute of Physical Organic and Coal Chemistry, National Academy of Sciences of Ukraine, Donetsk, Ukraine; e-mail: dulenko@infou.donetsk.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1310-1316, September, 2004. Original article submitted May 28, 2002. 0009-3122/04/4009-11312004 Springer Science+Business Media, Inc. 1131
O O 2 O
Cl(CH2)3COCl SnCl4
O + O 3 O 1 2 SnCl62 Cl
HClO4
O + O 1 O ClO4
Cl
The following nitrogen nucleophiles were used to study the recyclization of the perchlorate 1: Ammonia, primary amines, hydroxylamine, hydrazine and its derivatives. It was established that the reaction of the perchlorate 1 with ammonia under various conditions (liquid ammonia, alcohol and wateralcohol solutions of ammonia, ammonium acetate in acetic acid) led with yields close to quantitative to 8,9-dimethoxy-5-methyl-8,9-dimethoxy-2,3-dihydrobenzo[f]indolizinium perchlorate (4). The supposed intermediate -chloropropylisoquinoline 5 was not isolated even when liquid ammonia was used for the recyclization of the salt 1. In our opinion the initially formed isoquinoline 5 is quaternized as a result of an intramolecular reaction, leading to the isolation of the tricyclic benzoindolizinium perchlorate 4. Examples of the intramolecular quaternization of bases of the halogenoalkyl derivatives of pyridine known from the literature [10-13] demonstrate the high rate of this process. As a rule the recyclization of 1,3-dialkyl-substituted benzo[c]pyrylium salts by the action of hydrazine and hydroxylamine leads to N-substituted isoquinolinium salts or N-oxides [14]. During recyclization of the perchlorate 1 by the action of hydrazine, its derivatives, and hydroxylamine we isolated the quaternary salts in the form of perchlorates. It was established on the basis of elemental analysis and spectral characteristics that the recyclization of the perchlorate 1 with hydrazine, methylhydrazine, and hydroxylamine leads to quaternary derivatives of isoquinoline with annelation of a new ring, i.e., 9,10-dimethoxy-6-methyl-1,2,3,4tetrahydroisoquinolino[2,1-b]pyridazinium (6a), 9,10-dimethoxy-4,6-dimethyl-1,2,3,4-tetrahydroisoquinolino[2,1-b]pyridazinium (6b), and 9,10-dimethoxy-6-methyl-1,2,3,4-tetrahydroisoquinolino[2,1-b]-1,2-oxazinium (6c) perchlorates respectively.
O + O _ N ClO4 R Cl 8aj RNH2 1 NH2XH NH3
O O N Cl 5
O + O N X _ ClO4 6ac
O + O N
_ ClO4 XH Cl
O + O N
_ ClO4
7ac
6, 7 a X = NH, b X = NMe, c X = O; 8 a R = Me, b R = CH2Ph, c R = Ph, d R = p-MeC6H4, e R = p-MeOC6H4, f R = o-H2NC6H4, g R = -64, h R = NHPh, i R = NHCOMe, j R = NHCOPh
1132
As in the case of recyclization by the action of ammonia, the intermediate isoquinolinium derivatives 7ac were not isolated. This is fully explainable since the nucleophilic characteristics of the amino group in the intermediate N-aminoisoquinolinium cations 7a,b and the oxygen atom of the N-oxide 7c (in the deprotonated form) are very high, as confirmed earlier by alkylation and by the formation of derivatives with aldehydes (of the Schiff base type) [14]. The recyclization of the perchlorate 1 followed by spontaneous cyclization, observed under the influence of ammonia, hydrazine, methylhydrazine, and hydroxylamine, provides examples of tandem [15] reactions of cascade type. During the action of primary amines and aryl- and acylhydrazines, however, under the same conditions only the "normal" recyclization products, i.e., the N-substituted isoquinolinium salts 8a-j, are isolated. This is probably due to the reduced basicity and nucleophilicity of the exocyclic amino group and also, possibly, steric hindrances. The composition and structure of all the synthesized compounds were confirmed by elemental analysis and by IR and 1H NMR spectroscopy. Thus, in the IR spectra of compounds 1, 4, 6a-c, and 8a-j there are characteristic absorption bands in the regions of 1100 (ClO4) and 1620-1635 cm-1, while in the spectra of the salts 6a and 8f-j there are in addition bands in the region of 3230-3275 (NH), 3375-3455, and 3440 cm-1 (OH). In the 1H NMR spectra of the salts 4 and 6a,c the triplet for the protons of the methylene groups adjacent to the heteroatom are substantially downfield from the triplet of the -methylene group in the initial salt 1. In the
TABLE 1. The Characteristics of the Synthesized Compounds 1, 3, 4, 6a-c, and 8a-j

Compound 1 3 4 6a 6b 6c 8 8b 8c 8d 8e 8f 8g 8h 8i 8j Empirical formula C15H18Cl2O7 C15H18Cl4O3Sn1/2 C15H18ClNO6 C15H19ClN2O6 C16H21ClN2O6 C15H18ClNO7 C16H21Cl2NO6 C22H25Cl2NO6 C21H23Cl2NO6 C22H25Cl2NO6 C22H25Cl2NO7 C21H24Cl2N2O6 C21H23Cl2NO7 C21H24Cl2N2O6 C17H22Cl2N2O7 C22H24Cl2N2O7 Found, % Calculated, % Cl 4.8 4.7 4.0 4.1 5.2 5.3 5.4 5.3 5.5 5.7 5.0 4.8 5.1 5.4 5.5 5.4 5.1 5.2 5.3 5.4 5.0 5.2 5.1 5.0 4.9 5.1 5.1 5.0 5.1 5.0 4.8 4.6 18.4 18.6 32.1 31.7 10.2 10.3 9.8 10.0 9.7 9.5 9.9 10.0 17.9 18.0 15.1 15.1 15.5 15.3 14.8 15.1 14.8 14.6 15.0 14.9 15.0 15.2 15.0 15.2 16.2 16.2 13.4 13.6
mp, N 214-217 217-219 4.0 4.1 7.9 7.8 7.5 7.5 3.9 4.1 3.4 3.6 3.2 3.0 3.1 3.3 3.0 3.0 2.7 2.9 5.9 6.0 3.0 2.9 5.9 6.0 6.4 6.3 5.6 5.3 245-247 233-234 210-211 220-222 211-213 195-197 254-255 207-208 221-223 223-225 202-203 177-180 228-230 188-190
Yield, %
47.5 47.3 40.2 40.3 52.4 52.4 50.0 50.2 51.8 51.6 50.1 50.3 48.8 48.7 56.0 56.2 55.3 55.3 56.3 56.2 54.1 54.3 53.5 53.2 53.4 53.2 53.5 53.7 46.7 46.6 55.1 54.9
91 92 77-95 76 70 51 68 77 54 57 97 89 94 94 92 72
1133
TABLE 2. The 1H NMR Spectra of Compounds 1, 3, 4, 6a-c, and 8a-j

Compound 1 Chemical shifts, , ppm (SSCC, J, Hz) 2.35-2.50 (2, m, 1--2); 2.76 (3, s, 3-3); 3.70 (2, t, J = 6, 1--2); 3.77 (2, t, J = 6, 1--H2); 4.07 and 4.16 (6, 2 s, 6- and 7-3); 7.44 (1, s, H-5); 7.62 (1, s, H-8); 7.74 (1, s, H-4) 2.37-2.51 (2H, m, 1--2); 2.78 (3, s, 3-3); 3.70-3.83 (4, m, 1-- and -H2); 4.08 and 4.17 (6, 2 s, 6- and 7-3); 7.55 (1, s, H-5); 7.65 (1, s, H-8); 7.88 (1, s, H-4) 2.24-2.57 (2, m, 2-2); 2.73 (3, s, 5-3); 3.87 (2, t, J = 6, 1-H2); 4.00 and 4.02 (6, 2 s, 6- and 7-3); 4.78 (2, t, J = 6, 3-CH2), 7.52 (1, s, H-7); 7.59 (1, s, H-10); 7.96 (1, s, H-6) 2.05-2.18 (2, m, 2-2); 2.67 (3, s, 6-C3); 3.41-3.51 (2, m, 3-2); 3.59 (2, t, J = 7, 1-C2); 4.02 (6, s, 9- and 10-3); 6.15 (1, t, J = 7, H-4); 7.32 (1H, s, H-8); 7.43 (1, s, H-11); 7.78 (1, s, H-7) 2.05-2.16 (2, m, 2-2); 2.77 (3, s, 6-C3); 2.91 (3, s, 4-3); 3.30-3.55 (2, m, 3-C2); 3.65-3.85 (2, m, 1-C2); 4.02 and 4.03 (6, 2 s, 9- and 10-M); 7.33 (1, s, H-8); 7. 44 (1H, s, H-11); 7.81 (1, s, H-7) 2.33-2.47 (3, m, 2-2); 2.69 (3, s, 6-3); 3.63 (2, t, J = 7, 1-2); 4.03 (6, s, 9- and 10-3); 4.66 (2, t, J = 6, 3-2), 7.38 (1, s, H-8); 7.45 (1, s, H-11); 7.82 (1, s, H-7) 2.17-2.25 (2, m, 1--2); 2.79 (3, s, 3-3); 3.68-3.77 (2, t, J = 7, 1--H2); 3.93 (2, t, J = 7, 1--2); 4.04 (6, s, 6- and 7-3); 4.22 (3, s, 2-3); 7.54 (1, s, H-5); 7.66 (1, s, H-8); 8.06 (1, s, H-4) 2.15-2.25 (2, m, 1--2); 2.67 ( 3, s, 3-3); 3.45-3.55 (2, m, 1--2); 3.79 ( 2, t, J = 7, 1--C2); 4.04 and 4.08 (6, s, 6- and 7-3); 5.84 (2, s, 2-2); 6.95-7.02 (2, m, H-3' and H-5'); 7.33-7.41 (3, m, H-2', H-4' and H-6'); 7.42 (1, s, H-5); 7.56 (1, s, H-8); 7.95 (1, s, H-4) 2.05-2.25 (2, m, 1--2); 2.52 (3, s, 3-3); 3.15-3.25 (2, m, 1--2); 3.69 (2, t, J = 7, 1--C2); 4.04 and 4.08 (6, 2 s, 6- and 7-3); 6.95-7.02 (2, m, H-3' and H-5'); 7.33-7.41 (3, m, H-2', H-4' and H-6'); 7.42 (1, s, H-5); 7.56 (1, s, H-8); 7.95 (1, s, H-4) 2.03-2.16 (2, m, 1--2); 2.23 (3, s, 4'-3); 2.48 (3, s, 3-3); 3.22-3.32 (2, m, 1--2); 3.57 (2, t, J = 6, 1--2); 4.06 and 4.10 (6, 2 s, 6- and 7-3); 7.34 (2, d, J = 8, H-3' and H-5'); 7.46 (1, s, H-5); 7.53 (1, d, J = 8, H-2' and H-6'); 7.56 (1, s, H-8); 7.96 (1, s, H-4) 2.05-2.15 (2, m, 1--2); 2.30 (3, s, 3-3); 3.25-3.35 (2, m, 1--C2); 3.59 (2H, t, J = 6, 1--2); 3.90 (3H, s, 4'-O3); 4.05 and 4.09 (6, s, 6- and 7-3); 7.20 (2H, d, J = 7, H-3' and H-5'); 7.39 (2H, d, J = 7, H-2' and H-6'); 7.41 (1, s, H-5); 7.55 (1H, s, H-8); 7.97 (1H, s, H-4) 2.03-2.16 (2, m, 1--2); 2.33 (3, s, 3-3); 3.05-3.22 (2, m, 1--2); 3.45-3.55 (2, m, 1--2); 3.57 (2, t, J = 6, 1--2); 4.06 and 4.10 (6, s, 6- and 7-3); 4.40 (2, br. s, 2'-NH2); 6.92-7.46 (4, m, H-3', H-6'); 7.47 (1, s, H-5); 7.59 (1H, s, H-8); 8.03 (1, s, H-4) 2.03-2.12 (2, m, 1--2); 2.30 (3, s, 3-3); 3.15-3.45 (2, m, 1--2); 3.57 (2, t, J = 6, 1--2); 4.04 and 4.09 (6, 2 s, 6- and 7-3); 7.10-7.60 (4, m, H-3', H-6'); 7.44 (1, s, H-5); 7.56 (1, s, H-8); 7.97 (1, s, H-4) 2.15-2.26 (2, m, 1--2); 2.58 (3, s, 3-3); 3.35-3.55 (2, m, 1--2); 3.75 (2, t, J = 7, 1--2); 4.06 and 4.10 (6, s, 6- and 7-3); 6.65-7.25 (5, m, H-2', H-6'); 7.48 (1, s, H-5); 7.63 (1, s, H-8); 8.02 (1, s, H-4); 8.80 (1H, br. s, 2-NH) 2.05-2.25 (2, m, 1--2); 2.30 (3, s, 2-NCO3); 2.58 (3, s, 3-3); 3.32-3.75 (2, m, 1--2); 3.79 (2, t, J = 7, 1--2); 4.04 and 4.08 (6, 2 s, 6- and 7-3); 7.41 (1, s, H-5); 7.54 (1, s, H-8); 7.93 (1, s, H-4); 10.50 (1H, br. s, 2-NH) 2.05-2.20 (2, m, 1--2); 2.46 (3, s, 3-3); 3.15-3.55 (2, m, 1--2); 3.67 (2, t, J = 7, 1--2); 3.97 and 4.06 (6, 2 s, 6- and 7-3); 7.10-7.55 (5, m, H-2', H-6'); 7.46 (1, s, H-5); 7.56 (1, s, H-8); 7.96 (1, s, H-4); 10.60 (1H, br. s, 2-NH)
6a
6b
6c
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
1134
H NMR spectrum of the pyridazinoisoquinolinium salt 6a the signal for the protons of this methylene group is represented by a multiplet on account of spinspin coupling with the proton at the nitrogen atom (H-4). The signal of this proton with a chemical shift depending on the temperature and the solvent is represented by a triplet with J = 6 Hz. In the 1H NMR spectrum of the N-methyl salt 6b the signals of all three methylene groups are multiplets on account, probably, of complications in the transformations of the conformations of the tetrahydropyridazine ring due to the presence of the methyl substituent. Thus, our investigated recyclization reactions of the benzo[c]pyrylium salt 1 make it possible to obtain analogs of alkaloids widely found in nature [10-13, 16-18] and may in our opinion prove useful in the synthesis of new biologically active compounds.
EXPERIMENTAL The 1H NMR spectra were recorded on a Gemini-200 instrument (200 MHz) with MeCN-d3 as solvent and HMDS ( 0.055 ppm) as internal standard. The IR spectra were recorded on a Specord IR-75 instrument. After separation by filtration and washing with the solvent indicated in the specific method all the products obtained by the described procedures were washed with ether and dried. The characteristics and spectral data of the obtained compounds are given in Tables 1 and 2. 1-(3-Chloropropyl)-6,7-dimethoxy-3-methylbenzo[c]pyrylium Perchlorate (1). A. To a mixture of -chlorobutyryl chloride (5.6 ml, 0.05 mol) and 70% perchloric acid (0.8 ml, 0.01 mol), prepared with stirring and cooling, we added 3,4-dimethoxyphenylacetone 2 (1.94 g, 0.01 mol). The mixture was left at room temperature for 3 h. B. To a solution of the hexachlorostannate 3 (27.74 g, 0.062 mol) in methanol (560 ml) we added 70% perchloric acid (10 ml, 0.124 mol). The mixture was boiled for 5 min and cooled to room temperature, and the precipitate was washed with isopropyl alcohol. 1-(3-Chloropropyl)-6,7-dimethoxy-3-methylbenzo[c]pyrylium Hexachlorostannate (3). To a mixture of the ketone 2 (3.88 g, 0.02 mol) and -chlorobutyryl chloride (6.2 g, 0.044 mol) in methylene chloride (10 ml) with stirring we added stannic chloride (2.6 g, 0.01 mol). The mixture was boiled for 3 h with a reflux condenser and with agitation. After cooling 10-15 ml of ether was added to the reaction mixture, and the precipitate was washed with methyl ethyl ketone. 8,9-Dimethoxy-5-methyl-2,3-dihydrobenzo[f]indolizinium Perchlorate (4). A. To a suspension of the perchlorate 1 (0.7 g) in alcohol (10 ml) we added aqueous ammonia (5 ml). After brief agitation the initial salt dissolved. After 5-10 min a colorless crystalline precipitate of 4 separated. It was washed with water and with alcohol. B. A mixture of the salt 1 (0.76 g, 0.002 mol) and concentrated aqueous ammonia (0.5 ml) was boiled for 20 min in methanol (5 ml) and cooled. The precipitate was washed with isopropyl alcohol. C. A mixture of the salt 1 (0.76 g, 0.002 mol), methanol (5 ml), and concentrated aqueous ammonia (0.5 ml) was stirred at room temperature for 10 h. The precipitate was washed with isopropyl alcohol. To the salt 1 (0.76 g, 0.002 mol) we added liquid ammonia (5 ml). The mixture was kept until the solvent had completely evaporated, and the precipitate was washed with water and with methanol. 9,10-Dimethoxy-6-methyl-1,2,3,4-tetrahydroisoquinolino[2,1-b]pyridazinium Perchlorate (6a). To a solution of the salt 1 (0.76 g, 0.002 mol) in methanol (5 ml) we added 80% hydrazine hydrate (0.28 g, 0.0044 mol). The mixture was boiled for 30 min and was then cooled. The precipitate was washed with isopropyl alcohol. 9,10-Dimethoxy-4,6-dimethyl-1,2,3,4-tetrahydroisoquinolino[2,1-b]pyridazinium Perchlorate (6b). The compound was obtained similarly to the salt 6a.
1135
9,10-Dimethoxy-6-methyl-1,2,3,4-tetrahydroisoquinolino[2,1-b]-1,2-oxazinium Perchlorate (6c). To a solution of hydroxylammonium acetate, obtained from hydroxylamine hydrochloride (0.42 g, 0.006 mol) and an equimolar amount of sodium acetate by boiling in 6 ml of methanol, after filtration from the precipitate we added the perchlorate 1 (0.76 g, 0.002 mol). The mixture was boiled for 35 min and was then cooled, and the precipitate was washed with methanol. 1-(3-Chloropropyl)-6,7-dimethoxy-2,3-dimethylisoquinolinium Perchlorate (8a). To a solution of the salt 1 (0.76 g, 0.002 mol) in methanol (5 ml) we added aqueous methylamine (0.5 ml). The mixture was boiled for 2 h and cooled, and the precipitate was washed with isopropyl alcohol. 2-Benzyl-3-methyl-6,7-dimethoxy-1-(3-chloropropyl)isoquinolinium Perchlorate (8b). To a solution of the salt 1 (0.76 g, 0.002 mol) in methanol (5 ml) we added benzylamine (0.44 g, 0.0041 mol). The mixture was boiled for 2 h and diluted with water, and the product was washed with isopropyl alcohol. The perchlorates 8c-j were obtained similarly.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. A. T. Balaban, W. Schroth, and G. N. Fischer, Adv. Heterocycl. Chem., 10, 241 (1969). A. T. Balaban, A. Dinculescu, G. N. Dorofeenko, G. N. Fischer, A. V. Koblik, V. V. Mezheritskii, and W. Schroth, Adv. Heterocycl. Chem., Suppl. 2, Academic Press, New York, 1982. E. V. Kuznetsov, I. V. Shcherbakova, and G. N. Dorofeenko, Khim. Geterotsikl. Soedin., 1481 (1977). V. I. Dulenko, N. N. Alekseev, V. M. Golyak, and L. V. Dulenko, Khim. Geterotsikl. Soedin., 1135 (1977). V. I. Dulenko, N. N. Alekseev, and V. M. Golyak, USSR Inventor's Certificate 640991; Byull. Izobr., No. 1, 78 (1979). Yu. A. Nikolyukin, L. V. Dulenko, and V. I. Dulenko, Khim. Geterotsikl. Soedin., 999 (1986). S. L. Bogza, A. A. Malienko, T. A. Zaritovskaya, M. Yu. Zubritskii, S. Yu. Suikov, K. I. Kobrakov, and V. I. Dulenko, Zh. Org. Khim., 32, 596 (1996). Ya. P. Stradyn, Khim. Geterotsikl. Soedin., 1412 (1981). A. V. Kibal'nyi, V. Yu. Popov, and V. I. Dulenko, Carbonyl Compounds in the Synthesis of Heterocycles [in Russian], Izd. Saratov. Gos. Un-ta, Saratov (1992), Part 1, p. 66. B. Lning and C. Lundin, Acta Chem. Scand., 21, 2136 (1967). J. J. Fisch, H. Gopal, and D. A. Russo, J. Org. Chem., 39, 3110 (1974). J. Oliver and P. Sonnet, J. Org. Chem., 39, 2662 (1974). L. H. Groves and G. A. Swan, J. Chem. Soc., 650 (1952). G. N. Dorofeenko, E. I. Sadekova, and V. M. Goncharova, Khim. Geterotsikl. Soedin., 1308 (1970). S. E. Denmark and A. Thorarensen, Chem. Rev., 96, 137 (1996). G. V. Lazur'evskii and I. V. Terent'eva, Alkaloids and Plants [in Russian], Shtiintsa, Kishinev (1975). T. Uchida and K. Matsumoto, Synthesis, 209 (1976). A. G. Mikhailovskii and V. S. Shklyaev, Khim. Geterotsikl. Soedin., Khim. Geterotsikl. Soedin., 291 (1997).
1136
SYNTHESIS AND STRUCTURE OF DI-N-ARYLPYRROLO[1,2-c;5,6-c]CYCLOOCTANES

S. A. Vizer Di-N-arylpyrrolo[1,2-c;5,6-c]cyclooctanes were synthesized for the first time by the cyclization of N,N-dipropynylarylamines in a superbasic medium. Keywords: di-N-arylpyrrolo[1,2-c;5,6-c]cyclooctanes, N,N-dipropynylarylamine, superbasic medium, cyclization. The aim of the present work was to study the transformations of dialkynylarylamines in superbasic media. By the cyclization of acetylene-containing compounds it is possible to obtain heterocyclic compounds with various structures [1, 2]. Use of the so-called "superbasic media" for this purpose opens up new prospects [3]. By superbasic we mean media consisting of a strong base and a solvent or reagent capable of binding specifically with a cation, "baring" anion [4, 5]. Such systems can be produced on the basis of linear ethers, crown ethers, dipolar aprotic solvents (DMSO, sulfolane, HMPA, etc.), amides, liquid ammonia, amines, and so forth. We established that N,N-dipropynylarylamines 1a-d are readily transformed at room temperature in a superbasic medium (DMSO, potassium hydroxide) into polycyclic compounds having various structures with 100% conversion [6-11]. Some of them were isolated from the reaction mixtures in the individual form on account of their low solubility in various solvents and their relative stability. On the basis of data from elemental analysis, IR and 1H and 13C NMR spectroscopy, and mass spectrometry (Tables 1-4) the isolated compounds were assigned the structure of di-N-arylpyrrolo[1,2-c;5,6-c]cyclooctanes 2a-d.
1 6 5 4 3 2
N(CH2C R 1ad
CH)2
N R
2ad
1, 2 a R = H, b R = p-Cl, c R = m-Cl, d R = m-Br
According to elemental analysis, the obtained compounds were isomeric with the initial N,N-dipropynylarylamines 1a-d. According to mass spectrometry they were dimers giving a set of molecular ions corresponding to the isotopic composition of the halogen substituents (Cl, Br) [6].
__________________________________________________________________________________________ A. B. Bekturov Institute of Chemical Sciences, Ministry of Education and Science, Republic of Kazakhstan, Almaty 480100; e-mail: vizer@astel.kz. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1317-1322, September, 2004. Original article submitted February 19, 2002. 0009-3122/04/4009-11372004 Springer Science+Business Media, Inc. 1137
TABLE 1. The Physicochemical Characteristics of the Di-N-arylpyrrolo[1,2-c;5,6-c]cyclooctanes 2a-d

Empirical formula () Found, % Calculated, % C 85.14 85.17 70.46 70.77 70.94 70.77 57.98 57.08 H 6.54 6.55 5.08 4.95 5.33 4.95 4.38 4.06 Hal 17.67 17.41 17.41 17.41 32.09 32.20 N 8.31 8.28 6.74 6.88 6.87 6.88 5.87 5.65 256-258 302-304 179-180 202-205 0.7 0.6 0.6 0.8
Compound
mp, *
Rf *2
Yield, %*3 30 47 40 45 10 10 15 B
2a 2b 2c 2d
C24H22N (338.45) C24H20Cl2N2 (407.34) C24H20Cl2N2 (407.34) C24H20Br2N2 (496.28)
_______ * Crystallized from benzene (2a), xylene (2b), acetonemethanol (2c), and isopropanolDMSO (2d). *2 Silufol, benzenepetroleum ether 3:1 (2a), 1:1 (2b,c), and 2:1 (2d). *3 DMSOpotassium hydroxide (A), HMPAetherpotassium hydroxide (B).
The IR spectra of compounds 2a-d do not contain the absorption band for the stretching vibrations of the CH bond at 3300 cm-1 characteristic of the initial alkynylamines 1a-d, but new bands of medium or higher intensity characteristic of the stretching vibrations of the pyrrole ring appear in the region of 1380-1560 cm-1 [13]. The absorption bands for the stretching vibrations of the C=C bonds of the aryl substituents at 1500 and 1600 cm-1 remain [14]. Comparison of the experimental 1H and 13C NMR spectra with those calculated by means of the ChemOffice 4.5 Ultra software makes it possible to conclude that the experimental values of the resonance signals are close to those predicted for the structures of the di-N-arylpyrrolocyclooctanes 2a-d (Tables 3 and 4). In fact, only one singlet for the vinyl proton in the region of 6.6-7.0 ppm with overall integral intensity corresponding to four protons, as in the calculated spectra for the protons of the pyrrole rings (6.41 ppm), is observed in the experimental 1H NMR spectra. The chemical shift of the singlet for the methylene group in the region of 2.7-2.9 ppm coincides with the calculated chemical shift for the methylene groups of the cyclooctane ring at 2.70 ppm. The overall integral intensity of the multiplets for the aryl protons in the experimental spectra
TABLE 2. The Spectral Characteristics of the Cyclooctanes 2a-d

Compound IR spectrum (KBr), , cm-1 M+ CHal 2 2b 2c 2d 404-409 404-409 492-498 775 780 690 C=C (arom.) 1500, 1695 1500, 1600 1500, 1603 1490, 1590 =N (pyrr.) 1530, 1 560 1380, 1400 1527, 1550 1380, 1400 1533, 1380, 1440 1530, 1389, 1389, 1395 (arom.) 3050, 3130 3030, 3090 3070, 3130 3065
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corresponds to 8-10 protons, while the form depends on the type of substitution of the aryl ring and remains the same as in the initial arylamines 1a-d. This indicates that the aryl rings are not affected during cyclization. A similar pattern is observed in the 13C NMR spectra of the cyclic compounds 1a,c. The chemical shifts of the C(1), C(2), and C(3) atoms in the experimental spectra, where the assignment of the signals was made by recording the single-resonance spectra from the protons, practically coincide with those calculated for the structures of the dipyrrolocyclooctanes 2a,c (Table 4). If the isomerization of the amines 1b-d is conducted in 1:2 HMPAdiethyl ether, the yield of the respective cyclic dimers 2b-d decreases to 0-15% even if the amount of potassium hydroxide is increased to 3 mole equivalents. The amine 1a and N,N-dipropynyl-p-bromoaniline do not isomerize under these conditions, and N,N-dipropynyl-p-bromoaniline does not form the corresponding dipyrrolocyclooctane even during isomerization in the DMSO, potassium hydroxide medium. The initial N,N-dipropynylarylamines 1a-d were synthesized with yields of 80-90% by the procedures that we developed earlier from the corresponding arylamines and propargyl bromide on aluminum oxide [15] or in methanol solution in the presence of sodium acetate [16]. We have thus established that N,N-dipropargylarylamines 1a-d cyclodimerize under superbasic conditions (DMSO, potassium hydroxide) at room temperature with the formation of the corresponding di-N-arylpyrrolo[1,2-c;5,6-c]cyclooctanes 2a-d.
EXPERIMENTAL The 1H and 13C NMR spectra were recorded on a Varian Mercury 300 spectrometer (300 MHz for 1H, 75 MHz for 13C) and a Tesla BS-487A spectrometer (80 MHz for 1H) at 80C. The melting points of the obtained compounds were determined on a Boetius heating bench (heating rate 4 deg/min). The IR spectra were obtained on a UR-20 spectrometer (in potassium bromide), and the mass spectra were obtained on an MX-1331 instrument with ionizing electron energy 60-70 eV.
TABLE 3. The cyclooctanes 2a-d

Compound 2a 2b
H NMR Spectra of Di-N-arylpyrrolo[1,2-c;5,6-c]-
Spectrum Exp. Calc.* Exp. Calc.
Solvent, (, C) CDCl3 DMSO -d6 ( ~20) CDCl3 DMSO -d6 ( ~20) DMSO-d6 (80)
Chemical shifts, , ppm NCH= 6.85 (4, s) 6.41 7.03 (4, s) 6.41 6.65 (4, s) 7.14 (4, s) 6.41 7.00 (4, s) 6.41 CH22.85 (8, s) 2.70 2.69 (8, s) 2.70 2.72 (8, s) 2.75 (8, s) 2.70 2.75 (8, s) 2.70 Ar 7.11-7.39 (10, m) 7.3 7.34-7.45 (8, m) 7.20-7.30 7.00-7.20 (8, m) 7.17-7.30 (8, m) 7.10-7.30 7.30-7.60 (8, m) 7.20-7.40
2c
Exp. Exp. Calc.
2d
Exp. Calc.
_______ * Calc. indicates spectra calculated by means of the ChemOffice 4.5 Ultra software.
1139
1140
TABLE 4. The 13C NMR Spectra of Cyclooctanes 2a,c

Compound Spectrum* 2a Expt. ESS Solvent Dl3 Chemical shifts, ppm (J, Hz) C(5) C(6) 117.2 117.2 (d, J = 177.6) 120.2 119.4 117.2 117.2 (d, J = 167.2) 120.6 129.4 129.4 (dd, J1 = 161.2, J2 = 7.2) 129.1 135.2 133.7 133.7 (s) 134.4
(1) 28.3 28.3 (t, J = 124.5) 28.1 28.0 26.8 26.8 (t, J = 127.0) 28.1
C(2) 126.7 125.7 (s)
C(3) 119.3 119.3 (d, J = 164.6) 118.7 117.1 116.4 116.5 (d, J = 186.8) 118.7
C(4)
C(7) 124.6 124.6 (d, J = 163.7) 125.3 124.4 123.4 123.4 (d, J = 168.5) 125.7
C(8) 129.4 129.4 (dd., J1 = 161.2, J2 = 7.2) 129.1 130.3 130.7 130.7 (d, J = 164.9) 130.5
C(9) 117.2 117.2 (d, J = 177.6) 120.2 117.1 115.9 115.9 (d, J = 165.0) 118.3
140.5 140.5 (s)
2c
Calc. Expt. Expt. ESS Calc.
CHCl3 DMSO-d6
124.1 127.0 125.8 125.8 (s) 124.1
140.4 141.7 140.5 140.5 (s) 141.8
_______ * ESS indicates the experimental single-resonance spectrum, Calc. indicates the spectra calculated by means of the ChemOffice 4.5 Ultra software.
Di-N-arylpyrrolo[1,2-c;5,6-c]cyclooctanes 2a-d (General Procedure). To powdered potassium hydroxide (0.05 mol) in freshly distilled dry DMSO (20 ml) while stirring we added a solution of the amine 1a-d (0.01 mol) in dry DMSO (15 ml) in a stream of inert gas (argon, nitrogen). The reaction was monitored by TLC on Silufol in the benzenepetroleum ether system. When the initial amine 1a-d had disappeared from the reaction mixture, which required between 0.5 and 1.5 h, the whole reaction mixture was poured into 2-5 times the volume of water saturated with sodium chloride, and the pH was brought to 5-6 with ammonium chloride until the precipitate coagulated. The precipitate was filtered off, washed several times with water, and dried over calcium chloride in a desiccator until the mass of the precipitate stopped changing. The whole precipitate was then treated with a small amount of absolute ether. The insoluble part was filtered off, and the product was recrystallized from a suitable solvent.
REFERENCES 1. 2. 3. 4. 5. 6. R. Fuchs and H. G. Viehe, in: G. G. Viehe (editor), Chemistry of Acetylenes [Russian translation], Khimiya, Moscow (1973). J. Bastide and O. Henri-Rousseau, in: The Chemistry of the Carbon-Carbon Triple Bond, Wiley, Toronto, (1978). B. A. Trofimov and A. I. Mikhaleva, N-Vinylpyrroles [in Russian], Nauka, Sib. Otd., Novosibirsk (1984). B. A. Trofimov, Usp. Khim., 50, 248 (1981). J. Gordon, Organic Chemistry of Electrolytic Solutions [Russian translation], Mir, Moscow (1979). S. A. Vizer, K. B. Erzhanov, Z. N. Manchuk, E. Kh. Dedeshko, and A. A. Espenbetov, in: First AllRussia Conference on the Chemistry of Heterocycles in Memory of A. N. Kost. Abstracts [in Russian], Suzdal (2000), p. 132. N. B. Kurmankulov, S. A. Vizer, and K. B. Erzhanov, in: Third All-Russia Symposium on Organic Chemistry "Strategy and Tactics of Organic Synthesis". Abstracts [in Russian], Yaroslavl (2001), p. 70. S. A. Vizer, K. B. Erzhanov, E. Kh. Dedeshko, and A. T. Basenova, in: Modern Problems of Organic Chemistry, Ecology, and Biotechnology. First International Conference [in Russian], Luga (2001), Vol. 1, p. 117. S. A. Vizer, K. B. Erzhanov, N. B. Kurmankulov, and E. Kh. Dedeshko, in: V. G. Kartsev and G. A. Tolstikov (editors), Chemistry and Biological Activity of Synthetic and Natural Compounds. Nitrogen Heterocycles and Alkaloids [in Russian], Iridium Press, Moscow (2001), Vol. l, p. 303. S. A. Vizer, K. B. Erzhanov, E. Kh. Dedeshko, and A. A. Espenbetov, in: V. G. Kartsev and G. A. Tolstikov (editors), Chemistry and Biological Activity of Synthetic and Natural Compounds. Nitrogen Heterocycles and Alkaloids [in Russian], Iridium Press, Moscow (2001), Vol. 2, p. 65. S. A. Vizer, in: V. G. Kartsev and G. A. Tolstikov (editors), Chemistry and Biological Activity of Synthetic and Natural Compounds. Nitrogen Heterocycles and Alkaloids [in Russian] Iridium Press, Moscow (2001), Vol. 2, p. 379. V. V. Takhistov, Practical Mass Spectrometry of Organic Compounds [in Russian], Izd. Leningrad. Unta, Leningrad (1977). A. R. Katritzky, Physical Methods in the Chemistry of Heterocyclic Compounds [Russian translation], Khimiya, Moscow-Leningrad (1966). L. A. Kazitsyna and N. B. Kupletskaya, Application of UV, IR, NMR, and Mass Spectrometry in Organic Chemistry [in Russian], Izd. Mosk. Un-ta, Moscow (1979). S. A. Abdulganeeva and K. B. Erzhanov, Zh. Org. Khim., 25, 521 (1989). S. A. Abdulganeeva, K. B. Erzhanov, Z. N. Manchuk, M. I. Lelyukh, and K. T. Tantarova, Izv. NAN Respubliki Kazakhstan, Ser. Khim., No. 6, 43 (1995). 1141
7. 8.
9.
10.
11.
12. 13. 14. 15. 16.
REACTIONS OF HYDROXYAZOLIDINES WITH -DONOR HETEROCYCLES. 3*. REACTION OF 1-ACETYL-5-HYDROXYPYRAZOLIDINES WITH OXINDOLES
I. V. Dlinnykh1, G. A. Golubeva1, I. F. Leshcheva1, V. V. Nesterov1, M. Yu. Antipin2, and L. A. Sviridova1 The reaction of oxindoles with 5-hydroxypyrazolidines on the surface of potassium fluoride-modified alumina leads to 3-(5-pyrazolidinyl)oxindoles. The structure of these products was studied. Keywords: 5-hyroxypyrazolidine, oxindole, 3-(5-pyrazolidinyl)oxindoles, potassium fluoride on alumina. We have developed a method for the direct introduction of the pyrazolidine substituent into the pyrazolone ring by means of the reaction of 5-hydroxypyrazolines 1 with 5-pyrazolones on the surface of a heterogeneous catalyst in a nonpolar solvent [1, 2]. In the present work, we have extended this method to oxindoles 2 and synthesized a number of previously unreported 3-(5-pyrazolidinyl)oxindoles 3a-f. The use of potassium fluoride-modified alumina in benzene proved optimal for all the substrate pairs. The reaction is complete at 60C after 30-60 min. Chromatographic purification of the products was required in some cases to remove dark-red oily impurities formed likely as the result of the partial oxidation of the oxindole ring during the reaction.
R1 HO N + N Ph 1a,b 2ac R1 N R2 O KF / Al2O3 N R2 3af O N N Ac Ph
Ac
1 a R1 = H, b R1 = Me; 2 a R2 = H, b R2 = Me, c R2 = Et; 3 a, c, e R1 = H, b, d, f R1 = Me, a, b R2 = H, c, d R2 = Me, e, f R2 = Et
_______ * Communication 2, see ref. [2]. __________________________________________________________________________________________ M. V. Lomonosov Moscow State University, 119899 Moscow, Russia; e-mail: idlin@org.chem.msu.su. 2 A. N. Nesmeyanov Institute of Organoelement Compounds, 117813 Moscow, Russia. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1323-1330, September, 2004. Original article submitted March 1, 2002. 1142 0009-3122/04/4009-11422004 Springer Science+Business Media, Inc.
1
TABLE 1. Physical Characteristics of Products 3a-f

Compound 3a Reaction time, h 0.5 Empirical formula C19H19N3O2 Found, % Calculated, % H 5.81 5.92 IR spectrum Solvent 159-161 0.30 CCl4 , cm-1 53 70.88 71.03 12.83 13.08 1610, 1630, 1665, 1690, 1720, 1735, 3200-3350 (bound NH), 3450 (free NH) 1600, 1620, 1660, 1730, 3200-3300 (bound NH) 1605, 1635, 1675, 1730, 3430 3200-3350(bound NH), 3450 (free NH) 1605, 1620, 1670, 1690, 1720 1605, 1620, 1680, 1720 1605, 1630, 1670, 1720 1605, 1620, 1670, 1720
mp, N
Rf
Yield, %
Vaseline 3b 1 C20H21N3O2 72.03 71.64 6.42 6.27 12.29 12.54 167-169 0.35 CH2Cl2 CCl4 3c 3d 3e 3f* 0.5 1 0.5 1 C20H21N3O2 C21H23N3O2 C21H23N3O2 C22H25N3O2 72.73 72.83 6.97 6.89 11.57 11.17 71.70 71.64 72.10 72.21 6.42 6.27 6.72 6.59 12.38 12.54 11.78 12.03 146-148 115-117 127-129 110-112 0.45 0.53 0.53 0.58 Vaseline CH2Cl2 CH2Cl2 CH2Cl2
56
43 63 40 33
_______ * Mass spectrum of compound 3f, m/z (I, %): 349 [M]+ (8), 306 (7), 263 (3), 203 (9), 163 (7), 162 (5), 161 (45), 146 (100), 132 (7).
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The spectral data for compounds 3 given in Tables 1-3 indicate that the oxindole fragment in them exists only in the oxo form. A signal for H-3 is found in the 1H NMR spectra of 3, while their IR spectra show an oxindole carbonyl group band at 1720-1735 cm-1. The 1H and 13C NMR spectra of 3b have a double set of signals. A 1H NMR spectral study of these compound using the NOE technique showed that both sets of signals correspond to a pyrazolidinyloxindole having trans arrangement of the substituents in the pyrazolidine ring (Table 4). Thus, 3b is probably a mixture of diastereomer racemates. Products 3d,f also have a chiral site at C-3 of the pyrazolidine ring but no double signals were found for these compounds. Although we could not obtain spectral evidence for the hydroxyindole form of these compounds, the dynamic tautomeric transition in solution probably accounts for an averaged set of signals in the spectra of 3d,f. We should note that the signals of the pyrazolidine ring and its phenyl and acetyl substituents in the 1H and 13C NMR spectra of 3a,c,e, which lack a substituent at C-3', are very broadened, lack clear shape, and are given as regions. The 1H NMR NOE data indicate that 3d has trans arrangement of the substituents in the pyrazolidine ring (Table 2), which is analogous to pyrazolidinylpyrazolones studied in our previous work [2]. The nuclear Overhauser effect found between H-3 of the oxindole ring and H-4' of the pyrazolidine ring indicates their proximity in space. An X-ray diffraction structural analysis established the structure of 3d in the crystalline state (Fig. 1), while the bond lengths, bond angles, and major torsion angles are given in Tables 5-7. A benzene solvent molecule is found in a special position in the crystal of this compound obtained upon recrystallization from a mixture of ether and benzene. Thus, one-half solvent molecule is found per product molecule. The pyrazolidine ring in 3d has twist conformation: N(20) and C(10) are twisted to opposite sides of the plane of the other ring atoms by 0.140 and -0.380 , respectively. The methyl and acetyl groups are on the same side of the pyrazolidine ring. The dihedral angle between the planes of the oxindole and phenyl rings is 15.3. The observed mutual arrangement of the substituents in the molecule 3d stipulates the existence of the forced intramolecular nonvalent contacts: C(1)C(14), 3.270(2); C(12)O(24), 3.091(2); C(19)N(2), 3.339(2); C(19)C(3), 3.470; C(19)C(21), 3.469(2) , which are less than the sums of the van der Waals radii of the corresponding atom pairs [3]. The following intermolecular nonbonding contacts can be suggested to be in the crystal of 3d: C(5)C(21), 3.451(3) (1-x, -y, 1-z), C(10)O(23), 3.247(2) (-x, -z, 1-z), C(15)O(24), 3.208(3) (-x, -1-y, -z) (see Fig. 1b).
TABLE 2. 1H NMR Spectra of 3a-f

Compound 3a* 3b 3c 3d 3e 3f Chemical shifts, , ppm 4'-H, 5'-H, CH3CO, s 4'-H', m m 2.0-2.2 2.1; 2.4 1.9; 2.7 2.0-2.5 2.06, 2.83 2.0-2.3 2.1; 2.7 4.83 4.8, 4.8 5.1 5.15 4.95 5.0 2.08 2.0, 2.1 2.2 1.98 2.08 2.0
3-H 3.2 3.3, 3.4*2 3.4-4.0 3.6 3.4-4.0 3.3
3'-H, m 3.3-3.8 4.2, 4.2 3.20-3.50 4.3 3.30-3.50 4.3
3'-CH3, d 1.2, 1.25 1.27 1.26
R2 9.0 (NH) 9.3, 9.6 (NH) 3.0 (CH3) 2.68 (CH3) 1.17; 3.3-3.5 (C2H5) 1.28; 3.3 (C2H5)
_______ * Regions of appearance are given for 3a,c,e due to strong signal broadening. *2 Signals for pairs of diastereomer racemates are given.
1144
Fig. 1. General view of 3d in two projections (a and b).
The other geometrical parameters in this molecule have ordinary values [4].
1145
TABLE 3. 13C NMR Spectra of 3a-f

Atom (2)*2 (3) (3a) (4) (5) (6) (7) (7a) (3')*3 (4') (5') CH3(3') CH3CO CH3CO*2 PhCo Cp Cm Ci R2 116.0 121.0 129.17 150.5 Chemical shifts, , ppm 3c 3d 174.76 56.48 128.74 121.90 124.56 128.18 107.70 144.31 46.0-48.0 30.0 53.0 21.0 174.34 60.0 128.38 122.08 124.65 128.35 107.66 144.17 56.73 37.96 48.39 20.85 21.27 176.31 114.0 120.8 128.73 150.25 25.55 113.07 120.07 128.95 149.69 25.36 113.0-115.0 120.0-121.0 129.00 150.0-151.0 12.43;34.42 56.94 128.33 121.09 124.97 128.28 108.03 143.68 44.0-48.0 27.0-29.0 51.0-52.0 20.0-21.0
3a 177.5 57.06 128.41 121.95 124.94 128.26 110.0 142.0 46.0-48.0 28.0-32.0 52.0-54.0 21.0
3b* 176.49; 177.10 56.90; 58.60 128.20; 127.44 121.64; 122.18 124.57; 125.04 127.00; 127.44 109.93; 109.84 142.15; 141.68 60.59; 60.11 32.30; 36.39 49.75; 48.23 20.46; 20.46 21.30; 21.76 176.98; 176.94 114.32; 114.16 121.10; 121.90 129.05; 128.33 150.05; 149.72
3e
3f 174.04 60.23 128.20 121.65 124.57 126.63 107.84 143.39 56.87 38.12 48.88 20.83 20.98 176.35 113.84 120.49 128.88 149.82 12.20;34.16
_______ * Signals of pairs of diastereomer racemates are given. *2 The signal assignment may be reversed. *3 Regions of appearance are given for 3a,c,e due to strong broadening of some of the signals.
EXPERIMENTAL The IR spectra were taken on a UR-20 spectrometer, while the 1H and 13C NMR spectra were taken on a VXR-400 spectrometer at 400 and 100 MHz, respectively, for chloroform solutions at 28C with TMS as the internal standard. The NOEDIF program was used for the NOE experiments. X-ray Diffraction Structural Analysis. The unit cell parameters for triclinic crystals of 3d at -120C: a = 8.808(4), b = 9.748(5), c = 13.373(6) ; = 109.32(4), = 103.83(4), = 99.78(4); V = 1012(1) 3; dcalc = 1.274 g/cm3; Z = 2; space group P1. The unit cell parameters and intensities of 4454 independent 1146
TABLE 4. NOE Values for Compounds 3b,d*

Observed protons H-3' 3b H-3' H-4' H'-4' H-3 H-3' H-4' H'-4' H-5' H-3 , % Saturated protons*2 H-4' H'-4'
Compound
H-5' 3.0; 2.7 3.1; 1.5
H-3 2.14
3.26; 2.7*3 5.0
3d
6.5 9.1 8.1 7.6 17.6 19.7 9.0 9.5
4.6 9.0
_______ * For compound 3d: o-Ph (H-3') = 11.7; 4'-H (H-5') = 4.1. *2 H-4' is the downfield signal, while H'-4' is the upfield signal. *3 The values for individual diastereomer racemates.
TABLE 5. Bond Lengths (d) in 3d

Bond O(23)C(22) O(24)C(1) N(1)C(1) N(2)C(3) N(2)C(25) N(13)C(14) N(13)N(20) N(13)C(12) N(20)C(22) N(20)C(10) C(1)C(9) C(3)C(8) C(3)C(4) C(4)C(5) C(5)C(6) d, 1.224(2) 1.221(2) 1.371(2) 1.402(2) 1.445(3) 1.413(2) 1.423(2) 1.492(2) 1.375(3) 1.473(2) 1.530(3) 1.390(3) 1.393(2) 1.395(3) 1.383(3) Bond C(6)C(7) C(7)C(8) C(8)C(9) C(9)C(10) C(10)C(11) C(11)C(12) C(12)C(26) C(14)C(19) C(14)C(15) C(15)C(16) C(16)C(17) C(17)C(18) C(18)C(19) C(21)C(22) d, 1.402(2) 1.381(3) 1.508(2) 1.541(2) 1.536(2) 1.546(2) 1.524(2) 1.400(2) 1.401(2) 1.386(3) 1.392(3) 1.388(3) 1.391(2) 1.506(2)
reflections were measured on a four-circle automatic Syntex P2(1) diffractometer using MoK radiation, graphite monochromator, and /2 scanning up to max = 27. The structure was solved by the direct method with detection of all the non-hydrogen atoms and refined by the full matrix method of least squares anisotropically for the non-hydrogen atoms. All the hydrogen atoms were objectively found in the Fourier map and refined isotropically. The final R1 = 0.059 using 3597 reflections with I > 2 and Rw = 0.1706 using 4399 reflections. All the calculations were carried out using the PC version of the SHELXTL PLUS program package. The adsorbent catalyst was prepared by a modification of the method reported by Bergbreiter and Lalonde [5]. Potassium fluoride was dissolved in a minimal amount of hot water and a 20-30-fold excess of alumina (relative to the mass of KF) was added. The suspension obtained was thoroughly stirred and left overnight. Water was distilled off in vacuum. The final traces of water were removed by repeated distillation
1147
TABLE 6. Bond Angles () in 3d

Angle C(1)N(2)C(3) C(1)N(2)C(25) C(3)N(2)C(25) C(14)N(13)N(20) C(14)N(13)C(12) N(20)N(13)C(12) C(22)N(20)N(13) C(22)N(20)C(10) N(13)N(20)C(10) O(24)C(1)N(2) O(24)C(1)C(9) N(2)C(1)C(9) C(8)C(3)C(4) C(8)C(3)N(2) C(4)C(3)N(2) C(3)C(4)C(5) C(6)C(5)C(4) C(5)C(6)C(7) C(8)C(7)C(6) C(7)C(8)C(3) C(7)C(8)C9() C(3)C(8)C(9) , deg. 111.3(2) 123.5(2) 125.1(2) 116.1(1) 120.3(1) 107.9(1) 119.1(1) 120.9(1) 109.2(1) 124.9(2) 127.3(2) 107.8(2) 122.2(2) 109.8(2) 128.0(2) 116.9(2) 121.6(2) 120.4(2) 118.7(2) 120.1(2) 131.4(2) 108.5(2) Angle C(8)C(9)C(1) C(8)C(9)C(10) C(1)C(9)C(10) N(20)C(10)C(11) N(20)C(10)C(9) C(11)C(10)C(9) C(10)C(11)C(12) N(13)C(12)C(26) N(13)C(12)C(11) C(26)C(12)C(11) C(19)C(14)C(15) C(19)C(14)N(13) C(15)C(14)N(13) C(16)C(15)C(14) C(15)C(16)C(17) C(18)C(17)C(16) C(17)C(18)C(19) C(18)C(19)C(14) O(23)C(22)N(20) O(23)C(22)C(21) N(20)C(22)C(21) , deg. 102.6(1) 114.7(2) 117.5(1) 101.6(1) 113.5(1) 115.7(2) 105.3(1) 110.9(2) 104.7(1) 112.9(2) 118.9(2) 120.9(2) 120.0(1) 120.0(2) 121.3(2) 118.7(2) 121.0(2) 120.2(2) 121.0(2) 122.2(2) 116.7(2)
TABLE 7. Major Torsion Angles () in 3d

Angle C(12)N(13)N(20)C(10) C(14)N(13)N(20)C(22) O(24)C(1)C(9)C(10) N(2)C(1)C(9)C(10) C(22)N(20)C(10)C(9) C(1)C(9)C(10)N(20) C(8)C(9)C(10)C(11) , deg. 26.1(2) 103.0(2) -56.1(2) 126.3(2) -125.7(2) -68.1(2) 169.5(1) Angle C(14)N(13)C(12)C(26) C(10)C(11)C(12)N(13) C(10)C(11)C(12)C(26) N(20)N(13)C(14)C(15) C(12)N(13)C(14)C(15) N(13)N(20)C(22)C(21) C(10)N(20)C(22)C(21) , deg. -107.4(2) -14.9(2) -135.6(2) 165.7(1) 32.6(2) -18.7(2) -159.1(2)
with benzene. The mass was dried for 48 h in vacuum at 80-100C. The course of the reactions and purity of the products were monitored by thin-layer chromatography on Silufol UV-254 plates with 1:1 benzeneethyl acetate as the eluent. The plates were developed with iodine vapor and ethanolic FeCl3. The products were purified on a column packed with dry silica gel L 5/40. 1-Acetyl-5-hydroxy-2-phenylpyrazolidines 1a,b were prepared according to our previous procedure [6]. Oxindoles 2a-c were prepared according to Stolle from the corresponding chloroacetanilides [7]. 3-(1-Acetyl-2-phenyl-5-pyrazolidinyl)oxindoles 3a-f. A solution of oxindole 2 (5 mmol) in a minimal amount of benzene was added to adsorbent (5 g). The mixture was shaken and benzene was removed in vacuum. A solution of 4-hydroxypyrazolidine 1 (5 mmol) in benzene (30 ml) was added. The reaction mixture was stirred at 60C. At the end of the reaction as indicated by thin-layer chromatography, the products were extracted from the solid phase with chloroform. The combined extracts were evaporated in vacuum and the dry residue was crystallized from benzeneether (3b,d) or subjected to chromatography. 1148
REFERENCES 1. 2. 3. 4. 5. 6. 7. L. A. Sviridova, G. A. Golubeva, and I. V. Dlinnykh, Khim. Geterotsikl. Soedin., 1657 (1996). L. A. Sviridova, G. A. Golubeva, I. V. Dlinnykh, I. F. Leshcheva, L. D. Ashkinadze, V. V. Nesterov, and M. Yu. Antipin, Khim. Geterotsikl. Soedin., 1079 (1998). R. S. Rowland and R. Taylor, J. Phys. Chem., 100, 7384 (1996). F. H. Allen, O. Kennard, D. G. Watson, L. Brammer, A. G. Orpen, and R. Taylor, J. Chem. Soc., Perkin Trans. 2, No. 12, S1 (1987). D. E. Bergbreiter and J. J. Lalonde, J. Org. Chem., 52, 1601 (1987). A. V. Dovgilevich, K. N. Zelenin, A. A. Espenbetov, Yu. T. Struchkov, I. P. Bezhan, L. A. Sviridova, G. A. Golubeva, M. Yu. Malov, and Yu. G. Bundel', Khim. Geterotsikl. Soedin., 1242 (1985). G. I. Zhungietu, Oxindole and Its Derivatives [in Russian], Shtiintsa, Kishinev (1973), p. 45.
1149
HETEROCYCLIC DERIVATIVES OF FULLERENE C60. 2*. CYCLOADDITION TO FULLERENE C60 OF THE PRODUCTS OF DEHYDROCHLORINATION OF N-BENZYLTRIFLUOROACETIMIDOYL CHLORIDES
M. V. Reinov, M. A.Yurovskaya, A. V. Streletskiy, and O. V. Boltalina It has been shown that, depending on the structure, the products of dehydrochlorination of N-benzyltrifluoroacetimidoyl chlorides react with C60 under the action of triethylamine as a [3 + 2] cycloaddition (with the formation of fulleropyrrolines) or a [4 + 2] cycloaddition (with the formation of fulleropiperideines). Keywords: N-benzyltrifluoroacetimidoyl chloride, N-(methylbenzyl)trifluoroacetimidoyl chloride, N-(p-methoxybenzyl)trifluoroacetimidoyl chloride, fulleropiperideines, fulleropyrrolines, [3 + 2] cycloaddition, [4 + 2] cycloaddition. Cycloaddition reactions to fullerene C60 offer the most efficient possibility for functionalizing it and especially for constructing heterocyclic fragments on the fullerene sphere (see, for example, the review [2]). One of the main methods of synthesizing fulleropyrrolines is the 1,3-dipolar cycloaddition of nitrile ylides to C60 [4]. For the overwhelming majority of nitrile ylides, reaction with C60 leads exclusively to the closed [6,6]-cycloadduct (see for example [4]). An anomalous course for such a reaction was discovered for the first time for 1-(4-nitrophenyl)-3-phenylnitrile ylide, when together with the closed [6,6]-fulleropyrroline a mixture was formed of the diastereomeric open [5,6]-fulleroid adducts [5]. It subsequently turned out that this result was reproduced for other substituted 1,3-diarylnitrile ylides [6], especially those having a nitro group in the para and meta positions of the C-aryl substituent, however the reason for this phenomenon has not been finally clarified up to the present time. For a clear answer to the problem of the reasons for the generation of fulleroid cycloadducts it is necessary to investigate as many nitrile ylides of varied structure as possible. The present investigation has been carried out in just this key and is devoted to the study of [3 + 2] cycloaddition processes of nitrile ylides generated from N-benzyltrifluoroacetimidoyl chlorides 1a-c by the action of triethylamine. The monoadducts 4a,b and 5a,b were isolated as a result of the interaction of nitrile ylides, generated from N-benzyltrifluoroacetimidoyl chlorides 1a,b by the action of triethylamine, with fullerene in boiling chlorobenzene.
_______ * For Part 1 see [1]. __________________________________________________________________________________________ Moscow M. V. Lomonosov State University, Moscow 119234, Russia; e-mail: yumar@org.chem.msu.su. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1331-1335, September, 2004. Original article submitted November 1, 2003. 1150 0009-3122/04/4009-11502004 Springer Science+Business Media, Inc.
_ p-RC6H4 N 1a,b C60 Cl + NEt3 CF3 p-RC6H4 N 2a,b + H CF3

+
p-RC6H4 + N _ CF3 3a,b C60
p- RC6H4
CF3
p- RC6H4
CF3
5a,b 15 a R = H, b R = MeO
4a,b
For the analysis of the compounds obtained we have used MALDI (Matrix Assisted Laser Desorption/Ionization), one of the mildest methods of ionization in mass spectrometry. This method has successfully recommended itself as one of the most reliable analytical means for characterizing organic fullerene derivatives [7], which are, as a rule, subject to complete or significant fragmentation or degradation on using traditional methods (EI mass spectrometry). Adducts 4a,b, 1,2-[5-phenyl-2-trifluoromethyl-3,4-dihydro-2H-pyrrolo]fullerene-60 and 1,2-[5-(4-methoxyphenyl)-2-trifluoromethyl-3,4-dihydro-2H-pyrrolo]fullerene-60, are the main reaction products. Results obtained by MALDI mass spectrometry prove that these compounds are monoadducts. In the negative ion mass spectra the most intense peaks, with m/z 906 and 936 were assigned to the molecular ions of monoadducts 4a and 4b respectively, the content of the fragmentary anion of C60 was insignificant in both cases. The sole reliable method permitting determination of whether closed [6,6]-cycloadducts or open [5,6]-fulleroid structures are formed is 13C NMR spectroscopy. The appearance in a spectrum of signals of sp3-hydridized carbon atoms is characteristic of the formation of closed [6,6]-isomers. In the 13C NMR spectrum of compound 4b, apart from the signals of the carbon atoms of the fullerene, the aromatic nucleus and the CF3 and C=N groups, there were signals at 54.6 (CH3O) and at 73.4, 86.2, and 86.4 ppm for the sp3-hybridized carbon atoms, which correspond to the C(2), C(3), and C(4) atoms of the pyrroline ring, indicating the formation of a closed [6,6]-cycloadduct. When forming fulleroid structures the signals of the nuclei of atoms C(3) and C(4) must be absent from the aliphatic region. The 1H NMR spectra of these compounds give exhaustive information on the fine special features of the structure of the annelated pyrroline fragment. In the 1H NMR spectra of both adducts 4a and 4b quadruplet signals were observed at ~6.6 ppm corresponding to the methine protons located in the position to the CF3 group. The double C=N bond in the adducts proved to be displaced in comparison with the initial imidoyl halide. According to the data of [8, 9], N-benzyltrifluoroacetimidoyl chloride A may undergo conversion in the presence of base into the isomeric imidoyl chlorides B. It is possible that the AB rearrangement proceeds more rapidly than 1,3-dipolar addition to the fullerene, and nitrile ylides 3a,b, interacting with the fullerene with the formation of the main products 4a,b, are generated from imidoyl chlorides B.
1151
CF3 CF3 Cl 110 oC N Ar ~20 oC NEt3 Cl
Ar
110 oC NEt3
CF3 B
N Cl
Ar
Adducts 5a,b are formed in insignificant amounts, insufficient to obtain their 1H NMR spectra. However, according to the data of MALDI mass spectrometry, they are, like adducts 4a,b, products of monoaddition. We propose that 1,2-[2-phenyl-5-trifluoromethyl-3,4-dihydro-5H-pyrrolo]fullerene-60 and 1,2-[2-(4-methoxyphenyl-5-trifluoromethyl-3,4-dihydro-5H-pyrrolo]fullerene-60 are the products of addition of nitrile ylides 2a,b, generated from A. Unexpected results were obtained on going to N-(methylbenzyl)trifluoro-acetimidoyl chloride (1c). In place of the expected fulleropyrroline, 6-phenyl-2-trifluoromethyl-2,3,4,5-tetrahydropyridino[3',4':1,2]fullerene60 (6) was obtained.
Me Ph N 1c
Cl CF3
NEt3 Ph
Me N 7
Cl CF3
NEt3 HCl
C60 Ph N 8 6 CF3
3
Ph
N1
CF3
According to the data of MALDI mass spectra the main signal in the high mass region was the molecular ion of m/z 920, which corresponds to the molecular mass of adduct 6. In difference to the spectra of the pyrroline structures 4, the 1H NMR spectrum of compound 6 clearly indicates the formation of a six-membered ring. In fact the appearance in the spectrum of signals for an AB system of nonequivalent protons at position 5 of the annelated ring as two doublets at 4.70 and 5.06 ppm with J = 14.2 Hz serves as an argument in favor of this assertion. The remaining signals correspond to the proposed structure. The formation of compound 6 may be explained by a [4 + 2] cycloaddition of diene 8 to fullerene. Compound 8 may be formed from imidoyl chloride 1c by the proposed scheme. Probably the isomer of imidoyl chloride 7 is formed initially, according to the isomerization scheme given previously for imidoyl chlorides, and is subject to dehydrochlorination under the action of triethylamine, being converted into azadiene 8.
1152
EXPERIMENTAL The 1H and 13C NMR spectra were recorded on a Varian XL-400 instrument (400 and 100 MHz respectively), internal standard was TMS. Analysis by the MALDI method was carried out on a Vision 2000 time-of-flight mass spectrometer with a N2 lazer of radiation wavelength 336 nm. Orthorhombic sulfur was successfully used by us as matrix. The order of preparing samples of substances for analysis is as follows [10]. Several drops (less than 1 l) of a saturated toluene solution of the matrix were applied to a metal target with a fine capillary to form, after evaporation of the solvent, a thin film. A fraction of the substance being analyzed, obtained by TLC, was also dissolved in toluene. The surface of the matrix film was then wetted with several drops of this solution with the aid of a fine capillary. A check on the progress of reactions and the purity of the compounds obtained was effected by TLC on Silufol UV-254 plates. Separation and purification of substances was carried out on a column of silica gel L 40/100, eluting with hexanebenzene, 1 : 10. N-Benzyltrifluoroacetimidoyl Chlorides 1a-c and their precursor N-trifluoroacetamides were synthesized by the methods of [8, 9]. N-Benzyltrifluoroacetimidoyl Chloride (1a). Yield 35%; bp 110-112C (10 mm Hg). 1H NMR spectrum (CDCl3), , ppm: 4.83 (2H, s, CH2); 7.35 (5H, m, Ph). N-p-Methoxybenzyltrifluoroacetimidoyl Chloride (1b). Yield 40%; bp 96-100C (15 mm Hg). 1 H NMR spectrum (CDCl3), , ppm (J, Hz): 3.81 (3H, s, CH3O); 4.77 (2H, s, CH2); 6.90 (2H, d, J = 9.3, 3-, 5-HPh); 7.27 (2H, d, J = 9.3, 2-, 6-HPh). N-(Methylbenzyl)trifluoroacetimidoyl Chloride (1c). Yield 30%; bp 65-70C (12 mm Hg). 1H NMR spectrum (CDCl3), , ppm (J, Hz): 1.68 (3H, d, J = 7, CH3); 5.12 (1H, q, J = 7, CH); 7.50 (5H, m, Ph). Fulleropyrrolines 4a,b, 5a,b and Fulleropiperideine 6. A solution of imidoyl chloride (0.21 mmol) in dry chlorobenzene (10 ml) was added during 1 h to a solution of fullerene C60 (50 mg, 0.07 mmol) and triethylamine (100 l, 0.73 mmol) in boiling dry chlorobenzene. After the addition the mixture was boiled for a further 2 h. After distilling off the solvent in vacuum, the residue was treated with methanol, the solid filtered off, washed several times with methanol, and separated by column chromatography, eluent was benzenehexane, 1:3. 5-Phenyl-2-trifluoromethyl-3,4-dihydro-2H-pyrrolo[3',4':1,2]fullerene-60 (4a). Yield 25%. MALDI mass spectrum: m/z 906 [M] . 1H NMR spectrum (CS2acetone-d6, 5:1), , ppm (J, Hz): 6.68 (1H, q, J = 7.9, CF3CH); 7.53 (3H, m, 3-, 4-, 5-HPh); 8.10 (2H, d, 2-, 6-HPh). 5-(4-Methoxyphenyl)-2-trifluoromethyl-3,4-dihydro-2H-pyrrolo[3',4':1,2]fullerene-60 (4b). Yield 30%. MALDI mass spectrum: m/z 935 [M] . 1H NMR spectrum (CS2acetone-d6, 5:1), , ppm (J, Hz): 3.87 (3H, s, CH3O); 6.60 (1H, q, J = 7.8, CF3CH); 7.00 (2H, d, J = 9.3, 3-, 5-HPh); 8.18 (2H, d, J = 9.3, 2-, 6-HPh). 13C NMR spectrum (CS2acetone-d6, 5:1), , ppm: 54.6 (CH3O); 73.4 (Csp3); 86.2 (Csp3); 86.4 (Csp3); 116 (CF3), a group of signals for carbon nuclei at 120-161, 175 (C=N). Adduct 5a. MALDI mass spectrum: m/z 906 [M] . Adduct 5b. MALDI mass spectrum: m/z 935 [M] . 6-Phenyl-2-trifluoromethyl-2,3,4,5-tetrahydropyridino[3',4':1,2-]fullerene-60 (6). Yield 25%. MALDI mass spectrum: 920 [M] . 1H NMR spectrum (CS2acetone-d6, 5:1), , ppm (J, Hz): 4.70 (1H, d, J = 14.2, 5-H); 5.06 (1H, d, J = 14.2, 5'-H); 5.82 (1H, q, J = 7.5, CF3CH); 7.56 (3H, m, 2m-, p-HPh); 8.22 (2H, m, 2o-HPh). The authors are grateful to the Volkswagen Fund (project No. I-77/855) and the Russian Fund for Fundamental Investigations (RFFI) (project No. 03-03-32855) for partial material support.
1153
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. M. V. Reinov, M. A. Yurovskaya, D. V. Davydov, and A. V. Streletskiy, Khim. Geterotsikl. Soedin., 223 (2004). M. A. Yurovskaya and I. V. Trushkov, Izv. Russ. Akad. Nauk, Ser. Khim., 343 (2002). M. A. Yurovskaya and A. A. Ovcharenko, Khim. Geterotsikl. Soedin., 291 (1998). J. Averdung, E. Albrecht, J. Lauterwein, J. Mattay, H. Mohn, W. H. Muller, and H. U. ter Meer, Chem. Ber., 127, 787 (1994). A. A. Ovcharenko, V. A. Chertkov, A. V. Karchava, and M. A. Yurovskaya, Tetrahedron Lett., 38, 6933 (1997). P. P. Demenuk, M. V. Reinov, A. A. Ovcharenko, and M. A. Yurovskaya, Abstracts. 4th Biennial Int. Workshop in Russia "Fullerenes and Atomic Clusters", St-Petersburg (1999), P-188. T. Brown, N. L. Clipston, N. Simjee, H. Luftmann, H. Hungerbuhler, and T. Drewello, Int. J. Mass Spectrom., 210, 249 (2001). K. Tanaka, H. Daikaku, and K. Mitsuhashi, Chem. Lett., 1463 (1983). K. Tanaka, H. Daikaku, and K. Mitsuhashi, Heterocycles, 21, 611 (1984). A. V. Streletskiy, I. V. Kouvitchko, S. E. Esipov, and O. V. Boltalina, Rapid Commun. Mass Spectrom., 16, 99 (2002).
1154
INTERACTION OF 5-ACETYL(ALKOXYCARBONYL)- 3-ALKOXYCARBONYL6-METHYLPYRIDIN-2(1H)-ONES WITH PRIMARY AROMATIC AMINES AND HYDRAZINE HYDRATE
Zh. A. Krasnaya 5-Acetyl(alkoxycarbonyl)-3-alkoxycarbonyl-6-methylpyridin-2(1H)-ones have been obtained from enaminocarbonyl compounds. Their interactions with benzylamine, -phenylethylamine, and hydrazine hydrate have been studied, as a result of which a series of amides, hydrazides, and hydrazones of 2(1H)pyridones has been synthesized. Keywords: amides, hydrazides, hydrazones, 2(1H)-pyridones. The considerable attention paid to the synthesis and investigation of 2(1H)-pyridones is linked primarily with the broad spectrum of their biological activity. Among them are highly effective cardiotonics, tranquilizers, fungicides, antimicrobial preparations, etc. [1-4]. Certain functionally substituted pyridones proved to be inhibitors of the reverse transcriptase of HIV-1 [5], which opened new prospects for using them. The introduction of such "pharmacophoric" fragments as hydrazide, hydrazone, and amide functions proved to have a significant effect on the biological activity of pyridones [2, 6]. The hydrazide of isonicotinic acid and its derivatives display high antitubercular activity [6]. Compounds have been discovered among the hydrazones of heterocyclic ketones, which possess high antitumor, antimicrobial, antitubercular, and other forms of activity [7]. In the present work the interaction has been studied of 3-alkoxycarbonyl-6-methylpyridin-2(1H)-ones, functionally substituted at position 5, with aromatic primary amines (benzylamine, -phenylethylamine) and hydrazine hydrate, with the aim of synthesizing new derivatives of 2(1H)-pyridone, which are of interest as potential biologically active compounds. The initial substituted pyridin-2(1H)-ones were obtained by reacting enaminocarbonyl compounds with cyanoacetic esters. We discovered previously that the substituted pyridones 2a,b are formed on interacting ketone 1a and keto ester 1b with alkyl cyanoacetates [8].
Me Me N Me 1ad R O NCCH2COOR1 R Me N H 2ae O O O R1
1, 2 a R = Me, b R = COOEt, c R = COOMe, d R = COMe; 2 e R = COMe; 2 a,c,d R1 = Me, b,e R1 = Et
__________________________________________________________________________________________ N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow 117913; e-mail: kra@cacr.ioc.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1336-1342, September, 2004. Original article submitted January 16, 2002. 0009-3122/04/4009-11552004 Springer Science+Business Media, Inc. 1155
Using this method we obtained in high yield and under mild conditions (40C, 1 h) pyridone 2c from keto ester 1c and methyl cyanoacetate, and pyridones 2d,e from diketone 1d and alkyl cyanoacetates. On heating (160-165C, 30 min) pyridone 2a with an excess of benzylamine amide 3a is formed in 80% yield. In the case of pyridones 2b,c, containing two alkoxycarbonyl groups in positions 3 and 5, only one group (that located at position 3) reacts with benzylamine or -phenylethylamine under the same conditions, leading to the formation of amides 3b-e. The structures of products 3a-e were confirmed by the results of elemental analysis (Table 1) and by data of 1H NMR and UV spectra (Table 2), and the structure of amide 3c by the 13C NMR spectrum as well (Table 2). The fact that the ester group in position 5 did not react was established, using amide 3c as an example, with the aid of a 2D NOESY CH3/CH3O experiment. On interacting a large excess of hydrazine hydrate with pyridones 2b,c (80C, 30 min, i-PrOH) the monohydrazides 4a,b were formed in 90% yield. Bishydrazides were not obtained on more extended heating (10 h) of the reactants.

Compound 2a 2b 2c 2d 2e 3a 3b 3c 3d 3e 4a 4b 5a 5b 6 7 8 Empirical formula 911N3 C12H15NO5 C10H11NO5 C10H11NO4 C11H13NO4 C15H16N2O2 C16H16N2O4 C17H18N2O4 C17H18N2O4 C18H20N2O4 C9H11N3O4 C10H13N3O4 C17H18N2O3H2O C18H20N2O3H2O 23H23N3O2 C9H11N3O3 C9H13N5O2 Found, % Calculated, % 4.78 4.92 5.18 5.30 5.99 5.87 6.31 6.29 5.14 5.34 5.80 5.77 5.69 5.77 6.13 6.14 4.91 4.92 5.76 5.48 6.51 6.34 6.70 6.71 6.43 6.21 5.32 5.30 6.00 5.87
mp, N 6.31 6.22 6.78 6.70 6.38 6.28 10.86 10.93 9.21 9.34 8.98 8.91 9.01 8.91 8.84 8.53 19.06 18.66 17.58 17.57 8.92 8.89 8.97 8.48 11.51 11.25 19.90 20.09 31.29 31.38 215-216 [8] 185-187 [8] 199-201 208-209 170-171 212-213 258-260 253-255 255-256 198-200 >260 >260 203-204 169-170 165-166 246-247 260-261
Yield, %
53.02 53.33 57.27 57.41 58.84 59.18 69.97 70.29 63.85 64.00 65.30 64.95 65.02 64.95 65.76 65.84 47.77 48.00 49.82 50.20 64.58 64.70 65.33 65.44 73.78 73.97 51.74 51.67 48.64 48.42
70 73 80 74 76 81 90 80 89 80 90 90 87 90 65 86 85
1156

Y
5 3 1
Me
N H 28
Compound 1 2a 2b 2c 2d 2 3a 3b
UV spectrum (EtOH), max, nm () 2 208 (9300), 243 (7760) 345 (9100) 210 (15200), 263 (16700), 330 (8450) 210 (14050), 263 (16850), 330 (8450) 212 (18200), 280 (21800), 335 (11800) 212 (18500), 283 (21400), 338 (11900) 208 (21800), 240 (12800), 335 (16800) 208 (29400), 260 (16200), 325 (11100)
H NMR spectrum, , ppm* X 6 Y 7 2.15 (3H, s, CH3) 4.38 (2H, q, CH2); 1.40 (3H, t, CH3) 3.80 (3H, s, CH3) 2.55 (3, s, CH3) 2.55 (3, s, CH3) 2.10 (3, s, CH3) 3.85 (3, s, CH3)
-1 (1, br. s) 3 13.40 13.05 12.50 12.95 13.10 12.10 12.70
-4 (1, s) 4 8.10 8.80 8.50 8.75 8.70 8.20 8.76
6-3 (3, s) 5 2.55 2.82 2.60 2.85 2.85 2.30 2.68
3.90 (3H, s, CH3) 4.38 (2H, q, CH2); 1.40 (3H, t, CH3) 3.78 (3H, s, CH3) 3.95 (3H, s, CH3) 4.40 (2H, q, CH2); 1.40 (3H, t, CH3) 10.20 (1H, t, NH); 4.55 (2H, d, CH2); 7.20-7.40 (5H, m, C6H5) 9.73 (1H, t, NH); 4.55 (2H, d, CH2); 7.20-7.40 (5H, m, C6H5)
1157
1158
TABLE 2 (continued)
1 3c*2 2 210 (33000), 263 (16000), 328 (12950) 210 (28600), 260 (18900), 324 (12800) 210 (33200), 262 (19300), 325 (13100) 210 (17300), 263 (14100), 325 (10000) 210 (21800), 260 (17900), 325 (12800) 210 (18900), 275 (20200), 330 (10750) 210 (18800), 275 (20700), 328 (11300) 210 (82000), 255 (41000), 335 (36000) 210 (17200), 270 (16200), 325 (11300) 208 (11400), 255 (13400), 340 (8950) 3 12.65 4 8.70 5 2.65 6 9.80 (1H, d, NH); 5.10 (1, m, ); 1.45 (3H, d, CH3); 7.20-7.40 (5H, m, C6H5) 9.75 (1H, t, NH); 4.52 (2H, d, CH2); 7.20-7.40 (5H, m, C6H5) 9.80 (1H, d, NH); 5.15 (1, m, ); 1.50 (3H, d, CH3); 7.20-7.40 (5H, m, C6H5) 10.15 (1, s, NH) 3.80 (3H, s, CH3) 7
3d 3e 4a 4b 5a 5b 6
12.75 12.75
8.75 8.70 8.68 8.70 8.48 8.45
2.65 2.65 2.62 2.65 2.58 2.60 2.50
4.28 (2H, q, CH2); 1.30 (3H, t, CH3) 4.25 (2H, q, CH2); 1.30 (3H, t, CH3) 3.80 (3H, s, CH3) 4.25 (2H, q, CH2); 1.30 (3H, t, CH3)
3.80 (3H, s, CH3) 4.22 (2, m, 2); 1.25 (3H, d, CH3) 10.00 (1H, br. s, NH); 7.10-7.40 (10H, m, 2 C6H5)*3; 4.55 (2, d, 2) 10.20 (1, br. s, NHNH2) 5.70 (2, br. s, N2); 10.40 (1, br. s, NHN2)
12.45
8.40
2.45 (3H, s, CH3); 3.75 (2H, s, 2); 7.10-7.30 (5, m, C6H5) 2.35 (3, s, CH3); 3.75 (2H, s, CH2); 7.10-7.40 (5H, m, C6H5) 4.60 (2, s, 2); 2.25 (3, s, CH3)
7 8
8.70 12.10 8.17
2.6 2.30
2.45 (3, s, CH3) 1.95 (3, s, CH3); 4.80 (2, br. s, NH2)
_______ * Spectra were taken in CDCl3 (compounds 2a,b,d,e) and DMSO-d6 (compounds 2s, 3a-e, 4a,b, 5a,b, 6-8). In all cases when the signal was d, t, or q, J ~7 Hz. *2 13C NMR spectrum (DMSO-d6): 18.80 (CH3-C(6)); 22.57 (CH3CH); 48.11 (CHNH); 51.80 (CH3); 107.64 (C(5)); 116.81 (C(3)); 125.84 (o-CPh); 126.84 (p-CPh); 128.43 (m-CPh); 143.94 (C6H5); 144.04 (C(4)); 156.82 (C(6)); 161.62 (CONH); 162.55 (C(2)); 164.33 (COCH3). *3 Signals of the C6H5 group protons in substituents X and Y were superimposed, forming an aggregate multiplet.
O R 2ac N H N O H 3ae O 2b,c
R2 Ph
H2NCH(R2)Ph
Me
NH2NH2 . H2O
R Me N H 4a,b O
NHNH2
3 a R = Me, R2 = H, b R = COOMe, R2 = H, c R = COOMe, R2 = Me, d R = COOEt, R2 = H, e R = COOEt, R2 = Me, 4 a R = COOMe, b R = COOEt
We discovered that the structure of the products of the interaction of benzylamine and hydrazine hydrate with pyridones 2d,e, containing an acetyl group in position 5, depends on the reaction conditions when interacting equivalent quantities of pyridones 2d,e and benzylamine. At 20C azomethines 5a,b are formed in 87-90% yield.
O Me Me N H 2d,e Me 2 : PhCH2NH2, 1:3 160 oC PhCH2N Me N H 6 O 2 : H2NNH2 . H2O, 1:1 80 oC Me Me N H 7 2 : H2NNH2 . H2O, 1 : 17 80
oC
O OR O 2 : PhCH2NH2, 1:1 20 oC PhCH2N
Me
O OR N H 5a,b O NHCH2Ph O O
Me
O NHNH2 O
NNH2 Me Me N H 8
O NHNH2 O
5 a R = Me, b R = Et
1159
On heating pyridone 2d with an excess of benzylamine (160C, 20 min) the reaction proceeds at both the acetyl and ester groups and leads to amide 6 in 65% yield. From equimolar quantities of hydrazine hydrate and pyridone 2d or 2e hydrazide 7 is formed in 86% yield on boiling in i-PrOH solution (1 h). Under the same conditions, but using a large excess of hydrazine hydrate, the hydrazidohydrazone 8 is formed in 85% yield. The structures of products 5-8 were confirmed by data of elemental analysis (Table 1) and of 1H NMR and UV spectra (Table 2).
EXPERIMENTAL The 1H NMR spectra were recorded on a Bruker WM-250 (250 MHz) instrument, and the 13C NMR spectrum (62 MHz) and the 2D NOESY experiment on a Bruker DRX-500 instrument. The UV spectra were taken on a Specord UV-vis instrument in ethanol. Esters 2a,b were obtained by the known method of [8]. 3,5-Dimethoxycarbonyl-6-methylpyridin-2(1H)-one (2c). A mixture of 2-acetyl-3dimethylaminoacrylic acid methyl ester (1c) (10 g, 5.9 mmol) and methyl cyanoacetate (5.8 g, 5.9 mmol) was maintained for 1 h 30 min at 40C and 1 day at room temperature. Dry ether was then added to the copious yellow precipitate, the solid was filtered off, washed with ether, and recrystallized from methanol. Product 2c (10.5 g) was obtained. 5-Acetyl-3-methoxycarbonyl-6-methylpyridin-2(1H)-one (2d). A mixture of 3-(dimethylaminomethylene)pentane-2,4-dione (1d) (3 g, 2 mmol), methyl cyanoacetate (2.8 g, 2.8 mmol), and absolute methanol (7 ml) was maintained for 1 h at 40C, then for 1 day at room temperature. The bright-yellow solid (3.5 g) was filtered off, washed with methanol, and recrystallized from methanol. Product 2d (3.1 g) was obtained as a snow-white solid. 5-Acetyl-3-ethoxycarbonyl-6-methylpyridin-2(1H)-one (2e) was obtained analogously to pyridone 2d from diketone 1d (2 g, 1.3 mmol), ethyl cyanoacetate (2 g, 1.8 mmol), and absolute ethanol (5 ml). Compound 2e was recrystallized from ethanol. 3-Benzylcarbamoyl-5-ethoxycarbonyl-6-methylpyridin-2(1H)-one (3d). A mixture of pyridone 2b (1 g, 4 mmol) and benzylamine (1.3 g, 12 mmol) was heated on an oil bath. At 130-140C the reaction mixture became homogeneous, it was heated to 160-170C and maintained at this temperature for 15 min. After cooling, absolute ether was added to the copious colorless solid, the solid was filtered off, and washed thoroughly with absolute ether, and with methanol. Amide 3d (1.1 g) was obtained. 3-Benzylcarbamoyl-5-methoxycarbonyl-6-methylpyridin-2(1H)-one (3b) was obtained analogously to amide 3d from diester 2c (0.9 g, 4 mmol) and benzylamine (1.3 g, 12 mmol) with a yield of 1.05 g. 3-Benzylcarbamoyl-5,6-dimethylpyridin-2(1H)-one (3a) was obtained analogously to compounds 3b,d from pyridone 2a (0.3 g, 1.7 mmol) and benzylamine (0.27 g, 2.5 mmol) with a yield of 0.34 g. 5-Methoxycarbonyl-6-methyl-3-(1-phenylethyl)carbamoylpyridin-2(1H)-one (3c). A mixture of pyridone 2c (3 g, 12 mmol) and -phenylethylamine (4.4 g, 36 mmol) was maintained at 160-165C for 20 min. After cooling, the solid was filtered off, and washed with ether. Methanol was added to it, the mixture was boiled for 5-10 min, and cooled. The solid was filtered off, washed with methanol, and with dry ether. Amide 3c (3 g) was obtained. 5-Ethoxycarbonyl-6-methyl-3-(1-phenylethyl)carbamoylpyridin-2(1H)-one (3e). A mixture of pyridone 2b (1 g, 4 mmol) and -phenylethylamine (1.5 g, 12 mmol) was maintained at 160-165C for 35 min, then cooled, absolute ether was added, and the solid separated. Absolute ethanol was added to the solid, and the mixture boiled for 5-10 min. The solid was separated, washed with absolute ether, and amide 3e (1.05 g) was obtained.
1160
3-Carbazoyl-5-methoxycarbonyl-6-methylpyridin-2(1H)-one (4a). A mixture of diester 2c (0.9 g, 4 mmol), hydrazine hydrate (3 ml), and 2-propanol (5 ml) was boiled for 30 min. After cooling, the solid was filtered off, washed with methanol, and with ether. Product 4a (0.8 g) was obtained. 3-Carbazoyl-5-ethoxycarbonyl-6-methylpyridin-2(1H)-one (4b) was obtained analogously to pyridone 4a from diester 2b. 5-(1-Benzyliminoethyl)-3-methoxycarbonyl-6-methylpyridin-2(1H)-one (5a). A mixture of pyridone 2d (0.21 g, 1 mmol) and benzylamine (0.11 g, 1 mmol) was stirred vigorously at room temperature and maintained at the same temperature for 1 day. Absolute ether was then added, the precipitate was filtered off, and washed with absolute ether. Azomethine 5a (0.26 g) was obtained as the hydrate. 5-(1-Benzyliminoethyl)-3-ethoxycarbonyl-6-methylpyridin-2(1H)-one (5b) was obtained analogously to azomethine 5a from pyridone 2a, as the hydrate. 3-Benzylcarbamoyl-5-(1-benzyliminoethyl)-6-methylpyridin-2(1H)-one (6). A mixture of ester 2d (0.63 g, 3 mmol) and benzylamine (1.0 g, 9 mmol) was maintained at 160C for 20 min. The liquid reaction mixture was evaporated in vacuum, ether was added to it, the solid was filtered off, and boiled in acetone for 5-10 min. After cooling, the solid was filtered off, washed with acetone, and product 6 (0.72 g) was obtained. 5-Acetyl-3-carbazoyl-6-methylpyridin-2(1H)-one (7). A mixture of pyridone 2d (0.21 g, 1 mmol) and hydrazine hydrate (0.05 g, 1 mmol) in 2-propanol (0.85 ml) was boiled for 1 h. After cooling, the solid was filtered off, washed with methanol, and with ether, and boiled for 5-10 min in acetone. The solid was then filtered off, washed with acetone, with ether, and hydrazide 7 (0.18 g) was obtained. The same hydrazide 7 was obtained analogously from pyridone 2e. 3-Carbazoyl-5-(1-hydrazonoethyl)-6-methylpyridin-2(1H)-one (8). A mixture of pyridone 2d (0.21 g, 1 mmol), hydrazine hydrate (1 ml, 17 mmol), and 2-propanol (1.5 ml) was boiled for 1 h, cooled, the slightly yellowish solid was separated, and was thoroughly washed with absolute methanol, then with absolute ether. Compound 8 (0.19 g) was obtained.
REFERENCES 1. 2. V. P. Litvinov, S. G. Krivokolysko, and V. D. Dyachenko, Khim. Geterotsikl. Soedin., 579 (1999). L. A. Rodinovskaya, V. K. Promonenkov, Yu. A. Sharanin, V. P. Litvinov, and A. M. Shestopalov, in: Progress in Science and Technology, Organic Chemistry [in Russian], Vol. 17, All-Union Institute of Scientific and Technical Information (VINITI), Moscow (1983), p. 54. L. Mosti, P. Schenone, M. Iester, P. Dorigo, R. M. Gaion, and D. Fraccarollo, Eur. J. Med. Chem., 28, 853 (1993). L. Mosti, R. Boggia, and P. Fossa, Farmaco, 52, 331 (1997). W. S. Saari, J. M. Hoffman, J. S. Wai, T. E. Fisher, C. S. Rooney, A. M. Smith, C. M. Thomas, M. E. Goldmann, J. A. O'Brien, J. H. Nunberg, J. C. Quintero, W. A. Schleit, E. A. Emini, A. M. Stern, and P. S. Anderson, J. Med. Chem., 34, 2922 (1992). M. D. Mashkovskii, Drugs [in Russian], Vol. 2, Meditsina, Moscow (1993), p. 366. Yu. P. Kitaev and B. I. Buzykin, Hydrazones [in Russian], Nauka, Moscow (1974), p. 381. Zh. A. Krasnaya, T. S. Stytsenko, E. P. Prokof'ev, and V. F. Kucherov, Izv. Akad. Nauk SSSR, Ser. Khim., 2543 (1973).
3. 4. 5.
6. 7. 8.
1161
DERIVATIVES OF sym-TRIAZINE. 3*. SYNTHESIS AND SOME CONVERSIONS OF MONOAZIDES OF THE TRIAZINE SERIES
S. N. Mikhailychenko1, A. A. Chesniuk1, L. D. Koniushkin2, S. I. Firgang2, and V. N. Zaplishny1 A convenient preparative route has been developed for the synthesis of 2-azido-4-R-6-R'-sym-triazines, which are promising synthons in organic synthesis. A series of 2-(1-triazolyl)-sym-triazine derivatives has been synthesized for the first time from the obtained azides and acetylacetone or acetoacetic ester. Keywords: 2-azido-4-R-6-R'-sym-triazines, substituted 2-(1-triazolyl)-sym-triazines, (4-R-6-R'-sym-2triazinyl)trimethylammonium chlorides. Organic azides are extremely reactive and convenient synthons for the synthesis of many heterocyclic compounds promising for practical use [2]. However, azides of the sym-triazine series have not been described up to the present time. The problem of the present work consists of the development of a synthetic route and the study of certain properties of such compounds. Our numerous attempts at the synthesis of 4,6-disubstituted 2-azido-sym-triazines by the traditional method, the nucleophilic substitution of the chlorine atom in disubstituted monochloro-sym-triazines with the aid of sodium and potassium azides by the known procedure [3], were not crowned with success, in spite of a comprehensive variation of the conditions of carrying out the reaction. This is probably linked with the extremely weak lability of the chlorine atom in the indicated compounds and the complexity of obtaining diazonium salts from them. Previously [1,4] we synthesized and reported the relatively stable and simultaneously highly reactive (4-R-6-R'-sym-2-triazinyl)trimethylammonium chlorides of the type of 1. We have discovered that salts 1a-k react readily with sodium azide in aqueous solution even at room temperature. The desired previously unavailable monoazides of the sym-triazine series 2a-k were formed smoothly in good yield (65-94%) (Scheme 1). The synthesized azides 2a-k are extremely stable on extended storage, and are explosion-proof finely crystalline white powders, readily soluble in aromatic hydrocarbons and the usual polar organic solvents, poorly soluble in aliphatic hydrocarbons in the cold, and insoluble in water. Their homogeneity was verified by TLC and their composition and structures were confirmed by results of elemental analysis, and by data of IR, 1 H NMR, and mass spectra (Tables 1, 2).
_______ * For Part 2 see [1]. __________________________________________________________________________________________

2
Kuban State Agricultural University, Krasnodar 350044, Russia; e-mail: vlad_zpl@mail.ru. N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow 117913. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1343-1350, September, 2004. Original article submitted December 17, 2001; revision submitted July 10, 2002. 0009-3122/04/4009-11622004 Springer Science+Business Media, Inc.
1162
Scheme 1
+ _ NMe3 Cl N R N 1a _k N + R1 NaN3 R N N3 N N 2a_k R1 + NMe3 + NaCl
1, 2 ad, k R = I, eg R = II, h R = OMe, i, j R = III, a R1 = I, b, g, h R1 = OMe, c, e R1 = OEt, d, f R1 = II, i R1 = OMe, j R1 = III, k R1 = NPh2
I
N O,
II
III
Me
Intense absorption bands were present in the IR spectra of azides 2 characteristic of the stretching vibrations of the azide group at 2100-2110, and of the conjugated C=N bond of the triazine ring at 1505-1620 cm-1. In the 1H NMR spectra (Table 2) the resonance signals for the protons of all the substituents of the heterocycle were also sharply differentiated, however the singlet signal for the protons of the N+Me3 group, characteristic of the initial salts 1, was absent [4]. TABLE 1. Characteristics of Compounds 2-4
Compound 1 2 2b 2c 2d 2e 2f 2g 2h 2i 2j 2k 3 3b 3c 3d 3e 3f Empirical formula 2 C11H16N8O2 C8H11N7O2 C9H13N7O2 C12H18N8O C10H15N7O C13H20N8 C9H13N7O C5H6N6O2 C10H15N7O2 C15H24N8 C19H18N8O C16H22N8O3 C13H17N7O3 C14H19N7O3 C17H24N8O2 C15H21N7O2 C18H26N8O Found, % Calculated, % H 4 5.68 5.52 4.83 4.67 5.38 5.21 6.39 6.25 6.23 6.07 7.22 6.99 5.68 5.57 3.45 3.32 5.87 5.69 7.80 7.65 4.98 4.84 6.15 5.92 5.49 5.44 5.83 5.74 6.67 6.50 6.51 6.38 7.16 7.07 mp, N 5 38.48 38.39 41.43 41.33 39.12 39.03 38.67 38.59 39.40 39.34 38.96 38.88 41.78 41.68 46.28 46.14 37.10 36.96 35.58 35.42 30.06 29.93 29.32 29.23 30.83 30.83 29.55 29.42 30.21 30.09 29.68 29.59 30.35 30.25 6 185-185.5 116-17 104-105 113-114 74-75 96-97 85-86 82-83 92-93 116-117 161-162 203-204 198-199 192-193 178-179 140-141 184-185 Mol. ion, m/z* 7 292 237 251 290 249 288 235 182 265 316 374 374 319 333 372 331 370 Yield, % 8 68 94 84 72 90 65 91 69 75 75 80 79 85 76 86 85 75
C 3 45.49 45.20 40.77 40.50 43.19 43.02 49.83 49.63 48.29 48.18 54.33 54.14 46.23 45.95 33.20 32.97 45.42 45.27 57.09 56.94 61.13 60.95 51.49 51.32 49.04 48.89 50.58 50.44 54.99 54.82 50.48 50.36 58.46 58.35
1163
TABLE 1 (continued)
1 3g 3h 3i 4a 4b 4c 4d 4e 4f 4g 4h 4i 2 C14H19N7O2 C10H12N6O3 C15H21N7O2 C17H24N8O4 C14H19N7O4 C15H21N7O4 C18H26N8O3 C16H23N7O3 C19H28N8O2 C15H21N7O3 C11H14N6O4 C25H26N8O3 3 53.16 52.98 45.57 45.45 54.47 54.36 50.59 50.48 48.29 48.13 49.76 49.58 53.81 53.71 53.01 52.17 56.81 56.98 51.98 51.86 44.98 44.89 61.58 61.71 4 6.20 6.17 4.71 4.58 6.49 6.38 6.13 5.98 5.63 5.48 5.99 5.83 6.67 6.51 6.29 6.41 6.91 7.05 6.25 6.09 4.87 4.79 5.27 5.39 5 31.02 31.03 31.95 31.81 29.74 29.59 27.85 27.71 28.16 28.07 27.08 26.98 27.95 27.85 27.20 27.13 28.07 27.98 28.32 28.23 28.64 28.56 23.14 23.03 6 133-134 175-176 132-133 188-189 155-156 110-111 198-199 119-120 168-169 114-115 147-148 212-213 7 317 264 331 404 349 363 402 361 400 347 294 486 8 91 89 87 70 85 81 83 85 71 82 87 73
_______ * Mass spectral data may be obtained from the authors.
It is known that azidoazolopyridazines [5] and monoazidofurazans [6] form biheterocyclic systems with 1,3-dicarbonyl compounds. Since substances including similar systems display high biological activity [6], it seemed of interest to clarify the possibility of obtaining still unreported compounds with a single bond linking the sym-triazine and triazole rings. For this purpose we have studied the interaction of the synthesized azides 2a-k with such widely available dicarbonyl compounds as acetylacetone and acetoacetic ester. As a result, the corresponding products 3a-i and 4a-i were obtained in high yield (71-91%) (Scheme 2). Scheme 2
EtO O N N N N R N 4ai N R1 Me Me O O OEt; NEt3 Me 2ak R O O Me; NEt3 N N 3ai N N N N R1 Me Me O
3ad, 4ad, i R = I, 3eg, 4eg R = II, 3i R = OMe; 3,4 a R1 = I, b R1 = OMe, c,e R1 = OEt, d,f R1 = II, 3i R1 = III
I
N O,
II
III
Me
1164

Compound 1 2a 2b 2c 2d 2e 2f 2g 2h 2i IR spectrum, , cm-1 N3 or N=N, =N = and =-conj. 2 3 2110 2105 2100 2110 2105 2100 2110 2100 2100 1570, 1550 1565, 1505 1560, 1505 1550, 1530 1500, 1580 1620, 1550, 1505 1510, 1570 1580, 1540 1560, 1500
1
NMR spectrum, , ppm (SSCC, J, Hz) 4
3.55-3.75 (16H, m, 4NCH2, 4OCH2) 3.60-3.80 (8H, m, 2NCH2, 2OCH2); 3.85 (3H, s, OCH3) 1.30 (3H, t, J = 7.85, 3 in OEt); 3.60-3.80 (8H, m, 2 NCH2, 2OCH2); 4.35 (2H, q, J = 7.85, 2 in OEt) 1.47-1.70 (6H, m, 3CH2); 3.55-3.75 (12H, m, 4NCH2, 2OCH2) 1.33 (3H, t, J = 7.4, CH3 in OEt); 1.50-1.73 (6H, m, 3CH2); 3.70-3.80 (4H, m, 2NCH2); 4.34 (2H, q, J = 7.4, 2 in OEt) 1.40-1.62 (12H, m, 6CH2); 3.55-3.70 (8H, m, 4NCH2) 1.53-1.70 (6H, m, 3CH2); 3.70-3.80 (4H, m, 2NCH2); 3.86 (3H, s, OCH3) 3.85 (6H, s, 2OCH3) 1.19 (3H, d, J = 7.4, CHCH3); 1.32-1.80 (6H, m, 3CH2); 2.92-3.03 (1H, m, NCH); 3.87 (3H, s, OCH3); 4.44-4.99 (2H, m, NCH2) 1.19 (6H, d, J = 7.35, 2CHCH3); 1.32-1.80 (12H, m, 6CH2); 2.97-3.04 (2H, m, 2NCH); 4.48-4.98 (4H, m, 2NCH2) 3.25-3.75 (8H, m, 2OCH2, 2NCH2); 7.20-7.40 (10H, m, 2C6H5) 2.80 (3H, s, 5'-CH3); 2.62 (3H, s, COCH3); 3.60-3.85 (16, m, 42, 4NCH2) 2.63 (3H, s, COCH3); 2.85 (3H, s, 5'-CH3); 3.65-3.90 (8H, m, 2OCH2-, 2NCH2-); 4.00 (3, s, 3) 1.36 (3H, t, J = 7.0, CH3 in OEt); 2.63 (3H, s, COCH3); 2.82 (3H, s, 5'-CH3); 3.65-3.85 (8H, m, 2OCH2, 2NCH2); 4.43 (2H, q, J = 7.0, CH2 in OEt) 1.55-1.72 (6H, m, 3CH2), 2.65 (3H, s, COCH3), 2.80 (3H, s, 5-CH3), 3.63-3.84 (12H, m, 4NCH2, 2OCH2) 1.39 (3H, t, J = 7.0, CH3 in OEt); 1.57-1.75 (6H, m, 3CH2); 2.64 (3H, s, COCH3); 2.85 (3H, s, 5'-CH3); 3.80-3.88 (4H, m, 2NCH2); 4.44 (2H, q, J = 7.0, CH2 in OEt) 1.45-1.70 (12H, m, 6CH2); 2.63 (3H, s, COCH3); 2.80 (3H, s, 5'-CH3); 3.70-3.82 (8H, m, 4NCH2) 1.62-1.80 (6H, m, 3CH2); 2.65 (3H, s, COCH3); 2.87 (3H, s, 5'-CH3); 3.85-3.95 (4H, m, 2NCH2); 4.03 (3, s, 3) 2.65 (3H, s, COCH3); 2.70 (3H, s, 5'-CH3); 4.08 (6H, s, 23) 1.28 (3H, d, J = 7.3, CHCH3); 1.37-1.48 (1H, m, NCH); 1.62-1.83 (6H, m, 3CH2); 2.65 (3H, s, COCH3); 2.85 (3H, s, 5'-CH3); 3.87 (3, s, 3); 4.55-5.11 (2H, m, NCH2) 1.36 (3H, t, J = 6.6, CH3 in Et), 2.81 (3, s, 5-CH3); 3.61-3.86 (16H, m, 4OCH2, 4NCH2); 4.39 (2H, q, J = 6.6, CH2 in COOEt) 1.34 (3H, t, J = 7.4, CH3 in COOEt); 2.85 (3, s, 5'-CH3); 3.65-3.87 (8H, m, 2OCH2, 2NCH2); 3.97 (3, s, 3); 4.37 (2, q, J = 7.4, 2 in COOEt) 1.30-1.40 (6H, m, CH3 in Ot and COOEt); 2.85 (3H, s, 5'-CH3); 3.65-3.83 (8H, m, 2OCH2, 2NCH2); 4.35 (2H, q, J = 7.5, CH2 in COOEt); 4.45 (2H, q, J = 7.35, CH2 in Ot) 1.36 (3H, t, J = 7.4, CH3 in COOt); 1.53-1.73 (6H, m, 3CH2); 2.83 (3H, s, 5'-CH3); 3.65-3.85 (12H, m, 2OCH2, 4NCH2); 4.36 (2H, q, J = 7.4, CH2 in COOt)
2j 2k 3a 3b 3c
2110 2100 1680 1685 1705
1575, 1530 1550, 1520 1530, 1560 1540, 1565, 1595 1590, 1550, 1505 1590, 1535, 1510 1590, 1550, 1530 1620, 1590, 1535 1590, 1560, 1535 1580, 1550 1595, 1550, 1535
3d 3e
1670 1665
3f 3g
1680 1685
3h 3i
1690 1680
4a
1710
1550, 1510
4b
1715
1600, 1560, 1505 1590, 1550, 1505 1600, 1550
4c
1705
4d
1710
1165
TABLE 2 (continued)
1 4e 2 1700 3 1600, 1575, 1505 1600, 1545 4 1.37 (6H, m, CH3 in Ot and COOEt); 1.57-1.75 (6H, m, 3CH2); 2.85 (3H, s, 5'-CH3); 3.80-3.88 (4H, m, 2NCH2); 4.38 (2H, q, J = 7.0, CH2 in COOEt); 4.45 (2H, q, J = 7.0, CH2 in Ot) 1.34 (3H, t, J = 7.35, CH3 in COOt); 1.50-1.70 (12H, m, 6CH2); 2.80 (3H, s, 5'-CH3); 3.70-3.85 (8H, m, 4NCH2); 4.35 (2H, q, J = 7.35, CH2 in COOt) 1.37 (3H, t, J = 7.4, CH3 in COOt); 1.57-1.75 (6H, m, 3CH2); 2.85 (3H, s, 5'-CH3); 3.80-3.90 (4H, m, 2NCH2); 3.98 (3, s, 3); 4.36 (2H, q, J = 7.4, CH2 in COOt) 1.39 (3H, t, J = 7.4, CH3 in COOt); 2.56 (3H, s, 5'-CH3); 4.07 (6H, s, 2O3); 4.37 (2H, q, J = 7.4, CH2 in COOEt) 1.32 (3H, t, J = 7.35, CH3 in COOt); 2.42 (3H, s, 5'-CH3); 3.55-3.82 (8H, m, 2OCH2, 2NCH2); 4.32 (2H, q, J = 7.3, CH2 in COOt); 7.25-7.45 (10H, m, 2C6H5)
4f
1705
4g
1708
1605, 1580, 1510 1595, 1535 1580, 1540, 1510
4h 4i
1715 1720
It turned out that the reaction rate depended significantly on the type of dicarbonyl compound used. On interacting monoazides 2 with the more reactive acetylacetone the time for the synthesis at room temperature varied from 0.5-14 h. To obtain the same desired products 4a-i in the reaction with acetoacetic ester required far more time (in some cases up to 72 h) at 30-40C. As was to be expected the structure of the initial azide influences the reaction rate. The most reactive turned out to be azide 2h, containing the small volume OMe substituent in positions 4 and 6 of the triazine ring. The least reactive were azides 2j,k having residues of the sterically hindering diphenylamine and 2-methylpiperidine at the indicated positions. The synthesized triazolyltriazines 3a-i, 4a-i were white, finely crystalline powders, readily soluble in polar organic solvents and aromatic hydrocarbons, poorly soluble in petroleum ether in the cold, and insoluble in water. Their melting points always somewhat exceeded those of the corresponding initial azides 2. The homogeneity of the obtained compounds was confirmed by TLC, and their composition and structure by the results of elemental analysis, and data of IR, 1H NMR, and mass spectra. The absorption band for the stretching vibrations of the azide group at 2100-2110 was absent from the IR spectra of triazolyltriazines 3a-i, 4a-i, but there were intense absorption bands characteristic of the C=O group at 1665-1720, and also for conjugated C=C and C=N bonds at 1505-1630 cm-1 (Table 2). In all the 1H NMR spectra of compounds 3a-i, 4a-i (Table 2) signals were present for the protons of the substituents in positions 4 and 6 of the triazine ring, a singlet for the protons of the 5'-Me group of the triazole ring at 2.70-2.87 for compounds 4a-g, and at 2.42-2.56 ppm for compounds 4h,i (the displacement of the signal towards high field is probably linked with the effect of the substituents in positions 4 and 6 of the triazine ring). The singlet signal for the protons of the 4'-COMe group of the triazole ring of compounds 3a-i was observed at 2.62-2.65 ppm. There were characteristic signals in the spectra of compounds 4a-i for the 4'-COOEt group, a triplet at 1.30-1.42 (CH3) and a quartet at 4.28-4.48 ppm (CH2). The structures of the synthesized products 2-4 were also confirmed by data of mass spectroscopy. A simple and reliable procedure is proposed for the synthesis of the difficultly available monoazides of sym-triazines. An addition-cyclization reaction of these azides with dicarbonyl compounds has been studied and the dependence of reaction time on reactant structure has been shown. A series of substituted 2-(1-triazolyl)triazines has been obtained for the first time. These are promising as biologically active compounds.
1166
EXPERIMENTAL The IR spectra were recorded for suspensions of samples in nujol with a Specord IR-75 spectrometer. The H NMR spectra were taken for solutions of samples in DMSO-d6 on a Bruker WM-500 (500 MHz) radiospectrometer. The mass spectra were recorded on a Finnigan MAT INCOS 50 instrument (energy of ionizing electrons was 70 eV). Elemental analysis of the synthesized compounds was carried out with a CarloErba model 1106 analyzer. A check on the progress of reactions and the purity of the compounds obtained was effected by TLC on Silufol UV-254 plates in acetonehexane, 1:1. The initial 2-chloro-sym-triazines and salts 1a-k were obtained by the known procedures of [4, 8]. Triethylamine was dried over KOH directly before use, then subjected to fractional distillation. The main fraction was distilled once more over metallic sodium. DMF was purified and dried by the known procedure of [9]. 2-Azido-4,6-dimorpholino-sym-triazine (2a). A solution of sodium azide (30 mmol) in water (10 ml) was slowly added dropwise with stirring at 5-10C to a solution of compound 1a (15 mmol) in water (20 ml) . The reaction mixture was then stirred at room temperature for 3 h. The precipitated solid was filtered off, washed with water until chloride ion was absent from the washings, and dried to constant weight. Azide 2a was obtained having category A purity (content of main substance >99%), and did not require further purification. Monoazides 2b-k were obtained analogously. 6-(4-Acetyl-5-methyl-1,2,3-triazol-1-yl)-2,4-dimorpholino-sym-triazine (3a). A mixture of acetylacetone (68 mmol) and triethylamine (68 mmol) was added dropwise with stirring at room temperature to a solution of azide 2a (34 mmol) in dry DMF (10 ml). The reaction mixture was stirred at the same temperature for 0.5 h and then poured into cold water (100 ml) as a fine stream with continuous stirring. The precipitated solid of the desired product was filtered off, washed repeatedly with water, and dried. Triazolyltriazine 3a was obtained with category A degree of purity. Compounds 3b-i were obtained analogously. 6-(4-Ethoxycarbonyl-5-methyl-1,2,3-triazol-1-yl)-2,4-dimorpholino-sym-triazine (4a). A mixture of acetoacetic ester (68 mmol) and triethylamine (68 mmol) was added dropwise with stirring at room temperature to a solution of azide 2a (34 mmol) in dry DMF (10 ml). The reaction mixture was stirred at 30-40C for 48 h and after treatment as described above for compound 3a triazolyltriazine 4a was obtained with category A degree of purity. Compounds 4b-i were obtained analogously.
1
REFERENCES 1. 2. 3. 4. 5. 6. S. N. Mikhailychenko, A. A. Chesniuk, V. E. Zavodnik, S. I. Firgang, L. D. Koniushkin, and V. N. Zaplishny, Khim. Geterotsikl. Soedin., 326 (2002). D. H. R. Barton and W. D. Ollis (editors), Comprehensive Organic Chemistry, Vol. 3, Pergamon, Oxford (1979). Weygand-Hilgetag, Experimental Methods in Organic Chemistry [Russian translation], Khimiya, Moscow (1962). A. A. Chesniuk, S. N. Mikhailychenko, V. S. Zavodnov, and V. N. Zaplishny, Khim. Geterotsikl. Soedin., 197 (2002). A. Gorup, M. Kvacic, B. Kranjc-Skraba, B. Mihelcic, S. Simonic, B. Stanovnic, and M. Tisler, Tetrahedron, 30, 2251 (1974). L. V. Batog, V. Yu. Rozhkov, Yu. V. Khronov, N. V. Pyatakova, O. G. Busygina, I. S. Severina, and N. N. Makhova, Russian Patent 2158265; Byull. Izobret., No. 30, 187 (2000).
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7. 8. 9.
E. B. Nikolaenkova, V. P. Krivopalov, and O. P. Shkurko, in: Nitrogen Heterocycles and Alkaloids [in Russian], Vol. 2, Iridium Press, Moscow (2001), p. 300. G. M. Pogosyan, V. A. Pankratov, V. N. Zaplishny, and S. G. Matsoyan, in: Polytriazines [in Russian], Izd. Akad. Nauk ArmSSR, Erevan (1987), p. 615. A. J. Gordon and R. A. Ford, Chemists Companion, Handbook of Practical Data, Techniques and References, Wiley-Interscience, New York (1972), 560 pp.
1168
DERIVATIVES OF sym-TRIAZINES. 6*. SOME SPECIAL FEATURES OF THE ADDITION OF SUBSTITUTED ACETYLENES TO TRIAZINE MONOAZIDES
S. N. Mikhailychenko1, A. A. Chesniuk1, A. D. Koniushkin2, and V. N. Zaplishny1 The special features of the interaction of 2-azido-4-R-6-R'-sym-triazines with some acetylenic compounds have been investigated. A series of new derivatives of sym-triazine linked at position 2 with a 1,2,3-triazole ring has been synthesized. Keywords: 2-azido-4-R-6-R'-sym-triazines, substituted 2-(1,2,3-triazol-1-yl)-sym-triazines. We have described the synthesis and some conversions of oxygen- and nitrogen-containing derivatives of sym-triazines and have shown their promise as reactive and convenient intermediates for the synthesis of nitrogen-containing heterocyclic compounds [1,2]. It is known that azidoazolopyridazines, monoazidofurazans, and monoazidotriazines [2-4] form coupled biheterocyclic systems with 1,3-dicarbonyl compounds, which display high antibacterial and antidote activity, but 1,3-dipolar components (such as azides) add to acetylenes with the formation of five-membered heterocycles, the triazoles [5]. Since these reactions have still not been studied for monoazides of the sym-triazine series, it seemed of interest to investigate such reactions and the possibility of obtaining CN linked heterocyclic systems of triazolyl-sym-triazines. With this aim azides 1, synthesized by us previously, were used as starting materials in cycloaddition reactions with certain substituted acetylenes, which were carried out according to the following scheme.
R N N N R1 1ai R1 N3 R2 C C R3 N N R2 2ai R3 R N N N N
1, 2 a,b,i R = OMe, R1 = 4-morpholino; c R = R1 = 1-piperidino; d,g,h R = R1 = 4-morpholino; e R = OEt, R 1 = 1-piperidino; f R = R1 = OEt; 2 af R2 = H, R3 = Ph; g R2 = R3 = CH2OH; h,i R2 = H, R3 = CH2OH
_______ * For Part 5 see [1]. __________________________________________________________________________________________

2
Kuban State Agricultural University, Krasnodar 350044, Russia; e-mail: vlad_zpl@mail.ru. N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences (RAN), Moscow 117913. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1351-1356, September, 2004. Original article submitted July 4, 2002. 0009-3122/04/4009-11692004 Springer Science+Business Media, Inc. 1169
The reaction was carried out in dry toluene or benzene at the boiling point of the solvent. It turned out that the reaction rate depends significantly both on the type, character, and structure of the substituents in positions 4 and 6 of the triazine ring and on the structure of the acetylenic compound used. On interacting monoazides 1 with propargyl alcohol, which is inclined to polarize and is more reactive, in benzene at 80C the reaction time did not exceed 5 h. The symmetrical and nonpolar molecules of 2-butyne-1,4-diol are so less reactive that far longer heating in toluene at 110C was required, but the reaction was accompanied by resinification. With the sterically hindered molecules of phenylacetylene the cyclization reaction with monoazides 1 containing alkoxy substituents in positions 4 and 6 of the triazine ring is complete after 48-72 h. In the case of amides 1c,d,g,h, containing the bulky substituents morpholino or piperidino, the reaction time with phenylacetylene is increased. The application of catalysts, complex compounds and mercury salts [6], proved to have no significant effect on the cycloaddition reaction rate, as also UV irradiation of the reaction mixture, even on conducting the reaction in a quartz reactor. Probably this reaction takes place by a typical cycloaddition mechanism according to the following scheme.
H N N +N
C C _ N N
N N N
N N
H 2af
In view of the lower steric hindrance the probability of carrying out the process by scheme A is far higher than by the alternative route B.
N N B N N + N C C _ H N N N H N
2'af
In reality analysis of the reaction mixture by high resolution 1H NMR and TLC showed that, together with the 4'-substituted cycloadducts 2a-f, a small quantity of the 5'-substituted triazolyltriazines 2'a-f are formed in the reaction process. Comparison of the integral intensities of the signals of the appropriate protons shows that the ratio of the 2 and 2' isomers in the reaction mixture was in all cases ~9:1. Regretably, due to the instability of the liquid 2' adducts we were unable to isolate and characterize them. Yields of the 4'-substituted triazoles 2a-f were 59-84%. In the case of propargyl alcohol the cycloaddition reaction also proceeds by the two alternative routes A and B with the formation of compounds 2'h,i as minor products. Compounds 2a-i synthesized in this way were relatively high melting white finely crystalline powders, readily soluble in many polar organic solvents, insoluble in hydrocarbons and in water (Tables 1, 2). The composition and structure of triazolyltriazines 2a-i were confirmed by data of elemental analysis, IR, 1H NMR and mass spectra. The homogeneity of all the compounds was confirmed by TLC.
1170

Compound 2a 2b 2c 2d 2e 2f 2g 2h 2i Empirical formula C C16H17N7O2 C17H19N7O C21H26N8 C19H22N8O2 C18H21N7O C15H16N6O2 C15H22N8O4 C14H20N8O3 C11H15N7O3 56.40 56.62 60.39 60.52 64.43 64.59 57.63 57.85 61.70 61.52 57.39 57.68 47.49 47.61 48.04 48.26 44.95 45.09 Found, % Calculated, % H 5.13 5.05 5.73 5.68 6.80 6.71 5.80 5.62 6.29 6.02 4.98 5.16 6.03 5.89 5.93 5.79 5.32 5.16 mp, C N 28.93 28.89 29.12 29.06 28.79 28.70 28.55 28.41 28.12 27.90 26.94 26.88 29.80 29.62 32.30 32.17 33.59 33.43 176-177 174-175 189-190 309-310 172-173 138-139 232-233 235-236 184-185 Mol. ion, m/z * 339 337 390 394 351 312 378 348 293 Yield, % 80 78 82 84 59 63 62 65 55
_______ * Mass spectral data may be obtained from the authors.

Compound IR spectrum, , cm-1
1
C=C, C=N and Other groups N=N conj. 1630, 1610, 1510 1600, 1620, 1515 1595, 1500, 1485 1605, 1550, 1510 1610, 1590, 1530 1020, 1140 () 1060, 1095 () 1030, 1055 (COC)
H NMR spectrum, , ppm (SSCC, J, Hz)
2 2b
2c 2d 2e
2f
1600, 1580, 1540 1600, 1550, 1505 1615, 1575, 1515 1600, 1530, 1500
1130, 1050 (COC) 3470-3300 (br. s, OH) 3400-3250 (br. s, ) 3420-3280 (br. s, ), 1110, 1050 (COC)
2g 2h
2i
3.65-3.90 (8H, m, 2NCH2, 2OCH2); 4.03 (3H, s, 3); 7.32-8.00 (5, m, HPh); 9.28 (1H, s, =CH) 1.60-1.75 (6, m, 32 piperid.); 3.85-4.00 (4, m, 2NCH2); 4.02 (3, s, 3); 7.35-8.05 (5, m, HPh); 9.28 (1H, s, =CH) 1.50-1.70 (12H, m, 62 piperid.); 3.70-3.92 (8, m, 4NCH2); 7.35-8.05 (5, m, HPh); 9.30 (1H, s, =CH) 3.67-4.00 (16H, m, 4NCH2, 4OCH2); 7.30-7.97 (5H, m, HPh); 8.98 (1H, s, =CH) 1.43 (3H, t, J = 5.5, OCH2CH3); 1.60-1.80 (6, m, 32 piperid.); 3.85-4.03 (4H, m, 2NCH2); 4.49 (2, q, J = 5.5, 23); 7.30-8.00 (5, m, HPh); 9.02 (1H, s, =CH) 1.49 (6H, t, J = 7.0, 223); 4.60 (4H, q, J = 7.0, 223); 7.30-8.05 (5, m, HPh); 9.12 (1, s, =) 3.65-3.85 (16, m, 4NCH2, 4OCH2); 4.60-5.00 (6H, m, 2CH2O, 2OH) 3.65-3.85 (16, m, 4NCH2, 4OCH2); 4.89 (2, d, J = 5.7, 2); 5.19 (1, br. s, ); 7.62 (1, s, =) 3.65-3.85 (8, m, 2NCH2, 2OCH2); 4.03 (3H, s, OCH3); 4.89 (2, d, J = 5.5, 2); 5.19 (1, br. s, ); 7.62 (1, s, =)
1171
In difference to the initial azides 1, the intense absorption band at 2100-2110 cm-1 for the stretching vibrations of the azide group disappears from the IR spectra of triazolyltriazines 2. However the strong bands for the stretching vibrations of the conjugated C=C, C=N, and N=N bonds at 1500-1630 cm-1 are retained (Table 2). Characteristic signals were detected in the 1H NMR spectra of compounds 2a-i for all the protons of the substituents located at positions 4 and 6 of the triazine ring. Multiplets were detected in the spectra of compounds 2a-f for the phenyl ring protons at 7.30-8.05 ppm and singlets for the proton at position 5 of the triazole ring at 8.98-9.28 ppm. The protons of symmetrical HOCH2 substituents in positions 4 and 5 of the triazole ring (in compound 2g) were displayed as multiplets at 4.60-5.00 ppm, but unsymmetrical C-H and CH2OH substituents in the same positions of the triazole ring (compounds 2h,i) appeared as doublets at 4.60-4.93 ppm (CH2OH) and as broadened signals at 5.15-5.23 ppm (CH2OH), with a singlet at 7.62 ppm (CH in position 5). The homogeneity and structures of the synthesized triazolyltriazines were also confirmed by mass spectrometry. The reaction of monoazides of sym-triazines with acetylenic compounds has been investigated. New triazolyltriazines, linked in position 2 of the triazine and position 1 of the triazole, have been obtained for the first time by cycloaddition. These compounds have the prospect of being biologically active.
EXPERIMENTAL
The IR spectra were recorded for suspensions of samples in nujol with a Specord IR 75 Spectrometer. The 1H NMR spectra were taken on a Bruker WM 500 spectrometer (500 MHz) in DMSO-d6. The mass spectra were recorded on a Finnigan MAT INCOS 50 instrument (energy of ionizing electrons 70 eV). Elemental analysis of the synthesized compounds was carried out with a Carlo-Erba model 1106 analyzer. A check on the progress of reactions and the purity of the compounds obtained was effected by TLC on Silufol UV 250 plates in acetonehexane, 1:1. 4,6-Disubstituted 2-chloro-sym-triazines and (2-sym-triazinyl)trimethylammonium chlorides (DTTA) were obtained by the known procedure of [7, 8]. Azides 1 were synthesized by the reaction of DTTA with sodium azide according to [1]. Solvents were purified and dried directly before use according to the procedure of [9]. 2-Methoxy-4-morpholino-6-(5-phenyl-4H-1,2,3-triazol-1-yl)-sym-triazine (2a). Phenylacetylene (10.2 mmol) was rapidly added dropwise to a solution of azide 1a (5.1 mmol) in dry toluene (10 ml) and the mixture was then refluxed for 48 h. The reaction mixture was evaporated to dryness in the vacuum of a water-jet pump, washed thoroughly with water, and dried. After purification by crystallization from alcohol, triazolyltriazine 2a (1.39 g, 80%) was obtained. Compounds 2b-f were obtained analogously. 2,4-Dimorpholino-6-(4-hydroxymethyl-5H-1,2,3-triazol-1-yl)-sym-triazine (2h). Propargyl alcohol (4.8 mmol) in dry benzene (5 ml) was added with stirring to a solution of azide 1h (2.4 mmol) in dry benzene (10 ml) and the reaction mixture was refluxed for 5 h. Benzene was distilled off to 1/2 volume, the mixture was cooled, the precipitated solid was rapidly filtered off, washed sequentially with cold benzene (2 2 ml), methylene chloride (2 2 ml), and cold water (15 ml). After purification by crystallization from alcohol triazolyltriazine 2h (0.54 g, 65%) was obtained. Compound 2i was obtained analogously, but in the case of compound 2g the reaction mixture was boiled for 72 h.
1172
REFERENCES
1. 2. 3. 4. 5. 6. 7. 8. 9.
S. N. Mikhailychenko, A. A. Chesniuk, V. I. Suslov, A. I. Shkrebets, M. M. Yukhomenko, and V. N. Zaplishny, Izv. Vyssh. Uchebn. Zaved., Khim. Khim. Tekhnol., 45, No. 4, 136 (2002). S. N. Mikhailychenko, A. A. Chesniuk, V. E. Zavodnik, S. I. Firgang, L. D. Koniushkin, and V. N. Zaplishny, Khim. Geterotsikl. Soedin., 326 (2002). L. V. Batog, V. Yu. Rozhkov, Yu. V. Khronov, N. V. Pyatakova, O. G. Busygina, I. S. Severina, and N. N. Makhova, Russian Patent 2158265; Byull. Izobret., No. 30, 187 (2000). E. B. Nikolaenkova. V. P. Krivopalov, and O. P. Shkurko, in Nitrogen Heterocycles and Alkaloids [in Russian] Vol. 2, Iridium Press, Moscow (2001), p. 300. D. H. R. Barton and W. D. Ollis (editors), Comprehensive Organic Chemistry, Vol. 1, Pergamon, Oxford (1979). S. G. Grigoryan, K. G. Avetisyan, and A. A. Matnishyan, Zh. Org. Khim., 48 (1984). G. M. Pogosyan, V. A. Pankratov, V. N. Zaplishny, and S. G. Matsoyan, in Polytriazines [in Russian], Izd. Akad. Nauk ArmSSR, Erevan (1987), p. 615. A. A. Chesniuk, S. N. Mikhailychenko, V. S. Zavodnov, and V. N. Zaplishny, Khim. Geterotsikl. Soedin., 197 (2002). A. J. Gordon and R. A. Ford, Chemists Companion, Handbook of Practical Data, Techniques and References, Wiley-Interscience, New York (1972), 560 pp.
1173
REACTIONS OF 2,3-DIOXOPYRROLO[2,1-a]ISOQUINOLINES WITH AMMONIA AND ALIPHATIC AMINES

A. G. Mikhailovskii, N. N. Polygalova, T. S. Turova, G. A. Lobashova, and M. I. Vahrin 2,3-Dioxopyrrolo[2,1-a]isoquinolines, with either a tertiary amide substituent at position 1 or no substituent, react with ammonia and aliphatic amines with ring opening to form the corresponding enamino keto amides. Keywords: amides of (3,3-dialkylisoquinolinidene-1)pyruvic and 2-oxobutandioic acids, ammonia, 5,5-dialkyl-2,3-dioxopyrrolo[2,1-a]isoquinolines, methylamine, ethylamine. Derivatives of 2,3-dioxopyrrolo[2,1-a]isoquinoline [1-4] have promise as reagents in the chemistry of alkaloids and their analogs [5,6]. The reactions of these compounds with N-nucleophiles have not been studied satisfactorily up to the present. The ease of opening of the pyrrole ring may be explained by angular tension which probably arises because all four carbon atoms are sp2-hybridized which presupposes 120 angles which are not possible in a five-membered ring. We have shown previously that the reaction of 2,3-dioxopyrrolo[2,1-a]isoquinolines with hydrazine occurs with opening of the pyrrole ring [7]. The objective of the current work was to investigate the reactions of 2,3-dioxopyrrolo[2,1-a]isoquinolines with ammonia and the simplest aliphatic amines. The study showed compounds 1a-c react readily with ammonia, methylamine, and ethylamine. The reactions were carried out by bubbling gaseous ammonia or an amine through a solution of the corresponding carbonyl compound in benzene at 20C. The amides 3a-d reacted analogously. The products of the reactions are the keto amides 2a-c and 4a-h (Table 1). The process is readily monitored by the decoloration of the solutions (the starting materials 1a-c and 3a-d are bright red in color). With a sufficiently strong gas flow the reactions are completed in 5 min.
R1 R
1
R2 N R2 O O NH3
R1 R
1
R2 NH O O 2ac N H H
1ac
__________________________________________________________________________________________ Perm State Pharmacological Academy, Perm 614990, Russia; e-mail: pfa@degacom.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, 1357-1361, September 2004. Original article submitted July 25, 2002. 1174 0009-3122/04/4009-11742004 Springer Science+Business Media, Inc.
R R
2
2 2
R O O H2 NR3 X N O 4ah O NH O N
N X N O 3ad
H R3
As is seen in Table 1, the yields in all cases are practically quantitative. The 1H NMR spectra (Table 2) reflect the characteristics of the structures of amides 2 and 4. In contrast to the spectra of the starting materials, in the spectra of the amides 2a-c and 4a-h there are singlets for the NH group of the ring (11.6-12.67 ppm), the basic nature of which is confirmed by a shift to weaker field on addition of CF3COOH. Turning our attention to the fact in the primary amide group the protons of the NH2 group (compounds 2a-c, 4a,c,h) appear as two singlets, which indicates that they are not equivalent. It is possible that in this case one carbonyl group contributes to the formation of two H-chelate structures: with NH of the heterocycle and the NH of the amide. The formation of such chelates should favor restriction of rotation about the double bond in the amide group [8].

Compound* 2a 2b 2c 4 4b 4c 4d 4e 4f 4g 4h R3 Empirical formula C14H16N2O2 C16H18N2O2 C16H20N2O4 C19H23N3O3 C20H25N3O3 C20H25N3O3 C21H27N3O3 C22H29N3O3 C22H29N3O3 C23H31N3O3 C21H25N3O4 Found, % Calculated, % C H N 68.7 68.8 71.0 71.1 63.0 63.1 68.7 66.8 67.5 67.6 68.4 67.6 68.2 68.3 68.7 68.9 68.7 68.9 69.4 69.5 65.7 65.8 6.5 6.6 6.6 6.7 6.5 6.6 6.7 6.8 7.0 7.1 7.0 7.1 7.3 7.4 7.6 7.6 7.5 7.6 7.8 7.9 6.5 6.6 11.6 11.5 11.4 10.4 9.3 9.2 11.4 12.3 11.8 11.8 11.7 11.8 11.5 11.4 10.9 11.0 11.1 11.0 10.6 10.6 10.9 11.0 Yield, % 91 94 89 95 87 86 90 88 85 77 81
mp, C
H Me H Me Et Me Et H
CH2 CH2 CH2 (CH2)2 (CH2)2 O
213-215 222-223 229-231 166-167 177-179 141-142 146-148 142-143 159-160 164-166 169-171
_______ * 2a,b 4a-h R1 = H, 2c R1 = MeO; 2a,c, 4a-g R2R2 = Me2, 2b, 4h R2R2 = (CH2)4.
1175
1176

Compound Chemical shifts, , ppm N(CH2)2, m, Aromatic protons and O(CH2)2, m 2.80-3.20 (4) 2.75-3.20 (4) 2.80-3.15 (4) 2.65-3.20 (4) 2.70-3.23 (4) 2.70-3.40 (4) 2.60-3.45 (4) 2.65-3.50 (8) 7.30-7.83, m 7.35-7.82, m 6.67 s, 7.13 s 7.29-7.68, m 7.25-7.70, m 7.32-7.73, m 7.33-7.80, m 7.35-7.75, m 7.30-7.73, m 7.28-7.72, m 7.15-7.65, m
3-(CH3)2, s or 3-(CH2)4, m 1.30 1.63-1.80 1.23 1.45 1.43 1.42 1.44 1.42 1.50 1.45 1.31-1.95
4-CH2, s 2.97 3.03 2.85 2.97 3.02 2.98 3.02 3.0 3.10 3.13 3.05
C(CH2)nC, m 0.9-1.82 (4) 0.95-1.80 (4) 1.0-1.75 (6) 1.1-1.68 (6) 0.95-1.70 (6) 1.0-1.72 (8) 0.9-1.65 (8)
NH, amide, s 7.45, 7.68 7.40, 7.70 7.48, 7.53 7.36, 7.57 8.05 7.47, 7.70 8.0 8.05 8.10 8.10 7.39, 7.59
NH, ring, s 11.6 11.8 12.67 12.20 12.25 12.35 12.35 12.30 12.40 12.40 12.35
Other protons 7.50, s (=) 7.50, s (=) 3.73, s, and 3.75, s, (2CH3); 6.37, s (=) 2.65, s (H3N) 1.02, t (32), 2.93, q (32) 2.63, s (H3N) 1.0, t (32), 2.90, q (32)
2 2b 2c 4 4b 4c 4d 4e 4f 4g 4h
In the IR spectra of amides 2a-c in chloroform solution (0.01 mol/l) there are absorption bands in the region of 3220 ( ring NH) and 3410 (amide NH2) together with a broad band of the associated carbonyl of the amide groups (1600) and the conjugated ketone carbonyl (1700 cm-1). The IR spectra of compounds which contain both primary and tertiary amide groups (compounds 4a,c,h) contain absorption bands of the ring NH (3160) and amide NH groups (3360), two amide carbonyl groups (1600-1610) and a ketone carbonyl (1665 cm-1). The spectra of the secondary amides 4b, d-g have absorption bands for the amide NH (3300) and C=O groups (1610) and also for the ring NH (3200) and the ketone carbonyl (1660 cm-1). The structure of the compounds obtained is confirmed by the mass spectra. For example the mass spectrum of amide 2a has, apart from the molecular ion peak at 244* (10.1%), peaks corresponding to loss of the amide group (100%, 200). The mass spectra of amides 2b,c are analogous. In the mass spectra of amides 4 low intensity molecular ion peaks are observed, for example, 3.1% (341) and 1.9% (383) respectively for the diamides 4a and 4f respectively. Analysis of the mass spectra of these compounds shows that the first step after ionization is the loss of the lighter amide fragment C(O)NHR3. For example, for amide 4a the intensity of the peak corresponding to the loss of this group is 45.15% (297) and for amides 4f and 4g the intensities are 100 and 88,4% respectively (for both 325). In the mass spectra of all the diamides 4 the most intense peaks correspond to successive losses of the fragment C(O)NHR3, followed by the amino group found in the composition of the tertiary amide (96.5-100%, 228).
EXPERIMENTAL H NMR spectra of DMSO-d6 spectra containing HMDS as internal standard were recorded with a Bruker DRX 500 (500 MHz) spectrometer. IR spectra were recorded on a Specord-80 spectrometer. Mass spectra were recorded with a MAT-311 spectrometer (70 eV, EI). The purity of the compounds synthesized was determined by TLC on Silufol UV-254 strips with 1:3:6 acetoneethanolchloroform as eluent, and development with iodine vapor. All of the compounds synthesized were recrystallized from isopropanol. The synthesis of the starting materials 1a-c and 3a-d was described in [2, 9]. Amides of [3,3-(R2)2-6,7-(R1)2-1,2,3,4-Tetrahydroisoquinolinidene-1]pyruvic Acids (2a-c) and the Diamides of 3[3,3-(R2)2-1,2,3,4-Tetrahydroisoquinolinidene-1]-2-oxobutandioic Acids (4a-h) (General Method). Gaseous ammonia or the corresponding amine was bubbled through a solution of the corresponding dioxopyrroline 1a-c or 3a-h (10 mmol) in benzene (50-100 ml). The difficult to dissolve amides 2b,d dissolved on boiling and in these cases the syntheses were carried out at 50-60C. The reactions were carried out at 20 for all the other substances. When the solution was decolorized the solvent was evaporated in vacuum, the crystalline residue was filtered off, dried, and recrystallized.
1
REFERENCES 1. 2. 3. 4. A. G. Mikhailovskii and V. S. Shklyaev, Khim. Geterotsikl. Soedinen., 291 (1997). A. G. Mikhailovskii and V. S. Shklyaev, Khim. Geterotsikl. Soedinen., 946 (1994). A. G. Mikhailovskii, Khim. Geterotsikl. Soedinen., 685 (1996). A. G. Mikhailovskii and M. I. Vahrin, Khim. Geterotsikl. Soedinen., 228 (2002).
_______ * Here and later the values of m/z are given for the ion peaks. 1177
5. 6. 7. 8. 9.
T. Sano, J. Synth., Org. Chem. Jpn., 42, 340 (1984). T. Sano and Y. Tsuda, J. Synth., Org. Chem. Jpn., 46, 49 (1988). A. G. Mikhailovskii and M. O. Dekaprilevich, Khim. Geterotsikl. Soedinen., 1111 (1998). General Organic Chemistry [Russian translation], D. Barton and I. D. Ollis (Editors), Khimiya, Moscow (1983), Vol. 4, p. 427. V. S. Shklyaev, B. B. Aleksandrov, A. G. Mikhailovskii, and M. I. Vakhrin, Khim. Geterotsikl. Soedinen., 963 (1997).
1178
CONDENSED ISOQUINOLINES. 18*. ENAMINE PROPERTIES OF BENZIMIDAZO[1,2-b]ISOQUINOLIN-11(5H)-ONE IN THE MICHAEL REACTION

L. M. Potikha, N. V. Shkilna, V. M. Kisil, and V. A. Kovtunenko The reaction of benzimidazo[1,2-b]isoquinolin-11(5H)-one with activated olefins has been studied. The derivatives of 3,10-dioxo-3H,10H-benzimidazo[1,2,3-ij]benzo[c][1,8]naphthyridine formed are the result of an initial Michael reaction at C(6) followed by intramolecular heterocyclization. Keywords: heterocyclic enamines, derivatives of the 3,10-dioxo-3H,10H-benzimidazo[1,2,3-ij]benzo[c][1,8]naphthyridine system, the Michael reaction. The study of the properties and chemical reactions of enamines is one of the most actively developing regions of organic chemistry. Among the factors provoking the interest of chemists in this area the possibility of heterocyclization based on enamines occupies a special place [2-4], but the conjugated addition of activated olefins to heterocyclic enamines (the Michael reaction) as a method of heterocyclization has not been studied enough [5,6]. We have previously [1] studied the acylation and alkylation of benzamidazo[1,2-b]isoquinolin11(5H)-one (1) with alkyl halides and have shown that attack occurs at the enamine fragment of the structure with formation of products in positions 5 and 6 depending on the nature of the reagent and the reaction conditions. In the present study it is shown that the enamine fragment of the tetracycle 1 undergoes conjugated addition with activated olefins to construct a pyridine ring in the system and suggest a suitable one-step method for the synthesis of previously inaccessible 1-aryl-substituted derivatives of benzimidazo[1,2,3-ij]benzo[c][1,8]naphthyridine from benzimidazo[1,2-b]isoquinolin-11(5H)-one 1. The first examples of benzimidazo[1,2,3-ij]benzo[c][1,8]naphthyridines were obtained [7] by condensation of 6-formylbenzimidazo[1,2-b]isoquinolin-11(5H)-one with active methylene esters and acids. On boiling compound 1 in 2-propanol in the presence of Et3N with nitriles or esters of cyanocinnamic acid compounds 4a-c and 7a-c (method A) were obtained. They are products of consecutive reactions: conjugative Michael addition (attack at atom C(6) via intermediates of type 2 and 5) with subsequent intramolecular acylation in the intermediate at atom N(5) (compounds of type 3 4 and 6) (Scheme 1). In the case of cyanocinnamate esters, the reaction did not stop at this point but proceeded further on oxidation of the intermediate 6 to 7.
_______ * For Communication 17 see [1]. __________________________________________________________________________________________ Taras Shevchenko National University, Kiev 01033, Ukraine. e-mail: vkovtunenko@hotmail.com. Translated from Khimiya Geterotsiclicheskikh Soedinenii, No. 9, 1362-1367, September, 2004. Original article submitted December 3, 2002. 0009-3122/04/4009-11792004 Springer Science+Business Media, Inc. 1179
O
Ar
CN
O N NH H Ar H CN 2 ac CN
N
6 5
CN
NH
:B
1
COOEt CN Ar
:B
O N NH H Ar H CN 5 ac COOEt H Ar
O N N NH H CN 3 ac
O N N H Ar H CN 6 ac [O] O N N O CN 8
1
O N N O H Ar CN 4 ac [O] O N N
3
NH2
Ar CN 7 ac
a Ar = 4'-ClC6H4; b Ar = 4'-MeOC6H4; c Ar = 4'-Me2NC6H4
1180
TABLE 1. Spectroscopic Characteristics of Compounds 4a-c

IR spectra, , cm-1 C=O 2 1698 CN 3 2180 Other signals 4 3440, 3300 (s,asNH2) 3440, 3300 (s,asNH2), 1025 (COC) 3440, 3300 (s,asNH2)
1 H NMR spectra (DMSO-d6), , ppm (J, Hz) Signals of the protons of the benzimidazo[1,2,3-ij]benzo[c][1,8]naphthyridine nucleus H-8, d, H-11, d, H-5, d, H-13, t, H-6, t, H-14, d, H-7, t, H-12, t, H-1, s J = 8.0 J = 8.0 J = 8.0 J = 8.0 J = 8.0 J = 8.0 J = 8.0 J = 8.0 5 6 7 8 9 10 11 12 13
Compound 1 4a
Signals of substituents NH2, s 14 6.49 Ar 15 H-3', H-5'* 7.30 (2H, d, J = 8.0, H-2', H-6') 7.20 (2H, d, J = 8.0, H-2', H-6'), 6.76 (2H, d, J = 8.0, H-3', H-5'), 3.70 (3H, s, OCH3) 7.14 (2H, d, J = 8.0, H-2', H-6'), 6.58 (2H, d, J = 8.0, H-3', H-5'), 2.80 (6H, s, N(CH3)2)
8.60
8.32
7.94
7.59
7.47
4b
1695
2180
8.63
8.34
7.93
7.54
7.42
7.41-7.38 7.35 (4H, m, H-7, H-14, H-3', H-5') 7.387.30 (3H, m)
5.33
5.17
6.24
4c
1695
2180
8.62
8.33
7.94
7.59
7.47 (2H, m)
7.39
7.35
5.15
6.35
_______ * Superposition of signals of the benzimidazo[1,2,3-ij]benzo[c][1,8]naphthyridine nucleus and the signals of substituents, see columns 10 and 11.
1181
1182
TABLE 2. Spectroscopic Characteristics of Compounds 7a-c and 8

IR spectra, , cm-1 C=O 2 1697 1663 1700 1659 1694 1659 1700 1668 CN 3 2227 Other signals 4 H NMR spectra (DMSO-d6), , ppm (J, Hz) Signals of the protons of the benzimidazo[1,2,3-ij]benzo[c][1,8]naphthyridine nucleus H-5, d, H-8, d, H-11, d, H-7, t, H-6, t, H-13, t, H-12, t, H-14, d, H-1, s J = 8.0 J = 8.0 J = 8.0 J = 8.0 J = 8.0 J = 8.0 J = 8.0 J = 8.0 5 6 7 8 9 10 11 12 13
1
Compound 1 7a
Signals of substituents, Ar 14 7.73 (2H, d, J = 8.0, H-2', H-6'), H-3', H-5'* 7.39 (2H, d, J = 8.0, H-2', H-6'), 7.21 (2H, d, J = 8.0, H-3', H-5'), 3.95 (3H, s, OCH3) 7.26 (2H, d, J = 8.0, H-2', H-6'), 6.91 (2H, d, J = 8.0, H-3', H-5'), 3.30 (6H, s, N(CH3)2)
8.79
8.75
8.52
7.84-7.76 (2H, m) 7.83-7.75 (2H, m) 7.81-7.74 (2H, m) 7.80-7.72 (2H, m)
7b
2220
1035 (COC)
8.79
8.75
8.51
7.58-7.49 (4H, m, H-12, H-13, H-3', H-5') 7.54 7.48
6.86
6.92
7c
2222
8.77
8.74
8.50
7.53
7.48
7.10
2232
8.72
8.68
8.47 (2H, H-11, H-14)
7.66
7.94
*2
9.39
_______ * Superposition of signals of the benzimidazo[1,2,3-ij]benzo[c][1,8]naphthyridine nucleus and the signals of substituents, see columns 10 and 11. *2 Superposition of signals of the benzimidazo[1,2,3-ij]benzo[c][1,8]naphthyridine nucleus, see column 7.
Taking into account studies on the acylation and alkylation of benzimidazoisoquinoline 1 [1,2], we did not exclude the possibility of addition of the olefin at position N(5). As evidence of the structures of 3-amino-1aryl-10-oxo-1H,10H-benzimidazo[1,2,3-ij]benzo[c][1,8]naphthyridin-2-carbonitriles (4a-c) and 1-aryl-3,10dioxo-3H,10H-benzimidazo[1,2,3-ij]benzo[c][1,8]naphthyridin-2-carbonitriles (7a-c) we used the model compound 3,10-dioxo-3H,10H-benzimidazo[1,2,3-ij]benzo[c][1,8]naphthyridin-2-carbonitrile (8) [7]. We observed a great degree of similarity of the absorptions in the IR spectra of the carbonitrile 8 and compounds 7ac. The presence of absorption bands of two carbonyl groups (1700, 1660 cm-1) and v(CN) bands of medium intensity (222-2237 cm-1) were characteristic The signal of the C(1)H proton (in the region of 9.3 ppm), characteristic for structure 8 was absent from the 1H NMR spectra of compounds 7a-c, while the signals of the aromatic protons C(12)H and C(14)H in compounds 7a-c were observed at stronger fields (7.48 and 6.90 ppm respectively, see Table 2) than in compound 8 (7.94 and 8.47). The latter fact is fully explained by the electronic effect of the aryl substituent at C(1) on C(12)H and the additional effect of the magnetic anisotropy of the 1-aryl substituent on the resonance of C(14)H. In the 1H NMR spectra of compounds 4a-c the amino groups appear in the range 6.2-6.4 ppm as broad two proton signals and in the IR spectra as two bands, sNH2 (3440 cm-1) and asNH2 (3300 cm-1). A single band was observed in the carbonyl stretching region (1695 cm-1), while there is a low frequency shift of the nitrile vibration (2180 cm-1) relative to those for 7a-c, in agreement with lower electron acceptor properties of the substituents at C(3). We assign a one proton singlet in the region of 5.1-5.3 ppm region in the 1H NMR spectra of 4a-c to the proton C(1)H. According to the spectroscopic data, the iminoform tautomer 3 is absent. The 3,10-dioxo derivatives 7a-c were obtained in good yield (50-60%) on prolonged boiling of the 3-amino derivatives 4a-c in acetic acid, which indicates the link between systems obtained and with the structure 8.
EXPERIMENTAL Melting points of the compounds synthesized were measured on a Boetius block and were not corrected. IR spectra of KBr tablets were recorded with a Pye-Unicam SP3-300 instrument. 1H NMR spectra of DMSO-d6 solutions with TMS as internal standard were measured on a Mercury 400 (Varian) (400 MHz) instrument. Assignments of the signals of the aromatic protons were confirmed by COSY HH spectra for compounds 4c and 8. The progress of reactions and the purity of the compounds prepared were monitored by TLC on Silufol UV-254 strips. 5,11-Dihydrobenzimidazo[1,2-b]isoquinoline-11-one 1 was prepared according to [8], 2-arylidenemalonitriles and ethyl 3-aryl-2-cyano-2-propenoates according to [9], and 3,10-dioxo-3H,10Hbenzimidazo[1,2,3-ij]benzo[c][1,8]naphthyridin-2-carbonitrile 8 according to [7]. Their constants corresponded to those recorded. 3-Amino-1-aryl-10-oxo-1H,10H-benzimidazo[1,2,3-ij]benzo[c][1,8]naphthyridin-2-carbonitriles (4a-c). A mixture of benzimidazoisoquinoline 1 (2.34 g, 10 mmol), 2-arylidenemalonitrile (15 mmol), and Et3N (2 ml) in 2-propanol (20 ml) was refluxed for 6 h. The mixture was cooled, the yellow precipitate was filtered and carefully washed with ethanol. It was recrystallized from DMF. Compound 4a.Yield 3.08 g (73%); mp 335-337C (DMF). Found, %: C 70.93; H 3.60; Cl 8.30; N 13.26. C25H15ClN4O. Calculated, %: C 71.01; H 3.58; Cl 8.38; N 13.25. Compound 4b. Yield 3.09 g (74%); mp 283-285C (DMF). Found, %: C 74.60; H 4.28; N 13.41. C26H18N4O2. Calculated, %: C 74.63; H 4.34; N 13.39. Compound 4c. Yield 2.50 g (58%); mp 270-272C (DMF). Found, %: C 75.06; H 4.83; N 16.29. C27H21N5O. Calculated, %: C 75.16; H 4.91; N 16.23.
1183
1-Aryl-3,10-dioxo-3H,10H-benzimidazo[1,2,3-ij]benzo[c][1,8]naphthyridin-2-carbonitriles (7a-c) (General Method A). A mixture of benzimidazoisoquinoline 1 (2.34 g, 10 mmol), ethyl 3-aryl-2-cyano-2propenoate (15 mmol), and Et3N (2 ml) in 2-propanol (20 ml) was refluxed for 3 h and then cooled. The yellowish precipitate was filtered off, washed carefully with ethanol, and recrystallized from DMF. Compound 7a. Yield 2.15 g (51%); mp >340C (DMF). Found, % C 71.10; H 2.77; Cl 8.32; N 10.00. C25H12ClN3O2. Calculated, %: C 71.18; H 2.87; Cl 8.40; N 9.96. Compound 7b. Yield 2.21 g (53%); mp 326-328C (DMF). Found, %: 74.72; H 3.59; N 10.10. C26H15N3O3. Calculated, %: C 74.81; H 3.62; N 10.07. Compound 7c. Yield 2.02 g (47%); mp 325-326C (DMF). Found, %: C 75.35; H 4.11; N 13.03. C27H18N4O2. Calculated, %: C 75.34; H 4.21; N 13.02. Method B. A suspension of 3-amino-1-(4-dimethylaminophenyl)naphthyridine 4c (4.31 g, 10 mmol) in acetic acid (25 ml) was refluxed for 10 h, cooled, the precipitate was filtered off, washed with acetic acid and ethanol, and recrystallized from DMF to give 1-(4-dimethylaminophenyl)-3,10-dioxonaphthyridine 7c. The 3,10-dioxonaphthyridines 7a,b were prepared analogously. Compound 7a. Yield 2.44 g (58%). Compound 7b. Yield 2.09 g (50%). Compound 7c. Yield 2.37 g (55%).
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. L. M. Potikha, N. V. Shkilna, V. M. Kisil, and V. A. Kovtunenko, Khim., Geterotsikl. Soedin., 1214 (2004). L. M. Potikha, N. V. Shkilna, V. M. Kisil, and V. A. Kovtunenko, Khim., Geterotsikl. Soedin., 715 (2004). V. G. Granik, V. A. Makarov, and C. Parkanyi, Adv. Heterocycl. Chem., 72, 283 (1999). V. P. Litvinov, Ya. Yu. Yakunin, and V. D. Dyachenko, Khim. Geterotsikl. Soedin., 41 (2001). K. Nagarajan, V. R. Rao, R. K. Shah, S. J. Shenoy, H. Fritz, W. J. Richter, and D. Muller, Helv. Chim. Acta, 71, 77 (1988). A. A. Krauze, E. E. Liepinsh, Z. A. Kalme, Yu. E. Pelcher, and G. Ya. Dubur, Khim. Geterotsikl. Soedin., 1504 (1984). E. Schefczik, Liebigs Ann. Chem., 729, 97 (1969). E. Schefczik, Liebigs Ann. Chem., 729, 83 (1969). J. Zabicky, J. Chem. Soc., 683 (1961).
1184
STUDIES ON PYRAZINE DERIVATIVES. 38. SYNTHESIS, REACTIONS, AND TUBERCULOSTATIC ACTIVITY OF PYRAZINYL-SUBSTITUTED DERIVATIVES OF HYDRAZINOCARBODITHIOIC ACID
H. Foks1, I. Trapkowska1, M. Janowiec2, Z. Zwolska2, and E. Augustynowicz-Kopec2 The synthesis of N'-[amino(6-chloro- and 6-cycloaminopyrazin-2-yl)methylene]carbodithioic acid mono- and diesters and their reactions are described. Cyclization of monoesters with secondary amines in acidic media gave the 1,3,4-thiadiazole derivatives, while the cyclization of diesters with amines yielded 1,2,4-triazoles with the amine substituent in position 3. The in vitro tuberculostatic activity of the prepared compounds was tested. Keywords: 6-chloro-2-cyanopyrazine, amidrazones, mono- and diesters of hydrazinocarbodithioic acids, imino esters, 1,3,4-thiadiazole-2-thiol, 1,2,4-triazoles, carbon disulfide, tuberculostatics. Amidrazones can react easily with carbon disulfide. It is known that the reactions of phenyl- and pyridylamidrazones with carbon disulfide in neutral medium give exclusively 5-substituted 1,3,4-triazolo-2thiones [1]. We have reported [2, 3] that reactions of carbon disulfide with pyrazine derivatives of amidrazone give various products, depending on the reaction condition. It was found that carbon disulfide and amidrazone addition product can be alkylated to give mono- and diesters of pyrazinecarbiminodithiocarbazoic acid. The latter reacts with amines, yielding heterocyclic compounds difficultly obtainable by other methods. Some of these products showed high tuberculostatic activity. This paper presents reactions of 6-chloropyrazine-2-carbamidrazone with carbon disulfide, as well as application of the products formed to the syntheses of other organic compounds. The presence of chlorine in position 6 of the pyrazine ring opens new possibilities for the synthesis of pyrazine derivatives compared to those reported for unsubstituted pyrazinecarbamidrazone. CHEMISTRY In a first step of this study the possibility of formation of thiadiazoles bearing the thiol or S-alkyl group in position 2 of the ring was tested. As expected, carbon disulfide reacted easily with 6-chloropyrazinecarbamidrazone in ethanolic medium to give 5-(6-chloropyrazin-2-yl)-1,3,4-thiadiazole-2-thiol (1). Thus, the reaction proceeded analogously as reported earlier [1]. It was also found that addition of alkyl halide (MeI, ClCH2Ph) to the reaction mixture led to the corresponding S-alkylthiadiazole derivatives 2a-b. __________________________________________________________________________________________ Department of Organic Chemistry, Medical University of Gdansk, 80-416 Gdansk, Poland; e-mail: hfoks@farmacja.amg.gda.pl. 2 Department of Microbiology, Institute of Tuberculosis and Pulmonary Diseases 01-138 Warszawa, Poland. Published in Khimiya Geterotsiclicheskikh Soedinenii, No. 9, 1368-1376, September, 2004. Original article submitted March 25, 2002. 0009-3122/04/4009-11852004 Springer Science+Business Media, Inc. 1185
1
1186
R N N e Cl N N l R N N 7ae Cl C NH2 O N N N j O N N N 9 C NH
+
N N 6a,b
N R Cl
N N
N S 1 a
N SH
Cl
N N d
N S 2a,b
N SR
Cl
N N
C NH2 11a,b d
NNHC(=S)R
2, 3a R = Me, b R = CH2Ph, 6a, 7d, 8a,c, 11a, 12a, O 14a R = N
C =NN=C(SR)2 NH2 3a,b f
Cl
N N N N
C NH2 g CN k
N NH2
Cl
N N 4 h
C NH2
H N N C S C NH OBn SMe
Cl
N N
N S 14a,b
N R
6b, 7e, 8b,d, 11b, 12b 14b R =

N N Ph
e N N
e N S 8ad N R1
Cl
N N
7a R = N b R =N
N N=C(SMe)2
5 C NH2 NNHCSMe S d d N N H N N C
CN
N N 10
R =N
O
8a,d R1 = N
N N N S N SMe
h O Bn i O N C NH2 O R N
b, c R1 = N
N Ph
13 S 12a,b a) CS2, EtOH; b) KOH, RX, EtOH; c) CS2, KOH, MeI, EtOH; d) EtOH, H ; e) amines, boiling; f) CS2, KOH, EtOH, 2RX; g) H2NNH2, EtOH; h) H2NNHCSSMe, MeOH; i) H2NNHC(=S)NR; j) BnOH, benzene; k) morpholine, benzene; l) amines, DMF, boiling 0.25 h
TABLE 1. Characteristics of the Newly Synthesized Pyrazinyl Compounds

Compound 1 2a Empirical formula C C6H3ClN4S2 C7H5ClH4S2 31.41 31.24 34.43 34.36 48.90 48.67 34.73 34.84 56.02 56.13 32.27 32.12 52.85 52.99 66.81 66.79 46.26 46.43 48.34 48.12 49.74 49.68 44.26 44.15 53.76 53.84 45.94 45.88 Found, % Calculated, % H 1.53 1.31 2.12 2.06 3.11 2.83 3.82 3.65 4.33 4.24 3.19 3.08 6.14 6.03 6.50 6.25 5.97 5.84 6.36 6.21 6.83 6.55 5.71 5.56 5.93 5.77 5.16 4.95 mp, C (solvent for crystalization) 205-206 (EtOH) 102-103 (EtOHH2O) 100-102 (MeOH) 152-153 (EtOH) 133-134 (EtOH) 174360 (MeOH) 273-275 (dioxaneMeOH) 267-269 (dioxaneMeOH) 171-173 (EtOH) 153-154 (MeOH) 128-130 (MeOH) 158-159 (MeOH) 126-127 (MeOH) 273-275 (dioxaneEtOH) Yield, % (method) 64 40 (A) 65 (B) 95 (C) 30 82 63 45 (A) 60 (B) 40 40 80 95 95 90 95 35 (A) 75 (B) 55 (C) 45 (D) 30 85 (A) 75 (B) 85 50 80 65 55 70 50 90 90 70
N 24.43 24.28 23.02 22.89 17.52 17.46 25.56 25.39 16.42 16.36 26.70 26.75 31.13 30.90 27.13 26.96 27.18 27.07 25.86 25.90 24.96 24.83 25.62 25.74 24.56 24.42 23.20 22.93
2b 3a 3b 4 6a 6b 7a 7b 7c 7d 7e 8a
C13H9ClN4S2 C8H10ClN5S2 C20H18ClN5S2 C7H8ClN5S2 C14H19N7O2 C26H29N9 C12H18N6S2 C13H20N6S2 C14H22N6S2 C12H18N6OS2 C18H23N7S2 C14H18N6O2S
8b 8c 8d 9 10 11a 11b 12a 12b 13 14a 14b
C26H28N8S C20H23N7O3 C20H23N7O3 C16H18N4O2 C11H16N6OS2 C10H13ClN6OS C16H18ClN7S C14H21N7O2S C20H26N8OS C11H13N5OS2 C10H10ClN5OS C16H15ClN6S
64.61 64.43 58.77 58.67 58.81 58.67 64.58 64.41 42.51 42.29 40.14 39.93 51.24 51.13 47.96 47.85 56.47 56.32 14.91 14.73 42.42 42.33 53.50 53.55
5.96 5.82 5.82 5.66 5.62 5.66 6.17 6.08 5.32 5.16 4.51 4.36 4.97 4.83 6.18 6.02 6.26 6.14 4.62 4.44 3.78 3.55 4.26 4.21
23.37 23.12 24.18 23.94 23.98 23.94 18.92 18.78 27.03 26.90 28.12 27.94 26.18 26.08 28.12 27.90 26.38 26.27 23.93 23.71 24.84 24.68 23.57 23.42
244-247 (dioxane) 216-217 (dioxane) 249-250 (dioxane) 152-154 (benzene) 155280 (EtOH) 152-154 (EtOHdioxane) 124-126 (EtOH) 170-280 (EtOH) 180-182 (EtOH) 189-190 (dioxane) 181-182 (MeOH) 198-200 (EtOH)
1187
TABLE 2. IR and 1H NMR data for compounds 1-14

Compound 1 1 IR, cm-1 2 3109, 2965, 2864, 1433, 1398, 1231, 1166, 1143, 1070,1005, 743, 455 3051, 2930, 1511, 1346, 1311, 1164, 1150, 1008, 812, 453 3040, 1511, 1338, 1165, 1144, 1025, 1006, 715, 454 3469, 3355, 1615, 1486, 1435, 1401, 1174, 1039, 1010, 945, 876, 449 3494, 3387, 1614, 1494, 1434, 1170, 1017, 703 3433, 3283, 3061, 2916, 1625, 1502, 1368, 1318, 1170, 1006 3164, 3080, 2958, 2863, 1535, 1520, 1442, 1261, 1114, 923, 761 3175, 3061, 2829, 1599, 1538, 1518, 150, 1446, 1232, 1158, 940, 757, 692 3440, 3283, 2963, 2920, 2848, 1619, 1578, 1526, 1499, 1429, 1217, 1172, 1026, 848, 469 3459, 3288, 2921, 2851, 1621, 1571, 1524, 1498, 1427, 1258, 1215, 1181, 1125, 1024, 998, 934, 469 3446, 3300, 2923, 2848, 1614, 1569, 1524, 1438, 1154, 1024, 997 3449, 3307, 2952, 2851, 1613, 1571, 1525, 1440, 1260, 1205, 1117, 1022, 1003, 935 3482, 3368, 1615, 1573, 1523, 1494, 1446, 1232, 1002, 938, 756, 692 2960, 2902, 1510, 1446, 1253, 1198, 1115, 910 2822, 1599, 1493, 1452, 1264, 1229, 761, 695 2959, 2854, 1503, 1447, 1259, 1229, 1119, 936, 764 3058, 2959, 2851, 2827, 1599, 1567, 1497, 1446, 1267, 1234, 1116, 904, 758, 690 3275, 3062, 2965, 2843, 1648, 1574, 1530, 1476, 1448, 1348, 1267, 1238, 1118, 1002, 865, 733, 445 3394, 3279, 3123, 2858, 1668, 1601, 1533, 1414, 1297, 1262, 1117, 991, 877
1
H NMR, , ppm, solvent 3
DMSO-d6: 8.95 and 9.20 (2s, 2H pyrazine)
2a 2b 3a
CDCl3: 2.90 (3H, s, CH3); 8.68 and 9.45 (2s, 2H pyrazine) CDCl3: 4.65 (2H, s, CH2); 7.35-7.50 (m, 5H phenyl); 8.65 and 9.45 (2s, 2H pyrazine) CDCl3: 2.55 and 2.60 (6H, 2s, 2CH3); 6.00 (2H, br. s, NH2); 8.63 and 9.45 (2s, 2H pyrazine) CDCl3: 4.35 and 4.45 (4H, 2s, 2CH2); 5.80 (2H, br. s, NH2); 7.30-7.50 (10H, m, 2 phenyl); 8.60 and 9.40 (2s, 2H pyrazine) (CD5)2CO: 2.57 (3H, s, CH3); 6.98 (2H, br. s, NH2); 8.78 and 9.32 (2s, 2H pyrazine); 11.10 (1H, br. s, NH) DMSO-d6: 3.30-3.70 (2m, 16H morpholine); 8.33 and 8.36 (2s, 2H pyrazine) DMSO-d6: 3.37; 3.60 and 3.88 (16H, 3m, 2 pyrazine); 6.80-7.32 (3m, 10H phenyl); 8.42 and 8.45 (2s, 2H pyrazine) CDCl3: 1.95 and 3.40 (2m, 8H pyrolidine); 2.45 and 2.50 (6H, 2s, 2CH3); 5.90 (2H, br. s, NH2); 7.70 and 8.65 (2s, 2H pyrazine) CDCl3: 1.60:3.50 (2m, 10H piperidine); 2.42 and 2.50 (6H, 2s, 2CH3); 5.85 (2H, br. s, NH2); 8.05 and 8.65 (2s, 2H pyrazine) CDCl3: 1.40 and 1.90 (8H, 2m, 4CH2); 2.45 and 2.50 (6H, 2s, 2CH3); 3.60 (4H, t, 2CH2N); 5.90 (2H, br. s, NH2); 8.95 and 9.60 (2s, 2H pyrazine) CDCl3: 2.45 and 2.50 (6H, 2s, 2CH3); 3.40 and 3.90 (2m, 8H morpholine); 5.85 (2H, br. s, NH2); 8.10:8.75 (2s, 2H pyrazine) CDCl3: 2.52 and 2.58 (6H, 2s, 2CH3); 3.34 and 3.79 (2m, 8H piperazine); 6.97 (2H, br. s, NH2); 6.89:7.36 (2m, 5H phenyl); 8.23 and 8.86 (2s, 2H pyrazine) CDCl3: 3.60-3.90 (2m, 16H morpholine); 8.13 and 8.77 (2s, 2H pyrazine) CDCl3: 3.40 and 3.85 (2m, 16H piperazine); 7.20-7.35 (10H, 2m, 2 phenyl); 8.20 and 8.77 (2s, 2H pyrazine) DMSO-d6: 3.40-3.90 (16H, 4m, 8CH2); 7.00-7.40 (2m, 5H phenyl); 8.37 and 8.50 (2s, 2H pyrazine) CDCl3: 3.35-3.90 (16H, 3m, 8CH2); 6.95-7.40 (2m, 5H phenyl); 8.20 and 8.76 (2s, 2H pyrazine) DMSO-d6: 3.60-3.75 (m, 8H morpholine); 5.37 (2H, s, CH2); 7.32-7.50 (m, 5H phenyl); 8.27 and 8.49 (2s, 2H pyrazine); 9.28 (s, 1H, NH) (CD3)2CO: 2.44 (3H, s, SCH3); 2.55 (3H, s, SCH3); 3.65-3.85 (16H, 2m, 2 morpholine); 6.60 (2H, br. s, NH2); 8.33 (s, 1H pyrazine); 8.62 (d, 2H pyrazine); 8.69 (s, 1H pyrazine). Two isomers 1:1 [9]
3b
4 6a
6b
7a
7b
7c
7d
7e
8a 8b
8c
8d
10
1188
TABLE 2 (continued)
1 11a 2 3401, 3306, 3262, 2919, 2855, 1637, 1528, 1434, 1360, 1279, 1173, 1112, 1008, 848 3288, 3147, 1664, 1634, 1599, 1495, 1429, 1367, 1340, 1303, 1266, 1228, 1169, 1016, 927, 757, 692, 453 3476, 3359, 3276, 2972, 2857, 1677, 1560, 1527, 1429, 1303, 1260, 1116, 1024, 891 3383, 3033, 2853, 1664, 1598, 1532, 1427, 1347, 1301, 1260, 1233, 1118 3067, 2963, 2859, 1577, 1525, 1469, 1360, 1260, 1209, 1118, 1082, 993, 948, 859 2921, 2864, 1512, 1264, 1164, 1118, 1006, 906 1600, 1513, 1450, 1399, 1310, 1298, 1273, 1230, 1162, 1026, 1008, 933, 764, 696, 456 3 DMSO-d6: 3.50-3.90 (2m, 8H morpholine); 8.90 and 9.20 (2s, 2H pyrazine) CDCl3: 3.35 and 4.20 (2m, 8H piperazine); 6.95 and 7.30 (2m, 5H phenyl); 8.66 and 9.20 (2s, 2H pyrazine) DMSO-d6: 3.35-3.90 (16H, m, 2 morpholine); 8.57 and 8.60 (2s, 2H pyrazine); 12.67 (1H, s, NH) CDCl3: 3.28; 3.73; 3.87 and 4.20 (4m, 16H morpholine and piperazine); 6.30 (2H, br. s, NH2); 6.90-7.35 (2m, 5H phenyl); 8.31 and 8.40 (2s, 2H pyrazine); 13.36 (1H, s, NH) CDCl3: 2.84 (3H, s, CH3); 3.64 and 3.86 (2m, 8H morpholine); 8.18 and 8.79 (2s, 2H pyrazine) CDCl3: 3.51 and 3.90 (2m, 8H morpholine); 8.58 and 9.36 (2s, 2H pyrazine) CDCl3: 3.37 and 3.84 (2m, 8H morpholine); 7.00 and 7.32 (2m, 5H phenyl); 8.56 and 9.35 (2s, 2H pyrazine)
11b
12a
12b
13
14a 14b
The alkylation reaction proceeded differently in alkaline medium, and the reaction products depended on the molar ratios of the reagents. The use of at least double molar excess of the base and the alkyl halide produced pure dithiocarbazoic acid diesters 3a,b in very good yields, while the use of stoichiometric amounts of the reagents gave dithiocarbazoic acid monoester 4 as the main product, and only small amounts of the diester. The mixtures of mono and diesters were difficult to separate, and for this reason another way of monoester 4 synthesis was designed. Namely, benzyl-6-chloropyrazine-2-carbimide (5), synthesized according to the known method [4], was reacted with dithiocarbazoic acid methyl ester to give the desired compound. In the next step of the study, the reactivity of the synthesized dithiocarbazoic acid mono- and diesters towards secondary amines was tested. Because of the two potential reaction centers in the substrate molecules, namely, the halide and methylthio groups, the reaction products depended strongly on the solvent, molar ratios of the reagents, and the way the reactions were carried out. Prolonged heating of the diester 3a with morpholine and 4-phenylpiperazine led to the formation of 1,2,4-triazole derivatives 6a,b, with amine substituents in position 6 of the pyrazine ring and in position 3 of the triazole ring. Low-boiling amines, pyrrolidine, piperidine, and homopiperidine, in spite of long reflux, gave only the products of chlorine atom substitution. In addition, yields of the products 7a-e were poor, and the compounds were strongly contaminated. Good yields of pure compounds 7a-e were obtained in the reactions with all the amines upon heating for 15-30 min in dimethylformamide. The reactions of dithiocarbazoic acid monoester 4 with morpholine and 4-phenylpiperazine gave different products. In this case, attempts at selective substitution of the chlorine atom in the piperazine ring or the methylthio group failed. Short heating in the neat amines and in various solvents led to difficultly separable mixtures, while prolonged heating in neat amines produced compounds 8a and 8b formed by replacement of both chlorine atom and the methylthio group by the amine residue, and simultaneous cyclization to the 1,3,4-thiadiazole system. The structures of compounds 8a and 8b were confirmed by independent synthesis. Thus, imino esters 5 and 9 were reacted with hydrazinocarbodithioic acid methyl ester, as well as with hydrazino-, morpholino- and 1-phenylpiperazine-4-carbothioic acid hydrazide, to give compounds 11a,b and 10, 12a,b, respectively. 1189
Compounds 10 and 11a,b in acidic media underwent cyclization to the corresponding 1,3,4-triazole derivatives 13 and 14a,b, similarly as compound 2a obtained from methyl N'-[amino(6-chloropyrazin-2yl)methylene]hydrazinocarbodithioate (4). Heated in an excess of morpholine or 1-phenylpiperazine, compounds 2a, 13, and 14a,b yielded the pyrazinylthiadiazole derivatives 8a,b. The same compounds were formed by cyclization of compounds 12a,b in acidic media. Variation of the secondary amine in the above reactions would, presumably, make possible synthesis of analogues of compounds 8a,b with any desired amine substituent. The reactions of compounds 13 and 14a with 1-phenylpiperazine seem to confirm this presumption, as the phenylpiperazine substituent was found in position 2 of the 1,2,4-thiadiazole system of compound 8c and in the pyrazine ring of compound 8d.
MICROBIOLOGY The tuberculostatic activity of the new compounds was tested towards Myc. tbc H37Rv strain and two "wild" strains isolated from tuberculosis patients: one resistant to p-aminosalicylic acid (PAS), isonicotinic acid hydrazide (INH), ethambutol (EMB), and ryfampycine (RFP), and the other fully sensitive to the drugs administered. In vitro investigations were carried on by a classical test tube method [5] of successive dilutions with Youman's fluid medium containing 10% of bovine serum. The determined minimum concentrations inhibiting the growth of tuberculous strains (MIC) showed the tested group of compounds to be of low activity. MIC values for most of the compounds were within the limits 125-500 g/ml. The highest activity was shown by compound 8, with MIC value for H37Rv strain 32 g/ml, and 63 g/ml for both "wild" strains, and by compound 4, with MIC value 32 g/ml for all the strains used.
EXPERIMENTAL Melting points were determined with a Boetius apparatus and are uncorrected. The IR spectra were taken with a Satellite spectrophotometer. The 1H NMR spectra were taken with a Varian Gemini 200 spectrometer BS487c. Reaction yields and the physical constants of the compounds obtained are given in Table 1. 5-(6-Chloropyrazin-2-yl)[1,3,4]thiadiazole-2-thiol (1). To a solution of 6-chloropyrazinecarbamidrazone [5] (0.85 g, 5 mmol) in ethanol (25 ml), carbon disulfide (0.6 ml, 10 mmol) was added and the mixture was refluxed for 1 h. After cooling, the resulting precipitate was filtered off and recrystallized. 5-(6-Chloropyrazin-2-yl)-2-methylthio[1,3,4]thiadiazole (2a). A. To a solution of 6-chloropyrazinecarbamidrazone (0.85 g, 5 mmol) in ethanol (25 ml), carbon disulfide (0.5 ml, 8 mmol) was added and after 5 min MeI (0.35 ml, 5 mmol) was introduced to the reaction mixture, which was refluxed for 1 h. After cooling, the resulting precipitate was filtered off and recrystallized. B. Compound 1 (0.22 g, 10 mmol) was added to a solution of KOH (0.56 g, 10 mmol) in ethanol (5 ml), then MeI (0.6 g, 10 mmol) was introduced and the mixture was refluxed for 0.5 h. The product precipitated after cooling. C. To a solution of compound 4 (0.26 g, 1 mmol) in ethanol (5 ml) concentrated HCl (0.5 ml) was added and the mixture was heated to boiling. On cooling, 20 g of ice was added and the precipitated compound 2a filtered off. 3-Benzylthio-5-(6-chloropyrazin-2-yl)[1,3,4]thiadiazole (2b). This compound was obtained as described for 2a (see Method A) taking benzyl chloride (0.8 ml, 5 mmol) instead of MeI.
1190
N'-[Amino-(6-chloropyrazin-2-yl)methylene]hydrazinocarbodithioic Acid Dimethyl Ester (3a). A mixture of 6-chloropyrazinecarbamidrazone (10.3 g, 0.06 mmol), methanol (200 ml), triethylamine (20 ml, 0.15 mmol), CS2 (8 ml, 0.13 mmol), and MeI (10 ml, 0.16 mmol) was refluxed until homogenization and allowed to cool. After additional ice-cooling the precipitated compound 3a was filtered off and recrystallized. N'-[Amino-(6-chloropyrazin-2-yl)methylene]hydrazinocarbodithioic Acid Dibenzyl Ester (3b). Obtained as described for 3a, starting from chloroamidrazone (3.4 g, 20 mmol), methanol (20 ml), triethylamine (6 ml, 40 mmol), CS2 (2 ml, 33 mmol), and benzyl chloride (5.5 ml, 50 mmol). N'-[Amino-(6-chloropyrazin-2-yl)methylene]hydrazinocarbodithioic acid methyl ester (4). A. To 6chloropyrazinecarbamidrazone (8.5 g, 50 mmol) dissolved in ethanol (100 ml) a solution of KOH (2.8 g, 50 mmol) in ethanol (50 ml) was added, and then, through a reflux condenser, CS2 (3 ml, 5 mmol) was introduced. Water was added to the suspension until the solution clarified (ca 50 ml) and then MeI (3.2 ml, 50 mmol) was added dropwise. The mixture was allowed to stand for 0.5 h, then evaporated to half of its initial volume and cooled. The precipitate was collected and recrystallized. TLC analysis showed a small admixture of compound 3a. B. A warm solution of compound 5 [4] (2.5 g, 10 mmol) in methanol (10 ml) was treated with hydrazinocarbodithioic acid methyl ester [6] (1.2 g, 10 mmol) dissolved in methanol (20 ml) and stirred for 0.5 h. A few seconds after combining both solutions, a yellow crystalline precipitate appeared. After another hour of standing and cooling the mixture, the compound was filtered off. 3-Morpholino-5-(6-morpholinopyrazin-2-yl)[1,2,4]triazole (6a). Compound 3a (0.45 g, 2 mmol) and morpholine (2 ml, 25 mmol) were refluxed for 10 h. After cooling, methanol was added (5 ml) and the precipitated product was collected and recrystallized. 3-(4-Phenylpiperazin-1-yl)-5-[6-(4-phenylpiperazin-1-yl)pyrazin-2-yl][1,2,4]triazole (6b). Compound 3a (1.38 g, 5 mmol), 1-phenylpiperazine (3.5 ml, 20 mmol), and DMF (2 ml) were refluxed for 3 h. Methanethiol was evolved vigorously throughout the procedure. After cooling to ambient temperature, the mixture was treated with methanol (5 ml), ice-cooled, and a precipitate of compound 6b was collected. N'-[Amino(6-cycloaminopyrazin-2-yl)methylene]hydrazinocarbodithioic Acid Dimethyl Esters (7ae). Compound 3a (1.38 g, 5 mmol), the corresponding amine (3 ml), and DMF (3 ml) were refluxed for 15 min. The mixture was then poured on ice (30 g) and the precipitate was collected and recrystallized. 3-Morpholino-5-(6-morpholinopyrazin-2-yl)[1,3,4]thiadiazole (8a). A. Compound 4 (1.3 g, 5 mmol) and morpholine (5 ml, 50 mmol) were refluxed for 3 h. On cooling, a precipitate was formed. The solid was filtered off, washed with methanol, and crystallized. B. Compound 12a (0.9 g, 2.5 mmol) dissolved in warm methanol (10 ml) was treated with concentrated HCl (0.5 ml) and allowed to stand until cooled. The precipitate was collected and recrystallized. C. Compound 2a or 13 (2 mmol), morpholine (3 ml, 50 mmol), and DMF (2 ml) were refluxed till the methanethiol evolution ceased (about 20 h). On cooling, water (10 ml) was added, the mixture was allowed to cool, and the precipitate was filtered off. D. The compound was obtained as described above (see Method C) from 14c by heating in neat morpholine for 3 h. 2-(4-Phenylpiperazin-1-yl)-5-[6-(4-phenylpiperazin-1-yl)pyrazin-2-yl][1,3,4]thiadiazole (8b). Compound 4 (0.65 g, 2.5 mmol) and 1-phenylpiperazine (1.5 ml, 10 mmol) in anhydrous dioxane (5 ml) were refluxed for 20 h. Then water (20 ml) was added and the mixture was cooled in ice. The crystalline residue was, after decantation of the liquid, purified by recrystallization. 2-(4-Phenylpiperazin-1-yl)-5-(6-morpholinopyrazin-2-yl)[1,3,4]thiadiazole (8c). A. Compound 13 (0.26 g, 1 mmol), 1-phenylpiperazine (2 ml, 13 mmol), and DMF (1 ml) were refluxed for 4 h and allowed to stand for crystallization. Then MeOH (5 ml) was added and the product collected and recrystallized. B. A solution of compound 10 (0.3 g, 1 mmol) in chloroform (2 ml) was added to a solution of 4-phenylpiperazinecarbodithioic acid hydrazide (0.24 g, 1 mmol) in DMSO (2 ml) and the mixture was stirred for 48 h. Then methanol (10 ml) and concentrated HCl (1 ml) were added. The oily deposit crystallized while 1191
stirred. The whole was neutralized with saturated NaHCO3 solution. On cooling, the precipitate was filtered off, washed with water, and crystallized from MeOHwater mixture. 2-Morpholino-5-[6-(4-phenylpiperazin-1-yl)pyrazin-2-yl][1,3,4]thiadiazole (8d). Compound 14a (0.46 g, 2.5 mmol), 1-phenylpiperazine (1.5 ml, 10 mmol), and dioxane (3 ml) were refluxed for 2 h. On boiling, the amine hydrochloride deposited. After cooling to ambient temperature the mixture was additionally icecooled. The precipitate was collected and recrystallized from dioxane. 6-Morpholinopyrazine-2-carboimidic Acid Benzyl Ester (9). Obtained as described for compound 5; 2-cyano-6-morpholinopyrazine [8] (3.8 g, 20 mmol) and benzyl alcohol (3 ml, 30 mmol) were taken for the reaction. N'-[Amino(6-morpholinopyrazin-2-yl)-methylene]hydrazinocarbodithioic Acid Methyl Ester (10). Compound 9 (1.5 g, 5 mmol) was dissolved in hot MeOH (25 ml), and a solution of hydrazinecarbodithioic acid methyl ester [7] (1.22 g, 10 mmol) in MeOH (10 ml) was added. The mixture was stirred for 2 h. After strong cooling, the product was filtered off and recrystallized from ethanol. Morpholine-4-carbothioic Acid N'-[Amino(6-chloropyrazin-2-yl)methylene]hydrazide (11a). To compound 5 (1.28 g, 5 mmol) dissolved in hot MeOH (10 ml) a hot solution of morpholine-4-carbothioic acid hydrazide [7] (0.8 g, 5 mmol) in MeOH (15 ml) and water (5 ml) was added. The mixture was stirred for 2 h, then ice-cooled and the product filtered off. From the filtrate an additional portion of product was precipitated by water. 4-Phenylpiperazine-1-carbothioic Acid N'-[Amino(6-chloropyrazin-2-yl)methylene]hydrazide (11b). To a solution of 4-phenylpiperazinecarbothioic acid hydrazide (0.24 g, 1 mmol) in DMSO (2 ml), compound 4 (0.25 g, 1 mmol) was added and the mixture was stirred for 48 h. Then the reaction mixture was diluted with water (10 ml) and extracted twice with CHCl3 (3 30 ml). The combined extracts were dried with anhydrous MgSO4, chloroform was evaporated, and the residue was crystallized from ethanol. Morpholine-4-carbothioic Acid N'-[Amino(6-morpholinopyrazin-2-yl)methylene]hydrazide (12a). Obtained by analogy to compound 10; morpholine-4-carbothioic acid hydrazide (5 mmol) was taken for the reaction instead of H2NNHCSSMe. 4-Phenylpiperazine-1-carbothioic Acid N'-[Amino(6-morpholinopyrazin-2-yl)methylene]hydrazide (12b). Obtained as described for compound 11b; compound 9 was taken for the reaction instead of 4. 2-(5-Methylthio)-5-(6-morpholinopyrazin-2-yl)[1,3,4]thiadiazole (13). Compound 10 (1.1 g, 3.3 mmol) dissolved in hot MeOH (40 ml) was treated with concentrated HCl (1 ml) and allowed to cool down. After additional ice-cooling the product was filtered off. 5-(6-Chloropyrazin-2-yl)-2-morpholino[1,3,4]thiadiazole (14a). Obtained by analogy to compound 13 from compound 11a (1.5 g, 5 mmol). 5-(6-Chloropyrazin-2-yl)-2-(4-phenylpiperazino)[1,3,4]thiadiazole (14b). To a solution of 4-phenylpiperazine-1-carbodithioic acid hydrazide (0.24 g, 1 mmol) in DMSO (2 ml), compound 4 (0.25 g, 1 mmol) was added and the mixture was stirred for 48 h. Then the reaction mixture was diluted with water (10 ml) and treated with concentrated HCl (1 ml). On cooling, the deposited product was filtered off and crystallized from ethanol.
REFERENCES 1. 2. 3. 4. 5. S. Kubota, Y. Koida, T. Kossaka, and O. Kiuino, Chem. Pharm. Bull., 18, 1696 (1970). H. Foks, Cz. Orlewska, and M. Janowiec, Acta Pol. Pharm. Drug Res., 49, 47 (1992). Cz. Orlewska, H. Foks, M. Janowiec, and Z. Zwolska-Kwiek, Pharmazie, 50, 565 (1995). H. Foks, M. Buraczewska, W. Manowska, and J. Sawlewicz, Diss. Pharm. Pharmacol., 23, 49 (1971). B. Milczarska, H. Foks, M. Janowiec, and Z. Zwolska-Kwiek, Acta Pol. Pharm. Drug Research, 49, 41 (1992).
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6. 7. 8. 9.
J. Beger, J. Prakt. Chem., 321, 959 (1979). T. Sugowara, H. Masuya, T. Matsuoto, and T. Miki, Chem. Pharm. Bull., 28, 2116 (1980). H. Foks, M. Buraczewska, W. Manowska, and J. Sawlewicz, Diss. Pharm. Pharmacol., 24, 577 (1972). C. Orlewska, H. Foks, P. Sowinski, D. Martynowski, Al. Olczak, and M. L. Glowka, Pol. J. Chem., 75, 1237 (2001).
1193
SYNTHESIS OF SUBSTITUTED 1,2,4-TRIAZOLES AND 1,3,4-THIADIAZOLES

T. R. Hovsepian, E. R. Dilanian, A. P. Engoyan, and R. G. Melik-Ohanjanian The cyclization of 4-substituted 1-arylacetyl- and 1-aryloxyacetylthiosemicarbazides and also the potassium salt of (4-bromophenoxy)acetodithiocarbazinic acid in the presence of base gives the novel 3arylmethyl- and 3-aryloxymethyl-5-mercapto-1,2,4-triazoles and, in the presence of concentrated H2SO4, the novel 5-substituted 2-arylmethyl- and 2-aryloxymethyl-1,3,4-thiadiazoles. Keywords: thiadiazole, thiosemicarbazide, triazole, cyclization. Certain substituted 1,2,4-triazoles show anti-inflammatory [1], vasodilatory [2], and psychotropic [3] properties and derivatives of 5-amino-2-mercapto-1,3,4-thiadiazoles are active antimicrobial [4], hypoglycemic [5, 6], or antitumor [7] agents. In a search for novel, active compounds within this group we have synthesized, in this study, previously unrecorded 1,2,4-triazole and 1,3,4-thiadiazole derivatives having an arylmethyl or aryloxymethyl substituent.
R1 R2 1ai (1ac, fi) H2SO4 R1 N N R2 A S 3ag NHR A CNHNHCNHR O S (1ae) 2ae
1 2 3 4
R1 KOH R2 A N N N R SH
2d
R3Cl
N N Br OCH2 SR3 N Ph 4a,b
1a,b-3a,b R1 = Br, R2 = MeO, A = CH2, a R = Me, b R = Ph; 1c-f, 2c-e, 3c,d R1 = H, R2 = Br, A = OCH2, 1c-3c R = PhCH2; 1d, 2d R = Ph, 1e, 2e R = All, 1f, 3d R = PhCO, 1g, 3e R1 = H, R2 = MeO, A = CH2, R = Me; 1h,i, 3f,g R1 = Br, A = CH2, R = Ph, 1h, 3f R2 = i-Pr, 1i, 3g R2 = Bu; 4a R3 = PhCH2, 4b R3 = NH2COCH2
__________________________________________________________________________________________ A. L. Mndzhoyan Institute of Fine Organic Chemistry, Armenian Republic National Academy of Sciences, Yerevan 375014; e-mail: melik@cornet.am. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1377-1381, September, 2004. Original article submitted October 22, 2002; revision submitted March 1, 2004. 1194 0009-3122/04/4009-11942004 Springer Science+Business Media, Inc.
The starting 1,4-disubstituted thiosemicarbazides 1a-i were prepared by us by treatment of arylacetic and aryloxyacetic acid hydrazides with different isothiocyanates [8, 9]. Compounds 1a-e were cyclized in basic medium (4.5% aqueous KOH solution) with subsequent acidification of the reaction mixture using acetic acid to give the 3,4-disubstituted 5-mercapto-1,2,4-triazoles 2a-e. Dehydrative cyclization of the thiosemicarbazides 1a-c,f-i in the presence of conc. H2SO4 led to the corresponding 2,5-disubstituted 1,3,4-thiadiazoles 3a-g which occurred as white, crystalline materials, difficultly soluble in conventional organic solvents. The reaction of 5-mercaptotriazole 2d with benzyl chloride or chloroacetamide in basic medium gave the corresponding S-substituted triazoles 4a,b in close to quantitative yields. The potassium salt of 4-amino-3-(4-bromophenoxy)acetodithiocarbazinic acid (6) was used for the synthesis of 4-amino-3-(4-bromophenoxymethyl)-5-mercapto-1,2,4-triazole (2f) and 2-(4-bromophenoxymethyl)-5-mercapto-1,3,4-thiadiazole (5). The cyclization of 6 in hydrazine gave triazole 2f and in conc. H2SO4 the 1,3,4-thiadiazole 5.
NH2NH2 N N Br OCH2 2f H2SO4 SH N NH2
Br 6
OCH2CNHNHCSK O S
N N Br 5 OCH2 SH S
ClCH2COOMe
N N Br 7 OCH2 S SCH2COOMe
Thiadiazole 5 was treated with methyl chloroacetate to give the corresponding S-substituted derivative 7. The composition and structure of the synthesized compounds 1-5, 7 were confirmed by the results of elemental analysis (Table 1), 1H NMR spectroscopic data (Table 2), and mass spectrometry.
TABLE 1. Parameters for the Compounds Synthesized

Compound 1 2a 2b 2c 2d 2e Empirical formula 2 C11H12BrN3OS 16H14BrN3OS C16H14BrN3OS C15H12BrN3OS C12H12BrN3OS Found, % Calculated, % N 4 5 3.67 3.85 3.76 3.75 3.61 3.75 3.28 3.34 3.62 3.71 13.56 13.37 11.08 11.17 11.02 11.17 11.73 11.60 12.70 12.88 Yield, % 9 85.3 90.4 79.8 75.6 76.9
mp, S 6 9.88 10.20 8.67 8.52 8.63 8.52 8.57 8.85 9.64 9.83 7 224-226 203-205 193-195 211-213 132-133
Rf * 8 0.59 0.71 0.61 0.57 0.47
3 42.28 42.05 51.24 51.07 51.23 51.07 49.61 49.79 44.48 44.18
1195
TABLE 1 (continued)
1 2f 3a 3b 3c 3d 3e 3f 3g 4a 4b 5 7 2 C9H9BrN4OS C11H12BrN3OS C16H14BrN3OS C16H14BrN3OS C16H12BrN3O2S C11H13N3OS C18H18BrN3OS C19H20BrN3OS C22H18BrN3OS C17H15BrN4O2S C9H7BrN2OS2 C12H11BrN2O3S2 3 34.25 34.08 42.30 42.05 50.93 51.07 51.36 51.07 49.51 49.24 56.05 56.15 53.64 53.47 54.77 54.55 58.64 58.40 48.49 48.70 35.41 35.65 38.22 38.41 4 2.70 2.86 3.68 3.85 3.57 3.75 3.59 3.75 3.31 3.10 5.71 5.57 4.36 4.49 5.04 4.82 4.32 4.01 3.72 3.61 2.47 2.33 2.71 2.95 5 17.32 17.67 13.11 13.37 11.24 11.17 11.32 11.17 10.61 10.77 18.06 17.86 10.11 10.39 10.31 10.04 9.11 9.29 13.61 13.36 9.51 9.24 7.19 7.47 6 10.01 10.11 10.46 10.20 8.29 8.52 8.40 8.52 8.53 8.27 13.38 13.63 8.23 7.93 7.85 7.66 7.25 7.09 7.32 7.65 21.32 21.15 17.43 17.09 7 186-187 220-222 180-182 157-159 210-212 195-197 161-163 165-167 109-110 146-147 139-140 111-113 8 0.52 0.49 0.85 0.62 0.70 0.80 0.78 0.80 0.57 0.60 0.63 0.47 9 83.3 20.0 85.1 74.5 84.6 47.7 85.0 95.7 97.3 96.2 86.1 76.3
_______ * Solvent systems; methanolether, 1:1 (compounds 2a,b); dioxane benzene, 1:2 (compounds 2c-f, 3c,d 4a,b, 5, and 7); acetonebenzene, 1:1 (compounds 3a,b,e-g).
TABLE 2. 1H NMR Spectra of the Synthesized Compounds

Compound 2a 2b 2c 2d 2e 3a 3b 3d 4a 4b 5 7 Chemical shifts, , ppm (SSCC, J, Hz)* 3.37 (3H, s, NCH3); 3.88 (3H, s, OCH3); 4.03 (2H, s, CH2); 6.92-7.50 (3H, m, C6H3); 13.4 (1H, br. s, SH) 3.77 (2H, s, CH2); 3.85 (3H, s, OCH3); 6.80-7.55 (8H, m, C6H3, C6H5); 13.6 (1H, br. s, SH) 4.85 (2H, s, CH2); 5.25 (2H, s, OCH2); 6.62-7.42 (9H, m, C6H4, C6H5); 13.82 (1H, br. s, SH) 4.82 (2H, s, OCH2); 6.65-7.59 (9H, m, C6H4, C6H5); 13.82 (1H, br. s, SH) 4.70 (2H, d, J = 6.5, NCH2); 5.08 (2H, s, OCH2); 5.09-5.20 (2H, m, CH=CH2); 5.90 (1H, m, CH=CH2); 6.90-7.42 (4H, m, C6H4); 13.72 (1H, br. s, SH) 3.35 (3H, s, NCH3); 3.82 (3H, s, OCH3 ); 4.15 (2H, s, CH2); 6.82-7.35 (3H, m, C6H3); 10.10 (1H, br. s, NH) 3.86 (3H, s, OCH3); 4.17 (2H, s, CH2); 6.88-7.58 (8H, m, C6H3, C6H5); 10.00 (1H, br. s, NH) 5.43 (2H, s, OCH2); 6.90-8.20 (9H, m, C6H4, C6H5); 12.90 (1H, br. s, NH) 4.40 (2H, s, SCH2); 5.04 (2H, s, OCH2); 6.81-7.57 (14H, m, C6H4, 2C6H5) 3.87 (2H, s, SCH2); 5.03 (2H, s, OCH2); 6.78-7.60 (9H, m, C6H4, C6H5); 6.96 and 7.50 (2, two br. s, NH2) 5.50 (2H, s, OCH2); 6.85-7.42 (4H, m, C6H4); 14.40 (1H, br. s, SH) 3.69 (3H, s, OCH3); 4.13 (2H, s, SCH2); 5.40 (2H, s, OCH2); 6.90-7.40 (4H, m, C6H4)
_______ * Spectra recorded in DMSO-d6 (2-5) and CD3OD (7). 1196
EXPERIMENTAL H NMR spectra were recorded on a Mercury-300 (300 MHz) instrument and mass spectra on an MX-1320 spectrometer with direct introduction of the sample into the ion source. TLC was performed using Silufol UV-254 plates and revealed using iodine vapor. 3-(3-Bromo-4-methoxybenzyl)-4-R-5-mercapto-1,2,4-triazoles (2a,b) and 3-(4-Bromophenoxymethyl)-4-R-5-mercapto-1,2,4-triazoles (2c-e) (General Method). A solution of KOH (40 mmol) in water (30 ml) was added to a solution of the thiosemicarbazide 1a-e (25 mmol) and the mixture was refluxed for 2 h. The cooled solution was acidified with glacial acetic acid and the precipitated product 2a-e was filtered off and recrystallized from methanol. Mass spectrum of compound 2b, m/z (Irel, %): 375/377 [M]+ (96/100), 360/362 (29/29), 199/201 (14/15), 77 (50). 2-(3-R1-4-R2-Phenylmethyl)-5-NHR-1,3,4-thiadiazoles (3a,b,e-g) and 2-(3-R1-4-R2-Phenoxymethyl)-5-NHR-1,3,4-thiadiazoles (3c,d) (General Method). The thiosemicarbazide 1a-c, f-i (25 mmol) was dissolved portionwise in conc. H2SO4 (d = 1.836, 35 ml). The solution was poured into iced water (250 ml). The precipitated, white crystalline products 3a-g were filtered off, washed on the filter to neutral reaction of the water washes, and recrystallized from ethanol. Mass spectrum of compound 3b, m/z (Irel, %): 375/377 [M]+ (72/68), 257/259 (24/27), 199/201 (40/32), 77 (86). 5-Benzylthio- and 5-Acetamidothio-3-(4-bromophenoxymethyl)-4-phenyl-1,2,4-triazole (4a and 4b) (General Method). The triazole 2d (5 mmol) was dissolved in 15 ml of a solution of KOH (5 mmol) in methanol at 40C. Benzyl chloride or chloroacetamide (5 mmol) was added to the solution obtained and the mixture was refluxed for 1 h. After cooling, the precipitated product 4a,b was filtered off and recrystallized from methanol. 4-Amino-3-(4-bromophenoxymethyl)-5-mercapto-1,2,4-triazole (2f). A mixture of the salt 6 (10 mmol), hydrazine (95%, 20 mmol), and water (1 ml) was refluxed with stirring to the evolution of hydrogen sulfide. Iced water (50 ml) was added to the reaction mass and the mixture was acidified using conc. HCl. The precipitated product 2f was filtered off, washed on the filter with water, dried, and recrystallized from ethanol. Mass spectrum, m/z (Irel, %): 300/302 [M]+ (40/32), 172/174 (100/94), 129 (87), 75 (23). 2-(4-Bromophenoxymethyl)-5-mercapto-1,3,4-thiadiazole (5). The salt 6 (5 mmol) was added in small portions with stirring to H2SO4 (d = 1.836, 7 ml) at 0C. After complete addition of the salt the stirring was continued for a further 15 min and the solution was poured into ice (100 g). The precipitated crystalline product 5 was filtered off, washed with water, dried, and recrystallized from ethanol. 2-(4-Bromophenoxymethyl)-5-carboxymethylmethylthio-1,3,4-thiadiazole (7). Prepared from the thiadiazole 5 (5 mmol) and methyl chloroacetate (5 mmol) as in the method for the synthesis of the products 4a,b (see above).
1
REFERENCES 1. 2. 3. 4. 5. 6. M. Tandon, J. P. Bartwal, T. N. Bhalla, and K. P. Bhargava, Indian J. Chem., 20B, 1017 (1981); Chem. Abstr., 96, 162602 (1982). E. Tenor and R. Ludwig, Pharmazie, 534 (1971). L. Baiocchi, A. Chiari, A. Frigerio, and P. Ridolfi, Arzneim.-Forsch., 400 (1973). M. D. Mashkovskii, Drugs [in Russian], Meditsina, Vol. 2, Moscow (1986), p. 280. B. Hkfelt and A. Jhnsson, J. Med. Chem., 5, 247 (1962). A. Kh. Avetisyan, T. R. Ovsepyan, N. O. Stepanyan, and L. G. Sapondzhyan, Khim.-Farm. Zh., No. 6, 69 (1981).
1197
7. 8. 9.
R. P. Rao, J. Singh, and N. Vijnana, Parishad Anusandhan Patrika, 16, 73 (1973); Chem. Abstr., 79, 105151 (1973). T. R. Hovsepian, E. R. Dilanian, N. O. Stepanyan and Zh. M. Bunatyan, Arm. Khim. Zh., 37, 248 (1986). T. R. Hovsepian, Dzh. M. Terdzhanyan, F. G. Arsenyan, G. M. Stepanyan, and B. T. Garibdzhanyan, in: Chemotherapy of Cancer in the USSR [in Russian], Vol. 47, Moscow (1987), p. 46.
1198
ISOMERIZATION IN THE OXIDATIVE CYCLOCONDENSATION OF 2-AROYLMETHYL1H-BENZIMIDAZOLES WITH o-AMINOTHIOPHENOL

I. B. Dzvinchuk, A. V. Vypirailenko, and M. O. Lozinskii Oxidative cyclocondensation of 2-aroylmethyl-1H-benzimidazoles with o-aminothiophenol gave the previously unknown 3-aryl-2-(2-benzimidazolyl)-4H-1,4-benzothiazines and (or) the isomeric 2H-1,4-benzothiazines. 2-(4-Nitrophenacyl)-1H-benzimidazole and 2-phenacylbenzothiazole gave 4H-1,4-benzothiazines which are not liable to isomerize but the reaction of the first compound is complicated by a hydrolytic fission which yields 2-[2-(4-nitrobenzoylamino)phenylthiomethyl]benzimidazole. A mixture of dimethylsulfoxide, acetic acid, and water was used as oxidant and solvent. The effect of the substituent and of the solvent on the tendency of the products to undergo prototropic isomerization in the benzothiazine ring have been studied. Keywords: benzimidazoles, cyclocondensation. 1,4-benzothiazines, DMSO, isomerization, catalysis, selectivity,
We have previously shown that 2-acylmethyl-1H-benzimidazoles are similar in chemical properties to 1,3-dicarbonyl compounds and can serve as efficient synthons in the preparation of benzimidazolyl substituted pyrazoles [1-8], chalcones [9], and pyrimidines [10] and also of (o-aminoanilino)pyrazoles [11, 12]. It is also known that 1,3-dicarbonyl compounds undergo oxidative cyclocondensation with o-aminothiophenol (1) when heated in DMSO to give 4H-1,4-benzothiazines selectively (e.g. acetoacetic ester gave 2-carbethoxy-3-methyl4H-1,4-benzothiazine (2) [13]). With the aim of preparing previously unavailable benzimidazolyl substituted 1,4-benzothiazines we have used the 2-aroylmethylbenzimidazoles 3a-i as the methylcarbonyl component in this reaction. Treatment of reagents 1 and 3a-i using a known method (holding in DMSO at 145-150C) led to a mixture of products which was difficult to separate. The individual compounds could be obtained by holding the indicated reagents in mixtures of DMSOAcOHH2O at 85-90C. It was found that the structure of the products obtained depends on the nature of the aroylmethylbenzimidazole 3 Ar substituent and the composition of the solvent mixture used. Hence the 2-phenacylbenzimidazole (3a) in a mixture of DMSOAcOHH2O (5:1:1 by volume) and its 3-chlorophenacyl analog 3b in DMSOAcOH (1:1) gave the target 4H-1,4-benzothiazines 4a,b. The product 4a obtained in this way occurred as a crystalline solvate with DMSO (1:1 molecular composition). In a 1:1:1 mixture of DMSOAcOHH2O compounds 3a,b gave selectively the isomeric 2H-1,4-benzothiazines 5a,b.
__________________________________________________________________________________________ Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev 02094; e-mail: iochkiev@ukrpack.net. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1382-1390, September, 2004. Original article submitted October 23, 2002; revision submitted October 18, 2003. 0009-3122/04/4009-11992004 Springer Science+Business Media, Inc. 1199
CH2COAr NH2 + SH 1 3ah H N N
DMSOAcOHH2O, 5:1:1 (3a) DMSOAcOH, 1:1 (3b)
DMSOAcOHH2O, 1:1:1 (3ah)
N S H N N
H S Ar H N
N Ar N
4a,b
5ah
3-5 Ar = Ph, b Ar = 3-ClC6H4, c Ar = 4-ClC6H4, d Ar = 4-BrC6H4, e Ar = 3,4,5-(MeO)3C6H2, f Ar = 4-MeC6H4, g Ar = 4-MeOC6H4, h Ar = 2-thienyl
In the case of the 2-aroylmethylbenzimidazoles 3c-h (compounds with electron-donor or weakly electron-acceptor substituents in the aryl fragment) it was not possible to effect a selective conversion to the corresponding 4H-1,4-benzothiazines 4c-h. A mixture of DMSOAcOHH2O (1:1:1) gave the isomeric 2H-1,4-benzothiazines 5c-h. On the other hand, the same conditions with the 2-(p-nitrophenacyl)benzimidazole (3i) (a compound with a strong electron acceptor substituent in the aromatic fragment) gave the corresponding 4H-1,4benzothiazine 4i. The yield of the latter is only modest (51%) since the process is complicated by the formation of 2-[2-(4-nitrobenzoylamino)phenylthiomethyl]benzimidazole (6), evidently due to hydrolytic fission of the target 4i at the CC bond of the benzothiazine ring.
O N DMSOH2O, 1:1:1 S H N N H N Ar S H N Ar
COAr CH2 H N 1 + N
+
H N
3i
4i 3i, 4i, 6 Ar = 4-O2NC6H4
1200
The starting 2-aroylmethylbenzimidazoles 3a-i principally exist in solution in the enamino ketone form A [8, 14], i.e. as benzanilide vinylogs, hence their carbonyl group has a lowered electrophilicity. The protonation of the form 3A probably occurs at the oxygen atom to give the benzimidazolium derivatives 7a-i. In structure they resemble the enolized form of acetoacetic ester and, evidently, are more susceptible to reaction with nucleophiles than the nonprotonated forms A and B and this explains the role of acetic acid as catalyst in the cyclocondensation studied. It does not account for the exclusive formation of the isomers 4 or 5 (see also a detailed mechanism for similar reactions in [13]).
H N N O 3B ai 3A ai Ar H N N H O Ar + H+ _ H+
+
H N N H HO 7ai Ar
In order to analyze the obtained results (see below) we have studied the behaviour of a structural analog of compound 3a in this reaction, viz 2-phenacylbenzothiazole 8. In those conditions for the examples described above which favor the formation of the 2H-isomer product of the product 5 the process takes place markedly more slowly than for compound 3a (6 h instead of 2 h). None the less, the fully stable 2-(2-benzothiazolyl)-3phenyl-4H-1,4-benzothiazine (9) was obtained in 85% yield.
DMSOAcOHH2O, 1:1:1
S 1 + N 8 CH2COPh
S N Ph 9
S N H
The physicochemical parameters for the compounds synthesized are given in Table 1. When considering the reasons for the alternative formation of the isomeric forms of the studied reaction products it should be born in mind that the compounds 4a,b,i, 5a-h and 9 were obtained by us from the reaction mixture in an analytically pure state by a simple filtration. i.e. without crystallization. In the conditions for recording the 1H NMR spectra (DMSO-d6, 20-25C) the appearance of an admixture with the corresponding isomer was not observed. However, attempts to crystallize compound 4b from aqueous acetic acid or aqueous pyridine showed a tendency to form a mixture of the 2H- and 4H-1,4-benzothiazine isomers as seen in the 1 H NMR spectrum. Hence isomeric conversions have a high energetic barrier in this case and, very likely, are catalyzed by acids and water. In order to understand the tendency of the obtained 1,4-benzothiazines to exist in the 2H- or 4H-isomeric form it seemed reasonable to compare them with compounds 2 and 9. The latter are stabilized by an energetically favored conjugated system in the 4H-1,4-benzothiazine ring with a transfer of the electron-donor effect of the ring nitrogen atom via the vinyl fragment to the electron-acceptor substituent in position 2. Such a system constitutes a chromophoric chain and gives the compounds a red color. A similar conjugation in compounds of type 4 is apparently less energetically favored. This follows from data concerning the weakly developed electron-acceptor properties of a 2-benzimidazolyl fragment [15]. None the less, compound 4i does not appear prone to isomerization. In this it is possible that another system of conjugation is achieved with transfer of an electron-donor effect from the sulfur atom via the vinyl fragment to the strongly electron-acceptor p-nitrophenyl substituent. The presence of such a long chromophore is confirmed by the intense dark-cherry color of the compound. 1201
TABLE 1. Characteristics for the Compounds Synthesized

Compound 4a 4b 4i 5a 5b 5c 5d 5e 5f 5g 5h 6 9 Empirical formula C C21H15N3SC2H6OS C21H14ClN3S C21H14N4O2S C21H15N3S C21H14ClN3S C21H14ClN3S C21H14BrN3S C24H21N3O3S C22H17N3S C22H17N3OS C19H13N3S2 C21H16N4O3S C21H14N2S2 66.11 65.84 66.96 67.10 65.35 65.27 73.90 73.87 67.04 67.10 66.96 67.10 60.08 60.01 66.68 66.80 74.45 74.34 71.08 71.14 65.76 65.68 62.39 62.36 70.25 70.36 Found, % Calculated, % 4.98 5.04 3.71 3.75 3.68 3.65 4.37 4.43 3.75 3.75 3.80 3.75 3.33 3.36 5.00 4.91 4.80 4.82 4.66 4.61 3.80 3.77 3.94 3.99 4.02 3.94 Yield, %
mp, N 10.11 10.02 11.12 11.18 14.48 14.50 12.40 12.31 11.22 11.18 11.09 11.18 9.89 10.00 9.76 9.74 11.78 11.82 11.26 11.31 11.98 12.09 13.70 13.85 7.92 7.81 210-215 238-241 224-226 238-241 241-243 244-246 258-260 221-223 248-250 261-263 237-241 194-195 220-221
84 63 51 82 73 88 90 52 82 88 89 22 85
The lower stability of type 4 structures with a weakening of the electron-acceptor properties of the Ar substituent is likely attributable to the existence of a concurrent system of conjugation with the oppositely directed transmission of conjugation via the vinyl fragment of the electronic effect of thiazine amino group to the benzimidazole fragment. In addition, there can appear a marked steric hindrance between the aryl and benzimidazolyl substituents, positioned to one side of the ring vinyl group. Hence, a deviation of the component parts of the conjugated system from one plane and a lowering of the efficiency of orbital overlap should be expected. As a result, the tendency to prototropic shift with displacement of the multiple bond should be increased and this is found in the structures 5c-h. In the latter, steric hindrance is not significant. They are evidently additionally stabilized by intramolecular hydrogen bonding between the sulfur atom and the hydrogen atom of the imino group in the benzimidazole ring. A shorter conjugated system for the Ar substituent and the ring azomethine bond is achieved and the chromophoric system is not developed, hence the compounds are colorless or weakly yellowish in color. As regards the electronic effect on the remaining part of the molecule, the m-chlorophenyl substituent in the isomers 4b and 5b occupies an intermediate position in the series of Ar substituents used by us between the two indicated limiting examples (see the -constant scale [16]) and so both possible isomers can be obtained without particular complications. It seems likely that, in the synthesis using the DMSOAcOH mixture, protonation of the benzimidazole ring occurs and this increases its electron-acceptor properties to yield the relatively stable conjugated system corresponding to structure 4b. Treatment of the reaction mixture with water causes rapid hydrolytic decomposition of the salt with the weak acid to give the obtained product. The isomerization of the 1,4-benzothiazine ring occurs significantly more slowly and the product 4b can be crystallized out in good yield. On the other hand, prolonged heating in the presence of water can result in isomerization to give the product 5b. The orange color of 4b and yellow color of its isomer 5b point to a significant difference in the structure of the chromophoric systems in these compounds. 1202
Somewhat away from the indicated dependence is the example of compound 4a which is separated as a stable, crystalline solvate with DMSO. The latter is probably formed via a stable, intermolecular hydrogen bond between the oxygen atom of the DMSO and the hydrogen atom of the imino group in the benzimidazole ring. There arise specific hindrances to its isomerization in compound 5a which is stabilized by the intramolecular hydrogen bond. However, when heating is prolonged in a medium containing an increased aqueous acetic acid content the solvate is evidently disrupted and the isomerization can occur without complication. The isomers 4a and 5a differ significantly in color, the first being red-orange and the second pale yellow. The structural features for the synthesized compounds are confirmed by 1H NMR spectroscopic data (Table 2). The signals for the NH groups in compound 4a (the solvate) and 4b,i appear as two, single proton singlets to lower field than the aromatic proton signals in a region typical of benzimidazoles [1-12, 14] and 4H-1,4-benzothiazines [13]. Both signals disappear in the presence of D2O. It was found that, for these compounds, the H-4' and H-7' benzimidazole proton signals appear to be different. In fact, they appear as two resolved multiplets for the solvate 4a or as a generally broadened singlet signal in the remaining examples. These indicate, respectively, the inhibition and rapid migration of a proton between the ring nitrogen atoms. To
TABLE 2. 1H NMR Spectra of Compounds 4a,b,i, 5a-h, 6, and 9

Compound 4a DMSO 4b Chemical shifts, , ppm (J, Hz) 2.54 (6, s, 2CH3); 6.85-6.95 (3, m, H-5, H-6, H-7); 7.01-7.09 (3, m, 8-, H-5', H-6'); 7.17 (1, m, H-7'); 7.26-7.40 (5, m, C6H5); 7.46 (1, m, H-4'); 8.72 (1H, s, H-4); 11.35 (1H, s, H-1') 6.88-6.96 (3, m, H-5, H-6, H-7); 7.01-7.09 (4, m, H-8, H-5', H-6', 6-HAr); 7.30 (1H, dd, J 1 = 8.1, J 2 = 7.8, 5-H Ar ); 7.37 (2H, br. s, H-4', H-7'); 7.41-7.46 (2, m, 2-, 4-HAr); 8.82 (1H, s, H-4); 11.55 (1H, s, H-1') 6.88-6.96 (3, m, H-5, H-6, H-7); 7.04-7.11 (3, m, H-8, H-5', H-6'); 7.34 (2H, br. s, H-4', H-7'); 7.54, 8.17 (2 2, two d, J = 8.7, 2-, 6- and 3-, 5-HAr); 8.91 (1H, s, H-4); 11.69 (1H, s, H-1') 6.14 (1H, s, CH); 7.01-7.54 (9H, m, H-5, H-6, H-7, H-8, H-5', H-6', m- and -Ph); 7.34 (1H, m, H-7'); 7.52 (1H, m, H-4'); 8.13 (2H, m, o-HPh); 12.42 (1H, s, H-1') 6.20 (1H, s, CH); 7.01-7.64 (8H, m, H-5, H-6, H-7, H-8, H-5', H-6', 4,5-HAr); 7.37 (1H, m, H-7'); 7.54 (1H, m, H-4'); 8.09 (1H, m, 6-HAr); 8.20 (1H, m, 2-HAr); 12.46 (1H, s, H-1') 6.15 (1H, s, CH); 7.00-7.42 (7H, m, H-5, H-6, H-7, H-8, H-4', H-6); 7.51 (1H, m, H-4'); 7.59 and 8.15 (2 2H, two d, J = 8.4, 2-, 6- and 3-, 5-HAr); 12.45 (1H, s, H-1') 6.15 (1H, s, CH); 7.01-7.43 (7H, m, H-5, H-6, H-7, H-8, H-4', H-6'); 7.51 (1H, m, H-4'); 7.74 and 8.08 (2 2H, two d, J = 8.7, 2-, 6- and 3-, 5-HAr); 12.45 (1H, s, H-1') 3.75 (3H, s, O3); 3.86 (6H, s, 2 O3); 6.27 (1H, s, CH); 7.01-7.42 (6H, m, H-5, H-6, H-7, H-8, H-5', H-6); 7.35 (1H, m, H-7'); 7.51 (1H, m, H-4'); 7.52 (2H, s, 2-,6-HAr); 12.35 (1H, s, H-1') 2.37 (3H, s, 3); 6.11 (1H, s, CH); 7.01-7.43 (7H, m, H-5, H-6, H-7, H-8, H-4', H-6'); 7.33 and 8.05 (2 2H, two d, J = 8.7, 2-, 6- and 3-, 5-HAr); 7.49 (1H, m, H-4'); 12.39 (1H, s, H-1') 3.83 (3H, s, O3); 6.11 (1H, s, CH); 7.01-7.43 (6H, m, H-5, H-6, H-7, H-8, H-5', H-6'); 7.07 and 8.11 (2 2H, two d, J = 9.0, 2-, 6- and 3-, 5-HAr); 7.31 (1H, m, H-7'); 7.46 (1H, m, H-4'); 12.37 (1H, s, H-1') 6.15 (1H, s, CH); 7.02-7.40 (7H, m, H-5, H-6, H-7, H-8, H-5', H-6', 4-HAr ); 7.31 (1H, m, H-7); 7.42 (1H, m, H-4'); 7.85 (2H, m, 3-, 5-HAr); 12.40 (1H, s, H-1') 4.41 (2H, s, CH2); 7.08-7.11 (2H, m, H-5, H-6); 7.25-7.37 (4H, m, H-3',H-4', H-5', H-6'); 7.31 (1H, m, H-7); 7.74 (1H, m, H-4); 8.26 and 8.39 (2 2, two d, J = 8.7, 2-, 6- and 3-, 5-HAr); 10.84 (1H, s, NHCO); 12.45 (1H, s, H-1) 6.74-6.98 (4, m, H-5, H-6, H-7, H-8); 7.21 (1, m, H-5'); 7.36 (1, m, H-6'); 7.48-7.63 (5H, m, 65); 7.68 (1, m, H-7'); 7.77 (1, m, H-4'); 8.96 (1H, s, H-4)
4i
5a 5b
5c 5d 5e
5f
5g
5h 6
1203
a certain extent the absence of tautomerism in the solvate 4a is explained by the ring imino group being stably tied to the DMSO by a strong, intermolecular hydrogen bond. In compounds 4b,i there is no steric hindrance to the corresponding migration which might be due to a deviation of the benzimidazole fragment from the plane of the benzothiazine residue because of steric hindrance on the side of the 3-Ar substituent. The spectra of the 2H-1,4-benzothiazines 5a-h are significantly different to those of compound 4. In these there is noted the presence of a one proton singlet for the CH group which does not disappear in the presence of D2O and is found to high field of the aromatic protons signals. The singlet signal corresponding to the benzimidazole imino group is shifted by 1 ppm to low field of the analogous signal of the type 4 isomers. Generally, such a shift points to the participation of the imino group of the benzimidazole ring in the formation of an intramolecular hydrogen bond [7, 8, 14] which, in the specific examples, is possible only with the sulfur atom of the benzothiazine ring. Such a hydrogen bond hinders the migration of the proton between the nitrogen atoms of the benzimidazole ring and its H-4' and H-7' protons resonate separately. The spectrum of compound 6 shows two, one proton singlet signals for the NH groups to low field and these are lost in the presence of D2O. They correspond to a benzimidazole and an anilide in chemical shift. In the spectrum there are is also present a two proton singlet for the CH2 group and signals for the aromatic protons whose integrated intensity corresponds to that given in the structure 6. The separate appearance of the H-4' and H-7' signals of the benzimidazole fragment point to the formation of an intramolecular hydrogen bond between the proton at position 1 and the sulfur atom of the arylthiomethyl fragment. The structure of the key compounds was also supported by mass spectrometry (Table 3). Beside data for the molecular weight, essentially the information gives the pattern of molecular fission under electron impact conditions. Hence the spectra of the isomers 4a and 5a and also 4b and 5b are virtually identical and this supports a ready isomerization in the conditions for acquiring the mass spectra. The spectrum of compound 6 shows signals for the fragments formed by fission of the molecule at the amide CN bond with values of m/z of 150 and 254. A very strong peak for the fragment with mass 131 in it is also characteristic of stable cations. It evidently corresponds to a 2-methylenebenzimidazole cation which is formed as a result of the fission of the molecule at the thiomethylene bond with the capability of delocalizing the charge. Hence the majority of the discussed 3-aryl-2-(2-benzimidazolyl)-1,4-benzothiazines exist preferentially in the 2H-form due to the weakly expressed electron acceptor properties of the benzimidazole ring and the tendency of its imino group to form an intramolecular bond with the benzothiazine sulfur atom. Stabilization of the 4H-form is a consequence of the strong acceptor substituent in the 3-aryl fragment.
TABLE 3. Mass Spectra of Compounds 4a,b, 5a,b, and 6

Compound 4a 4b 5a 5b 6 m/z (I, %)* 341 [M]+ (100), 308 (29), 238 (84), 223 (58), 170 (22), 78 [M+, DMSO] (20), 63 (24) 375 [M]+ (59), 257 (49), 245 (21), 238 (100), 170 (20) 341 [M]+ (86), 308 (22), 296 (25), 238 (100), 223 (67) 375 [M]+ (47), 257 (48), 238 (100) 404 [M]+ (48), 254 (65), 131 (100), 104 (22), 77 (20)
_______ * Signals with intensities no lower than 20% are given.
1204
EXPERIMENTAL H NMR spectra were recorded on a Varian VXR-300 (300 MHz) spectrometer using DMSO-d6. Mass spectra were taken on an MX 1321 instrument (70 eV, 220C). Monitoring of the course of the reaction and the purity of the synthesized compounds was performed by the TLC method on Silufol UV-254 plates in the system benzeneethanol (9:1) and revealed in UV light. The investigated compounds were held in a Fisher drying pistol under water pump vacuum (115C, 6 h) before carrying out the melting point, elemental analysis, or spectroscopic investigations. 2-(2-Benzimidazolyl)-3-phenyl-4H-1,4-benzothiazine (4a). A mixture of compound 3a (2 mmol), compound 1 (2.3 mmol), DMSO (14 mmol), and aqueous acetic acid (50%, 0.5 ml) was held for 2 h at 85-90C. The cooled reaction mixture was filtered and the product 4a was washed on the filter with 2-propanol. 2-(2-Benzimidazolyl)-3-(3-chlorophenyl)-4H-1,4-benzothiazine (4b). A mixture of compound 3b (2 mmol), compound 1 (2.3 mmol), DMSO (8 mmol) and glacial acetic acid (1.0 ml) was held for 2 h at 85-90C. Water (1.0 ml) was added to the cooled reaction mixture and the mixture was warmed with stirring to complete crystallization. The cooled product was filtered and the product 4b was washed with 2-propanol. 2-(2-Benzimidazolyl)-3-(4-nitrophenyl)-4H-1,4-benzothiazine (4i) and 2-[2-(4-Nitrobenzoylamino)phenylthiomethyl]benzimidazole (6). A mixture of compound 3i (2 mmol), compound 1 (2.3 mmol), DMSO (8 mmol), and aqueous acetic acid (50%, 1.0 ml) was heated for 8 h at 85-90C. Aqueous acetic acid (50%, 1.0 ml) was then added and stirred for 5 min. After cooling, the precipitated product 4i was filtered off and washed with 2-propanol. The filtrate was held for 8 h at 85-90C until compound 4i had disappeared (using TLC). Water (5 ml) was added followed by stirring and cooling in running water. The aqueous layer was poured off, the remaining oil was dissolved in glacial acetic acid (1.5 ml), and concentrated hydrochloric acid (0.5 ml) was added to the solution. Compound 6 hydrochloride fractionally crystallized out at room temperature and it was filtered off and washed with 2-propanol and then converted to the base by the addition to the precipitate of 2-propanol (1.5 ml) and concentrated aqueous ammonia solution (0.5 ml). Crystallization from aqueous pyridine (1:1) gave compound 6. 2-(2-Benzimidazolyl)-3-phenyl-2H-1,4-benzothiazine (5a). A mixture of compound 3a (2 mmol), compound 1 (2.3 mmol), DMSO (8 mmol), and aqueous acetic acid (50%, 1.0 ml) was held for 2 h at 85-90C with stirring for the first 5-10 in until homogeneous. After cooling, the precipitated product 5a was filtered off and washed with 2-propanol. In the same way the aroylmethylbenzimidazoles 3b-h or phenacylbenzothiazole 8 gave compounds 5b-h or 9 respectively. For the separation of the product 5e the reaction mixture was diluted with water (2.0 ml). For the preparation of compound 9 the heating was prolonged to 6 h.
1
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. I. B. Dzvinchuk, A. V. Vypirailenko, and M. O. Lozinskii, Khim. Geterotsikl. Soedin., 1136 (1997). I. B. Dzvinchuk, A. V. Vypirailenko, and M. O. Lozinskii, Zh. Org. Khim., 34, 727 (1998). I. B. Dzvinchuk, A. V. Vypirailenko, and M. O. Lozinskii, Ukr. Khim. Zhurn., 78 (1999). I. B. Dzvinchuk, A. V. Vypirailenko, E. B. Rusanov, A. N. Chernega, and M. O. Lozinskii, Zh. Obshch. Khim., 69, 856 (1999). I. B. Dzvinchuk, A. V. Vypirailenko, V. V. Pirozhenko, and M. O. Lozinskii, Khim. Geterotsikl. Soedin., 1512 (1999). A. V. Vypirailenko, I. B. Dzvinchuk, and M. O. Lozinskii, Khim. Geterotsikl. Soedin., 419 (2000). I. B. Dzvinchuk and M. O. Lozinskii, Khim. Geterotsikl. Soedin., 606 (2001). I. B. Dzvinchuk, A. V. Vypirailenko, and M. O. Lozinskii, Khim. Geterotsikl. Soedin., 1195 (2001).
1205
9. 10. 11. 12. 13. 14. 15. 16.
I. B. Dzvinchuk, A. V. Vypirailenko, M. O. Lozinskii, and T. V. Makitruk, Ukr. Khim. Zhurn., 111 (1999). I. B. Dzvinchuk, T. K. Makitruk, and M. O. Lozinskii, Khim. Geterotsikl. Soedin., 536 (2003). I. B. Dzvinchuk, A. V. Vypirailenko, and M. O. Lozinskii, Zh. Org. Khim., 32, 1759 (1996). I. B. Dzvinchuk, A. V. Vypirailenko, and M. O. Lozinskii, Zh. Org. Khim., 33, 116 (1997). S. Miyano, N. Abe, R. Sumoto, and K. Teramoto, J. Chem. Soc., Perkin Trans. 1, 1146 (1976). I. B. Dzvinchuk, M. O. Lozinskii, and A. V. Vypirailenko, Zh. Org. Khim., 30, 909 (1994). A. F. Pozharskii, Theoretical Basis of Organic Chemistry [in Russian], Khimiya, Moscow (1985), p. 116. A. Gordon and R. Ford, The Chemist's Companion [in Russian], Khimiya, Moscow (1976), p. 167
1206
UNEXPECTED DIRECTION OF IODOCYCLIZATION OF 3-ALLYLTHIO-5-PHENYL-4H-1,2,4-TRIAZOLE

V. I. Shmygarev and D. G. Kim The reaction of 3-allylthio-5-phenyl-4H-1,2,4-triazole with iodine to give a mixture of 5,6-dihydro-5iodomethyl-3-phenyl[1,3]thiazolo[2,3-c][1,2,4]triazole, 6,7-dihydro-6-iodo-3-phenyl-5H-[1,2,4]triazolo[3,4-b][1.3]thiazine, 5,6-dihydro-6-iodomethyl-2-phenyl[1,3]thiazolo[3,2-b][1,2,4]triazole, and 6,7-dihydro-6-iodo-2-phenyl-5H-[1,2,4]triazolo[5,1-b][1,3]thiazine has been studied. The structure of the products obtained was established using 1H NMR spectroscopy of their dehydriodination products. Keywords: 3-allylthio-5-phenyl-4H-1,2,4-triazole, 5,6-dihydro-5-iodomethyl-3-phenyl[1,3]thiazolo[2,3-c][1,2,4]triazole, 6,7-dihydro-6-iodo-3-phenyl-5H-[1,2,4]triazolo[3,4-b][1,3]thiazine, 5,6-dihydro6-iodomethyl-2-phenyl[1,3]thiazolo[3,2-b][1,2,4]triazole, 6,7-dihydro-6-iodo-2-phenyl-5H-[1,2,4]triazolo[5,1-b][1,3]thiazine. The electrophilic cyclization of S-alkynyl [1-3] and S-allenyl [3] derivatives of 5-phenyl-4H-1,2,4triazole-3-thiol under action of acids and mercury salts has been reported. The authors [1, 3] report the formation of only one regioisomer which is the product of cyclization at the N(2) atom whereas the authors of [2] observe the formation of two isomers simultaneously, the ratio of which is determined by the reaction conditions. We have studied for the first time the electrophilic iodocyclization of 3-allylthio-5-phenyl-4H-1,2,4triazole (1) in the presence of iodine. Compound 1 was prepared by the reaction of 5-phenyl-4H-1,2,4-triazole-3thiol with allyl bromide in aqueous NaOH solution at 5-7C. The iodocyclization was carried out in dichloromethane at room temperature over several days. It was found (see scheme) that not only the two expected five-membered cyclization products 5,6-dihydro-5-iodomethyl-3-phenyl[1,3]thiazolo[2,3-c][1,2,4]triazole (3) and 5,6-dihydro-6-iodomethyl-2-phenyl[1,3]thiazolo[3,2-b][1,2,4]triazole (5) were formed but also the six-membered isomeric products 6,7-dihydro-6-iodo-3-phenyl-5H-[1,2,4]triazolo[3,4-b][1,3]thiazine (2) and 6,7-dihydro-6-iodo-3-phenyl-5H-[1,2,4]triazolo[3,4-b][1,3]thiazine (4) were obtained. In the mixture of reaction products thiazine 2 predominated (46%) and this was similar to thiazole 3 (which was present at a level of 30%) in both chromatographic behavior and solubility. The products of cyclization at atom N(2) (compounds 4 and 5) were formed in smaller amounts (19 and 5% respectively). They are also close in chromatographic behavior and solubility but significantly less polar than the isomers 2 and 3 (Scheme 1). The structures of thiazoles 3 and 5 were established by the synthesis from them of the products of fission of HI in methanolic KOH solution to give 5-methyl-2-phenyl[1,3]thiazolo[2,3-c][1,2,4]triazole (6) from isomer 3 and 6-methyl-2-phenyl[1,3]thiazolo[3,2-b][1,2,4]triazole (7) from isomer 5. In both melting point and 1H NMR spectra they were identical to those reported previously [2, 4-6] (Table 1).
__________________________________________________________________________________________ Chemistry Faculty, Chelyabinsk State University, Chelyabinsk 454021, Russia; e-mail: bobas@csu.ru, kim@csu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1391-1395, September, 2004. Original article submitted April 23, 2002. 0009-3122/04/4009-12072004 Springer Science+Business Media, Inc. 1207
Scheme 1
N
3 2 1
N
8a
N S8
7
N N S
N N S
Ph
N 4
5 6
KOH / MeOH Ph
Ph
I I2 / CH2Cl2 2
2 1
8a
8b
N Ph N H 1
N
3
N S I2 / CH2Cl2 Ph I
4
N
7a
N S7
6
N N S 6
N
5
Ph Me
I2 / CH2Cl2
2
7 6
N Ph N
3
N
3a
I N Ph N 9a N S
5
+
Ph
N N
N S 9b
S4
I2 / CH2Cl2
Me N
3a 6
Ph
2 3N
I Ph
N N 7
N S
S
4
The 1H NMR spectra of the products of elimination of HI from thiazines 2 and 4 were taken for mixtures of the compounds isomeric by double bond positions in the thiazine ring (8a,b and 9a,b respectively) and were similar to the spectrum of sulfide 1 since they contain a similar vinyl fragment. The six-membered isomers 2 and 4 show a set of multiplets, the proton spin-spin coupling constants of which were calculated by the known rules for higher order spectra [7]. The SSCC seen in thiazines 2 and 4 between the H-6 proton and the protons of the CH2N and CH2S groups point to their existence in a conformation with pseudoequatorial positioning of the iodine atom. The 1H NMR spectra of the five-membered isomers 3 and 5 showed both signals for the protons of the aromatic ring and an H-5 multiplet in isomer 3 or H-6 in compound 5 together with four quartets for the protons of the thiazole ring and the iodomethyl group. Their spin-spin coupling constants point to a major contribution of the conformers 10a and 10b with unsymmetrical positioning of the hydrogen atoms of the iodomethyl group relative to the Hx proton (H-5 in compound 3 and H-6 in compound 5).
HX I HA HB HX I HA HX HB
HB
HA
10a
10b
10c
1208
TABLE 1. 1H NMR Spectral Characteristics of Compounds 1-9

Compound 1 Chemical shifts (CDCl3), , ppm (J, Hz) 14.4 (1H, s, NH); 7.9-8.1 (2H, m, C6H5); 7.4-7.6 (3H, m, C6H5); 5.97 (1H, m, CH=); 5.27 (1H, dt, 3Jcis = 15.7, =CHH); 5.09 (1H, dt, 3Jtrans = 9.9, =CHH); 3.82 (2H, dt, 4J = 1.3, CH2CH) 7.5-7.7 (5H, m, C6H5); 4.92 (1, m, CHI); 4.55* (1, q, 3JMX = 3.7, 2JMN = 13.0, NCHHM); 4.45* (1, q, 3JNX = 8.3, NCHNH); 3.61* (1H, q, 3JAX = 2.2, 2JAB = 12.9, SCHHAI); 3.59* (1, q, 3JBX = 9.6, SCHHBI) 7.65-7.80 (2H, m, C6H5); 7.4-7.5 (3H, m, C6H5); 4.99 (1, m, NCH); 4.38 (1, q, 4 JMB = 1.3, 3JMX = 7.3, 2JMN = -11.9, SCHHM); 3.82 (1, q, 3JNX = 1.9, SCHNH); 3.36 (1H, q, 3JAX = 10.5, 2JAB = -10.5, CHHAI); 3.11 (1, d, 3JBX = 3.0, CHHBI) 7.95-8.05 (2H, m, C6H5); 7.35-7.55 (3H, m, C6H5); 4.74* (1, m, CHI); 4.81* (1, dd, 4JMB = 1.6, 3JMX = 5.0, 2JMN = 13.8, NCHHM); 4.54 (1, sext., 3JNX = 9.5, NCHNH); 3.67* (1H, dd, 3JAX = 10.6, 2JAB = -12.6, SCHHAI); 3.55* (1, d, 3JBX = 3.3, SCHHBI) 8.08.1 (2H, m, C6H5); 7.4-7.5 (3H, m, C6H5); 4.55 (1, m, NCH); 4.16 (1, q, 3JMX = 8.1, 2JMN = -11.9, SCHHM); 3.84 (1, q, 3JNX = 5.4, SCHNH); 3.70 (1H, q, 3JAX = 3.0, 2JAB = -10.6, CHHAI); 3.51 (1, q, 3JBX = 9.1, CHHBI) 7.4-7.7 (5H, m, C6H5); 6.55 (1, q, 4J = 1.3, H-6); 2.12 (3H, d, CH3) 8.1-8.2 (2H, m, C6H5); 7.4-7.6 (3H, m, C6H5); 6.59 (1, q, 4J = 1.2, H-5); 2.58 (3H, d, CH3) 7.5-7.7 (5H, m, C6H5); 6.41 (1, dt, 3J = 10.0, 4J = 1.7, SCH=); 5.96 (1, dt, CH=); 4.79 (2, dd, 3J = 3.7, NCH2) 7.5-7.7 (5H, m, C6H5); 6.89 (1, dt, 3J = 8.0, 4J = 1.4, NCH=); 5.76 (1, dt, CH=); 3.61 (2, dt, 3J = 5.4, SCH2) 7.4-8.0 (5H, m, C6H5); 6.31 (1, dt, 3J = 10.0, 4J = 1.9, SCH=); 5.99 (1, dt, CH=); 5.04 (2, dd, 3J = 3.4, NCH2) 7.4-8.0 (5H, m, C6H5); 7.10 (1, dt, 3J = 8.5, 4J = 1.5, NCH=); 5.51 (1, dt, CH=); 3.72 (2, dt, 3J = 5.3, SCH2)
6 7 8a*2 8b*2 9a*2 9b*2
_______ * As part of a multiplet. *2 As a mixture of isomers. The spin-spin coupling constant values are in good agreement with relative stability of conformers for all of the cyclization products 2-5 as determined by a full energy semiempirical PM3 calculation (Table 2). Thus, according to the calculations, the conformers with pseudoequatorial iodine atom have a greater stability in the six-membered products 2 and 4 and in thiazoles 3 and 5 the conformer 10a is more stable in which the iodine atom is placed out of the plane of the thiazole ring. The calculation also showed that, for thiazole 3, the conformation 10b does not overall exist in a potential energy minimum, probably due to the unfavorable steric interaction of the iodine atom with the phenyl group. TABLE 2. Relative Energy (E) of the Conformers of the Cyclization Products 2-5*
Conformer 10a 10b 10c Axial iodine atom Equatorial iodine atom E, kJ/mol 2 21.0 0.0 3 31.1 Unstable 53.7 4 23.7 0.1 5 36.3 58.4 56.7
_______ * The energy of the most stable conformer was used as the zero energy value. 1209
EXPERIMENTAL H NMR spectra were recorded on a Bruker (200 MHz) spectrometer. TLC was carried out on Sorbfil PTSK-V-UV plates and revealed using UV irradiation or iodine vapor. 3-Allylthio-5-phenyl-4H-1,2,4-triazole (1). 5-Phenyl-4H-1,2,4-triazole-3-thiol (10.0 g, 56.4 mmol) and NaOH (3.40 g, 85 mmol) were dissolved in water (200 ml) in a flat-bottomed flask. The solution was cooled to 5-7C and allyl bromide (5.37 ml, 62.1 mmol) was added dropwise. The mixture was stirred at reduced temperature for 3-4 h, acidified with acetic acid (1.5 ml) to pH 7, and the precipitated sulfide 1 was filtered off, washed with water, and dried. The yield after drying was 11.2 g (91%). Recrystallization from a mixture of benzene (35 ml) and hexane (30 ml) gave 9.97 g of a needle-shaped crystalline product; mp 104C, Rf 0.29 (CHCl3acetone, 10:1). Found, %: S 14.7. C11H11N3S. Calculated, %: S 14.8. 5,6-Dihydro-5-iodomethyl-3-phenyl[1,3]thiazolo[2,3-c][1,2,4]triazole (3) and 6,7-Dihydro-6-iodo-3phenyl-5H-[1,2,4]triazolo[3,4-b][1,3]thiazine (2); 5,6-Dihydro-6-iodomethyl-2-phenyl[1,3]thiazolo[3,2-b][1,2,4]triazole (4) and 6,7-Dihydro-6-iodo-2-phenyl-5H-[1,2,4]triazolo[5,1-b][1,3]thiazine (5). Sublimed iodine (19.02 g, 75.0 mmol) was added to suspension of compound 1 (6.51 g, 30.0 mmol) in CH2Cl2 (200 ml). The mixture was held at room temperature in the dark for several days, then CH2Cl2 was distilled off under reduced pressure. The residue was dissolved in acetone (70 ml) and solution of Na2S2O35H2O (27.07 g, 105 mmol) and Na2CO3 (3.81 g, 36.0 mmol) in water (300 ml) was added with cooling. The precipitated mixture of cyclization products was separated and dried (9.80 g, 95%). For the separation of the cyclization products 4 and 5 the mixture was treated with benzene (200 ml) at room temperature. The insoluble part (7.15 g, a mixture of 2 and 3) was recrystallized from 70% acetic acid to give 3.80 g (37% based on sulfide 1) of thiazine 2. The mother liquor was evaporated at reduced pressure and suspended in water, the insoluble precipitate after two recrystallizations from ethanol giving 1.93 g (19% based on compound 1) of thiazole 3. The benzene extract containing the mixture of isomers 4 and 5 was evaporated and the residue (2.24 g) was chromatographed on alumina column using benzene as eluent to give 0.40 g (4% based on sulfide 1) of thiazole 5 (fraction I) and 1.50 g (14% based on sulfide 1) of thiazine 4 (fraction II). The mixture of isomers 2 and 3 (500 mg) was quantitatively separated on alumina chromatographic column (ethyl acetate as eluent) to give 195 mg (39% based on 500 mg of the mixture of 2 and 3) of thiazole 3 and 290 mg (58% based on 500 mg of the mixture of 2 and 3) of thiazine 2. The mixture of isomers 4 and 5 (500 mg) was quantitatively separated on the alumina chromatographic column (benzene as eluent) to give 105 mg (21% based on 500 mg of the mixture of 4 and 5) of thiazole 5 and 388 mg (78% based on 500 mg of the mixture of 4 and 5) of thiazine 4. 6,7-Dihydro-6-iodo-3-phenyl-5H-[1,2,4]triazolo[3,4-b][1,3]thiazine (2). Mp 194C (70% AcOH), Rf 0.21 (ethyl acetate). Found, %: I 36.5; S 9.4. C11H10IN3S. Calculated, %: I 37.0. S 9.3. 5,6-Dihydro-5-iodomethyl-3-phenyl[1,3]thiazolo[2,3-c][1,2,4]triazole (3). Mp 189C (ethanol), Rf 0.24 (ethyl acetate). Found, %: I 36.6; S 9.3. C11H10IN3S. Calculated, %: I 37.0; S 9.3. 6,7-Dihydro-6-iodo-2-phenyl-5H-[1,2,4]triazolo[5,1-b][1,3]thiazine (4). Mp 138C (benzenehexane), Rf 0.32 (ethyl acetatehexane, 2:3). Found, %: I 36.8; S 9.3. C11H10IN3S. Calculated, %: I 37.0; S 9.3. 5,6-Dihydro-6-iodomethyl-2-phenyl[1,3]thiazolo[3,2-b][1,2,4]triazole (5). Mp 115C (i-PrOH), Rf 0.34 (ethyl acetatehexane, 2:3). Found, %: I 36.9; S 9.5. C11H10IN3S. Calculated, %: I 37.0; S 9.3. 5-Methyl-3-phenyl[1,3]thiazolo[2,3-c][1,2,4]triazole (6). Compound 3 (343 mg, 1.00 mmol) was dissolved in 5% KOH solution in methanol (15 ml), heated to reflux, and left for several hours at room temperature. Methanol was evaporated at reduced pressure, the residue was extracted with chloroform (3 10 ml) and the combined extract was dried with anhydrous sodium sulfate and chloroform evaporated. The residue was recrystallized from a mixture of benzene and hexane to give thiazole 6 (118 mg, 55%); mp 150C (mp 150C [4]), Rf 0.28 (ethyl acetate). 6-Methyl-2-phenyl[1,3]thiazolo[3,2-b][1,2,4]triazole (7) was prepared similarly from compound 5 in 108 mg (50%) yield; mp 125C (mp 124C [4]), Rf 0.37 (ethyl acetatehexane, 2:3). 1210
1
Mixture of 3-Phenyl-5H-[1,2,4]triazolo[3,4-b][1,3]thiazine (8a) and 3-Phenyl-7H-[1,2,4]triazolo[3,4-b][1,3]thiazine (8b). Removal of HI from thiazine 2 (100 mg, 0.29 mmol) was carried out similarly to the preparation of compound 6. Evaporation of solvent gave 59 mg (95%) of the mixture of the isomers 8a and 8b. Mixture of 2-Phenyl-5H-[1,2,4]triazolo[5,1-b][1,3]thiazine (9a) and 2-Phenyl-7H-[1,2,4]triazolo[5,1-b][1,3]thiazine (9b) was prepared similarly from compound 4 in 61 mg (98%) yield.
REFERENCES 1. 2. 3. 4. 5. 6. 7. V. P. Upadhyaya, T. G. S. Nath, and V. R. Srinivasan, Synthesis, 288 (1978). A. Mignot, H. Moskowitz, and M. Miocque, Synthesis, 52 (1979). V. P. Upadhyaya and V. R. Srinivasan, Indian J. Chem., 20B, 161 (1981). K. T. Potts and S. Husain, J. Org. Chem., 36, 10 (1971). Y. Tamura, H Hayashy, J. H. Kim, and M. Ikeda, J. Heterocycl. Chem., 10, 947 (1973). I. Simiti and A. Marie, Rev. Roum. Chim., 27, 273 (1982). B. I. Ionin, B. A. Ershov, and A. I. Koltsov, NMR Spectroscopy in Organic Chemistry [in Russian], Khimiya, Leningrad (1983).
1211
REACTION OF 10-METHYL(PHENYL)5,10-DIHYDROPHENARSAZINE 10-OXIDES WITH HYDRIODIC ACID

V. I. Gavrilov1, A. A. Karavanov1, R. R. Musin1, F. R. Garieva1, and R. Z. Musin2 We have studied the reaction of 10-methyl(phenyl)-5,10-dihydrophenarsazine 10-oxides with hydriodic acid and we have established the structure of the products by high-resolution mass spectrometry. We have shown that when the methyl group is replaced by a phenyl group in 5,10-dihydrophenarsazine 10-oxides, cleavage of the endocyclic arseniccarbon bonds occurs. Keywords: hydriodic acid, 10-methyl-5,10-dihydrophenarsazine 10-oxide, 10-phenyl-5,10-dihydrophenarsazine 10-oxide, mass spectra. When 10-alkyl-5,10-dihydrophenarsazine 10-oxides 1 and 10-aryl-5,10-dihydrophenarsazine 10-oxides 2 react with hydrochloric, hydrobromic, trichloroacetic acids, and pentachlorophenol, only protonation at the oxygen atom occurs with formation of addition products in salt form AsOHX [1]. In the case of hydriodic acid, we have observed [2] rather facile cleavage of the arseniccarbon bond. Thus upon heating in an alcoholwater medium, as the major product of reaction between As oxides 1 and HI we identified 10-iodo-5,10-dihydrophenarsazine (3), while in the case of As oxides 2 we identified diphenylamine (4) (see reactions (1) and (2)).
Alk HN As O
HI
HN
As
(1)
Ar HN As O
HI
HN
(2)
2
1
__________________________________________________________________________________________ Kazan State Technical University, Kazan 420015, Russia; e-mail: toons@kstu.ru. 2 A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Science Center, Russian Academy of Sciences, Kazan 420088; e-mail: musin@iopc.kcn.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 13961399, September, 2004. Original article submitted January 7, 2002; revision submitted January 22, 2003. 1212 0009-3122/04/4009-12122004 Springer Science+Business Media, Inc.
The goal of this work was to study the mechanism of the process, using as an example the reaction of 10-methyl-5,10-dihydrophenarsazine 10-oxide (1a) and 10-phenyl-5,10-dihydrophenarsazine 10-oxide (2a) with HI. The synthesis was carried out according to the procedure described in [2]. We used high-resolution mass spectrometry to study the starting compounds, the reaction mixtures, and the isolated products (Table 1). Based on the mass spectrometric data obtained, we can hypothesize that reaction of compounds 1a and 2a with HI occurs according to the scheme presented below. In the first step of the reaction, protonation of the oxygen atom on the tetracoordinated arsenic atom occurs, with formation of arsonium cations 5, which then are reduced to form the tertiary arsines 6 and 7. Oxidation of the latter by iodine in an alcoholwater medium has been well studied [3], and is a reversible process. In reaction of 10-methyl-5,10-dihydrophenarsazine 10-oxide (1), the arsonium cation 5 (R = Me) formed in the first step as a result of attack by the iodide anion according to an SN2 mechanism can be converted to 10-hydroxy-5,10-dihydrophenarsazine (8), which when treated with HI gives compound 3; reaction (1) does not occur for compound 2. Dihydrophenarsazine 6 or 7 formed in the first step then is protonated at the benzene ring of the 5,10-dihydrophenarsazine system, where the endocyclic arseniccarbon bonds are broken to form diphenylamine (4) and methyldiiodoarsine (9) or diphenylamine and phenyldiiodoarsine (10).
HN
As
C OH
I MeI
+ HI HN As OH H2O 3
_ +I
R HN As O
+ 2HI HN
As
R OH
+ I + HI
HN
As
H2O + I2
1a,2a
5 H+ H +
6, 7
_ HN As R +I HN As
R I
+H
+ HN As
_ R I +I 4
RAsI2 9,10
H+ 1a, 5, 6, 9 R = Me, 2a, 7, 10 R = Ph
1213
TABLE 1. Components of Filtrates for Reactions (1) and (2) (From Mass Spectrometry Data)
Molecular ion* empirical formula (1) HI C12H9AsIN (3) CH3I I2 C12H11N (4) CH3AsI2 (9) C13H12AsN (6) C18H14AsNO (2a) HI I2 C12H11N (4) C6H5AsI2 (10) C18H14AsN (7) m/zfound 127.9107 368.8990 141.9270 253.8094 169.0928 343.7624 257.0174 335.0263 127.9129 253.8043 169.0804 405.7643 319. 0387 m/zcalc 127.9123 368.8996 141.9280 253.8090 169.0892 343.7541 257.0186 335.0291 127.9123 253.8090 169.0892 405.7697 319.0342
Reaction
(2)
_______ * Ion peaks containing the most abundant isotopes are indicated.
EXPERIMENTAL The mass spectra were obtained on an MX 1310 spectrometer with ionizing electron energy of 70 eV, electron collector current of 30 A. The substance was injected directly into the ion source by the SVP-5 direct injection system at 120C. The exact values of the masses were determined automatically from the reference peaks of perfluorokerosene with 15000 resolution. The Reaction of 10-Methyl-5,10-dihydrophenarsazine 10-Oxide with Hydriodic Acid was carried out according to the procedure in [2]. 50% Hydriodic acid (d = 1.56 g/cm3) (4.5 ml, 27.4 mmol), purified by distillation over mercury to remove traces of iodine, was added to solution of 10-methyl-5,10dihydrophenarsazine 10-oxide (1a) (2.01 g, 7.5 mmol) in ethanol (40 ml). The mixture was boiled for 4 h and then the solvent was distilled off to 1/5 of the initial volume. The precipitate formed upon cooling was filtered off and, after recrystallization from 1-propanol, was dried at 20-30 mm Hg above P2O5. Yield of compound 3 was 1.65 g (61%); mp 218-219C (219-221C [4]). The mass spectrum corresponded to 10-iodo-5,10dihydrophenarsine (3) [5]. Mass spectrum, m/z (Irel, %), composition of [M+] ion: 369 (2.7), 242 (100.0), 214 (0.5), 167 (20.5), 166 (8.0), 151 (1.2), 139 (3.6), 125 (0.8), 113 (0.7), 77 (1.5). The filtrate was studied by mass spectrometry (Table 1). Reaction of 10-Phenyl-5,10-dihydrophenarsazine 10-Oxide with Hydriodic Acid. Hydriodic acid (50%, 2.3 ml, 14.0 mmol) was added to solution of 10-phenyl-5,10-dihydrophenarsazine 10-oxide (2a) (1.00 g, 3.1 mmol) in ethanol (60 ml). The mixture was boiled for 4 h and then the solvent (3/4 of volume) was distilled off. The residue was dissolved in acetone (30 ml) and treated with a mixture of solution of potassium hydroxide (1.57 g) in water (100 ml) and benzene (100 ml) and then filtered; the benzene layer was removed and dried with anhydrous calcium chloride. The residue after distilling off the solvent, recrystallized from aqueous ethanol (1:1), has mp 53C (compare with literature data in [6]). Yield 0.20 g (39%). The mass spectrum corresponds to diphenylamine. Mass spectrum, m/z (Irel, %), composition of the ion: 170 (12.2), 169 (100.0) [M+], 168 (47.3), 167 (28.1), 166 (6.1), 77 (11.2), 66 (9.5), 65 (7.1), 51 (13.8), 39 (7.3). The filtrate was studied by mass spectrometry (Table 1). 1214
REFERENCES 1. 2. 3. 4. 5. 6. V. I. Gavrilov, L. A. Batina, B. D. Chernokal'skii, and G. Kh. Kamai, Zh. Obshch. Khim., 41, 564 (1971). V. I. Gavrilov, B. D. Chernokal'skii, and G. Kh. Kamai, Zh. Obsh. Khim., 41, 560 (1971). G. A. Razuvaev and V. S. Malinovskii, ZhRFKhO, 61, 2173 (1930). V. Shpanskii, Zh. Obshch. Khim., 4, 658 (1934). R. R. Musin, Dissertation in competition for the academic degree of Candidate of Chemical Sciences, Kazan (1998). V. P. Nikol'skii (editor), The Chemist's Handbook [in Russian], Khimiya, Moscow (1971), Vol. 2, p. 658.
1215
NOVEL ROUTE TO 2,6-DIPHENYL-1,4-DITHIINE

L. G. Shagun, L. P. Ermolyuk, I. A. Dorofeev, L. N. Il'icheva, and M. G. Voronkov Keywords: diphenacyl sulfide, 2,6-diphenyl-1,4-dithiine, sodium sulfide, thiophenacyl (2-mercapto-2phenylvinyl) sulfide, 1-phenyl-2-chloroethane-1,1-dithiol. 1,4-Dithiine and its derivatives have not been well studied [1]. We synthesized 2,6-diphenyl-1,4-dithiine for the first time [2] by hydrothiolysis of diphenacyl sulfide at -20C. The reaction occurs through a step of formation of thiophenacyl (2-mercapto-2-phenylvinyl) sulfide [3]. Continuing a study of the chemical properties of -halo-gem-dithiols [4], we observed that the reaction of an ether solution of 1-phenyl-2-chloroethane-1,1-dithiol (1) with an aqueous solution of sodium sulfide at -5C leads to formation of thiophenacyl (2-mercapto-2-phenylvinyl) sulfide (2).
SH 2 Ph SH 1 Cl S
Na2S Ph SH S 2 Ph
2 NaCl
The latter, when treated with hydrogen chloride in methanol solution at -10C, readily eliminates hydrogen sulfide and undergoes ring closure to form 2,6-diphenyl-1,4-dithiine (3) in 80% yield.
S
HCl
H2S
Ph
S
3
Ph
Thus we have found a novel approach to synthesis of difficultly accessible 2,6-substituted derivatives of 1,4-dithiine, starting from highly reactive -halo-gem-dithiols. Thiophenacyl (2-Mercapto-2-phenylvinyl) Sulfide (2). Na2S (0.4 g, 0.16 mmol) in water (3 ml) was added with stirring to a solution (cooled down to -5C) of gem-dithiol 1 (0.4 g, 2 mmol) in ether (20 ml). The reaction mixture was stirred for 2 h until the starting dithiol 1 disappeared. The ether layer was removed and dried above Na2SO4. After removal of ether, we obtained 0.25 g (85%) of sulfide 2 in the form of a thick __________________________________________________________________________________________ A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, Irkutsk 664033; e-mail: tim@irioch.irk.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1400-1401, September, 2004. Original article submitted April 8, 2004. 1216 0009-3122/04/4009-12162004 Springer Science+Business Media, Inc.
yellow-orange oil, identical to the product described previously in [3]. 13C NMR spectrum (400 MHz, CDCl3, HMDS), , ppm: 45.3 (CH2); 128-135 (CPh); 147 (C-SH); 194 (C=S). IR spectrum (thin film), , cm-1: 2550 (SH). Found, %: C 63.10; H 4.80; S 31.28. C16H14S3. Calculated, %: C 63.56; H 4.63; S 31.78. 2,6-Diphenyl-1,4-dithiine (3). Dry HCl was passed into solution of sulfide 2 (0.25 g) in anhydrous methanol (20 ml) for 2 h at -10C. The reaction mixture was poured over finely crushed ice. The precipitate formed was filtered off, washed with water, and dried under vacuum. We obtained 0.19 g (86%) of dithiine 3 as yellow crystals; mp 78-79C. The physicochemical characteristics of dithiine 3 were identical to those obtained in [2].
REFERENCES 1. 2. 3. 4. Choi Keun Soo, Akiyama Jsao, Hoshino Masamatsu, and Nakayama Juso, Bull. Chem. Soc. Jpn., 66, 623 (1993). M. G. Voronkov, L. G. Shagun, V. A. Usov, and L. E. Protasova, Khim. Geterotsikl. Soedin., 419 (1987). M. G. Voronkov, V. A. Usov, L. G. Shagun, T. L. Usova, L. E. Protasova, and L. V. Klyba, Zh. Org. Khim., 24, 2464 (1988). L. G. Shagun, I. A. Dorofeev, L. P. Ermolyuk, G. I. Sarapulova, and M. G. Voronkov, Zh. Org. Khim., 37, 1273 (2001).
1217
3-ARYL-2-CHLOROPROPANALS IN HANTZSCH SYNTHESIS OF PYRROLES

V. S. Matiychuk, R. L. Martyak, N. D. Obushak, Yu. V. Ostapiuk, and N. I. Pidlypnyi Keywords: 3-aryl-2-chloropropanals, pyrroles, Hantzsch reaction, cyclization. Pyrroles have been obtained by the Hantzsch method, by reaction of -halocarbonyl and 1,3-dicarbonyl compounds in the presence of ammonia [1-3]. However, the range of -halo-substituted aldehydes used in this synthesis is quite limited [1-4]. In this paper, we show that in this reaction we can use 3-aryl-2-chloropropanals 1a-d, obtained by Meerwein chloroarylation of acrolein [5]. We have established that aldehydes 1a-d react under mild conditions with acetoacetic and benzoylacetic esters in the presence of ammonia to form ethyl esters of 4(R1-benzyl)-2-methyl(phenyl)pyrrole-3-carboxylic acids 2a-e. Dehydrochlorination of -chloro aldehydes 1a-d does not occur in this case. Pyrrole is formed as a result of C-alkylation of the intermediate enamine followed by cyclization. The proposed method allows us to obtain trisubstituted pyrroles containing benzyl substituents in the 4 position.
R1C6H4 Cl 1ad O
+
R
2
O OEt
NH3
O Cl R1C6H4 O
O OEt OEt R1 2ae N H R

2
+
H2N R
2
1 a R1 = 3-Me, b R1 = 4-Me, c R1 = 3-Cl, d R1 = 4-Cl; 2 a R1 = 4-Me, R2 = Me; b R1 = 3-Cl, R2 = Me; c R1 = 4-Cl, R2 = Me; d R1 = 3-Me, R2 = Ph; e R1 = 4-Me, R2 = Ph
3-Aryl-2-chloropropanal 1a-d (0.015 mol) was added to mixture of acetoacetic or benzoylacetic ester (0.015 mol) and 25% aqueous ammonia (7 ml) in ethanol (10 ml). This was allowed to stand for 48 h and then extracted with ether. The ether layer was washed with 10% aqueous solution of NaOH, 5% hydrochloric acid, and water. Ether was evaporated and the residue was recrystallized from a 1:1 etherpetroleum ether mixture.
__________________________________________________________________________________________ Ivan Franko Lvov National University, L'vov 79005, Ukraine; e-mail: obushak@in.lviv.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1401-1403, September, 2004. Original article submitted February 25, 2004. 1218 0009-3122/04/4009-12182004 Springer Science+Business Media, Inc.
3-Ethoxycarbonyl-2-methyl-4-(4-methylbenzyl)-1H-pyrrole (2a). Yield 48%; mp 80-80.5C. H NMR spectrum (300 MHz, DMSO-d6), , ppm (J, Hz): 1.18 (3H, t, CH3CH2); 2.24 (3H, s, CH3C6H4); 2.38 (3H, s, CH3); 3.88 (2H, s, CH2); 4.08 (2H, q, CH3CH2); 6.26 (1H, d, J = 1.5, H-5); 7.04 (4H, s, C6H4); 11.00 (1H, br. s, NH). Found, %: C 74.40; H 7.32; N 5.39. C16H19NO2. Calculated, %: C 74.68; H 7.44; N 5.44. 4-(3-Chlorobenzyl)-3-ethoxycarbonyl-2-methyl-1H-pyrrole (2b). Yield 42%; mp 82-83C. 1H NMR spectrum, , ppm (J, Hz): 1.15 (3H, t, CH3CH2); 2.38 (3H, s, CH3); 3.93 (2H, s, CH2); 4.08 (2H, q, CH3CH2); 6.43 (1H, d, J = 1.5, H-5); 7.09-7.30 (4H, m, C6H4); 11.08 (1H, br. s, NH). Found, %: C 64.78; H 5.69; N 5.13. C15H16ClNO2. Calculated, %: C 64.87; H 5.81; N 5.04. 4-(4-Chlorobenzyl)-3-ethoxycarbonyl-2-methyl-1H-pyrrole (2c). Yield 44%; mp 125-126C. 1 H NMR spectrum, , ppm (J, Hz); 1.15 (3H, t, CH3CH2); 2.38 (3H, s, CH3); 3.91 (2H, s, CH2); 4.05 (2H, q, CH3CH2); 6.36 (1H, d, J = 1.5, H-5); 7.16 (2H, d, J = 8.1, C6H4); 7.28 (2H, d, C6H4); 11.07 (1H, br. s, NH). Found, %: C 64.59; H 5.78; N 4.95. C15H16ClNO2. Calculated, %: C 64.87; H 5.81; N 5.04. 3-Ethoxycarbonyl-4-(3-methylbenzyl)-2-phenyl-1H-pyrrole (2d). Yield 38%; mp 114-115C. 1 H NMR spectrum, , ppm (J, Hz): 1.07 (3H, t, CH3CH2); 2.28 (3H, s, CH3C6H4); 3.98 (2H, s, CH2); 4.03 (2H, q, CH3CH2); 6.55 (1H, d, J = 2.1, H-5); 6.98 (1H, d, J = 7.5, C6H4); 7.03 (1H, d, J = 8.1, C6H4); 7.07 (1H, s, C6H4); 7.17 (1H, t, J = 7.5, C6H4); 7.30-7.52 (5H, m, C6H5); 11.41 (1H, br. s, NH). Found, %: C 78.71; H 6.75; N 4.45. C21H21NO2. Calculated, %: C 78.97; H 6.63; N 4.39. 3-Ethoxycarbonyl-4-(4-methylbenzyl)-2-phenyl-1H-pyrrole (2e). Yield 43%; mp 125-126.5C. 1 H NMR spectrum, , ppm (J, Hz): 1.04 (3H, t, CH3CH2); 2.25 (3H, s, CH3C6H4); 3.95 (2H, s, CH2); 4.02 (2H, q, CH3CH2); 6.50 (1H, d, J = 2.1, H-5); 7.06 (2H, d, J = 8.1, C6H4); 7.11 (2H, d, C6H4); 7.28-7.49 (5H, m, C6H5); 11.39 (1H, br. s, NH). Found, %: C 79.05; H 6.57; N 4.27. C21H21NO2. Calculated, %: C 78.97; H 6.63; N 4.39.
1
REFERENCES 1. 2. 3. 4. 5. R. C. Elderfield and T. N. Dodd, in: R. Elderfield (editor), Heterocyclic Compounds [Russian translation], Izdat. Inostr. Lit., Moscow (1953), Vol. 1, p. 104. M. W. Roomi and S. F. MacDonald, Canad. J. Chem., 48, 1689 (1970). K. Kirschke, B. Costisella, M. Ramm, and B. Schulz, J. Prakt. Chem., 332, 143 (1990). A. W. Trautwein, R. D. Suessmuth, and G. Jung, Bioorg. Med. Chem. Lett., 8, 2381 (1998). H. D. Obushak, V. S. Matiichuk, and N. I. Ganushchak, Zh. Org. Khim., 33, 1081 (1997).
1219
SYNTHESIS OF AMINO ACID ESTERS: DERIVATIVES OF 1,2,3,4-TETRAHYDROISOQUINOLINE

N. N. Polygalova and A. G. Mikhailovskii Keywords: amino acids, 2,3-dioxopyrrolo[2,1-a]isoquinolines, esters of N-[3-(3,3-dimethyl-1,2,3,4tetrahydro-1-isoquinolinidene)-2-oxopropanoyl]glycine and -L-phenylalanine. Isoquinoline derivatives that have an amino acid residue within their structure have not been well studied. One of the few examples of such compounds are amidines [1], which exhibit antiarrhythmic and antithrombotic activity. The goal of our studies was synthesis of compounds which would not only combine amino acid and isoquinoline moieties within their molecules but also would contain functional groups making possible further modification of the molecule, such as an ester group. In continuing the study of reactions of derivatives of pyrrolo[2,1-a]isoquinoline with N-nucleophiles [2, 3], we observed that compounds 1a,b at a temperature of 20C readily undergo ring opening when treated with amino acid esters to form enaminoketo amides 2a,b.
R1 R1 1a,b Me N Me O O 2a,b R2 R1 R1 Me Me NH R2
H2NCHCO2R3
HCCCNHCHCO2R3 OO
1, 2 a R1 = MeO, b R1 = H, 2 a R2 = H, R3 = Et, b R2 = Bn, R3 = Me
The amides obtained are synthons, including chiral synthons, containing an amino acid residue. Ethyl Ester of N-[3-(3,3-Dimethyl-1,2,3,4-tetrahydro-1-isoquinolinidene)-2-oxopropanoyl]glycine (2a). Ethyl ester of glycine (1.54 g, 15 mmol) was added to compound 1a (2.87 g, 10 mmol) in alcohol (20 ml). When the mixture was stirred for 20-30 min (20C), the red color of the solution disappeared; after 3-4 h at a temperature of 5-10C, a precipitate formed which was filtered off, dried, and recrystallized from ethanol. Yield 63%; mp 143-145C. IR spectrum (CHCl3, 0.01 mol/l), , cm-1: 1605, 1630, 1690 (C=O); 3080, 3240 (NH). 1H NMR spectrum (100 MHz, CDCl3), , ppm: 1.15 (3H, t, CH3CH2O); 1.30 (6H, s, 2CH3); 2.75 (2H, s, 4-CH2); 3.83 (3H, s, CH3O); 3.85 (3H, s, CH3O); 3.95-4.15 (2H, s, NCH2 and 2H, q, OCH2CH3); 6.45 (1H, s, HC=); 6.60 (1H, s, 5-CH); 7.10 (1H, s, 8-CH); 7.80 (1H, s, NH); 11.50 (1H, s, NH). Found, %: C 61.38; H 6.52; N 7.34. C20H26N2O6. Calculated, %: C 61.52; H 6.71; N 7.18. Methyl Ester of N-[3-(3,3-Dimethyl-1,2,3,4-tetrahydro-1-isoquinolinidene)-2-oxopropanoyl]-Lphenylalanine (2b) was obtained similarly from compound 1b (2.27 g, 10 mmol) and methyl ester of L-phenylalanine (2.70 g, 15 mmol). Yield 61%; mp 135-137C. IR spectrum (CHCl3, 0.01 mol/l), , cm-1: 1610, __________________________________________________________________________________________ Perm State Pharmaceutical Academy, Perm 614990, Russia; e-mail: pfa@degacom.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1403-1404, September, 2004. Original article submitted March 18, 2004. 1220 0009-3122/04/4009-12202004 Springer Science+Business Media, Inc.
1630, 1685 (C=O); 3080 and 3240 (NH). 1H NMR spectrum (100 MHz, CDCl3), , ppm: 1.27 (6H, s, 2CH3); 2.80 (2H, s, 4-CH2); 3.10 (2H, d, CH2CH); 3.59 (3H, s, CH3O); 4.80 (1H, t, CH2CH); 6.55 (1H, s, HC=); 7.037.90 (9H, m, Ar); 8.07 (1H, s, NH); 11.45 (1H, s, NH). Found, %: C 70.81; H 6.28; N 7.03. C24H26N2O4. Calculated, %: C 70.91; H 6.45; N 6.89.
REFERENCES 1. 2. 3. B. Ya. Syropyatov, A. A. Gorbunov, V. S. Shklyaev, Yu. V. Shklyaev, and E. S. Boronenkova, Khim.Farm. Zh., No. 11, 13 (1996). A. G. Mikhailovskii and M. O. Dekaprilevich, Khim. Geterotsikl. Soedin., 1111 (1998). A. G. Mikhailovskii, M. O. Dekaprilevich, and V. S. Shklyaev, in: Abstracts, Eighteenth Ukrainian Conference on Organic Chemistry [in Russian], Dnepropetrovsk (1998), p. 265.
1221
NOVEL VARIANT OF RECYCLIZATION OF N-ARYLMALEIMIDES WHEN REACTED WITH AMINOAZOLES

Yu. A. Kovygin, D. V. Krylski, A. V. Zorina, and Kh. S. Shikhaliev Keywords: 2-aminobenzimidazole, 2-aminotriazole, arylmaleimides, recyclization. Recyclization reactions of N-arylmaleimides (1) have been described when they are reacted with 1,2-N,N-binucleophiles (o-phenylenediamine) [1] and 1,1-N,S-binucleophiles (thioamides, thiourea) [2, 3]. The reaction includes a step of addition of an amino group (in the first case) or a mercapto group (in the second case) at the activated double bond of maleimide and opening of the imide ring with transamidation relative to the free amino group of the binucleophilic substrate. In this case, depending on the direction of nucleophilic attack, isomers can form in which the methylene group occupies an endo or an exo position. In this work, we have extended the reaction under consideration to aminoazoles: 2-aminobenzimidazole and 2-aminotriazole, which are 1,1-N,N-binucleophiles. In addition to the possibility of formation of tetrahydropyrimidine or dihydroimidazole rings as a result of recyclization, this case is complicated by the probability of formation of regioisomers, since the nucleophilic centers are not equivalent.
O N N X O 1 2 N H N O Hc N H 3 N N N O 4 N H X 5 HN X N O O NH O X
+
N H
NH2
N Hb Ha O
H N
Detailed analysis of the 1H NMR spectra let us establish that the reaction of N-(4-methoxyphenyl)maleimide 1 (X = 4-MeO) with aminobenzimidazole 2 leads exclusively to 2-oxo-1,2,3,4tetrahydrobenzo[4,5]imidazo[1,2-a]pyrimidine-4-carboxy(4-methoxyanilide) (3), while the isomeric __________________________________________________________________________________________ Voronezh State University, Voronezh 394006, Russia; e-mail: chocd261@chem.vsu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1404-1406, September, 2004. Original article submitted March 4, 2004. 1222 0009-3122/04/4009-12222004 Springer Science+Business Media, Inc.
compounds 4 and 5 are not formed. This conclusion is drawn based on the assignment of the following signals: the doublet Hb with = 2.91 ppm, 2Jbc = 16.7 Hz [4]; the doublet of doublets Hc with = 3.50 ppm, 2Jbc = 16.7, 3 Jac = 7.8 Hz, and the doublet Ha with = 5.37 ppm, 3Jac = 7.8 Hz (3Jab = 0). In structure 4, the proton Ha should be a doublet of doublets because of additional splitting at the proton of the adjacent NH group, which is not observed. In structure 5, the protons Hb and Hc should be magnetically equivalent. Analogous analysis of the 1H NMR spectrum of the product of reaction between maleimide 1 and aminotriazole 6 allowed us to assign it the structure of 7-oxo-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine5-carboxy-(4-fluoroanilide) (7).
N N N N 1 N NH2 O N H X 7 H N O
+
N H 6
2-Oxo-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrimidine-4-carboxy(4-methoxyanilide) (3). Mixture of N-(4-methoxyphenyl)maleimide (2.03 g, 10 mmol) and 2-aminobenzimidazole (1.33 g, 10 mmol) in dioxane (10 ml) was boiled for 2 h. The precipitated product was filtered off, washed with acetone, and recrystallized from DMF. Yield 2.1 g (64%); mp >300C. 1H NMR spectrum (Bruker AM 300 (300 MHz), DMSO-d6), , ppm (J, Hz): 2.91 (1H, d, 2Jbc = 16.7, Hb); 3.50 (1H, dd, 2Jbc = 16.7, 3Jac = 7.8, Hc); 3.72 (3H, s, OCH3); 5.37 (1H, d, 3Jac = 7.8, Ha); 6.88 (2H, d, arom.); 7.08-7.19 (2H, m, arom.); 7.48-7.56 (4H, m, arom.); 10.50 (1H, s, NH); 11.54 (1H, s, NH). Found, %: C 64.12; H 4.88; N 16.50. C18H16N4O3. Calculated, %: C 64.28; H 4.79; N 16.66. 7-Oxo-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine-5-carboxy(4-fluoroanilide) (7). Mixture of N-(4-fluorophenyl)maleimide (1.91 g, 10 mmol) and 3-aminotriazole (0.84 g, 10 mmol) in dioxane (10 ml) was boiled for 2 h. The precipitated product was filtered off, washed with acetone, and recrystallized from DMF. Yield 1.98 g (72%); mp >300C. 1H NMR spectrum (Bruker AM 300 (300 MHz), DMSO-d6), , ppm (J, Hz): 2.87 (1H, d, 2Jbc = 3.3, Hb); 3.34 (1H, dd, 2Jbc = 16.5, 3Jac = 7.9, Hc); 5.32 (1H, d, 3Jac = 7.8, Ha); 7.14-7.27 (2H, m, arom.); 7.55-7.68 (2H, m, arom.); 8.37 (1H, s, CH-triazole); 10.60 (1H, s, NH); 11.57 (1H, s, NH). Found, %: C 52.12; H 3.78; N 25.50. C12H10FN5O2. Calculated, %: C 52.37; H 3.66; N 25.44.
REFERENCES 1. 2. 3. 4. V. D. Romanenko, N. E. Kul'chitskaya, and S. I. Burmistrov, Khim. Geterotsikl. Soedin., 264 (1973). T. Takido, S. Tamura, K. Sato, H. Kamijo, T. Nakazava, T. Hata, and M. Seno, J. Heterocycl. Chem., 35, 437 (1998). M. Yu. Krysin, Kh. S. Shikhaliev, D. V. Krylski, and V. V. Petrov, in: Abstracts, Organic Chemistry in the Twentieth Century [in Russian], Zvenigorod, Moscow (2000), p. 58. A. J. Gordon and R. A. Ford, The Chemist's Companion [Russian translation], Mir, Moscow (1976), p. 297.
1223
REDUCTIVE CYCLIZATION OF N-(2,4-DINITROPHENYL)PYRIDINIUM CHLORIDE BY TIN(II) CHLORIDE

R. S. Begunov and G. A. Ryzvanovich Keywords: 7-aminopyrido[1,2-a][1,3]benzimidazole, 1,2-dipyrido[1,2-a][1,3]benzimidazol-7-yldiazene oxide, 7-nitropyrido[1,2-a][1,3]benzimidazole, N-(2,4-dinitrophenyl)pyridinium chloride, reductive cyclization. Reactions of N-(2,4-dinitrophenyl)pyridinium chloride with various nucleophilic agents are widely used in organic synthesis [1, 2]. We propose to use the reductive cyclization of N-(2,4-dinitrophenyl)pyridinium chloride (1) by treatment with SnCl2 for synthesis of pyrido[1,2-a][1,3]benzimidazoles, which are potential biologically active drugs [3, 4]. The reaction was conducted at a temperature of 20C. Different end products are formed depending on the process conditions, which is explained by the higher reactivity of the ortho nitro group compared with the para nitro group in compound 1.
_ Cl + N _ O N+ 1 O SnCl2 O N+ _ O
O N N +_ N 2 O N NH2 N 3 N N N 4 O N N N
When the reaction is conducted in a homogeneous medium with mole ratio 1:SnCl2 1:3, reduction of only the ortho nitro group and formation of 7-nitropyrido[1,2-a][1,3]benzimidazole (2) occur. Reduction of the para nitro group was also observed when the amount of SnCl2 was doubled. As a result, we obtained 7-aminopyrido[1,2-a][1,3]benzimidazole (3). Carrying out the cyclization in a heterogeneous medium with a __________________________________________________________________________________________ P. G. Demidov Yaroslavl State University, Yaroslav 150000, Russia; e-mail: begunov@bio.uniyar.ac.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1407-1408, September, 2004. Original article submitted February 6, 2004. 1224 0009-3122/04/4009-12242004 Springer Science+Business Media, Inc.
ratio 1:SnCl2 of 1:6 leads to accumulation in the reaction mass of products of incomplete reduction of the para nitro group (nitroso- and hydroxylamino derivatives) and condensation of the latter to form 1,2-dipyrido[1,2-a][1,3]benzimidazol-7-yldiazene oxide (4). Thus, by changing the reaction conditions for reaction of N-(2,4-dinitrophenyl)pyridinium chloride with SnCl2, we can obtain different pyrido[1,2-a][1,3]benzimidazoles. 7-Nitropyrido[1,2-a][1,3]benzimidazole (2). Solutions of N-(2,4-dinitrophenyl)pyridinium chloride (5 g, 0.0178 mol) in ethyl alcohol (20 ml) and SnCl22H2O (12 g, 0.0533 mol) in 3% hydrochloric acid (20 ml) were added simultaneously to a three-necked flask with rapid stirring. After 10 min, the reaction mixture was alkalinized with 25% aqueous solution of ammonia to pH 7-8 and extracted with several portions of chloroform ( = 200 ml). After distilling off chloroform, we obtained 3.44 g (91% yield) of 7-nitropyrido[1,2-a][1,3]benzimidazole; mp 290-292C. 1H NMR spectrum (DMSO-d6, 500 MHz), , ppm (J, Hz): 9.13 (1H, d, J = 7, H-1); 8.64 (1H, d, J = 1.5, H-6); 8.50 (1H, d, J = 8.5, H-9); 8.20 (1H, dd, J = 8.5, J = 2, H-8); 7.78 (1H, d, J = 9, H-4); 7.67 (1H, t, J = 7.5, H-3); 7.11 (1H, t, J = 7, H-2). Mass spectrum, m/z (Irel, %): 213 [M]+ (100), 183 (4), 167 (91), 155 (14), 140 (28), 78 (12). Found, %: C 61.6; H 3.1; N 20.0. C11H7N3O2. Calculated, %: C 62.0; H 3.3; N 19.7. 7-Aminopyrido[1,2-a[[1,3]benzimidazole (3). Solution of N-(2,4-dinitrophenyl)pyridinium chloride (5 g, 0.0178 mol) in ethyl alcohol (20 ml) was added to solution of SnCl22H2O (24 g, 0.107 mol) in 3% hydrochloric acid (20 ml). After 10 min, the reaction mixture was alkalinized with 25% aqueous solution of ammonia to pH 7-8 and extracted with several portions of chloroform ( = 200 ml). After distilling off chloroform, we obtained 3.16 g (97% yield) of 7-aminopyrido[1,2-a][1,3]benzimidazole; mp 180-182C. 1 H NMR spectrum (DMSO-d6, 500 MHz), , ppm (J, Hz): 8.82 (1H, d, J = 7, H-1); 7.9 (1H, d, J = 9.5, H-9); 7.47 (1H, d, J = 10, H-4); 7.38 (1H, t, J = 7.5, H-3); 6.85 (1H, t, J = 7, H-2); 6.82 (1H, d, J = 1.5, H-6); 6.7 (1H, dd, J = 10, J = 2, H-8); 5.1 (2H, s, NH2). Mass spectrum, m/z (Irel, %): 183 [M]+ (100), 166 (4), 155 (15), 78 (12). Found, %: C 71.9; H 4.5; N 23.3. C11H9N3. Calculated, %: C 72.1; H 4.9; N 23.0. 1,2-Dipyrido[1,2-a][1,3]benzimidazol-7-yldiazene Oxide (4). Solution of SnCl22H2O (24 g, 0.107 mol) in 3% hydrochloric acid (20 ml) was added to emulsion of N-(2,4-dinitrophenyl)pyridinium chloride (5 g, 0.0178 mol) in ethyl alcohol (10 ml). After 10 min, the reaction mixture was alkalinized with 25% aqueous solution of ammonia to pH 7-8 and was extracted with several portions of chloroform ( = 200 ml). After distilling off chloroform, we obtained 2.32 g (69% yield) of 1,2-dipyrido[1,2-a][1,3]-benzimidazol-7-yldiazene oxide; mp >300C. 1H NMR spectrum (DMSO-d6, 500 MHz), , ppm (J, Hz): 9.13 (1H, d, J = 6.8, H-1); 9.05 (1H, d, J = 6.8, H-1'); 8.88 (1H, d, J = 1.5, H-6); 8.73 (1H, d, J = 1.5, H-6'); 8.49 (1H, dd, J = 8.8, J = 1.5, H-8); 8.42 (1H, dd, J = 8.8, J = 1.5, H-8'); 8.36 (1H, d, J = 8.8, H-9); 8.05 (1H, d, J = 8.8, H-9'); 7.75 (1H, d, J = 9.3, H-4); 7.70 (1H, d, J = 9.5, H-4'); 7.65 (1H, t, J = 8, H-3); 7.56 (1H, t, J = 8.3, H-3'); 7.08 (1H, t, J = 7.5, H-2); 7.04 (1H, t, J = 7.8, H-2'). Mass spectrum, m/z (Irel, %): 378 [M]+ (30), 197 (5), 181 (87), 167 (100), 155 (38), 78 (39), 44 (57). Found, %: C 70.6; H 3.6; N 22.7. C22H14N6O. Calculated, %: C 69.84; H 3.7; N 22.2.
REFERENCES 1. 2. 3. 4. T. L. Gilchrist, Heterocyclic Chemistry [Russian translation], Mir, Moscow (1996), p. 152. R. C. Elderfield, ed., Heterocyclic Compounds [Russian translation], Izdat. Inostr. Lit., Moscow (1953), Vol. 1, p. 311. E. Badawey and T. Kappe, Eur. J. Med. Chem., 30, 327 (1995). B. E. Maryanoff, W. Ho, D. F. McComsey, A. B. Reitz, P. P. Grous, S. O. Nortey, R. P. Shank, B. Dubinsky, R. J. Taylor, and J. F. Gardocki, J. Med. Chem., 38, 16 (1995).
1225
REACTION OF 10-CYANOTETRAHYDROBENZO[b][1,6]NAPHTHYRIDINES WITH ACETYLENEDICARBOXYLIC ESTER

L. G. Voskressensky, T. N. Borisova, I. V. Vorobiev, and A. V. Varlamov Keywords: naphthyridine, tetrahydropyridine, quinoline, Stevens rearrangement. We recently showed that the tetrahydropyridine moiety in tetrahydropyrrolo[3,2-c]pyridines and tetrahydro--carbolines, when treated with activated alkynes, depending on the solvent used is either cleaved to form alkoxy derivatives 1 [1] or expands to an eight-membered ring to form condensed azocines 2 [2]. While studying the reaction of tetrahydrobenzo[b][1,6]naphthyridine (3) [3] (where the -deficient 4cyanoquinoline moiety is condensed with the tetrahydropyridine moiety) with acetylenedicarboxylic ester (ADCE) in methanol, instead of the expected azocinoquinoline we obtained the product of a Stevens rearrangement: dimethyl ester of 2-(2-methyl-10-cyano-1,2,3,4-tetrahydrobenzo[b][1,6]naphthyridin-1-yl)but-2enedioic acid (4).
N R N N 3 N H + N R N A N E R N N 4 E = COOMe; R = i-Pr E N B _ E E N _ + N E R E E E
__________________________________________________________________________________________ Russian People's Friendship University, Moscow 117198; e-mail: lvoskressensky@sci.pfu.edu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1409-1410, September, 2004. Original article submitted April 3, 2004. 1226 0009-3122/04/4009-12262004 Springer Science+Business Media, Inc.
The reaction probably occurs via formation of a zwitterion A, and due to the electron-acceptor effect of the quinoline moiety, the protons of the 1-CH2 group can be eliminated by the anionic center of the zwitterion A, as a result of which the ylide B is formed. Rearrangement of the latter leads to benzonaphthyridine 4. The structure of compound 4 was established using X-ray diffraction analysis and confirmed by the set of spectral data. Dimethyl Ester of (Z)-2-(2-Isopropyl-1,2,3,4-tetrahydro-10-cyanobenzo[b][1,6]-naphthyridin-1yl)butene-2-dioic Acid (4). A mixture of benzonaphthyridine 3 (0.5 g, 2.0 mmol) and ADCE (0.31 ml, 2.5 mmol) in absolute methanol (5 ml) was stirred for 4 h at ~20C (monitored by TLC, Silufol, ethanol). The methanol was distilled off under vacuum, the residue was recrystallized from an ethyl acetatehexane mixture. We obtained 0.30 g (38%) of compound 4: light yellow crystals; mp 135-137C. Mass spectrum, m/z (Irel, %) 393 [M]+ (16), 378 (30), 350 (21), 334 (23), 251 (20), 250 (100), 234 (18), 208 (40), 206 (20), 193 (15). 1 H NMR spectrum (400 MHz, CDCl3), , ppm (J, Hz): 8.13 (2H, m, H-6, H-9); 7.80 (1H, m, H-7); 7.68 (1H, m, H-8); 5.84 (1H, s, =CHCO2Me); 5.32 (1H, s, H-1); 3.79 (3H, s, OCH3); 3.70 (3H, s, OCH3); 3.39 (1H, m, CH-i-Pr); 3.22-2.9 (4H, m, 3-, 4-CH2); 1.14 (3H, d, J = 6.0, CH3); 1.11 (3H, d, J = 6.0, CH3). 13C NMR spectrum (100 MHz, CDCl3), , ppm: 166.8, 164.5, 157.9, 150.2, 146.5, 131.5, 130.9, 129.2, 128.4, 124.7, 124.6, 122.8, 117.4, 113.9, 61.2, 52.1, 51.8, 50.4, 39.9, 31.2, 20.9, 18.4. Found, %: C 67.32; H 5.92; N 10.91. C22H23N3O4. Calculated, %: C 67.16; H 5.89; N 10.68. We would like to thank the Russian Foundation for Basic Research for financial support (grant No. 02-03-32941).
REFERENCES 1. 2. 3. 4. T. N. Borisova, L. G. Voskressensky, L. N. Kulikova, T. A. Soklakova, and A. V. Varlamov, Molecular Diversity, 6, 207 (2003). A. V. Varlamov, T. N. Borisova, L. G. Voskressensky, T. A. Soklakova, L. N. Kulikova, A. I. Chernyshev, and G. G. Alexandrov, Tetrahedron Lett., 43, 6767 (2002). F. Gatto, M. Rosaria del Giudice, and C. Mustazza, J. Heterocycl. Chem., 33, 1807 (1996). J. H. Brewster and M. M. Kline, J. Am. Chem. Soc., 74, 5179 (1953).
1227
UNEXPECTED REACTION OF THIOSEMICARBAZIDE WITH 3,6-BIS(VINYLSULFONYL)-1,2,4,5-TETRAFLUOROBENZENE

S. V. Amosova, G. M. Gavrilova, V. G. Cherkashina, and A. I. Albanov Keywords: 3,6-bis(vinylsulfonyl)-1,2,4,5-tetrafluorobenzene, thiosemicarbazide, nucleophilic addition and nucleophilic intramolecular substitution. We have observed an unexpected direction for the reaction of thiosemicarbazide with 3,6-bis(vinylsulfonyl)-1,2,4,5-tetrafluorobenzene (1), leading to formation of the fluorinated derivative of a condensed nitrogen- and sulfur-containing heterocyclic compound: 2-amino-8,9-difluoro-10-(2thiosemicarbazidoethylsulfonyl)-5,6-dihydrobenzo[h,i]-1,4-thiazino[4,3-d]-1,3,4-thiadiazine-7,7-dioxide (2).
S O2S F F O2S 1 F F H2N N H NH2 F F O2S 2 NH HN S NH2 O2S N S N NH2
Compound 2 was obtained as a result of nucleophilic addition of thiosemicarbazide to the activated vinyl group of sulfone 1 and subsequent intramolecular substitutions of the fluorine atoms of the benzene ring in the ortho position with participation of the NH group, and in the meta position with participation of the second nucleophilic center of the thiosemicarbazide, the sulfur atom. We described examples of simultaneous participation of the NH2 group of amines in nucleophilic addition and substitution reactions [1,2]. The reaction proceeds with a four-fold molar excess of thiosemicarbazide in DMF at 70C. The structure of compound 2 was proven by IR and NMR (1H, 13C, 19F, and 15N) spectroscopy. The 1 H, 13C, 19F, and 15N NMR spectra were recorded on a Bruker DPX 400. Operating frequencies: 1H 400.13 MHz, 13 C 100.61 MHz, 19F 376.50 MHz, and 15N 40.54 MHz. The 15N NMR spectrum, obtained by the DEPT technique with 15N-H spin-spin coupling constants of 90 Hz, contains only the chemical shifts for the nitrogen atoms directly bonded to protons. __________________________________________________________________________________________ A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, Irkutsk 664033; e-mail: amosova@irioch.irk.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1410-1412, September, 2004. Original article submitted December 27, 2003. 1228 0009-3122/04/4009-12282004 Springer Science+Business Media, Inc.
2-Amino-8,9-difluoro-10-(2-thiosemicarbazidoethylsulfonyl)-5,6-dihydrobenzo[h,i]-1,4-thiazino[4,3-d]-1,3,4-thiadiazine 7,7-Dioxide (2). Yield 54%; mp 235C (decomposition). IR spectrum, , cm-1: 1134 and 1326 (SO2), 3314 (NH), 3454 (NH2). 1H NMR spectrum (DMF-d7), , ppm: 3.38 (2H, m, CH2SO2); 3.85 [2H, m, CH2SO2 (ring)]; 3.89 (2H, m, CH2N); 4.15 [2H, m, CH2N (ring)]; 5.40 (1H, br. s, CH2NH); 6.77 (2H, br. s, NH2C=N); 7.81, 7.50 (2H, br. s, NH2C=S); 8.85 (1H, s, NHC=S). 13C NMR spectrum, , ppm (J, Hz): 43.84 (CH2NH); 47.75 [CH2N (ring)]; 49.38 [CH2SO2 (ring)]; 53.05 (CH2SO2); 119.90 (C(4), Ar, d, 2 JC,F-8 = 12.93); 122.23 (C(6), Ar); 128.45 (C(1), d, 2JC(1),F-9 = 10.78); 138.87 (C(5), Ar); 143.51 (C(2), dd, 1 JC(2),F-9 = 260; 2JC(2),F-8 = 17.7); 146.74 (C(3), dd, 1JC(3),F-8 = 256, 2JC(3),F-9 = 16); 148.62 (C=N); 181.33 (C=S). 19 F NMR spectrum, , ppm (J, Hz): -138.63 (1F, d, 3JF-8,F-9 = 23.5, F-9); -142.75 (1F, d, 3JF-8,F-9 = 23.5, F-8). 15 N NMR spectrum (internal standard, MeNO2), , ppm: -308.8 (NH2C=N); 307.44 [NHNHC(S)]; 276.33 (NH2C=S); -243.78 (NHC=S). Found, %: C 29.89; H 3.12; F 8.52; N 17.08; S 27.13. C12H14F2N6O4S4. Calculated, %: C 30.50; H 2.99; F 8.04; N 17.78; S 27.14. This research was done with the financial support of the Russian Foundation for Basic Research (project No. 02-03-32844).
REFERENCES 1. 2. S. V. Amosova, V. I. Gostevskaya, G. M. Gavrilova, V. N. Nesterov, and Yu. T. Struchkov, Izv. Akad. Nauk, Ser. Khim., 430 (1996). S. V. Amosova, V. I. Gostevskaya, G. M. Gavrilova, V. N. Nesterov, Yu. T. Struchkov, and L. N. Il'icheva, Khim. Geterotsikl. Soedin., 1195 (1996).
1229
REACTIVITY OF PYRROL-2-ONES. (REVIEW)

A. Yu. Egorova and Z. Yu. Timofeeva Published data on the chemical transformations of pyrrol-2-ones are reviewed and analyzed. The extensive synthetic possibilities of compounds containing a pyrrolone ring in the synthesis of various heterocyclic compounds with complex structures are demonstrated. The reactions are arranged according to the reaction centers of the pyrrol-2-ones: The methylene unit, the C=C double bond, the electron-deficient carbon atom of the carbonyl group. Keywords: 3H-pyrrol-2-ones, 5H-pyrrol-2-ones, reaction center. Five-membered nitrogen heterocycles of nonaromatic type (pyrrol-2-ones) rightly occupy a special position in contemporary organic chemistry in connection with the discovery of their fragments in natural compounds and also with the production of substances with various types of biological activity from them. In recent years the greatest attention has been paid to the investigation of pyrrol-2-ones and pyrrol-3ones, which are present in natural biologically active compounds and their analogs [1-47].
Me Me Me HO N H 1 O Me N Me O O Me O N Me Me 2 O HN N H O 3 O H _ O OH + NH3
Me O Me
Me
Me N O O O N O Me Me
Me _ O + H3N O HO O
Me O
O
HO
Me Me
OH OH
O HO
N Me
O 4
__________________________________________________________________________________________ N. G. Chernyshevskii Saratov State University, Saratov, Russia. E-mail: TimofejiwaSU@info.sgu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1443-1463, October, 2004. Original article submitted December 9, 2002. 0009-3122/04/4010-12432004 Springer Science+Business Media, Inc. 1243
The most important factor that has stimulated development of the chemistry of pyrrol-2-ones is their high chemical potential, which makes it possible to produce from them a whole new series of heterocyclic compounds and technically valuable substances. Their structural fragments are present in such natural substances as porphyrins, bile pigments (biliverdin, phycocyanobilin), natural alkaloids (lilidine 1, Jatropha macrorrhiza, Mirabimides A-D 2) and also in compounds having antibiotic [Malonomicin (3)] and pharmacological activity. Among the antimetabolites, antibacterial agents, and enzymes, including inhibitors, there are substances containing a pyrrol-2-one ring: a-Lipomycin 4 and streptolydigin, which inhibits the synthesis of RNA by the bacterium Bacillus megaterium, thereby retarding their development [44, 45]. On account of their prototropic tautomerism the pyrrol-2-ones can exist in three isomeric forms A, B, and C [48].
R N H A O R N H B O R N H C OH
It was noted that -hydroxypyrroles C exist in the tautomeric form of pyrrolones with a double bond at the 3H (A) or 5H (B) positions [49, 50]. Unsubstituted 2-hydroxypyrrole and its 3-alkyl and 3-acetyl derivatives exist predominantly in the form of the 5H isomers B, as shown by analysis of the NMR spectra. If, however, the acyl or ether substituents occupy position 4, the 3H isomer A predominates. The review on the chemistry of pyrrol-2-ones published in 1972 [51] is now obsolescent. In the present review we attempted to summarize, analyze, and classify for the first time data from investigations of the reactivity of pyrrol-2-ones at various reaction centers. Pyrrol-2-ones have several reaction centers that make them attractive subjects for study, i.e., the heteroring, the activated methylene unit, and the C=C and C=O double bonds.
N
R
R = H, Alk, Ar
1. Reactions Taking Place at the Methylene Unit of the Heterocycle The structure of carbonyl-containing pyrrol-2-ones presupposes high mobility for the hydrogen atoms at the position of the heterocycle. This is due to the activating effect of the carbonyl group, which depends on the nature of the heteroatom attached to it. The reactivity of the methylene unit of pyrrol-2-ones has been studied for various condensation reactions Knoevenagel, Michael, VilsmeierHaack, azo coupling. The condensation of N-unsubstituted 5-alkyl(aryl)-3H-pyrrol-2-ones 5 with aldehydes of the benzene and furan series in acetic anhydride in the presence of sodium acetate with prolonged heating leads to compounds 6 with yields of 25-30% [52, 53].
CHAr O R N H 5 O MeCOONa Ac2O R N H 6 O
Ar
C H
R = Am, C7H15, Ph; Ar = Ph, C6H4NO2-3, C6H4OH-2
1244
Arylidene derivatives of pyrrol-2-ones are potential biologically active compounds, and substances possessing herbicidal [11, 40-42] and antimicrobial activity [54] have been found among them. For this reason a synthesis was proposed for this series of compounds based on their oxahetero analogs already containing an arylidene substituent. Ammonolysis of 5-R-3-arylidene-3H-furan-2-ones 7 takes place through opening of the furanone ring and cyclization of the amides of the oxoalkanoic acids to 3-arylidene-3H-pyrrol-2-ones.
CHAr
+
R
NH3
O O 7 R = Am, C7H15, Ph; Ar = Ph, C6H4NO2-3, C6H4OH-2
H2O
It was shown on the basis of the spectral data of compounds 6 that of the possible isomeric forms (lactam, lactim, iminolactam) the lactam form is actually realized in the series of N-substituted 3-arylidene-3Hpyrrol-2-ones. The 3-arylidene derivatives of pyrrol-2-ones containing an aromatic substituent at the nitrogen atom of the heterocycle could not be obtained from 1,5-disubstituted pyrrol-2-ones or compounds 7 in a single stage [54].
CHAr 7 CHAr O NHAr1 Ac2O H2O R N O
H2NAr1
RCCH2C O
1 8 9 Ar R = Ph, C6H4Me; Ar = Ph, C6H4NO2-3, C6H4OMe, C6H4OH-2; Ar1 = Ph, C6H4Me
The low nucleophilicity of the nitrogen atom in aromatic amines makes it possible to stop the ammonolysis of the arylidene derivatives of furan-2-ones 7 at the stage of the formation of the substituted amides of 4-oxo acids 8, which are isolated with quantitative yields. Further intramolecular cyclization of the latter takes place successfully in the presence of dehydrating agents with the formation of compounds 9. The reactivity of the methylene group of the pyrrol-2-ones was studied also for the case of the reaction of 5-(3,4-dichlorophenyl)-3H-pyrrol-2-one with acetophenone, fluorenone, and isatin. Reaction with prolonged heating (10 h) in xylene or acetic anhydride led to the formation of 5-aryl-3-arylidene-3H-pyrrol-2-ones 11 [55].
R Ac2O 3,4-Cl2C6H3 N H 11 O R1
3,4-Cl2C6H3
N H 10
R O
R1
R = Me, Et, Ph; R1 = Me, Ph, MeCO, PhCO
N-Unsubstituted pyrrol-2-one 12, which exists 98% in the 5H form, condenses with acetone in an alkaline medium at the methylene unit at position 5 [56]. If equimolar amounts of the reagents are used, 5-isopropylidene-5H-pyrrol-2-one (13) is obtained.
1245
+
N H 12 O 1
Me 1 O
Me
KOH EtOH
Me Me N H 13
Increase in the concentration of acetone leads to an decrease in the yield of the condensation product and is accompanied by the formation of another condensation product 14 involving position 3 of the ring.
Me 12 1
+
:
2
Me O
Me
13
OH Me Me Me N H 14 O
In the series of 1,5-disubstituted 3H-pyrrol-2-ones 15 the active methylene group makes it possible to realize VilsmeierHaack formylation by the action of the DMFphosphorus oxychloride complex at -30C. The authors isolated the aminomethylation product dimethylaminomethylenepyrrol-2-one 16, from which it was then possible to obtain either the transamination products 17 or the formyl derivatives 18 and 19 [57, 58].
NMe2 DMF Ph N Me 15 O H Ph N Me 18 Cl Ph N Me 19 O POCl3 Ph N Me 16 POCl3 NaOH O H OH O Ph N Me 17 O N R1 R1
Under the influence of the Vilsmeier complex the N-unsubstituted 3,4-dimethylpyrrol-2-one 20 gives a good yield of the immonium salt 20a, the alkaline hydrolysis of which gives 2-formyl-5-chloropyrrole 21 [59-61].
Me O Me H N H 20 H DMF POCl3 Cl Me Me _ Cl N Me NaOH Cl N H 21 CHO Me
Me + N
Me
20a
A condensation of the Vilsmeier type in the N-unsubstituted pyrrol-2-ones 22 by the action of phosphorus oxychloride and pyrrole leads to a good yield of the bispyrrole 23 [62]. 1246
R N H
+
22
R N H O
POCl3
R N H 23 N H
N-Substituted pyrrol-2-ones dimerize with N-R-pyrrolid-2-ones during the action of protic and aprotic acids with yields of up to 79% [63]. The reaction of 4-ethoxycarbonyl-3H-pyrrol-2-one with pyrrole in acetic acid also leads to the bispyrroles [64]. Michael condensation takes place with higher speed the more readily the enolic form is transformed into the ketone form [65]. Pyrrol-2-ones are present entirely in the lactam form, and this determines their ability to participate in the Michael condensation [66]. 5-Aryl(alkyl)-3H-pyrrol-2-ones 24 are capable of acting as methylene component (addend) in the Michael reaction with electron-deficient unsaturated ketones under the conditions of base catalysis [65-75]. The reaction with benzylideneacetophenone and also with chalcones having an electron-withdrawing substituent leads to good yields of the condensation products, which exist in the stable 1,5-dioxo form 25.
R2 R2 EtONa O Ph EtOH R1 N R 25 O O Ph
R1
N R 24
R = H, Ph; R1 = Bu, C5H11, Ph; R2 = Ph, C6H4NMe2-4, C6H4OMe-4
Under the conditions of alkaline catalysis the 5-alkoxypyrrolone 26, acting as electron acceptor, gives Michael condensation products 27 with methyl acetoacetate [1].
O O O i-Pr O 26 N Me O Me Et3N DMF O MeO O O i-Pr O 27 N Me O Me
MeO
3,4-Dimethyl-5H-pyrrol-2-ones 28 react with aromatic nitro compounds in an watermethanol solution of alkali. If the reaction is carried out in ethanol/2N sodium ethoxide, it is possible to increase the yield of the final product to 55% [76].
Me ArNO2 Me MeOH / H2O N R 28 R = H, Me; Ar = Ph, C6H4CHO-p, C6H4Me-p O NaOH 0.8 N N Ar N R 29 O Me Me
1247
The condensation of 3,4-disubstituted 5H-pyrrol-2-ones 30 with the immonium salt I leads to the formation of the enamines 31 with a yield of 35% [77].
R
R
R
R
R
N
+
O
+ N _ Cl
I
R
Me
N H 30
Me
N H
31
Me
R = Me, Ph
In the series of 1,5-disubstituted pyrrol-2-ones azo coupling with arenediazonium salts takes place in alcohol solution under mild conditions at +1 to -5C.
N 24 N Ar
_ [PhN2] + Cl
N Ph 32
...
R = Am, Ph
In the investigated compounds 24, of the two reaction centers capable of reacting with the diazo component the reaction takes place at position 3 with the formation of 5-aryl-3-(4-nitrophenyldiazo)-3H-pyrrol2-ones 32 as red crystals [54].
2. Reactions Taking Place at the Ethylene Bond of the Heterocycle Data on research into the reactivity of the ethylene bond in the investigated heterocycles are represented by few papers in the literature. Most of the information concerns reduction reactions using various types of reducing agents. The pentaphenyl-substituted pyrrol-2-one 33 undergoes oxidation by chromic anhydride in acidic and basic media [78]. It was established that the C=C bond of the heterocycle is cleaved during oxidation, and in an acidic medium the decomposition products are diphenylacetophenone 34 and benzoylanilide 35. In an alkaline medium N-phenylacetamide 36 and benzoic acid are formed in addition to the above-mentioned compounds.
Ph Ph Ph N Ph 33 Ph O Ph _ OH Ph O Ph Cr2O3 Ph O O Ph O Ph O N Ph H + Ph O Ph 34 Ph
Ph O
N Ph H 35
Ph
Ph Ph O 36
N Ph H
Ph O
N Ph H
PhCOOH
1248
During bromination of the polysubstituted 5H-pyrrol-2-ones 37 with bromine in chloroform in a molar ratio of 1:1 substitution takes place at the allylic position, and the C=C bond is not affected. Amino-substituted pyrrol-2-ones react with the formation of the monobromo-substituted compounds 38 with yields up to 60% [79].
Ph NHR Br2 PhH2C N R 37 R = m-C6H4NO2 O CHCl3 Br PhH2C N R 38 O Ph NHR
Brief contact between 3,3,5-tribenzyl-3H-pyrrol-2-one 39 and a solution of bromine in chloroform leads to the isolation of dibromo-substituted derivatives 40 and 41 with the halogen at various positions [80]. The authors proposed a reaction mechanism that explains the preferential attack of the halogen at the exocyclic C=C bond.
CH2Ph CH2Ph PhH2C N Me 39 CH2Ph CH2Ph Ph Br N Me CH2Ph CH2Ph Ph Br N Me 40 O O Ph Br N Me CH2Ph CH2Ph N Me 41 O O PhHC N Me CH2Ph CH2Ph O Br2 CHCl3
CH2Ph CH2Ph O Br2
Br
Br
+
Ph
Br
The bromination of 5-substituted 1-phenyl-3H-pyrrol-2-ones [54] using various brominating agents a solution of bromine in chloroform and also dioxane dibromide under mild conditions at 18-20C in a equimolar ratio gave 5-alkyl(aryl)-4-bromo-1-(4-bromophenyl)-3H-pyrrol-2-ones with yields of up to 65%.
Br R N O
Br2 HBr
42 R = Bu, Am
Br 43
1249
The reduction of the ethylene bond was studied for 1,5-disubstituted 5H-pyrrol-2-ones 44 under conditions of catalytic hydrogenation with palladium on charcoal as catalysis [81].
H2 / PdC O O 44 N Bz O O O 45 N Bz O
N-Aryl-4-ethoxycarbonyl-3H-pyrrol-2-one is reduced to pyrrolidone in the presence of nickel [82]. 5-Pyridyl-substituted 5H-pyrrol-2-one 46 readily reduces the olefinic fragment of the hetero ring during hydrogenation in the presence of Pd/C [83].
MeO N N 46 Me O H2 / PdC N MeO N Me 47 O
The oxidation of 1,5-disubstituted 5H-pyrrol-2-one with potassium permanganate solution under the conditions of phase-transfer catalysis with crown-18 as catalyst [81] leads to a mixture of isomeric 3,4-dihydro derivatives.
HO 44 KMnO4 CH2Cl2 / 18-crown-6 O O N Bz 70% O OH HO OH
+
:
48 30%
O O
N Bz
Dichlorocarbene reacts readily with 5-alkyl(aryl)-3H-pyrrol-2-ones 24 in the two-phase water chloroform system in the presence of TEBA even at 20C [84, 85]. The reaction products are 6-alkyl(aryl)-5oxo-1-phenylhydropyridin-2-ones 49, the structure of which was established on the basis of the data from 1H and 13 C NMR spectroscopy. The authors propose a mechanism for the formation of the reaction products. Of the several reaction centers in the molecule of compound 24 the C=C bonds of the heterocycle are capable of reacting with dichlorocarbene by a [1+2] cycloaddition mechanism with subsequent cyclopropylallylic rearrangement, accompanied by enlargement of the five-membered ring.
CHCl3 / NaOH TEBA O R N Ph R = Bu, Am, Ph 49 O
24
The bisalkylation of the chiral nonracemic (-lactam) N-substituted 5H-pyrrol-2-one at the -position to the carbonyl group results in the formation of a new chiral center in the molecule of the pyrrol-2-one 50 [86-90].
1250
R N Ph O OH RX cat. Ph R1X N O OH cat. Ph 50 R = Et, Pr; R1 = PhCH2 N
R1 R O OH
Thermolysis of 4-azidopyrrol-2-ones 51 in benzene leads to ring contraction and to the production of the E-isomers of the -lactams. The yield of the reaction products 52 amounts to between 55 and 90% depending on the substituent in the initial compounds [91, 92].
N3 R N R1 51 Cl 90 oC O C6H6 R N C O N + R1 Cl _ Cl O NC R N 52 R1
R1 = Me, Et, i-Pr; R = OMe, OEt, OCH2Ph
4-Carbamoylmethyl-3H-pyrrol-2-one is produced by the reaction of maleimide with 3-aminocrotonate. When boiled in alcohol solution the 4-carbamoyl-3H-pyrrol-2-ones 53 undergo cyclization to pyrrolo[2,3-b]pyrroles 54 [93].
R Me H O N H O R NH2 H2N Me R = CO2Et, CN O H2N O R O N H 54 R = CO2H, CONH2 N R Me O N H O N H
N H 53
Me
The effect of stereochemical factors on the addition of certain 3H-pyrrol-2-ones to diphenylketene was studied. In the opinion of the authors, the reaction takes place through the formation of the intermediate A, and its direction of cyclization is determined by the energy of the immonium ion, by steric factors, and by the reaction conditions. Thus, in reaction with diphenylketene 3,3,5-triphenyl-3H-pyrrol-2-one gives the cyclization product 55 (through the C atom), while N-methyl-3,3,5-triphenyl-3H-pyrrol-2-one gives the cyclization product 56 (through the oxygen atom) [94].
1251
Ph Ph Ph Ph N R O Ph Ph C O _ Ph O Ph Ph
Ph Ph Ph N R + O
30 min Ph
60C Ph H Ph Ph O N Ph H Ph 55 R = H, Me Ph Ph
5 days Ph Ph H O O
room temp.
Ph Ph O N
O O Ph
Ph
Me
56
In an acidic medium and in protic solvents pyrrol-2-one is capable of acting as electrophile with respect to activated aromatic and heteroaromatic substrates, and arylation and hetarylation take place at position 5 of the pyrrole ring. Among the obtained compounds 57 there are substances having effective anticonvulsive activity [95, 96].
ArH
+
N H
H O
+ Ar N H O
57 5090%
Ar = C6H4OH, C6H3(OH)2, 2-furyl, 2-NR-pyrrolyl, 4-MeEtNC6H4, 2-hydroxynaphthyl
The 1,3-dipolar cycloaddition of diaryl nitrones was investigated for 1-aryl-substituted pyrrol-2-ones and takes place at the double bond of the heterocycle.
Ph N O PhN=CH N O R N O O R
NO2 R = H, 3-NO2, 4-Br, 4-Me, 4-OMe, 4-NMe2
NO2
58
1252
The stereospecificity of the process is due to the exo approach of the reagent with cis-stereospecific addition of the trans form of the N-diaryl nitrones to the double bond of the heterocycle with the formation of the cyclic adduct 58 [97-100].
3. Reactions with Participation of the Functional Groups The authors [101, 102] obtained the substituted pyrrole 59, which is the product of a skeletal rearrangement taking place during reduction. The formation of a partially saturated structure was not observed here.
Ph
Ph Ph N R O
Ph LiAlH4 Ph N R
Ph
Ph Ph H OH
H+
Ph
Ph
Ph
N R 59
Ph
Ph
Ph Ph H N
H R R = Me, H, Ph, C6H4NMe2, C6H4Me, C6H4OMe
Ph
Reduction of 4-alkoxypyrrol-2-ones 60 with diisobutylaluminum hydride also takes place at the C=O bond without affecting the heterocycle. The mechanism of the reaction was investigated, the intermediates were isolated, and the method made it possible to obtain preparative yields of the 3-alkoxypyrroles 61 [103].
R1O i-Bu2AlH N R 60 i-Bu2AlH R1O N O
R1O N R 61
OAl(Bu-i)2
R R = H, Me, CH2Ph; R1 = Et
Acylation of N-unsubstituted and N-alkyl-substituted pyrrol-2-ones with acetic anhydride leads to the formation of the monoacyl 63 and diacyl 62 derivatives [104].
1253
EtOOC Ac2O, H R N H O 30 min
EtOOC + R N H 62 Ac2O, H+ 5 min EtOOC R
COMe
OCOMe
N H 63
OCOMe
R = Me, Et, Pr
It was noticed that the structure of the final reaction products depended on the length of contact between the reagents and the sulfuric acid used as catalyst. Heating for 5 min led to the O-acylation products 63, and further increase in the contact time between the reagents led to the products from both O- and C-alkylation 62 [104]. Enzymatic alkylation was studied for the case of 5-hydroxypyrrol-2-ones using acetic and propionic anhydrides. Lipase was used as catalyst [105].
(RCO)2O HO N H O lipase PS R O R = Me, Et O N H 64 O
Use of the enzyme makes it possible to conduct the reaction at room temperature and, accordingly, to avoid resin formation from the initial compounds and the reaction products, which is unavoidable with other catalysts. It was also shown that the direction of acylation depends on the temperature regime and on the substituents. Thus, the O-acylation products 65 were isolated in the reaction of N-unsubstituted 3,4,5-triphenyland 3,3,4,5-tetraphenylpyrrol-2-ones with a strong acylating agent (acetyl chloride) at room temperature [106].
Ph O Ph Me C Cl Ph N H O room temp. Ph N H 65 O COMe Ph Ph
Increase in temperature to 160C leads to the formation of the products from N-acylation 66.
Ph Ph Ph Ph N H O 160 oC O Me C Cl Ph N Ph Ph Ph O
COMe 66
1254
The reaction of 3-acyl-5-benzyl-4-hydroxy-5H-pyrrol-2-one with acetic anhydride and tosyl chloride in pyridine leads to tetrasubstituted pyrroles [107]. The diazotization of compound 67, which has a secondary amino group, with sodium nitrite in acetic acid leads to the nitroso derivative 68 with a yield of 64% [79].
Ph PhH2C NHR1 NaNO2, AcOH N R1 67 R1 = C6H4NO2-3 O 0 oC PhH2C N R1 68 O Ph N R1 NO
The diazotization of 3-aminopyrrol-2-ones in DMF gives diazopyrrolones 69, which exist in the form of salts 70 in a strongly acidic medium [108].
NH2 O NH2 NaNO2 / HCl N R O DMF N R 69 R = CH2Ph, Bu O O NH2 N2 HCl Ph N R 70 O_ Cl O + NH2 N2
The obtained diazo-substituted pyrrol-2-ones react with triphenylphosphine and with prolonged contact give quantitative yields of phosphazines [108]. Pyrrol-2-ones 71 substituted at the nitrogen atom with a polyfunctional chain underwent degradation during the action of a Grignard reagent and hydrazine, giving NH-pyrrol-2-ones with a yield of 35% [109].
MeO Me N O 71
O OH Cl Me Cl Cl Me Cl
MeMgBr 0 oC
MeO Cl Cl Me N H 72 O
OH
O OMe
Me Cl Cl Me
H2NNH2 25 oC
MeO
Cl Cl
OH
O NHNH2
+
Me N H O
Me Cl Cl Me
1255
Compounds with condensed pyrrole rings were synthesized in the search for compounds with antibiotic activity. The reaction of 4-amino-3-benzylidene-1-benzoylpyrrol-2-one with ethyl -chloroacetoacetate in alcohol in the presence of triethylamine led to the formation of the amide 73, which underwent cyclization in a boiling alcohol solution of sodium ethoxide to form a derivative of pyrrolo[3,2-b]pyrrole 74 [33].
H2N N COPh H N O PhHC COMe O N COPh 73 Cl EtONa EtOH O N COPh 74 COMe H N CHPh O COMe
Cl H
O OEt
Et3N
PhHC
The photochemical rearrangement of 5-dimethyl- and 5-methylphenylaminopyrrol-2-ones 75 has been described. It leads to cyclopropyl isocyanates, which after treatment with dimethylamine give the corresponding cyclopropylureas 76 with yields of 80-90% [110].
O Me R N h N H 75 O NCO N R 76 R = Me, Ph Me Me2NH NHCNMe2 N R Me
When heated in concentrated hydrochloric acid 1,5-disubstituted 4-ethoxalylacetyltetrahydro-5H-pyrrol2-ones 77 undergo cyclization to 6-methyl-5-phenyl- and 5,6-diaryl-4,7-dioxo-2-carboxy-5,7dihydropyrrolo[2,3-b]pyrans 78, which are esterified by treatment with ethanol to the corresponding ethyl esters 79 [111].
HO COCH2COCOOEt conc. HCl, t O N R1 77 R2 EtOH R1 N O O 79 COOEt O R2 O R1 R2 N O 78 COOH O
In reaction with pyridine in the presence of benzoyl chloride 3,4-dimethyl-5H-pyrrol-2-ones form 3,4-dimethyl-2,5-dipyridylpyrroline 81 with a yield of 35% [112]. 1256
Me
Me pyridine N R 80 R = H, Me O PhCOCl N
Me
Me N
N R 81
A dimerization mechanism, taking place during acid catalysis and leading to compounds 82, was proposed in the series of methyl-substituted pyrrol-2-ones [18].
Ph Ph Me N Me O +H + Me + N Me Ph Ph O H+ H2C N Me Ph Ph O
Ph Ph Me + N Me O
Ph
Ph Ph O + N Me CH2 Me N Me
Ph Ph O
Ph H2C N Me O
Ph Ph O N Me 82 CH2 Me N Me
Ph Ph O
The authors [113] found a new type of Wittig reaction for the production of derivatives of pyrromethenone. Condensation of 4-methyl-5-tosyl-3-(2-tosyl)-5H-pyrrol-2-one with 5-tert-butoxycarbonyl-4(2-methoxycarbonylethyl)-3-methylpyrrole in the presence of a catalyst gave compound 83, which is a potential equivalent to the C/D-ring component of phytochromobilin, with a yield of 73%.
Me Ts NH HN O 83 COOBu-t COOMe
The pyrromethene structures based on pyrrol-2-ones were studied in a series of papers [50, 114-119]. Pyrrol-2-ones are also intermediates or final compounds in the synthesis of biologically active materials [1, 5, 6, 120-131]. Thus, in the series of pyrrol-2-ones there are various condensations that take place at the methylene unit. Classical oxidation and reduction with various types of reducing agents are observed.
1257
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1261
PHENYL-SUBSTITUTED PORPHYRINS. 1. SYNTHESIS OF meso-PHENYLSUBSTITUTED PORPHYRINS

S. A. Syrbu, T. V. Lyubimova, and A. S. Semeikin A method was developed for the synthesis of a series of meso-phenyl-substituted octaalkylporphyrins with various numbers of phenyl groups at various positions. Some of their properties were studied. Keywords: octaalkylporphyrins, phenyl-substituted porphyrins. At present their readily available synthetic analogs meso-(5,10,15,20)-tetraphenylporphyrins, produced by the condensation of pyrrole with benzaldehydes, are mainly used to study the properties of porphyrins. In certain cases, however, they are not very suitable since unlike natural porphyrins they do not have alkyl or pseudoalkyl substituents at the -positions of the porphyrin ring whereas all the meso positions, on the other hand, are substituted. The octaalkylporphyrins that are closer to the natural materials are also not always convenient since they do not have substituents that can be used to "tie" the active groups for immobilization. Of great interest, therefore, are compounds that combine the advantages of these two types of porphyrins such as, for example, meso-substituted octaalkylporphyrins. Fairly effective methods have now been developed for the synthesis of some such porphyrins by the condensation of -unsubstituted pyrroles and their linear derivatives with benzaldehydes in the presence of acidic catalysts [1] (Scheme 1). By these methods we synthesized a series of monophenyl-substituted octaalkylporphyrins 2 and also symmetrical 5,15-diphenyl- and 5,10,15,20-tetraphenyloctaalkylporphyrins 4 and 6 (Tables 1 and 2). Since meso-(5,10,15,20)-tetraphenyloctaalkylporphyrins have a distorted saddle-like structure and their physicochemical characteristics differ substantially from those of the usual flat porphyrins [2], it was of great interest to study the effect of the number of peripheral substituents on the properties of the porphyrins. However, there have not until now been any suitable methods for the synthesis of the least symmetrical 5,15-diphenyl- and 5,10,15-triphenyloctaalkylporphyrins (4 and 5). In all such methods difficultly obtainable starting compounds are used, and a mixture of porphyrins requiring separation is formed during the synthesis [3]. Starting from all the facts discussed above we developed a method for the synthesis of a series of mesophenyl-substituted octaalkylporphyrins with various numbers of meso-phenyl groups at various positions on the basis of the acid-catalyzed condensation of a mixture of 3,4-dialkylpyrroles and 3,4-dialkyl-2hydroxymethylpyrroles with benzaldehydes followed by oxidation of the obtained mixture of porphyrinogens with p-chloroanil (Scheme 2). The obtained mixture of porphyrins can be separated fairly easily and completely by successive column chromatography on aluminum oxide and silica gel. We carried out three series of __________________________________________________________________________________________ Ivanovo State University of Chemistry and Technology, Ivanovo, Russia; e-mail: s_serg@isuct.ivanovo.su. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1464-1472, October, 2004. Original article submitted December 29, 2001. 1262 0009-3122/04/4010-12622004 Springer Science+Business Media, Inc.
Scheme 1
R R + H NH _ N Br + NH H N R R R NH N HN R R 2 R R N H NH R R R R Ar R R R Ar R R [O] R NH N R R R Ar 4 R R R R Ar R R [O] Ar NH HN R R Ar R R R R Ar 6 R Ar N HN R R NH N R Ar R R Ar R N HN R R Ar R R R H+ N R R Ar R R
+
R
ArCHO
R R R
+ ArCHO
H+
NH
HN
NH HN
+
N H
ArCHO
NH Ar
HN
reactions with various substituted pyrroles and benzaldehydes (Series 1: 1A, R = Me, Ar = H; 2A-6A, R = Me, Ar = Ph. Series 2: 1B, R = Me, Ar = H; 2B-6B, R = Me, Ar = 3,5-t-Bu2C6H3. Series 3: 1C, R = Et, Ar = H; 2C-6C, R = Et, Ar = Ph). During the synthesis we were unable to separate the mixture of octamethylporphyrin 1A and 5,15-diphenyloctamethylporphyrin 3A on account of their low solubility in the majority of organic solvents. It proved possible to separate these isomers as a result of the increased solubility of the trans isomer 3 with the introduction of tert-butyl groups into the benzene rings. For the separation of the porphyrins their mixture was first chromatographed on a short column with aluminum oxide (to separate the products from reduction of the p-chloroanil). Then, by repeated chromatography on aluminum oxide the mixture was separated into a "readily mobile fraction" containing monophenyl-, trans-diphenyl-, and octaalkylporphyrins (2, 3, and 1 respectively) and a "poorly mobile fraction" containing cis-diphenyl-, triphenyl-, and tetraphenyloctaalkylporphyrins (4, 5, and 6 respectively). The readily mobile fraction was separated into the individual porphyrins by further chromatography on silica gel, while the poorly mobile fraction was separated on aluminum oxide. The insoluble octamethylporphyrin 1A, obtained in the first series of reactions, was purified by dissolving in a mixture of chloroform and 0.5% trifluoroacetic acid followed by precipitation of the porphyrin with the addition of
1263
Scheme 2
R R R R HBr ArCHO MeOH p-Chloroanil THF
+
N H R R NH N R R 1 R N HN N H Ar
+
CH2OH
Mixture of porphyrinogens
R R R
R R Ar N HN R
NH
+
R
Ar R R 3 R
R R NH
Ar
R R Ar
N HN
+
N R R Ar 5 R
triethylamine until the color of the solution changed. The yield and some properties of the synthesized porphyrins are given in Tables 1 and 2. Since some of the porphyrins have "blurred" ESR, the spectra of their protonated forms were recorded. Although the yield of the individual porphyrins in this synthesis is lower than in their production according to Scheme 1 (Table 1), the proposed method makes it possible to obtain the previously unobtainable cis-diphenyl- and triphenyloctaalkylporphyrins 4 and 5, especially as their yield can be increased by using different proportions of the 3,4-dialkylpyrrole, 3,4-dialkyl-2-hydroxymethylpyrrole, and the respective benzaldehyde (in our case 1:1:1). The reason for the different ratios of the yields of the porphyrins in all three series of reactions using the various substrates, when the statistical mixture of compounds 1, 2, 3, 4, 5, and 6 in ratios of 1:4:2:4:4:1 should be obtained in all cases [4], is not clear. Optimization of the structure of the synthesized porphyrins by molecular mechanics (HyperChem software, MM+ force field) showed that the distortion of the porphyrin ring increases with increase in the number of substituting groups (compounds 1 < 2 < 3 < 4 < 5 < 6). Comparison of the physical characteristics of the obtained porphyrins also shows that with increase in the number of groups substituting the periphery of the porphyrin macrocycle the changes increase in the same order and are particularly marked in the transition from the trans-diphenyloctaalkylporphyrins 3 to their cis isomers 4 and then to the triphenyl- and tetraphenyloctaalkylporphyrins 5 and 6. This shows up in a marked decrease of the mobility of the porphyrins on the sorbents, in the nonadditive bathochromic shift of all the bands in the electronic absorption spectra with change in the actual form of the spectra (Table 1), and in the downfield shift of the signals for the NH protons and the upfield shift of the signals for the meso protons and the signals for the -alkyl substituents in the 1 H NMR spectra, due probably to decrease in the ring current of the macrocycle (Table 2). 1264
TABLE 1. The Characteristics of meso-Phenyl-substituted Octaalkylporphyrins

Porphyrin 1 1A Empirical formula 2 C28H30N4 Found, % Calculated, % 4 7.1 6.9 Rf * N 5 13.3 13.1 6 I 7 620 (3.65) 590 (3.90) 620 (3.74) 624 (3.45) sh 624 (3.23) 624 (3.54) 627 (3.23) 619 (3.87) 626 (3.38) 627 (3.30) sh II 8 568 (3.68) sh 568 (3.86) 571 (3.81) 559 (4.22) 571 (3.56) 573 (3.90) 575 (3.82) 572 (4.12) 574 (3.89) 575 (3.87) 586 (3.79) UV spectrum, max, nm (log ) III 9 535 (3.96) 548 (4.23) 535 (4.04) 537 (3.85) sh 537 (3.61) 538 (3.97) 542 (3.70) sh 539 (3.78) 542 (3.76) sh IV 10 500 (4.60) 499 (4.15) 504 (4.16) 504 (3.86) 505 (4.24) 508 (4.19) 508 (4.25) 508 (4.25) 515 (4.17) Soret 11 400 (5.61) 401 (5.60) 400 (5.25) 404 (5.26) 418 (5.53) 405 (4.92) 405 (5.31) 409 (5.29) 430 (5.46) 409 (5.36) 410 (5.35) 417 (5.25) Solvent 12 (Cl2CH)2 CHCl31% CF3CO2H CHCl3 CHCl3 CHCl31% CF3CO2H CHCl3 CHCl3 CHCl3 CHCl31% CF3CO2H CHCl3 CHCl3 CHCl3 Yield, %*2 13 34.8 (62.0)
3 79.6 79.9
1C 2A
C36H86N4 C34H34N4
75.2 75.3 81.9 82.3
15.0 15.2 6.9 6.7
9.8 9.5 11.2 11.0
0.83 (A), 0.57 (B) 0.65 (A)
4.0 (70.0) 4.0 (56.0)
2B 2C 3A
C38H42N4 C42H90N4 C40H38N4
82.3 82.7 77.5 75.8 83.6 83.5
7.6 7.4 13.9 14.0 6.7 6.6
10.1 9.9 8.6 8.2 9.7 9.9
0.58 (A) 0.87 (A), 0.47 (B) 0.75 (A)
5.5 (38.2) 43.7 (62.0) 9.2*3 (64.0)
3B 3C 4A
C44H46N4 C48H94N4 C40H38N4
83.8 84.2 79.3 79.8 83.6 84.0
7.3 7.1 13.0 12.7 6.7 6.5
8.9 8.7 13.0 12.8 9.7 9.5
0.88 (A) 0.93 (A), 0.59 (B) 0.18 (A)
8.5 (46.1) 7.9 (46.0) 4.9
1265
1266
TABLE 1 (continued)
1 4B 4C 5A 2 C44H46N4 C48H94N4 C46H42N4 3 83.8 83.3 79.3 78.8 84.9 84.5 4 7.3 7.5 13.0 13.3 6.5 6.6 5 8.9 9.2 7.7 7.9 8.6 8.9 6 0.17 (A), 0.37 (C) 0.18 (A), 0.92 (D) 0.34 (C) 7 sh sh 666 (3.32) sh 668 (3.67) 667 (3.79) 694 (3.96) 687 (4.40) 692 (3.72) 700 (4.56) 696 (3.75) 691 (4.53) 8 582 (3.82) 578 (3.89) 600 (3.74) 653 (4.24) 597 (3.81) 608 (3.91) 602 (3.91) sh 595 (3.95) sh 598 (3.82) sh 9 sh sh sh 598 (3.99) sh sh sh sh sh sh sh 10 512 (4.20) 510 (4.25) 528 (4.13) 526 (4.16) 534 (4.14) 553 (3.97) 549 (4.06) 551 (4.14) 11 414 (5.29) 413 (5.39) 430 (5.24) 451 (5.40) 429 (5.28) 438 (5.28) 454 (5.21) 466 (5.32) 450 (5.28) 473 (5.40) 452 (5.34) 471 (5.50) 12 CHCl3 CHCl3 CHCl3 CHCl31% CF3CO2H CHCl3 CHCl3 CHCl30.5% NEt3 CHCl31% CF3CO2H CHCl30.5% NEt3 CHCl31% CF3CO2H CHCl30.5% NEt3 CHCl31% CF3CO2H 13 3.5 12.4 13.5
5B 5C 6A
C50H50N4 C54H98N4 C52H46N4
84.9 85.4 80.7 81.1 85.9 85.6
7.2 7.0 12.3 12.1 6.4 6.5
7.9 7.6 7.0 6.8 7.7 7.9
0.19 (C), 0.87 (E) 0.15 (A), 0.86 (D) 0.16 (C)
36.0 10.8 5.2 (65.0)
6B
C56H54N4
85.9 86.5
7.0 6.8
7.1 6.7
0.35 (E)
7.5 (44.0)
6C
C60H102N4
81.9 81.5
11.7 11.9
6.4 6.6
0.30 (D)
6.7 (31.2)
_______ * Eluent (solvent): benzene (A), benzenehexane, 1:1 (B), benzenemethanol, 10:1 (C), benzenemethanol, 1:1 (D), benzenemethanol, 10:2 (E). *2 The yield of the porphyrins synthesized according to Scheme 1 is given in parentheses. *3 Mixture with octamethylporphyrin 1A.
TABLE 2. The 1H NMR Spectra of meso-Phenyl-substituted Octaalkylporphyrins

Chemical shifts, , ppm Porphyrin meso-H 10.74, s 10.10, s 10.13, s; 9.92, s 10.50, s; 10.37, s 10.13, s; 9.91, s 10.18, s; 9.93, s 10.34, s 10.22, s 10.23, s 9.79, s 9.99, s Ar o-H 8.02, m 8.26, m 7.89, s 8.21, d 8.26, m 7.91, s 8.21, d 8.13, m 8.36, m; 8.28, m 7.94, s 8.30, d m-, p-H 7.75, m R NH -4.45, s -3.75, s -3.20, s; -3.30, s -2.99, s; -4.21, s -3.25, s -3.02, s; -3.15, s -3.07, s -2.45, s -2.08, s 1.46, s; -3.02, s -1.31, s; -2.23, s; -3.84, s 1.25, s; -3.14, s -2.72, br. s Solvent CDCl3CF3CO2H CDCl3 CDCl3 CDCl3CF3CO2H CDCl3 CDCl3 CDCl3CF3CO2H CDCl3 CDCl3 CDCl3 CDCl3CF3CO2H
1A 1C 2A
2B 2C 3A 3B 3C 4A
3.68, s 4.11, q; 1.92, t 3.58, s; 3.52, s; 2.46, s 8.01, m 3.58, s; 3.32, s; 2.27, s 7.80, s; 3.61, s; 3.58, s; 1.49, s (Bu) 3.52, s; 2.42 s 7.79, d; 4.12, m; 1.89, m; 7.66, t 2.78, m; 1.18, m 7.95, m 3.26, s; 2.27, s 7.80, s; 3.54, s; 1.50, s (Bu) 2.46, s 7.78, d; 4.09, q;9, 7.67, t t;2.79, q; 1.18, t 7.76, m 3.49, s; 3.29, s; 2.08, s 7.97, m 3.17, s; 2.22, s; 1.81, s 3.54, s; 3.40, s; 2.26, s; 2.10, s 3.92, q; 1.80, t; 3.80, q; 1.57, t; 2.65, q; 0.63, t; 2.25, q; 0.44, t 7.72, m 3.25, s; 2.25, s; 1.95, s; 1.86, s 7.96, m 3.13, s; 2.24, s; 1.84, s; 1.81, s 7.74, s; 3.30, s; 2.26, s; 1.51, s (Bu) 1.97, s; 1.87, s 7.71, m 3.75, q; 1.56, t; 2.70, q; 0.72, t; 2.25, m; 0.46, t; 0.37, t 7.87, m 1.77, s 7.93, m 1.84, s 7.70, s; 1.82, br. s 1.49, s (Bu) 7.90, s; 1.79, s 1.49, s (Bu) 7.71, m 2.52, br. s; 0.47, br. s 7.88, m 2.42, q; 2.16, q; 0.17, t 7.77, s; 1.49, s (Bu) 7.75, d; 7.67, t
4B 4C
9.84, s 9.63, s
CDCl3 CDCl3
5A
9.56, s 9.79, s
8.22, m 8.36, m; 8.23, m 7.99, s 8.32, m
5B 5C
9.64, s 9.45, s
1.41, s; -2.35, s -1.26, s; -2.47, s -2.45, s -2.09, s
CDCl3 CDCl3CF3CO2H CDCl3 CDCl3
6A 6B
8.41, m 8.35, m 8.13, s 8.22, s 8.36, m 8.46, m
0.80, s -1.14, s 0.84, s -0.40, s -0.19, s
CDCl3 CDCl3CF3CO2H CDCl3 CDCl3CF3CO2H CDCl3 CDCl3CF3CO2H
6C
The broadening and destructuring of the signals for the alkyl substituents and the NH protons in the H NMR spectra of the tetraphenyloctaalkylporphyrins 6B and 6C is apparently due to the existence of several conformations, which change from one to the other at a rate close to the "proton relaxation" time. Protonation of the porphyrins excludes the possible existence of conformations on account of repulsion of the positive charges.
1
1267
This leads to restoration of the fine structure in the 1H NMR spectra of these porphyrins and to splitting of the components of the signal for the CH2 protons of the ethyl groups in the porphyrin 6C into two due to their nonequivalence. Interesting is the splitting of the signals for the meta and para protons of the phenyl rings in the ethyl derivatives of phenyl-substituted porphyrins, which is not observed in the tetraphenylporphyrins not substituted at the position. There is also a strong downfield shift of the signals for the protons of the CH3 fragments of the ethyl groups adjacent to the phenyl rings for the -ethyl-substituted porphyrins, arising on account of the strong screening action of the ring current of the phenyl rings. Thus, change in the number of peripheral substituents in the porphyrin ring (distortion of the macrocycle) can provide a tool for smooth adjustment of the physicochemical characteristics of porphyrins without significant change in the internal structure of the macrocycle. At the present time the most interesting of the synthesized porphyrins are being studied by X-ray crystallographic analysis, and the kinetics of complexation and protonation in solutions are being investigated.
EXPERIMENTAL The electronic absorption spectra were recorded on a Lambda 20 instrument. The 1H NMR spectra were recorded on a Bruker AC-200 instrument at 200 MHz with HMDS as internal standard ( 0.05 ppm). The individuality and purity of the compounds were established by TLC (Silufol). 3,4-Dialkyl-2-hydroxypyrroles. The compounds were synthesized by the reduction of 3,4-dialkyl-2formylpyrroles with sodium borohydride by analogy with data in [5]. The latter were obtained by the formylation of 3,4-dimethylpyrrole [6] or 3,4-diethylpyrrole [7] by the Vilsmeier method [8]. The -unsubstituted tetraalkylpyrrolylmethanes and octaalkylbiladienes-a,c were obtained from the corresponding 3,4-dialkyl-5-ethoxycarbonyl-2-methylpyrroles by methods similar to those described in [9]. Synthesis and Separation of the Mixture of meso-Phenyloctaalkylporphyrins. To a solution of 3,4-dialkyl-2-hydroxymethylpyrrole (13.6 mmol), 3,4-dialkylpyrrole (13.6 mmol), and benzaldehyde (13.6 mmol) in methanol (35 ml) in an inert atmosphere we added concentrated hydrobromic acid (1 ml). The mixture was stirred at room temperature for 4 h. The white precipitate of the porphyrinogens was filtered off, washed with methanol, and dissolved in THF (40 ml). To the obtained solution we added a solution of p-chloroanil (5 g, 20 mmol) in THF (50 ml), and we stirred the mixture for 5 h at ~20C. The solvent was distilled under vacuum, and the residue was washed with 10% sodium hydroxide solution and with water and dried at room temperature to constant weight. The precipitate was dissolved in chloroform (200 ml) (when necessary the insoluble precipitate was filtered off) and chromatographed on a column (3 15 cm) with aluminum oxide of III activity, eluting the mixture of porphyrins with chloroform. The eluate was evaporated and rechromatographed on a column (2.5 50 cm) with aluminum oxide of III activity with chloroform as eluant. The mixture was separated into two fractions a readily mobile fraction and a poorly mobile fraction. The readily mobile fraction was chromatographed on a column (2.5 60 cm) of silica gel (L 100/250) with benzene as eluant. For separation into the individual porphyrins the poorly mobile fraction was chromatographed on a column (2.5 60 cm) of aluminum oxide of III activity with chloroform as eluant. After evaporation of the eluates the porphyrins were finally precipitated with methanol (50 ml), filtered, and dried to constant weight at room temperature. The residue insoluble in chloroform was dissolved in a mixture of chloroform and 0.5% trifluoroacetic (50 ml) acid with subsequent precipitation of the porphyrin by the addition of triethylamine until the color of the solution had changed. The porphyrin was filtered off, washed with chloroform (50 ml), and dried to constant weight at ~20C. Series 1. From a mixture of 2-hydroxymethyl-3,4-dimethylpyrrole, 3,4-dimethylpyrrole, and benzaldehyde we obtained: A mixture of octamethylporphyrin 1A and 5,15-diphenyloctamethylporphyrin 3A, yield 360 mg; 5-phenyloctamethylporphyrin 2A, yield 90 mg; 5,10-diphenyloctamethylporphyrin 4A, yield 200 mg; 5,10,15-triphenyloctamethylporphyrin 5A, yield 400 mg; 75,10,15,20-tetraphenyloctamethylporphyrin 6A, yield 130 mg. 1268
Series 2. From a mixture of 2-hydroxymethyl-3,4-dimethylpyrrole, 3,4-dimethylpyrrole, and 3,5-di-tertbutylbenzaldehyde we obtained: Octamethylporphyrin 1B, yield 500 mg; 5-(3,5-di-tertbutylphenyl)octamethylporphyrin 2B, yield 150 mg; 5,15-di(3,5-di-tert-butylphenyl)octamethylporphyrin 3B, yield 460 mg; 5,10-di(3,5-di-tert-butylphenyl)octamethylporphyrin 4B, yield 200 mg; 5,10,15-tri(3,5-di-tertbutylphenyl)octamethylporphyrin 5B, yield 1600 mg; 5,10,15,20-tetra(3,5-di-tert-butylphenyl)octamethylporphyrin 6B, yield 1600 mg. Series 3. From a mixture of 3,4-diethyl-2-hydroxymethylpyrrole, 3,4-diethylpyrrole, and benzaldehyde we obtained: Octaethylporphyrin 1C, yield 90 mg; 5-phenyloctaethylporphyrin 2C, yield 1200 mg; 5,15-diphenyloctaethylporphyrin 3C, yield 370 mg; 5,10-diphenyloctaethylporphyrin 4C, yield 580 mg; 5,10,15-triphenyloctaethylporphyrin 5C, yield 370 mg; 5,10,15,20-tetraphenyloctaethylporphyrin 6C, yield 190 mg. Octaethylporphyrins (1). To a solution of 3,4-dialkyl-2-hydroxymethylpyrrole (8.0 mmol) in methanol (10 ml) in an inert atmosphere we added concentrated hydrobromic acid (0.3 ml). The mixture was stirred at ~20C for 2 h. The white precipitate of the porphyrinogen was filtered off, washed with methanol, and dissolved in THF (15 ml). To the obtained solution we added a solution of p-chloroanil (1.2 g, 5 mmol) in THF (50 ml), and we stirred the mixture for 5 h at ~20C. The solvent was distilled under vacuum, and the residue was washed with a 10% solution of sodium hydroxide and with water and dried to constant weight at room temperature. The octamethylporphyrin 1A (1B) was purified by reprecipitation from a mixture of chloroform and trifluoroacetic acid. Yield 520 mg. The octaethylporphyrin 1C was isolated by column chromatography (2.5 60 cm) with aluminum oxide of III activity and with chloroform as eluant. Yield 750 mg. 5-Phenyloctaalkylporphyrins (2). A solution of octaalkylbiladiene-a,c (1.0 mmol), the respective benzaldehyde (10 mmol), and concentrated hydrobromic acid (1 ml) in ethanol (50 ml) was boiled for 4 h, iodine (0.26 g, 1 mmol) was then added, and the mixture was boiled for a further 15 min. The mixture was cooled and neutralized with a concentrated solution of ammonia (2 ml). The precipitate was filtered off, washed with ethanol, and dried. The porphyrins were dissolved in chloroform (100 ml) and chromatographed on a column (2.6 60 cm) of aluminum oxide of III activity with chloroform as eluent. The eluate was evaporated, the porphyrin was precipitated with methanol (30 ml), and after filtration it was dried to constant weight at ~20C. 5-Phenyloctamethylporphyrin 2A, yield 280 mg; 5-(3,5-di-tert-butylphenyl)octamethylporphyrin 2B, yield 230 mg; 5-phenyloctaethylporphyrin 2C, yield 380 mg. 5,15-Diphenyloctaalkylporphyrins (3). To a solution of the respective benzaldehyde (2.5 mmol) and ptoluenesulfonic acid (0.13 g, 6.0 mmol) in methanol (30 ml) in an inert atmosphere we added a solution of tetraalkyldipyrrolylmethane (2.5 mmol) in methanol (20 ml). The mixture was stirred at ~20C for 3 h and kept overnight with cooling. The precipitated porphyrinogen was then filtered off, washed with methanol, and dissolved in THF (100 ml). To the obtained solution we added a solution of p-chloroanil (0.9 g, 3.75 mmol) in THF (50 ml), and we stirred the mixture at ~20C for 4 h. The solvent was distilled under vacuum, and the residue was washed with a 10% solution of sodium hydroxide and with water and dried at ~20C to constant weight. 5,15-Diphenyloctamethylporphyrin 3A was purified by reprecipitation from a mixture of chloroform and trifluoroacetic acid. Yield 450 mg. 5,15-Di(3,5-tert-butylphenyl)octamethylporphyrin 3B and 5,15-diphenyloctaethylporphyrin 3C were purified by column chromatography (2.5 60 cm) of aluminum oxide with III activity with chloroform as eluent. Yield 460 mg and 400 mg respectively. 5,10,15,20-Tetraphenyloctaalkylporphyrins (6). To a solution of 3,4-dialkylpyrrole (9.0 mmol) and benzaldehyde (9.0 mmol) in methanol (50 ml) in an inert atmosphere we added concentrated hydrobromic acid (2 ml). The mixture was stirred at ~20C for 4 h, and the white precipitate of the porphyrinogen was filtered off, washed with methanol, and dissolved in THF (40 ml). To the obtained solution we added a solution of p-chloroanil (1.9 g, 7.7 mmol) in THF (30 ml), and we stirred the mixture at ~20C for 5 h. The solvent was distilled under vacuum, and the residue was washed with a 10% solution of sodium hydroxide and with water and dried to constant weight at ~20C. The precipitate was dissolved in chloroform (100 ml) and chromatographed twice on a column (2.5 60 cm) of aluminum oxide of III activity with chloroform as eluent. 1269
The eluate was evaporated, and the porphyrin was precipitated with methanol (30 ml), filtered off, and dried to constant weight at ~20C. 5,10,15,20-Tetraphenyloctamethylporphyrin 6A, yield 1.1 g. 5,10,15,20-Tetra(3,5-ditert-butylphenyl)octamethylporphyrin 6B, yield 1.2 g. 5,10,15,20-Tetraphenyloctaethylporphyrin 6C, yield 0.6 g.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. O. Golubchikov (editor), Advances in the Chemistry of Porphyrins [in Russian], NII Khimii SPBGU, St. Petersburg (1997), Vol. 1, p. 52. C. J. Medforth, M. D. Berber, and K. M. Smith, Tetrahedron Lett., 31, 3719 (1990). Y. Aoyama, K. Saita, H. Toi, H. Ogoshi, and Y, Okamoto, Tetrahedron Lett., 28, 4853 (1987). F. A. Walker, J. A. Barry, V. L. Balke, G. A. McDermott, M. Z. Wu, and P. F. Linde, Electrochem. and Spectrochem. Studies of Biological Redox Components (1981), p. 377. G. P. Gurinovich, A. N. Sevchenko, and K. N. Solov'ev, Spectroscopy of Chlorophyll and Related Compounds, Nauka i Tekhnika, Minsk (1968), p. 52. K. Ichimura, S. Ichikawa, and K. Imamura, Bull. Chem. Soc. Jpn., 4, 1157 (1976). H. W. Whitlock and R. J. Hanauer, J. Org. Chem., 33, 2169 (1968). A. W. Johnson and I. T. Kay, J. Chem. Soc., 1620 (1965). N. S. Dudkina, E. M. Kuvshinova, and A. S. Semeikin, Zh. Obshch. Khim., 68, 2042 (1998).
1270
DERIVATIVES OF INDOLE. 143.* SYNTHESIS OF PHOTOCHROMIC DERIVATIVES OF 2-ARYLINDOLES

E. O. Gogrichiani1, E. A. Katsadze1, N. G. Gavtadze1, Sh. A. Samsoniya1, and H. Drr2 New derivatives of 2-arylindoles containing (4-pyridyl)alkyl substituents at various positions of the pyrrole ring were synthesized. They react with 2,3-dimethoxycarbonylspirofluorenylcyclopropene with the formation of light-sensitive systems belonging to the photochromic dihydroindolizine class. Keywords: 2-arylindoles, dihydroindolizines, pyridylindoles, photochromism. Photochromic dihydroindolizines form a rich and varied class of light-sensitive compounds [2, 3]. Among the multitude of photochromic materials they are distinguished by high their efficiency, their cheapness, and their accessibility. This forms the basis of their prospective use in optical lenses, the recording and storage of data [4], and dental materials [5]. In the present work we describe the synthesis and photochromic characteristics of novel 2-arylindole systems containing a dihydroindolizine ring. It seemed to us important to couple the qualities of 2-arylindoles, which form the fundamental unit in many biologically active systems [6, 7], and those of photochromic molecules. Model systems of such a type are promising for use as marker molecules in the study of biological processes. A standard and effective method for the production of photochromic dihydroindolizines is the addition of electron-excessive N-heterocyclic bases to spirocyclopropene. Such bases for us were the 1- and 3-(4-pyridyl)alkyl-substituted 2-arylindoles 4a-d and 5a-c that we had synthesized. Indolepyridine is the main structural element of many natural products [8], among which there are antitumor [9] and antidiabetic [10] agents. On this basis compounds 4a-d and 5a-c are of interest in themselves as possible biologically active substances. The initial bases 4a-d and 5a-c were produced by alkylation of the respective 2-arylindoles, obtained by the Fischer method [11] (Scheme 1). The 1-(4-pyridylmethyl)-2-arylindoles 4a-d were obtained by N-alkylation of 2-arylindoles (1) with 4-(chloromethyl)pyridine in the 50% aqueous potassium hydroxidebenzene two-phase system in the presence of tetrabutylammonium bromide. It is known that 4-vinylpyridine in an acidic medium alkylates the indole ring at position 3 [12]. In our case too by boiling 2-arylindoles 1a-c with 4-vinylpyridine 3 we obtained the corresponding 3-[2-(4-pyridyl)ethyl] derivatives 5a-c. _______ * For Communication 142, see [1]. __________________________________________________________________________________________ Iv. Javakhishvili Tbilisi State University, Tbilisi, Georgia; e-mail: shsam@wanex.net. 2 Universitt des Saarlandes, Saarbrcken, Germany; e-mail: ch12hd@rz.uni-sb.de. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1473-1482, October, 2004. Original article submitted November 20, 2003. 0009-3122/04/4010-12712004 Springer Science+Business Media, Inc. 1271
1
Scheme 1
CH2Cl . HCl HC CH2
N 2 N H R
N 3 N H 5ac R
N 4ad
1ad 1, 4, 5 a R = H, b R = Ph, c R = Br; 1, 4 d R = NO2
The bases 4a-d and 5a-c react with 2',3'-dimethoxycarbonylspirofluorenylcyclopropene 6 in the dark at room temperature with the formation of the light-sensitive compounds 9a-d and 10a-c (Scheme 2). Scheme 2
N CH2
R C 4ad 5ac MeO2C CO2Me CO2Me MeO2C +N CO2Me _
+ N MeO2C _ C
N H 7ad hv 8ac hv
CO2Me CO2Me N CH2 R N
N CO2Me CO2Me 9ad N H 10ac
7-10 a R = H, b R = Ph, c R = Br; 7, 9 d R = NO2
1272
During exposure to UV light the light-yellow solutions of compounds 9a-d and 10a-c become darkgreen as a result of opening of the dihydroindolizine ring and transformation into the betaine forms 7a-d and 8a-c. In the dark the color of the solutions is restored as a result of 1,5-electrocyclization of the betaines with the formation of the initial dihydroindolizines 9a-d and 10a-c. Fig. 1 shows as an example the electronic absorption spectra of compound 8b before (a) and after (b) exposure. In spectrum (a) strong absorption bands appear at 248 and 307 nm with a comparatively weak band at 383 nm. After exposure the peak at 383 nm, assigned to the dihydroindolizine fragment, disappears, and two new absorption bands appear in the visible region at 450 and 600 nm, which correspond to the colored open form.
Absorption
, nm
Fig. 1. The electronic absorption spectra of compound 8b before (a) and after (b) exposure.
Absorption,
, nm
Fig. 2. The spectrum for the thermal decolorization of compound 10b with the formation of the betaine 8b in methylene chloride solution. Time interval 15 sec. 1273
Fig. 2 shows the electronic absorption spectra of the exposed solutions of compound 8b recorded in the dark for 5 min at intervals of 15 sec. The decrease in the intensity of the absorption bands in the visible region and their final disappearance and also the increase in the intensity of the peak at 383 nm clearly indicate electrocyclization of the betaine form. The half-conversion times t1/2 of the betaines (Table 4), which vary in the range of 0.5-1 min, were determined on the basis of the kinetic data. The physicochemical and spectral characteristics of compounds 4a-d, 5a-c, 9a-d, and 10a-c are given in Tables 1-4.
TABLE 1. The 1H NMR Spectra of Compounds 4a-d, 5a-c, 9a-d, and 10a-c
Compound 1 4 Chemical shifts, , ppm (J, Hz) 2 5.50 (2H, s, CH2); 6.69 (1H, s, H-3); 6.85 (2H, d, J = 5.3, -H); 7.08-7.10 (2H, m, H-5, H-6); 7.34 (1H, d, Jo = 8.0, H-7); 7.39-7.49 (5H, m, Ar-H); 7.62 (1H, dd, Jm = 1.3, Jo = 7.1, H-4); 8.41 (2H, dd, J = 1.3, J = 5.7, -H) 5.56 (2H, s, CH2); 6.76 (1H, s, H-3); 6.89 (2H, d, J = 5.7, -H); 7.12 (2H, q, Jm = 1.8, Jo =7.5, H-5, H-6); 7.34 (1H, d, Jo= 8.0, H-7); 7.38 (1H, t, Jo = 7.5, H-1"); 7.48 (2H, t, Jo = 8.0, H-2", H-6"); 7.57 (2H, d, Jo= 8.0, H-3", H-5''); 7.64 (1H, dd, Jm = 1.8, Jo = 6.6, H-4); 7.71 (2H, d, Jo= 7.1, H-2', H-6'); 7.76 (2H, d, Jo= 8.4, H-3', H-5'); 8.43 (2H, dd, J = 1.3, J = 5.8, -H) 5.50 (2H, s, CH2); 6.73 (1H, s, H-3); 6.84 (2H, dd, J = 1.7, J = 5.72, -H); 7.09-7.17 (2H, m, H-5, H-6); 7.36 (1H, d, Jo= 8.4, H-7); 7.43 (2H, d, Jo = 9.3, A-H); 7.65 (3H, d, Jo = 8.4, B-H, H-4); 8.42 (2H, dd, J = 1.8, J = 6.2, -H) 5.59 (2H, s, CH2); 6.85 (2H, d, J = 5.7, -H); 6.93 (1H, s, H-3); 7.14 (1H, t, Jo = 7.5, H-5); 7.21 (1H, t, Jo = 7.5, H-6); 7.43 (1H, d, Jo = 8.0, H-7); 7.69 (1H, d, Jo = 7.5, H-4); 7.78 (2H, d, Jo = 8.4, B-H); 8.27 (2H, d, Jo = 8.8, B-H ); 8.41 (2H, d, J = 5.7, -H) 2.94 (2H, m, J = 10.6, J = 8.8, 1'-CH2); 3.14 (2H, m, J = 10.2, J = 8.8, 2'-CH2); 7.02 (1H, t, Jo = 8.0, H-5); 7.11 (1H, t, Jo = 7.1, H-6); 7.21 (2H, d, J = 5.8, -H); 7.37 (2H, t, Jo=7.5, H-7, Ar-H); 7.49 (2H, t, Jo = 7.8, Ar-H); 7.55 (2H, d, Jo=7.8, Ar-H); 7.61 (1H, d, Jo = 8.0, H-4); 8.40 (2H, d, J = 5.7, -H); 11.15 (1H, s, NH) 2.98 (2H, t, J = 5.8, 1'-CH2); 3.18 (2H, t, J = 5.8, 2'-CH2); 7.03 (1H, t, Jo = 7.0, H-5'); 7.12 (1H, t, Jo = 7.1, H-6); 7.26 (2H, dd, J = 1.8, J = 6.2, -H); 7.39 (2H, t, Jo = 7.5, H-7, H-1''); 7.50 (2H, t, Jo = 8.0, H-2'', H-6''); 7.62 (1H, d, Jo = 7.5, H-4); 7.67 (2H, d, Jo = 8.4, H-3'', H-5''); 7.76 (2H, dd, Jm = 1.3, Jo = 7.1, H-2', H-6'); 7.82 (2H, d, J = 8.4, H-3', H-5'); 8.42 (2H, dd, J = 1.8, J = 6.2, -H); 11.23 (1H, br. s, NH) 2.92 (2H, m, J = 8.8, 1'-CH2); 3.12 (2H, m, J = 8.4, 2'-CH2); 7.02 (1H, t, Jo = 7.5, H-5); 7.13 (1H, t, Jo= 8.0, H-6); 7.21 (2H, d, J = 5.8, -H ); 7.37 (1H, d, Jo = 8.4, H-7); 7.50 (2H, d, J = 8.4, A-H) 7.62 (1H, d, Jo = 8.0, H-4); 7.69 (2H, m, J = 8.6, B-H); 8.40 (2H, d, J = 5.8, -H); 11.21 (1H, s, NH) 3.18 (3H, s, 2'-COOCH3); 3.91 (3H, s, 3'-COOCH3); 3.98 (1H, s, H-8'a); 4.50 (2H, br. s, CH2); 4.91 (1H, dd, J8'6' = 1.4, J8'8'a = 7.5, H-8'); 5.45 (1H, br. s, H-6'); 6.43 (1H, br. s, H-5'); 6.67 (1H, d, Jo = 7.5, Ar-H); 6.91 (1H, d, Jo = 7.5, Ar-H); 7.00-7.04 (2H, td, Jo = 7.0, Jm = 1.3, Ar-H); 7.24-7.45 (11H, m, Ar-H); 7.58 (1H, d, Jo = 7.5, Ar-H); 7.75 (2H, t, Jo = 7.5, Ar-H) 3.19 (3H, s, 2'-COOCH3); 3.92 (3H, s, 3'-COOCH3); 4.04 (1H, s, H-8'); 4.56 (2H, br. s, CH2); 4.96 (1H, d, J6'5' = 5.8, H-6'); 5.49 (1H, s, H-8'); 6.50 (1H, s, H-3); 6.71 (1H, d, J5'6' = 5.8, H-5'); 6.94 (1H, d, Jo = 6.6, Ar-H); 7.00-7.06 (2H, m, Ar-H); 7.24 (1H, t, Jo = 5.8, Ar-H); 7.30-7.43 (7H, m, Ar-H); 7.47 (1H, d, Jo = 6.6, Ar-H); 7.52 (2H, t, Jo = 6.2, Ar-H) 7.58 (1H, d, Jo = 5.8, Ar-H); 7.72-7.77 (6H, m, Ar-H) 3.18 (3H, s, 2'-COOCH3); 3.92 (3H, s, 3'-COOCH3); 3.97 (1H, s, H-8'a); 4.50 (2H, br. s, CH2); 4.80 (1H, d, J8'8'a = 7.5, H-8'); 5.45 (1H, br. s, H-6'); 6.47 (1H, br. s, H-5'); 6.92-7.06 (3H, m, Ar-H); 7.18 (2H, d, Jo = 7.5, A-H); 7.25-7.41 (6H, m, Ar-H); 7.47 (1H, d, Ar-H); 7.57 (1H, d, Ar-H); 7.61 (2H, d, Jo = 8.4, B-H); 7.77 (2H, t, Ar-H)
4b
4c
4d
5a
5b
5c
9a
9b
9c
1274
TABLE 1 (continued)
1 9d 2 3.18 (3H, s, 2'-COOCH3); 3.91 (3H, s, 3'-COOCH3); 3.93 (1H, s, H-8'a); 4.58 (1H, d, Jgem = 17.2, CH2); 4.63 (1H, d, Jgem = 17.7, CH2); 4.88 (1H, dd, J8'6' = 1.3, J8'8'a = 7.5, H-8'); 5.40 (1H, d, J6' 8' = 1.3, H-6'); 6.68 (2H, t, J5'6' = 7.5, H-5', H-3); 7.02-7.19 (3H, m, Ar-H); 7.23-7.38 (5H, m, Ar-H); 7.51-7.56 (4H, m, Ar-H); 7.72-7.75 (2H, m, Jo = 7.5, Jm = 1.3, Ar-H); 8.32 (2H, dd, Jo = 7.7, Ar-H) 2.10 (2H, m, 2'-CH2); 2.65 (1H, m, 1'-CH2); 2.79 (1H, m, 1'-CH2); 3.20 (3H, s, 2'-COOCH3); 3.95 (3H, s, 3'-COOCH3); 4.01 (1H, s, H-8'); 5.26 (1H, dd, J6'8' = 1.3, J6'5' = 7.5, H-6'); 5.38 (1H, s, H-8'a); 6.67 (1H, d, J5'6' = 7 .5, H-5'); 6.95 (1H, t, Jo = 8.0, H-5); 7.07 (1H, t, J = 8.0, H-6); 7.28-7.44 (4H, m, Ar-H); 7.52-7.59 (5H, m, Ar-H); 7.69-7.75 (4H, m, Jo = 8.4, Ar-H); 7.82 (2H, d, Jo = 7.5, Ar-H); 11.12 (1H, s, NH) 2.09 (2H, m, 2'-CH2); 2.63 (1H, m, 1'-CH2) 2.72 (1H, m, 1'- CH2); 3.20 (3H, s, 2'-COOCH3); 3.98 (3H, s, 3'-COOCH3); 4.01 (1H, s, H-8'); 5.15 (1H, d, J6'5' = 7.0, H-6'); 5.36 (1H, s, H-8'a); 6.66 (1H, d, J5'6' = 6.6, H-5'); 6.91 (1H, t, Jo = 7.5, H-5); 7.06 (1H, t, Jo = 7.0, H-6); 7.10-7.61 (17H, m, Ar-H); 7.84 (2H, d, Jo = 7.1, Ar-H); 11.05 (1H, s, NH) 2.08 (2H, m, 2'-CH2); 2.56 (1H, m, 1'-CH2); 2.72 (1H, m, 1'-CH2); 3.21 (3H, s, 2'-COOCH3); 3.96 (3H, s, 3'-COOCH3); 4.01 (1H, s, H-8'); 5.23 (1H, d, J6'5' = 7.5, H-6'); 5.36 (1H, s, H-8'a); 6.66 (1H, d, J5'6' = 7.5, H-5'); 6.94 (1H, t, J = 8.0, H-5); 7.07 (1H, t, J = 8.0, H-6); 7.20 (2H, m, Ar-H); 7.29-7.37 (7H, m, Ar-H); 7.57-7.61 (3H, m, J = 8.8, Ar-H); 7.84 (2H, d, J = 7.6, Ar-H); 11.10 (1H, br. s, NH)
10a
10b
10c
TABLE 2. The Data from Elemental Analysis of Compounds 4a-d, 5a-c, 9a-d, and 10a-c
Compound 4 4b 4c 4d 5 5b 5c 9 9b 9c 9d 10 10b 10c Empirical formula C C20H16N2 C26H20N2 C20H15Br N2 C20H15N3O2 C21H18N2 C27H22N2 C21H17BrN2 C39H30N2O4 C45H34N2O4 C39H29BrN2O4 C39H29N3O6 C40H32N2O4 C46H36N2O4 C40H36BrN2O4 84.28 84.51 86.46 86.67 66.40 66.11 72.86 72.95 84.00 84.56 86.82 86.63 66.75 66.84 79.52 79.32 80.00 81.08 69.17 70.95 73.75 73.70 79.80 79.47 81.00 81.18 70.20 70.28 H 5.85 5.63 5.39 5.55 4.41 4.13 4.56 4.60 5.73 6.04 5.28 6.88 4.38 4.51 5.40 5.08 5.08 5.10 4.60 4.33 4.31 4.57 5.00 5.30 5.20 5.29 4.52 4.54 Found, % Calculated, % N 9.85 9.86 8.00 7.77 7.55 7.71 12.90 12.76 9.80 9.39 8.00 7.48 7.49 7.43 4.48 4.74 4.00 4.20 3.91 4.18 6.50 6.61 4.60 4.63 4.08 4.12 4.05 4.10 Br
21.02 22.04
21.08 21.22
11.52 11.96
11.69 11.71
1275
TABLE 3. The Physicochemical and Spectral Characteristics of Compounds 4a-d, 5a-c, 9a-d, and 10a-c
Compound 4a 4b 4c 4d 5 5b 5c 9 9b mp, 114-115 165-167 142-142.5 183-184 191-192 214-216 225-227 104-105 124-126 Rf * 0.28 0.45 0.36 0.30 0.27 0.59 0.36 0.30 0.44 IR spectrum, , cm-1 1530 (C=N arom.), 1530 (C=C) 1580 (C=N arom.), 1610 (C=C) 1590 (C=C), 1595 (C=N arom.) 1375 (NO2), 1410 (C=C), 1590 (C=N arom.) 1580 (C=N arom.), 3270 (NH) 1590 (C=N arom.), 1465 (C=C), 3120 (NH) 1590 (C=N arom.), 1630 (C=C), 3310 (NH) 1600 (C=C), 1695, 1735 (CO ester) 1560 (C=N arom.), 1690, 1740 (CO ester) 1590 (C=C), 1680, 1740 (CO ester) 1510 (NO2), 1590 (C=N arom.), 1690, 1740 (CO ester) 1695, 1735 (CO ester), 3310 (NH) 1685, 1740 (CO ester), 3250 (NH) 1590 (C=N arom.), 1695, 1740 (CO ester), 3460 (NH) UV spectrum, max, nm (log ) 248 (4.27), 294 (4.36) 240 (4.34), 303 (4.19) 235 (4.35), 300 (4.20) 259 (4.38) 232 (4.35), 240 (4.34), 305 (4.10) 229 (4.32), 257 4.25), 317 (4.27) 230 (5.59), 244 (5.41), 307 (4.31) 384 (4.44) 231 (2.88), 260 (3.50), 262 ( 3.52), 310 (2.36), 388 (0.87) 247 (3.65), 303 (2.66), 388 (4.13) 428 (4.40) Yield, % 53 56 50 48 63 39 37 44 42
9c 9d
162-163 135-136
0.37 0.26
45 53
10
120-121
0.23
10b 10c
125-127 190-190.5
0.59 0.36
235 (4.43), 265 sh. (4.37), 305 (4.30), 362 (4.09) 234 (4.43), 259 (4.49), 319 (4.38) 248 (4.51), 307 (2.57), 383 (4.06)
32
48 35
_______ * Solvent systems: 1:1 benzeneether for compounds 4a-d, benzene for 5a-c, 1:5 hexaneether for 9a-d, 1:1 hexaneether for 10a-c. TABLE 4. The Kinetic Data for the Thermal Reverse Reaction the Transformation of the Betaines into Cyclic Structures 7a-d 9a-d and 8a-c 10a-c
Compound 7-c, 8-c, max, nm 603 612 605 609 587 590 588 9-d, 10-c, max*, nm 384 388 388 428 362 319 383 k, 1/s (7-c 9-d) (8-c 10-c) 1.26102 0.80102 2.17102 1.58102 1.27102 1.37102 1.03102 t1/2, s (7-c 9-d) (8-c 10-c) 55 52 32 44 50 54 67
7/9 7b/9b 7c/9c 7d/9d 8a/10a 8b/10b 8c/10c
_______ * = 24, = 10-4 moll-1 in CH2Cl2. 1276
EXPERIMENTAL The IR spectra were recorded on a UR-20 instrument in vaseline oil, and the electronic absorption spectra were recorded on an FT-UV/VIS HP 8453 spectrophotometer in methylene chloride. The 1H NMR spectra were recorded on a Bruker AM-400 instrument at 400 MHz in DMSO-d6 with TMS as internal standard. Elemental analysis was performed on an LECO CHNS-932 analyzer. The melting points were determined on Buchi spm-20 apparatus. The reaction and the purity of the compounds were monitored and the Rf values were determined on Silufol-254 plates. Silica gel 100/250 was used as sorbent for column chromatography. 2-Phenyl-1-(4-pyridylmethyl)indoles 4a-d (General Procedure). To the two-phase system consisting of 50% aqueous potassium hydroxide (10 ml) and benzene we added 4-(chloromethyl)pyridine hydrochloride (2) (3.5 mmol). The mixture was stirred vigorously at 0C for 15 min, and tetrabutylammonium bromide (0.15 mmol) and a solution of the respective 2-phenylindole 1 (3 mmol) were added. The mixture was boiled for 4 h, cooled, and extracted with benzene. The extract was washed with water and dried with anhydrous calcium chloride. The product was chromatographed on a column of silica gel with the following eluents: 7:1 chloroformether (4a), 4:1 carbon tetrachlorideether (4b,c), and 5:1 benzeneether (4d). The products were recrystallized from benzene, and compound 4a from hexane. Colorless crystals were obtained, and compound 4d was isolated in the form of yellow needles. 2-Aryl-3-[2-(4-pyridyl)ethyl]indoles 5a-c (General Procedure). To a solution of 2-phenylindole 1a (5 mmol) in acetic acid (15 ml) we added a solution of 4-vinylpyridine 3 (10 mmol) in acetic acid (10 ml), and we boiled the mixture for 2 h. After cooling the reaction mixture was poured in a stream into iced water and neutralized with an aqueous solution of potassium hydroxide to pH 7. The precipitate was filtered off and recrystallized from isopropyl alcohol. Colorless crystals were obtained. Dihydroindolizines 9a-d and 10a-c (General Procedure). To a solution of 2',3'-dimethoxycarbonylspirofluorenylcyclopropene (6) (0.5 mmol) in absolute ether (40 ml) we added the compound 4a-d or 5a-c (0.5 mmol). The mixture was stirred in the dark at room temperature for 24 h. The solvent was evaporated, and the residue was chromatographed on a column in the following systems: 20:1 benzeneether for 9a,b, 1:2 benzenehexane for 9c, benzene for 9d, 3:2 hexaneether for 10a, 5:3 hexaneether for 10b, and 2:1 hexane ether for 10c. Yellow crystals were obtained. 2',3'-Dimethoxycarbonyl-7'-(2-phenyl-1-indolylmethyl)spiro[fluorene[9,1']-1',8'a-dihydroindolizine] (9a). Yield 0.13 g. 2',3'-Dimethoxycarbonyl-7'-[2-(4'-biphenylyl)-1-indolylmethyl]spiro[fluorene[9,1']-1',8'a-dihydroindolizine] (9b). Yield 0.17 g. 2',3'-Dimethoxycarbonyl-7'-[2-(p-bromophenyl)-1-indolylmethyl]spiro[fluorene[9,1']-1',8'a-dihydroindolizine] (9c). Yield 0.14 g. 2',3'-Dimethoxycarbonyl-7'-[2-p-nitrophenyl)-1-indolylmethyl]spiro[fluorene[9,1']-1',8'a-dihydroindolizine] (9d). Yield 0.136 g. 2',3'-Dimethoxycarbonyl-7'-[2-(p-nitrophenyl)-1-indolylmethyl]spiro[fluorene[9,1']-1',8'a-dihydroindolizine] (10a). Yield 0.098 g. 2',3'-Dimethoxycarbonyl-7'-{2-[2-(4'-biphenylyl)-3-indolyl]ethyl}spiro[fluorene[9,1']-1',8'a-dihydroindolizine (10b). Yield 0.20 g. 2',3'-Dimethoxycarbonyl-7'-[2-(2-p-bromophenyl-3-indolyl)ethyl]spiro[fluorene-[9,1']-1',8'a-dihydroindolizine] (10c). Yield 0.069 g. We express our gratitude to the German Research Society "Deutsche Forschungsgemeinschaft" (DFG) (project No. 436 GEO 113/3/0 R/S) for financial support.
1277
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. I. Sh. Chikvaidze, Sh. A. Samsoniya, and T. G. Narindoshvili, Khim. Geterotsikl. Soedin., 524 (2004). H. Drr, in: H. Drr and H. Bous-Laurent (editors), Studies in Organic Chemistry. 40: Photochromism: Molecules and Systems, Elsevier, Amsterdam (1999), p. 223. C. B. McArdle, in: Applied Photochromic Polymer Systems, Blackie and Son Ltd., Glasgow (1992), p. 225. W. Willner and S. Rubin, Angew. Chem. Int. Ed. Engl., 35, 367 (1996). H. Drr, Praxis Naturwiss. Chem., 4/40, 22 (1991). V. N. Pathak, R. Guptra, M. Gard, and V. M. Rao, Ind. J. Heterocycl. Chem., 11, 107 (2001). L. Chu, I.-L. Lo, Y.-T. Jang, K. Chend, R. G. Smith, M. H. Fisher, M. J. Wyvratt, and M. T. Goulet, Bioorg. Med. Chem. Lett., 11, 515 (2001). A. Akkerman and H. Veldstra, Rec. Trav. Chim., 73, 629 (1954). A. Gray and W. Archer, J. Am. Chem. Soc., 79, 3554 (1957). L. Schrader, Chem. Ber., 104, 941 (1971). A. Gray, W. Archer, E. Spinner, and G. Gavallito, J. Am. Chem. Soc., 79, 3805 (1957). A. P. Grey and W. L. Archer, J. Am. Chem. Soc., 79, 3554 (1957).
1278
POLYFUNCTIONAL PYRAZOLES. 3.* SYNTHESIS OF 3-(3-ARYL-4-FORMYL1-PYRAZOLYL)PROPIONIC ACIDS AND THEIR AMIDES

M. K. Bratenko1, V. A. Chornous1, and M. V. Vovk2 3-(3-Aryl-4-formyl-1-pyrazolyl)propionic acids were synthesized by the reaction of 3-aryl-1-(2cyanoethyl)-4-formylpyrazoles with concentrated hydrochloric acid. They were converted into the corresponding amides by the carbodiimide method. Keywords: amides, dicyclohexylcarbodiimide, 3-(4-formyl-1-pyrazolyl)propionic acids, 1-(2-cyanoethyl)4-formylpyrazoles, hydrolysis. Earlier [2] we described the synthesis of 3-aryl-1-(2-cyanoethyl)-4-formylpyrazoles and the corresponding thiosemicarbazides. On the basis of the last reactions with monochloroacetic acid and maleic anhydride unsymmetrical azines with 3-aryl-1-(2-cyanoethyl)-4-methylidenepyrazole and 2-thiazolidinylen-4one fragments having antimicrobial activity were obtained [3]. The present communication presents the results from selective modification of the 2-cyanoethyl substituent in the 4-formylpyrazoles 1a-e to a 2-carboxyethyl substituent. We showed that during the action of boiling concentrated hydrochloric acid the nitrile group of compounds 1a-e is readily hydrolyzed and forms 3-(3-aryl-4-formyl-1-pyrazolyl)propionic acids 2a-e with yields of 78-93%. It is remarkable that cleavage of the CN bond of neither the -cyanoethyl nor the -carboxyethyl substituent with the nitrogen atom of the pyrazole ring was observed under the reaction conditions [4].
CHO Ar N N CN 1ae 2ae
H2O / HCl
CHO Ar N N
R1R2NH
CHO Ar N N O 3ae R 2 R 1N DCC COOH
1, 2 Ar = Ph, b Ar = 4-FC6H4, c Ar = 4-ClC6H4, d Ar = 4-BrC6H4, e Ar = 4-MeOC6H4; 3a,b,d-g R1 = H, c R1R2 = (CH2)2O(CH2)2; a Ar = Ph, R2 = 2-methyl-5-quinolinyl; b Ar = 4-FC6H4, R2 = 4-MeOC6H4; c Ar = 4-FC6H4,; d Ar = 4-ClC6H4, R2 = 5-quinolinyl; e Ar = 4-BrC6H4, R2 = 4-MeC6H4; f Ar = 4-BrC6H4, R2 = 3-pyridyl; g Ar = 4-MeOC6H4, R2 = Ph
_______ * For Communication 2, see [1]. __________________________________________________________________________________________

2
Bukovinian State Medical Academy, Chernovtsy, Ukraine; e-mail: chornous@chv.ukrpack.net. Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev, Ukraine; e-mail: hetfos@ukrpack.net. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1483-1486, October, 2004. Original article submitted May 15, 2001. 0009-3122/04/4010-12792004 Springer Science+Business Media, Inc. 1279
The acids 2a-e are colorless or light-yellow crystalline substances, the structure of which agrees with the results from elemental analysis and the IR and 1H NMR spectra (Tables 1 and 2). The IR spectra of the solid samples contain absorption bands of the C=O bonds of the formyl (1640-1660 cm-1) and carboxyl (1705-1720 cm-1) groups and also broad absorption bands of OH groups with a hydrogen bond (2900-3200 cm-1), and this confirms their dimeric nature [5]. In the 1H NMR spectra the carboxyl group has hardly any effect on the chemical shifts of the 5-CH= proton of the pyrazole ring and leads to slight upfield shifts of the signals for the aldehydic protons (by 0.09-0.22 ppm) and to more pronounced shifts of the signals for the protons of the CH2 groups (by 0.25-0.45 ppm). Published data [6, 7] make it possible to regard 3-heterylpropionic acids and their derivatives as subjects with potential biological activity. We attempted the synthesis of 3-(1-pyrazolyl)propionamides, the most suitable approach to which seemed to be through the respective acid chlorides. However, it was found that the reaction of acids of type 2 with thionyl chloride takes place ambiguously, and as a result it is not possible to isolate products with individual structures. For this reason direct acylation of the amines with the acids 2a-e in the presence of dicyclohexylcarbodiimide (DCC) was used. This made it possible to obtain the amides 3a-e with yields of 5183% (Tables 1 and 2).
EXPERIMENTAL The IR spectra were recorded on a UR-20 instrument in tablets with potassium bromide. The 1H NMR spectra were obtained on a Varian Gemini instrument (300 MHz) in DMSO-d6. 3-(3-Aryl-4-formyl-1-pyrazolyl)propionic Acids (2a-e). To 3-aryl-1-(2-cyanoethyl)-4-formylpyrazole 1a-e (50 mmol) we added concentrated hydrochloric acid (20 ml). The mixture was heated to boiling and left at room temperature for 12 h. We then added water (50 ml). The precipitate was filtered off, dried, and crystallized from a 1:5 mixture of acetic acid and water. TABLE 1. The Characteristics of the Synthesized Compounds 2a-e and 3a-g
Compound 2 2b 2c 2d 2e 3a 3b 3c 3d 3e 3f 3g Empirical formula C13H12N2O3 C13H11FN2O3 C13H11ClN2O3 C13H11BrN2O3 C14H14N2O4 C23H20N4O2 C20H18FN3O3 C17H18FN3O3 C22H17ClN4O2 C20H18BrN3O2 C18H15BrN4O2 C20H19N3O3 Found, % Calculated, % 4.78 4.92 4.08 4.20 4.20 3.95 3.24 3.41 4.85 5.11 5.28 5.20 4.71 4.90 5.83 5.48 4.07 4.20 4.19 4.36 3.41 3.75 5.30 5.44
mp, N 11.31 11.48 10.31 10.69 9.83 10.05 8.31 8.67 10.07 10.21 14.36 14.58 11.18 11.44 12.58 12.68 13.60 13.84 9.93 10.19 13.82 14.03 11.80 12.03 121-122 144-145 140-141 124-125 125-126 169-170 137-138 119-120 196-197 185-186 140-141 118-119
Yield, %
63.67 63.93 59.33 59.54 55.77 56.01 48.13 48.30 60.93 61.31 71.60 71.87 65.17 65.39 61.51 61.62 65.03 65.26 57.90 58.22 53.76 54.13 68.33 68.76
82 87 91 93 78 58 76 51 78 58 64 67
1280
TABLE 2. The Spectral Characteristics of Compounds 2a-e and 3a-g

IR spectrum, , cm-1 Compound C=O OH NH CH=O (1H, s) 9.86 9.84 9.85 9.85 9.82 3360 3320 9.88 9.84 9.86 9.85 5-CH= (1H, s) 8.47 8.51 8.52 8.52 8.44 8.53 8.55 8.56 8.57 NMR spectrum, , ppm (J, Hz) Ar, R2 -CH2 (2H, t, CH3 J = 7.5) arom. (3H, s)
1
-CH2 (2H, t, J = 7.5) 2.88 2.89 2.88 2.88 2.87 3.15 2.96 3.01 3.10
COOH (1H, br. s) 12.39 12.44 12.40 12.41 12.38
NH (1H, s)
2a 2b 2c 2d 2e 3a 3b 3c* 3d
1645, 1715 1650, 1710 1640, 1720 1655, 1715 1660, 1705 1645, 1660 1650, 1655 1650, 1665 1650, 1660
2950, 3200 2900, 3180 2900, 3150 2950, 3200 2900, 3130
3290
3e
1660, 1675
3350
9.84
8.52
3f
1680, 1700
3260
9.86
8.53
3g
1660, 1670
3250
9.83
8.46
7.40-7.44 (3H, m); 7.78-7.81 (2H, m) 7.19-7.23 (2H, m); 7.86-7.89 (2H, m) 7.44 (2H, d, J = 8.7); 7.87 (2H, d, J = 8.7) 7.61 (2H, d, J = 8.5); 7.79 (2H, d, J = 8.5) 7.77 (2H, d, J = 8.6); 6.95 (2H, d, J = 8.6) 8.18 (1H, d, J = 8.8); 7.23-7.82 (9H, m) 6.88 (2H, d, J = 8.6); 7.28-7.30 (2H, m); 7.44 (2H, d, J = 8.6); 7.85-7.88 (2H, m) 7.28-7.30 (2H, m); 7.88-7.91 (2H, m) 7.34 (1H, dd, Jo = 8.6, Jm = 2.9); 7.46 (2H, d, J = 8.7); 7.69-7.93 (5H, m); 8.28 (1H, d, J = 8.6); 8.84 (1H, d, J = 8.6) 7.05 (2H, d, J = 8.6); 7.43 (2H, d, J = 8.6); 7.57 (2H, d, J = 8.5); 7.82 (2H, d, J = 8.5) 7.25-7.27 (1Hpyr, m); 7.58 (2H, d, J = 8.5); 7.82 (2H, d, J = 8.5); 8.03 (1Hpyr, d, J = 8.6); 8.21 (1Hpyr, d, J = 8.6); 8.67 (1Hpyr, s) 6.96 (2H, d, J = 8.6); 7.24-7.27 (3H, m); 7.57-7.59 (2H, m); 7.75 (2H, d, J = 8.6)
4.42 4.42 4.42 4.42 3.84 2.64 3.71 4.40 4.60 4.51 4.54 4.59
10.07 9.91
10.12
2.32
4.51
2.95
9.88
4.55
3.04
10.23
3.81
4.51
2.99
10.01
_______ * The multiplet signals of the protons of the morpholine ring are at 3.29-3.44 (4H) and 3.52-3.57 ppm (4H).
1281
3-(3-Aryl-4-formyl-1-pyrazolyl)propionamides (3a-g). To a solution of the acid 2a-e (3 mmol) in THF (15 ml) we added the respective amine (3 mmol) and DCC (0.61 g, 3 mmol). The mixture was stirred at room temperature for 12 h and then at 50C for 1 h. After cooling the precipitated dicyclohexylurea was filtered off and washed with THF (2 10 ml). The filtrate was evaporated, diethyl ether (20 ml) was added to the residue, and the mixture was left for 6 h. The precipitate was filtered off, dried, and crystallized from ethanol.
REFERENCES 1. 2. 3. 4. 5. 6. 7. M. K. Bratenko, V. A. Chornous, and M. V. Vovk, Khim. Geterotsikl. Soedin., 515 (2001). M. K. Bratenko, V. A. Chornous, N. V. Voloshin, and M. V. Vovk, Khim. Geterotsikl. Soedin., 1219 (1999) M. K. Bratenko, V. A. Chornous, N. V. Voloshin, and M. V. Vovk, Physiologichno Aktivny Rechoviny, No. 2, 20 (1999). M. Michaelis and O. Schmidt, Berichte, 43, 2117 (1910). D. Barton and W. D. Ollis (Eds.), Comprehensive Organic Chemistry [Russian translation], Vol. 4, Khimiya (1983), p. 45. B. Unterhalt and N. Kissenbeck, Sci. Pharm., 2, 97 (1999). M. S. Amine, A. M. Eissa, A. F. Shaaban, A. El-Sany, and R. El-Sayed, Indian J. Chem., 11B, 1153 (1998).
1282
A NOVEL SPIROHETEROCYCLIZATION: SYNTHESIS OF 1-ETHOXYCARBONYLMETHYLIDENE8-(2'-ETHOXYCARBONYLMETHYLIDENE5',5'-DIMETHYL-3'-PYRROLIDINYLIDENE)3,3,6-TRIMETHYL-2-AZASPIRO[4,5]DECA-6,9-DIENE

Yu. V. Shklyaev1, Yu. V. Nifontov1, M. I. Kodess2, and M. A. Ezhikova2 It was shown that isobutyraldehyde and cyanoacetic ester enter into reaction with meta-xylene initially at the fourth carbon atom with the formation of a spiropyrroline ring and then at the newly formed exomethylene bond with closure of the 1-ethoxycarbonylmethylidene-8-(2'-ethoxycarbonylmethylidene5',5'-dimethyl-3'-pyrrolidinylidene)-3,3,6-trimethyl-2-azaspiro[4,5]deca-6,9-diene system. Keywords: isobutyraldehyde, meta-xylene, cyanoacetic ester, Ritter reaction, spiroheterocyclization. The reaction of ortho- and para-xylenes, isobutyraldehyde, and nitriles leads to the production of 1-substituted 3,3,6,7- or 3,3,5,8-tetramethyl-3,4-dihydroisoquinolines [1]. It seemed of interest to bring metaxylene also into reaction with nitriles.
Me Me
+
Me
CHO Me NC COOEt
Me Me Me Me NH COOEt 1 Me 2 Me Me Me NH COOEt
On general considerations a concerted orientation of the substituents (ortho-, para-) could be expected for the reaction, and this should lead to the formation of 1-substituted 3,3,5,7-tetramethyl-3,4dihydroisoquinolines 1. By virtue of steric hindrances the formation of 1-substituted 3,3,6,8-tetramethyl-3,4__________________________________________________________________________________________ Institute of Technical Chemistry, Urals Branch of the Russian Academy of Sciences, Perm. 2 Institute of Organic Synthesis, Urals Branch, Russian Academy of Sciences, Ekaterinburg; e-mail: onchup@ios.ural.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1487-1491, October, 2004. Original article submitted October 23, 2001. 0009-3122/04/4010-12832004 Springer Science+Business Media, Inc. 1283
1
dihydroisoquinolines 2 could be expected in so far as the substituent in the forthcoming position 8 of the ring does not prevent the formation of isoquinoline [2]. In fact, during the three-component reaction between meta-xylene, isobutyraldehyde, and cyanoacetic ester after neutralization of the reaction mass a product having basic character was isolated. In the 1H NMR spectra all the signals of the aliphatic protons are split, but the methyl groups in the aromatic ring give one signal corresponding in intensity to only one methyl group. The mass spectrum gave a molecular ion peak at 440 (with I 70%), indicating the participation of two molecules of isobutyraldehyde and two molecules of cyanoacetic ester to one molecule of meta-xylene in the reaction. It can be concluded from the experimental data that the reaction leads to the production of compounds 3 or 4. It should be noted that the two proposed versions have different directions for the initial attack by the protonated form of the isobutyraldehyde, i.e., at the position with highest electron density (the ortho-ortho orientation, position 2 of the ring) and at position 4 of the ring (ortho-para concerted orientation).
Me Me Me NH COOEt Me COOEt NH Me Me Me Me N H 3 COOEt Me Me N H EtOOC 4
As shown by the data from 1D and 2D NMR experiments, the investigated compound has structure 3:
Me Me 5 ' HN
EtOOC
4' 3' 2' 2 '' 1''
Me
7 8 9 6 5 1 10 2''' 4 3
Me
Me NH
1''' COOEt
In the 1H NMR spectrum it was possible to detect fine structure in the resonance signals of the H(7), H(9), and CH3C(6) protons. The signal of the H(7) proton at 6.18 ppm is split into a doublet of quartets on account of long-range interactions (4J) with the H(9) proton and with the protons of the methyl group at C(6), while the signal of the H(9) proton at 6.97 ppm is split into a doublet of doublets. The spinspin couplings between the discussed protons are supported by 1H{1H} double resonance experiments. The signals of the protonated carbon atoms were assigned by means of a HETCOR heteronuclear correlation 2D experiment. The data from an inversion HMBC 2D experiment, based on the long-range spinspin couplings 2JCH 3 and JCH, made it possible to assign the quaternary carbon atoms and to confirm the structure of compound 3. In the HMBC spectra there cross peaks between the nodal atoms C(5) and the H(7), H(9), H(10), and C(6)CH3 protons of the six-membered ring and the N(2)H and C(4')H2 protons. In addition correlation is observed on account of interactions through two and three bonds between the protons and carbon atoms in each individual ring and the corresponding side chains. It was not possible to make an unambiguous assignment on account of the overlap of the signals of the carbonyl and ethyl groups. 1284
Information on the steric proximity of the protons, obtained from the 2D NOESY spectrum, made it possible on the one hand to confirm the assignment of the resonance signals of the protons and on the other to draw conclusions about the configuration of the double bonds in the molecule of compound 3. In particular, correlation on account of dipoledipole interaction is observed for the following pairs of protons: H(2") and H(9), C(4')H2 and H(7), H(2"") and C(6)CH3, and H(10) and one of the methyl groups at the C(3) atom. Thus, clearly, the steric hindrances created by the two methyl groups make attack at the fourth and not the second carbon atom (the position with the highest electron density) energetically more favorable. The scheme for the formation of the product 3 can be represented as follows:
Me Me Me
Me
Me
CHO
Me Me
NC + Me
COOEt
Me Me + N Me Me
Me
Me Me NH
Me Me CHO
COOEt Me Me Me NH Me + Me EtOOC Me N Me + Me Me NH COOEt COOEt NC
COOEt
COOEt
Me Me Me N H EtOOC
Me Me NH
Me
COOEt
A special feature of compound 3 is its comparatively high hydrolytic stability in sulfuric acid at the isolation stage. During isolation the 1-R-3,3-dimethyl-2-azaspiro[4,5]deca-1,6,9-trien-8-ones that we described [3] with R groups other than thiomethyl undergo dienonephenol rearrangement and give open-chain products derivatives of 2-(4'-hydroxyphenyl)ethylamine exclusively. Thus, we have shown for the first time that not only alkoxyarenes but also alkyl aromatic compounds can enter into spiroheterocyclization, and this opens up broad possibilities for the use of -branched aldehydes in these reactions.
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TABLE 1. The 1H and 13C NMR Spectra of Compound 3

Atom/ group = = (1) (2') C(6) C(10)H
1 NMR spectrum, , ppm (J, Hz)
NMR spectrum, , ppm.

13
Atom/ group
1 NMR spectrum, , ppm (J, Hz)
13 NMR spectrum, , ppm.
5.94 (d, J = 10)
171.29 171.08 166.81 159.59 140.97 135.96
C(3) OCH2 OCH2 (5') (5) (4)2
C(8)
130.34
(4')H2
C(3') C(7)H
(9)
C(2'')H C(2''')H
6.18 (dq, 4 J = 1.5, 4 J = 1.3) 6.97 (dd, 3 J = 10, 4 J = 1.5) 4.92 4.21
129.93 124.55
(3)(H3)2 C(5')(H3)2
4.12 (q, J = 7.1) 4.07 (center of system) 2.15, 1.87 ( system, JAB = 13.8) 2.68, 2.62 ( system, JAB = 15.6) 1.41, 1.40 1.31, 1.30
61.01 58.64 58.64 58.28 55.79 47.95
43.73
32.06, 30.78 29.51, 29.50
120.08
C(6)H3 3(C2H5) 3(C2H5)
1.86 (d, J = 1.3)
19.90
78.84 77.23
1.27 (t, J = 7.1) 1.24 (t, J = 7.1)
14.71 14.58
EXPERIMENTAL The IR spectrum was recorded in vaseline oil on a UR-20 spectrophotometer. The 1H NMR spectra were obtained on a Bruker AM 300 spectrophotometer (300 MHz) in deuterochloroform with TMS as internal standard. The 1D and 2D NMR experiments in deuterochloroform solution were conducted on a Bruker DRX-400 spectrometer (400 and 100 MHz for 1H and 13C) using the standard pulse sequences contained in the Bruker software. The mass spectrum was recorded on a Finnigan MAT instrument (electron impact, 70 eV) under standard conditions. The course of the reaction and the purity of the obtained compounds were monitored by TLC on Silufol UV-254 plates (9:1 chloroformacetone) with a 0.5% solution of chloranil in toluene as developer. 1-Ethoxycarbonylmethylidene-8-(2'-ethoxycarbonylmethylidene-5',5'-dimethyl-3'-pyrrolidinylidene)3,3,6-trimethyl-2-azaspiro[4,5]deca-6,9-diene (3). A mixture of meta-xylene (50 mmol), isobutyraldehyde (7.2 g, 100 mmol), and cyanoacetic ester (100 mmol) was added dropwise with stirring at 0-5C over 15-20 min to concentrated sulfuric acid (50 ml). The mixture was stirred for 30 min, poured into water (300 ml), and extracted with toluene (50 ml). The organic layer was rejected, and the aqueous layer was neutralized to pH 8-9 with ammonium carbonate. The separated substance was filtered off, washed with water, dried, and crystallized. We obtained 19.8 g (45%) of compound 3; mp 178-179C (ethanol). IR spectrum, , cm-1: 3355, 3335, 1735, 1723, 1650, 1600, 1580, 1500. Mass spectrum m/z (Irel, %): 440 [M]+ (100); 425 [M - CH3]+ (10); 395 [M - OEt]+ (20); 367 [M - COOEt]+ (45); 327 [M - NCCH2COOEt]+ (98); 312 [M - NCCH2COOEt - CH3]+ (95). Found %: 71.00; H 8.10; N 6.47. C26H36N2O4. Calculated %: 70.91; H 8.18; N 6.36. The work was carried out with financial support from the Russian Fundamental Research Fund (grant No. 01-03-96479). 1286
REFERENCES 1. Yu. V. Shklyaev, Yu. V. Nifontov, and V. A. Glushkov, Scientific-Technical Potential of the West Urals in the Region of Conversion of Military-Industrial Complex, Reports of International Seminar [in Russian], Perm (2001), p. 396. Yu. V. Shklyaev and Yu. V. Nifontov, in: Prospects for Development of Natural Sciences in the High School, Collection of Papers of Scientific Conference [in Russian], Vol. 1, Perm (2001), p. 63. V. A. Glushkov, Yu. Shklyaev, and V. I. Sokol, Mendeleev Commun., 170 (1999).
2. 3.
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[3 + 3] CYCLOCONDENSATION OF 1-ALKYL3,4-DIHYDROISOQUINOLINES WITH -KETO ESTERS. NEW ANNELATION REACTION IN A SERIES OF CYCLIC SCHIFF'S BASES
O. V. Gulyakevich1, A. A. Govorova1, P. V. Kurman2, A. S. Lyakhov3, and A. L. Mikhal'chuk1 A new annelation reaction in a series of cyclic Schiff's bases is described with examples of [3 + 3] cyclocondensation of 1-alkyl-3,4-dihydroquinolines and acetoacetic esters. Keywords: azomethines, benzo[a]quinolizines, 3,4-dihydroisoquinolines, ketimines, -keto esters, Schiff's bases, pyrido[2,1-a]isoquinolines, annelation, heterocyclization, cyclocondensation. The multifunctionality of cyclic ketimines and derivatives of carbonyl compounds permits exceptionally wide possibilities for the synthesis of condensed nitrogen-containing heterocycles with an angular nitrogen atom [1-5], particularly alkaloids [6,7], and heterocyclic analogs of steroids (azasteroids) [3-5]. We previously studied the reaction of azomethines 1 with aminovinylcarbonyl (2, X = 2H) and dicarbonyl (2, X = O) compounds, leading to the condensed system 3 (Scheme 1) [5]. It seemed of interest to extend this reaction to other carbonyl compounds, particularly to -keto esters. An additional stimulus for studying such reactions were the numerous data on the interaction of -dicarbonyl compounds (1,3-dielectrophiles) with bifunctional nitrogen bases, such as hydrazine [8], hydroxylamine [9], and others [10]. Scheme 1
O N: R [H+ ] NH .. _ R E +
+ NR'2 X 2 R
X 3
R = H, Alk; R' = Alk, (CH2)n; X = 2H, O
__________________________________________________________________________________________ Institute of Bioorganic Chemistry, National Academy of Sciences of the Republic of Belarus, Minsk 220141; e-mail: mikhalch@imaph.bas-net.by. 2 EKOMIR Center, National Academy of Sciences of the Republic of Belarus, Minsk 220012. 3 Research Institute for Physicochemical Problems, Belarussian F. Scorina State University, Minsk 220050. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1492-1500, October, 2004. Original article submitted August 5, 2002. 1288 0009-3122/04/4010-12882004 Springer Science+Business Media, Inc.
1
In contemporary theory and practice of organic chemistry the enamine tautomers of Schiff's bases are usually considered as C-nucleophiles [11-15]. However the results of theoretical investigations [16] and experimental data [5] enable these compounds to be considered as 1,3-dinucleophiles, capable of interacting with dielectrophiles. Paying attention to the results of the previous investigations [17,18], and also to the ability of 1alkyl substituted 3,4-dihydroisoquinolines (cyclic ketimines) to act both as imine (4I) and as enamine (4E) tautomers [19], and the 1,3-dielectrophilic nature of -keto esters, we have studied the interaction of 3,4-dihydroisoquinolines 4a,b with acetoacetic esters 5a-d. It was discovered that, as a result of these interactions, a previously unknown heterocyclization reaction is effected, leading to pyrido[2,1-a]isoquinolines (benzo[a]quinolizines, 6a-d). As a result of the interaction of the indicated substrates it is theoretically possible to expect the formation of both derivatives 6a-d and derivatives 7 isomeric with them. However the sole products of the interaction studied proved to be derivatives 6a-d. Scheme 2
R N .. R NH .. O
R I
+ R1
O + OEt 5ad
_ E
4a,b
7 9 6
R O R
3
A R
10
B N C
1
R1 7
R1
6ad
4a, 6c,d R = H, 4b, 6a,b R = OMe, 5a, 6a R1 = Me, 5b, 6c R1 = i-Bu, 5c, 6d R1 = CH2CH2COMe, 5d, 6b R1 = CH2Ph
The condensation of 3,4-dihydroquinolines 4a,b with acetoacetic esters 5a-d was effected by heating mixtures of them at 140-220C. The reaction products were isolated after cooling and were purified by crystallization. In individual cases flash chromatography (Silica gel L 40/5 from Chemapol, eluent chloroform) was used for isolation and purification of the product [20]. The enhanced tendency of derivatives 6a-d to form crystal hydrates should be noted. These are extremely stable and lose the water of crystallization with difficulty even on heating under reduced pressure over phosphoric anhydride. On the strength of this it is necessary to use anhydrous solvents to obtain samples without solvated water. The structure ascribed to the product of interaction of 3,4-dihydroisoquinolines 4a,b with acetoacetic esters 5a-d was confirmed by data of physicochemical investigations, and for compound 6a also by data of X-ray structural analysis. In the IR spectra of derivatives 6a-d intense broadened and asymmetric absorption bands (AB) were observed at 1590-1620, 1570-1585, and 1485-1550 cm-1 caused by C=O and C=C stretching vibrations of the -pyridone C rings and the benzene A rings [21], and also AB at 1440-1470 cm-1 which are caused by the CH deformation vibrations of methylene and methyl groups [22]. 1289
Interesting regularities were traced in the electronic absorption spectra of derivatives 6a-d. In the spectra of derivatives 6a,b, characterizing the presence in their structure of methoxy substituents at positions 9 and 10, about three AB were observed in the 235-310 nm region at ~240, 260, and 308 nm, while for derivatives 6c,d (9,10-desmethoxy derivatives) only two AB were observed in the indicated region of the spectrum at ~255 and 286 nm. Proceeding from the indicated differences of derivatives 6a,b and 6c,d and in accordance with the data of [23], the AB of derivatives 6a,b displayed at ~240 nm should be assigned to an electronic transition of the methoxy-substituted benzene rings A. The AB located in the long wave region of the spectrum (250-310 nm) are caused by the electronic transitions of the -pyridone rings C linked by the C(11a)C(11b) bond with the benzene rings A. The AB displayed in the region below 220 nm are caused by electronic transitions of rings A [23]. In the 1H NMR spectra of derivatives 6a-d the signals of the methylene groups C(6)H2 and C(7)H2 and the methyl groups at atoms C(1) and C(4) were common for all the described compounds. These were displayed as characteristic two-proton triplets (J = 6-7 Hz) at 3.95-4.00 and 2.90-2.96 ppm and three-proton singlets at ~2.36 and 2.46 respectively. The presence of a -pyridone ring C (6a-d) in the obtained compounds and not the -pyridone ring (7) isomeric with it was finally established from the X-ray structural analysis of compound 6a. Compound 6a crystallizes as a molecular complex with a molecule of water. The bond lengths and valence angles (Tables 1 and 2) are in good agreement with the corresponding values in the molecular compounds containing analogous fragments [24]. The structure of the pyrido[2,1-a]isoquinoline 6a molecule and the numbering of the atoms are shown in Figure 1.
TABLE 1. Bond Lengths (d) in the Compound 6a Molecule

Bond C(1)C(11b) C(1)C(2) C(1)C(12) C(2)O(2) C(2)C(3) C(3)C(4) C(3)C(13) C(4)N(5) d, 1.3731(18) 1.4345(19) 1.5012(18) 1.2680(16) 1.4327(19) 1.3682(19) 1.5086(19) 1.3733(18) Bond C(4)C(14) N(5)C(11b) N(5)C(6) C(6)C(7) C(7)C(7a) C(7a)C(11a) C(7a)C(8) C(8)C(9) d, 1.5055(19) 1.3836(17) 1.4882(16) 1.511(2) 1.4972(19) 1.3888(18) 1.393(2) 1.382(2) Bond C(9)O(9) C(9)C(10) C(10)O(10) C(10)C(11) C(11)C(11a) C(11a)C(11b) C(15)O(9) C(16)O(10) d, 1.3633(18) 1.4059(19) 1.3675(17) 1.3799(19) 1.4012(19) 1.4852(19) 1.425(2) 1.4168(18)
TABLE 2. Valence Angles () in the Compound 6a Molecule

Angle C(11b)C(1)C(2) C(11b)C(1)C(12) C(2)C(1)C(12) O(2)C(2)C(1) O(2)C(2)C(3) C(1)C(2)C(3) C(4)C(3)C(2) C(4)C(3)C(13) C(2)C(3)C(13) C(3)C(4)N(5) C(3)C(4)C(14) N(5)C(4)C(14) , deg. 119.97(12) 123.92(12) 116.06(11) 120.61(12) 121.70(12) 117.67(12) 120.02(12) 122.75(13) 117.21(12) 120.65(12) 122.56(13) 116.74(12) Angle C(4)N(5)C(11b) C(4)N(5)C(6) C(11b)N(5)C(6) N(5)C(6)C(7) C(7a)C(7)C(6) C(11a)C(7a)C(8) C(11a)C(7a)C(7) C(8)C(7a)C(7) C(9)C(8)C(7a) O(9)C(9)C(8) O(9)C(9)C(10) C(8)C(9)C(10) , deg. 121.04(11) 119.97(11) 118.89(11) 110.73(11) 108.37(12) 119.96(13) 116.28(12) 123.62(12) 120.93(13) 125.19(13) 115.43(13) 119.35(13) Angle O(10)C(10)C(11) O(10)C(10)C(9) C(11)C(10)C(9) C(10)C(11)C(11a) C(7a)C(11a)C(11) C(7a)C(11a)C(11b) C(11)C(11a)C(11b) C(1)C(11b)N(5) C(1)C(11b)C(11a) N(5)C(11b)C(11a) C(9)O(9)C(15) C(10)O(10)C(16) , deg. 124.26(13) 116.08(12) 119.65(13) 121.01(12) 119.07(12) 119.53(12) 121.31(11) 120.07(12) 124.21(12) 115.68(11) 117.66(13) 117.23(11)
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O1w C15 C7 C8 O9 C9 C7a C6 N5 C11b C11a O10 C10 C11 C1 C2 C12 C16 O2 C4 C3 C13 C14
Fig. 1. Structure of the compound 6a molecule. Analysis of the bond lengths in the -pyridone ring C shows the presence of significant conjugation in the ring. Rings A and C in the pyrido[2,1-a]isoquinoline 6a molecule are planar, the deviation of individual atoms from the mean square planarity of the rings was 0.008(1) for ring A and 0.029(1) for ring C. Since these rings are separated by the C(11a)C(11b) bond it might be right to expect interaction or interference between them. However, as in the case of the 8-azasteroid derivatives with -pyridone rings C studied previously [25,26], the planes of rings A and C for derivative 6a are tilted relative to one another by 36.46(4). It is evident that such a relative disposition of these rings excludes interaction (overlap) of their -electron clouds. This is confirmed by the fact that the C(11a)C(11b) bond is only 0.012 shorter than the C(7)C(7a) bond. Ring B has the conformation of a strongly distorted boat since the C(7), C(7a), C(11a), and C(11b) atoms lie practically in one plane [the deviations of the atoms from mean square planarity are 0.0099(8) ], and the C(6) and N(5) atoms emerge from it by 1.002(3) and 0.644(2) . In a generalized form the reaction discovered by us may be represented by Scheme 3 and is a convenient method of forming a -pyridone ring by the heterocyclization of azomethines 1 with -keto esters 8 with the formation of condensed nitrogen-containing heterocycles containing a -pyridone structural fragment of type 9. No close analogies to this reaction were found in the accessible periodical [11-15], monograph [27], or reference literature (Chemical Abstracts). This enables us to affirm that the new reaction is straightforward, probably has a general character, and enables the synthesis in one step of condensed nitrogen-containing Scheme 3
O N: + R I 1 + NH .. _ R E
R' + R'' Z AlkOH, H2O R O 9 R'' N R' Z
AlkO
+ O 8
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heterocycles with an angular nitrogen atom. One of the most obvious applications of it may be the synthesis of alkaloids and heterocyclic analogs of steroids by annelation of 1-alkyl-3,4-dihydroisoquinolines of type 4 or 1-alkyl-3,4-dihydro--carbolines with alkoxycarbonyl derivatives of cycloalkanones and heterocyclic ketones, such as pyranones, thiopyranones, piperidones, etc.
EXPERIMENTAL The 3,4-dihydroisoquinolines 4a,b used in the work were obtained by the cyclodehydration of the corresponding phenylethylamides under the action of polyphosphoric acid (4a) and phosphorus oxychloride (4b) under the conditions of the BischlerNapieralski reaction [28]. A check on the progress of reactions and the purity of products was effected by TLC on Silufol UV 254 plates, eluent was chloroformmethanol, 9:1, visualizing in UV light or iodine vapor with subsequent roasting at 250-350C. Melting points were determined on a Boetius heating block. The IR spectra were obtained on a UR 20 instrument in KBr disks. The UV spectra were taken on a Specord M 400 spectrophotometer in ethanol. The 1H NMR spectra were obtained on a Bruker AC 200 (200 MHz) radiospectrometer in CDCl3, internal standard was TMS. The mass spectra of derivatives 6ad were measured on a HP 5890/5972 GC/MS chromato-mass spectrometer (quartz capillary column HP 5MS, 30 m 0.25 mm 0.25 m, carrier gas helium at 0.7-1 l/min, evaporator temperature 250C, temperature program 40-300C, 6C/min), energy of ionizing electrons 70eV. X-Ray Structural Investigation of Compound 6a. A prismatic crystal of dimensions 0.74 0.40 0.36 mm was selected for the analysis. A three-dimensional set of X-ray diffraction data was obtained on a Nicolet R3m automatic four-circle diffractometer, MoK radiation, graphite monochromator, /2 scanning, 2max = 55. The total number of reflections measured was 4183, 3755 were independent (Rint = 0.0147). The crystal was triclinic, space group P1. Parameters of the unit cell were a = 7.566(2), b = 8.899(1), c = 12.397(3) ; = 88.52(2), = 81.94(2), = 80.06(2); V = 814.0(3) 3; Z = 2; dX-ray = 1.295 g/cm3; = 0.91 cm-1. The structure of the compound was solved by the direct method (SIR97 [29]). The positions of the hydrogen atoms were calculated geometrically, except for the hydrogen atoms of the water molecule, the positions of which were determined by a Fourier difference synthesis. Refinement (SHELXL-97 [30]) was carried out by the full-matrix least squares method allowing for the anisotropy of the thermal vibrations of the nonhydrogen atoms. The hydrogen atoms were refined with a rider model (protons of the water molecule were refined isotropically). Final values of the uncertainty factors were R1 = 0.0429, wR2 = 0.1241 [I >2(I)]; R1 = 0.0562, wR2 = 0.1380 (all data); goodness of fit GOOF = 1.055. The coordinates and equivalent isotropic parameters of the displacement of atoms may be obtained from the authors. 9,10-Dimethoxy-1,3,4-trimethyl-6,7-dihydro-2H-pyrido[2,1-a]isoquinolin-2-one (6a). A mixture of isoquinoline 4b (1.1 g, 5 mmol) and ester 5a (0.79 ml, 5.5 mmol) was heated for 6 h at 140-160C. The reaction mixture was then diluted with alcohol and left at +5C overnight. The separated substance was filtered off and recrystallized from alcoholether. Pyridoisoquinoline 6a (1.16 g, 73%) was obtained as colorless prismatic crystals; mp 186-188C. IR spectrum, , cm-1: 3250-3350, 2820-3050, 1612, 1585, 1500-1540, 1470, 1448, 1376, 1350, 1275, 1260, 1235, 1228, 1205, 1150, 1105, 1040, 1012, 880, 842, 822, 780, 768. UV spectrum, max, nm (): 215 (20680), 238.8 (23880), 260 (21635), 307.1 (17358); min, nm (): 205 (19265), 225 (17510), 249.4 (16690), 274.1 (11165). 1H NMR spectrum, , ppm (J, Hz): 2.20 (3H, s, C(3)CH3); 2.38 (3H, s, C(1)CH3); 2.42 (3H, s, C(4)CH3); 2.90 (2H, t, J = 6.0, C(7)H2); 3.62 (2H, s, H2O); 3.92 (3H, s, OCH3); 3.96 (3H, s, OCH3); 4.00 (2H, t, J = 6.0, C(6)H2); 6.79 (1H, s, C(8)H); 7.16 (1H, s, C(11)H). Mass spectrum, m/z (Irel, %): 300 (13.4) [M+1]+; 299 (79.6) [M]+; 298 (100) [M-1]+; 285 (11.0); 284 (60.7); 282 (16.1); 271 (10.7); 256 (42.2); 254 (15.6); 253 (15.1); 227 (10.1); 226 (10.9); 213 (19.1); 212 (16.5); 184 (13.5); 127 (10.1); 120 (14.5); 115 (12.2); 105 (10.7). Found, %: C 68.00; H 7.32; N 4.31. C18H21NO3.H2O. Calculated, %: C 68.12; H 7.30; N 4.41. M 317.38.
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3-Benzyl-9,10-dimethoxy-1,4-dimethyl-6,7-dihydro-2H-pyrido[2,1-a]isoquinolin-2-one (6b). A mixture of isoquinoline 4b (1.65 g, 7.5 mmol) and ester 5d (2.7 ml, 11.3 mmol) was heated for 9 h at 140-160C. The excess of -keto ester was distilled off, the residue was dissolved in alcohol, and the mixture left to crystallize at +5C. The separated crystals were filtered off, washed on the filter with cold 70% alcohol, and recrystallized from 70% alcohol. Pyridoisoquinoline 6b (1.9 g, 64.4%) was obtained as white flaky crystals; mp 168.5-170.5C. IR spectrum, , cm-1: 3280, 2800-3100, 1595-1620, 1585, 1490-1545, 1440-1465, 1384, 1352, 1344, 1319, 1255-1285, 1232, 1225, 1138, 1075, 1044, 1025, 882, 840, 780, 733, 702. UV spectrum, max, nm (): 240 (39850), 262.4 (36325), 308.8 (28160); min, nm (): 228 (31080), 250 (27250), 286.2 (20170). 1 H NMR spectrum, , ppm (J, Hz): 2.36 (3H, s, C(1)CH3); 2.42 (3H, s, C(4)CH3); 2.51 (2H, s, H2O); 2.90 (2H, t, J1,2 = 6.0, C(7)H2); 3.92 (3H, s, OCH3); 3.95 (2H, t, J1,2 = 6.0, C(6)H2); 3.97 (3H, s, CH3); 4.14 (2H, s, C(14)H2); 6.78 (1H, s, C(8)H); 7.18 (1H, s, C(11)H); 7.10-7.36 (5H, m, C(2)H, C(3)H, C(4)H, C(5)H, C(6)H). Mass spectrum, m/z (Irel, %): 375 (100) [M]+; 374 (83.2 ) [M-1]+; 360 (30.1); 358 (14.9); 285 (11.9); 284 (62.8); 207 (19.1); 187 (48.4); 180 (14.2); 165 (13.7); 157 (13.1); 142 (13.7); 141 (10.2); 135 (12.3); 129 (13.9); 128 (26.7); 127 (20.3); 115 (22.9); 102 (10.6); 91 (27.9); 78 (11.8); 77 (18.8). Found, %: C 73.19; H 6.95; N 3.45. C24H25NO3.H2O. Calculated, %: C 73.26; H 6.92; N 3.45. M 393.48. 3-Isobutyl-1,4-dimethyl-6,7-dihydro-2H-pyrido[2,1-a]isoquinolin-2-one (6c). A mixture of isoquinoline 4a (1.19 g, 7.5 mmol) and ester 5b (1.58 g, 8.5 mmol) was heated in a stream of argon at 160-180C for 12 h. The reaction mixture was then diluted with ether, and after rubbing with a glass rod, was left to crystallize. The substance which separated was filtered off, washed with ether, and recrystallized from an alcoholether mixture. Pyridoisoquinoline 6c (1.6 g, 74.9%) was obtained as white flaky crystals; mp 169-171C. IR spectrum, , cm-1: 3250-3300, 2830-3100, 1590-1620, 1570, 1520-1550, 1485, 1450, 1429, 1380, 1365, 1283, 1252, 1230, 1077, 768, 752. UV spectrum, max, nm (): 208.7 (20100), 256.7 (28475), 291.5 (10050); min, nm (): 228.6 (7370), 271.7 (9380). 1H NMR spectrum, , ppm (J, Hz): 0.96 (6H, d, J = 7.0, C(14)H3, C(15)H3); 1.95 (1H, m, C(13)H); 2.13 (1H, br s, 0.5H2O); 2.34 (3H, s, C(1)CH3); 2.42 (3H, s, C(4)CH3); 2.58 (2H, d, J = 7.0, C(12)H2); 2.95 (2H, t, J = 7.0, C(7)H2); 3.95 (2H, t, J = 7.0, C(6)H2); 7.28 (1H, m, C(8)H); 7.34 (2H, m, C(9)H, C(10)H); 7.63 (1H, m, C(11)H). Mass spectrum, m/z (Irel, %): 281 (21.69) [M}+; 280 (14.2) [M-1]+; 267 (13.7); 266 (68.9); 240 (16.7); 239 (100); 238 (71.5); 236 (14.4); 225 (11.5); 224 (27.0); 210 (18.6); 194 (13.8); 128 (15.2); 115 (12.1). Found, %: C 78.29; H 8.68; N 4.66. C19H23NO.0.5H2O. Calculated, %: C 68.12; H 7.30; N 4.41. M 290. 1,4-Dimethyl-3-(3-oxobutyl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinolin-2-one (6d). A mixture of isoquinoline 4a (1.19 g, 7.5 mmol) and ester 5c (1.18 g, 9 mmol) was heated in a stream of argon for 15 h at 200-220C. The reaction mixture was then evaporated, the residue dissolved in chloroform, washed with potassium carbonate solution, with water, dried over magnesium sulfate, and filtered through silica gel (5 g). The solution obtained was evaporated under reduced pressure, and the dry residue crystallized from a chloroform hexane mixture. Pyridoisoquinoline 6d (1.29 g, 58%) was obtained as colorless finely prismatic crystals; mp 191-194C (decomp.). IR spectrum, , cm-1: 2830-3100, 1715, 1610, 1575, 1530-1550, 1486, 1455, 1435, 1404, 1355-1385, 1286, 1251, 1163, 1074, 785, 774, 754. UV spectrum, max, nm (): 205 (33075), 254.6 (35035), 281.9 (12960); min, nm (): 229.6 (11700), 271.9 (12330). 1H NMR spectrum, , ppm (J, Hz): 2.19 (3H, s, C(15)H3); 2.34 (3H, s, C(1)CH3); 2.48 (3H, s, C(4)CH3); 2.77 (2H, m, C(12)H2); 2.92 (2H, m, C(13)H2); 2.96 (2H, t, J = 6.5, C(7)H2). 3.96 (2H, t, J = 6.5, C(6)H2); 7.26-7.43 (3H, m, C(8)H, C(9)H, C(10)H); 7.62 (1H, m, C(11)H). Mass spectrum, m/z (Irel, %): 295 (11.0) [M]+; 253 (20.3); 252 (100); 236 (15.2). Found, %: C 77.20; H 7.15; N 4.65. C19H21NO2. Calculated, %: C 77.26; H 7.17; N 4.74. M 295.38. The authors are grateful to Academician Afanasii Andreevich Akhrem for his interest in the investigation in progress, for fruitful discussions, and helpful comments when discussing the experimental data and the theoretical research.
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REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. R. Dyagutite and A. Shachkus, Khim. Geterotsikl. Soedin., 499 (1993). B. Oussaid, M. J. Aurell, B. Garrigues, and M. Soufiaoui, Phosphorus, Sulfur, Silicon Relat. Elem., 85, Nos. 1-4, 17 (1993). O. V. Gulyakevich and A. L. Mikhalchuk, Mendeleev Commun., 72 (1997). O. V. Gulyakevich and A. L. Mikhal'chuk, Dokl. Ross. Akad. Nauk, 350, 781 (1996). A. L. Mikhal'chuk, O. V. Gulyakevich, V. P. Peresada, A. M. Likhosherstov, and A. A. Akhrem, Dokl. Ross. Akad. Nauk, 356, 769 (1997). A. A. Akhrem, A. M. Moiseenkov, V. S. Malishevskii, and Yu. G. Chernov, Izv. Akad. Nauk SSSR, Ser. Khim., 1308 (1973). A. A. Akhrem and Yu. G. Chernov, Synthesis, 996 (1980). V. I. Sokol, V. V. Davydov, Yu. V. Shklyaev, V. A. Glushkov, and V. S. Sergienko, Izv. Akad. Nauk, Ser. Khim., 966 (1999). K. N. Zelenin and A. Yu. Ershov, Khim. Geterotsikl. Soedin., 1385 (1990). J. P. Bouillou, V. Bouillou, C. Wynants, Z. Janousek, and H. G. Viehe, Heterocycles, 37, 915 (1994). A. G. Cook (editor), Enamines: Synthesis, Structure and Reactions, Marcel Dekker, New York, London (1967), 515 pp. J. V. Greenhill, Chem. Soc. Rev., 277 (1977). P. W. Hickmott, Tetrahedron, 38, 1975 (1982). P. W. Hickmott, Tetrahedron, 38, 3363 (1982). P. W. Hickmott, Tetrahedron, 40, 2989 (1984). V. P. Feshin and M. Yu. Kon'shin, Zh. Obshch. Khim., 64, 125 (1994). O. V. Gulyakevich, A. L. Mikhal'chuk, and A. A. Akhrem, Izv. Akad. Nauk, Ser. Khim., 1358 (1997). O. V. Gulyakevich, A. L. Mikhal'chuk, V. P. Peresada, A. M. Likhosherstov, and A. A. Akhrem, Khim. Geterotsikl. Soedin., 972 (1997). A. L. Mikhal'chuk, O. V. Gulyakevich, Yu. V. Shklyaev, V. S. Shklyaev, and A. A. Akhrem, Khim. Geterotsikl. Soedin., 681 (1998). J. T. Sharp, I. Gosney, and A. G. Rowley (editors), Practical Organic Chemistry. A Student Handbook of Techniques, Chapman & Hall, London (1989), 199 pp. A. D. Cross, Introduction to Practical Infrared Spectroscopy, Butterworths, London (1960), 80 pp. A. R. H. Cole in A. Weissberger (editor), Technique of Organic Chemistry, Vol. 11, Elucidation of Structures by Physical and Chemical Methods. Pt. 1, Interscience, New York (1963), p. 133. O. V. Sverdlova, Electronic Spectra in Organic Chemistry [in Russian], Khimiya, Leningrad (1973), 245 pp. F. H. Allen and O. Kennard, Chem. Des. Automation News, 8, 31 (1993). O. V. Gulyakevich, A. S. Lyakhov, and A. L. Mikhal'chuk, Dokl. Ross. Akad. Nauk, 349, 202 (1996). A. S. Lyakhov, A. A. Govorova, O. V. Gulyakevich, and A. L. Mikhal'chuk, Kristallografiya, 42, 870 (1997). K. V. Vatsuro and G. L. Mishchenko, Named Reactions in Organic Chemistry [in Russian], Khimiya, Moscow (1976), p. 213. V. M. Whaley and T. R. Govindachari, Organic Reactions, Vol. 6, Wiley, New York (1951), p. 151. A. Altomare, M. C. Burla, M. Camalli, G. Cascarano, G. Giacovazzo, A. Guagliardi, A. G. G. Moliterni, G. Polidori, and R. Spagna, J. Appl. Crystallogr., 32, 115 (1999). G. M. Sheldrick, SHELXL-97. Program for Crystal Structure Refinement, Univ. of Gttingen, Gttingen, Germany (1997).
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CHEMISTRY OF ACYL(IMIDOYL)KETENES. 8*. THERMOLYSIS OF 3-ALKOXYCARBONYL5-PHENYL-1,2,4,5-TETRAHYDROPYRROLO[1,2-a]QUINOXALINE-1,2,4-TRIONES. STRUCTURE OF 2-(3-OXO-4-PHENYL-3,4-DIHYDRO-2-QUINOXALINYL)2,4-DI(ETHOXYCARBONYL)-6-PHENYL-2,3,5,6-TETRAHYDRO1H-PYRIDO[1,2-a]QUINOXALINE-1,3,5-TRIONE

A. N. Maslivets1, Z. G. Aliev2, O. P. Krasnykh1, O. V. Golovnina1, and L. O. Atovmyan2 3-Alkoxycarbonylmethylene-1-phenyl-1,2,3,4-tetrahydro-2-quinoxalones, obtained by the interaction of dialkyl esters of oxaloacetic acid and N-phenyl-o-phenylenediamine, react with oxalyl chloride with the formation of 3-alkoxycarbonyl-5-phenyl-1,2,4,5-tetrahydropyrrolo[1,2-a]quinoxaline-1,2,4-triones. Alkoxycarbonyl(2-oxo-1-phenyl-1,2-dihydro-3-quinoxalinyl)ketenes, generated on thermal decarbonylation of the latter, are stabilized by participation in a [4+2] cyclodimerization reaction with the formation of 2,4-di(alkoxycarbonyl)-2-(3-oxo-4-phenyl-3,4-dihydro-2-quinoxalinyl)-6-phenyl2,3,5,6-tetrahydro-1H-pyrido[1,2-a]quinoxaline-1,3,5-triones. The crystal and molecular structure of the di(ethoxycarbonyl) derivative have been investigated by X-ray structural analysis. Keywords: alkoxycarbonyl(imidoyl)ketene, acyl(imidoyl)ketene, pyrroledione, crystal and molecular structure, [4 + 2] cyclodimerization. Two routes have been described for the stabilization of acyl(imidoyl)ketenes in which the imidoyl fragment is part of a heterocyclic system. Alkoxycarbonyl(2-oxo-1,2-dihydro-3-quinoxalinyl)ketenes A are cyclized intramolecularly as a result of acylation of the hydroxy group of the tautomeric hydroxyimine form by the ketene fragment [2]. Aroyl(2-oxo3,4-dihydro-2H-1,4-benzoxazin-3-yl)ketenes B and aroyl(3-aryl-2-quinoxalinyl)ketenes C, in the absence of partners for interaction, participates in a [4 + 2] cyclodimerization reaction [1,3,4]. The role of diene is played by the imidoylketene fragment of one ketene molecule, and the role of dienophile by the C=C bond of the ketene fragment of the other molecule. A [1,3]-migration of the aroyl group occurs in the [4 + 2] cycloadducts formed initially. The thermolytic conversion of 3-alkoxycarbonyl-5-phenyl-1,2,4,5-tetrahydropyrrolo[1,2-a]quinoxaline1,2,4-triones 2a,b has been investigated in the present work. _______ * For Part 7 see [1]. __________________________________________________________________________________________ Perm State University, Perm 614000, Russia; e-mail: koh@psu.ru. 2 Institute of the Problems of Chemical Physics, Russian Academy of Sciences, Chernogolovka 142432, Moscow region. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1501-1506, October, 2004. Original article submitted April 2, 2002. 0009-3122/04/4010-12952004 Springer Science+Business Media, Inc. 1295
1
H N
O R
Ar
R = OAlk A N N C O OH OAlk O
N C O
O B, C
R = Ar
N O
COAr O COAr N
[1,3]COAr N N H O COOAlk N O N
COAr OCOAr
For alkoxycarbonyl(2-oxo-1-phenyl-1,2-dihydro-3-quinoxalinyl)ketenes 1a,b, generated by the thermal decarbonylation of compounds 2a,b, an intramolecular cyclization of the type described above [2] is structurally impossible and there are alternative possibilities for participation in intramolecular cycloaddition reactions for both the alkoxycarbonylketene and the imidoylketene fragments. Synthesis of the pyrroloquinoxalinetriones 2a,b was carried out by the known method by the interaction of oxalyl chloride and Z-3-alkoxycarbonylmethylene-1-phenyl-1,2,3,4-tetrahydro-2-quinoxalones 3a,b, obtained in turn, by the reaction of dialkyl esters of oxaloacetic acid and N-phenyl-o-phenylenediamine. On maintaining solutions of pyrroloquinoxalinetriones 2a,b in dowtherm A [5] at 185-187C for 5-7 min 2,4-di(alkoxycarbonyl)-2-(3-oxo-4-phenyl-3,4-dihydro-2-quinoxalinyl)-6-phenyl-2,3,5,6-tetrahydro-1Hpyrido[1,2-a]quinoxaline-1,3,5-triones 4a,b* are formed. The structure of the di(ethoxycarbonyl) derivative 4b was identified on the basis of data of X-ray structural analysis. Probably ketenes 1a,b, formed on thermal decarbonylation of pyrroloquinoxalinetriones 2a,b, are stabilized by participating in a [4 + 2] cyclodimerization reaction analogously [1, 4]. The [1,3]-acylotropic shift of alkoxycarbonyl groups, described in [1, 3, 4] for the aroyl analogs, does not occur in the resulting cycloadducts 4a,b, probably as a result of their lower stability compared with the readily migrating aroyl groups.
_______ * See preliminary communication [6]. 1296
NHPh NH2
Ph N N H 3a,b O (COCl)2
AlkOCOCH2COCOOAlk
COOAlk Ph N O COOAlk O COOAlk Ph N N
Ph N N O 2a,b O COOAlk CO
Ph N O OAlk C N C O 1a,b 14 a Alk = Me, b Alk = Et 4a,b O O O N
As a result of an X-ray structural investigation it became clear that specially grown crystals of compound 4b cocrystallized with benzene and water molecules in a ratio of 1:1:1. The general shape of the compound 4b molecule is shown in Fig. 1. The tricyclic fragment of the molecule deviates significantly from a planar structure. The pyrazine ring has a boat conformation. Twists along the line C(8)C(11) and C(9)C(10) were 19.8 and 13.2 respectively, and the deviations of the N(1) and N(2) atoms from the plane of the four carbon atoms were 0.24 and 0.15 . The phenyl substituent at the N(2) atom has a strictly bisecting orientation. The pyridine ring is also non-planar and has an envelope conformation. The twist along the N(1)C(2) line was 28.6. The deviation of the C(1) atom from the plane of the remaining five ring atoms was 0.37 to the side of the quinoxaline substituent at the C(2) atom. The orientations of the ethoxycarbonyl groups are characterized by
Fig. 1 Structure of the compound 4b molecule.
1297
torsion angles C(3)C(4)C(5)O(4) of 72.7 and C(3)C(2)C(22)O(7) of 144.9. The quinoxaline group at C(2) was planar. The torsion angle C(3)C(2)C(25)N(3) was equal to 112.6 and the plane of the phenyl substituent at the N(4) atom was orthogonal to the plane of the quinoxaline. The C(4)=C(8) and N(3)=C(25) double bonds [1.350(3) and 1.273(3) respectively] were localized, without significant participation in conjugation. The remaining bond lengths in the molecule have the usual values and require no comment. Unlike the benzene molecule the water of crystallization molecule was randomized statistically at two crystallographic positions. Since both these positions are close to the center of inversion with coordinates 0.5 0 0, the water molecule is in fact randomized statistically with a weighting of 1/4 at four positions at the corners of a square with side 1.70 . Hydrogen bonds and other shortened contacts were absent from the crystal.
EXPERIMENTAL The IR spectra of the synthesized compounds were recorded on a UR 20 spectrometer in nujol, the H NMR spectra on a Bruker DRX 400 (400 MHz) instrument in DMSO-d6, internal standard was HMDS ( 0.05 ppm), and the mass spectrum on a MX 1410 instrument with ionising voltage 70 eV. The homogeneity of the obtained compounds was confirmed by TLC on Silufol plates in the system benzeneethyl acetate, 5:1. Z-3-Methoxycarbonylmethylene-1-phenyl-1,2,3,4-tetrahydro-2-quinoxalone (3a). A solution of N-phenyl-o-phenylenediamine (10 mmol) in dioxane (15 ml) was added to a solution of oxaloacetic acid dimethyl ester (10 mmol) in dioxane (5 ml). The mixture was boiled for 1 h 30 min, cooled, and the precipitated solid compound 3a filtered off. Yield 2.65 g (90%); mp 194-195C (dioxane). IR spectrum, , cm-1: 2980 br (NH), 1680 (C(2)=O), 1612 br (COO). 1H NMR spectrum, , ppm: 3.71 (3H, s, CH3O); 5.59 (1H, s, CH); 6.25-7.95 (9H, m, C6H5 + C6H4); 11.15 (1H, s, NH). Found, %: C 69.40; H 4.83; N 9.45. C17H14N2O3. Calculated, %: C 69.38; H 4.79; N 9.52. Z-3-Ethoxycarbonylmethylene-1-phenyl-1,2,3,4-tetrahydro-2-quinoxalone (3b). Yield 2.62 g (85%); mp 161-163C (toluene). IR spectrum, , cm-1: 3015 br (NH), 1685 (C(2)=O), 1630 (COO). 1H NMR spectrum, , ppm: 1.31 (3H, t, CH3); 4.21 (2H, q, CH2); 5.61 (1H, s, CH); 6.32 (1H, d, o-CH in C6H5); 6.81-7.69 (8H, m, 2C6H4); 11.22 (1H, s, NH). Found, %: C 70.07; H 5.18; N 9.14. C18H16N2O3. Calculated, %: C 70.12; H 5.23; N 9.09. 3-Methoxycarbonyl-5-phenyl-1,2,4,5-tetrahydropyrrolo[1,2-a]quinoxaline-1,2,4-trione (2a). A solution of compound 3a (10 mmol) and oxalyl chloride (10 mmol) in absolute chloroform (50 ml) was boiled for 1 h, cooled, and the precipitated solid compound 2a filtered off. Yield 3.13 g (90%); mp 187-189C (chloroform). IR spectrum, , cm-1: 1770 (C(1)=O), 1750 (COO), 1730 (C(2)=O), 1690 (C(4)=O). 1H NMR spectrum, , ppm: 3.74 (3H, s, CH3O); 6.69 (1H, d, o-CH in C6H5); 7.39-8.35 (8H, m, 2C6H4). Found, %: C 65.50; H 3.51; N 8.01. C19H12N2O5. Calculated, %: C 65.52; H 3.47; N 8.04. 3-Ethoxycarbonyl-5-phenyl-1,2,4,5-tetrahydropyrrolo[1,2-a]quinoxaline-1,2,4-trione (2b). Yield 3.26 g (90%); mp 185-187C (chloroform). IR spectrum, , cm-1: 1765 (C(1)=O), 1725 (COO, C(2)=O), 1675 (C(4)=O). 1 H NMR spectrum, , ppm: 1.31 (3H, t, CH3); 4.27 (2H, q, CH2); 6.56 (1H, d, o-CH in C6H5); 7.00-7.70 (7H, m, C6H4 + C6H3); 7.85 (1H, d, o-CH in C6H5). Found, %: C 66.28; H 3.87; N 7.76. C20H14N2O5. Calculated, %: C 66.30; H 3.89; N 7.73. 2,4-Di(methoxycarbonyl)-2-(3-oxo-4-phenyl-3,4-dihydro-2-quinoxalinyl)-6-phenyl-2,3,5,6-tetrahydro1H-pyrido[1,2-a]quinoxaline-1,3,5-trione (4a). A solution of compound 2a (1 mmol) in dowtherm A (4 ml) was maintained at 185-187C for 7 min, cooled, and the precipitated solid compound 4a filtered off. Yield 0.33 g (52%); mp 235-237C (decomp., from benzene). IR spectrum, , cm-1: 1740, 1720 (COOCH3), 1675 (CO). 1H NMR spectrum, , ppm: 3.30 (6H, s, 2CH3); 6.42-7.80 (18H, m, 2C6H5 + 2C6H4). Found, %: C 67.48; H 3.77; N 8.72. C36H24N4O8. Calculated, %: C 67.50; H 3.78; N 8.75.
1
1298
2,4-Di(ethoxycarbonyl)-2-(3-oxo-4-phenyl-3,4-dihydro-2-quinoxalinyl)-6-phenyl-2,3,5,6-tetrahydro1H-pyrido[1,2-a]quinoxaline-1,3,5-trione (4b). A solution of compound 2b (1.66 mmol) in dowtherm A (4 ml) was maintained at 185-187C for 5 min, cooled, and the precipitated solid 4b filtered off. Yield 0.27 g (40%); mp 209-211C (decomp., from benzene). IR spectrum, , cm-1: 1720 (COOC2H5), 1645 (CO). 1H NMR spectrum, , ppm, (J, Hz): 1.24 (3H, t, J = 7.0, CH3); 1.42 (3H, t, J = 7.0, CH3); 4.17 (2H, q, J = 7.0, CH2); 4.50 (2H, q, J = 7.0, CH2); 6.40-8.03 (18H, m, 2C6H5 + 2C6H4). Mass spectrum, m/z (I, %): 668 [M]+. Found, %: C 68.31; H 4.25; N 8.41. C38H28N4O8. Calculated, %: C 68.26; H 4.22; N 8.38. X-ray Structural Investigation of Compound 4b. For the X-ray structural investigation compound 4b was repeatedly crystallized from aqueous benzene. The yellow well-defined crystals of C38H28N4O8C6H6H2O were triclinic: a = 13.556(3), b = 17.452(3), c = 9.244(2) ; = 95.70(3), = 104.29(3), = 100.28(3); V = 2061.5(7) 3; M = 764.77; Z = 2; dcalc = 1.232 g/cm3; space group P1. Unit cell parameters and the set of experimental reflections were measured with an automatic 4-circle KM-4 diffractometer (Kuma Diffraction) with CuK radiation in the angle range 2.6 < < 80.3. The structure was determined by the direct statistical method. Hydrogen atoms were fixed geometrically. A full-matrix anisotropic (for non-hydrogen atoms) refinement by the method of least squares was carried out to R = 0.0612 for 5041 reflections with I > 2(I) from the overall group of 8498 reflections measured. GooF = 1.065. No corrections for absorption were introduced ( = 0.719 mm-1). All calculations were carried out with the SHELX-97 set of programs [7]. The work was carried out with the financial support of the Russian Fund for Fundamental Investigations (project No. 01-03-32641).
REFERENCES 1. 2. 3. 4. 5. 6. 7. A. N. Maslivets, N. Yu. Lisovenko, O. P. Krasnykh, O. P. Tarasova, Z. G. Aliev, and L. O. Atovmyan, Izv. Akad. Nauk, Ser. Khim., 785 (2002). Z. G. Aliev, A. N. Maslivets, O. V. Golovnina, O. P. Krasnykh, and L. O. Atovmyan, Izv. Akad. Nauk, Ser. Khim., 1255 (2001). Z. G. Aliev, O. P. Krasnykh, A. N. Maslivets, Yu. S. Andreichikov, and L. O. Atovmyan, Izv. Akad. Nauk, Ser. Khim., 2154 (1999). N. Yu. Lisovenko, O. P. Krasnykh, Z. G. Aliev, E. S. Vostrov, O. P. Tarasova, and A. N. Maslivets, Khim. Geterotsikl. Soedin., 1429 (2001). L. Fieser and M. Fieser, Reagents for Organic Synthesis, Vol. 1, Wiley, New York (1967), 1457 pp. A. N. Maslivets, O. V. Golovnina, O. P. Krasnykh, and Z. G. Aliev, Khim. Geterotsikl. Soedin., 699 (2000). G. M. Sheldrick, SHELX-97. Programs for Crystal Structure Analysis, Univ. of Gttingen, Gttingen, Germany (1997).
1299
REACTION OF 3-ACYLAMINOAND 3-ALKOXYBENZO[c]PYRILIUM SALTS WITH HYDRAZINE

S. L. Bogza1, S. Yu. Suikov2, N. M. Bogdan2, V. I. Dulenko2, and K. I. Kobrakov1 The reaction of 3-acylamino- and 3-alkoxybenzo[c]pyrilium perchlorates with hydrazine has been studied. It was discovered that the direction of the recyclization of the pyran ring depends on the type of substituent in position 3 and on the ratio of reactants. Derivatives of isoquinoline and benzo-2,3diazepine were obtained. Keywords: benzo-2,3-diazepine, benzo[c]pyrilium, hydrazine, isoquinoline, recyclization. In the whole variety of reactions of benzo[c]pyrilium salts with nucleophilic reagents that has been studied a limited number of works has been published on the interaction of them with hydrazine and its derivatives. It is known that benzo[c]pyrilium salts may be converted into derivatives of 2-aminoisoquinoline or benzo-2,3-diazepine [1-3]. Previously [4, 5] we reported conversions of benzo[c]pyrilium salts with functional substituents in position 4 (ester, cyano group) in the presence of hydrazine and phenylhydrazine, and certain factors determining the direction of recyclization. There are no data in the literature on analogous conversions of benzo[c]pyrilium salts containing functional substituents in position 3. The aim of the present work was to study the reactions of 3-acylamino-1-alkylbenzo[c]pyrilium salts 1 [6] and 3-alkoxy-1-alkylbenzo[c]pyrilium salts 2 [7] with hydrazine and also to search for new possibilities for obtaining nitrogen-containing heterocycles from them. The structure of the products of reacting salts 1 and 2 with hydrazine is regulated by the substituent at position 3 and by the salthydrazine ratio. On interacting perchlorates 1a,b and hydrazine hydrate in ratios from 1:1 to 1:3 the 1-alkyl-3-hydroxyisoquinolines 3 are formed, previously obtained by the action of ammonia [7]. Probably under these conditions the hydrazine molecule acts as a base and the oxonium cation, as in the case of the interaction with ammonia [7] and inorganic bases [8], undergoes an autorecyclization with the participation of the nitrogen atom of the acylamino group. An increase in the ratio to 1:5 leads to the formation of 1-alkyl-2aminoisoquinolin-3(2H)-ones 4. Increasing the amount of nucleophile further does not affect the course of the reaction. Replacement of the acylamino group in position 3 by an alkoxy substituent changes the character of the conversions of the benzo[c]pyrilium cation. On interacting 1-alkyl-3-ethoxybenzo[c]pyrilium perchlorates 2a,b with an equimolar amount of hydrazine hydrate at room temperature, a mixture is formed of compound 4 and the ketoester hydrazone 5, but on heating only the isoquinolone 4 is obtained, which may be isolated both as the perchlorate and as the base. Compound 4 was also obtained in the reaction of salt 2 with hydrazine __________________________________________________________________________________________ Moscow A. N. Kosygin State Textile University, Moscow 117983, Russia; e-mail: serge_zh@yahoo.com. 2 L. M. Litvinenko Institute of Physical Organic and Coal Chemistry, National Academy of Sciences of the Ukraine, Donetsk 83114. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No.10, pp. 1507-1511, October, 2004. Original article submitted March 5, 2002. 1300 0009-3122/04/4010-13002004 Springer Science+Business Media, Inc.
1
O N O O + O R 1a,b O 4a,b 1, 3, 4 a R = Me; b R = Et R O R NH H2NNH2 _ ClO4 5M O N 1-3 M O 3a,b R
OH
O NH2
dihydrochloride. Heating perchlorates 2 with an excess of hydrazine hydrate in 2-propanol leads to isoquinolone 4 and 1-alkylbenzo-2,3-diazepin-4(5H)-one 6. The yield of diazepines grows with an increase in the ratio of pyrilium salthydrazine from 1:3 to 1:5. Satisfactory yields of diazepinones 6 were obtained on cyclizing 2-acyl4,5-dimethoxyphenylacetic acid esters 7 with hydrazine, however in this case also the minor product 4 was present in the reaction mixture at 5-7%.
O O O 5a,b O + O R 2a,b AcOH / H2O O O OEt O 7a,b R O H2NNH2 O _ ClO4 5 mol O O NH O 6a,b R N OEt H2NNH2 1 mol R N OEt O O N 4a,b R NH2
+
NH2
2, 6, 7 a R = Me; b R = Et
According to the experimental data salts 1 and 2 are convenient starting materials for the synthesis of 2-aminoisoquinolin-3(2H)-ones, but not for benzo-2,3-diazepine derivatives. At the same time, it was shown in [4, 9, 10] that the recyclization of 4-substituted derivatives of benzo[c]pyrilium proceeds successfully with the formation of derivatives of 5-R-benzo-2,3-diazepine and 5-R-benzo-2,3-diazepin-4(5H)-one. It may be 1301
TABLE 1. Physicochemical Characteristics of Compounds 4-6, 9

Compound 4a 4b 5a 5b 6a 6b 9 Empirical formula C C12H14N2O3 C13H16N2O3 C14H20N2O4 C15H22N2O4 C12H14N2O3 C13H16N2O3 C15H18N2O5 61.4 61.5 62.7 62.9 59.9 60.0 61.0 61.2 61.4 61.5 62.8 62.9 59.0 58.8 Found, % Calculated, % H 5.9 6.0 6.5 6.5 7.0 7.2 7.5 7.5 5.9 6.0 6.4 6.5 6.0 5.9
mp, N 12.0 12.0 11.4 11.3 10.2 10.0 9.7 9.5 12.0 12.0 11.5 11.3 9.1 9.1 223-225 199-200 127-129 111-113 214-216 187-189 167-169
Yield, %
78 73 50 42 47 39 60
suggested that compounds of the benzo-2,3-diazepine series, including benzo-2,3-diazepin-4(5H)-ones, may be obtained in satisfactory yield by reacting hydrazine with benzo[c]pyrilium salts with a substituent in the 4 position. Confirmation of this hypothesis for derivatives of 3-alkoxybenzo[c]pyrilium salts comes from the recyclization carried out by us of 3,6,7-trimethoxy-4-(methoxycarbonyl)methylbenzo[c]pyrilium perchlorate (8) [9] into 6,7-dimethoxy-1-methyl-5-(methoxycarbonyl)methylbenzo-2,3-diazepin-4(5H)-one (9), isolated after purification in a yield of more than 50%. TABLE 2. Spectral Characteristics of Compounds 4-7, 9
Compound 4a IR spectrum, , cm-1 3250, 3170, 1620
1
4b
3240, 3165, 1620
5a
3360, 3300,1735, 1625 3380, 3300,1730, 1625 3210, 1635, 1615
5b
6a
6b
3200, 1630, 1615
7a
1740, 1685
7b
1730, 1680
2.78 (3, s, 3); 3.80 (3, s, 3); 3.82 (3, s, 3); 6.37 (1, s, arom.); 6.71 (2, s, N2); 6.73 (1, s, arom.); 7.00 (1, s, arom.) 1.25 (3, t, 3); 3.29 (2, q, 2); 3.82 (6, s, 2 3); 6.38 (1, s, arom.); 6.58 (2, s, N2); 6.74 (1, s, arom.); 6.93 (1, s, arom.) 1.12 (3, t, 3); 2.14 (3, s, 3); 3.75 (3, s, 3); 3.79 (3, s, 3); 3.85 (2, s, 2); 4.01 (2, q, 2); 6.85 (1, s, arom.); 7.03 (1, s, arom.) 1.01 (3, t, 3); 1.26 (3, t, 3); 2.80 (2, q, 2); 3.75 (3, s, 3); 3.77 (3, s, 3); 3.87 (2, s, 2); 4.02 (2, q, 2); 6.85 (1, s, arom.); 6.92 (1, s, arom.) 2.42 (3, s, 3); 3.21 (2, s, 2); 3.80 (3, s, 3); 3.83 (3, s, 3); 6.87 (1, s, arom.); 7.03 (1, s, arom.); 10.35 (1, s, NH) 1.14 (3, t, 3); 2.90 (2, q, 2); 3.11 (2, s, 2); 3.80 (3, s, 3); 3.93 (3, s, 3); 7.27 (1, s, arom.); 7.51 (1, s, arom.); 10.20 (1, s, NH) 1.12 (3, t, 3); 2.14 (3, s, 3); 3.75 (3, s, 3); 3.79 (3, s, 3); 3.85 (2, s, 2); 4.01 (2, q, 2); 6.85 (1, s, arom.); 7.03 (1, s, arom.) 1.01 (3, t, 3); 1.36 (3, t, 3); 2.80 (2, q, 2); 3.75 (3, s, 3); 3.77 (3, s, 3); 3.87 (2, s, 2); 4.02 (2, q, 2); 6.85 (1, s, arom.); 6.92 (1, s, arom.) 2.30 (3, s, 3); 2.75 (1, dd, JAB = 16.8, JA = 4.7, HA); 3.14 (1, dd, JAB = 16.8, J = 10.5, HB); 4.69 (1, dd, JA = 4.7, J = 10.5, HC); 3.58 (3, s, 3); 3.78 (3, s, 3); 3.81 (3, s, 3); 6.81 (1, s, arom.); 7.02 (1, s, arom.); 8.85 (1, br. s, NH)
1302
CO2Me O + O Me 8 O _ ClO4 9 OMe H2NNH2 O
CO2Me O NH O Me N
In our opinion, on forming a seven-membered ring the role of the substituent at position 4 of the benzo[c]pyrilium cation results in disturbance of the planarity of the intermediate formed on opening the pyran ring with a molecule of hydrazine, which makes possible the formation of the energetically disadvantageous, compared with a six-membered, diazepine ring.
EXPERIMENTAL The IR spectra were recorded in nujol on a UR 20 spectrophotometer, and the 1H NMR spectra on a Varian Gemini 200 (200 MHz) spectrometer in DMSO-d6, internal standard was TMS. The physicochemical and spectral characteristics of the synthesized compounds are given in Tables 1 and 2. Keto ester 7 was characterized only by spectral methods. Procedures providing the best yields are given for compounds 4 and 6. 2-Amino-1-R-6,7-dimethoxyisoquinolin-3(2H)-ones (4) and Hydrazones of Ethyl 2-Acyl-4,5dimethoxyphenylacetates (5). Perchlorate 2 (10 mmol) was added to a solution of hydrazine hydrate (20 mmol) in 2-propanol (15 ml), the mixture was stirred until solution was achieved, and then left overnight. The reaction mixture was poured into water and the solid hydrazone 5 filtered off. The filtrate was evaporated to dryness in vacuum, and the residue separated in a mixture of dichloromethaneaqueous sodium bicarbonate solution. The organic layer was washed with water, dried over anhydrous MgSO4, the solvent evaporated, and aminoisoquinolone 4 crystallized from alcohol. 2-Amino-1-R-6,7-dimethoxyisoquinolin-3(2H)-ones (4). A mixture of perchlorate 2 (10 mmol) and hydrazine hydrate (10 mmol) in alcohol (20 ml) was boiled for 2-3 h, and evaporated to dryness in vacuum. The residue was dissolved in water, and sodium acetate (10 mmole) added. The mixture was stirred for 10-15 min, an equimolar amount of Na2CO3 was added, and the mixture stirred for a further 30-60 min. The reaction mixture was evaporated to dryness in vacuum, the residue was dissolved in dichloromethane, and the solution washed once with water. The organic layer was dried over anhydrous MgSO4, the solvent evaporated, and isoquinolone 4 crystallized from alcohol. 1-R-7,8-Dimethoxybenzo-2,3-diazepin-4(5H)-ones (6). A mixture of keto ester 7 (10 mmol) and hydrazine hydrate (30 mmol) in 2-propanol was heated for 2-3 h, then left overnight. The precipitated solid diazepinone 6 was filtered off and recrystallized three times from 2-propanol. Isoquinolone 4 was isolated from the alcoholic filtrates. Ethyl 2-Acyl-4,5-dimethoxyphenylacetates (7). Perchlorate 2 was dissolved with heating in 50% acetic acid. The cooled solution was poured into water, and left overnight. The solid was filtered off, washed with water, and dried.
1303
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. K. Blount and R. Robinson, J. Chem. Soc., 555 (1933). G. N. Dorofeenko, V. I. Dulenko, L. V. Dulenko, and S. V. Krivun, Zh. Org. Khim., 1, 1171 (1965). E. V. Kuznetsov, I. V. Scherbakova, and A. T. Balaban, Adv. Heterocycl. Chem., 50, 158 (1988). S. L. Bogza, Yu. A. Nikolyukin, and V. I. Dulenko, Khim. Geterotsikl. Soedin., 1475 (1993). S. L. Bogza, Yu. A. Nikolyukin, M.Yu. Zubritskii, and V. I. Dulenko, Khim. Geterotsikl. Soedin., 317 (1995). G. N. Dorofeenko, S. V. Krivun, and E. I. Sadekova, Khim. Geterotsikl. Soedin., 730 (1971). G. N. Dorofeenko and V. G. Korobkova, Khim. Geterotsikl. Soedin., 1601 (1971). Yu. A. Nikolyukin, S. L. Bogza, T. T. Zaritovskaya, and V. I. Dulenko, dep. in VINITI 17.04.86, No. 2800 V 86. S. L. Bogza, A. A. Malienko, S. Yu. Suikov, M. Yu. Zubritskii, K. I. Kobrakov, and V. I. Dulenko, Zh. Org. Khim., 32, 596 (1996). J. Korosi and T. Lang, Chem. Ber., 107, 2883 (1974).
1304
DEHYDRATION OF 4-HYDROXY-4-METHYL3-PHENYLAMINO-OXAZOLIDIN-2-ONES
A. A. Bogolyubov1, N. B. Chernysheva1, V. V. Nesterov2, M. Yu. Antipin2, and V. V. Semenov1 The dehydration of two 5,5-disubstituted 4-hydroxy-4-methyl-3-phenylaminooxazolidin-2-ones into the corresponding 4-methylene-3-phenylaminooxazolidin-2-ones has been carried out. The structure of the products was confirmed by X-ray diffraction analysis. Keywords: 4-hydroxy-4-methyl-3-phenylaminooxazolidin-2-ones, oxazolidin-2-ones. 4-methylene-3-phenylamino-
The dehydration of 5,5-disubstituted 4-hydroxy-4-methyloxazolidin-2-ones with aryl substituent at position 3 was considered by us previously [1]. Based on analysis of 1H NMR, IR, and mass spectral data the structure of the reaction products was established unequivocally and no doubts were raised.
R O O N Ar OH MeCN / TsOH H2O O O N Ar R
In the present report the dehydration is described of oxazolidinones 1a,b bearing a specific substituent, namely PhNH, at position 3. According to the data of [2], where many examples were given of expansion and contraction of rings of related heterocyclic compounds under conditions of acid catalysis, rearrangement of oxazolidinones 1 might have been expected, for example, into 1,3,4-oxadiazinones A.
R R N O O A Ph O H2O O 1a,b 1, 2 a R = Me, b R = Et N N Ph H H2O O O N N Ph H OH R
NH
2a,b 6972%
Such a rearrangement, however, is not observed, but the reaction occurs as usual [1] and leads to 4-methylene derivatives 2. As established on the example of the conversion of compound 1a into methylene derivative 2a, the reaction may also occur without acid catalysis. __________________________________________________________________________________________ N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow 119991; e-mail: vs@cacr.ioc.ac.ru. 2 A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Moscow 119991; e-mail: mishan@xray.ineos.ac.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1512-1517, October, 2004. Original article submitted January 23, 2002. 0009-3122/04/4010-13052004 Springer Science+Business Media, Inc. 1305
1
The expected two doublets of the C=CH2 group protons were present in the 1H NMR spectra of the dehydration products. In the IR spectrum there was an absorption band for this group and there were also absorption bands for NH and C=O. Since on the basis of only IR and 1H NMR spectra it is difficult to make a final conclusion in favor of the six-membered (A) or five-membered (2) products, we carried out an X-ray diffraction analysis of the substance obtained from oxazolidinone 1b. It is five-membered oxazolidinone 2b (Fig. 1, Tables 1 and 2). In this molecule the five-membered heterocycle O(1)C(2)N(3)C(4)C(5) is exactly planar (the planarity is fulfilled with a precision of 0.004 ). The dihedral angle between it and the plane of the phenyl substituent [C(11)C(16)] is 85.5, and the torsion angles C(2)N(3)N(10)C(11) and N(3)N(10) C(11)C(12) at 101.6 and -26.4 respectively indicate the twist of these fragments of the molecule relative to one another. In the crystal the hydrogen atom of the amino group participates in the formation of an intermolecular hydrogen bond N(10)H(10N)O(2) (-x; + y; 1 - z) [N(10)O(2) 3.035(2), N(10)H(10N) 0.86(2), H(10N)O(2) 2.18(2) , angle N(10)H(10N)O(2) 135(2)]. These H bonds link the molecules in endless chains (Fig. 2, projection bc, the intermolecular hydrogen bonds NHO are shown by dotted lines). The remaining geometric parameters (bond lengths and bond angles) in the investigated molecule have standard values [3]. No other shortened intermolecular nonvalence contacts were detected.
TABLE 1. Bond Lengths in Oxazolidinone 2b

Bond O(1)C(2) O(1)C(5) O(2)C(2) N(3)C(2) N(3)N(10) N(3)C(4) N(10)C(11) C(4)C(9) C(4)C(5) C(5)C(7A) C(5)C(7) d, 1.338(2) 1.478(3) 1.201(2) 1.366(2) 1.383(2) 1.393(2) 1.411(2) 1.308(3) 1.510(3) 1.437(9) 1.455(6) Bond C(5)C(6) C(5)C(6A) C(7)C(8) C(7A)C(8A) C(11)C(12) C(11)C(16) C(12)C(13) C(13)C(14) C(14)C(15) C(15)C(16) d, 1.636(8) 1.627(10) 1.462(9) 1.481(10) 1.383(3) 1.386(3) 1.387(3) 1.362(4) 1.367(4) 1.385(3)
Fig. 1. Structure of the molecule of oxazolidinone 2b. 1306
Fig. 2. Packing of oxazolidinone 2b molecules in the crystal.
TABLE 2. Bond Angles in Oxazolidinone 2b

Angle C(2)O(1)C(5) C(2)N(3)N(10) C(2)N(3)C(4) N(10)N(3)C(4) N(3)N(10)C(11) O(2)C(2)O(1) O(2)C(2)N(3) O(1)C(2)N(3) C(9)C(4)N(3) C(9)C(4)C(5) N(3)C(4)C(5) C(7A)C(5)O(1) C(7)C(5)O(1) C(7A)C(5)C(4) C(7)C(5)C(4) O(1)C(5)C(4) , deg. 110.9(2) 122.1(14) 113.2(2) 124.8(2) 117.2(2) 123.7(2) 127.9(2) 108.4(2) 126.0(2) 129.5(2) 104.6(2) 114.3(7) 115.7(4) 126.9(6) 117.8(4) 102.9(2) Angle C(7)C(5)C(6) O(1)C(5)C(6) C(4)C(5)C(6) C(7A)C(5)C(6A) O(1)C(5)C(6A) C(4)C(5)C(6A) C(5)C(7)C(8) C(5)C(7A)C(8A) C(12)C(11)C(16) C(12)C(11)N(10) C(16)C(11)N(10) C(11)C(12)C(13) C(14)C(13)C(12) C(13)C(14)C(15) C(14)C(15)C(16) C(15)C(16)C(11) , deg. 106.8(4) 105.0(3) 107.7(4) 105.5(7) 99.3(6) 104.2(6) 104.2(5) 91.8(8) 119.3(2) 122.4(2) 118.2(2) 119.6(2) 121.1(2) 119.4(2) 120.8(2) 119.8(2)
1307
TABLE 3. Coordinates (104) and Isotropic (for non-hydrogen atoms equivalent) Temperature Parameters of Atoms in Oxazolidinone 2b
Atom O(1) O(2) N(3) N(10) C(2) C(4) C(5) C(6) C(7) C(8) C(6A) C(7A) C(8A) C(9) C(11) C(12) C(13) C(14) C(15) C(16) H(10N) H(91) H(92) H(12) H(13) H(14) H(15) H(16) x 2970(2) 52(2) 1556(2) 126(2) 1376(2) 3295(3) 4337(3) 5584(8) 5489(6) 4278(10) 4700(18) 5990(11) 5215(18) 3842(4) -126(2) 472(3) 52(3) -935(3) -1509(3) -1099(3) 55(29) 2988(36) 5072(41) 1144(31) 467(37) -1267(34) -2219(35) -1515(27) y 328(1) 123(1) 1879(1) 2544(2) 723(2) 2297(2) 1265(2) 652(7) 1572(9) 1911(10) 1741(14) 768(14) 414(20) 3360(3) 2584(2) 1662(2) 1702(3) 2638(3) 3559(3) 3549(2) 3262(24) 3960(28) 3564(28) 1006(24) 1020(30) 2683(24) 4204(26) 4233(22) z 7580(1) 7529(1) 8058(1) 8246(1) 7703(1) 8202(2) 7873(2) 8730(6) 7242(5) 6441(4) 6914(9) 8304(8) 9090(8) 8544(2) 9135(1) 9732(1) 10577(2) 10830(2) 10245(2) 9400(1) 8008(16) 8744(19) 8640(20) 9532(16) 10976(21) 11419(19) 10396(18) 8992(15) U 66(1) 52(1) 42(1) 41(1) 43(1) 59(1) 92(1) 108(3) 98(2) 92(2) 124(9) 125(7) 92(5) 87(1) 38(1) 52(1) 64(1) 67(1) 66(1) 51(1) 60(7) 87(8) 98(10) 67(7) 93(9) 81(8) 81(8) 56(6)
EXPERIMENTAL The 1H NMR spectra were recorded on a Bruker WM 250 (250 MHz) instrument in CDCl3, internal standard was TMS. The IR spectra were taken on a Perkin-Elmer 577 instrument in KBr. TLC was carried out on Silufol UV 254 plates, using the system benzeneethyl acetate, 4:1. Oxazolidinones 1a,b were obtained by us previously [4,5]. Colorless crystals of oxazolidinone 2b were obtained by slow crystallization during 3 days. The crystals of compound 2b (C13H16N2O2) are monoclinic; at 25C: a = 7.678(1), b = 10.852(2), c = 15.354(3) ; = 99.41(2); V = 1262(1) 3; dcalc = 1.222 g/cm3; Z = 4; space group P21/c. The parameters of the unit cell and the intensities of 3269 reflections were measured on a Siemens automatic four-circle diffractometer P3/PC [(MoK), graphite monochromator, /2 scanning, max = 27]. The structure was solved by the direct method and refined by the full-matrix least-squares method in anisotropic mode for the non-hydrogen atoms. The C(6), C(7), and C(8) atoms of the methyl and ethyl substituents in the molecule were randomized at two positions with different populations (2:1). The hydrogen atoms were localized objectively with a Fourier difference synthesis and were refined in isotropic mode. The positions of the hydrogen atoms at C(6), C(7), C(8), and C(6A), C(7A), and C(8A) were calculated geometrically and included in the refinement as a rider model. The final values of the divergence factors were wR2 = 0.144 at 2958 independent reflections [R1 = 0.056 for 2077 independent reflections with I >2(I)]. 1308
All calculations were carried out on an IBM PC/AT 586 computer with programs SHELXTL PLUS and SHELXL 93 [4]. 5,5-Dimethyl-4-methylene-3-phenylaminooxazolidin-2-one (2a). Molecular sieve 4 (6.54 g) and p-toluenesulfonic acid monohydrate (5-10 mg) were added to oxazolidinone 1a (0.236 g, 1 mmol) in acetonitrile (10 ml). The mixture was boiled under reflux for 8.5 h (check by TLC). Zeolite 4A was separated, washed with acetonitrile (3 10 ml) by boiling for 15 min, the solution and washings were combined, the solvent removed in vacuum, the residue dried, and 0.190 g (87%) of slightly yellow crystals were obtained. If necessary (check by TLC) the substance was recrystallized from mixture (0.74 ml) of benzeneacetonitrile 70:4, and white crystals (0.150 g, 69%) were obtained; mp 159-161C, Rf 0.61. IR spectrum, , cm-1: 1665, 1745, 3310. 1H NMR spectrum, , ppm (J, Hz): 1.64 (6H, s, 5,5-CH3); [4.11 (1H, d, J = 2.6); 4.40 (1H, d, J = 2.6)] (C=CH2); 6.12 (1H, s, NH); 6.75 (2H, d, J = 8.5, 2',6'-HPh); 6.98 (1H, q, 4'-HPh); 7.22-7.31 (2H, m, 3',5'-HPh). Found, %: C 66.16; H 6.46; N 12.82. C12H14N2O2. Calculated, %: C 66.06; H 6.42; N 12.84. 5-Ethyl-5-methyl-4-methylene-3-phenylaminooxazolidin-2-one (2b). Oxazolidinone 1b (11.30 g, 45.2 mmol), benzene (45 ml), and acetonitrile (2 ml) were boiled with a DeanStark trap for 3.5 h. The precipitated slightly yellow crystals (7.85 g, 75%) were recrystallized from benzene (25 ml) plus acetonitrile (2-3 drops) and snow-white crystals (6.15 g) were obtained. The mother liquors were combined, boiled with activated carbon, evaporated, and a further 1.34 g of substance, slightly cream-colored but pure by TLC, were obtained. Overall yield of product was 7.58 g (72%); mp 124-126C, Rf 0.60. IR spectrum, , cm-1: 1655, 1780, 3280. 1H NMR spectrum, , ppm (J, Hz): 1.02 (3H, t, CH2CH3); 1.62 (3H, s, 5-CH3); 1.70-2.00 (2H, m, CH2CH3); [4.08 (1H, d, J = 1.5), 4.45 (1H, d, J = 1.5)] (C=CH2); 6.12 (1H, s, NH); 6.78 (2H, d, J = 8.5, 2',6'-HPh); 6.95 (1H, q, 4'-HPh); 7.22-7.31 (2H, m, 3',5'-HPh). Found, %: C 67.26; H 6.95; N 12.05. C13H16N2O2. Calculated, %: C 67.24; H 6.90; N 12.07. The X-ray structural investigations were carried out with the financial support of the Russian Foundation for Fundamental Investigations (RFFI), grants Nos. 97-03-33783, 96-15-97367, 96-07-89187.
REFERENCES 1. 2. 3. 4. 5. 6. N. B. Chernysheva, A. A. Bogolyubov, and V. V. Semenov, Khim. Geterotsikl. Soedin., 241 (1999). O. P. Shvaika and V. N. Artemov, Usp. Khim., 41, 1789 (1972). F. H. Allen, O. Kennard, D. G. Watson, L. Brammer, A. G. Orpen, and R. Taylor, J. Chem. Soc., Perkin Trans. 2, No. 12, Suppl. 1 (1987). N. B. Chernysheva, A. A. Bogolyubov, and V. V. Semenov, Khim. Geterotsikl. Soedin., 1303 (2004). www.chemical-block.com G. M. Sheldrick, SHELXTL Version 5, Software Reference Manual, Siemens Industrial Automation, Madison, Wisconsin (1994).
1309
REGIOSELECTIVITY OF THE INTERACTION OF (1S,2S)-2-AMINO1-(4-NITROPHENYL)-1,3-PROPANEDIOL WITH SOME SYMMETRICAL KETONES

M. Madesclaire1, P. Coudert1, V. P. Zaitsev2, and Yu. V. Zaitseva2 The interaction of (1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediol with a series of symmetrical ketones has been studied. As a result isomeric oxazolidines are formed in a ratio of 85:15. These oxazolidines were shown to decompose readily under the action of hydrazine. Keywords: (1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediol, acetone, oxazolidine, cyclohexanone, cyclopentanone, symmetrical ketones, regioselectivity. Study of the regioselectivity of organic reactions is of considerable interest. We showed previously that (1S,2S)-2-arylmethylamino-1-(4-nitrophenyl)-1,3-propanediols interact regioselectively with paraformaldehyde [1]. The first step of the method proposed for using the side product of the manufacture of the levomycetin analog thiamphenicol is based on the regioselectivity of the interaction of (1S,2S)-2-amino-1-(4-nitrophenyl)1,3-propanediol with acetone [2]. On interacting (1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediol (1) with the symmetrical ketones 2a-d it is possible to form two isomeric oxazolidines 3 and 4.
O
NO2
NO2
NO2
2ad
H2O
+
CH O
R
CH OH 1
CH
CH2
CH NH
R
CH2 OH
CH
CH
CH2 O
R
NH2 OH
OH HN
R
3ad
4ad
24 a R+R = (CH2)5, b R+R = (CH2)4, c R+R = (CH2)6, d R = Me
The use of this reaction [2] assumes a high degree of regioselectivity for it with the preferential formation of isomer 3, but there are no data in this work on the regioselectivity of the reaction. Meanwhile it is known that secondary alcoholic groups of 1,2-diols are more inclined than primary to form cyclic acetals [3]. __________________________________________________________________________________________ Universite d'Auvergne, Faculte de Farmacie, Clermont-Ferrand, France; e-mail: michel.madesclaire@u-clermont1.fr. 2 Samara State University, Samara 443011, Russia; e-mail: vzaitsev@ssu.samara.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1518-1523, October, 2004. Original article submitted June 18, 2002; revision submitted December 20, 2003. 1310 0009-3122/04/4010-13102004 Springer Science+Business Media, Inc.
1
Symmetrical ketones are frequently used to form O-alkylidene protection, possessing various stability depending on the structure of the ketone used [3]. In the present work we have investigated the conditions of interaction of a series of symmetrical ketones 2a-d with 2-amino-1,3-propanediol 1, the regioselectivity of this reaction, and the stability of oxazolidines obtained towards hydrazinolysis [4]. The interaction of compound 1 with ketones was carried out in boiling benzene with azeotropic distillation of water. The criterion for completion of the reaction is the dissolution of the solid and cessation of water distillation, after which the reaction mixture was boiled for a further 30 min. Benzene was then distilled off on a rotary evaporator and the excess of ketone on vacuum equipment to constant weight, which corresponded to quantitative conversion of 2-amino-1,3-propanediol. The compounds obtained were spectrally pure and were not subjected to additional purification before assessing regioselectivity. As is evident from Table 1, the reactivity of ketones falls in the series, cyclohexanone > cyclopentanone >> cycloheptanone. In the reaction cyclic ketones were taken in 30% excess in the case of cyclohexanone and cyclopentanone and in 80% excess in the case of cycloheptanone. Since the boiling point of acetone is less than the boiling point of benzene and it accumulates in the DeanStark stillhead, acetone is introduced into the reaction in a large excess. Under the conditions indicated it displays a greater reactivity than cycloheptanone but less than cyclopentanone. Recently, semiempirical quantum-mechanical methods of calculation, particularly AM1 and PM3, have been widely used to predict the results of reactions and the structure of the resulting products [5,6]. We selected isomers 3a and 4a, the products of the interaction of compound 1 with cyclohexanone, as model compounds. Four optimal conformers were considered for each of the isomers, two with R and S configuration of the nitrogen atom, and the following energy values (kcal/mol) were obtained for the conformers being considered: AM1 (3a): -4144.1; -4146.2; -4146.5; -4147.8; PM3 (3a): -4152.5; -4153.8; -4155.1; -4158.2. AM1 (4a): -4146.7; -4147.7; -4147.7; -4147.8; PM3 (4a): -4155.6; -4156.5; -4157.2; -4157.4. It is evident that the difference in energy values will be of the same order for other pairs of compounds 3 and 4. In spite of the fact that the energy values obtained indicate some preference for isomer 4a, it is impossible from these data to draw a conclusion on the preference of forming one of the isomers, since the difference in the obtained values is less than the admissible error of the calculation, which may reach 5 kcal/mol [7]. However it is possible to conclude from these data that the regioselectivity of this reaction may not be high [8]. The 1H NMR spectra of the reaction products were taken for an experimental assessment of the regioselectivity of the reaction. It turned out that the spectra taken in CDCl3 and DMSO-d6 differed strongly (Fig. 1). The signals of the ArCH and NCH methine protons of isomers 3 and 4 have different chemical shifts only in deuterochloroform, so it is possible to assess the regioselectivity of the reaction investigated by the 1 H NMR spectrum of the reaction mixtures in deuterochloroform. Independent on the nature of ketone taken the ratio of isomers was approximately 85:15 (Fig. 1, Table 1) and did not change with time or after purification on a chromatographic column. TABLE 1. Data on the Interaction of Compound 1 (2.1 g, 0.01 mol) with Ketones 2a-d
Ketone 2 Cyclohexanone (a) Cyclopentanone (b) Cycloheptanone (c) Acetone (d) Amount of ketone, g (mol) 1.3 g (0.013) 1.1 g (0.013) 2.1 g (0.018) 10 ml (0.14) Reaction time, min* 15/45 45/75 180/210 60/90 Ratio of isomers 3 and 4, as % (data of 1H NMR) 84 : 16 85 : 15 83 : 17 83 : 17
_______ * The time required for complete solution of 1 is given in the numerator, the total reaction time is given in the denominator. 1311
Fig. 1. Region of the 1H NMR spectrum of the interaction products of compound 1 with cyclohexanone used for assessment of the regioselectivity of the reaction, a) in CDCl3 and b) in DMSO-d6. The 1H NMR spectra of the reaction mixture formed on interacting compound 1 with cyclohexanone were taken in the presence of Eu(fod)3 to confirm the structure of the main reaction product. This reaction product was selected because of its better solubility in deuterochloroform. The signals of the methine proton close to the aromatic ring are readily discernible in both cases (Fig. 1a). The proton being considered in isomer 4a is closer to the shift reagent and under its influence correspondingly must have a larger shift of signal in the 1 H NMR spectrum, which is in fact observed (Fig. 2).
Fig. 2. Signals of the ArCH methine proton of isomers 3a and 4a in the presence of Eu(fod)3. The molar ratio of Eu(fod)3/substrate is a) 0.03; b) 0.04; c) 0.07; d) 0.09. 1312
This enables structure 3a to be assigned unequivocally to the main reaction product.

NO2 NO2
CHCHCH2 O NH OH Eu 3+ 3a
CHCHCH2 HO NH O Eu3+
4a
Acetal protection is widely used for the protection of neighboring hydroxyl groups. It is known that acetals formed with 1,2-diols possess differing stability depending on the nature of ketone used. Methylene acetals are the most stable to acid hydrolysis, which also causes their infrequent use [3]. We showed previously that oxazolidines formed on interacting 1,2-amino alcohols with paraformaldehyde are decomposed on treatment with alcoholic solution of hydrazine [4]. In the present work the stability of the various oxazolidine systems has been studied. For this purpose the mixture of oxazolidines formed on interacting compound 1 with cyclohexanone, cyclopentanone, cycloheptanone, and acetone was dissolved in ethyl alcohol and hydrazine hydrate was added. Even after 15-20 min precipitation of the solid initial compound 1 from the reaction mixture had begun, which indicates the low stability of these oxazolidines under hydrazinolysis conditions. In all the experiments the yield of compound 1 was ~80%. The described oxazolidines began to decompose straight away under the action of hydrazine, consequently a quantitative assessment of their relative stability was not carried out.
EXPERIMENTAL The 1H NMR spectra were recorded on a Bruker Avance DRX 200 (200 MHz) spectrometer in CDCl3, internal standard was TMS. Spectra were processed with the MESTREC computer program. Melting points were determined on a Kofler block. (1S,2S)-2-Amino-1-(4-nitrophenyl)-1,3-propanediol (1) (Akrikhin works (Kupavna, Moscow region)) recrystallized from alcohol was used in the work. Ketones 2a-c were commercial preparations of Aldrich, silica gel type SDS was from France. Column chromatography was carried out on column (3 40 cm) packed with silica gel 35-70 m. Eluent was ethyl acetatecyclohexane, 1:1. Interaction of Compound 1 with Ketones 2a-d. Compound 1 (2.1 g, 0.01 mol), cyclohexanone 2a (1.3 g, 0.013 mol), and benzene (50 ml) were placed in a round-bottomed flask fitted with a DeanStark stillhead. The reaction mixture was boiled for 15 min until complete dissolution of compound 1 and then for a further 30 min. Benzene was distilled off on a rotary evaporator, and the excess of cyclohexane on vacuum equipment. Crude product (2.9 g, 100%) was obtained. The 1H NMR spectrum was determined in deuterochloroform to determine the ratio of isomers 3a and 4a. Reactions with cyclopentanone 2b, cycloheptanone 2c, and acetone 2d were carried out by an analogous procedure. The yields of crude product 3b-d were 98-100%. The crude product was purified by chromatography. (1S,2S)-2-Amino-1,2-O,N-cyclohexylidene-1-(4-nitrophenyl)-1,3-propanediol (3a). Oil. 1H NMR spectrum, , ppm (J, Hz): 7.53, 8.21 (4H, two d, J = 8, Harom); 4.80 (1H, d, J = 8, CHAr); 3.66-3.92 (2H, two dd, J = 4, J = 12, diastereotopic CH2); 3.14-3.20 (1H, m, CHN); 2.90 (2H, br. s, OH, NH); 1.49-1.87 (10H, m, (CH2)5). Found, %: C 61.87; H 7.12. C15H20N2O4. Calculated, %: C 61.61; H 6.90. 1313
(1S,2S)-2-Amino-1,2-O,N-cyclopentylidene-1-(4-nitrophenyl)-1,3-propanediol (3b). Oil. 1H NMR spectrum, , ppm (J, Hz): 7.57, 8.24 (4H, two d, J = 8, Harom); 4.78 (1H, d, J = 8, CHAr); 3.70-3.90 (2H, two dd, J = 4, J = 12, diastereotopic CH2); 3.16-3.22 (1H, m, CHN); 2.78 (2H, br. s, OH, NH); 1.70-1.93 (8H, m, (CH2)4). Found, %: C 60.63; H 6.71. C14H18N2O4. Calculated, %: C 60.40; H 6.52. (1S,2S)-2-Amino-1,2-O,N-cycloheptylidene-1-(4-nitrophenyl)-1,3-propanediol (3c). Mp 63-65C. 1 H NMR spectrum, , ppm (J, Hz): 7.53, 8.23 (4H, two d, J = 8, Harom); 4.74 (1H, d, J = 8, CHAr); 3.66-3.92 (2H, two dd, J = 4, J = 12, diastereotopic CH2); 3.03-3.09 (1H, m, CHN); 2.90 (2H, br. s, OH, NH); 1.49-1.89 (12H, m, (CH2)6). Found, %: C 62.92; H 7.39. C16H22N2O4. Calculated, %: C 62.71; H 7.24. (1S,2S)-2-Amino-1,2-O,N-isopropylidene-1-(4-nitrophenyl)-1,3-propanediol (3d). Mp 41-43C. 1 H NMR spectrum, , ppm (J, Hz): 7.53-8.23 (4H, two d, J = 8, Harom); 4.82 (1H, d, J = 8, CHAr); 3.69-3.94 (2H, two dd, J = 4, J = 12, diastereotopic CH2); 3.16-3.21 (1H, m, CHN); 2.90 (2H, br. s, OH, NH); 1.56 [6H, s, C(CH3)2]. Found, %: C 56.91; H 7.23. C12H16N2O4. Calculated, %: C 56.66; H 7.14. Hydrazinolysis of the Products of Interaction of Compound 1 with Ketones 2a-d. Mixtures obtained by reacting compound 1 (5 g) with the appropriate quantity of ketones 2a-d were dissolved in alcohol (10 ml) and hydrazine hydrate (5 ml) was added. The mixtures were left overnight, the precipitated crystals 1 were filtered off, washed with a small amount of alcohol, and dried. Yield for 2a was 4.05 g (81%), and for 2b-d (8082%). In all cases mp 164-166C (163-164C [4]).
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. J. Couquelet, M. Madesclaire, F. Leal, V. P. Zaitsev, and S. Kh. Sharipova, Khim. Geterotsikl. Soedin., 536 (1999). C. Giordano, S. Cavicchioli, S. Levi, and M. Villa, J. Org. Chem., 56, 6114 (1991). T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, Chichester, Brisbane, Toronto, Singapore (1991), p. 473. J. Couquelet, M. Madesclaire, F. Leal, V. P. Zaitsev, and S. Kh. Sharipova, Khim. Geterotsikl. Soedin., 78 (2002). N. H. Morgon, Y. Takahata, and A. C. Gaudio, J. Mol. Struct. Theochem., 498, 93 (1999). Yavari Issa and Dadgar Mohsen, J. Mol. Struct.Theochem, 467, 156 (1999). N. F. Stepanov and V. I. Pupyshev, Quantum Mechanics of Molecules and Quantum Chemistry [in Russian], Publ. House. MGU, Moscow (1991), p. 383. E. L. Eliel, N. L. Allinger, S. J. Angyal, and G. A. Morrison, Conformational Analysis, Interscience (Wiley), New York (1965), 524 pp.
1314
NOVEL SCHEMES FOR THE SYNTHESIS OF PYRROLOCOUMARINS

V. V. Suslov, E. N. Gordeev, and V. F. Traven Two novel schemes have been developed for the synthesis of pyrrolocoumarin derivatives. A series of previously unknown 4,9-dimethylpyrano[3,2-e]indol-7(3H)-ones have been prepared. Keywords: benzo[a]pyrano[2,3-g]carbazol-3(7H)-one, indole, carbazole, coumarin, pyrano[3,2-e]indol7(3H)-one, pyrano[2,3-c]carbazol-3(7H)-one, pyrrolocoumarin, Fischer reaction. Since pyrrolocoumarins are promising compounds in the search for novel antitumor agents [1] it is currently of interest to develop novel synthetic routes for the preparation of differently structured pyrrolocoumarins. In this study we propose two novel schemes for the synthesis of pyrano[3,2-e]indol-7(3H)one derivatives. Analysis of the literature data shows that there are two possible routes for the construction of pyrrolocoumarin molecules. The first route is based on the formation of the pyrrole fragment condensed with coumarin ring. The second route introduces pyrone fragment into appropriate hydroxyindole or hydroxyindoline molecule. The first synthetic route is achieved using Bischler and Fischer reactions. The Bischler reaction was used for the preparation of 4,9-dimethyl-1,2-diphenylpyrano[3,2-e]indol-7(3H)-one [2]. The Bischler synthesis needs drastic conditions and the halo or hydroxycarbonyl compounds which are not always available and so this narrows its use. An alternative route is based on the reaction of the corresponding arylhydrazine with carbonyl compounds and subsequent Fischer indolization of hydrazones obtained and this is more versatile. It has been used successfully in the preparation of differently structured pyrrolocoumarins [1, 3]. However, in this case the starting coumarinylhydrazines are prepared directly before the synthesis of pyrrolocoumarins and are used as solution of arylhydrazine hexachlorostannate in hydrochloric acid. The procedure significantly limits the possibility of carrying out the cyclization and in some cases does not permit preparation of pyrrolocoumarins of the desired structure. In the second route (i.e. from hydroxyindoles) pyrrolocoumarins are also prepared by two routes. One of these includes the formylation of the starting 5-hydroxyindole and subsequent cyclization of aldehyde obtained with acetic anhydride [4]. The second scheme is based on Pechmann cyclization of 5-hydroxyindole with acetoacetic ester [5]. The Pechmann reaction is also used for the preparation of 8-ethyl-4-methylpyrano[3,2-e]indol-2(8H)-one from the corresponding hydroxyindoline [6]. The use of this second synthetic route for pyrrolocoumarins is limited by the complexity of preparing the starting hydroxyindoles and hydroxyindolines. __________________________________________________________________________________________ D. I. Mendeleev Chemical Technological University, Moscow 125047; e-mail: traven@muctr.edu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No 10, pp. 1524-1532, October, 2004. Original article submitted February 22, 2002. 0009-3122/04/4010-13152004 Springer Science+Business Media, Inc. 1315
In the current work we report two novel schemes for the synthesis of 4,9-dimethylpyrano[3,2-e]indol7(3H)-ones with different substituents in positions 1 and 2. Both schemes are simple in use and are suitable for obtaining preparative amounts of the target compounds with different structures. In the first scheme, diazonium chloride obtained from 6-amino-4,7-dimethylcoumarin 1 [2] was treated with sodium sulfite to give 4,7-dimethylcoumarin sodium 6-diazosulfonate (2) in 75% yield. It was reduced with zinc in acetic acid to give 4,7-dimethylcoumarin sodium 6-hydrazinosulfonate (3) (80% yield).
Me H2N Me 1 NaO S O N N Me 2 O O Me Zn AcOH O O NaO S NH HN Me 3 O O Me O O O 1) NaNO2, H + _ 2) Na2SO3, OH
The reaction of compound 3 with ketones 4 leads to the formation of the corresponding hydrazones, isolation of which was not expedient. From a series of experiments we have found that the use of the system TsOHH2O-acetic acid at this stage gives good yields of the target pyrrolocoumarins without separation of the intermediate hydrazones. Hence reaction of compound 3 with acetophenones 4a-g gave 2-arylindoles 5a-g in a single stage.
X O X 4ag 3 AcOH, TosOH Me 5ag 4, 5 a X = H, b X = 4'-NO2, c X = 3'-NO2, d X = 4'-F, e X = 4'-Cl, f X = 4'-Br, g X = 4'-I O O Me HN Me
Good results were achieved using these conditions in the synthesis of 1,2-dialkylindoles 5h-k and also in the preparation of carbazole derivatives 5l,m (Scheme 1) The scheme discussed seems quite versatile. It is characterized by good yields and simplicity of separation of the target pyrrolocoumarins.
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Scheme 1
Me HN O 5h O 4h 3 TosOH, AcOH Me Me Me HN O 5j 4 h = MeCOEt, i = Et2CO, j = Bu2CO, k = Am2CO O HN O 5k O Me 4j 4k Me Me 4i Me Me HN O 5i O Me Me Me
Me
Me
Me
Me
O Me HN 3 Me 5l O O TosOH, AcOH TosOH, AcOH Me 5m O O O HN Me
In the second scheme, diazonium chloride obtained from 6-amino-4,7-dimethylcoumarin 1 in the presence of sodium acetate readily undergoes azo coupling with 1,3-dicarbonyl compounds: -methyl, -ethyl, and -benzylacetoacetic ester. As a result of the reaction azo compounds 6a-c were formed and these were used immediately for the preparation of the indole derivatives.
O 1) NaNO2, HCl 1 010 oC 2) O Me O O 6ac O R Me O Me O O N N Me Me
Me R AcONa, AcOH 6 a R = H, b R = Me, c R = Ph
Because the coupling product 6c is an oil, for convenience of separation and identification it was subjected to fission to hydrazone 7c using hydrochloric acid at room temperature. 1317
Ph O 6c HCl, H2O 2025 AcOH

oC
N O HN Me 7c
Me
Me O O
We have used solution of p-toluenesulfonic acid in acetic acid for the preparation of compound 8a. Upon cyclization of coupling products 6b and 7c (R = Me, Ph) to 8b and 8c, respectively, an alcohol solution, prepared by a careful stirring of ethanol with thionyl chloride, was used as an acid reagent.
O EtOC TosOH .H2O, AcOH, 110 6a,b, 7c SOCl2, EtOH, 80 oC (R = Me, Ph) Me 8ac O O
oC
R Me
(R = H) HN
8 a R = H, b R = Me, c R = Ph
The yields and spectroscopic parameters for the synthesized pyrrolocoumarins are given in Tables 1-3.
TABLE 1. Characteristics of 4,9-Dimethylpyrano[3,2-e]indol-7(3H)-ones and Intermediate Products

Compound 1 5a 5b 5c 5d 5e 5f 5g 5h 5i 5j 5k Empirical formula 2 C19H15NO2 C19H14N2O4 C19H14N2O4 C19H14FNO2 C19H14ClNO2 C19H14BrNO2 C19H14INO2 C15H15NO2 C16H17NO2 C20H25NO2 C22H29NO2 Found, % Calculated, % 4 5.40 5.23 4.26 4.22 4.53 4.22 4.70 4.59 4.55 4.36 3.95 3.83 3.81 3.40 6.34 6.27 6.90 6.71 8.15 8.09 8.76 8.61
mp, N 5 4.88 4.84 8.73 8.38 8.87 8.38 6.24 6.18 4.30 4.33 4.01 3.80 3.45 3.37 5.94 5.80 5.59 5.49 4.81 4.50 4.26 4.13 6 278 >310 >315 >300 >310 >300 325 (with dec.) 276-278 226-227 143-145 119-121
Rf 7 0.52 0.43 0.41 0.52 0.53 0.54 0.51 0.61 0.55 0.73 0.66
Yield, % 8 72 65 36 22 65 70 67 85 85 72 72
3 79.09 78.87 68.40 68.26 68.31 68.26 74.34 74.26 71.01 70.48 62.08 61.97 55.12 54.96 74.95 74.67 45.48 45.27 77.81 77.14 78.01 77.84
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TABLE 1 (continued)
1 5l 5m 6 6b 7c 8a 8b 8c 2 C17H17NO2 C21H17NO2 C18H20N2O5 C19H22N2O5 C22H22N2O4 C16H15NO4 C17H17NO4 C22H19NO4 3 76.48 76.38 80.11 79.98 62.78 63.00 63.68 63.83 69.83 69.62 67.36 67.39 68.22 67.98 73.12 73.11 4 6.60 6.41 5.66 5.43 5.85 5.81 6.19 6.31 5.86 5.92 5.30 5.25 5.72 5.68 5.30 5.28 5 5.29 5.24 4.92 4.44 8.13 8.15 7.82 7.80 7.40 7.34 4.91 4.89 4.68 4.73 3.88 3.77 6 305-306 319-320 84-85 88-90 160-162 >300 178-180 223-225 7 0.64 0.56 0.87 0.83 0.88 0.77 0.71 0.74 8 90 90 87 86 70 36 85 50
EXPERIMENTAL H NMR spectra were recorded on a Bruker WR-200SV instrument (200 MHz) with TMS as internal standard and mass spectra were taken on a Finnigan MAT SSQ-710 instrument with ionization energy 70 eV. The course of the reactions was monitored using TLC on Silufol UV-254 plates in the system chloroform acetone (25:1). Sodium (E,Z)-2-(4,7-Dimethyl-2-oxo-2H-chromen-6-yl)-1-diazosulfonate (2). Solution of NaNO2 (22 g, 0.32 mol) in water (50 ml) was added at once with vigorous stirring to solution of 6-amino-4,7dimethylcoumarin (1) (51 g, 0.27 mol) in hydrochloric acid (73 ml) at -5C. The diazo solution was stirred at 0-10C for 2-3 h and then immediately and with vigorous stirring poured into solution of Na2SO3 (52 g,
1
TABLE 2. Mass Spectral Characteristics of the Novel 4,9-Dimethylpyrano[3,2-e]indol-7(3H)-ones and Intermediate Products
Compound 5a 5b 5c 5d 5e 5f 5g 5h 5i 5j m/z (Irel, %) 289 []+ (100), 261 [+ ] (93) 334 []+ (93), 306 [+ ] (93) 334 []+ (68), 306 [+ ] (67) 307 []+ (100), 279 [+ ] (97) 323 []+ (56), 295 [+ ] (41) 369 []+ (100), 341 [+ ] (89) 415 []+ (92), 387 [+ ] (54) 241 []+ (100), 198 [+ CH3] (82) 255 []+ (100), 212 [+ CH3] (80) 311 []+ (66), 282 [+ 32] (97) Compound 5k 5l 5m 6a 6b 7c 8a 8b 8c m/z (Irel, %) 339 []+ (72), 296 [+ 3] (92) 267 []+ (45), 239 [+ ] (14) 315 []+ (100), 272 [+ 3] (35) 302 [M+ CH2=C=O] (9), 271 [M+ COOEt] (25) 330 [M+ CH2=CH2] (7), 316 [M+ CH2=C=O] (6) 378 [M]+ (75) 285 [M]+ (81), 257 [M+ CH2=CH2] (11) 299 [M]+ (80) 361 [M]+ (85)
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TABLE 3. 1H NMR Spectral Characteristics of the Novel 4,9-Dimethylpyrano[3,2-e]indol-7(3H)-ones and Intermediate Products
Compound 2 3 5a 5b 5c Chemical shifts, , ppm (J, Hz)* 2.4 (3H, d, J = 1, 4-3); 2.6 (3H, s, 7-3); 6.4 (1H, d, J = 1.0, H-3); 7.4 (1H, s, H-8); 7.6 (1, s, H-5) 2.2 (3H, s, 7-3); 2.4 (3H, s, 4-3); 5.9 (1H, s, 2-N); 6.2 (1H, s, 1-N); 6.4 (1, s, H-3); 7.0 (1H, s, H-5); 7.4 (1H, s, H-8) 2.6 (3H, s, 4-3); 2.8 (3H, d, J = 1.0, 9-3); 6.2 (1H, d, J = 1.0, H-8); 7.0 (1H, s, H-5); 7.3 (1, d, J = 2.0, H-1); 7.4-8.1 (5H, m, 65); 11.5 (1H, s, NH) 2.7 (3H, d, J = 0.5, 4-3); 2.8 (3H, d, J = 1.0, 9-3); 6.2 (1H, d, J = 1.0, H-8); 7.0 (1H, d, J = 0.5, H-5); 7.6 (1, d, J = 2.0, H-1); 8.3 (4H, s, 64); 11.7 (1H, s, NH) 2.7 (3H, s, 4-3); 2.8 (3H, s, 9-3); 6.2 (1H, s, H-8); 7.0 (1H, s, H-5); 7.5 (1, d, J = 2.0, H-1); 7.7 (1, t, J = 7, H-5); 8.2 (1, d, J = 7, H-6); 8.5 (1, d, J = 7, H-4); 8.9 (1, s, H-2); 11.8 (1H, s, NH) 2.8 (3H, s, 4-3); 2.9 (3H, d, J = 1.0, 9-3); 6.2 (1H, d, J = 1.0, H-8); 7.0 (1H, s, H-5); 7.1 (1, d, J = 2.0, H-1); 7.2 (2H, d, J = 8.0, H-2, 6); 7.9 (2H, d, J = 8, H-3, 5); 1.0 (1H, s, NH) 2.6 (3H, s, 4-3); 2.8 (3H, s, 9-3); 6.2 (1H, s, H-8); 7.0 (1H, s, H-5); 7.4 (1, d, J = 1.5, H-1); 7.8 (4H, dd, J = 100, J = 8, 64); 11.54 (1H, s, NH) 2.6 (3H, s, 4-3); 2.7 (3H, s, 9-3); 6.2 (1H, s, H-8); 7.0 (1H, s, H-5); 7.4 (1, d, J = 1.5, H-1); 7.9 (4H, dd, J = 70, J = 8, 64); 11.5 (1H, s, NH) 2.6 (3H, s, 4-3); 2.7 (3H, d, J = 1.0, 9-3); 6.2 (1H, d, J = 1.0, H-8); 7.0 (1H, s, H-5); 7.4 (1, d, J = 2.0, H-1); 7.8 (4H, s, 64); 11.5 (1H, s, NH) 2.3 (3H, s, 1-3); 2.4 (3H, s, 2-3); 2.5 (3H, d, J = 0.4, 4-3); 2.7 (3H, d, J = 1.0, 9-3); 6.1 (1H, d, J = 1.0, H-8); 6.8 (1H, s, H-5); 11.1 (1H, s, NH) 1.2 (3H, t, J = 7.5, 2-23); 2.4 (3H, s, 1-3); 2.5 (3H, s, 4-3); 2.6 (3H, s, 9-3); 2.8 (2, q, J = 7.5, 223); 6.1 (1H, s, H-8); 6.8 (1H, s, H-5); 11.0 (1H, s, NH) 0.8-1.0 (6H, m, 1-(CH2)2CH3, 2-(CH2)33); 1.4-1.7 (6H, m, 1-2CH2CH3, 2-2(CH2)23); 2.5 (3H, s, 4-3); 2.6 (3H, d, J = 1.0, 9-3); 2.8-2.9 (4, m, 1-223, 2-2(2)23); 6.2 (1H, d, J = 1.0, H-8); 6.9 (1H, s, H-5); 8.2 (1H, s, NH) 0.8-1.0 (6H, m, 1-(CH2)3CH3, 2-(CH2)43); 1.3-1.7 (10H, m, 1-2(CH2)2CH3, 2-2(CH2)33); 2.5 (3H, d, J = 0.5, 4-3); 2.6 (3H, d, J = 1.0, 9-3); 2.7-2.8 (4, m, 1-2(2)23, 2-2(2)33); 6.2 (1H, d, J = 1.0, H-8); 6.94 (1H, d, J = 0.5, H-5); 8.1 (1H, s, NH) 1.8-1.9 (4H, m, 9-CH2, 10-C2); 2.5 (3H, s, 6-3); 2.6 (3H, d, J = 1.3, 1-3); 2.8-3.0 (4H, m, 8-C2, 11-C2); 6.2 (1H, d, J = 1.3, H-2); 6.7 (1H, s, H-5); 8.0 (1H, s, NH) 2.6 (3H, s, 6-3); 2.7 (3H, s, 1-3); 2.8-3.2 (4, m, 22); 6.2 (1H, s, H-2); 6.9 (1H, s, H-5); 7.2-7.9 (4, m, 64); 11.5 (1H, s, NH) 1.3 (3, t, J = 7.5, 23); 1.7 (3, s, 2-3); 2.3 (3H, s, 7-3); 2.4 (3, d, J = 1.6, 4-3); 2.6 (3H, s, 3); 4.3 (2, q, J = 7.5, 23); 6.3 (1H, d, J = 1.6, H-3); 7.3 (1H, s, H-8); 7.6 (1, s, H-5) 1.0 (3, t, J = 7.5, 2-23); 1.3 (3, t, J = 7.5, 23); 2.3 (2, q, J = 7.5, 2-23); 2.3 (3H, s, 7-3); 2.4 (3, d, J = 1.8, 4-3); 2.6 (3H, s, 3); 4.3 (2, q, J = 7.5, 23); 6.3 (1H, d, J = 1.8, H-3); 7.3 (1H, s, H-8); 7.6 (1, s, H-5) 1.3 (3, t, J = 7.3, 23); 2.4 (3H, d, J = 0.3, 7-3); 2.4 (3, d, J = 1.0, 4-3); 3.9 (2, s, CH2C6H5); 4.3 (2, q, J = 7.3, 23); 6.2 (1H, d, J = 1.0, H-3); 7.1 (1H, d, J = 0.3, H-8); 7.3 (5, m, C6H5); 7.6 (1, s, H-5); 12.2 (1, s, NH) 1.4 (3, t, J = 7.5, 23); 2.6 (3H, d, J = 1.0, 4-3); 2.7 (3, d, J = 1.3, 9-3); 4.5 (2, q, J = 7.5, 23); 6.3 (1H, d, J = 1.3, H-8); 7.2 (1H, d, J = 1.0, H-5); 7.6 (1, d, J = 2.1, H-1); 9.1 (1, s, NH) 1.4 (3, t, J = 7.5, 23); 2.6 (3H, d, J = 0.8, 4-3); 2.7 (3, d, J = 1.1, 9-3); 2.8 (3, s, 1-3); 4.5 (2, q, J = 7.5, 23); 6.2 (1H, d, J = 1.1, H-8); 7.1 (1H, d, J = 0.8, H-5); 9.1 (1, s, NH) 1.1 (3, t, J = 7.5, 23); 1.6 (3, d, J = 1.0, 9-3); 2.6 (3H, d, J = 0.8, 4-3); 4.2 (2, q, J = 7.5, 23); 6.0 (1H, d, J = 1.0, H-8); 7.2 (1H, d, J = 0.8, H-5); 7.4 (5H, m, C6H5); 9.3 (1, s, NH)
5d 5e 5f 5g 5h 5i 5j
5k
5l* 5m 6a
6b
7c
8a
8b
8c
_______ * Spectra of compounds 2, 3, 5a-i,m recorded in DMSO-d6 and of compounds 5j-l, 6a,b, 7c, 8a-c in CDCl3.
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0.41 mol) and NaOH (11 g, 0.275 mol) in water (250 ml) cooled to 0C. The yellow solution obtained (pH > 5.5) was stirred for 4 h and the precipitated diazosulfonate was filtered off, washed with isopropanol (10 ml), and dried to give compound 2 as a bright yellow powder (yield 61.5 g, 75%). Sodium 2-(4,7-Dimethyl-2-oxo-2H-chromen-6-yl)-1-hydrazinosulfonate (3). Zinc dust (2.2 g) was added to suspension of diazosulfonate 2 (10 g, 0.033 mol) in acetic acid (10 ml) and the reaction product was stirred for 3-5 h at 50-60C until the yellow color had disappeared. It was then treated with water (50 ml), heated to reflux, and the insoluble residue was filtered off and washed with boiling water (30 ml). The filtrate was cooled and the precipitate of hydrazinosulfonate was filtered off. Drying gave compound 3 as white, crystalline needles (yield 8 g, 80%). 4,9-Dimethylpyrano[3,2-e]indol-7(3H)-ones (5) (General Method). Suspension of compound 3 (1 g, 0.326 mmol), ketone 4 (0.326 mmol), and p-toluenesulfonic acid (1 g, 0.52 mmol) in glacial acetic acid (10-15 ml) was refluxed with stirring under argon atmosphere for 7-12 h and monitored by TLC. The product was cooled and poured into water (150 ml). The precipitated solid was filtered off, washed with water and cold ethanol, and dried to give compounds 5a-m. 4,9-Dimethyl-2-phenylpyrano[3,2-e]indol-7(3H)-one (5a). Yield 0.679 g. 4,9-Dimethyl-2-(4-nitrophenyl)pyrano[3,2-e]indol-7(3H)-one (5b). Recrystallized from DMF with activated carbon. Yield 0.708 g. 4,9-Dimethyl-2-(3-nitrophenyl)pyrano[3,2-e]indol-7(3H)-one (5c) was purified similarly to compound 5b. Yield 0.391 g. 2-(4-Fluorophenyl)-4,9-dimethylpyrano[3,2-e]indol-7(3H)-one (5d). The compound obtained was suspended in refluxing ethanol, cooled and the precipitate was filtered off and dried to give compound 5d. Yield 0.217 g. 2-(4-Chlorophenyl)-4,9-dimethylpyrano[3,2-e]indol-7(3H)-one (5e) was purified similarly to compound 5d. Yield 0.691 g. 2-(4-Bromophenyl)-4,9-dimethylpyrano[3,2-e]indol-7(3H)-one (5f) was purified similarly to compound 5d. Yield 0.844 g. 2-(4-Iodophenyl)-4,9-dimethylpyrano[3,2-e]indol-7(3H)-one (5g) was purified similarly to compound 5d. Yield 0.914 g. 1,2,4,9-Tetramethylpyrano[3,2-e]indol-7(3H)-one (5h). Yield 0.669 g. 2-Ethyl-1,4,9-trimethylpyrano[3,2-e]indol-7(3H)-one (5i). Yield 0.707 g. 2-Butyl-4,9-dimethyl-1-propylpyrano[3,2-e]indol-7(3H)-one (5j). Yield 0.731 g. 1-Butyl-4,9-dimethyl-2-pentylpyrano[3,2-e]indol-7(3H)-one (5k). Yield 0.787 g. 1,6-Dimethyl-8,9,10,11-tetrahydropyrano[2,3-c]carbazol-3(7H)-one (5l). Yield 0.784 g. 1,6-Dimethyl-12,13-dihydrobenzo[a]pyrano[2,3-g]carbazol-3(7H)-one (5m). Yield 0.925 g. Azo Coupling Products (6a,b) (General Method). Concentrated HCl (25 ml) and then, at once and with vigorous stirring, solution of sodium nitrite (4 g, 0.055 mol) in water (10 ml) were added to solution of aminocoumarin 1 (9.45 g, 0.05 mol) in acetic acid (50 ml) cooled to -5C such that the temperature did not exceed 5C. The reaction product was stirred at this temperature for 2 h and poured into solution of -alkylacetoacetic ester (0.051 mol) in acetic acid (75 ml) cooled in ice to 0C and containing crystal hydrate MeCOONa3H2O (50 g, 2.5 mol). The pH should be 5.5. The product was then left for 10 h at room temperature, diluted with equal volume of water, the precipitated solid filtered off, carefully pressed on the filter, and then washed with alcohol and with water, and dried to give ethyl 2-[(E,Z-2-(4,7-dimethyl-2-oxo-2H-chromen-6yl)azo]-2-methyl-3-oxobutanoate (6a), yield 15.0 g or ethyl 2-[(E,Z-2-(4,7-dimethyl-2-oxo-2H-chromen-6yl)azo]-3-oxo-2-ethyl-butanoate (6b), yield 15.4 g. Ethyl 2-[(E,Z)-2-(4,7-Dimethyl-2-oxo-2H-chromen-6-yl)hydrazino]phenylpropionate (7c). Concentrated HCl (25 ml) and then, at once and with vigorous stirring, solution of sodium nitrite (4 g, 0.055 mol) in water (10 ml) was added to solution of aminocoumarin 1 (9.45 g, 0.05 mol) in acetic acid (50 ml)
1321
cooled to -5C at such a rate that the temperature did not exceed 5C. The reaction product was stirred at this temperature for 2 h and poured into solution of -benzylacetoacetic ester (11.22 g, 0.51 mol) in acetic acid (75 ml) cooled in ice to 0C and containing crystal hydrate MeCOONa3H2O (50 g, 2.5 mol). The pH should be 5.5. The product was then left for 10 h at room temperature, diluted with equal volume of water. The organic phase was separated and treated with hydrochloric acid (20%, 30 ml). After 3 h the solid precipitate was filtered off, carefully pressed on the filter, and washed with alcohol and with water, and dried to give compound 7c, yield 13 g. Ethyl 4,9-Dimethyl-7-oxo-3,7-dihydropyrano[3,2-e]indole-2-carboxylate (8a). p-Toluenesulfonic acid (1 g) was added to glacial acetic acid (10 ml), the mixture taken to reflux and compound 6a (1 g, 0.35 mmol) was added, and the product was stirred under reflux for 12 h. The mixture was cooled, poured into ice water (200 ml) and the precipitate was filtered, washed with water, and crystallized from 1,4-dioxane with activated carbon after drying to give compound 8a. Yield 0.3 g. Ethyl 1,4,9-Trimethyl-7-oxo-3,7-dihydropyrano[3,2-e]indole-2-carboxylate (8b). Thionyl chloride (10-15 ml) was added portionwise to ethanol (30 ml), then compound 6b (12.4 g, 0.035 mol) was added and the mixture was refluxed under stirring for 12 h. It was then cooled and the precipitate was filtered off, washed with alcohol and with water, and dried to give compound 8b. Yield 8.8 g. Ethyl 4,9-Dimethyl-7-oxo-1-phenyl-3,7-dihydropyrano[3,2-e]indol-2-carboxylate (8c). Thionyl chloride (10-15 ml) was added portionwise to ethanol (40 ml), then compound 7c (10.5 g, 0.028 mol) was added and the mixture was refluxed under stirring for 12 h. It was then cooled and the precipitate was filtered off, washed with alcohol and water, and dried to give compound 8c. Yield 5 g.
REFERENCES 1. 2. 3. 4. 5. 6. A. Guiotto, A. Chilin, P. Manzini, F. Dall'Acqua, F. Bordin, and P. Rodighiero, Farmaco, 50, 479 (1995). H. Meyer, Acta Chem. Scand., Ser. B, 29, 133 (1975). M. Khan and B. Morley, J. Heterocycl. Chem., 16, 997 (1979). S. P. Hiremath, P. S. Badami, and M. G. Purohit, Indian J. Chem., B22, 437 (1983). S. P. Hiremath, G. R. Badiger, A. S. Jivangi, and M. G. Purohit, Indian J. Chem., B31, 583 (1992). E. Quanten, P. Adriaens, F. C. De Schryver, R. Roelandts, and H. Degreef, Photochem. Photobiol., 43, 485 (1986).
1322
RECYCLIZATION OF 2-IMINOCOUMARINS USING NUCLEOPHILIC REAGENTS. 6*. REACTION OF 2-IMINOCOUMARIN-3-CARBOXAMIDES WITH 2-AMINOBENZOPHENONES
S. V. Rusanova, I. A. Zhuravel', S. N. Kovalenko, V. P. Chernykh, and V. N. Baumer It has been shown that the reaction of 2-iminocoumarin-3-carboxamides with substituted 2-aminobenzophenones occurs in accordance with recyclization mechanism to form substituted 3-(4-phenylquinazolin-2-yl)coumarins. The structure of the compounds obtained was confirmed by spectroscopic data and by X-ray analysis. Keywords: 2-aminobenzophenones, 3-(4-arylquinazolin-2-yl)coumarins, 2-iminocoumarins, X-ray analysis, recyclization. In previous reports we have shown that, depending on the conditions, the reaction of 2-imino-2H-1benzopyran-3-carboxamides with N-nucleophilic reagents can take place both via formation of 2-N-substituted iminocoumarins (acid medium, 20C) [2-7] and by recyclization mechanism to give 3-substituted coumarins (neutral medium, 120-200C) [2, 7]. In certain examples the use of binucleophilic reagents (o-substituted anilines, arenecarboxylic acid hydrazides, thiosemicarbazides, anthranilic acid derivatives) gives 3-heterylcoumarins which are the products of their subsequent cyclization [1, 6-8]. In this study we continue to investigate the reaction of 2-imino-2H-1-benzopyran-3-carboxamides with nucleophilic reagents and to study the behavior of these compounds when reacting with substituted 2-aminobenzophenones. The starting R1-substituted 2-iminocoumarin-3-carboxamides 1 were prepared by known methods and introduced into the reaction with substituted 2-aminobenzophenones 2. As shown by us, the recyclization products R1-substituted 3-[6-R2-4-(R3-phenyl)quinazolin-2-yl]coumarins 7a-u (see Scheme 1 and Table 1) rather than the expected 2-substituted coumarins 3 are formed in glacial acetic acid, even in the cold. Analysis of the 1H NMR spectra of the reaction products shows that the signals for the protons of the imino group (12-13 ppm) and the protons of the amide group (9.0-9.2, 7.7-7.9 ppm), which are characteristic of the spectra of the starting 2-iminocoumarin-3-carboxamides 1 [9], are lost in the course of the reaction. The presence in the 1H NMR spectra of the overlapping signals for the aromatic protons of the coumarin and quinazoline fragments in the region of 6.54-8.70 ppm and the singlet signal for the H-4 proton of the coumarin ring (8.65-9.49 ppm) agree fully with the proposed structure (Table 2).
_______ * For Communication 5 see [1]. __________________________________________________________________________________________ National Pharmaceutical University, Kharkov, 61002, Ukraine; e-mail: ulk@ukrfa.kharkov.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1533-1542, October, 2004. Original article submitted April 24, 2003. 0009-3122/04/4010-13232004 Springer Science+Business Media, Inc. 1323
Scheme 1
O R1 O 1 O R1 O N NH2 O R3 NH2 NH R2 2 NH2 O R3
+
NH3
NH3
3 O R1 O NH2
R2 O NH2 R1 R3 OH HO HN N
N HO NH2
R3 4 R2 5
R2
R3 N R1 N CONH2 OH 6 R2 N NH3 R1 O O 7a-u N
R3 R2
7a R1 = R3 = H; b R1 = H, R3 = Cl; c R1 = 7-OH, R3 = H; d R1 = 6-Br, R3 = H; e R1 = 6-Br, R3 = Cl; f R1 = 6-Br, R3 = H; g R1 = 6-Cl, R3 = H; h R1 = 6-Cl, R3 = Cl; i R1 = 6-OMe, R3 = H; 1 j R = 6-OMe, R3 = H; k R1 = 7-OMe, R3 = H; l R1 = 7-OMe, R3 = Cl; m R1 = 7-OEt, R3 = H; n R1 = 7-NEt2, R3 = H; o R1 = 8-OMe, R3 = H; p R1 = 8-OMe, R3 = Cl; q R1 = 8-OEt, R3 = H; r R1 = 8-OEt, R3 = Cl; s R1 = 8-CH2CH = CH2, R3 = H; t R1 = 5,6-benzo, R3 = H; u R1 = 6-n-C6H13-7-OH, R3 = H; a-e,g-u R2 = Cl, f R2 = Br
The IR spectra of the compounds prepared show the absence of the NH stretching vibrations of the imine and amide fragments (3400-3300 cm-1) and those of the amide carbonyl group (1670-1690 cm-1) seen in the starting 2-iminocoumarin-3-carboxamides 1 [9] but the appearance of a strong stretching vibration band for the lactone C=O (1713-1763 cm-1) and a weak band for the C=N stretching vibrations (1632-1694 cm-1) which, 1324
in some examples, may be overlapped by the more intense aromatic C=C stretching vibration bands (Table 1). The existence of an intense molecular ion peak (m/z 414, I = 100%) and characteristic coumarin fragmentation ions (m/z: 414.9999 [M]+, 379.3037 [M-Cl]+. 190.1656, 177.2742 [M-C14H8ClN2]+, 127.1440) in the case of the molecule of 3-(6-chloro-4-phenylquinazolin-2-yl)-8-methoxycoumarin (7o) also confirms the correctness of the proposed structure. These facts have allowed us to propose that the given reaction occurs according to the recyclization mechanism [5] which includes the stage of forming intermediate 2-[(2-aroylaryl)imino]-2H-1-benzopyran-3carboxamides 3 which could not be isolated. The instability of these structures is evidently connected with the activation of the carbonyl group of the benzophenone fragment under the action of ammonium ion liberated in the first stage and this leads to the formation of the novel intermediates amino alcohols 4. Further, as a result of the attack of the amino group on the carbon atom of the C=N bond of iminocoumarin the iminolactone ring is opened followed by a cis-trans isomerization of the intermediate 5 to 6 and then its cyclization to give R1-substituted 3-[6-R2-4-(R3-phenyl)quinazolin-2-yl)coumarins 7a-u.
TABLE 1. R1-Substituted 3-[6-R2-4-(R3-Phenyl)quinazolin-2-yl]coumarins

Compound 7a 7b 7c 7d 7e 7f 7g 7h 7i 7j 7k 7l 7m 7n 7o 7p 7q 7r 7s 7t 7u Empirical formula 23H13ClN2O2 23H12Cl2N2O2 23H13ClN2O3 23H12BrClN2O2 23H11BrCl2N2O2 23H12Br2N2O2 23H12Cl2N2O2 23H11Cl3N2O2 24H15ClN2O3 24H14Cl2N2O3 24H15ClN2O3 24H14Cl2N2O3 25H17ClN2O3 27H22ClN3O2 24H15ClN2O3 24H14Cl2N2O3 25H17ClN2O3 25H16Cl2N2O3 26H17ClN2O2 27H15ClN2O2 29H25ClN2O3 Found N, % Calculated N, % 7.30 7.28 6.67 6.68 6.96 6.99 6.07 6.04 5.60 5.62 5.50 5.51 6.68 6.68 6.20 6.17 6.77 6.75 6.20 6.23 6.77 6.75 6.21 6.23 6.55 6.53 9.21 9.22 6.77 6.75 6.20 6.23 6.55 6.53 6.03 6.05 6.60 6.59 6.41 6.44 5.77 5.78 mp, 240-242 194-196 301-303 223-225 204-206 242-244 235-237 237-239 238-240 230-232 207-209 218-220 193-195 197-199 224-226 235-237 206-208 218-220 178-180 >300 253-255 IR spectrum, , cm-1 C=O C=N C=C 1751 1736 1713 1751 1739 1753 1763 1747 1743 1719 1727 1743 1739 1715 1738 1739 1741 1724 1746 1759 1720 1671 1680 1687 1671 1694 1632 1650 1640 1651 1604 1603 1613 1612 1605 1596 1600 1600 1604 1570 1615 1612 1616 1615 1605 1603 1602 1616 1596 1600 1616 Yield, % 71 68 52 84 87 85 78 71 73 70 66 59 73 51 75 77 78 74 80 63 55
1325
1326
TABLE 2. 1H NMR Spectral Characteristics of R1-Substituted 3-[6-R2-4-(R3-Phenyl)quinazolin-2-yl]coumarins

Compound 1 7a 7b 7c 7d 7e 7f 7g 7h 7i Coumarin ring 2 7.32-7.38 (2H, m, H-6, -8); 7.76 (1H, d, J = 8, H-5); 8.80 (1H, s, H-4) 6.80 (2H, m, H-6, H-8); 7.64 (1H, m, H-7); 7.90 (1H, m, H-5); 8.78 (1H, s, H-4) 6.80 (2H, m, H-6, H-8); 8.03 (1H, m, H-5); 8.71 (1H, s, H-4) 7.40 (1H, d, J = 10, H-8); 7.54 (1H, m, H-7); 7.73 (1H, d, J = 8, H-5); 8.76 (1H, s, H-4) 7.43 (1H, d, J = 9, H-8); 7.57 (1H, m, H-7); 7.86 (1H, dd, J1 = 10, J2 = 1, H-5); 8.77 (1H, s, H-4) 7.38 (1H, d, J = 10, H-8); 7.43 (1H, m, H-7); 7.74 (1H, dd, J1 = 8, J2 = 1, H-5); 8.73 (1H, s, H-4) 7.47 (1H, d, J = 9, H-8); 7.65 (1H, m, H-7); 7.58 (1H, m, H-5); 8.75 (1H, s, H-4) 7.47 (1H, d, J = 9, H-8); 7.58 (1H, m, H-7); 7.70 (1H, m, H-5); 8.77 (1H, s, H-4) 7.28 (1H, dd, J1 = 10, J2 = 1, H-8); 7.62 (1H, m, H-7); 7.87 (1H, m, H-5); 8.80 (1H, s, H-4) 7.26 (1H, dd, J1 = 10, J2 = 1, H-8); 7.40 (1H, d, J = 9, H-7); 7.50 (1H, d, J = 5, H-5); 8.77 (1H, s, H-4) Chemical shifts, , ppm (SSCC, J, Hz) Aromatic protons Quinazoline ring 3 7.91 (1H, dd, J1 = 8, J2 = 1, H-7); 8.15 (1H, d, H-8); 8.18 (1H, s, H-5) 8.11 (3H, m) 8.02 (3H, m) 7.96 (1H, m, H-7); 8.09 (1H, m, H-5); 8.18 (1H, m, H-8) 8.09 (1H, dd, J1 = 9, J2 = 1, H-5); 8.20 (2H, m, H-7, H-8) 8.08 (2H, m, H-5, H-7); 8.24 (1H, s, H-8) 7.65 (1H, dd, J1 = 7, J2 = 1, H-7); 8.09 (1H, m, H-5); 8.14 (1H, d, J = 7, H-8) 8.08 (2H, dd, J1 = 10, J2 = 1, H-5, H-7); 8.20 (1H, d, J = 10, H-8), 8.06-8.12 (3H, m, H-5, H-7, H-8)
Benzene ring 4 7.62 (3H, m); 7.84 (2H, m) 7.52-7.90 (4H, m) 7.62-7.97 (5H, m) 7.54 (3H, m); 7.90 (2H, m) 7.62-7.70 (4H. m) 7.43-8.08 (5H, m) 7.65-8.05 (5H, m) 7.58-7.70 (4H, m) 7.43-7.52 (4H, m); 7.87 (1H, m) 7.50-7.70 (4H, m)
Other protons 5
10.80 (1H, s, OH)
3.81 (3H, s, OCH3)
7j
7.70 (1H, m, H-7); 8.17 (1H, dd, J1 = 9, J2 = 1, H-5); 8.40 (1H, d, J = 9, H-8)
3.77 (3H, s, OCH3)
TABLE 2 (continued)
1 7k 7l 7m 7n 7o 7p 7q 7r 7s 2 7.00 (1H, dd, J1 = 9, J2 = 1, H-6); 7.07 (1H, d, J = 5, H-8); 7.87 (1H, m, H-5); 8.80 (1H, s, H-4) 6.96 (1H, dd, J1 = 9, J2 = 1, H-6); 7.02 (1H, d, J = 5, H-8); 7.80 (1H, d, J = 9, H-5); 8.72 (1H, s, H-4) 6.92 (1H, dd, J1 = 9, J2 = 1, H-6); 7.00 (1H, d, J = 5, H-8); 7.64 (1H, m, H-5); 8.74 (1H, s, H-4) 6.54 (1H, d, J = 5, H-8); 6.71 (1H, dd, J1 = 8, J2 = 1, H-6); 7.58 (1H, m, H-5); 8.65 (1H, s, H-4) 7.26 (1H, t, J = 7, H-6); 7.81 (2H, m, H-5, H-7); 8.70 (1H, s, H-4) 7.32 (1H, t, J = 8, H-6); 7.65 (2H, m, H-5, H-7); 8.75 (1H, s, H-4) 7.28 (1H, t, J = 8, H-6); 7.46 (1H, dd, J1 = 8, J2 = 1, H-5); 7.65 (1H, m, H-7); 8.80 (1H, s, H-4) 7.34 (1H, d, J = 6, H-6); 7.58 (1H, d, J = 6, H-7); 7.64 (1H, m, H-5); 8.78 (1H, s, H-4) 7.31 (1H, t, J = 8, H-6); 7.62 (1H, m, H-7); 7.74 (1H, d, J = 8, H-5); 8.71 (1H, s, H-4) 3 8.04-8.14 (3H, m, H-5, H-7, H-8) 7.61 (1H, m, H-7); 8.02 (1H, dd, J1 = 9, J2 = 1, H-5); 8.14 (1H, d, J = 9, H-8) 8.00-8.12 (3H, m, H-5, H-7, H-8) 7.94 (1H, d, J = 8, H-7); 7.98 (1H, d, J = 9, H-5); 8.06 (1H, dd, J1 = 9, J2 = 1, H-8) 7.92 (1H, d, J = 9, H-7); 8.10 (1H, s, H-5); 8.25 (1H, d, J = 9, H-8) 8.03 (1H, d, J = 6, H-5); 8.18 (1H, d, J = 5, H-8) 8.06-8.17 (3H, m, H-5, H-7, H-8) 7.72 (1H, d, J = 5, H-7), 8.10 (1H, dd, J1 = 7, J2 = 1, H-5); 8.24 (1H, d, J = 5, H-8) 8.00-8.12 (3H, m, H-5, H-7, H-8) 4 7.66 (3H, m); 7.87 (2H, m) 7.52-7.70 (4H, m) 7.64-7.85 (5H, m) 7.58-7.86 (5H, m) 7.36 (2H, m); 7.65 (2H, m); 7.81 (1H, m) 7.55-7.74 (4H, m) 7.30 (1H, m); 7.65 (2H, m); 7.88 (2H, m) 7.32 (2H, m); 7.64-7.72 (2H, m) 7.50 (1H, d); 7.64 (2H, m); 7.86 (2H, m) 5 3.90 (3H, s, CH3) 3.86 (3H, s, CH3) 1.34 (6H, t, J = 7, 2H2CH3); 4.11 (2H, q, J = 7, 2H2CH3) 1.15 (6H, t, J = 7, 2H2CH3); 3.45 (4H, q, J = 7, 2H2CH3) 4.02 (3H, s, CH3) 3.91 (3H, s, CH3) 1.42 (3H, t, J = 7, H2CH3); 4.20 (2H, q, J = 7, H2CH3) 1.42 (3H, t, J = 7, H2CH3); 4.20 (2H, q, J = 7, H2CH3) 3.57 (2H, d, J = 9, H2H=CH2); 5.07 (2H, dd, J1 = 18, J2 = 7, H2H=CH2); 6.02 (1H, m, H2H=CH2)
7t 7u
7.65-8.06 (6H, m); 9.49 (1H, s, H-4) 7.55 (1H, s, H-8); 7.77 (1H, m, H-5); 8.70 (1H, s, H-4)
8.20 (1H, m, H-7); 8.26 (1H, m, H-5); 8.56 (1H, d, J = 8, H-8) 8.00-8.10 (3H, m, H-5, H-7, H-8)
7.63-7.90 (5H, m) 7.62 (3H, m); 7.85 (2H, m) 0.88 (3H, m); 1.29 (6H, s, (CH2)2(H2)3CH3); 1.53 (2H, s, CH2(H2)4CH3); 2.50 (2H, s, CH2CH2(H2)3CH3); 3.20 (1H, s, OH)
1327
With the object of confirming the structure of the final products we have carried out an X-ray investigation of 3-(6-chloro-4-phenylquinazolin-2-yl)-7-hydroxycoumarin 7c. The assignment of crystal of this compound to hexagonal syngony proved quite unexpected, but as the verification of the presence of twinning in the polarizing microscope proved negative, the refinement was carried out in the hexagonal cell by a direct method with subsequent electron density synthesis. It was found that the structure of compound 7c was made up of triads of the molecules formed through OHO hydrogen bonding. The atomic coordinates can be obtained from the authors; the bond lengths and bond angles in the structure are given in Tables 3 and 4. Figure 1 shows the numbering scheme for the atoms in the basic molecular structures. Three molecules of the compound make up the independent cell unit. In each molecule the coumarin and benzimidazole fragments lie in virtually one plane. Differences are observed in torsional angles between the planes of the phenyl substituent and the quinazoline fragment. As a result of the geometrical requirements in the least-squares refinement and the existence of pseudosymmetry it can be proposed that the standard deviations of the obtained geometrical parameters of the molecules (Tables 3 and 4) are reduced when compared with the actually observed scatter in the bond lengths and bond angles.
TABLE 3. Bond Lengths (d) in the Triad of Basic Molecules of Compound 7c

Bond Cl(1)C(19) O(1)C(10) O(1)C(2) C(2)O(11) C(2)C(3) C(3)C(4) C(3)C(14) C(4)C(5) C(5)C(6) C(5)C(10) C(6)C(7) C(7)C(8) C(8)C(9) C(8)O(12) C(9)C(10) N(13)C(22) N(13)C(14) C(14)N(15) N(15)C(16) C(16)C(17) C(16)C(23) C(17)C(18) C(17)C(22) C(18)C(19) C(19)C(20) C(20)C(21) C(21)C(22) C(23)C(24) C(23)C(28) C(24)C(25) C(25)C(26) C(26)C(27) C(27)C(28) d, 1.787(4) 1.414(4) 1.414(5) 1.194(5) 1.382(5) 1.329(5) 1.471(2) 1.521(4) 1.384(4) 1.382(4) 1.375(4) 1.378(4) 1.380(3) 1.431(4) 1.381(3) 1.322(2) 1.352(2) 1.310(2) 1.347(2) 1.507(5) 1.532(4) 1.380(3) 1.383(3) 1.378(4) 1.382(4) 1.378(3) 1.378(4) 1.3956(15) 1.3946(18) 1.3957(18) 1.3977(19) 1.3946(19) 1.3949(15)
1.784(4) 1.401(4) 1.415(4) 1.198(5) 1.377(5) 1.331(5) 1.467(2) 1.501(4) 1.367(4) 1.375(4) 1.378(4) 1.381(3) 1.382(3) 1.426(4) 1.381(3) 1.321(2) 1.350(2) 1.313(2) 1.344(2) 1.496(5) 1.527(4) 1.373(3) 1.390(3) 1.374(4) 1.379(4) 1.377(3) 1.378(4) 1.3953(19) 1.3967(19) 1.3973(19) 1.397(2) 1.3962(19) 1.3953(19)
1.784(4) 1.403(4) 1.408(5) 1.192(5) 1.375(5) 1.333(5) 1.471(2) 1.511(4) 1.374(4) 1.378(4) 1.376(4) 1.385(4) 1.381(3) 1.434(4) 1.384(3) 1.321(2) 1.350(2) 1.310(2) 1.345(2) 1.497(5) 1.524(4) 1.382(3) 1.390(3) 1.381(4) 1.379(4) 1.378(3) 1.381(3) 1.3941(19) 1.3959(19) 1.3948(19) 1.3955(15) 1.3954(19) 1.3960(19)
1328
TABLE 4. Bond Angles () in The Triad of Basic Molecules of Compound 7c

Angle C(10)O(1)C(2) O(11)C(2)C(3) O(11)C(2)O(1) C(3)C(2)O(1) C(4)C(3)C(2) C(4)C(3)C(14) C(2)C(3)C(14) C(3)C(4)C(5) C(6)C(5)C(10) C(6)C(5)C(4) C(10)C(5)C(4) C(5)C(6)C(7) C(6)C(7)C(8) C(7)C(8)C(9) C(7)C(8)O(12) C(9)C(8)O(12) C(10)C(9)C(8) C(5)C(10)C(9) C(5)C(10)O(1) C(9)C(10)O(1) C(22)N(13)C(14) N(15)C(14)N(13) N(15)C(14)C(3) N(13)C(14)C(3) C(14)N(15)C(16) N(15)C(16)C(17) N(15)C(16)C(23) C(17)C(16)C(23) C(18)C(17)C(22) C(18)C(17)C(16) C(22)C(17)C(16) C(17)C(18)C(19) C(18)C(19)C(20) C(18)C(19)Cl(1) C(20)C(19)Cl(1) C(21)C(20)C(19) C(20)C(21)C(22) N(13)C(22)C(21) N(13)C(22)C(17) C(21)C(22)C(17) C(24)C(23)C(28) C(24)C(23)C(16) C(28)C(23)C(16) C(23)C(24)C(25) C(24)C(25)C(26) C(27)C(26)C(25) C(28)C(27)C(26) C(27)C(28)C(23) , deg 122.7(4) 133.5(4) 107.1(3) 119.4(4) 119.2(3) 118.2(3) 122.7(3) 124.0(4) 115.5(4) 128.6(4) 115.0(3) 124.3(4) 115.9(4) 123.7(4) 111.7(3) 124.5(3) 116.4(4) 123.5(4) 119.1(3) 117.0(3) 116.6(3) 129.8(3) 110.9(3) 119.4(3) 113.0(3) 122.3(3) 116.0(4) 117.7(3) 121.9(3) 124.1(3) 113.1(2) 113.3(4) 129.3(4) 115.1(3) 115.1(3) 113.1(4) 122.2(3) 116.6(3) 123.4(3) 120.0(3) 120.01(11) 127.1(4) 112.7(4) 119.86(12) 119.68(13) 119.82(12) 120.05(12) 119.91(12)
120.7(4) 132.4(3) 106.1(3) 121.4(4) 118.8(3) 118.0(3) 123.2(3) 122.3(4) 117.0(3) 125.4(4) 117.3(3) 123.4(4) 116.5(3) 122.8(3) 111.6(3) 124.3(3) 116.3(3) 123.2(3) 119.3(3) 117.4(3) 116.2(3) 130.2(3) 109.8(3) 120.0(3) 112.9(3) 123.4(3) 116.2(3) 119.8(3) 121.1(3) 125.6(3) 113.1(2) 113.9(4) 128.6(4) 115.7(3) 114.8(3) 114.0(4) 121.0(3) 115.3(3) 123.6(3) 120.9(3) 119.94(12) 120.7(4) 119.2(4) 119.84(13) 119.41(15) 119.56(15) 119.90(13) 119.93(12)
B 124.3(4) 133.8(4) 107.2(3) 118.5(4) 118.9(3) 117.7(3) 123.0(3) 124.6(4) 113.5(3) 131.1(4) 115.0(3) 126.4(4) 113.9(4) 125.7(3) 110.8(3) 123.4(3) 113.7(4) 126.1(3) 118.6(3) 115.1(3) 116.0(3) 130.5(3) 109.5(3) 119.6(3) 113.0(3) 123.8(3) 116.3(4) 119.8(3) 122.3(3) 124.9(3) 112.7(2) 113.3(4) 128.9(4) 115.3(3) 115.7(3) 113.0(4) 122.8(4) 116.9(3) 123.8(3) 119.0(3) 120.01(12) 122.2(4) 117.8(4) 120.01(12) 119.99(12) 119.85(13) 119.85(13) 119.90(12)
1329
Fig. 1. Atom numbering in the triad of the basic molecules of 3-(6-chloro-4-phenylquinazolin-2-yl)7-hydroxycoumarin (7c). Hence the reaction of 2-iminocoumarin-3-carboxamides with substituted 2-aminobenzophenones in glacial acetic acid in the cold occurs in accordance with recyclization mechanism to give substituted 3-(4-arylquinazolin-2-yl)coumarins and is a convenient method for the synthesis of this series of 3-heterylcoumarins.
EXPERIMENTAL IR spectra for the synthesized compounds were recorded on a Specord M-80 spectrophotometer for KBr tablets. H NMR spectra were recorded on a Varian WXR-400 (200 MHz) instrument using DMSO-d6 and TMS as internal standard. Electron impact mass spectra were obtained on a Finnigan MAT 4615B instrument with ionization energy of 70 eV and with ballistic heating of the sample. X-ray analysis was carried out on a Siemens P3/PC four-circle, automatic diffractometer. R1-Substituted 2-Iminocoumarin-3-carboxamides 1 were prepared by the method in [9]. 3-(4-Arylquinazolin-2-yl)coumarins 7a-u (General Method). The corresponding 2-aminobenzophenone 2 (2 mmol) was dissolved with heating in glacial acetic acid (10 ml). 2-Iminocoumarin-3carboxamide 1 (2 mmol) was added to the warm solution (30-40C) and it was refluxed using a reflux condenser for 20-30 min. A heavy precipitate was formed upon cooling the reaction mixture. This was filtered off, washed with water and with ethanol, and recrystallized from mixture of ethanolwater (compounds 7c,d,g,s-u) or from ethanolDMF (compounds 7a,b,e,f,t).
1
1330
X-ray Analysis of 3-(6-Chloro-4-phenylquinazolin-2-yl)-7-hydroxycoumarin (7c). Measurement of the intensities was carried out by the 2/ scanning method in the range of angles 4<2<50 at a rate of from 2 to 30 deg./min to give 2724 nonzero, nonequivalent reflections, of which 1954 were observed with I > 2(I). The crystals are hexagonal with space group P61; Mr = 400.80; T = 293(2) K; C23H13ClN2O3; a = 20.520(6), c = 22.915 (10) ; V = 8356(5) 3; Z = 18; dcalc = 1.434 g/cm3; F000 = 3708; (MoK) = 0.234 mm-1. The structure was refined by full-matrix, least-squares analysis using the SHELX-97 computer program. Due to the presence of pseudosymmetry in the molecular packing (the presence of a third order pseudoaxis led to a strong correlation of the refined parameters) in the refinement of the structure there are additional geometrical requirements superimposed, e.g. all of the aromatic rings are constrained to be given as planar, identical bonds in the different molecules equal to one another, etc. The overall number of such geometrical restraints was 945. The hydrogen atoms were brought into the refinement on geometrical grounds and specifically attached to the corresponding non-hydrogen atom. The final confidence coefficients were R1 = 0.0430, wR2 = 0.1098 for those observed and R1 = 0.0471, wR2 = 0.1114 for all reflections S = 0.975.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. S. N. Kovalenko, V. A. Zubkov, V. P. Chernykh, A. V. Turov, and S. M. Ivkov, Khim. Geterotsikl. Soedin., 186 (1996). Y. V. Bilokin, S. M. Kovalenko, I. E. Bylov, and V. P. Chernykh, Heterocycl. Commun., 4, 257 (1998). Y. V. Bilokin, M. V. Vasylyev, O. V. Branytska, S. M. Kovalenko, and V. P. Chernykh, Tetrahedron, 55, 13757 (1999). M. V. Vasylyev, Y. V. Bilokin, O. V. Branytska, S. M. Kovalenko, and V. P. Chernykh, Heterocycl. Commun., 5, 241 (1999). S. N. Kovalenko, K. M. Sytnik, V. M. Nikitchenko, S. V. Rusanova, V. P. Chernykh, and A. O. Porokhnyak, Khim. Geterotsikl. Soedin., 190 (1999). S. M. Kovalenko, I. E. Bylov, K. M. Sytnik, V. P. Chernykh, and Y. V. Bilokin, Molecules, 5, 1146 (2000). S. N. Kovalenko, M. V. Vasil'ev, I. V. Sorokina, V. P. Chernykh, A. V. Turov, and S. A. Rudnev, Khim. Geterotsikl. Soedin., 1664 (1998). S. N. Kovalenko, I. E. Bylov, Ya. V. Belokon', and V. P. Chernykh, Khim. Geterotsikl. Soedin., 1175 (2000). V. A. Zubkov, S. N. Kovalenko, V. P. Chernykh, and S. M. Ivkov, Khim. Geterotsikl. Soedin., 760 (1994).
1331
INTRAMOLECULAR CYCLIZATION OF 5-ARYL-3-ARYLAMINO-4-BENZOYL-1H-3-PYRROLIN2-ONES TO PYRROLO[3,4-b]QUINOLINES

V. L Gein, E. N. Bezmaternykh, L. F. Gein, and I. V. Krylova It has been shown that 5-aryl-3-arylamino-4-benzoyl-1H-3-pyrrolin-2-ones cyclize in the presence of conc. H2SO4 to give pyrrolo[3,4-b]quinolines. Keywords: 5-aryl-3-arylamino-4-benzoyl-1H-3-pyrrolin-2-ones, pyrrolo[3,4-b]quinolines. 3-Arylamino derivatives of 4-ethoxycarbonyl-3-pyrrolin-2-ones can undergo cyclization to a condensed pyrroloquinoline system [1-4]. In this connection it was of interest to investigate the possibility of a similar cyclization for the previously prepared 5-aryl-3-arylamino-4-benzoyl-1H-3-pyrrolin-2-ones (1a,b,d,e) [5] and also for the novel 5-(p-bromophenyl)-3-(p-methoxyphenyl)amino-4-benzoyl-1H-3-pyrrolin-2-one (1c). We have shown that compounds 1a-e undergo an intramolecular cyclization to the 1-aryl-(5,7)-R-9phenylpyrrolo[3,4-b]quinolin-3-ones (2a-e) when heated for a short time and then held for a prolonged period at room temperature in conc. H2SO4 medium.
PhOC H N R1 R2 conc. H2SO4 Ar N H 1ae O HN 2 O 2ae Ar H
1 3
Ph R2
9 4 8 7 6 5
N R1
1, 2 ac R1 = H, d, e R1 = Me; a R2 = Br, b R2 = Me, c R2 = OMe, d, e R2 = H; a, b, d Ar = Ph; c, e Ar = 4-BrC6H4
The intramolecular cyclization observed apparently occurs by an electrophilic substitution mechanism where the sulphuric acid aids the formation of electrophilic species which protonate the carbonyl group of the benzoyl fragment. Compounds 2a-e are colorless, crystalline materials with a high melting point and are readily soluble in DMSO and DMF (Table 1). Their 1H NMR spectra show the presence of the singlet for the methine proton of the pyrrole ring at 5.75-5.80 ppm, a multiplet centered at 7.2-7.5 ppm for the aromatic protons, and also a singlet for the NH group proton of the pyrrole fragment at 9.45-9.60 ppm. The signal for the second NH group present in the 1H NMR spectrum of the starting materials 1a-e at 8.3-8.6 ppm is absent in the spectra of compounds 2a-e and this supports the proposed structure (Table 2). __________________________________________________________________________________________ Perm State Pharmaceutical Academy, Perm 614990, Russia; e-mail: pba@degacom.ru, gein@permoline.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1543-1545, October, 2004. Original article submitted July 10, 2002. 1332 0009-3122/04/4010-13322004 Springer Science+Business Media, Inc.
TABLE 1. Characteristics of Compounds 2a-e

Compound Empirical formula Found, % Calculated, % H N 3.65 3.62 5.12 5.14 3.80 3.82 5.17 5.14 3.91 3.96 6.77 6.75 8.04 8.00 6.25 6.29 8.03 8.00 6.56 6.54 18.65 18.63 17.93 17.96 mp, (solvent)
Yield, %
C 66.56 66.52 82.33 82.29 64.78 64.73 82.24 82.29 67.09 67.15
Br 19.29 19.26
2a 2b 2c 2d 2e
C23H15BrN2O 2418N2O C24H17BrN2O2 C24H18N2O C24H17BrN2O
300-302 (1-butanol) 282-284 (ethanol) 286-288 (ethanol) 260-262 (ethanol) 279-281 (2-propanol)
61.0 91.4 62.5 82.9 60.5
TABLE 2. IR and 1H NMR Spectra of Compounds 2a-e

Compound IR spectrum, , cm-1 = NH 1714 3188
1
NMR spectrum, , ppm NH, s 9.60 Other protons
-4, s 5.80
ArH 6.50 (1H, d, H); 7.05 (5H, m, C6H5); 7.50 (5H, m, C6H5); 7.65 (1H, s, H-8); 7.90 (1H, d, H-6) 7.20 (13H, m) 7.65 (12H, m) 6.50-6.75 (3H, m, H-6,7,8); 7.05 (5H, m, 65); 7.50 (5H, m, C6H5) 6.55 (3, m, H-6,7,8); 7.30 (9, m, 65, -BrC6H4)
2a
2b 2c 2d
1726 1720 1708
3216 3208 3170
5.75 5.75 5.75
9.50 9.51 9.45
2.40 (3H, s, CH3) 3.65 (3H, s, 3) 2.90 (3H, s, CH3)
2e
1710
3199
5.75
9.50
2.90 (3H, s, CH3)
The IR spectrum of compound 2e shows the presence of a lactam carbonyl absorption band at 1710 and an NH group at 3199 cm-1. The mass spectrum of compound 2b has a peak for the molecular ion at m/z (I, %) 350 (100) together with peaks for the fragment ions: 273 [M-C6H5]+ (80), 245 [M-C6H5-CO]+ (30), and 70 (30). The mass spectrum of compound 2a shows a peak for the molecular ion with m/z 414-416 (20) which is in agreement with the structure proposed.
EXPERIMENTAL H NMR spectra were recorded on Bruker AM-300 (300 MHz) and NR-60 (60 MHz) spectrometers using DMSO-d6 and HMDS internal standard ( 0.05 ppm). IR spectra were recorded in vaseline oil on a UR-20 spectrometer. Mass spectra were taken on an MX-1320 instrument with an electron ionizing energy of 70 eV. The purity and identification of the compounds were determined by TLC on Silufol-254 plates in the system benzeneacetonehexane (3:1:1) and revealed using iodine vapor. 5-Aryl-3-arylamino-4-benzoyl-3-hydroxy-1H-3-pyrrolin-2-ones (1a,b,d,e) were prepared as described in [5].
1
1333
5-(p-Bromophenyl)-3-(p-methoxyphenyl)amino-4-benzoyl-1H-3-pyrrolin-2-one (1c) was prepared using the same method [5]. Yield 40.5%; mp 165-167C (xylenehexane, 2:1). IR spectrum, , cm-1: 1724 (C=O), 3312 (NH). 1H NMR spectrum, , ppm: 3.75 (3H, s, OCH3); 5.76 (1H, s, H-5); 7.42 (13H, m, Ar); 8.29 (H, s, NH); 9.56 (1H, s, NH,). Found, %: C 62.18; H 4.03; Br 17.32; N 6.1. C24H19BrN2O3. Calculated, %: C 62.22; H 4.10; Br 17.26; N 6.05. 1-Aryl-(5,7)-R-9-phenylpyrrolo[3,4-b]quinolin-3-ones 2a-e. A solution of compound 1 (1 mmol) in conc. H2SO4 (5 ml) was heated for 10-15 min until the color had changed from reddish to greenish-brown. The reaction mixture was then poured into cold water (200 ml) and the precipitate was filtered off, washed on the filter with dilute sodium carbonate solution and then water, dried, and recrystallized. The work was carried out with the financial support of the Russian Fund for Basic Research (project No. 04-03-96042).
REFERENCES 1. 2. 3. 4. 5. R. Madhav, R. F. Dufresne, and P. L Southwick, J. Heterocycl. Chem., 10, 225 (1973). J. P. Yevich, J. R. Murphy, R. F. Dufresne, and P. L. Southwick, J. Heterocycl. Chem., 15, 1463 (1978). C. A. Snyder, M. A. Thorn, J. E. Klijanowicz, and P. L Southwick, J. Heterocycl. Chem., 19, 603 (1982). R. Madhav and P. L. Southwick, J. Heterocycl. Chem., 9, 443 (1972). V. L. Gein, L. F. Gein, E. N. Bezmaternykh, and S. N. Shurov, Zh. Obshch. Khim., 70, 1737 (2000).
1334
SYNTHESIS OF 7-OXOPYRROLO[3,2-d]PYRIMIDINE 5-OXIDES BY THE REARRANGEMENT OF 6-ALKYNYL5-NITROPYRIMIDINES

S. Tumkevicius, I. Susvilo, and A. Brukstus A method is proposed for the synthesis of 6-substituted 4-amino-7-oxopyrrolo[2,3-d]pyrimidine 5-oxides which includes a Sonogashira reaction of 4-amino-6-chloro-5-nitropyrimidine with terminal alkynes and subsequent rearrangement of the 6-alkynyl-5-nitropyrimidines obtained. Keywords: alkynes, nitropyrimidines, palladium, pyrrolo[3,2-d]pyrimidines, catalysis, rearrangement. One of the routes for the synthesis of the pyrrolo[3,2-d]pyrimidine heterocyclic system involves the formation of a pyrrole ring by an intramolecular cyclization of the corresponding substituted pyrimidine. Analysis of the literature has shown that 5-aminopyrimidines are most frequently chosen as starting materials in achieving this goal [1-8]. There are only a few reports in the literature concerning the synthesis of pyrrolo[3,2-d]pyrimidines from 6-alkynylpyrimidines [9] and 5-nitropyrimidines [10-15]. The latter usually form pyrrolopyrimidines under reductive cyclization conditions. However, according to our study of the literature, the synthesis of pyrrolo[3,2-d]pyrimidines from 5-nitropyrimidines having alkyl substituents in the position 6 has not been reported. We have recently published a preliminary report of the possible synthesis of pyrrolo[3,2d]pyrimidine 5-oxides by the rearrangement of certain 1-(4-amino-5-nitro-6-pyrimidinyl)-2-arylethynes in pyridine solution [16]. In the current work we continue the investigation to provide additional data for the synthesis of 7-oxo-7H-pyrrolo[3,2-d]pyrimidine 5-oxides. These compounds are aza analogs of isatogens [1719] and are of interest as materials which bind radicals in a biological medium. The readily prepared 4-amino-6-chloro-5-nitropyrimidine (1) [10] was chosen as the starting material in the synthesis. Investigation of the cross conjugation reaction of compound 1 with terminal alkynes in the presence of PdCl2(PPh3)2 and CuI catalysts in triethylamine has shown that the best results are achieved by carrying out this reaction with a small excess of the appropriate acetylene at 40C. The compounds 2a-e are formed in 68-89% yields. Study of the properties of the alkynylpyrimidines has shown that, when heated for a short time (15 min) in pyridine, they undergo a rearrangement to form the 6-substituted 4-amino-7-oxopyrrolo[2,3-d]pyrimidine 5-oxides 3a-d (method A). The yields of compounds 3a-d are 87-95%. Only the reaction of compound 2e occurs differently. In this case a complex mixture of products is formed along with tarring of the reaction mixture and the expected product could not be separated. The reason could be the instability of compound 2e, which is partially decomposed even when attempts are made to purify it using column chromatography or crystallization. __________________________________________________________________________________________ Organic Chemistry Department, Vilnius University, Vilnius LT-03225, Lithuania; e-mail: sigitas.tumkevicius@chf.vu.lt. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10. pp. 1546-1550, October, 2004. Original article submitted July 7, 2004. 0009-3122/04/4010-13352004 Springer Science+Business Media, Inc. 1335
NH2 N N 1 NO2 Cl 1. R , Pd cat., CuI 2. C5H5N, 40C N
NH2
_ O N+ R
N 3ad O
R , Pd cat., CuI 40C NH2 N N 2ae R NO2 C5H5N, 40C
a R = Bu, b R = Ph, c R = 4-MeC6H4, d R = 4-F-C6H4, e R = SiMe3
In view of the fact that the preparation of the alkynylpyrimidines and the conversion of compounds 2a-e to the pyrrolo[3,2-d]pyrimidine 5-oxides 3a-e occur in the presence of a tertiary amine base it seemed appropriate to us to study the possible preparation of compound 3 in a single stage, directly from the chloropyrimidine 1. It was found that the triethylamine used in the cross conjugation stage does not cause the rearrangement of the alkynylpyrimidines formed. At the reflux temperature of triethylamine only a tarring of the reaction mixture occurs which markedly lowers the yields of the alkynylpyrimidines and hinders their separation. The formation of compound 3 was not observed. Upon addition of pyridine to the reaction mixture and carrying out the reaction at 40C the 6-substituted 7-oxopyrrolo[3,2-d]pyrimidine 5-oxides 3a-c are formed (method B). The yields of compounds 3a-c as obtained using method B were less than the overall yields via the synthesis in the two stage method A. However, method B has the advantage that it avoids the procedure of the separation and purification of the intermediate alkynylpyrimidines. The data obtained shows that pyridine can serve as catalyst in the rearrangement of the 6-alkynyl-5nitropyrimidines to the corresponding 7-oxopyrrolo[2,3-d]pyrimidine 5-oxides. Evidently the pyridine adds to the triple bond and activates the alkyne. Subsequent nucleophilic attack on the oxygen of the nitro group leads to formation of an isoxazole derivative which then rearranges to the 7-oxopyrrolo[2,3-d]pyrimidine 5-oxide.
_ NH2 O N N 2 .. N R N + O NH2 O N N + N N _ + O _ R N N R N + NH2 N O O _
NH2 O N N N+ N _ O R N N O NH2 O N R _ + N N
_ NH2 N N O O R + N 3 C5H5N
1336
A catalytic role for the pyridine was also noted in a study of the photochemical isomerization of 2-nitrotolanes [20]. It was also shown that electron-acceptor substituents stabilize the carbanion formed and facilitate the reaction. In our case the electron deficient pyrimidine ring is such a group. It evidently also dictates that the 6-alkynyl-5-nitropyrimidines 2 readily undergo rearrangement to the 7-oxopyrrolo[2,3-d]pyrimidine 5-oxides 3 in the absence of UV irradiation. We therefore propose a novel and convenient method for the synthesis of compounds of type 3 from 6-alkynyl-5-nitropyrimidines which are readily prepared by a Sonogashira reaction of 6-chloro-5nitropyrimidine with terminal alkynes.
EXPERIMENTAL IR spectra were recorded using vaseline oil on an FT-IR Spectrum BX II spectrometer (Perkin-Elmer). H NMR spectra were taken on a Tesla 587A (80 MHz) or a Varian INOVA (300 MHz) spectrometer using TMS as internal standard. The course of the reaction and the purity of the compounds obtained were monitored using TLC on Alufol Silica Gel 60 F254 plates (Merck). The characteristics of the compounds 2b-d, 3b-d are given in [16]. 1-(4-Amino-5-nitro-6-pyrimidinyl)-2-substituted Acetylenes 2a-e (General Method). A mixture of compound 1 (0.2 g, 1.16 mmol), PdCl2(PPh3)2 (0.015 g, 0.021 mmol), and CuI (1.98 mg, 0.0105 mmol) in dry triethylamine (5 ml) was stirred in an argon atmosphere for 1-3 min. The corresponding acetylene (1.25 mmol) was added and the reaction mixture was stirred for 2-3 h at 40C. After cooling, the precipitate was filtered off and recrystallized (in the case of compounds 2a-d) or washed with water (in the case of compound 2e) to give the compounds 2a-e. Compound 2a. Yield 70%; mp 159C (octane). IR spectrum, , cm-1: 3382, 3220 (NH2), 2209 (CC), 1569 (NO2). 1H NMR spectrum (CDCl3), , ppm (J, Hz): 0.98 (3H, t, J = 5.6, CH3); 1.56 (4H, m, CH2CH2CH2CH3); 2.85 (2H, t, J = 5.6, CH2); 7.88 (2H, br. s, NH2); 8.74 (1H, s, H-2). 13C NMR spectrum (CD2Cl2): 13.48, 21.01, 22.03, 37.49, 84.47, 87.06, 122.48, 144.91, 162.82, 167.91. Found, %: C 54.48; H 5.42; N 25.38. C10H12N4O2. Calculated, %: C 54.54; H 5.49; N 25.44. Compound 2b [16]. Yield 75%. Compound 2c [16]. Yield 89%. Compound 2d [16]. Yield 68%. Compound 2e. Yield 86%; mp 149-150C. IR spectrum, , cm-1: 3344, 3198 (NH2), 2215 (CC), 1568 1 (NO2). H NMR spectrum (DMSO-d6), , ppm: 0.26 (9H, s, Si(CH3)3); 8.45 (1H, s, H-2); 9.02 (2H, br. s, NH2). 6-Substituted 4-Amino-7-oxo-7H-pyrrolo[3,2-d]pyrimidine 5-Oxides 3a-d. A. A solution of the corresponding compounds 2a-d (1 mmol) in anhydrous pyridine (5 ml) was refluxed for 15 min. After cooling to room temperature the precipitate was filtered off and the filtrate was concentrated at reduced pressure. The precipitate formed was combined with that obtained previously and recrystallized to give compounds 3a-d. B. A mixture of compound 1 (0.2 g, 1.16 mmol), PdCl2(PPh3)2 (0.015 g, 0.021 mmol), CuI (1.98 mg, 0.0105 mmol), and dry triethylamine (5 ml) was stirred under an argon atmosphere for 1-3 min. The corresponding acetylene (1.25 mmol) was added and the reaction mixture was stirred for 30 min at 40C. Pyridine (0.5 ml) was added and stirring was continued for a further 2-24 h. The reaction mixture was cooled and the precipitate filtered off and recrystallized to give compounds 3a-c. Compound 3a. Yield 92% (method A), 36% (method B, reaction time 24 h); mp 223C (benzene). IR spectrum, , cm-1: 3341, 3299 (NH2), 1736 (CO), 1348 (NO). 1H NMR spectrum (DMSO-d6), , pm (J, Hz): 1.05 (3H, t, J = 5.6, CH3); 1.51 (4H, m, CH2CH2CH2CH3); 2.99 (2H, t, J = 5.6, CH2); 6.80 (1H, br. s, NH); 7.75 (1H, br. s, NH); 8.10 (1H, s, H-2). 13C NMR spectrum (DMSO-d6), , ppm: 13.28, 22.01, 22.63, 29.75,122.45, 136.96, 150.28, 154.89, 166.98, 187.93. Found, %: C 54.45; H 5.68; N 25.29. C10H12N4O2. Calculated, %: C 54.54; H 5.49; N 25.44. Compound 3b. Yield 95% (method A) [16], 49% (method B, reaction time 2 h). Compound 3c. Yield 90% (method A) [16], 38% (method B, reaction time 4 h).
1
1337
This work was carried out with the financial support of the Lithuanian Fund for Science and Education, grant No. T-04220.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. M. Pfleiderer, Chem. Ber., 90, 738 (1957). N. Kawahara, T. Nakajima, T. Itoh, and H. Ogura, Chem. Pharm. Bull., 33, 4740 (1985). O. S. Sizova and R. G. Glushkov, Pharm. Chem. J. (Eng. Ed.), 18, 420 (1984). M. Brahta and G. D. Daves, J. Chem. Soc., Perkin Trans. 1, 1883 (1992). T. Sakamoto, C. Satoh, Y. Kondo, and H. Yamanaka, Chem. Pharm. Bull., 41, 81 (1993). Y. Okamoto, K. Takagi, A. Takada, and T. Ueda, J. Org. Chem., 49, 908 (1984). K. C. Majumdar, U. Das, and N. K. Jana, J. Org. Chem., 63, 3550 (1998). R. L. De Jong, J. G. Davidson, G. J. Dozeman, P. J. Fiore, P. Giri, M. E. Kelly, T. P. Puls, and R. E. Seamans, Org. Process Res. Dev., 5, 216 (2001). A. L. Rodriguez, C. Koradin, N. Dohle, and P. Knochel, Angew. Chem. Int. Ed., 39, 2488 (2000). T. L. Cupps, D. S. Wise, and L. B. Townsend, J. Org. Chem., 48, 1060 (1983). Yu. N. Tkachenko, E. B. Tsupak, and A. F. Pozharskii, Khim. Geterotsikl. Soedin., 368 (2000). T. L. Cupps, D. S. Wise, and L. B. Townsend, Tetrahedron Lett., 23, 4759 (1982). M. Otmar, M. Masojidkova, and A. Holy, Collect. Czech. Chem. Commun., 61, 49 (1996). M. Otmar, M. Masojidkova, M. Budesinsky, and A. Holy, Tetrahedron, 54, 2931 (1998). G. B. Evans, R. H. Furneaux, T. L. Hutchison, H. S. Kezar, P. E. Morris, L. T. Schramm, and P. C. Tyler, J. Org. Chem., 66, 5723 (2001). I. Susvilo, A. Brukstus, and S. Tumkevicius, Synlett, 1151 (2003). R. Nepveu, J.-P. Souchard, Y. Rolland, G. Dorey, and M. Spedding, Biochem. Biophys. Res. Commun., 242, 272 (1998). G. M. Rosen, P. Tsai, E. D. Barth, G. Dorey, P. Casara, M. Spedding, and H. J. Halpern, J. Org. Chem., 65, 4460 (2000). V. B. Genisson, A.-V. Bouniol, and F. Nepveu, Synlett, 700 (2001). R. Huisgen, Angew. Chem. Int. Ed., 2, 565 (1963).
1338
SYNTHESIS OF DERIVATIVES OF 7,8-DIHYDROTHIAZOLO[2,3-i]PURINE BY HALOCYCLIZATION OF 6-ALLYLTHIOPURINE

D. G. Kim and Yu. R. Galina 7-Halomethyl-7,8-dihydrothiazolo[2,3-i]purines were synthesized by the reaction of bromine and iodine with 6-allylthiopurine. Keywords: 6-allylthiopurine, 7-bromomethyl-7,8-dihydrothiazolo[2,3-i]purine, dihydrothiazolo[2,3-i]purine, halocyclization. 7-iodomethyl-7,8-
7,8-Dihydrothiazolo[2,3-i]purine and its derivatives were obtained by the reaction of 6-mercaptopurine (1) and substituted 6-mercaptopurines with 1,2-dibromoethane [1, 2] and also by the interaction of 6-(2-hydroxyalkyl)thiopurines with SOCl2 [3], and by treatment of 6-(2-aminoethyl)thiopurines with hydrochloric acid [4]. We have developed a new preparative synthesis of 7-substituted 7,8-dihydrothiazolo[2,3-i]purine by the halocyclization of 6-allylthiopurine (2). The sulfide 2 was obtained by allylation of purine 1 with allyl bromide in HMPA in the presence of alkali at room temperature. According to [5], alkylation of purine occurs primarily at the sulfur atom.
SH N N 1 N H N Br N KOH N 2 N H N S
The structure of sulfide 2 was confirmed by 1H NMR and chromato-mass spectroscopy. The molecular ion M+ (m/z 192) and the maximum peak 2 with m/z 177, corresponding to the elimination of a methyl radical are present in the mass spectrum. Apparently the molecular ion-radical cyclizes to give the ion radical 1, which loses the methyl radical to form the aromatic thiazolo[2,3-i]purine cation 2 (Scheme 1). When compound 2 reacted with bromine or iodine in chloroform compounds are formed containing approximately 2 mol of halogen to 1 mol of substrate. Apparently they are trihalides of 7-halomethyl-7,8dihydrothiazolo[2,3-i]purine 3a,b. The tribromide 3a gave 7-bromomethyl-7,8-dihydrothiazolo[2,3-i]purine (4a) on treatment with acetone, while the triiodide 3b gave 7-iodomethyl-7,8-dihydrothiazolo[2,3-i]purine (4b) on treatment with sodium iodide in acetone (Scheme 2). __________________________________________________________________________________________ Chelyabinsk State University, Chelyabinsk 454021, Russia; e-mail: kim@csu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, 1551-1553, October, 2004. Original article submitted January 21, 2002. 0009-3122/04/4010-13392004 Springer Science+Business Media, Inc. 1339
Scheme 1
H2C +
.
S S N N 1 N H _. CH + N
3
2 M + 192
+ N
N N N H
2 m/z 177
Scheme 2
_ X3 + X 2 X2 N N S N N H X _ X3 N+ N 3a,b S N N H HX, X2
S X N+ N 4a,b (A) 3, 4 a X = Br; b X = I N N _ X
8 7 6
S N
5
9 1
N
2
N
4
N
3
4a,b (B)
It should be noted that in the 1H NMR spectra the signals of the protons of the purine ring (H-2 and H-5) in the halocyclization products 4a,b resonate at weaker field than the corresponding protons (H-2 and H-8) in the allylsulfide 2. This evidently indicates that these compounds exist in the bipolar form 4a,b (A).
EXPERIMENTAL H NMR spectra in (CD3)2SO were recorded with a Bruker WP-250 (250 MHz) spectrometer and 13C NMR spectra in (CD3)2SO were recorded with a Bruker AM-300 (75 MHz) spectrometer with TMS as internal standard. Mass spectra were recorded on a GC/MS instrument consisting of a HP-5890 chromatograph and a HP5972 mass selective detector. 6-Allylthiopurine (2). Allyl bromide (0.29 ml, 3.2 mmol) was added to a solution of KOH (0.180 g, 3.2 mmol) and 6-mercaptopurine (0.510 g, 3.0 mmol) in HMPA (2 ml). The reaction mixture was stirred at room temperature for 1.5 h, after which it was diluted to 45 ml with water. Calcium chloride (3 g) was added to the solution which was then kept for 6 h. The precipitate was filtered off and washed with water to give compound 2, 0.290 g (50%); mp 153C. 1HNMR spectrum, , ppm (J, Hz): 4.03 (2H, d, 3J =6.9, SCH2); 5.11 (1H, dd, CH=CH2); 5.34 (1H, dd, CH=CH2); 5.97 (1H, m, CH=CH2); 8.23 (1H, s, H-8); 8.58 (1H, s, H-2); 13.30 (1H, br. s, NH). Found, %: C 49.45; H 4.43; S 16.35. C8H8N4S. Calculated, %: C 49.98; H 4.19; S 16.68. 1340
1
3-Bromomethyl-2,3-dihydrothiazolo[2,3-i]purine (4a). A solution of bromine (0.052 ml, 1 mmol) in chloroform (4 ml) was added dropwise to a solution of 6-allylthiopurine (0.100 g, 0.5 mmol) in chloroform (6 ml). A precipitate formed was separated, treated with acetone and filtered off to give 4a (0.120 g, 88%); mp 191C (dec.). 1H NMR spectrum, , ppm (J, Hz): 3.96 (1H, dd, SCH2); 4.19 (1H, dd, SCH2); 4.34 (2H, m, CH2Br); 6.15 (1H, m, H-7); 8.89 (1H, s, H-2); 9.61 (1H, s, H-5). 13C NMR spectrum, , ppm: 33 (CH2Br), 133 (C-2), 108 (C-3a), 162 (C-5), 64 (C-7), 33 (C-8), 168 (C-9a). Found, %: Br 29.56; S 11.38. C8H7BrN4S. Calculated, %: Br 29.47; S 11.83. 3-Iodomethyl-2,3-dihydrothiazolo[2,3-i]purine (4b). A solution of 6-allylthiopurine (0.100 g, 0.5 mmol) in chloroform (5 ml) was added to a solution of iodine (0.254 g, 1.0 mmol) in chloroform (3 ml). A deep-red precipitate which separated over 48 h was treated with a saturated solution of NaI in acetone (6 ml). The yellow precipitate was filtered off and washed with acetone to give compound 4b (0.154 g, 93%); mp 204C (dec.). 1H NMR spectrum, , ppm: 3.86 (1H, dd, SCH2); 3.97 (2H, m,CH2I); 4.25 (1H, dd, SCH2); 5.84 (1H, m, H-7); 8.87 (1H, s, H-2); 9.47 (1H, s, H-5). 13C NMR spectrum, , ppm: 7 (CH2I), 146 (C-3a), 68 (C-7), 38 (C-8), 158 (C-9), 151 (C-9b). Found, %: I 39.01; S 9.86. C8H7IN4S. Calculated, %: I 39.89; S 10.08.
REFERENCES 1. 2. 3. 4. 5. R. W. Balsiger, A. L. Fikes, T. P. Johnston, and J. A. Montgomery, J. Org. Chem., 26, 3446 (1961). J. A. Montgomery, R. W. Balsiger, A. L. Fikes, and T. P. Johnston, J. Org. Chem., 27, 3446 (1962). P. M. Kochergin, E. V. Aleksandrova, and E. V. Rusinova, Khim. Geterotsikl. Soedin., 1434 (1993). T. P. Johnston and A. Gallagher, J. Org. Chem., 28, 1305 (1963). G. W. Grigg, Y. Iwai, D. J. Brown, K. N. McAndrew, T. Nagamatsu, and R. Heeswyck, Austral. J. Chem., 32, 2713 (1979).
1341
CONDENSED PYRIDOPYRIDIMINES. 8*. SYNTHESIS OF NEW DERIVATIVES OF PYRANO[3',4':6,7]PYRIDO[2,3-d]PYRIMIDINE

A. Sh. Oganessyan, A. S. Noravyan, and M. Zh. Grigoryan New substituted 8,8-dimethyl-4-oxopyrano[3',4':6,7]pyrido[2,3-d]pyrimidines have been synthesized from 2-amino-3-ethoxycarbonyl-7,7-dimethylpyrano[4,3-b]pyridine. Keywords: pyranopyridine, tetrahydropyran, synthesis. pyranopyridopyrimidine, pyridine, pyridopyrimidine, pyridimine,
We have previously prepared some derivatives of pyrano[3',4':6,7]pyrido[2,3-d]pyrimidine [2,3]. In a continuing search for biologically active compounds, we have synthesized new examples of this series containing various substituents in positions 2 and 3 of the pyrimidine ring. 3-Substituted 4-oxo-2-thiopyranopyridopyrimidines 1a-c were synthesized by two methods: A) by boiling ethanolic solutions of 2-amino-3-ethoxycarbonylpyrano[4,3-b]pyridine 2 [2] with the isothiocyanates 3ac with subsequent heterocyclization of the 2-(N'-R-thioureido) derivatives 4a-c under the influence of KOH; B) by condensation of pyranopyridine 2 with the isothiocyanates 3a-c at 130-140C.
O
COOEt N NH2
RNCS 3ac EtOH,

boiling
COOEt N C S KOH O NH R
NH
2
3ac
4ac
130140 oC O
O
N N N
R R1
R1X 5ac
N N N H
R S
6ai
1ac
1a, 3a, 4a, 6a,d,g R = CH2Ph; 1b, 3b, 4b, 6b,e,h R = CH2CH=CH2; 1c, 3c, 4c, 6c,f,i R = C6H4OMe-4; 5a, 6ac R1 = Et, X = I; 5b, 6df R1 = CH2COPh, X = Br; 5c, 6gi R1 = CH2CONH2, X = Cl
_______ * For part 7 see [1]. __________________________________________________________________________________________ A. L. Mndzhoyan Institute of Fine Organic Chemistry, National Academy of Sciences of the Armenian Republic, Erevan 375014; e-mail: west@msrc.am. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, 1554-1557, October, 2004. Original article submitted May 19, 2000; revision submitted March 5, 2004. 1342 0009-3122/04/4010-13422004 Springer Science+Business Media, Inc.
TABLE 1. Characteristics of the Compounds Synthesized, 1, 4, and 6

Compound 1a 1b 1c 4a 4b 4c 6a 6b 6c 6d 6e 6f 6g 6h 6i Empirical formula C C19H19N3O2S C15H17N3O2S C19H19N3O3S C21H25N3O3S C17H23N3O3S C21H25N3O4S C21H23N3O2S C17H21N3O2S C21H23N3O3S C27H25N3O3S C23H23N3O3S C27H25N3O4S C21H22N4O3S C17H20N4O3S C21H22N4O4S 64.5 64.6 59.5 59.4 62.1 61.8 63.2 63.1 58.6 58.4 61.0 60.7 63.65 63.5 61.8 61.6 63.6 63.5 68.7 68.8 65.7 65.6 67.1 66.5 61.6 61.5 56.5 56.7 60.0 59.2 Found, % Calculated, % H N 5.4 5.4 5.6 5.6 5.7 5.2 6.1 6.3 6.5 6.6 6.0 6.2 5.5 5.8 6.2 6.3 5.6 5.8 5.0 4.9 5.7 5.9 4.8 5.1 5.3 5.4 5.6 5.6 4.9 5.2 11.8 11.9 13.8 13.9 11.8 11.4 10.6 10.5 12.1 12.0 10.8 10.1 10.7 10.6 13.0 12.7 11.1 10.6 8.7 8.9 10.3 10.0 8.4 8.6 13.5 13.7 15.9 15.6 13.4 13.2
mp, C S 9.1 9.1 10.6 10.6 8.1 8.7 8.1 8.0 9.0 9.2 6.7 7.7 8.2 8.1 9.6 9.8 7.9 8.1 7.1 6.8 6.8 7.6 6.8 6.6 7.9 7.8 8.4 8.8 7.3 7.5 310-312 238-240 300 191-192 155-156 157-159 181-183 123-125 175-177 210-212 165-167 194-196 150-152 162-164 208-210
Rf *
Yield, %
0.61 0.64 0.67 0.58 0.61 0.63 0.57 0.60 0.64 0.58 0.53 0.57 0.62 0.63 0.67
88 (A) 92 (B) 75.5 (A) 89 (B) 87 (A) 90 (B) 50 51.2 52 92.3 90.3 75.7 89.3 82.5 80 81.5 73.5 75
_______ *Solvent systems: chloroformbenzeneether, 2:1:1 (1a-c); chloroform ether, 1:2 (4a); chloroformetherisooctane, 1:2:1 (4b,c]; chloroformether heptane, 1:1:1 (6a-i).
It should be noted that the single stage route B gave higher yields of the required products 1. The corresponding S-alkylsubstituted 6a-i were obtained as the result of interaction of compounds 1a-c with the halogeno derivatives 5a-c.
EXPERIMENTAL IR spectra of nujol mulls were recorded on a UR-20 spectrometer, 1H NMR spectra of DMSO-d6 (1a-c, 4a,c, 6a,c,d), CDCl3 (4b), and pyridine-d5 (6h,i) solutions were recorded with a Varian Mercury 300 (300 MHz) machine. TLC was carried out on Silufol UV-254 plates with development with iodine vapor. Characteristics of the compounds synthesized are given in Table 1. 2-(N'-benzylthioureido)-3-ethoxycarbonyl-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine (4a). A mixture of 2 (2.5 g, 0.01 mol) and benzyl isothiocyanate 3a (3.2 g, 0.02 mol) in ethanol (50 ml) was boiled for 10 h. The crystalline product 4a which separated on cooling was filtered off, washed with ether and recrystallized from ethanol. IR spectrum (thin film), , cm-1: 1470 (C=S), 1630 (C=N), 1690 (C=O), 3200 (NH). 1 H NMR spectrum, , ppm (J, Hz): 11.90 (1H, s, HNHet); 8.20 (1H, s, H-4), 7,17 (5H, s, C6H5); 6.86 (1H, t, 1343
J = 5.0, NHR); 4.60 (2H, d, 3J = 5.0, CH2C6H5); 4.53 (2H, s, 2H-5); 4.13 (2H, q, 3J = 7.0, OCH2CH3); 2.60 (2H, s, 2H-8); 1.25 (3H, t, 3J = 7.0, OCH2CH3); 1.20 (6H, br. s, 2CH3-7). 2-(N'-Allylthioureido)-3-ethoxycarbonyl-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine (4b) was obtained from compound 2 (2.5 g, 0.01 mol) and allyl isothiocyanate 3b (2.0 g, 0.02 mol) by the method described above. IR spectrum (thin film), , cm-1: 1460 (C=S), 1630 (C=N), 1680 (C=O), 3250 (NH). 1H NMR spectrum, , ppm (J, Hz): 11.90 (1H, s, NHHet); 8.20 (1H, s, H-4); 6.93 (1H, t, 3J = 5.8, NHR); 6.22-4.95 (3H, m, CH=CH2); 4.60 (2H, s, 2H-5); 4.23 (2H, q, 3J = 6.0, OCH2CH3); 4.02 (2H, t, 3J = 5.8, NHCH2); 2.67 (2H, s, 2H-8); 1.28 (3H, t, 3J = 6.0, OCH2CH3); 1.23 (6H, s, 2CH3-7). 3-Ethoxycarbonyl-2-[(N'-4-methoxyphenyl)thioureido]-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine (4c) was obtained from compound 2 (2.5 g, 0.01 mol) and 4-methoxyphenyl isothiocyanate 3c (3.3 g, 0.01 mol) by the method described above. IR spectrum (thin film), , cm-1: 1470 (C=S), 1620 (C=N), 1680 (C=O), 3300 (NH). 1H NMR spectrum, , ppm (J, Hz): 13.60 (1H, s, NHR); 11.21 (1H, s, NHHet); 8.20 (1H, s, H-4); 7.60-6.85 (4H, m, C6H4); 4.75 (2H, s, 2H-5); 4.40 (2H, q, 3J = 7.0, OCH2CH3); 3.80 (3H, t, 3J = 7.0, OCH3); 2.80 (2H, s, 2H-8); 1.40 (3H, t, 3J = 7.0, OCH2CH3); 1.20 (6H, s, 2CH3-7). 3-Substituted 8,8-Dimethyl-4-oxo-2-thioxo-8,9-dihydro-6H-pyrano[3',4':6,7]pyrido[2,3-d]pyrimidines 1a-c. A. A mixture of thioureide 4a-c (0.01 mol), KOH (0.02 mol), and 70% ethanol (50 ml) was boiled for 1 h, cooled, and treated with 10% hydrochloric acid until slightly acidic. The crystals of the products 1a-c which precipitated were filtered off, washed with water, dried, and recrystallized from butanol. B. A mixture of compound 2 (2.5 g) and an isothiocyanate 3a-c (3 ml) was maintained at 130-140C for 7h. The crystals of compound 1a-c which separated on cooling after treating with ethanol were filtered off, washed with ether, and recrystallized from butanol. IR spectrum (thin film), , cm-1, 1a-c: 1460 (C=S), 1670 (C=O). 1H NMR spectra, , ppm (J, Hz): 1a: 8.20 (1-H, s, 5-H); 7.70-7.20 (5H, m, C6H5); 6.00 (2H, s, NCH2); 4.73 (2H, s, 2H-6); 2.98 (2H, s, 2H-9); 1.26 (6H, s, 2CH3-8); 1b: 8.50 (1H, s, NH); 8.15 (1H, s, H-5); 6.35-5.15 (3H, m, CH=CH2); 5.03 (2H, br. s, NCH2); 4.63 (2H, s, 2H-6); 2.82 (2H, s, 2H-9); 1.23 (6H, s, 2CH3-8),; 1c: 13.17 (1H, s, NH); 8.02 (1H, s, H-5); 7.09-6.83 (4H, m, C6H4); 4.80 (2H, s, 2H-6); 3.80 (3H, s, OCH3); 2.80 (2H, s, 2H-9); 1.24 (6H, s, 2CH3-8). 3-Substituted 2-Ethylthio-8,8-dimethyl-4-oxo-8,9-dihydro-6H-pyrano[3',4':6,7]pyrido[2,3-d]pyrimidines 6a-c. Ethyl iodide 5a (1.56 g, 0.01 mol) was added dropwise with stirring to a solution of compound 1a-c (0.01 mol) and KOH (0.56 g, 0.01 mol) in 90% ethanol (20 ml) heated to 40C. The crystals of the product 6a-c which separated were filtered off, washed with water and ether, and recrystallized from ethanol. 1 H NMR spectra, , ppm (J, Hz): 6a: 8.20 (1H, s, H-5); 7.21 (5H, s, C6H5); 5.25 (2H, s, CH2C6H5); 4.80 (2H, s, 2H-6); 3.38 (2H, m, SCH2); 2.81 (2H, s, 2H-9); 1.42 (3H, m, CH2CH3); 1.26 (6H, s, 2CH3-8); 6c: 8.20 (1H, s, H5); 7.10, 7.20 (4H, two d, 3J1 = 3J2 = 8.8, C6H4); 4.81 (2H, s, H-6); 3.90 (3H, s, OCH3); 3.19 (2H, m, SCH2); 2.87 (2H, s, 2H-9); 1.40-1.22 (9H, m, CH2CH3, 2CH3-8). 3-Substituted 2-(Benzoylmethyl)thioxo-8,8-dimethyl-4-oxo-8,9-dihydro-6H-pyrano[3',4':6,7]pyrido[2,3-d]pyrimidines 6d-f were obtained from a mixture of compound 1a-c (0.01 mol) and bromoacetophenone 5b (2.0 g, 0.01 mol) by the method used for the synthesis of compounds 6a-c. IR spectrum (thin film), , cm-1, 6d-f: 1620 (C=N), 1680 (amide C=O), 1700 (C=O). 1H NMR spectrum, , ppm (J, Hz), 6d : 8.20-7.40 (11H, m, H-5, CH2C6H5, O=CC6H5); 6.00 (2H, s, CH2C6H5); 4.80 (4H, s, CH2-6, SCH2); 2.82 (2H, s, 2H-9); 1.30 (6H, s, 2CH3-8). 3-Substituted 2-(Carbamoylmethyl)thioxo-8,8-dimethyl-4-oxo-8,9-dihydro-6H-pyrano[3',4':6,7]pyrido[2,3-d]pyrimidines 6g-i. A mixture of compound 1a-c (0.01 mol), chloroacetamide 5c (1.0 g, 0.01 mol), and KOH (0.56 g, 0.01 mol) in 90% ethanol (20 ml) was boiled for 4 h. The crystals of product 6g-i which formed on cooling the reaction mixture was filtered off, washed with water, and recrystallized from ethanol. IR spectra (thin film), , cm-1, 6g-i: 1630 (C=N), 1670, 1680 (amide C=O), 3400 (NH2). 1H NMR spectrum, , ppm (J, Hz), 6h: 8.33 (2H, br. s, NH2); 6.20-5.07 (3H, m, CH=CH2); 4.93 (2H, m, NCH2); 4.83 (2H, s, 2H-6); 4.43 (2H, s, SCH2); 3.13 (2H, s, 2H-9); 1.28 (6H, s, 2CH3-8); 6i, 8.20 (1H, s, H-5); 7.41-7.00 (6H, m, NH2, C6H4); 4.81 (2H, s, 2H-6); 3.83 (5H, m, SCH2, OCH3); 2.90 (2H, s, 2H-9); 1.33 (6H, s, 2CH3-8). 1344
This work was carried in the program of the International Scientific and Technical Union.
REFERENCES 1. 2. 3. Arzh. Sh. Oganisyan, A. S. Noravyan, M. Zh. Grigoryan, and Art. Sh. Oganisyan, Khim. Geterotsikl. Soed., 82 (2004). A. Sh. Oganisyan, A. S. Noravyan, M. Zh. Grigoryan, and Arzh. Sh. Oganisyan, Khim. Geterotsikl. Soed., 1239 (1999). A. Sh. Oganisyan, A. S. Noravyan, and M. Zh. Grigoryan, Khim. Geterotsikl. Soed., 1372 (2003).
1345
FORMATION OF THE PYRROLINE N-OXIDE RING BY INTERACTION OF -ISONITROSOKETONES DERIVATIVES OF TETRAHYDROBENZOFURAZAN AND -FUROXAN WITH ALDEHYDES AND MORPHOLINE AND SOME OF THE REACTIONS OF THESE COMPOUNDS
V. A. Samsonov
-Isonitroso ketones, derivatives of tetrahydrobenzofurazan and furoxan, react with aldehydes

(acetaldehyde and propionaldehyde) and morpholine to form derivatives of tetrahydropyrrolo[2,3-e]2,1,3-benzoxadiazole 6-oxide. Treatment of the latter with hydrazine hydrate gave derivatives of 4,5-dihydro-1,2,5-oxadiazolo[3,4-f]cinnoline which are readily dehydrogenated with tetrachlorobenzoquinone to derivatives of 1,2,5-oxadiazolo[3,4-f]cinnoline. Reduction of tetrahydropyrrolo[2,3-e]2,1,3-benzoxadiazole 6-oxides with sodium borohydride gave derivatives of N-hydroxyhexahydropyrrolo[2,3-e]-2,1,3-benzoxazole. Keywords: enamines, -isonitroso ketones, indolines, pyrroline N-oxides, 4,5,6,7-tetrahydrobenzofurazans, 4,5,6,7-tetrahydrobenzofuroxans, cinnolines. 5-Hydroximino-4-oxo-4,5,6,7-tetrahydrobenzofurazan (1) and 5-hydroximino-4-oxo-4,5,6,7-tetrahydrobenzofuroxan (2) react easily with both ketones and amines and with enamines to give derivatives of pyrroline N-oxide [1]. In a continuation of the study of this reaction, we have investigated the reaction of the -isonitroso ketones 1 and 2 with aldehydes (acetaldehyde and propionaldehyde) and morpholine. The reaction gave high yields of the pyrroline N-oxides 3a,b and 4a,b (Table 1) which are colorless crystalline compounds, soluble in ethanol and water. The presence in the 1H NMR spectra of compounds 3 and 4 of doubled sets of signals permits the conclusion that compounds 3a,b and 4a,b, are mixtures of diastereomeric products (Tables 2 and 3), just as in the case of pyrroline N-oxides derived from ketones [1]. In the case of compounds 3a and 4a,b the ratio of isomers is approximately 1:1, whereas for compound 3b the ratio is 1:10. It should be noted that since the compounds are mixtures of isomers and the molecules of the compounds are not planar (see [1]), the 1H NMR spectra of these compounds are complex and not very informative. The 13C NMR spectra are considerably more informative (Table 3). As is the case with pyrroline N-oxides obtained from ketones [2,3], compounds 3a,b and 4a,b reacted with hydrazine hydrate to give the corresponding derivatives of dihydrocinnoline 5a,b and 6a,b, which are easily dehydrogenated with tetrachlorobenzoquinone to the derivatives of cinnoline 7a,b and 8a,b. Treatment of compounds 3a,b and 4a,b with sodium borohydride to give derivatives of N-hydrocinnoline 9a,b and 10a,b. It must be noted that, according to their 1H and 13C NMR spectra, compounds 9a and 10a,b are individual isomers __________________________________________________________________________________________ Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Novosibirsk 630090; e-mail: Samson@nioch.nsc.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, 1558-1563. October, 2004. Original article submitted February 15, 2002. 1346 0009-3122/04/4010-13462004 Springer Science+Business Media, Inc.
although the starting materials were mixtures of diastereomers, while compound 9b is a mixture of two stereoisomers in the ratio 1:4, although the starting material was a relatively pure isomer. Evidently the reduction of the nitrone group with elimination of morpholine occurs stereoselectively as we noted previously [3].
O N + N ( O)n 1, 2 O NOH O N + 3 N ( O)n
4 5 2 1
O RCH2CH + HN R = H, Me O
OH R
8 8a 5a 7
N O
N+
6
3a,b, 4a,b
NaBH4 O N + OH R N ( O)n N OH 9a,b 10a,b

O Cl Cl O Cl Cl
2 1
NH2NH2. H2O
_ ( O) n
+ 3N
O N
9a
9 8
4 5
5a
N
6
N
7
5a,b 6a,b
+ ( O)n
O N N
N 7a,b, 8a,b
1, 3, 5, 7, 9 n = 0; 2, 4, 6, 8, 10 n = 1; 3-10 a R = H, b R = Me

Compound 1 3 3b 4 4b Empirical formula 2 C12H16N4O4 C13H18N4O4 C12H16N4O5 C13H18N4O5 Found, % Calculated, % 4 5.70 5.75 6.20 6.16 5.42 5.44 5.85 5.85 UV spectrum, max (log ) 7 252 (3.98) 252 (3.90) 268 (3.95) 270 (3.97) Yield, % 8 70 73 82 70
mp, * N 5 20.00 19.99 19.12 19.04 18.90 18.91 18.10 18.06 6 146-149 (dec.) 185-187 (dec.) 169-171 (dec.) 192-195 (dec.)
3 51.30 51.42 53.10 53.05 48.60 48.64 50.30 50.31
1347
TABLE 1 (continued)
1 5 2 C8H6N4O 3 55.15 55.17 57.40 57.44 50.50 50.53 52.95 52.94 55.90 55.82 58.10 58.06 51.00 51.07 53.42 53.46 48.68 48.72 51.20 51.17 45.10 45.07 47.60 47.57 4 3.45 3.47 4.40 4.29 3.20 3.18 4.00 3.95 2.34 2.34 3.25 3.25 2.14 2.14 3.00 2.99 5.60 5.62 6.20 6.20 5.20 5.20 5.80 5.77 5 32.20 32.17 30.00 29.77 29.50 29.47 27.50 27.44 32.60 32.55 30.10 30.10 29.82 29.78 27.68 27.72 21.35 21.31 19.90 19.90 19.75 19.71 18.50 18.49 6 108-110 7 246 (3.90), 254 (3.88), 277 (3.77) 255 (4.02) 237 (4.12), 278 (3.79) 240 (4.14) 243 (4.32), 274 (3.90), 285 (3.74) 240 (4.30), 274 (3.60), 312 (3.30) 271 (4.30), 330 (3.94) 254 (4.24), 269 (4.08), 330 (3.94) 267 (3.84) 270 (3.70) 8 75
5b 6 6b 7
C9H8N4O C8H6N4O2 C9H8N4O2 C8H4N4O
155-158 123-125 148-150 139-141
82 75 80 65
7b
C9H6N4O
156-157
70
8 8b
C8H4N4O2 C9H6N4O2
155-157 167-169
68 62
9 9b 10 10b
C8H11N3O3 C9H13N3O3 C8H11N3O4 C9H13N3O4
128-130 122-125 105-107 118-120
73 72 68 65
_______ * Compounds 3a,b and 4a,b were recrystallized from ethanol, compounds 5a,b-8a,b from ethyl acetate, and compounds 9a,b and 10a,b from a 1:1 mixture of ethyl acetate and hexane.

Compound* 1 3 3b Chemical shifts, , ppm (J, Hz)*2 2 2.20-2.75 (4, m, 22); 2.75-3.20 (4, m, 22); 3.20-3.35 (2, m, 2); 3.38-3.75 (4, m, 22); 4.70-4.85; 5.15-5.30 (1, m, C(7)); 6.70, 6.82 (1, s, ) 1.17, 1.29 (3H, d, J = 7, CH3); 2.49-2.80 (6H, m, 32); 2.80-3.10 (1, m, ); 3.10-3.25 (2, m, 2); 3.40-3.25 (4, m, 22 morpholine); 4.60-4.75 (1, m, C(7)); 6.38, 6.70 (1, s, ) 2.15-2.90 (6H, m, 32); 2.90-3.35 (4H, m, 22); 3.45-3.60 (4H, m, 22 morpholine); 4.65-4.75, 5.15-5.25 (1H, m, (7)); 6.76, 6.90 (1, s, ) 1.24, 1.27 (3H, d, J = 7, 3); 2.48-2.60 (2H, m, 2); 2.60-2.90 (4H, m, 22); 3.00-3.20 (1H, m, ); 3.28-3.35 (2H, m, 2); 3.50-3.58 (4H, m, 22 morpholine); 4.32-4.34, 4.60-4.75 (1, m, C(7)); 6.44, 6.85 (1, s, ) 3.40-3.60 (4, m, C(4,5)2); 9.04 (1, d, J = 5, (9)); 9.28 (1H, d, J = 5, C(8)H) 2.62 (3, s, 3); 3.30-3.32 (2, m, (4)2); 3.42-3.44 (2, m, (5)2); 9.24 (1, s, (8)) 3.10-3.20 (2, m, (4)2); 3.52-3.62 (2, m, (5)2); 8.06 (1, d, J = 5, (9)); 9.22 (1, d, J = 5, (8)) 2.67 (3, s, 3); 3.05-3.16 (2, m, (4)2); 3.47-3.56 (2, m, (5)2); 9.17 (1, s, (8))
4b
5 5b 6 6b
1348
TABLE 2 (continued)
1 7 7b 8 8b 9 9b 2 8.14 (1, d, J = 10, (4)); 8.25 (1, d, J = 10, (5)); 8.65 (1, d, J = 6, (9)); 9.63 (1, d, J = 6, (8)) 2.97 (3, s, 3); 8.11 (1, d, J = 9, (4)); 8.17 (1, d, J = 9, (5)); 9.49 (1, s, (8)) 8.03 (1, d, J = 10, (4)); 8.12 (1, d, J = 10, (5)); 8.40 (1, d, J = 5, (9)); 9.51 (1, d, J = 5, (8)) 2.80 (3, s, 3); 7.63 (1, d, J = 9, (4)); 7.85 (1, d, J = 9, (5)); 9.45 (1, s, (8)) 1.70-2.35 (4, m, (4,5)2); 2.70-2.95 (4, m, (7,8)2); 3.00-3.20 (1, m, (5a)); 6.14 (1, s, ); 8.02 (1, s, NOH) 0.91, 1.11 (3H, d, J = 7, 3); 1.60-2.45 (4H, m, (4,5)2); 2.50-2.53 (1H, m, ); 2.53-3.20 (2H, m, 2); 3.30-3.50 (1H, m, (5a)); 5.88, 6.05 (1, s, ); 7.97, 8.00 (1, s, NOH) 1.80-2.42 (4, m, (4,5)2); 2.40-2.60 (2, m, (8)2);2.80-3.10 (2, m, (7)2); 3.15-3.25 (1H, m, (5a)); 5.24 (1, s, ); 7.35 (1, s, -NOH) 1.19 (3, d, J = 7, 3); 1.80-2.60 (6, m, (4,5,7)2); 3,04 (1, t, J = 3, (5a)); 3.38 (1, dd, J1 = 8, J2 = 9, (8)); 4.90 (1, s, ); 7.40 (1, s, NOH)
10 10b
_______ * Compounds 3a, 4a,b two isomers, 1:1; compound 3b two isomers, 1:10; compound 9b two isomers 1:4. *2 1H NMR spectra of compounds 5a,b , 6a,b , 7a,b , 9b and 10b were recorded in (CD3)2CO, compounds 3a,b, 4a,b, 8a,b, 9a and 10a were recorded in (CD3)2SO.
TABLE 3. 13C NMR Spectra of Compounds 3-10

Compound* 1 3 Chemical shifts, , ppm*2 2 16.39, 16.51, 17.18, 17.28 (C(4) and C(5)); 35.52, 35.65 ((8)); 47.37, 48.02, 66.50 (2 morpholine); 69.27, 69.95 ((8)); 90.50, 91.71 ((7)); 141.23, 141.36 ((5)); 151.72, 151.77, 155.23, 156.40 (=N) 9.72 (3), 16.45 ((4)); 17.27 ((5)); 47.99, 66.72 (2 morpholine); 38.70 ((8)); 69.69 ((8)); 95.18 ((7)); 141.29 ((5)); 151.65, 154.81 (C=N) 14.99, 15.20, 17.00 (C(4) and C(5)); 34.54, 39.28 (C(8)); 47.42, 47.94, 66.46, 66.51 (2 morpholine); 70.07, 70.81 ((8)); 90.53, 91.66 (C(7)); 111.94, 111.99 (=NO); 140.47 ((5)); 158.83, 159.92 (C=N) 9.91, 16.28 (3); 14.92, 15.22, 16.99, 17.43 (C(4,5)); 38.16, 41.66 (C(8)); 48.02, 48.34, 66.49, 66.71 (2 morpholine); 70.36, 73.96 ((8)); 95.30, 98.03 (C(7)); 111.81, 112.70 (=NO); 140.56, 141.02 ((5)); 157.45, 158.70 (C=N) 18.29 (C(4)); 28.74 (C(5)); 121.76 (C(9)); 122.36 (C(9a)); 151.79 ((8)); 149.00, 153.32 (=N); 158.95 ((5)) 17.20 (C(4)); 17.49 (3); 27.80 (C(5)); 120.81 ((9)); 134.74 ((9)); 149.09, 153.10 (=N); 153.10 (C(8)); 157.49 ((5)) 17.59 (C(4)); 28.13(C(5)); 111.30 (=NO); 120.10 (C(9)); 123.30 ((9)); 151.76 (C(8)); 152.59, 158.76 ((5), =N) 17.61 (C(4)); 18.06 (CH3); 28.53 (C(5)); 154.08 (C(8)); 111.81 (=NO); 122.19 (C(9)); 134.98 ((9)); 153.61, 158.05 ((5), =N) 119.50 (C(4)); 119.72 (C(9a)); 121.72 (C(9)); 135.40 (C(5)); 147.77, 148.39 (=N); 150.68 (C(8)); 152.63 (C(5)) 18.74 (3); 119.36 (C(4)); 119.36 (C(9a)); 135.77 (C(5)); 136.13 ((9)); 148.06, 149.62 (=N); 152.16 ((5); 152.40 (C(8)) 108.14 (C=NO); 117.32 (C(9a)); 119.01 (C(9)); 120.86 (C(4)); 134.33 (C(5)); 150.10, 151.12 (C(5), =N); 159.96 (C(8))
3b*3 4
4b
5 5b 6 6b 7 7b 8
1349
TABLE 3 (continued)
1 8b 9 9b 10 10b 2 17.95 (3); 111.40 (C=NO); 115.62 (C(4)); 118.60 (C(9a)); 131.30 (C(5)); 134.45 (C(9)); 150.35, 151.18 (C(5), =N); 151.48 (C(8)) 14.56 (C(4)); 19.23 (C(5)); 35.61 (C(8)); 54.40 (C(7)); 69.70 (C(5a)); 72.23 (C(8)); 151.39, 157.98 (C=N) 12.01, 16.79 (CH3); 14.65, 14.90 (C(5)); 19.65, 20.65 (C(4)); 38.77, 40.62 (C(8)); 61.69, 62.98 (C(7)); 70.74, 73.64 ((8)); 72.82, 73.24 (C(5)); 151.5, 152.4, 154.4, 156.1 (C=N) 14.48 (C(5)); 18.25 (C(4)); 34.49 (C(8)); 54.20 (C(7)); 70.55 (C(8)); 71.72 ((5)); 111.94 (=NO); 161.68 (C=N) 12.82 (3); 15.77 (C(5)); 20.85 (C(4)); 39.23 (C(8)); 64.31 (C(7)); 73.03 (C(8)); 73.44 ((5)); 112.10 (=N); 162.02 (=N)
_______ * Compounds 3a, 4a,b two isomers, 1:1; compound 3b two isomers, 1:10; compound 9b two isomers 1:4. *2 13C NMR spectra of compounds 5a,b, 6a,b, 7a,b, 9b and 10b were recorded in (CD3)2CO, compounds 3a,b, 4a,b, 8a,b, 9a and 10a were recorded in (CD3)2SO. *3 The 13C NMR spectrum of the predominant isomer.
EXPERIMENTAL IR spectra of KBr discs (c = 0.25%) were recorded on a Specord M-80 spectrometer. UV spectra of ethanol solutions were recorded on a Specord UV-vis spectrometer. 1H and 13C NMR spectra were recorded on a Bruker AC-200 Machine (200 and 50 MHz respectively); 13C NMR spectra of compounds 3a and 4a were recorded on a Bruker AM- 400 machine (100 MHZ). Analytical and spectroscopic characteristics of the synthesized compounds are reported in Tables 1-3. 8a-Hydroxy-7-(N-morpholinyl)-4,5,8,8a-tetrahydro-7H-pyrrolo[2,3-e]-2,1,3-benzoxadiazole 6-Oxide (3a), 8a-Hydroxy-8-methyl-7-(N-morpholinyl)-4,5,8,8a-tetrahydro-7H-pyrrolo[2,3-e]-2,1,3-benzoxadiazole 6-Oxide (3b), 8a-Hydroxy-7-(N-morpholinyl)-4,5,8,8a-tetrahydro-7H-pyrrolo[2,3-e]-2,1,3-benzoxadiazole 3,6-Dioxide (4a), 8a-Hydroxy-8-methyl-7-(N-morpholinyl)-4,5,8,8a-tetrahydro-7H-pyrrolo[2,3-e]-2,1,3benzoxadiazole 3,6-Dioxide (4b). The corresponding aldehyde (0.015 mol) was added to a solution of the isonitroso ketone 1 or 2 (0.01 mol) in methanol (60 ml), then a solution of morpholine (0.01 mol) in methanol (10 ml) was added dropwise with stirring at 5-10C. The reaction mixture was stirred for 3 h at 0-5C. The precipitate was filtered off, washed with cold methanol, and dried. 4,5-Dihydro-1,2,5-oxadiazolo[3,4-f]cinnoline (5a), 9-Methyl-4,5-dihydro-1,2,5-oxadiazolo[3,4-f]cinnoline (5b), 4,5-Dihydro-1,2,5-oxadiazolo[3,4-f]cinnoline 3-Oxide (6a), 9-Methyl-4,5-dihydro-1,2,5oxadiazolo[3,4-f]cinnoline 3-Oxide (6b). Hydrazine hydrate (0.4 mol) and acetic acid (15 ml) were added to a suspension of pyrroline N-oxide 3a,b or 4a,b (0.1 mol) in water (150 ml). The reaction mixture was boiled for 20 min. The solvents were removed under reduced pressure, water (20 ml) was added to the residue which was cooled. The residue was filtered off, washed with ice water, and dried. 1,2,5-Oxadiazolo[3,4-f]cinnoline (7a), 9-Methyl-1,2,5-oxadiazolo[3,4-f]cinnoline (7b), 1,2,5-Oxadiazolo[3,4-f]cinnoline 3-Oxide (8a), 9-Methyl-1,2,5-oxadiazolo[3,4-f]cinnoline 3-Oxide (8b). Chloranil (0.055 mol) was added to a solution of dihydrocinnoline 5a,b or 6a,b (0.05 mol) in toluene (50 ml) and the reaction mixture was boiled for 3 h. The solvent was removed under reduced pressure and the residue was chromatographed on Al2O3 with 1:1 ethyl acetatehexane as eluent.
1350
6,8a-Dihydroxy-4,5,6,7,8,8a-hexahydropyrrolo[2,3-e]-2,1,3-benzoxadiazole (9a), 6,8a-Dihydroxy-8methyl-4,5,6,7,8,8a-hexahydropyrrolo[2,3-e]-2,1,3-benzoxadiazole (9b), 6,8a-Dihydroxy-4,5,6,7,8,8ahexahydropyrrolo[2,3-e]-2,1,3-benzoxadiazole 3-Oxide (10a), 6,8a-Dihydroxy-8-methyl-4,5,6,7,8,8ahexahydropyrrolo[2,3-e]-2,1,3-benzoxadiazole 3-Oxide (10b). NaBH4 (0.01 mol) was added to pyrroline N-oxide 3a,b or 4a,b (0.005 mol) in ethanol (50 ml). The mixture was stirred for 48 h at room temperature and then evaporated. Water (50 ml) was added to the residue which was then extracted with ethyl acetate (3 50 ml). The extract was dried over MgSO4 and evaporated. The residue was triturated with hexane.
REFERENCES 1. 2. 3. V. A. Samsonov, L. B. Volodarskii, I. Yu. Bagryanskaya, Yu. V. Gatilov, and K. E. Lakman, Khim. Geterotsikl. Soedin., 199 (1994). V. A. Samsonov, L. B. Volodarskii, I. Yu. Bagryanskaya, and Yu. V. Gatilov, Khim. Geterotsikl. Soedin., 1055 (1996). V. A. Samsonov and L. B. Volodarskii, Khim. Geterotsikl. Soedin., 303 (1998).
1351
NEW METHOD FOR THE SYNTHESIS OF THIENO[2,3-d]PYRIMIDINES

O. B. Ryabova1, M. I. Evstratova1, V. A. Makarov1, V. A. Tafeenko2, and V. G. Granik1 The reaction of 5-formyl-4-thiocyanatopyrimidines with nitromethane was studied under various conditions. The reaction was found unexpectedly to proceed with closure of a thiophene ring to give thieno[2,3-d]pyrimidines. The use of ammonium acetate as the catalyst leads to a side reaction involving closure of an isothiazole ring to give isothiazolo[5,4-d]pyrimidines. X-ray diffraction crystallographic analysis was used to confirm the structure of thieno[2,3-d]pyrimidine. Keywords: isothiazolo[5,4-d]pyrimidine, nitromethane, thieno[2,3-d]pyrimidine, 5-formylpyrimidine. In a continuation of a study of 4-dialkyldithiocarbamoyl-5-nitropyrimidines and some of the chemical and physicochemical properties of these compounds [1], we investigated 4-thiocyanatopyrimidines, which have a nitroethylene group at C(5). The properties of alkyl- and arylthiocyanates have been studied rather extensively since these compounds have high insecticidal activity [2]. The synthetic methods for thiocyanate derivatives are based, as a rule, on the reaction of the corresponding halides, sulfates, or sulfonates with ammonium or alkali metal thiocyanates [3, 4]. 4,6-Dichloro-5-formylpyrimidines 1a,b were prepared according to reported procedures by the Vilsmeier formylation of 4,6-dihydroxypyrimidines with the concurrent replacement of the hydroxy groups by chlorine atoms [5, 6]. In the first stage, we synthesized 6-amino derivatives 2a-d by treating dichloropyrimidines 1a,b in dioxane with an aqueous solution of amine in the presence of an equimolar amount of acetic acid added to prevent the replacement of the second chlorine atom. The presence of the electron-withdrawing formyl group at C(5) permits us to replace the second chlorine atom in 6-amino-4-chloro derivatives 2a-d by a thiocyanato group by treating the corresponding chloro derivative with potassium thiocyanate in methanol or DMF. Thiocyanates 3a-d were obtained in high yield (Scheme 1). Since the lability of the chlorine atoms in 1a,b is less than in the analogous 5-nitropyrimidines, we were able to replace only one of the chlorine atoms by a thiocyanate group in 2-methylmercapto derivative 1b [7-9]. The reaction was carried out in methanol at 17C and monitored by thin-layer chromatography. It proved necessary to stop this reaction when about half of the starting compound still remained in the reaction mixture since the reaction is complicated by the formation of a large amount of impurities. Dilution of the reaction mixture with water and recrystallization of the precipitate gave monothiocyano derivative 2e in 27% yield.
__________________________________________________________________________________________
2
State Antibiotics Research Center, 117105 Moscow, Russia; e-mail: makar-cl@ropnet.ru. M. V. Lomonosov Moscow State University, 119234 Moscow, Russia. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1564-1571, October, 2004. Original article submitted June 8, 2004. 1352 0009-3122/04/4010-13522004 Springer Science+Business Media, Inc.
Scheme 1
Cl N R N 1a,b CHO HR1 Cl R N N 2ad Cl N MeS N 2e
1 a R = H, b R = SMe; 2, 3 a, b R = H, c, d R = SMe; a, c R1 = NMe2, b, d R1 = N(CH2)5
Cl CHO KSCN R
1
SCN N R N 3ad CHO R

1
CHO SCN
Since aromatic aldehydes condense with nitromethane to give nitroethylene derivatives [10-12], we studied the reaction of formylthiocyanates 2e and 3a-d with nitromethane. The reaction of thiocyanate 3a in nitromethane at reflux in the presence of ammonium acetate led to a tarry mixture of products, from which we were able to obtain a crystalline compound only in 4% yield. The yield was increased to 20% when the reaction was carried out in 2-propanol at reflux.
SCN N R N 4 R
1
NO2 MeNO2 R N
SCN CHO MeNO2 N 2e, 3ad R

1
S N R N 5ae R
NO2
5 a, b R = H, ce R = SMe; a, c R1 = NMe2, b, d R1 = N(CH2)5 , e R1 = Cl
The IR spectrum of this product lacked the CN group stretching band. NMR spectroscopy, mass spectrometry, and elemental analysis were not in accord with the presumed condensation product 4. The reaction was found unexpectedly to proceed to give thieno[2,3-d]pyrimidine 5a. The structure of this compound was demonstrated by NMR spectroscopy and X-ray diffraction structural analysis (Fig. 1). Some of the bond lengths and angles in the structure of 5a are given in Table 1. The reactions of thiocyanates 2e and 3b-d proceed similarly with varying yields (Table 2). Dimethylamino derivative 3a reacts with nitromethane in the presence of trimethylamine even at 0C. The pure cyclic product precipitates out of the reaction mixture in 50% yield. The reaction of piperidine derivative 3b with nitromethane in the presence of Et3N in 2-propanol is accompanied by tar formation but thiophene derivative 5b was also obtained in this case in 10% yield. Breakage of the SCN bond in thiocyanates may proceed by the action of mild nucleophiles such as CH-acid anions [13]. Hence, we supposed that the nontrivial formation of 6-nitrothieno[2,3-d]pyrimidines may be depicted as follows:
1353
SCN N R N CHO R
1
SCN CH2NO2 MeNO2 R H S NO2 OH H N R

1
NC Et3N R N
CHNO H OH
N N R
1
H OH
S N R N R
NO2
HCN Et3N
N R
O11 C14 N10 C8 N13 C9 C15 C5 N4 C3
O12 C6 S C1
N2
Fig. 1. Molecular structure of 5a from X-ray diffraction structural data. TABLE 1. Bond Lengths (l) and bond angles () in 5a
Bond C(1)N(2) C(1)C(6) C(1)S(7) N(2)C(3) C(3)N(4) N(4)C(5) C(5)C(6) C(5)N(13) C(6)C(9) S(7)C(8) C(8)C(9) C(8)N(10) N(10)O(11) N(10)O(12) N(13)C(14) N(13)C(15) l, 1.3021 1.4207 1.7320 1.3635 1.3822 1.3963 1.3948 1.4097 1.4431 1.7514 1.3775 1.4006 1.2422 1.2459 1.5375 1.5082 Angle C(6)C(1)S(7) N(2)C(1)S(7) N(2)C(1)C(6) C(1)N(2)C(3) N(2)C(3)N(4) C(3)N(4)C(5) N(4)C(5)N(13) N(4)C(5)C(6) C(6)C(5)N(13) C(1)C(6)C(5) C(5)C(6)C(9) C(1)C(6)C(9) C(1)S(7)C(8) S(7)C(8)N(10) S(7)C(8)C(9) C(9)C(8)N(10) C(6)C(9)C(8) C(8)N(10)O(12) C(8)N(10)O(11) O(11)N(10)O(12) C(5)N(13)C(15) C(5)N(13)C(14) C(14)N(13)C(15) , deg. 112.59 118.80 128.32 117.07 118.51 123.96 112.36 117.07 130.54 114.38 132.83 112.72 89.44 118.19 115.74 126.04 109.47 113.61 116.74 129.49 122.36 118.13 107.54
1354
TABLE 2. Physicochemical and Mass Spectral Data of Products

Empirical formula C 2e 3a 3b 3c 3d 5a 5b 5c 5d 5e 6a C7H4ClN3OS2 C8H8N4OS C11H12N4OS C9H10N4OS2 C12H14N4OS2 C8H8N4O2S C11H12N4O2S C9H10N4O2S2 C12H14N4O2S2 C7H4ClN3O3S2 C7H8N4S 33.85 34.22 46.11 46.14 53.35 53.20 42.35 42.50 48.91 48.96 43.07 42.85 50.49 49.98 40.48 40.00 46.40 46.43 32.31 32.13 47.09 46.65 Found, % Calculated, % H N 1.58 1.64 3.66 3.87 4.84 4.87 4.00 3.96 4.82 4.97 3.48 3.59 4.70 4.58 3.80 3.73 4.12 4.56 1.46 1.54 4.41 4.47 16.72 17.10 26.92 26.91 22.21 22.56 22.37 22.03 19.18 19.03 24.87 24.99 21.03 21.20 20.80 20.73 18.08 18.05 15.98 16.06 31.00 31.09 Solvent for crystallization Benzene 2-Propanol Ethanol Ethanol Ethanol 2-Propanol Ethanol Acetonitrile Benzene 2-Propanol Heptane [M]+
Compound
mp, S 26.08 26.10 15.40 15.59 12.88 12.91 25.00 25.22 21.80 21.78 14.47 14.30 12.13 12.62 23.71 23.72 20.61 20.66 177-178 124-126 121-123 177-179 168-171 192-193 119-121 200-202 215-218 182-184 17.86 17.72 169-171
Yield, %
245 208 248 254 294 224 264 270 310 261 180
27 71 70 73 20 50 42 67 54 10 33
1355
In a study of the mother liquors after separation of the thiophene derivatives when ammonium acetate was used as catalyst, we found side products in addition to the thienopyrimidine major products. These side products were identified as isothiazolo[5,4-d]pyrimidines 6a,b using spectral data.
S AcONH4 3a,b or NH3 R N N R 6a,b
1
6 a, b R = H, a R1 = NMe2; b R1 = N(CH2)5
To study the process of their formation "blank" experiment was carried out without nitromethane. Thiocyanates 3a,b were heated at reflux in 2-propanol in the presence of ammonium acetate. As a result the mixture was obtained which after the preparative chromatography gave the main compound 6a,b. According to spectral characteristics these compounds were identical to those obtained in the reactions with nitromethane. In the presence of ammonium acetate, ammonia probably adds at the formyl group with subsequent elimination of HCN and closure of the isothiazole ring. Product 6a was also obtained by treating thiocyanate 3a with methanolic ammonia. A similar closure of an isothiazole ring starting from ortho-formylthiocyanates has been described for derivatives of benzene [14] and pyridine [15].
EXPERIMENTAL The IR spectra were taken on a PerkinElmer spectrometer for vaseline mulls. The NMR spectra were taken on a Bruker AC-200 spectrometer at 200 MHz in DMSO-d6 with TMS as the internal standard. The mass spectra were obtained on a Varian SSQ-700 mass spectrometer with direct inlet into the ion source and 70 eV ionizing voltage. Purity of the products and the reaction course were monitored by thin-layer chromatography on Merck 60 F-254 plates. The physicochemical data of the starting compounds 1a,b [5, 6], 2a [16], 2b [17], 2c,d [18] were in accord with the literature values. 6-Chloro-5-formyl-2-methylthio-4-thiocyanatopyrimidine (2e). A solution of pyrimidine 1b (3.26 g, 15 mmol) and potassium thiocyanate (1.75 g, 18 mmol) in methanol was stirred for 10 h at 17C. The reaction mixture was diluted with water and the white precipitate formed was filtered off. The precipitate was dried in vacuum and recrystallized from benzene to give 0.8 g thiocyanate 2e. Hexane was added to the mother liquor and an additional 0.22 g pyrimidine 2e was obtained. The total yield of 2e was 27%. 2-R-5-Formyl-4-thiocyanato-6-R1-pyrimidines 3a-d. A solution of chloro derivative 2a-d (15 mmol) and KSCN (16 mmol) in DMF (20 ml) was stirred at 80-85C (in the case of 2b, the reaction was carried out in methanol at reflux for 5 h). After cooling to room temperature, the reaction mixture was diluted with water. The precipitate was filtered off, washed with water, and dried. 4-Dimethylamino-6-nitrothieno[2,3-d]pyrimidine (5a). A. A solution of pyrimidine 3a (0.42 g, 2 mmol), nitromethane (0.5 ml, 17 mmol), and ammonium acetate (0.2 g, 2.5 mmol) in 2-propanol (5 ml) was heated at reflux for 2.5 h. The precipitate formed after cooling was filtered off and recrystallized from 2-propanol to give 0.09 g (20%) of cyclic derivative 5a. B. Triethylamine (0.8 ml, 6 mmol) was added dropwise to a suspension of pyrimidine 3a (2.1 g, 1 mmol) in nitromethane (10 ml) cooled to 0C until starting 3a had disappeared as indicated by thin-layer chromatography. The precipitate formed during the reaction was filtered off, washed with 2-propanol, and dried to give 1.13 g thienopyrimidine 5a identical in its physicochemical data to a sample obtained by method A. 1 H NMR spectrum, , ppm: 8.54 (1H, s, CH pyrimidine); 8.46 (1H, s, H thiophene); 3.40 (6H, s, NMe2). 1356
Light-yellow crystals of thienopyrimidine 5a obtained by the slow evaporation of a solution of this compound in 2-propanol were studied on a four-circle automatic CAD4 diffractometer using MoK radiation, graphite monochromator, and -scanning. The unit cell parameters were determined relative to 25 reflections at 7-10 by self-induction and refined relative to 24 reflections at 12-15; a = 9.522(2), b = 15.457(4), c = 13.458(4) ; = 106.54(2); V = 1904.8(9) 3; space group P21/c; Z = 4. A total of 2997 nonzero reflections were measured in the range 2-24. No correction for absorption was introduced. The structure was solved by the direct method (MULTAN) using the SDP program package. The positional and temperature parameters of the non-hydrogen atoms were refined in the full-matrix anisotropic approximation using the SHELXL-93 program package. The hydrogen atom coordinates were determined both from the Fourier difference maps and calculations. Rf = 0.059 for 1358 reflections with I > 2(I) (Table 1, Fig. 1). 6-Nitro-4-piperidinothieno[2,3-d]pyrimidine (5b) and 4-Piperidinoisothiazolo[5,4-d]pyrimidine (6b). A. A solution of pyrimidine 3b (1.5 g, 6 mmol), nitromethane (1.5 ml), and ammonium acetate (0.56 g, 7 mmol) in 2-propanol (20 ml) was heated at reflux for 2 h. The solution was cooled and 0.6 g (40%) of starting 3b was filtered off. The mother liquor was evaporated. The residue was dissolved in methylene chloride, placed on a silica gel column, and eluted with methylene chloride to give a fraction containing 0.28 g (18%) of thienopyrimidine 5b. The second fraction eluted with methanol gave 0.01 g of isothiazole 6b with [M]+ 220. B. Triethylamine was added dropwise to a suspension of 3b (0.9 g, 36 mmol) and nitromethane (0.5 ml, 10 mmol) in 2-propanol (10 ml) cooled to 0C until the suspension was at pH 8-9. The reaction mixture was stirred for 7 h at 5-10C, periodically adding triethylamine to pH 8-9, and then evaporated. The residue was dissolved in chloroform. The solution was passed through a silica gel layer and evaporated to give 0.4 g of thienopyrimidine 5b, identical in its physicochemical data to the product obtained using method A. 1H NMR spectrum, , ppm: 8.51 (1H, s, CH pyrimidine); 8.48 (1H, s, H thiophene); 3.93 (4H, m, N(CH2)2); 1.69 (6H, br. s, (CH2)3). 4-Dimethylamino-2-methylthio-6-nitrothieno[2,3-d]pyrimidine (5c). Triethylamine was added dropwise to a suspension of 2-methylmercaptopyrimidine 3c in nitromethane (3 ml) cooled to 0C. The solution was stirred for 4 h at 7C. The precipitate formed was filtered off and washed with 2-propanol to give 0.37 g of thienopyrimidine 5c. 1H NMR spectrum, , ppm: 8.43 (1H, s, H thiophene); 3.37 (6H, s, N(CH3)2); 3.26 (3H, s, SCH3). 2-Methylthio-6-nitro-4-piperidinothieno[2,3-d]pyrimidine (5d). A sample of triethylamine (0.23 g, 22 mmol) was added to a suspension of 2-methylmercaptopyrimidine 3d (0.65 g, 22 mmol) and nitromethane (1 ml, 22 mmol) in 2-propanol (20 ml) at 15C. The reaction mixture was stirred for 5 h at 50C, cooled, and filtered to give 0.54 g of thienopyrimidine 5d. 4-Chloro-2-methylthio-6-nitrothieno[2,3-d]pyrimidine (5e). Triethylamine was added dropwise to a suspension of thiocyanate 2e (0.79 g, 3 mmol) in nitromethane (6 ml) cooled to 15C until the suspension was at pH 8-9. The reaction mixture was stirred for 2 h at 15C, periodically adding triethylamine to pH 8-9, and then evaporated. The residue was dissolved in benzene and placed on a silica gel column. Elution with benzene gave 0.1 g of thienopyrimidine 5e. 6-Dimethylaminoisothiazolo[5,4-d]pyrimidine (6a). A. A solution of thiocyanate 3a (0.42 g, 2 mmol) and ammonium acetate (0.2 g, 0.3 mmol) in 2-propanol (10 ml) was heated at reflux for 30 h. The reaction mixture was treated with activated charcoal, filtered, and evaporated. The residue was dissolved in methanol and subjected to chromatography on a preparative silica gel plate (Merck 160160) with elution using 50:1 chloroformmethanol. The zone with Rf 0.6 was separated, extracted with chloroform, and evaporated to give 0.06 g of isothiazole derivative 6a. B. A mixture of thiocyanate 3a (0.45 g, 2.16 mmol) and 20% methanolic ammonia (10 ml) was stirred for 4 h at -10C and then for 10 h at room temperature. The precipitate of 6a (0.13 g) was filtered and found identical in its physicochemical data to the sample obtained using method A.
1357
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. O. B. Ryabova, V. A. Makarov, V. V. Chernyshev, and V. G. Granik, Izv. Akad. Nauk, Ser. Khim., 4 (2004). S. C. Mitchell, Biological Interactions of Sulfur Compounds, Taylor & Francis, New York (1996), p. 177. S. Oae, Organic Chemistry of Sulfur, Plenum Press, New York (1977), Ch. 2. E. Campaigne, Y. I. Puzin, M. Yokoyama, G. V. Leplyanin, H. Togo, and S. Kondo, Adventures in Organic Sulfur Chemistry, Taylor & Francis, New York (1990), p. 236. W. Klotzer and M. Herberz, Monatsch. Chem., 96, 1573 (1965). A. A. Santilli, D. H. Kim, and S. V. Wanser, J. Heterocycl. Chem., 8, 445 (1974). J. Clark and J. Gelling, J. Chem. Soc., Chem. Commun., 859 (1967). J. Clark, M. Curphey, and J. W. Southon, J. Chem. Soc., Perkin Trans. 1, 1611 (1974). J. Clark, J. Gelling, J. W. Southon, and M. S. Morton, J. Chem. Soc., C, 494 (1970). G. J. T. Kuster, R. H. J. Steeghs, and H. W. Scheeren, Eur. J. Org. Chem., 3, 553 (2001). D. Trachsel, Helv. Chim. Acta, 85, 3019 (2002). H. Harada, Y. Hirokawa, K. Suzuki, Y. Hiyama, M. Oue, H. Kawashima, N. Yoshida, and Y. Furutani, Bioorg. Med. Chem. Lett., 13, 1301 (2003). C. Iijima, E. Hiyoshi, and A. Miyashita, Chem. Pharm. Bull., 40, 1090 (1992). M. Muehlstaedt, R. Braemer, and B. Schulze, J. Prakt. Chem., 318, 507 (1976). A. Taurins and V. T. Khouw, Canad. J. Chem., 51, 1741 (1973). J. Clark, M. S. Shahhet, D. Korakas, and G. Varvounis, J. Heterocycl. Chem., 30, 1065 (1993). J. Clark, B. Parvizi, and J. W. Southon, J. Chem. Soc., Perkin Trans. 1, 125 (1976). A. Kaminskas, M. Dailide, and S. Tumkevicius, Pol. J. Chem., 76, 725 (2002).
1358
ANNELATION OF 3,4-DIHYDROISOQUINOLINES BY 3-ACYL-5,5-DIMETHYLTHIOPYRAN-2,4-DIONES. SYNTHESIS AND PROPERTIES OF 8-AZA17-THIA-D-HOMOGONA-12,17a-DIONES

M. V. Budnikova, O. V. Gulyakevich, T. A. Zheldakova, A. L. Mikhal'chuk, and D. B. Rubinov We have used annelation of 3,4-dihydroisoquinolines by 3-acyl-5,5-dimethylthiopyran-2,4-diones to obtain the corresponding 8-aza-17-thia-D-homogonanes, which are novel representatives of heterosteroids. We have studied the tautomerism of 3-acylthiopyran-2,4-diones using NMR spectroscopy and H/D-isotope exchange. We have obtained 2H-isotopomers of 3-acylthiopyran-2,4diones. Keywords: 8-aza-17-thia-D-homogonanes, azomethines, 3-acyl-5,5-dimethyltetrahydrothiopyran-2,4diones, heterosteroids, 3,4-dihydroisoquinolines, Schiff's bases, thiopyrano[3',4':5,6]pyrido[2,1-a]isoquinolines, annelation, [2+4] cyclocondensation. Among heterocyclic analogs of steroids, the most well known today are the aza analogs, in particular those exhibiting quite valuable properties as inhibitors of 5-reductase and antiandrogens, 4-aza steroids [1, 2], and also 8-aza steroids, which are of considerable practical and theoretical interest as low molecular weight immunomodulators [3-5]. Studies of the structurefunction relations in the 8-aza steroid series have shown [3, 57] that by means of structural and functional group transformations, we can change both the direction and the level of their immunomodulating effect. A quite promising approach to controlling the immune activity of 8-aza steroids is to introduce additional heteroatoms into their tetracyclic ring [8]. So far 8,16-diaza- [9], 8-aza-16-oxa[10], 8-aza-16-thia- [11], 8,17-diaza-D-homo- [12], and 8-aza-17-oxa-D-homogonanes have been synthesized and studied [13]. At the same time, compounds in the 8-aza-17-thia-D-homogonane series have been described only recently [14]. With the aim of expanding the indicated series, we have studied the reaction of 3,4dihydroisoquinolines 1a-d with 3-acyl-6,6-dimethylthiopyran-2,4-diones 2a,b, obtained from 6,6-dimethyltetrahydrothiopyran-2,4-dione (3). In this case, it was also important to clarify the effect of the sulfur atom in the ring of the original dione 2 on the activity of the latter in the reaction with compounds 1. We have established that when 3,4-dihydroisoquinolines 1a,b, unsubstituted in the 1 position, are boiled in ethanol with diones 2a,b, the corresponding tetracyclic derivatives 4a-d are formed: the products of an annelation reaction ([2+4] cyclocondensation) at the C=N bond (Scheme 1). However, we were unable to obtain products of type 3 from 1-methyl-substituted dihydroisoquinolines 1c,d and the same diones 2a,b. The data presented
__________________________________________________________________________________________ Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Minsk 220141; e-mail: rubinov@ns.iboch.ac.by. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1572-1583, October, 2004. Original article submitted July 6, 2001; revision submitted April 4, 2002. 0009-3122/04/4010-13592004 Springer Science+Business Media, Inc. 1359
Scheme 1
R2 O R1 R1
1 2 3
O
3 4 2 5 1S 6
R3
1ad
R2 = H R3 R1 R2 A R1 B
11
O C 9 N8
7 14
O D
15
2a,b R2 = Me 4
1 1
S 17
4ad 1a,c, 4a,c R = H; 1b,d, 4b,d R = OMe; 1a,b, 4ad R = H; 1 c, d R2 = Me; 2a, 4a,b R3 = H; 2b, 4c,d R3 = Me
2
along with the results of previous studies [8, 9, 15, 16] allow us to say that in this case, the reaction is hindered by the 1-Me group in dihydroisoquinolines 1c,d and also by the sulfur atom and the gem-dimethyl group in the position 6 of diones 2a,b. In order for the described reaction to occur, which ultimately involves formation of the C(9)C(11) and N(8)C(14) bonds closing the 2,3-dihydropiperidinone ring C of 8-aza-17-thia steroids 4a-d, both substrates should be at least bifunctionalized. In azomethines 1a-d, the C=N bond is polarized, and as a result the azomethine carbon atom, which has electrophilic properties, reacts with nucleophiles while the nucleophilic nitrogen atom reacts with electrophiles [17]. According to modern theories, ,'-tricarbonyl compounds, in particular acylthiopyrandiones 2a,b, exist as a mixture of interconverting tautomeric endo(21, 22) and exo (23, 24) enols (Scheme 2) [18, 19], for which we may expect the presence of four sets of resonance signals in the 1 H NMR spectrum. However, due to the low population of individual tautomers, rapid interconversion between them, and other factors, the actually observed number of signals is generally significantly lower. Thus in the 1 H NMR spectrum of compound 2a, along with the four major signals (integrated intensity 93%), there are additional signals at 17.06 ppm and 2.82 ppm (I = 7%) corresponding to the enol and methylene protons of the C(5)H2 group respectively. Scheme 2
R3 O O H O 21 S R3 O H O S O 22
R3 O O H O 23 S R3 O
H O S O 24
1360
This may be either a consequence of significantly faster interconversion rates between the endo and exo enols 2 23 and 22 24 than can be distinguished on the NMR time scale [18], or else the tautomers 21, 23 and 22, 24 degenerate to betaine chelate complexes 25 and 26 due to 1,5(O,O')-tunneling proton transfer [20]. According to the data in [21], the indicated major signals are assigned to the complex 25 while the minor signals are assigned to the complex 26. However, we cannot explain the nucleophilicity of the acyl group in the acylthiopyran diones 2a,b within such a theory [18].
1
Scheme 3
R3 O O H+ O 25 S R3 O 26 O S H+ O
Azomethines 1a-d are bases [22], while the ,'-tricarbonyl compounds 2a,b are acids [23]. Consequently, the initial event in their reaction is formation of the salt 5.
R2 R1 R1 Cat 5 + NH R3
O _
O S
.
O An
The mesomeric azomethine cation 5Cat, as was shown earlier in [15], exists as an equilibrium mixture of immonium and enammonium tautomers. The acylthiopyrandione anion 5An is also mesomeric, and hypothetically can exist as a heptad mesomer 5An1, pentad mesomers 5An2-5An4, or triad mesomers 5An5-5An8.
R3 O R3 O 5An1 _ S O R3 O 5An2 O _ O S O O 5An3 _ O R3 S O 5An4 O _ S O
R3 O O _ O 5An5 S
R3 O O _ O 5An6 S R3
O R3 S
O S
O 5An7
O 5An8
1361
Due to structural (planarity) and conformational factors, the mesomeric anions 5An2, 5An5, and 5An8, which permit free rotation of the acyl side chain, probably have the highest populations in this series. An isotope exchange study for acetylthiopyrandione 2a in CDCl3 and Py-d5 in the presence of D2O at 20C showed that under neutral conditions (CDCl3), H/D isotope exchange occurs only for the chelated proton of the enol, while under basic conditions (Py-d5) such exchange also occurs for the protons of the methyl (methylene) group of the acyl side chain and the methylene group C(5)H2. This suggests that for anions 5, as for anions of 2-acylcycloalkane-1,3-diones [15, 24, 25] and anions of 3-acylthiotetronic acids [16], a tautomeric equilibrium is established between the forms [5An2, 5An5-5An8] and [5An9-5An12], where both the ' protons of the acyl substituents and the protons of the C(5)H2 groups are involved in H/D isotope exchange (Scheme 4). The physicochemical characteristics (1H NMR, 13C NMR, and mass spectra) of the 2H-isotopomers 6a,b obtained are given in the experimental section. According to 1H NMR data, as a result of H/D isotope exchange for the acylthiopyrandiones 2a,b in Py-d5 (D2O) solutions, H/D isotope exchange also occurs for the chelated enol proton, which during separation of the isotopomers is regenerated due to D/H exchange with atmospheric moisture. As a result, we cannot obtain isotopomers with a chelated deuterium isotope under the described experimental conditions. Analysis of the physicochemical characteristics of 2H isotopomers 6a,b suggests that their isotopic frequency is ~90%. Scheme 4
R3 5An8 R3 ' OH O _ S O 5An7 5An6 5An9 R3 ' S O O H O 5An11 O 2a,b Py-d5 D2O S D D OH D D 6a,b O R3 O 5An12 ' O H O 5An10 _ O S
R3 O _ H
'
O S
5An5
5An2
In light of these data and the theories, we can understand the mechanism for the appearance of nucleophilicity in the ' position of the acylthiopyrandiones 2a,b, and the electrophilicity of the C(4) atom in the tautomers 5An2, 5An5-5An12 is obvious as a consequence of polarization and alternation effects. Considering the above discussion, the mechanism of the reaction of annelation of 3,4-dihydroisoquinolines 1a-d by acylthiopyrandiones 2a,b can be represented by Scheme 5.
1362
Scheme 5
1 OH O O _ + S S + N OH TS 7 H2O 4ad
5 OH O
NH
The proposed mechanism, in contrast to what has been discussed earlier in [9, 10, 12] and in accordance with the studies in [11], assumes concerted formation of the CC and C=N bonds, closing the dihydro-pyridinone ring C of product 4 via a six-membered transition state TS. The hypothetical alcohol 6 is either metastable and dehydrated to form the end product under the reaction conditions, or else it is generally not formed as an intermediate but rather the conversion 5 3a-d occurs with elimination of a water molecule directly during formation of the pyridone ring C. Considering the data in [26], the second route is preferred. The composition and structure of the synthesized compounds 2a,b and 4a-d are supported by elemental analysis data and physicochemical studies. Thus in the mass spectra of azathia steroids 4b-d, there are characteristic sets of signals corresponding to radical molecular ions with mass numbers from [M+2] to [M-2], and also split signals (typical od sulfur-containing compounds) that involve the sulfur atom of the radical ions formed upon fragmentation of the molecular ions. In the IR spectra of diones 2a,b there are strong (~80-90%) broadened and asymmetric absorption bands at ~1630, ~1570, and ~1470 cm-1 that are due to vibrations of the enolized ,'-tricarbonyl moiety [19]. The bands at ~1630 cm-1 have quite extended high-frequency slopes going into the ~1800 cm-1 region, suggesting that they have a complex composition. We may assume that they include absorption bands for symmetric and asymmetric stretching, bending and other vibrations of the C=O groups of the ,'-tricarbonyl moiety. The bands at ~1570 can be assigned to vibrations of the C=C bonds, while the intense and asymmetric absorption bands in the 1500-1300 cm-1 region can be assigned to bending vibrations of the CH bonds in the methylene and methyl groups adjacent to the ,'-tricarbonyl moiety. A distinguishing feature of the IR spectra of derivatives 2a,b is the presence of intense absorption bands in the 870 cm-1 region, probably due to stretching vibrations of the CS bonds. For the IR spectra of derivatives 4a-d, characteristic features are the strong broadened and asymmetric absorption bands at ~1680 cm-1, which obviously include absorption bands for stretching vibrations of the CO and C(O)S groups, and bands at ~1530 cm-1 due to stretching vibrations of the C=C bond of the enolized ,'-tricarbonyl moiety [27]. Intense absorption bands in the 1500-1300 cm-1 region probably belong to bending vibrations of the CH bonds of the methylene groups, while the bands in the 800-700 cm-1 region probably belong to vibrations of the CN bond. In contrast to the cycloalkane-1,3-diones in [19], in the electronic absorption spectra of 3-acylthiopyran2,4-diones 2a,b we observe three absorption bands, where two long-wavelength absorption bands (240-320 nm) have well-resolved maxima and the short-wavelength absorption band (210-240 nm) has a pronounced absorption maximum in the case of derivative 2a while in the case of derivative 2b it appears as a faint shoulder on the high-frequency slope of the spectral line. The refined values for the absorption maxima and minima for diones 2a,b (obtained by taking the derivatives of the experimental spectral lines) are: for acetylthiopyrandione 2a, max 225, 255, and 285 nm; min 207.7, 240, 269.6, and 303.1 nm; for propionylthiopyrandione 2b, max 226.2, 255.4, 285.4, and 418.9 nm; min 210.4, 242.3, 270, 303.9, 404.6, and 440 nm. While the numerical values for the two intense (log > 4) long-wavelength absorption bands correlate well with the absorption bands 1363
observed for alicyclic ,'-tricarbonyl compounds in [19] and consequently can be assigned to * electronic transitions in the ,'-tricarbonyl moiety, the short-wavelength absorption band may be due to the sulfur atom present in the structure of these compounds and probably can be assigned to electronic transitions in the thiolactone group. In addition to the absorption bands discussed above, for compound 2b we can observe very broad (~60-100 nm) low-intensity absorption bands ( < 100) in the long-wavelength region of the spectrum that are due to n * electronic transitions. In the electronic absorption spectra of azathia-D-homogonanes 4a,c, there are two intense absorption bands (log > 4) at ~270 nm and ~315 nm that are typical of compounds containing an -acyl-aminovinylcarbonyl (AAVC) group N(8)C(14)=C(13)(C(12)=O)C(17/17a)=O [5, 11, 12]. In the spectra of derivatives 4b,d, along with what has been indicated, there are also asymmetric absorption bands in the ~230 nm region (of about the same intensity), probably due to electronic transitions of the methoxy-substituted aromatic ring A [5, 12, 13] and the thiolactone moiety. Evidence in favor of such a conclusion is the fact that the intensity of absorption bands due to only the methoxy-substituted aromatic ring A is generally significantly lower [5, 12, 13]. The NMR data were the most informative for the structural studies. Thus in the 1H NMR spectra of compounds 4a-d, there are resonance signals from all the protons of the proposed structures, with a characteristic pattern of spinspin couplings revealed using the double resonance method. The position of the sulfur atom in products 4 was established based on analysis of long-range spinspin couplings, showing that for all the indicated compounds, we observe a direct and a reverse NOE (nuclear Overhauser effect) for protons in the positions 7 and 15, which clearly confirms position 15 for the methylene unit and accordingly position 17 for the sulfur atom. The series of homogonane diones 4a-d obtained also provided the opportunity to observe and study the individual and combined effect on the spectral characteristics of these compounds from the methoxy substituents on the aromatic ring A and the methyl group on the pyridine ring C. The effect of the methoxy group on the benzyl proton H-9 is worth noting: it is expressed in a 20-40 Hz upfield shift of the signal from the latter (diones 4b,d). It may be due either to a hyperconjugation effect [17] or to stereoelectronic interactions between the indicated proton and the -electron cloud of ring A through space. We can easily track the effect of the 11-CH3 group from the downfield shift we see in all cases for the signal from the equatorial proton H-7. This effect can be explained by perturbation of the planarity of the aminovinyldicarbonyl moiety. The remaining 1H signals for compounds 4a-d are found in regions typical for spectra of 8-aza-D-homogonanes [19, 21, 26]. The most pronounced differences between the homogonane diones 4a-d are observed in their 13C NMR spectra. These differences are connected not only with the appearance of additional signals as we go from the unsubstituted dione 4a to the 2,3-dimethoxy or the 11-methyl derivatives 4b-d, but also with different positions for some of the 13C atoms common to all the structures. Thus introducing OMe electron-donor substituents onto the aromatic ring A causes quite obvious changes in the multiplicity and position of the signals for the 13C atoms forming it, while substitution of the proton in the 11-CH2 group by a methyl substituent leads to a change in the multiplicity and position of the 13C(11) signal. However, the shifts of signals for nuclei far away from the positions where structural changes occur are more meaningful for studying and understanding the stereoelectronic changes in the molecules of the considered series of compounds. Thus the 11-methyl derivatives 4c,d differ from their 11-unsubstituted analogs 4a,b in the signals for the 13C(9), 13C(7), 13C(13) atoms that are shifted downfield by ~4.0 ppm, 1.0 ppm, and 1.5 ppm respectively, and also in the signal for the 13C(12) atom, which is found ~3 ppm upfield. These shifts are certainly connected with differences in the electronic environment of the indicated atoms, and those differences in turn are connected with a change in the planarity of the AAVC moiety. The change in the planarity of the AAVC moiety when a methyl group is introduced into the position 11 may be explained by stereoelectronic effects involving interaction of the group with the -electrons of the aromatic ring A. This conclusion is quite consistent with X-ray diffraction data for 8-aza steroids [28] and
1364
the results of examination of Dreiding models for compounds 4a-d, which shows that due to bending of the molecular frameworks at the N(8)C(9) bond, the 11-Me group is found in a region of anisotropy of the -electron cloud of ring A. Thus as a result of our studies we have established that reaction of 3,4-dihydroisoquinolines 1a,b with acylthiopyrandiones 2a,b leads to the previously unknown 8-aza-17-thia-D-homogona-12,17a-diones 4a-d. Products of annelation with an angular 9-Me group are not formed from 3,4-dihydroisoquinolines 1c,d and acylthiopyrandiones 2a,b; the reaction mixtures become tarry and the original substrates cannot be recovered. Attempts to obtain salts 5 from 3,4-dihydroisoquinolines 1c,d and acylthiopyrandiones 2a,b remained unsuccessful, which is probably connected with the lability of the latter. We have shown that anions of acylthiopyrandiones 5An exist as an equilibrium mixture of "enolanion tautomers" 5An9-5An12, where the tautomerism involves the hydrogen atoms of the methylene (methyl) groups adjacent to the ,'-tricarbonyl moiety. From acylthiopyrandiones 2a,b, we obtained 2H-isotopomers 6a,b, which are of interest for physicochemical and biological studies.
EXPERIMENTAL The IR spectra were obtained on a UR-20 in KBr disks. The UV spectra were taken on a Specord M-400 spectrophotometer in ethanol. The derivatives of the experimental spectral curves were taken using the built-in software of the instrument. The mass spectra of derivatives 2a,b and their isotopomers 6a,b were measured on an HP 5890/5972 GC/MS chromatograph/mass spectrometer (quartz capillary column HP 5MS 30 m 0.25 mm 0.25 m; carrier gas, helium, 0.7-1 l/min; vaporizer temperature, 250C; temperature program 40-300C, 6C/min). The mass spectra of the azathia steroids 4b-d were taken on a high-resolution MicroMass MasSpec mass spectrometer with direct injection of the sample and electron ionizing energy 70 eV. The 1H and 13C NMR spectra were obtained on a Bruker AC-200 (1H, 200 MHz and 13C, 50 MHz) and a Bruker DRX-500 (1H, 500 MHz and 13C, 125 MHz) rf spectrometer, internal standard TMS. The course of the reactions was monitored using TLC on Silufol UV-254 plates, eluent 9:1 chloroform methanol. The melting points were determined on a Boetius heating stage. The 3,4-dihydroisoquinolines 1a-d used in this work were obtained by cyclodehydration of the corresponding phenethylamides when treated with PPA (azomethines 1a,b) or phosphorus oxychloride (azomethines 1c,d) under BischlerNapieralski reaction conditions [29]. 3-Acylthiopyran-2,4-diones 2a,b were obtained by acylation of thiopyrandione 3 [30] by acetyl and propionyl chlorides in the presence of pyridine, followed by ClaisenHaase O,C-isomerization [29] of the enol acylates formed as intermediates by treatment with 4-dimethylaminopyridine [31]. Since 3-acylthiopyran-3,4-diones 2a,b have been described only in patent literature [31], where there are no details given for the synthesis and their physicochemical characteristics are not indicated, we considered it advisable to give the general procedure for obtaining these compounds and data from physical and chemical investigation methods. 3-Acyl-6,6-dimethyltetrahydro-2H-thiopyran-2,4-diones (2a,b) (General Procedure). Dry pyridine (0.97 ml, 12 mmol) and the corresponding acid chloride (11 mmol) were added while stirring to thiopyrandione 3 (1.58 g, 10 mmol) in dry toluene (40 ml). The reaction mixture was stirred for 1 h (monitored by TLC, visualized with an iron chloride solution). Then the reaction mixture was washed with a 1% HCl solution, water, and a Na2CO3 solution; then it was dried with Na2SO4 and filtered. Dimethylaminopyridine (0.25 g, 2 mmol) was added to the filtrate; the mixture was stirred while protected from moisture for 6-8 h (monitored by TLC). The reaction mixture was extracted with a 10% NaOH solution until the -triketone 2 was completely recovered (extract 1). Extract 1 was acidified with a 10% HCl solution and extracted with chloroform (4 20 ml, extracts 2). The combined extracts 2 were dried with Na2SO4 and then filtered. The filtrate was evaporated down on a rotary evaporator and the residue was crystallized from ether.
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3-Acetyl-6,6-dimethyltetrahydro-2H-thiopyran-2,4-dione (2a). Dione 2a (1.32 g) was obtained as cream-colored crystals from thiopyrandione 3 (1.58 g, 10 mmol) [30] and acetyl chloride (0.78 ml, 11 mmol). Yield 66%; mp 100C (ether). IR spectrum, , cm-1: 3450, 1630, 1560, 1545, 1450, 1420, 1395, 1370, 1325, 1295, 1260, 1240, 1205, 1160, 1130, 1115, 1045, 1030, 985, 935, 880. UV spectrum, max, nm (lg ): 229.6 (4.02), 256.6 (4.05), 280.4 (4.07); min, nm (log ): 240 (4.00), 267.3 (4.03). 1H NMR spectrum (CDCl3), , ppm (J, Hz): 1.50 (6H, s, 6-CH3); 2.58 (3H, s, 8-CH3); 2.96 (2H, s, 2H-5); 18.40 (1H, s, OH). 13C NMR spectrum (Pyd5), , ppm: 27.616 (C-8); 29.348 (6-CH3); 42.988 (C-6); 49.791 (C-5); 112.885 (C-3); 189.095 (C-2); 197.226 (C-4); 199.762 (C-7). Mass spectrum, m/z (Irel, %): 202.05 [M+2]+ (5.8); 201.05 [M+1]+ (11.3); 200.05 [M]+ (100); 185.05 [M-15]+ (15.3); 172.10 (12.1); 167.10 (15.4); 158.05 (3.2); 157.05 (20.0); 153.05 (5.1); 151.05 (6.6); 145.05 (13.5); 144.05 (13.1); 126.00 (10.0); 125.10 (4.3); 115.95 (9.1); 110.95 (7.1); 100.95 (9.0); 99.00 (3.1); 98.00 (50.9); 89.00 (5.9); 24.65 (87.9); 85.00 (19.9); 84.00 (74.3); 83.00 (63.8); 76.95 (3.2); 74.95 (13.9); 73.95 (9.5); 70.95 (3.0); 69.95 (11.5); 68.95 (30.4); 66.95 (5.6); 60.95 (3.3); 58.90 (20.2); 57.90 (3.2); 57.00 (6.6); 56.00 (9.7); 55.00 (21.2); 53.00 (7.2); 45.00 (7.5); 44.00 (5.8); 43.00 (77.6); 42.10 (5.0). Found, %: C 53.79, 53.87; H 5.92, 5.85; S 16.12, 15.84. C9H12O3S. Calculated, %: C 53.98; H 6.04; S 16.01. M 200.26. 6,6-Dimethyl-3-propionyltetrahydro-2H-thiopyran-2,4-dione (2b). Propionylthiopyrandione 2b (1.28 g) was obtained as colorless crystals from thiopyrandione 3 (1.58 g, 10 mmol) [30] and propionyl chloride (0.96 ml, 11 mmol). Yield 60%; mp 53C (ether). IR spectrum, , cm-1: 3450, 1630, 1580, 1560, 1450, 1420, 1395, 1370, 1310, 1270, 1260, 1140, 1130, 1085, 985, 940, 870. UV spectrum, max, nm (log ): 257.7 (4.09), 280.8 (4.10), 413.5 (2.51); min, nm (log ): 205 (3.56), 270 (4.07), 365 (2.38). 1H NMR spectrum (CDCl3), , ppm (J, Hz): 1.18 (3H, t, J = 7.0, 9-CH3); 1.50 (6H, s, two 6-CH3); 2.90 (2H, s, two H-5); 3.04 (2H, q, J = 7.0, two H-8); 18.54 (1H, s, OH). 13C NMR spectrum (Py-d5), , ppm: 8.852 (C(9)); 29.301 (6-CH3); 33.582 (C(8)); 43.043 (C(6)); 49.391 (C(5)); 112.415 (C(3)); 188.982 (C(2)); 196.402 (C(4)); 204.084 (C(7)). Mass spectrum, m/z (Irel, %): 216.10 [M+2]+ (5.77); 215.10 [M+1]+ (12.2); 214.10 [M]+ (98.9); 199.05 [M-15]+ (4.2); 186.05 (4.2); 185.05 (35.6); 182.10 (3.1); 181.10 (28.2); 180.10 (8.0); 172.00 (5.6); 171.10 (11.6); 165.10 (25.7); 158.95 (4.6); 157.95 (6.1); 156.95 (3.6); 153.05 (3.6); 140.00 (7.6); 138.00 (3.2); 130.00 (16.5); 125.00 (9.2); 124.00 (3.9); 116.95 (4.7); 111.95 (19.3); 110.95 (6.4); 101.95 (17.3); 100.95 (6.8); 99.00 (8.9); 98.00 (23.6); 97.00 (14.8); 89.00 (5.9); 86.90 (3.2); 83.00 (100); 76.95 (3.8); 74.95 (14.4); 73.95 (7.7); 70.95 (4.1); 69.95 (5.4); 68.95 (51.6); 66.95 (3.6); 60.95 (5.4); 58.90 (18.1); 57.90 (4.8); 57.00 (67.5); 56.00 (9.5); 55.00 (27.4); 53.00 (8.8); 51.00 (3.1); 45.00 (7.3); 44.00 (5.3); 43.00 (11.8); 42.10 (4.7). Found, %: C 55.87, 55.93; H 6.53, 6.46; S 14.82, 15.05. C10H14O3S. Calculated, %: C 56.05; H 6.59; S 14.96. M 214.28. rac-16,16-Dimethyl-8-aza-17-thia-D-homogona-1,3,5(10),13-tetraene-12,17a-diones (General Procedure). An equimolar mixture of 3,4-dihydroisoquinoline 1a-d and acylthiopyrandione 2a,b in an ~3-5-fold volume of alcohol was boiled under a stream of argon; the course of the reaction was followed using TLC. It took 15-24 h to complete the process. Then the reaction mixture was evaporated down to one-third of the original volume and held at 0 to +5C. The separated product 4 was filtered out and recrystallized from alcohol. rac-16,16-Dimethyl-8-aza-17-thia-D-homogona-1,3,5(10),13-tetraene-12,17a-dione (4a). Product 4a (0.21 g) was obtained as colorless crystals from isoquinoline 1a (0.13 g, 1 mmol) and dione 2a (0.2 g, 1 mmol). Yield 67%; mp 227-230C (alcohol). IR spectrum, , cm-1: 3100-2830, 1680, 1620, 1590, 1530, 1500, 1480, 1445, 1420, 1380, 1320, 1300, 1270, 1250, 1230, 1200, 1160, 1150, 1120, 1070, 1040, 1010, 985, 955, 905, 890, 880, 840, 800, 760. UV spectrum, max, nm (log ): 273.80 (4.25), 315.30 (4.35); min, nm (log ): 236.45 (3.77), 288.80 (4.06). 1H NMR spectrum (CDCl3), , ppm (J, Hz): 1.48 (3H, s, 16-CH3); 1.52 (3H, s, 16-CH3); 2.70 (1H, dd, J1 = 15.0, J2 = 15.5, 11-HB); 2.90 (1H, dd, J1 = 15.5, J2 = 4.0, 11-HA); 2.98 (2H, s, two 15-H); 3.02 (2H, m, two 6-H); 3.50 (1H, m, 7-Ha); 4.20 (1H, tt, J1 = 13.0, J2,3 = 4.0, 7-He); 5.94 (1H, dd, J = 15.0, J = 4.0, 9-HX); 7.20 (4H, m, 1-, 2-, 3-, 4-H). 13C NMR spectrum (CDCl3), , ppm: 29.40 (16-CH3), 29.62 (16-CH3), 30.14 (C(6)), 42.79 (C(11)), 43.30 (C(16)), 45.94 (C(15)), 46.68 (C(7)), 57.59 (C(9)), 107.98 (C(13)), 127.03 (C(4)),
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128.33 (C(1)), 128.46 (C(3)), 129.04 (C(2)), 132.06 (C(10)), 136.11 (C(5)), 170.55 (C(14)), 189.89 (C(17a)), 194.49 (C(12)). Found, %: C 69.09, 68.92; H 6.05, 6.20; N 4.38, 4.34; S 10.12, 10.36. C18H19NO2S. Calculated, %: C 68.98; H 6.11, N 4.47; S 10.23. M 313.40. rac-2,3-Dimethoxy-16,16-dimethyl-8-aza-17-thia-D-homogona-1,3,5(10),13-tetraene-12,17a-dione (4b). Product 4b (0.264 g) as colorless crystals was obtained from isoquinoline 1b (0.19 g, 1 mmol) and dione 2a (0.2 g, 1 mmol). Yield 70.7%; mp 259-261C (alcohol). IR spectrum, , cm-1: 3100-2830, 1680, 1620, 1600, 1525, 1510, 1455, 1420, 1380, 1340, 1310, 1265, 1230, 1210, 1150, 1120, 1065, 1055, 1020, 990, 960, 870, 835, 780. UV spectrum, max, nm (log ): 202.4 (4.73), 230.6 (4.14), 275.00 (4.25), 315.30 (4.29); min, nm (log ): 225.05 (4.40), 246.75 (3.90), 292.95 (4.14). 1H NMR spectrum (CDCl3), , ppm (J, Hz): 1.48 (3H, s, 16-CH3); 1.52 (3H, s, 16-CH3); 2.65 (1H, dd, J = 15.0, J = 15.5, 11-HB); 2.86 (1H, dd, J = 15.5, J = 3.5, 11-HA); 2.89 (1H, m, 6-He); 2.96 (2H, s, two 15-H); 3.05 (1H, m, 6-Ha); 3.42 (1H, tt, J = 11, J = 3.6, 7-Ha); 3.85 (3H, s, OCH3); 3.88 (3H, s, OCH3); 4.20 (1H, tt, J = 13, J = 4, 7-He); 4.85 (1H, dd, J = 15.1, J = 3.5, 9-HX); 6.63 (1H, s, 4-H); 6.68 (1H, s, 1-H). 13C NMR spectrum (CDCl3), , ppm: 29.38 (16-CH3); 29.68 (16-CH3); 29.80 (C(6)); 43.31 (C(16)); 43.32 (C(11)); 45.86 (C(15)); 46.72 (C(7)); 56.30 (3-OCH3); 56.46 (2-OCH3); 57.85 (C(9)); 107.95 (C(13)); 110.07 (C(4)); 111.95 (C(1)); 124.83 (C(10)); 128.40 (C(5)); 149.40 (C(3)); 149.79 (C(2)); 170.38 (C(14)); 189.79 (C(17a)); 194.72 (C(12)). Mass spectrum, m/z (Irel, %): 375 [M+2]+ (8.4), 374 [M+1]+ (25.1), 373 [M]+ (100); [M-1]+ 372 (13.3), 359 (7.2), 358 [M-15]+ (27.4), 346 (9.1), 345 (40.8), 341 (12.5), 340 (45.5), 331 (12.5), 330 (33.0), 313 (8.5), 312 (16.5), 302 (11.5), 299 (14.8), 298 (39.5), 284 (12.3), 271 (18.8), 270 (24.5), 256 (6.3), 243 (17.9), 242 (16.5), 204 (8.3), 192 (8.1), 191 (13.7), 190 (30.0), 188 (10.5), 177 (8.1), 176 (12.3), 146 (8.5), 115 (5.0), 107 (7.5), 91 (5.5), 77 (9.5), 59 (8.5). Found: m/z 373.133661 [M]+ C20H23NO4S. Calculated: M 373.134780. rac-11,16,16-Trimethyl-8-aza-17-thia-D-homogona-1,3,5(10),13-tetraene-12,17a-dione (4c). Product 4c (0.25 g) was obtained as colorless crystals from isoquinoline 1a (0.13 g, 1 mmol) and dione 2b (0.21 g, 1 mmol). Yield 77%; mp 223-225C (alcohol). IR spectrum, , cm-1: 3100-2830, 1680, 1600, 1530, 1505, 1475, 1450, 1380, 1360, 1320, 1300, 1270, 1265, 1240, 1200, 1150, 1130, 1110, 1060, 1030, 1010, 990, 970, 940, 885, 835, 800, 760. UV spectrum, max, nm (log ): 273.25 (4.26), 315.00 (3.36); min nm (log ): 237.35 (3.82), 288.55 (4.06). 1H NMR spectrum (CDCl3), , ppm (J, Hz): 0.82 (3H, d, 11-CH3); 1.48 (3H, s, 16-CH3); 1.52 (3H, s, 16-CH3); 2.68 (1H, m, 11-H); 3.02 (4H, m, two H-15, two 6-H); 3.40 (1H, m, 7-Ha); 4.32 (1H, m, 7-He); 5.04 (1H, d, J = 2.7, 9-Ha); 7.26 (4H, m, 1-, 2-, 3-, 4-H). 13C NMR spectrum (CDCl3), , ppm: 9.46 (11-CH3), 29.39 (16-CH3), 29.63 (16-CH3), 30.09 (C(6)), 43.24 (C(16)), 46.79 (C(15)), 47.61 (C(7)), 49.51 (C(11)), 61.68 (C(9)), 109.46 (C(13)), 125.53 (C(3)), 126.78 (C(4)), 129.29 (C(1)), 129.10 (C(2)), 134.76 (C(10)), 135.24 (C(5)), 171.40 (C(14)), 188.79 (C(17a)), 189.94 (C(12)). Mass spectrum, m/z (Irel, %): 329 [M+2]+ (9.8), 328 [M+1]+ (31.9), 327 [M]+ (100), 326 [M-1]+ (9.0), 325 [M-2]+ (5.5), 313 (11.6), 312 [M-15]+ (41.5), 299 (19.5), 298 (6.0), 296 (6.5), 295 (12.0), 294 (48.9), 285 (9.5), 284 (24.7), 278 (7.0), 267 (6.1), 266 (12.0), 253 (11.5), 252 (29.1), 238 (8.5), 225 (7.8), 224 (12.6), 209 (5.8), 210 (7.6), 197 (13.1), 196 (20.5), 182 (10.2), 181 (8.6), 132 (26.5), 131 (10.1), 130 (35.9), 129 (8.9), 128 (12), 117 (11.9), 116 (8.6), 115 (15.8), 108 (9.8), 106 (5.5), 105 (6.4), 103 (7.4), 91 (9.2), 77 (12.8), 59 (8.5). Found: m/z 327.129547 [M]+ C19H21NO2S. Calculated: M 327.129301. rac-2,3-Dimethoxy-11,16,16-trimethyl-8-aza-17-thia-D-homogona-1,3,5(10),13-tetraene-12,17a-dione (4d). Product 4c (0.29 g) as colorless crystals was obtained from isoquinoline 1b (0.19 g, 1 mmol) and dione 2b (0.21 g, 1 mmol). Yield 72%; mp 268-270C (alcohol). IR spectrum, , cm-1: 3100-2830, 1685, 1660, 1620, 1600, 1520, 1460, 1450, 1380, 1360, 1340, 1320, 1310, 1270, 1235, 1210, 1155, 1130, 1110, 1085, 1040, 1025, 995, 940, 880, 825, 795. UV spectrum, max, nm (log ): 202.35 (4.55), 231.45 (4.09), 275.00 (4.18), 314.40 (4.22); min, nm (log ): 222.05 (4.05), 247.05 (3.85), 290.00 (4.09). 1H NMR spectrum (CDCl3), , ppm (J, Hz): 0.8 (3H, d, J = 7, 11-CH3); 1.47 (3H, s, 16-CH3); 1.51 (3H, s, 16-CH3); 2.62 (1H, m, 11-Ha); 2.86 (1H, dd, J1 = 15.6, J2 = 2.8, 11-Ha); 2.96 (4H, m, two 6-H, two 15-H); 3.34 (1H, ddd, J1,2 = 12.4, J3 = 2.3, 7-Ha); 3.85 (3H, s, OCH3); 3.89 (3H, s, OCH3); 4.30 (1H, tt, J1 = 12.4, J2,3 = 2.3, 7-He);4.96 (1H, d, 9-Ha); 6.58 (1H, s, 4-H); 1367
6.67 (1H, s, 1-H). 13C NMR spectrum (CDCl3), , ppm: 9.51 (11-CH3), 29.41 (16-CH3), 29.59 (16-CH3), 29.75 (C(6)), 43.36 (C(16)), 45.02 (C(15)), 47.52 (C(11)), 47.68 (C(7)), 56.51 (2-OCH3), 56.34 (3-OCH3), 61.87 (C(9), 109.54 (C(13)), 110.29 (C(4)), 112.32 (C(1)), 126.78 (C(10)), 127.44 (C(5)), 149.57 (C(2)), 149.57 (C(3)), 174.41 (C(14)), 189.18 (C(17a)), 190.41 (C(12)). Mass spectrum, m/z (Irel, %): 390 [M+2]+ (8.0), 388 [M+1]+ (26.5), 387 [M]+ (100), 386 [M-1]+ (13.0), 373 [M-2]+ (6.8), 372 [M-15]+ (26.8), 359 (8.7), 355 (7.2), 354 (26.5), 350 (8.5), 349 (24.5), 326 (7.2), 312 (11.5), 285 (6.0), 284 (9.0), 270 (5.1) 266 (5.0), 242 (6.2), 192 (13.1), 191 (24.8), 190 (18.8), 177 (8.5), 176 (13.0), 107 (5.8). Found: m/z 387.147285 [M]+ C21H25NO4S. Calculated: M 387.147058. [5,5,8,8,8-(5)2H]-3-Acetyl-6,6-dimethyltetrahydro-2H-thiopyran-2,4-dione (6a). 1H NMR spectrum (CDCl3), , ppm (J, Hz): 1.50 (6H, s, 6-CH3); 18.6 (1H, s, OH). 13C NMR spectrum (CDCl3), , ppm: 29.348 (two CH3); 42.988 (C(6)); 112.885 (C(3)); 189.095 (C(2)); 197.226 (C(4)); 199.762 (C(7)). Mass spectrum, m/z (Irel,%): 206.20 [M+1]+ (13.2); 295.20 [M]+ (80.9); 204.20 [M-1]+ (64.8); 203.15 (16.6); 190.05 [M-15]+ (10.1); 189.05 (8.4); 177.10 (8.9); 176.10 (7.1); 171.10 (8.5); 179.10 (7.8); 162.05 (16.3); 161.05 (13.6); 148.05 (14.02); 147.05 (18.5); 146.05 (9.0); 131.00 (7.4); 130.00 (7.4); 118.95 (9.5); 117.95 (5.3); 113.95 (5.4); 103.05 (44.4); 102.05 (41.3); 101.05 (12.6); 92.00 (5.1); 91.00 (30.1); 90.00 (15.9); 89.00 (9.6); 88.00 (18.6); 87.00 (82.4); 86.00 (44.6); 85.00 (18.9); 84.00 (84.3); 83.00 (17.4); 74.95 (30.8); 73.95 (23.1); 72.95 (6.1); 69.95 (16.4); 68.95 (42.2); 67.95 (5.7); 60.95 (5.2); 59.95 (6.0); 58.90 (39.5); 58.00 (20.2); 57.00 (21.3); 56.00 (14.1); 55.00 (5.6); 54.00 (6.0); 47.00 (5.1); 46.00 (100); 45.00 (69.5); 44.00 (23.4); 43.00 (14.4); 42.00 (12.7). [5,5,8,8-(4)2H]-6,6-Dimethyl-3-propionyltetrahydro-2H-thiopyran-2,4-dione (6b). 1H NMR spectrum (CDCl3), , ppm (J, Hz): 1.18 (3H, s, 9-H3); 1.50 (6H, s, two 6-CH3); 18.95 (1H, s, OH). 13C NMR spectrum (CDCl3), , ppm: 8.852 (C(9)); 29.301 (two 6-CH3); 43.043 (C(6)); 112.415 (C(3)); 188.982 (C(2)); 196.402 (C(4)); 204.084 (C(7)). Mass spectrum, m/z (Irel, %): 219.10 [M+1]+ (13.0); 218.10 [M]+ (45.6); 217.10 [M-1]+ (37.1); 216.10 (7.0); 188.05 (11.6); 187.05 (22.2); 186.05 (6.4); 184.15 (12.5); 183.10 (11.6); 182.10 (5.6); 175.10 (6.5); 174.00 (8.1); 168.10 (9.3); 167.10 (12.3); 159.95 (5.8); 143.05 (5.0); 132.00 (11.7); 131.00 (10.5); 127.00 (5.7); 126.00 (6.5); 115.95 (9.5); 114.95 (14.9); 113.95 (7.7); 112.95 (6.0); 103.95 (14.3); 102.95 (15.9); 101.95 (8.4); 100.95 (10.7); 100.00 (21.3); 99.00 (24.0); 98.00 (12.5); 91.00 (7.0); 88.00 (6.2); 87.00 (11.7); 86.00 (12.3); 85.00 (24.4); 84.00 (100); 83.00 (24.80); 74.95 (22.2); 73.95 (13.5); 72.95 (5.2); 71.95 (5.1); 70.95 (8.6); 69.95 (20.4); 68.95 (82.4); 67.95 (7.7); 60.95 (8.4); 59.95 (8.2); 59.00 (88.7); 58.00 (68.8); 57.00 (33.9); 56.00 (26.5); 55.00 (12.6); 54.00 (9.2); 53.00 (7.3); 46.00 (6.0); 45.00 (20.1); 44.00 (17.7); 43.00 (24.5); 42.00 (19.8). We would like to sincerely thank Academician Afanasii Andreevich Akhrem for his attention to the studies conducted and useful comments in discussion of the experimental data and theoretical studies.
REFERENCES 1. 2. 3. 4. 5. 6. Li Xun, S. M. Singh, and F. Labrie, J. Med. Chem., 38, 1158 (1995). M. Lourdusamy, J. Cote, S. Laplante, F. Labrie, and S. M. Singh, Bioorg. Med. Chem., 5, 305 (1997). A. A. Akhrem, F. A. Lakhvich, L. G. Lis, and B. B. Kuz'mitskii, Vestsi AN BSSR, Ser. Khim. Navuk, No. 6, 81 (1982). A. A. Akhrem, B. B. Kuz'mitskii, F. A. Lakhvich, V. A. Khripach, and Yu. L. Zhuravkov, in: The Chemistry and Biology of Immunoregulators [in Russian], Zinatne, Riga (1985), p. 265. N. A. Konoplya, O. V. Gulyakevich, A. L. Mikhal'chuk, and B. B. Kuz'mitskii, Vestsi AN Belarusi, Ser. Khim. Navuk, No. 3, 91 (1994). B. B. Kuz'mitskii, I. G. Dad'kov, Yu. L. Zhuravkov, N. A. Konoplya, G. S. Lyubin, A. E. Mashkovich, V. M. Nasek, O. V. Gulyakevich, V. N. Pshenichnyi, and V. A. Khripach, Vestsi AN BSSR, Ser. Khim. Navuk, No. 1, 64 (1989).
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7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31.
G. S. Lyubin, I. G. Dad'kov, O. V. Gulyakevich, and B. B. Kuz'mitskii, Vestsi AN BSSR, Ser. Khim. Navuk, No. 2, 93 (1990). F. A. Lakhvich, L. G. Lis, and A. A. Akhrem, Usp. Khim., 53, 1014 (1984). V. N. Pshenichnyi, O. F. Lakhvich, and V. A. Khripach, Vestsi AN BSSR, Ser. Khim. Navuk, No. 5, 70 (1991). A. A. Akhrem, F. A. Lakhvich, L. G. Lis, and V. N. Pshenichnyi, Zh. Org. Khim., 15, 1396 (1979). M. V. Budnikova, D. B. Rubinov, L. G. Lis, and A. L. Mikhal'chuk, Mendeleev Commun., 5, 208 (1999). M. von Strandtmann, M. P. Cohen, and J. Shavel, Jr., J. Org. Chem., 31, 797 (1966). A. A. Akhrem, A. M. Moisenkov, and V. A. Krivoruchko, Izv. Akad. Nauk SSSR, Ser. Khim., 1302 (1973). M. V. Budnikova, T. A. Zheldakova, D. B. Rubinov, and A. L. Mikhal'chuk, Zh. Org. Khim., 37, 306 (2001). A. L. Mikhal'chuk, O. V. Gulyakevich, Yu. V. Shklyaev, V. S. Shklyaev, and A. A. Akhrem, Khim. Geterotsikl. Soedin., 681 (1998). M. V. Budnikova, A. L. Mikhal'chuk, and D. B. Rubinov, Khim. Geterotsikl. Soedin., 265 (2004). G. Bekker, Introduction to the Electronic Theory of Organic Reactions [Russian translation from German by V. M. Potapov], Mir, Moscow (1977), 658 pp. V. I. Minkin, L. P. Olekhnovich, and Yu. A. Zhdanov, Molecular Design of Tautomeric Systems [in Russian], Izdat. Rost. Univ., Rostov (1977), 272 pp. A. L. Mikhal'chuk, O. V. Gulyakevich, A. A. Zenyuk, A. V. Korchik, L. G. Lis, V. A. Khripach, L. I. Ukhova, and A. A. Akhrem, Dokl. Akad. Nauk, 317, 1397 (1991). K. H. Grellman and J. S. Stephan, in: Abstracts, 210th ACS Division of Physical Chemistry National Meeting, Chicago, Illinois, August 20-24 (1995), Washington, D.C. A. L. Mikhal'chuk, O. V. Gulyakevich, D. B. Rubinov, and A. A. Akhrem, Khim. Geterotsikl. Soedin., 374 (1993). Azomethines. Structure, Properties, and Application [in Russian], Izdat. Rost. Univ., Rostov-na-Donu (1967), p. 293. O. A. Reutov, I. P. Beletskaya, and K. P. Butin, CH Acids [in Russian], Nauka, Moscow (1980), 247 pp. A. L. Mikhal'chuk and O. V. Gulyakevich (BY), Belarus Patent Appl. 19990626; Afitsyiny Byuleten. Vynakhodnitstvy, Karystnyya Madeli, Pramyslovyya Uzory, No. 4, 36 (2000). A. L. Mikhal'chuk and O. V. Gulyakevich (BY), Belarus Patent Appl. 19990627; Afitsyiny Byuleten. Vynakhodnitstvy, Karystnyya Madeli, Pramyslovyya Uzory, No. 4, 36 (2000). A. L. Mikhal'chuk, O. V. Gulyakevich, D. B. Rubinov, and I. L. Rubinova, Zh. Org. Khim., 34, 956 (1998). A. A. Akhrem, N. A. Borisevich, A. A. Govorova, O. V. Gulyakevich, A. S. Lyakhov, A. L. Mikhal'chuk, I. V. Skornyakov, and G. B. Tolstorozhev, Zh. Prirodn. Soedin., 69, 303 (2001). O. V. Gulyakevich, I. L. Rubinova, D. B. Rubinov, A. A. Govorova, A. S. Lyakhov, and A. L. Mikhal'chuk, Mendeleev Commun., 208 (1999). K. V. Vatsuro and G. L. Mishchenko, Name Reactions in Organic Chemistry [in Russian], Khimiya, Moscow (1976), 528 pp. K. Schweiger, Monatsh. Chem., 113, 1283 (1982). H.-J. Wroblowsky, J. Stetter, L. Eue, R. R. Schmidt, and H.-J. Santel, Ger. Pat. 3421351; Chem. Abstr. 105:42651 (1986).
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FIRST EXAMPLE OF HYDROTHIOPHOSPHORYLATION OF 3-THIOLENE 1,1-DIOXIDE

N. K. Gusarova, N. I. Ivanova, M. V. Bogdanova, L. M. Sinegovskaya, B. G. Sukhov, L. I. Kopylova, and B. A. Trofimov Keywords: bis(2-phenylethyl)phosphine sulfide, 3-[di(2-phenylethyl)thiophosphoryl]tetrahydro-1Hthiophene-1,1-dione, 3-thiolene 1,1-dioxide, nucleophilic addition. Functionalized derivatives of 3-thiolene 1,1-dioxide (1) continue to attract attention as building blocks for organic synthesis, intermediates for obtaining biologically active substances, complexing solvents, and models for studying substituent effects in dihydrothiophenes [1-4]. Synthesis of phosphorus-containing sulfolanes based on thiolene 1 opens up new prospects for constructing functionalized extraction and complexing agents as well as special solvents and ligands for metal complex catalysts. Information about reactions of thiolene 1 with PH acids includes data on nucleophilic and radical addition of dialkylphosphites [5, 6], and also addition of primary and secondary phosphines and phosphine oxides [7]. With the aim of further extending our knowledge about the reactivity of 3-thiolene 1,1-dioxide with respect to PH-acids and also in order to obtain new representatives of phosphorus-containing tetrahydrothiophenes, we have studied for the first time the reaction of thiolene 1 with secondary phosphine sulfides, using as an example bis(2-phenylethyl)phosphine sulfide (2) which can be readily obtained from the accessible bis(2-phenylethyl)phosphine [[8] and sulfur. Since phosphine sulfides are ambident compounds [9] and prototropism is possible in thiolene 1, the direction and outcome of the reaction under study were not predictable. We found that under mild conditions (45-50C, 1 h, KOH, DMSO), phosphine sulfide 2 can add to thiolene 1 chemospecifically and regiospecifically, forming 3-[di(2-phenylethyl)thiophosphoryl]tetrahydro-1Hthiophene-1,1-dione (3) in 72% yield. We did not observe the SH tautomer of phosphine sulfide 2a in the reaction mixture among the products of hydrothiophosphorylation of thiolene 1. Without KOH and also under radical initiation conditions (65C, 6 h, AIBN [azoisobutyronitrile]) and with all other conditions the same, hydrothiophosphorylation of thiolene 1 does not occur. This is support for the nucleophilic nature of this reaction, probably occurring through the electrophilic isomer 1a formed as a result of a prototropic shift of the double bond in the dihydrothiophene ring [7].
__________________________________________________________________________________________ A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, Irkutsk 664033; e-mail: gusarova@irioch.irk.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1584-1586, October, 2004. Original article submitted August 2, 2004. 1370 0009-3122/04/4010-13702004 Springer Science+Business Media, Inc.
Ph P KOH O S O 1 O 1a S O Ph 2
Ph H S Ph 2a P SH
S P S O O 3
Thus the reaction of the commercially available thiolene 1 with secondary phosphine sulfides opens up a new and convenient approach to atom-economical ("green") synthesis of functionalized tertiary phosphine sulfides, which are already attractive as unique ligands for designing metal complex catalysts [10, 11]. 3-[Di(2-phenylethyl)thiophosphoryl]tetrahydro-1H-thiophene-1,1-dione (3). A mixture of thiolene 1 (0.24 g, 2 mmol), bis(2-phenylethyl)phosphine sulfide (0.54 g, 2 mmol), KOH (0.11 g, 2 mmol), and DMSO (7 ml) was purged with argon, stirred at 45-50C for 1 h, and cooled down. Then water (20 ml) was added and it was extracted with chloroform. The chloroform extract was washed with a saturated aqueous solution of sodium chloride and then dried with sodium sulfate. The chloroform was driven off under reduced pressure; the residue was washed with small portions of acetone and dried under vacuum. We obtained 0.56 g (72%) of phosphine sulfide 3; mp 151-152C (benzene). IR spectrum (KBr), , cm-1: 3103, 3082, 3064, 3022 (C=H); 2967, 2945, 2903, 2867 (CH); 1600, 1582, 1495, 1452 (C=C); 1408 (CH2); 1315 as(SO2); 1295, 1268, 1240, 1201 (CH2); 1121 s(SO2); 1071, 943, 908, 887 (CH2); 722 (PC); 753, 741 (=CH); 720 (PC); 700 (=CH); 604 (CCC); 553, 572 (P=S); 500 (PCC); 468 (SO2). 1H NMR spectrum (400 MHz, CDCl3), , ppm: 2.07-2.26 (4H, m, CH2P); 2.46 (1H, m, H-3); 2.70-3.02 (8H, m, H-4,5, CH2Ph); 3.19-3.3 (2H, m, H-2); 7.147.32 (10H, m, C6H5). 13C NMR spectrum (101 MHz, CDCl3), , ppm (J, Hz): 21.81 (C-4), 28.28 (CH2Ph), 31.01 (d, 1JPC = 47.5, CH2P), 31.79 (d, 1JPC = 47.5, CH2P), 34.82 (d, 1JPC = 50.1, C-3), 49.95 (C-5), 50.02, C(2), 126.57 (Cp), 127.77 (Co), 128.53 (Cm), 139.34 (d, 3JPC = 13.3, Cipso). 31P NMR spectrum (161 MHz, CDCl3), , ppm: 54.72. Found, %: C 61.41; H 6.50; P 7.82; S 16.69. C20H25O2PS2. Calculated, %: C 61.20; H 6.42; P 7.89; S 16.34. This work was done with the financial support of a grant from the President of the Russian Federation for Supporting Leading Scientific Schools (grant No. NSh-2241.2003.3) and the Russian Foundation for Basic Research (grant N0. 04-03-32045-a).
REFERENCES 1. 2. V. M. Berestovitskaya, I. A. Litvinov, I. E. Efremova, L. V. Lapshina, D. B. Krivolapov, and A. T. Gubaidullin, Zh. Obshch. Khim., 72, 1189 (2002). G. S. Andrade, J. E. Berkner, C. L. Liotta, C. Eckert, D. A. Schiraldi, A. Andersen, and D. M. Collard, Synth. Commun., 33, 3643 (2003). 1371
3. 4. 5. 6. 7. 8. 9. 10. 11.
H. Takayama, J. Pharm. Soc. Jpn., 122, 127 (2002). O. Finikova, A. Cheprakov, I. Beletskaya, and S. Vinogradov, Chem. Commun., 261 (2001). T. E. Bezmenova, The Chemistry of Thiolene-1,1-Dioxides [in Russian], Naukova Dumka, Kiev (1981). R. L. McConnell and N. H. Sheare, US Pat. 2882278; Ref. Zh. Khim., 43958 P (1960). S. F. Malysheva, N. I. Ivanova, N. A. Belogorlova, M. Ya. Khil'ko, L. I. Larina, N. K. Gusarova, and B. A. Trofimov, Khim. Geterotsikl. Soedin., 1195 (1998). B. A. Trofimov, L. Brandsma, S. N. Arbuzova, S. F. Malysheva, and N. K. Gusarova, Tetrahedron Lett., 35, 7647 (1994). M. I. Kabachnik and T. A. Mastryukova, Phase Transfer Catalysis in Organophosphorus Chemistry [in Russian], Editorial URSS, Moscow (2002), p. 199. M. Hayashi, H. Takezaki, Y. Hashimoto, K. Takaoki, and K. Saigo, Tetrahedron Lett., 39, 7529 (1998). J. W. Faller, J. C. Wilt, and J. Parr, Org. Lett., 6, 1301 (2004).
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SYNTHESIS OF 3-CHLORO-6,6-DIPHENYL6,11-DIHYDROPYRIDO[1',2':1,2]IMIDAZO[4,5-b]QUINOLINE BASED ON REACTION OF 2-CHLOROMETHYL-4,4-DIPHENYL4H-3,1-BENZOXAZINE WITH 2-AMINO-5-CHLOROPYRIDINE

E. V. Gromachevskaya and G. D. Krapivin Keywords: 4H-3,1-benzoxazines, 6,11-dihydropyrido[1',2':1,2]imidazo[4,5-b]quinoline, alkylation, mass spectral decomposition. In an extension of research on synthesis and study of the properties of substituted 4H-3,1-benzoxazines [1], we have carried out reactions of 2-chloromethyl-4,4-diphenyl-4H-3,1-benzoxazine (1) with a number of nucleophiles. We found that reaction of benzoxazine 1 with 2-amino-5-chloropyridine (boiling the starting materials in absolute alcohol in the presence of K2CO3 [2]) occurs in an unusual manner and leads to formation of a novel heterocyclic system. We have established that both nitrogen atoms of the reagent enter into the reaction. We hypothesize that alkylation of the pyridine nitrogen atom occurs first. After this, a 1,3-prototropic shift occurs in the initial alkylation product 2, leading to intermediate 3, and then opening of the oxazine ring at the C(2)O
Ph Ph O N 1 Ph
1' 2'
H2N N CH2Cl
Cl
Ph
Ph H2N O N. 2 N+ Cl
Ph
Ph H2N O N H 3 N + Cl
Ph OH
8 2 3 7
Ph
6 11
Ph
5
4 3
NH H
1
N N
12 1
Cl
2
N+
2a
H3O
9 10
N H 5
N4
5 7 6
Cl
__________________________________________________________________________________________ Kuban State University of Technology, Krasnodar 350072, Russia; e-mail: organics@kubstu.ru. Soedinenii, No. 10, pp. 1586-1588, October, 2004. Original article submitted December 20, 2003. 0009-3122/04/4010-13732004 Springer Science+Business Media, Inc. 1373
bond leads to formation of an imidazo[1,2-a]pyridine system 4. Then as a result of intramolecular electrophilic substitution of the proton at C(3) of the imidazole ring, closure of the dihydropyridine ring occurs and the tetracyclic structure 5 is formed. 3-Chloro-6,6-diphenyl-6,11-dihydropyrido[1',2':1,2]imidazo[4,5-b]quinoline (5). Yield 50%; mp >235C (alcohol). IR spectrum (vaseline oil), , cm-1: 3300 (NH), 1580 (C=C), 1540 (C=N). 1H NMR spectrum (Bruker WM-350, SF = 250 MHz, DMSO), , ppm (J, Hz): 6.75 (1H, m, H-10); 6.90 (1H, d, J1-2 = 5.0, H-1); 7.25 (15H, m, 13Harom+H2+H4); 9.60 (1H, s, NH). Mass spectrum (Varian CH-6), m/z (Irel, %)*: 407 (10); 332 (35); 330 (100); 294 (13); 203 (3); 163 (7); 147 (3); 135 (6); 91 (3); 83 (5); 78 (6). Found, %: C 76.35; H 4.85; Cl 10.55; N 8.42; m/z 407 [M]+*. C26H18ClN3. Calculated, %: C 76.56; H 4.42; Cl 10.31; N 8.71. Initial decomposition of compound 5 is characterized by abstraction of a phenyl radical from the molecular ion and then elimination of an HCl molecule.
Ph
Ph
N
N H
Cl
+. C6H5
M+ m/z 407
Ph
N
Cl
HCl
+ N
2+ m/z 330
H 1 m/z 330
REFERENCES 1. 2. E. V. Gromachevskaya, V. G. Kul'nevich, D. P. El'chinov, T. P. Kosulina, and A. L. Chekhun, Khim. Geterotsikl. Soedin., 475 (1993). Lakhan Ram and R. L. Singh, J. Prakt. Chem., 330, 299 (1988).
_______ * The values of m/z for the ions were calculated based on the 35Cl isotope. 1374
ANNIVERSARIES AND DATES
A. N. NESMEYANOV INSTITUTE OF ORGANOELEMENT COMPOUNDS (INEOS), RUSSIAN ACADEMY OF SCIENCES: 50 YEARS

This year the A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences (INEOS), one of the leading chemical institutes of the Russian Academy of Sciences, observes its 50th anniversary. The Institute was created in 1954 within the N. D. Zelinsky Institute of Organic Chemistry. A tremendous contribution to the creation and growth of INEOS was made by the outstanding scientist who directed the Institute for 26 years and was President of the Academy of Sciences of the USSR (1951-1961): Academician A. N. Nesmeyanov, creating the new heteroorganic chemistry as an independent scientific discipline linking organic chemistry, coordination chemistry, and inorganic chemistry. In 1980, the Institute was named after A. N. Nesmeyanov. The next directors of the Institute were Academicians A. V. Fokin (1980-1988) and M. E. Vol'pin (1989-1996). Since 1996, the director of the Institute has been Academician Yu. N. Bubnov. The international reputation of the Institute is associated with the names of the outstanding scientists who initiated new research directions in organic, heteroorganic, polymer, and physical chemistry and physics such as Academicians K. A. Andrianov, M. E. Vol'pin, M. I. Kabachnik, I. L. Knunyants, V. V. Korshak, I. V. Obreimov, S. R. Rafikov, O. A. Reutov, and A. V. Fokin; Corresponding Members of the Academy of Sciences D. N. Kursanov, Yu. T. Struchkov, and R. Kh. Freidlina. The well-known professors V. T. Aleksanyan, N. F. Anisimov, V. M. Belikov, D. A. Bochvar, N. N. Bubnov, N. I. Gel'man, L. S. German, A. A. Zhdanov, L. I. Zakharkin, A. I. Kitaigorodskii, A. F. Kolomiets, A. M. Sladkov, V. A. Sergeev, V. N. Setkina, M. I. Rybinskaya, D. Ya. Tsvankin and others have worked at INEOS. INEOS is one of the leading scientific centers in the field of heteroorganic and polymer chemistry. The following major scientific research directions have been established and successfully developed at the Institute: development of new methods for synthesis of heteroorganic compounds and their application in organic synthesis and catalysis; basic research in the field of heteroorganic and organic chemistry, including study of new structures, chemical reactivity and kinetics; creation of new methods for catalytic asymmetric synthesis; obtaining biologically active compounds with a broad spectrum of action for use in medicine and agriculture; study of fundamental problems in the synthesis, structure, and properties of polymers and composites, various heteroorganic and organometallic polymers, and methods for introducing organometallic and metallic fragments into a polymer matrix; study of new experimental approaches to analysis of organic and heteroorganic compounds.
____________________________________________________________________________________________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1589-1595, October, 2004. 0009-3122/04/4010-13752004 Springer Science+Business Media, Inc. 1375
New structures and classes of heteroorganic compounds have been predicted and synthesized and a number of internationally recognized discoveries have been made at INEOS. Carboranes (boron framework compounds) and then many carborane derivatives were obtained here (L. I. Zakharkin, 1963). A third form of carbon was discovered and studied: carbyne (V. V. Korshak, A. M. Sladkov et al., 1971), with cumulated and conjugated bonds. A fourth form of carbon, fullerene C60, was predicted by theorists at the Institute (D. A. Bochvar and E. G. Gal'pern, 1973) and brilliantly confirmed in subsequent experiments by foreign scientists in 1985. Work on chemical binding of molecular nitrogen (M. E. Vol'pin and V. B. Shur, 1967) and other small molecules under mild conditions has been internationally recognized. In 1973, the phenomenon of 1,2-rearrangement of polyhalogenated aliphatic radicals in the liquid phase was observed (A. N. Nesmeyanov, R. Kh. Freidlina et al.). In 1966, electrophilic ionic hydrogenation was discovered, which makes it possible to reduce alkenes, carbonyl compounds, and heteroaromatic compounds, including thiophenes (D. N. Kursanov and Z. N. Parnes et al.). In 1992, a certificate was awarded for the discovery of the "Ability of achiral molecular structures to help recognize enantiomers," (V. A. Davankov, S. V. Rogozhin et al.), which led to ligandexchange chromatography. Finally, in 1998 the discovery of "The phenomenon of cyclic migration of an unpaired electron through polyvalent atoms of non-transition elements" was recorded (M. I. Kabachnik et al.). Closely associated with the name of the Institute is the concept of "synthetic food," including "synthetic caviar," where development of the latter was used as an example by a group of Institute staff members, under the direction of S. V. Rogozhin and G. L. Slonimskii, of implementation of the idea of A. N. Nesmeyanov concerning application of advanced chemical technology methods to include inefficiently utilized natural proteins in human nutrition. Many processes have been developed and many materials have been created for both technical and biomedical purposes using inventions of the Institute: Ferroceron, VIK and PORK, Perfluoran, Ftorazol, Fluoroxane, Aman, Loeran, Cyacrin, Carbyne, Vitlan, Bloksil, Vinalan, Etilan, Styrosorb, and also the recently created Carbylan, Porocoll, Bupranal, and Intercide. INEOS today is a large research center where 760 people work, including 558 scientists (2 Academicians, 4 Corresponding Members, 78 Doctors and 262 Candidates in the sciences). Organizationally, the Institute includes 58 science laboratories and research groups. About 2000 scientific papers and 13 monographs have been published on the results of scientific research conducted over the past five years. In those years, mutually advantageous contracts have been concluded with more than 150 universities, institutes, and industrial centers in Russia and abroad. In the past 20 years, the Institute has participated in the organization of more than 100 conferences, symposia, and seminars. INEOS was awarded the Order of Lenin for major achievements in 1967. Institute staff have been awarded 8 Lenin Prizes, 30 State Prizes, and the Russian Federation Government Prize in the field of science and technology; 4 Institute staff members have been honored with the title Hero of Socialist Labor, 9 individuals have been named Honored Scientist of the Russian Federation, and one has been named Honored Inventor of the RSFSR. One of the most important forward-looking tasks of the Institute is training of highly educated young specialists with extensive knowledge and mastery of the entire arsenal of modern research methods, which is possible only by integrating the educational process and basic scientific research while drawing on the scientific potential and technical instrumentation of the institutes of the Russian Academy of Sciences. In order to meet this challenge in the fields of heteroorganic chemistry, the physical chemistry of polymers, the chemistry of biologically active compounds, and biomedical chemistry, 6 scientific teaching centers were created within INEOS which today have been transformed to the Science Education Center (Russian Academy of Sciences), INEOS Division. The Center includes a division for training INEOS scientists (graduate program) and the basic departments: Organometallic Chemistry, jointly with the Chemistry Department of M. V. Lomonosov Moscow State University; Biomedical Chemistry and Organosilicon and Inorganic Polymers, jointly with the D. I. Mendeleev Russian Chemical Technological University; Physiologically Active Compounds, jointly with the M. V. Lomonosov Moscow State Academy of Fine Chemical Technology; Physical Chemistry of
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Polymers, jointly with the Physics Department of Moscow State University; and Physical Research Methods in Chemistry, jointly with the Higher Chemical College of the Russian Academy of Sciences. More than 2000 students total have obtained specialized higher education at the INEOS Science Education Center of the Russian Academy of Sciences. More than 80 INEOS scientists participate in teaching lecture courses and conducting seminar and laboratory work with the students. From the very beginning of INEOS, there has been an organic linkage between synthetic and theoretical research in the field of heteroorganic and polymer chemistry on the one hand and all the required physical and physicochemical research on the other hand, so the scientific activity of many INEOS laboratories is at the junction between several branches of chemistry and physics. As A. N. Nesmeyanov said metaphorically, this defines the "growth points" of modern scientific and technical progress. In addition to traditional time-tested interdisciplinary sciences (including the chemistry of heteroorganic compounds itself), the accumulated valuable experience has given birth to a number of new scientific research directions characterized by a unique linkage of knowledge in the fields of organic chemistry, heteroorganic chemistry, coordination chemistry, physical chemistry, and the chemistry of high molecular weight compounds and natural biologically active compounds. Thus a new research direction appeared at the junction of organic, organometallic, and coordination chemistry: the chemistry of organic compounds of transition metals, -complexes of metals and clusters. The unique properties of these compounds made it possible to create new organometallic catalysts and to develop processes for activation of small molecules, including nitrogen, carbon oxides, hydrocarbons, etc. Linkage of organic and heteroorganic chemistry on the one hand and modern experimental and theoretical methods of physical chemistry on the other hand led to growth of research on reactivity and obtaining fundamentally new data in the area of the structural chemistry and molecular dynamics of heteroorganic compounds. Linking heteroorganic chemistry, biochemistry, pharmacology, and toxicology made it possible to discover the secrets of the mechanisms responsible for the effect of organophosphorus compounds on biological structures and living organisms. Significant progress was achieved in the area of new anticancer drugs with selective action and physiologically active heteroorganic compounds, including fluorine-containing compounds. A number of functional derivatives of the closo-dodecaborate anion have been synthesized; optically active aminocarboranes and aminocarborane-based derivatives have been obtained, which are of great interest for use in boron neutron capture therapy for cancer; and stereoselective synthesis of ferrocenyl alkyl azoles, which have an antitumor effect, has been accomplished. Considerable advances have been made in the area of heterocyclic compounds. An original method has been discovered for obtaining bicyclic and tricyclic heterocycles with a bridging nitrogen atom, containing an aziridine moiety, based on reductive allylation of 3,5-dibromopyridine and 4-bromoisoquinoline, metathesis reactions with ring closure catalyzed by ruthenium carbenium complexes; and a series of derivatives of cyclic -polyfluoromethyl -imino acids have been obtained with five-membered, six-membered, and sevenmembered rings. Based on derivatives of pyridine, proline, and chiral amines, new catalysts have been created with chiral centers in amine moieties and/or with a chiral phosphorus atom, and new substrates for a large number of asymmetric reactions: phase-transfer alkylation of CH-acids, allyl sulfonylation, amination, and alkylation, making it possible to achieve record-breaking chemical and enantiomeric yields. Unique optically active palladium complexes of C60 and C70 fullerenes have been synthesized with two axially chiral diphosphine ligands in the dithienyl series, which are efficient catalysts for homogeneous enantioselective hydrogenation. Original methods have been developed for constructing azabicyclodecadienes and azaspiroalkenes, based on two sequential processes: reductive allylboration of pyridines, isoquinolines, and lactams, leading to diallylated nitrogen-containing heterocycles, and intramolecular metathesis catalyzed by a Grubbs ruthenium catalyst. The bicyclic and tricyclic systems obtained are the basic structural components for a number of important alkaloids (cytisine etc.) For a number of novel pyridazino[4,3-b]indoles, a connection has been discovered between the high antitubercular activity, the monooxidase inhibiting effect, and the ortho effect of the 4-aryl substituent.
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Work at the junction of organic and inorganic chemistry, study of polymer formation processes and also structureproperty relations led to development of the chemistry of polymers with heteroorganic and inorganic chains of molecules, and has opened up routes to new classes of linear, bilinear, and network polymers and dendrimers. Based on these polymers, materials have been developed with high thermal, catalytic, sorption, and electrophysical characteristics, structural plastics, heat-stable composites and adhesives, membranes and polymers for electronics and medicine. Research in the area of heteroorganic and organic chemistry includes the study of new structures, chemical activity and kinetics, the study of organometallic and coordination complexes with -, -, and n-bonds, the development of new methods for synthesis of heteroorganic compounds with polyhedral substituents (carboranes, fullerenes), multidecker compounds, clusters, anti-crowns, and also the study of their geometry, electronic structure, and chemical behavior (stereochemistry, tautomerism, molecular dynamics) by modern experimental and calculation methods. An important role is played by use of organometallic compounds in asymmetric synthesis and catalysis. A number of laboratories have been successfully working on obtaining biologically active compounds with a broad spectrum of action for use in medicine and agriculture. Broad studies have been conducted on fundamental problems in the synthesis, structure, and properties of polymers and composites, and computer-assisted design of macromolecules has improved methods for synthesis of monomers and polymers. An important role is played by synthesis of aromatic and heterocyclic polymers, including polyconjugated, ultrarigid, and network polymers, the study of their physical and physicochemical properties, and study of heteroorganic and organometallic polymers and methods for introducing organometallic and metallic fragments into a polymer matrix. Nanostructures in polymers and synthesis of different types of nanoparticles using polymer systems as well as liquid-crystal polymers and their properties have been widely studied; studies have been conducted on the properties of polyelectrolytes; and processes of modification of polymers have been investigated, including surface modification, thermal and photochemical conversions in organic and heteroorganic polymers. Among the interesting results of studies conducted by Institute staff, we may note the synthesis of multidecker sandwich metallocenes, synthesis of novel classes of -, -, and mixed complexes of metals with olefins, acetylene, vinylidene, and cumulene ligands, novel types of clusters, azole complexes, etc. There has been development of the chemistry of cyclopentadienyl carbonyl compounds of transition metals, the most interesting of which is cymantrene, an effective antiknock compound. Aluminum, tin, boron, fluorine, phosphorus, etc. derivatives are widely used in modern organic synthesis, and INEOS has also developed synthesis methods for these compounds. The first examples were obtained of anti-crown complexes, containing three mercury atoms in the macrocycle, with a complicated complexed hexacyanoferrate anion, which expands the limits for practical application of these unusual crown compounds. Metallocenes have been used as the basis for synthesizing next-generation chelate complexes of rhodium, iridium, and platinum containing tridentate PCP ligands, which can be used in production of very important raw material for petrochemistry and an environmentally friendly energy carrier (hydrogen) and in fuel cells. At the Institute, considerable attention has been focused on medical, environmental, conversion, and other practical problems. Polyacrylic acid and hydroxyapatite have been used as the basis for creating original biocompatible polymer/mineral implants for maxillofacial surgery ("artificial bone"). An environmentally friendly method has been developed for synthesis and modification of polymers in supercritical media. Micellar polymerization in aqueous medium has been used to synthesize self-associating hydrophobically modified ternary copolymers (terpolymers). The studies conducted made possible targeted control of the properties of gels depending on the practical problems to be solved, especially for enhancement of petroleum recovery. Samples have been obtained of carbon-containing suture monofilaments (Vitlan filaments) equipped with atraumatic needles, which are better for biomedical purposes than the threads used in surgical practice. Radiative matrix/gas-phase copolymerization on stretched polyamide films has been used to obtain polymer
1378
semiconductors with a fundamentally new structure and high electrical conductivity. The novel materials may be used in various areas, in particular for creating cheap large solar batteries. The activating effect of new reaction media (environmentally friendly ionic liquids obtained on the basis of imidazole) on polymer formation processes has been established. Methods have been developed for obtaining cheap and efficient bidentate extraction agents and sorbents for transuranium elements: methylcarbamoyl methylphosphinic acids and their derivatives. A series of phosphite, phosphate, and phosphonate fire-extinguishing agents, based on lower primary alkanols and polyfluoroalkanols, have been obtained that are more effective than trifluorobromomethane (the production of which is banned by the Montreal protocol). Catalysts have been discovered for polycyclotrimerization of diisocyanates that simultaneously function as dyes. This makes it possible to synthesize colored gradient polymer materials that are ready for practical use. Development and supply of improved cyanoacrylate composite for electronics technology products continues. A synthesis method based on 2,4,6-trinitrotoluene has been developed for a monomer whose polymerization with dianhydrides of aromatic tetracarboxylic acids yields film-forming polyamides that are soluble in organic solvents and combine high thermal and mechanical characteristics with a low dielectric constant, which means they can be used as interlayer insulators for multiple integrated circuits. In conjunction with the S. A. Lavochkin Design Bureau, polymer coatings have been created for friction assemblies capable of operating exposed in outer space, resulting in prolonged functionality of aerospace systems and apparatus. More detailed information about the Institute and its staff can be found at the Institute website (http:/www.ineos.ac.ru). Yu. N. Bubnov and K. A. Kochetkov
The Editorial Board of this journal is pleased to offer our regards to all at INEOS on the day of its happy anniversary. Our anniversary wish for you all is new brilliant ideas and outstanding achievements in both science and practical implementation of your developments. We hope that our fruitful cooperation continues to grow.
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ANTIBIOTICS PRODUCED AT THE G. F. GAUZE SCIENTIFIC-RESEARCH INSTITUTE OF NEW ANTIBIOTICS, RUSSIAN ACADEMY OF MEDICAL SCIENCES (MARKING THE FIFTIETH ANNIVERSARY OF THE INSTITUTE). (REVIEW)*
E. N. Olsufyeva and M. N. Preobrazhenskaya The major achievements of the G. F. Gauze Scientific-Research Institute of New Antibiotics, Russian Academy of Medical Sciences, over the last 50 years are reviewed. The structures of antibiotics and related compounds discovered at the Institute and important for medical practise and/or of theoretical interest as new compounds with high biological activity are described. Keywords: antibiotics, oxygen-, nitrogen-, and sulfur-containing heterocyclic antibiotics, macrocyclic peptides, antibacterial activity, antiproliferative activity, antiviral activity, hypolipidemic activity, chemical modification. The Institute of New Antibiotics was created in 1953 from the Laboratory of Antibiotics, Academy of Medical Sciences of the USSR, and its organizer was Academician of the Academy of Medical Sciences of the USSR Prof. G. F. Gauze. As one of the pioneers in the field of antibiotics Gauze postulated that antibiotics represent a chemical weapon used by microorganisms in their struggle for existence. This postulate was supported by the isolation of a large number of extraordinarily diverse chemical structures with various antimicrobial properties from the microorganisms. As a result of the tremendous work at the Institute hundreds of new natural antibiotics were obtained and characterized. Although all the natural antibiotics were isolated from original strains of the producer organisms, the structures of many compounds proved identical with those of already known compounds. However, previously unknown compounds were also discovered, and the structure of many of them has been unravelled. The most valuable antibacterial and antitumor antibiotics were introduced into medical practise following the creation of industrial strains and rational methods of isolation suitable for industrial production. The traditional direction of research at the Institute has been the search for and study of antibiotics and related compounds having antitumor, antimicrobial, immunomodulating, and hypolipidemic activity. An important aspect of the creation of new biologically active compounds is the chemical modification of natural _______ * Dedicated to the memory of Director of the G. F. Gauze Scientific-Research Institute of New Antibiotics, Russian Academy of Medical Sciences, and Corresponding Member of the Russian Academy of Medical Sciences Prof. Yu. V. Dudnik (1938-2003). __________________________________________________________________________________________ G. F. Gauze Scientific-Research Institute of New Antibiotics, Russian Academy of Medical Sciences, Moscow, Russia. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1603-1618, November, 2004. Original article submitted July 1, 2004. 0009-3122/04/4011-13812004 Springer Science+Business Media, Inc. 1381
antibiotics and also the synthesis of their analogs. Many antibiotics contain the most diverse heterocycles in their structures, including macrocyclic peptides. The structures of antibiotics and related compounds discovered at the Institute over 50 years are described below. 1. Gramicidin S (S = "Soviet") is the cyclic decapeptide 1. The producer organism is Bacillus brevis var. Gauze-Brazhnikova. The first national antibiotic, it was discovered in 1942 by G. F. Gauze and M. G. Brazhnikova [1]. The production of gramicidin S was started in 1944-1945, and many lives were saved on the front lines of the Second World War as a result of its use. The wide-spectrum antibiotic is used externally in the treatment of suppurative processes. The antibiotic has not lost its practical significance up to the present time [2].
Val Orn Leu D-Phe Pro
Pro
D-Phe
Leu 1
Orn
Val
2. Lincomycin 2 is an aminosugar acylated with a derivative of proline and is active against grampositive bacteria [3]. The producer organism is Streptomyces roseolus VKPM-S1082.*
Me HO N Me CO H N OH HO Me O OH SMe
3. Monomycin A (paromomycin I) 3, tobramycin 4, and apramycin 5 are aminoglycoside antibiotics (aminocyclitols). Monomycin is produced by the strain Actinomyces circulatus var. monomycini [4]. The strain Streptoallteichus cremeus subsp. tobramycini VKPM-S1084 produces tobramycin 4 and apramycin 5 simultaneously. The latter contains the unusual sugar diaminooctose [5]. All the antibiotics of this group are active against gram-positive bacteria. Tobramycin has a wide spectrum of activity and is used for the treatment of serious life-threatening infections. Apramycin is used in veterinary practise for the treatment of animals with general and septic infections.
HO
O
H2 N
H2 N
O
HO
HO
NH2
HO
H2 N
O
HO O
NH2
O
HO
H2 N
H2 N
H2 N
HO
HO
O
HO
HO
OH
H2 N
OH
HO
NH2
_______ * VKPM represents the All-Union Collection of Industrial Microorganisms. 1382
HO H2N HO HO
Me OH NH O O O H2N 5 O HO HO H2N NH2
4. Actinoidins A and B 6a,b, ristomycin A (ristocetin) 7, and eremomycin 8 are polycyclic glycopeptide antibiotics of the vancomycin group, discovered at the Institute at various times.
OH H2N OMe Me H2N O O HO HO 7 O O OH OH HO OH OH 6 a,b 6 a R = H, b R = Cl OH H N O O 6 O N H 5 H N O O O Cl O 4 O N H 2 O O 2 H N O OH O NH2 N H 1 R Cl O HO Me HO OH
The producer organisms of 6a,b and 7 are Nocardia actinoides and Nocardia fructiferi var. ristomycini respectively. Eremomycin 8 has antibacterial activity 3-8 times higher than that of vancomycin against grampositive bacteria, including methicyllin-resistant staphylococci. There is a highly active strain of producer organism Amycolatopsis orientalis subsp. eremomycini VKPM-S892 for eremomycin, and a pilot-scale procedure has been developed for its production [7]. The polycyclic structure is based on a heptapeptide skeleton containing aromatic acids, the radicals of which, linked to each other, form three additional macrocycles M(2-O4), M(4-O-6), and M(5-7) in the case of actinoidin 6a,b and eremomycin 8. In the structure of ristomycin 7 in addition to the three above-mentioned macrocycles there is a fourth macrocycle M(1-O-3) [8]. 5. The main directions in the selective chemical modification of eremomycin 8 are indicated by arrows: Alkylation of the amino groups (a), amidation and esterification (b, c), aminomethylation of the resorcinol ring (d), removal of the amino acid residue of N-methylleucine (1) and modification of the hexapeptide core (e), hydrolysis of the amino group in the side radical of the asparagine residue (3) and its amidation (f), successive removal of the sugar residues (g), and so forth [9, 10]. Some semisynthetic derivatives of eremomycin are active against glycopeptide-resistant enterococci and staphylococci. The mechanisms of action have been studied
1383
OH HO O OH HO O O HO OH Me NH2 HO HO O O O HO O HO 7 O O OH OH HO OH OH 7 H N O 6 O N H 5 HO Me H N O 4 O N H 3 O OH O O O 2 H N O OH O N H 1 NH2 O Me HO OH HO O O OH
for antibiotics of this group and their semisynthetic analogs containing hydrophobic substituents [11]. The antiviral activity of the hydrophobic derivatives of these antibiotics was discovered for the first time [12].
a H2N OH Me H2N b,c O HO HO d 7 OH O H N O Me O g O 6 O N H 5 OH 8 f H N O 4 O N H 3 O O g O O 2 H N O O NH2 OH O N H e a
+
OH Me Me
HO OH O
OH g Cl
Me NH2 1 Me
Me
6. The -lactam antibiotics penicillin N 9 and cephamycin C 10 were first isolated from rare forms of actinomycetes Actinomyces (Streptomyces) cineorectus [13] and Streptomyces filipensis var. cephamycini var. nov. [14] respectively.
1384
COOH H2N
O N H O S N COOH Me Me H2N
COOH
O OMe N H N O S CH2OCONH2 COOH
10
7. Rifamycin B 11 is an antibiotic of the ansamycin group and was obtained at the Institute from the original highly productive strain of Nocardia asiatica sp. nov. 2379 [15]. The antibiotic 11 is the starting compound for the production of semisynthetic rifampicin (rifampin) 12, which is one of the most important preparations for the treatment of tuberculosis [16].
Me MeCOO MeO OH OH Me OH OH H N Me O O O Me O OCH2COOH Me O O OH O Me Me MeCOO MeO Me OH Me Me OH OH OH H N O N Me N N Me Me Me Me
11
12
8. Cyclosporin A 13 is a cyclic undecapeptide isolated from an original culture of the fungus Fusarium javanicum var. radicicola [17]. The antifungal antibiotic with selective immunodepressive activity caused a revolution in transplantation.
Me Me Me Me N O Me N Me O O Me H N Me N Me O O O H N Me Me Me Me N Me OH N H O O N Me Me Me Me Me N O O H N O Me Me N Me Me
Me
13
9. Heliomycin (resistomycin) 14 is a polycyclic antibiotic produced by a strain of Actinomyces flavochromogenes var. heliomycini [18]. It has antibacterial and antiviral activity and is used externally for the treatment of various skin diseases and burns. 10. Chlorobiocin 15a and its new 5-demethyl analog 15b from the group of coumarin glycosides, containing the two heterocyclic systems 3-amino-4,7-dihydroxy-8-chlorocoumarin and 2-pyrrolecarboxylic acid [19], has antibacterial activity against gram-positive bacteria, including methicillin-resistant staphylococci. 1385
Me HO Me
Me OH O OH MeO MeO O OMe O OH O Cl O
NHCO O Me Me
OH
OH
R N H
14
15 a,b 15 a R = Me, b R = H
11. Streptothricin F 16 was isolated from a culture of Streptomyces glaucus 1136. Antibiotics of this group have a wide spectrum of activity and are active against gram-negative and gram-positive bacteria. The formation of antibiotics of the streptothricin group by a strain of S. glaucus was first described in [20]. 12. Cervinomycin A2 17a and its new analog 18-O-demethylcervinomycin A2 17b were obtained from a mutant of an inactive wild strain of Amycolata autotrophica 167 [21].
OH OCONH2 O
O
H N
H N
N
O
O OH O O R
Me
NH
HO
HN
CO CH2CH(NH2) (CH2)3NH2
O
16
OMe
O 17 a,b a R = OMe, b R = OH
13. New antibacterial antibiotics of the lantibiotic group A-3802-V-4 and A-3802-VI-7 18a,b (p. 1387) were isolated from a strain of the producer organism Actinoplanes brasiliensis INA 3802. The antibiotics are polypeptides, similar in structure to actagardin, and contain the sulfur-containing amino acids lanthionine (Ala-S-Ala), -methyllanthionine (Ala-S-Abu), and -methyllanthionine sulfoxide (Ala-SO-Abu), on account of which four macrocycles (1-S-6), (7-S-12), (9-S-17), and (14-SO-19) are formed [22]. The antibiotics have bacteriostatic activity against gram-positive bacteria and are promising as food preservatives. 14. Bleomycetin (bleomycin A5) is a glycopeptide antitumor antibiotic and contains a thiazolylthiazole group, a fragment of substituted 1,3-pyrimidine, and hydroxyhistidine. A strain of Streptomyces griseocarneus subsp. Bleomycini VKPM S1086 produces only one component (bleomycin A5) 19. Unlike the Japanese bleomycin, which consists of a complex of bleomycins A2, B2, and others differing in the radical R, the national (i.e., Russian or Soviet) bleomycin has lower toxicity while having equal antitumor activity against various forms of planocellular cancer (skin, tumors of the head and neck, the penis, etc. and also tumoral pleurisy) [23]. 15. Bruneomycin (streptonigrin) is a substituted quinoxalinedione 20a. The strain of the producing organism is Streptomyces albus subsp. bruneomycini. It was used in clinics in the USSR for the treatment of lymphogranulomatosis, lympho- and reticulosarcoma, and other tumors [24, p. 67]. It also has antiretroviral activity but is not used as an antiviral product on account of its high cytotoxicity. It is an inhibitor of
1386
O S S S
AcAlaSerGlyTrpValAlaAbuLeuAbuIleGluAlaGlyAbuValIleAlaAlaAlaCOX
1 5 10
COX S
15
19
18 a,b a X = OH (A-3802-V-4); b X = OMe (A-3802-VI-7) O S H 2C H 2N COOH H2N Ala-S-Ala CH2 H 2C COOH H2 N S H Me C S H 2C COOH H2N Ala-SO-Abu H Me C COOH
COOH H2N
COOH H2N
Ala-S-Abu
1387
CONH2 H N N H2N Me HN O OH HO OH O O N
NH2 NH2 O O HO O O N H N N H OH O O OH O NH2 19 OH R = HN(CH2)3NH(CH2)4NH2 Me HO Me S Me O NH N N S O R
H N
NO-dependent guanylatecyclase [25]. A series of derivatives of streptonigrin at the carboxyl and phenol groups were produced and studied [26]. Streptonigrin is decarbonylated by the action of Pd catalyst and forms the antibiotic streptonigrone, identical with the natural product 20b [27].
HOOC N
Me OMe HO NH2 OMe
O HN
Me OMe NH2 HO OMe
N O MeO O NH2
N O MeO O NH2
20a
20b
16. Nocamycin (21) is a new antitumor antibiotic related to thirandamycins. It was isolated from a culture of Nocardiotopsis siringae sp. nov. [28]. Its structure contains a fragment of 3-substituted 4-hydroxy-3pyrrol-2-one and an epoxy group. 17. Virenomycins V and M (22a,b) contain a chromophore in the form of substituted benzo[d]naphtho[1,2-b]pyran-6-one coupled by a C-glycosidic bond with 6-deoxy-3-C-methyl--Dgulopyranose and possess antitumor activity [29]. They are similar in structure to the C-glycosidic antibiotics of the naphthalene group toromycin and gilvocarcin.
1388
Me O
COOMe
OH
OMe OMe
Me O Me O O HO OH Me Me Me O N H OH 22a,b 22 a R = CH=CH2; b R = Me Me O O OH O R
21
18. Olivomycin 23 is an antitumor antibiotic from the aureolic acid group (chromomycin, mitramycin) [30, 31]. The structure was finally established in [32]. The producer organism is Streptomyces olivoreticuli. It was use in clinics in the USSR for the treatment of tumors of the testis, chorionepithelioma of the uterus, and other tumors [24, p. 12]. According to recent data, the antibiotic suppresses transcription and causes apoptosis of tumor cells at nanomolar concentrations.*
OMe HO O Me O OAc Me O O OMe OH OH O OH Me O HO O OH O O Me
Me i- Pr CO2 Me HO O
HO
Me O
23
19. Sibiromycin is an antibiotic of the pyrrolo-1,4-benzodiazepine group [33]. The final structure of the antibiotic was established in 1988 (24a) [34]. It possesses high antitumor activity. The mechanism of action involves covalent bonding with the amino group of the guanidine base of the DNA molecule 24b.
O OH H N N O O HO OH 24a 24b Me sibiromycin OH H HN NH2Gua DNA H N H HN H N N N DNA
Me Me MeHN
_______ * V. S. Simonova, A. V. Samusenko, A. N. Tevyashova, L. S. Lyniv, G. I. Kulik, V. F. Chekhun, and A. A. Shtil', Onkologiya (2005), in press. 1389
1390
MeO
N
OH
CO N H H C CO CH2 O Me HO Me CO C H N Me CO C N CO H2 Me C H2 N C H N H C HC C H2 CO N C H H2 OCOMe CO
Me N C H2 H2 C MeOCO N H CO CH C H N
Me CO N H C N CO H C CO O CH2
Me OH Me
CH N H
CO HO
N OMe
25
20. The cyclopeptide antitumor antibiotic 308-I (BBM-928A) 25 (rp. 1390) consists of two symmetrical pentapeptides linked "head to tail." Fragments of the unusual heterocyclic acids trans-(3S,4S)-2,3,4,5tetrahydropyridazine-3-carboxylic and 3-hydroxy-6-methoxyquinoline-2-carboxylic acids were detected in the structure of the antibiotic. The highly effective ESI-MS method was used to obtain evidence for the structure [35]. 21. Rubomycin (daunorubicin, daunomycin) 26a, doxorubicin (adriamycin) 26b, and carminomycin 26c are natural anthracycline antibiotics with high antitumor activity [33, p. 18]. The producer organism of rubomycin 26a is Streptomyces coeruleorubidis subsp. rubomycini INA-1550. Doxorubicin 26b is widely used in the clinics of the Russian Federation and abroad for the treatment of dense tumors. Carminomycin is effective in the treatment of sarcoma of soft tissues and acute leukemias. It is absorbed through the gastrointestinal tract and is promising for peroral application. Original methods of synthesis starting from rubomycin were developed at the Institute for doxorubicin 26b [36] and carminomycin 26c [37] starting from rubomycin 26a. Like the parent antibiotic 26c the new semisynthetic derivatives of carminomycin are also capable of overcoming the resistance of tumor cells [38].
O
O OH
OH N
Me Me
O CH2X OH
N O OH 27a O OH H
OR
O Me
OH O NH2
OH
26 a,b,c
N O OH
H N HO
Me OH
26 a R = Me, X = H; b R = Me, X = OH; c R = X = H
27b
22. New indole analogs of anthracyclines 3-dimethylaminomethyl-4,11-dihydroxynaphtho[2,3-f]indole5,10-dione (27a) and 1-[N-(1,3-dihydroxy-2-methyl-2-propyl)aminopropyl]-4,11-dihydroxynaphtho[2,3-f]indole-5,10-dione (27b) were synthesized. They have antiproliferative activity against multiresistant tumor cells [39, 40]. 23. New synthetic analogs of antitumor antibiotics of the staurosporine-rebeccamycin group and a powerful inhibitor of proteinkinase C from the bis(3-indolyl)maleimide group NInd-ethoxyarcyriaflavin A 28a and isomers of a new type of maleimidoindolocarbazoles 28b were obtained [41]. Among them the compound 28a had the highest antiproliferative activity.
H N O H N O N
N N OEt 28a 28b N H
1391
24. Ascorbigen 29 is a natural derivative of ascorbic acid and indole that accumulates in vegetables of the cruciferous family. It is an important component of the human diet and, as shown by experiments on animals, an immunomodulator with antibacterial and antitumor activity. It was established that by the action of acid in the stomach part of the ascorbigen dissociates with the release of L-ascorbic acid (not more than 20%) while in the intestines and in the blood at a weakly alkaline or neutral pH decarboxylation of the ascorbigen leads to the formation of two deoxyketoses 1-deoxy-1-(3-indolyl)--L-sorbopyranose 30a and 1-deoxy-1-(3-indolyl)--Ltagatopyranose 30b. The properties of the these compounds were also studied [42, 43].
OH
OH
OH
N H
29
OH H2 C
OH H2 C
+
O
HO
O
HO
OH
HO
30a
N H
HO
OH
30b
N H
25. Enniatin B 31 is a cyclic hexapeptide of the class of ionophoric antibiotics with hypolipidemic activity [44] and was isolated from the fungus Fusarium lateridium. Evidence for its structure was obtained by X-ray crystallographic analysis [45].
Me Me N O Me Me Me O O Me N Me O Me Me Me O N Me O O Me Me Me O O Me
31
26. Ascofuranon 32 is an antibiotic with hypolipidemic activity and was isolated from a culture of the fungus Paecilomyces variotii Bainier 199 [49].
O H Me Cl OH Me Me Me
Me Me
32
1392
27. Lentinacin (eritadenine) 33 is an antibiotic with hypolipidemic activity and was isolated from the filtrate of the culture liquid from the immersed mycelium of the medicinal and edible shiitake mushroom, the strain Lentinus edodes (Berk.) Sink. 15. The wide-spectrum antibacterial and antifungal agent lentinamycin B 34 was isolated from the same strain [47].
NH2 N N N N CH2 HO CH HO CH COOH
HC
C H
C H
C C H2 H2
OH
34
33
28. Lagopodin B [48]. The producer organism is the fungus Coprinus radiatus (Boston) Gray (1938). The antibiotic can exist in two forms 35a and 35b depending on the concentration in the solution. The semiacetal form 35b is mainly formed in concentrated solutions. The antibiotic is active against resistant forms of grampositive bacteria staphylococcus and leuconostoc.
O Me Me Me O Me Me Me
Me O
OH
Me O
OH
35a
35b
REFERENCES 1. 2. 3. 4. 5. 6. 7. G. F. Gauze and M. G. Brazhnikov, Zh. Mikrobiol., Epidemiol. Immunobiol., No. 4-5, 74 (1943). Yu. O. Sazykin and S. N. Orekhov, Antibiotiki i Khimioterapiya, 48, No. 12, 3 (2004). N. P. Nechaeva, G. V. Kochetkova, and R. S. Ukholina, Antibiotiki, 19, 877 (1974). G. F. Gauze, T. P. Preobrazhenskaya, L. P. Ivanitskaya, and V. K. Kovalenkova, Antibiotiki, 5, 3 (1960). O. P. Sinyagina and O. A. Lapchinskaya, Antibiotiki, 28, 262 (1983). N. S. Egorov (editor), Polypeptide Antibiotics [in Russian], Izd. MGU, Moscow (1987), p. 205. Yu. V. Dudnik, G. S. Katrukha, V. M. Bukhman, G. B. Fedorova, T. F. Berdnikova, A. V. Laiko, S. T. Filopposyants, and E. T. Gladkikh, in: First International Seminar "Results of Fundamental Investigations for Investments." Abstracts [in Russian], RFTRI'98, St. Petersburg, May 25-27, 1998, p. 31. N. N. Lomakina, G. S. Katrukha, M. G. Brazhnikova, A. B. Silaev, L. I. Murav'eva, Zh. P. Trifonova, N. L. Tokareva, and B. Diarra, Antibiotiki, 27, 248 (1982). A. Yu. Pavlov and M. N. Preobrazhenskaya, Bioorgan. Khim., 24, 644 (1998). M. N. Preobrazhenskaya, O. V. Miroshnikova, A. Yu. Pavlov, and E. N. Olsuf'eva, Khim. Geterotsikl. Soedin., 1605 (1998).
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1393
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S. S. Printzevskaya, A. Y. Pavlov, E. N. Olsufyeva, E. P. Mirchink, E. B. Isakova, M. I. Reznikova, R. C. Goldman, A. A. Branstrom, E. R. Baizman, C. B. Longley, F. Sztaricskai, G. Batta, and M. N. Preobrazhenskaya, J. Med. Chem., 45, 1340 (2002). J. Balzarini, C. Pannecouque, E. De Clercq, A. Y. Pavlov, S. S. Printsevskaya, O. V. Miroshnikova, M. I. Reznikova, and M. N. Preobrazhenskaya, J. Med. Chem., 46, 2755 (2003). V. A. Chugasova and L. P. Terekhova, Antibiotiki, 19, 195 (1974). G. F. Gauze, V. A. Chugasova, L. P. Terekhova, N. N. Lomakina, and G. B. Fedorova, Antibiotiki, 21, 1059 (1976). I. V. Tolstykh, N. V. Konstantinova, I. A. Grishin, L. S. Pokras, and A. S. Mezentsev, Antibiotiki, 20, 222 (1975). V. A. Shorin, S. P. Shapovalova, and I. V. Malkova, Antibiotiki, 19, 1084 (1974). G. F. Gauze, L. P. Terekhova, T. S. Maksimova, M. G. Brazhnikova, and V. N. Borisova, Antibiotiki, 28, 243 (1983). N. O. Blinov, I. D. Ryabova, T. A. Uspenskaya, and A. S. Khokhlov, Antibiotiki, 7, 708 (1962). L. N. Lysenkova, M. G. Brazhnikova, V. N. Borisova, G. B. Fedorova, L. M. Rubasheva, N. P. Potapova, and B. V. Rozynov, Antibiotiki, 25, 483 (1980). T. P. Preobrazhenskaya, O. A. Galatenko, O. L. Ol'khovatova, N. D. Malkina, Yu. V. Boikova, G. B. Fedorov, and I. V. Tolstykh, Antibiotiki i Meditsinskaya Biotekhnologiya, 31, 321 (1986). N. D. Malkina, Y. V. Dudnik, L. N. Lysenkova, E. I. Lazhko, O. A. Galatenko, and G. S. Katrukha, J. Antibiot., 47, 342 (1994). G. S. Katrukha, G. B. Fedorova, N. M. Arkhangel'skaya, M. Yassein, A. V. Laiko, and Zh. P. Trifonova, Antibiotiki i Khimioterapiya, 44, No. 5, 6 (1999). V. A. Zenkova, M. S. Yurina, N. N. Lomakina, L. E. Gol'dberg, V. S. Bazhanov, and I. A. Kunrat, Antibiotiki, 24, 175 (1979). G. F. Gauze and Yu. V. Dudnik, Antitumor Antibiotics [in Russian], Meditsina, Moscow (1987). S. Severina, N. V. Pyatakova, A. B. Postnikov, M. N. Preobrazhenskaya, and Y. V. Khropov, Eur. J. Pharmacol., 483, 127 (1987). V. V. Tolstikov, M. N. Preobrazhenskaya, J. Balzarini, and E. De Clercq, J. Antibiot., 45, 1002 (1992). M. N. Preobrazhenskaya, N. V. Holpne-Kozlova, and E. I. Lazhko, J. Antibiot., 45, 227 (1992). G. Horvath, M. G. Brazhnikova, N. V. Konstantinova, I. V. Tolstykh, and N. P. Potapova, J. Antibiot., 32, 555 (1979). M. G. Brazhnikova, M. K. Kudinova, V. V. Kulyaeva, N. P. Potapova, L. M. Rubasheva, B. V. Rozynov, and G. Khorvat, Antibiotiki, 29, 884 (1984). Yu. A. Berlin, O. A. Kiseleva, and M. N. Kolosov, Nature (London), 218, 193 (1968). Yu. A. Berlin, Thesis for Doctor of Chemical Sciences [in Russian], Moscow (1971). J. Thiem and B. Meyer, Tetrahedron, 37, 551 (1981). G. F. Gauze, in: J. W. Corcoran and F. E. Hahn (editors), Antibiotics. Mechanism of Action of Antimicrobial and Antitumor Agents, Springer Verlag, Berlin (1975), Vol. 3, p. 269. J. D. Leber, R. E. Hoover, K. G. Holden, R. K. Johnson, and S. M. Hecht, J. Am. Chem. Soc., 110, 2992 (1988). B. V. Rozynov, G. B. Fedorova, O. S. Reshetova, G. S. Katrukha, V. N. Borisova, and V. L. Sadovskaya, Antibiotiki i Khimioterapiya, 33, 420 (1988). L. E. Gol'dberg, S. T. Filipposyants, H. G. Shepelevtseva, and T. P. Vertogradova, Antibiotiki, 28, 298 (1983). E. N. Olsuf'eva, A. N. Tevyashova, and M. N. Preobrazhenskaya, Russian Patent Appl. No. 20044105794/15 (006186), 27.02.2004 (positive decision on grant of patent). N. Tevyashova, A. A. Shtil, E. N. Olsufyeva, V. S. Simonova, A. V. Samusenko, and M. N. Preobrazhenskaya, J. Antibiot., 57, 143 (2004).
1394
39. 40. 41. 42. 43. 44. 45. 46.
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A. E. Shchekotikhin, T. A. Sidorova, A. A. Shtil', V. N. Buyanov, and M. N. Preobrazhenskaya, Ros. Bioterapevt. Zh., 3, No. 2, 44 (2004). A. E. Shchekotikhin, V. N. Buyanov, and M. N. Preobrazhenskaya, Bioorg. Med. Chem., 12, 3923 (2004). S. A. Lakatosh, J. Balzarini, G. Andrey, R. Snoeck, E. De Clercq, and M. N. Preobrazhenskaya, J. Antibiot., 55, 768 (2002). M. N. Preobrazhenskaya, V. M. Bukhman, A. M. Korolev, and S. A. Efimov, Pharmac. Ther., 60, 301 (1993). M. N. Preobrazhenskaya and A. M. Korolev, Bioorgan. Khim., 26, 97 (2000). A. S. Trenin, I. V. Tolstykh, L. P. Terekhova, V. A. Zenkova, M. A. Makarova, E. G. Gladkikh, O. P. Bychkova, G. S. Katrukha, and Yu. V. Dudnik, Antibiotiki i Khimioterapiya, 45, No. 4, 6 (2000). N. E. Zhukhlistova, G. N. Tishchenko, I. V. Tolstych, and V. A. Zenkova, Crystallogr. Rep., 44, 8 (1999). L. P. Terekhova, A. S. Trenin, S. M. Ozernaya, Yu. A. Rudenskaya, T. S. Maksimova, G. S. Katrukha, I. V. Tolstykh, V. A. Zenkova, G. B. Fedorova, N. P. Potapova, and V. A. Kosykh, Mikrobiologiya, 66, 611 (1997). N. Yu. Soboleva, L. M. Krasnopol'skaya, G. B. Fedorova, and G. S. Katrukha, in: Advances in Medical Mycology. Second All-Russia Congress on Medical Mycology. Abstracts [in Russian], National Academy of Mycology, Moscow (2004), Vol. 3, p. 240. O. V. Tikhonova, L. M. Lur'e, E. Yu. Ershova, G. S. Katrukha, V. V. Kulyaeva, I. G. Sumarokova, O. V. Efremenkova, and Yu. V. Dudnik, in: Advances in Medical Mycology. First All-Russia Congress on Medical Mycology. Abstracts [in Russian], National Academy of Mycology, Moscow (2003), Vol. 1, p. 311.
1395
SELF-OSCILLATING REACTION IN THE FURAN SERIES

T. I. Gubina1, A. N. Pankratov2, V. I. Labunskaya1, and S. M. Rogacheva3 It was found for the first time that the acid hydrolysis of 2,5-dimethylfuran in waterethanol solutions has self-oscillating character. Oscillations in the concentrations of the two products 2,5-hexanedione and an unidentified compound X were detected by GLC. The ranges of hydrochloric acid and ethanol concentrations in which these oscillations appear were determined. It is suggested that the formation of compound X results from tautomeric transformations of 2,5-hexanedione under the reaction conditions. Quantum-chemical calculations showed that the possible tautomers are formed with equal probability. Keywords: 2,5-dimethylfuran, tautomers, self-oscillating reaction, acid hydrolysis. During the development of a method for the production of thiophenes and selenophenes by the recyclization of furans in waterethanol media under the conditions of acid catalysis it was shown that the reaction takes place in two directions, one of which includes a stage involving the formation of a diketone, i.e., hydrolysis. Kinetic investigations of the hydrolysis of 2,5-dimethylfuran (1) in 50% ethanol under the influence of HCl revealed the formation of 2,5-hexanedione (2) and an unidentified compound X. During the reaction the ratio of the concentrations of the products varied with some degree of periodicity, i.e., as it accumulated one product changed into the other, and these transformations were self-oscillating in nature [1, 2]. Study of the behavior of furan compounds in aqueous and wateralcohol media under the conditions of acid catalysis is of great theoretical and practical interest in so far as oscillating chemical reactions take place in various types of processes that determine the vital activity of living organisms [3], while furan derivatives are physiologically active substances. In the present work in order to determine the boundary conditions for the appearance of the abovementioned transformations the kinetics of the hydrolysis of dimethylfuran 1 in 50% aqueous ethanol with various hydrochloric acid concentrations (1.5, 2.0, 3.0, 3.5 N) were investigated by GLC. The results of the experiments are presented in Fig. 1. As seen, the fluctuations in the contents of the dione 2 and compound X in the reaction medium are observed at HCl concentrations (c) of 1.5-2.0 M. At c = 3 M both products are formed, but the ratio of their amounts in the reaction medium does not change with time. The experiments in 60 and 80% ethanol at HCl concentrations of 2.0 and 2.5 N (the dimethylfuran is poorly soluble in the 40% alcohol) showed that in 80% alcohol at the indicated acid concentrations only the hexanedione 2 is formed, while in 60% ethanol the concentrations of compound 2 and X oscillate in both cases (Fig. 2).
__________________________________________________________________________________________ Saratov State Technical University, Saratov, Russia; e-mail: aus@sstu.saratov.su. 2 Saratov State University, Saratov, Russia. 3 Saratov Military Institute of Radiation, Chemical, and Biological Protection, Saratov, Russia. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1619-1625, November, 2004. Original article submitted January 3, 2002; revision submitted October 25, 2002. 1396 0009-3122/04/4011-13962004 Springer Science+Business Media, Inc.
1
, min
Fig. 1. The kinetic curves for the hydrolysis of dimethylfuran 1 in 1.5 (1), 2.0 (2), 3.0 (3), and 3.5 N (4) solutions of HCl in 50% aqueous ethanol; c2 is the concentration of hexanedione 2; cX is the concentration of compound X.
, min
Fig. 2. The kinetic curves for the hydrolysis of dimethylfuran 1 in 2.0 (1) and 2.5 N (2) solutions of HCl in 60% aqueous ethanol.
The oscillations in the concentrations of the hexanedione 2 and compound X are in our opinion explained by the formation of dimethylfuran 1 from the reaction products and its subsequent hydrolysis. This was confirmed by the following experiment: The dione 2 was kept in a 2 N solution of hydrochloric acid in 50% 1397
, min
Fig. 3. The kinetic curves for the protolytic reaction: 1) Hexanedione 2 in a 2.0 N solution of hydrochloric acid in 50% aqueous ethanol; 2) after the addition of dimethylfuran 1 to the reaction mixture.
ethanol, compound X was found, and its content oscillated with a very small amplitude (Fig. 3, curve 1). The addition of dimethylfuran 1 to the reaction mixture led to a significant increase in the amplitude of oscillation (Fig. 3, curve 2). Thus, we had found that the hydrolysis of dimethylfuran 1 in acidic waterethanol media is an autocatalytic reaction. During attempts to establish the structure of compound X it was assumed that it may represent a ketal or semiketal of hexanedione 2, since hydrolysis was conducted in a waterethanol medium [1]. However, it was not possible to isolate compound X from the reaction mixture during distillation of an ether extract; it was converted into hexanedione 2. According to GLC, the same dione and a small amount of the product X (~8-10%) were mainly formed during hydrolysis of the dimethylfuran 1 in a 2 N aqueous solution of hydrochloric acid, but without oscillation in the concentrations. This made it possible to exclude the formation of a ketal or semiketal of hexanedione. Since the hydrolysis of compound 1 includes a proton transfer stage, we assumed that the formation of compound X results from the appearance of ketoenol tautomerism in the hexanedione 2, while the substance X is its tautomer. The following scheme of mutual transformations was proposed: The hexanedione 2 is formed from the dimethylfuran 1 in the acidic medium; this can exist in several tautomeric forms, which are transformed spontaneously from one to the other. In turn, the enol form of the dione 2 is readily transformed into dimethylfuran 1, which again undergoes hydrolysis:
X Me O 1 Me Me OO 2 Me
In order to confirm the presented scheme we recorded the electronic spectra of compounds 1 and 2 in 50 and 96% ethanol, water, and hexane and also the electronic spectra of the reaction mixture after various time intervals (Fig. 4). Dimethylfuran 1 has absorption bands at 216 (in 50% ethanol), 218 (in 96% ethanol), 216 (in 1398
, nm
Fig. 4. The electronic spectra of dimethylfuran 1 (1) and hexanedione 2 (2) in 50% ethanol and of the reaction mixture (3) 40 min after the beginning of the reaction.
water), and 224 (in hexane). Hexanedione 2 absorbs at 264 nm in water and waterethanol solution, at 280 nm in hexane, and at 266 nm in 96% ethanol. The absorption band of dimethylfuran 1 (216-224 nm) is characterized by high intensity and corresponds to the permitted * transition. The absorption band of hexanedione 2 at 264-280 nm has low intensity and belongs to the n* transition localized in the carbonyl group. The type of electronic transition here (n*) is confirmed by the hypsochromic shift of the absorption band with increase in the polarity of the solvent. In the waterethanol solution the absorption band of the substrate at 218 nm becomes weaker with time but does not disappear throughout the whole period of the observations (5 h). A weak band for the n* transition appears at 288 nm and probably corresponds to the carbonyl chromophore. The spectra indicate that hydrolysis of the dimethylfuran 1 with the formation of the saturated diketone 2 in the waterethanol medium takes place with great dilution with the solvent and even in the absence of the acid. If the reaction is carried out in the cuvette (50% ethanol, 2 N HCl) three absorption bands are recorded in the reaction mixture: One of them (216 nm) corresponds to the dimethylfuran 1, the second (264 nm) to the hexanedione 2, and the third (283 nm) to the unknown product. According to data in [4], this last band may correspond to 2-hydroxy-2,5-dimethyl-3dihydrofuran. Thus, the data from electronic spectroscopy indicate indirectly that the hexanedione 2 undergoes tautomeric transformations under the investigated reaction conditions. In order to identify possible tautomers and also to compare acetone and its enol quantum-chemical calculations of the standard entropies, the heats of formation, the Gibbs energies of formation, and the dipole moments of the electronic structures of hexanedione 2 and its tautomers 2A-F were undertaken (Table 1). According to the calculations, hexanedione 2 is the most thermodynamically stable. Its ability to undergo enolization is greater than that of the monoketone acetone. The cis- and trans-ketoenols 2A-C, like their isomer 2-hydroxy-2,5-dimethyl-2,3-dihydrofuran 2D, are energetically equivalent, which does not contradict their possible existence in the reaction medium. The formation of the dienol tautomers of hexanedione 2E,F is less likely than monoenolization. The formation of the dienols is energetically comparable with the enolization of acetone. 1399
Me O O 2
Me
Me
Me . OH . . O cis-2A
Me OH Me cis-2B
HO Me O trans-2C
Me
OH Me O 2D Me Me OH OH cis-2E
Me
Me OH Me trans-2F
OH
TABLE 1. The Dipole Moments (), Standard Heats of Formation (Hj), Entropies (S), and Gibbs Energies of Formation (Gf) (the M3 Method)
Compound 2 2A 2B 2C 2D 2E 2F Acetone Acetone enol , D 2.45 3.06 2.15 2.49 1.24 2.52 0.026 2.78 1.95 f, kcal/mol -96.59 -89.11 -88.93 -88.48 -88.44 -84.62 -83.16 -53.32 -38.78 S, kcal/molK 99.92 94.37 95.24 96.23 88.64 96.28 98.26 70.93 70.88 Gf, kcal/mol -62.81 -53.68 -53.60 -53.76 -51.30 -49.76 -48.89 -38.03 -23.48
On the basis of our investigations the scheme of the oscillating reaction may have the following form:
1
[ 2E
2A
2D ]
We studied the oscillating processes in the protolytic hydrolysis of dimethylfuran 1. The oscillations in the concentrations of the reaction products (hexanedione 2 and compound X) only occur under specific reaction conditions (at HCl concentrations of 1.5-2.5 M in 50 and 60% ethanol). It is not possible to isolate the unknown product and establish its structure by the usual chemical methods. The electronic spectra indicate the possible formation of tautomers of hexanedione 2, but the effect requires further investigation, which we will be undertaking.
EXPERIMENTAL The reactions were monitored and qualitative and quantitative analysis of the reaction mixtures was performed by GLC and UV spectroscopy. Gas-liquid chromatography was conducted on a Tsvet-101 chromatograph with a flame-ionization detector on columns (1 m 3 mm and 3 m 3 mm) with 15% Apiezon L on Chromaton N-AW: Thermostat temperature 100C, carrier gas (helium) flow rate 2 l/h.
1400
The UV spectra were recorded on an HP 8452A spectrometer in the region of 200-300 nm at steps x = 2 nm. The quantum-chemical computations were performed by the SCF LCAO MO PM3 method using MOPAC software by analogy with [5]. Compounds 1 and 2 were prepared by the usual procedures [6]. Kinetic Investigations of the Hydrolysis of 2,5-Dimethylfuran 1. General Procedure. In a 50-ml reaction vessel provided with a thermostated jacket (reaction temperature 40C) in a vibroscope we placed dimethylfuran 1 (0.48 g, 5 mmol), o-xylene (0.15 g) (internal standard), and the calculated amounts of twicedistilled water, 90% ethanol, and 12 N hydrochloric acid to create alcohol concentrations of 80, 60, and 50% and acid concentrations of 3.5, 3.0, 2.5, 2.0, and 1.5 N in 20 ml of solution. At specific intervals 1-ml samples were taken from the reaction mixture, concentrated potassium hydroxide (sodium hydroxide) (2 ml) was added to each, and the mixture was extracted with ether (1 ml). The contents of the components in the mixture were determined by GLC with an internal standard. Hydrolysis of 2,5-Dimethylfuran 1. Hydrolysis was conducted in a 2 N solution of hydrochloric acid according to the procedure described above (dimethylfuran 1 (0.48 g, 5 mmol) in 20 ml of solution). Quantitative control of the reaction was realized by GLC. 2,5-Hexanedione (2). The compound was kept in a 2 N aqueous solution of hydrochloric acid in 50% ethanol under conditions similar to those described above, using hexanedione 2 (0.57 g, 5 mmol). After 2 h dimethylfuran 1 (0.48 g, 5 mmol) was added to the solution (Fig. 3).
REFERENCES 1. 2. 3. 4. 5. 6. T. I. Gubina, V. I. Labunskaya, G. K. Kornienko, L. A. Borodina, and V. G. Kharchenko, Khim. Geterotsikl. Soedin., Khim. Geterotsikl. Soedin., 624 (1995). T. I. Gubina, A. N. Pankratov, V. I. Labunskaya, and V. G. Kharchenko, in: Abstracts of 36th Congress of IUPAC, Geneva, Switzerland (1997), p. 494. D. Garel and O. Garel, Oscillating Chemical Reactions [Russian translation], Mir, Moscow (1986). A. Gillem and E. Stern, Electronic Absorption Spectra of Organic Compounds [Russian translation], Izd. Inostr. Lit., Moscow (1957). T. I. Gubina, A. N. Pankratov, V. I. Labunskaya, S. P. Voronin, and V. G. Kharchenko, Khim. Geterotsikl. Soedin., 1035 (1997). V. G. Kharchenko, T. I. Gubina, and I. A. Markushina, Zh. Org. Khim., 18, 394 (1982).
1401
HETEROCYCLIC SYNTHESIS USING NITRILE IMINES. 4*. SYNTHESIS OF 3-SUBSTITUTED 1-ARYL-1,2,4-TRIAZASPIROALK-2-ENES

H. M. Dalloul Cycloalkanone oximes react with C-(2-furoyl)-, C-(2-thenoyl)- and C-(phenylaminocarbonyl)nitrile imines to give unexpected 3-substituted 1-aryl-1,2,4-triazaspiroalk-2-enes rather than the cycloaddition or the cyclocondensation products. Keywords: cycloalkanone oxime, nitrile imines, 1,2,4-triazaspiro[4,5]dec-2-ene, cycloaddition. 1,3-Dipolar cycloaddition reactions of nitrile imines with dipolarophiles containing C=N bond represent an important synthetic route to substituted 1,2,4-triazoles [2]. The reaction of nitrile imines with methyl hydrazones of aliphatic ketones is reported to give the cyclocondensation products, viz 1,2,4,5-tetrazines rather than the cycloaddition products at C=N, 1,2,4-triazoles apparently, because of the strong nucleophilicity of the nitrogen atom carrying the methyl group, where the reaction starts [1, 3, 4]. Simple hydrazones react in a similar manner giving initially the acyclic electrophilic addition products, which cyclize to 1,2,4,5-tetrazines upon heating with charcoal [5-7]. Recently, Ferwanah and co-workers [8-10] described a versatile and efficient one-pot synthesis of 5,5-disubstituted 3-acetyl-1-aryl-1H1,2,4-triazoles utilizing available ketoximes and hydrazonoyl halides (precursors of nitrile imines, the reactive 1,3-dipolar species). In this work, the reaction of nitrile imines 1a-d with cycloalkanone oximes 2-7 is investigated. Initially, it was thought that the reaction will produce cycloaddition products 1,2,4-triazoles 8 or cyclocondensation products 1,2,4,5-oxatriazines 9, but the spectral data of the resulting products indicated unexpected 3-substituted 1-aryl-1,2,4-triazaspiroalk-2-enes 10-15 (Scheme). The formation of compounds 10-15 is assumed to involve cycloaddition adducts 8 which tautomerize to amine oxide-type intermediates that are deoxygenated by triethylamine [10]. The structures of products 10-15 were elucidated on the basis of analytical and spectral data. The electron impact (EI) mass spectra (Table) display the correct molecular ions in accordance with the suggested structures. The base peak in all these compounds is that of the conjugated vinyltriazole cation. This occurs at M+ - 29, C2H5 for compounds containing cyclopentane moiety, M+ - 43, C3H7 for compounds containing cyclohexane moiety, M+ - 57, C4H9 for compounds containing cycloheptane and methyl cyclohexane moiety, M+ - 71, C5H11 for compounds containing cyclooctane moiety, and M+ - 99, C7H15 for compounds containing _______ * For Part 3 see Ref. 1. __________________________________________________________________________________________ Department of Chemistry, Faculty of Applied Sciences, Al-Aqsa University of Gaza, P. O. Box 4051, Gaza Strip via Israel; e-mail: dalloul15@hotmail.com, dalloul-15@mail.com. Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1626-1631, November, 2004. Original article submitted September 14, 2003. 1402 0009-3122/04/4011-14022004 Springer Science+Business Media, Inc.
tert-butyl cyclohexane moiety. This fragmentation pattern is well known for cycloalkanones [11]. The 1H NMR spectra of products 10-15 show a signal at 5.5 ppm, which is characteristic for the N-H of the five-membered ring, and in compounds containing PhNHCO group another signal of N-H appears at 9.5 ppm (Experimental).
Ar' Cl(Br) Ar N 16ad C NHAr '

Ar N N OH
oC
NEt3 / 0 + N
8
N N
Ar '
Ar
_ NHAr '
HO
N 27
THF/ r. t.
Ar N H Ar ' N N
1ad
10ad 15ad A
Ar O N
Ar' =
X;
a, b, d X = Cl, c X = H; 2, 10 A = (CH2)2, 3, 11 A = (CH2)3,
4, 12 A = CH2CHMeCH2, 5, 13 A = CH2CH(t-Bu)CH2, 6, 14 A = (CH2)4, 7, 15 A = (CH2)5;
1, 1016 a Ar =
CO, b Ar =
CO , c, d Ar =
NHCO
The 13C NMR spectra account for the different carbons of these triazoles. The signal at 85-95 ppm, which is attributed to C(5) (spiro carbon) of the triazole ring is of special significance. This is similar to reported values of spiro carbons flanked by two nitrogens in five-membered heterocycles [9, 10, 12].
EXPERIMENTAL Melting points were determined on Electrothermal Melting Temperature Apparatus and are uncorrected. IR spectra were obtained by using Satellite 3000 Mid infrared spectrometer (KBr discs). 1H and 13C NMR spectra were recorded on a Bruker instrument (400 MHz for 1H and 100 MHz for 13C) in CDCl3 using TMS as an internal reference. Chemical shifts () are expressed in ppm downfield from internal TMS. Electron impact mass spectra were run on LCT Electrospray mass spectrometer. Elemental analysis was performed at Cairo University, Egypt. Hydrazonoyl halides (16a) [13], (16b) [14], and (16c,d) [15], cycloalkanone oximes (2-7) [16, 17] were prepared according to known literature procedures.
1403
TABLE 1. Physical Properties and Elemental Analyses of Compounds 10-15

Compound 10b 10d 11a 11b 11c 11d 12a 12b 12c 12d 13a 13b 13d 14a 14b 14c 15b 15d Empirical formula, M+ C17H16ClN3OS 345/347 C19H19ClN4O 354/356 C18H18ClN3O2 343/345 C18H18ClN3OS 359/361 C20H22N4O 334 C20H21ClN4O 368/370 C19H20ClN3O2 357/359 C19H20ClN3OS 373/375 C21H24N4O 348 C21H23ClN4O 382/384 C22H26ClN3O2 399/401 C22H26ClN3OS 415/417 C24H29ClN4O 424/426 C19H20ClN3O2 357/359 C19H20ClN3OS 373/375 C22H28N4O 364 C20H22ClN3OS 387/389 C22H25ClN4O 396/398 Found, % Calculated, % H 4.50 4.66 5.60 5.40 5.40 5.28 5.10 5.04 6.50 6.63 5.60 5.74 5.70 5.63 5.30 5.39 7.10 6.94 5.90 6.05 6.70 6.55 6.40 6.30 6.80 6.88 5.70 5.63 5.40 5.39 7.80 7.74 5.90 5.72 6.50 6.35
mp, C N 12.10 12.15 15.60 15.79 12.30 12.22 11.70 11.68 16.80 16.75 15.30 15.19 11.60 11.74 11.10 11.24 15.90 16.08 14.50 14.63 10.60 10.51 9.90 10.10 13.20 13.18 11.60 11.74 11.30 11.24 15.20 15.37 10.70 10.83 14.00 14.12 109-111 123-125 131-133 140-142 148-150 158-160 123-125 117-119 149-151 160-162 134-136 146-148 163-165 129-131 138-140 152-154 126-128 160-162
Yield, %
C 58.80 59.04 64.50 64.31 63.10 62.88 59.90 60.06 71.60 71.83 64.90 65.12 63.90 63.77 60.80 61.03 72.50 72.39 66.10 65.88 66.20 66.07 63.70 63.52 67.60 67.83 63.90 63.77 60.90 61.03 72.30 72.50 62.10 61.92 66.70 66.57
55 50 60 61 59 60 52 54 59 62 58 60 61 58 60 57 55 48
Synthesis of Substituted Heterocyclic Spiro Compounds 10-15 (General procedure). Triethylamine (0.05 mol) in absolute THF (10 ml) was added dropwise to a stirred solution of hydrazonoyl halides 16a-d (0.01 mol) and the respective cycloalkanone oxime 2-7 (0.025 mol) in THF (100 ml) at room temperature. Stirring was continued overnight, the solvent was then evaporated in vacuo, and the residual solid was washed with water to get rid of triethylamine salt. The crude product was collected and recrystallized from ethanol. The following compounds were synthesized using this method: 1-(4-Chlorophenyl)-3-(2-thenoyl)-1,2,4-triazaspiro[4.4]non-2-ene (10b). 1H NMR, , ppm; 8.2-7.2 (7H, m, aromatic), 5.5 (1H, s, NH), 2.3-1.6 (8H, m, cyclopentane protons). 13C NMR, , ppm: 174.3 (C=O), 146.9 (C=N), 141.5, 140.2, 135.2, 135.0, 129.1, 128.2, 128.0, 120.8 (8 aromatic carbons), 87.9 (spiro carbon), 34.9, 24.9 (cyclopentane carbons). IR, , cm-1: 3370 (NH), 1660 (C=O). 1-(4-Chlorophenyl)-3-phenylaminocarbonyl-1,2,4-triazaspiro[4.4]non-2-ene (10d). 1H NMR, , ppm: 9.6 (1H, s, C6H5NH), 7.6-7.1 (9H, m, aromatic), 56 (1H, s, NH), 2.3-1.7 (8H, m, cyclopentane protons). 13 C NMR, , ppm: 159.8 (C=O), 146.9 (C=N), 141.3, 135.3, 134.8, 132.4, 129.1, 127.9, 127.5, 115.9 (8 aromatic carbons), 87.4 (spiro carbon), 34.7, 24.8 (cyclopentane carbons). IR, , cm-1: 3350 (NH), 1655 (C=O). 1404
1-(4-Chlorophenyl)-3-(2-furoyl)-1,2,4-triazaspiro[4.5]dec-2-ene (11a). 1H NMR, , ppm: 8.3-7.1 (7H, m, aromatic), 5.5 (1H, s, NH), 1.9-1.1 (8H, m, cyclohexane protons). 13C NMR, , ppm: 174.2 (C=O), 147.4 (C=N), 141.6, 140.1, 135.1, 135.0, 128.9, 128.1, 127.9, 120.6 (8 aromatic carbons), 87.8 (spiro carbon), 35.5, 24.7, 23.1 (cyclohexane carbons). IR, , cm-1: 3360 (NH), 1665 (C=O). 1-(4-Chlorophenyl)-3-(2-thenoyl)-1,2,4-triazaspiro[4.5]dec-2-ene (11b). 1H NMR, , ppm: 8.3-7.1 (7H, m, aromatic), 5.5 (1H, s, NH), 1.9-1.1 (10H, m, cyclohexane protons). 13C NMR, , ppm: 174.2 (C=O), 147.4 (C=N), 141.6, 140.1, 135.1, 135.0, 128.9, 128.1, 127.9, 120.6 (8 aromatic carbons), 87.8 (spiro carbon), 35.5, 24.7, 23.1 (cyclohexane carbons). IR, , cm-1: 3375 (NH), 1660 (C=O). 1-Phenyl-3-phenylaminocarbonyl-1,2,4-triazaspiro[4.5]dec-2-ene (11c). 1H NMR, , ppm: 9.6 (1H, s, C6H5NH), 7.5-7.0 (10H, m, aromatic), 5.5 (1H, s, NH), 2.1-1.4 (10H, m, cyclohexane protons). 13C NMR, , ppm: 159.9 (C=O), 147.2 (C=N), 141.5, 135.4, 134.7, 132.6, 129.2, 127.8, 123.2, 115.8 (8 aromatic carbons), 88.2 (spiro carbon), 35.7, 24.8, 22.9 (cyclohexane carbons). IR, , cm-1: 3350 (NH), 1655 (C=O). 1-(4-Chlorophenyl)-3-phenylaminocarbonyl-1,2,4-triazaspiro[4.5]dec-2-ene (11d). 1H NMR, , ppm; 9.7 (1H, s, C6H5NH), 7.7-7.0 (9H, m, aromatic), 5.5 (1H, s, NH), 2.1-1.4 (10H, m, cyclohexane protons). 13C NMR, , ppm: 159.9 (C=O), 147.0 (C=N), 141.3, 135.3, 134.8, 132.2, 129.0, 127.9, 127.6, 115.7 (8 aromatic carbons), 88.1 (spiro carbon), 35.6, 24.7, 23.0 (cyclohexane carbons). IR, , cm-1: 3350 (NH), 1650 (C=O). 1-(4-Chlorophenyl)-3-(2-furoyl)-8-methyl-1,2,4-triazaspiro[4.5]dec-2-ene (12a). 1H NMR, , ppm: 8.2-7.1 (7H, m, aromatic), 5.5 (1H, s, NH), 2.0-1.1 (9H, m, cyclohexane protons), 0.9 (3H, s, CH3). 13C NMR, , ppm: 173.5 (C=O), 147.4 (C=N), 141.5, 140.2, 135.2, 135.0, 129.1, 128.2, 128.0, 120.8 (8 aromatic carbons), 87.9 (spiro carbon), 35.2, 28.4, 22.6 (cyclohexane carbons), 31.4 (CH3 at cyclohexane ring). IR, , cm-1: 3365 (NH), 1665 (C=O). 1-(4-Chlorophenyl)-8-methyl-3-(2-thenoyl)-1,2,4-triazaspiro[4.5]dec-2-ene (12b). 1H NMR, , ppm: 8.2-7.1 (7H, m, aromatic), 5.5 (1H, s, NH), 2.0-1.1 (9H, m, cyclohexane protons), 0.9 (1H, s, CH3). 13C NMR, , ppm: 174.2 (C=O), 146.4 (C=N), 141.3, 140.0, 134.8, 134.6, 128.9, 127.9, 127.7, 120.1 (8 aromatic carbons), 89.0 (spiro carbon), 34.8, 29.3, 22.1 (cyclohexane carbons), 31.3 (CH3 at cyclohexane ring). IR, , cm-1: 3370 (NH), 1665 (C=O). 8-Methyl-1-phenyl-3-phenylaminocarbonyl-1,2,4-triazaspiro[4.5]dec-2-ene (12c). 1H NMR, , ppm: 9.8 (1H, s, C6H5NH), 7.6-7.1 (10H, m, aromatic), 5.5 (1H, s, NH), 1.9-1.1 (9H, m, cyclohexane protons), 0.9 (3H, s, CH3). 13C NMR, , ppm: 159.9 (C=O), 146.9 (C=N), 141.8, 135.3, 134.8, 132.2, 129.0, 127.9, 123.6, 115.7 (8 aromatic carbons), 88.9 (spiro carbon), 34.9, 28.1, 22.1 (cyclohexane carbons), 31.2 (CH3 at cyclohexane ring). IR, , cm-1: 3355 (NH), 1655 (C=O). 1-(4-Chlorophenyl)-8-methyl-3-phenylaminocarbonyl-1,2,4-triazaspiro[4.5]dec-2-ene (12d). 1H NMR, , ppm: 9.6 (1H, s, C6H5NH), 7.6-7.0 (9H, m, aromatic), 5.6 (1H, s, NH), 2.1-1.2 (9H, m, cyclohexane protons), 1.0 (3H, s, CH3). 13C NMR, , ppm: 159.8 (C=O), 146.8 (C=N), 141.3, 135.3, 134.8, 132.2, 129.0, 127.9, 127.6, 115.7 (8 aromatic carbons), 89.0 (spiro carbon), 34.8, 27.9, 22.3 (cyclohexane carbons), 31.3 (CH3 at cyclohexane ring). IR, , cm-1: 3350 (NH), 1650 (C=O). 8-tert-Butyl-1-(4-chlorophenyl)-3-(2-furoyl)-1,2,4-triazaspiro[4.5]dec-2-ene (13a). 1H NMR, , ppm: 8.0-7.2 (7H, m, aromatic), 5.5 (1H, s, NH), 1.9-0.9 (9H, m, cyclohexane protons), 0.8 (9H, s, (CH3)3C). 13 C NMR, , ppm: 173.3 (C=O), 147.3 (C=N), 141.5, 140.2, 135.2, 135.0, 129.1, 128.2, 128.0, 120.8 (8 aromatic carbons), 87.9 (spiro carbon), 47.0, 35.5, 32.4, 27.6, 24.1 (tert-butyl carbons). IR, , cm-1: 3360 (NH), 1660 (C=O). 8-tert-Butyl-1-(4-chlorophenyl)-3-(2-thenoyl)-1,2,4-triazaspiro[4.5]dec-2-ene (13b). 1H NMR, , ppm: 8.3-7.2 (7H, m, aromatic), 5.6 (1H, s, NH), 2.1-1.1 (9H, m, cyclohexane protons), 0.9 (9H, s, (CH3)3C). 13 C NMR, , ppm: 174.1 (C=O), 147.2 (C=N), 141.4, 140.2, 135.1, 134.9, 129.1, 128.3, 128.0, 120.8 (8 aromatic carbons), 87.8 (spiro carbon), 47.1, 35.7, 32.4, 27.6, 24.1 (tert-butyl carbons). IR, , cm-1: 3370 (NH), 1665 (C=O).
1405
8-tert-Butyl-1-(4-chlorophenyl)-3-phenylaminocarbonyl-1,2,4-triazaspiro[4.5]dec-2-ene (13d). H NMR, , ppm: 9.6 (1H, s, C6H5NH), 7.6-7.0 (9H, m, aromatic), 5.5 (1H, s, NH), 2.0-1.0 (9H, m, cyclohexane protons), 0.9 (9H, s, (CH3)3C). 13C NMR, , ppm: 159.9 (C=O), 146.9 (C=N), 141.3, 135.3, 134.8, 132.2, 129.0, 127.9, 127.6, 115.7 (8 aromatic carbons), 88.9 (spiro carbon), 46.9, 35.7, 32.4, 27.5, 24.0 (tert-butyl carbons). IR, , cm-1: 3360 (NH), 1655 (C=O). 1-(4-Chlorophenyl)-3-(2-furoyl)-1,2,4-triazaspiro[4.6]undec-2-ene (14a). 1H NMR, , ppm: 7.8-6.8 (7H, m, aromatic), 5.6 (1H, s, NH), 2.3-1.5 (12H, m, cycloheptane protons). 13C NMR, , ppm: 173.6 (C=O), 147.6 (C=N), 141.5, 140.2, 135.2, 135.0, 129.1, 128.2, 128.0, 120.8 (8 aromatic carbons), 88.9 (spiro carbon), 39.3, 28.0, 22.2 (cycloheptane carbons). IR, , cm-1: 3365 (NH), 1660 (C=O). 1-(4-Chlorophenyl)-3-(2-thenoyl)-1,2,4-triazaspiro[4.6]undec-2-ene (14b). 1H NMR, , ppm; 8.2-7.1 (7H, m, aromatic), 5.6 (1H, s, NH), 2.4-1.6 (12H, m, cycloheptane protons). 13C NMR, , ppm: 174.2 (C=O), 147.3 (C=N), 141.2, 139.9, 135.0, 134.9, 128.7, 127.9, 127.6, 120.1 (8 aromatic carbons), 88.7 (spiro carbon), 39.4, 28.2, 22.3 (cycloheptane carbons). IR, , cm-1: 3360 (NH), 1660 (C=O). 1-Phenyl-3-phenylaminocarbonyl-1,2,4-triazaspiro[4.6]undec-2-ene (14c). 1H NMR, , ppm: 9.9 (1H, s, C6H5NH), 7.6-7.1 (10H, m, aromatic), 5.6 (1H, s, NH), 2.4-1.6 (12H, m, cycloheptane protons). 13 C NMR, , ppm: 159.9 (C=O), 147.1 (C=N), 141.8, 135.3, 134.8, 132.2, 129.0, 127.9, 123.4, 115.7 (8 aromatic carbons), 88.9 (spiro carbon), 39.6, 28.4, 22.4 (cycloheptane carbons). IR, , cm-1: 3355 (NH), 1650 (C=O). 1-(4-Chlorophenyl)-3-(2-thenoyl)-1,2,4-triazaspiro[4.7]dodec-2-ene (15b). 1H NMR, , ppm: 8.3-7.1 (7H, m, aromatic), 5.6 (1H, s, NH), 2.4-1.2 (14H, m, cyclooctane protons). 13C NMR, , ppm: 174.3 (C=O), 147.1 (C=N), 141.6, 140.2, 135.1, 135.0, 129.1, 128.1, 128.0, 120.5 (8 aromatic carbons), 88.6 (spiro carbon), 41.9, 36.5, 27.2, 21.8 (cyclooctane carbons). IR, , cm-1: 3370 (NH), 1665 (C=O). 1-(4-Chlorophenyl)-3-phenylaminocarbonyl-1,2,4-triazaspiro[4.5]dodec-2-ene (15d). 1H NMR, , ppm: 10.0 (1H, s, C6H5NH), 7.8-7.2 (9H, m, aromatic), 5.6 (1H, s, NH), 2.3-1.1 (14H, m, cyclooctane protons). 13C NMR, , ppm: 159.9 (C=O), 147.2 (C=N), 141.3, 135.3, 134.8, 132.2, 129.0, 127.9, 127.6, 115.7 (8 aromatic carbons), 88.9 (spiro carbon), 42.0, 36.6, 27.2, 21.9 (cyclooctane carbons). IR, , cm-1: 3360 (NH), 1655 (C=O).
1
Author wishes to thank Dr. P. H. Boyle, Trinity College, Dublin 2, Ireland, for obtaining the NMR and mass spectra.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 1406 H. M. Dalloul, P. H. Boyle, Heterocycl. Commun., 9, 507, 2003. J. B. Polya, in Comprehensive Heterocyclic Chemistry, A. R. Katritzky, C. W. Rees (Eds.), Pergamon Press, 1984, 5, p. 733. M. M. El-Abadelah, A. Q. Hussein, M. R. Kamal, K. H. Al-Adhami, Heterocycles, 27, 917 (1988). A. M. Awadallah, E. M. El-Sawi, A. S. Ferwanah, H. M. Dalloul, Asian J. Chem., 14, 1230 (2002). A. Q. Hussein, J. Chem. Res. (S), 174 (1996). A. Q. Hussein, J. Chem. Res. (M), 949 (1996). E. M. El-Sawi, A. M. Awadallah, A. S. Ferwanah, H. M. Dalloul, Asian J. Chem., 14, 1225 (2002). A. S. Ferwanah, Asian J. Chem., 11, 480 (1999). A. S. Ferwanah, N.G. Kandile, A. M. Awadallah, O. A. Miqdad, Synth. Commun., 32, 2017 (2002). A. S. Ferwanah, A. M. Awadallah, N. A. Khafaja, Asian J. Chem., 13, 1203 (2001). M. Hesse, H. Meier, B. Zeeh, Spectroscopic Methods in Organic Chemistry, Georg Thieme Verlag, Stuttgart, 1997, p. 229. S. Morrochi, A. Ricci, Chim. Ind. (Ital.), 49, 629 (1967). H. M. Hassaneen, A. S. Shawali, N. M. Elwan, A. A. Ibrahim, Arch. Pharm. Res., 14, 266 (1991).
14. 15. 16. 17.
A. M. Farag, H. M. Hassaneen, I. M. Abbas, A. S. Shawali, M. S. Algharib, Phosphorus and Sulfur, 39, 243 (1988). A. S. Shawali, H. M. Hassaneen, A. A. Fahmi, N. M. Abu Nada, Phosphorus, Sulfur and Silicon, 53, 259 (1990). R. Shriner, R. Fuson, D. Curtin, T. Morrill, The Systematic Identification of Organic Compounds, 6th Ed., John Wiley & Sons, New York, 1980, p. 537. B. Furniss, A. Hannaford, V. Rogers, P. Smith, A. Tachell, Vogel's Text Book of Practical Organic Chemistry, Including Qualitative Organic Analysis, 4th Ed., Longman, London, 1978, p. 1113.
1407
CHEMISTRY OF 3-HETARYLCOUMARINS. 2*. 3-(2-THIAZOLYL)COUMARINS

O. V. Khilya, O. V. Shablykina, M. S. Frasinyuk, A V. Turov, V. V. Ishchenko, and V. P. Khilya 3-(2-Thiazolyl)coumarins were obtained by the reaction of substituted salicylaldehydes with 2-thiazolylacetonitriles. Methylation, acylation, and aminomethylation were studied for the 7-hydroxysubstituted products. Keywords: 8-aminomethyl-7-hydroxy-3-(2-thiazolyl)coumarins, 7-acyloxy-3-(2-thiazolyl)coumarins, 7-methoxy-3-(2-thiazolyl)coumarins, 3-(2-thiazolyl)coumarins. Many synthetic coumarins have a wide spectrum of biological activity [2-5] and also fluorescence [2-5]. This makes it possible to use them as fluorescent probes, markers, and laser media [6, 7]. The heterocyclic analogs of coumarins are of particular interest with respect to the effect of the nature of the heterocycle on their characteristics and the possibility of their practical application. Earlier we obtained and studied 3-(2-benzimidazolyl)- and 3-(2-benzimidazolyl)coumarins [1]. The subjects of the present work are 3-(2-thiazolyl)coumarins 1a-i with alkyl and aryl substituents at position 4 of the thiazole ring. Such compounds are usually obtained by Knoevenagel condensation of salicylaldehydes and 2thiazolylacetonitriles followed by hydrolysis of the obtained 2-iminocoumarins (the most convenient and frequently used method) [8, 9], by the reaction of 2-iminocoumarin-3-thiocarboxamides with -halocarbonyl compounds (in this case partial hydrolysis of the imino group occurs) [8-11], and by the reaction of hetarylacetonitriles or the corresponding esters with Schiff base (azomethine) derivatives of salicylaldehydes [12]. The spectral characteristics of some 3-(2-thiazolyl)coumarins [13, 14] and their potential pharmacological activity [15] have been investigated. The 3-(2-thiazolyl)coumarins 1a-i were synthesized by the condensation of 4-hydroxy-, 5-bromo-, 5-nitro-, and 5-chlorosalicylaldehydes with methyl- or aryl-substituted 2-thiazolylacetonitriles in the presence of piperidine followed by hydrolysis of the obtained iminocoumarins with 3% sulfuric acid. The products 1a-i are high-melting crystalline substances mostly yellow in color, insoluble in water, and with the exception of 1a poorly soluble in organic solvents (Table 1). In their 1H NMR spectra in the downfield region there is a singlet for H-5 of the thiazole ring (7.0-8.5 ppm) and also a full set of signals for the remaining protons of the coumarin fragment and signals for the substituent R2 (Table 2).
_______ * For Communication 1, see [1]. __________________________________________________________________________________________ Taras Shevchenko Kiev University, Kiev, Ukraine; e-mail: shablykina@mail.univ.kiev.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1632-1644, November, 2004. Original article submitted April 8, 2002. Revision received March 23, 2004. 1408 0009-3122/04/4011-14082004 Springer Science+Business Media, Inc.
CHO R1 OH
NC N
N H
+
R2 N
R2 R2 N
R1 O NH
H+
S R1 O 1ai O
1 a-d R1 = 7-OH, e, f R1 = 6-Br, g, h R1 = 6-NO2, i R1 = 6-Cl; a R2 = Me, b, e, g R2 = C6H4Br-4, c, f, h, i R2 = C6H4NO2-3, d R2 = C6H3OCH2O-3,4
Methylation, acylation, and aminomethylation were studied for compounds 1a-d, which contain an active hydroxyl group. The methylation of the coumarins 1a-d by the action of dimethyl sulfate in acetone in the presence of potassium carbonate led to 7-methoxycoumarins 2a-d, and acylation with acid chlorides in pyridine gave 7-acyloxycoumarins 3a-w (Table 1). The 1H NMR spectra of the synthesized derivatives show a slight downfield shift of the signals for the protons of the coumarin fragment compared with the initial compounds and also the presence of signals for the protons of the methoxy group (3.90-3.95 ppm) or the acyl substituent R3CO (Table 2). For the assignment of the complex multiplet signals in the 1H NMR spectra of compounds 3m and 3v two-dimensional COSY spectroscopy was used (Fig. 1). It is known that aminomethylation takes place readily in the isoflavone series, and the obtained Mannich bases are biologically active [16, 17]. For the synthesis of such bases from 7-OH-3-thiazolylcoumarins 1a-d (aminomethylation does not occur in the absence of a strong donating substituent the hydroxy group) we used aminals, since when the reaction is conducted under standard conditions (by the action of amine hydrochlorides in alcohol) the nitrogen of the thiazole ring is protonated, and this deactivates the coumarin system in
Compound 3m Compound 3v Fig. 1. 1409
electrophilic substitution reactions [1]. If the coumarin is boiled with a small excess of the aminal (10-20%) in dioxane for 1 h 30 min to 2 h, the respective 8-aminomethyl derivative 4a-o is formed exclusively with a fairly high yield. The reaction had the longest duration (3 h) during the synthesis of compound 4h, which has the largest substituent at the nitrogen atom, and the yield was the lowest (51%) (Table 1).
R2 Me2SO4; acetone; K2CO3 HO R2 N S S MeO O 2ad R2 N S R COO
3
N S O 1ad O N X2CH2; dioxane R2
R3COCl; Py
HO X
O 4ap
HCl, CHCl3 + HN S HO O + XH 5ak O _ 2Cl R2
O 3aw
2a, 3 a,b R2 = Me, 2b, 3c-i R2 = C6H4Br-4, 2c, 3 j-p R2 = C6H4NO2-3, 2d, 3q-w R = C6H3OCH2O-3,4; 3 a,c,j,q R3 = Me, b,i,p,w R3 = 2-furyl, d,k,r R3 = Et, e,l,s R3 = CMe3, f,m,t R3 = C6H4Me-2, g,n,u R3 = C6H4OMe-4, h,o,v R3 = C6H3(OMe)2-3,4, 4 a-c R2 = Me, d-h R2 = C6H4Br-4, i-l R2 = C6H4NO2-3, m-p R2 = C6H3OCH2O-3,4; a X = N(CH2)4, b X = N(CH2)2CHMe(CH2)2, c X = N(CH2)4CHEt; d,i,m X = NMe2, e,j,n X = N(CH2)4, f,k,o X = N(CH2)5, g,l,p X = N(CH2)2NMe(CH2)2, h X = NCHMe(CH2)3CHMe; 5a-c R2 = C6H4Br-4; d-g R2 = C6H4NO2-3, h-k R2 = C6H3OCH2O-3,4, a,d,h X = NMe2, b,e,i X = N(CH2)4, c,f,j X = N(CH2)5, g,k X = N(CH2)2NMe(CH2)2
2
The aminomethyl derivatives dissolve better in organic solvents than the initial compounds, many are moderately soluble in dilute mineral acids, and some are soluble in water. Solutions of compounds 4a-c,d-g,m-p in organic solvents (ethanol, acetone), like the corresponding initial coumarins and their methyl and acyl derivatives, fluoresce during excitation by visible light. In the 1H NMR spectra of the synthesized Mannich bases there are signals for the protons of the aminoalkyl groups; the signals of the H-5 and H-6 protons (doublets with 3 J = 8.5-9.0 Hz) are shifted upfield compared with the analogous signals of the initial coumarins (Table 3); the signal of the H-8 proton is absent. If the solutions of the Mannich bases 4d-f,i-l,m-p are saturated with HCl the corresponding hydrochlorides 5a-k are precipitated. Protonation takes place at the two nitrogen atoms, as shown by the data from elemental analysis of the obtained salts (see Experimental). The salts 5a-k are hygroscopic compounds, which decompose to the initial base with the release of HCl when heated above ~60C. They are very poorly soluble in organic solvents but dissolve readily in water; the aqueous solutions of the hydrochlorides 5a-k fluoresce strongly. In the 1H NMR spectra of the salts 5a-k there is a significant downfield shift of the signals for the protons of the aminoalkyl groups compared with the analogous signals of the bases 4d-f,i-l,m-p (Table 3). 1410
TABLE 1. The Characteristics of the Synthesized Compounds 1-4

Compound 1 1a 1b 1c 1d 1e 1f 1g 1h 1i 2a 2b 2c 2d 3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3m 3n 3o Empirical formula 2 C13H9NO3S C18H10BrNO3S C18H10N2O5S C19H11NO5S C18H9Br2NO2S C18H9BrN2O4S C18H9BrN2O4S C18H9N3O6S C18H9ClN2O4S C14H11NO3S C19H12BrNO3S C19H12N2O5S C20H13NO5S C15H11NO4S C18H11NO5S C20H12BrNO4S C21H14BrNO4S C23H18BrNO4S C26H16BrNO4S C26H16BrNO5S C27H18BrNO6S C23H12BrNO5S C20H12N2O6S C21H14N2O6S C23H18N2O6S C26H16N2O6S C26H16N2O7S C27H18N2O8S 18.30 18.07 17.89 17.51 16.86 16.50 15.74 15.42 15.06 14.95 14.50 14.16 16.42 16.17 7.07 6.85 6.91 6.63 5.98 6.22 5.72 5.78 5.57 5.60 5.39 5.28 19.66 19.29 7.23 7.37 4.02 3.69 4.51 4.65 8.90 9.21 34.94 34.51 18.17 18.62 18.83 18.62 20.12 19.96 Hal 3 Found, % Calculated, % N 4 5.47 5.40 7.38 7.65 4.14 3.83 3.14 3.02 6.11 6.53 6.30 6.53 10.14 10.63 6.92 7.28 5.34 5.13 Yield, % 7 98 78 93 79 76 79 81 71 86 78 85 79 91 92 91 88 55 75 90 88 90 82 82 76 76 51 68 75
mp, S 5 12.39 12.36 8.19 8.01 9.10 8.75 8.99 8.78 6.72 6.92 7.27 7.27 7.07 7.27 7.70 8.11 8.06 8.33 11.65 11.73 7.89 7.74 8.31 8.43 8.36 8.45 10.40 10.64 8.76 9.07 7.41 7.25 6.91 7.03 6.49 6.62 6.28 6.19 5.97 6.00 5.89 5.68 6.61 6.43 8.04 7.85 7.86 7.69 7.16 7.12 6.58 6.62 6.43 6.41 6.38 6.04 6 295-296 >330 321-325 305 (dec.) 246-247 262-264 232-233 308-309 300 (dec.) 208-211 285-286 259-261 242-245 179-184 201-203 238-239 213-215 217-219 220-223 241-243 237-237.5 252-254 230-232 222-222.5 227-229 232-233 243-243.5 258-260
1411
TABLE 1 (continued)
1 3p 3q 3r 3s 3t 3u 3v 3w 4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l 4m 4n 4o 4p 2 C23H12N2O7S C21H13NO6S C22H15NO6S C24H19NO6S C27H17NO6S C27H17NO7S C28H19NO8S C24H13NO7S C18H18N2O3S C20H22N2O3S C21H24N2O3S C21H17BrN2O3S C23H19BrN2O3S C24H21BrN2O3S C24H22BrN3O3S C26H25BrN2O3S C21H17N3O5S C23H19N3O5S C24H21N3O5S C24H22N4O5S C22H18N2O5S C24H20N2O5S C25H22N2O5S C25H23N3O5S 17.87 17.47 16.24 16.63 16.47 16.07 15.82 15.59 16.41 16.06 3.21 3.05 8.38 8.18 7.44 7.56 7.50 7.28 6.11 6.13 6.01 5.80 5.48 5.63 8.38 8.20 5.89 5.63 10.18 9.92 9.66 9.35 9.23 9.07 12.38 11.71 6.69 6.63 6.47 6.25 5.80 6.06 8.83 8.80 3 4 6.04 6.08 5 7.24 6.96 7.99 7.86 7.32 7.61 6.92 7.13 6.56 6.63 6.41 6.42 6.06 (5.86) 7.11 6.98 9.54 9.36 8.49 8.66 8.51 8.34 7.01 (7.26) 6.63 6.63 6.70 6.45 6.38 6.25 6.68 6.45 7.84 7.57 6.96 7.13 6.81 6.92 6.91 6.70 7.71 7.59 7.19 7.15 7.14 6.93 6.96 6.71 6 246-250 232-232.5 251-252 255-258 237-238 215-218 242-243 224-226 175-178 202-209 78-81 214-215 228-230 238-240 206-208 220 (dec.) 225-226 212-213 235-237 240-243 198-199 213-215 228-230 212-213 7 58 90 86 78 85 89 77 71 95 87 82 92 85 87 86 51 71 84 73 76 93 89 88 83
Thus, the condensation of salicylaldehydes with 2-thiazolylacetonitriles provides a preparative method for the synthesis of 3-(2-thiazolyl)coumarins. The presence of the hydroxyl group in the latter makes it possible to obtain their alkyl and acyl derivatives and to realize aminomethylation by the action of formaldehyde aminals.
1412
TABLE 2. The 1H NMR Spectra of Substituted 7-Hydroxy-, 6-Halo-, 6-Nitro-, 7-Methoxy-, and 7-Acyloxycoumarins 1-3
Chemical shifts, , ppm (SSCC, J, Hz) Compound 1 1a Coumarin residue H-4 (1, s) 2 8.85 H-5 (1) 3 7.81 (d, 3J = 8.0) 7.80 (d, J = 8.5)
3
-6 (1) 4 6.64 (dd, 3J = 8.0, 4 J = 2.5) 6.8 (dd, 3J = 8.5, 4 J = 1.5) 6.88 (dd, 3J = 8.5, 4 J = 1.5) 6.89 (dd, 3J = 8.5, 4 J = 1.5)
H-7 / R 5 10.91 (1H, br. s, )
H-8 6 6.83 (d, 4J = 2.5) 6.70 (d, J = 1.5)

4
H-5 of thiazole (1, s) 7 7.36 2.44 (3H, s, CH3)
R2 8
1b
9.00
10.9 (1H, br. s, )
8.24
7.65 (2H, d, 3J = 8.0, H-2,6); 8.20 (2, d, 3J = 8.0, H-3,5) 8.92 (1, br. s, H-2); 8.48 (1H, d, 3J = 8.0, H-4); 7.75 (1H, t, 3J = 8.0, H-5); 8.26 (1H, br. d, 3 J = 8.0, H-6) 7.62 (1H, d, 4J = 1.0, H-2); 6.99 (1H, d, 3J = 8.0, H-5); 7.61 (1H, dd, 3J = 8.0, 4J = 1.0, H-6); 6.07 (2H, s, OCH2O) 7.65 (2H, d, 3J = 8.0, H-2,6); 8.00 (2, d, 3 J = 8.0, H-3,5) 8.92 (1, br. s, H-2); 8.48 (1H, d, 3J = 8.0, H-4); 7.75 (1H, t, 3J = 8.0, H-5); 8.26 (1H, br. d, 3 J = 8.0, H-6) 7.67 (2H, d, 3J = 8.0, H-2,6); 8.03 (2, d, 3 J = 8.0, H-3,5) 8.84 (1, br. s, H-2); 8.49 (1H, d, 3J = 8.0, H-4); 7.78 (1H, t, 3J = 8.0, H-5); 8.22 (1H, br. d, 3 J = 8.0, H-6)
1c
8.99
7.88 (d, 3J = 8.5) 7.82 (d, 3J = 8.5) 8.21 (d, J = 2.0) 8.03 (d, 4J = 2.0)
4
10.80 (1H, br. s, )
6.81 (d, 4J = 1.5) 6.82 (d, 4J = 1.5) 7.4 (d, 3J = 8.5) 7.44 (d, 3J = 8.5) 7.68 (d, 3J = 8.5) 7.69 (d, 3J = 8.5)
8.44
1d
8.99
10.89 (1H, br. s, )
8.03
1e 1f
8.96 9.03
7.80 (1H, dd, 3J = 8.5, 4J = 2.0) 7.81 (1H, dd, 3J = 8.5, 4J = 2.0)
8.21 8.56
1g 1h
9.22 9.28
8.94 (d, 4J = 2.0) 9.05 (d, 4J = 2.0)
8.45 (1H, dd, 3J = 8.5, 4J = 2.0) 8.43 (1H, dd, 3J = 8.5, 4J = 2.0)
8.28 8.64
1413
1414
TABLE 2 (continued)
1 1i 2 9.06 3 8.17 (d, 4J = 1.5) 7.81 (d, 3J = 8.0) 7.95 (d, 3J = 8.5) 7.94 (d, 3J = 8.5) 7.91 (d, 3J = 8.0) 7.67 (d, 3J = 8.0) 7.72 (d, 3J = 8.0) 8.07 (d, 3J = 8.5) 7.72 (d, J = 8.5)
3
5 8.48 (1H, dd, 3J = 8.0, 4J = 1.5)
6 7.51 (d, 3J = 8.0) 7.04 (d, 4J = 2.5) 7.13 (d, 4J = 1.5) 7.06 (d, 4J = 1.5) 7.08 (d, 4J = 1.5) 7.22 (d, 4J = 2.5) 7.36 (d, 4J = 2.5) 7.39 (d, 4J = 1.5) 7.21 (d, J = 1.5)
4
7 8.55
8 8.83 (1, br. s, H-2); 8.64 (1H, d, 3J = 8.0, H-4); 7.71 (1H, t, 3J = 8.0, H-5); 8.24 (1H, br. d, 3 J = 8.0, H-6) 2.47 (3H, s, CH3)
2a
8.85
2b
9.03
2c
9.00
2d
9.00
3a
8.81
3b 3c
8.84 9.08
3d
8.94
3e
9.04
8.07 (d, 3J = 8.5)
6.96 (dd, 3J = 8.0, 4 J = 2.5) 7.07 (dd, 3J = 8.5, 4 J = 1.5) 7.02 (dd, 3J = 8.5, 4 J = 1.5) 7.07 (dd, 3J = 8.0, 4 J = 1.5) 7.31 (dd, 3J = 8.0, 4 J = 2.5) 7.26 (dd, 3J = 8.0, 4 J = 2.5) 7.26 (dd, 3J = 8.5, 4 J = 1.5) 7.26 (dd, 3J = 8.5, 4 J = 1.5) 7.22 (dd, 3J = 8.5, 4 J = 1.5)
3.90 (3H, s, CH3O)
7.22
3.95 (3H, s, CH3O)
8.23
7.68 (2H, d, 3J = 8.0, H-2,6); 8.05 (2, d, 3 J = 8.0, H-3,5) 8.72 (1, br. s, H-2); 8.48 (1H, d, 3J = 8.0, H-4); 7.74 (1H, t, 3J = 8.0, H-5); 8.18 (1H, br. d, 3 J = 8.0, H-6) 7.61 (1H, d, 4J = 1, H-2); 6.97 (1H, d, 3 J = 8.0, H-5); 7.62 (1H, dd, 3J = 8.0, 4 J = 1.0, H-6); 6.07 (2H, s, OCH2O) 2.54 (3H, s, CH3)
3.95 (3H, s, CH3O)
8.48
3.91 (3H, s, CH3O)
8.01
2.36 (3H, s, CH3CO)
7.10
7.45 (1, br. s, H-3); 6.64 (1, m, H-4); 7.73 (1, br. s, H-5) 2.32 (3H, s, CH3CO)
7.11 8.32
2.50 (3H, s, CH3) 7.67 (2H, d, 3J = 8.0, H-2,6); 8.06 (2, d, 3 J = 8.0, H-3,5) 7.58 (2H, d, 3J = 8.0, H-2, H-6); 7.89 (2, d, 3 J = 8.0, H-3,5) 7.66 (2H, d, 3J = 8.0, H-2,6); 8.04 (2, d, 3 J = 8.0, H-3,5)
1.29 (3, t, 3J = 8.0, CH3); 2.63 (2, q, 3J = 8.0, 2) 1.35 (9, s, (CH3)3C)
7.68
7.35 (d, 4J = 1.5)
8.29
TABLE 2 (continued)
1 3f 2 9.19 3 8.14-8.18 (m) 7.81 (d, 3J = 8.5) 8.13 (d, 3J = 8.0) 4 7.45-7.47 (m) 7.29 (dd, 3J = 8.5, 4 J = 1.5) 7.42 (dd, 3J = 8.0, 4 J = 2.0) 7.43 (dd, 3J = 8.0, 4 J = 1.5) 7.56 (dd, 3J = 8.5, 4 J = 2.0) 7.20 (dd, 3J = 8.5, 4 J = 2.0) 7.18 (dd, 3J = 8.5, 4 J = 2.0) 7.43-7.46 (3, m) 7.35 (dd, 3J = 8.5, 4 J = 2.0) 5 2.63 (3H, s, 2-CH3); 7.45-7.47 (2, m, H-3,5); 7.61-7.65 (1, m, H-4); 8.14-8.18 (1, m, H-6) 3.92 (3, s, 4-CH3); 7.03 (2, d, 3 J = 8.0, -3,5); 8.17 (2, d, 3 J = 8.0, -2,6) 3.89 (3H, s, 3-CH3O); 3.87 (3H, s, 4-CH3O); 7.60 (1, d, 4J = 1.5, -2); 7.17 (1, d, 3J = 8.5, -5); 7.81 (1, dd, 3J = 8.5, 4J = 1.5, -6) 7.61 (1, br. s, H-3); 6.85 (1, m, H-4); 8.17 (1, br. s, H-5) 2.32 (3H, s, CH3CO) 6 7.61-7.65 (m) 7 8.42
3
8 7.72 (2H, d, 3J = 8.0, H-2,6); 8.05 (2, d, J = 8.0, H-3,5)
3g
8.99
7.34 (d, 4J = 1.5) 7.58 (d, 4J = 2.0)
7.73
7.59 (2H, d, 3J = 8.0, H-2,6); 7.92 (2, d, 3 J = 8.0, H-3,5) 7.70 (2H, d, 3J = 8.0, H-2,6); 8.07 (2, d, 3 J = 8.0, H-3,5)
3h
9.15
8.39
3i
9.15
8.14 (d, 3J = 9.0) 8.11 (d, 3J = 8.5) 7.80 (d, 3J = 8.5) 8.05 (d, 3J = 8.5) 8.14 (d, 3J = 8.0) 7.90 (d, 3J = 8.5)
7.65 (d, 4J = 1.5) 7.39 (d, 4J = 2.0) 7.26 (d, 4J = 2.0) 7.30 (d, 4J = 2.0) 7.60-7.64 (m) 7.45 (d, 4J = 2.0)
8.32
7.67 (2H, d, 3J = 8.5, H-2,6); 8.06 (2, d, 3 J = 8.5, H-3,5) 8.85 (1, br. s, H-2); 8.51 (1H, d, J = 8.0, H-4); 7.77 (1H, t, 3J = 8.0, H-5); 8.21 (1H, br. d, 3 J = 8.0, H-6) 8.92 (1, br. s, H-2); 8.31 (1H, d, J = 8.0, H-4); 7.64 (1H, t, 3J = 8.0, H-5); 8.23 (1H, br. d, 3 J = 8.0, H-6) 8.77 (1, br. s, H-2); 8.44 (1H, d, 3J = 8.0, H-4); 7.72 (1H, t, 3J = 8.0, H-5); 8.18 (1H, br. d, 3 J = 8.0, H-6) 8.90 (1, br. s, H-2); 8.55 (1H, d, 3J = 8.0, H-4); 7.81 (1H, t, 3J = 8.0, H-5); 8.25 (1H, br. d, 3 J = 8.0, H-6) 8.93 (1, br. s, H-2); 8.38 (1H, d, 3J = 8.0, H-4); 7.68 (1H, t, 3J = 8.0, H-5); 8.24 (1H, br. d, 3 J = 8.0, H-6)
3j
9.12
8.57
3k
9.02
1.31 (3, t, 3J = 8.0, CH3); 2.66 (2, q, 3J = 8.0, 2) 1.35 (9, s, (CH3)3)
7.84
3l
9.01
8.48
3m
9.20
3n
9.08
2.63 (3H, s, 2-CH3); 7.43-7.46 (2, m, -3,5); 7.60-7.64 (1, m, -4); 8.19 (1, d, 3J = 8.0, H-6) 3.93 (3, s, 4-CH3); 7.04 (2, d, 3 J = 8.0, -3,5); 8.18 (2, d, 3 J = 8.0, -2,6)
8.63
7.96
1415
1416
TABLE 2 (continued)
1 3o 2 9.15 3 8.16 (d, 3J = 8.5) 4 7.42 (dd, 3J = 8.5, 4 J = 2.0) 7.44 (dd, 3J = 8.0, 4 J = 1.5) 7.25 (dd, 3J = 8.5, 4 J = 1.5) 7.17 (dd, 3J = 8.5, 4 J = 1.5) 7.23 (dd, 3J = 8.5, 4 J = 1.5) 7.42-7.45 (3, m) 7.28 (dd, 3J = 8.5, 4 J = 1.5) 7.43 (dd, 3J = 8.5, 4 J = 1.5) 7.43 (dd, 3J = 9.5, 4 J = 1.5) 5 3.89 (3H, s, 3-CH3O); 3.87 (3H, s, 4-CH3O); 7.60 (1, d, 4J = 1.5, -2); 7.17 (1, d, 3J = 8.5, -5); 7.81 (1, dd, 3J = 8.5, 4J = 1.5, -6) 7.62 (1, br. s, H-3); 6.86 (1, m, H-4); 8.17 (1, br. s, H-5) 2.32 (3H, s, CH3CO) 6 7.56 (d, 4J = 2.0) 7 8.60 8 8.86 (1, br. s, H-2); 8.52 (1H, d, 3J = 8.0, H-4); 7.79 (1H, t, 3J = 8.0, H-5); 8.23 (1H, br. d, 3 J = 8.0, H-6) 8.90 (1, br. s, H-2); 8.55 (1H, d, 3J = 8.0, H-4); 7.81 (1H, t, 3J = 8.0, H-5); 8.25 (1H, br. d, 3 J = 8.0, H-6) 7.67 (1H, d, 4J = 1.0, H-2); 6.99 (1H, d, 3J = 8.0, H-5); 7.67 (1H, dd, 3J = 8.0, 4J = 1.0, H-6); 6.09 (2H, s, OCH2O) 7.51 (1H, d, 4J = 1.0, H-2); 6.90 (1H, d, 3J = 8.0, H-5); 7.45 (1H, dd, 3J = 8.0, 4J = 1.0, H-6); 6.09 (2H, s, OCH2O) 7.66 (1H, d, 4J = 1.0, H-2); 7.01 (1H, d, 3J = 8.0, H-5); 7.65 (1H, dd, 3J = 8.0, 4J = 1.0, H-6); 6.09 (2H, s, OCH2O) 7.67 (1H, d, 4J = 1.0, H-2); 7.04 (1H, d, 3J = 8.0, H-5); 7.65 (1H, dd, 3J = 8.0, 4J = 1.0, H-6); 6.09 (2H, s, OCH2O) 7.54 (1H, d, 4J = 1.0, H-2); 6.90 (1H, d, 3J = 8.0, H-5); 7.54 (1H, dd, 3J = 8.0, 4J = 1.0, H-6); 6.09 (2H, s, OCH2O) 7.69 (1H, d, 4J = 1.0, H-2); 7.05 (1H, d, 3J = 8.0, H-5); 7.68 (1H, dd, 3J = 8.0, 4J = 1.0, H-6); 6.10 (2H, s, OCH2O) 7.62 (1H, d, 4J = 1.0, H-2); 6.99 (1H, d, 3J = 8.0, H-5); 7.61 (1H, dd, 3J = 8.0, 4J = 1.0, H-6); 6.09 (2H, s, OCH2O)
3p
9.19
8.19 (d, J = 8.0)

3
7.69 (d, J = 1.5)

4
8.59
3q
9.07
8.05 (d, 3J = 8.5) 7.77 (d, 3J = 8.5) 8.08 (d, 3J = 8.5) 8.13 (2, br. d, H-2) 7.76 (d, 3J = 8.5) 8.13 (d, 3J = 8.5)
7.37 (d, 4J = 1.5) 7.24 (d, 4J = 1.5) 7.39 (d, 4J = 1.5) 7.60-7.67 (m) 7.34 (d, 4J = 1.5) 7.61 (d, 4J = 1.5)
8.10
3r
8.95
1.30 (3, t, 3J = 8.0, CH3); 2.65 (2, q, 3J = 8.0, 2) 1.34 (9, s, (CH3)3)
7.58
3s
9.08
8.14
3t
9.15
3u
8.97
3v
9.17
3w
9.17
8.13 (d, 3J = 9.5)
2.62 (3H, s, 2-CH3); 7.42-7.45 (2, m, -3,5); 7.60-7.67 (1, m, -4); 8.13 (1, br. d, 3J = 8.0, H-6) 3.93 (3, s, 4-CH3O); 7.02 (2, d, 3 J = 8.0, -3,5); 8.17 (2, d, 3 J = 8.0, -2,6) 3.89 (3H, s, CH3O); 3.87 (3H, s, CH3O); 7.60 (1H, d, 4J = 1.5, H-2); 7.18 (1H, d, 3J = 8.0, H-5); 7.83 (1H, dd, 3J = 8.0, 4J = 1.0, H-6) 7.62 (1, br. s, H-3); 6.85 (1, m, H-4); 8.17 (1, br. s, H-5)
8.17
7.55
8.20
7.65 (d, 4J = 1.5)
8.20
TABLE 3. The 1H NMR Spectra of Mannich Bases 4a-p and Hydrochlorides 5a-k
Chemical shifts, , ppm (SSCC, J, Hz)* -5 of thiazole X (1, s) 6 7 7.01 7.00 6.97 8.12 8.14 8.21 7.38 8.19 8.39 8.35 8.42 8.39 7.97 2.52 (3, s, CH3) 2.51 (3, s, CH3) 2.49 (3, s, CH3) 7.68 (2H, d, 3J = 8.0, H-2,6); 8.05 (2, d, 3J = 8.0, H-3,5) 7.67 (2H, d, 3J = 8.0, H-2,6); 8.03 (2, d, 3J = 8.0, H-3,5) 7.66 (2H, d, 3J = 8.0, H-2,6); 8.05 (2, d, 3J = 8.0, H-3,5) 7.50 (2H, d, 3J = 8.0, H-2,6); 7.84 (2, d, 3J = 8.0, H-3,5) 7.65 (2H, d, 3J = 8.0, H-2,6); 8.04 (2, d, 3J = 8.0, H-3,5) 8.86 (1, br. s, H-2); 8.52 (1H, d, J = 8.0, H-4); 7.79 (1H, t, J = 8.0, H-5); 8.23 (1H, br. d, J = 8.0, H-6) 8.86 (1, br. s, H-2); 8.52 (1H, d, 3J = 8.0, H-4); 7.79 (1H, t, 3J = 8.0, H-5); 8.23 (1H, br. d, 3J = 8.0, H-6) 8.83 (1, br. s, H-2); 8.51 (1H, d, 3J = 8.0, H-4); 7.77 (1H, t, 3J = 8.0, H-5); 8.21 (1H, br. d, 3J = 8.0, H-6) 8.80 (1, br. s, H-2); 8.48 (1H, d, 3J = 8.0, H-4); 7.73 (1H, t, 3J = 8.0, H-5); 8.17 (1H, br. d, 3J = 8.0, H-6) 7.63 (1H, d, 4J = 1.0, H-2); 7.00 (1H, d, 3J = 8.0, H-5); 7.62 (1H, dd, 3J = 8.0, 4J = 1.0, H-6); 6.07 (2H, s, OCH2O)
Compound 1 4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l 4m
-4 (1H, s) 2 8.73 8.72 8.69 8.92 8.88 8.94 8.80 8.92 8.92 8.87 8.95 8.92 8.92
-5*2 3 6.80 7.44 7.37 7.71 7.67 7.74 7.48 7.67 7.74 7.68 7.67 7.77 7.71
-6*2 4 7.44 6.79 6.79 6.67 6.64 6.74 6.81 6.65 6.68 6.63 6.73 6.79 6.71
Coumarin residue 8-2 (2H, s) 5 4.23 4.08 4.20 4.07 4.19 4.05 4.07 4.25 4.07 4.20 4.06 3.98 4.05
R2 8
1.92 (4, m, 22); 2.77 (4, m, 22N) 1.7 (3, m, 3); 2.29 (5, m, CH2CH2); 3.03 (4, m, 22N) 0.93 (5H, m, 3, 4-2); 1.65 (6-, m, 32); 2.9 (3, m, H2NCH) 2.53 (6, s, 2CH3) 1.88 (4, m, 22); 2.92 (4, m, 22N) 1.55 (6, m, 32); 2.71 (4, m, 22N) 2.31 (3, s, 3); 2.71 (8, m, 42) 1.09 (6, m, 23); 1.66 (6H, m, 32); 2.80 (2, m, 2N) 2.50 (6, s, 2CH3) 1.88 (4, m, 22); 2.92 (4, m, 22N) 1.57 (6, m, 32); 2.74 (4, m, 22N) 2.20 (3, s, 3); 2.65 (8, m, 42) 2.50 (6, s, CH3)
1417
1418
TABLE 3 (continued)
1 4n 4o 4p 5a 5b 5c 5d 5e 5f 5g 5h 5i 5j 5k 2 8.90 8.94 8.95 8.99 9.04 9.02 9.08 9.04 9.01 9.02 9.03 9.05 9.01 9.04 3 7.62 7.73 7.78 7.95 7.99 7.98 8.03 8.00 7.79 8.01 7.97 7.97 7.97 7.79 4 6.66 6.75 6.73 7.31 7.28 7.30 7.29 7.28 7.27 7.67 7.29 7.27 7.29 7.26 5 4.19 4.05 3.99 4.40 4.50 4.36 4.42 4.47 4.30 4.50 4.41 4.20 4.38 4.2 6 1.86 (4, m, 22); 2.90 (4, m, 22N) 1.56 (6, m, 32); 2.70 (4, m, 22N) 2.18 (3, s, 3); 2.64 (8, m, 42) 2.83 (6, s, CH3) 1.99 (4, m, 22); 3.44 (4, m, 22N) 1.81 (6, m, 32); 3.38 (4, m, 22N) 2.35 (6, s, CH3) 1.99 (4, m, 22); 3.40 (4, m, 22N) 1.83 (6, m, 32); 3.39 (4, m, 22N) 2.83 (3, s, 3); 3.66 (8, m, 42) 2.82 (6, s, CH3) 2.0 (4, m, 22); 3.36 (4, m, 22N) 1.84 (6, m, 32); 3.82 (4, m, 22N) 2.82 (3, s, 3); 3.64 (8, m, 42) 7 7.95 7.99 8.02 8.25 8.31 8.28 8.54 8.50 8.48 8.49 8.07 8.10 8.07 8.10
4
8 7.63 (1H, d, J = 1.0, H-2); 7.00 (1H, d, 3J = 8.0, H-5); 7.63 (1H, dd, 3J = 8.0, 4J = 1.0, H-6); 6.07 (2H, s, OCH2O) 7.63 (1H, d, 4J = 1.0, H-2); 7.00 (1H, d, 3J = 8.0, H-5); 7.63 (1H, dd, 3J = 8.0, 4J = 1.0, H-6); 6.08 (2H, s, OCH2O) 7.62 (1H, d, 4J = 1.0, H-2); 7.00 (1H, d, 3J = 8.0, H-5); 7.61 (1H, dd, 3J = 8.0, 4J = 1.0, H-6); 6.08 (2H, s, OCH2O) 7.65 (2H, d, 3J = 8.0, H-2,6); 8.03 (2, d, 3J = 8.0, H-3,5) 7.69 (2H, d, 3J = 8.0, H-2,6); 8.07 (2, d, 3J = 8.0, H-3,5) 7.67 (2H, d, 3J = 8.0, H-2,6); 8.06 (2, d, 3J = 8.0, H-3,5) 8.87 (1, br. s, H-2); 8.55 (1H, d, 3J = 8.0, H-4); 7.79 (1H, t, 3J = 8.0, H-5); 8.23 (1H, br. d, 3J = 8.0, H-6) 8.85 (1, br. s, H-2); 8.51 (1H, d, J = 8.0, H-4); 7.77 (1H, t, J = 8.0, H-5); 8.22 (1H, br. d, J = 8.0, H-6) 8.81 (1, br. s, H-2); 8.50 (1H, d, J = 8.0, H-4); 7.76 (1H, t, J = 8.0, H-5); 8.18 (1H, br. d, J = 8.0, H-6) 8.83 (1, br. s, H-2); 8.51 (1H, d, J = 8.0, H-4); 7.77 (1H, t, J = 8.0, H-5); 8.20 (1H, br. d, J = 8.0, H-6) 7.64 (1H, d, 4J = 1.0, H-2); 7.00 (1H, d, 3J = 8.0, H-5); 7.64 (1H, dd, 3J = 8.0, 4J = 1.0, H-6); 6.08 (2H, s, OCH2O) 7.66 (1H, d, 4J = 1.0, H-2); 7.02 (1H, d, 3J = 8.0, H-5); 7.67 (1H, dd, 3J = 8.0, 4J = 1.0, H-6); 6.07 (2H, s, OCH2O) 7.64 (1H, d, 4J = 1.0, H-2); 7.00 (1H, d, 3J = 8.0, H-5); 7.64 (1H, dd, 3J = 8.0, 4J = 1.0, H-6); 6.07 (2H, s, OCH2O) 7.66 (1H, d, 4J = 1.0, H-2); 7.01 (1H, d, 3J = 8.0, H-5); 7.66 (1H, dd, 3J = 8.0, 4J = 1.0, H-6); 6.07 (2H, s, OCH2O)
_______ * It was not possible to determine the position of the signals for the 7-OH groups on account of their strong broadening. *2 1H, d, 3J = 9.0-9.5 Hz.
EXPERIMENTAL The reactions and the purity of the obtained compounds were monitored by TLC on Silufol UV-254 plates with 9:1 and 19:1 chloroformmethanol as eluents. The 1H NMR spectra were measured on Bruker WP 100SY and Varian Mercury 400 instruments (100 and 400 MHz respectively) in DMSO-d6 with TMS as internal standard. 6- or 7-R1-Substituted 3-(4-R2-2-thiazolyl)coumarins 1a-i. In the smallest amount of ethanol or 2-propanol at 50-60C we dissolved the substituted salicylaldehyde (100 mmol) and the respective 2-thiazolylacetonitrile (0.1 mol). (During the synthesis of compounds 1e-i a suspension of the indicated amounts of the reagents in 50 ml of alcohol was prepared.) To the solution we added piperidine (3-5 drops). The reaction mixture was kept at room temperature for 24 h. The precipitated 2-iminocoumarin was filtered off, washed with alcohol, and hydrolyzed by boiling with a 3% aqueous solution of sulfuric acid (50 ml) for 6-48 h. The coumarin that formed was filtered off, washed with water, dried, and crystallized from DMF. 7-Methoxy-3-(4-R2-2-thiazolyl)coumarins 2a-d. To a suspension of the coumarin 1a-d (2.5 mmol) and freshly calcined potassium carbonate (1 g) in acetone (40 ml) we added dimethyl sulfate (3 mmol). The mixture was boiled with stirring for 1 h 30 min to 2 h 30 min. The reaction mass was then poured into water (100 ml), and the precipitated product 2a-d was filtered off, washed with water, dried, and crystallized from DMF. 7-Acyloxy-3-(4-R2-2-thiazolyl)coumarins 3a-w. To a solution or suspension of the 7-hydroxycoumarin 1a-d (2.5 mmol) in pyridine (5 ml) we added the acid anhydride or chloride (5.0 mmol). The mixture was kept at room temperature for 24 h. The precipitated product 3a-w was filtered off, washed with 2-propanol, dried, and crystallized from DMF. 8-Aminomethyl-7-hydroxy-3-(4-R2-2-thiazolyl)coumarins 4a-p. A mixture of the coumarin 1a-d (2.5 mmol) and the respective formaldehyde aminal (3 mmol) was boiled in absolute dioxane (25 ml) until a transparent solution had formed. The reaction mixture was cooled, and the separated crystals of the product 4a-p were filtered off and crystallized from DMF. The Hydrochlorides of the Mannich Bases 4a-p (5a-k). A solution of the aminomethyl derivative of coumarin 4a-p (0.2 g) in the smallest amount of chloroform was saturated with hydrogen chloride and kept at room temperature for 20-30 min. The crystals that separated were filtered off and washed with chloroform. Compound 5b. Found, %: Cl 12.61. C23H21BrCl2N2O3S. Calculated, %: Cl 12.75. Compound 5c. Found, %: Cl 12.17. C24H23BrCl2N2O3S. Calculated, %: Cl 12.43. Compound 5d. Found, %: Cl 14.09. C21H19Cl2N3O5S. Calculated, %: Cl 14.27. Compound 5e. Found, %: Cl 13.32. C23H21Cl2N3O5S. Calculated, %: Cl 13.57. Compound 5f. Found, %: Cl 13.02. C24H23Cl2N3O5S. Calculated, %: Cl 13.22. Compound 5g. Found, %: Cl 12.99. C24H24Cl2N4O5S. Calculated, %: Cl 12.86. Compound 5h. Found, %: Cl 14.31. C21H20Cl2N2O5S. Calculated, %: Cl 14.31. Compound 5i. Found, %: Cl 13.87. C24H22Cl2N2O5S. Calculated, %: Cl 13.60. Compound 5j. Found, %: Cl 13.09. C25H24Cl2N2O5S. Calculated, %: Cl 13.24. Compound 5k. Found, %: Cl 12.73. C25H25Cl2N3O5S. Calculated, %: Cl 12.88.
REFERENCES 1. 2. 3. 4. O. V. Khilya, M. S Frasinyuk, A. V. Turov, and V. P. Khilya, Khim. Geterotsikl. Soedin., 1120 (2001). K. Kuriyama, Y. Hiyama, and Y. Ito, Jpn. J. Pharmacol., 50, 111 (1989). D. Chiarino, G. C. Grancini, V. Frigeni, and A. Carenzi, Eur. Patent Appl. EP 284017; Chem. Abstr., 110, 114824 (1989). I. A. Zhuravel', S. N. Kovalenko, V. M. Markova, E. N. Kvach, and A. O. Prokhnyak, in: Republican Scientific Conference. 1991. Abstracts [in Russian], Kharkov (1991), p. 126. 1419
5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
16. 17.
K. M. Lyakin, T. V. Smirnova, G. M. Vishnyakova, E. G. Lobanova, N. V. Novikova, and V. I. Sklyarenko, Khim.-Farm. Zh., 10, 1212 (1989). S. S. Anufric, V. V. Tarkovskii, and V. M. Nikitchenko, Appl. Spectrosc., 66, 772 (1999). A. A. Karasev, L. L. Lukatskaya, M. I. Rubtsov, Z. A. Sizova, and A. O. Doroshenko, Vestn. Khar'kovskogo Un-ta, 454, 146 (1999). O. V. Silin, Authors' Abstract of Thesis for Candidate of Chemical Sciences, Kharkov (1998). Ya. V. Belokon', S N. Kovalenko, A. V. Silin, and V. M. Nikitchenko, Khim. Geterotsikl. Soedin., 1345 (1997). P. Czekney and H. Hartman, J. Prakt. Chem., 325, 551 (1983). C. Vamvacaris, M. Patsch, and W. Mach, Ger. Offen. 2807761; Chem. Abs., 92, 41931 (1979). P. Czekney and H. Hartman, J. Prakt. Chem., 324, 21 (1982). H. Takeshi, O. Yoshyuki, N. Nishizono, O. Kazuaki, and M. Mashida, Chem. Pharm. Bull., 48, 1702 (2000). A. V. Silin, and V. M. Nikitchenko, Vestn. Khar'kovskogo Un-ta, 395, 257 (1997). M. Orita, S. Yamamoto, N. Katayama, M. Aoki, K. Takayama, Y. Yamagiva, N. Seki, H. Suzuki, H. Kurihara, H. Sakashita, M. Takeuchi, S. Fujita, T. Yamada, and A. Tanaka, J. Med. Chem., 44, 540 (2001). M. H. Khan and S. Giri, Indian J. Chem., 32B, 984 (1993). J. N. Cadre and S. Raote Prasad, Indian J. Chem., 32B, 1285 (1993).
1420
REACTIONS OF 4-CYANOBENZO[c]PYRYLIUM SALTS WITH NITROGENCONTAINING NUCLEOPHILES

S. L. Bogza1, S. Yu. Suikov2, N. M. Bogdan2, Yu. A. Nikolyukin2, and V. I. Dulenko2 The recyclization reactions of 4-cyanobenzo[c]pyrylium salts with ammonia, primary amines,and hydrazines have been studied. New derivatives of isoquinoline, benzo-2,3-diazepine, and pyrazolo[5,4-c]isoquinoline have been obtained. Keywords: benzo-2,3-diazepine, benzo[c]pyrylium, pyrazolo[5,4-c]isoquinoline, recyclization. Conversions of 4-acetyl- and 4-ethoxycarbonylbenzo[c]pyrylium salts have been described in [1-3]. While continuing the investigation of the reactivity of benzo[c]pyrylium cation involving electron-withdrawing substituents, we studied the recyclization of 4-cyanobenzo[c]pyrylium perchlorates [4] under the action of nitrogen-containing nucleophiles. The presence of the nitrile group, as well as other withdrawing substituents [5], in the pyrylium nucleus enables its conversion under mild conditions. 1,3-Dialkyl- (1a-c) and 4-cyano-1-methyl-3-phenylbenzo[c]pyrylium (1d) perchlorates, like 4-acetyl- and 4-ethoxycarbonyl derivatives, are converted into 4-cyanoisoquinolines 2a-d at room temperature in aqueous alcoholic ammonia solution.
CN O + O 1ad O _ R2 ClO4 2ad R1 NH3 O O R2 N CN R1
1, 2 a R1 = R2 = Me, b R1 = Me, R2 = Et; c R1 = Me, R2 = Pr; d R1 = Ph, R2 = Me
Salts 1a and 1d were used to study the reaction with other nitrogen-containing nucleophiles. Compounds 1a and 1d were isolated in preparatively acceptable yields on acylation of the appropriate -keto nitriles. The yields of perchlorates 1b,c with ethyl and propyl substituents in position 1 were low as a result of the formation of side products, viz. 4(3H)-oxo-1,3-oxazinium perchlorates [4]. Reactions of perchlorates 1a and 1d with ptoluidine, primary aliphatic amines, hydrazine hydrate, and phenylhydrazine have been investigated. On interacting equimolar amounts of salt 1a and primary amine or hydrazine in 2-propanol at 20-40C 2-R-4-cyanoisoquinolinium perchlorates 3a-e were formed in high yields. __________________________________________________________________________________________ Moscow A. N. Kosygin State Textile University, Moscow 117983, Russia; e-mail: serge_zh@yahoo.com. 2 L. M. Litvinenko Institute of Physical Organic and Coal Chemistry, National Academy of Sciences of Ukraine, Donetsk 83114, Ukraine. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1645-1651, November, 2004. Original article submitted March 5, 2002. 0009-3122/04/4011-14212004 Springer Science+Business Media, Inc. 1421
1
CN O 1a 1 mol/l RNH2 O 3ae +N Me Me R
_ ClO4
3 a R = p-Tol, b R = CH2Ph, c R = furfuryl, d R = NH2, e R = NHPh
Heating salt 1a with fivefold amount of p-toluidine was also completed by the formation of compound 3a, which was not subjected to further conversions in the presence of highly basic amines (benzylamine, butylamine). This may be caused by the redistribution of electron density of the isoquinolinium cation involving the -electron sextet of the N-aryl substituent. On using an excess of benzylamine the recyclization of the pyran ring of salt 1a into pyridinium cation is accompanied by substitution of the 6-methoxy group by residue of amine and 2-benzyl-6-benzylamino-4-cyano-7-methoxy-1,3-dimethylisoquinolinium perchlorate (4) is formed. Compound 4 was also obtained on treating 2-benzyl-4-cyanoisoquinolinium salt 3b with an excess of benzylamine, which enables compound 3b to be considered as an intermediate in the conversion of 1 4. The IR and 1H NMR spectra of isoquinolinium salt 4 and the data of elemental analysis correspond to the proposed structure. In the known recyclization of 4-ethoxycarbonylbenzo[c]pyrylium derivatives with primary amines the 2-R-4-ethoxycarbonylisoquinolinium cation is also an intermediate in one of the conversions, however the reaction products are derivatives of 1-naphthylamine [3]. When heating salt 1a or perchlorates 3d,e with excess of hydrazine or phenylhydrazine the compounds are formed, the spectral and analytical characteristics of which correspond to benzo-2,3-diazepine derivatives 5a,b. Absorption bands are present in the IR spectrum of 5-cyano-7,8-dimethoxy-1,4-dimethylbenzo-2,3(3H)diazepine (5a) for the nitrile group (2200), for C=C and C=N bonds of seven-membered ring (1640, 1610, 1585), and there is also an absorption band at 3250 cm-1, that corresponds to the vibrations of an NH bond.
H N 3b PhCH2NH2 Ph O 4 1a NC 3d,e RNHNH2 O O Me 5a,b 5 a R = H, b R = Ph N R N Me +N Me CN Me Ph
_ ClO4
In the 1H NMR spectrum recorded in DMSO-d6 solution there were singlets for two methyl and for two methoxy groups and two signals for the aromatic protons of the benzene nucleus. The singlet with chemical shift of 6.02 ppm and integral intensity 1H belongs to the H-3 proton of the diazepine ring. On heating a solution of sample from 18 to 40C a drift of the proton signal occurs from 6.02 to 5.9 ppm, which in view of the presence in the IR spectrum of an absorption band for the NH bond, confirms the attachment of the proton to the 1422
nitrogen atom at position 3 and the character of the disposition of the bonds in the seven-membered ring. A strong low field shift is observed of the singlet for the H-6 proton (8.92 ppm) in the spectrum of diazepine 5b. This effect is caused most of all by the reduction in the distance between the H-6 proton and the nitrile group due to distortion of the diazepine ring geometry as a result of the introduction of a bulky phenyl substituent into it.
CN O 1d PhCH2NH2 O HN 6 H2NNH2 Ph CN H2NHN + O 7 N Ph O N NH N 8 Me Ph Ph
+
O
NH2 _ Me ClO4
Ph O O N Ac2O / HClO4 NH NH2
TABLE 1. Physicochemical Characteristics of Compounds 2-8

Compound 1 2a 2b 2c 2d 3a 3b 3c 3d 3e Empirical formula 2 C14H14N2O2 C15H16N2O2 C16H18N2O2 C19H16N2O2 C19H21ClN2O6 C21H21ClN2O6 C19H19ClN2O7 C14H16ClN3O6 C20H20ClN3O6 Found, % Calculated, % H N 4 5 5.9 5.8 6.4 6.2 6.5 6.7 5.2 5.3 5.1 5.2 5.0 4.9 4.4 4.5 4.3 4.5 4.5 4.6 11.5 11.6 11.2 11.0 10.5 10.4 9.5 9.4 6.9 6.8 6.7 6.5 6.6 6.5 11.9 11.7 9.9 9.7 Yield, % 8 65 63 60 65 86 80 69 87 77
mp, Cl 6 7 243-244 223-224 194-195 214-216 8.6 8.7 8.1 8.2 8.0 8.2 10.1 9.9 6.8 7.0 219-221 (dec.) 220-222 (dec.) 198-200 (dec.) 283-285 (dec.) 241-243 (dec.)
C 3 69.7 69.4 70.0 70.3 71.3 71.1 75.1 75.0 55.6 55.8 58.2 58.3 53.9 54.0 46.8 47.0 55.2 55.4
1423
TABLE 1 (continued)
1 4 5a 5b 6 7 8 2 C27H26ClN3O5 C14H15N4O2 C20H19N3O2 C26H22N2O2 C18H18ClN5O5 C19H17N3O2 3 63.7 63.8 65.6 65.3 72.0 72.0 79.0 79.1 51.9 51.5 71.5 71.5 4 5.1 5.1 5.9 5.9 5.6 5.7 5.5 5.6 4.2 4.3 5.6 5.3 5 8.5 8.3 16.3 16.3 12.7 12.6 7.3 7.1 16.9 16.7 13.3 13.2 6 6.9 7.0 7 237-238 (dec.) 203-204 179-180 157-158 8.9 8.5 267-269 272-273 8 74 73 66 65 35 40
On replacing the methyl group at position 3 of the 4-cyanobenzo[c]pyrylium cation by phenyl substituent the direction of the reaction is changed. Interaction of perchlorate 1d with benzylamine leads to 1-benzylamino-4-cyano-6,7-dimethoxy-3-phenylnaphthalene (6) irrespective of the reactant ratio. 2-Amino-4-cyano-6-hydrazino-7-methoxy-1-methyl-3-phenylisoquinolinium perchlorate (7) and 7,8-dimethoxy-5-methyl-1-phenylpyrazolo[3,4-c]isoquinoline (8) were isolated on heating salt 1d with hydrazine hydrate at a ratio of 1:10. The structure of pyrazoloisoquinoline (8) was also confirmed by an alternate synthesis, by the acylation of 5-amino-4-(3,4-dimethoxyphenyl)-3-phenylpyrazole [6] in acetic anhydride in the presence of perchloric acid. Probably, on interaction of salt 1d with hydrazine under conditions of excess of reactant, the coordinated effect of the substituents on the electron sheath of the benzo[c]pyrylium cation makes possibility of the equally probable attack of hydrazine molecule at atoms C(1) and C(6). This determines the further course of the reaction and the structure of the final products. The practically equal yields of compounds 7 and 8 are indirect confirmation of the reliability of this hypothesis. We discovered an analogous result, caused by the close reactivity of the C(1) and C(6) atoms, in the case of the interaction of 1,3-dialkyl-4-ethoxycarbonylbenzo[c]pyrylium perchlorates with benzylamine [3]. The reactions of 4-cyanobenzo[c]pyrylium salts studied show that the introduction of cyano group, as well as other electron-withdrawing substituents, into the benzo[c]pyrylium cation facilitates its recyclization and broadens the possibilities of converting it.

Compound 1 2a 2b IR spectrum, , cm-1 2 2220, 1615 2220, 1620
1
NMR spectrum, , ppm (J, Hz)* 3
2c
2220, 1615
2d 3a
2220, 1610 2220, 1620, 1100
2.57 (3, s, 3); 2.73 (3, s, 3); 3.67 (3, s, 3); 3.80 (3, s, 3); 7.07 (1, s, arom.); 7.17 (1, s, arom.) 1.07 (3, t, 3); 2.50 (3, s, 3); 3.03 (3, q, 2); 3.67 (3, s, 3); 3.77 (3, s, 3); 7.07 (1, s, arom.); 7.15 (1, s, arom.) 0.60 (3, t, 3); 1.50 (2, m, 2); 2.50 (3, s, 3); 2.97 (2, t, 2); 3.63 (3, s, 3); 3.73 (3, s, 3); 7.07 (1, s, arom.); 7.15 (1, s, arom.); 7.05 (1, s, arom.); 7.17 (1, s, arom.) 2.83 (3, s, 3); 3.90 (3, s, 3); 3.97 (3, s, 3); 7.16-7.85 (7, m, arom.) 2.47 (3, s, 3); 3.13 (3, s, 3); 3.45 (3, s, 3); 3.98 (3, s, 3); 4.15 (3, s, 3); 7.53-7.75 (3, m, arom.); 7.85 (1, s, arom.); 8.08 (2, d, arom.)
1424
TABLE 2 (continued)
1 3b 2 2225, 1620, 1100 2225, 1625, 1100 3 3.10 (3, s, 3); 3.27 (3, s, 3); 4.20 (3, s, 3); 4.30 (3, s, 3); 6.03 (2, s, 2); 7.10-7.55 (5, m, arom.); 7.67 (1, s, arom.); 7.83 (1, s, arom.) 2.57 (3, s, 3); 2.72 (3, s, 3); 3.85 (3, s, 3); 3.90 (3, s, 3); 4.06 (2, s, 2 Fur); 6.07 (1, s, arom. Fur); 6.55 (1, s, arom. Fur); 6.68 (1, s, arom. Fur); 7.09 (1, s, arom.); 8.01 (1, s, arom.) 2.90 (3, s, 3); 3.13 (3, s, 3); 3.96 (3, s, 3); 4.03 (3, s, 3); 7.23 (1, s, arom.); 7.67 (1, s, arom.) 2.56 (3, s, 3); 3.14 (3, s, 3); 4.07 (3, s, 3); 4.09 (3, s, 3); 6.58 (2, d, arom.); 6.99 (1, t, arom.); 7.12 (1, s, arom.); 7.32 (2, t, arom.); 7.82 (1, s, arom.); 11.72 (1, br. s, NH) 2.83 (3, s, 3); 2.95 (3, s, 3); 3.97 (6, s, 23); 4.55 (2, s, 2); 5.63 (2, s, 2); 6.60 (1, s, arom.); 6.77-7.27 (11, m, arom.) 1.57 (3, s, 3); 1.88 (3, s, 3); 3.73 (3, s, 3); 3.76 (3, s, 3); 6.02 (1, br. s, N); 6.69 (1, s, arom.); 6.91 (1, s, arom.) 1.93 (3, s, 3); 3.78 (3, s, 3); 3.82 (3, s, 3); 6.84 (1, s, arom.); 7.05-7.20 (1, t, J = 7.5, arom.); 7.43 (2, t, J = 7.5, arom.); 7.73 (2, d, J = 7.5, arom.); 8.92 (1, s, arom.) 3.54 (3, s, 3); 3.61 (3, s, 3); 4.00 (2, d, 2, J = 6.2); 6.52-6.67 (3, m, arom.); 7.04-7.32 (10, m, arom.); 10.50 (1, t, J = 6.2, NH) 3.17 (3, s, 3); 4.10 (3, s, 3); 7.43-7.87 (7, m, arom.) 3.23 (3, s, 3); 3.80 (3, s, 3); 4.07 (3, s, 3); 7.67 (7, s, arom.)
3c
3d
3e
3370, 3300, 2230, 1635, 1100 3250, 2220, 1630, 1100
3320, 2230, 1605, 1100 3250, 2200, 1640 2200, 1640
5a
5b
3400, 2200
7 8
3200, 2225, 1640, 1610, 1100 1620
_______ * The 1H NMR spectra were taken in CF3COOH (for compounds 2a-d, 3a,b,d, 4, 7, and 8) and in DMSO-d6 (for compounds 3c,e, 5a,b, and 6).
EXPERIMENTAL The IR spectra were recorded in nujol on a UR 20 spectrophotometer, and the 1H NMR spectra were taken on a Varian Gemini 200 (200 MHz) spectrometer, internal standard was TMS. The physicochemical and spectral characteristics of the compounds synthesized are given in Tables 1 and 2. 4-Cyano-6,7-dimethoxyisoquinolines 2a-d. Perchlorate 1 (5 mmol) was added in one portion to mixture of aqueous 25% ammonia solution (5 ml) and 2-propanol (8 ml). The reaction mixture was stirred for 1-2 h, isoquinoline 2 was filtered off, washed with water, and crystallized from alcohol. 1,3-Dialkyl-4-cyano-6,7-dimethoxy-2-R-isoquinolinium Perchlorates 3a-e. Perchlorate 1 (5 mmol) was added to solution of primary amine or hydrazine (5.5 mmol) in 2-propanol (10 ml) and the mixture stirred at 20-40C until complete dissolution. After 4-6 h solid isoquinoline perchlorate 3 was filtered off, washed with alcohol, and with ether, and dried. 2-Benzyl-6-benzylamino-4-cyano-7-methoxy-1,3-dimethylisoquinolinium Perchlorate (4). A. Mixture of perchlorate 1 (5 mmol) and benzylamine (25 mmol) was boiled in ethanol for 6 h, then left overnight. The precipitated solid was filtered off, and crystallized from ethanol. 1425
B. Mixture of isoquinolinium perchlorate 3b (5 mmol) and benzylamine (25 mmol) was boiled in ethanol for 6 h. The reaction mixture was treated as in method A. 1-Benzylamino-4-cyano-6,7-dimethoxy-3-phenylnaphthalene (6) was obtained by the recyclization of perchlorate 1d under the conditions described for compound 4. 5-Cyano-7,8-dimethoxy-1,4-dimethyl-3-R-benzo-2,3(3H)-diazepines (5a,b). Perchlorate 1a or isoquinolinium perchlorates 3d,e were heated with fivefold quantity of appropriate hydrazine in ethanol for 5-6 h and left overnight. The reaction mixture was poured into water, the precipitate was filtered off, washed with water, dried, and crystallized from xylene. 7,8-Dimethoxy-5-methyl-1-phenylpyrazolo[3,4-c]isoquinoline (8) and 2-Amino-4-cyano-6hydrazino-7-methoxy-1-methyl-3-phenylisoquinolinium Perchlorate (7). Mixture of perchlorate 1d (3 mmol) and hydrazine hydrate (30 mmol) in acetonitrile was boiled for 2 h and cooled. The precipitated solid pyrazoloisoquinoline 8 was filtered off, dried, and crystallized from m-xylene. The filtrate was poured into ether (50 ml), and the precipitated oil triturated with water. Perchlorate 7 was filtered off, washed with water, and dried, then crystallized from ethanol.
REFERENCES 1. 2. 3. 4. 5. 6. S. L. Bogza and Yu. A. Nikolyukin, Khim. Geterotsikl. Soedin., 1475 (1993). S. L. Bogza, Yu. A. Nikolyukin, and V. I. Dulenko, Khim. Geterotsikl. Soedin., 1290 (1994). S. L. Bogza, Yu. A. Nikolyukin, M. Yu. Zubritskii, and V. I. Dulenko, Khim. Geterotsikl. Soedin., 317 (1995). S. L. Bogza, Yu. A. Nikolyukin, and V. I. Dulenko, Khim. Geterotsikl. Soedin., 465 (1990). E. V. Kuznetsov, I. V. Shcherbakova, and A. T. Balaban, Adv. Heterocycl. Chem., 50, 158 (1988). Yu. A. Nikolyukin, L. V. Dulenko, and V. I. Dulenko, Khim. Geterotsikl. Soedin., 1092 (1990).
1426
CONCERNING THE PRODUCT OF [2 + 2] CYCLODIMERIZATION OF 9-ALLENYLCARBAZOLE

O. I. Kharaneko1, S. V. Shishkina2, O. V. Shishkin2, A. V. Kibalnyi1, and V. I. Dulenko1 The isomerization of 9-propargylcarbazole in alcoholic alkali leads to the product of dimerization of 9-allenylcarbazole, 1,2-bis(9-carbazolylmethylene)cyclobutane, the structure of which was established by X-ray diffraction analysis. Keywords: allenylcarbazole, 1,2-bis(9-carbazolylmethylene)cyclobutane, cyclodimerization. We have synthesized 9-propargylcarbazole 1 with the aim of studying its properties and application in synthesis of acetylene derivatives of carbazole. This was achieved by the action of propargyl bromide on carbazolylsodium, prepared in 80% yield by heating metallic sodium and carbazole in dioxane. This compound was obtained previously by the action of propargyl bromide on the sodium derivative of carbazole in liquid ammonia [1,2], in DMF [3], or in acetonitrile [4]. The patented procedure [5] differed in the use of potassium derivative of carbazole.
1. Na 2. BrCH2C N H Dioxane CH N 1 H
Both on carrying out the synthesis and on studying the Favorsky rearrangement of 9-propargylcarbazole 1 (heating in alcoholic alkali) we noted the formation of a difficultly soluble product, which became predominant on boiling compound 1 in alcoholic KOH solution for 8 h. The formation of difficultly soluble solid on rearranging compound 1 has been observed previously. For example, the authors of [1], while studying the isomerization of N-propargyl-substituted heterocycles, assumed it to be a polymer. We have established that under the conditions indicated above the main product of isomerization of carbazole 1 is an individual compound having the same elemental composition as the initial carbazole 1. The structures of the isomeric 9-allenylcarbazole 2 and 9-propynylcarbazole 3 are excluded according to the spectral characteristics, by the __________________________________________________________________________________________ L. M. Litvinenko Institute of Physical Organic and Coal Chemistry, National Academy of Sciences of Ukraine, 70 R. Luxemburg St, Donetsk 83114, Ukraine; e-mail: kibalny@infou.donetsk.ua. 2 Department of Alkali Halide Crystals STC, Institute for Single Crystals, National Academy of Sciences of Ukraine, 60 Lenina Ave, Kharkov 61001, Ukraine; e-mail: shishkin@xray.isc.kharkov.com. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1652-1661, November, 2004. Original article submitted April 13, 2001. 0009-3122/04/4011-14272004 Springer Science+Business Media, Inc. 1427
1
lack of carbonyl group absorption band, and also of allenic and acetylenic bonds (at 1950-1980 and 2100-2200 cm-1) and by the presence in the 1H NMR spectrum of a complete set of signals for the aromatic protons of carbazole nucleus substituted at position 9.
_ OH 1 N N OH _
Dimer 4 3
The compound obtained is neither an oxidation product of propargylcarbazole 1, nor the hydrolysis product of allene 2, nor the cyclization product of the latter into a derivative of pyrrolocarbazole, which might have been expected on the basis of the results of [6]. The molecular weight measured by the Rast method, proving to be double the molecular weight of the initial compound 1, enabled the dimeric structure to be proposed, i.e. bis(9-carbazolylmethylene)cyclobutane (4), the product of [2 + 2] cyclodimerization of 9-allenylcarbazole 2. The significant predominance of allene 2 in the equilibrium mixture compared with the other isomers 1 and 3, recorded by the authors of [1] on carrying out the isomerization using alkaline catalysts, also points in favor of allene dimer. According to the data of the same authors, this special feature is probably most widely expressed among carbazole derivatives. On isomerizing propargylcarbazole under certain other conditions (potassium hydroxide in DMSO at room temperature) used by the authors of [3,7], 9-allenylcarbazole 2 was isolated in almost quantitative yield. We have shown that in the simpler and more convenient way dimer 4 may be obtained from the available [8] epoxypropylcarbazole 5, as shown in the Scheme.
_ SOCl2 N N Cl OH
Cl
The dimerization of allenes [8] may lead to 1,2- and 1,3-disubstituted derivatives of cyclobutane, and on the basis of the data obtained it is not possible to make an unequivocal choice between the structures of 1,2- and 1,3-bis(9-carbazolylmethylene)cyclobutane (4a and 4b respectively). We therefore carried out an X-ray diffraction investigation of the dimerization product 4, showing unequivocally that the obtained dimer corresponds to structure 4a (Fig. 1, Tables 1-3).
N
N
4a
4b
1428
Fig. 1. Structure of 1,2-bis(9-carbazolylmethylene)cyclobutane 4a molecule.
TABLE 1. Coordinates (104) and Equivalent Isotropic Thermal Parameters (103) of the Non-hydrogen Atoms in the Structure of Compound 4a
Atom 1 N(1A) N(2A) C(1A) C(2A) C(3A) C(4A) C(5A) C(6A) C(7A) C(8A) C(9A) C(10A) C(11A) C(12A) C(13A) C(14A) C(15A) C(16A) C(17A) C(18A) C(19A) C(20A) C(21A) C(22A) C(23A) C(24A) x 2 6189(7) 6316(7) 7760(9) 8749(9) 10327(10) 11011(10) 10005(10) 8438(10) 7153(9) 7005(10) 5602(11) 4294(10) 4405(9) 5794(10) 5171(8) 4883(8) 4068(9) 4669(9) 5336(8) 5936(8) 5285(10) 3762(10) 3017(9) 3846(10) 5355(10) 6140(9) 3 3687(2) 4418(2) 3805(3) 3595(3) 3768(3) 4138(3) 4339(3) 4176(3) 4278(3) 4599(3) 4598(3) 4284(3) 3961(3) 3961(3) 3325(2) 3272(2) 2835(3) 3072(2) 3525(2) 3976(3) 4642(3) 4497(3) 4800(3) 5218(3) 5355(3) 5063(2) y 4 9927(5) 12725(6) 10852(8) 12177(7) 12885(7) 12277(9) 10955(9) 10223(7) 8810(7) 7662(8) 6447(7) 6327(7) 7430(7) 8650(7) 10146(7) 11310(6) 11721(7) 13224(7) 12706(6) 13342(6) 11373(8) 10422(7) 9201(7) 8931(7) 9900(7) 11153(7) z Ueq, 2 5 40(1) 39(1) 39(2) 44(2) 60(2) 67(2) 58(2) 44(2) 49(2) 56(2) 61(2) 65(2) 52(2) 42(2) 46(2) 43(2) 58(2) 55(2) 40(2) 48(2) 41(2) 45(2) 53(2) 57(2) 52(2) 42(2)
1429
TABLE 1 (continued)
1 C(25A) C(26A) C(27A) C(28A) C(29A) C(30A) N(1B) N(2B) C(1B) C(2B) C(3B) C(4B) C(5B) C(6B) C(7B) C(8B) C(9B) C(10B) C(11B) C(12B) C(13B) C(14B) C(15B) C(16B) C(17B) C(18B) C(19B) C(20B) C(21B) C(22B) C(23B) C(24B) C(25B) C(26B) C(27B) C(28B) C(29B) C(30B) 2 7637(10) 8972(9) 10253(11) 10239(10) 8982(10) 7683(9) 8176(7) 8080(6) 8564(9) 9974(10) 10034(10) 8718(13) 7307(10) 7211(9) 5961(10) 4364(10) 3392(9) 4052(10) 5613(10) 6591(10) 9235(7) 9489(7) 10365(9) 9761(9) 9055(8) 8460(8) 6688(10) 5366(9) 4090(10) 4086(11) 5405(11) 6712(9) 8216(9) 9014(11) 10547(13) 11397(9) 10620(10) 9090(10) 3 5119(3) 5468(3) 5415(3) 5021(3) 4668(3) 4724(2) 2540(2) 1833(2) 2265(2) 2256(3) 1942(3) 1633(3) 1644(3) 1965(3) 2066(3) 1900(3) 2114(3) 2483(3) 2655(3) 2426(2) 2908(2) 2967(2) 3416(3) 3184(3) 2719(2) 2274(2) 1536(3) 1605(3) 1257(3) 863(3) 795(3) 1126(2) 1167(3) 877(3) 1010(3) 1437(3) 1736(3) 1609(3) 4 12417(7) 12819(7) 14141(9) 15083(8) 14672(8) 13367(7) 9548(6) 6736(5) 10826(6) 12073(8) 13180(7) 13036(8) 11803(8) 10666(7) 9249(8) 8540(8) 7204(8) 6605(8) 7264(7) 8595(7) 9364(6) 8191(6) 7825(7) 6287(7) 6793(6) 6130(6) 6086(8) 4760(8) 4394(8) 5310(9) 6604(9) 7014(7) 8266(7) 9514(8) 10487(9) 10262(7) 9045(7) 8066(7) 5 46(2) 55(2) 70(3) 71(2) 55(2) 38(2) 41(2) 39(1) 42(2) 53(2) 60(2) 67(2) 58(2) 42(2) 45(2) 55(2) 65(2) 60(2) 51(2) 37(2) 40(2) 41(2) 58(2) 59(2) 44(2) 44(2) 47(2) 51(2) 70(2) 72(2) 61(2) 42(2) 43(2) 56(2) 67(3) 57(2) 45(2) 40(2)
This variant of the dimerization of 9-allenylcarbazole 2 is effected in our opinion as a result of the association of the heterocyclic fragments in solution with the formation of eximers (resonance interaction). There are two molecules (A and B) in the symmetrically independent part of the unit cell. The molecule of compound 4a has a conformation in which the two -electron systems are disposed practically parallel one above the other (the angle between them is 12.9 in molecule A and 12.4 in molecule B). The conjugated cyclic systems are not entirely planar, the angle between the planes of the benzene rings is 4.2 and 5.1 in A and 5.1 and 3.6 in B. The cyclobutane ring is bent somewhat along the C(15)C(17) bond (the angle between the planes of C(14), C(15), C(17) and C(15), C(16), C(17) is 6.7 in conformer A and 7.3 in conformer B). The exocyclic double bonds C(13)C(14) and C(18)C(17) are twisted somewhat relative to one another [torsion angle C(13) C(14)C(17)C(18) is 19(2) in A and -16(2) in B]. The conjugation between the tricyclic
1430
fragments and the double bonds is disturbed to a significant extent as a result of their noncoplanarity [torsion angle C(1)N(1)C(13)C(14) is 48.1(9) in A, 139.9(7) in B and C(19)N(2)C(18)C(17) is 47.0(9) in A, 136.3(7) in B]. Such a conformation of the molecule is probably caused by significant steric stress as shown by shortened intramolecular contacts for H(2A)C(14A) at 2.84 (sum of van der Waals radii 2.87 [11]), H(2A)C(17A) 2.82 (2.87), H(11A)C(13A) 2.84 (2.87), H(20A)C(14A) 2.75 (2.87), H(20A)C(17A) 2.81 (2.87), C(20A)C(12A) 3.38 (3.42), C(20A)C(13A) 3.32 (3.42), C(20A)C(14A) 3.31 (3.42), C(20A)C(17A) 3.31 (3.42), N(2A)C(1A) 3.17 (3.21), C(19A)N(1A) 3.15 (3.21), C(19A)C(1A) 3.30 (3.42), C(21A)C(11A) 3.39 (3.42), C(18A)C(2A) 3.38 (3.42), H(11B)C(14B) 2.85 (2.87), H(11B)C(17B) 2.82 (2.87), H(29B)C(14B) 2.77 (2.87), H(29B)C(17B) 2.82 (2.87 ).
TABLE 2. Bond Lengths (l) in the Structure of Compound 4a

Bond N(1A)C(1A) N(1A)C(12A) N(2A)C(18A) C(1A)C(2A) C(2A)C(3A) C(4A)C(5A) C(6A)C(7A) C(7A)C(12A) C(9A)C(10A) C(11A)C(12A) C(14A)C(17A) C(15A)C(16A) C(17A)C(18A) C(19A)C(24A) C(21A)C(22A) C(23A)C(24A) C(25A)C(30A) C(26A)C(27A) C(28A)C(29A) N(1B)C(12B) N(1B)C(13B) N(2B)C(18B) C(1B)C(2B) C(2B)C(3B) C(4B)C(5B) C(6B)C(7B) C(7B)C(12B) C(9B)C(10B) C(11B)C(12B) C(14B)C(17B) C(15B)C(16B) C(17B)C(18B) C(19B)C(24B) C(21B)C(22B) C(23B)C(24B) C(25B)C(26B) C(26B) C(27B) C(28B)C(29B) l, 1.367(8) 1.396(8) 1.411(8) 1.384(9) 1.371(9) 1.38(1) 1.449(9) 1.42(1) 1.39(1) 1.348(8) 1.469(8) 1.530(8) 1.325(8) 1.402(9) 1.401(9) 1.396(9) 1.396(9) 1.369(9) 1.37(1) 1.381(8) 1.413(8) 1.403(8) 1.373(8) 1.38(1) 1.365(9) 1.439(9) 1.398(9) 1.39(1) 1.405(9) 1.466(8) 1.557(9) 1.320(8) 1.414(9) 1.38(1) 1.37(1) 1.393(9) 1.36(1) 1.379(9) Bond N(1A)C(13A) N(2A)C(30A) N(2A)C(19A) C(1A)C(6A) C(3A)C(4A) C(5A)C(6A) C(7A)C(8A) C(8A)C(9A) C(10A)C(11A) C(13A)C(14A) C(14A)C(15A) C(16A)C(17A) C(19A)C(20A) C(20A)C(21A) C(22A)C(23A) C(24A)C(25A) C(25A)C(26A) C(27A)C(28A) C(29A)C(30A) N(1B)C(1B) N(2B)C(19B) N(2B)C(30B) C(1B)C(6B) C(3B)C(4B) C(5B)C(6B) C(7B)C(8B) C(8B)C(9B) C(10B)C(11B) C(13B)C(14B) C(14B)C(15B) C(16B)C(17B) C(19B)C(20B) C(20B)C(21B) C(22B)C(23B) C(24B)C(25B) C(25B)C(30B) C(27B)C(28B) C(29B)C(30B) l, 1.390(8) 1.374(8) 1.426(8) 1.427(9) 1.41(1) 1.357(9) 1.398(9) 1.352(9) 1.373(9) 1.336(8) 1.495(8) 1.507(8) 1.359(8) 1.385(9) 1.351(9) 1.432(8) 1.42(1) 1.40(1) 1.365(9) 1.399(8) 1.377(9) 1.407(8) 1.39(1) 1.38(1) 1.403(9) 1.380(9) 1.39(1) 1.353(9) 1.329(8) 1.532(8) 1.544(9) 1.392(9) 1.38(1) 1.37(1) 1.426(8) 1.443(9) 1.41(1) 1.361(9)
1431
This leads to a lengthening of bonds N(1)C(13) 1.390(8) (A), 1.413(8) (B), and N(2)C(18) 1.411(8) (A), 1.403(68) (B) compared with the mean value of 1.355 [10]. Such a sterically stressed conformation of the molecule is probably stabilized to a significant degree by fairly strong stacking interactions between the -systems of the tricyclic fragments. Their close-to-parallel orientation and the distances between the fragment atoms being in the range 3.15 to 3.8 indicates this. The compound 4a molecules in the crystal form mutually perpendicular stacks along the crystallographic directions (1 0 0) and (0 0 1). The angle between the planes of the tricyclic fragments of neighboring molecules (0.7) and the distance between the spatially adjacent -systems (3.55 ) suggests the presence of intermolecular stacking interactions also. Shortened intermolecular contacts were detected in the crystal between molecules located in the independent part of the unit cell, H(13A)C(12B) 2.83 (x, y, z) and H(13B)C(1A) 2.85 (x, y, z). The presence in the crystal structure of compound 4a of intra- and intermolecular stacking interactions creates conditions for carrying out various topochemical reactions, which may lead to both intra- and intermolecular cyclization involving the tricyclic fragments.
TABLE 3. Bond Angles () in the Structure of Compound 4a

Angle 1 C(1A)N(1A)C(13A) C(13A)N(1A)C(12A) C(30A)N(2A)C(19A) N(1A)C(1A)C(2A) C(2A)C(1A)C(6A) C(2A)C(3A) C(4A) C(6A)C(5A)C(4A) C(5A)C(6A)C(7A) C(8A)C(7A)C(12A) C(12A)C(7A)C(6A) C(8A)C(9A)C(10A) C(12A)C(11A)C(10A) C(11A)C(12A) C(7A) C(14A)C(13A)N(1A) C(13A)C(14A)C(15A) C(14A)C(15A)C(16A) C(18A)C(17A)C(14A) C(14A)C(17A)C(16A) C(20A)C(19A)C(24A) C(24A)C(19A)N(2A) C(20A)C(21A)C(22A) C(22A)C(23A)C(24A) C(23A)C(24A)C(25A) C(30A)C(25A)C(26A) C(26A)C(25A)C(24A) C(26A)C(27A)C(28A) C(30A)C(29A)C(28A) C(29A)C(30A)C(25A) C(12B)N(1B)C(1B) C(1B)N(1B)C(13B) C(19B)N(2B)C(30B) C(2B)C(1B)C(6B) , deg. 2 126.7(5) 124.5(6) 108.7(6) 130.3(7) 119.0(7) 122.2(7) 122(1) 134.7(8) 118.0(7) 107.3(6) 120.7(6) 118.9(7) 121.6(6) 127.4(6) 129.5(6) 89.1(5) 139.0(6) 91.0(5) 123.6(7) 107.0(6) 120.9(7) 120.0(7) 134.4(7) 119.1(7) 133.4(7) 120.4(7) 119.2(7) 121.5(7) 109.4(6) 123.3(6) 109.2(7) 121.4(6) Angle 3 C(1A)N(1A)C(12A) C(30A)N(2A)C(18A) C(18A)N(2A)C(19A) N(1A)C(1A)C(6A) C(3A)C(2A)C(1A) C(5A)C(4A)C(3A) C(5A)C(6A)C(1A) C(1A)C(6A)C(7A) C(8A)C(7A)C(6A) C(9A)C(8A)C(7A) C(11A)C(10A)C(9A) C(11A)C(12A)N(1A) N(1A)C(12A)C(7A) C(13A)C(14A)C(17A) C(17A)C(14A)C(15A) C(17A)C(16A)C(15A) C(18A)C(17A)C(16A) C(17A)C(18A)N(2A) C(20A)C(19A)N(2A) C(19A)C(20A)C(21A) C(23A)C(22A)C(21A) C(23A)C(24A)C(19A) C(19A)C(24A)C(25A) C(30A)C(25A)C(24A) C(27A)C(26A)C(25A) C(29A)C(28A)C(27A) C(29A)C(30A)N(2A) N(2A)C(30A)C(25A) C(12B)N(1B)C(13B) C(19B)N(2B)C(18B) C(18B)N(2B)C(30B) C(2B)C(1B)N(1B) , deg. 4 108.6(6) 125.7(6) 125.4(6) 110.5(6) 119.2(8) 117.4(8) 120.1(7) 105.1(6) 134.7(8) 119.8(7) 120.9(7) 129.9(7) 108.4(6) 138.8(6) 91.2(5) 88.4(5) 129.8(5) 127.2(5) 129.5(7) 117.0(7) 120.7(6) 117.7(7) 107.6(6) 107.5(6) 118.9(7) 120.7(7) 129.5(7) 108.9(6) 127.1(5) 125.1(6) 125.7(6) 130.5(7)
1432
TABLE 3 (continued)
1 C(6B)C(1B)N(1B) C(2B)C(3B)C(4B) C(4B)C(5B)C(6B) C(1B)C(6B)C(7B) C(8B)C(7B)C(12B) C(12B)C(7B)C(6B) C(8B)C(9B)C(10B) C(10B)C(11B)C(12B) N(1B)C(12B)C(11B) C(14B)C(13B)N(1B) C(13B)C(14B)C(15B) C(14B)C(15B)C(16B) C(18B)C(17B)C(14B) C(14B)C(17B)C(16B) N(2B)C(19B)C(20B) C(20B)C(19B)C(24B) C(20B)C(21B)C(22B) C(24B)C(23B)C(22B) C(23B)C(24B)C(25B) C(26B)C(25B)C(24B) C(24B)C(25B)C(30B) C(26B)C(27B)C(28B) C(30B)C(29B)C(28B) C(29B)C(30B)C(25B) 2 108.0(6) 121.1(7) 119.4(7) 107.0(6) 119.8(7) 107.5(6) 119.7(7) 116.4(8) 129.7(7) 125.9(5) 128.0(6) 88.1(5) 139.7(6) 91.0(5) 129.3(7) 121.2(7) 122.0(7) 120.1(8) 133.8(7) 135.7(7) 107.4(6) 121.8(7) 120.3(8) 121.9(6) 3 C(1B)C(2B)C(3B) C(5B)C(4B)C(3B) C(1B)C(6B)C(5B) C(5B)C(6B)C(7B) C(8B)C(7B)C(6B) C(7B)C(8B)C(9B) C(11B)C(10B)C(9B) N(1B)C(12B)C(7B) C(7B)C(12B)C(11B) C(13B)C(14B)C(17B) C(17B)C(14B)C(15B) C(17B)C(16B)C(15B) C(18B)C(17B) C(16B) C(17B)C(18B)N(2B) N(2B)C(19B)C(24B) C(21B)C(20B)C(19B) C(23B)C(22B)C(21B) C(23B)C(24B)C(19B) C(19B)C(24B)C(25B) C(26B)C(25B)C(30B) C(27B)C(26B)C(25B) C(29B)C(28B)C(27B) C(29B)C(30B)N(2B) N(2B)C(30B)C(25B) 4 118.6(7) 120.6(7) 119.0(7) 134.0(7) 132.5(7) 118.7(8) 123.3(7) 108.0(6) 121.9(7) 139.8(6) 92.1(5) 88.3(5) 129.0(5) 126.1(5) 109.5(6) 117.1(7) 120.2(7) 119.3(7) 106.9(6) 116.8(7) 120.7(8) 118.5(8) 131.2(7) 106.9(6)
EXPERIMENTAL The 1H NMR spectra were recorded on a Gemini 200 (200 MHz) instrument, internal standard was TMS. The IR spectra were taken on a Specord IR 75 instrument in KBr disks. The numbering of the carbon atoms in the compound 4a molecule is given in Fig. 1. X-Ray Diffraction Investigation of Compound 4a. The crystals of compound 4a are monoclinic, C30H22N2, at 20C: a = 9.036(2), b = 25,645(7), c = 10.291(2) ; = 115.10(2); V = 2159.5(9) 3; Mr = 410.50; Z = 4; space group P21; dcalc = 1.263 g/cm3; (MoK) = 0.074 mm-1; F(000) = 864. The parameters of the unit cell and the intensities of 4034 reflections (3795 independent, Rint = 0.04) were measured on a Siemens automatic P3/PC four-circle diffractometer (MoK, graphite monochromator, 2/ scanning, 2max = 50). The structure was solved by the direct method with the SHELX97 [12] set of programs. The positions of the hydrogen atoms were clarified by an electron density difference synthesis and refined with a rider model with Uiso = 1.2 Ueq. The structure was refined according to F2 by a full-matrix least-squares method with an anisotropic approach for the nonhydrogen atoms to wR2 = 0.134 for 3795 reflections (R1 = 0.049 for 1998 reflections with F > 4(F), S = 0.894). The final coordinates of atoms are given in Table 1, and values of bond lengths and bond angles in Tables 2 and 3. 9-Propargylcarbazole (1). Mixture of carbazole (16.7 g, 0.1 mol) and metallic sodium (2.3 g, 0.1 mol) in anhydrous dioxane (50 ml) was boiled with stirring until complete dissolution of sodium. Propargyl bromide (46.7 g, 0.4 mol) was added with stirring to the boiling mixture. At the end of the intense exothermic reaction the mixture was boiled for a further 15 min, and poured into cold water (500 ml). The separated oil was removed, washed several times with warm water, and left for ~16 h at room temperature. The separated crystals 1433
were filtered off, washed with water, dried, and recrystallized from cyclohexane. Yield 16.4 g (80%); mp 101-102C. After recrystallization from methanol the compound had mp 106-107C (mp 108C [1]). 9-(2,3-Dichloro-1-propyl)carbazole (6). Mixture of 9-epoxypropylcarbazole 5 (22.3 g, 0.1 mol), benzene (50 ml), DMF (0.5 ml), and SOCl2 (12 ml) was heated under reflux on a water bath. After the exothermic reaction had passed the solvent was distilled off, and the residue was recrystallized from cyclohexane. Yield 25 g (90%); mp 90-92C. 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 4.0 (2H, d, J ~ 3.9, N-CH2); 4.6-4.9 (3H, m, CH and CH2); 7.2 (2H, t, J ~ 7.9, H-2,7); 7.4 (2H, t, J ~ 8.0, H-3,6); 7.6 (2H, d, J ~ 7.9, H-1,8); 8.1 (2H, d, J ~ 8.0, H-4,5). Found, %: C 64.5; H 4.9; Cl 25.6; N 5.2. C15H13Cl2N. Calculated, %: C 64.77; H 4.71; Cl 25.49; N 5.04. 1,2-Bis(9-carbazolylmethylene)cyclobutane (4a). A. Mixture of 9-propargylcarbazole 1 (1.93 g, 0.01 mol), ethanol (5 ml), and KOH (0.1 g) was boiled in nitrogen atmosphere for 8 h. The precipitated solid was filtered off, washed with acetone, and with water, dried in the air, and crystallized from pyridine. Yield 1.5 g (78%) of pale yellow prisms; mp 224-225C. IR spectrum (KBr), , cm-1: 3040, 2960, 2910, 1640, 1620, 1590, 1450, 740, 715. 1H NMR spectrum (Py-d5), , ppm (J, Hz): 2.85 (4H, s, 2H-15, 2H-16); 6.54 (2H, s, H-13,18); 6.85 (4H, t, J ~ 7.5, H-3,10,21,28); 6.9 (4H, d, J ~ 8.1, H-2,11,20,29); 7.1 (4H, t, J ~ 7.5, H-4,9,22,27); 7.35 (4H, d, J ~ 7.8, H-5,8,23,26). Found, %: C 87.6; H 5.5; N 6.9. C30H22N2. Calculated, %: C 87.77, H 5.40; N 6.82. B. Mixture of compound 6 (27.8 g, 0.1 mol) and KOH (22.4 g, 0.4 mol) in 2-propanol (50 ml) was boiled with stirring for 24 h. After cooling, the solid was filtered off, washed with acetone, and with water, dried, and crystallized from pyridine. Product 4a was obtained (9.4 g, 46%); mp 224-225C. A mixing test with a sample obtained by method A gave no depression of melting point.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. A. J. Hubert and H. Reimlinger, J. Chem. Soc. C, 606 (1968). J-.L. Dumont, Compt. Rend., 261, 1710 (1965). J-.L. Dumont, W. Chodkievicz, and P. Cadiot, Bull. Soc. Chim. Fr., 1197 (1967). S. M. Fomin, A. N. Flerova, G. N. Gerasimov, and E. N. Teleshov, USSR Inventor's Certificate 1384578; Byull. Izobret., No. 12, 78 (1988). K. C. Yee, US Patent 4125534; Chem. Abstr., 90, 88046 (1979). J. Reisch and R. Salchi-Artimani, Monatsh. Chem., 116, 1099 (1985). G. Broggini, L. Bruche, and G. Zecchi, J. Chem. Soc., Perkin Trans. 1, 533 (1990). I. P. Zherebtsov, N. M. Rovkina, V. P. Lopatinskii, and T. P. Katerinich, USSR Inventor's Certificate 486014; Byull. Izobret., No. 36, 62 (1975). H. F. Schuster and G. M. Coppola, in Allenes in Organic Synthesis, Wiley, New York (1984), p. 317. H-.B. Burgi and J. D. Dunitz, in Structure Correlation, Vol. 2, VCH, Weinheim (1994), p. 741. Yu. V. Zefirov and Yu. V. Zorkii, Usp. Khim., 58, 713 (1989). G. M. Sheldrick, SHELX97. PC Version. A System of Computer Programs for Crystal Structure Solution and Refinement, Rev. 2 (1998).
1434
NEW DERIVATIVES OF 3-AMINOINDOLE. SYNTHESIS OF 2-ARYL(HETARYL)3-(3,5-DIMETHYL-1-PYRAZOLYL)INDOLES

N. M. Przheval'skii, N. S. Skvortsova, and I. V. Magedov The interaction of arylhydrazines with -(3,5-dimethyl-1-pyrazolyl)acetophenones and acetyl(2thiophene) leads to arylhydrazones, which are converted by Fischer cyclization into 2-aryl(thienyl)-3(3,3-dimethyl-1-pyrazolyl)indoles with substituents in positions 1, 5, and 7. Keywords: arylhydrazines, arylhydrazones, pyrazolylindoles. In a continuation of investigations on the synthesis of 3-aminoindole derivatives [1, 2] we have developed a method for obtaining new systems containing pyrazole nucleus in position 3 (for a preliminary communication see [3]). These compounds are promising from the point of view of biological activity, since indoles and pyrazoles are widely known in this field [4]. Boiling a mixture of a small excess of arylhydrazines 1 with ketones 2 in ethanol in the presence of catalytic quantities of AcOH leads to arylhydrazones 3, which were converted without isolation into indoles 4 by heating in ethanol with three moles of thionyl chloride (Fischer indolization). Ketones 2 were synthesized by the alkylation of 3,5-dimethylpyrazole with -haloacetophenones and -chloro-2-acetylthiophene by the procedure of [5] (Table 1).
Me Me N Ar 2ac Me Me N + NH4 R 4ao
2a, 4a-d Ar = Ph, 2b, 4e-i Ar = p-chlorophenyl, 2c, 4j-o Ar = 2-thienyl; 4 a,e,j R = H, b,f,k R = 5-Me, c,h,l R = Cl, d,m R = 5-F, g R = 5-Br, i,n R = 5-OMe, o R = 7-Me, a-h, j-o R1 = H, i R1 = CH2Ph
Me N H
R 1
N R1
NH2
+
O
+ R N R1 3 N Ar
N N Me
N Ar . HCl
N R1
__________________________________________________________________________________________ Moscow K. A. Timiryazev Agricultural Academy, Moscow 127550, Russia; e-mail: ibs@ibisc.msk.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1662-1669, November, 2004. Original article submitted July 5, 2002; revision submitted October 10, 2002. 0009-3122/04/4011-14352004 Springer Science+Business Media, Inc. 1435
1436
TABLE 1. Physicochemical and Spectral Characteristics of Compounds 2a-c

Found, % Calculated, % C 52.50 52.90 47.42 47.37 43.92 43.86 H 5.07 5.12 4.31 4.28 4.33 4.35 N 9.41 9.49 8.29 8.50 9.18 9.30
1
Compound*
Empirical formula
mp, (i-PrOH)
NMR spectrum, , ppm (J, Hz) Pyrazole ring 6.01 (1H, s, H-4); 2.33 (3H, s, CH3-3); 2.15 (3H, s, CH3-5) 6.28 (1H, s, H-4); 2.35 (3H, s, CH3-3); 2.31 (3H, s, CH3-5) 6.27 (1H, s, H-4); 2.37 (3H, s, CH3-3); 2.31 (3H, s, CH3-5) CH2 (2H, s) 5.76
Ar 8.05 (2H, d, J = 8.3, H-2,6); 7.72 (1H, t, J = 7.2, J = 1.3, H-4); 7.59 (2H, t, J = 8.3, J = 7.2, H-3,5) 8.18 (2H, d, J = 8.8, H-2,6); 7.72 (2H, d, J = 8.8, H-3,5) 8.25 (1H, d, J = 3.8, H-3); 8.21 (1H, d, J = 4.9, H-5); 7.38 (1H, m, H-4)
Yield, %
2a
C13H14N2OHBr C13H13ClN2OHBr C11H12N2OSHBr
162-163
61
2b 2c
193-194 212-213
6.13 6.04
60 54
_______ * (3,5-Dimethyl-1H-1-pyrazolyl)methyl phenyl ketone hydrobromide (2a), (3,5-dimethyl-1H-1-pyrazolyl)methyl 4-chlorophenyl ketone hydrobromide (2b), (3,5-dimethyl-1H-1-pyrazolyl)methyl 2-thienyl ketone hydrobromide (2c).
TABLE 2. 1H NMR Spectral Characteristics of Compounds 4a-o

Compound 1 4a 4b 4c 4d 4e Chemical shifts, , ppm. (J, Hz)* R1 4 11.91 (1H, br. s) 11.80 (1H, br. s) 12.68 (1H, br. s) 10.17 (1H, br. s) 12.35 (1H, br. s)
Indole ring 2 7.51 (1H, s, H-7); 7.23 (1H, m, H-6); 7.16 (1H, m, H-4); 7.08 (1H, m, H-5) 7.44 (1H, m, H-7); 7.07 (1H, d, J = 8.3, H-6); 7.00 (1H, s, H-4) 7.68 (1H, d, J = 8.3, H-7); 7.28 (1H, s, H-4); 7.26 (1H, d, J = 8.3, H-6) 7.44 (1H, m, H-7); 7.00 (1H, td, JH-H = 8.3, JH-F = 9.4, H-6); 6.88 (1H, dd, JH-F = 9.4, H-4) 7.61 (1H, d, J = 7.7, H-4); 7.28 (1H, m, H-5); 7.26 (1H, d, J = 7.7, H-7); 7.14 (1H, t, J = 7.7, H-6) 7.47 (1H, m, H-7); 7.03 (1H, d, J = 8.2, H-6); 6.10 (1H, s, H-4) 7.47 (1H, d, J = 8.8, H-7); 7.34 (1H, d, J = 8.8, H-6); 7.24 (1H, s, H-4) 7.57 (1H, d, J = 8.8, H-7); 7.23 (1H, d, J = 8.8, H-6); 7.10 (1H, s, H-4)
Ar 3
R 5 2.28 (3H, s, CH3)
Pyrazole ring 6 6.18 (1H, s, H-4); 2.26 (3H, s, CH3-3); 1.86 (3H, s, CH3-5) 6.14 (1H, s, H-4); 2.38 (3H, s, CH3-3); 1.91 (3H, s, CH3-5) 6.31 (1H, s, H-4); 2.36 (3H, s, CH3-3); 1.96 (3H, s, CH3-5) 6.07 (1H, s, H-4); 2.25 (3H, s, CH3-3); 1.87 (3H, s, CH3-5) 6.29 (1H, s, H-4); 2.33 (3H, s, CH3-3); 1.98 (3H, s, CH3-5) 6.22 (1H, s, H-4); 2.31 (3H, s, CH3-3); 1.95 (3H, s, CH3-5) 6.10 (1H, s, H-4); 2.23 (3H, s, CH3-3); 1.83 (3H, s, CH3-5) 6.10 (1H, s, H-4); 2.23 (3H, s, CH3-3); 1.83 (3H, s, CH3-5)
7.40-7.30 (5H, m, Harom) 7.42-7.39 (5H, m, Harom) 7.49-7.40 (5H, m, Harom) 7.32 (2H, d, J = 8.7, H-2,6); 7.20 (3H, m, H-3,4,5.) 7.49 (2H, d, J = 8.8, H-2,6); 7.46 (2H, d, J = 8.8, H-3,5) 7.47 (2H, m, H-2,6); 7.41 (2H, d, J = 8.8, H-3,5) 7.48 (2H, d, J = 8.8, H-2,6); 7.26 (2H, d, J = 8.8, H-3,5) 7.48 (2H, d, J = 8.8, H-2,6); 7.27 (2H, d, J = 8.8, H-3,5)
4f 4g 4h
12.00 (1H, br. s) 12.10 (1H, br. s) 12.08 (1H, br. s)
2.38 (3H, s, CH3)
1437
1438
TABLE 2 (continued)
1 4i 2 7.43 (1H, d, J = 8.3, H-7); 6.86 (1H, m, H-6); 6.60 (1H, s, H-4) 7.26 (1H, m, H-7); 7.12-7.00 (3H, m, H-4,5,6) 3 7.43 (2H, d, J = 8.8, H-2,6); 7.27 (2H, d, J = 8.8, H-3,5) 4 7.25-7.21 (3H, m, H-3,4,5); 6.90 (2H, m, H-2,6); 5.45 (2H, s, CH2) 10.09 (1H, br. s) 5 3.70 (3H, s, OCH3) 6 5.93 (1H, s, H-4); 2.16 (3H, s, CH3-3); 1.79 (3H, s, CH3-5) 6.10 (1H, s, H-4); 2.32 (3H, s, CH3-3); 2.04 (3H, s, CH3-5) 6.14 (1H, s, H-4); 2.22 (3H, s, CH3-3); 1.90 (3H, s, CH3-5) 6.17 (1H, s, H-4); 2.23 (3H, s, CH3-3); 1.91 (3H, s, CH3-5)
4j
4k
4l
4m
4n
4o
7.05 (1H, d, J = 4.4, H-5); 6.63 (1H, d, J = 3.3, H-3); 6.55 (1H, m, H-4) 7.35 (1H, m, H-7); 7.02 (1H, d, J = 8.3, H-6); 7.53 (1H, d, J = 4.9, H-5); 7.32 (1H, m, H-3); 7.10 (1H, t, 6.85 (1H, s, H-4) J = 4.9, J = 3.9, H-4) 7.48 (1H, d, J = 8.3, H-7); 7.21 (1H, d, J = 8.3, 7.59 (1H, d, J = 3.9, H-5); H-6); 7.04 (1H, s, H-4) 7.38 (1H, d, J = 3.3, H-3); 7.13 (1H, t, J = 3.9, J = 3.3, H-4) 7.64 (1H, d, J = 4.9, H-5); 7.56 (1H, m, H-7); 7.00 (1H, td, JH-H = 8.3, 7.54 (1H, d, J = 3.9, H-3); JH-F = 9.4, H-6); 6.88 (1H, d. d, JH-F = 9.4, H-4) 7.16 (1H, t, J = 4.9, J = 3.9, H-4) 7.42 (1H, m, H-7); 6.88 (1H, d, J = 8.8, H-6); 7.57 (1H, d, J = 4.9, H-5); 6.85 (1H, s, H-4) 7.39 (1H, d, J = 3.9, H-3); 7.13 (1H, t, J = 4.9, J = 3.9, H-4) 7.10-7.04 (3H, m, H-4,5,6) 7.76 (1H, d, J = 3.9, H-3); 7.61 (1H, d, J = 4.9, H-5); 7.16 (1H, t, J = 4.9, J = 3.9, H-4)
11.79 (1H, br. s)
2.33 (3H, s, CH3)
12.23 (1H, br. s)
12.40 (1H, br. s)
6.26 (1H, s, H-4); 2.30 (3H, s, CH3-3); 2.02 (3H, s, CH3-5)
11.90 (1H, br. s)
3.77 (3H, s, OCH3)
6.19 (1H, s, H-4); 2.27 (3H, s, 3-CH3); 2.00 (3H, s, CH3-5)
11.85 (1H, br. s)
2.63 (3H, s, CH3)
6.33 (1H, s, H-4); 2.34 (3H, s, CH3-3); 2.03 (3H, s, CH3-5)
_______ * The 1H NMR spectra were taken in DMSO (compounds 4a,g-i,k,l), DMF (compounds 4b,s,e,f,m-o), CD3CN (compound 4d), and CDCl3 (compound 4j).
TABLE 3. Characteristics of Indoles 4

Compound* 4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k* 4l 4m 4n 4o Empirical formula C19H17N3HCl C20H19N3HCl C19H16ClN3HCl C19H16FN3 C19H16ClN3HCl C20H18ClN3HCl C19H15BrClN3HCl C19H15l2N3HCl C27H24ClN3 C17H15N3S C18H17N3S C17H14lN3SHCl C17H14FN3SHCl C18H17N3OSHCl C18H17N3SHCl Found, % Calculated, % H 5.70 5.60 5.90 5.97 4.74 4.78 5.26 5.28 4.70 4.78 5.18 5.14 3.74 3.69 4.07 4.11 5.39 5.47 5.11 5.15 5.66 5.57 4.25 4.15 4.35 4.35 5.00 5.04 5.33 5.28
Name C 3-(3,5-Dimethyl-1H-1-pyrazolyl)-2-phenyl-1H-indole hydrochloride 3-(3,5-Dimethyl-1H-1-pyrazolyl)-5-methyl-2-phenyl1H-indole hydrochloride 5-Chloro-3-(3,5-dimethyl-1H-1-pyrazolyl)-2-phenyl1H-indole hydrochloride 5-Fluoro-3-(3,5-dimethyl-1H-1-pyrazolyl)-2-phenyl1H-indole 2-(4-Chlorophenyl)-3-(3,5-dimethyl-1H-1-pyrazolyl)1H-indole hydrochloride 2-(4-Chlorophenyl)-3-(3,5-dimethyl-1H-1-pyrazolyl)-5-methyl1H-indole hydrochloride 5-Bromo-2-(4-chlorophenyl)-3-(3,5-dimethyl-1H-1-pyrazolyl)1H-indole hydrochloride 5-Chloro-2-(4-chlorophenyl)-3-(3,5-dimethyl-1H-1-pyrazolyl)1H-indole hydrochloride 1-Benzyl-2-(4-chlorophenyl)-5-methoxy-3-(3,5-dimethyl1H-1-pyrazolyl)-1H-indole 3-(3,5-Dimethyl-1H-1-pyrazolyl)-2-(2-thienyl)-1H-indole 3-(3,5-Dimethyl-1H-1-pyrazolyl)-5-methyl-2-(2-thienyl)1H-indole 5-Chloro-3-(3,5-dimethyl-1H-1-pyrazolyl)-2-(2-thienyl)1H-indole hydrochloride 5-Fluoro-3-(3,5-dimethyl-1H-1-pyrazolyl)-2-(2-thienyl)1H-indole hydrochloride 5-Methoxy-3-(3,5-dimethyl-1H-1-pyrazolyl)-2-(2-thienyl)1H-indole hydrochloride 3-(3,5-Dimethyl-1H-1-pyrazolyl)-7-methyl-2-(2-thienyl)1H-indole hydrochloride 70.54 70.47 71.20 71.10 63.61 63.70 74.86 74.74 63.73 63.70 64.39 64.52 52.27 52.20 58.80 58.11 73.46 73.38 69.47 69.60 70.47 70.33 55.92 56.05 58.79 58.70 60.25 60.09 63.10 62.87
mp, N 12.72 12.98 12.16 12.44 11.70 11.73 13.48 13.76 11.52 11.73 10.96 11.29 9.55 9.61 10.53 10.70 9.47 9.51 14.30 14.32 13.51 13.67 11.20 11.53 11.87 12.08 11.34 11.68 12.08 12.22 189-190 (aq. EtOH) 290-291 (aq. EtOH) 292-293 (aq. EtOH) 242-243 (aq. EtOH) 209-210 (aq. i-PrOH) 310-311 (aq. EtOH) 307-308 (aq. i-PrOH) 302-303 (aq. EtOH) 195-196 (aq. EtOH) 230-231 (C6H6C6H14) 263-264 (aq. EtOH) 280-281 (aq. EtOH) 230-231 (aq. CH3CN) 257-258 (aq. i-PrOH) 227-228 (aq. i-PrOH)
Yield, %
46 48 38 40 38 57 25 40 38 46 56 24 38 29 32
_______ * Compounds 4d,i-k are bases.
1439
The structures of indoles 4 were demonstrated by 1H NMR method (Table 2) and confirmed by data of elemental analysis (Table 3). The influence of the substituents in the benzene ring of arylhydrazines 1 on the yield of pyrazolylindoles 4 was on the whole as described previously for 2-phenyl-3-(N-acylamino)indoles [2]. A methyl group increases the yield of indoles somewhat compared with unsubstituted phenylhydrazine (cf. 4b and 4a, 4f and 4e, 4k and 4j). Other substituents (Cl, Br, F, MeO) reduce the yield, which was discovered for the three groups of the studied indoles containing various aromatic groups in position 2 [cf. for example, for R = Cl and R = H: 4c and 4a (38 and 46%, phenyl), 4h and 4e (40 and 57%, p-chlorophenyl), 4l and 4j (24 and 46%, 2-thienyl)]. The indicated aromatic substituents (Ar) in ketones 2 , as might have been expected, had little effect on the yield of pyrazolylindole (4), 4a-d, 38-46% (phenyl); 4e-i, 24-57% (p-chlorophenyl); 4j-o, 24-56% (2-thienyl). The proposed scheme enables the preparation of compounds containing three of the most important pharmacophoric groups, indole, pyrazole, and thiophene, in one molecule (4j-o). Attempts to introduce an imidazole ring into indole position 3 proved to be unsuccessful. The reaction between -(1-imidazolyl)acetophenone and phenylhydrazine under various conditions (thionyl chloride in EtOH, PPA [polyphosphoric acid], or HBr in EtOH) led to complex mixtures of unidentified products.
EXPERIMENTAL The 1H NMR spectra of compounds 2 and 4 were recorded on a Bruker WM 250 (250 MHz) instrument. A check on the progress of reactions was effected by TLC on Sorbfil plates in the system CCl4EtOAc, 6 : 1. Commercial arylhydrazines (from Lancaster and Aldrich) were used in the work. The sodium salt of 2-(4-methoxyphenyl)hydrazinesulfonic acid was synthesized by the procedure of [6]. -(3,5-Dimethyl-1-pyrazolyl)acetophenones and (3,5-Dimethyl-1-pyrazolyl)methyl 2-Thienyl Ketone (2a-c) were synthesized by the procedure given in [5] for pyrazole. 1H-1-Imidazolylmethyl Phenyl Ketone Hydrobromide was obtained by the alkylation of imidazole with -bromoacetophenone in alcohol at 0C, yield 55%, mp 245-246C (EtOH). 1H NMR spectrum (DMSO), , ppm (J, MHz): 9.07 (1H, s, H-2 Imid); 8.07 (2H, d, J = 7.8, H-2,6 Phe); 7.78 (3H, m, H-4,5 Imid, H-4 Phe); 7.65 (2H, t, J = 7.8, J = 7.1, H-3,5 Phe). Found, %: C 49.29; H 4.00; N 10.16. C11H10N2O.HBr. Calculated, %: C 49.46; H 4.15; N 10.49. Hydrazones (3) (General Procedure). Glacial AcOH (several drops) or AcONa (6.3 mmol) was added to solution of phenylhydrazine base or hydrochloride 1 (3.3 mmol) respectively and ketone hydrobromide 2 (3.0 mmol) in the minimum volume of EtOH (10 ml). The mixture was boiled under reflux for 3 h. The resulting precipitate of NaCl and NaBr was removed from the solution by hot filtration. Alcohol was evaporated, the resulting oil was used without further purification to prepare indoles 4. Indoles 4a-m,o (General Procedure). Solution of thionyl chloride (9.0 mmol) in EtOH (5 ml) was added to solution of hydrazone 3a-m,o (3.0 mmol) in EtOH (5 ml), and the mixture was boiled under reflux for 3-4 h. Alcohol was evaporated, the residue washed from the NH4Cl formed with water, then either crystallized to obtain hydrochlorides of pyrazolylindoles (4a-c,e-h,l,m,o) or pyrazolylindoles were isolated as bases (4d,i-k) by column chromatography (silica gel L 100 250 m, eluent CCl4EtOAc, 8:1). 5-Methoxy-3-(3,5-dimethyl-1H-1-pyrazolyl)-2-(2-thienyl)-1H-indole (4n). Solution of thionyl chloride (9.0 mmol) in EtOH (5 ml) was added to solution of 2-(4-methoxyphenyl)hydrazinesulfonic acid sodium salt (4.0 mmol) and ketone hydrobromide 2c (3.0 mmol) in EtOH (10 ml) and the mixture was boiled under reflux for 16 h. Alcohol was evaporated, and the residue washed with water to remove ammonium salt formed. The residue was recrystallized from 2-PrOH.
1440
REFERENCES 1. 2. 3. 4. 5. 6. N. M. Przheval'skii, N. S. Skvortsova, and I. V. Magedov, Khim. Geterotsikl. Soedin., 1210 (2002). N. M. Przheval'skii, N. S. Skvortsova, and I. V. Magedov, Khim. Geterotsikl. Soedin., 189 (2003). N. M. Przheval'skii, N. S. Skvortsova, and I. V. Magedov, in: Abstr. 9th Blue Danube Symp. Het. Chem., Vysoke Tatry, Slovak Republic (2002), p. 198. A. T. Soldatenkov, N. M. Kolyadina, and I. V. Shendrik, Principles of the Organic Chemistry of Medicinal Substances, Khimiya, Moscow (2001). T. W. J. Solomons, F. W. Fowler, and J. Calderazzo, J. Am. Chem. Soc., 87, 528 (1965). J. Altschul, Chem. Ber., 25, 1842 (1892).
1441
ALKYLATION OF 3-CYANO-4-METHOXYMETHYL6-METHYL-2(1H)-PYRIDONE BY ACTIVE HALOMETHYLENE COMPOUNDS. THE MOLECULAR STRUCTURE OF 3-AMINO-2-BENZOYL4-METHOXYMETHYL-6-METHYLFURO[2,3-b]PYRIDINE

E. A. Kaigorodova, V. K. Vasilin, E. A. Sidorova, V. E. Zavodnik, and G. D. Krapivin The alkylation of 3-cyano-4-methoxymethyl-6-methyl-2(1H)-pyridone by active halomethylene compounds has been studied. It was shown that the reaction of the pyridone with methyl- and ethylchloroacetates and phenacyl and p-bromophenacyl bromides occurs to give N- and O-structural isomers. Only the N-derivatives are separated from the reaction mixture when the pyridone is alkylated with iodoacetamide. It was found that 2-aroylmethyl-3-cyano-4-methoxymethyl-6-methylpyridines cyclize in the presence of KOH to 3-amino-2-aroyl-4-methoxymethyl-6-methylfuro[2,3-b]pyridines. The molecular structure of 3-amino-2-benzoyl-4-methoxymethyl-6-methylfuro[2,3-b]pyridine has been studied using an X-ray analytical method. Keywords: 2-aroylmethoxy-3-cyanopyridines, alkylation, molecular structure. furo[2,3-b]pyridine, 3-cyano-2(1H)-pyridones,
Interest in 3-cyano-2(1H)-pyridones and their derivatives is due to their wide range of practical uses (medicinal compounds, vitamins, dyes, and intermediate compounds in fine organic synthesis) [1-4]. We have previously studied the alkylation of 3-cyano-4-methoxymethyl-6-methyl-2(1H)-pyridone (1) using alkyl halides and benzyl and allyl chlorides. Antiviral activity has been observed in a series of synthesized products [5]. The aim of this work was to study the reaction of the pyridone 1 with active halomethylene compounds. In solution in the presence of base the 3-cyano-2(1H)-pyridones form ambident anions which can be alkylated both at the nitrogen atom (a "soft" nucleophilic center) via an SN2 mechanism and at the oxygen atom (a "hard" nucleophilic center) through an SN1 mechanism [6, 7] (see Scheme 1). We have used the methyl and ethyl esters of chloroacetic acid 2a and 2b, iodoacetamide 2c, substituted chloroacetic acid amides 2d-k, and phenacyl and p-bromophenacyl bromides 2l and 2m as the alkylating agents. The reactions were carried out in DMF in the presence of an equimolar amount of KOH with a pyridone to alkylating agent reagent ratio of 1:1. In this work it was found that the reaction of the pyridone 1 with methyl- and ethylchloroacetate and with phenacyl bromide occurs at the two reactive centers to give a mixture of N- and O-structural isomers 3a,b,l,m and 4a-d respectively. The products can be separated through their different solubilities in nonpolar
__________________________________________________________________________________________ Kuban State Technological University, Krasnodar 350072, Russia, e-mail: organics@kubstu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1670-1682, November, 2004. Original article submitted February 6, 2003. 1442 0009-3122/04/4011-14422004 Springer Science+Business Media, Inc.
Scheme 1
O CN N H 1 O RCH2X 2am KOH N CH2R 3am 4ad CN O CN
+
O N OCH2R
2-4 a R = COOMe, b R = COOEt; 2, 3 R = CONH2, d R = CONHPh, e R = CONHC6H3Cl2-2,4, f R = CONHC6H4CF3-3, g R = CONHC6H4CF3-2, h R = CONHC6H4F-4, i R = CONHC6H4OMe-4, j R = CONHC6H4COMe-4, k R = CONHC10H7-1; 2l, 3l, 4c R = COPh, 2m, 3m, 4d R = COC6H4Br-4; 2 , b, d-k X = Cl, X = I, l, m X = Br
solvents. Extraction of the mixture of structural isomers formed as a result of the reaction using hot hexane gave the O-derivatives 4a-d. The residue after extraction contained the N-substituted pyridones 3a,b,l,m. When the pyridone 1 was alkylated using iodoacetamide or the N-substituted chloroacetamides 2d-k only the N-derivatives 3c-k could be separated from the reaction mixture. In this case the completion of the reaction occurs in a heterogeneous system. Analysis of the reaction mixture by TLC and of the raw products using 1H NMR spectroscopy did not reveal the presence of the O-structural isomers. It might be expected that the carbon atom of the amide carbonyl group in the iodoacetamide and the N-substituted chloroacetamides is a "softer" electrophilic center when compared with the carbonyl carbon atom in the phenacyl and p-bromophenacyl bromides and with the alkoxycarbonyl group of the chloroacetates and attacks the "soft" nucleophilic center of pyridone 1 to give only the one kind of N-alkylated products. The N-substituted 3-cyano-4-methoxymethyl-6-methyl-2-pyridones 3a-m and the 2-alkoxy-3-cyano-4methoxymethyl-6-methylpyridines 4a-d are colorless crystals and the O-derivatives have lower melting points than the corresponding N-isomers (Table 1). The IR spectra of the N-alkylated derivatives obtained shown strong CO bands at 1625-1660 cm-1 which points to the retention of the cyclic amide carbonyl group in the six-membered ring and contrasts with the IR spectra of the corresponding alkoxypyridines where only the carbonyl group absorption band for the substituent in position 2 is observed (Table 2). The 1H NMR spectra of the products of alkylating the pyridone 1 are unhelpful in proving their structure (Table 2). However, comparison of the spectra of the N- and O-isomers shows that the signal for the pyridine ring proton in the O-derivatives 4a-d is found to lower field ( = 0.61-0.65 ppm) and this is evidently related to the formation of the conjugated aromatic ring system. Attention is drawn to the unusual position and multiplicity of proton signals in the orthotrifluoromethylphenyl-substituted compound 3g. The signal for the H-6 proton is strongly broadened when compared with the rest of the signals. The broadening of the H-6 signal is perhaps due to an intramolecular contact with the ortho-carbonyl acylamide group. The position and multiplicity of the H-4 proton signal in the phenyl ring are also unusual. The signal for this proton is shifted to high field when compared with the other ring protons, evidently as a result of the electron-donor effect of the para-related amino group. The high multiplicity of the H-4 proton is apparently a result of, on the one hand, a spin-spin interaction with the neighboring H-3 proton (the signal for the latter is a doublet with a spin-spin coupling of J = 9.0 Hz and typical of ortho-protons) but not with the neighboring (also ortho) H-5 proton (the signal for which is a singlet). On the other hand, the additional splitting of the H-4 proton signal is likely due to a further spin-spin interaction through a W5 type bond system with the fluorine atoms of the trifluoromethyl group (the spin-spin coupling of which has a large value 5JHF = 6.0 Hz). 1443
1444
TABLE 1. Physicochemical and Spectroscopic Characteristics for Compound 3-5

Compound 1 3 3b 3c 3d 3e 3f 3g 3h 3i Empirical formula 2 1214N24 1316N24 1113N33 1717N33 1715Cl2N33 1816F3N33 1816F3N33 1716FN33 1819N34 Found, % Calculated, % 4 5.60 5.64 6.13 6.10 5.59 5.57 5.48 5.50 3.99 3.98 4.23 4.25 4.19 4.25 4.89 4.90 5.58 5.61 UV spectrum, max, nm (log ) 7 218 (4.12), 2340 (4.02) 218 (4.14), 340 (4.01) 230 (4.35), 343 (4.15) 243 (4.40), 344 (4.08) 250 (4.17), 343 (4.01) 209 (4.60), 245 (4.52), 343 (4.21) 274 (3.61). 344 (3.94) 247 (3.37), 345 (3.65) 250 (3.32), 294 (3.86), 344 (4.02)
mp, N 5 11.17 11.19 10.55 10.60 17.79 17.86 13.47 13.50 11.01 11.05 11.02 11.08 10.99 11.08 12.73 12.76 12.28 12.31 6 138139 129-130 272-273 178-179 239-240 195196 227-228 193-194 240-241
Yield, % 8 29 26 85 91 89 86 87 65 79
3 57.54 57.59 59.26 59.08 56.31 56.16 65.56 65.58 53.65 53.70 56.93 56.99 56.94 56.99 62.04 62.00 63.31 63.33
TABLE 1 (continued)
1 3j 3k 3l 3m 4 4b 4c 4d 5 5b 2 1919N34 2119N33 1716N23 1715 BrN23 1214N24 1316N24 1716N23 1715 BrN23 1716N23 1715 BrN23 3 64.53 64.58 69.76 69.79 69.12 68.91 54.40 54.42 57.55 57.59 59.00 59.08 69.10 68.91 54.39 54.42 68.94 68.91 54.38 54.42 4 5.39 5.42 5.31 5.30 5.47 5.44 4.00 4.03 5.62 5.64 6.07 6.10 5.45 5.44 4.01 4.03 5.41 5.44 4.03 4.03 5 11.84 11.89 11.58 11.63 9.42 9.45 7.44 7.47 11.15 11.19 10.63 10.60 9.44 9.45 7.45 7.47 9.43 9.45 7.43 7.47 6 187-188 201-202 143-144 163 (sublimes) 69-70 49-50 79-80 119-120 132-133 157-158 7 290 (4.31), 340 (4.06) 254 (4.17), 345 (4.07) 215 (4.17), 340 (4.01) 214 (4.21), 261 (4.16), 345 (3.82) 207 (4.45), 242 (4.25), 295 (3.90) 207 (4.46), 242 (4.28), 295 (3.93) 208 (4.23), 234 (3.90), 293 (3.93) 210 (4.52), 259 (4.36), 294 (4.01) 209 (4.17), 253 (4.21), 304 sh. (4.18), 390 (4.20) 206 (4.22), 259 (4.19), 317 (4.07), 400 (4.18) 8 82 86 33 25 29 18 24 26 30 28
1445
1446
TABLE 2. Spectroscopic Characteristics for Compounds 3-5

Compound 1 3 3b 3 3d N 2 2205 2220 2215 2205 IR spectrum, , cm-1 = 3 1725, 1645 1725, 1660 1680, 1640 1640, 1625
1 H NMR spectrum, , ppm (J, Hz) 2, s Py, s 8 9
NH 4 3360, 3200 3310, 3130
3, s 5 2.44 2.38 2.39 2.49
3, s 6 3.47 3.47 3.40 3.44
2, s 7 4.49 4.52 4.52 4.49
Other signals 10
4.85 4.78 4.94 4.90
6.43 6.42 7.03 6.42
3.77 (3, s, 3) 1.30 (3, t, J = 7.1, 23); 4.25 (2, q, J = 7.1, 23) 7.26 (2, br. s, NH2) 7.03 (1, dd, J4,3 = J4,5 = 8.5, H-4); 7.34 (2, dd, J3,4 = J3,2 = J5,4 = J5,6 = 8.5, H-3,5); 7.57 (2, d, J2,3 = J6,5 = 8.5, H-2,6); 10.23 (1H, br. s, NH) 7.28 (1, d, J = 8.6, -6); 7.44 (1, s, -3); 7.90 (1, d, J = 8.6, -5); 9.82 (1, br. s, NH) 7.31 (1, d, J4,5 = 8.8, -4); 7.47 (1H, dd, J5,4 = 8.8, J5,6 = 8.8, -5); 7.78 (1, d, J6,5 = 8.8, -6); 8.02 (1, s, -2); 10.59 (1, br. s, NH) 7.37 (1H, m, J4,CF3 = 6.0, J4,3 = 9.0, -4); 7.57 (1, s, -5); 7.59 (1H, br. s, H-6); 7.65 (1, d, J3,4 = 9.0, -3); 9.80 (1, br. s, NH) 6.96 (2, d, J = 8.8, -3,5); 7.08 (2, d, J = 8.8, -2,6); 10.25 (1, br. s, NH) 3.74 (3, s, ArOCH3); 6.80 (2, d, J = 8.8, -3,5); 7.48 (2, d, J = 8.8, -2,6); 10.09 (1, br. s, NH)
3e 3f
2210 2210
1650 1650
3370, 3260 3265, 3220 3270, 3220 3280, 3230, 3160 3240, 3180
2.48 2.50
3.47 3.48
4.49 4.49
5.04 4.92
6.41 6.42
3g
2210
1650
2.44
3.44
4.47
4.98
6.39
3h
2210
1630
2.49
3.45
4.47
4.88
6.41
3i
2200
1630
2.48
3.45
4.47
4.88
6.41
TABLE 2 (continued)
1 3j 2 2200 3 1690, 1660 1625 1625 4 3280 5 2.49 6 3.47 7 4.49 8 4.93 9 6.42 10 2.50 (3, s, ArCOCH3); 7.71 (2, d, J = 8.7, -2,6); 7.88 (2, d, J = 8.7, -3,5); 10.58 (1, br. s, NH) 7.47 (1, dd, J6,5 = 8.3, J6,7 = 8.3, -6); 7.51 (1, dd, J3,2 = 8.3, J3,4 = 8.3, -3); 7.55 (1, dd, J7,6 = 8.3, J7,8 = 8.3, -7); 7.70 (1, d, J2,3 = 8.3, -2); 7.79 (1, d, J4,3 = 8.3, -4); 7.87 (1, d, J5,6 = 8.3, -5); 8.18 (1, d, J8,7 = 8.3, -8); 10.22 (1, br. s, NH) 7.48-8.08 (5, m, Ph) 7.75 (2H, d, J = 8.9, H-3,5); 8.10 (2H, d, J = 8.9, H-2,6) 5.01 (3, s, 3) 1.21 (3, t, J = 7.1, OCH2CH3); 4.25 (2, q, J = 7.1, OCH2CH3) 7.55-8.00 (5, m, C6H5) 7.70 (2H, d, J = 8.8, H-3,5); 7.92 (2H, d, J = 8.8, H-2,6) 7.02 (2, br. s, NH2); 7.48-8.20 (5, m, Ph) 7.05 (2H, br. s, NH2); 7.67 (1H, d, J = 8.8, H-3,5); 8.11 (2H, d, J = 8.8, H-2,6)
3k
2200
3295, 3200
2.52
3.47
4.49
5.12
6.41
3l 3m 4a 4b 4c 4d 5a 5b
2210 2200 2210 2220 2220 2220
1680, 1630 1630 1725, 1640 1725, 1640 1705 1695 1610 1605
3455, 3340 3330, 3460
2.35 2.36 2.48 2.39 2.35 3.35 2.57 2.60
3.50 3.47 3.47 3.40 3.43 3.45 3.45 3.46
4.54 4.50 4.56 4.52 4.58 4.58 4.84 4.84
5.53 5.63 4.99 4.93 5.84 5.75
6.46 6.46 7.08 7.03 7.07 7.03 7.48 7.12
1447
In the UV spectra of the N-substituted 3-cyano-2(1H)-pyridones (Table 1) the long wave absorption band corresponds to a -* transition of the conjugated system of the pyridone ring and is practically unchanged from that of the starting 2(1H)-pyridone spectrum whereas in the spectra of the O-derivatives max is hypsochromically shifted by about 40 nm to 295-293 nm. An additional absorption maximum also appears in the region 234-242 nm in the spectra of compounds 4a-d and this corresponds to a -* transition in the aromatic conjugated system of the pyridine ring. We have found that when the pyridone 1 is alkylated by phenacyl and p-bromophenacyl bromides in the presence of KOH or EtONa base in greater than equimolar quantities there are formed in the reaction mixture the furo[2,3-b]pyridines 5a,b which are the products of a ThorpeZiegler isomerization of the corresponding O-alkylated derivatives. This was also similarly noted by the authors in [8]. However, we did not observe the cyclization of the N-alkyl derivatives to indolizines as was suggested by the authors in [8] (Scheme 2). According to our results, using alkyl chloroacetates for the alkylation of the pyridone 1 causes the reaction to stop at the stage of formation of the alkylation products and the latter do not cyclize whether an excess of base is used or not. In contrast to the noncyclic isomers 4, the furo[2,3-b]pyridines 5 are bright yellow crystalline materials which dissolve readily in polar solvents. The appearance of absorption bands in the range 390-400 nm in the spectra of the furopyridines 5 correspond to a -* transition in the common conjugated system in the molecule formed (Table 1). Scheme 2
Br O
O NH2 O
X
2 KOH
5a,b 5 a X = H, b X = Br
The IR spectra of the furopyridines 5 show absorption bands for the amino and carbonyl groups but the signal for the latter is shifted to lower frequency (1610-1605 cm-1) under the influence of the amino-containing conjugated system. In the 1H NMR spectra of the cyclization products 5a,b compared with the spectra of the corresponding O-alkyl derivatives 4c,d the signals for the protons of the OCH2 group are replaced by a broad signal for the amino group protons at 7.02 and 7.05 ppm respectively. In addition, characteristic changes in the position of the signals for the corresponding protons are observed before and after cyclization. The mass spectra of the compounds 5a,b show strong peaks of molecular ions, the positive charge on which is likely localized principally on the aminofuryl fragment. The process of ion fission of [M]+ for 5a,b (Scheme 3) takes place in the same way with the elimination of a methyl group (1) or of methanol (2) in the first stage. Stabilization of these ions is brought about via a peri-interaction with the amino group. The ion 1 then eliminates a molecule of the aromatic substituent to form the ion 3 and in the ion 2 the furan ring decomposes with loss of an ArCOCO fragment and migration of hydrogen atoms to form the ion 4. As might be expected, the mass spectra of both compounds also show strong peaks for the ArCO+ and Ar+ ions.
1448
Scheme 3
OMe CH2 NH2 Me N +. Me Me N A1 MeOH Me CH2 NH +. COAr Me N A2 O + ArCOCO Me N A4 (m/z 131) N N O O + NH2 CO Ar ArH O + NH C O A3 (m/z 203)
COAr
The structure of the 3-amino-2-benzoyl-4-methoxymethyl-6-methylfuro[2,3-b]pyridine (5a) has been studied using X-ray analysis (Fig. 1). The investigation carried out in the crystal state revealed four intramolecular contacts, two of which O(1)H(15) and O(3)H(11) should evidently be considered as unusual intramolecular hydrogen bonds involving a hydrogen atom bonded to an sp2-hybridized carbon atom whereas the two O(2)H(2n) and O(3)H(3n) are typical hydrogen bonds. The six-membered exocycle containing the O(3)H(3n) hydrogen bond is nonplanar with the following parameters: length 2.218 , angle N(2)H(3n)O(3) 122.5 and angle C(9)O(3)H(3n) 104.4. The parameters for other intramolecular contacts are: bond length O(1)H(15) 2.176 , angles C(6)O(1)H(15) and O(1)H(15)C(15) 100.0 and 127.9 respectively. Hydrogen bond length O(2)H(2n) 1.957 , angle C(8)O(2)H(2n) 111.2, angle N(2)H(2n)O(2) 155.0; contact length O(3)H(11) 2.392 , angle C(9)O(3)H(11) 84.0, angle C(11)H(11)O(3) 100.8.
Fig. 1. Spatial projection of the molecular structure of the 3-aminofuro[2,3-b]pyridine 5a. 1449
As a result of the participation of the unshared electron pair on the nitrogen atom of the amino group in the conjugated system the C(5)N(2) bond is markedly shortened (1.344(5) ). On the other hand, the C=O bond is somewhat lengthened and this is in a great deal a result of the mutual influence of these groups. The angle between the benzene and furopyridine rings planes is 6.3. In its turn, the furopyridine fragment is virtually planar (the mean deviation from the plane being 0.016 ). The angle between the furan and pyridine rings is 2.6. The geometrical parameters in the molecule of compound 5a were also determined by a quantum chemical calculation. The semiempirical AM1 method was selected (HyperChem v.5.01 software package) as, in fact, giving the most reliable results for heterocyclic compounds [9]. With the exclusion of the CH bonds, the experimental (X-ray) and calculated (AM1) results are given in Table 3. Several valence and torsional angles for the molecule discussed are given in Table 4.
TABLE 3. Experimental (X-Ray) and Calculated (AM1) Interatomic Distances in the Molecule of Furo[2,3-b]pyridine 5a
Bond C(1)C(2) C(1)C(16) C(2)C(3) C(3)C(4) C(3)C(8) C(4)C(5) C(4)C(7) C(5)C(6) N(1)C(1) N(1)C(7) N(2)C(5) O(1)C(6) d, 1.400(6) 1.498(7) 1.380(6) 1.407(5) 1.507(6) 1.447(5) 1.385(5) 1.391(5) 1.336(5) 1.326(5) 1.344(5) 1.409(4) AM1 1.421 1.496 1.396 1.395 1.493 1.462 1.440 1.403 1.355 1.352 1.362 1.419 Bond C(6)C(9) C(9)C(10) C(10)C(11) C(11)C(12) C(12)C(13) C(13)C(14) C(14)C(15) C(15)C(10) O(1)C(7) O(2)C(8) O(2)C(17) O(3)C(9) d, 1.412(6) 1.507(4) 1.390 1.390 1.390 1.390 1.390 1.390 1.354(5) 1.383(5) 1.416(6) 1.247(4) AM1 1.449 1.477 1.402 1.393 1.395 1.395 1.394 1.399 1.394 1.430 1.419 1.247
TABLE 4. Some Valence () and Torsional () Angles in the Molecule of 5a

Angle C(7)O(1)C(6) C(7)N(1)C(1) N(1)C(1)C(2) C(3)C(2)C(1) C(2)C(3)C(4) C(7)C(4)C(3) C(7)C(4)C(5) C(3)C(4)C(5) N(2)C(5)C(6) (3)(9)(10)(11)* H(2n)N(2)C(5)C(4)* , deg. AM1 105.9(3) 113.9(4) 122.6(4) 122.3(5) 115.6(4) 116.8(4) 105.1(4) 138.1(4) 126.2(4) -7.0 -11.8 105.7 114.1 123.9 120.9 117.0 117.8 105.5 136.8 127.1 -30.8 -26.4 Angle N(2)C(5)C(4) C(6)C(5)C(4) C(5)C(6)O(1) C(5)C(6)C(9) N(1)C(7)C(4) O(1)C(7)C(4) O(3)C(9)C(6) O(3)C(9)C(10) C(15)C(10)C(9) (2)(8)(3)(4)* C(5)C(6)C(9)O(3)* , deg. AM1 127.1(4) 106.6(4) 109.7(3) 127.8(4) 128.8(4) 112.7(4) 117.4(4) 118.5(4) 123.8(2) 33.6 -2.8 126.4 106.3 111.4 128.7 126.3 111.0 119.0 120.9 122.2 58.3 -2.4
_______ * Torsional angles and their values.
1450
Comparison of the geometrical parameters for the molecule of compound 5a using the X-ray and AM1 methods shows a high degree of similarity. A significant difference from the experimental values was noted only for the C(4)C(3)C(8)O(2) and O(3)C(9)C(10)C(11) torsional angles (the actual molecule being
TABLE 5. Distribution of Electron Density in the Molecule of Compound 5a (Calculated using the AM1 method)*
Atom C(1) C(2) C(3) C(4) C(5) C(6) C(7) C(8) Electron density 0.031 -0.214 0.033 -0.172 0.141 0.226 0.106 0.004 Atom C(9) C(10) C(11) C(12) C(13) C(14) C(15) Electron density 0.356 -0.133 -0.078 -0.147 -0.105 -0.145 -0.074 Atom C(16) C(17) N(1) N(2) O(1) O(2) O(3) Electron density -0.179 -0.080 -0.125 -0.319 -0.068 -0.282 -0.343
_______ * HyperChem calculates the charge density on the atom as the sum of the molecular orbital densities, each of which is a square of the orbital wave function.
TABLE 6. Atomic Coordinates* (104) and Equivalent Isotropic Thermal Parameters (Ueq) (103) in the Molecule of Compound 5a
Atom O(1) O(2) O(3) N(1) N(2) C(1) C(2) C(3) C(4) C(5) C(6) C(7) C(8) C(9) C(10) C(11) C(12) C(13) C(14) C(15) C(16) C(17) x 4641(2) 3169(2) 5396(2) 3975(3) 4452(3) 3556(3) 3338(3) 3562(3) 4016(3) 4419(3) 4806(3) 4187(3) 3357(4) 5308(3) 5749(2) 6136(2) 6566(2) 6610(2) 6223(2) 5793(2) 3358(6) 2944(5) y 2622(4) -902(4) 5431(4) -54(6) 2087(7) -1751(7) -2407(8) -1367(6) 411(6) 1958(6) 3262(6) 912(6) -2261(8) 4971(6) 6244(4) 7969(4) 9220(4) 8746(5) 7021(5) 5770(4) -2964(13) -1745(9) z 3526(1) 4853(1) 4461(1) 3196(1) 4713(1) 3271(2) 3700(2) 4078(1) 4004(1) 4266(1) 3965(1) 3565(1) 4526(2) 4061(1) 3712(1) 3863(1) 3564(1) 3114(1) 2963(1) 3262(1) 2868(2) 5269(2) Ueq, 2 58(1) 76(1) 60(1) 62(1) 60(1) 62(1) 58(1) 50(1) 47(1) 47(1) 50(1) 51(1) 65(1) 50(1) 48(1) 62(1) 78(2) 79(2) 78(2) 67(1) 93(2) 74(2)
_______ * The atomic coordinates for hydrogen are not given but may be obtained from the authors. 1451
significantly more flattened that its AM1 structure) and this is likely to be a result of an intermolecular interaction in the crystal which is not considered in the calculation. The overall charges on the atoms in the molecule studied as calculated by the AM1 method are given in Table 5.
EXPERIMENTAL UV spectra were recorded on Specord UV-vis and Specord M-40 instruments using ethanol. IR spectra were taken on a Specord 71 UR-20 spectrophotometer for a suspension in vaseline oil, 1H NMR spectra on a Bruker WM-250 (250 MHz) instrument, and mass spectra on a Varian MAT (70 eV) instrument. Monitoring of the course of the reaction and the purity of the final products was carried out by TLC on Silufol UV-254 plates with dioxaneacetoneammonia (10:10:3) or hexaneacetone (1:1) as eluents and they were revealed using iodine vapour. X-Ray Structural Investigation of the Monocrystal of Compound 5a with the linear parameters 0.52 0.26 0.05 mm was carried out at 20C on an Enraf-Nonius CAD-4 four circle, automatic diffractometer (MoK irradiation, relative scanning rate /2 = 1.36, = 22.85, spherical segment 0 h 15, -0 k 7, -0 l 30). In all, 1535 reflections were collected, of which 925 are symmetrically independent (Rint = 0.0358). Crystals of compound 5a are orthorhombic with a = 14.378(3), b = 6.9020(10), c = 29.985(6) ; = = = 90; V = 2975.6(10) 3; M = 296.32; Z = 8; dcalc = 1.323 g/cm3; = 0.092 mm-1; space group Pbca. The structure was solved by a direct method and refined through least squares analysis in the full matrix anisotropic approximation using the SHELXTL [10] program package and the 925 independent reflections with I > 2(I) to difference factors of R1 = 0.0387 and wR2 = 0.0958. The atomic coordinates are given in Table 6. N-Benzoylmethyl-3-cyano-4-methoxymethyl-6-methyl-2-pyridone (3l) and 2-Benzoylmethyl-3cyano-4-methoxymethyl-6-methylpyridine (4c). A 10% aqueous solution of KOH (11.2 ml, 0.02 mol) was added to a suspension of the pyridone 1 (3.56 g, 0.02 mol) in DMF (35 ml) and the reaction product was stirred at 50-55C until homogeneous. Phenacyl bromide (3.98 g, 0.02 mol) was added and the stirring was continued for a further hour. The solvent was evaporated by a half, reaction mixture was cooled, and treated with water (15 ml). The precipitated solid was separated, dried, and extracted with hot petroleum ether. Evaporation of the petroleum ether gave compound 4c (1.42 g, 24%). The residue was recrystallized from ethanol to give the N-alkylated product (1.98 g, 33%). Compounds 3a,b,m and 4a,b,d were prepared similarly. N-(N-Phenylcarbamoylmethyl)-3-cyano-4-methoxymethyl-6-methyl-2-pyridone (3d). A mixture of the pyridone 1 (1.78 g, 0.01 mol), DMF (25 ml), 10% aqueous KOH (5.6 ml, 0.01 mol), and N-phenylchloroacetamide (1.70 g, 0.01 mol) was refluxed for 7 h. After cooling, the reaction mixture was diluted with twice the amount of water. The residue was separated, washed with water, dried, and recrystallized from alcohol. Yield 2.83 g (91%). Compounds 3c,e-k were prepared similarly 3-Amino-2-benzoyl-4-methoxymethyl-6-methylfuro[2,3-b]pyridine (5a). A 10% aqueous solution of KOH (11.2 ml, 0.02 mol) was added to a suspension of the pyridone 1 (3.56 g, 0.02 mol) in DMF (35 ml) and the product was stirred at 50-55C until homogeneous. Phenacyl bromide (3.98 g, 0.02 mol) was added and mixture was stirred for 30 min. Further 10% aqueous KOH (11.2 ml, 0.02 mol) was added over 30 min. When the reaction mixture was cooled, there appeared after 10 min the crystalline furopyridine 5a which was separated, washed with hot water, and recrystallized from ethanol. Yield 1.78 g (30%). Mass spectrum, m/z (I, %): 296 [M]+ (58), 295 (40), 281 (10), 265 (12), 264 (6), 263 (19), 235 (12), 203 (13), 131 (9), 119 (5), 105 (44), 104 (14), 78 (10), 77 (100), 65 (11).
1452
Furo[2,3-b]pyridine 5b was prepared similarly. Mass spectrum, m/z (I, %): 374* (73), 359* (12), 342* (28), 263 (8), 203 (10), 183* (100), 155* (37), 131 (9), 119 (3) (the starred ions designate those containing 79Br).
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. V. P. Litvinov, S. G. Krivokolysko, and V. D. Dyachenko, Khim. Geterotsikl. Soedin., 579 (1999). V. P. Litvinov, L. A. Rodinovskaya, U. A. Sharanin, A. M. Shestopalov, and A. Senning, Sulfur Reports, No. 13, 1 (1992). V. P. Litvinov, Phosphorus, Sulfur and Silicon, 74, 139 (1993). T. P. Kosulina, E. A. Kaigorodova, V. G. Kul'nevich, A. Ya. Sapunov, and S. V. Govorova, Khim.-Farm. Zh., No. 4, 30 (1990). V. G. Kul'nevich, E. A. Kaigorova, I. S. Arustamova, L. V. Korobchenko, G. V. Vladyko, and E. I. Boreko, Khim. -Farm. Zh., No. 2, 132 (1990). Z. A. Bomika, M. B. Andaburskaya, E. Yu. Pelcher, and G. Ya. Dubur, Khim. Geterotsikl. Soedin., 1089 (1976). N. Kornblum, R. A. Smiley, and R. K. Blackwood, J. Am. Chem. Soc., 77, 6269 (1955). K. Gewald and H. J. Jansch, J. Prakt. Chem., 318, 313 (1976). V. I. Minkin, B. Ya. Simkin, and R. M. Minyaev, Theory of Molecular Structure [in Russian], Phoenix, Rostov-on-Don (1979). G. M. Sheldrick, Computational Crystallography, Oxford University Press, New York (1982), p. 506.
1453
SYNTHESIS AND REDUCTIVE REACTIONS OF 2,3-DIOXO-2,3-DIHYDROBENZO[b]FURO[2,3-f]-, -[2,3-g]-, AND -[3,2-e]INDOLES

T. E. Khoshtariya, M. M. Matnadze, N. T. Mirziashvili, L. N. Kurkovskaya, M. I. Sikharulidze, and T. O. Dzhashi The Sandmeyer reaction was used to prepare 2,3-dioxo-2,3-dihydrobenzo[b]furoindoles which could be reduced with diborane or with complex hydrides to give the corresponding unsubstituted as well as the 3-hydroxybenzo[b]furoindoles. Keywords: benzo[b]furoindoles, 3-hydroxybenzo[b]furoindoles, diborane, 2,3-dioxo-2,3-dihydrobenzo[b]furoindoles, complex hydrides, reduction. We have previously shown [1] that 3-aminodibenzo[b,d]furan undergoes a Sandmeyer reaction to give isomeric dioxodihydro-1H-benzo[b]furoindoles. These can be used in the preparation of unsubstituted indole containing tetracyclic systems and their hydroxy derivatives with varied linking to the pyrrole ring relative to the starting tricyclic system. Using the same scheme in this work we have prepared three other isomeric dioxodihydrobenzo[b]furoindoles and studied the mechanism of their formation. 2,3-Dioxo-2,3-dihydro-1H-benzo[b]furo[2,3-g]- (5), 2,3-dioxo-2,3-dihydro-1H-benzo[b]furo[2,3-f]- (6), and 1,2-dioxo-1,2-dihydro-1H-benzo[b]furo[3,2-e]indoles (7) were prepared by us under Sandmeyer reaction conditions [2, 3]. The 1- and 2-aminodibenzofurans (1, 2) were used in the synthesis of the heterocyclic systems indicated. The starting amines were converted to the isonitrosoacetamidodibenzofurans 3, 4, cyclization of which in the presence of sulfuric acid allowed us to prepare the corresponding dioxodihydro-1H-benzo[b]furoindoles 5-7 in 16-88% yields. The cyclizations of the 2-isonitrosoacetamidobenzofuran led to a mixture of the two isomeric linear (6) and angular (7) structures. Separation of the isomers was brought about by the successive treatment of an alkaline solution of the mixture of compounds 6 and 7, initially with acetic acid to pH 3 and, after filtration of the crystals formed, by treatment of the filtrate with conc. HCl to pH 1. The first procedure gave compound 6 (66%) and the second gave compound 7 (16%). As was expected, compound 5 was formed as a single isomer. Through a study of the properties of the indicated heterocyclic systems it was found that compounds 5-7 undergo reduction to the corresponding benzo[b]furoindoles 8-10 and the yield of the latter depends both on the nature of the reducing agent and on the reaction conditions. __________________________________________________________________________________________ Georgian Technical University, Tbilisi 380075; e-mail: ibsge@hotmail.com. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No 11, pp. 1683-1689, November, 2004. Original article submitted May 21, 2002. 1454 0009-3122/04/4011-14542004 Springer Science+Business Media, Inc.
R1
1 2
R1 R2
3
O
1 2
CCl3CHO, NH2OH . HCl H2SO4 O 3, 4
R2 OH
3
O
a 2
H2SO4
10 9 8 7 d e
NH
3 4 5
O 1,2
9 8
+
LiAlH4, NaBH4 HO
1
O
6
10 f e d
H N1
a c b 3 2
7 B2 H 6
1
7 6
O
5
O LiAlH4, NaBH4
6 B 2H 6
9 8 7 6 f e d 10
H2SO4
10 9 d e
2 c ba
NH
3 4 5 9 8
10 d e 7
b a
NH
3
+
4 5
10
H N1
c a b
9 2 3 8 7 6
10 f e d
H N1
c a b
8 2 3 7
O
6
O
6
+ 9 OH O
10
13
O
5
O
5
12
9
1 2 a c g d f e 4 5 b 3 10 1
HN
10 9 8 7
HN B 2H 6
9 8 7 g f e 5
2 a b c d 4 3
O LiAlH4, NaBH4
10 9
2 a b c
HN
g 8 7 f e
OH
3
d 4 5
O 8
O
6
O
6
11
1 R1 = NH2, R2 = H; 2 R1 = H, R2 = NH2; 3 R1 = NHX, R2 = H; 4 R1 = H, R2 = NHX; X = COCH=NOH;
1455
We have previously shown [1] that the reduction of similar isatins (but with an alternative linking of the pyrrole rings) using lithium aluminiumhydride in absolute pyridine or with sodium borohydride in 2-propanol forms a mixture of the corresponding hydroxybenzo[b]furoindoles with a small amount of unsubstituted benzo[b]furoindoles and unreacted starting materials. However, the use of diborane in THF as reducing agent leads to good yields of the unsubstituted benzo[b]furoindoles [1]. In fact, the unsubstituted benzo[b]furoindoles 8-10 were synthesized by us in 60-66% yields using diborane in THF as the reducing agent. Using the aluminium or borohydride gave results which were identical to those reported in [1], i.e. the reduction stops at the formation of the -monohydroxy derivatives 11-13. Hence it was again confirmed that the dioxodihydrobenzo[b]furoindoles can be used to prepare unsubstituted tetracyclic pyrrole-containing condensed systems. The corresponding 1- and 3-hydroxy derivatives 11-13 which were separated and characterized in the reduction process, has not been reported in the literature. The compounds 11-13 are of interest from a pharmacological viewpoint [4]. The IR spectra of compounds 3 and 4 show absorption bands for the carbonyl group at 1680 and 1675 cm-1. The absorption bands at 3290 and 3280 cm-1 indicate the presence of the NH group in the indicated compound. The absorption bands for the C=O group in compounds 5-7 (1710, 1700, 1710 cm-1 respectively) are similar to the corresponding bands in isatin. Unfortunately the UV spectra of compounds 5-7 could not be recorded because of their low solubility . Assignment of the 1H NMR spectra signals (Table 1) for compounds 5-7 could be made on the basis of the difference in multiplicity of the signals in the indole part of the molecule. The presence in the spectrum of an AB system typical of an o-proton spin-spin coupling supports the angular ring attachment in 5 and 7 and the two singlets for weakly interacting p-protons the linear structure for the molecule in compound 6. The mass spectra of the isomeric annelated isatins 5-7 show a strong peak for the molecular ion [M]+ with m/z 237 and the nature of the subsequent fragmentation (confirmed by the metastable transitions) does not contradict the proposed structure. The melting points of the compounds 8-10 as well as their IR and UV spectra are similar to those of compounds prepared by us previously [5]. The mass spectra of all three isomers of the benzo[b]furoindoles 8-10 show a strong peak for the molecular ion [M]+ with m/z 207 and the nature of the subsequent fragmentation (confirmed by the metastable transitions) does not contradict the proposed structure.
9 10 f 7 6 e d
179 (6)*
H2CN
H N1
a c b
+.
2 3
H 206 (16)
O
5
207 (100) m 156.5 HCN CO m 128.4
151 (13)
180 (11)
152 (20)
_______ * Here, and subsequently, values for m/z are quoted (Irel for the ion peaks, % of the maximum) and m are the metastable transitions. 1456
TABLE 1. 1H NMR Spectra of Compounds 5-8, 11-13*

Compound 5 6 7 8 Chemical shifts, , ppm -5 -6 -7 8.11 7.71 ~7.60 7.14 ~7.90 ~7.60 ~7.63 7.25 J, Hz J4.5 = 8.7 J4.10 = 0.8 J4.5 = 8.5 J1.2 = 2.0; J1.3 = 1.7; J2.3 = 2.9; J4.5 = 8.1 J4.5 = 8.4 J4.10 = 0.9 J4.5 = 8.8
-1 10.04 10.13 11.51
-2 ~7.40
-3 9.93 7.03
-4 7.92 7.63 7.82 7.50
-8 7.42 ~7.43 ~7.64 7.35
-9 7.55 8.26 ~7.54 7.43
-10 8.45 7.84 8.60 8.81
11 12 13
11.42 11.14
~7.40 7.34 7.43
11.01
7.51 7.60 7.40
7.70 7.50
7.53
8.00 7.52 7.52
7.42 7.44 ~7.45
7.41 7.93 ~7.44
8.85 8.14 8.36
8.19 8.15 8.13
_______ * Compounds 5-7 were taken in acetone-d6 and 8, 11-13 in DMSO-d6.
1457
The IR spectra of compounds 11-13 show absorption peaks typical of a hydroxyl group at 3490-3510, 3490-3500, and 3500-3510 cm-1 respectively and the UV spectra resemble the spectrum of indole. The 1H NMR spectrum of these compounds show a sharp singlet for the hydroxyl group proton at 8.19, 8.15, and 8.13 ppm respectively.
EXPERIMENTAL Monitoring of the reaction course and the purity of the compounds was carried out on bonded Silufol UV-254 silica gel plates. UV spectra were recorded on a Specord UV-vis spectrophotometer using ethanol. IR spectra were taken in vaseline oil on a UR-20 instrument using NaCl and LiF prisms. Mass spectra were recorded on an MX-1303 instrument with direct introduction of the sample into the ion source and an ionization energy of 50 eV. 1H NMR spectra were measured on a Bruker WP-200 SY instrument (200 MHz) with TMS internal standard and with an accuracy of measurement of 0.05 ppm in chemical shift and 0.1 Hz in spin-spin coupling. 1-Isonitrosoacetamidodibenzofuran (3). To a solution of chloral hydrate (3.2 g, 0.02 mol) in water (46 ml) there were successively added crystalline sodium sulphate (51.5 g, 0.16 mol), a solution of the 1-aminobenzofuran 1 (3.2 g, 0.02 mol) in hot water (400 ml), with addition of conc. HCl (3 ml), and a solution of hydroxylamine hydrochloride (4.3 g, 0.06 mol) in water (20 ml). The mixture was refluxed with continuous stirring for 2 h, cooled with water, and the precipitated crystals were filtered, carefully washed with water, and dried. Yield 3.3 g (75%); mp 175-177C. IR spectrum, , cm-1: 3290 (NH), 1680 (C=O). UV spectrum, max, nm (log ): 244 (4.49), 288 (4.10), 295 (4.15), 333 (4.25), 350 (4.00). Found, %: C 66.0; H 4.3; N 10.8. C14H10N2O3. Calculated, %: C 66.1; H 4.0; N 11.0. 2-Isonitrosoacetamidodibenzofuran (4) was prepared similarly from the 2-aminodibenzofuran 2 (3.2 g, 0.02 mol). Yield 3.7 g (84%); mp 197-198C. IR spectrum, , cm-1: 3280 (NH), 1675 (C=O). UV spectrum, max, nm (log ): 235 (4.41), 265 (4.10), 285 (4.15), 333 (4.05), 350 (4.00). Found, %: C 66.3; H 4.1; N 11.2. C14H10N2O3. Calculated, %: C 66.1; H 4.0; N 11.0. 2,3-Dioxo-2,3-dihydrobenzo[b]furo[2,3-g]indole (5). Dry compound 3 (3.4 g, 0.01 mol) was added in small portions with constant stirring to 80% H2SO4 (34 ml, 0.3 mol) at 50C. The reaction mixture was heated for 1 h at 80C, cooled, and poured into a 10-12-fold amount of crushed ice. After 1 h the precipitate was filtered off and washed with water. The dry product was suspended in a 5-fold amount of hot water and a 40% solution of NaOH was added until fully dissolved. Hydrochloric acid (12%) was carefully added until a precipitate began to form. The precipitate was filtered off and discarded. The filtrate was once more acidified to an acid reaction and left for 2.5 h. The precipitate was then filtered off, carefully washed with water, and dried to give compound 5 (2.8 g, 88%); mp 274-277C. IR spectrum, , cm-1: 3400 (NH), 3260 (NHO=C), 1710 (C=O). UV spectrum, max, nm (log ): 235 (4.41), 265 (4.10), 285 (4.15), 333 (4.05), 350 (4.00). Found, %: C 70.8; H 3.3; N 5.7. C14H7NO3. Calculated, %: C 70.9; H 3.0; N 5.9. 2,3-Dioxo-2,3-dihydro-1H-benzo[b]furo[2,3-f]indole (6) and 1,2-Dioxo-1,2-dihydro-1H-benzo[b]furo[3,2-e[indole (7) were prepared similarly from compound 4 (3.4 g, 0.01 mol). The difference related only to the work up of the product. The mixture of compounds 6 and 7 obtained was dissolved in a dilute solution of NaOH, treated with 12% hydrochloric acid, acetic acid was carefully added to pH 3, and left for 2.5 h. The precipitate was filtered off, carefully washed with water, and dried to give the isomeric material 6 (2.1 g, 66%); mp 255-257C. IR spectrum, , cm-1: 3415 (NH), 3250 (NHO=C), 1700 (C=O). Found, %: C 70.7; H 3.2; N 6.2. C14H7NO3. Calculated, %: C 70.9; H 3.0; N 5.9. After the separation of compound 6, the filtrate was acidified using conc. HCl to pH 1 and left for 1 h. The precipitated crystals were again filtered, carefully washed with water to neutral reaction, and dried to give compound 7 (0.5 g, 15.7%); mp 278-285C. IR spectrum, , cm-1: 3390 (NH), 3245 (NHO=C), 1710 (C=O). Found, %: C 71.7; H 2.9; N 5.8. C14H7NO3. Calculated, %: C 70.9; H 3.0; N 5.9. 1458
Benzo[b]furo[2,3-g]indole (8). A solution of diborane (1.7 g, 0.06 mol) (prepared in situ from sodium borohydride and boron trifluoride etherate) was added dropwise with stirring to a solution of compound 5 (2.37 g, 0.01 mol) in absolute THF (2.5 ml) at -78C. The product was then held for 30 h at 0C, poured into water (1.5 l), slightly acidified, and then extracted with ether. The extract was washed with water and dried over anhydrous Na2SO4. After distillation of solvent the product was purified on a silica gel column to give compound 8 (1.34 g, 64.8%); mp 146-147C. IR spectrum, , cm-1: 3410 (NH). UV spectrum, max, nm (log ): 219 (4.44), 239 (4.67), 251 (4.88), 273 (4.31), 289 (4.35), 312 (4.62), 320 (4.30). Found, %: C 81.0; H 4.1; N 6.4. C14H9NO. Calculated, %: C 81.1; H 4.4; N 6.8. Benzo[b]furo[2,3-f]indole (9) was prepared similarly to the previous experiment from compound 7. Yield 60%; mp 197-198C [5]. Benzo[b]furo[3,2-e]indole (10) was prepared similarly. Yield 60%; mp 127-128C [5]. 3-Hydroxy-1H-benzo[b]furo[2,3-g]indole (11). A. Lithium aluminiumhydride (2.4 g, 0.063 mol) was mixed with cooling in absolute pyridine (240 ml) and dry compound 5 (5.1 g, 0.02 mol) was added portionwise with stirring such that the reaction medium did not exceed a temperature of 25C. The product was stirred for 8 h, water (20 ml) was added dropwise, and then tartaric acid (240 g) in water (960 ml). The product was purified on a silica gel column to give the crystalline material 11 (1.1 g, 53%) with mp 229-233C. IR spectrum, , cm-1: 3280 (NH), 3490-3510 (OH). UV spectrum, max, nm (log ): 240 (4.50), 265 (4.60), 290 (4.75), 273 (4.31), 300 (4.39). Found, %: C 75.4; H 4.2; N 6.0. C14H9NO2. Calculated, %: C 75.3; H 4.0; N 6.3. B. Compound 5 (0.01 mol) was added with stirring to a solution of sodium borohydride (0.04 mol) in 2-propanol (50 ml) at ~ 20C. The mixture was heated to 50C over 3 h and left overnight at ~ 20C. Dilute hydrochloric acid was then added carefully until hydrogen evolution ceased. The product was extracted from the solution obtained using small portions of ether. The extracts were carefully washed with water and dried over Na2SO4. The solvent was distilled off and compound 11 was purified on a silica gel column. Yield 42%. 3-Hydroxy-1H-benzo[b]furo[2,3-f]indole (12) was prepared similarly from the annelated isatin 6. Yield 30%; mp 201-204C. IR spectrum, , cm-1: 3290 (NH), 3490-3500 (OH). UV spectrum, max, nm (log ): 240 (4.44), 265 (4.75), 280 (4.70), 330 (4.50). Found, %: C 75.2; H 3.3; N 6.6. C14H9NO2. Calculated, %: C 75.3; H 4.0; N 6.3. 1-Hydroxy-1H-benzo[b]furo[3,2-e]indole (13) was prepared similarly from the annelated isatin 7. Yield 30%; mp 219-221C. IR spectrum, , cm-1: 3300 (NH), 3500-3510 (OH). UV spectrum, max, nm (log ): 225 (4.40), 252 (4.60), 270 (4.60), 310 (4.45). Found, %: C 75.7; H 4.1; N 6.1. C14H9NO2. Calculated, %: C 75.3; H 4.0; N 6.3. Mixed samples of compounds 11-13 prepared using methods A and B did not give a depression of melting point.
REFERENCES 1. 2. 3. 4. 5. T. E. Khoshtariya, T. O. Dzhashi, and L. N. Kurkovskaya, Khim. Geterotsikl. Soedin., 1419 (1999). I. Sandmeyer, Helv. Chim. Acta, 2, 230 (1919). B. R. Baker, J. Org. Chem., 17, 150 (1952). M. Muller and R. Schmiedel, Acta Biol. Med., 14, 158 (1965). T. E. Khoshtariya, M. L. Kakhabrishvili, L. N. Kurkovskaya, and N. N. Suvorov, Khim. Geterotsikl. Soedin., 1366 (1984).
1459
SYNTHESIS OF 3,9,9,9a-TETRAMETHYL1,2,3,9a-TETRAHYDRO-9H-IMIDAZO[1,2-a]INDOL-2-ONES BY REACTION OF 2,3,3-TRIMETHYL3H-INDOLE WITH 2-BROMOPROPIONAMIDES

E. Valaityte, V. Martynaitis, and A. Sackus Alkylation of 2,3,3-trimethyl-3H-indole with 2-bromopropionamide and the subsequent treatment of the formed 1-(1-carbamoylethyl)-2,3,3-trimethyl-3H-indolium bromide with a base afforded 3,9,9,9a-tetramethyl-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-one. Condensation of the 1-(1-carbamoylethyl)-2,3,3-trimethyl-3H-indolium salt with 2-hydroxy-1-naphthaldehyde gave a mixture of diastereomeric 1-(1-carbamoylethyl)spiro[2H-indole-2,3'-[3H]naphtho[2,1-b]pyrans]. Keywords: 2-bromopropionamide, imidazo[1,2-a]indole, spiro[2H-indole-2,3'-[3H]naphtho[2,1-b]pyran], 2,3,3-trimethyl-3H-indole. N-Alkylated derivatives of 2,3,3-trimethyl-3H-indole are useful starting materials for the synthesis of cyanine dyes and photochromic indolinobenzopyrans [1, 2]. The reaction of 2,3,3-trimethyl-3H-indole with such bifunctional reagents as -haloacetamides and subsequent treatment of the formed 1-carbamoylmethyl-3Hindolium salts with a base leads to the formation of 1-carbamoylmethyl-3,3-dimethyl-2-methylene-2,3-dihydro1H-indoles, which may then undergo cyclization to give 1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-one derivatives [3]. It was found that the presence of such substituent as allyl or benzyl group at the amide nitrogen atom promotes nucleophilic addition of the mentioned nitrogen atom to the -carbon of the indole nucleus, while phenyl substituent suppress imidazolidine ring closure [4]. 1-Carbamoylmethyl-3,3-dimethyl-2-methylene-2,3dihydro-1H-indoles and their cyclic forms have found application in the preparation of photochromic indoline spiropyrans [5] and thermochromic styrylimidazo[1,2-a]indoles [6, 7]. It was found recently, that 1-(Nsubstituted carbamoylmethyl)indoline spiropyrans under influence of a strong base rearrange to pyrrolo[1,2a]indole derivatives via short-living methylides [8, 9]. In the present work, we studied annelation of a five-membered lactam ring to the indole nucleus by the reaction of 2,3,3-trimethyl-3H-indole with 2-bromopropionamides. Alkylation of indole 1a with 2-bromopropionamide was carried out at 135C in xylene. Treatment of the formed salt 2a with a strong base gave 3,9,9,9a-tetramethyl-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-one 3a. The structure of compound 3a was confirmed by means of NMR spectroscopy. Compound 3a has two chiral centers at C-3 and C-9a. However, the 1H NMR spectrum shows only one set of proton signals, thus pointing to the formation of 3a as a single diastereomer in a racemic form. In the 1H NMR spectrum three __________________________________________________________________________________________ Department of Organic Chemistry, Kaunas University of Technology, LT-3028 Kaunas, Lithuania; e-mail: algirdas.sackus@ktu.lt. Published in Khimiya Geterotsiklicheskikh Soedinenii, No 11, pp. 1690-1694, November, 2004. Original article submitted July 7, 2003. 1460 0009-3122/04/4011-14602004 Springer Science+Business Media, Inc.
singlets of 10,10,10a-CH3 groups are present in the 1.16-1.49 ppm region and a doublet of CH3-3 group appears at 1.55 ppm (J = 15.5 Hz). The 13C NMR spectrum of 3a contains the characteristic signals of annelated imidazolidinone ring skeleton carbons at 63.91 (C-3), 89.19 (C-9a), and 177.31 ppm (C=O). The absorption band at 1720 cm-1 that is due to the carbonyl group and the band at the 3190 cm-1 that corresponds to stretching vibrations of the NH bond are observed in the IR spectrum of 3a.
Me Me R Me N 1a,b Me Me Me N Me O 2af 3ad
1 a R = H, b R = Me; 2 a R = R1 = H, b R = H, R1 = Bn, c R = Me, R1 = Bn, d R = H, R1 = Ph, e R = R1 = H, f R = Me, R1 = Bn; a-d X = Br, e, f X = ClO4; 3a R = R1 = H; b R = H, R1 = Bn; c R = Me, R1 = Bn; d R = H, R1 = Ph
MeCHBrCONHR1
Me Me R + N X Me Me +HX NHR1 HX
NR1 O
1-Benzyl-3,9,9,9a-tetramethyl-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-ones 3b,c were obtained as single diastereomers from 3H-indoles 1a,b and N-benzyl-2-bromopropionamide. The characteristic signal in the 1 H NMR spectra of the compounds 3b,c is an AB-quadruplet of diastereotopic benzyl protons in the area of 4.06-5.10 ppm. Reaction of 3H-indole 1a with N-phenyl-2-bromopropionamide and the subsequent treatment of the reaction mixture with a base afforded 3,9,9,9a-tetramethyl-1-phenyl-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-one 3d as the only isolable product. It has been shown earlier that a similar reaction of 1a with N-phenyl-1-chloroacetamide gave 2-methylene-1-(N-phenylcarbamoyl)methyl-2,3-dihydro-1H-indole, which did not undergo further cyclization to imidazo[1,2-a]indole [4]. Therefore, it could be assumed that the presence of the methyl group instead of the hydrogen atom at the carbon atom located between indole ring nitrogen and carbonyl group of the salt 2d facilitates ring closure. A similar effect of easy ring closure induced by gem-dialkyl groups, known as the ThorpeIngold effect, is explained by a significant entropy change when an open branched chain molecule transforms to a small or medium size cycle [10]. The structure of compound 3d is confirmed by the presence of the signal of sp3-hybridized -carbon (C-9a) of the indole ring system at 91.51 ppm. Opening of the imidazolidine ring occurred, and formation of 3H-indolium perchlorates 2e,f took part, when compounds 3a,c were treated with perchloric acid. The structure of perchlorate 2f is proved by the presence in the 1H NMR spectrum of the benzyl CH2 group doublet at 4.25 ppm (J = 6.8 Hz), and absorption bands in the IR spectrum at 3330 (NH), 1685 (C=O) and 1550 cm-1 (amide II) characteristic of the secondary amides. Synthesis of diastereomeric indoline spiropyrans in a racemic form with chiral centers at C-2 and C-3 of the indole moiety was described in [11]. Coupling of (3R)-1,3-dimethyl-2-methylene-3-propylindoline with 5-nitro-salicylaldehyde afforded optically active diastereomeric (2R,3R)- and (2S,3R)-indoline spiropyrans, which demonstrated switchable optical activity [12]. 1461
piperidine, EtOH 2e
OHC HO
reflux
Me Me
Me Me
N O O NH2 H 4a Me
+
O
N O H Me 4b
NH2
Condensation of perchlorate 2e with 2-hydroxy-1-naphthaldehyde in ethanol containing a catalytic amount of piperidine afforded a mixture of two diastereomeric 1-(1-carbamoyl)ethylindoline naphtho[2,1-b]pyrans 4a,b as racemates. Compounds 4a,b possess chiral centers at C-2 of the indole ring system and C-1 of the N-(1-carbamoyl)ethyl side chain. 1H and 13C NMR spectra indicated a 3:2 ratio of the diastereomers in the mixture. The 1H NMR spectrum of the mixture of 4a,b contains overlapped doublets of H-2' at 5.74 (J = 10.5 Hz) and 5.76 ppm (J = 10.5 Hz) for the major and minor isomers, respectively. The signals of spiro atom C-2,3' at 104.35 (minor isomer) and 105.54 ppm (major isomer) in the 13C NMR spectrum of the mixture 4a,b were identified by the DEPT method.
EXPERIMENTAL All melting points were determined with a Kleinfeld melting point apparatus and are uncorrected. H NMR spectra were recorded with JEOL FX-100 (100 MHz, compounds 3b,c, 2e,f) and Bruker ASW 300 instruments (300 MHz, CDCl3, compounds 3a,d, 4a,b). 13C NMR spectra were obtained on a Bruker ASW 300 instrument (75 MHz, CDCl3). Chemical shifts (ppm) are given relative to tetramethylsilane (TMS). IR spectra were recorded on a PerkinElmer Spectrum BXII spectrometer (KBr pellets). Mass spectra were recorded on a Waters ZQ 2000 spectrometer (ion spray). For thin layer chromatographic (TLC) analyses, Merck precoated TLC plates (silica gel 60 F254) were used. 3,9,9,9a-Tetramethyl-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-one (3a). A mixture of 2,3,3-trimethyl-3H-indole 1a (1.99 g, 12.5 mmol) and 2-bromopropionamide (2.10 g, 13.8 mmol) was heated at 135C for 12 h in an atmosphere of nitrogen. The reaction mixture was dissolved in 15 ml of acetone and poured into 150 ml of 5% hydrochloric acid. The solution was extracted with ether (2 20 ml); then the acidic layer was alkalified with 10% potassium hydroxide and extracted with ether (3 20 ml). The extract was washed with 1% hydrochloric acid (2 20 ml) and water (20 ml), and dried over calcium chloride. The solvent was evaporated under reduced pressure and the residue crystallized from ethanol to give 0.92 g (32%), of compound 3a; mp 180181C. 1H NMR spectrum, , ppm (J, Hz): 1.16 (3H, s, CH3-9); 1.21 (3H, s, CH3-9); 1.49 (3H, s, CH3-9a); 1.55 (3H, d, J = 7.5, CH3-3); 3.72 (1H, q, J = 7.5, H-3); 6.65-7.10 (4H, m, ArH); 8.11 (1H, br. s, NH). 13C NMR spectrum, , ppm: 19.77 (CH3); 24.98 (CH3); 25.80 (CH3); 26.51 (CH3); 47.50 (C-9); 63.91 (C-3); 89.19 (C-9a); 112.77 (CH); 122.11 (CH); 122.51 (CH); 127.96 (CH); 139.18 (C); 151.01 (C); 177.31
1462
(C=O). Mass spectrum (ES+), m/z (rel. intensity): 253 (M+Na, 100), 231 (M+1, 26); mass spectrum (ES-), m/z (rel. intensity): 229 (M-1, 100). Found, %: C 73.31; H 7.70; N 12.09. C14H18N2O. Calculated, %: C 73.01; H 7.88; N 12.16. 1-Benzyl-3,9,9,9a-tetramethyl-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-one (3b). A mixture of 3H-indole 1a (3.18 g, 20 mmol) and 2-bromo-N-benzylpropionamide (7.26 g, 30 mmol) was heated at 135C for 6 h. The reaction mixture was dissolved in 20 ml of acetone, poured into 200 ml of 5% hydrochloric acid, and extracted with ether (2 30 ml). The acidic layer was basified with 10% potassium hydroxide and extracted with ether (2 20 ml). The extract was washed with 1% hydrochloric acid (2 20 ml) and water (20 ml), dried over calcium chloride, and evaporated under reduced pressure. The residue was purified by flash chromatography on aluminum oxide (eluent acetonehexane, 3:5) to give 3.01 g (47%) of compound 3b as a pale yellow oil. 1H NMR spectrum (CDCl3), , ppm (J, Hz): 0.93 (3H, s, CH3-9); 1.18 (3H, s, CH3-9); 1.41 (3H, s, CH3-9a); 1.60 (3H, d, J = 6.6, CH3-3); 3.79 (1H, q, J = 6.6, CH); 4.06-5.08 (2H, AB-q, J = 15.4, CH2); 6.74-7.40 (9H, m, ArH). Found, %: N 8.61. C21H24N2O. Calculated, %: N 8.74. 1-Benzyl-3,7,9,9,9a-pentamethyl-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-one (3c) was obtained similarly to compound 3b from (3.46 g, 20 mmol) of 3H-indole 1b (3.46 g, 20 mmol) and 2-bromo-Nbenzylpropionamide (7.26 g, 30 mmol). Yield of 3c was 3.61 g (54%); mp 71-72C (ether). 1H NMR spectrum (CDCl3), , ppm (J, Hz): 0.94 (3H, s, CH3-9); 1.18 (3H, s, CH3-9); 1.39 (3H, s, CH3-9a); 1.60 (3H, d, J = 6.6, CH3-3); 2.24 (3H, s, CH3-7); 3.75 (1H, q, J = 6.6, CH), 4.06-5.10 (2H, AB-q, J = 15.4, CH2); 6.66-7.47 (8H, m, ArH). Found, %: N 8.50. C22H26N2O. Calculated, %: N 8.38. 3,9,9,9a-Tetramethyl-1-phenyl-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-one (3d). The reaction of 3H-indole 1a (1.99 g, 12.5 mmol) and 4.28 g (18.75 mmol) of 2-bromo-N-phenylpropionamide was carried out according to the procedure described for compound 3a and yielded 0.95 g (25%) of the title compound; mp 132134C (ethanol). IR spectrum: 1703 cm-1 (C=O). 1H NMR spectrum, , ppm (J, Hz): 1.15 (3H, s, CH3-9); 1.24 (3H, s, CH3-9); 1.41 (3H, s, CH3-9a); 1.60 (3H, d, J = 6.9, CH3-3); 3.97 (1H, q, J = 6.9, H-3); 6.84-7.40 (9H, m, ArH). 13C NMR spectrum, , ppm: 21.32 (CH3); 21.81 (CH3); 26.45 (CH3); 30.33 (CH3); 50.26 (C-9); 61.06 (C3); 91.51 (C-9a); 114.47 (CH); 122.25 (CH); 122.84 (CH); 127.71 (CH); 128.18 (3CH); 129.11 (2CH); 136.75 (C); 142.53 (C); 147.87 (C); 174.28 (C=O). Found, %: C 78.02; H 7.40; N 9.16. C20H22N2O. Calculated, %: C 78.40; H 7.23; N 9.14. 1-(1-Carbamoylethyl)-2,3,3-trimethyl-3H-indolium Perchlorate (2e). To a solution of compound 3a (0.46 g, 2 mmol) in 3 ml of ethanol, 60% perchloric acid was added to pH 2 and the solution was stored at 0C for 14 h. The precipitated crystals were isolated by filtration and recrystallized from ethanol to yield 0.40 g (60%) of perchlorate 2e; mp 139-140C. IR spectrum, , cm-1: 3420 (NH), 3220 (NH), 1720 (C=O), 1115 (ClO4-). 1H NMR spectrum (TFA + acetone-d6), , ppm (J, Hz): 1.53 (6H, s, CH3-3,3); 1.98 (3H, d, J = 7.2, CHCH3); 2.87 (3H, s, CH3-2); 5.90 (1H, q, J = 7.2, CHCH3); 7.42-8.05 (6H, m, ArH, CONH2). Found, %: C 50.55; H 6.08; N 7.98. C14H19ClN2O5. Calculated, %: C 50.84; H 5.78; N 8.47. 1-[1-(N-Benzylcarbamoyl)ethyl]-2,3,3,5-tetramethyl-3H-indolium Perchlorate (2f) was obtained similarly to 2e from 3c (2.01 g, 6 mmol) and 60% perchloric acid in 1.10 g (42%) yield; mp 138-139C (ethanol). IR spectrum, , cm-1: 3330 (NH), 1685 (C=O), 1550 (amide II), 1110 (ClO4-). 1H NMR spectrum (TFA), , ppm (J, Hz): 1.21 (3H, s, CH3-3); 1.25 (3H, s, CH3-3); 1.70 (3H, d, J = 7.4, CHCH3); 2.11 (3H, s, CH3-5); 2.50 (3H, s, CH3-2); 4.25 (2H, d, J = 6.8, NHCH2); 5.51 (1H, q, J = 7.4, CHCH3); 6.91-7.18 (8H, m, ArH). Found, %: Cl 8.40. C22H27ClN2O5. Calculated, %: Cl 8.15. 1-[(R*)-1-(Carbamoyl)ethyl](2R*)-3,3-dimethyl-1,3-dihydrospiro[2H-indole-2,3'-[3H]naphtho[2,1-b]pyran] (4a) and Its (2R*)-1-[(S*)-1-(Carbamoyl)ethyl]isomer (4b). To a solution of perchlorate 2e (0.33 g, 1.0 mmol) and 2-hydroxy-1-naphthaldehyde (0.19 g, 1.1 mmol) in ethanol (4 ml) was added 2 drops of piperidine and the mixture was refluxed for 5 h. Then the reaction mixture was poured into 5% sodium acetate (30 ml) and extracted with ether (2 15 ml). The organic extract was washed with water (15 ml) and dried over MgSO4; the solvent was evaporated and the residue crystallized from ethanol to afford 0.23 g (60%) of a 1463
mixture of diastereomers 4a,b. 1H NMR spectrum of the mixture of 4a,b, , ppm (J, Hz): 1.17 (3H, s, CH3, major isomer); 1.22 (3H, s, CH3, minor isomer); 1.33 (3H, s, CH3, major isomer); 1.37 (3H, s, CH3, minor isomer); 1.45 (3H, d, J = 7.2, CHCH3, minor isomer); 1.55 (3H, d, J = 7.2, CHCH3, major isomer); 4.22 (1H, q, J = 7.2, CHCH3, minor isomer); 4.44 (1H, q, J = 7.2, CHCH3, major isomer); 5.35 (1H, br. s, NH, major isomer); 5.55 (1H, br. s, NH, minor isomer); 5.74 (1H, d, J = 10.5, H-2', major isomer); 5.76 (1H, d, J = 10.5, H-2', minor isomer); 6.41 (1H, br. s, NH, minor isomer); 6.52-8.03 (22H, m, ArH, major and minor isomers; NH, major isomer). 13C NMR spectrum, , ppm: 11.91, 14.89, 19.94, 20.18, 26.32, 26.80, 51.85, 52.28, 52.43, 52.77, 104.35, 105.54, 107.76, 109.98, 110.09, 110.70, 116.42, 116.47, 117.23, 117.72, 119.36, 120.30, 120.56, 120.74, 122.07, 122.20, 123.62, 123.89, 125.93, 126.53, 127.01, 127.19, 127.29, 127.51, 128.67, 127.70, 128.92, 129.18, 129.77, 129.80, 130.68, 130.85, 135.81, 137.33, 142.92, 143.09, 151.31, 151.59, 173.95, 175.25. Found, %: C 78.27; H 6.08; N 7.35. C25H24N2O2. Calculated, %: C 78.10; H 6.29; N 7.29.
REFERENCES 1. R. Raue, Methine Dyes and Pigments, in: B. Elvers, S. Hawkins, and G. Schultz (editors), Ullmann's Encylopedia of Industrial Chemistry, 5th Ed., VCH, Weinheim, Basel, Cambridge, New York, 1990, A16, p. 487. R. C. Bertelson, Spiropyrans, in: J. C. Crano and R. J. Guglielmetti (editors), Organic Photochromic and Thermochromic Compounds, Plenum Press, New York, London, 1999, 1, p. 11. Yu. A. Degutis, A. A. Sackus, and A. G. Urbanavicius, Khim. Geterotsikl. Soedin., 933 (1985). A. A. Sackus and Yu. A. Degutis, Khim. Geterotsikl. Soedin., 1485 (1986). S. Yamamoto and T. Taniguchi, Jpn. Kokai 62242686; Chem. Abstr., 108, 229708 (1988). H. Psaar and R. Raue, Ger. Offen. 3622009; Chem. Abstr., 108, 169175 (1988). A. Sackus and V. Amankaviciene, Khim. Geterotsikl. Soedin., 931 (2002). N. Kleiziene, V. Martynaitis, U. Berg, and A. Sackus, Khim. Geterotsikl. Soedin., 562 (2001). V. Martynaitis, A. Sackus, and U. Berg, J. Heterocycl. Chem., 39, 1123 (2002). E. L. Eliel and S. H. Wilen, Stereochemistry of Organic Compounds, John Wiley and Sons, New York, Chichester, Brisbane, Toronto, Singapore, 1994, 683. I. Gruda and R. M. Leblanc, Can. J. Chem., 54, 576 (1976). L. Eggers and V. Buss, Angew. Chem. Int. Ed. (Engl.), 36, 881 (1997).
2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.
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SYNTHESIS OF 1,2,3,9a-TETRAHYDRO9H-IMIDAZO[1,2-a]INDOLE-2-THIONE AND 1,5,6,10b-TETRAHYDROIMIDAZO[2,1-a]ISOQUINOLINE-2(3H)-THIONE DERIVATIVES

E. Valaityte, V. Martynaitis, and A. Sackus Thionation of 1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-one derivative with Lawesson's reagent in boiling toluene afforded 1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indole-2-thione derivative. Alkylation of the latter with ethyl iodide in DMF in the presence of a strong base gave 2-ethylthio-9,9,9a-trimethyl9,9a-dihydro-3H-imidazo[1,2-a]indole. 1,5,6,10b-Tetrahydroimidazo[2,1-a]isoquinoline-2(3H)-thiones were synthesized by thionation of the corresponding carbonyl substrates. Keywords: imidazo[1,2-a]indole, imidazo[2,1-a]isoquinoline, lactam, Lawesson's reagent, thionation. Thionation of heterocyclic compounds bearing lactam moieties is most commonly performed using phosphorus pentasulfide [1, 2] or 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawessons's reagent) [3, 4]. The latter reagent usually gives the expected thiolactams, while heating of the lactam moiety containing heterocycles, e.g., 2,3,4,5-tetrahydro-1,5-benzodiazepin-2-one derivative, with phosphorus pentasulfide in pyridine affords a mixture of tautomeric thiolactam and imino thiol [2]. In the present work we investigated the replacement of carbonyl oxygen of five-membered lactam-type rings annelated to the a-edge of indole or isoquinoline nucleus by the use of Lawessons's reagent as a thionation agent. Starting imidazo[1,2-a]indol-2-one derivatives 1a,b were obtained from 2,3,3-trimethyl- and 2,3,3,5-tetramethyl-3H-indoles by the method described in [5]. Compound 1c was prepared from 4a-methyl2,3,4,4a-tetrahydro-1H-carbazole by a similar way [6]. Thionation reactions of compounds 1a-c with Lawesson's reagent were carried out in boiling toluene and furnished thiolactams 2a-c in fairly good yields (63-72%). No tautomerization of the thiolactam moiety or possible rearrangement of the annelated imidazolidine ring to the thiazolidine ring via ring opening-closure was observed. The structure of prepared compounds 2a-c was proved by IR, 1H and 13C NMR, and microanalyses. In the IR spectrum of 2a NH stretching vibrations characteristic of secondary thioamides [7] were observed at 3135 cm-1, and no absorption band characteristic of stretching vibrations of C=O group of 1a at 1700 cm-1 was found. A comparison of the chemical shifts of the 1H and 13C nucleus of imidazo[1,2-a]indol-2-one 1a and the corresponding thione 2a showed that substitution of carbonyl oxygen for sulfur at C-2 induces significant lowfield shifts of the imidazolidine ring atom nucleus. In the 1H NMR spectrum (CDCl3) of 2a, the diastereotopic __________________________________________________________________________________________ Department of Organic Chemistry, Kaunas University of Technology, LT-3028 Kaunas, Lithuania; e-mail: algirdas.sackus@ktu.lt. Published in Khimiya Geterotsiklicheskikh Soedinenii, No 11, pp. 1695-1700, November, 2004. Original article submitted July 28, 2003. 0009-3122/04/4011-14652004 Springer Science+Business Media, Inc. 1465
Me R1 R N 1ac R NH O EtI, KOH DMF, r.t. Me Me Me NEt N 4 O Lawesson's reagent Me

2
Me R1 Lawesson's reagent R N 2ac R2 NH S EtI, KOH DMF, r.t. Me Me Me N N SEt 3
N 5
Me Me NEt S
1, 2 a R = H, R1 = R2 = Me; b R = R1 = R2 = Me; c R = H, R1 + R2 = CH2CH2CH2CH2
geminal protons on C-2 gave an AB-quadruplet at 4.23-4.38, and the signal of the NH proton of the thiolactam moiety was observed at 9.13 ppm, while the corresponding signals of the starting 1a were present at 3.72-3.92 and 7.44 ppm, respectively. In the 13C spectrum of 2a, the signal attributed to the thiocarbonyl carbon was observed at 199.22 ppm, and no signal of the carbonyl carbon of 1a at 174.50 ppm was detected. The C-3 and C-9a chemical shift values for compound 2a were found at 66.90 and 98.86 ppm, respectively, while the corresponding values in starting compound 1a were found at 55.21 and 91.25 ppm. Similar low-field shift effects were observed when C=O groups of polylactams were converted to C=S groups [4]. In our previous work, it was found that alkylation of imidazo[1,2-a]indol-2-one derivative 1a by alkyl iodides in aprotic polar solvent in the presence of a strong base afforded a mixture of N- and O-alkylated products, in a ratio ~5:1 [8]. However, it is known that alkylation of the thiolactam moiety usually gives S-alkylated products only [2, 9]. When imidazo[1,2-a]indole-2-thione 2a was treated with ethyl iodide in DMF in the presence of sodium hydroxide as a strong base, the only isolable product was cyclic imidoyl thioester 3. The 1H NMR spectrum of 3 showed three singlets and one triplet of four methyl groups in the 1.26-1.47 ppm interval together with a quadruplet of the SCH2 group at 2.99 and the AB-system of the NCH2 group in the 4.00-4.11 ppm interval. However, the 1H NMR spectrum gave no conclusive evidence regarding the structure of the ethylated product formed. For compound 3 the 13C chemical shift value of the methylene carbon in the ethyl substituent was especially valuable for the estimation of the S-ethylated product present. In the 13C NMR spectrum of 3 the signal atributed to the mentioned carbon (SCH2) is observed at 25.31, while the corresponding methylene group carbon signal (NCH2) of 4 is situated at 37.13 ppm. The 13C chemical shift value of the methylene carbon of the model compound, ethyl sulfide, is 25.5 ppm [10]. N-Ethylimidazo[1,2-a]indole-2-thione 5 was obtained by thionation of compound 4. In the 13C NMR spectrum of 5, the signal of the methylene carbon of the ethyl group is present at 41.61. The observed upfield shift of ~16 ppm on going from 3 to 5 can be explained by the higher electronegativity of the nitrogen atom in comparison with the sulfur atom.
R R N Me HN O 6a,b
6, 7a R = H; b R = OMe
Lawesson's reagent
R R N Me HN S 7a,b
1466
Further, we investigated thionation of imidazo[2,1-a]isoquinolinone derivatives. Starting compound 6a was synthesized by the known method [11], and compound 6b was obtained in a similar way. Heating to refluxing of compounds 6a,b with Lawesson's reagent in toluene afforded 7a,b. However, yields of the target products in such case did not exceed 30-32%. The 13C NMR spectra of 7a,b contained characteristic signals of the thiocarbonyl group carbon at 198.57 and 196.93 ppm, respectively.
EXPERIMENTAL All melting points were determined on a Kleinfeld melting point apparatus and are uncorrected. Infrared spectra were obtained on a PerkinElmer Spectrum BXII spectrometer (KBr pellets). 1H NMR spectra were measured with a Jeol FX-100 (100 MHz) and Varian Gemini 2000 (300 MHz) spectrometers. The 13C NMR spectra were recorded at 75 MHz using Varian Gemini 2000. The chemical shifts are reported in ppm downfield from tetramethylsilane, using residual CHCl3 (7.24 ppm) as reference for the proton spectra and CDCl3 (77 ppm) as reference for the carbon spectra. For thin layer chromatographic (TLC) analyses, Merck precoated TLC plates (Silica Gel 60 F254) were used. Column chromatography was performed with Silica Gel 60 (230-400 mesh) from Merck. 9,9,9a-Trimethyl-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-one (1a) was obtained in accordance with the method [5]. IR spectrum, , cm-1: 3175 (NH), 1700 (C=O). 1H NMR (300 MHz, CDCl3), , ppm (J, Hz): 1.18 (3H, s, CH3); 1.37 (3H, s, CH3); 1.51 (3H, s, CH3); 3.72-3.92 (2H, AB-system, 2JAB = 16.5, CH2CO); 6.70-7.17 (4H, m, ArH); 7.44 (1H, br. s, NH). 13C NMR spectrum (CDCl3), , ppm: 21.17 (CH3); 22.41 (CH3); 27.43 (CH3); 46.63 (C-9); 55.21 (C-3); 91.25 (C-9a); 112.63 (CH); 122.36 (CH); 122.51 (CH); 127.95 (CH); 138.70 (C-8a); 150.71 (C-4a); 174.50 (C=O). 9,9,9a-Trimethyl-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indole-2-thione (2a). To a stirred solution of imidazo[1,2-a]indolone 1a (3.68 g, 17 mmol) in 30 ml of toluene, Lawesson's reagent (3.44 g, 8.5 mmol) was added and the mixture was refluxed for 2.0 h. The reaction mixture was then cooled to room temperature and poured into 100 ml of 10% sodium carbonate solution. The mixture was extracted with ether (3 30 ml) and the combined organic extracts were washed with water (30 ml) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the residue recrystallized from ethanol to yield 2.72 g (69%) of thione 2a; mp 192-193C. IR spectrum, , cm-1: 3135 (NH). 1H NMR spectrum (300 MHz, CDCl3), , ppm (J, Hz) : 1.19 (3H, s, CH3); 1.42 (3H, s, CH3); 1.52 (3H, s, CH3); 4.23-4.38 (2H, AB-system, 2JAB = 17.4, NCH2); 6.73-7.18 (4H, m, ArH); 9.13 (NH). 13C NMR spectrum (CDCl3), , ppm: 19.57 (CH3); 22.57 (CH3); 27.68 (CH3); 46.68 (C-9); 66.90 (C-3); 98.86 (C-9a); 112.81 (CH); 122.41 (CH); 122.80 (CH); 128.18 (CH); 137.89 (C); 149.80 (C); 199.22 (C=S). Found, %: C 67.60; H 6.93; N 11.84; S 14.11. C13H16N2S. Calculated, %: C 67.20; H 6.94; N 12.06; S 13.80. 7,9,9,9a-Tetramethyl-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indole-2-thione (2b) was obtained similarly to compound 2a from compound 1b (1.50 g, 6.5 mmol) and Lawesson's reagent (1.31 g, 3.25 mmol) in 1.15 g (72%) yield; mp 197-198C (ethanol). IR spectrum, , cm-1: 3140 (NH). 1H NMR spectrum (100 MHz, CDCl3), , ppm: 1.17 (3H, s, CH3); 1.40 (3H, s, CH3); 1.50 (3H, s, CH3); 2.27 (3H, s, CH3-7); 4.27 (2H, s, NCH2); 6.59-6.98 (3H, m, ArH); 9.09 (1H, br. s, NH). Found, %: C 68.27; H 7.42; N 11.08; S 12.65. C14H18N2S. Calculated, %: C 68.25; H 7.36; N 11.37; S 13.02. 7a-Methyl-5,6,7,7a-tetrahydro-1H,4H-imidazo[2,1-k]carbazole-2(3H)-thione (2c) was obtained similarly to compound 2a from 1c (0.30 g, 1.24 mmol) and Lawesson's reagent (0.25 g, 0.62 mmol) in 0.20 g (63%) yield; mp 231-232C (ethanol). IR spectrum, , cm-1: 3125 (NH). 1H NMR spectrum (100 MHz, CDCl3), , ppm (J, Hz): 1.26-2.15 (8H, m, 4 CH2); 1.45 (3H, s, CH3); 4.15-4.55 (2H, AB-system, 2JAB = 16.3, NCH2); 6.76-7.31 (4H, m, ArH), 9.32 (1H, br. s, NH). Found, %: C 69.93; H 6.91; N 10.82; S 12.07. C15H18N2S. Calculated, %: C 69.73; H 7.02; N 10.84; S 12.41.
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2-Ethylthio-9,9,9a-trimethyl-9,9a-dihydro-3H-imidazo[1,2-a]indole (3). To a stirred solution of compound 2a (651 mg, 2.8 mmol) in dry DMF (8 ml) was added finely ground potassium hydroxide (219 mg, 5.6 mmol). After 10 min, ethyl iodide (0.46 ml, 5.6 mmol) was added dropwise at room temperature over a period of 20 min. The mixture was stirred for 1 h, poured into water (50 ml), and extracted with ether (3 15 ml). The combined extracts were washed with water (10 ml), dried with Na2SO4, and concentrated in vacuo to give a residue, which was purified by column chromatography on silica gel (eluent acetonehexane, 1:3) to yield 452 mg (62%) of 3 as an oil. 1H NMR spectrum (300 MHz, CDCl3), , ppm (J, Hz): 1.26 (3H, s, CH3); 1.26 (3H, t, 3J = 7.5, CH2CH3); 1.33 (3H, s, CH3); 1.47 (3H, s, CH3); 2.99 (2H, q, 3J = 7.5, SCH2); 4.00-4.11 (2H, AB-system, 2JAB = 15.2, NCH2); 6.68-7.12 (4H, m, ArH). 13C NMR spectrum (CDCl3), , ppm: 14.34 (CH3); 19.91 (CH3); 24.27 (CH3); 25.31 (SCH2); 28.37 (CH3); 46.59 (C-9); 63.34 (NCH2); 106.85 (C-9a); 112.77 (CH); 121.93 (CH); 122.36 (CH); 127.45 (CH); 140.33 (C-8a); 151.13 (C-4a); 165.20 (C=N). Found, %: C 69.43; H 7.90. C15H20N2S. Calculated, %: C 69.19; H 7.74. 1-Ethyl-9,9,9a-trimethyl-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-one (4) was obtained in accordance with the method [8]. 1H NMR spectrum (300 MHz, CDCl3), , ppm (J, Hz): 1.04 (3H, s, CH3); 1.29 (3H, t, 3J = 7.2, CH2CH3); 1.41 (3H, s, CH3); 1.47 (3H, s, CH3); 3.00-3.11 (1H, m, CHAHBCH3); 3.57-3.68 (1H, m, CHAHBCH3); 3.68 (1H, d, 2J = 15.3, CHAHBCO); 4.04 (1H, dd, 2J = 15.3, lng rangeJ = 0.3, CHAHBCO); 6.72-7.17 (4H, m, ArH). 13C NMR spectrum (CDCl3), , ppm: 13.88 (CH2CH3); 22.87 (CH3); 23.63 (CH3); 28.81 (CH3); 37.13 (CH2CH3); 49.46 (C-9); 54.74 (C-3); 92.01 (C-9a); 113.83 (CH); 121.97 (CH); 122.04 (CH); 128.20 (CH); 140.83 (C-8a); 148.44 (C-4a); 170.94 (C=O). 1-Ethyl-9,9,9a-trimethyl-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indole-2-thione (5) was obtained similarly to compound 2a from 4 (0.95 g, 3.9 mmol) and Lawesson's reagent (0.80 g, 2 mmol). Purification of the crude product by column chromatography on silica gel (eluent acetonehexane, 1:3) gave 0.41 g (40%) of compound 5 as an oil. 1H NMR spectrum (300 MHz, CDCl3), , ppm (J, Hz): 1.07 (3H, s, CH3); 1.41 (3H, t, 3 J = 7.2, CH2CH3); 1.47 (3H, s, CH3); 1.56 (3H, s, CH3); 3.27-3.38 (1H, m, CHAHBCH3); 4.14-4.24 (1H, m, CHAHBCH3); 4.18-4.60 (2H, AB-system, 2JAB = 16.8, CH2CO); 6.74-7.20 (4H, m, ArH). 13C NMR spectrum (CDCl3), , ppm: 12.31 (CH2CH3); 23.07 (CH3); 23.55 (CH3); 28.79 (CH3); 41.61 (CH2CH3); 50.29 (C-9); 67.06 (C-3); 90.04 (C-9a); 114.34 (CH); 122.09 (CH); 122.72 (CH); 128.64 (CH); 136.5 (C-8a); 149.60 (C-4a); 196.10 (C=S). Found, %: C 69.11; H 7.57. C15H20N2S. Calculated, %: C 69.19; H 7.74. 8,9-Dimethoxy-10b-methyl-1,5,6,10b-tetrahydroimidazo[2,1-a]isoquinolin-2(3H)-one (6b). A mixture of 6,7-dimethoxy-1-methyl-3,4-dihydroisoquinoline (6.16 g, 30 mmol) and -chloroacetamide (4.21 g, 45 mmol) was heated to reflux in 10 ml of acetonitrile for 5 h and then left at room temperature for 18 h. The crystalline solid that separated was filtered off and recrystallized from ethanol. The obtained salt (5.90 g) was dissolved in 100 ml of ice-cooled water and to the solution saturated sodium carbonate solution added until pH 9. The product was extracted with chloroform (5 50 ml), the combined extracts were washed with water (50 ml), dried with MgSO4, and evaporated under reduced pressure, and the residue was recrystallized from acetone to give 4.14 g (53%) of 6b; mp 162-163C. 1H NMR spectrum (300 MHz, CDCl3), , ppm (J, Hz): 1.64 (3H, s, CH3-10b); 2.46-3.06 (4H, m, CH2CH2); 3.35-3.57 (2H, AB-system, 2JAB = 14.9, CH2CO); 3.82 (6H, s, OCH3-8,9); 6.50 (1H, s, ArH); 6.75 (1H, s, ArH); 9.01 (1H, br. s, NH). 13C NMR spectrum (CDCl3), , ppm: 22.60 (CH3-10b); 29.36 (C-6); 43.09 (C-5); 52.60 (C-3); 55.38 (OCH3); 55.52 (OCH3); 75.81 (C-10b), 108.68 (CH); 110.34 (CH); 124.22 (C); 130.47 (C); 147.62 (C); 147.73 (C); 173.67 (C=O). Found, %: C 64.05; H 6.94; N 10.62. C14H18N2O3. Calculated, %: C 64.11; H 6.92; N 10.68. 10b-Methyl-1,5,6,10b-tetrahydroimidazo[2,1-a]isoquinoline-2(3H)-thione (7a). To a solution of compound 6a (2.02 g, 10 mmol) in 15 ml of toluene a solution of Lawesson's reagent (2.02 g, 5 mmol) was added and the mixture was heated to reflux for 1.5 h. The reaction mixture was cooled to room temperature, poured into 100 ml of 10% sodium carbonate solution, and extracted with ether (3 30 ml). The combined organic extracts were washed with water (30 ml) and dried over Na2SO4, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel (eluent tolueneethyl
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acetate, 1:5) to give 0.70 g (32%) of compound 7a; mp 70-71C (ethanol). IR spectrum, , cm-1: 3091 (NH). 1 H NMR spectrum (300 MHz, CDCl3), , ppm (J, Hz): 1.63 (3H, s, CH3); 2.72-3.07 (4H, m, CH2CH2); 3.73-4.19 (2H, AB-system, 2JAB = 17.0, CH2CS); 7.03-7.29 (4H, m, ArH); 9.72 (1H, br. s, NH). 13C NMR spectrum (CDCl3), , ppm: 26.21 (CH3); 28.98 (C-6); 45.97 (C-5); 66.97 (C-3); 84.19 (C-10b); 126.17 (CH); 127.07 (CH); 127.87 (CH); 128.79 (CH); 133.68 (C); 135.75 (C); 198.57 (C=S). Found, %: C 65.74; H 6.60; N 12.58; S 15.00. C12H16N2S. Calculated, %: C 66.02; H 6.46; N 12.83; S 14.68. 8,9-Dimethoxy-10b-methyl-1,5,6,10b-tetrahydroimidazo[2,1-a]isoquinoline-2(3H)-thione (7b) was obtained similarly to compound 7a from 6b (2.62 g, 10 mmol) and Lawesson's reagent (2.02 g, 5 mmol). Purification of the crude product by column chromatography on silica gel (eluent tolueneethyl acetate, 1:3) gave 0.84 g (30%) of compound 7b; mp 123-124C (ethanol). 1H NMR spectrum (300 MHz, CDCl3), , ppm (J, Hz) : 1.63 (3H, s, CH3-10b); 2.54-3.07 (4H, m, CH2CH2); 3.72-4.14 (2H, AB-system, 2JAB = 16.9, CH2CS); 3.78 (3H, s, OCH3); 3.84 (3H, s, OCH3); 6.49 (1H, s, ArH); 6.76 (1H, s, ArH); 10.33 (1H, br. s, NH). 13C NMR spectrum (300 MHz, CDCl3), , ppm: 24.22 (CH3), 27.77 (C-6); 44.46 (C-5); 54.77 (OCH3); 55.19 (OCH3); 64.48 (C-3); 83.11 (C-10b); 107.81 (CH); 109.84 (CH); 124.74 (C); 126.62 (C); 147.05 (C); 147.51 (C); 196.93 (C=S). Found, %: C 60.50; H 6.56. C14H18N2O2S. Calculated, %: C 60.41; H 6.52.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. Z. F. Solomko, P. A. Sharbatyan, A. A. Gaponov, and V. I. Avramenko, Khim. Geterotsikl. Soedin., 396 (1990). R. Janciene, Z. Stumbreviciute, L. Pleckaitene, and B. Puodziunaite, Khim. Geterotsikl. Soedin., 837 (2002). A. A. El-Barbary, S. Carlsson, and S.-O. Lawesson, Tetrahedron, 38, 405 (1982). Y. Inoue, T. Kanbara, and T. Yamamoto, Tetrahedron Lett., 44, 5167 (2003). Yu. A. Degutis, A. A. Sackus, and A. G. Urbanavicius, Khim. Geterotsikl. Soedin., 933 (1985). A.Sackus, S. Krikstolaityte, and V. Martynaitis, Khim. Geterotsikl. Soedin., 645 (1999). G. Socrates, Infrared Characteristic Group Frequencies, John Wiley and Sons, Chichester, New York, Brisbane, Toronto, 172 (1998). A. A. Sackus and Yu. A. Degutis, Khim. Geterotsikl. Soedin., 49 (1988). J. Girniene, D. Gueyrard, A. Tatibouet, A. Sackus, and P. Rollin, Tetrahedron Lett., 42, 2977 (2001). M. Hesse, H. Meier, and B. Zeeh, Spectroscopic Methods in Organic Chemistry, Georg Thieme Verlag, Stutgart, New York, p. 195 (1997). R. Degutyte, A. Sackus, and U. Berg, J. Chem. Res. (S), 540 (2001).
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REACTIONS OF 5-DIAZOIMIDAZOLES WITH STEROID HYDRAZONES

E. V. Sadchikova, E. A. Kureneva, E. A. Shtokareva, and I. S. Selezneva The reaction of 5-diazoimidazoles with steroid hydrazones was studied. The structure of the steroid derivative was found to have a significant effect on the direction of the nitrogen transfer in the unstable intermediate tetrazene. The presence of a labile proton in the reaction mixture permits stabilization of one of the tetrazene forms such that only direction was found for the nitrogen transfer in all the reactions studied, leading to imidazole azides and iminosteroid derivatives. Keywords: 5-azidoimidazoles, 3-hydrazono-5-hydrazono-5-androstan-17-ol, 17-hydrazonoestra1,3,5(10)-trien-3-ol, 5-diazoimidazoles, 3-imino-5-androstan-17-ol, 17-iminoestra-1,3,5(10)-trien-3ol, tetrazenes. Nitrogen-transfer reactions between aromatic diazo compounds and aliphatic hydrazine have been studied by Tishler [1, 2]. Depending on the nature of the reagents, the reaction product may lead either to a stable tetrazene, which can be isolated as a solid, or products of tetrazene decomposition. In the latter case, nitrogen transfer occurs, leading to the formation either of an aromatic azide and aliphatic amine or of an aromatic amine and aliphatic azide. In the present work, we studied the reaction of 5-diazoimidazoles 1a-d possessing antitumor and antibacterial activity [3-5] with steroid hydrazones 2 and 3, which also display antitumor activity [6]. The products, tetrazenes 4 and 5, may hold interest since they display selective penetration into tumors both as diazoimidazoles and steroid hormones. We might have expected the formation of a mixture of multiple products, which would be difficult to separate into individual components, since nitrogen transfer upon decomposition of the tetrazene could occur concurrently in two directions. Furthermore, 5-diazoimidazole-4-carboxamide (1a) and 5-diazoimidazole-4-(Nmethylcarboxamide) (1b) may undergo intramolecular cyclization leading to imidazotriazines 6a and 6b [5, 7, 8]. The reaction course and composition of the reaction mixture were monitored by thin-layer chromatography with reference to known standards. Thus, azidoimidazoles 7a-c were obtained according to our previous procedure [9, 10]. The ethyl ester of 5-azidoimidazole-4-carboxylic acid (7d) was obtained for the first time from the reaction of the ethyl ester of 5-diazoimidazole-4-carboxylic acid (1d) with sodium azide in aqueous ethanol. Unfortunately, we were unable to obtain the corresponding steroid references either by reduction with NaBH4, LiAlH4, Na2S2O4, Ni/Ra, or Pd/C or by diazotization of steroid hydrazones due to the instability of the corresponding amine and azide products.
__________________________________________________________________________________________ Urals State Technical University, 620002 Yekaterinburg, Russia; e-mail: selena@htf.ustu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1701-1708. Original article submitted February 28, 2002, submitted after revision November 26, 2003. 1470 0009-3122/04/4011-14702004 Springer Science+Business Media, Inc.
The reaction of 5-diazoimidazoles 1a-d with 17-hydrazono-1,3,5(10)-trien-3-ol (2) was carried out at room temperature in the dark by adding the chloroform extract of the corresponding diazo derivative to a solution of steroid 2 in ethanol. Two products are obtained in the reactions of 5-diazo-4-nitroimidazole 1c and 1d, one of which corresponds in chromatographic mobility with the corresponding azidoimidazole 7c or 7d obtained in our previous work. The Rf values of the second product proved identical. Furthermore, treatment of the chromatographic plate with iodine vapor gave blue spots, which is characteristic for steroid derivatives [11]. Scheme 1
H2N N R N N 1ad N2 HO 2
N R N N H N N H N 4ad NH N OH
R N N H 7ad N N +_ N
+
HO 8
N N 6a,b N
N H
1, 4, 7 a R = CONH2, b R = CONHMe, c R = NO2, d R = COOEt; 6 a R1 = H, b R1 = Me
Three products were found in the analysis of the mixture obtained in the reactions of 5-diazoimidazoles 1a and 1b. One of these products, as in previous cases, has the same chromatographic mobility as azides 7a and 7b. The second product is a steroid and the third has an Rf value corresponding to imidazotriazinones 6a and 6b. In all the cases studied, the reaction of the 5-diazoimidazoles with hydrazone 2 leads to a single steroid product. This product was isolated from the reaction mixture as a white precipitate upon the addition of cold water. The elemental analysis as well as 1H NMR and IR spectroscopy indicate that this product is 17-iminoestra-1,3,5-trien-3-ol (8). We found that the unstable intermediate tetrazenes 4a-d, formed in the reaction of diazoimidazoles 1a-d with steroid hydrazone 2, decompose immediately to give imidazole azides 7a-d and estratrienimine 8. In contrast to previous findings [1, 2, 9], the direction of the nitrogen transfer in the case of steroid 2 is independent of the structure of the diazoimidazoles (Scheme 1). In the next stage of this work, we studied the reaction of diazoimidazoles 1a-d with 3-hydrazono-5androstan-17-ol (3). This reaction was carried out similarly to the reaction with hydrazone 2. Azidoimidazole 7c was found upon chromatographic analysis of the reaction mixture in the case of diazoimidazole 1c. The
1471
decomposition of the tetrazene formed proceeds in the same direction as in the reaction with 2. Support for this conclusion was obtained in the isolation and identification of the second reaction product, which proved to be imine 9 (Scheme 2). Scheme 2
OH
1ad
N H2N 3
R N N H N N H N N OH
R N N H N H N N N OH
R N N H N H N N
H N OH
5ad
OH
7ad
+
HN HO 9
6a,b
R N
+
N3 11
+
N H
NH2 10ac
5, 10 a R = CONH2, b R = CONHMe; 5c R = NO2; 5d, 10c R = COOEt
1472
Chromatographic analysis of the reaction mixtures obtained in the reactions of 5-diazoimidazoles 1a and 1b with hydrazone 3 unexpectedly showed the formation of five products rather than three as in the case of steroid 2. Relative to their chromatographic mobility, three of these products were characterized as azidoimidazoles 7a and 7b, aminoimidazoles 10a and 10b, and azoamino coupling products 6a and 6b. These findings and consideration of the possible directions for tetrazene decomposition suggested that the two remaining products might be imine 9 and azide 11. Thus, the decomposition of intermediate tetrazene 5a and 5b probably proceeds concurrently through two opposite directions. Unfortunately, it proved impossible to separate this mixture and identify its individual components due to the similar chromatographic mobility and instability of these components. The reaction of ester 1d and steroid 3 gave two products, one of which could be isolated. The isolated product was identified as the ethyl ester of 5-aminoimidazole-4-carboxylic acid (10c), identical to an authentic sample. According to the decomposition scheme, the second product might be steroid azide 11. Unfortunately, this product could not be isolated as a pure sample and identified as in previous attempts upon the diazotization of hydrazone 3. A study of the reaction of diazoimidazoles 1a-d with steroid hydrazone 3 showed that the direction of the nitrogen transfer in this case varies depending on the structure of the starting diazo compound and three possible pathways are possible for decomposition of the tetrazene (Scheme 2). Analysis of these results showed that the pathways for the nitrogen transfer in the reactions of the ethyl ester of imidazocarboxylic acid 1d with hydrazones 2 and 3 are completely divergent. Let us attempt to explain this difference on the basis of the structure of the starting steroid hydrazones. Thus, the hydroxy group in hydrazone 3 is attached to a saturated aliphatic ring, while this group is attached to an aromatic ring in steroid 2. This might affect the stabilities of the various forms of intermediate tetrazene 4a-d. Hence, we attempted to obtain an experimental model for stabilization of a specific form of the intermediate tetrazene by adding a compound with an analogous structural fragment to the reaction mixture of the diazoimidazoles with hydrazone 3. Phenol was selected as the simplest model compound. The reaction of diazoimidazoles 1a-d and hydrazone 3 with added phenol (the phenol/steroid mole ratio was 1:1) at room temperature in ethanolic chloroform was carried out in the dark (Scheme 3). The reaction mixture was analyzed immediately after mixing the reagents. In the case of diazoimidazole 1c, the same products were found as in the case without added phenol. Chromatographic analysis of the products of the reaction of 5-diazoimidazoles 1a and 1b with steroid 3 in the presence of phenol showed the formation of the formation of three products instead of five: azides 7a and 7b, steroid imine 9, and the corresponding imidazotriazinones 6a and 6b, i.e., the direction of the nitrogen transfer was altered. Scheme 3
PhOH
1ad +
[ 5ad ]
+ 7ad
6a,b
The reaction of diazo ester 1d with hydrazone 3 also features a change in the direction of the nitrogen transfer upon adding phenol to the reaction mixture. Azido ester 7d and steroid imine 9 were detected chromatographically, while amino ester 10c is formed in the analogous reaction without phenol. Thus, the addition of phenol leads to stabilization of a tetrazene form different from the structure formed in the reaction of these same reagents without phenol. The steroid derivative isolated from this reaction proved identical in its physicochemical properties, elemental analysis data, and chromatographic mobility to a sample of 3-imino-5-androstan-17-ol (9) obtained in our previous work. The imidazole NH group acid fragment probably plays the role of the acid fragment in the case of 5-diazo-4-nitroimidazole 1c analogously to the aromatic OH group in phenol or hydrazone 2. 1473
We attempted to elucidate if the amount of phenol affects the reaction course and composition of the reaction mixture. Diazoester 1d was selected from the four diazo compounds studied for this investigation since no change occurs in the direction of the nitrogen transfer in the reaction with steroid 3 and phenol in the case of 5-diazo-4-nitroimidazole 1c, while an azoamino coupling side-product is formed in the case of 1a and 1b, which complicates the analysis and monitoring of these reactions. Thus, phenol was added to the reaction mixture containing diazo ester 1d and hydrazone 3 in the following mole ratios relative to the starting steroid: 1:1, 0.8:1, 0.6:1, 0.4:1, 0.3:1, and 0.2:1. We found that the direction of the nitrogen transfer is altered for ratios 1:1, 0.8:1, 0.6:1, and 0.4:1, while the same products are formed in the case of lower phenol/steroid ratios as in the reaction without phenol. Therefore, the ratio of phenol to the starting steroid of 0.4:1 is sufficient to change the direction of the nitrogen transfer. In the next phase of our investigation, we studied the effect of the phenol structure on the rate and direction of the nitrogen transfer. 2,4-Diaminophenol, 3,4-dimethylphenol, and p-nitrophenol were used as the phenol components. The reactions were carried out according to the procedure described above and showed that, in all cases, the same products were formed over identical time periods as in the reaction with phenol. Therefore, the structure of the phenol added does not affect the direction of the nitrogen transfer. It is also interesting to note that the addition of phenol and phenol derivatives in the reaction of diazoimidazoles 1a-d with 2 does not alter the product composition. This supports our hypothesis that the hydroxy group attached to the benzene ring is involved in stabilizing one of the forms of the intermediate tetrazene derivative in the reactions of diazo compounds 1a-d with hydrazones 2 and 3. The role of phenol is likely related to its stabilization of the enamine form of tetrazenes 5a-d due to the addition of the acidic proton from the phenol or aromatic OH group of 2 to the CH bond at the double bond or formation of an intermediate complex of the starting steroid with the phenol, which then reacts with the diazo compound to give intermediate tetrazenes 5a-d, mainly in a form such that decomposition would lead to formation of azidoimidazoles 7a-d and iminosteroid 9. In the case of hydrazone 2, the analogous complex is probably formed from two molecules of starting steroid 2 due to the OH group on the aromatic ring. We should note that not only phenol and its derivatives but also concentrated acetic acid added in 1:1 ratio relative to the starting steroid has an analogous effect on the outcome of the reaction of diazoimidazoles 1a-d with 3 under the same conditions. Thus, the results of our study of the nitrogen transfer in acid media support our hypothesis of stabilization of one of the forms of the intermediate tetrazenes by the action of hydrogen ions.
EXPERIMENTAL The IR spectra of the products were taken for KBr pellets on a Specord IR-75 spectrometer. The H NMR spectra were taken on a Bruker WR-80 spectrometer at 80 MHz for solutions in DMSO-d6 with TMS as the internal standard. The reaction course and purity of the samples were monitored by thin-layer chromatography on Silufol UV-254 plates with STKh-1 silica gel and the following solvent systems: a) 3:1 chloroformethanol, b) 6:1 chloroformethanol, c) 15:1 chloroformethanol, and d) 4:1:1 1-butanolacetic acid water. Samples of 17-hydrazonoestra-1,3,5(10)-trien-3-ol (2) and 3-hydrazono-5-androstan-17-ol (3) were obtained according to our previous procedure [6]. Samples of 5-diazoimidazoles 1a-d were prepared according to reported procedures [9, 12-15], while samples of the 5-aminoimidazoles were prepared according to Allsebrook [16], Mokrushin [17, 18], and Gireva [19]. Ethyl Ester of 5-Azidoimidazole-4-carboxylic Acid (7d). A solution of sodium azide (0.09 g, 1.39 mmol) in water (3 ml) was added to a cooled solution of ethyl ester of 5-diazoimidazole-4-carboxylic acid 1d (0.23 g, 1.39 mmol) in ethanol (5 ml). The mixture was maintained for 15 min in the cold. The product was extracted with ether and the solvent was distilled off to give 0.1 g (40%) 7d; Rf 0.71 (b). IR spectrum, , cm-1:
1
1474
1705 (C=O), 2125 (N3), 3350 (NH). 1H NMR spectrum, , ppm, (J, Hz): 1.35 (3H, t, J = 7.0, CH3); 4.42 (2H, d, J = 7.0, CH2); 7.81 (1H, s, H(2)); 12.76 (1H, br. s, NH). Found, %: C 39.58; H 3.74; N 38.84. C6H7N5O2. Calculated, %: C 39.78; H 3.89; N 38.66. 17-Iminoestra-1,3,5-trien-3-ol (8). A. A solution of diazoimidazole 1a-d (1 mmol) in chloroform was added to a suspension of hydrazone 2 (1 mmol) in ethanol (5 ml). The mixture was maintained at room temperature and stirred in the dark. The precipitate was filtered off and crystallized from 96% aq. ethanol to give 8 in 75-80% yield; mp >300C, Rf 0.91 (a). IR spectrum, , cm-1: 1040-1150 (CC), 1370 (OH), 1610 (arom. CH), 1440, 2860 (CH3), 3270-3440 (NH2), 3270 (C=NH). 1H NMR spectrum, , ppm, (J, Hz): 0.9 (1H, s, CH3); 1.0-3.0 (15H, CH, CH2); 6.45 (1H, s, H(4)); 6.5 (1H, d, J = 8.2, H(1)); 7.1 (1H, d, J = 8.2, H(2)); 8.95 (1H, s, OH). Found, %: C 80.13; H 3.81; N 5.19. C18H23NO. Calculated, %: C 80.26; H 8.61; N 5.20. B. A sample of phenol (1 mmol) was added to a suspension of hydrazone 2 (1 mmol) in ethanol (5 ml), followed by diazoimidazole 1a, c, or 1d (1 mmol) in chloroform. The mixture was maintained at room temperature and stirred in the dark. The precipitate was filtered off and crystallized from 96% aq. ethanol to give 8 in 70-75%. Reaction of Diazoimidazoles 1a, 1b, and 1d with Hydrazone. A solution of diazoimidazole 1a, 1b, or 1d (1 mmol) in chloroform was added to a suspension of hydrazone 3 (1 mmol) in ethanol (5 ml). The mixture was maintained at room temperature and stirred in the dark. 3-Imino-5-androstan-17-ol (9). A. A solution of 5-diazo-4-nitroimidazole 1c (0.14 g, 0.99 mmol) in chloroform was added to a suspension of hydrazone 3 (0.3 g, 0.99 mmol) in ethanol (5 ml). The mixture was maintained at room temperature and stirred in the dark. Then, cold water (10 ml) was added. The precipitate was filtered off and crystallized from 96% aq. ethanol to give 0.2 g (70%) of compound 9; mp 235-238C, Rf 0.72 (b). IR spectrum, , cm-1: 1050 (OH), 1050-1110 (CC), 1380, 1440 (CH3), 1640, 3400 (C=NH), 2850 (CH). 1 H NMR spectrum, , ppm: 0.64 (1H, s, CH3); 0.89 (1H, s, CH3); 0.7-3.0 (23H, m, CH, CH2); 3.43 (1H, m, NH); 4.22 (1H, d, OH). Found, %: C 77.68; H 10.12; N 5.28. C19H31NO. Calculated, %: C 78.80; H 10.73; N 4.84. B. A sample of phenol (1 mmol) was added to a suspension of hydrazone 3 (1 mmol) in ethanol (5 ml), followed by diazoimidazole 1a-d (1 mmol) in chloroform. The mixture was maintained at room temperature and stirred in the dark. Then, cold water (10 ml) was added. The precipitate was filtered off and crystallized from 96% aq. ethanol to give 9 in 50% yield. Reaction of Diazoimidazoles 1a-d with Hydrazone 3 in the Presence of Acetic Acid. A sample of acetic acid (1 mmol) was added to a suspension of hydrazone 3, followed by a solution of diazoimidazole 1a-d (1 mmol) in chloroform. The mixture was maintained at room temperature and stirred in the dark. This work was carried out with the financial support of the Russian Basic Research Fund (Grant No. 01-03-96433a).
REFERENCES 1. 2. 3. 4. 5. 6. M. Tishler and B. Stanovik, Heterocycles, 4, 1115 (1976). M. Tishler and B. Stanovik, Khim. Geterotsikl. Soedin., 579 (1980). J. Yamamoto, Biochem. Pharmacol., 18, 1463 (1969). H. Iwata, J. Yamamoto, and H. Muraki, Biochem. Pharmacol., 20, 297 (1971). Y. F. Shealy, R. F. Struck, L. B. Holum, and J. A. Montgomery, J. Org. Chem., 26, 2396 (1961). E. A. Shtokareva, V. I. Nifontov, N. D. Lagova, Z. P. Sof'ina, V. I. Kiselev, Z. S. Smirnova, A. B. Syrkin, O. I. Konyaeva, L. N. Volovel'skii, V. V. Natarov, and I. A. Rastrepina, USSR Inventor's Certificate 1240038 (1986); Chem. Abstr., 126, 305673 (1997). J. K. Horton and M. F. G. Stevens, J. Chem. Soc., Perkin Trans. 1, 1433 (1981).
7.
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8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.
V. S. Mokrushin, E. F. Golovina, V. I. Nifontov, V. A. Bakulev, T. A. Pospelova, and V. K. Usova, Khim. Geterotsikl. Soedin., 1552 (1983). V. S. Mokrushin, I. S. Selezneva, T. A. Pospelova, V. K. Usova, S. M. Malinskaya, G. M. Anoshina, T. E. Zubova, and Z. V. Pushkar'eva, Khim.-farm. Zh., 16, 303 (1982). V. S. Mokrushin, I. S. Selezneva, V. I. Nifontov, and Z. V. Pushkareva, Khim. Geterotsikl. Soedin., 1536 (1980). L. Fieser and M. Fieser, Steroids [Russian translation], Mir, Moscow (1964). M. F. G. Stevens and G. U. Baig, J. Chem. Soc., Perkin Trans. 1, 665 (1981). M. Kocevar, D. Kolman, H. Krajnc, S. Polanc, B. Porovne, B. Stanovik, and M. Tisler, Tetrahedron, 32, 725 (1976). V. S. Mokrushin, V. I. Ofitserov, T. V. Rapakova, A. G. Tsaur, and Z. V. Pushkareva, Khim. Geterotsikl. Soedin., 556 (1976). V. I. Nifontov, I. S. Selezneva, V. S. Mokrushin, Z. V. Pushkareva, and V. A. Trofimov, Khim. Geterotsikl. Soedin., 984 (1979). W. E. Allsebrook, J. M. Gulland, and L. F. Story, J. Chem. Soc., 232 (1942). V. S. Mokrushin, N. A. Belyaev, M. Yu. Kolobov, and A. N. Fedotov, Khim. Geterotsikl. Soedin., 1421 (1983). V. S. Mokrushin, V. I. Nifontov, Z. V. Pushkareva, and V. I. Ofitserov, Khim. Geterotsikl. Soedin., 1421 (1971). R. N. Gireva and N. S. Dobychina, Izv. Tomsk. Politekhn. Inst., 102, 108 (1959).
1476
SYNTHESIS OF 2-R-4,5,7-TRIMETHYL-1-VINYL4,5,6,7-TETRAHYDROPYRROLO[3,2-c]PYRIDINES
T. N. Borisova, Nsabimana Bonifas, L. G. Voskresenskii, A. I. Chernyshev, A. V. Varlamov, and A. P. Krapivko The synthesis of 1-vinyltetrahydropyrrolo[3,2-c]pyridines substituted at C(2) has been accomplished, based on 4,5,7-trimethyl-1-vinyl-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridine and its 2-formyl-substituted derivative. Keywords: tetrahydropyrrolopyridine, aminomethylation, condensation, elimination. N-Vinylpyrrroles have been well studied [1]. However their structural analogs, the 1-vinyltetrahydropyrrolo[3,2-c]pyridines, have scarcely been investigated. It has only been shown that formylation and nitration of 4,5,7-trimethyl-1-vinyl-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridine (1) occurs at the -position of the pyrrole ring to give the 2-formyl and 2-nitro derivatives [2,3]. Tetrahydropyrrolo[3,2-c]pyridines are of interest as anti-aggregating compounds [4], synthons for the preparation of polymers and more complex structures containing the tetrahydropyrrolopyridine unit. In this report we present the results of our work on the synthesis of 1-vinyl-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridines, substituted at position 2, based on N-vinyltetrahydropyrrolopyridine 1 [3] and its 2-formyl-substituted derivative 2 [2]. Trifluoroacetylation of compound 1 in methylene chloride in the presence of pyridine and Mannich aminomethylation proceeds at the -position of the pyrrole ring to give the 2-trifluoroacetyl, 2-(N,N-dimethylamino)methyl, and 2-(N-morpholino)methyl derivatives 3-5.
Me Me N (CF3CO)2O N Me 3 Me Me CH2O, NHR2 N N Me 4, 5 CH2NR2 COCF3 Me 1 N Me N Me
4 R2 = Me2; 5 R2 = (CH2CH2)2O
__________________________________________________________________________________________ Russian People's Friendship University, Moscow 117198; e-mail: avarlamov@sci.pfu.edu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, 1709-1716, November, 2004. Original article submitted September 25, 2002. 0009-3122/04/4011-14772004 Springer Science+Business Media, Inc. 1477
A second group of tetrahydropyrrolo[3,2-c]pyridines substituted at position 2 was obtained by transformation of the formyl group of the 2-formyl-substituted derivative 2. Reduction, and condensation with hydroxylamine and malononitrile were carried out. All the reactions occurred in almost quantitative yield to give the 2-hydroxymethyl-, 2-hydroxyiminomethyl-, and 2-,-dicyanovinyl-substituted derivatives 6-8 respectively. A series of new substituted tetrahydropyrrolo[3,2-c]pyridines were obtained by reactions of compound 8. Its condensation with malononitrile in the presence of NaOH [5] gave 2-(6'-amino-3',5'-dicyano-2'-ethoxypyridin-4yl)-4,5,7-trimethyl-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridine (9) in 15% yield. Elimination of the dicyanomethenyl group occurs when compound 8 is treated with hydrazine hydrate to give the azine 10. N-Devinylation of compound 8 to give the NH-tetrahydropyrrolopyridine 11 under conditions of acid solvolysis. Devinylation of N-vinylpyrroles under acid hydrolysis conditions has been reported in [6].
Me Me N N NaBH4 Me Me N N Me 6 Me N N CH2(CN)2 NaOH Me Me N N Me 9 Me N N H Me 11 NC OEt Me CH=C(CN)2 Me 10 NC NH2 Me N HCl EtOH N 2 N Me 8 CH2OH Me 2 CHO
NH2OH Me Me N N Me 7 CH=C(CN)2 CH=NOH
CH2(CN)2 Me
NH2NH2 Me _ CH=N
The structures of compounds 3-11 have been confirmed by IR, 1H NMR, and mass spectroscopic data. Molecular ion peaks corresponding to the molecular formula were observed in the mass spectra of all these compounds, as a rule with low intensity. The basic decomposition of the ions [M]+ is via elimination of methyl groups. The fragment ions [M -15]+ have the maximum intensity for all these compounds. The IR spectra of compounds 3-10 are characterized by the presence of sharp intense bands for the stretching of the NCH=CH2 in the 1637-1670 cm-1 [1]. In the IR spectra of compounds 7 and 10 the C=N stretching frequency of the imino 1478
group occurs at 1625 and 1615 cm-1 respectively, while there are broad bands for the associated NH bond in compounds 9 and 11 with maxima at 3400 and 3150 cm-1 respectively. Apart from this the characteristic bands of the functional groups appear in the IR spectra of the tetrahydropyrrolopyridines: 1670 COCF3 (compound 3), 3348 and 3320 OH (compounds 6 and 7), 2220-2310 cm-1 CN (compounds 8, 9, 11). The 1H NMR spectra of compounds 3-11 (Table 1) contain the signals of all the hydrogens in the molecules with the corresponding chemical shifts and coupling constants. The protons of the N-vinyl groups are observed as three groups of signals with chemical shifts 4.65-5.33 (H-trans), 4.89-5.61 (H-cis), and 6.78-7.33 ppm (H-x) and vicinal coupling constants 3Jtrans = 15.6-16.2 and 3Jcis = 8.2-9.2 Hz. The signal for proton H-3 in the 1H NMR spectra of compounds 4-10 is observed as a singlet, while in compounds 3 and 11 it appears as a quartet and a broad singlet as a result of spin-spin coupling with fluorine atoms and H-N respectively. The oxime 7 is formed as a mixture of two isomers (ratio 2:3) as shown by the presence in its 1H NMR spectrum of two signals for each of the protons. Particular notice should be payed to the large difference in the chemical shifts of the H-3 protons = 0.85 ppm whereas this difference for isomers of 2-hydroxyiminomethyl4,5,7-trimethyl-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridine without a substituent at the pyrrolo nitrogen is only 0.08 ppm [2]. It is assumed from these data that compound 7 has the pyrrole ring and the C=N in the s-cis conformation as a result of steric interaction between the N-vinyl groups and the azomethine fragment of the isomers.
Me Me N N Me Z-7 Me Me N N Me 8 H H N C C N HO N: Me E-7 Me N N H Me
..
OH
To establish the configuration of the isomers of oxime 7 we used the values of the chemical shift of the azomethine proton HC=N, which underwent a weak field shift when cis to the unshared pair of the nitrogen atom, and also the value of the chemical shift of proton H-3 which also should show the influence of this pair in the s-cis configuration of the oxime. On this basis the isomer with weaker field signal for the azomethine proton HC=N and the stronger field signal for the proton H-3 was assigned the Z-configuration, and the isomer with the stronger field signal for HC=N and the weaker field signal for H-3 was assigned the E-configuration. The ratio of the Z- to E-isomers was 2:3. The analogous weak field shift by 0.83 ppm of the H-3 proton in the 1H NMR spectrum of 2--dicyanovinyl-1-vinyltetrahydropyrrolo[3,2-c]pyridine 8 in comparison with its analog without a substituent at the pyrrole nitrogen atom 11, also permits the conclusion that the pyrrole ring and the dicyanovinyl unit are in the s-cis configuration in compound 8. Thus we have accomplished the synthesis of new substituted 1-vinyltetrahydropyrrolo[3,2-c]pyridines and we have proposed on the basis of their 1H NMR spectra the steric interaction of the 1-N-vinyl group with the substituents at position 2 which determines the conformational configuration of the substituents and the pyrrole ring.
1479
1480
TABLE 1. 1H NMR Spectra of 2-Substituted Tetrahydropyrrolo[3,2-c]pyridines 3-11

Compound 1 3 Chemical shifts, , ppm. (J, Hz) -3 2 7.00, q (J = 0.9) -4 3 3.31,q (J = 6.4) -6 4 2.25, dd (J = 11.9, J = 8.5); 3.10, dd (J = 11.9, J = 5.8) 2.18, dd (J = 11.3, J = 7.9); 3.03, dd (J = 11.3, J = 5.5) 2.20, dd (J = 11.6, J = 7.6); 3.03, dd (J = 11.6, J = 5.8) 2.20, dd (J = 11.6, J = 7.6); 3.02, dd (J = 11.6, J = 5.5) 2.20-2.30, m, 3.00-3.45, m -7, m 5 3.30 CH3-4, d 6 1.34 (J = 6.4) CH3-5, s 7 2.44 CH3-7, d 8 1.21 (J = 6.4) -cis 9 5.31, d (J = 8.5) =ct -trans 10 5.27,d (J = 15.9) 2-R , dd 11 7.33 (J = 15.9, J = 8.5) 6.96 (J = 15.9, J = 8.9) 6.98 (J = 16.2, J = 9.2) 6.90 (J = 15.9, J = 8.9) 6.85 (J = 15.6, J = 8.2) 12
5.81, s
3.15-3.32,q (J = 6.4)
3.15-3.32
1.26 (J = 6.4)
2.41
1.18 (J = 6.4)
4.89, d (J = 8.9)
5.22, d (J = 15.9)
2.19 (N(CH3)2); 3.10 (J = 13.4, NCHAHB); 3.44 (J = 13.4, NCHAHB) 2.302.55 ((CH2)2N); 3.22 (J = 13.4, NCHAHB); 3.47 (J = 13.4, NCHAHB); 3.66 (CH2)2O) 4.50 (J = 12.8, OCHAHB); 4.59 (J = 12.8, OCHAHB)
5.82, s
3.00-3.30, q (J = 6.4)
3.00-3.30
1.25 (J = 6.4)
2.41
1.19 (J = 6.7)
4.90, d (J = 9.2)
5.31, d (J = 16.2)
5.95, s
3.27, qd (J = 6.4, J = 1.5) 3.00-3.45, q (J = 6.7),
3.15
1.26 (J = 6.4)
2.40
1.20 (J = 6.4)
4.98, d (J = 8.9)
5.33, d (J = 15.9)
-7
7.15, s
3.00-3.45
1.32 (J = 6.7)
2.43
1.19 (J = 6.4)
5.32, d (J = 8.2)
5.23, d (J = 15.6)
7.44 (CH=N)
TABLE 1 (continued)
1 Z-7 2 6.30, s 3 3.00-3.40, q (J = 6.4) 3.40, q (J = 6.4) 3.15-3.30, g (J = 6.1) 3.30, q (J = 6.7) 4 2.2-2.3, m, 3.0-3.45, m 2.29, dd (J = 9.5, J = 8.9), 3.0-3.2, m 2.30, m 3.15-3.30, m 2.25, dd (J = 11.6, J = 7.9), 3.05, dd (J = 11.6, J = 5.8) 2.27, dd (J = 11.6, J = 10.1), 3.03, dd (J = 11.6, J = 5.5) 5 3.00-3.45 6 1.30 (J = 6.4) 1.31 (J = 6.4) 1.29 (J = 6.1) 1.31 (J = 6.7) 7 2.43 8 1.19 (J = 6.4) 1.24 (J = 6.4) 1.29 (J = 6.1) 1.22 (J = 6.4) 9 5.11, d (J = 8.5) 5.61, dd (J = 8.2, J = 0.9) 4.94, d (J = 8.9) 5.17, d (J = 8.5) 10 5.14, d (J = 15.6) 5.29, dd (J = 15.6, J = 0.9) 4.65, d (J = 15.6) 5.19, d (J = 15.9) 11 7.09 (J = 15.6, J = 8.5) 6.78 (J = 15.6, J = 8.2) 6.95 (J = 15.6, J = 8.9) 7.33 (J = 15.9, J = 8.5) 12 8.03 (CH=N)
7.49, s
3.00-3.20
2.43
7.50 (CHC)
6.46, s
3.43
2.43
1.42 t, 4.44 (q, EtO); 5.50 (NH2) 8.49 (CH=N)
10
6.60, s
3.20-3.30
2.42
11
6.66, br. s
3.19, q (J = 6.4)
3.19
1.36 (J = 6.4)
2.44
1.25 (J = 6.7)
7.32 (CH=C); 9.43 (br. s, NH)
1481
EXPERIMENTAL IR spectra of KBr disks (solid samples) or films (for liquids) were recorded on an IR-75 spectrometer. Mass spectra were recorded with a Varian MAT-112 instrument with direct introduction into the ion source (ionization voltage 70 eV). 1H NMR spectra of ~3% solutions of the synthesized compounds in CDCl3 were recorded at 30C with a Bruker WP-200 (200 MHz) machine. Chemical shifts were measured relative to TMS as internal standard. Alufol and Silufol UV-254 plates were used for TLC and Al2O3 (Brockman activity II) was used for column chromatography. 4,5,7-Trimethyl-2-trifluoroacetyl-1-vinyl-4,5,6-7-tetrahydropyrrolo[3,2-c]pyridine (3). Trifluoroacetic anhydride (0.66 g, 3.2 mmol) in CH2Cl2 (2 ml) was added dropwise at 5C to a solution of N-vinylpyrrolopyridine 1 (0.15 g, 0.79 mmol) and pyridine (0.07 g, 0.9 mmol) in CH2Cl2 (5 ml). The reaction mixture was heated to 30 until the reaction was completed (TLC). It was cooled, made alkaline to pH 8 with 10% sodium hydroxide, extracted with ether and the ether extract was dried over MgSO4. The residue after evaporation of the ether was purified on a column (1.2 17 cm) with 2:1 ethyl acetatehexane as eluent to give compound 3 (0.1 g, 48%) as a yellow oil, Rf 0.34 (Silufol, ethanol). IR spectrum, , cm-1: 1642 (NCH=CH2), 1670 (CO). Mass spectrum, m/z (Irel, %): 286 [M]+ (0.5), 271 (100), 255 (15), 243 (8), 228 (23), 174 (7), 132 (5), 131 (9), 42 (7). Found, %: C 58.53; H 6.01; N 9.45. M+ 286. C14H17F3N2O. Calculated, %: C 58.74; H 5.94; N 9.79. M 286. 2-N,N-Dimethylaminomethyl-4,5,7-trimethyl-1-vinyl-4,5,6-7-tetrahydropyrrolo[3,2-c]pyridine (4). Compound 1 (0.4 g, 2.1 mmol), dimethylamine (0.28 g, 6.3 mmol, 33% aqueous solution), formaldehyde (0.19 g, 6.3 mmol, 40% aqueous solution), acetic acid (0.25 g, 4.2 mmol), and methanol (10 ml) were mixed at -7C. The mixture was heated to 20C and kept there until the reaction was completed (TLC). After removal of the methanol the mixture was made basic to pH 8 with 10% NaOH and extracted with ether. The ether extract was dried over MgSO4. After removal of the ether the residue was purified on a column (1.2 x 15 cm) with 5:1 ethyl acetatehexane as eluent to give compound 4 (0.39 g, 75%) as a yellow oil, Rf 0.32 (Alufol, 1:4 ethyl acetate heptane). IR spectrum, , cm-1: 1650 (NCH=CH2). Mass spectrum, m/z (Irel, %): 247 [M]+ (3.5), 232 (100). Found, %: C 72.31; H 10.00; N 16.85. M+ 247. C15H25N3. Calculated, %: C 72.87; H 10.12; N 17.00. M 247. 2-(N-Morpholinylmethyl)-4,5,7-trimethyl-1-vinyl-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridine (5). Compound 5 (0.24 g, 80%) was prepared by the same method from compound 1 (0.19 g, 1 mmol), morpholine (0.17 g, 2.1 mmol), formaldehyde (0.06 g, 2.1 mmol, 40% aqueous solution), acetic acid (0.25 g, 4.2 mmol), and methanol (8 ml). Yellow oil, Rf 0.35 (Alufol, 1:4 ethyl acetateheptane). IR spectrum, , cm-1: 1640 (NCH=CH2). Mass spectrum, m/z (Irel, %): 289 [M]+ (2.5), 274 (100), 203 (10), 187 (14), 161 (17), , 160 (31), 146 (16), 144 (12), 94 (17), 86 (10), 77 (15), 56 (21), 42 (23), 41 (13). Found, %: C 70.10; H 9.20; N 14.25. M+ 289. C17H27N3O. Calculated, %: C 70.59; H 9.34; N 14.53. M 289. 2-Hydroxymethyl-4,5,7-trimethyl-1-vinyl-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridine (6). NaBH4 (0.21 g, 5.7 mmol) was added to a solution of compound 2 (0.3 g, 1.37 mmol) in ethanol (15 ml). After 5 h (monitored by TLC) the ethanol was evaporated in vacuum, water (10 ml) was added, and the mixture was extracted with ether (4 20 ml), the extract was dried over MgSO4, and the ether evaporated to give compound 6 (0.27 g, 90%) as a colorless oil, Rf 0.53 (Alufol, 1:4 ethyl acetateheptane). IR spectrum, , cm-1: 1635 (NCH=CH2), 3348 (OH). Mass spectrum, m/z (Irel, %): 220 [M]+ (6), 205 (100). Found, %: C 70.57; H 8.80; N 13.10. M+ 220. C13H20N2O. Calculated, %: C 70.91; H 9.10; N 12.73. M 220. 2-Hydroxyiminomethyl-4,5,7-trimethyl-1-vinyl-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridine (7). A solution of compound 2 (0.3 g, 1.37 mmol), hydroxylamine hydrochloride (0.19 g, 2.75 mmol), and sodium acetate (0.54 g, 4.2 mmol) in ethanol (15 ml) was boiled for 3 h (monitored by TLC). Water (20 ml) was added to the residue after evaporation the ethanol, the solution was extracted with chloroform, and the chloroform extract was dried over MgSO4. The chloroform was evaporated and the residue was recrystallized from an ethyl acetateheptane mixture to give compound 7 (0.29 g, 91%) as white crystals; mp 140-142C, Rf 0.34 (Alufol, 1482
2:1 ethyl acetateheptane). IR spectrum, , cm-1: 1627 (C=N), 1637 (NCH=CH2), 3250 (OH). Mass spectrum, m/z (Irel, %): 233 [M]+, 218 (100). Found: 67.21; H 7.92; N 17.83. M+ 233. C13H19N3O. Calculated, %: C 66.95; H 8.15; N 18.02. M 233. 2-(2',2'-Dicyanovinyl)-4,5,7-trimethyl-1-vinyl-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridine (8). A solution of compound 2 (0.3 g, 1.37 mmol) and malononitrile (0.09 g, 1.37 mmol) in ethanol (15 ml) was boiled for 0.5 h. After evaporation of the ethanol, the residue was crystallized from a mixture of heptane and ethyl acetate to give yellow crystals of compound 8 (0.33 g, 90%); mp 96-98C, Rf 0.52 (Alufol, 1:1 ethyl acetate heptane). IR spectrum, , cm-1: 1637 (NCH=CH2), 2232 (CN). Mass spectrum, m/z (Irel, %): 266 [M]+ (3), 251 (100). Found, %: C 72.31; H 7.01; N 21.12. M+ 266. C16H18N4. Calculated, %: C 72.18; H 6.77; N 21.05. M 266. 2-(6'-Amino-3',5'-dicyano-2'-ethoxypyridin-4-yl)-4,5,7-trimethyl-1-vinyl-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridine (9). A solution of compound 8 (0.16 g, 0.6 mmol), malononitrile (0.4 g, 0.6 mmol), and NaOH (0.01 g, 0.25 mmol) in ethanol (10 ml) was boiled for 1 h (monitored by TLC). The residue after removal of the ethanol was crystallized from ethyl acetate to give yellow crystals of compound 9 (0.04 g, 15%); mp 125-126C, Rf 0.52 (Alufol, ethyl acetate). IR spectrum, , cm-!: 1647 (NCH=CH2), 2200 (CN), 3210 (NH2). Mass spectrum, m/z (Irel,%): 376 [M]+, 361 (100), 333 (15), 42 (12). Found, %: C 66.85; H 6.08; N 22.01. M+ 376. C21H24N6O. Calculated, %: C 67.02; H 6.38; N 22.34. M 376. N,N'-Bis(4,5,7-trimethyl-1-vinyl-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-2-ylmethylene)hydrazine (10). A solution of compound 8 (0.2 g, 0.75 mmol) and hydrazine hydrate (0.056 g, 1.1 mmol) in methanol (14 ml) was boiled for 0.5 h (monitored by TLC). The methanol was evaporated, water (20 ml) was added and the mixture was extracted with ether (4 30 ml). The extract was dried over MgSO4. The ether was evaporated and the residue was crystallized from a mixture of heptane and ethyl acetate to yellow crystals of compound 10 (0.12 g, 75%); mp 190-192C, Rf 0.45 (Alufol, 1:2 ethyl acetateheptane). IR spectrum, , cm-1: 1615 (C=N), 1637 (NCH=CH2). Mass spectrum, m/z (Irel, %): 432 [M]+ (42), 417 (100), 241 (15), 216 (12), 201 (45), 200 (62), 186 (48), 173 (96), 159 (21), 158 (20), 157 (21), 144 (15), 132 (8), 131 (9), 130 (10), 42 (19). Found, %: C 71.92; H 8.80; N 19.10. M+ 432. C26H36N6. Calculated, %: C 72.22; H 8.33; N 19.44. M 432. 2-(2',2'-Dicyanovinyl)-4,5,7-trimethyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (11). A solution of compound 8 (0.15 g, 0.56 mmol) and 25 drops of conc. HCl in ethanol (3 ml) was kept at 20C until the reaction was complete (monitored by TLC). The solution was made alkaline to pH 8-9 with Na2CO3 solution, then extracted with chloroform, and the extract was dried over MgSO4. After evaporation of the chloroform the residue was purified on a column (eluent 1:2 ethyl acetateheptane) to give white crystals of compound 11 (0.03 g, 21%); mp 122-123C, Rf 0.33 (Alufol, ethyl acetate). IR spectrum, , cm-1: 3210 (CN), 3250 (NH). Mass spectrum, m/z (Irel %): 240 [M]+, (10), 225 (100), 223 (12), 209 (12), 197 (48), 182 (35), 112 (10), 42 (25), 41 (32), 40(52). Found, %: C 70.32; H 6.53; N 23.70. M+ 240. C14H16N4. Calculated, %: C 70.00; H 6.67; N 23.33. M 240. This study was carried out with a RFFI subvention (grant No. 02-03-32941).
REFERENCES 1. 2. 3. B. A Trofimov and A. I. Mikhaleva, N-Vinylpyrroles [in Russian], Nauka, Novosibirsk (1984). A. V. Varlamov, T. N. Borisova, A. E. Aliev, I. A. Stazharova, A. A. Sinitsina, and E. A. Sakhnova, Khim. Geterotsikl. Soedin., 681 (1993). T. N. Borisova, I. A. Stazharova, A. E. Aliev, N. S. Prostakov, and A. V. Varlamov, Khim. Geterotsikl. Soedin., 1375 (1991).
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4. 5. 6. 7.
C. Altomare, L. Summo, S. Cellamare, A. V. Varlamov, L. G. Voskresenskii, T. N. Borisova, and A. Carotti, Bioorg. Chem. Lett., 581 (2000). L. Fuentes and J. L. Soto, An. Quim., 73, 1349 (1977). B. A. Trofimov, S. E. Korostova, A. I. Mikhaleva, L. N. Sobenina, and A. N. Vasil'ev, Khim. Geterotsikl. Soedin., 1631 (1982). A. E. Aliev, Diss. Cand. Chem. Sci., Moscow (1988).
1484
SYNTHESIS OF 6-ARYL-1,6-DIHYDRODIPYRAZOLO[3,4-b:4,3-c]PYRIDINES
M. V. Vovk, N. V. Mel'nichenko, V. A. Sukach, and N. G. Chubaruk 6-Azido-1H-pyrazolo[3,4-b]pyridino-5-carbaldehydes react with aromatic amines to give the corresponding N-arylimines which cyclize on heating in boiling toluene to give 6-aryl-1,6dihydrodipyrazolo[3,4-b:4,3-e]pyridines. Keywords: N-aryl-6-azido-1H-pyrazolo[3,4-b]pyridine-5-carbaldimines, 6-aryl-1,6-dihydrodipyrazolo[3,4-b:4,3-e]pyridines, thermolysis. Dipyrazolo[3,4-b:4,3-e]pyridines are examples of condensed heterocyclic compounds with notable pharmacological activity, for example bactericidal [1], sedative [2], and antiasthmathic [3]. Substances with electroluminescent properties are also found among them [4,5]. Only 1,7-disubstituted dipyrazolo[3,4-b:4,3-e]pyridines can be synthesized by the reported cyclization of 2,6-dichloro-3,5-diformylpyridine with hydrazines [6], 5-aminopyrazoles with carbonyl compounds [7-10], and pyrazolin-5-ones with aldehydes and arylimines [11]. The intramolecular cyclocondensation of the hydrazone of 6-chloropyrazolo[3,4-b]pyridine-5-carbaldehyde was used to prepare 3-methyl-1-phenyl-1,7-dihydrodipyrazolo[3,4-b:4,3-e]pyridine [12].
Me N N Ph N Cl H C NNH2 Me EtOH, , 18 h N N Ph N N H N
There are no reports of 1,6-dihydro analogs of these heterocyclic systems in the literature. It is for this reason that we examine preparatively suitable routes to their synthesis in this paper. 6-Chloro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (1), synthesized from 5-acetylamino-3-methyl-1-phenylpyrazole by the VilsmeierHaack method [12] was proposed as the starting material for the synthesis of the desired materials. Compound 1, like 5-chloropyrazole-4-carbaldehyde [13-15], was converted in 85% yield to 6-azidopyrazolo[3,4-b]pyridine-5-carbaldehyde 2 by reaction with NaN3 in DMSO in the presence of the phase transfer catalyst Bu4N+I-. An investigation of the thermal properties of compound 2 showed that, in contrast to its close analog, 2-azido-7-methylquinoline-3-carbaldehyde, which is converted into the corresponding tetrazoloquinoline even at 40C, it is quite stable and only underwent cyclization to pyrazolo[3,4-e][1,2,3,4]tetrazolo[1,5-a]pyridine 3 on refluxing in toluene for 6 h. It was therefore suggested that when the condensation of the azidoaldehyde 2 with
__________________________________________________________________________________________ Institute of Organic Chemistry, Ukraine National Academy of Sciences, Kiev 02094; e-mail: mvovk@i.com.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, 1717-1722, November, 2004. Original article submitted July 5, 2002. 0009-3122/04/4011-14852004 Springer Science+Business Media, Inc. 1485
Me N N Ph 3 N
H C O
N N N
110C, 6 h
Me N N Ph 1 4c N
H C O NaN3 Cl DMSO
Me N N Ph 2 N
H C O ArNH2 4af N3
Me N N Ph N 5af 110 oC
H C NAr N3
N2
Me N N Ph 7 N
H C NC6H4Me- 4 Cl
Me NaN3, DMSO
N2
N N Ph N 6af N
N Ar
4-6 a Ar = Ph, b Ar = 4-ClC6H4, c Ar = 4-MeC6H4, d Ar = 3-MeOC6H4, e Ar = 4-MeOC6H4, f Ar = 3,4-Me2C6H3
arylamines was carried out under milder conditions the azido group would be retained in the reaction products. In fact, heating compound 2 with the arylamines 4a-f in boiling ethanol for 4-5 h gave the N-arylamines 5a-f, from which compounds 5c and f were isolated analytically pure and were characterized. According to [17], 2-substituted indazoles were isolated in high yield from the thermolysis of o-azidobenzylidene amines. From this it seemed expedient to use the thermolysis of the azido imines 5a-f for the pyrazoloannelation of the pyridine ring. It was found that the 6-aryl-1,6-dihydrodipyrazolo[3,4-b:4,3-e]pyridines 6a-f were formed on refluxing compounds 5a-f in toluene for 5-6 h. We note that to simplify the process compounds 5a-f were not subjected to additional purification and were used for thermolysis after removal of the ethanol. We also investigated the possibility of synthesizing compounds of type 6 by first converting the aldehyde into an azomethine group with subsequent replacement of the chlorine atom by an azide group. As an example imine 7 was obtained by reaction of aldehyde 1 with p-toluidine, and converting 7 into the dipyrazolopyridine 6a by heating with sodium azide in DMSO at 70-72C for 20 h. However the yield of compound 6a under these conditions decreased by 19% in comparison with the first version of the reaction. The deceleration of the process is evidently caused by a decrease in the mobility of the chlorine atom caused by the lower acceptor power of the imino groups, and the requirement of a lower temperature regime. The synthesized compounds 6a-f (Table 1) are high melting yellow crystalline compounds with a light yellow fluorescence in 2:1 DMSOCCl4 solution. Their structures are in agreement with their 1H NMR and mass spectra (Table 2). The presence of molecular ion peaks with Imax 100% is characteristic for the mass spectra of all the compounds.
1486

Compound 2 3 5c 5f 6a 6b 6c 6d 6e 6f 7 Empirical formula C 1410N6O C14H10N6O C21H17N7 C22H19N7 C20H15N5 C20H14ClN5 C21H17N5 C21H17N5O C21H17N5O C22H19N5 C21H17ClN4 60.70 60.42 60.69 60.42 68.71 68.65 68.94 69.27 74.08 73.83 66.99 66.76 74.70 74.31 71.34 70.97 70.72 70.97 74.46 74.76 70.93 70.71 Found, % Calculated, % H 3.54 3.62 3.54 3.62 4.72 4.66 5.18 5.02 4.72 4.65 4.11 3.92 5.18 5.04 4.91 4.82 4.89 4.82 5.43 5.42 4.48 4.62 mp, (solvent) N 30.05 30.20 29.62 30.20 26.33 26.69 25.91 25.71 21.39 21.52 19.03 19.46 20.27 20.63 20.05 19.71 19.56 19.71 20.03 19.82 15.30 15.11 174-175 (MeCN) 245-246 (MeCN) 151-154 (EtOHH2O) 161-163 (MeCN) 194-196 (MeCN) 242-243 (MeCN) 223-224 (MeCN) 175-176 (MeCN) 227-229 (MeCNdioxane) 230-231 (MeCN) 200-201 (MeCN) 85 76 78 74 325 360 339 355 355 353 73 66 74 65 72 68 67 [M]+, m/z
Yield, %
The structure of compounds 6 was also confirmed by the 13C NMR spectrum of compound 6c:
Me
3 2 4 3a 4a 5 6 2'' 3'' 4''
N
1N 8a
N N
8 2' 7a
1''
Me
N
7
6''
5''
6' 5'
1'
3' 4'
, ppm: 12.33 (3-3), 20.49 (CH3-4''), 112.77 (C-3a), 117.60 (C-4a), 118.84 (C-2', 6'), 120.19 (C-2'', 6''), 124.25 (C-4), 125.90 (C-5), 126.12 (C-4'), 128.92 (C-3'', 5''), 130.07 (C-3', 5'), 137.40 (C-1'), 138.17 (C-1''), 139.61 (C-4''), 144.68 (C-3), 152.06 (C-8a), 157.78 (C-7a)
EXPERIMENTAL The course of reactions and the purity of the synthesized compounds was monitored by chromatography on Silufol UV-254 strips with 20:1 chloroformmethanol as eluent. IR spectra of KBr disks were measured with a UR-20 instrument. 1H and 13C NMR spectra of solutions in 2:1 DMSO-d6CDCl3 with TMS as internal standard were measured with a Varian-Gemini spectrometer (300 and 75 MHz respectively). Mass spectra were recorded on an MX-121 mass spectrometer with direct injection into the ion source, energy of the ionizing electrons 70 eV, temperature of the ionizing chamber 150C. 1487

Compound 2 3 5c Chemical shifts, , ppm (SSCC, J, Hz) 2.60 (3H, s, CH3-3); 7.32 (1H, t, J = 7.6, H-4'); 7.52 (2H, t, J = 7.8, H-3', 5'); 8.18 (2H, d, J = 8.1, H-2', 6'); 8.65 (1H, s, H-4); 10.17 (1H, s, CH=O) 2.62 (3H, s, CH3-3); 7.26 (1H, t, J = 7.9, H-4'); 7.53 (2H, t, J = 8.1, H-3', 5'); 8.31 (2H, d, J = 8.2, H-2', 6'); 8.94 (1H, s, H-4); 10.12 (1H, s, CH=O) 2.36 (3H, s, CH3-4''); 2.58 (3H, s, CH3-3); 7.14-7.32 (5H, m, HAr); 7.50 (2H, t, J = 7.8, H-3', 5'); 8.21 (2H, d, J = 7.8, H-2', 6'); 8.62 (1H, s, 5-CH=); 8,78 (1H, s, H-4) 2.26 (3H, s, CH3-4''); 2.28 (3H, s, CH3-3''); 2.59 (3H, s, CH3-3); 6.94-7.30 (3H, m, HAr); 7.50 (2H, t, J = 7.8, H-3', 5'); 8.21 (2H, d, J = 7.5, H-2', 6'); 8.62 (1H, s, 5-CH=); 8.77 (1H, s, H-4) 2.64 (3H, s, CH3-3); 7.22 (1H, t, J = 7.8, H-4'); 7.46-7.62 (5H, m, HAr); 8.18 (2H, d, J = 7.8, H-2'', 6''); 8.45 (2H, d, J = 8.1, H-2', 6'); 8.80 (1H, s, H-4); 9.37 (1H, s, H-5) 2.63 (3H, s, CH3-3); 7.22 (1H, t, J = 7.6, H-4'); 7.52 (2H, t, J = 7.8, H-3', 5'); 7.62 (2H, d, J = 8.7, H-3'', 5''); 8.20 (2H, d, J = 8.7, H-2'', 6''); 8.44 (2H, d, J = 7.8, H-2', 6'); 8.76 (1H, s, H-4); 9.36 (1H, s, H-5) 2.47 (3H, s, CH3-4''); 2.65 (3H, s, CH3-3); 7.21 (1H, t, J = 7.5, H-4'); 7.39 (2H, d, J = 8.7, H-3'', 5''); 7.53 (2H, t, J = 7.8, H-3', 5'); 8.05 (2H, d, J = 8.7, H-2'', 6''); 8.46 (2H, d, J = 8.1, H-2', 6'); 8.80 (1H, s, H-4); 9.31 (1H, s, H-5) 2.64 (3H, s, CH3-3); 3.92 (3H, s, OCH3-3''); 7.01 (2H, d, J = 8.1, H-4''); 7.22 (1H, t, J = 7.6, H-4'); 7.51-7.75 (5H, m, HAr); 8.47 (2H, d, J = 7.8, H-2', 6'); 8.78 (1H, s, H-4); 9.38 (1H, s, H-5) 2.65 (3H, s, CH3-3); 3.87 (3H, s, OCH3-4''); 7.12 (2H, d, J = 9.0, H-3'', 5''); 7.22 (1H, t, J = 7.6, H-4'); 7.52 (2H, t, J = 7.8, H-3', 5'); 8.08 (2H, d, J = 9.0, H-2'', 6''); 8.46 (2H, t, J = 8.4, H-2', 6'); 8.77 (1H, s, H-4); 9.24 (1H, s, H-5) 2.31 (3H, s, CH3-4''); 2.36 (3H, s, CH3-3''); 2.64 (3H, s, CH3-3); 7.26 (1H, t, J = 7.8, H-4'); 7.37 (1H, d, J = 8.4, H-5''); 7.56 (2H, d, J = 7.8, H-3', 5'); 7.89 (1H, d, J = 8.4, H-6''); 7.99 (1H, s, H-2''); 8.43 (2H, d, J = 8.4, H-2', 6'); 8.89 (1H, s, H-4); 9.37 (1H, s, H-5) 2.37 (3H, s, CH3-4''); 2.67 (3H, s, CH3-3); 7.20-7.36 (5H, m, HAr); 7.54 (2H, t, J = 7.9, H-3', 5'); 8.19 (2H, d, J = 8.1, H-2', 6'); 8.88 (1H, s, H-4); 8.96 (1H, s, 5-CH=)
5f
6a
6b
6c
6d
6e
6f
6-Azido-3-methyl-1-phenylpyrazolo[3,4-b]pyridine-5-carbaldehyde (2). NaN3 (2.58 g, 40 mmol) and Bu4N I (1.48 g, 4 mmol) were added to a solution of aldehyde 1 (9.0 g, 33 mmol) in DMSO (45 ml) and the mixture was stirred at 50C for 8 h. The reaction mixture was poured into ice water, the precipitate was filtered off, dried, and crystallized. IR spectrum, , cm-1: 1700 (C=O), 2120 (N3). 3-Methyl-1-phenyl-1H-pyrazolo[3,4-e][1,2,3,4]tetrazolo[1,5-a]pyridine-5-carbaldehyde (3). A suspension of the azidoaldehyde 2 (0.280 g, 1mmol) in toluene (15 ml) was refluxed for 6 h. After cooling the reaction mixture the solid was filtered off and crystallized. IR spectrum, , cm-1: 1635 (C=C). N-(p-Tolyl)-6-azido-3-methyl-1-phenylpyrazolo[3,4-b]pyridine-5-carbaldimine (5c). p-Toluidine (0.26 g, 2.4 mmol) was added to a suspension of azidoaldehyde 2 (0.56 g, 2 mmol) in ethanol (15 ml) and the mixture was refluxed for 4 h. After cooling the reaction mixture the solid was filtered off and crystallized. Compound 5f was prepared analogously. 6-Aryl-3-methyl-1-phenyl-1,6-dihydrodipyrazolo[3,4-b:4,3-e]pyridines, 6a-f. An arylamine (4a-f, 2.4 mmol) was added to a suspension of azidoaldehyde 2 (2 mmol) in ethanol (30 ml) and the mixture was refluxed for 4 h. The ethanol was then evaporated , toluene (25 ml) was added to the residue, and the mixture was refluxed again for 6 h. The reaction mixture was cooled, the solid was filtered off and crystallized. N-(p-Tolyl)-6-chloro-3-methyl-1-phenyl[3,4-b]pyridine-5-carbaldimine (7). p-Toluidine (0.21 g, 2 mmol) was added to a suspension of the chloroaldehyde 1 (0.54 g, 2 mmol) in ethanol (25 ml) and the mixture was refluxed for 4 h. The precipitate was filtered and crystallized.
+ -
1488
The Reaction of Compound 7 with NaN3. NaN3 (0.08 g, 1.2 mmol) and Bu4N+I-(0.44 g, 0.12 mmol) were added to a solution of imine 7 (0.37 g, 1 mmol) in 20 ml DMSO and the mixture was stirred at 70-72C for 20 h. The reaction mixture was poured into ice water (40 ml), the precipitate was filtered off, dried, and crystallized to give compound 6c (55% yield). We thank our senior scientific co-worker A. V. Mazene of the A. V. Bogatskii Physical Chemistry Institute, Ukraine National Academy of Sciences, for recording the mass spectra.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. K. C. Joshi, K. Dubey, and A. Dandia, Pharmazie, 36, 336 (1981). H. Hoehn and T. Denzel, Pat BRD 2159600; Chem. Abstr., 77, 114401 (1972). H. Hoehn and E. Schulze, Pat BRD 2333603; Chem. Abstr., 77, 108514 (1974). G.-H. W. Milburn, P. Tomasik, A. Daniel, Z. He, and D. Rasola, PCT Int. Appl. WO 98 28,296; Chem. Abstr., 129, 115441 (1998). G.-H. W. Milburn, P. Tomasik, A. Daniel, and Z. He, PCT Int. Appl. WO 98 49,219; Chem. Abstr., 129, 343818 (1998). M. Weissenfels and S. Kaubisch, Z. Chem., 22, 23 (1982). M. A. Mikhalev, L. N. Il'chenko, and V. P. Mamaev, Khim. Geterotsikl. Soed., 823 (1974). L. Hennig, J. Hofmann, M. Alva-Astudillo, and G. Mann, J. Prakt. Chem., 333, 351 (1990). L. Hennig, T. Mller, and M. Groshe, J. Prakt. Chem., 332, 693 (1990). V. K. Ahliwalia, A. Dahiya, and V. K. Gard, Indian J. Chem., 36B, 692 (1997). V. K. Ahliwalia, P. Sharma, and B. Goual, Indian J. Chem., 36B, 1059 (1997). A. Simay, K. Takacs, and L. Toth, Acta Chim. Hung., 109, 175 (1982). P. Molina, A. Argues, and M. V. Vinadei, J. Org. Chem., 53, 4654 (1988). J. Becher, P. L. Jorgensen, K. Plute, N. K. Krake, and B. Falt-Hansen, J. Org. Chem., 57, 2127 (1996). V. K. Ahluwalia and B. Goual, Synth. Commun., 26, 1341 (1991). O. Meth-Cohn, B. Narine, B. Tarnowski, R. Hayaes, A. S. Rhouati, and A. Robinson, J. Chem. Soc., Perkin Trans 1, 2509 (1981). L. Krbechek and Takimoto, J. Org. Chem., 29, 1150 (1964).
1489
A CONVENIENT ONE-POT SYNTHESIS OF BENZOPYRIMIDO[1,8]NAPHTHYRIDINES BY KNOEVENAGEL CONDENSATION

R. Nandha Kumar, T. Suresh, and P. S. Mohan A series of 1-oxo-2,4-diphenyl-3-thioxobenzo[g]pyrimido[6,5-b]-1,8-naphthyridines has been synthesized by Knoevenagel condensation from 3-formyl-2-oxoquinolines and N,N-diphenyl-2thiobarbituric acid on refluxing with liquid ammonia in absolute ethanol. Keywords: benzopyrimidonaphthyridines, oxoquinoline, Knoevenagel condensation. N,N-diphenyl-2-thiobarbituric acid, 3-formyl-2-
2-Aminonicotinaldehyde was used as a potential starting material for the synthesis of 1,8-naphthyridines via Friedlander condensation [1-3]. In the present work an alternative route for the synthesis of 1,8-naphthyridines from 3-formyl-2-oxoquinoline in a one-pot method by Knoevenagel condensation [4-7] is discussed. Quinoline derivatives [8-11], quinoline amines [12-15], and 1,8-naphthyridines [16-20] are pharmacologically important. So, these moieties attract considerable attention as active biocidal agents and prompted us to synthesize a series of 1,8-naphthyridines.
O
R3 R2 R1
CHO 4N HCl N Cl
R3 R2 R1 1af
CHO
+
N H O
O N
N S
R3 Liq. NH3, dry EtOH reflux, 5 h R2 R1 3af N N

N N S
1, 3 a R1 = R2 = R3 = H; b R1 = Me, R2 = R3 = H; c R1 = R3 = H, R2 = Me; d R1 = R2 = H, R3 = Me; e R1 = OMe, R2 = R3 = H; f R1 = R2 = H, R3 = OMe
__________________________________________________________________________________________ Departament of Chemistry, Bharathiar University, Coimbatore-641046, TamilNadu, India; e-mail: ps_mohan_in@yahoo.com. Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 11, 1723-1725, November, 2004. Original article submitted September 2, 2002. 1490 0009-3122/04/4011-14902004 Springer Science+Business Media, Inc.
3-Formyl-2-oxoquinoline 1 [21, 22], N,N-diphenyl-2-thiobarbituric acid (2) [23, 24], and liquid ammonia were refluxed in absolute ethanol for 5 h to give the product (74% yield), whose IR spectrum showed strong absorption bands at 1325 cm-1 due to the C=S group, 1680 cm-1 for the C=O group, and 1620 cm-1 and 1595 cm-1 for the C=N groups. Its 1H NMR and mass spectra as well as data of elemental analysis corroborated with the structure of 1-oxo-2,4-diphenyl-3-thioxobenzo[g]pyrimido[6,5-b]-1,8-naphthyridine (3a). Other compounds 3 were obtained similarly (Table 1). In conclusion, the reaction proceeds smoothly through the Knoevenagel condensation between the formyl moiety and the active methylene group of N,N-diphenyl-2-thiobarbituric acid to give after elimination of a water molecule the desired substituted 1-oxo-3-thioxobenzo[g]pyrimido[6,5-b]-1,8-naphthyridines.
EXPERIMENTAL Thin layer chromatography was used to access the reaction course and the purity of products. Melting points were determined on a Boetius Microheating Table and Mettler-FP5 Melting apparatus and are uncorrected. IR spectra were recorded in a Shimadzu-8201FT instrument in KBr discs and only significant absorption levels (reciprocal centimeter) are listed. 1H NMR spectra were recorded in an AMX-400 MHz spectrometer in CDCl3 solution; chemical shifts are expressed in ppm () relative to TMS. Mass spectra were recorded on a Jeol-D-300 mass spectrometer. CHN analyses were carried out on Carlo Erba 106 and Perkin Elmer Model 240 analyzers.
TABLE 1. Characteristics of Synthesized Compounds 3a-f

Compound 3a Empirical formula (Mol. Wt.) Found, % Calculated, % C H N 3.64 3.73 12.87 12.96 mp, C 280 IR spectrum, , cm-1 1680, 1620, 1595, 1325
1
H NMR spectrum, Yield, % , ppm 74
C26H16N4OS 72.02 72.21 (432.46)
3b
C27H18N4OS 72.71 72.63 (446.49)
4.13 4.06
12.48 12.55
183
1690, 1635, 1585, 1330
3c
C27H18N4OS 72.52 72.63 (446.49)
4.01 4.06
12.46 12.55
240
1685, 623, 1580, 1320
3d
C27H18N4OS 72.60 72.63 (446.49)
3.98 4.06
12.59 12.55
215
1670, 1610, 1590, 1323
3e
C27H18N4O2S 70.02 70.12 (462.49)
3.80 3.92
12.17 12.12
174
1668, 1605, 1587, 1328
3f
C27H18N4O2S 70.16 70.12 (462.49)
3.86 3.92
12.08 12.12
195
1660, 1615, 1593, 1322
8.1 (1H, s, C11-H); 8.4 (1H, s, C12-H); 6.8-7.9 (14H, m, ArH) 2.3 (3H, s, CH3); 8.0 (1H, s, C11-H); 8.5 (1H, s, C12-H); 7.1-7.8 (13H, m, ArH) 2.5 (3H, s, CH3); 8.1 (1H, s, C11-H); 8.7 (1H, s, C12-H); 7.0-8.0 (13H, m, ArH) 2.4 (3H, s, CH3); 8.2 (1H, s, C11-H); 8.6 (1H, s, C12-H); 7.0-7.9 (13H, m, ArH) 3.9 (3H, s, OCH3); 8.3 (1H, s, C11-H); 8.5 (1H, s, C12-H); 7.1-8.1 (13H, m, ArH) 3.9 (3H, s, OCH3); 8.2 (1H, s, C11-H); 8.6 (1H, s, C12-H); 6.9-8.0 (13H, m, ArH)
82
68
79
73
80
1491
Synthesis of Benzopyrimido[1,8]naphthyridines. 3-Formyl-2-oxoquinoline 1a-f (1 mmol) and N,N-diphenyl-2-thiobarbituric acid (2) (1 mmol) were dissolved in anhydrous ethanol with 2 ml of liquid ammonia and refluxed on a water-bath for about 5 h. After the completion of the reaction, inferred through TLC studies, the volume was reduced to half. The separated product was collected and recrystallized with chloroformmethanol. A series of compounds 3a-f was synthesized and their characteristic data are presented in Table 1. The authors thank CSIR, New Delhi for the award of Senior Research Fellowship (R.N.K.) and Bharathiar University for the award of University Research Fellowship (T.S.). SIF, Indian Institute of Science, Bangalore and Central Drug and Research Institute, Lucknow supported the spectral details.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. M. T. Chary, K. Mogilaiah, and B. Sreenivasulu, J. Indian Chem. Soc., 64, 488 (1987). K. R. Reddy, K. Mogilaiah, and B. Sreenivasulu, J. Indian Chem. Soc., 64, 193 (1987). K. R. Reddy, K. Mogilaiah, and B. Sreenivasulu, J. Indian Chem. Soc., 63, 443 (1986). G. Jones, Org. Reactions, 15, 204 (1967). P. S. Kwoi, Y. M. Kim, C. J. Kang, and T. W. Kwon, Synth. Commun., 27, 4091 (1997). S. A. Ayoubi, F. Texier-Boullet, and D. Hamelin, Synthesis, 258 (1994). A. K. Bose, M. S. Manhas, M. Ghosh, V. S. Raju, K. Tabei, and Z. Urbanczyk-Lipkowska, Heterocycles, 30, 741 (1990). M. Kidwai, N. Negi, and S. R. Chowdary, Acta Pharm., 45, 511 (1995). M. Kidwai, K. Kumar, Y. Goel, and K. C. Srivastava, Bioorg. Med. Chem. Lett., 6, 871 (1996). M. Kidwai, N. Gupta, and K. C. Srivastava, Indian Drugs, 8, 377 (1993). M. Kidwai, S. Kohli, A. K. Goel, and M. P. Dubey, Indian J. Chem. (B), 37, 1063 (1998). K. Hino, Y. Nagai, and H. Uno, Chem. Pharm. Bull., 35, 2819 (1987). S. F. Campbell, J. D. Hardstone, and M. J. Palmer, J. Med. Chem., 31, 1031 (1988). H. Gilman, I. Zarember, and J. A. Beel, J. Am. Chem. Soc., 74, 3177 (1952). R. Rodriguez, US Pat. 3737540; Chem. Abstr., 79, 42554 (1973). G. B. Barlin and W. L. Tan, Aust. J. Chem., 37, 1065 (1984). J. Matsumoto, Y. Nishimura, and S. Nakamura, Fr. Pat. 2531084; Chem. Abstr., 101, 505088 (1984). P. L. Ferrarini, C. Mori, M. Badawneh, C. Manera, A. Martinelli, M. Miceli, F. Romagnoli, and G. Saccomanni, J. Heterocycl. Chem., 34, 1501 (1997). K. J. D. Gorecki and E. M. Hawes, J. Med. Chem., 20, 124 (1977). M. Kidwai and S. Kohli, Indian J. Chem. (B), 40, 248 (2001). O. Meth-Cohn and B. Narine, Tetrahedron, 19, 2045 (1978). M. M. Ali Tasneem, K. C. Rajanna, and P. K. Prakash, Synlett, 251 (2001). S. C. Nagam, G. S. Saharia, and H. R. Sharma, Def. Sci. J., 31, 15 (1981). I. N. D. Das and S. Dutt, Proc. Indian Sci. Acad., 8A, 145 (1938).
1492

CYCLIZATION OF -[(S)-1-PHENYLETHYL]AMINO ALCOHOLS TO FORM CHIRAL 1,3-DISUBSTITUTED PHTHALANES
I. N. Shishkina, A. A. Kuznetsova, and V. M. Dem'yanovich Keywords: 1,3-dihydroisobenzofurans (phthalanes), chiral -(1-phenylethyl)amino alcohols, cyclization of iodomethylates. In studying the possibility of replacing the dimethylamino group in chiral -(1-phenylethyl)amino alcohols 1a-c [1-3] by reaction of their iodomethylates 2a-c with morpholine in the presence of sodium acetate, we observed that cyclization occurs with formation of optically active 1,3-disubstituted 1,3-dihydroisobenzofurans (phthalanes) 3a-c. The dihydroisobenzofuran moiety is encountered in molecules of some natural and synthetic biologically active compounds [4], but there is almost no data available on chiral phthalanes. Further study of this reaction showed that it occurs similarly in DMF and DMSO, and in the presence of a number of salts (sodium and copper acetates, NaCl, NaCN, Na2S) and NaOH, its rate increases considerably.
H Me (S) NMe2 1. BuLi 2. RCOR1 H Me MeI
(S) NMe2 OH R (S) R1 1ac Me AcONa DMF R (S) 3ac

1
Me
NMe3I
(S) H OH R (S) R1 2ac

1
(R) O R1
1-3 a R = R = Ph; b R+R = C5H10; c R = 2,4-Me2C6H3, R1 = Ph
In cyclization of iodomethylates 2a,b the optically active phthalanes 3a,b are formed, i.e., the reaction occurs stereoselectively. In order to estimate the stereoselectivity, we conducted the cyclization of the iodomethylate of amino alcohol 2c with two chiral centers. We obtained only one (according to 1H NMR __________________________________________________________________________________________ M. V. Lomonosov Moscow State University, Moscow 119922, Russia; e-mail: demyan@org.chem.msu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1726-1727, November, 2004. Original article submitted June 11, 2004. 0009-3122/04/4011-14932004 Springer Science+Business Media, Inc. 1493
spectral data) out of the two possible diastereomeric 3-methyl-1-(2,4-dimethylphenyl)-1-phenyl-1,3dihydroisobenzofurans (3c), which is evidence for stereospecificity of the reaction. We assume that cyclization of iodomethylates 2a-c occurs as an intramolecular nucleophilic substitution according to an SN2 mechanism, i.e., with inversion of the configuration of the site that is attacked (the chiral center of the starting amine, which had an (S)-configuration). Thus in the phthalanes 3a-c obtained, the C-3 atom should have an (R)-configuration. In the literature, (+)-3-methyl-1,3-dihydroisobenzofuran is described [5], for which an (R)-configuration has been established. The positive rotation we observed ([]D 131) for phthalane 3a may be confirmation for the (R)-configuration of the C-3 atom in this compound and consequently for the proposed mechanism. It is also likely that phthalanes 3b,c are formed with inversion of the configuration of the center. The increase in the reaction rate in the presence of salts and NaOH may be explained by the fact that the anions, having properties of bases, to some extent promote ionization of the hydroxyl group and its conversion to a good nucleophile, which intramolecularly attacks the benzyl carbon atom on the side opposite to the leaving trimethylammonium group. We also isolate a small amount of the corresponding amino alcohol 1a-c from the reaction mixture (1-2%, if the reaction is carried out in the presence of salts; and 10% in the absence of salts), the formation of which may be assumed to be the result of nucleophilic attack on the methyl group. The 1H NMR spectra were taken on a Varian XL-400 (400 MHz) in CDCl3, internal standard TMS. 3-Methyl-1,1-diphenyl-1,3-dihydroisobenzofuran (3a). MeI (0.02 mmol) at 0C was added to a solution of amino alcohol 1a (5 mmol) in dry acetone (50 ml). The precipitated iodomethylate 2a was filtered out and washed with dry ether; mp 232C (decomposes). []D -84 (c 1, ethanol). A mixture of iodomethylate 2a (5 mmol), sodium acetate (25 mmol) in freshly distilled DMF (20 ml) was refluxed for 5 h and then the DMF was driven off under vacuum; the residue was dissolved in water, alkalinized to pH 10-11, and extracted with ether. The ether extracts were washed with 1 N HCl solution and dried with MgSO4. The ether was distilled off and the phthalane 3a obtained (98% yield) was recrystallized from alcohol; mp 92C, []D 131 (c 1, ethanol). 1H NMR spectrum, , ppm: 1.62 (3H, d, CH3CH); 5.30 (1H, q, CH CH3); 7.10-7.40 (14H, m, arom.). Found, %: C 87.79; H 6.43. C21H18O. Calculated, %: C 88.08; H 6.33. 3'-Methyl-3'-H-spiro[cyclohexane-1,1'-isobenzofuran] (3b) was obtained similarly from iodomethylate 2b; mp 204C (decomposes), []D 10 (c 1, ethanol), and was purified chromatographically on a column with silica gel (Silica gel 60) in a benzeneacetone system, 10:1, Rf 0.8. Yield 50%. []D -8 (c 2, ethanol). 1H NMR spectrum, , ppm: 1.50 (3H, d, CH3CH); 1.60-1.90 (10H, m, C6H10); 5.28 (1H, q, CHCH3); 7.08-7.30 (4H, m, arom.). 3-Methyl-1-(2,4-dimethylphenyl)-1-phenyl-1,3-dihydroisobenzofuran (3c) was obtained similarly from the corresponding iodomethylate 2c; mp 232C (decomposes); []D 33 (c 1, ethanol), yield 70%; mp 75C; []D -257 (c 1, ethanol). 1H NMR spectrum, , ppm: 1.38 (3H, d, CH3CH); 1.95 (3H, s, p-CH3); 2.30 (3H, s, o-CH3); 5.45 (1H, q, CHCH3); 6.75-7.30 (12H, m, arom.).
REFERENCES 1. 2. 3. 4. 5. V. M. Dem'yanovich, I. N. Shishkina, and A. I. Vedernikov, Zh. Org. Khim., 27, 2658 (1991). V. M. Dem'yanovich, I. N. Shishkina, K. A. Potekhin, and Yu. T. Struchkov, Dokl. Akad. Nauk, 333, 183 (1993). V. M. Demyanovich, I. N. Shishkina, and N. S. Zefirov, Chirality, 16, 486 (2004). J. F. DeBernardis, D. L. Arendsen, J. J. Kyncl, and D. J. Kerkman, J. Med. Chem., 30, 178 (1987). K. Tomooka, L.-F. Wang, F. Okazaki, and T. Nakai, Tetrahedron Lett., 41, 6121 (2000).
1494
EFFICIENT ROUTE TO SUBSTITUTED 2-AMINOQUINOLINE

V. D. Dyachenko and A. G. Kudryavtseva Keywords: 1,3-aminophenol, 4-hydroxyphenylmethylene cyanothioacetamide, substituted 2-aminoquinoline, acylation, Michael reaction. 1,3-Aminophenol undergoes a Michael addition to 4-hydroxyphenylmethylene malononitrile followed by intramolecular cyclization to form substituted 2,7-diamino-4H-benzo[b]pyran [1]. We observed that reacting 4-hydroxyphenylmethylene cyanothioacetamide (2) with 1,3-aminophenol 1 in ethanol in the presence of morpholine leads to formation of 2-amino-3-cyano-7-hydroxy-4-(4-hydroxyphenyl)quinoline (3). Thus 1,3-aminophenol 1 does not initially add to activated alkene 2 at the 6 position, which would lead to the corresponding pyran, but rather to position 4 with formation of the Michael adduct 4. The latter, when treated with morpholine, even at room temperature undergoes intramolecular cyclization to form substituted 2-aminoquinoline 3. Refluxing it in acetic anhydride allows us to obtain the corresponding tetraacyl derivative 5, which is promising for drug discovery [2].
OH OH
HO 1
NH2 S 2
CN NH2 .. NH2 S 4 OH
CN HO NH2
OAc
Ac2O H2S, 2[H] HO N 3 CN NH2 AcO N 5 CN N(Ac)2
The 1H NMR spectra were taken on a Bruker DR-500 (500 MHz) in DMSO-d6. __________________________________________________________________________________________ Taras Shevchenko Lugansk State Pedagogical University, Lugansk 91011, Ukraine; e-mail: dvd-lug@online.lg.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1728-1729, November, 2004. Original article submitted September 8, 2004. 0009-3122/04/4011-14952004 Springer Science+Business Media, Inc. 1495
2-Amino-3-cyano-7-hydroxy-4-(4-hydroxyphenyl)quinoline (3). Yield 76%; mp 198-200C (EtOH). IR spectrum (vaseline oil), , cm-1: 3304, 3420, 3495 (NH2, OH); 2218 (CN); 1673 (NH2). 1H NMR spectrum, , ppm (J, Hz): 11.32 and 10.11 (1H each, both br. s, 2OH); 8.21 (2H, br. s, NH2); 7.34 (3H, m, Harom); 7.06 (1H, s, H-8); 6.98 (3H, m, Harom). Mass spectrum, m/z (Irel, %): 278 [M+1]+ (27), 277 [M]+ (100), 260 (12), 249 (25). Found, %: C 69.14; H 3.82; N 15.36. C16H11N3O2. Calculated, %: C 69.31; H 4.00; N 15.15. 7-Acetoxy-3-cyano-2-diacetylamino-4-(4-acetoxyphenyl)quinoline (5). Yield 70%; mp 168C (AcOH). IR spectrum (vaseline oil), , cm-1: 2216 (CN); 1694 (C=O). 1H NMR spectrum, , ppm (J, Hz): 7.95 (1H, s, H-8); 7.88 (1H, d, J = 9.30, H-6); 7.70 (2H, d, J = 7.74, H-3 and H-5 Ar); 7.68 (1H, d, J = 9.30, H-5); 7.48 (2H, d, J = 7.74, H-2 and H-6 Ar); 2.35 (12H, s, 4CH3). Mass spectrum, m/z (Irel, %): 445 [M]+ (6), 403 (29), 388 (25), 361 (32), 346 (41), 319 (40), 304 (42), 277 (43), 43 [Ac]+ (100). Found, %: C 64.61; H 4.12; N 9.50. C24H19N3O6. Calculated, %: C 64.72; H 4.30; N 9.43.
REFERENCES 1. 2. G. V. Klokol, L. G. Sharanina, V. N. Nesterov, V. E. Shklover, Yu. A. Sharanin, and Yu. T. Struchkov, Zh. Org. Khim., 23, 412 (1987). D. Barton and W. D. Ollis (editors), Comprehensive Organic Chemistry [Russian translation], Khimiya, Moscow (1985), Vol. 8, p. 196.
1496
NOVEL CYCLOCONDENSATION OF 2-ACYLETHYNYL-1-AMINO- AND 2-ALKOXYCARBONYLETHYNYL-1-AMINOANTHRAQUINONES WITH PYRIDINES

I. I. Barabanov Keywords: 2-acylethynyl-1-aminoanthraquinones, 2-alkoxycarbonylethynyl-1-aminoanthraquinones, substituted 5,6,9,14,15,15a-hexahydropyrido[2,1-b]quinazoline-9,14-diones, pyridine and its derivatives, cyclocondensation. Acetylene derivatives of quinones are a promising group of key intermediates in the synthesis of various condensed heterocyclic quinoid systems [1]. In many cases, heterocyclization of these compounds is achieved by preliminary addition of N-nucleophilic reagents (secondary or primary amines, hydrazine) at the triple bond, followed by cyclization of the adducts. Continuing research in this direction, we have established the possibility of cyclocondensation of some acetylenyl quinones when treated with such nitrogen-containing nucleophiles as azines. We have found that 1-amino-2-benzoylethynylanthraquinone 1 and the ethyl ester of (1-aminoanthraquinon-2-yl)propiolic acid (2), when dissolved in pyridine and its derivatives, react with the latter to form substituted 5,6,9,14,15,15a-hexahydropyrido[2,1-b]quinazoline-9,14-diones 3a-d.
R1 O NH2 C C C R O 1, 2 O 1 R = Ph; 2 R = OEt, 3ac R = Ph; a R1 = H, b R1 = Me, c R1 =
C H
N O C H C R
3ad CH2 , d R = OEt, R1 = H
Cyclocondensation of compounds 1, 2 takes 4-15 h at 35C. The yields of compounds 3a-d are as high as 90%. According to TLC monitoring, conversion of 1, 2 to 3a-d is not accompanied by accumulation of any intermediates in the reaction mass. An attempt to carry out this reaction in the benzene series was unsuccessful. __________________________________________________________________________________________ Institute of Chemical Kinetics and Combustion, Siberian Branch of the Russian Academy of Sciences, Novosibirsk 630090; e-mail: shvarts@kinetics.nsc.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1729-1731, November, 2004. Original article submitted April 23, 2004. 0009-3122/04/4011-14972004 Springer Science+Business Media, Inc. 1497
Thus ortho-benzoylethylaniline did not react with pyridine at 20C over a period of several days even with brief heating to the boiling point. 1 H NMR spectra of the synthesized compounds were recorded on a Bruker DPX-200 (200 MHz) spectrometer in CDCl3. Synthesis of Compounds 3a-d (General Procedure). A solution of quinone 1 or 2 in pyridine or its derivative was stirred at 35C and diluted with excess water or hexane. The product (dark violet crystals) was filtered out and recrystallized from a mixture of benzene or CHCl3 with hexane. 6-Benzoylmethylene-5,6,9,14,15,15a-hexahydropyrido[2,1-b]quinazoline-9,14-dione (3a) was obtained by reaction of quinone 1 (0.14 g, 0.40 mmol) with pyridine (5.0 ml) for 6.5 h. Compound 3a (0.14 g, 82%) was isolated; mp >100C (decomposes). 1H NMR spectrum, , ppm (J, Hz): H-1-4, 14a: 5.15-5.30 (1H, m), 5.55-5.75 (2H, m), 6.17 (1H, d, J = 7.6), 6.25-6.40 (1H, m); 6.66 (1H, s, =CH); 7.40-7.60 (3H, m, m- and p-C6H5); 7.73 (1H, d, J = 8.3, H-6(7)); 7.70-7.85 (2H, m, H-10,11); 7.95-8.05 (2H, m, o-C6H5); 8.16 (1H, d, J = 8.3, H-7(6)); 8.20-8.35 (2H, m, H-9,12); 9.38 (1H, br. s, NH). Found, %: C 77.83; H 4.21; N 6.40. C28H18N2O3. Calculated, %: C 78.13; H 4.21; N 6.51. 6-Benzoylmethylene-2-methyl-5,6,9,14,15,15a-hexahydropyrido[2,1-b]quinazoline-9,14-dione (3b) was obtained by reaction of quinone 1 (0.14 g, 0.40 mmol) with -picoline (5.0 ml) for 4 h. Compound 3b (0.13 g, 74%) was isolated; mp >100C (decomposes). 1H NMR spectrum, , ppm (J, Hz): 1.91 (3H, s, CH3); H-1,3,4,14a: 5.05-5.15 (1H, m), 5.35-5.60 (2H, m), 6.14 (1H, d, J = 7.7); 6.65 (1H, s, =CH); 7.35-7.55 (3H, m, m- and p-C6H5); 7.74 (1H, d, J = 8.3, H-6(7)); 7.70-7.85 (2H, m, H-10,11); 7.95-8.05 (2H, m, o-C6H5); 8.16 (1H, d, J = 8.3, H-7(6)); 8.20-8.35 (2H, m, H-9,12); 9.34 (1H, br. s, NH). Found, %: C 78.18; H 4.57; N 6.26. C29H20N2O3. Calculated, %: C 78.36; H 4.54; N 6.30. 6-Benzoylmethylene-2-vinyl-5,6,9,14,15,15a-hexahydropyrido[2,1-b]quinazoline-9,14-dione (3c) was obtained by reaction of quinone 1 (0.10 g, 0.28 mmol) with 4-vinylpyridine (6.5 ml) for 5 h. Compound 3c (0.11 g, 85%) was isolated; mp >100C (decomposes). 1H NMR spectrum, , ppm (J, Hz): 1,3,4,14a-H, 2-vinyl: 5.30 (1H, d, J = 10.8), 5.45-5.70 (4H, m), 6.20-6.50 (2H, m); 6.69 (1H, s, =CH); 7.40-7.60 (3H, m, m- and p-C6H5); 7.74 (1H, d, J = 8.3, H-6 (7)); 7.75-7.85 (2H, m, H-10,11); 7.95-8.10 (2H, m, o-C6H5); 8.18 (1H, d, J = 8.3, H-7(6)); 8.20-8.35 (2H, m, H-9,12); 9.40 (1H, br. s, NH). Found, %: C 78.58; H 4.46; N 5.91. C30H20N2O3. Calculated, %: C 78.93; H 4.42; N 6.14. 6-(Ethoxycarbonyl)methylene-5,6,9,14,15,15a-hexahydro[2,1-b]quinazoline-9,14-dione (3d) was obtained by reaction of compound 2 (0.15 g, 0.47 mmol) with pyridine (4.7 ml) for 15 h. Compound 3d (0.16 g, 86%) was isolated. Compound 3d was characterized as a complex with benzene of composition C24H18N2O40.5C6H6; mp 130-132C (decomposes) (benzenehexane). 1H NMR spectrum, , ppm (J, Hz): 1.30 (3H, t, J = 7.1, CH3); 4.05-4.35 (2H, m, OCH2 cis- and trans-isomers); H-1-4,14a: 5.10-5.20 (1H, m), 5.50-5.70 (2H, m), 6.16 (1H, d, J = 7.3), 6.25-6.40 (1H, m); 5.76 (1H, s, =CH); 7.35 (3H, s, benzene); 7.68 (1H, d, J = 8.3, H-6(7)); 7.70-7.85 (2H, m, H-10,11); 8.03 (1H, d, J = 8.3, H-7(6)); 8.20-8.30 (2H, m, H-9,12); 9.31 (1H, br. s, NH). Found, %: C 74.08; H 4.71; N 6.52. C27H21N2O4. Calculated, %: C 74.13; H 4.84; N 6.40.
REFERENCES 1. M. S. Shvartsberg, I. I. Barabanov, and L. G. Fedenok, Usp. Khim. 73, 171 (2004).
1498
UNEXPECTED REACTION OF 3-BENZOYL-4-HYDROXY-1-METHYL4-PHENYLPIPERIDINE WITH 1,2-DIAMINOBENZENE

A. T. Soldatenkov, S. V. Kutyakov, S. V. Volkov, Zh. A. Mamyrbekova, and K. B. Polyanski Keywords: benzo[b]-1,4,8-triazacycloundeca-2,4,11-triene, 3-benzoyl-4-phenyl-4-piperidol, 1,2-diaminobenzene, 1,2-di(2-benzoylethylamino)benzene. In a study of the condensation of 3-benzoylpiperidol (1) [1] and 1,2-diaminobenzene (2), we observed an unexpected direction for the reaction. In fact, by crystallization we isolated the product of N(1),N(2)-dialkylation of diaminobenzene 3 in 67% yield from the reaction mixture obtained after boiling these reagents for four hours in toluene, in the presence of catalytic amounts of p-toluenesulfonic acid. In subsequent chromatography of the residue obtained from the mother liquor, we isolated benzo[b]triazacycloundecatriene 4 and aminopropanone 5 (the latter was converted to the diacetate 6). Furthermore, we established by chromatography/mass spectrometry that the indicated residue also contained the 2,3-dihydro derivative of 1H-benzo-1,5-diazepine 7 and vinyl phenyl ketone 8. If we consider heterocycle 4 as a double Schiff base, then it becomes obvious that it was formed as a result of the following reaction cascade: first of all, retroaldol decyclization of the starting piperidol 1 leads to amino diketone A, and then tandem reaction of the latter with phenylene diamine 2 occurs: imination and cyclization. The most likely route to formation of Mannich bases 4 and 5 can be assumed to be deamination of amino ketone A to form vinyl phenyl ketone 8 according to a Michael retroreaction. In the case of subsequent reaction of the phenylenediamine molecule with one or two equivalents of this unsaturated ketone, Mannich bases 5 or 4 respectively are generated. Intramolecular cyclocondensation of amino ketone 5 leads to the derivative of 1,5diazepine 7. We should note that in the case of 10-minute microwave treatment of the solid mixture of the starting compounds 1 and 2 (without addition of the catalyst), the reaction becomes more selective with respect to amino ketone 5, isolated in 61% yield. According to the predictions of the Internet program PASS [2], compound 4 may exhibit psychotropic and nootropic activity (70-80%); compound 5 may have the properties of an interferon agonist (70%), and its diacetate 6 may have the properties of a fibrinogen receptor antagonist (76%); diketone 3 may exhibit antileishmanial activity (74%). The 1H NMR spectra were taken on a Bruker WP-400 (400 MHz) in CDCl3; the mass spectra (electron impact) were taken on a Finnigan MAT Incos 50 mass spectrometer (70 eV).
__________________________________________________________________________________________ Russian University People's Friendship, Moscow 117198; e-mail: asoldatenkov@sci.pfu.edu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1731-1733, November, 2004. Original article submitted July 12, 2004. 0009-3122/04/4011-14992004 Springer Science+Business Media, Inc. 1499
O HO MW, 10 min N Me 1 Ph N N N 4 Ph 5 O NHCH2CH2COPh N Ph Me NH2 Ph O Ph NH2 Ph N Me
O Ph
+
2
NH2
, PhMe, 4 h
+
NHCH2CH2COPh
+
NHCH2CH2COPh 3
+
N H 7
+
8
Ph
Reaction of 3-Benzoyl-4-hydroxy-1-methyl-4-phenylpiperidol (1) with 1,2-Diaminobenzene (2). A solution of piperidol 1 (2.4 g, 8 mmol), diaminobenzene 2 (0.43 g, 4 mmol), and TsOH (10 mg) in toluene (40 ml) was refluxed for 4 h in a device with a DeanStark trap. The solvent was evaporated and the residue was recrystallized from ether (crystals of compound 3 were obtained). The mother liquor was evaporated and the residue was separated by column chromatography on silica gel, eluting first with a 5:1 hexanechloroform mixture (compound 4 was isolated) and then with a 5:1 hexaneacetone mixture (compound 5 was obtained). Benzo[b]-1,4,8-triazacycloundeca-2,4,11-triene (4). Yield 0.17 g (12%). Thick oil. 1H NMR spectrum, , ppm (J, Hz): 2.15 (3H, s, CH3); 2.81 and 3.73 (2H each, both t, J = 6.5, CH2); 3.11 and 3.51 (2H each, both t, J = 7.1, CH2); 7.04-7.97 (14H, m, H arom.). Mass spectrum, m/z (Irel, %): 367 [M]+ (0), 336 (100), 321 (12), 295 (7), 282 (8), 259 (32), 232 (27), 194 (11), 115 (16), 103 (10), 91 (7), 77 (11). Found, %: C 81.85; H 6.72; N 11.35. C25H25N3. Calculated, %: C 81.74; H 6.81; N 11.44. 3-(2-Aminophenyl)amino-1-oxo-1-phenylpropane (5). Yield 0.13 g (15% calculated on the basis of compound 2). Thick oil. 1H NMR spectrum, , ppm (J, Hz): 3.03 and 3.87 (3H each, both t, J = 8.0, NCH2 and CH2CO); 3.5 (3H, br. s, NH, NH2); 6.68 and 6.96 (2H each, both m, C6H4N2); 7.30-7.97 (5H, m, COC6H5). Its diacetate 6. Mp 136-138C. IR spectrum (KBr), , cm-1: 1630 (NC=O), 1670 (CC=O), 3210 (NH). 1H NMR spectrum, , ppm (J, Hz): 1.77 and 2.34 (3H each, s, CH3); 2.73, 3.62, and 4.55 (1H, 2H, and 1H respectively, all m, CH2); 7.13 and 7.37 (2H and 1H respectively, both m, C6H4N2); 7.48, 7.62, and 7.96 (2H, 1H, and 2H respectively, all m, C6H5CO); 8.43 (1H, d, J = 8.3, C6H4N2); 9.34 (1H, br. s, NHCO). Mass spectrum, m/z (Irel, %): 324 [M]+ (60), 309 (10), 281 (50), 265 (80), 264 (42), 163 (44), 145 (23), 132 (37), 119 (82), 105 (100), 77 (75), 43 (92). Found, %: C 70.52; H 6.42; N 8.45. C19H20N2O3. Calculated, %: C 70.37; H 6.17; N 8.64. Also obtained by irradiation of a similar mixture in a household microwave oven (5 times, 2 min each) in 61% yield. 1,2-Di(2-benzoylethylamino)benzene (3). Yield 1.01 g (67%); mp 134-135C. IR spectrum (KBr), , cm-1: 1686 (C=O), 3322 and 3433 (NH). 1H NMR spectrum, , ppm (J, Hz): 3.30 and 3.55 (4H each, both t, J = 6.1, CH2CO and NCH2); 3.74 (2H, br. s, NH); 6.71 and 6.76 (2H each, both m, NC6H4N); 7.45 and 7.55 (4H and 2H respectively, both m, C6H5CO); 7.96 (4H, d, J = 7.8, C6H5CO). Mass spectrum, m/z (Irel, %): 372
1500
[M]+ (0), 240 (8), 222 (31), 221 (18), 220 (9), 219 (11), 194 (37), 132 (38), 119 (26), 108 (925), 105 (100), 77 (98). Found, %: C 77.42; H 6.57; N 7.42. C24H24N2O2. Calculated, %: C 77.42; H 6.45; N 7.53. 4-Phenyl-2,3-dihydro-1H-benzo-1,5-diazepine (7) was determined by chromatography/mass spectrometry. Mass spectrum, m/z (Irel, %): 222 [M]+ (38), 221 (26), 220 (20), 219 (28), 194 (100), 193 (20), 119 (16), 118 (10), 105 (24), 77 (19), Vinyl Phenyl Ketone (8) was determined by chromatography/mass spectrometry. Mass spectrum, m/z (Irel, %): 132 [M]+ (45), 131 (15), 105 (100), 104 (10), 77 (65), 55 (9), 51 (24).
REFERENCES 1. 2. J. T. Plati and W. Wenner, J. Org. Chem., 14, 543 (1949). A. V. Sadym, A. A. Lagunin, D. A. Filimonov, and V. V. Poroikov, Khim.-Farm. Zh., 36, 21 (2002).
1501
METHOD FOR SYNTHESIS OF 2-AMINO5-(2-THIENYLMETHYL)THIAZOLE

V. S. Matiychuk, Yu. O. Teslenko, and M. D. Obushak Keywords: thiazole derivatives, 2-chloro-3-(2-thienyl)propanal, heterocyclization, Pd catalysis, reaction with thiourea. -Halo-substituted aldehydes are convenient reagents in synthesis of thiazole derivatives. However, the range of such aldehydes is limited, and so 5-substituted thiazoles are less accessible than thiazole derivatives containing substituents in the 4 position, which are obtained from -halo ketones [1, 2]. We previously developed a method for synthesis of 2-amino-5-(R-benzyl)thiazoles from 3-aryl-2-chloropropionic aldehydes, obtained by reaction of arenediazonium chlorides with acrolein [3]. In this report, we propose a method for synthesis of thiazoles containing a 2-thienylmethyl group in the 5 position. We obtained 2-chloro-3-(2-thienyl) propanal (2) by reaction of (2-thienyl)mercury chloride 1 with acrolein in the presence of Li2PdCl4 and excess copper(II) chloride (a variant of the Heck reaction [4, 5]). Aldehyde 2, when reacted with thiourea, undergoes ring closure to form compound 3.
S 1
HgCl
Li2PdCl4 CuCl2
Cl O S 2
(H2N)2C=S S 3
N S NH2
The 1H NMR spectra were taken on a Mercury 400 (400 MHz) in DMSO-d6. 2-Chloro-3-(2-thienyl)propanal (2). A mixture of (2-thienyl)mercury chloride 1 (16 g, 50 mmol), acrolein (5 ml, 70 mmol), CuCl22H2O (38.5 g, 226 mmol), LiCl (2 g), and PdCl2 (80 mg) in acetic acid (30 ml) was stirred for 4 days. The reaction mixture was diluted with water (350 ml) and then filtered. The filtrate was extracted with chloroform and dried with Na2SO4; the solvent was evaporated and the residue was distilled under vacuum. Yield 3.6 g (41%); bp 93C (5 mm Hg), nD20 1.5513. Found, %: C 47.82; H 3.96; Cl 20.13. C7H7ClOS. Calculated, %: C 48.14; H 4.04; Cl 20.30. 2-Amino-5-(2-thienylmethyl)thiazole (3). A solution of thiourea (1.5 g, 20 mmol) and aldehyde 2 (3.3 g, 19 mmol) in ethanol (10 ml) was refluxed for 30 min. This was mixed with water (40 ml), acidified with HCl, and heated. The transparent solution was separated from the residue and alkalinized with ammonium hydroxide. The precipitate formed was filtered out, washed with water, dried, and recrystallized from ethanol. __________________________________________________________________________________________ Ivan Franko Lvov National University, Lvov 79005, Ukraine; e-mail: obushak@in.lviv.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1733-1735, November, 2004. Original article submitted June 2, 2004. 1502 0009-3122/04/4011-15022004 Springer Science+Business Media, Inc.
Yield 1.9 g (51%); mp 113C. 1H NMR spectrum, , ppm (J, Hz): 4.12 (2H, s CH2); 6.74 (1H, s, H-4 thiazole); 6.78 (2H, s, NH2); 6.89 (1H, br. s, H-3 thiophene); 6.94 (1H, m, H-4 thiophene); 7.35 (1H, d, J = 4.0, H-5 thiophene). Found, %: C 48.75; H 4.03; S 32.52. C8H8N2S2. Calculated, %: C 48.95; H 4.11; S 32.67.
REFERENCES 1. 2. 3. 4. 5. J. M. Sprague and A. H. Land, in: R. C. Elderfield (editor), Heterocyclic Compounds [Russian translation], Izdat. Inostr. Lit., Moscow (1961), Vol. 5, p. 395. I. K. Moiseev, M. N. Zemtsova, and N. V. Makarova, Khim. Geterotsikl. Soedin., 867 (1994). N. D. Obushak, V. S. Matiychuk, and N. I. Ganushchak, Zh. Org. Khim., 33, 1081 (1997). R. F. Heck, J. Am. Chem. Soc., 90, 5538 (1968). R. F. Heck, J. Am. Chem. Soc., 90, 5518 (1968).
1503
UNUSUAL REACTION OF 3,6-DIMETHOXYBENZONORBORNADIENE WITH 2-CHLOROSULFENYL-1-PYRIDINE 1-OXIDE

A. V. Borisov, V. K. Osmanov, I. G. Sokolov, G. N. Borisova, and Zh. V. Matsulevich Keywords: alkenes, sulfenyl chlorides, heterocyclization. In reactions of 3,6-dimethoxybenzonorbornadiene (1) with sulfenyl chlorides, usually mixtures of 1,2-addition and WagnerMeerwein rearrangement products are obtained, and the yield of rearrangement products is significantly increased in the presence of salt additives [1, 2]. We have found that the primary direction of the reaction of the unsaturated compound 1 with 2-chlorosulfenyl-1-pyridine 1-oxide (2) in methylene chloride at 20C is polar exo-cis cycloaddition of the sulfenylating reagent at the multiple bond, with closure of the ring by the oxygen atom of the N-oxide group and formation of polycyclic system 3a in 45% yield. The other direction of the reaction, the WagnerMeerwein rearrangement, leads to -chloro sulfide 4, the yield of which is 34%. Formation of exclusively the product of polar cycloaddition 3b (the perchlorate analog of salt 3a) in 82% yield occurs upon sulfenylation of compound 1 in nitromethane in the presence of lithium perchlorate.
OMe MeNO2 LiClO4 MeO CH2Cl2 + N O _ 2 _ O OMe + N O _ Cl S MeO 3a MeO 4 OMe + Cl S + N SCl
3b
Thus even under conventional conditions, sulfenyl chloride 2 reacts with unsaturated compound 1 preferentially according to a [4+ + 2] cycloaddition scheme [3]. To our knowledge, such data for reactions of sulfenyl chlorides with alkenes were obtained for the first time in [4-7]. __________________________________________________________________________________________ Nizhny Novgorod State Technical University, Nizhny Novgorod 603606, Russia; e-mail: ifxf@nntu.nnov.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1736-1737, November, 2004. Original article submitted June 30, 2004. 1504 0009-3122/04/4011-15042004 Springer Science+Business Media, Inc.
The 1H and 13C NMR spectra were taken on a Bruker DRX-500 (500 MHz and 125 MHz respectively) in DMSO-d6. Reaction of Compounds 1 and 2 in Methylene Chloride. A solution of sulfenyl chloride 2 (1.61 g, 10 mmol) in methylene chloride (30 ml) was added to a solution of compound 1 (30 ml) in methylene chloride (30 ml) at 20C. After 10 min, the solvent was evaporated under vacuum. By extraction with hexane, we obtained 1.23 g (34%) of compound 4. After recrystallization of the residue from a 3:1 methylene chloride hexane mixture, we obtained 1.63 g (45%) of compound 3a. exo-14,17-Dimethoxy-3-oxa-10-thia-4-azoniapentacyclo[10.6.1.02,11.04,9.013,18]nonadeca-4,6,8,13,15,17hexaene Chloride (3a). Mp 142-144C. IR spectrum (KBr), , cm-1: 1498, 1464, 1256, 1078, 710. 1H NMR spectrum, , ppm (J, Hz): 9.42 (1H, d, 3J = 6.6, Het); 8.40 (1H, t, 3J = 8.1, 3J = 7.3, Het); 8.33 (1H, d, 3J = 8.1, Het); 7.97 (1H, t, 3J = 7.3, 3J = 6.6, Het); 6.83 (2H, s, HC(15), HC(16)); 5.07 (1H, d, 3J = 5.1, CHO); 4.01 (1H, s, HC(1)); 3.89 (1H, s, HC(12)); 3.83 (1H, d, CHS); 3.77 and 3.75 (6H, s and s, 2OCH3); 2.77 (1H, d, 2J = 8.8, H-anti-C(19)); 2.12 (1H, d, H-syn-C(19)). 13C NMR spectrum, , ppm: 152.10, 142.81, 141.88, 131.46, 125.61 (CHet); 147.38, 143.18 (CArO); 130.53, 129.18 (C(13,18)); 111.44 (C(16)); 110.57 (C(15)); 92.68 (CHO); 57.71 (CHS); 55.73 (2CH3O); 50.01 (C11); 43.39 (C(12)); 36.24 (C(19)). Found, %: C 59.89; H 4.83; N 3.71; S 8.98. C18H18ClNO3S. Calculated, %: C 59.42; H 4.99; N 3.85; S 8.81. 2-[exo-9-Chloro-3,6-dimethoxytricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-11-yl-exo-sulfanyl]-1pyridine-1-oxide (4). Oil. IR spectrum (film), , cm-1: 3064-2944, 2832, 1714, 1608, 1586, 1550, 1496, 1464, 1418, 1300, 1260, 1140, 1080, 972, 838, 792, 730, 708. 1H NMR spectrum, , ppm (J, Hz): 8.22 (1H, d, 3J = 6.6, Het); 7.17-7.32 (3H, m, Het); 6.72 (2H, s, HC(4), HC(5)); 3.88 (1H, m, CHCl); 3.82 (1H, s, HC(8)); 3.80 (1H, s, HC(1)); 3.71 (6H, s, 2OCH3); 2.54 (1H, dt, 2J = 13.2, 3J = 4.4, 3J = 3.7, H-exo-C(10)); 2.09 (1H, dd, 2J = 13.2, 3 J = 6.6, H-endo-C(10)). Found, %: C 59.95; H 4.80; N 3.69; S 8.68. C18H18ClNO3S. Calculated, %: C 59.42; H 4.99; N 3.85; S 8.81. Reaction of Compounds 1 and 2 in the Lithium PerchlorateNitromethane System. A solution of LiClO4 (1.06 g, 10 mmol) in nitromethane (30 ml) and a solution of sulfenyl chloride 2 (1.61 g, 10 mmol) in nitromethane (10 ml) were added to a solution of compound 1 (2.26 g, 10 mmol) in nitromethane (20 ml) at 20C. After 10 min, the LiCl precipitate was filtered out; the filtrate was evaporated under vacuum. After recrystallization of the residue from methylene chloride, we obtained 3.51 g (82%) of compound 3b. exo-14,17-Dimethoxy-3-oxa-10-thia-4-azoniapentacyclo[10.6.1.02,11.04,9.013,18]nonadeca-4,6,8,13,15,17hexaene Perchlorate (3b). Mp 160-162C. IR spectrum (KBr), , cm-1: 1496, 1456, 1270, 976, 764, 738; 1088 (ClO4). Found, %: C 50.97; H 4.33; N 3.31; S 7.61. C18H18ClNO7S. Calculated, %: C 50.53; H 4.24; N 3.27; S 7.49.
REFERENCES 1. 2. 3. 4. 5. 6. 7. N. S. Zefirov, N. K. Sadovaja, L. A. Novgorodtseva, R. Sh. Achmedova, S. V. Baranov, and I. V. Bodrikov, Tetrahedron, 35, 2759 (1979). N. S. Zefirov and A. S. Kozmin, Sov. Sci. Rev. B. Chem., Harwood, Amsterdam (1985), Vol. 7, p. 297. R. R. Schmidt, Angew. Chem. Intern. Ed., 12, 212 (1973). E. Kuhle, The Chemistry of the Sulfenic Acids, Thieme Verlag, Stuttgart (1973), p. 163. L. P. Rasteikene, D. I. Greichute, M. T. Lin'kova, and I. L. Knunyants, Usp. Khim., 46, 1041 (1977). Yu. G. Gololobov and N. I. Gusar', Sulfenyl Chlorides [in Russian], Nauka, Moscow (1989), p. 177. I. V. Koval', Usp. Khim., 64, 781 (1995).
1505
NOVEL METHOD FOR SYNTHESIS OF POLYNUCLEAR HETEROCYCLIC SYSTEMS WITH A PYRIDAZINE RING
C. L. Bogza1, V. I. Dulenko1, S. Yu. Zinchenko1, K. I. Kobrakov2, and I. V. Pavlov2 Keywords: aminopyrazoles, diazo compounds, pyrazolo[3',4':5,6]pyridazino[3,4-b]indole, pyrazolo[3,4-c]cinnolines, diazotization, nitrosation. Examples of diazotization of 5-aminopyrazoles, which lead to pyrazolyl-5-diazonium salts, are well known [1, 2]. In the case of aminopyrazoles 1a-c, the reaction does not stop at the diazotization step. When they are nitrosated in acetic acid by sodium nitrite at room temperature, the intermediate diazo compound 2 undergoes an intramolecular azo coupling reaction to form 1-R1-3-R2-7,8-dimethoxypyrazolo[3,4-c]cinnolines 3a-c.
R1 O O 1ac R1 N O O 1, 3 a R1 = Me, R2 N 3ac = H; b R1 = Ph, R2 = H; c R1 = Me, R2 = Ph N N R2 R1 N N NH2 R2 NaNO2 / AcOH O O N 2 N N N + R2
Ph
N NH NH2 N H 4 NaNO2 / AcOH
Ph
N NH N
N H 5
__________________________________________________________________________________________ L. M. Litvinenko Institute of Physical Organic and Coal Chemistry, National Academy of Sciences of Ukraine, Donetsk 83114, Ukraine. 2 A. N. Kosygin Moscow State Technical University, Moscow 119991, Russia; e-mail: office@msta.ac.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1738-1739, November, 2004. Original article submitted September 26, 2003. 1506 0009-3122/04/4011-15062004 Springer Science+Business Media, Inc.
1
5-Amino-4-(3-indolyl)-3-phenylpyrazole (4) under the same conditions undergoes ring closure to form pyrazolo[3',4':5,6]pyridazino[3,4-b]indole (5), which is a novel heteroaromatic system. The method we have developed for synthesis of polynuclear heterocycles with a central pyridazine ring does not have any analogs in the literature. The 1H NMR spectra were taken on a Varian Mercury (200 MHz) in DMSO-d6. 7,8-Dimethoxy-1-methylpyrazolo[3,4-c]cinnoline (3a). Yield 77%; mp 320-322C (decomposes). IR spectrum, , cm-1: 3280, 1630, 1605. 1H NMR spectrum, , ppm: 2.84 (3H, s, CH3); 4.01 (3H, s, OCH3); 4.08 (3H, s, OCH3); 7.55 (1H, s); 7.97 (1H, s); 14.1 (1H, s, NH). Found, %: C 59.0; H 4.95; N 22.9. C12H12N4O2. Calculated, %: C 59.2; H 5.0; N 23.0. 7,8-Dimethoxy-1-phenylpyrazolo[3,4-c]cinnoline (3b). Yield 70%; mp 313-315C (decomposes). IR spectrum, , cm-1: 3235, 1630, 1605. 1H NMR spectrum, , ppm: 3.92 (3H, s, OCH3); 4.04 (3H, s, OCH3); 7.32 (1H, s); 7.55 (2H, t); 7.62 (1H, t); 7.76 (2H, d); 7.83 (1H, s); 13.8 (1H, s, NH). Found, %: C 66.6; H 4.6; N 18.3. C17H14N4O2. Calculated, %: C 66.8; H 4.7; N 18.4. 7,8-Dimethoxy-1-methyl-3-phenylpyrazolo[3,4-c]cinnoline (3c). Yield 84%; mp 227C (decomposes). IR spectrum, , cm-1: 1630, 1605. 1H NMR spectrum, , ppm (J, Hz): 2.87 (3H, s, CH3); 4.01 (3H, s, OCH3); 4.07 (3H, s, OCH3); 7.37 (1H, t, J = 7.5); 7.47 (1H, s); 7.60 (2H, t, J = 7.5); 7.93 (1H, s); 8.34 (2H, d, J = 7.5). Found, %: C 67.5; H 5.0; N 17.5. C18H16N4O2. Calculated, %: C 67.5; H 5.2; N 17.6. 1-Phenyl-3,6-dihydropyrazolo[3',4':5,6]pyridazino[3,4-b]indole (5). Yield 63%; mp >400C. IR spectrum, , cm-1: 3250, 3200, 1640. 1H NMR spectrum, , ppm (J, Hz): 7.10 (1H, t, J = 9); 7.44 (1H, d, J = 9); 7.57 (1H, d, J = 9); 7.60-7.72 (4H, m); 7.76-7.83 (2H, m); 12.8 (1H; 14.3 (1H, s). Found, %: C 71.4; H 3.8; N 24.7. C23H18N4O2. Calculated, %: C 71.57; H 3.89; N 24.55.
REFERENCES 1. 2. H. Reimlinger and A. Van Overstaeten, Chem. Ber., 99, 3350 (1966). M. H. Elnagdi, D. H. Fleita, E. A. Hafiz, and S. M. Fahmi, J. Org. Chem., 41, 3781 (1976).
1507
UNEXPECTED OXIDATION OF AZAFLUOREN9-ONES UNDER BAEYERVILLIGER CONDITIONS

Le Tuan Anh, S. V. Volkov, K. B. Polyanski, and A. T. Soldatenkov Keywords: azafluoren-9-ones, benzaldehyde, azafluoren-9-one N-oxides, manganese dioxide, Baeyer Villiger reaction, oxidation. Oxidative rearrangement of alicyclic ketones to form lactones (the BaeyerVilliger reaction) occurs under the action of hydrogen peroxide, peracids [1-4], and also less hazardous modified oxidative systems such as, for example, oxygenbenzaldehydemanganese dioxide [5]. In this work, when using this modified system for oxidation of 9-oxo-1-azafluorene (1), we unexpectedly isolated 1-azafluoren-9-one N-oxide (2) in good yield instead of a lactone of type A.
O2 / PhCHO / MnO2 N O 1 O H B O O N O Ph
PhCOOH
N O O A O 2
N O
Analogous mild oxidation of another isomer, 9-oxo-4-azafluorene (3), and also its oxidation under conventional BaeyerVilliger reaction conditions (35% H2O2 solution at 40C in the presence of catalytic amounts of p-toluenesulfonic acid [4]) in both cases led to only its N-oxide (4). At the same time, oxidation of 1or 4-azafluorenes that do not have an oxo group at the C-9 atom did not occur at all under the same modified BaeyerVilliger reaction conditions. Thus only the presence of an 9-oxo group in substrates 1 and 3 ensures formation of N-oxides 2 and 4. This fact suggests first of all that possibly the first step of the BaeyerVilliger reaction occurs and secondly that rearrangement of adduct B to lactone A is impossible due to the fact that the pyridine nitrogen atom plays the role of an effective trap for the active oxygen atom. We should also note that in a separate analogous experiment, N-oxide 2 also did not undergo a BaeyerVilliger reaction. __________________________________________________________________________________________ Russian People's Friendship University, Moscow 117198; e-mail: asoldatenkov@sci.pfu.edu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1740-1741, November, 2004. Original article submitted July 12, 2003. 1508 0009-3122/04/4011-15082004 Springer Science+Business Media, Inc.
Accordingly it becomes understandable why oxidation of cycloalkanes in [5] did not occur when 2-formylpyridine was used instead of benzaldehyde (the authors did not comment on the reason for this). Mild and nonhazardous oxidation conditions and also the preparative usefulness of the method we found for converting azafluorenones to their N-oxides may prove to be the deciding factors when chemists are selecting a method for oxidation of nitrogen-containing heteroaromatic compounds having a carbonyl group, in order to form the corresponding N-oxides. Oxidation of 1-Azafluoren-9-one (1). A mixture of substrate 1 (0.28 g, 1.4 mmol), MnO2 (0.28 g), benzaldehyde (1.5 ml, 9 mmol) in 1,2-dichloroethane (15 ml) was stirred at 35-40C in a slow stream of oxygen until (according to TLC) the starting azafluorenone disappeared (4 h). The reaction mixture was separated from the MnO2 and purified by column chromatography on silica gel (eluent: acetonechloroform, 1:1). Obtained 0.21 g (75%) of 1-azafluoren-9-one N-oxide (2); mp 218-220C (mp 221-223C [6]). IR spectrum (KBr), , cm-1: 1726 (C=O), 1286 (NO). 1H NMR spectrum (400 MHz, DMSO-d6), , ppm (J, Hz): 7.43 (1H, br. s, J1/2 = 7.6, H3); 7.53 (1H, br. s, J1/2 = 7.5, H-7); 7.65 (2H, br. s, H-6,8); 7.83 (1H, br. s, H-5); 8.24 (1H, br. s, H-4); 8.56 (1H, br. s, J1/2 = 7.5, H-2). Mass spectrum (electron impact, 70 eV), m/z: 197 [M]+. Oxidation of 4-Azafluoren-9-one (3). A. Oxidation of compound 3 (0.65 g, 3.6 mmol) in a mixture with MnO2 (0.065 g, 7.4 mmol), benzaldehyde (1.2 ml, 7.4 mmol), and 1,2-dichloroethane (15 ml) (40C, 4 h, under a slow stream of oxygen) was carried out similarly to oxidation of compound 1, and we obtained 0.5 g (70%) of 4-azafluoren-9-one N-oxide (4); mp 253-255C (mp 257-259C [6]). IR spectrum (KBr), , cm-1: 1717 (C=O), 1270 (NO). 1H NMR spectrum (400 MHz, CDCl3), , ppm (J, Hz): 7.24 (1H, t, J = 7.4 and J = 6.7, H-2); 7.51 (1H, dt, J = 7.6 and J = 0.8, H-7); 7.55 (1H, br. d, J = 7.41, H-8); 7.66 (1H, dt, J = 7.5 and J = 1.2, H-6); 7.78 (1H, br. d, J = 7.2, H-1); 8.24 (1H, d, J = 6.7, H-3); 8.60 (1H, d, J = 7.5, H-5). Mass spectrum (electron impact, 70 eV), m/z (Irel, %): 197 [M]+ (100), 181 [MO]+ (30), 180 (7), 179 (8), 170 [MHCN]+ (14), 169 [M CO]+ (14), 153 [MCO2]+ (33), 140 (20), 127 (21), 126 (27), 114 (25), 113 (16). B. When a solution of ketone 3 (0.18 g, 1 mmol) and TsOH (10 mg) in acetonitrile (10 ml) was oxidized by hydrogen peroxide (35% aqueous solution of hydrogen peroxide, added dropwise over a period of 30 min) and then the mixture was stirred at 40C for 15 h, we obtained 0.13 g (66%) of the N-oxide 4.
REFERENCES 1. 2. 3. 4. 5. 6. 7. K. V. Vatsuro and G. L. Mishchenko, Name Reaction in Organic Chemistry [in Russian], Khimiya, Moscow (1976), p. 29. M. Hudlicky, Oxidation in Organic Chemistry. ACS Monograph 186, American Chemical Society, Washington (1990), p. 186. P. Laszlo, The Logic of Organic Synthesis [Russian translation], Mir, Moscow (1998), Vol. 1, p. 185. V. Z. Shirinyan, M. M. Krayushkin, L. I. Belen'kii, L. G. Vorontsova, Z. A. Starikova, A. Yu. Martynkin, V. L. Ivanov, and B. M. Uzhinov, Khim. Geterotsikl. Soedin., 86 (2001). T. Inokuchi, M. Kanazaki, T. Sugimoto, and S. Torii, Synlett., 1037 (1994). K. Kloc, J. Mlochowski, and Z. Szulc, Can. J. Chem., 57, 1506 (1979). J. N. Chatterjee and K. Prasad, J. Indian Chem. Soc., 32, 371 (1955).
1509
SPIROTHIAZOLO[4',2]- AND THIAZOLO[3,4-a]QUINOXALINES BASED ON 3-(-BROMOETHYL)QUINOXALIN-2-ONES AND THIOUREA

A. A. Kalinin, O. G. Isaikina, and V. A. Mamedov Keywords: 3--bromoethyl)quinoxalin-2-ones, spirothiazoloquinoxalines, thiazolo[3,4-a]quinoxalines, thiourea. We have observed that 3-(-bromoethyl)quinoxalin-2-ones 1a,b [1], when reacted with thiourea, form spirothiazoloquinoxalines 2a,b which, when briefly heated in acetic anhydride, are converted to thiazolo[3,4-a]quinoxalines 3a,b [2]. Formation of the thiazolo[3,4-a]quinoxaline system in the presence of acetic anhydride probably occurs through an open-chain isothioureide tautomeric form 4, in which intramolecular nucleophilic attack by the nitrogen atom of the pyrazine ring on the carbon atom of the isothioureide moiety easily occurs, with elimination of an ammonia molecule in the form of ammonium acetate from the intermediate acyl derivatives of compounds 2a,b.
NH N Br O 1. NH2C(S)NH2 2. NaHCO3 N R 1a,b 1. NH2C(S)NH2 2. Ac2O 3. NaHCO3 AcN S N Ac2O, N R 3a,b a R = H, b R = Et O N R 2a,b H N S N O NH2 N R 4 O N S NH2
Judging from the IR and 1H NMR spectra, spirothiazoloquinoxalines 2 are also mixtures of tautomers, the ratio of which depends on the nature of the substituent R. When treated with acetic anhydride, they all are converted to thiazolo[3,4-a]quinoxalines 3. __________________________________________________________________________________________ A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Science Center, Russian Academy of Sciences, Kazan 420088; e-mail: mamedov@iopc.kcn.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1742-1744, November, 2004. Original article submitted May 26, 2004. 1510 0009-3122/04/4011-15102004 Springer Science+Business Media, Inc.
Compounds 3 are formed in good yields when the reaction is carried out in a single reactor without isolating intermediate spirothiazoloquinoxalines 2a,b. Evidence in favor of the formation of spirothiazoloquinoxalines comes from the ~1 ppm upfield shift of the signals from the benzo moiety of the quinoxaline system in the 1H NMR spectra and the presence in the 13 C NMR spectra of a signal at 89 ppm which is typical for a spiro atom [3], and the signal for the H-9 proton in the 1H NMR spectrum, which resonates relatively downfield (9.9 ppm) [2,4] compared with other aromatic protons and is diagnostic for azolo[a]annelation of quinoxalines, indicates formation of a 1-iminothiazolo[3,4-a]quinoxaline system. The IR spectra were taken for mulls of the studied compounds in vaseline oil on a Bruker Vector-22 spectrometer in the frequency range 400-3600 cm-1. The 1H NMR spectra of compound 1b were recorded on a Bruker WM-250 spectrometer (250 MHz); the 1H NMR spectra for the rest of the compounds were taken on a Bruker MSL-400 (400 MHz). The 13C NMR spectra were taken on a Bruker MSL-400 (100 MHz) in DMSO-d6. The melting points were determined on a Boetius stage. 3-(-Bromoethyl)-1-ethylquinoxalin-2-one (1b). Bromine (0.13 ml, 2.48 mmol) at 10-12C was added to a solution of 1,3-diethylquinoxalin-2-one (0.50 g, 2.48 mmol) in dioxane (10 ml). The reaction mixture was stirred for 4 h at a temperature of 10-12C; the precipitated crystals were filtered out and treated with a 5% aqueous solution of NaHCO3 and then washed with water. Yield 58%; mp 87-89C (dioxane). IR spectrum (vaseline), , cm-1: 463, 521, 561, 596, 667, 710, 761, 972, 1063, 1171, 1203, 1308, 1443, 1558, 1602, 1650. 1 H NMR spectrum, , ppm (J, Hz): 1.40 (3H, t, J = 7.2, CH3CH); 2.10 (3H, d, J = 6.7, CH3CH2); 4.20-4.50 (2H, m, NCH2); 5.73 (1H, q, J = 6.7, CHBr); 7.35 (1H, d, J = 8.1, H-8); 7.36 (1H, dd, J1 = 8.0, J2 = 6.7, H-6 or H-7); 7.58 (1H, dd, J1 = 8.4, J2 = 7.8, J2 = 1.27, H-6 or H-7); 7.91 (1H, dd, J = 8.0, J = 1.7, H-5). Found, %: C 51.45; H 4.80; N 9.78. C12H13BrN2O. Calculated, %: C 51.27; H 4.66; N 9.96. Spiro-2-amino-5-methyl-4,5-dihydrospiro(thiazolo-4,2'-1,2,3,4-tetrahydroquinoxaline)-3'-one (2a). Thiourea (0.14 g, 1.84 mmol) was added to a solution of compound 1a (0.30 g, 1.25 mmol) in dioxane (10 ml). The reaction mixture was stirred for 5 h at room temperature and allowed to stand overnight; then it was treated with a 5% aqueous solution of NaHCO3. The crystals formed were filtered out and washed with water. Yield 85%; mp 183-185C. IR spectrum (vaseline), , cm-1: 435, 709, 740, 822, 858, 972, 1148, 1184, 1274, 1315, 1505, 1578, 1606, 1633, 1691, 2500-3445. 1H NMR spectrum, , ppm (J, Hz): 1.37 (3H, d, J = 6.9, CH3CH); 4.89 (1H, q, J = 7.0, CHS); 6.35 (1H, S, NH); 6.49 (2H, br. s, NH2); 6.59-6.66 (1H, m, H-6 or H-7); 6.71-6.79 (2H, m, H-7 or H-6,8); 6.89 (1H, d, J = 6.9, H-5); 10.33 (1H, s, NHC(O)). 13C{1H} NMR spectrum, , ppm: 14.88, 49.82, 89.03, 114.64, 114.85, 118.24, 122.63, 126.09, 133.89, 159.95, 165.51. Found, %: C 53.44; H 4.76; N 22.80; S 12.78. C11H12N4OS. Calculated, %: C 53.21; H 4.87; N 22.56; S 12.91. Spiro-2-amino-4'-ethyl-5-methyl-4,5-dihydrospiro(thiazolo-4,2'-1,2,3,4-tetrahydroquinoxaline)-3'one (2b) was obtained similarly to compound 2a from compound 1b. Yield 79%; mp 170C-173C. IR spectrum (vaseline), , cm-1: 723, 993, 1140, 1173, 1256, 1308, 1350, 1403, 1508, 1582, 1657, 2600-3100, 3305, 3363. 1 H NMR spectrum, , ppm (J, Hz): 1.39 (3H, t, J = 7.2, CH3CH2); 2.10 (3H, d, J = 6.7, CH3CH); 4.24-4.47 (2H, m, CH2CH3); 5.73 (1H, q, J = 6.7, CHCH3); 7.36 (2H, m, H-6 or H-7,8); 7.58 (1H, m, H-7 or H-6); 7.91 (1H, dd, J1 = 8.0, J2 = 1.7, H-5). 13C{1H} NMR, , ppm: 12.77, 14.74, 37.15, 49.86, 88.67, 109.76, 113.98, 115.51, 118.61, 122.84, 127.11, 135.12, 160.06, 164.34. Found, %: C 56.38; H 5.75; N 20.40; S 11.53. C13H16N4OS. Calculated, %: C 56.50; H 5.84; N 20.27; S 11.60. 1-Acetylimino-3-methylthiazolo[3,4-a]quinoxaline-4(5H)-one (3a). Thiourea (0.15 g, 1.97 mmol) was added to a mixture of compound 1a (0.20 g, 0.83 mmol) in THF (20 ml); the reaction mixture was stirred for 6 h at room temperature and allowed to stand overnight, then acetic anhydride (10 ml) was added and it was boiled for 10 min. The reaction mixture was cooled, the precipitated crystals were filtered out and washed with THF, a 5% aqueous solution of NaHCO3, and water. Yield 57%. B. Acetic anhydride (1 ml) was added to compound 2a (0.10 g, 0.42 mmol) and boiled for 10 min. The reaction mixture was cooled, the precipitated crystals were filtered out and washed with i-PrOH. Yield 87%; mp >350C. IR spectrum (vaseline), , cm-1: 462, 598, 654, 763, 800, 947, 979, 1023, 1105, 1145, 1167, 1237, 1511
1276, 1309, 1332, 1426, 1447, 1498, 1580, 1618, 1693, 3062, 3144, 3201. 1H NMR spectrum, , ppm (J, Hz): 2.34 (3H, s, CH3C(O)): 2.76 (3H, s, CH3CS); 7.17-7.24 (2H, m, H-6 or H-7, 8)(; 7.28-7.36 (1H, m, H-7 or H-6); 9.90 (1H, d, J = 8.3, H-9); 11.29 (1H, s, NHC(O)). Found, %: C 56.15; H 3.98; N 15.48; S 11.85. C13H11N3O2S. Calculated, %: C 57.13; H 4.06; N 15.37; S 11.73. 1-Acetylimino-5-ethyl-3-methylthiazolo[3,4-a]quinoxalin-4-one (3b). A. Obtained similarly to compound 3a according to method A from compound 1b. Yield 62%. B. Obtained similarly to compound 3a according to method B from compound 2b. Yield 68%; mp 221-223C. IR spectrum (vaseline), , cm-1: 405, 458, 468, 489, 555, 573, 647, 666, 742, 755, 769, 864, 912, 944, 977, 1010, 1036, 1062, 1092, 1145, 1171, 1235, 1266, 1279, 1300, 1344, 1366, 1394, 1420, 1450, 1501, 1608, 1659, 1719. 1H NMR spectrum, , ppm (J, Hz): 1.27 (3H, t, J = 6.9, CH2CH3); 2.34 (3H, s, CH3C(O)); 2.77 (3H, s, CH3CS); 4.17 (2H, q, J = 6.9, CH2CH3); 7.28-7.34 (1H, m, H-6 or H-7); 7.43-7.47 (2H, m, H-7 or H-6,8); 10.08 (1H, d, J = 8.3, H-9). Found, %: C 59.32; H 4.97; N 13.78; S 10.50. C15H15N3O2S. Calculated, %: C 59.78; H 5.02; N 13.94; S 10.64. This work was done with the financial support of the Russian Foundation for Basic Research (grant No. 03-03-32865) and the President of the Russian Federation (Program for Supporting Leading Scientific Schools, grant NSh 2030.2003.3).
REFERENCES 1. 2. 3. A. A. Kalinin, O. G. Isaikina, and V. A. Mamedov, in: Seventeenth Mendeleev Congress on General and Applied Chemistry [in Russian], Kazan (2003), p. 382. V. A. Mamedov, A. A. Kalinin, A. T. Gubaidullin, I. A. Litvinov, and Ya. A. Levin, Khim. Geterotsikl. Soedin., 1664 (1999). E. Breitmaier, W. Voelter, Carbon-13 NMR Spectroscopy (High-Resolution Methods and Application in Organic Chemistry and Biochemistry). Third Edition, completely revised. VCH Verlagsgesellschaft mbH, D-6940 Weinheim (Federal Republic of German) (1989), pp. 277,467. G. W. H. Cheeseman and B. Tuck, J. Chem. Soc.(C), 13, 1164 (1967).
4.
1512
4,7-DIHYDRO-, 4,5,6,7-TETRAHYDRO-, AND OCTAHYDROISOINDOLES (AND METHANOISOINDOLES). (REVIEW)

G. E. Marinicheva1 and T. I. Gubina2 Data on the synthesis and biological characteristics of hydrogenated isoindoles and methanoisoindoles are reviewed and analyzed. Keywords: isoindoles, biological activity, mechanism, synthesis. 4,7-Dihydro-, 4,5,6,7-tetrahydro-, and octahydroisoindoles (and methanoisoindoles) were first obtained half a century ago [1]. Since then a considerable amount of information has accumulated on the synthesis and characteristics of isoindoles with a hydrogenated carbocycle, but it has not, however, been included in any of the reviews on the chemistry of isoindoles [2-6]. Some uncoordinated data on the "bridged" analogs of isoindole have also not been classified. In the mean time isoindoles and methanoisoindoles, well known as substances with clearly defined physiological activity [7-10], provide the basis for the creation of the modern highly effective hypertensive agent tripamide [11-13]. The 4,5,6,7-tetrahydroisoindole fragment is present in the molecules of LSD-25 [14] and cycloprodiogiosin [15, 16]. The only isoindole found in nature [17] has a 4,7-dihydro structure. The aim of the present review was to gather and analyze data on the synthesis and biological characteristics of iso- and methanoisoindoles with a partly or completely hydrogenated carbocycle. Analysis of the biological activity of such compounds is of interest specifically for the synthesis of such substances with specific physiological characteristics.
1. SYNTHESIS OF 4,7-DIHYDROMETHANOISOINDOLES)
AND
4,5,6,7-TETRAHYDROISOINDOLES
(AND
1.1. Intermolecular Cyclization of 1,2-Disubstituted Cyclohexenes and Cyclohexanes The first representatives of isoindoles with a hydrogenated carbocycle 1 and 2 were obtained by the reaction of 1,2-bifunctional derivatives of cyclohexene and cyclohexane 3 with nitrogen reagents ammonia [1] and p-nitroaniline [18, 19] in an acidic medium.
__________________________________________________________________________________________ Scientific-Research Institute of Chemistry, Saratov State University, Saratov 410054, Russia; e-mail: eco@sstu.saratov.ru. 2 Saratov State Technical University, Saratov 410026, Russia; e-mail: smrol3@land.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1763-1782, December, 2004. Original article submitted June 6, 2001. Revision submitted December 1, 2004. 0009-3122/04/4012-15172004 Springer Science+Business Media, Inc. 1517
1
R R R R 3 COMe H2NC6H4NO2-p COMe NH3 R R NH R R = H, Me R 1 Me Me R R
Me N C6H4NO2 -p
Me 2
Compounds 1 proved unstable, but compounds 2 were isolated with yields of 80-90%. In [20] the Knorre reaction was examined as applied to the synthesis of 4,5,6,7-tetrahydroisoindoles. The reaction of 2-formylcyclohexanone (4) with aminomalonic ester in acetic acid resulted in the formation of 2-ethoxycarbonyl-4,5,6,7-tetrahydroisoindole (5). In addition to spectral methods its structure was demonstrated by chemical transformations, i.e., by saponification followed by decarboxylation to unsubstituted tetrahydroisoindole 6. The condensation of compound 4 with glycine ethyl ester hydrochloride in alcohol in the presence of triethylamine gave the enamine 7, which underwent cyclization by the action of acetic anhydride into 2-acetyl-4,5,6,7-tetrahydroisoindole (8). In an alkaline medium the latter was converted into compound 6 with a yield of 6%.
O CHO 4 Et3N H2NCH2CO2Et O
H2NCH(CO2Et)2 MeCOOH
O CH NCH(COOEt)2
O CH NHCH(COOEt)2
CHNHCH2CO2Et 7 Ac2O OH C CH N COMe 8 _ H 2O OH 5 _ H2O OH COOH NH 6 NH COOEt NH (COOEt)2 NH
1518
The synthesis of tetrahydroisoindoles 9 unsubstituted at the nitrogen atom by the reaction of compound 4 with aminomalonates has been used for the production of symmetrical porphyrins [21]. The tetrahydroisoindoles 9 are also produced by the reaction of 1-nitrocyclohexene with isocyanoacetates in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) [21].
COOR 4 H2NCH(CO2R)2 AcOH 9 R = Me, Et, t-Bu NH CNCH2CO2R DBU
NO2
The synthesis of the tetrahydroisoindoles 11 and 12 from aminomethylene derivatives of 2-formylcyclohexanone 10 was realized successfully in the presence of glycine salts [22].
O H2NCH2CO2K R 10 CHNMe2 R 11 N COMe R 12 NH
R = NEt2, NH2, NHCOMe
With tetramethylammonium glycinate it was possible to obtain high yields of the N-acetyl derivatives of isoindoles 11, which were easily transformed by saponification into the analogs 12 unsubstituted at the nitrogen atom [23]. The production of the tetrahydroisoindole 13 by the reaction of 1,2-diformylcyclohexane with 4-chloro2-fluoro-5-propargyloxyaniline was described in [24]. Compound 13 is distinguished by high herbicidal activity against weeds in rice.
OCH2C N F 13 Cl
CH
One type of intermolecular cyclization in the 1,2-bifunctional derivatives of cyclohexene with primary amines provides a method for the synthesis of 4,7-dihydroisoindoles, including "bridged" compounds 14. This method is based on transformations of adducts 15 from the diene condensation of 2,3-dimethyl-1,3-butadiene and 1,3-cyclohexadiene with the monoacetal of acetylenedicarbaldehyde 16 (Scheme 1) [25]. The methods for the synthesis of hydrogenated isoindoles described above have many stages and involve poorly available reagents.
1519
Scheme 1
CHO R A R C R A C 14 R1NH2 R A R CH(OEt)2 CH(OEt)2 R 15 CH(OEt)2 CHO
CH=NR1 NaBH4
R A R
CH2NHR1 traces of HCOOH CHCl3 CH(OEt)

2
R NaBH4 MeOH A R
CH2OH CH(OEt)2 R = H, Me; R1
R A R
CH2Br CHO
R1NH2
R A R 16 (4580%) NR1
= H, Me, Ph; A = CH2CH2, 2H
1.2. Intramolecular Cyclization of Pyrroles One method for the construction of the carbocycle in isoindoles is intramolecular cyclization of 3-substituted and 3,4-disubstituted pyrroles. This is the easiest method of obtaining synthetic analogs of the natural 6-methoxy-2,5-dimethyl-4,7-dihydroisoindole-4,7-dione (17), which was isolated from a fungus of the Reniera species in 1982 [17]. The structure of 17 was confirmed by independent syntheses from 3,4-dimethoxy1-methylcarbonylpyrrole. The latter was converted into the diketone 18, which underwent cyclization to compound 17 in the presence of sodium hydride.
O MeOOC COOMe NaH N Me 18 DMF Me N Me MeO O 17 (30%)
The 4-oxo-4,5,6,7-tetrahydroisoindoles 20 were formed when 3-pyrrolepropanecarboxylic acids 19 were heated in the presence of phosphoric acid [26].
(CH2)3COOMe H3PO4 R1 N R 19 R, R1, R2 = H, Me, Ph R2 R2 20 O R1 N R
1520
The cyclization of 3,4-di(bromoacetyl)-1,2,5-trimethylpyrrole (21) in DMSO at 50C leads to 4,7-dioxo4,5,6,7-tetrahydroisoindole 22, which is converted by the action of chloranil into 4,7-dioxo-4,7-dihydroisoindole 23 [47].
O BrH2C BrH2C O 21 chloranil Me N Me Me O Me N Me Me O 23 (80%) Zn + Cu, DMSO NaHCO3, NaI O Me O Me N Me
22 (60%)
A method for the synthesis of 4,5,6,7-tetrahydroisoindoles 24 through the diene condensation of thienopyrrole oxide 25 with dimethyl fumarate, dimethyl maleate,and trans-1,2-bis(phenylsulfonyl)ethylene was described in [28]. The adduct 26 is converted by the elimination of SO2 into the diene 27, which enters into diene condensation with another molecule of the dienophile. Retrodiene rearrangement of the formed adduct 28 leads to the separation of the dienophile and the formation of compounds 24:
E E O2S 25 E NR 27 E E NR E 24 (7191%) R = Me, CH2Ph, COPh, CO2CH2Ph, Ts; E = CO2Me; SO2Ph E E E 28 E NR E NR O2S NR E 26 E E SO2
E E
With heating in a sealed tube at 170-240C the reaction takes 10-38 h. By debenzyloxycarbonylation in the case where R = CO2CH2Ph and E = SO2Ph the isoindole 29 was obtained.
MeO2C NCO2CH2Ph MeO2C Pd / C, H2 THF MeO2C NH MeO2C 29 (80%)
1521
1.3 Transformations of the Isoindole Ring Isoindoles with a partly or fully saturated carbocycle are produced during the reduction of aromatic isoindoles or during the dehydrogenation or oxidation of the octahydro derivatives of isoindole. Depending on the substituent at the nitrogen atom, the reduction of 1-methoxycarbonylisoindoles 30 in the presence of 10% Pd/C at increased hydrogen pressure and at 50C takes place either at the carbocyclic fragment leading to compounds 31 or in the pyrrole ring with the formation of the isoindoline 32 [29].
COOMe N R 31 (5765%) H2 Pd / C 30 31 R = H, Me, CH2Ph; 32 R = Ph COOMe N R H2 Pd / C 32 N R
During the hydrogenation of 1-chloro-3-formyl-2-(-phenylethyl)isoindole (33) at Pd/BaSO4 4,5,6,7-tetrahydroisoindole 34 is formed through reduction of the carbonyl group to alcohol and the elimination of chlorine [30].
CHO N Cl (CH2)2Ph H2 Pd / BaSO4 34 CH2OH N (CH2)2Ph
33
4-Oxo-4,5,6,7-tetrahydroisoindole 36 was obtained by the dehydrogenation of 4-oxooctahydroisoindole 35 with manganese dioxide in boiling THF [31].
N CH2Ph O 35
MnO2
N CH2Ph O 36 (50%)
4,7-Methano-4,5,6,7-tetrahydroisoindole 38 was isolated with a yield of 67% by the oxidation of substituted octahydro-4,7-methanoisoindole 37, which had been previously obtained by the reaction of norbornene with an aziridine derivative, by chloranil in p-cymene [32]:
COOMe
COOMe
N C6H4OMe- p
COOMe 37
N C6H4OMe- p
COOMe 38
1522
1.4. Other Syntheses Analogs of natural 4,7-dihydroisoindole 17 were obtained by azacyclization of the dialkynes 39 with nitrosobenzene in boiling benzene. The yields of compounds 40 amounted to 5-15% [33]:
O R R C C O C C C Ph R N Ph C 39 Ph R = Me, Ph R O 40 Ph O Ph
A different approach to the syntheses of such compounds was proposed in [34-36]. Azomethine ylides were produced by heating -amino acids with carbonyl compounds, and they formed the 4,7-dioxo-4,7dihydroisoindoles 41 as a result of cycloaddition to quinones.
O R N Me R1 R2 O 41 R = H, Me; R1 = OMe, N(Me)Ph, SPh; R2 = Ph, CH=CHPh
1-Acetyl-3-iodo-4,5,6,7-tetrahydroisoindole [37] and 1,3-diphenyl-4,5-dihydro-4,7-methanoisoindole were used as intermediates for the synthesis of more complicated molecules [38]. 1,3-Di(cyanomethyl)-2phenyl-4,5,6,7-tetrahydroisoindole [39] was obtained with a yield of up to 0.5% from 2-phenylhexahydrophthalimide and Ph3P=CHCN. Thus, most of the methods for the synthesis of isoindoles with a partly or fully hydrogenated carbocycle described above were carried out on a small number of examples and do not have preparative significance.
1.5. Recyclization of Diene Synthesis Adducts Based on Methoxydihydrofurans with Primary Amines One of us in conjunction with coauthors developed a convenient method for the synthesis of 4,7-dihydro- and 4,5,6,7-tetrahydroisoindoles (and methanoisoindoles). The DielsAlder adducts 42 obtained on the basis of 2,5-dimethoxy-2,5-dihydrofurans and also their hydrogenated analogs 43 are transformed when heated with primary amines under the conditions of acid catalysis into compounds of the isoindole series 44 and 45 [40-42]:
R R A R R 44 R R N R1 R1NH2 R A R R OMe R R R OMe O H2 Ni cr. R R OMe R A R R OMe O R1NH2 R R 45 R R A R N R1
R R 43 42 1 = Alk, cyclo-Hex, CH CH OH, Ar A = 2H, CH2; R = H, Me; R 2 2
1523
The use of adducts with a spiroacetal structure 46 in the reaction leads to the formation of alcohols of the isoindole series 47 [43, 44].
R A R O R1 46 47 OMe O R2NH2 R CH2CH2CHOH R1 A R N R2
= 2, Me; R = H, Me; R1 = H, Alk, Ar; R2 = cyclo-Hex, CH2CH2OH, Ph, 4-MeC6H4
The method is simple to use, is based on fairly accessible reagents (the products of the electrolytic methoxylation of furan compounds [45-51]), and in most cases leads to high yields of the hydrogenated isoindoles (up to 97%). The reaction with amines is conducted in acetic or propionic acid at 70-120C for 0.5-6 h. Synthesis in an inert atmosphere is preferred for adducts with the spiroacetal structure. The basicity of the amine is important in this reaction. Aliphatic amines that readily form salts in an acidic medium are partially passivated under the reaction conditions and only react with the adducts at elevated temperature and with prolonged heating (3-5 h, 100-120C). The 2-aryl-substituted dihydro- and tetrahydroisoindoles (and methanoisoindoles) are formed most readily and with high yields; aromatic amines react with the adducts at 70-100C in 0.5-1 h. It was established by a potentiometric method that a weakly acidic medium (pH 6.8) is an important condition for the addition of amines to the adducts [52]. A series of investigations were carried out in order to establish the mechanism of the supposed recyclization of the adducts of dimethoxydihydrofurans or methoxyspirononenes to dihydro- and tetrahydroisoindoles (and methanoisoindoles) [53-55]. In the case of the synthesis of 2-(2-hydroxyethyl)-4,5,6,7-tetrahydro-4,7-methanoisoindole (49) it was shown by means of data from GLC and TLC that the reaction of the adduct 48 and the amine begins with cleavage of the tetrahydrofuran ring in the acidic medium with the formation of the 1,4-dicarbonyl compound 50 [53].
OMe O 48 OMe H + CHO CHO 50 H2NCH2CH2OH + H H2NCH2CH2OH 49 N CH2CH2OH
In order to confirm the reaction scheme the bicycloheptane-1,2-dial 50 was synthesized, and it was shown by PMR spectroscopy that it had the cis configuration [56]. It was established by GLC that it was the main intermediate of the reaction. Thus, in accordance with the generally accepted scheme for such processes [57] the proposed recyclization is based on initial cleavage of the tetrahydrofuran ring to the dialdehyde followed by nucleophilic attack at one carbonyl group with the formation of an aminal and subsequent intramolecular azacyclization and dehydration stages. The nature of the medium plays an important role; it is not possible to synthesize the isoindoles in an aprotic medium [53]. 1524
The method we developed for the synthesis of hydrogenated isoindoles has a wide range of application and can be extended to various compounds with acetal structures, including those with spiro atoms [48-51]. This makes it possible to obtain isoindoles with functional groups in the side chain at the -position of the pyrrole ring. The 4,7-dihydro- and 4,5,6,7-tetrahydroisoindoles exhibit all the typical characteristics of 3,4-disubstituted pyrroles, including the ability to undergo electrophilic substitution at the -position of the pyrrole ring. The formylation of 2-phenyl-4,7-dihydro- and 4,5,6,7-tetrahydroisoindoles 51 by the Vilsmeier Haack method was described in [58, 59].
DMF POCl3 51 R = H, Me R CHO 51a
N Ph R
N Ph
The aldehydes 51a were obtained with yields of 52-75%, and their functional derivatives (semicarbazones and 2,4-dinitrophenylhydrazones) were obtained with quantitative yields. The recyclization of diene condensation adducts based on methoxydihydrofurans with primary amines has found use in the synthesis of biologically active compounds having specific characteristics [43, 59-69] and also in the production of the 4,5,6,7-tetrahydroisoindole fragments of porphyrins [70].
2. METHODS FOR THE PRODUCTION OF HEXA- AND OCTAHYDROISOINDOLES (AND METHANOINDOLES) Many derivatives of octahydroisoindole and octahydromethanoisoindole have been synthesized as analogs of reserpine [71-73], dopamine [74], and substance P antagonists [75-77]. Preparative methods have been described for the synthesis of octahydroisoindoles by reduction of the carbonyl groups of phthalimides and phthalimidines, by intra- and intermolecular heterocyclization of acyclic systems in a diene condensation scheme, by catalytic hydroamination of 1,2-derivatives of cyclohexane, and by catalytic hydrogenation of unsaturated isoindoles.
2.1. Reduction of Carbonyl Groups in Phthalimides and Phthalimidines Phthalimides and phthalimidines are similar in structure to isoindoles, are easily obtainable, and are therefore often used in the synthesis of isoindoles [2, 3, 5] and their isologs [7-10, 78-86]. Reduction of the carbonyl groups in hydrogenated phthalimides and phthalimidines with lithium aluminum hydride is most often used. Rice and coauthors [7, 8, 78-80] obtained series of hexa- and octahydroisoindoles and their "bridged" derivatives 52 with various substituents at the nitrogen.
R N 52 R = H, Me O N
1525
On the basis of these compounds quaternary salts 53 with clearly defined biological activity were obtained, e.g., see [7].
R R R N Me + _ X
N (CH2)2 N +_ + _ X X 53 R = Alk; X = Cl, Br, I
In [81, 82] the Rice approach was applied to bridged hexa- and octahydroisoindoles, and special attention was paid to the stereochemical structure of methanoisoindoles 54-58 not substituted at the nitrogen atom.
LiAlH4 O endo O NH3 O O endo O O NR 6794% O RNH2 O NH3 O O O NH O NH 54 82% ether NH
H2, PtO2 EtOH, 20 oC NH 55 90%
LiAlH4 ether 56 98% R = Me, cyclo-Hex NR
LiAlH4 ether 57 68% H2 PtO2 NH
NH 58 89%
Stereospecific syntheses of hydrogenated isoindoles and methanoisoindoles have played an enormous role in the development of methods for the preparation of highly active medicinal products, like some already used in medicine. Their syntheses are based on reduction of the C=O groups in the imides and imidines of tetraand hexahydrophthalic acids and their "bridged" analogs with lithium aluminum hydride. Guanisoline 59 [83] and preparation "865-123" 60 [9, 84, 85], which are analogs of guanetidine exhibiting the characteristics of adrenoblockers and hypotensive agents, and also tripamide 61, which is a modern hypotensive drug and an effective diuretic [11-13, 86-92], were obtained in this way.
1526
H NH N H 59 H H N N H H H 61 C O (CH2)2NHC NH2 60 H
H N (CH2)2NHC
NH NH2
SO2NH2 Cl
In [71] stereospecific syntheses of reserpine-like derivatives of cis-octahydroisoindole 62 from N-substituted tetrahydrophthalimides through epoxidation of the latter were described:
H (MeO)3H2C6CO N CHRCH2R1 MeO H 62 R = H, Me; R1 = Ph, 3-indolyl, 1-naphthyl
Methods for the production of highly active diuretic and psychotropic agents based on hexa- and octahydroisoindoles (and methanoisoindoles) 63, starting from phthalimides and phthalimidines, have been patented [10, 93-95], for example [10]:
O NH O NAC6H4R- p 63 R = NH2, NO2, MeSO2, MeCO, MeCONH; X = NH2, NCO, NHCOOEt, NHCOCl; A = SO2NHCO, SO2NH, SO2NHCONH LiAlH4 NH RC6H4SO2X-p
Neuropsychotropic agents as analogs of dopamine 64 and 65 [74, 76], analgesics 66 [97], antidepressants 67 [98], and medicines for the treatment of diabetes 68 [99-103] were synthesized in a similar way:
H N H 64, 65 (CH2)2 F R2 66 R = Me, Ac; R1 = H; R2 = Ph; R1R2 = bond R1 N (CH2)2 OR OR
1527
OnZCH2OH 68
N(NH)nCONHSO2C6H4R-p
67 n = 0, 1; Z = bond, CH2, CHMe, CH2CH2
n = 0, 1; R = Ac, AcNH, NO2, MeSO2
A method for the production of analogs of the analgesic profadol 70 was based on the transformations of 2-methyl-7a-phenyl-3a,b-epoxy-2,3,6,7-tetrahydroisoindol-1-one (69) [104]. One of the stages is reduction of the carbonyl group with lithium aluminum hydride.
Ph O 69 AcO H2 10% Pd/C H R = H, OH, OAc H 70 Ph O N Me LiAlH4 HO Ph N Me O N Me H2 PtO2 O Ph O N Me Ac2O BF3Et2O AcO Ph O N Me
2.2. Intra- and Intermolecular Heterocyclization of Acyclic and Alicyclic Systems An original method for construction of the octahydroisoindole ring 71 using organotin and organopalladium reagents was described in [105].
Br H2C C C N Ph MeO2C H2C=CHCO2Me CO2Me C CO2Me Bu3SnH C6H6 N Ph SnBu3 H2C CO2Me
N Ph 71
During a study of the stereoselectivity of the DielsAlder reaction in the series of 4-azanonatrienes [106] and 1-R-2,3-methoxycarbonylaziridines with norbornene [32] tetra- and octahydroisoindoles (and methanoisoindoles) were obtained. In [32] the yield of octahydromethanoisoindole 37 amounted to 94%. The synthesis of a large group of entiomerically pure octahydroisoindoles, obtained as antagonists of substance P [75-77, 107-110], is based on the cyclocondensation of 4,4-diphenylcyclohexen-2-one with PhCH2N(CH2OBu)CH2SiMe3. Subsequent transformations lead to various isoindoles with general formula 72. 1528
R5 R
R5 N CCHR1R2 Z R4
R R3 72
R = H, RR = bond; R1 = Ph, cyclohexyl, naphthyl, heterocyclyl; R2 = H, Hal, OH, alkyl, alkNH, alkO-, alkyl-S-, acyloxy, carboxy, NH2, AcNH, benzyloxycarbonyl; R3 = Hal, OH; R4= H, Hal; R5= Hal, Me, Ph; Z= O, NH
The adduct of 2,3-bis(bromomethyl)-1,3-butadiene 73 with propiolic acid can be converted into hydrogenated N-substituted isoindoles 74 [111].
Br Br HOOC 73 Br Br
Br Br MeOOC MeOOC 74 R = CH2Ph, CH2CH2OH, NHCO2Me
N R
2.3. Catalytic Reductive Amination and Hydrogenation A convenient method for the synthesis of octahydroisoindoles 76 was proposed in [112], i.e., the catalytic reductive amination of 1,2-bis(hydroxymethyl)cyclohexane 75 by aliphatic nitriles at an industrial coppermagnesium catalyst. The method is based on the use of the readily available diethyl phthalate as raw material.
CO2Et CO2Et H2 cat. CO2Et CO2Et 75 N CH2R 76 (~65%) R = Alk LiAlH4 CH2OH RCN, H2 CH2OH cat.
The optimum conditions for the reduction process are: 240C, hydrogen pressure 1.5 MPa, volume delivery rate of reaction mixture 0.5 h-1. The structure of compounds 76, which represent a 1:1.5 mixture of cis and trans isomers, was confirmed by the data from IR, 1H NMR, and mass spectra. Catalytic reductive amination was used in the synthesis of octahydro-4,7-methanoisoindoles 77 [68] based on the adducts 40 and 41 obtained according to [45]. 1529
OMe O OMe RNH2, H2 RuO2, R1COOH 77 R = t-Bu, c-Hex, CH2CH2OH; R1 = Me, Et N R
Compounds 77 were isolated in the form of mixtures of isomers with overall yields of 51-55%. The endo-exo isomers of octahydroisoindole (R = t-Bu) were isolated in the pure form, and their structures were supported by the data from the 1H NMR spectra. As a rule, the catalytic hydrogenation of isoindoles leads to isoindolines [2]. Under harsh conditions the reaction products may be octahydroisoindoles [113]. Thus, the hydrogenation of 2-methyl-1,3-diphenylisoindole at Raney nickel in dioxane gives the octahydro derivative 78.
Ph N Me Ph H2 Ni Raney Ph 78 Ph N Me
The catalytic reduction of N-ethoxycarbonyl-8-azatricyclo[4,3,0,07,9]nonane (79) leads to cleavage of the ring with the formation of octahydroisoindole 80 [114].
H H N CO2Et H H 79 H2 Pd / C H 80 H N CO2Et
As a result of the hydrogenation (at initial hydrogen pressure 10 MPa) of 4,5,6,7-tetrahydroisoindoles 43, synthesized by the methods in [40-42], the octahydroisoindoles 81-84 were obtained and used for pharmacological investigation [65, 115].
H2 cat. H2 cat. N R H2 cat. R 83 N R1 H2 cat. 84 N R1 H2 cat. R 82 (80%) R 81 (85%) N
N R
N CH2CH2OH R
N CH2CH2OH
R = H, Me; R1 = t-Bu, CH2CH2OH, Ph
1530
The effect of temperature, the type of catalyst (Raney nickel, RuO2, PtO2, Rh/Al2O3), the nature of the solvent (acetic acid, ethanol, isopropyl alcohol), and the nature of the substituent at the nitrogen atom on the direction of the reaction and the yield of the products was determined. At the ruthenium and rhodium catalysts at 60C simultaneous reduction of the pyrrole and benzene rings occurs. Under these conditions in the "bridged" isoindole 84 the phenyl substituent remains unchanged even at 100-120C. Platinum dioxide exhibits selectivity at room temperature, making it possible to reduce the pyrrole ring without affecting the benzene ring. In the presence of PtO2 compounds 82 are only formed at 100C. The effect of the solvent on the yield of the final products is insignificant, but the isomeric composition of the octahydroisoindoles depends on it. The nature of the substituent at the nitrogen determines the duration of reduction; under identical conditions compounds with a hydroxyethyl group are hydrogenated more slowly than the cyclohexyl and phenyl derivatives. The isomeric composition of the reaction products was determined from the data of GLC and the 1H NMR spectra.
3. BIOLOGICAL CHARACTERISTICS OF HYDROGENATED ISOINDOLES A large amount of factual information has now accumulated from study of the biological characteristics of hydrogenated isoindoles. The types of physiological activity and their applications in medicine have been mentioned in previous sections. Among them there are compounds with sets of important properties: hypotensive agents with a strong diuretic effect [10, 93-95]; psychotropic [74, 96] and antidiabetic [29, 103] agents; inhibitors of phosphodiesterase and antithrombotic substances [116]; anticancer and simultaneously antibacterial compounds [117]. Natural isoindole and its analogs are characterized by high bactericidal activity [17]. Hydrogenated isoindoles condensed with benzene, quinoline, cyclohexane, and other fragments exhibit significant activity against rhinoviruses [118, 119], and among them there are also analgesics and antidepressants [120, 121]. We made a systematic pharmacological study of the biological characteristics of isoindoles [43, 59-67, 69]. As a result of the tests substances with neurotropic, hypotensive, radioprotective, diuretic, bactericidal, antihelminthic, and fungicidal characteristics were found. The low toxicity of hydrogenated isoindoles was noted. Their biological activity is determined by the degree of saturation of the ring and by the nature of the substituent at the nitrogen atom [61]. It is necessary to mention particularly the methanoisoindoles, which exhibit a significant diuretic effect in trials on mice, rats, and dogs [62-64]. Certain compounds, by withdrawing sodium, simultaneously reduce the excretion of potassium, which distinguishes them favorably from usual diuretics. Thus, to summarize all the foregoing a conclusion can be drawn about the significance of investigations in this region and the expediency of comprehensive study of the biological and other useful characteristics of hydrogenated isoindoles.
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1535
SYNTHESIS OF 5-AMINO-4-HETARYL2,3-DIHYDRO-1H-3-PYRROLONES
A. V. Tverdokhlebov, A. B. Lyashenko, Yu. M. Volovenko, and A. A. Tolmachev 2-Hetaryl-3-oxo-4-phthalimidobutyronitriles (and pentanonitriles) were obtained with high yields by C-acylation of hetarylacetonitriles with N-phthaloylglycine and -alanine chlorides respectively under the conditions of base catalysis. Hydrazinolysis of the phthaloyl protection in these compounds leads to the formation of 5-amino-4-hetaryl-2,3-dihydro-1H-3-pyrrolones. Keywords: 5-amino-4-hetaryl-2,3-dihydro-1H-3-pyrrolones, hetarylacetonitriles, -phthalimidonitriles, N-phthaloylamino acids. The interest in derivatives of 2-aminopyrrole has arisen in connection with their prospective use as medicines [1-8] and as components of dyes in photography [9-11]. The principal methods for the synthesis of these compounds are the condensation of methylene-active nitriles with derivatives of -aminocarbonyl compounds [12-17] or amination of substituted 4-halobutyronitriles [18-24] or their synthetic equivalents [2527]. Both approaches have been successfully applied to the synthesis of 1-R1-2,2-R2,R3-5-amino-4-hetaryl-2,3dihydro-3-pyrrolones [28-37]. However, they cannot be used for the production of similar derivatives unsubstituted at position 1 since, on the one hand, the N-unsubstituted -aminocarbonyl compounds quickly dimerize to pyrazine derivatives and, on the other, the use of ammonia in the reaction together with the need for heat and a nonaqueous medium give rise to certain technical difficulties. For this reason we developed a different method for the synthesis of N-unsubstituted 2,3-dihydro-1H-3-pyrrolones 1a-h, and this method is described here. The key compounds in the synthesis of the dihydropyrrolones 1 are 2-hetaryl-3-oxo-4phthalimidobutyronitriles 2a-e and the corresponding pentanonitriles 2f-h, obtained by acylation of the hetarylacetonitriles 3a-e with the chlorides of N-phthaloylglycine 4a and alanine 4b (see the scheme). It should be noted that acylation of the sodium salts of simple methylene-active compounds with the chlorides [38-41] and esters [17, 42, 43] of protected -amino acids was used earlier for construction of the pyrrole ring. However, the acid chlorides often gave the products from bis-C,C- and bis-C,O-acylation [38, 40] of complex mixtures [39], while the esters gave the enolates of the corresponding acyl derivatives. During transformation of the latter into the conjugate acids it was not always possible to avoid side processes associated with hydrolysis of the protecting groups [42, 43]. We obtained the monoacyl derivatives 2a-h with yields of more than 90% as the only products (Scheme 1). The composition and structure of the nitriles 2a-h were confirmed by the results of elemental analysis (Table 1) and also by data from the IR and 1H NMR spectra (Table 2). According to the spectral data, compounds 2a-h exist exclusively in the form of NH tautomers with an intramolecular hydrogen bond, as known for the acyl derivatives of hetarylacetonitriles [44]. Thus, the 1H NMR spectra of the butyronitriles 2a-e __________________________________________________________________________________________ Taras Shevchenko Kiev University, Kiev, Ukraine; e-mail: atver@mail.univ.kiev.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1783-1790, December, 2004. Original article submitted December 27, 2001; revision submitted October 26, 2004. 1536 0009-3122/04/4012-15362004 Springer Science+Business Media, Inc.
Scheme 1
R1 O N R2 O
+
X CN 3ae Cl R3
N O
4a,b
O R1 R2 O N X CN R3 N O H R1 N O
O N O R3 R2 X 2ah O _ O NH NH N2 H4 CN
R2 R1 N
3'
6
X O H
2' 5'
R1 N R2 R3 X
H O R3 CN 5ah NH2
N H
N H 1ah
1-3 a,f X = NH, b,g X = NMe, c-e,h X = S; a-c,f-h R1 + R2 = CH=CHCH=CH, d R = 4-BrC6H4, e R1 = 3,4-(MeO)2C6H3; d,e R2 = H; 1a-e 3a-e, 4a R3 = H, 1f-h 3f-h, 4b R3 = Me
1
contain a two-proton singlet for the methylene group in the region of 4.60-4.75 ppm, a four-proton symmetrical multiplet for the phthaloyl fragment at 7.85-7.90 ppm, and a signal for the chelated proton in the region of 12.8-13.2 ppm. (It exchanges with D2O.) In the 1H NMR spectra of the pentanonitriles 2f-h instead of the signal for the methylene group there are signals of an AX3 spin system at 5.15-5.25 ppm (a quartet) and 1.60-1.80 ppm (a doublet). The protons of the heterocyclic substituent absorb in their characteristic regions. The IR spectra of compounds 2a-h contain a strong band for the stretching vibrations of the conjugated nitrile group at 2180-2200 cm-1 and also two bands for the symmetrical and asymmetrical stretching vibrations of the CONCO system at 1700-1720 and 1760-1780 cm-1 respectively. We assigned the strong band in the region of 1600-1625 cm-1 to the stretching vibrations of the carbonyl group attached to the NH group by a hydrogen bond. Such a significant shift toward lower frequencies in relation to the average value for a conjugated carbonyl group is due, first, to its inclusion in the -enamino ketone fragment and, second, to its participation in an intramolecular hydrogen bond. 1537
TABLE 1. The Characteristics of 5-Amino-4-hetaryl-3-oxo-2,3-dihydro-1Hpyrrolones 1a-h, 2-Hetaryl-3-oxo-4-phthalimidobutyronitriles 2a-e, and the Pentanonitriles 2f-h
Compound 1a 1b 1c 1d* 1e 1f 1g 1h 2 2b 2c 2d* 2e 2f 2g 2h
3 2
Empirical formula C11H10N4O C12H12N4O C11H9N3OS C13H10BrN3OS C15H15N3O3S C12H12N4O C13H14N4O C12H11N3OS C19H12N4O3 C20H14N4O3 C19H11N3O3S C21H12BrN3O3S C23H17N3O5S C20H14N4O3 C21H16N4O3 C20H13N3O3S
C 61.69 61.67 63.21 63.15 57.08 57.13 46.37 46.44 56.79 56.77 63.13 63.15 64.52 64.45 58.68 58.76 66.24 66.28 67.09 67.03 63.19 63.15 54.06 54.09 61.78 61.74 66.94 67.03 67.80 67.73 63.92 63.99
Found, % Calculated, % H N 4.79 4.71 5.26 5.30 3.99 3.92 3.03 3.00 4.69 4.76 5.22 5.30 5.89 5.82 4.53 4.52 3.48 3.51 4.01 3.94 2.99 3.07 2.62 2.59 3.84 3.83 4.06 3.94 4.31 4.33 3.52 3.49 26.09 26.15 24.49 24.55 18.07 18.17 12.55 12.50 13.18 13.24 24.43 24.55 23.05 23.12 17.10 17.13 16.34 16.27 15.62 15.63 11.60 11.63 8.94 9.01 9.33 9.39 15.67 15.63 14.98 15.05 11.11 11.19
mp, S 273 261 13.87 13.86 9.49 9.54 10.16 10.10 >300 248 226 >300 238 13.01 13.07 297 >300 >300 8.91 8.87 6.93 6.88 7.12 7.17 >300 259 231 >300 242 8.48 8.54 271
Yield %
57 50 61 43 44 50 51 41 97 95 98 93 93 93 91 91
_______ * Compounds 1a,b were identical with those described in [45] (IR spectra and mixed melting tests). *2 Found, %: Br 23.66. Calculated, %: Br 23.77. *3 Found, %: Br 17.10. Calculated, %: Br 17.14.
Removal of the phthaloyl protection from the phthalimidonitriles 2a-h leads to the formation of the intermediates 5a-h, having the structures of -amino nitriles. According to data in [18-24, 28-37], such aminonitriles undergo heterocyclization on account of intramolecular addition of the amino group to the nitrile group, which in this case should lead to the formation of the desired pyrrolones 1. In fact, the desired products 1a-h were obtained with yields of 40-60% by the action of a 3-4-fold excess of hydrazine hydrate on compounds 2a-h. It should be noted that according to TLC and 1H NMR spectra this transformation takes place quantitatively. The moderate yields of the products 1a-h indicated above are due to losses that arise during their purification from the second product phthalazinedione 6. We isolated the latter from the reaction mixture with yields of 60-70%. It is noticeable that reaction of the excess hydrazine hydrate either with the -oxonitrile fragment of compounds 2a-h or with the carbonyl group of the pyrrolones 1a-h was not observed in the course of the reaction. This agrees with data for derivatives of 5-amino-3-pyrrolones substituted at position 1 [36].
1538
The composition and structure of compounds 1a-h were supported by data from elemental analysis (Table 1), the 1H NMR spectra (Table 2), and also by the identity of the pyrrolones 1a,b with samples that we synthesized earlier by a different more complicated method [45]. In the IR spectra of the derivatives 1a-h there is strong absorption above 3000 cm-1, due to the stretching vibrations of the NH bonds, and there is also a strong broad band in the region of 1560-1600 cm-1, which is not present in the spectra of the initial nitriles 2a-h. It is probably due to the deformation vibrations of the primary amino group, although it is quite likely that it may also include the stretching vibrations of the strongly polarized [17, 46] C=C bond of the pyrrolone ring. In some cases this band has a clearly defined shoulder at 1640-1645 cm-1, which can be assigned to the stretching vibrations of the carbonyl group contained in the -enamino ketone fragment. The absence of the absorption of the conjugated nitrile group in the IR spectra of compounds 1a-h indicates conclusively that it participates in heterocyclization. The signals of the phthaloyl residue are absent both in the IR spectra and in the 1H NMR spectra of the dihydropyrrolones 1a-h. The 1H NMR spectra of compounds 1a-e in DMSO-d6 contain a
TABLE 2. The 1H NMR Spectra of Compounds 1a-h and 2a-h

Compound 1a 1b 1c Chemical shifts, , ppm SSCC, J, Hz) 3.80 (2H, s, CH2); 7.04 (2H, m, Harom ); 7.48 (2H, m, Harom ); 7.61 (1H, s, H-1); 8.07 (2H, s, NH2); 11.80 (1H, s, NH) 3.75 (2H, s, CH2); 3.92 (3H, s, NCH3); 7.17 (2H, m, Harom ); 7.49 (3H, NH and 2Harom ); 7.92 (2H, s, NH2) 3.75 (2H, s, CH2); 7.17 (1H, deg. t, J = 7.8, Harom-6); 7.33 (1H, deg. t, J = 7.8, Harom-5); 7.69 (2H, m, NH and Harom-7); 7.83 (1H, d, J = 7.8, Harom-4); 8.07 (1H, s, HNH2); 8.27 (1H, s, HNH2N) 3.73 (2H, s, CH2); 7.42 (1H, s, -5); 7.64 (3H, m, Harom-3,5 and NH); 7.94 (3H, m, Harom-2,6 and HNH2); 8.19 (1H, s, HNH2N) 3.71 (2H, s, CH2); 3.79 (3H, s, CH3); 3.85 (3H, s, CH3); 6.94 (1H, d, J = 8.1, Harom-5); 7.36 (1H, s, -5); 7.45 (3H, NH and Harom-2,6); 7.86 (1H, s, HNH2); 8.12 (1H, s, HNH2N) 1.31 (3H, d, J = 7.0, 3); 3.99 (1H, q, J = 7.0, CH3); 7.31 (2H, m, Harom ; 7.66 (2H, m, Harom ); 8.19 (2H, s, NH and HNH2); 8.49 (1H, s, HNH2N); 11.21 (1H, s, -1) 1.28 (3H, d, J = 7.2, 3); 3.71 (1H, q, J = 7.2, CH3); 3.93 (3H, s, NCH3); 7.09 (2H, m, Harom-5,6); 7.34 (1H, m, Harom-7); 7.42 (1H, m, Harom-4); 7.64 (1H, s, NH); 7.72 (1H, s, HNH2); 8.33 (1H, s, HNH2N) 1.29 (3H, d, J = 6.8, 3); 3.79 (1H, q, J = 6.8, CH3); 7.21 (1H, deg. t, J = 7.5, Harom-6); 7.34 (1H, deg. t, J = 7.5, Harom-5); 7.71 (1H, d, J = 7.5, Harom-7); 7.88 (2H, m, NH and Harom-4); 8.07 (1H, s, HNH2); 8.29 (1H, s, HNH2N) 4.64 (2H, s, CH2); 7.24 (2H, m, Harom ); 7.48 (2H, m, Harom ); 7.91 (4H, m, Phth); 12.90 (2H, s, 2NH) 3.97 (3H, s, NCH3); 4.70 (2H, s, CH2); 7.32 (2H, m, Harom ); 7.60 (2H, m, Harom ); 7.90 (4H, m, Phth); 13.10 (1H, s, NH) 4.72 (2H, s, CH2); 7.42 (2H, m, Harom-5,6); 7.71 (1H, d, J = 8.0, Harom-4); 7.89 (5H, m, Harom-7 and Phth); 12.84 (1H, s, NH) 4.69 (2H, s, CH2); 7.50 (1H, s, -5); 7.69 (4H, br. s, arom ); 7.90 (4H, m, Phth); 12.93 (1H, s, NH) 3.81 (3H, s, CH3); 3.85 (3H, s, CH3); 4.67 (2H, s, CH2); 7.00 (1H, d, J = 8.4, Harom-5); 7.28 (3H, m, Harom-2,6 and -5); 7.89 (4H, m, Phth); 12.50 (1H, s, NH) 1.73 (3H, d, J = 7.6, 3); 5.17 (1H, q, J = 7.6, CH3); 7.24 (2H, m, Harom ); 7.49 (2H, m, Harom ); 7.87 (4H, m, Phth); 12.80 (2H, s, NH) 1.79 (3H, d, J = 7.2, 3); 3.98 (3H, s, NCH3); 5.25 (1H, q, J = 7.2, CHCH3); 7.27 (2H, m, Harom-5,6); 7.53 (1H, d, J = 7.5, Harom-4); 7.64 (1H, d, J = 7.2, Harom-7); 7.85 (4H, m, Phth); 13.25 (1H, s, NH) 1.67 (3H, d, J = 7.2, 3); 5.18 (1H, q, J = 7.2, CH3); 7.31 (1H, deg. t, J = 7.5, Harom-6); 7.44 (1H, deg. t, J = 7.5, Harom-5); 7.64 (1H, d, J = 7.5, Harom-4); 7.86 (5H, m, Harom-7 and Phth); 12.76 (1H, s, NH)
1d 1e 1f 1g
1h
2 2b 2c 2d 2e 2f 2g
2h
_______ * Phth phthaloyl. 1539
two-proton singlet for the methylene group at 3.7-3.8 ppm,* whereas the methyl-substituted compounds 1f-h are characterized by the signals of an AX3 system at 3.7-3.9* (a quartet) and 1.25-1.30 ppm (a doublet). Signals for the proton at position 1 of the dihydropyrrolone ring and the protons of the amino group are observed in the 1 H NMR spectra of compounds 1a-h in the form of three one-proton singlets (one narrow and two broad) in the region of 7.5-8.5 ppm. The latter clearly belong to the protons of the amino group, which are magnetically nonequivalent as a result of the formation of an intramolecular hydrogen bond, as was observed earlier for analogous systems [28-37]. The protons of the heterocyclic substituent resonate in their characteristic regions. Thus, according to the spectral data, the dihydropyrrolones 1a-h exist exclusively in the amino ketone tautomeric form both in the solid phase and in solution. Thus, the present investigation resulted in the development of a two-stage preparative method for the synthesis of 2-(2-amino-4-oxo-4,5-dihydro-1H-pyrrol-3-yl)benzimidazoles 1a,b,f,g, the thiazoles 1d,e, and the benzothiazoles c,h, involving the acylation of hetarylacetonitriles with the chlorides of N-phthaloyl-protected amino acids followed by removal of the protection from the obtained products 2a-h by hydrazinolysis. The method is based on readily obtainable starting compounds, and the overall yield of the targeted products in the two stages amounts to 45-50%.
EXPERIMENTAL The IR spectra were obtained on a Pye-Unicam SP 3-300 instrument for tablets in potassium bromide. The H NMR spectra were recorded in DMSO-d6 on Bruker WP-100SY (100 MHz) and Varian VXR-300 (300 MHz) instruments. The reactions and the individuality of the obtained compounds were monitored by TLC on Silufol UV254 plates in 9:1 benzeneethanol. The melting points were determined in sealed capillaries in Thiele melting point apparatus, previously heated to 180-200C, and the substances melted almost exactly at the melting point; when the capillary was heated slowly from room temperature, the substances melted over a wide range on account of partial decomposition. The hetarylacetonitriles 3b-d were synthesized by the usual methods [47-49]. Phthaloylglycine and phthaloylalanine were obtained from the respective amino acids and were converted into the chlorides 4a,b by standard procedures. Benzimidazol-2-ylacetonitrile 3a and cyanothioacetamide are commercially available and were used without additional purification. 4-(3,4-Dimethoxyphenyl)thiazol-2-ylacetonitrile (3e). To a warm solution (40-50C) of cyanothioacetamide (10 g, 0.1 mol) in ethanol (80 ml) we added 3,4-dimethoxyphenacyl bromide (25.9 g, 0.1 mol) [50]. The mixture heated and boiled for a few minutes, and the hydrobromide of compound 3e was precipitated. The reaction mass was kept on a boiling water bath for a further 1 h and was then cooled. The precipitated salt 3eHBr was filtered off. The salt was suspended in 15-20% aqueous ammonia for 40 min and was then filtered off and washed with water. After recrystallization from 2-propanol 22 g (85%) of the product 3e was obtained; mp 101C. 1H NMR spectrum, , ppm (J, Hz): 3.80 (3H, s, CH3O); 3.84 (3H, s, CH3O); 4.52 (2H, s, CH2); 6.96 (1H, d, J = 8.4, 5-Harom); 7.49 (2H, m, 2,6-Harom); 7.90 (1H, s, 5-H). Found %: C 60.01; H 4.61; N 10.69; S 12.38. C13H12N2O2S. Calculated %: C 59.98; H 4.65; N 10.76; S 12.32. 2-Hetaryl-3-oxo-4-phthalimidobutyronitriles (2a-e) and Pentanonitriles (2f-h) (General Procedure). To a warm solution (~50C) of the hetarylacetonitrile 3a-e (0.01 mol) and pyridine (0.8 ml, 0.01 mol) in dioxane (30-60 ml) we added the acid chloride 4a or 4b (0.01 mol). The obtained mixture was kept
1
_______ * In the 1H NMR spectra of the nitriles 2a-h the respective protons resonate 0.9-1.4 ppm downfield. This is probably due to the descreening effect of the magnetically anisotropic carbonyl groups of the phthalimide fragment. 1540
on a boiling water bath for 1.5-2 h and cooled. The precipitate was filtered off and washed thoroughly with water. After recrystallization from dioxane (for 2a-e) or alcohol (for 2f-h) we obtained the phthalimidonitriles 2a-h. 2-(2-Amino-4-oxo-4,5-dihydro-1H-pyrrol-3-yl)benzimidazole (1a), 2-(2-Amino-4-oxo-4,5-dihydro1H-pyrrol-3-yl)-1-methylbenzimidazole (1b), 2-(2-Amino-4-oxo-4,5-dihydro-1H-pyrrol-3-yl)benzothiazole (1c), 2-(2-Amino-4-oxo-4,5-dihydro-1H-pyrrol-3-yl)-4-(4-bromophenyl)thiazole (1d), 2-(2-Amino-4-oxo4,5-dihydro-1H-pyrrol-3-yl)-4-(3,4-dimethoxyphenyl)thiazole (1e), 2-(2-Amino-5-methyl-4-oxo-4,5dihydro-1H-pyrrol-3-yl)benzimidazole (1f), 2-(2-Amino-5-methyl-4-oxo-4,5-dihydro-1H-pyrrol-3-yl)-1methylbenzimidazole (1g), and 2-(2-Amino-5-methyl-4-oxo-4,5-dihydro-1H-pyrrol-3-yl)benzothiazole (1h). A (for compounds 1a,b,d-g). To a solution of phthalimidonitrile 2 (0.005 mol) in n-butanol (25 ml) we added hydrazine hydrate (1 ml, 0.02 mol). The obtained mixture was heated on a boiling water bath for 1.5 h. After cooling the precipitate that separated was filtered off, washed with n-butanol, and recrystallized from n-butanol. We obtained ~0.5 g (~60%) of the phthalazinedione 6. The combined filtrates were evaporated to dryness under vacuum. The residue was rubbed with ether, filtered, and recrystallized from ethanol (for 1a,b,f,g) of glacial acetic acid (for 1d,e), after which the analytically pure pyrrolones (1a,b,d-g) were obtained. B (for compounds (1c,d,e,h). To a solution of the phthalimidonitrile 2 (0.005 mol) in dioxane (30 ml) we added hydrazine hydrate (1 ml, 0.02 mol). The obtained mixture was kept on a boiling water bath for 2 h. After cooling the precipitate was filtered off and recrystallized from glacial acetic acid. (Compounds 1e,h were recrystallized twice.) The pyrrolones 1c,d,e,h were obtained with yields comparable with the yields of the corresponding samples obtained by method A. By evaporation of the mother solution under vacuum followed by recrystallization of the residue from n-butanol it is possible to obtain the phthalazinedione 6 with an overall yield of 60-70%.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. A. Trani and E. Bellasio, Farmaco Ed. Sci., 38, 940 (1983). C. Yaroslavsky, P. Bracha, and R. Glaser, J. Heterocycl. Chem., 26, 1649 (1989). O. M. Z. Howard, J. J. Oppenheim, M. G. Melinda, J. M. Covey, and J. Bigelow, J. Med. Chem., 41, 2184 (1998). H.-M. Eggenweiler, R. Jonas, M. Wolf, M. Gassen, and T. Welge, Ger. Patent 19953025; Chem. Abstr., 134, 344596(2001). M. Tanaka, M. Tsuda, and A. Nakamura, PCT Int. Appl. WO Pat. 9936068; Chem. Abstr., 131, 97597 (1999). M. K. Ibrahim, Egypt. J. Pharm. Sci., 39, 519 (1998). O. Attanasi, S. M. Colombani, L. De Crescentini, R. Giorgi, S. Monti, A. Perrone, F. R. Perrulli, A. R. Renzetti, and S. Santeusanio, Farmaco, 54, 64 (1999). M. Tsuda, M. Tanaka, and A. Nakamura, PCT Int. Appl. WO Pat. 9640634; Chem. Abstr., 126, 117863 (1997). H. Mizukawa, T. Nakamine, and J. Ogasawara, Jpn. Patent 2000347368; Chem. Abstr., 134, 63772 (2001). N. Yanagihara, Jpn. Patent 2000327657; Chem. Abstr., 134, 18555 (2001). S. Ikesu, H. Kita, and Y. Kaneko, Jpn. Patent 07128823; Chem. Abstr., 123, 289615 (1995). C. E. Stephens and J. W. Sowell, J. Heterocycl. Chem., 35, 933 (1998). C. E. Stephens and J. W. Sowell, J. Heterocycl. Chem., 33, 1615 (1996). M. Yumoto, T. Kawabuchi, K. Sato, and M. Takashima, Jpn. Patent 10316654; Chem. Abstr., 130, 66386 (1998). K. A. M. El-Bayouki, W. M. Basyouni, H. Hosni, and A. S. El-Deen, J. Chem. Res. (S), 314 (1995). 1541
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A. M. Almerico, G. Cirrincione, P. Diana, S. Grimaudo, G. Dattolo, and E. Aiello, J. Heterocycl. Chem., 32, 985(1995). A. Gola, E. Samartzi, V. Bardakos, M. Petroliagi, O. Igglessi-Markopoulou, J. Markopoulos, and J. V. Barkley, J. Heterocycl. Chem., 37, 681 (2000). K. Gewald and M. Hentschel, J. Prakt. Chem., 318, 663 (1976). H. J. Teuber, G. Sobutz, and B. Erkenbrecher, Arch. Pharm. (Weinheim, Ger.), 313, 851 (1980). M. Suesse and S. Johne, J. Prakt. Chem., 323, 647 (1981). K.-J. Boosen, Helv. Chim. Acta, 60, 1246 (1977). Y. L. Chen, R. S. Mansbach, S. M. Winter, E. Brooks, J. Collins, M. L. Corman, A. R. Dunaiskis, W. S. Faraci, R. J. Gallaschu, A. Schmidt, and D. W. Schultz, J. Med. Chem., 40, 1749 (1997). C. G. Dave and N. D. Desai, J. Heterocycl. Chem., 36, 729 (1999). C. G. Dave and R. D. Shah, J. Heterocycl. Chem., 35, 1295 (1998). C. N. Hodge, P. E. Aldrich, Z. R. Wasserman, C. H. Fernandez, G. A. Nemeth, A. Arvanitis, R. S. Cheeseman, R. J. Chorvat, E. Ciganek, T. E. Christos, P. J. Gilligan, P. Krenitsky, E. Scholfield, and P. Strucely, J. Med. Chem., 42, 819 (1999). V. Levacher, C. Leroy, G. Dupas, J. Bourguignon, and G. Queguiner, Synth. Commun., 24, 2697 (1994). M. C. Cesta, R. Curti, L. Nicolini, and M. Mantovanini, PCT Int. Appl. WO 0029411; Chem. Abstr., 132, 349291 (2000). Yu. M. Volovenko, L. V. Gofman, and F. S. Babichev, Dokl. Akad. Nauk UkrSSR, Ser. B, 621 (1978). F. S. Babichev, Yu. M. Volovenko, and L. V. Gofman, USSR Inventor's Certificate 687070; Byull. Izobr., No. 35, 106 (1979). Yu. M. Volovenko, L. V. Gofman, and F. S. Babichev, Ukr. Khim. Zh., 45, 857 (1979). Yu. M. Volovenko, T. V. Shokol, and F. S. Babichev, Ukr. Khim. Zh., 51, 205 (1985). Yu. M. Volovenko, T. V. Shokol, A. S. Merkulov, and F. S. Babichev, Ukr. Khim. Zh., 59, 55 (1993). A. V. Tverdokhlebov, Yu. M. Volovenko, and T. V. Shokol, Khim. Geterotsikl. Soedin., 50 (1998). F. S. Babichev and Yu. M. Volovenko, Ukr. Khim. Zh., 43, 711 (1977). Yu. M. Volovenko and F. S. Babichev, Khim. Geterotsikl. Soedin., 557 (1977). E. V. Resnyanskaya, T. V. Shokol, Yu. M. Volovenko, and A. V. Tverdokhlebov, Khim. Geterotsikl. Soedin., 1412 (1999). Yu. M. Volovenko, T. A. Volovnenko, A. V. Tverdokhlebov, and I. G. Ryabokon', Zh. Org. Khim., 37, 1389 (2001). J. Scheiber and H. Reckleben, Berichte, 46, 2412 (1913). E. Pfaehler, Berichte, 46, 1702 (1913). J. Scheiber, Berichte, 46, 1100 (1913). S. Gabriel, Berichte, 46, 1319 (1913). O. Igglessi-Markopoulou and C. Sandris, J. Heterocycl. Chem., 19, 883 (1982). O. Igglessi-Markopoulou and C. Sandris, J. Heterocycl. Chem., 22, 1599 (1985). Yu. M. Volovenko, A. G. Nemazanyi, I. G. Ryabokon', and F. S. Babichev, Ukr. Khim. Zh., 54, 295 (1988). Yu. M. Volovenko, A. V. Tverdokhlebov, and T. A. Volovnenko, Khim. Geterotsikl. Soedin., 952 (2001). Yu. M. Volovenko, A. V. Tverdokhlebov, A. P. Gorulya, S. V. Shishkina, R. I. Zubatyuk, and O. V. Shishkin, Eur. J. Org. Chem., 663 (2002). W. Ozegowski and D. Krebs, J. Prakt. Chem., 301, 18 (1965). K. Saito, S. Kambe, and Y. Nakano, Synthesis, 210 (1983). Imperial Chemical Industries Ltd., Netherlands Patent Appl. 6614130; Chem. Abstr., 68, 68976 (1968). C. Mannich and F. L. Hahn, Berichte, 44, 1542 (1911).
1542
2-(1-ADAMANTYL)-7-METHYLIMIDAZO[1,2-a]PYRIDINE AND ITS REACTIONS WITH N-BROMOSUCCINIMIDE

R. I. Yurchenko, A. D. Ponomarenko, N. S. Savina, and A. A. Tolmachev In reaction with equimolar amount or twice the amount of N-bromosuccinimide 2-(1-adamantyl)-7methylimidazo[1,2-a]pyridine, obtained from 2-amino-4-methylpyridine and bromomethyl 1-adamantyl ketone, is converted into 2-(1-adamantyl)-3-bromo-7-methylimidazo[1,2-a]pyridine. With three times the amount of N-bromosuccinimide it gives 2-(1-adamantyl)-3-bromo-7-formylimidazo[1,2-a]pyridine. Keywords: 2-(1-adamantyl)-7-methylimidazo[1,2-a]pyridine, N-bromosuccinimide, bromination. Investigations of the reaction of 2-(1-adamantyl)-7-methylimidazo[1,2-a]pyridine (1), which we obtained in [1], with N-bromosuccinimide (NBS) showed that its reaction with one or two moles of N-bromosuccinimide led, without affecting the methyl group, to the introduction of a bromine atom only at position 3 of the imidazole ring, i.e., to compound 2. In reaction with three times the amount of N-bromosuccinimide in the presence of trace quantities of water 2-(1-adamantyl)-3-bromo-7-formylimidazo[1,2-a]pyridine (3) is formed. We suppose that compound 3 is the product from hydrolysis of 2-(1-adamantyl)-3bromo-7-dibromomethylimidazo[1,2-a]pyridine (a) formed during the reaction.
Me + N NH2 O Me
6
Br
Me
7 8 9 4N 3
+ N
NH2 _ Br
N1
2
HBr
O 4 1
__________________________________________________________________________________________ National Technical University of Ukraine, "Kiev Polytechnical Institute," Kiev; e-mail: ag@xtf.ntu-kpi.kiev.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1791-1793, December, 2004. Original article submitted December 13, 2002. 0009-3122/04/4012-15432004 Springer Science+Business Media, Inc. 1543
Me 1(2) NBS N Br 2 1 CHBr2 H2O N Br a HN N O2N NO2 N Br 5 N H N Br 3 N N O H N
3 NBS
Compound 3 exhibits typical chemical properties of carbonyl compounds. Thus, it forms hydrazone 5 with 2,4-dinitrophenylhydrazine.
EXPERIMENTAL The 1H NMR spectra were recorded on a JNM-FX900 instrument (90 MHz) with TMS as internal standard. 2-(1-Adamantyl)-7-methylimidazo[1,2-a]pyridine (1). Solution of pyridinium bromide 4 (10 mmol) in glacial acetic acid was boiled for 1 h. The reaction mixture was then treated with water, the precipitate was separated, then kept in 40% solution of sodium hydroxide for 1 h. 1H NMR spectrum (deuterochloroform), , ppm (J, Hz): 1.80 (6H, s, -H); 2.02 (6H, s, -H); 2.08 (3H, s, -H); 2.35 (3H, s, CH3); 6.54 (1H, d, J65 = 7.2, H-6); 7.20 (1H, s, H-8); 7.32 (1H, s, H-3); 7.90 (1H, d, J56 = 7.2, H-5). Found, %: N 10.41. 1822N2. Calculated, %: N 10.52. 2-(1-Adamantyl)-3-bromo-7-methylimidazo[1,2-a]pyridine (2). Mixture of equimolar amounts (3.8 mmol) of compound 1 and N-bromosuccinimide, catalytic amounts of benzoyl peroxide, and carbon tetrachloride (30 ml) was boiled until N-bromosuccinimide precipitate had completely disappeared. Succinimide was separated, and the filtrate was evaporated under vacuum. The residue was treated with hexane, and the precipitate was separated. Yield 51%; mp 161-163C (aqueous ethanol). 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 1.80 (6H, s, -H); 2.12 (3H, s, -H); 2.20 (6H, s, -H); 2.44 (3H, s, CH3); 6.90 (1H, d, J65 = 7.2, H-6); 7.33 (1H, s, H-8); 8.18 (1H, d, J56 = 7.2, H-5). Found, %: Br 22.95. 1821BrN2. Calculated, %: Br 23.14. 1544
2-(1-Adamantyl)-3-bromo-7-formylimidazo[1,2-a]pyridine (3). This compound was obtained similarly to compound 2 from compound 1 (3 mmol) and N-bromosuccinimide (9 mmol) with the addition of one drop of water. Yield 57%; mp 129-131C (aqueous ethanol). 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 1.80 (6H, s, -H); 2.10 (3H, -H); 2.17 (6H, s, -H); 7.40 (1H, d, J65 = 7.2, J68 = 1.5, H-6); 8.24 (1H, s, H-8); 8.40 (1H, d, J56 = 7.2, H-5); 10.01 (1H, s, CHO). Found, %: Br 22.00. C18H19rN2. Calculated, %: Br 22.24. N-[2-(1-Adamantyl)-3-bromoimidazo[1,2-a]-7-pyridylmethylene]-N-(2,4-dinitrophenyl)hydrazine (5). Mixture of solutions of equimolar amounts (3 mmol) of compound 3 and 2,4-dinitrophenylhydrazine in dioxane was boiled for 1 h and treated with a small amount of water. The precipitate that separated after cooling was separated. Yield 40%; mp 273-275C. 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 1.78 (6H, s, -H); 2.10 (3H, s, -H); 2.18 (6H, s, -H); 7.68-8.85 (7H, m, ArH, CH=N); 11.70 (1H, s, NH). Found, %: Br 14.70. 2423BrN64. Calculated, %: Br 14.81. 1-[3-(1-Adamantyl)-2-oxoethyl]-2-amino-3-methylpyridinium Bromide (4). To boiling solution of 2amino-4-methylpyridine (3.2 mmol) in ethyl acetate (10 ml) we added with stirring a solution of bromomethyl 1adamantyl ketone (3.2 mmol) in ethyl acetate (3 ml). The reaction mass was boiled for 1 h, and the precipitate was separated. Yield 75%; mp 248-250C (ethanolether). Found, %: Br 22.54. C17H23rN2. Calculated, %: Br 22.75.
REFERENCES 1. R. I. Yurchenko, N. N. Svarovskaya, A. D. Ponomarenko, and A. A. Tolmachev, Khim. Geterotsikl. Soedin., 852 (2001).
1545
PREPARATION OF 1-AMINO4-METHYLPIPERAZINE
P. M. Kushakova1, A. N. Chernobroviy2, V. A. Kuznetsov1, and A. V. Garabadgiu1 The selectivity of the formation of N-di(2-chloroethyl)methylamine in reactions with various chlorinating agents has been investigated and the optimum chlorinating agent has been found. 1-Amino-4methylpiperazine has been obtained for the first time by the cyclization of N-di(2chloroethyl)methylamine with aqueous hydrazine. A possible mechanism has been proposed for the cyclization reaction. Keywords: 1-amino-4-methylpiperazine, haloalkylamines, N,N-di(2-chloroethyl)methylamine, N-(2-chloroethyl)-N-methylaziridinium chloride, N-(2-chloroethyl)-N-(2-hydrazinoethyl)methylamine. 1-Amino-4-methylpiperazine (5) is used widely as an intermediate in the synthesis of medicinal preparations [1]. Several methods of obtaining it are known. The industrial application is a two-stage method of synthesis, starting from piperazine with subsequent nitrosation and reduction [2,3]. However this method has several drawbacks, mainly its low selectivity, the high toxicity of the intermediate products, and the difficulty of isolating the desired product [3].
CH2CH2OH
CH2CH2OH
1 + Me N 2 SOCl2, chloroform
CH2CH2Cl
Me N
Me N
NH2NH2 50% aqueous
CH2CH2Cl
CH2CH2Cl
3
Me N
CH2CH2NHNH2
CH2CH2Cl
Me N
5
N NH2
Me N
6
CH2CH2NHNH2
CH2CH2NHNH2
The method of synthesis developed by us also contains two stages, the chlorination of methyldiethanolamine (1) and subsequent cyclization of N,N-di(2-chloroethyl)methylamine (2) in aqueous hydrazine. When carrying it out we investigated the selectivity of forming compound 2 in reactions with various __________________________________________________________________________________________ Saint-Petersburg State Technical University, Saint-Petersburg 190013, Russia; e-mail: gar@sitecs.spb.ru. 2 "Olainfarm", Riga LV-2114, Latvia; e-mail: alchern@olainfarm.lv. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1794-1797, December, 2004. Original article submitted August 2, 2004. 1546 0009-3122/04/4012-15462004 Springer Science+Business Media, Inc.
1
chlorinating agents and the dependence of the completeness of the cyclization reaction on the ratio of compound 2 and 50% aqueous hydrazine. The chlorination of diethanolamine 1 has been studied in a fairly detailed manner [4-6]. On interacting compound 1 with gaseous hydrogen chloride at 120C, with phosgene, and with phosphorus trichloride, the target product 2 is formed in only trace amounts [4]. The use of thionyl chloride as chlorinating agent leads to the formation of chloro derivatives in almost quantitative yield (95%) [5, 6]. Regretably there is no systematic investigation in the literature of the effect of various factors on the yield of the target product, which does not enable a conclusion to be drawn on the optimal conditions for carrying out the synthesis. We have investigated experimentally the effect of the solvent on the selectivity of the chlorination reaction, and have also studied by mathematical planning the dependence of the yield of compound 2 on the reaction temperature, the concentration of compound 1 in solution, and the molar ratio of SOCl2 and compound 1. In the course of the investigation we established that chloroform (yield of product 2 95%) is the best of the solvents used (chloroform, chlorobenzene, trichloroethylene, benzene, toluene). As a result investigation of the effect of the remaining factors on the yield of chloro derivative 2 was carried out in chloroform. Analysis of the results of the mathematical treatment of the experiment showed that the yield of compound 2 essentially depends only on the molar ratio of SOCl2 and compound 1. The maximum yield of product (95.6%) was observed at SOCl2:1 equal to 3:1. It has therefore been established that the chlorination of compound 1 with thionyl chloride proceeds in the best yield in chloroform at a molar ratio of reactants of 3:1. Numerous investigations of the conversion of haloalkylamines on interaction with N-nucleophiles in aqueous alkaline medium or in the nucleophile showed that it proceeds according to a general scheme through the formation of an aziridinium ion [7]. However, on going over to di(2-haloalkyl)amines competition at ring closure is possible with the formation of three- and six-membered rings [3]. Although the reaction to obtain nitrogen-containing heterocycles by the interaction of haloalkylamines of general formula RR1NCH2CH2Cl with N-nucleophiles is not new [8], we obtained 1-amino-4methylpiperazine 5 by the reaction of dihaloamine 2 with aqueous hydrazine solution for the first time. We carried out a series of investigations on the interaction of dichloro derivative 2 with aqueous hydrazine solution at a substrate 2 ratio to 50% N2H4 of 1:50, 1:10, and 1:5 at 20-30C. It should be noted that the system of dihaloamine 2:aqueous hydrazine was two-phase when using molar ratios of reactants less than 40:1. Visually the reaction mixture becomes homogeneous only after 90% conversion of compound 2. In the case of two media the interaction of dihaloamine 2 with hydrazine is possible both in aqueous and in organic media. We have investigated the dynamics of the change of chloride ion concentration in the organic layer after mixing the reactants. The data obtained enable us to assert with a definite degree of probability that the reaction proceeds only in the aqueous hydrazine medium. Our investigations established that the maximum yield of cyclization product 5 (87%) was achieved at a ratio of substrate 2 to 50% N2H4 of 1:10. Analysis of the reaction mixture using data of GLC, chromato-mass spectrometry, and 13C NMR spectra showed that, in addition to the target product 5, a series of contaminants is formed, which we have identified. In particular, di(2-hydrazinoethyl)methylamine (6) (up to 2%) was detected by chromato-mass spectrometry, and at a degree of conversion of substrate 2 <80% N-(2-chloroethyl)-N-(2hydrazinoethyl)methylamine (4) was established to be present in the reaction mixture (Scheme 1). Our investigations permit a possible mechanism to be proposed for the cyclization of compound 2 in aqueous hydrazine through the formation of the reactive intermediate 3. In addition to the identified compounds 4-6, after distilling off the desired product 5, substances remained in the still which we attribute to quaternary ammonium bases 7 and 8. The latter are most probably formed by secondary reactions between the target compound 5 and the reactive compound 3.
1547
Scheme 1
+
Me
N N
_ Cl
NH2
N
Me
NH2NH2 50% aqueous
H2N
N H
7
+
H2N
N N
_ Cl
Me
N
Me
H2N
N H
EXPERIMENTAL The 13C NMR spectra were recorded on a Bruker DPX-200 (50 MHz) spectrometer, internal standard was D2O. The elemental composition of compounds was determined by high resolution mass spectrometry on a Varian MAT 311A instrument, the gas was xenon, accelerating voltage 2-6 kV, current 0.1-0.5 mA, resolution 30,000. A check on the progress of reaction was effected by TLC on Silufol UV 254 plates, eluent chloroform hexane, 2:1 or chloroformmethanol, 9:1. N,N-Di(2-chloroethyl)methylamine Hydrochloride (2). Solution of thionyl chloride (40.5 g, 30 mmol) in chloroform (120 ml) was added dropwise with vigorous stirring to solution of methyldiethanolamine 1 (11.9 g, 10 mmol) in chloroform (120 ml). The reaction mixture was kept at room temperature for 2 h, and chloroform then removed at atmospheric pressure. The residue was recrystallized from 2-propanol. Yield 14.9 g (96%); mp 108-110C (110C [6]). Mass spectrum (EI, 70eV), m/z (Irel, %): 192 (12.5) [M]+, 157 (10.2) [M-Cl]+, 122 (35.3) [M-2Cl]+. Found, %: C 31.23; H 6.17; N 7.32 C5H12Cl3N. Calculated, %: C 31.19; H 6.28; N 7.28. 1-Amino-4-methylpiperazine (5) was obtained by the method of [9]. Yield 26.5 g (87%); bp 128-131C (13 mm Hg). 13C NMR spectrum, , ppm: 57.51 (NCH2); 54.15 (CH2N); 45.01 (CH3). Mass spectrum (EI, 70 eV), m/z (Irel, %): 116 (5.5) [M+1]+, 115 (79.5) [M]+, 99 (73.9) [M-NH2]+, 98 (21.3) [M-NH3]+, 58 (20.6) [M-CH3N(CH2)2]+, 57 (24.5) [M-NH2N(CH2)2]+. Found, %: C 52.58; N 11.21; N 36.39. C5H13N3. Calculated, %: C 52.14; H 11.38; N 36.48.
REFERENCES 1. 2. 3. B. T. Golding and M. J. Kebbell, J. Chem. Soc., Perkin Trans. 2, 1859 (1988). P. D. Barleff, S. D. Ross, and C. C. Swain, J. Am. Chem. Soc., 69, 2971 (1947). V. S. Borisenko, V. A. Bobylev, and G. F. Tereshchenko, Zh. Obshch. Khim., 55, 1141 (1985).
1548
4. 5. 6. 7. 8. 9.
H. W. Vallender and F. M. Woodward, J. Am. Chem. Ind., 68, 280 (1949). K. A. Jensen and F. Lundquist, Dansk Tid. Farm., 15, 201 (1941). K. Ward, J. Am. Chem. Soc., 57, 914 (1935). V. A. Surkin, I. G. Zenkevich, P. S. Lobanov, and A. A. Potekhin, Zh. Org. Khim., 19, 2288 (1983). S. M. Rida, A. S. Issa, and Y. A. Beltagy, Pharmazie, 33, 711 (1978). P. M. Kushakova, V. A. Kuznetsov, A. N. Chernobroviy, and A. V. Garabadgiu, Khim. Geterotsikl. Soedin., 1111 (2004).
1549
INVESTIGATION OF THE PRODUCTS OF INTERACTION OF CYCLIC DIKETONES WITH NITROGEN-CONTAINING 1,4-BINUCLEOPHILES

N. N. Kolos, E. N. Yurchenko, V. D. Orlov, S. V. Shishkina, and O. V. Shishkin The interaction of arylbis(5,5-dimethylcyclohexane-1,3-dion-2-yl)methanes with o-phenylenediamine and o-aminophenol leads to the preparation of 3,3-dimethyl-11-aryl-2,3,4,5,10,11hexahydrobenzo[b,e]-1,4-diazepin-1-ones and 3,3,6,6-tetramethyl-9-aryl-10-(2-hydroxyphenyl)2,4,5,7,9-decahydroacridine-1,8-diones respectively. A one-pot method is proposed for the synthesis of derivatives of hexahydrodibenzo[b,e]-1,4-diazepin-1-ones. The structure of the first member of this series was confirmed by X-ray diffraction analysis. Keywords: o-aminophenol, arylbis(5,5-dimethylcyclohexane-1,3-dion-2-yl)methanes, hexahydrodibenzo[b,e]-1,4-diazepin-1-ones, decahydroacridine-1,8-diones, dimedone, o-phenylenediamine, cyclocondensation. In cyclic 1,5-diketones the position of the carbonyl groups determines exclusively the ease of their cyclization and makes them as convenient basis for the synthesis of nitrogen-, oxygen-, and sulfur-containing heterocycles [1, 2]. The aim of the present work is the study of the reactivity of the Michael adducts 1a-j [3, 4], obtained from dimedone and aromatic aldehydes or furfural (adduct 1j), in relation to the bidentatic nucleophiles o-phenylenediamine 2 and o-aminophenol 3. The cyclic tetraketones 1a-j exist in the enolic form which makes them structurally close to ,-unsaturated ketones, the reactivity of which in relation to 1,4-dinucleophiles has been studied previously [5, 6]. The electronic character of the substituents in R influence the direction of the interaction of compounds 1a-i with o-phenylenediamine 2 on boiling these reactants in 2-propanol (method A). The corresponding hexahydrodibenzodiazepinones 4a-f were obtained from tetraketones 1a (R = Ph) and 1b-f (electronwithdrawing substituents in R: 4-F, 4-Cl, 4-Br, 4-NO2). When electron-donating substituents (4-OMe, 4-NMe2, 2-OH) are present in R, as in compounds 1g-i, either decomposition of the latter takes place (in the case of tetraketones 1g,h) with the formation of the corresponding azomethines 5a,b, or conversion into decahydroacridinedione 6 occurs (from tetraketone 1i). Hexahydrodibenzodiazepinone 4j is obtained from hetaryl-substituted tetraketone 1j (R = 2-furyl). Tetraketones 1a-d,g,h do not react with o-aminophenol 3 under the conditions mentioned above (method A). Only on boiling these reactants in DMF the interaction products, decahydroacridinediones 7a-f, were obtained in good yield. The results obtained enable the interaction of compounds 1 with binucleophiles 2 and 3 to be represented in the following way. __________________________________________________________________________________________ Kharkov V. N. Karazin National University, Kharkov 61077, Ukraine; e-mail: orlov@univer.kharkov.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1798-1808, December, 2004. Original article submitted November 5, 2002; revision submitted February 5, 2004. 1550 0009-3122/04/4012-15502004 Springer Science+Business Media, Inc.
OH NH2
O i-PrOH,
+
OH O 2 NH2 1ak
H N OH H2N 8aj
8af,j 8i O R H N NH2 N H 4ag 5a,b N=CHR N X 8g,h O R O
6, 7af
O i-PrOH 1ad,g,h NH2
+
OH 3
DMF, H N OH HO
9af O O 2
+
HO
i-PrOH AcOH
H2N N H 11
RCHO 10ao
4ao
1, 4, 7-10 R = Ph, b R = 4-FC6H4, c R = 4-ClC6H4, d R = 4-BrC6H4; 1, 4, 8, 10 e R = 4-O2NC6H4, f R = 3-O2NC6H4, g R = 4-MeOC6H4, h R = 4-Me2NC6H4, i R = 2-HOC6H4, j R = 2-furyl; 4, 10 k R = 2-HO-3-MeOC6H3, l R = 2-thienyl, m R = 2-(5-nitrothienyl), n R = PhCO, o R = 4-O2NC6H4CO; 5a, 7e, 9e R = 4-MeOC6H4; 5b, 7f, 9f R = 4-Me2NC6H4; 6 X = NH2; 7af X = OH
The formation of products of type 4, 6, 7 includes a stage of nucleophilic addition at the -position of an enone system in which the amino group of compounds 2 and 3 participates. Subsequent conversion of the intermediate enamines 8 and 9 may proceed by two routes. The first includes nucleophilic attack of the sp3-hybrid center of the primary amino group with elimination of a molecule of dimedone, while the second is attack at the activated vinylene bond by the electron pair of the enamine nitrogen atom with the formation of the 1551
acridine nucleus. The presence of substituents increasing the partial positive charge on the sp3-hybrid center aids the formation of the diazepine ring. The formation of acridones is a consequence of reduction of the charge at the sp3-hybrid carbon atom (synthesis of product 6) or the low nucleophilicity of the neighboring nucleophilic center (synthesis of products 7a-f). Under the conditions of an one-pot synthesis using o-phenylenediamine, dimedone, and aldehydes 10a-o the sole products were hexahydrobenzodiazepinones 4. Compounds 4a-o were synthesized on boiling dimedone with diamine 2 in 2-propanol for 30-40 min in the presence of catalytic amounts of AcOH and subsequent addition of aromatic aldehyde 10a-o to the reaction mixture (method B). Diazepines 4g-i, containing electrondonating groups in R, and also products 4n,o with a substituent ArCO at position 11 (the appropriate glyoxals were put into the reaction mixture in place of aldehydes) were obtained by the same method. Compounds 4a-o were obtained in better yield under conditions of the one-pot synthesis (Table 1), and the reaction time was reduced significantly (see Experimental). The intermediate enamine 11 was not isolated by us under these conditions but its presence has been confirmed as a fact in [7]. The formation of enamine determines the direction of the overall process, since in experiments with simultaneous participation of diamine 2, dimedone, and aromatic aldehyde 10, 2-arylbenzimidazoles were obtained exclusively, i.e. the rate of interaction of diamine with aldehyde was greater than the rate of enamine formation, which is in good agreement with our data [8]. The composition and structure of compounds 4a-o, 6, 7a-f were confirmed by data of elemental analysis, IR and 1H NMR spectra (Tables 1 and 2), and in the case of compound 4a, also by X-ray diffraction analysis (Fig. 1 and Tables 3-5). According to the data of X-ray diffraction analysis product 4a is 3,3-dimethyl-11-phenyl-2,3,4,5,10,11hexahydrodibenzo[b,e]-1,4-diazepin-1-one. In the independent part of the unit cell of the compound 4a crystal there are two molecules (I and II) which differ in the conformation of the cyclohexene fragment. The sixmembered ring in molecule I has the form of a distorted chair. The deviations of the C(8) and C(9) atoms from the mean square plane of the remaining ring atoms are 0.52 and 0.13 respectively. In molecule II the cyclohexene fragment is in the sofa conformation. The deviation of the C(8') atom from the mean square plane of the remaining ring atoms is 0.65 . The diazepine ring in both molecules has a shape intermediate between a twist-chair and a twist-boat. The deviations of the N(2) and C(13) atoms from the mean square plane of the remaining ring atoms are 0.84 and 0.22 for molecule I and 1.01 and 0.55 for molecule II respectively. The phenyl substituent at C(12) atom (Fig. 1) has an axial orientation [the torsion angle C(6)C(11) C(12)C(16) is 96.2(2) in molecule I and 84.1(2) in molecule II] and is twisted relative to the C(11)C(12) bond [the torsion angle C(11)C(12)C(16)C(21) is 44.9(3) in molecule I and 29.4(3) in molecule II]. The formation of intermolecular hydrogen bond N(1')H(1N')O(1) (1 - x, y - 0.5, 0.5 - z) (H'O is 2.11, N'H'O 169) leads to lengthening of bonds O(1)C(10) 1.253(2) (I), 1.254(2) (II), C(6)C(11) 1.384(3) (I), 1.394(3) in (II) and shortening of bond C(10)C(11) 1.448(3) (I), 1.439(3) (II) in comparison with mean values of 1.210, 1.340, and 1.464 respectively. Shortened contacts were detected in the structure at O(1)H(12) of 2.36 (I) and 2.33 (II), H(15B)C(10) 2.83 (I) and 2.81 (II), and H(15B')C(6') 2.77 for total sum of the van der Waals radii of OH 2.45 and HC 2.87 . The closeness of the spectral characteristics of compounds 4a and 4b-o (see Tables 1, 2) permits their assignment to one series of isomers. In their IR spectra there are bands for the stretching vibrations of the enamine carbonyl group of low intensity at 1615-1650 cm-1, and also two bands at 3230-3350 cm-1 assigned to the stretching vibrations of the secondary amino group. The 1H NMR spectra of compounds 4 were more informative. The position, shape, and intensity of the recorded proton signals correspond to the structure of hexahydrodibenzodiazepinones indicated in the scheme (Table 2). The singlets in the region of 6.0 and 8.50 ppm, disappearing under deuterium exchange conditions, were assigned to the imine and enamine protons respectively.
1552
TABLE 1. Characteristics of Compounds 4, 6, 7

Compound 4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l 4m 4n 4o 6 7a 7b 7 7d 7e 7f Empirical formula 2122N2O 2121FN2O 2121ClN2O 2121BrN2O 2121N3O3 2121N3O3 2224N2O2 2327N3O 2122N2O2 C22H24N2O3 1920N2O2 1920N2OS 1919N3O3S 2222N2O2 2221N3O4 2932N2O3 2931NO3 2930FNO3 2930ClNO3 2920BrNO3 3033NO4 C31H36N2O3 Found N, % Calculated N, % 8.29 8.81 8.30 8.33 8.18 7.94 7.35 7.05 12.00 11.57 11.44 11.57 8.12 8.04 11.01 11.63 8.20 8.38 7.99 7.69 9.19 9.09 8.69 8.64 11.76 11.38 8.34 8.09 10.84 10.74 5.96 6.14 3.00 3.17 2.95 3.05 3.15 2.94 2.89 2.69 2.91 2.97 5.54 5.78 mp, C 251-252 237-239 239-240 241-242 274-275 144-146 203-205 228-230 164-166 216-218 269-270 227-229 243-245 233-234 210-212 205-206 244-246 298-300 286-288 283-284 260-262 290-291 IR spectrum, , cm-1 C=O NH 1628 1608 1620 1638 1627 1635 1615 1640 1650 1630 1622 1635 1635 1678 1675 1620, 1648 1622, 1649 1620, 1642 1622, 1643 1625, 1640 1620, 1645 1624, 1650 3318, 3292 3245, 3303 3288, 3233 3235, 3303 3353, 3280 3235, 3315 3246, 3315 3240, 3310 3250, 3305 3236, 3303 3350, 3285 3265, 3303 3285, 3347 3360, 3303 3370, 3320 3465, 3370 3610 3610 3610 3610 3610 3612 Yield, % (method) 65 (A), 70 (B) 55 (A), 63 (B) 71 (A), 74 (B) 60 (A), 64 (B) 80 (A), 86 (B) 70 (A), 73 (B) 60 (B) 64 (B) 70 (B) 68 (B) 52 (A), 60 (B) 62 (B) 68 (B) 75 (B) 65 (B) 60 (A) 64 65 67 65 72 68
Product 6 differs significantly in spectral characteristics from the compounds of type 4 considered above. In its 1H NMR spectrum (Table 2) the proton signals of the methylene and methyl groups have double intensity, there were not two protons subjected to deuterium exchange as in 4 ( 6.00 and 8.50 ppm), but three. The two-proton signal is found at high field ( 3.93 ppm) and the one-proton signal at low field (9.42 ppm). The first signal refers to the NH2 group, and the second to OH (enolic form). There were also significant differences in the IR spectrum of compound 6. Two intense carbonyl group absorption bands were observed at 1620-1650 cm-1, and also bands for a primary amino group in the range of 3350-3470 cm-1. All this confirms the structure of product 6 as 3,3,6,6-tetramethyl-9-(2-hydroxyphenyl)-10-(2-aminophenyl)-2,4,5,7,9-decahydroacridine-1,8-dione. 1553
1554
TABLE 2. 1H NMR Spectral Characteristics of the Synthesized Compounds

Chemical shifts, , ppm (SSCC, J, Hz) Compound 1 4a 4b 4c* 4d 4e 4f 4g 4h 4i 4k 4j* 3, s (H) 2 1.08 (3) 1.03 (3) 1.07 (3) 1.03 (3) 1.08 (3) 1.05 (3) 1.05 (3) 1.01 (3) 1.05 (3) 1.05 (3) 1.09 (3) H3, s (H) 3 1.14 (3) 1.07 (3) 1.15 (3) 1.08 (3) 1.15 (3) 1.17 (3) 1.11 (3) 1.05 (3) 1.10 (3) 1.11 (3) 1.17 (3) (4)2 (1, d, 1, d, J = 16.0) 4 2.10, 2.18 2.03, 2.20 2.10, 2.20 2.04, 2.22 2.10, 2.20 2.03, 2.24 2.05, 2.20 2.05, 2.15 2.04, 2.19 2.03, 2.20 2.02, 2.16 (2)2 (2H, d, J = 16.2) 5 2.56 2.60 2.55 2.50 2.58 2.60 2.56 2.54 2.55 2.70 2.62 N(10) (1H, s) 6 6.17 6.07 4.39 6.03 6.36 6.21 5.90 5.98 5.85 5.85 4.43 N(5) (1H, s) 7 8.75 8.70 6.72 8.63 8.96 8.75 8.55 8.61 8.75 8.70 6.75 C(11) (s or C(9)H) (H) 8 5.65 (1) 5.65 (1) 5.90 (1) 5.63 (1) 5.77 (1) 5.80 (1) 5.65 (1) 5.55 (1) 5.30 (1) 5.50 5.10 (1) , NH2, OCH3 N(CH3)2, s (3) 9 Harom, m (H) 10 6.55-7.25 (9) 6.49-7.16 (8) 6.40-7.10 6.42-7.25 (8) 6.52-8.00 (8) 6.45-8.00 (8) 6.49-7.39 (8) 6.40-6.93 (8) 6.39-6.91 (8) 6.16-6.93 (7) 6.20-7.15 (7)
3.66 (3) 2.52 (6) 9.63 (1) 8.95 (1), 3.62 (3)
TABLE 2 (continued)
1 4l 4m 4n 4o 6 7a 7b 7c 7d 7e 7f 2 1.01 (3) 1.02 (3) 0.88 (3) 0.84 (3) 0.88 (6) 0.68 (3), 0.87 (3) 0.70 (6) 0.68 (3), 0.87 (3) 0.70 (3), 0.87 (3) 0.68 (3), 0.87 (3) 0.69 (3), 0.87 (3) 3 1.04 (3) 1.05 (3) 1.35 (3) 1.05 (3) 0.98 (6) 0.72 (6) 0.87 (6) 0.73 (6) 0.73 (6) 0.72 (6) 0.72 (6) 4 2.05, 2.21 2.04, 2.24 2.02, 2.18 2.00, 2.19 *2 1.60-2.20 (8H, m) 1.70-2.20 (8H, m) 1.70-2.20 (8H, m) 1.70-2.20 (8H, m) 1.65-2.20 (8H, m) 1.60-2.10 (8H, m) 5 2.50 2.58 2.50 2.55 2.24 (4H, s) 6 6.10 6.40 6.17 6.22 7 8.70 8.92 8.84 8.90 8 5.90 (1) 5.91 (1) 6.17 (1) 6.17 (1) 5.28 (1) 5.03 (0.5), 4.93 (0.5) 4.99 (1) 5.01 (0.5), 4.91 (0.5) 5.01 (0.5), 4.91 (0.5) 4.88 (1) 4.85 (0.5), 4.95 (0.5) 9 10 6.60-7.09 (7) 6.68-7.05 (6) 6.40-7.95 (9) 6.49-8.37 (8) 6.77-7.26 (8) 7.00-7.54 (9) 6.93-7.27 (8) 6.95-7.52 (8) 7.00-7.45 (8) 6.95-7.45 (8) 6.50-7.38 (8)
3.93 (2), 9.42 (1) 10.45 (0.5), 10.34 (0.5) 9.99 (1) 10.45 (0.5), 10.34 (0.5) 10.43 (0.5), 10.33 (0.5) 10.40 (1), 3.69 (3) 10.20 (0.5), 10.27 (0.5), 2.80 (6)
_______ * Spectra were measured in CDCl3 (compounds 4c,j and 6) and DMSO-d6 (remaining compounds). *2 , ppm: 1.83 (2H, d, J = 18), 2.19 (2H, d, J = 18).
1555
Fig. 1. Structure of the Compound 4a Molecule. The considered spectra have much in common with the analogous spectra of products 7a-f obtained on boiling aminophenol 3 with compounds 1a-d,g,h in DMF. In addition, there are absorption bands for hydroxyl groups at 3610 cm-1 in the IR spectra of products 7a-f. On this basis the indicated compounds 7a-f were assigned the structure of decahydroacridine-1,8-diones containing an o-hydroxyphenyl group at position 10. In the 1H NMR spectra of compounds 7a,c,e,f at room temperature doubling of the signals of protons of the H-9 methine group and of hydroxyl group was observed, linked evidently with the development of atropoisomerism caused by restriction of rotation around the NAr bond and by the presence of an ortho substituent in the aromatic nucleus. The ratio of rotamers in 7 proved to be close to 1:1. Doubling of the signals was not recorded in the spectrum of compound 7b containing p-fluorophenyl substituent in position 9, nor in compound 6 having ortho-substituted aryl radicals in positions 9 and 10.
TABLE 3. Bond Lengths (l) in the Compound 4a Molecule

Bond O(1)C(10) N(1)C(5) N(2)C(12) C(1)C(13) C(3)C(4) C(5)C(13) C(6)C(7) C(8)C(9) C(8)C(14) C(10)C(11) C(12)C(16) C(16)C(21) C(18)C(19) C(20)C(21) N(1')C(6') N(2')C(13') C(1')C(2') C(2')C(3') l, 1.253(2) 1.413(3) 1.487(3) 1.395(3) 1.386(3) 1.401(3) 1.513(3) 1.524(3) 1.541(3) 1.448(3) 1.531(3) 1.390(3) 1.378(4) 1.386(3) 1.365(2) 1.402(2) 1.384(3) 1.381(3) Bond C(4')C(5') C(6')C(11') C(7')C(8') C(8')C(9') C(9')C(10') C(11')C(12') C(16')C(21') C(17')C(18') C(19')C(20') N(1)C(6) N(2)C(13) C(1)C(2) C(2)C(3) C(4)C(5) C(6)C(11) C(7)C(8) C(8)C(15) C(9)C(10) l, 1.397(3) 1.394(3) 1.537(3) 1.534(3) 1.520(3) 1.511(3) 1.386(3) 1.389(4) 1.372(4) 1.368(2) 1.411(3) 1.386(3) 1.384(3) 1.393(3) 1.384(3) 1.535(3) 1.528(3) 1.514(3) Bond C(11)C(12) C(16)C(17) C(17)C(18) C(19)C(20) O(1')C(10') N(1')C(5') N(2')C(12') C(1')C(13') C(3')C(4') C(5')C(13') C(6')C(7') C(8')C(15') C(8')C(14') C(10')C(11') C(12')C(16') C(16')C(17') C(18')C(19') C(20')C(21') l, 1.513(3) 1.390(3) 1.389(4) 1.380(4) 1.254(2) 1.419(2) 1.487(3) 1.393(3) 1.383(3) 1.404(3) 1.512(3) 1.529(4) 1.534(3) 1.439(3) 1.531(3) 1.395(3) 1.375(4) 1.399(3)
1556
TABLE 4. Bond Angles () in Structure 4a

Angle C(6)N(1)C(5) C(2)C(1)C(13) C(2)C(3)C(4) C(4)C(5)C(13) C(13)C(5)N(1) N(1)C(6)C(7) C(6)C(7)C(8) C(9)C(8)C(7) C(9)C(8)C(14) C(7)C(8)-C(14) O(1)C(10)C(11) C(11)C(10)C(9) C(6)C(11)C(12) N(2)C(12)C(11) C(11)C(12)(16) C(1)C(13)N(2) C(17)C(16)(21) C(21)C(16)(12) C(19)C(18)C(17) C(19)C(20)C(21) C(6')N(1')C(5') C(2')C(1')C(13') C(2')C(3')C(4') C(4')C(5')C(13') C(13')C(5')N(1') N(1')C(6')C(7') C(6')C(7')C(8') C(15')C(8')C(14') C(15')C(8')C(7') C(14')C(8')C(7') O(1')C(10')C(11') C(11')C(10')C(9') C(6')C(11')C(12') N(2')C(12')C(11') C(11')C(12')C(16') C(1')C(13')C(5') C(21')C(16')C(17') C(17')C(16')C(12') C(19')C(18')C(17') C(19')C(20')C(21') , deg. 133.4(2) 122.0(2) 118.7(2) 119.4(2) 124.2(2) 111.3(2) 115.7(2) 107.5(2) 110.0(2) 108.8(2) 121.4(2) 119.4(2) 126.1(2) 113.0(2) 115.5(2) 120.7(2) 118.0(2) 123.1(2) 120.4(2) 120.6(3) 132.9(2) 121.6(2) 119.7(2) 119.2(2) 123.6(2) 113.4(2) 113.7(2) 110.5(2) 110.3(2) 109.0(2) 121.9(2) 119.9(2) 122.6(2) 111.2(2) 115.9(2) 118.6(2) 117.6(2) 119.0(2) 119.7(2) 119.8(3) Angle C(13)N(2)C(12) C(3)C(2)C(1) C(3)C(4)C(5) C(4)C(5)N(1) N(1)C(6)C(11) C(11)C(6)C(7) C(9)C(8)C(15) C(15)C(8)C(7) C(15)C(8)C(14) C(10)C(9)C(8) O(1)C(10)C(9) C(6)C(11)C(10) C(10)C(11)(12) N(2)C(12)C(16) C(1)C(13)C(5) C(5)C(13)N(2) C(17)C(16)(12) C(18)C(17)C(16) C(18)C(19)C(20) C(20)C(21)C(16) C(13')N(2')C(12') C(3')C(2')C(1') C(3')C(4')C(5') C(4')C(5')N(1') N(1')C(6')C(11') C(11')C(6')C(7') C(15')C(8')C(9') C(9')C(8')C(14') C(9')C(8')C(7') C(9')C(8')C(7') C(10')C(9')C(8') O(1')C(10')C(9') C(10')C(11')C(12') N(2')C(12')C(16') C(1')C(13')N(2') N(2')C(13')C(5') C(21')C(16')C(12') C(18')C(17')C(16') C(20')C(19')C(18') C(16')C(21')C(20') , deg. 119.6(2) 119.9(2) 122.0(2) 116.4(2) 126.9(2) 121.8(2) 110.7(2) 110.4(2) 109.4(2) 114.4(2) 119.1(2) 119.3(2) 114.6(2) 110.8(2) 118.0(2) 121.2(2) 118.8(2) 120.9(3) 119.2(2) 120.8(2) 115.3(2) 119.7(2) 121.2(2) 117.1(2) 125.9(2) 120.7(2) 110.3(2) 109.7(2) 106.9(2) 114.9(2) 118.2(2) 119.8(2) 117.3(2) 110.9(2) 121.0(2) 120.4(2) 123.2(2) 121.4(2) 120.3(3) 121.1(2)
EXPERIMENTAL The IR spectra were taken on a Specord IR 75 instrument for KBr disks and solutions in CHCl3 (OH for compounds 7a-f). The 1H NMR spectra were obtained on a Varian VXR 200 (200 MHz) in DMSO-D6 and CDCl3, internal standard was TMS. The purity of compounds was checked by TLC on Silufol UV 254 plates, eluent was chloroform. X-Ray Investigation of Compound 4a. Crystals of compound 4a are monoclinic, C21H22N2O, at 20C: a = 10.666(4), b = 13.214(6), c = 25.098(10) ; = 92.82; V = 3533(3) 3, Mr = 318.41, Z = 8, space group P21/c, dcalc = 1.197 g/cm3, (MoK) = 0.074 mm-1, F(000) = 1360. The unit cell parameters and the intensities of 6531 reflections were measured on a Siemens automatic P3/PC 4-circle diffractometer (MoK, graphite 1557
TABLE 5. Coordinates (x - 104, y - 104, z - 104) of the Nonhydrogen Atoms in Structure 4a

Atom O(1) N(1) N(2) C(1) C(2) C(3) C(4) C(5) C(6) C(7) C(8) C(9) C(10) C(11) C(12) C(13) C(14) C(15) C(16) C(17) C(18) C(19) C(20) C(21) x 5588(2) 4202(2) 3707(2) 1864(2) 1136(2) 1417(2) 2430(2) 3176(2) 4931(2) 5912(2) 6429(2) 6743(2) 5687(2) 4846(2) 3965(2) 2906(2) 7627(2) 5460(2) 2741(2) 2292(2) 1136(3) 410(3) 859(2) 2011(2) y 5387(1) 4022(1) 6126(1) 6052(2) 5576(2) 4596(2) 4113(2) 4587(2) 4100(2) 3272(2) 3018(2) 4016(2) 4783(2) 4830(2) 5728(2) 5584(2) 2377(2) 2424(2) 5582(2) 6376(2) 6311(2) 5453(3) 4651(2) 4713(2) z 2097(1) 393(1) 680(1) 67(1) -331(1) -479(1) -223(1) 174(1) 855(1) 894(1) 1460(1) 1741(1) 1717(1) 1247(1) 1229(1) 319(1) 1420(1) 1761(1) 1514(1) 1814(1) 2044(1) 1978(1) 1692(1) 1461(1) Atom C(7') C(8') C(9') C(10') C(11') C(12') C(13') C(14') C(15') C(16') C(17') C(18') C(19') C(20') C(21') C(1') C(2') C(3') C(4') C(5') C(6') O(1') N(1') N(2') x 5712(2) 7004(2) 6766(2) 5824(2) 4883(2) 4056(2) 3098(2) 7734(3) 7728(2) 2735(2) 2098(2) 854(3) 233(3) 841(2) 2092(2) 2201(2) 1285(2) 1238(2) 2135(2) 3083(2) 4839(2) 5910(2) 4033(2) 4001(2) y -1249(2) -1515(2) -2141(2) -1682(2) -992(2) -487(2) 956(1) -2151(2) -550(2) -930(2) -793(2) -1087(2) -1531(2) -1696(2) -1394(2) 1674(2) 1988(2) 1572(2) 873(2) 569(2) -744(2) -1913(1) -71(1) 626(1) z 1951(1) 1744(1) 1235(1) 829(1) 1001(1) 574(1) 1005(1) 2166(1) 1623(1) 484(1) -9(1) -95(1) 312(1) 799(1) 884(1) 845(1) 1180(1) 1684(1) 1855(1) 1526(1) 1504(1) 348(1) 1754(1) 657(1)
monochromator, 2/ scanning, 2max = 50). The structure was solved by the direct method with the SHELXL-97 program set [10]. The positions of the hydrogen atoms were calculated geometrically and refined with a rider model with Uiso = nUeq of the non-hydrogen atom linked with a given hydrogen atom (n = 1.5 for methyl groups and 1.2 for the remainder). The structure was refined according to F2 by a full-matrix leastsquares method in an anisotropic approach to wR2 = 0.139 on 6183 reflections [R1 = 0.050 on 3608 reflections with F >4(F), S = 0.976]. 3,3-Dimethyl-11-phenyl-2,3,4,5,10,11-hexahydrodibenzo[b,e]-1,4-diazepin-1-one (4a). A. Tetraketone 1a (1.84 g, 5 mmol) and o-phenylenediamine (0.54 g, 5 mmol) were boiled in 2-propanol (20 ml) for 5 h. The reaction mixture was cooled, the precipitated solid was filtered off, and crystallized from 50% aqueous ethanol. Diazepines 4b-f,j were obtained analogously from tetraketones 1b-f,j on boiling for 1-10 h (check by TLC), also acridinedione 6 from compound 1i, and azomethines 5a (40% yield) and 5b (45% yield) from compounds 1g,h. Compound 5a had mp 101C (101-102C [9]), compound 5b had mp 146C (147C [9]). 11-(4-Methoxyphenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydrodibenzo[b,e]-1,4-diazepin-1-one (4g). B. Compound 2 (0.54 g, 5 mmol) and dimedone (0.7 g, 5 mmol) were boiled in ethanol (10 ml) with acetic acid (2-3 drops) for 40 min, then anisaldehyde (10g) (5 mmol) was added, and the mixture boiled for 1 h further. After cooling, the precipitated product was filtered off, and crystallized from 50% aqueous ethanol. Compounds 4a-f,h-o were obtained analogously from aldehydes 10a-f,h-o. The boiling time after adding aldehyde was from 20 min to 1 h (check by TLC). 10-(2-Hydroxyphenyl)-3,3,6,6-tetramethyl-9-phenyl-2,4,5,7,9-decahydroacridine-1,8-dione (7a). Solution containing compound 1a (0.74 g, 2 mmol) and amine 3 (0.22 g, 2 mmol) in DMF (10 ml) was boiled for 1 h. After cooling, water (5 ml) was added to the reaction mixture. The precipitate of product was filtered off, and compound 7a (0.56 g) was obtained. Compounds 7b-f were obtained analogously from tetraketones 1b-d,g,h. 1558
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Yu. M. Shchekotikhin, T. T. Nikolaeva, G. M. Shub, and A. P. Kriven'ko, Khim.-farm. Zh., 35, No. 4, 29 (2001). V. E. Kharchenko and S. N. Chala, 1,5-Diketones, Izd. Sarat. Gos. Univ. (1977). P. Margaretta and O. Polansky, Monatsh. Chem., 101, 824 (1970). Ya. K. Lemba, and I. E. Lielbriedis, Izv. Akad. Nauk LatvSSR, Ser. Khim.,598 (1973). V. D. Orlov, N. N. Kolos, M. Tueni, E. Yu. Yur'eva, and S. M. Ivkov, Khim. Geterotsikl. Soedin., 947 (1992). V. D. Orlov, N. N. Kolos, E. V. Zhidkova, and I. Z. Papiashvili, Khim. Geterotsikl. Soedin., 250 (1991). E. Cortes, A. Hernandez, and O. Mellando, J. Heterocycl. Chem., 39, 55 (2002). V. D. Orlov, N. N. Kolos, and B. M. Zolotarev, Khim. Geterotsikl. Soedin., 390 (1983). A. G. Shering, Belg. Patent 66733; Chem. Abstr., 65, 7185 (1965). G. M. Sheldrick, SHELXL PLUS PC Version. A System of Computer Programs for the Determination of Crystal Structure from X-ray Diffraction Data. Rev. 5.02 (1998).
1559
INVESTIGATION OF NAPHTHYRIDINES. 16*. SYNTHESIS OF DERIVATIVES OF 2,5-DIOXO-1,2,5,6,7,8-HEXAHYDRO1,6-NAPHTHYRIDINE-3-CARBOXYLIC ACIDS FROM ANILIDES (HYDRAZIDES) OF 6-OXO-2-STYRYLNICOTINIC ACIDS
A. B. Deyanov, M. E. Konshin, and Z. N. Semenova Heating anilides (hydrazides) of 5-cyano-6-oxo-2-styrylnicotinic acids in polyphosphoric acid (PPA) leads to amides of 7-aryl-2,5-dioxo-6-phenyl(amino)-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3carboxylic acids, which on heating with perchloric acid in acetic acid give the corresponding acids. Keywords: anilides, hydrazides, styrylnicotinic acids, cyclization. 2,5-dioxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridines, 6-oxo-2-
Amides of 2-styrylnicotinic acid are cyclized on heating in PPA into derivatives of 5-oxo-5,6,7,8tetrahydro-1,6-naphthyridine [2]. The aim of the present work was to extend the limits of this reaction and to obtain new derivatives of 1,6-naphthyridine from anilides and hydrazides of 5-cyano-6-oxo-2-styrylnicotinic acid. The investigations showed that ring closure in compounds 1a-d occurs on heating them in PPA at 165C for 3 h. Amides of 7-aryl-2,5-dioxo-6-phenyl(amino)-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxylic acids 2a-d were formed in this way (Table 1).
O NC N H CONH R2 PPA or HClO4 R3 N O N H R2 C6H4 R1
C6H4 R1
1a _ f
2a _ i
1, 2 R1 = 4-Me2N, R2 = Ph; b R1 = 3-Br, R2 =Ph; c R1 = 4-Me2N, R2 = NH2; d R1 = 3-Br, R2 = NH2; e R1 = 4-MeO, R2 = Ph; 1f R1 = 4-Br, R2 = NH2; 2 f R1 = 4-Me2N, R2 = Ph, 1 g R = 3-Br, R2 = Ph, h R1 = 4-Me2N, R2 = NH2; i R1 = 4-Br, R2 = NH2; a-d R3 = CONH2, e-i R3 = COOH
_______ * For Part 15 see [1]. __________________________________________________________________________________________ Perm State Pharmaceutical Academy, Perm 614600, Russia; e-mail: pfa@degacom.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1809-1812, December, 2004. Original article submitted April 18, 2002. 1560 0009-3122/04/4012-15602004 Springer Science+Business Media, Inc.
TABLE 1. Characteristics of Compounds 2a-i

Empirical formula C 2a 2b 2c 2d 2e 2f 2g 2h 2i C23H22N4O3 C21H16 BrN3O3 C17H19N5O3 C15H13BrN4O3 C22H18N2O5 C23H21N3O4 C21H15BrN2O4 C17H18N4O4 C15H12BrN3O4 68.64 68.71 57.58 57.79 59.81 60.04 47.76 48.00 67.69 67.40 68.47 68.76 57.40 57.67 59.64 59.76 47.64 47.67 Found, % Calculated, % H 5.51 5.33 3.68 3.39 5.61 5.49 3.47 3.27 4.65 4.92 5.25 5.33 3.44 3.28 5.30 5.01 3.20 2.95 Br __ 18.24 18.52 __ 21.18 20.90 __ __ 18.19 18.25 __ 21.13 21.39 N 13.92 14.20 9.59 9.76 20.52 20.50 14.85 14.63 7.18 6.87 10.42 10.66 6.38 6.50 16.36 16.49 10.11 10.84 262-263 216-218 213-215 259-262 276-278 268-270 240-242 238-241 201-204 41 44 42 37 41 34 48 62 69 500 500 125 1000 500 500 500 500 1000 1000 500 1000 Antimicrobial activity, minimum inhibitory concentration (MIC), g/ml St. aureus E. coli
Compound
mp, C
Yield, %
1561
The IR spectra of naphthyridines 2a-d, unlike the spectra of the corresponding compounds 1a-d [3], did not contain absorption bands for nitrile group but had absorption bands at 1668-1676 cm-1 (C=O amide) and also bands for the stretching vibrations of the amide NH group at 3462-3480 cm-1. In the 1H NMR spectra of compounds 2, in difference to the spectra of the initial anilides and hydrazides 1, proton signals appeared at 7.19-7.67 (2H, br. s, CONH2), 3.32-3.48 (2H, d, CH2), and 5.37-5.52 ppm (1H, t, CH). In the mass spectrum of compound 2a the molecular ion 402* [M]+ splits off a molecule of water and is converted into the 384 ion [M-H2O]+. Further fragmentation of this ion is linked either with loss of a molecule of HCN, which is characteristic of nitriles [4], or with detachment of phenylnitrene. Detachment of a molecule of HCN leads to the formation of the stable 357 ion, the intensity of the peak of which is 100%, which is probably determined by the distribution of the positive charge inside the formed aromatic pyridine ring. Fragmentation of the 357 ion proceeds in three directions (fission of O, CO, and CH2=NMe) with the formation of 341, 329, and 314 ions respectively. The latter eliminates either phenyl and gives a 237 ion or phenylnitrene and forms the 223 ion. On detachment of phenylnitrene from the 384 [M-H2O]+ ion the 293 ion is formed which sequentially eliminates hydrogen cyanide and a fragment of dimethylamine with the emergence of the stable 266 and 223 ions. It was further established that 7-aryl-2-oxo-1,2,5,6,7,8-hexahydro-6-phenyl(amino)-1,6-naphthyridine-3carboxylic acids 2e-i were formed on heating a solution of stilbazoles 1a-c,e,f in glacial acetic acid in the presence of perchloric acid. The 1H NMR spectra of naphthyridines 2e-i differed from the spectra of compounds 1a-c,e,f [3] by the absence of a broadened singlet for the NH2 group at 7.19-7.67 ppm and by the presence of a singlet for the carboxyl group proton at 8.68-9.31 ppm, and in the IR spectrum by the presence of bands at 1704-1744 (C=O carboxyl group) and at 3555-3580 cm-1 (OH). The antimicrobial activity of compounds 2c,e-i was studied in relation to Staphylococcus aureus and Escherichia coli. The minimum inhibitory concentration (MIC) was determined by serial dilution [5]. Ethacridine lactate was used as reference standard and inhibits growth of both St. aureus and E. coli at concentration of 500 g/ml. The investigations showed that the majority of the compounds did not supersede the reference standard in activity towards St. aureus but compound 2g was 4 times more potent.
EXPERIMENTAL The IR spectra were obtained on a UR 20 instrument in CCl4, c = 0.05 M (compound 2e) and in nujol (remaining compounds). The 1H NMR spectra were recorded on a PC 60 (60 MHz) spectrometer in DMSO-d6, internal standard was HMDS ( 0.05 ppm). The mass spectra were obtained on a MX 1303 instrument with direct insertion of samples into the ion source, ionizing voltage was 70 eV, reference standard was 200Hg. Amides of 6-Amino(phenyl)-7-aryl-2,5-dioxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxylic Acids 2a-d. The appropriate compound 1a-d (0.01 mol) was heated with PPA (10 ml) for 3 h at 165C. The mixture was poured into water (100 ml) and neutralized with ammonia solution. The solid was filtered off, and crystallized from dioxane (compound 2a) or aqueous ethanol (compounds 2b-d). IR spectrum, , cm-1: 3366-3396, 3172-3194 (CONH2), 3360-3480 (NH), 1668-1684 (C(3)C=O), 1656-1672 (C(2)=O), 1632-1664 (C(5)=O); compounds 2c,d 3272-3280, 3208 (NH2). 1H NMR spectrum, , ppm: 8.43-8.78 (1H, s, H-4); 7.25-7.65 (1H, s, NH); 7.19-7.67 (2H, s, CONH2); 5.08-5.37 (1H, t, H-7); 3.32-3.50 (2H, d, H-8); compounds 2a,b 6.96-7.42 (9H, m, arom.); compounds 2c,d 6.68-7.00 (4H, m, C6H4); 3.77-4.18 (2H, s, NH2). Mass spectrum of compound 2a, m/z (Irel, %): 402 (97) [M]+, 384 (26), 357 (100), 341 (12), 329 (25), 314 (19), 293 (67), 266 (98), 237 (52), 223 (99), 183 (25), 146 (26), 134 (66). _______ * Here and subsequently m/z values are given for ion peaks. 1562
6-Amino(phenyl)-7-aryl-1,5-dioxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxylic Acids 2e-i. The appropriate compound 1a-c,e,f (0.01 mol) was added to freshly prepared solution (30 ml) of perchloric acid in glacial acetic acid with a small amount of acetic anhydride (perchloric acid content 10-12%). The mixture was heated at ~100C for 2 h, poured into water (150 ml), and neutralized with sodium bicarbonate solution. The solid was filtered off and crystallized from aqueous DMF. IR spectrum, , cm-1: 3530-3589 (COOH), 3372-3452 (NH), 1704-1744 (C(3)C=O), 1642-1682 (C(2)=O), 1620-1668 (C(5)=O), compounds 2h,i 3280-3288, 32063212 (NH2). 1H NMR spectrum, , ppm: 8.68-9.31 (H, s, COOH); 8.46-8.78 (1H, s, H-4); 7.07-7.65 (1H, s, NH); 5.05-5.55 (1H, t, H-7); 3.24-3.76 (2H, d, 2H-8); compounds 2e-g 6.87-7.48 (9H, m, arom.); compounds 2h,i 6.68-6.97 (4H, m, C6H4); 4.01-4.39 (2H, s, NH2).
REFERENCES 1. 2. 3. 4. 5. S. V. Ukhov and M. E. Kon'shin, Khim. Geterotsikl. Soedin., 92 (1992). V. I. Sigova and M. E. Kon'shin, Khim. Geterotsikl. Soedin., 783 (1984). A. B. Deyanov and M. E. Konshin, Khim. Geterotsikl. Soedin., 547 (2004). P. B. Terent'ev and A. P. Stankyavichus, Mass Spectroscopic Analysis of Biologically Active Nitrogen Bases [in Russian], Mokslas, Vilnius (1987). G. B. Pershin, Methods of Experimental Chemotherapy [in Russian], Meditsina, Moscow (1959), pp. 109, 456.
1563
NEW SYNTHESIS OF THE DIHYDROINDOLIZINOQUINOLINE SYSTEM BY INTRAMOLECULAR CYCLIZATION OF SULFUR YLIDE

F. Z. Galin, S. N. Lakeev, I. Z. Myllagalin, and I. O. Maydanova An efficient method is proposed for obtaining the dihydroindolizinoquinoline system by intramolecular cyclization of keto-stabilized sulfonium ylide obtained from -alanine and quinoline-2,3-dicarboxylic acid anhydride. Keywords: keto-stabilized sulfur ylide, 6-methylthio-8,9-dihydroindolizino[1,2-b]quinoline-7,11-dione, intramolecular cyclization. The indolizinoquinoline system is a structural fragment of certain natural compounds, such as alkaloid camptothecin and its closest analogs, which possess anticancer activity [1-3]. Previously we discovered a new intramolecular cyclization of sulfur ylides [4-6], synthesized from substituted - and -amino acids [7], which opened a convenient route for constructing nitrogen-containing condensed heterocyclic systems. In the present work a method is proposed for the synthesis of 6-methylthio-8,9-dihydroindolizino[1,2-b]quinoline-7,11-dione (1) by the cyclization of sulfur ylide 2 containing quinoline-2,3-dicarboximide fragment. Sulfonium ylide 2 was obtained by the procedure of [7] from quinoline-2,3-dicarboxylic acid anhydride (3) [8] and -alanine. N-Substituted -alanine 4 was converted into diazo ketone 5. The yield of diazo ketone 5 synthesized by interacting CH2N2 with acid 4 chloride [7] was 50%. On using the mixed anhydride formed by interacting acid 4 with methyl chloroformate the yield of diazo ketone 5 became practically quantitative and the obtained diazo ketone did not require additional purification. On sequential treatment of diazo ketone with 48% HBr solution and Me2S sulfonium salt 6 is formed, the deprotonation of which with a mixture of saturated K2CO3 solution and 12.5 N NaOH gives ylide 2 in 91% yield. Heating ylide 2 in the presence of equimolar quantity of benzoic acid in toluene solution leads to 6-methylthio-8,9-dihydroindolizino[1,2-b]quinoline-7,11dione (1) in 90% yield (Scheme 1). We investigated the possibility of obtaining compound 1 by the one-pot method directly from diazo ketone 5. Ylide 2 is formed on catalytic decomposition of diazo ketone 5 with rhodium acetate in the presence of Me2S at 40C. The ylide, without isolation from the reaction mixture, becomes involved in an intramolecular cyclization giving product 1 in 60% yield. The intramolecular cyclization of sulfonium ylide 2 proceeds regioselectively with the formation of one isomer of 1. The nucleophilic character of sulfur ylide enables the suggestion that the cyclization comprises interaction of the carbanionic center with the electron-deficient carboximide carbon atom located in the position to the nitrogen atom of the pyridine ring. In the 13C NMR spectrum of compound 1 taken in modulation mode at the CH constant the signals from the C(8) and C(9) atoms are defined unequivocally, being displayed as two triplets at 36.90 and 35.95 ppm respectively, and the singlets of the carbonyl carbon atoms were at 190.78 and __________________________________________________________________________________________ Institute of Organic Chemistry, Ufa Scientific Center of the Russian Academy of Sciences (RAN), Ufa 450054; e-mail: galin@anrb.ru, irina_m@anrb.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1813-1816, December, 2004. Original article submitted February 11, 2002. 1564 0009-3122/04/4012-15642004 Springer Science+Business Media, Inc.
Scheme 1
O O N O 3 O N N O 5 Rh2(OAc)4, Me2S O N N O 2
1 12
-Ala N
O N O 4 O N2 N HBr 7 CO2H
SOCl2 or ClCO2Me, CH2N2
O HBr N O
O Br
Me2S O + SMe2 O N N HBr O

11a
K2CO3, NaOH
+ SMe2 Br
O 6
PhCO2H
4
N N
5 5a 5b 6
MeS
162.92 ppm. The signals of the C(5a) and C(6) atoms were displayed as singlets at 146.18 and 116.02 ppm. Comparison of the chemical shifts obtained for compound 1 with calculated values and with the chemical shifts of the carbon atoms of dihydrodiazafluorenedione derivative studied by us previously [9], the structure of which is identical to the main fragment of the compound 1 molecule, confirmed the above hypothesis on the structure of the cyclization product obtained. The structures of all the obtained compounds were confirmed by IR and NMR spectroscopic methods, and by data of elemental analysis. We have therefore proposed a simple and efficient method of obtaining the dihydroindolizinoquinoline structure, which opens a new route to the synthesis of biologically active compounds.
EXPERIMENTAL The IR spectra were obtained on UR 20 and Specord M 80 instruments (in thin films or in nujol). The 1H and C NMR spectra were recorded on a Bruker AM 300 spectrometer (300 and 75 MHz respectively), internal standard was TMS. The progress of reactions was followed by TLC on Silufol UV 254 plates with detection of substances in UV light or after spraying plates with a solution of ninhydrin developer and then heating at 100120C. Reaction products were isolated by column chromatography on silica gel. Solvents were purified by distillation. Toluene and dioxane were boiled and distilled over sodium.
13
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3-(1,3-Dioxo-1,3-dihydro-2H-pyrrolo[3,4-b]quinolin-2-yl)propionic Acid (4). Mixture of anhydride 3 [8] (1 g, 5 mmol) and -alanine (0.44 g, 5 mmol) in dry dioxane (20 ml) was boiled with stirring in the presence of molecular sieves 4A, checking the progress of the reaction by TLC. At the end of the reaction the solution was filtered hot and cooled to room temperature. The precipitated crystals were filtered off. Yield 0.81 g (65%); mp 208-210C, Rf 0.5 (EtOHH2O, 7:3). IR spectrum (nujol), , cm-1: 1685 CON), 1740 (CO), 3300 (OH). 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 2.7 (2H, t, J = 7.4, CH2N); 3.9 (2H, t, J = 7.3, CH2CO); 7.6-8.9 (5H, m, C9H5N). 13C NMR spectrum, , ppm: 31.11, 34.82, 123.0, 127.29, 128.36, 129.0, 130.34, 132.49, 132.71, 149.53, 150.80, 165.57, 165.9, 172.02. Found, %: C 61.95; H 3.45; N 10.25. C14H10N2O4. Calculated, %: C 62.22; H 3.73; N 10.37. 2-(4-Diazo-3-oxobutyl)pyrrolo[3,4-b]quinoline-1,3(2H)-dione (5). Methyl chloroformate (0.085 ml, 1.1 mmol) was added dropwise with stirring to suspension of acid 4 (0.27 g, 1 mmol) in CH2Cl2 (60 ml), and the mixture stirred for 2 h. Then NEt3 (0.14 ml, 1.1 mmol) was added in two portions with an interval of 1 h. After adding the second portion the resulting mixture was stirred for 1 h further. An ether solution of diazomethane, obtained from nitrosomethylurea (0.2 g, 2 mmol), was then added dropwise to the stirred solution at 0C, and the mixture kept at this temperature for a further 12 h. The solvent was evaporated. The residue was chromatographed through a thin layer of SiO2 (chloroformacetone, 15:1). Yield 0.29 g (99%); mp 148C (decomp.), Rf 0.47 (chloroformacetone, 15:1). IR spectrum (nujol), , cm-1: 1700 (CON), 1750 (CO), 2130 (C=N2). 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 2.8 (2H, t, J = 7.7, CH2N); 3.4 (1H, s, CH=N2); 3.9 (2H, t, J = 7.4, CH2CO); 7.5-8.9 (5H, m, C9H5N). 13C NMR spectrum, , ppm: 32.24, 34.08, 62.79. 123.04, 128.46, 129.42, 129.77, 130.42, 132.64, 132.88, 149.67, 150.74, 165.68, 165.79, 182.11. Found, %: C 60.85; H 3.35; N 18.25. C15H10N4O3. Calculated, %: C 61.22; H 3.43; N 19.04. 2-(4-Bromo-3-oxobutyl)pyrrolo[3,4-b]quinoline-1,3(2H)-dione Hydrobromide (7). 48% HBr solution (0.51 ml) was added dropwise to stirred solution of diazo ketone 5 (0.45 g, 1.53 mmol) in CH2Cl2 (100 ml). The solution was stirred for 1 h, dried over MgSO4, and the solvent evaporated. Yield 0.46 g (71%); mp 181-182C. IR spectrum (nujol), , cm-1: 1710 (CON), 1730 (CO). 1H NMR spectrum (DMSO-d6), , ppm: 2.6 (2H, m, CH2N); 3.9 (2H, m, CH2CO); 4.1 (2H, s, CH2Br); 7.7-9.0 (5H, m, C9H5N). 13C NMR spectrum, , ppm: 32.11, 33.74, 60.13, 122.87, 128.3, 129.25, 130.3, 132.46, 132.52, 132.95, 149.53, 150.57, 165.5, 165.71, 197.9. Found, %: C 41.83; H 2.45; Br 36.85; N 6.18. C15H12Br2N2O3. Calculated, %: C 42.09; H 2.83; Br 37.33; N 6.54. {4-(1,3-Dioxo-1,3-dihydro-2H-pyrrolo[3,4-b]quinolin-2-yl)-2-oxobutyl}dimethylsulfonium Bromide Hydrobromide (6). Dimethyl sulfide (0.186 g, 3 mmol) was added with stirring to solution of bromo ketone 7 (0.42 g, 0.9 mmol) in CH2Cl2 (40 ml). The solution was kept for 12 h. The precipitated crystals were filtered off. Yield 0.29 g (66%); mp 146-148C. IR spectrum (nujol), , cm-1: 1700, 1720 (CON), 1790 (CO). 1H NMR spectrum (CF3COOH), , ppm: 2.8 [6H, s, S(CH3)2]; 3.2 (2H, s, CH2N); 4.1 (2H, s, CH2CO); 4.6 (2H, s, CH2S); 7.9-9.4 (5H, m, C9H5N). 13C NMR spectrum, , ppm: 25.28, 34.02, 39.21, 54.61, 122.85, 123.88, 131.85, 132.29, 133.27, 139.64, 140.03, 144.47, 144.81, 160.79, 163.81, 198.75. Dimethylsulfonio{4-(1,3-dioxo-1,3-dihydro-2H-pyrrolo[3,4-b]quinolin-2-yl)-2-oxobutyl}ylide (2). Mixture of 12.5 N NaOH (0.125 ml) and saturated K2CO3 solution (0.71 ml) was added in one portion to stirred suspension of sulfonium salt 6 (0.243 g, 0.5 mmol) in CHCl3 (10 ml) at 10C. The reaction mixture was then stirred at this temperature for a further 20 min. The organic layer was separated, dried over K2CO3, and the solvent evaporated. Yield 0.15 g (91%). IR spectrum (nujol), , cm-1: 1710, 1720 (CON), 1555 (CO). 1H NMR spectrum (CDCl3), , ppm (J, Hz): 2.5 (2H, t, J = 6.93, CH2N); 2.8 [6H, s, S(CH3)2]; 3.6-3.8 (1H, br s, CH); 4.1 (2H, t, J = 6.87, CH2CO); 7.7-8.6 (5H, m, C9H5N). 13C NMR spectrum, , ppm: 28.28, 36.79, 39.07, 51.91, 123.11, 128.78, 129.4, 129.94, 131.38, 132.44, 132.61, 150.7, 150.76, 165.86, 166.17, 186.86. Found, %: C 61.91; H 4.55; N 8.78; S 9.85. C17H16N2O3S. Calculated, %: C 62.18; H 4.91; N 8.53; S 9.76.
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6-(Methylthio)-8,9-dihydroindolizino[1,2-b]quinoline-7,11-dione (1). Ylide 2 (0.1 g, 0.304 mmol) was dissolved in hot toluene (30 ml). Benzoic acid (0.037 g, 0.304 mmol) was then added to the hot solution and the mixture was boiled under reflux for 1 h. The progress of the reaction was checked by TLC (chloroform acetone, 9:1). At the end of the reaction the solvent was evaporated. The product was isolated by column chromatography (chloroformacetone, 9:1). Yield 0.08 g (90%); mp 175-177C. IR spectrum (nujol), , cm-1: 1710 (CON), 1725 (CO). 1H NMR spectrum (CDCl3), , ppm (J, Hz): 2.6 (3H, s, SCH3); 2.9 (2H, t, J = 7.35, CH2N); 4.3 (2H, t, J = 8.07, CH2CO); 7.7-8.7 (5H, m, C9H5N). 13C NMR spectrum, , ppm: 18.42, 35.95, 36.9, 116.02, 121.5, 127.12, 128.72, 129.55, 131.0, 132.08, 132.66, 146.18, 150.4, 152.45, 162.92, 190.78. Found, %: C 64.61; H 3.85; N 9.18; S 10.55. C16H12N2O2S. Calculated, %: C 64.85; H 4.08; N 9.45; S 10.82. Preparation of Compound 1 from Diazo Ketone 5 without Isolating Ylide 2. Solution of diazo ketone 5 (0.05 g, 0.165 mmol) in CH2Cl2 (6 ml) was added dropwise to solution of Rh2(OAc)4 (0.07 g, 0.016 mmol) and Me2S (0.5 g, 15.6 mmol) in toluene (20 ml) with stirring at 40C. The mixture was stirred at 40C for 1 h. The progress of the reaction was checked by TLC (chloroformacetone, 9:1) for the disappearance of the diazo ketone spot. After this, benzoic acid (0.02 g, 0.165 mmol) was added, and the mixture was boiled under reflux for 1 h. The solvent was evaporated. The residue was chromatographed through a thin layer of SiO2 (chloroformacetone, 9:1). Yield 0.029 g, (60%). The work was carried out with the financial support of FTsP Integratsiya (Integration), Goskontrakt (State Contract) No. 53 (1.5/2000).
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. M. Potsmeil and H. Pinedo (editors), Camptothecins: New Anticancer Agents, CRC Press, Boca Raton (1995). D. P. Curran, J. Sisko, P. E. Yeske, and H. Liu, Pure Appl. Chem., 65, 1153 (1993). C. R. Hutchinson, Tetrahedron, 37, 1047 (1981). G. A. Tolstikov, F. Z. Galin, and S. N. Lakeev, Izv. Akad. Nauk SSSR, Ser. Khim., 1209 (1989). F. Z. Galin, S. N. Lakeev, and G. A. Tolstikov, Khim. Geterotsikl. Soedin., 1693 (1989). F. Z. Galin, S. N. Lakeev, and G. A. Tolstikov, Izv. Akad. Nauk, Ser. Khim., 165 (1996). G. A. Tolstikov, F. Z. Galin, S. N. Lakeev, L. M. Khalilov, and V. S. Sultanova, Izv. Akad. Nauk SSSR, Ser. Khim., 612 (1990). J. Moriconi and F. A Spano, J. Am. Chem. Soc., 86, 38 (1964). F. Z. Galin, S. N. Lakeev, L. F. Chertanova, and G. A. Tolstikov, Izv. Akad. Nauk, Ser. Khim., 2376 (1998).
1567
QUANTUM-CHEMICAL STUDY OF THE STRUCTURE AND THERMOCHEMICAL PROPERTIES OF NITROPIPERAZINES AND NITROSOPIPERAZINES
V. L. Korolev1, T. V. Petukhova2, T. S. Pivina1, A. B. Sheremetev1, E. A. Miroshnichenko3, and V. P. Ivshin2 We have used MNDO and PM3 approximations and the density functional method (6-31G*) for a quantum chemical study of the structure and some physicochemical properties of N-nitro and N-nitroso derivatives of piperazine, furazano[3,4-b]piperazine, and bisfurazano[3,4-b;3',4'-e]piperazine. We have analyzed the structural, electronic, and thermochemical characteristics and the enthalpies of formation for the compounds in the gas phase and in the solid phase. We have found a correlation between the strength of the NN bond and the NN bond length, the pyramidality of the nitrogen atom of the piperazine ring, and the size of the energy gap between the frontier orbitals. Based on calculations by the density functional method, we have carried out a comparative analysis of the thermochemical stability of the compounds in homolytic reactions. Keywords: bisfurazano[3,4-b;3',4'-e]piperazines, N-nitropiperazines and N-nitrosopiperazines, furazano[3,4-b]piperazines, quantum-chemical calculations, thermochemical characteristics. Nitramines (N-nitro compounds) occupy a central position among components of high energy compositions [1-5]. In the field of design of high energy substances as a whole and nitramines in particular, considerable attention has been paid to developing methods for theoretical analysis of their structure and prediction of the properties of these compounds before the synthesis stage [2, 4, 6, 7]. The piperazine ring is rather widely used as the base structure in designing high energy substances. Thus N-nitropiperazines and N-nitrosopiperazines and their polynitrogen annelated derivatives have been suggested as components of explosive compositions, propellants, and rocket fuels [8-12]. The compounds in this group in future may be considered as components of gas-generating compositions. The "parent" compound of this series, N,N'-dinitropiperazine, is a quite thermally stable compound with decomposition temperature 190-200C [5]. The stability of its analogs containing substituents or annelated heterocycles on the carbon atoms is different, and is determined by the nature of their structural differences. Some known nitropiperazines and their decomposition temperatures are given below:
__________________________________________________________________________________________ N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow 119991; e-mail: tsp@ioc.ac.ru. 2 Mari-El State University, Yoshkar-Ola 424000, Russia. 3 N. N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow 117977. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1817-1839, December, 2004. Original article submitted July 29, 2004. 1568 0009-3122/04/4012-15682004 Springer Science+Business Media, Inc.
1
NO2 N O N NO2
H N N H
NO2 N N NO2
H N O N H
NO2 NO2 N N N O N
H N N O2N
NO2 N N NO2
NO2 N O N H
NO2 NO2
190-200 [5]
302C [10]
236C [13]
238C [10]
O2N
NO2
NO2
O2N
NO2
NO2
NO2
N O N H
N N
NO2
220C [10]
N O N
H
N O N O2N
N N
NO2
N O N
NO2
O
N N
N N
NO2
210C [10]
134C [12]
NO2 N O N N NO2 N
NO2 N O N H O N N
NO2 NO2 N N N O N N N
NO2 NO2 N N N N N O N NO2 NO2

99C [9]
NO2 NO2
148C [9]
206C [8]
Thermal decomposition of most secondary N-nitramines begins with homolytic breaking of the NNO2 bond [14, 15]. It is hypothesized that decomposition also begins with homolytic breaking of the NN bond in N-nitroso compounds [16]. In this case, if the nitrogen atom bonded to the nitro group is involved in conjugation processes or nonvalence orbital interactions with the functional group on the adjacent carbon atom, the strength of the NN bond is observed to decrease, which facilitates either breaking of the bond according to a radical mechanism or a 1,3-sigmatropic shift of the nitro group. As a result, the thermal stability of such compounds decreases [17]. Piperazine derivatives are no exception in this sense, and so analysis of the relations between structural variations and properties of derivatives of nitrosopiperazine and nitropiperazine is certainly of interest. In extending our studies of high energy derivatives of furazan [18-20], for which high thermal stability is typical [15, 21], it seemed of interest to estimate the characteristics of nitro and nitroso derivatives and some other polycyclic compounds that include both furazan and piperazine rings. Various aspects of the chemistry of furazanopiperazines have been discussed in a recent review [22]. The aim of this work was to study the geometric and electronic structure and enthalpies of formation for nitro and nitroso derivatives of piperazine 1, furazano[3,4-b]piperazine 2, bisfurazano[3,4-b;3',4'-e]piperazine 3, 5,6-dioxofurazano[3,4-b]piperazine 4, and 5,6-dihydroximinofurazano[3,4-b]piperazine 5. Estimation of the relative strength of the NN bonds and also the enthalpies of reaction for homolytic decomposition of compounds in these series was an integral part of the investigation:
R1 N O N R2 N N R2 N R1 N O N N R2 N N R1 N N O O N N R
2
R1 N N O O O N N
R1 N N R2 NOH NOH
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For the calculations, we used the MOPAC [23] and WINMOPAC [24] software packages. The geometric parameters, like the charge distributions, were estimated using the MNDO method [23] as the most applicable in calculations of these characteristics for N,O-containing molecules. The dipole moments, ionization potentials, and energies of frontier molecular orbitals were calculated by the MNDO and PM3 methods [23]; the enthalpies of formation for the compounds in the gas phase were estimated based on the PM3 method, and in the solid phase they were estimated using additive schemes [25-27]. In cases when the existence of several conformers is possible for the molecule, we estimated the characteristics of only the most thermodynamically stable characteristics.
CALCULATION OF GEOMETRIC PARAMETERS OF THE MOLECULES According to the results of our study estimating the geometric characteristics of the compounds (Tables 1 and 2), both for the nitro and the nitroso derivatives, as we go from the monofurazanoannelated and then to the difurazanoannelated compounds the NN bond length increases, which suggests the bond is weakened in this order. Thus in the nitroso compounds 1b,d,e, the bond length is 1.34 , increasing up to 1.36 in compounds 2b,d,e and up to 1.38 in the corresponding derivatives of series 3 and 4. Analogous changes were detected by X-ray diffraction; thus the NN bond length in N,N'-dinitropiperazine (1d) [28] is equal to 1.34 , while in N,N'-dinitrosofurazano[3,4-b]piperazine (2d) [29] the bond length increases up to 1.36 . In nitro derivatives 1, according to the calculations, the NNO2 bond is equal to 1.40 (1c), 1.42 (1e), and 1.41-1.42 (1f), increasing in the corresponding monofurazanoannelated and then the difurazanoannelated derivatives up to 1.44 (2c), 1.43 (2e), and 1.44 (2f). The calculations are supported by the results of the X-ray diffraction studies: thus , the NNO2 bond has a length of 1.37 * in N,N'-dinitropiperazine (1f), while in N,N'dinitrofurazano[3,4-b]piperazine (2f) the bond length is 1.38 [30]. The calculations presented in Table 1 allow us to conclude that for both nitro and nitroso derivatives, adding any functional group to the carbon atom of the piperazine ring that involves the nitrogen atom of this ring in conjugation processes or nonvalence orbital interactions is accompanied by lengthening of the NN bond and a decrease in the bond strength. Substitution of each CH2CH2 moiety of the piperazine ring by a furazan ring also leads to lengthening of the NN bond by 0.02 on the average for nitroso derivatives and by 0.04-0.06 for nitro derivatives. The data obtained and the trends found are consistent with the results of experimental investigations (1d [28], 1f*, 2d [29], 2f [30], 3a [31]). Comparison of the quantum-chemical calculations for the geometric parameters of the molecules in the gas phase with the X-ray diffraction results for the crystals indicates lengthening (by 1.3-3.6%) of the NN bonds in the gas phase compared with the solid phase. Let us also consider such a characteristic of the spatial structure of the compounds as the pyramidality () (i.e., the difference between 360 and the sum of the bond angles at the N atom) of the nitrogen atom of the piperazine ring. We know that in piperazine and its N-alkyl derivatives, the nitrogen atom has a pyramidal configuration [32]. In contrast, nitrosopiperazines (Table 1) are practically planar (0-0.9). For nitropiperazines, the pyramidality of the ring nitrogen atom is rather distinctive and depends on the structural variations of the base molecule. Thus the angle of deviation of the NNO2 bond of the nitro group from the CNC plane of the piperazine ring, which also characterizes the pyramidality of the nitrogen atom, covers the interval from 1.7 (4e) to 18.5 (5e).
_______ * Here and in the following, for compound 1f the data from R. Gillardi (private communication) are marked with an asterisk. 1570
TABLE 1. Calculated (MNDO method) Characteristics of the Spatial Structure and Indices of the Change in Strength [36, 37] of the NN Bond in Compounds 1-5*
Compound*2 1a 1b 1c 1d 1e 1f 2a 2b 2c 2d 2e 2f 3a 3b 3c 3d 3e 3f 4a 4b 4c 4d 4e 4f 5a 5b 5c 5d 5e 5f lNN, 1.34 1.40 1.34 1.34/1.42 1.42/1.41 1.36 1.44 1.36 1.37/1.43 1.44 1.38 1.46 1.38 1.38/1.46 1.46 1.38 1.44 1.38 1.38/1.44 1.44 1.37 1.44 1.37 1.38/1.44 1.45 iNN, % 7.2 0 18.3/18.2 17.5/ 6.3 9.7/7.9 4.9 0.1 4.2/4.3 3.4/11.5 -2.5/-0.1 -5.9 -18.1 -6.7/-6.8 -7.4/-15.1 -18.6/-18.1 -3.3 -5.7 -5.0/-4.1 -4.9/-6.9 -3.4/-2.9 -1.8 -11.5 -3.3/-3.2 -3.0/-16.2 -9.0/-9.6 , deg. 26.63/27.24 25.02/0.85 24.64/10.36 0.23/0.36 0.15/11.87 6.58/10.73 18.50/18.54 18.91/0.41 17.55/8.10 0.44/0.49 0.34/10.18 7.94/10.21 16.77/17.32 16.90/0.02 14.18/15.03 0/0.01 0.08/4.94 14.26/15.38 -0.01/0 0.01/0 0.06/1.80 0/0.02 0.04/1.70 2.77/4.33 0.11/0.17 0.45/0 15.73/15.73 0.63/0.86 0.01/18.50 15.02/15.03
_______ * lNN is the NN bond length; iNN is the index of the change in strength of the NN bond; is the pyramidality of the nitrogen atoms (i.e., the difference between 360C and the sum of the angles at the N atom of the piperazine ring). *2 1-5 a-c R1 = H, d,e R1 = NO, f R1= NO2; a R2 = H, b,d R2 = NO, c,e,f R2 = NO2.
Upon condensation of the furazan ring with a piperazine ring, the pyramidality of the nitrogen atoms bonded to the nitro group increases (compounds 4 are an exception) and this is accompanied by lengthening of the NNO2 bond. The strength of the NN bond consequently decreases, which is consistent with experimental data on the thermal stability of secondary nitramines [33-35]. Let us consider the conformations of the piperazine ring of the studied series of compounds, taking the dinitro derivatives as an example. The results of calculations of the geometry for molecules 1 suggest that the piperazine ring in those molecules has a chair conformation (Fig. 1). This is consistent with X-ray diffraction data for N,N'-dinitrosopiperazine (1d) [28] and N,N'-dinitropiperazine (1f).
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TABLE 2. Calculated Characteristics of the Electronic Structure and Enthalpies of Formation for Compounds 1-5 in the Gas and Solid Phases*
, D Compound 1 1a 1b 1c 1d 1e 1f 2a 2b 2c MNDO 3 2.02 2.40 3.97 0.02 1.73 1.59 5.01 4.98 5.65 PM3 4 2.04 2.56 3.24 0.00 1.52 1.54 5.19 5.01 5.18 Ionization potential, eV MNDO 5 9.908 10.048 10.585 10.417 10.876 11.408 9.819 10.099 10.570 PM3 6 9.224 9.629 9.854 9.956 10.210 10.912 9.502 9.898 10.087 MNDO 7 -9.908/2.873 (12.781) -10.048/0.512 (10.560) -10.585/-0.233 (10.352) -10.417/0.278 (10.695) -10.876/-0.535 (10.341) -11.408/-0.715 (10.693) -9.819/-0.259 (9.560) -10.099/-0.685 (9.414) -10.570/-1.223 (9.347) , eV PM3 8 -9.224/2.562 (11.786) -9.629/0.313 (9.942) -9.854/-0.012 (9.842) -9.956/0.042 (9.914) -10.210/-0.222 (9.988) -10.912/-0.378 (10.534) -9.502/-0.510 (8.992) -9.898/-0.868 (8.982) -10.087/-1.082 (9.005) Hf0, kcak/mol PM3 Additive scheme (MOPAC) (solid phase) (gas phase) 9 10 -11.7 22.0 5.8 26.6 -3.9 -33.5 55.0 82.1 52.3 -10.9 (-10.9)*2 5.0 -7.0 22.2 8.0 -13.2 (-12.7)*3 38.0 70.0 59.0
TABLE 2 (continued)
1 2d 2e 2f 3a 3b 3c 3d 3e 3f 4a 4b 4c 4d 3 3.92 7.15 4.24 1.79 1.41 2.99 0.07 1.97 0.39 0.07 1.43 2.92 0.35 4 3.59 6.50 4.00 0.99 1.53 1.52 0.06 0.29 0.39 0.41 1.33 1.16 0.09 5 10.371 10.423 11.286 10.184 10.335 10.794 9.919 10.933 11.396 10.402 10.707 10.976 11.016 6 10.307 10.030 10.799 9.801 10.063 10.128 9.718 10.391 10.490 10.130 10.423 10.428 10.815 7 -10.307/-0.949 (9.422) -10.423/-1.205 (9.218) -11.286/-1.675 (9.611) -10.184/-1.261 (8.923) -10.335/-1.370 (8.965) -10.794/-1.987 (8.807) -9.919/-1.042 (8.877) -10.933/-2.090 (8.843) -11.396/-2.366 (9.030) -10.402/-1.305 (9.097) -10.707/-1.458 (9.249) -10.976/-1.768 (9.208) -11.016/-1.563 (9.453) 8 -10.307/-1.225 (9.082) -10.030/-1.206 (8.824) -10.799/-1.479 (9.320) -9.801/-1.528 (8.273) -10.063/-1.640 (8.423) -10.128/-1.849 (8.279) -9.718/-1.350 (8.368) -10.391/-1.988 (8.403) -10.490/-1.997 (8.493) -10.130/-1.564 (8.566) -10.423/-1.640 (8.783) -10.428/-1.829 (8.599) -10.815/-1.628 (9.187) 9 110.7 79.3 84.0 130.5 162.1 130.3 194.3 168.0 141.3 -27.2 5.8 28.9 39.3 10 105.0 91.0 84.0 93.4 135.0 124.0 187.0 173.0 184.9 -51.3 -35.2 -21.1 -19.0
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1574
TABLE 2 (continued)
1 4e 4f 5a 5b 5c 5d 5e 5f 3 1.76 0.28 4.27 4.99 5.47 4.95 4.79 4.06 4 0.28 0.17 3.79 4.60 4.33 4.52 4.25 3.92 5 11.315 11.618 9.771 10.052 10.278 10.374 10.661 11.143 6 10.851 10.886 9.554 9.831 9.839 10.264 10.362 10.460 7 -11.315/-1.945 (9.370) -11.618/-2.374 (9.244) -9.771/-0.783 (8.988) -10.052/-0.861 (9.191) -10.278/-1.449 (8.829) -10.374/-1.028 (9.346) -10.661/-1.554 (9.107) -11.143/-1.801 (9.342) 8 -10.851/-1.956 (8.895) -10.886/-2.097 (8.807) -9.554/-1.118 (8.436) -9.831/-1.168 (8.665) -9.839/-1.422 (8.417) -10.274/-1.259 (9.015) -10.362/-1.572 (8.790) -10.460/-1.646 (8.814) 9 8.2 -21.6 70.5 100.2 70.6 131.4 101.3 76.5 10 -34.7 -50.4 82.2 98.3 82.6 114.5 98.8 83.1
_______ * is the dipole moment; is the HOMO/LUMO energies; Hf0 is the enthalpy of formation; the charges on the atoms (MINDO) are given on pp. 1572, 1573. *2 In parentheses we give the experimental value of Hf0 in the solid phase [26, 40]. *3 The value of Hf0 in the solid phase [41].
Charges on the Atoms in Compounds 1-5
H
0.320 O
H N 0.330 H N 0.323
0.250 N O
N O N
H N 0.148 N O N H N 0.148
O N N N
N O N
0.242
H N O
N H
N 0.250
O N 0.320 H
N N 0.225 H
O H
1a
2a
O N
3a
O N N O N N H N 0.149 O N N H N
4a
5a
NO N 0.405 0.321 H N
0.329 N O O
NO 0.244 N N
O N
0.337 O
H 0.290 N O
N O N
N 0.247
O 0.317
N H
1b
0.236
O H
2b
NO2 N 0.323 H N N 0.252 NO2 0.347 N N 0.222 N O
O N N H N
3b
NO2 N 0.109 N O N 0.159 O N N
4b
NO2 0.349 N O
5b
NO2 0.198 N N H O
N O
O N 0.314 H
1c
N N 0.240 H
O H
2c
3c
4c
5c
1575
1576
O N
NO N 0.409 0.409 ON N
N O
N
0.245 N O
O 0.342 O
O N N
O N 0.290 N N H O
0.331 N O
O N N N O N N
N O N O
N 0.331
0.245
1d
O
O N 0.346 N
N O N
0.291
O H
2d
O N
N 0.416 ON N NO2 0.340
3d
NO2 0.115 N N O N N N 0.247 NO
4d
O N O N N O 0.331 NO2
O N
5d
N N 0.343 O
O N N
H 0.290 N O
0.334 N O
O
1e
0.243 NO2
N N 0.207 NO2
O H
2e
NO2
3e
NO2 0.132 N N O N N N 0.129 NO2
4e
NO2 0.329 N O
5e
NO2 0.201 N N H O
NO2 N 0.357 0.353 O2N N
0.255 N O
O N
N O N
N O
N 0.237
O 0.328
1f
NO2
NO2
N N 0.205 NO2
O H
2f
3f
4f
5f
Fig. 1. Spatial structure of the N,N'-dinitropiperazine molecule 1f. For compounds 2d,f, we observe flattening of the piperazine ring and its transition to a half-chair conformation 2d and 2f (Fig. 2). The X-ray diffraction results for compounds 2d [29] and 2f [30] also indicate that in the crystalline state, the piperazine ring has a half-chair form in these compounds. When a second furazan ring is introduced into compounds of series 3, the piperazine ring has a boat conformation (3a,c,f) or a half-chair conformation (3b,e) (Fig. 3). We note that for the compounds in this series, X-ray diffraction data are known only for bisfurazano[3,4-b;3',4'-e]piperazine (3a) [31]; in the crystalline state, the entire tricyclic system is planar. Our calculations of the geometry of the 3d molecule indicate that in this compound, the tricyclic system is planar (Fig. 3b).
Fig. 2. Spatial structure of the molecules: a) N,N'-dinitrosofurazano[3,4-b]piperazine 2d; b) N,N'-dinitrofurazano[3,4-b]piperazine 2f. 1577
Fig. 3. Spatial structure of the molecules: a) N,N'-dinitrobisfurazano[3,4-b;3',4'-e]piperazine 3f; b) N,N'-dinitrosobisfurazano[3,4-b;3',4'-e]piperazine 3d.
In the compounds of series 4a,b, the furazan and piperazine rings and also both carbonyl oxygen atoms are located in one plane. The presence of nitro and nitroso groups in the molecules 4c-f (Fig. 4) leads to a slight distortion of the twist conformation of the piperazine moiety. In this case, the dihedral angles O=CC=O successively increase in the following order: 4c (4.8) < 4d (5.1) < 4e (15.2) < 4f (23.6). Substitution of the carbonyl oxygen atoms (series 4) by hydroximine groups (series 5) leads to significant distortion of the molecular geometry. Thus in series 5, only structure 5a, which does not contain substituents on both nitrogen atoms of the piperazine ring, proved to be planar. All the nitro and nitroso derivatives of this series have a twist conformation for the piperazine ring. The hydroximine groups are skewed relative to each other by 9.5 (5b), 41.5 (5c), 57.4 (5d), 33.0 (5e), 60.1 (5f, Fig. 5). The ONN bond angle of the nitroso group in the studied nitroso derivatives is within the range 117.9-119.0. The ONO bond angle in the nitro derivatives 1c,e,f varies from 119.4 to 122.2; in 2c,e,f, it varies from 127.7 to 121.8; in 3c,e,f, from 125.1 to 127.5; in 4c,e,f, from 123.7 to 125.0; and in 5c,e,f,
Fig. 4. Spatial structure of the N,N'-dinitro-5,6-dioxofurazano[3,4-b]piperazine molecule 4f.
1578
Fig. 5. Spatial structure of the N,N'-dinitro-5,6-dihydroximinofurazano[3,4-b]piperazine molecule 5f. from 123.3 to 124.1. These data may be used in quantum-chemical calculations of the spatial structure and estimation of some physicochemical properties of similar compounds without carrying out the procedure for full optimization of the geometric parameters, which considerably shortens the calculation time. We note that varying the substituents (H, NO, NO2) on the nitrogen atoms of the piperazine ring does not affect the bond lengths and bond angles of the heterocyclic skeletons of the molecules (Fig. 6). Comparing the results of optimization of the geometric structure of the studied compounds, we can conclude that the chair conformation is most favorable for the piperazine moiety. Upon annelation with a furazan ring, the piperazine ring is flattened. In Fig. 6, we show the average calculated values of the intramolecular parameters of the base skeletons of molecules in series 1-5.
ELECTRONIC STRUCTURE OF THE COMPOUNDS We carried out quantum-chemical calculations of the electronic structure parameters of the compounds: the charges on the ring nitrogen atoms, the dipole moments of the molecules, the ionization potentials, the energies of the frontier molecular orbitals (HOMO and LUMO) and the energy gap between them (), and also the enthalpies of formation for the compounds in the gas phase and in the solid phase (Table 2). From the results obtained it follows that introducing nitroso groups into the molecules of the investigated compounds increases the electron density on the N atom of the piperazine ring. In compounds of the series under consideration, the "increment" in electron density on the ring N atom compared with the electron density of the corresponding atom in piperazine (1a) on the average is 0.080 in 1; 0.082 for series 2; 0.097 for 3; 0.023 for 4; and 0.048 in the compounds of series 5. Introducing nitro groups leads to an increase in the negative charge on the nitrogen atom bonded to it by 0.026 in compounds 1 and by 0.013 in 4. For compounds in the remaining series, however, we observe a decrease in the charge on this atom: by 0.013 in series 2, by 0.027 in 3, and by 0.035 in compounds 5. Annelation of mononitroso and dinitroso derivatives of piperazine 2c,e,f with the acceptor furazan ring leads to delocalization of the negative charge on the nitrogen atom of the piperazine ring and a decrease in the charge by 0.077 on the average. For mononitro derivatives, this decrease is 0.125, while in dinitro derivatives it is 0.110. Going to bisfurazanopiperazines 3 decreases the negative charge on the nitrogen atom of the piperazine ring in the nitroso compounds by another 0.086 compared with the corresponding compounds in series 2, and by 0.114 in the nitro derivatives.
1579
1.56+0
1.55+0
1.47+0.01
.62 113 1. 4 9+ 0. 0 1
113.32
114.40
N
1
.01 +0 .48
N
2
1 1.35+ 0.0 0 0+ 1.4
1 1 . 42+ +0.0 0.0 1 .3 5 1
110.92
N
3
0. 0
1.35
106.97
1.46+0.01
1.46+0
114.89
107.13
117.46
N
4
Fig. 6. Average values of the bond lengths and bond angles for the molecules in compounds 1-5.
124.62
1. + 0 39+0 1.35 .0
1. 22 + 0. .01 01 +0 .44 1
1. 31+ 0 .01 .01 +0 4 1.4

o
N1.29+0.01 OH
11 9. 7
.78 127
119
. 88
.46 121
106.99
10 5.9 0
.82
114.04
3 1.3 .01 +0
01 +0. +0.0 1 1.40 o 122 .54 o .95 105
N
116.65
o
1. 4
1 .01 .22+0.0 1 o 1 21 .32 o .75 119

1.54+0
o
4+ 0
1.35 01 +0.0 +0. 1 1.40 123 o .21 o 2 6.1 o 10 114.22 o 10 5.6 o 93 22. 9 1 1 0 . 40+ .35+ 1 0.0 1
106.98
o
N 1.45+0.0
o
123.36
01 1 1.31+0.
o
1.29+0.01
OH
o
1. 3 1+
1+
.42 119
117
1.3
. 06
o
o
118
.41 116
1.3
1+ 0.0 1
. 58
107.16
.27
10 5.8 3
.18 124
107.24
107.31 1.3 1+ 0.0 1
113
.00 114 1. 4 9+ 0.0 1
123
.70 105
113.85
1.3
.88 110
.67 122
. 01
2+ 0
12 3.9 1
1580
.01 8+0 1.4 110 .64 o
N
o
1. 4
7+ 0
. 01
1.55+0
.01 9+0 1.4 113 . 38 o
N .39+0.01
114.45
o
1.47+0.01
+0 1 .3 5 105 .86 o
114.13
.01 +0
1.35 1 +0.0 0.0 1 .41+ 1 o 124 .28 o .58 105

o
o
N 1.41+0
110.94
o
0.01 1.35+ o 1 05 .57 o .25 124

.01
1.47+0.01
1.3 0 1+
1 0. 0 2+ 1.3 o 107.32
115.74
107.29
114.21 o 6 o 5.7 10 1 . 35 + .01 0.0 +0 1 .42
107.23
o
1 1.3
113.20
11 7 9.7
1.50+0.01
0 1+ 1.3
Introducing carbonyl groups into the piperazine ring of piperazinofurazans 2 increases the electron density on the nitrogen atom of the piperazine ring for both the mononitroso and dinitroso derivatives by 0.010, while for the mononitro and dinitro derivatives (series 4), the increment is 0.096. The electron density on the piperazine nitrogen atom in dihydroximines 5 is lower than in compounds of group 2: 0.034 lower for nitro derivatives, and 0.041 lower for nitroso derivatives. Let us consider the calculated values of as an integral characteristic of the polarity of the molecules. Introducing one NO or NO2 group increases the dipole moment of the molecules (Table 2); an exception is compounds 2b and 3b (MNDO calculations). Introducing two identical substituents (either nitro or nitroso groups) lowers the of the molecules (except for compounds 4d,f and 5d). According to the results obtained, diketones 4 are less polar than piperazines 1; dioximes 5 are less polar than monoannelated compounds 2 but more polar than diannelated compounds 3. The results of calculations of the ionization potentials, the frontier molecular orbitals (HOMO and LUMO) and the energy gap () between the MOs (Table 2) suggest that condensation of the piperazine ring with a furazan ring does not affect the ionization potential but decreases between the frontier orbitals in the nitroso derivatives by 1.210 according to MNDO calculations and by 0.896 eV according to PM3 calculations. In the nitro derivatives, is equal respectively to 1.044 eV and 1.026 eV. Introducing a second furazan ring additionally enhances this effect on the average by 0.542 eV (MNDO) and 0.706 eV (PM3). For dioxo derivatives 4, between the HOMO and LUMO is less than in furazano[3,4-b]piperazines 2 on the average by 1.287 eV (MNDO) and 1.214 eV (PM3), while for dihydroximines it is 1.398 eV lower (MNDO) and 1.330 eV lower (PM3). These data may be used for analysis of the reactivity of the studied compounds in charge-controlled and orbital-controlled reactions.
THERMOCHEMICAL CHARACTERISTICS OF PIPERAZINE DERIVATIVES AND THEIR RELATION TO THE STRUCTURE OF THE COMPOUNDS Chemical bond strength. To estimate the thermochemical characteristics of the piperazine derivatives, we calculated the enthalpies of formation and also the strength indices [36, 37] of the NN bond, reflecting changes in the relative thermodynamic stability of the compounds upon structural changes in the molecules. Thermal decomposition of most N-nitramines [13-15] and N-nitrosamines [15, 16] begins with homolytic breaking of the NN bond, so we specifically considered this bond. The indices for the change in strength of the NN bond in nitro and nitroso derivatives 1-5 were calculated using the formula:
iNN =
ENN ENN (reference) ENN (reference)
100%,
where ENN is the two-center component of the total chemical bond energy [23]. As the "reference" (0%) we selected the strength of the NN bond in N-nitropiperazine (1c). The calculation results (Table 1) suggest that N-nitroso derivatives are more stable than the corresponding N-nitro derivatives. In compounds 1-5, the strongest bond is the NN bond in monocyclic piperazines (series 1). Upon annelation with a furazan ring, the NNO2 and NNO bonds become weaker (series 2), an effect which is even more appreciable when a second furazan ring is introduced (series 3). Such a change in the NN bond strength when acceptor furazan moieties are introduced into the system can be explained by delocalization of electrons from the unshared electron pairs of the nitrogen atoms of the piperazine ring.
1581
Analysis of the calculations of the NN bond strength indices in compounds of groups 4 and 5 indicates that the strength of the bond between the NO group and the ring N atom is higher than the strength of the analogous bond with the NO2 group. Mononitroso and dinitroso derivatives of series 4 are less stable than compounds in series 5. This dependence is inverted for mononitro and dinitro derivatives. Enthalpies of formation (Hf0). As indicated above, the enthalpies of formation for the compounds in the gas phase were estimated by the semiempirical PM3 method, and in the solid phase it was estimated using additive schemes [25-27]. Comparing the results of the Hf0 calculations (Table 2), we may note that on going from the compounds in series 1 to the compounds in series 2, i.e., upon condensation with a furazan ring, both for the mononitroso and mononitro derivatives of piperazine we observe an increase in Hf0 by about 46-60 kcal/mol (in the gas phase) and 65-66 kcal/mol (in the solid phase). Introducing a second furazan moiety into the molecule additionally increases Hf0 by 78-80 kcal/mol (for the gas) and 65 kcal/mol (for the solid phase). For the dinitroso derivatives of piperazine, the increase in enthalpy of formation for each annelation with a furazan ring is 82-84 kcal/mol for both the gas and the solid. For the dinitro derivatives of piperazine, the analogous increment is even higher: up to 100 kcal/mol in the solid phase, and in the gas phase Hf0 increases by 117 kcal/mol when the first furazan ring is introduced, while upon condensation with the second furazan moiety the increment in the enthalpy of formation is 57 kcal/mol. Introducing carbonyl substituents into the compounds of series 2 lowers their enthalpies of formation both in the gaseous state and in the solid state over a broad range: from 23 to 106 kcal/mol (gas) and from 80 to 134 kcal/mol (solid phase). Modification of furazano[3,4-b]piperazines 2 to form the dihydroximines of series 5 increases the enthalpy of formation for the mononitroso and mononitro derivatives by 18 kcal/mol (gas) and 24-28 kcal/mol (solid phase). In the dinitroso derivatives, the increase in Hf0 for the solid phase is ~10 kcal/mol, while for the gas phase the increase is 20 kcal/mol. The enthalpy of formation of the dinitro derivatives in the solid phase is virtually unchanged, while in the gas phase it is decreased by 7 kcal/mol. Thus the enthalpy of formation for N-nitro derivatives in series 1-5 is lower than for the corresponding N-nitroso derivatives. Introducing a second NO group into the molecule of the mononitro derivative increases the enthalpies of formation for compounds 1-5. These results on the whole are consistent with some of the available experimental data [15, 20]. Enthalpies of reaction for homolytic decomposition (Hr). For a comparative estimate of the thermodynamic stability of the compounds, we considered the enthalpies of reaction for their homolytic decomposition, calculated by the density functional DFT B3LYP method in a 6-31 G* basis: Hr = H0products H0starting materials For neutral molecules, the calculations were performed based on the restricted HartreeFock method (RHF), and for radicals we used the unrestricted HartreeFock method (UHF) [38]. As the most probable decomposition route, we selected homolytic breaking of the NN bond to form two radicals [15]. The decomposition reactions and their corresponding Hr values for piperazine derivatives 1 are shown in Scheme 1. For compound 1f, the experimental value [39] for the enthalpy of reaction for breaking of the NN bond is 38.2 kcal/mol, which is close to our calculated value (Hr = 40.69 kcal/mol). Nitro derivatives of piperazine are less stable (reactions (3), (4), Scheme 1) than their nitroso analogs (reactions (1), (2)). The difference between the enthalpies of reaction for homolysis is ~2 kcal/mol. N-Nitropiperazine (1c) and compound 1f are not very different in stability, which is also the case for nitroso derivatives 1b and 1d. For N-nitroso-N'-nitropiperazine (1e), in principle two decomposition variants are possible (reactions (5) and (6), Scheme 1). The data represented in Scheme 1 show that detachment of the NO2 group is most likely.
1582
Scheme 1*
H N N NO NO N N NO H N N NO2 40.91 H N N . N NO 41.37 N N . + NO2 42.92 NO N N . 42.64 H N N . NO2 NO2 40.69 N N . NO2 N + NO2 (4) N NO2 N (1)
.
+ NO
.
+ NO (2) NO2 N 42.33 . N
.
+ NO (5)
.
+ NO2 (3)
NO
(6)
The decomposition routes for derivatives of furazanopiperazine 2 are presented in Scheme 2. The difference between the enthalpies of reaction for decomposition of nitroso and nitro derivatives of furazano[3,4-b]piperazine is ~4 kcal/mol. As for the piperazine derivatives, the nitro derivatives in this series are less stable than the nitroso derivatives. For N-nitroso-N'-nitrofurazano[3,4-b]piperazine (2e), the most favorable decomposition involves detachment of a nitro group (reactions (11) and (12), Scheme 2). We note that introducing a furazan moiety into the piperazine derivatives lowers the stability of the nitroso derivatives by a factor of 1.5, and lowers the stability of the nitro derivatives by a factor of 1.7. Scheme 2
H N O N N NO NO N O N N NO H N O N N NO2 N 24.54 O N N N H N N 28.82 N O N N
O N N NO 24.71 N O N N NO
H 28.17 O N N N N
NO2
NO2 23.76 O N N N N
+ NO (7)
N O N
N N NO2
+ NO2 (10)
NO N
NO2
. NO
N N
(8)
N
NO2 N
O 27.63 N
+ NO (11)
. NO
(9)
+ NO2 (12)
_______ * Here and in the following, the values given on the schemes above the arrows are measured in kcal/mol. 1583
The likely initial reactions for decomposition of the compounds in group 3 (derivatives of bisfurazano[3,4-b;3',4'-e]piperazine) and the enthalpies characterizing them are presented in Scheme 3. Scheme 3
NO N O N N H NO N O N N NO NO2 N O N N H NO2 N O N N NO2 N NO N O N N NO2 O N N . N N 8.43 N N 12.68 N O O N N NO2 NO N N O N N N N O 9.02 N O N N NO2 N N N N N O 6.73 O N N H N N N N N N O 14.04 N O N N NO N N N N O 11.91 N O N N H N
.
N N O
.
+
NO
(13)
.N
N O
.
NO
(14)
N O
NO2 (15)
N O
NO2 (16)
N O
.
NO
(17)
NO2 (18)
For compounds 3, we observe an appreciable difference in thermodynamic stability between the nitro and nitroso derivatives, and the latter compounds are more stable. The difference between the enthalpies in the reactions of decomposition of these compounds is ~5 kcal/mol. Thus N-nitrosobisfurazano[3,4-b;3',4'-e]piperazine (3b) is more stable (Hr = 11.91 kcal/mol) than the corresponding mononitro derivative 3c (Hr = 6.73 kcal/mol). N,N'-Dinitrosobisfurazano[3,4-b;3',4'-e]piperazine (3d) (Hr = 14.04 kcal/mol) is more 1584
stable than the dinitro derivative (3f) with Hr = 9.02 kcal/mol. For N-nitro-N'-nitrosobisfurazano[3,4-b;3',4'-e]piperazine (3e), initial breaking of the NNO2 bond is most likely (reaction (18), Scheme 3). Introducing a second furazan moiety reduces the stability of N-nitroso, N,N'-dinitroso, and N,N'-dinitro derivatives by a factor of 2-2.5. The enthalpy of reaction for homolytic decomposition of N-nitrobisfurazano[3,4-b;3',4'-e]piperazine 3b (reaction (15), Scheme 3) is a factor of 3.6 lower than the enthalpy of reaction for the corresponding derivative of N-nitrofurazano[3,4-b]piperazine 2c (reaction (9), Scheme 2). The results of estimation of the enthalpies Hr for compounds 4 (Scheme 4) show that N-nitroso-5,6dioxofurazano[3,4-b]piperazine (4b) is more stable (Hr = 23.82 kcal/mol) than the corresponding N-nitro derivative (4c) with Hr = 20.35 kcal/mol. Scheme 4
H N O N N NO H N O N N NO2 O N O 20.35 O N N N H N O NO2 O N O 23.82 O N N N H N O
.
+
NO
(19)
(20)
As in the case of the compounds in series 1-3, the nitroso derivatives of series 4 are more stable than the nitro derivatives. We note that introducing two carbonyl oxygen atoms into the structure of the nitro and nitroso derivatives of furazanopiperazine 2 decreases the stability of the corresponding molecules 4 in decomposition reactions, but not so much as introducing a second furazan ring (compounds in series 3). Comparison of the results of calculations of the enthalpies of reaction for homolytic decomposition for compounds in series 5 and 3 allows us to conclude that introducing two NOH groups (instead of a furazan ring) into the molecules for nitro- and nitrosofurazanopiperazines decreases Hr considerably. Thus compounds 5b (Scheme 5, reaction (21)) and 5c (reaction (22)) are less stable than the corresponding derivatives of bisfurazano[3,4-b;3',4'-e]piperazine (reactions (13) and (15), Scheme 3). Scheme 5
H N O N N NO H N O N N NO2 NOH N NOH 3.60 O N N N H N NOH NOH N NOH 7.94 O N N N H N NOH
.
+
NO (21)
NOH
+ NO2 (22)
NOH
1585
Based on analysis of the first stage of the decomposition reaction for the studied compounds, we can conclude that introducing a furazan moiety into the system for nitro and nitroso derivatives of piperazine 1 (series 2) decreases their thermodynamic stability in decomposition reactions. Annelation with a second furazan ring reduces the stability of these compounds even more.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. Yu. A. Orlova, The Chemistry and Technology of High Explosives [in Russian], Khimiya, Leningrad (1980). G. A. Olah and R. Squire, in: G. A. Olah (editor), Chemistry of Energetic Materials, Academic Press, San Diego (1991), p. 212. J. Kohler and R. Meyer, Explosives, 4th Edition, revised and extended, VCH, Weinheim (1993). P. L. Marinkas, in: P. L. Marinkas (editor) Organic Energetic Compounds, Nova Sci. Publ., New York (1996), p. 425. B. P. Zhukov (editor), High-Energy Condensed Systems [in Russian], 2nd Edition, Yanus-K, Moscow (2000). A. A. Porollo, D. E. Lushnikov, T. S. Pivina, and V. P. Ivshin, J. Mol. Struct. (THEOCHEM), 391, 117 (1997). M. S. Molchanova, T. S. Pivina, E. A. Arnautova, and N. S. Zefirov, J. Mol. Struct. (THEOCHEM), 465, 11 (1999). R. L. Willer, Propellants, Explosives, Pyrotech., 8, 65 (1983). Hu Rongzu, Sun Lixia, Fu Xiayun, Liang Yanjun, Wu Shanxiang, and Wang Yuan, Thermochim. Acta, 171, 31 (1990). M. Vedachalam, V. T. Ramakrishnan, J. H. Boyer, I. J. Dagley, K. A. Nelson, H. G. Adolph, R. Gilardi, C. George, and J. L. Flippen-Anderson, J. Org. Chem., 56, 3413 (1991). A. T. Nielsen, A. P. Chafin, S. L. Christian, D. W. Moore, M. P. Nadler, R. A. Nissan, D. J. Vanderah, R. D. Gilardi, C. F. George, and J. L. Flippen-Anderson, Tetrahedron, 54, 11793 (1998). R. L. Willer and D. W. Moove, J. Org. Chem., 50, 5123 (1985). J. M. Burov and G. M. Nazin, in: Proceedings of the Theory and Practice of Energetic Materials, Shenzhen, China (1997). Ch. K. Lowe-Ma, J. W. Fischer, and R. L. Willer, Acta Crystallogr., C46, 1853 (1990). G. B. Manelis, G. M. Nazin, Yu. I. Rubtsov, and V. A. Strunin, Thermal Decomposition and Combustion of Explosives and Propellants [in Russian], Nauka, Moscow (1996). O. F. Golovanova, G. V. Sitonina, V. I. Pepekin, B. L. Korsunskii, and F. I. Dubovitskii, Izv. Akad. Nauk SSSR, Ser. Khim., 1012 (1988). V. P. Ivshin, A. A. Porollo, and T. S. Pivina, in: The Structure and Dynamics of Molecular Systems [in Russian], Khimiya, Moscow (1998), p. 8. Yu. N. Surikova, T. S. Pivina, A. B. Sheremetev, I. L. Yudin, N. Shubina, V. L. Korolev, and V. P. Ivshin, in: Proceedings, Thirty-Third International Annual Conference ICT - Energetic Materials: Synthesis, Production, and Application, June 25-June 28, Karlsruhe, Germany (2002), p. 59/1-7. M. Yu. Antipin, A. B. Sheremetev, and B. B. Averkiev, in: High-Energy Condensed Systems, AllRussian Conference [in Russian], October 28-31, 2002, Chernogolovka; Yanus-K, Moscow (2002), p. 7. A. V. Sheremetev, I. L. Yudin, N. S. Aleksandrova, S. M. Aronova, and I. A. Kryazhevskikh, in: Proceedings, Thirty-Fourth International Annual Conference ICT - Energetic Materials: Reactions of Propellants, Explosives and Pyrotechnics, June 24-June 27, Karlsruhe, Germany (2003), p. 101/1. T. B. Brill and T. B. Patil, Termochim. Acta, 235, 225 (1994). A. B. Sheremetev and I. L. Yudin, Usp. Khim., 72, 93 (2003).
19. 20.
21. 22. 1586
23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41.
T. Clark, A Handbook of Computational Chemistry [Russian translation], Mir, Moscow (1990). [Original: Wiley, New York (1985)]. R. Shchepin and D. Litvinov, WinMOPAC 7.21. E. A. Miroshnichenko, V. P. Lebedev, Yu. N. Matyushin, A. B. Vorob'ev, Ya. O. Inozemtsev, and V. N. Vorob'eva, Khim. Fiz., 21, No. 6, 8 (2002). J. B. Pedley, R. D. Naylor, and C. P. Kirby, Thermochemical Data of Organic Compounds, Chapman and Hall, London/New York (1986). Yu. N. Matyushin, V. I. Pepekin, and Yu. A. Lebedev, Izv. Akad. Nauk SSSR, Ser. Khim., 1786 (1974). K. Sekido, K. Okamoto, and S. Hirokawa, Acta Crystallogr., C41, 741 (1985). C. K. Lowe-Ma, J. W. Fischer, and R. L. Willer, Acta Crystallogr., C46, 1853 (1990). Y. Oyumi, A. L. Rheingold, and T. B. Brill, J. Phys. Chem., 90, 4686 (1986). I. B. Starchenkov, V. G. Andrianov, and A. F. Mishnev, Khim. Geterotsikl. Soedin., 250 (1997). R. J. Gillespie and I. Hargittai, The VSEPR [Valence Shell Electron Pair Repulsion] Model and Molecular Geometry [Russian translation], Mir, Moscow (1992). T. B. Brill and Y. Oyumi, J. Phys. Chem., 2679 (1986). G. M. Nazin, V. G. Prokudin, and G. B. Manelis, Izv. Akad. Nauk, Ser. Khim., 231 (2000). Yu. Shu, B. L. Korsunskii, and G. M. Nazin, Usp. Khim., 73, 320 (2004). N. D. Chuvylkin, G. M. Zhidomirov, and V. B. Kazansky, J. Catal. 38, 214 (1975). L. I. Belen'kii and N. D. Chuvylkin, Khim. Geterotsikl. Soedin., 1535 (1996). Gaussian-98 Software Package, Center for Computer Software for Chemical Research, Russian Academy of Sciences. Yu. M. Burov and G. N. Nazin, Kinet. Katal., 23, 12 (1982). J. D. Cox and G. Pilcher, Thermochemistry of Organic and Organometallic Compounds, Academic Press, London (1970). V. I. Pepekin, M. N. Makhov, and Yu. A. Lebedev, Dokl. Akad. Nauk SSSR, 232, 852 (1977).
1587
2-R-6-ETHYL-7-HYDROXY-3-(5-PHENYL1,3,4-THIADIAZOLYL-2)CHROMONES
T. V. Shokol, V. V. Semenyuchenko, and V. P. Khilya
-(5-Phenyl-1,3,4-thiadiazolyl-2)-6-ethyl-2,4-dihydroxyacetophenone
was synthesized by the condensation of 4-ethylresorcinol with 2-cyanomethyl-5-phenyl-1,3,4-thiadiazole. Interaction of the former with carboxylic acid anhydrides and halides and subsequent hydrolysis gave 2-R-6-ethyl-7hydroxy-3-(5-phenyl-1,3,4-thiadiazoyl)chromones.
Keywords: 2-R-7-acyloxy-6-ethyl-3-(5-phenyl-1,3,4-thiadiazolyl-2)chromones, 2-R-6-ethyl-7-hydroxy3-(5-phenyl-1,3,4-thiadiazolyl-2)chromones, -(5-phenyl-1,3,4-thiadiazolyl-2)-6-ethyl-2,4-dihydroxyacetophenone. 3-Hetarylchromones, the synthetic analogs of natural isoflavones, possess a wide range of biological effects [1-3]. Derivatives of 3-thiazolylchromones have anticancer activity which is increased by the introduction of a phenyl group into the thiazole ring [4]. It seemed of interest to follow the change in activity on substituting a carbon atom in the thiazole ring by a heteroatom, in particular nitrogen, i.e., to synthesize the thiadiazole analogs of isoflavone with a phenyl radical in the thiadiazole ring and to investigate their properties. 2-Cyanomethyl-5-phenyl-1,3,4-thiadiazole (1) was chosen as the starting material for this objective [5]. The 7-dialkylamino-3-(5-phenyl-1,3,4-thiadiazolyl-2)coumarines, isomeric to chromones, were synthesized by condensation of the starting nitrile 1 with 4-dialkylamino-2-hydroxybenzaldehyde and have found use as yellowgreen fluorescent materials in textiles and plastics [6]. However 3-(5-phenyl-1,3,4-thiadiazolyl-2)-chromones have not been obtained. An attempt to synthesize 7-hydroxy-3-(-5-phenyl-1,3,4-thiadiazolyl-2)-chromone from the corresponding 2-hydroxyacetophenone using acetoformic anhydride was reported in the literature, but the reaction was only carried out qualitatively and the reaction products were not isolated [7]. With the objective of synthesizing the previously unknown 2-R-6-ethyl-7-hydroxy-3-(5-phenyl-1,3,4thiadiazolyl-2)chromones nitrile 1 was used in the Hess reaction with 4-ethylresorcinol and boron trifluoride etherate to give, after hydrolysis, the key product -(5-phenyl-1,3,4-thiadiazolyl-2)-5-ethyl-2,4-dihydroxyacetophenone (2) in 55% yield. It should be noted that, in contrast to the thiazole analogs [8,9] the reaction was carried out at room temperature because heating the reaction mixture led to a considerable decrease in the yield of the required product (Scheme 1). Compound 2 can exist in keto and enol forms. The presence in the 1H NMR spectrum, recorded in deuteroacetone (and also CDCl3 and CD3OD), of a two proton singlet for the methylene group at 5.05 ppm and only two weak field singlets for the hydroxy groups at 12.13 and 9.75 ppm indicates that compound 2 exists exclusively in the keto form in these solvents. Of the two hydroxy groups 2-OH, which can form a hydrogen bond with the oxygen atom of the carbonyl group, absorbs at weaker field, whereas the 4-OH group cannot
__________________________________________________________________________________________ Taras Shevchenko Kiev National University, Kiev 01033, Ukraine; e-mail: vikhilya@mail.univ.kiev.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, 1840-1847, December, 2004. Original article submitted July 11, 2002; revision submitted September 29, 2004. 1588 0009-3122/04/4012-15882004 Springer Science+Business Media, Inc.
undergo such an interaction but underwent deuterium exchange on the addition of D2O. The product 2 also exists as the keto form in CDCl3 and CD3OD. When the 1H NMR spectrum of 2 was recorded in DMSO-d6 both tautomers were observed as demonstrated by the appearance of a singlet for the methylene group at 6.60 ppm in addition to the singlet at 4.96 ppm and of a weak field singlet for the enol proton at 13.79 ppm. Doubling of the signals of the hydroxy groups and the aromatic protons were also observed. According to the integrated intensities, the tautomeric equilibrium consists of 85% ketone and 15% enol. Scheme 1
HO OH
N Ph S
N CH2CN
1.
Et
, Et2O BF3 /HCl 2. H2O
Et HO HO OH
S
OH O
Ph N 2
Et
OH
S N Ph N
Ac2O/Py
O Me C O Et OH OH HO
NH2OH HCl (MeO)2SO2/K2CO3

OH
S N Ph N MeO Et
OH Et N
S N N OH 5 Ph
3 OMe S N Ph N
On acetylation of compound 2 with an equimolar mixture of acetic anhydride and pyridine in the cold the monoacetylated derivative 3 was formed as indicated by the presence in the 1H NMR spectrum, recorded in DMSO-d6, along with the signals of the ethyl and aromatic protons, of a three proton singlet of the acetyl group at 2.71 ppm and a signal of only one OH group (10.29 ppm) in position 2. The weak field singlet of the enolic proton at 12.76 ppm and the singlet of the methine proton 6.28 ppm, together with the absence of a signal in the region for methylene protons indicates that the acetoxy derivative 3 in DMSO-d6 solutions exists only in the enol form in contrast to the starting material 2. The monomethyl derivative was not obtained when compound 2 was alkylated with an equimolar amount of dimethyl sulfate in the presence of potassium carbonate in either acetone or benzene solution. In both cases the reaction went further and the dimethoxy derivative 4 was obtained on the addition of a further mole of dimethyl sulfate. This was confirmed by the appearance in the 1H NMR spectrum, recorded in deuteroacetone, 1589
of two three proton singlets at 3.87 (CH3O-4) and 4.00 ppm (CH3O-2) and just one weak field singlet at 13.90 ppm which we ascribe to the enol proton. Two singlets at 6.69 and 6.40 ppm were observed in the 6 ppm region, one of which belongs the methyne proton of the enol and the other to proton H-3. On addition of D2O to the sample, the signals of the enol and methyne protons are extinguished as a result of deuterium exchange, while the singlet of the H-3 proton is unaffected (6.42 ppm). Thus, in contrast to the ketone starting material 2, the dimethoxy derivative 4 exists as the enol form in deuteroacetone. The oxime 5 was obtained by reaction of the ketone 2 with hydroxylamine hydrochloride in pyridine. 1 The H NMR spectrum of 5 has three monoprotonic weak field singlets at 11.67 (N-OH), 10.92 (2-OH), and 9.45 ppm (4-OH) and a two proton singlet for the methylene group at 4.63 ppm. Compounds 2, 3, and 5 form chelate complexes with iron(III) chloride with green, blue, and violet colors respectively. Reaction of ketone 2 with an excess of trifluoroacetic anhydride or ethyl oxalyl chloride in pyridine did not stop at the stage of the diacyl derivative but was accompanied by cyclodehydration to give condensation products. After treatment of the reaction mixture with water 2-trifluoromethyl- or 2-ethoxycarbonyl-6-ethyl-7hydroxy-3-(5-phenyl-1,3,4-thiadiazolyl-2)chromones (6a,b) respectively were isolated.

Compound 2 3 4 5 6a 6b 6c 6d 6e 6f 7a 7b 7d 7e 7f 7g Empirical formula 18H16N2O3S C20H18N2O4S C20H20N2O3S C18H15N3O3S C20H13F3N2O3S C22H18N2O3S C22H18N2O5S C20H16N2O3S C21H18N2O3S C19H14N2O3S C22H15F3N2O4S C24H20N2O6S C22H18N2O4S C24H22N2O4S C21H16N2O4S C22H16Cl2N2O4S Found, % Calculated, % N S 8.50 8.23 7.58 7.33 7.57 7.62 8.12 7.93 6.53 6.70 6.79 6.63 6.85 6.63 7.85 7.69 7.66 7.40 8.07 8.00 6.22 6.09 6.11 6.03 7.09 6.89 6.53 6.45 7.33 7.14 6.12 5.89 9.64 9.42 8.60 8.38 8.63 8.73 9.19 9.07 7.87 7.66 7.89 7.59 7.83 7.59 8.90 8.80 8.75 8.47 9.30 9.15 7.26 6.93 7.19 6.90 8.06 7.89 7.52 7.38 8.32 8.17 6.97 6.75 Recrystallization solvent Ethanol Ethanol Ethyl acetate Ethyl acetate Dioxane Dioxane Ethanol DMF DMF DMF Ethyl acetate Ethyl acetate Ethyl acetate Ethyl acetate Ethyl acetate Acetonitrile Yield, % 50 85 63 58 86 82 72 95 84 * 75 89 86 89 81 89
mp,
239 333 185 222 256 261 282 317 272 316 155 199 188 167 197 193
_______ * Yield 46 (A) and 71% (B).
1590
For the reaction of compound 2 with succinic anhydride to form 2-(-carboxyethyl)-6-ethyl-7-hydroxy3-(5-phenyl-1,3,4-thiadiazolyl-2)chromone (6c) only a brief heating until the reagents had dissolved was necessary. For the condensation of compound 2 with acetic and propionic anhydrides in triethylamine only heating for solution of 2 is necessary, further heating (in contrast to the thiazole analogs) leads only to blackening of the product and a decrease in yield. In these cases, in contrast to products 6a-c, treatment of the reaction mixture with water did not lead to removal of the acyl group at position 7; instead 2-methyl- or 2-ethylsubstituted 7-acyloxy-6-ethyl-3-(5-phenyl-1,3,4-thiadiazolyl-2)chromones (7d,e) were formed. The required 7-hydroxy derivatives 6d,e were obtained refluxing the 7-acyloxy derivatives 7d,e for a short time with dilute sodium hydroxide. The interaction of ketone 2 with chloracetyl chloride in pyridine occurred extremely vigorously even in the cold to give a tarry product. Chromatographically pure 7-chloracetoxy-2-chloromethyl-6-ethyl-3-(5-phenyl1,3,4-thiadiazolyl-2)chromone (7g) was formed in high yield by refluxing compound 2 with a two fold excess of chloroacetyl chloride and pyridine in dioxane. 6-Ethyl-7-hydroxy-3-(5-phenyl-1,3,4-thiadiazolyl-2)chromone (6f) was synthesized by two methods: by heating the initial ketone with ethyl orthoformate and pyridine in the presence of a catalytic amount of piperidine and by Wilsmeier formylation in the presence of boron trifluoride etherate. In the latter case the reaction goes practically at room temperature and the product obtained is purer and in much higher yield.
HO 1. S 2. Et O 6af 2 Ac2O/Py 5 % NaOH N N
2' 3' 4'
R
6' 5'
3.
C O
O Et
R S Ph
O O 1. (CF3CO)2O ; 2. H2O ; 7a,b,dg
N N
O ; ClCCO2Et ; CH(OEt)3 / Py or DMF, PCl5, BF3 . Et2O; O O

O
3. Ac2O , (EtCO)2O/Et3N or ClCH2COCl, Py /

O
6 a R = CF3, b R = CO2Et, c R = CH2CH2COOH, d R = Me, e R = Et, f R = H; 7a R = CF3, R1 = Me; b R = CO2Et, R1 = Me; d R = R1 = Me; e R = R1 = Et; f R = H, R1 = Me; g R = R1 = CH2Cl
The 7-hydroxychromones 6a,b,f are easily acylated with acetic anhydride in pyridine in the cold to give the 7-acetoxy derivatives 7a, b, f in high yield. However acylation of product 6c under the same conditions was unsuccessful.
1591

Compound 2 Chemical shifts, , ppm (J, Hz)* 1.25 (3H, t, J = 7, CH3); 2.65 (2H, q, J = 7, CH2CH3); 5.06 (2H, s, CH2C(O)); 6.43 (1H, s, H-3); 7.57 (3H, m, HPh-3',4',5'); 7.93 (1H, s, 6-H); 8.04 (2H, m, HPh-2',6'); 9.75 (1H, s, OH-4); 12.13 (1H, s, OH-2) 1.18 (3H, t, J = 7, CH3CH2); 2.53 (2H, q, J = 7, CH2CH3); 2.71 (3H, s, CH3C(O)O); 6.28 (1H, s, =CH); 7.39 (1H, s, H-3); 7.57 (3H, m, HPh-3',4',5'); 7.89 (2H, d, J = 7, HPh-2',6'); 8.31 (1H, s, H-6); 10.29 (1H, s, OH-2); 12.76 (1H, s, HOC=) 1.16 (3H, t, J = 7, CH3CH2); 2.54 (2H, q, J = 7, CH2CH3); 3.87 (3H, s, CH3O-4); 4.00 (3H, s, CH3O-2); 6.40 (1H, s, H-3); 6.69 (1H, s, =CH); 7.56 (3H, m, HPh-3',4',5'); 7.73 (1H, s, H-6); 7.89 (2H, m, HPh-2',6'); 13.90 (1H, s, HOC=) 1.14 (3H, t, J = 7, CH3); 2.54 (2H, q, J = 7, CH2CH3); 4.63 (2H, s, CH2C=NOH); 6.28 (1H, s, H-3); 7.29 (1H, s, H-6); 7.49 (3H, m, HPh-3',4',5'); 7.89 (2H, m, HPh-2',6'); 9.45 (1H, s, OH-4); 10.92 (1H, s, OH-2); 11.67 (1H, s, NOH) 1.24 (3H, t, J = 7, CH3 ); 2.69 (2H, q, J = 7, CH2 ); 6.99 (1H, s, H-8); 7.57 (3H, m, HPh -3',4',5'); 7.84 (1H, s, H-5); 8.06 (2H, m, HPh-2',6'); 11.25 (1H, s, OH) 1.26 (3H, t, J = 7, CH2CH3-6); 1.32 (3H, t, J = 7, CO2CH2CH3-2); 2.71 (2H, q, J = 7, CH2CH3 -6); 4.24 (2H, q, J = 7, CO2CH2CH3 -2); 6.99 (1H, s, H-8); 7.56 (3H, m, HPh-3',4',5'); 7.89 (1H, s, H-5); 8.04 (2H, m, HPh-2',6'); 11.12 (1H, s, OH) 1.25 (3H, t, J = 7, CH2CH3-6); 2.70 (2H, q, J = 7, CH2CH3-6); 2.83 (2H, t, J = 7, CH2CH2COOH-2); 3.66 (2H, t, J = 7, CH2CH2COOH-2); 6.90 (1H, s, H-8); 7.53 (3H, m, HPh-3',4',5'); 7.84 (1H, s, H-5); 8.03 (2H, m, HPh-2',6'); 10.88 (1H, s, OH); 12.27 (1H, br. s, COOH) 1.26 (3H, t, J = 7, CH2CH3-6); 2.67 (2H, q, J = 7, CH2CH3-6); 3.04 (3H, s, CH3-2); 6.92 (1H, s, H-8); 7.52 (3H, m, HPh-3',4',5'); 7.84 (1H, s, H-5); 8.02 (2H, m, HPh-2',6'); 10.82 (1H, s, OH) 1.25 (3H, t, J = 7, CH2CH3-6); 1.46 (3H, t, J = 7, CH2CH3-2); 2.67 (2H, q, J = 7, CH 2 CH 3 -6); 3.44 (2H, q, J = 7, CH 2 CH 3 -2); 6.92 (1H, s, H-8); 7.52 (3H, m, H Ph -3',4',5'); 7.83 (1H, s, H-5); 8.03 (2H, m, HPh-2',6'); 10.85 (1H, s, OH) 1.25 (3H, t, J = 7, CH3 ); 2.67 (2H, q, J = 7, CH 2 ); 6.98 (1H, s, H-8); 7.53 (3H, m, HPh -3',4',5'); 7.89 (1H, s, H-5); 8.02 (2H, m, HPh-2',6'); 9.29 (1H, s, H-2); 10.94 (1H, s, OH) 1.25 (3H, t, J = 7, CH2CH3-6); 2.39 (3H, s, CH3C(O)O-7); 2.69 (2H, q, J = 7, CH2CH3-6); 7.58 (3H, m, HPh-3',4',5'); 7.68 (1H, s, H-8); 8.07 (3H, m, H-5 and HPh-2',6') 1.26 (3H, t, J = 7, CH2CH3-6); 1.32 (3H, t, J = 7, CO2CH2CH3-2); 2.39 (3H, s, CH3C(O)O-7); 2.69 (2H, q, J = 7, CH2CH3-6); 4.45 (2H, q, J = 7, CO2CH2CH3-2); 7.56 (3H, m, HPh-3',4',5'); 7.63 (1H, s, H-8); 8.06 (2H, m, HPh-2',6'); 8.12 (1H, s, H-5) 1.26 (3H, t, J = 7, CH2CH3-6); 2.38 (3H, s, CH3C(O)O-7); 2.69 (2H, q, J = 7, CH2CH3-6); 3.06 (3H, s, CH3-2); 7.51 (1H, s, H-8); 7.55 (3H, m, HPh-3',4',5'); 8.04 (2H, m, HPh-2',6'); 8.08 (1H, s, H-5) 1.25 (6H, t, J = 7, CH2CH3-6 and CH3CH2C(O)O-7); 1.46 (3H, t, J = 7, CH2CH3-2); 2.70 (4H, m, CH2CH3-6 and CH3CH2C(O)O-7); 3.46 (2H, q, J = 7, CH2CH3-2); 7.51 (1H, s, H-8); 7.55 (3H, m, HPh-3',4',5'); 8.02 (2H, m, HPh-2',6'); 8.07 (1H, s, H-5) 1.27 (3H, t, J = 7, CH2CH3-6); 2.38 (3H, s, CH3C(O)O-7); 2.68 (2H, q, J = 7, CH2CH3-6); 7.53 (3H, m, HPh-3',4',5'); 7.59 (1H, s, H-8); 8.03 (2H, m, HPh-2',6'); 8.13 (1H, s, H-5); 9.44 (1H, s, H-2) 1.28 (3H, t, J = 7, CH2CH3-6); 2.73 (2H, q, J = 7, CH2CH3-6); 4.70 (2H, s, ClCH2C(O)O-7); 5.51 (2H, s, CH2Cl-2); 7.56 (3H, m, HPh-3',4',5'); 7.72 (1H, s, H-8); 8.07 (2H, m, HPh-2',6'); 8.14 (1H, s, H-5)
6a 6b
6c
6d
6e
6f
7a 7b
7d
7e
7f
7g
_______ * Spectra were recorded in deuteroacetone (compounds 2 and 4) and DMSOd6 (the rest).
The chromones 6 are colorless high melting compounds. In their 1H NMR spectra there are signals of the ethyl group protons at position 6, signals of the aromatic protons of the phenyl groups, singlets of the aromatic protons of chromone H-8 (6.90-6.99 ppm and H-5 (7.83-7.89 ppm), a weak field singlet of the 7-OH group in the 10.82-11.25 ppm range, and also for the corresponding substituents at position 2 (Table 2).
1592
The stretching vibrations of the C=O groups of the chromone ring were observed in the range 1635-1610 cm in their IR spectra. In the 1H NMR spectra of the 7-acetoxy derivatives 7a,b,d,f the weak field singlet s missing and a three proton singlet of the acetoxy groups appears in the 2.38-2.39 ppm range. In the spectrum of the 7-propionyl derivative 7e the signals of this group and of the ethyl group in position 6 overlap, but the signals of the 2-CH2CH3 group appear at weaker field. The 1H NMR spectrum of compound 7g is characterised by two singlets for the methylene groups of the 7-chloracetoxy group at 4.70 ppm and of the 2-CH2Cl group at 5.51 ppm. In the IR spectra of the 7-acyloxy compounds 7 the C=O stretch of the chromone ring occurs at 1640-1650 cm-1 and that for the acyl groups in the 1750-1770 cm-1 region. Thus starting from -(5-phenyl-1,3,4-thiadiazolyl-2)-2,4-dihydroxy-5-acetophenone a series of 7-hydroxy-3-(5-phenyl-1,3,4-thiadiazolyl-2)-6-ethylchromones with different positions at position 2 and their 7-acyloxy derivatives have been synthesized.
-1
EXPERIMENTAL The purity of the compounds synthesized was monitored by TLC on Silufol UV-254 strips with 9:1 chloroform as eluant. 1H NMR spectra were recorded on a Mercury 400 (Varian) (400 MHz) machine and IR spectra of KBr discs on a Pye-Unicam SP 3-300 spectrophotometer. The characteristics of compounds are given in Table 1 and their 1H NMR spectra in Table 2. -(5-Phenyl-1,3,4-thiadiazolyl-2)-5-ethyl-2,4-dihydroxyacetophenone (2). A stream of dry hydrogen chloride was passed through a stirred suspension of 2-cyanomethyl-5-phenyl-1,3,4-thiadiazole (1) (20.1 g, 100 mmol) in borontrifluoride etherate (100 ml) for 6 h at room temperature. After 1 day the reaction mixture was added in portions to hot water (700 ml) and was refluxed for 3 h with 1 ml of sulphuric acid.. The precipitate which formed was filtered hot. The crude product was reprecipitated from 5% sodium hydroxide solution with 20% acetic acid and was then refluxed in ethanol. -(5-Phenyl-1,3,4-thiadiazolyl-2)-4-acetoxy-5-ethyl-2-hydroxyacetophenone (3). Acetic anhydride (0.2 g, 2 mmol) was added to a solution of ketone 2 (0.68 g, 2 mmol) in pyridine (4 ml). The mixture was kept in a refrigerator for 48 h and the precipitate which formed was filtered off. -(5-Phenyl-1,3,4-thiadiazolyl-2)-5-ethyl-2,4-dimethoxyacetophenone (4). A mixture of ketone 2 (0.34 g, 1 mmol), freshly dried potassium carbonate (0.7 g, 4.5 mmol), and dimethyl sulfate (0.14 g, 1.1 mmol) was refluxed for 6 h in benzene or acetone. More dimethyl sulfate (0.14 g, 1.1 mol) was then added and the mixture was refluxed for further hour. The course of the reaction was monitored by TLC. The potassium carbonate was filtered off and the mother liquor evaporated. -(5-Phenyl-1,3,4-thiadiazolyl-2)-5-ethyl-2,4-dihydroxyacetophenone oxime (5). A solution of ketone 2 (1.02 g, 3 mmol) and hydroxylamine hydrochloride (0.63 g, 9 mmol)in absolute pyridine was refluxed for 1 h and was then kept at room temperature for 12 h. Th reaction mixture was poured into water (100 ml) and the water was changed until the oil formed did not crystallize and the residue was then filtered. 6-Ethyl-7-hydroxy-3-(5-phenyl-1,3,4-thiadiazolyl-2)-2-trifluoromethylchromone (6a). Trifluoroacetic anhydride (4.2 g, 20 mmol) was added dropwise to a solution of ketone (2) (1.7 g, 5 mmol) in pyridine (10 ml) cooled to 0C. The mixture was kept at room temperature for 48 h, poured into ice water (100 ml), and the precipitate was filtered off. 2-Ethoxy-6-ethyl-7-hydroxy-3-(5-phenyl-1,3,4-thiadiazolyl-2)chromone (6b) was synthesized analogously from ketone 2 (1.7 g, 5 mmol) and ethyl oxalyl chloride (1.56 g, 11.4 mmol). 2-(-Carboxyethyl)-6-ethyl-7-hydroxy-3-(5-phenyl-1,3,4-thiadiazolyl-2)chromone (6c). A mixture of ketone 2 (1.7 g, 5 mmol) and succinic anhydride (3.5 g, 30 mmol) in pyridine (5 ml, 60 mmol) was heated rapidly until all had dissolved and was then kept at room temperature. After 12 h the precipitate was filtered off, washed with methanol, transferred into water (50 ml), filtered, and washed with water and methanol. 1593
2-Alkyl-7-alkoxy-6-ethyl-3-(5-phenyl-1,3,4-thiadiazolyl-2)chromones (7d,e). A mixture of ketone 2 (1.7 g, 5 mmol), triethylamine (2.52 g, 25 mmol), and acetic or propionic anhydride (25 mmol) was rapidly heated until all had dissolved and was then kept at room temperature for 12 h. The product was isolated as for 6c. 2-Alkyl-6-ethyl-7-hydroxy-3-(5-phenyl-1,3,4-thiadiazolyl-2)chromones (6d,e). A 5% solution of sodium hydroxide (1 ml) and water (25 ml) were added to a solution of the corresponding 7-alkoxy derivative 7d,e (1 mmol) in ethanol (50 ml). The mixture was refluxed for 5 min, more water (25 ml) was added, the mixture was cooled, neutralized to pH 7 with hydrochloric acid, and the precipitate was filtered off. 6-Ethyl-7-hydroxy-3-(5-phenyl-1,3,4-thiadiazolyl-2)chromone (6f). A. Piperidine (3 drops) was added to a solution ketone 2 (0.68 g, 2 mmol) and ethyl orthoformate (2.1g, 12 mmol) in pyridine (4 ml) and the mixture was heated at 100C for 45 min. . The mixture was cooled , the precipitate was filtered off an washed with water. Yield 0.32 g (46%). B. Boron trifluoride etherate (4.23 g, 30 mmol) was added dropwise to a stirred suspension of ketone 2 (1.7 g, 5 mmol) in DMF (7.3 g, 0.1 mmol), then phosphorus pentachloride (1.25 g, 6 mmol) was added in portions, and the mixture was kept at 50C for 15 min.. The mixture was poured into water (10 ml), refluxed for 15 min, cooled and the precipitate was filtered off. Yield 1.24 g (71%). 2-R-7-Acetoxy-6-ethyl-3-(5-phenyl-1,2,4-thiadiazolyl-2)chromones (7a,b,f). The corresponding 7-hydroxyproduct 6a,b,f (2 mmol) was dissolved in a mixture of pyridine (2 ml) and acetic anhydride (0.82 g, 8 mmol) and kept at room temperature for 24 h. The precipitate was filtered off and washed with methanol and water. 7-Chloracetoxy-2-chloromethyl-6-ethyl-3-(5-phenyl-1,3,4-thiadiazolyl-2)chromone (7g). Pyridine (0.34 g ,4.4 mmol) and chloroacetyl chloride (0.5 g, 4.4 mmol) were added to a solution of ketone 2 (0.68 g, 2 mmol) in absolute dioxane (15 ml) and the mixture was refluxed for 6 h. The mixture was cooled, the precipitate was filtered off, the mother liquor was evaporated, treated with water and an additional amount of product was filtered off.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. A. L. Kazakov, V. P. Khilya, V. V. Mezheritskii, and Yu. Litkei, Natural and Modified Isoflavonoids [in Russian]. Izd-vo Rost. Un-ta, (1985). N. V. Gorbulenko and V. P. Khilya, Ukr. Khim. Zhurn., 60, No. 1, 79 (1994). M. S. Frasinyuk and V. P. Khilya, Khim. Geterotsikl. Soedin. 3 (1999). V. P. Khilya, L. G. Grishko, and D. V. Vikhman, Khim.-Pharm. Zhurn., 10, No. 8, 74 (1976). H. Eilingsfeld, Chem. Ber., 98, 1308 (1965). M. Patsch and C. Vamvakaris, Ger. Offen., 2529434; Chem. Abstr., 86, 122953 (1977). V. G. Pivovarenko and V. P, Khilya, Khim. Geterotsikl. Soedin., 625 (1991). V. P. Khilya, V. Sabo, L. G. Grishko, D. V. Vikhman, and F. S. Babichev, Zh. Org. Khim., 9, 2561 (1973). V. P. Khilya, T. M. Tkachuk, I. P. Kupchevskaya, and G. M. Golubushina, DAN UkrSSR, Ser B., No. 5, 61 (1980).
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REACTIONS OF -ACETYLENIC KETONES WITH N-3-AMIDINOTHIOUREAS. 1. SYNTHESIS AND PROPERTIES OF NEW DERIVATIVES OF 1,3-THIAZINE
T. E. Glotova, N. I. Protsuk, L. V. Kanitskaya, G. V. Dolgushin, and V. A. Lopyrev [4-Phenyl-2H-1,3-thiazin]-2-ylideneguanidinium perchlorate or acetoxytrifluoroborate respectively was obtained from the reaction of benzoylacetylene with N-amidinothiourea in glacial AcOH in the presence of an equimolar quantity of HClO4 or BF3Et2O. These compounds underwent hydrolysis at the amidine unit on treatment with acid or base. For example, the perchlorate on heating in HClO4 was converted into 2-imino-4-phenyl-2H-1,3-thiazinium perchlorate, while treatment with aqueous NaOH in DMSO gave the free base 6-phenyl-1,2-dihydropyrimidine-2-thione. Keywords: N-amidinothiourea, benzoylacetylene, 4-phenyl-1,2-dihydropyrimidine-2-thione, [4-phenyl2H-1,3-thiazin]-2-ylideneguanidinium perchlorate and acetoxytrifluoroborate, heterocyclization. In a continuation of the study of the reactions of -acetylenic ketones with sulfur- and nitrogencontaining ambident nucleophiles [1-3] as a suitable method for the synthesis of N,S-containing heterocyclic compounds, we have investigated the reaction of benzoylacetylene 1 with N-amidinothiourea 2. The choice of compound 2 as the subject for this investigation is because it contains both thioamide and guanidine units, is a potential polydentate nucleophile with several reaction centers arising from intramolecular mesomorphic interactions. Condensation of thioamides and thiourea with ,-unsaturated ketones, esters of propiolic and acetylenedicarboxylic acids [4-7] is one of the basic methods for the preparation of substituted 1,3thiazines which are used as fungicides, pharmaceuticals, and vulcanizing agents [8]. Moreover guanidine is involved in the classical heterocyclization reaction which leads to biologically important derivatives of pyrimidine, and guanidine is a structural fragment of nucleic acids and streptomycin. The reaction of benzoylacetylene 1 with N-amidinothiourea 2 (1 : 2 = 1:1) was carried out in glacial acetic acid at 20C with the addition of an equimolar quantity of HClO4 or BF3Et2O. Under these conditions the reaction proceeded directly to [4-phenyl-2H-1,3-thiazin]-2-ylideneguanidinium perchlorate or acetoxytrifluoroborate (3a and 3b respectively). The formation of the substituted 1,3-thiazines 3a,b probably occurs via the intermediate formation the benzoylvinylisothiouronium salts 4 which were not isolated under these conditions. However when the reaction of benzoylacetylene 1 with 3-amidino-2-thiourea 5 (specially synthesized by us) was carried out in glacial acetic acid at 20C 3-amidino-2-benzoylvinylisothiourea perchlorate 4a was obtained, which on heating in acetic acid was converted in high yield to the corresponding 1,3-thiazine 3a as a result of attack by the nitrogen atom of the thioamide unit on the electron poor carbon atom of the carbonyl group. __________________________________________________________________________________________ A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, Irkutsk 664033; e-mail: k301@irioch.irk.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1848-1852, December, 2004. Original article submitted July 30, 2002; revision submitted November 25, 2003. 0009-3122/04/4012-15952004 Springer Science+Business Media, Inc. 1595
H2NCNHCNH2 HClO4 5 NH S
2
NH2 PhCCH=CHSC=N O 4a AcOH, _H O 2 Ph C CH CH S C N C + 3a,b H2NC N Ph C NH2 + NH2 _ ClO4 AcOH, _H O

2
AcOH, 20 oC
NH2
+ NH2
_ ClO4
Ph C C CH 1 O
NH2 S C NH C NH2 2
Ph C NaOH / DMSO _ 2NH3, CO2 NH2 _ X HClO4, N
CH CH NH C S 9 NaOH/EtOH
+
HN
AcOH, 20 oC a) HClO4 . b) BF3 Et2O
NH2
H2NCNH2 7 S PhCCH O CHSC 8
CH CH S C + NH 6
2
HClO4 / AcOH, 20 oC
_ ClO4
_ _ a X = ClO4, b X = AcOBF3
According to their 1H NMR spectra, the synthesized 1,3-thiazines 3a,b are immonium salts as indicated by the presence of two signals of the NH2 group. The proton donor in the formation of the immonium salts was either HClO4 or the solvent molecule (AcOH) when the reaction was carried out with BF3Et2O. When the perchlorate 3a was heated with perchloric acid cyanamide was evolved and the reaction product was 2-imino-4-phenyl-2H-1,3-thiazinium perchlorate (6). We carried out a retrosynthesis of this compound by the reaction of benzoylacetylene 1 with thiourea 7 in acetic acid in the presence of HClO4 at 20C with the isolation of the intermediate S-(benzoylvinyl)isothiouronium perchlorate (8) using a published method [8]. Treatment of the perchlorate 3a with 0.1 N NaOH in DMSO led to complete hydrolysis of the amidine unit (with evolution of ammonia and carbon dioxide) and recyclization of the 1,3-thiazine ring into pyrimidine2-thione 9. This compound is completely identical with the free base which we obtained by the analogous treatment of 2-imino-4-phenyl-2H-1,3-thiazinium perchlorate 6. The structure 9 is in agreement with the results of [8] where the isolated compound was identified as 4-phenyl-1,2-dihydropyrimidine-2-thione (9). Second tautomeric form is possible for compound 9 1,2-dihydro-6-phenylpyrimidine-2-thione (9A).
Ph N S 9 N H Ph H N S 9A N
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According to our ab initio (RHF/6-31G*) [9] calculations on the two tautomers, the phenyl and pyrimidine rings are at 18 and 42 to each other in molecules 9 and 9A respectively. The experimentally observed shift of the equilibrium towards structure 9 may be explained by its greater stability on account of increased conjugation between the two rings.
EXPERIMENTAL IR spectra of KBr disks were recorded with Bruker-25 instrument. 1H and 13C NMR spectra of DMSO-d6 solution were recorded with a Bruker DPX-400 instrument (400 and 100 MHz respectively). N-amidinothiourea 2 was prepared according to [10]. [4-Phenyl-2H-1,3-thiazin]-2-ylideneguanidinium Perchlorate (3a). Benzoylacetylene 1 (0.65 g, 5 mmol) and HClO4 (58%, 0.58 ml) in glacial AcOH (10 ml) was added to a solution of N-amidinothiourea 2 (0.59 g, 5 mmol) in glacial AcOH (10 ml) and the mixture was stirred for 1 h at 20C and kept for 24 h. The precipitate was filtered off, washed with glacial AcOH (5 ml) and absolute ether until the smell of acetic acid disappeared, and dried in vacuum to give compound 3a (1.19 g, 72%) as lemonish crystals; mp 165-167C (AcOH). IR spectrum, , cm-1: 3216-3379 (NH, N+H), 1658 (NH def.) 1534 -1576 (C=C, C=N), 1053-1120 (ClO4-). 1H NMR spectrum, , ppm (J, Hz): 7.57- 8.12 (5H, m, C6H5); 8.02 (1H, d, 3J = 5.30, C(6)H); 8.82 (1H, d, 3 J = 5.30, C(5)H); 9.49 (2H, br. s, NH2); 10.00 (2H, br. s, N+H2). 13C NMR spectrum, , ppm; 116.25 (C(5)); 127.69, 129.66, 132.63, 134.79 (C6H5); 159.68 (C(6)); 164.71 (C(4)); 165.00 (C(2)); 165.04 (Camidine). Found, %: C 39.68; H 3.45; Cl 10.63; N 16.82; S 9.45. C11H10N4SHClO4. Calculated, %: C 39.94; H 3.33; C 10.74; N 16.94; S 9.68. [4-Phenyl-2H-1,3-thiazin]-2-ylideneguanidinium Acetoxytrifluoroborate (3b) was obtained analogously to compound 3a from compound 2 (0.59 g, 5 mmol), benzoylacetylene 1 (0.65 g, 5 mmol), and BF3Et2O (0.63 ml) in glacial AcOH (20 ml). Yield of compound 3b 1.2 g (67%), colorless crystals; mp 145-146C. IR spectrum, , cm-1: 3240-3370 (NH, N+H); 1660 (NH def.); 1534-1575 (C=C, C=N); 1000-1102 (BF). 1H NMR spectrum, , ppm (J, Hz): 1.91 (3H, s, CH3); 7.61-8.16 (5H, m, C6H5); 7.96 (1H, d, 3 J = 5.34, C(6)H); 8.86 (1H, d, 3J = 5.34, C(5)H); 9.51(2H, br. s, NH2); 9.98 (2H, br. s, N+H2). 13C NMR spectrum, , ppm: 21.08 (CH3); 115.91 (C(5)); 127.44, 129.35, 132.30, 134.60 (C6H5); 159.50 (C(6)); 164.13 (C(4)); 164.73 (C(2)); 164.77 (Camidine). Found, %: C 43.30; H 3.58; F 15.55; N 15.83; S 8.79. C11H10N4SCH3COOHBF3. Calculated, %: C 43.58; H 3.91; F 15.92; N 15.64; S 8.94. N-Amidinothiourea Perchlorate (5). N-amidinothiourea 2 (3 g, 25 mmol) was heated in 58% HClO4 (30 ml) for 15 min, the solution was cooled, the precipitate was filtered off and washed with cold EtOH (5 ml) and absolute ether and dried in vacuum to give colorless crystals of perchlorate 5 (5 g, 92%); mp 140-141C. 13C NMR spectrum, , ppm: 156.10 (C=N); 180.74 (C=S). Found, %: C 10.93; H 3.35; Cl 16.38; N 25.18; S 14.83. C2H6N4SHClO4. Calculated, %: C 10.99; H 3.23; Cl 16.22; N 25.63; S 14.67. 3-Amidino-2-benzoylvinylisothiourea Perchlorate (4a) and [4-Phenyl-2H-1,3-thiazin]-2ylideneguanidinium Perchlorate (3a). A solution of benzoylacetylene 1 (0.65 g, 5 mmol) in AcOH (10 ml) was added slowly to a suspension of the perchlorate of N-amidionthiourea 5 (1.09 g, 5 mmol) in glacial AcOH (10 ml), the mixture was stirred for 2h, the precipitate was filtered off, washed with AcOH (5 ml) and absolute ether, and dried in vacuum to give compound 4a (1.4 g, 80%) as a yellow powder; mp 148-150C. IR spectrum, , cm-1: 3216-3411 (NH, N+H); 1642 (br, C=O, NH def.); 1538-1599 (C=C, C=N); 1060-1119 (ClO4-). 1N NMR spectrum, , ppm (J, Hz): 7.48 (1H, d, 3J = 9.68, cis-isomer, CH); 8.15 (1H, d, 3J = 9.68, CH); 7.59-8.07 (5H, m, C6H5); 7.83 (2H, br. s, NH2); 8.25 (2H, br. s, NH2); 8.40 (2H, br. s, N+H2). 13C NMR spectrum, , ppm: 118.44 (C); 128.43, 129.24, 133.71, 136.80 (C6H5); 141.96 (C); 161.28, 163.07 (2C, 2C=N); 189.10 (C=O). Found, %: C 38.22; H 3.82; Cl 10.18; N 16.27; S 9.06. C11H12N4OSHClO4. Calculated, %: C 37.88; H 3.73; Cl 10.19; N 16.07; S 9.18.
1597
Compound 4a (1.05 g, 3 mmol) was dissolved in glacial acetic acid (10 ml), the temperature was slowly increased to 50C and kept at the temperature for 0.5 h. The reaction mixture was then kept at 20C for 24 h. The precipitate was filtered off, washed with absolute ether and dried in vacuum to give compound 3a (0.83 g, 84%) identical to that prepared previously. S-(Benzoylvinyl)isothiuronium Perchlorate (8) and 2-Imino-4-phenyl-2H-1,3-thiazinium Perchlorate (6). A solution of benzoylacetylene 1 (0.65 g, 5 mmol) and 58% HClO4 (0.58 ml) in AcOH (10 ml) was added to a stirred solution of thiourea 7 (0.38 g, 5 mmol) in glacial AcOH (10 ml). The reaction mixture was stirred for 1 h at 20C, the precipitate was filtered off, washed with AcOH and absolute ether and dried in vacuum to give yellow crystals of perchlorate 8 (1.0 g, 65%); mp 156-158C. IR spectrum, , cm-1: 3178-3386 (NH, N+H); 1675 (NH def.); 1638 (C=O, conj.); 1552-1594 (C=C, C=N); 1048-1118 (ClO4-). 1N NMR spectrum, , ppm (J, Hz): 7.71 (1H, d, 3J = 9.42, cis-isomer, CH); 7.84 (1H, d, 3J = 9.42, CH); 7.59-8.08 (5H, m, C6H5); 9.30 (2H, br. s, NH2); 9.70 (2H, br. s, N+H2). 13C NMR spectrum, , ppm: 120.32 (C); 128.57, 129.26, 134.09, 136.05 (C6H5); 139.26 (C); 168.74 (C=N); 189.52 (C=O). Found, %: C 39.38; H 3.37; Cl 11.75; N 9.29; S 10.37. C10H10N2OSHClO4. Calculated, %: C 39.15; H 3.59; Cl 11.58; N 9.13; S 10.44. After removal of compound 8 the mother liquor was reduced to about half by passage of nitrogen and was kept at 20 for 24 h. The additional precipitate was filtered off, washed with AcOH and absolute ether, and dried in vacuum to give lemonish crystals of 1,3-thiazinium perchlorate 6 (0.29 g, 20%); mp 162-164C. IR spectrum, , cm-1: 3192-3376 (NH, N+H); 1628 (NH def.); 1573-1590 (C=C, C=N); 1077-1121 (ClO4-). 1 H NMR spectrum, , ppm (J, Hz): 8.21 (1H, d, 3J = 9.84, C(6)H); 8.92 (1H, d, 3J = 9.84, C(5)H); 7.67-8.30 (5H, m, C6H5); 10.94 (2H, br. s, N+H2). 13C NMR spectrum, , ppm: 115.48 (C5); 129.53, 129.57, 134.83, 135.13 (C6H5); 149.73 (C6); 171.27 (C4); 172.87 (C2). Found, %: C 41.32; H 3.01; Cl 12.54; N 9.71; S 11.21. C10H8N2SHClO4. Calculated, %: C 41.59; H 3.12; Cl 12.30; N 9.70; S 11.09. By increasing the time of reaction at 20C to 6 h or by carrying it out at 50C for 1 h increased the content of compound 6 in the reaction mixture to 40-50%. On recrystallizing perchlorate 8 from AcOH it was partially converted to compound 6. Reaction of [4-Phenyl-2H-1,3-thiazin]-2-ylideneguanidinium Perchlorate (3a) with Perchloric Acid. Compound 3a (0.3 g, 0.91 mmol) was heated in 58% HClO4 to 50C, kept at that temperature for 0.5 h, the solution was then cooled, the precipitate was filtered off, triturated, dried in vacuum to give 1,3-thiazinium perchlorate (0.15 g, 58%) identical to that prepared previously. Reaction of Perchlorate 3a with Alkali. A solution of perchlorate 3a (0.33 g, 1 mmol) in DMSO (5 ml) was cooled to 8-10C and 0.1 N NaOH (12 ml) was added with vigorous stirring, the stirring was continued for 0.5 h, distilled water (25 ml) was added, the temperature of the mixture was raised to 20C, the precipitate was filtered off, washed with water and dried in vacuum over CaCl2 to give 1,2-dihydro-4phenylpyrimidine-2-thione (9) as yellowish crystals (0.14 g, 76%); mp 158-160C (water). IR spectrum, , cm-1: 3123 (NH); 1558-1605 (C=C, C=N). 1H NMR spectrum, , ppm (J, Hz): 7.43 (1H, d, 3J = 6.52, C(4)H); 8.07 (1H, d, 3J = 6.52, C(5)H); 7.55-8.15 (5H, m, C6H5); 13.73 (1H, s, NH). 13C NMR spectrum, , ppm: 105.70 (C(5)), 128.03, 129.08, 132.41, 135.23 (C6H5), 146.90 (C(6)), 166.11 (C(4)), 180.92 (C=S). Found, %: C 63.64; H 4.39; N 14.98; S 16.89. C10H8N2S. Calculated, %: C 63.80; H 4.28; N 14.88; S 17.03. Reaction of Perchlorate 6 with Base. 0.1 N NaOH (45 ml) was added to a stirred solution 1,3-thiazinium perchlorate 6 (1.22 g, 4.2 mmol) in EtOH (20 ml) and the mixture was stirred for 3 h at 20C. The precipitate was filtered off, washed with water, and dried in vacuum over CaCl2 to give pyrimidine-2-thione 9 (0.67 g, 85%), identical to that obtained previously from perchlorate 3a.
1598
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. T. E. Glotova, A. S. Nakhmanovich, and N. S. Mabarakshina, Khim. Geterotsikl. Soedin., 705 (1988). T. E. Glotova, A. S. Nakhmanovich, T. N. Komarova, and M. V. Sigalov, Khim. Geterotsikl. Soedin., 1142 (1990). T. E. Glotova, T. N. Komarova, A. S. Nakhmanovich, and V. A. Lopyrev, Izv. Akad. Nauk, Ser. Khim., 11, 1947 (2000). C. Giordano, Gazz. Chim. Ital., 104, 849 (1974). F. G. Baddar, F. H. Al-Hajjar, N. R. El-Rayyes, J. Heterocycl. Chem., 15, 105 (1978). M. M. Chincholkar, B. S. Kakadr, and V. S. Jamodr, Ind. J. Chem., 17, 629 (1980). R. M. Acheson and J. D. Wallis, J. Chem. Soc., Perkin Trans. 1, 2, 415 (1981). D. Barton and J. D. Ollis (editors), General Organic Chemistry [Russian translation], Khimiya, Moscow (1985), Vol. 9, p. 604 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, V. G. Zakrzewski, J. A. Montgomery, Jr., R. E. Stratmann, J. C. Burant, S. Dapprich, J. M. Millam, A. D. Daniels, K. N. Kudin, M. C. Strain, O. Farkas, J. Tomasi, V. Barone, M. Cossi, R. Cammi, B. Mennucci, C. Pomelli, C. Adamo, S. Clifford, J. Ochterski, G. A. Petersson, P. Y. Ayala, Q. Cui, K. Morokuma, D. K. Malick, A. D. Rabuck, K. Raghavachari, J. B. Foresman, J. Cioslowski, J. V. Ortiz, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. Gomperts, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayakkara, C. Gonzalez, M. Challacombe, P. M. W. Gill, B. Johnson, W. Chen, M. W. Wong, J. L. Andres, C. Gonzalez, M. Head-Gordon, E. S. Replogle, and J. A. Pople, Gaussian 98, Revision A 7. Gaussian Inc., Pittsburgh, USA (1998). Synthesis of Organic Compounds [ Russian translation], Izd-vo Instr. Lit., Moscow (1956), Pt. 7, p.25.
10.
1599
SYNTHESIS AND PROPERTIES OF (THIENO[2,3-b]PYRIDIN-3-YL)IMINOTRIPHENYLPHOSPHORANES. MOLECULAR STRUCTURE OF (2-BENZOYL-4-METHOXYMETHYL-6-METHYLTHIENO[2,3-b]PYRIDIN-3-YL)IMINOTRIPHENYLPHOSPHORANE

E. A. Kaigorodova, V. K. Vasilin, M. M. Lipunov, V. E. Zavodnik, and G. D. Krapivin Iminophosphoranes containing a thieno[2,3-b]pyridine fragment were obtained through a sequence of reactions: 1) alkylation of 3-cyano-2(1H)-pyridinethiones in alkaline medium by an -halocarbonyl compound with subsequent ThorpeZiegler cyclization of the resultant 2-thioalkylpyridines to give 3-aminothieno[2,3-b]pyridines, 2) diazotization of the amino group and nucleophilic substitution of the diazonium group by an azido group without isolation of the diazonium salts, and 3) reaction of the 3-azidothieno[2,3-b]pyridines with triphenylphosphine. Keywords: 3-aminothieno[2,3-b]pyridines, 3-azidothieno[2,3-b]pyridines, 3-cyano-2(1H)-pyridinethiones, (thieno[2,3-b]pyridin-3-yl)-iminotriphenylphosphoranes, molecular structure, synthesis. Iminophosphoranes, in light of their electronic structure, are promising intermediates for the synthesis of many compounds of different types [1-3]. In the present work, we synthesized thieno[2,3-b]pyridinyliminophosphoranes, for which no data have been available in the literature, and studied the physicochemical properties of these compounds. Pyridinethione 1, -haloacetic acid derivatives 2a-d, and phenacyl bromide 2e served as the starting compounds for the preparation of (thieno[2,3-b]pyridin-3-yl)iminotriphenylphosphoranes. The reaction of pyridinethione 1 with -halocarbonyl compounds 2a-e were carried out in the presence of two equivalents of KOH to bind the hydrogen halide liberated and provide for the ThorpeZiegler isomerization of intermediate S-alkyl derivatives 3a-e to give 3-aminothieno[2,3-b]pyridines 4a-e (Scheme 1). 3-Aminothieno[2,3-b]pyridines 4 are bright-yellow compounds, which are highly soluble in polar solvents (Table 1). Pyridines 4a and 4e have already been prepared and some of their properties have been reported in our previous work [4, 5]. The structure of the 3-aminothieno[2,3-b]pyridines was confirmed by IR, UV, and 1H NMR spectroscopy (Table 2). The IR spectra of 4a-e lacked the nitrile group band at 2210 cm-1 and thioamide group band at 1215 cm-1 characteristic for starting pyridinethione 1 but have stretching bands for the amino group NH bond at 3465-3400 and 3330-3255 cm-1 as well as stretching bands for the conjugated carbonyl group in ester 4a __________________________________________________________________________________________ Kuban State Technological University, 350072 Krasnodar, Russia; e-mail: organics@kubstu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1853-1862, December, 2004. Original article submitted July 5, 2002; revision submitted May 10, 2004. 1600 0009-3122/04/4012-16002004 Springer Science+Business Media, Inc.
Scheme 1
O
O CN
X R 2ae KOH N
O CN KOH
O NH2 O N S 4ae R
N H
S O
3ae
2-4 R = OEt, b R = N(CH2Ph)2, c R = NPh2, d R = morpholino, e R = Ph; , = Br, b-d = Cl
at 1660 cm-1, amides 4b-d at 1600-1590 cm-1, and ketone 4e at 1595 cm-1. The 1H NMR spectra of 4a-e have signals for the protons of all the groups; the broad singlet of the amino group is found at 6.13-8.12 ppm.
TABLE 1. Physicochemical Properties of 3-Aminothieno[2,3-b]pyridines 4a-e, 3-Azidothieno[2,3-b]pyridines 6a-e, and (Thieno[2,3-b]pyridin-3-yl)iminotriphenylphosphoranes 7a-e
Compound 4a 4b 4c 4d 4e 6a 6b 6c 6d 6e 7a 7b 7 7d 7e Empirical formula 13H16N2O3S C25H25N3O2S C23H21N3O2S 1519N3O3S C17H16N2O2S C13H14N4O3S C25H23N5O2S C23H19N5O2S C15H17N5O3S C17H14N4O2S C31H29N2O3PS 43H38N3O2S C41H34N3O2S C33H32N3O3S C35H29N2O2PS Found, % Calculated, % N 55.68 55.70 69.53 69.58 68.64 68.46 56.02 56.06 65.31 65.36 50.97 50.93 65.63 65.59 64.32 64.27 51.86 51.85 60.28 60.34 68.82 68.87 74.66 74.65 74.16 74.19 68.13 68.14 73.38 73.41 5.76 5.75 5.84 5.84 5.24 5.25 5.94 5.96 5.13 5.16 4.61 4.58 5.07 5.00 4.46 4.43 4.93 4.91 4.17 4.20 5.38 5.41 5.50 5.54 5.15 5.16 5.52 5.54 5.10 5.10 9.95 9.99 9.70 9.74 10.39 10.41 13.05 13.07 8.93 8.97 18.29 18.22 15.31 15.27 16.31 16.30 20.16 20.14 16.49 16.56 5.14 5.18 6.03 6.07 6.29 6.33 7.19 7.22 4.86 4.89 mp, (or dec. p.) 147.5-148 128-129 187-188 157-158 137-138 (118-119) 56-58 (177-178) (138-139) 115-117 235-236 214-215 289-290 238-239 215-216 208 (4.83), 246 (4.32), 286 (4.37), 388 (3.99) 209 (4.97), 217 (4.42), 340 (3.76) 206 (4.80), 250 (4.77), 394 (3.83) 208 (4.89), 263 (4.39), 340 (3.82) 208 (4.85), 280 (4.23), 322 (4.15), 442 (3.86) UV spectrum, max, nm (log ) 208 (4.35), 240 (4.05), 288 (4.61), 373 (3.81) 207 (4.56), 243 (3.93), 293 (3.27), 367 (3.59) 207 (4.62), 298 (4.28), 393 (3.91) 207 (4.33), 242 (3.95), 290 (4.27), 366 (3.61) 212 (4.44), 283 (4.23), 311 (4.40), 415 (4.05) Yield, % 78
69 90 71 92 82 82 97 50 74 69 47 72 64 56
1601
1602
TABLE 2. Spectral Data of Products

Compound 1 4a IR spectrum, , cm-1 NH2 COC (N3) 3 4 3420, 3330 3400, 3305 3410, 3310 3420, 3310 3465, 3255 (2130) 1275*, 1190*, 1120 1145, 1100, 1070 1110, 1070 1120, 1090, 1065 1095 1280*, 1190*, 1130, 1100, 1050 1120, 1085 1120, 1090 3 (3H, s) 5 2.56 3 (3H, s) 6 3.41 2 (2H, s) 7 4.82 H NMR spectrum, , ppm (J, Hz) Py (1H, s) 8
1
= 2 1660
other signals 9
7.20
1.32 (3, t , J = 7.2, 2CH3); 4.30 (2, q, J = 7.2, CH2CH3); 6.92 (2, br. s, NH2) 4.71 (4H, s, NCH2); 7.25-7.35 (10, m, 265); 6.62 (2, br. s, NH2) 7.20-7.44 (10, m, 2C6H5); 7.25 (2, br. s, NH2) 3.653.70 (8, m, morpholino); 6.13 (2H, br. s, NH2)
4b
1595
2.80
3.43
4.81
7.08
4c 4d
1600 1590
2.50 2.58
3.40 3.41
4.80 4.79
7.14 7.10
4e 6a
1595 1720
2.66 2.55
3.45 3.41
4.80 4.88
7.0
7.277.89 (5H, m, C6H5); 8.12 (2H, br. s, NH2) 1.38 (3H, t , J = 7.2, CH2CH3); 4.27 (2H, q, J = 7.2, CH2CH3)
6b 6c
1620 1635
(2115) (2120)
2.59 2.54
3.52 3.46
4.93 4.92
4.67 (4, s, NC2); 7.20-7.36 (11, m, Py,65) 7.22-7.45 (11, m, Py, 65)
TABLE 2 (continued)
1 6d 6e 7 2 1625 1625 1680 3 (2115) (2110) 4 1120, 1070 1110 1255*, 1170*, 1120, 1080 1100, 1080 1120, 1070 1115, 1085 1120, 1080 5 2.64 2.50 2.50 6 3.51 3.38 3.08 7 4.94 4.76 4.86 8 7.33 7.26 7.18 9 3.66-3.70 (8, m, 2, NCH2) 7.07-7.62 (5H, m, C6H5) 0.79 (3, t , J = 7.2, 23); 3.55 (2, q, J = 7,2, 23); 7.48-7.62 (15, m, 65) 4.08 (4, s, N2); 7.00-7.67 (26, m, Py, 65) 6.67-7.69 (26, m, Py , 65) 7.15 3.05 (4, s, N2); 3.42 (4, s, 2); 7.44-7.64 (15, m, 65) 6.87-7.85 (21, m, Py, 65)
7b 7c 7d 7e
1620 1640 1605 1600
2.50 2.47 2.55 2.53
3.10 3.21 3.20 3.15
4.87 5.04 4.99 4.96
_______ * Bands for ester .
1603
The diazotization of 3-aminothieno[2,3-b]pyridines 4a-e was carried out in acetic acid in the presence of conc. sulfuric acid. Diazonium salts 5a-e obtained in solution were used for nucleophilic substitution by means of sodium azide immediately after eliminating excess nitrous acid.
O +N 2 4ae NaNO2 H2SO4 N S 5ae
_ HSO4 O R NaN3 N
O N3 O S 6ae R
5, 6 a R = OEt, b R = N(CH2Ph)2, c R = NPh2, d R = N(CH2CH2)2O, e R = Ph
The resultant 3-azidothieno[2,3-b]pyridines 6a-e are colorless or light-yellow compounds, which decompose upon storage (Table 1). The IR spectral data provide the most helpful information for establishing the structure of 3-azidothieno[2,3-b]pyridines 6 (Table 2). The substitution of the amino groups at C(3) in thieno[2,3-b]pyridines 4 by azido groups leads to the disappearance of the two NH stretching bands and a shift in the carbonyl group band toward higher frequencies: by 60 cm-1 for ester 6a, by 25-65 cm-1 for amides 6b-d, and by 30 cm-1 for ketone 6e. The characteristic band for the azido group appears at 2130-2110 cm-1. The 1H NMR spectra of azides 6 lack the amino group proton signals found in the spectra of starting thieno[2,3-b]pyridines 4 (Table 2). The reaction of 3-azidothieno[2,3-b]pyridines 6 with triphenylphosphine was carried out in benzene. This reaction proceeds with the liberation of nitrogen. The cessation of nitrogen liberation indicates the end of this reaction.
Ph O _ N 6ae PPh3 N S 7ae + Ph P Ph O R
7 a R = OEt, b R = N(CH2Ph)2, c R = NPh2, d R = N(CH2CH2)2O, e R = Ph
The resultant iminophosphoranes 7a,c,e are yellow, while 7b and 7d are colorless. These products form crystals with high melting points (Table 1). The presence of the heteroaromatic substituent at the nitrogen atom in triphenylphosphoranes 7 provides for their resistance to the action of water. Phosphoranes 7 are insoluble in alkanes and diethyl ether but have moderate solubility in ethanol and good solubility in DMF and DMSO. In comparison to the IR spectra of the corresponding azides, the spectra of iminophosphoranes 7 (Table 2) lack the azido group band and show stronger CHar stretching bands. The structure of iminosphosphoranes 7 was confirmed by their 1H NMR spectra. An X-ray diffraction structural analysis was carried out for iminophosphorane 7e which has a benzoyl substituent at C(2) of the thiophene system (Fig. 1, Tables 3 and 4).
1604
Fig. 1. Projection of the structure of 7e.
The steric strain in the O(2)C(11)C(2)C(1)N(2)P(1) fragment leads to significant distortions of the bond angles at these atoms. Thus, the C(24)P(1)C(30), N(2)P(1)C(24), and N(1)P(1)C(30) bond angles are expanded to 113.59, 115.74, and 114.34, respectively, probably due to the repulsion of the
TABLE 3. Bond Lengths (d) in 7e Obtained in an X-Ray Diffraction Structural Analysis

Bond S(1)C(3) S(1)C(2) P(1)N(2) P(1)C(24) P(1)C(30) P(1)C(18) O(1)(9) O(1)C(10) O(2)C(11) N(1)C(4) N(1)C(3) N(2)C(1) C(1)C(2) C(1)C(7) C(2)C(11) C(3)C(7) C(4)C(5) C(4)C(8) C(5)C(6) C(6)C(7) C(6)C(9) C(11)C(12) C(12)C(17) d, 1.723(3) 1.763(3) 1.575(2) 1.799(3) 1.814(3) 1.817(3) 1.404(4) 1.416(4) 1.231(3) 1.330(4) 1.346(3) 1.354(3) 1.403(4) 1.458(4) 1.432(4) 1.397(4) 1.394(4) 1.502(4) 1.374(4) 1.405(4) 1.495(4) 1.498(4) 1.376(4) Bond C(12)C(13) C(13) C(14) C(14)C(15) C(15)C(16) C(16)C(17) C(18)C(23) C(18)C(19) C(19)C(20) C(20)C(21) C(21)C(22) C(22)C(23) C(24)C(29) C(24)C(25) C(25)(26) C(26)C(27) C(27)C(28) C(28)C(29) C(30)C(35) C(30)C(31) C(31)C(32) C(32)C(33) C(33)C(34) C(34)C(35) d, 1.378(4) 1.373(4) 1.365(5) 1.357(5) 1.386(5) 1.379(4) 1.379(4) 1.377(5) 1.366(6) 1.368(6) 1.384(5) 1.382(4) 1.391(4) 1.375(5) 1.359(6) 1.370(6) 1.388(5) 1.386(4) 1.389(4) 1.381(5) 1.359(6) 1.364(6) 1.388(5)
1605
TABLE 4. Bond Angles () in 7e Obtained in an X-Ray Diffraction Structural Analysis

Angle C(3)S(1)C(2) N(2)P(1)C(24) N(2)P(1)C(30) C(24)P(1)C(30) N(2)P(1)C(18) C(24)P(1)C(18) C(30)P(1)C(18) C(9)O(1)C(10) C(4)N(1)C(3) C(1)N(2)P(1) N(2)C(1)C(2) N(2)C(1)C(7) C(2)C(1)C(7) C(1)C(2)C(11) C(1)C(2)S(1) C(11)C(2)S(1) N(1)C(3)C(7) N(1)C(3)S(1) C(7)C(3)S(1) N(1)C(4)C(5) N(1)C(4)C(8) C(5)C(4)C(8) C(6)C(5)C(4) C(5)C(6)C(7) C(5)C(6)C(9) C(7)C(6)C(9) C(3)C(7)C(6) C(3)C(7)C(1) C(6)C(7)C(1) O(1)C(9)C(6) O(2)C(11)C(2) O(2)C(11)C(12) C(2)C(11)C(12) , deg 91.16(13) 115.74(13) 114.34(13) 113.59(13) 104.81(13) 104.56(13) 101.74(13) 111.8(3) 115.2(3) 137.5(2) 130.9(2) 118.3(2) 110.8(2) 127.5(2) 112.5(2) 119.3(2) 126.5(3) 120.4(2) 113.1(2) 122.7(3) 117.2(3) 120.2(3) 121.9(3) 116.8(3) 120.7(3) 122.5(2) 116.9(2) 112.5(2) 130.6(2) 110.5(2) 122.4(3) 117.8(3) 119.7(2) Angle C(17)C(12)C(13) C(17)C(12)C(11) C(13)C(12)C(11) C(14)C(13)C(12) C(15)C(14)C(13) C(16)C(15)C(14) C(15)C(16)C(17) C(12)C(17)C(16) C(23)C(18)C(19) C(23)C(18)P(1) C(19)C(18)P(1) C(20)C(19)C(18) C(21)C(20)C(19) C(20)C(21)C(22) C(21)C(22)C(23) C(18)C(23)C(22) C(29)C(24)C(25) C(29)C(24)P(1) C(25)C(24)P(1) C(26)C(25)C(24) C(27)C(26)C(25) C(26)C(27)C(28) C(27)C(28)C(29) C(24)C(29)C(28) C(35)C(30)C(31) C(35)C(30)P(1) C(31)C(30)P(1) C(32)C(31)C(30) C(33)C(32)C(31) C(32)C(33)C(34) C(33)C(34)C(35) C(30)C(35)C(34) , deg 118.6(3) 124.0(3) 117.3(3) 120.8(3) 120.0(4) 120.1(3) 120.3(3) 120.1(3) 118.7(3) 123.4(3) 117.9(2) 120.9(4) 119.9(4) 120.1(4) 120.1(4) 120.3(4) 118.5(3) 124.4(2) 117.0(2) 120.9(4) 120.1(4) 120.2(4) 120.5(4) 119.8(4) 119.2(3) 119.5(2) 121.1(2) 119.8(3) 120.7(4) 120.1(4) 120.6(4) 119.6(3)
C(24)C(29) and C(30)C(35) benzene rings and C(1)O(1) carbonyl group. This repulsion would also account for the expansion of the bond angle at N(2) (by 17.5) relative to the standard value for sp2-hybridized nitrogen. The phosphorus atom is found in an sp3-hybridized state: the mean value of the bond angles at the phosphorus atom is 109.12. The phenyl ring of the benzoyl substituent is extruded from the plane of the heterocyclic system by 65.2 as the result of repulsion of the sulfur atom and hydrogen atom at C(17). The S(1)C(3) bond (1.723 ) is shortened relative to the S(1)C(2) bond (1.763 ) due to displacement of an electron pair of this sulfur atom toward the pyridine ring with -electron deficiency.
1606
EXPERIMENTAL The UV spectra were taken in ethanol on Specord UV-vis and Specord M-40 spectrometers at 200-700 nm in quartz cells; the path length was 10 mm. The IR spectra were taken on Specord-71 and UR-20 spectrometers at 3600-650 cm-1 using NaCl and KBr plates. The crystalline compounds were taken in vaseline mull. The 1H NMR spectra were taken on a Bruker WM-250 spectrometer at 250 MHz in DMSO-d6 with TMS as the internal standard. N,N-Diphenyl-3-amino-4-methoxymethyl-6-methylthieno[2,3-b]pyridine-2-carboxamide (4c). 10% aq. KOH (5.6 ml, 10 mmol) was added to a suspension of 3-cyano-2(1H)-pyridinethione 1 (1.94 g, 10 mmol) in DMF (20 ml). Then, N,N-diphenylchloracetamine (2c) (2.46 g, 10 mmol) was added with stirring. The mixture was maintained for 10-15 min at room temperature. Then, an additional 10% aq. KOH (5.6 ml, 10 mmol) was added and the reaction mixture was stirred for 6 h at 80-85C. After cooling of the reaction mixture, the precipitate formed was separated, washed consecutively with water and 1:1 ethanolwater, and dried in the air. The filtrate was diluted with a two-fold volume of water and the flocculent precipitate was separated, washed with water, and dried. The product was recrystallized from ethanolDMF. The total yield was 3.63 g (90%). Products 4b,d,e were similarly obtained. N,N-Diphenyl-3-azido-4-methoxymethyl-6-methylthieno[2,3-b]pyridine-2-carboxamide (6c). Compound 4c (2.02 g, 5 mmol) was dissolved in glacial acetic acid (12 ml) and conc. sulfuric acid (0.6 ml) was added. The reaction mixture was cooled in an ice bath to 5-9C and then, a solution of NaNO2 (0.48 g, 7 mmol) in water (2 ml) was added slowly in small portions. The mixture was stirred for 20 min and then, the excess nitrous acid was neutralized by adding urea (monitored by iodinestarch paper). A solution of NaN3 (0.46 g, 7 mmol) in water (2 ml) was added dropwise over 10 min. The mixture was stirred for 1 h and then slowly poured into water containing finely ground ice. The precipitate of azide 6c was separated, washed on the filter with cold water until the wash water was neutral, and dried over conc. sulfuric acid in the absence of light to give 2.08 g (97%) of 6c. 3-Azidothieno[2,3-b]pyridines 6a,b,d were similarly obtained. (2-Benzoyl-4-methoxymethyl-6-methylthieno[2,3-b]pyridin-3-yl)iminotriphenylphosphorane (7e). Triphenylphosphine (2.62 g, 10 mmol) was added to a solution of 3-azidothieno[2,3-b]pyridine 6e (3.38 g, 10 mmol) in benzene (100 ml). The reaction mixture was stirred until gas bubbles were no longer observed and left overnight. The precipitate formed was filtered off, washed with benzene, and dried in the air. The filtrate was evaporated in vacuum and the residue was triturated with diethyl ether. The crystals formed were filtered off, washed with benzene, and dried in the air. The product was recrystallized from ethanolDMF. The total yield of 7e was 3.2 g (56%). Yellow monoclinic crystals of 7e were obtained by crystallization from ethanol. The unit cell parameters are as follows: a = 9.869(2), b = 16.644(3), c = 17.853(4) , = 92.58(3), V = 2929.6(10) 3, space group P2(1)/n, Z = 4. The unit cell parameters and intensities of 2293 independent reflections were measured on a CAD-4 automatic diffractometer using MoK radiation, -filter, and /2-scanning to 2max = 44.6. The structure was deciphered by the direct method using the SHELXTL program package [6] and refined anisotropically for the nonhydrogen atoms and isotropically for the hydrogen atoms to R1 = 0.0268 and Rw = 0.0709. Products 7a,c were similarly obtained. (N-Morpholyl-2-carbamoyl-4-methoxymethyl-6-methylthieno[2,3-b]pyridin-3-yl)iminotriphenylphosphorane (7d). Triphenylphosphine (2.62 g, 10 mmol) was added to a solution of 3-azidothieno[2,3-b]pyridine 6d (3.47 g, 10 mmol) in benzene (100 ml). The reaction mixture was stirred until there was no further liberation of gas and left overnight. The mixture was then evaporated in vacuum by 4/5 and hexane (10 ml) was added. The crystals formed were filtered off, washed with hexane, and dried in the air. The product was recrystallized from ethanolDMF. The total yield of 7d was 3.66 g (63%). Product 7b was similarly obtained.
1607
This work was carried out with the financial support of the Russian Basic Research Fund (RFFI) (Grant No. 03-03-96636).
REFERENCES 1. 2. 3. 4. 5. 6. J. Schweng and E. Zbiral, Tetrahedron, 31, 1823 (1975). J. Schweng and E. Zbiral, Monatsch. Chem., 107, 537 (1976). H. Alcock, PhosphorusNitrogen Compounds [Russian translation], Mir, Moscow (1976), pp. 177, 355. E. A. Kaigorodova, L. D. Konyushkin, M. E. Niyazymbetov, S. N. Kvak, V. N. Zaplishny, and V. P. Litvinov, Izv. Akad. Nauk, Ser. Khim., 2215 (1994). S. N. Mikhailichenko, N. Ya. Gubanova, E. A. Kaigorodova, V. A. Kovardakov, L. G. Bogachuk, and V. N. Zaplishnyi, Izv. Vuzov, Khim. Khim. Tekhnol., 41, No. 1, 63 (1998). G. M. Sheldrick, Computational Crystallography, Oxford Univ. Press, New YorkOxford (1982).
1608
STUDY OF NITROGEN- AND SULFUR-CONTAINING HETEROCYCLES. 54.* PROPERTIES AND CONVERSIONS OF PYRIMIDO[4,5-b]-1,4-BENZOTHIAZEPINES. SYNTHESIS OF A NOVEL HETEROCYCLIC SYSTEM: PYRIMIDO[5,4-c]ISOQUINOLINE
T. S. Safonova1, M. P. Nemeryuk1, N. A. Grineva1, A. F. Keremov2, O. S. Anisimova1, and N. P. Solov'eva1 We have studied some properties and conversions of pyrimido[4,5-b]-1,4-benzothiazepines: reduction, oxidation, reactions with nucleophilic reagents (methanol, hydrazine, hydroxylamine, o-methylhydroxylamine, and thiosemicarbazide). We have synthesized derivatives of a novel heterocyclic system: pyrimido[5,4-c]isoquinoline. Keywords: pyrimidyl aryl sulfides, pyrimido[4,5-b]-1,4-benzothiazepine, pyrimido[5,4-c]isoquinoline. In previous work [2, 3], we described synthesis of derivatives of 1,4-thiazine tricyclic systems, which include substances with antitumor and psychotropic activity. In continuing these studies, we have developed a method for obtaining 4-alkoxy(amino)-8-nitro derivatives of pyrimido[4,5-b]-1,4-benzothiazepines 1a-d [1]. This work is devoted to study of the properties of compounds 1a-d and synthesis of novel derivatives of this heterocyclic system which are of interest for biological tests. In the first step of this work, we studied reduction of pyrimidobenzothiazepines 1a-c. We established that when these substances are treated with sodium borohydride in ethanol medium at 18-20C, the dihydropyrimidobenzothiazepines 2a-c are smoothly formed. Their structure has been confirmed by the presence of absorption bands in the IR spectra of compounds 2a,b for the NH group in the 3280 cm-1 and 3380 cm-1 region respectively. For the example of compounds 1b and 2b, we established that their reduction by iron filings in acetic acid leads to 8-amino derivatives 2d and 2e. The compound 2e is also formed when pyrimidobenzothiazepine 2d is treated with sodium borohydride under the conditions for synthesis of derivatives 2a-c. Reactions of compound 2d with phenyl isocyanate and phenyl isothiocyanate yield derivatives 2f,g.
_______ * For Communication 53, see [1]. __________________________________________________________________________________________ Center for Drug Chemistry/All-Russian Scientific Research Pharmaceutical Chemistry Institute, Moscow 119815; e-mail: sedov@drug.org.ru. 2 Dagestan State University, Makhachkala 367010, Russia. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1863-1872, December, 2004. Original article submitted March 25, 2002. 0009-3122/04/4012-16092004 Springer Science+Business Media, Inc. 1609
1
R N N
H C NO2 S NaBH4 from 1a,b N
H N
H H C NO2
1ad
Fe from 1b
N Fe
2ac
from 2b H H C NH2 N PhNCX R N N S N H C NHCNHPh X S
R N N
H N C NH2 S
NaBH4 N
H N
2d
2e
2f, g
1a, 2a R = OMe, 1b, 2b,dg R = NMe2, 1c, 2c R = NHMe, 1d R = NH2; 2f X = O; 2g X = S
In this work, we also studied the reactivity of the azomethine group in pyrimidobenzothiazepines 1a-c with respect to nucleophilic reagents. We observed that when compound 1a is heated in methanol in the presence of KOH, a molecule of this alcohol is added to the azomethine group N=CH with formation of an NHCH(OMe) bond. As a result, compound 1a is smoothly converted to compound 2h (89% yield). Compound 2h (90% yield) was also obtained by an alternate synthesis from 5-amino-6-mercapto-4methoxypyrimidine and 6-chloro-3-nitrobenzaldehyde in methanol in the presence of 2 moles of KOH.
MeO MeOH
4 3
5N
H H C
OMe
6
OMe
1a
N
2
NO2 N
1
N N
NH2 OHC + SH Cl
NO2
2h
The structure of compound 2h has been confirmed by the presence of an absorption band in the IR spectrum for the NH group at 3350 cm-1. In the 1H NMR spectrum in pyridine-d5, besides signals from the two OMe groups at 3.75 ppm and 3.37 ppm we observe two doublet signals at 5.70 ppm and 6.54 ppm, each with an intensity of one proton unit. These signals are due to coupling of the H-5,6 protons, which is confirmed when we record the spectrum in the presence of deuteromethanol. In this case, as a result of substitution of the H-5 proton by deuterium, in the spectrum we observe only a singlet signal from the H-6 proton at 5.74 ppm. The reactions of thiazepines 1a-c with hydrazine hydrate 3a occur with opening of the thiazepine ring, as a result of which pyrimidyl aryl sulfides 4a-c are formed. We obtained compound 4a and also substances 4d-f with a similar structure by reaction of dihydrothiazepine 2h with hydrazine hydrate, hydroxylamine (3b), Omethylhydroxylamine (3c), and thiosemicarbazide (3d) respectively.
1610
1ac
H2NR1 (3a) H2NR1 (3ad) N
NH2 HC
NR
R NO2 N N
H N
NHR 1 H C NO2 S
2h
S 4af (A)
(B)
3 R1 = NH2, b R1 = OH, c R1 = OMe, d R1 = NHCSNH2; 4 ,df R = OMe; b R = NMe2, c R = NHMe, ac R1 = NH2, d R1 = OH, e R1 = OMe, f R1 = NHCSNH2
When alkaloids of the dihydroisoquinoline series, which contain an azomethine group, react with phenylhydrazine, hydroxylamine, and a number of other similar compounds, they form cyclic derivatives that are in equilibrium with the corresponding open form [4]. In analogy with these data, we might hypothesize that compounds 4a-f exist both in open form A and in the isomeric cyclic form B or as an equilibrium mixture of these forms. When choosing between the open and cyclic structures A and B, we decided in favor of A based on the IR, 1H NMR, and mass spectra of compounds 4a-e. Thus in the IR spectrum of o-methyloxime 4e, we see absorption bands for the NH2 group at 3400-3500 cm-1. The IR spectral data for oxime 3d in the region of the stretching vibrations of the NH2 group are difficult to interpret because of the presence of the hydroxyl group. However, the presence of a free amino group in compound 4d is supported by the significant decrease in the intensity of the absorption band for the bending vibrations of this group at 1610 cm-1 that we observe upon deuteration. Furthermore, when the IR spectra of compounds 4d,e were recorded in CCl4, we did not observe absorption bands for the NH group characteristic of the cyclic form B. The existence of compounds 4a-d preferentially in the open form A is supported by the presence in the 1 H NMR spectra of a signal from the methine proton at the double bond with 8.24-8.44 ppm, characteristic of form A. If compounds 4a-d had a cyclic structure B or existed as a mixture of forms A and B, then in their 1 H NMR spectra we should have observed a doublet signal from the H-6 proton, split as a result of coupling with the H-5 proton, as was observed in the case of compound 2h. According to the mass spectral data for compounds 4a-d, they are found in the gas phase as a mixture of cyclic B and open A forms, with a significant predominance of the latter. Thus in the mass spectra* of compounds 4a-d, besides the molecular ion peaks 320, 333, 319, and 321 respectively, we observed ions characteristic for the open form. The most intense peak in the spectra of hydrazones 4a-c is the ion peak [MNH2]+, respectively 304, 317, and 303. Analogous decomposition is also observed for oxime 4d, as a result of which the ions [MOH]+ 304 and [MH2O]+ 303 are formed. A common feature of fragmentation of compounds 4a-d is elimination of the NR1 group (present in the A structure) from the molecular ion to form ions with m/z 320 (for substances 4a,d), 303 (for 4b), and 289 (for 4c). The correctness of the assignment is proven by the corresponding shift of the mass number for the peak of this fragment when the substituents R and R' are varied. In the mass spectra of compounds 4a-d, the most intense peaks are those for ions with m/z 157 (for substances 4a,d), 170 (for 4b), and 156 (for 4c). The structure A1 is assigned to these ions, which is supported by the change in the mass number of these ions depending on the substituent R on the C(4) atom. The A1 fragment is missing in the mass spectra of pyrimidobenzothiazepines 1a-c, which are the model compounds in this case. Consequently, the presence of the A1 fragment in the mass spectra of compounds 4a-d may be due to decomposition of the open form A.
_______ * Here and in the following, we give the m/z values for the ion peaks. 1611
R NH2 HC N N S H (A)
R1 NO2
N
R NH2 N SH
(A1)
Furthermore, in the mass spectra of compounds 4a-d there are ion peaks corresponding to decomposition of the cyclic form B. Thus, for example, we observe low-intensity ion peaks with m/z 288 (for substances 4a,d), 301 (for 4b), and 287 (for 4c). These ions correspond to detachment of an NH2R1 group (characteristic of cyclic form B) from the molecular ion. In the case of the oxime 4d, we obtained the mass spectrum of its deutero analog derivative D-4d. We noted that the mass number for the 288 fragment was retained just as in the mass spectrum of the undeuterated compound 4d. These data suggest that the eliminated ND2OD group contains all three mobile hydrogen atoms present in the cyclic form of compound 4d. Analogous decomposition is also observed for 2,6-dimethoxypyrimidobenzothiazepine 2h, which is the model compound for the cyclic structure.
D MeO N N S N H NDOD C NO2 ND2OD MeO N N S 288 H C NO2 +
D-4d 2h
MeOH
Fragmentation of compound 2h to form the ion [MMeOH]+ with m/z 288 is predominant. Further decomposition of the [MMeOH]+ ion and also compound 4d exactly matches the decomposition of 4-methoxypyrimidobenzothiazepine 1a, which has an azomethine group. The data presented support the idea that the [MNH2R1]+ ion peaks observed in the mass spectra of hydrazones 4a-c and oxime 4d are the consequence of fragmentation of cyclic form B for these substances. Thus using spectral data we have established that compounds 4a-d in crystals and in solutions exist predominantly in the open form A, while in the gas phase they exist as a mixture of the cyclic B and open A forms, with predominance of the latter. Then we studied oxidation of pyrimidobenzothiazepines 1a-c by hydrogen peroxide. We observed that treatment of the 4-methoxy derivative 1a with hydrogen peroxide in acetic acid at 60-65C leads to formation of a mixture of compounds, from which we could isolate sulfoxide 5a and sulfone 5b in pure form. The initial step of this reaction is probably addition of a water molecule to the azomethine group to form the unstable intermediate compound C. Oxidation of the latter occurs both at the carbon atom in the 6 position and at the sulfur atom, and leads to formation of a mixture of compounds 5a and 5b.
H OH C NO2 N S C MeO N N S O H N O C NO2 MeO H N O C NO2 N O S O
MeO
H N
1a
H2O2 (+ H2O)
5a
5b
1612
Unexpected results were obtained upon oxidation of 4-amino-substituted 8-nitropyrimidobenzothiazepines 1b-d under the conditions indicated above (H2O2 + AcOH, 60-65C). In this case, we obtained derivatives of a novel heteroaromatic system pyrimido[5,4-c]isoquinolines 6a-c in satisfactory yields. Derivatives of the isomeric system pyrimido[4,5-c]isoquinoline, obtained by heating 4-amino-5arylpyrimidines with excess formic acid in the presence of phosphorus trichloride, have been described earlier in [5]. Compounds 6a-c do not contain a sulfur atom; in their mass spectra, there are intense molecular ion peaks with m/z 269, 255, and 241 corresponding to their structures. In the 1H NMR spectra, we observe a set of signals from aromatic protons in the 8.58-9.53 ppm region with integrated intensity corresponding to five proton units. This suggests a tricyclic structure for compounds 6a-c and rules out the alternative Schiff's base structure D, in the 1H NMR spectra of which there should be signals from six aromatic protons. Formation of pyrimidoisoquinolines 6a-c upon oxidation of compounds 1b-d is obviously a consequence of elimination of a sulfur atom in the thiazepine ring with formation of a CC bond between the pyrimidine and benzene rings, with simultaneous contraction of the seven-membered ring down to a sixmembered ring. For the example of 8-nitropyrimidoisoquinoline 6a, we studied its reduction by iron filings in acetic acid to form the corresponding amine 6d, from which we obtained the chloroacetyl derivative 6e by acylation with chloroacetyl chloride.
R N N N H C
NO2
D
R
4 5
1bd
H2O2
3
N
2
N
6
N
1 10 9 8
NO2
6ac
NMe2 NMe2 N ClCH2COCl
N N
6a
Fe
N N
NH2
NHCOCH2Cl
6d
6e
6 R = NMe2, b R = NHMe, c R = NH2
Biological studies of the synthesized compounds showed that pyrimidobenzothiazepines 1a,b and 2d exhibit neuroleptic activity. The pyrimidobenzaldehyde thiosemicarbazone 4f and pyrimidoisoquinoline 6b suppress the growth of the tuberculosis bacillus in in vitro experiments, while compound 4f additionally inhibits growth of lactic acid bacteria.
1613

Compound 2 2b 2c 2d 2e 2f 2g 2h 4a 4b 4c 4d 4e 4f 5a 5b 6 6b 6c 6d 6e Empirical formula C C12H10N4O3S C13H13N5O2S C12H11N5O2S C13H13N5S C13H15N5S C20H18N6OS C20H18N6S2 C13H12N4O4S C12H12N6O3S C13H15N7O2S C12H13N7O2S C12H11N5O4S C13H13N5O4S C13H13N7O3S2 C12H8N4O5S C12H8N4O6S C13H11N5O2 C12H9N5O2 C11H7N5O2 C13H13N5 C15H14ClN5O 49.86 49.66 51.52 51.48 49.93 49.90 57.29 57.56 57.20 57.14 61.46 61.54 58.96 59.11 49.01 48.70 44.85 45.00 47.01 46.84 44.96 45.14 44.89 44.86 46.86 46.57 41.73 41.16 44.72 45.00 43.09 42.85 58.00 58.00 56.30 56.47 54.60 54.77 65.18 65.40 57.61 57.05 Found, % Calculated, % H N 3.39 3.45 4.33 4.29 3.65 3.81 4.79 4.79 5.51 5.49 4.39 4.82 4.62 4.43 3.87 3.76 3.60 3.75 4.46 4.50 4.02 4.07 3.44 3.43 3.96 3.88 3.12 3.43 2.57 2.50 2.55 2.37 4.01 4.08 3.48 3.52 2.74 2.90 5.78 5.45 4.00 4.43 19.73 19.31 23.20 23.10 24.17 24.20 25.67 25.83 25.68 25.64 21.64 51.54 20.45 20.68 17.56 17.50 26.42 26.25 29.79 29.42 31.01 30.72 22.00 21.81 21.00 20.89 17.57 17.50 16.61 16.67 26.36 26.10 27.42 27.45 28.89 29.00 29.70 29.40 22.21 22.18 Yield, % 89 93 92 43 66-83 54 52 89-90 76-90 76 87 80 96 91 36 52 63 67 66 25 58
mp, * S 11.04 11.03 10.64 10.56 11.20 11.10 11.72 11.80 8.44 8.20 15.37 15.76 10.14 10.00 16.80 16.88 10.19 10.00 9.84 9.52 *2 216-218 190-192 262-264 179-181 169-171 215-216 167-170 195-200 199-201 190-192 213-214 177-179 170-172 329-331 (dec.) 140-142 250-252 246-248 251-253 >300 219-221 199-201
_______ * Solvents for crystallization: methanol (compounds 2a,d-f,h, 4b,e), ethanol (compounds 2b,c,g, 4a,d, 5a,b, 6a,b,d), DMFwater, 1:1 (compounds 4c,f), and DMF (compounds 6c,e). *2 Found, %: Cl 11.19. Calculated, %: Cl 11.30. EXPERIMENTAL The IR spectra were obtained on a PerkinElmer 457 spectrometer in vaseline oil and in CCl4 solution. The H NMR spectra were recorded on a Varian XL-200 (200 MHz), internal standard TMS. The mass spectra were obtained on an MX-1303 mass spectrometer with injection of the substance directly into the ion source with ionizing electron energy 30 eV and temperature 125C. The course of the reactions and the purity of the compounds were monitored by TLC on Silufol UV-254 plates in a 5:5:1.5 benzeneethyl acetateethanol system. Visualization in UV light.
1
1614
TABLE 2. Spectral Characteristics of Synthesized Compounds

Compound 2 2b 2c 2h 4a 4b 4c 4d 4e 5a 5b 6 6b 6c 3310, 3230, 1610 3500, 400, 1600 3200, 1650, 1065 3170, 1660, 1160 3360 3470, 3400 IR spectrum, , cm-1 3380 3280 3340 3350 3400, 3300, 1630
1
NMR, , ppm*
Mass spectrum, M+, m/z
7.48 (1, d, NH), 7.61 (2, d, 2)
5.76 (1, d, NH), 6.55 (2, d, 2-6), 3.75 (3, s, 3-4), 3.37 (3, s, 3-6) 8.24 (1, s, =NR1), 8.12 (1H, s, H-2), 8.74-7.74 (benzene ring protons) 8.24 (1, s, =NR1), 7.24 (1H, s, H-2), 8.82-7.74 (benzene ring protons) 8.42 (1, s, =NR1), 8.29 (1H, s, H-2), 8.72-7.74 (benzene ring protons) 8.34 (1, s, =NR1), 7.92 (1H, s, H-2), 8.50-8.00 (benzene ring protons) 8.44 (1, s, =NR1), 7.90 (1H, s, H-2), 8.08-8.05 (benzene ring protons)
320, 288, 157 320, 304, 288, 157 333, 317, 303, 301, 170 319, 303, 289, 287, 156 379, 320, 304, 303, 288, 157
8.58-9.36 (aromatic protons) 8.60-9.42 (aromatic protons) 8.70-9.53 (aromatic protons)
_______ * The 1H NMR spectra were taken in pyridine-d5 (compounds 2a,h and 4a-d) and in DMSO-d6 (compounds 6a-c).
The physicochemical and spectral characteristics of the compounds obtained are presented in Tables 1 and 2. 4-Methoxy(dimethylamino, methylamino, amino)-8-nitropyrimido[4,5-b]-1,4-benzothiazepines 1a-d were obtained by the method in [1]. 4-Methoxy-8-nitro-5,6-dihydropyrimido[4,5-b]-1,4-benzothiazepine (2a). NaBH4 (0.19 g, 5 mmol) was added with vigorous stirring to a suspension of 4-methoxy-8-nitropyrimido[4,5-b]-1,4-benzothiazepine (1a) (0.57 g, 2 mmol) in anhydrous ethanol (10 ml). The mixture was stirred for 3 h at 20C and evaporated under vacuum to dryness. Water (5 ml) was added to the residue and then it was acidified with 10% HCl down to pH 5-6; the precipitate was filtered out, washed with water, and dried. Compound 2a (0.52 g) was obtained. Compounds 2b,c were obtained similarly. 8-Amino-4-dimethylaminopyrimido[4,5-b]-1,4-benzothiazepine (2d). Iron filings (1.6 g) and glacial acetic acid (2 ml) were added to a suspension of 4-dimethylamino-8-nitropyrimido[4,5-b]-1,4-benzothiazepine (1b) (0.8 g, 2.7 mmol) in methanol (65 ml). The mixture was boiled for 8 h and filtered. The solution was evaporated under vacuum to dryness. Water (20 ml) was added to the residue and it was alkalinized with aqueous NaOH up to pH 6-7 and then extracted with ethyl acetate. The solution was dried with Na2SO4, filtered, and evaporated under vacuum to dryness. Obtained 0.31 g of compound 2d. 8-Amino-4-dimethylamino-5,6-dihydropyrimido[4,5-b]-1,4-benzothiazepine (2e). A. Iron filings (2 g) and glacial acetic acid (2 ml) were added to a suspension of 4-dimethylamino-8-nitro-5,6dihydropyrimido[4,5-b]-1,4-benzothiazepine (2b) (1.0 g, 3.3 mmol). The mixture was boiled for 12 h and then was treated as indicated in the synthesis of compound 2d. Obtained 0.6 g (66%) of compound 2e. B. NaBH4 (0.19 g, 5 mmol) was added with vigorous stirring to a suspension of compound 2d (0.6 g, 2.2 mmol) in anhydrous ethanol (10 ml). The mixture was stirred for 4 h at 20C and then treated as described in 1615
synthesis of compound 2a. Obtained 0.5 g (83%) of compound 2e, identical to the compound synthesized by method A with respect to melting point and spectral characteristics. 4-Dimethylamino-8-(3-phenylureido)pyrimido[4,5-b]-1,4-benzothiazepine (2f). Phenylisocyanate (0.22 g, 1.8 mmol) was added to a suspension of compound 2d (0.5 g, 1.8 mmol) in ethyl acetate (20 ml). The mixture was boiled for 3 h and then cooled; the precipitate formed was filtered out and then dried. Obtained 0.39 g of compound 2f. 4-Dimethylamino-8-(3-phenylthioureido)pyrimido[4,5-b]-1,4-benzothiazepine (2g). Phenylisothiocyanate (0.22 g, 1.6 mmol) was added to a suspension of compound 2d (0.22 g, 0.81 mmol) in ethanol (10 ml). The mixture was boiled for 20 min and cooled; the precipitate formed was filtered out and dried. Obtained 0.17 g of compound 2g. 4,6-Dimethoxy-8-nitro-5,6-dihydropyrimido[4,5-b]-1,4-benzothiazepine (2h). A. A suspension of compound 1a (0.5 g, 1.73 mmol) in MeOH (23 ml), containing KOH (0.12 g, 2.14 mmol), was heated for 2 h at 65C and then cooled down; the precipitate formed was filtered out and dried. Obtained 0.5 g (89%) of compound 2h. B. A solution of 6-chloro-3-nitrobenzaldehyde (0.59 g, 3.18 mmol) in MeOH (20 ml) was added to a solution of 5-amino-6-mercapto-4-methoxypyrimidine (0.5 g, 3.18 mmol) in MeOH (25 ml) containing KOH (0.3 g, 5.37 mmol). The mixture was heated for 2 h at 65C and then cooled; the precipitate formed was filtered out and dried. Obtained 0.9 g (90%) of compound 2h, identical to the compound synthesized by method A with respect to melting point and spectral characteristics. 6-(5-Amino-4-methoxy-6-pyrimidyl)-3-nitromercaptobenzaldehyde Hydrazone (4a). A. A mixture of compound 1a (0.5 g, 1.73 mmol), MeOH (40 ml), and hydrazine hydrate (1 ml) was heated for 4 h at 60-63C and then cooled down; the precipitate was filtered out and dried. Obtained 0.42 g (76%) of compound 4a. Hydrazones 4b,c were obtained similarly from compounds 1b,c. B. A mixture of compound 2h (0.5 g, 1.57 mmol), MeOH (60 ml), and hydrazine hydrate (1 ml) was heated and treated as described above. Obtained 0.42 g of compound 4a. An additional 0.1 g of this substance was isolated by evaporation of the mother liquor. Total yield 0.45 g (90%). Compound 4a was identical to the substance synthesized by method A with respect to melting point and spectral characteristics. 6-(5-Amino-4-methoxy-6-pyrimidyl)-3-nitromercaptobenzaldehyde oxime (4d). Compound 2h (0.5 g, 1.57 mmol) was added to a mixture of hydroxylamine hydrochloride (0.2 g, 2.88 mmol), ethanol (10 ml), and pyridine (1 ml). The solution was boiled for 4 h, evaporated down under vacuum to dryness, and the residue was triturated with water (5 ml). The insoluble precipitate was filtered out, washed with water, and dried. Obtained 0.4 g of compound 4d. Compounds 4e,f were synthesized similarly. 4-Methoxy-8-nitro-6-oxo-5,6-dihydropyrimido[4,5-b]-1,4-benzothiazepine sulfoxide (5a) and 4methoxy-8-nitro-6-oxo-5,6-dihydropyrimido[4,5-b]-1,4-benzothiazepine sulfone (5b). A 30% aqueous solution of H2O2 (1 ml) was added to a suspension of 1a (0.2 g, 0.695 mmol) in glacial acetic acid (20 ml). The mixture was heated with stirring for 4 h at 63-65C and then cooled down, and the precipitate formed was filtered out. Obtained 0.12 g of sulfone 5b. The filtrate was evaporated down under vacuum to dryness; the solid residue was triturated with ethanol (5 ml) and then the precipitate was filtered out, washed with ethanol (3 ml), and dried. Obtained 0.08 g of sulfoxide 5a. 4-Dimethylamino-8-nitropyrimido[5,4-c]isoquinoline (6a). A 30% aqueous solution of H2O2 (2 ml) was added to a suspension of compound 1b (0.52 g, 1.8 mmol) in glacial acetic acid (40 ml). The mixture was heated for 3 h at 60-63C and then evaporated down under vacuum to dryness; the residue was triturated with water and the insoluble precipitate was filtered out, washed with water, and dried. Obtained 0.30 g of compound 6a. Compounds 6b,c were obtained similarly.
1616
8-Amino-4-dimethylaminopyrimido[5,4-c]isoquinoline (6d). Iron filings (0.9 g) and glacial acetic acid (2 ml) were added to a suspension of the nitro compound 6a (0.9 g, 3.35 mmol) in MeOH (50 ml). The mixture was boiled for 12 h and then filtered to remove solids. The filtrate was then evaporated down under vacuum to dryness. The residue was dissolved in water (10 ml) and then the solution was alkalinized with an aqueous solution of NaOH up to pH 6-7 and extracted with ethyl acetate. The extract was dried with Na2SO4 and filtered out; then the filtrate was evaporated down under vacuum to dryness. Obtained 0.2 g of compound 6d. 8-Chloroacetylamino-4-dimethylaminopyrimido[5,4-c]isoquinoline (6e). A solution of chloroacetyl chloride (0.12 g, 1.23 mmol) was added dropwise to a suspension of compound 6d (0.2 g, 0.83 mmol) in acetone (20 ml). The mixture was stirred for 6 h at 18-20C and then evaporated under vacuum to dryness. The residue was triturated with water (5 ml) and then the precipitate was filtered out, washed with water, and dried. Obtained 0.15 g of compound 6e.
REFERENCES 1. 2. 3. 4. 5. T. S. Safonova, M. P. Nemeryuk, N. A. Grineva, M. A. Keremov, and M. M. Likhovidova, Khim. Geterotsikl. Soedin., 270 (2001). T. S. Safonova, in: Targeted Discovery of New Anticancer and Antiviral Drugs [in Russian], Zinatne, Riga (1978), p. 51. A. M. Polezhaeva, L. F. Roshchina, A. S. Sokolova, M. P. Nemeryuk, M. V. Pykhova, T. S. Safonova, and M. D. Mashkovskii, Khim.-Farm. Zh., 15, No. 11, 45 (1981). D. Beke, in: Advances in Heterocyclic Chemistry (A. R. Katritzky, ed.), Academic Press, New York/London (1963), Vol. 6, p. 167. T. Koyama, T. Hirota, I. Shinohara, S. Fukuoka, M. Yamato, and S. Ohmori, Chem. Pharm. Bull., 23, 494 (1975).
1617
STUDY OF REACTION OF 5-ARYL-2,3-DIHYDRO2,3-FURANDIONES WITH N-CYANOTRIPHENYLPHOSPHINIMINE. MOLECULAR AND CRYSTAL STRUCTURE OF THE SOLVATE OF 6-p-TOLYL2-TRIPHENYLPHOSPHINIMINO-4H1,3-OXAZIN-4-ONE WITH ACETONITRILE
D. D. Nekrasov, S. N. Shurov, and Yu. T. Struchkov We have used X-ray diffraction to establish the structure of 6-p-tolyl-2-triphenylphosphinimino-4H-1,3oxazin-4-one. We have modeled its formation from 5-p-toluoylketene and N-cyanotriphenylphosphinimine using the semiempirical SCF MO LCAO method in the MNDO-PM3 approximation. We show that the reaction occurs according to a concerted mechanism. Keywords: 5-aryl-2,3-dihydro-2,3-furandiones, 6-aryl-2-triphenylphosphinimino-4H-1,3-oxazin-4-ones, aroylketenes, N-cyanotriphenylphosphinimine, transition state, semiempirical SCF MO LCAO method, X-ray diffraction. In a preliminary report [1], we hypothesized that the products of reaction between 5-aryl-2,3-dihydro2,3-furandiones 1a,b and N-cyanotriphenylphosphinimine (3) are 6-aryl-2-triphenylphosphinimino-4H-1,3oxazin-4-ones 5a,b. In order to more reliably establish the structure of the products of this reaction, we carried out an X-ray diffraction study of a single crystal of 6-p-tolyl-2-triphenylphosphinimino-4H-1,3-oxazin-4-one (5b), which we found forms a solvate (1:1) with acetonitrile, the solvent used for recrystallization. The general form of the molecule is shown in Fig. 1; the bond lengths and bond angles are given in Tables 1 and 2, and the coordinates of the non-hydrogen atoms are given in Table 3. The phosphorus atom has the usual distorted tetrahedral bond configuration. The PC(Ph) distances 1.798(2)-1.816(2) (average 1.807(2) ) are typical for four-coordinate phosphorus compounds [2]. The bond angles at the phosphorus atom are within the range 103.7(1)-117.3(1), and the average value of the CP(9)N(8) angle (111.4(1)) is somewhat greater than the CP(9)C angle (107.3(3)). The P(9)=N(8) bond length, equal to 1.619(1) , corresponds to a double bond. The bond angle C(2)N(8)P(9) is 118.9 and close to the standard value of 120 for an sp2-hybridized atom. According to the known relationship between the bond angle at the nitrogen atom and the P=N bond length in phosphinimines [3], the value found for the angle at the N(8) atom should correspond to a P=N bond length of ~1.62 , which is also observed experimentally. __________________________________________________________________________________________ Perm State University, Perm 614600, Russia; e-mail: koh@psu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1873-1882, December, 2004. Original article submitted June 5, 2002. 1618 0009-3122/04/4012-16182004 Springer Science+Business Media, Inc.
Scheme 1
O C O H CO Ar 2a,b O C O N C 3 N PPh3 Ar O A1 O C _ Ar 3 O 4a,b + N CN PPh3 N CN PPh3 N Ar O 5a,b N PPh3 O
Ar
O 1a,b
CN N PPh3
CN N
O PPh3
Ar
O A2
Ar
O 6a,b
Ph3PO
Ar
O 7a,b
N CN
1, 2, 47 Ar = Ph, p-Me64
1619
(35)
(36) N(37)
Fig. 1. Molecular structure of compound 5b.
All the atoms forming the heterocycle are located in the same plane (within ~0.002 ). The bond lengths in the heterocyclic moiety have intermediate values between single bond and double bond lengths, probably due to conjugation. The C(2)N(8) bond length (1.326(2) ) is shorter than the length of the formally single bond N(sp2)C(sp2) (1.43 ) [4], and has a partially double bond character (its -bond order, estimated from the bond length vs. bond order graph in [5], is ~0.54). The intracyclic angle O(1)C(2)N(3) is increased up to 123.6(2), but the planarity of the bonds formed by the C(2) is retained. The torsional angles P(9)=N(8)C(2)=N(3) and P(9)=N(8)C(2)O(1) are equal respectively to -2.6(3) and 177.2(1), i.e., the P(9)=N(8) bond is slightly turned away from the plane of the heterocycle and has a trans orientation relative to the O(1)C(2) bond. The deviation of the N(8) and P(9) atoms from the plane of the heterocycle is 0.087 and 0.192 , which allows for the possibility of conjugation between the heterocycle and the N(8)=P(9) bond. The bond lengths and bond angles in the phenyl substituents have the typical values and do not require any commentary. The orientation of the phenyl substituents at the phosphorus is propeller-like, and the dihedral angles between the planes of the phenyl rings are: C(10)C(15)/C(16)C(21) 65.1, C(10)C(15)/C(22)C(27) 72, C(16)C(21)/C(22)C(27) 70.6. The scheme for formation of 1,3-oxazines 5a,b includes thermal decarbonylation of furandiones 1a,b [6], leading to generation of aroylketenes 2a,b [7] which then react with cyanoimine 3. The reaction of compounds 2 and 3 may occur in a concerted manner (with participation of the activated complex A1a,b) or stepwise through the nitrilium form 4a,b. We should note that obtaining substituted 1,3-oxazines 5a,b in the reaction of furandiones 1 with N-cyanoimine 3 is rather unexpected. In fact, furandiones 1 react with compounds containing the P=N bond, for example N-phenyltriphenylphosphinimine (8) (Scheme 2), at temperatures lower than needed for thermal decarbonylation, and yield 5-aryl-2-(N-phenylimino)-2,3-dihydro-3-furanones (9) [8]. For this reason, formation of 5-aryl-2-(N-cyanoimino)-2,3-dihydro-3-furanones (7a,b) was more justifiable in the reaction under discussion, but they were not observed among the reaction products. With the aim of determining the mechanism of the reaction of compounds 1 and 3, we used the semiempirical SCF MO LCAO method to perform calculations for the molecules and also possible intermediates and activated complexes participating in this conversion. We first calculated the geometry of the 1,3-oxazine molecule 5b in the MNDO [9], AM1 [10], and MNDO-PM3 [11] approximations (Table 4). 1620
Scheme 2
O Ph 1
PhN 8
PPh3 Ar O A
N O PPh3
O Ph N Ar O O PPh3 Ph3PO Ar O 9a,b 9 Ar = Ph, -MeC6H4
N Ph
According to the data obtained, all the approximations used satisfactorily describe the geometry of the heterocyclic moiety of the molecule, but the AM1 approximation significantly overestimates the size of the bond angle C(2)N(8)=P(9) (162.6) and predicts values for the N(8)=P(9) bond length (1.477 ) and the P(9)C bond length (from 1.622 to 1.627 ) that are too low. This approximation probably should not be used in calculations for molecules containing the indicated bonds. The overestimation of the repulsion between nonvalence bonded atoms that is typical for the MNDO approximation is expressed in the substantial rotation of the p-tolyl moiety relative to the heterocyclic moiety. For this reason, in the following we used the MNDO-PM3 approximation. Since we could not find data on the electronic structure of compound 3 in the literature, we also performed the calculation for this molecule. We also performed the calculation in parallel for the N-phenyltriphenylphosphinimine 8 molecule which, as was shown earlier, reacts with 5-aryl-2,3-dihydro-2,3-furandiones as a nucleophile according to the Staudinger reaction scheme [8].
TABLE 1. Basic Bond Lengths (d) in the 5b Molecule According to X-ray Diffraction Data
Bond O(1)C(2) O(1)C(6) C(2)N(3) C(2)N(8) N(3)C(4) C(4)C(5) C(4)O(7) C(5)C(6) C(6)C(28) N(8)P(9) P(9)C(10) P(9)C(16) P(9)C(22) C(10)C(11) d, 1.384(2) 1.377(2) 1.305(2) 1.362(2) 1.376(2) 1.457(2) 1.232(3) 1.331(3) 1.477(2) 1.619(1) 1.807(2) 1.816(2) 1.798(2) 1.392(3) Bond (10)(15) C(11)C(12) (12)(13) (13)(14) (14)(15) (16)(17) (16)(21) (17)(18) (18)(19) (19)(20) (20)(21) (22)(23) (22)(27) d, 1.391(2) 1.385(3) 1.383(3) 1.388(4) 1.389(3) 1.408(3) 1.389(3) 1.386(3) 1.383(3) 1.388(3) 1.386(4) 1.401(2) 1.390(3) Bond (23)(24) C(24)C(25) (25)(26) (26)(27) (28)(29) (28)(33) (29)(30) (30)(31) (31)(32) (31)(34) (32)(33) (35)(36) (36)(37) d, 1.386(3) 1.379(3) 1.388(3) 1.391(3) 1.387(3) 1.379(3) 1.392(3) 1.372(4) 1.378(4) 1.514(3) 1.395(3) 1.458(6) 1.110(4)
1621
TABLE 2. Basic Bond Angles () in the 5b Molecule According to X-ray Diffraction Data
Angle (1)(2)N(3) O(1)C(2)C(8) O(1)C(6)C(5) O(1)C(6)C(28) C(2)O(1)C(5) C(2)N(3)C(4) C(2)N(8)P(9) N(3)C(2)N(8) N(3)C(4)C(5) N(3)C(4)O(7) C(4)C(5)C(6) C(5)C(4)O(7) C(5)C(6)C(28) C(6)C(28)C(29) C(6)C(28)C(33) N(8)P(9)C(10) N(8)P(9)C(16) N(8)P(9)C(22) , deg 123.6(2) 110.6(1) 120.4(1) 112.3(2) 118.1(1) 120.3(1) 118.9(1) 125.1(1) 117.0(2) 120.3(1) 120.5(2) 122.7(2) 127.3(2) 120.0(2) 121.4(2) 113.3(1) 117.3(1) 103.7(1) Angle P(9)C(10)C(11) P(9)C(10)C(15) P(9)C(16)C(17) P(9)C(16)C(21) P(9)C(22)C(23) P(9)C(22)C(27) C(10)P(9)C(16) C(10)P(9)C(22) C(10)C(11)C(12) C(10C(15)C(14) C(11)C(10)C(15) C(11)C(12)C(13) C(12)C(13)C(14) C(13)C(14)C(15) C(16)P(9)C(22) C(16)C(17)C(18) C(16)C(21)C(20) C(17)C(16)C(21) , deg. 118.8(1) 121.8(2) 120.0(2) 120.9(2) 120.0(1) 120.1(1) 106.8(1) 108.3(1) 120.3(2) 120.2(2) 119.3(2) 120.3(2) 119.8(2) 120.0(2) 106.9(1) 119.5(2) 120.7(2) 119.1(2) Angle (17)C(18)C(19) (18)C(19)C(20) (19)C(20)C(21) (22)C(23)C(24) (22)C(27)C(26) (23)C(22)C(27) C(23)(24)C(25) C(24)(25)C(26) C(25)C(26)C(27) C(28)C(29)C(30) C(28)C(33)C(32) C(29)C(28)C(33) C(29)C(30)C(31) C(30)C(31)C(32) C(30)(31)C(34) C(31)C(32)C(33) C(32)C(31)C(34) C(35)C(36)C(37) , deg. 121.0(2) 119.7(2) 120.0(2) 119.6(2) 119.8(2) 119.8(2) 120.5(2) 120.1(2) 120.1(2) 120.0(2) 120.5(2) 118.6(2) 121.8(2) 117.9(2) 120.6(2) 121.2(2) 121.5(2) 175.2(5)
According to the calculations, in the molecule of compound 3 the nitrogen atoms are characterized by the following values of the charges: -0.241 (N-nitrile) and -0.621 (N-imine). For comparison, the nitrogen atom in imine 8 has a large partial negative charge (-0.718). The highest occupied molecular orbital (HOMO) of the cyanoimine molecule 3 lies lower on the energy scale than the HOMO of imine 8 (the corresponding values are equal to -8.69 and -7.47 eV). These indices characterize N-cyanotriphenylphosphinimine (3) as a less effective nucleophile compared with compound 8, and the passivity of the former in a Staudinger type reaction with 5-aryl-2,3-dihydro-2,3-furandiones becomes understandable to some extent. As noted above, the absolute value of the negative charge on the nitrile nitrogen atom of the cyanoimine molecule 3 is less than the charge on the imine atom. However, the occupancy of the 2s-AO of the nitrile nitrogen atom, on which the unshared electron pair is located (1.771), is higher than for the imine nitrogen atom (1.702). This is important to bear in mind, assuming that their unshared electron pairs participate in formation of new bonds by these atoms. Since the static electronic indices of the nitrogen atoms of the cyanoimine molecule 3 do not allow us to confidently predict the chemical behavior of this molecule, we modeled the reaction of aroylketenes 2a,b with imine 3. According to current opinion, the reaction of aroylketenes with compounds containing a CN bond is a concerted [4s + 2s] cycloaddition reaction [12]. This mechanism assumes that the reagents approach each other in parallel planes. However, we could not localize the transition state for this type of approach of the reagents. We found that the activated complex corresponding to the transition state for the reaction (the correct localization of which is supported by the one negative value of the Hesse matrix) has a quite different geometry (the basic bond lengths, bond angles, and dihedral angles are given in Table 5). As follows from the calculations, the O(1), C(2), C(4), C(5), and C(6) atoms lie practically in one plane, while the N(3) atom deviates from that plane by 0.1 . The interatomic distances O(1)C(2) and N(3)C(4) in the activated complexes suggest that formation of the indicated bonds is an asynchronous but concerted process. Attempts to look for a zwitterionic intermediate of the nitrilium cation type 4 proved to be unsuccessful. Probably in the step of formation of the activated complex, the N(3)C(4) bond is formed at a faster pace, while in the step of its conversion to the reaction product the O(1)C(2) bond is formed faster. 1622
TABLE 3. Coordinates of Non-hydrogen Atoms (10) of the 5b Molecule and Their Equivalent Isotropic Temperature Factors (103)
Atom P(9) O(1) O(7) N(3) N(8) N(37) C(2) C(4) C(5) C(6) C(10) C(11) C(12) C(13) C(14) C(15) C(16) C(17) C(18) C(19) C(20) C(21) C(22) C(23) C(24) C(25) C(26) C(27) C(28) C(29) C(30) C(31) C(32) C(33) C(34) C(35) C(36) x 922(1) -2248(2) 1020(2) 213(2) -693(2) 5855(4) 830(2) -6(2) -1482(2) -2541(2) 1142(2) -214(2) -98(3) 1365(3) 2720(3) 2612(20) 2825(2) 3562(2) 5000(3) 5721(3) 5000(3) 3572(2) 650(2) 1724(3) 1546(3) 315(3) 761(3) -594(2) -4091(2) -4415(3) -5891(3) -7053(3) -6709(3) -5243(3) -8666(3) 2939(5) 4610(4) y 2847(1) 4767(1) 3206(1) 3378(1) 3761(1) 391(3) 3923(1) 3681(2) 4577(2) 5079(2) 1427(2) 1180(2) 92(2) -760(2) -524(2) 567(2) 3052(1) 3529(2) 3699(2) 3407(2) 2932(2) 2744(2) 2975(2) 2202(2) 2333(2) 3212(2) 3974(2) 3858(2) 5987(2) 6580(2) 7419(2) 7685(2) 7110(2) 6261(2) 8576(2) 558(4) 456(2) z 460(1) 2635(1) 4346(1) 2757(1) 1147(1) 2734(3) 2197(1) 3830(1) 4308(1) 3713(1) 804(1) 1316(2) 1553(2) 1283(2) 762(2) 530(2) 484(1) -382(2) -346(2) 527(2) 1379(2) 1349(2) -905(1) -1722(2) -2778(2) -3028(2) -2221(2) -1157(2) 4071(2) 5053(2) 5400(2) 4796(2) 3811(2) 3450(2) 5211(3) 3574(5) 3135(3) U, 2 24(1) 30(1) 45(1) 29(1) 27(1) 113(2) 26(1) 31(1) 34(1) 29(1) 27(1) 36(1) 44(1) 46(1) 49(1) 41(1) 25(1) 31(1) 28(1) 39(1) 42(1) 35(1) 26(10) 35(1) 43(1) 44(1) 40(1) 30(1) 32(1) 51(1) 58(1) 46(1) 53(1) 46(1) 67(1) 109(2) 73(1)
The 2py-AO of the C(1) atom of the aroylketene molecule 2 and the 2s-AO of the nitrile nitrogen atom of the cyanoimine participate in formation of the N(3)C(4) bond. This is supported by the insignificant change in the CN bond length in the dienophile compared with the isolated molecule. Participation of the 2pz- or 2py-AOs of the nitrogen in formation of the N(3)C(4) bond should have led to a larger increase in the CN bond length in the cyano moiety of the activated complexes. The O(1)C(2) bond is formed by the orbital in which one of the unshared electron pairs of the oxygen atom is localized and by the 2py-AO of the carbon atom. The calculated enthalpies of formation (Hf) of the activated complexes A1a and A1b respectively are equal to 471.1 and 431.9 kJ/mol. If we assume that before the reaction the distance between the reagents is infinite and the Hf for such a supermolecule is equal to the sum of the corresponding Hf (2+3) values, we can estimate the activation energy (Eact) as the difference Hf (A1) Hf (2+3). The value calculated in this way for the reaction A2a + 3 is Eact = 4.8 kJ/mol, while for A2b + 3 it is 5.7 kJ/mol. 1623
TABLE 4. Basic Bond Lengths (d) and Bond Angles () in the 5b Molecule, Calculated by the MNDO, AM1, and MNDO-PM3 Semiempirical Methods
d, Bond MNDO 1.372 1.333 1.409 1.491 1.364 1.370 1.230 1.357 1.658 1.766 1.763 1.765 AM1 1.441 1.337 1.397 1.480 1.352 1.380 1.247 1.303 1.477 1.623 1.624 1.627 MNDOPM 1.376 1.341 1.424 1.476 1.352 1.381 1.220 1.352 1.675 1.803 1.793 1.793 Angle MNDO 124.2 119.9 116.3 119.5 121.1 119.0 110.6 125.2 120.5 119.1 124.6 110.0 115.9 103.9 , deg. AM1 123.5 119.7 117.9 119.6 122.2 116.9 108.9 127.5 162.6 121.1 120.1 111.8 112.9 112.7 MNDOPM 126.2 118.3 116.6 119.9 122.4 116.6 106.5 127.3 125.2 118.6 124.8 114.0 115.7 106.0
O(1)C(2) C(2)N(3) N(3)C(4) C(4)C(5) C(5)C(6) C(6)O(1) C(4)=O(7) C(2)N(8) N(8)=P(9) PC(Ph1) PC(Ph2) PC(Ph3)
O(1)C(2)N(3) C(2)N(3)C(4) N(3)C(4)C(5) C(4)C(5)C(6) C(5)C(6)O(1) C(6)O(1)C(2) O(1)C(2)N(8) N(3)C(2)N(8) C(2)N(8)=P(9) N(3)C(4)=O(7) C(5)C(4)=O(7) N(8)=P(9)C(10)(Ph1) N(8)=P(9)C(16)(Ph2) N(8)=P(9)C(22)(Ph3)
With the aim of determining the reasons for the passivity of compound 3 in the Staudinger type reaction with furandiones 1, we modeled their [2+2] cycloaddition. For comparison, analogous calculations were performed for furandione 1b and imine 8. We found that for the latter reaction we have Eact = 63.0 kJ/mol, while for the reaction 1b + 3 we have 71.9 kJ/mol. According to the calculations, the processes can occur in a concerted fashion, but formation of CN bonds should be faster than formation of PO bonds. The transition state for the reaction 1b + 3 is delayed, i.e., it begins to form at shorter interatomic distances lCN = 1.674 and lPO = 2.959 . For comparison, the corresponding values for the activated complex for the reaction 1b + 8 are equal to 1.846 and 3.199 .
TABLE 5. Basic Bond Lengths (d), Bond Angles (), and Dihedral Angles () in Activated Complexes for Reactions of Benzoyl and p-Toluoylketenes with N-cyanotriphenylphosphinimine, Calculated by the MNDO-PM3 Method
Bond d, A1a A1b 2.037 1.235 1.469 1.428 1.391 1.277 1.218 2.038 1.235 1.469 1.428 1.392 1.277 1.218 Angle , deg. A1a A1b 103.5 134.2 117.6 124.0 123.7 116.2 113.0 129.5 151.4 129.9 103.4 134.2 117.6 124.0 123.7 116.2 113.0 129.5 151.4 129.9 Angle , deg. A1a A1b 11.5 11.6 -12.2 -12.3 3.1 3.2 1.6 1.7 -0.8 -1.0 -4.9 -4.8 168.7 168.6 -159.0 -159.0 61.7 61.2
O(1)C(2) C(2)N(3) N(3)C(4) C(4)C(5) C(5)C(6) C(6)O(1) C(4)=O(7) C(2)N(8) N(8)=P(9)
O(1)C(2)N(3) C(2)N(3)C(4) N(3)C(4)C(5) C(4)C(5)C(6) C(5)C(6)O(1) C(6)O(1)C(2) N(3)C(4)=O(7) C(5)C(4)=O(7) N(3)C(2)N(8) C(2)N(8)=P(9)
O(1)C(2)N(3)C(4) C(2)N(3)C(4)C(5) N(3)C(4)C(5)C(6) C(4)C(4)C(6)O(1) C(5)C(6)O(1)C(2) C(6)O(1)C(2)N(3) C(2)N(3)C(4)=O(7) N(8)C(2)N(3)C(4) P(9)=N(8)C(2)O(1)
1.303 1.303 1.685 1.685
1624
We do not rule out the possibility that the first step of the Staudinger type reaction between furandiones 1 and phosphinimine 3 is irreversible, while elimination of the triphenylphosphine oxide from the [2+2] cycloadducts 6a,b requires significant consumption of energy. Thermal decarbonylation of the furandiones occurs irreversibly; the reaction of aroyl ketenes 2a,b and compound 3 is characterized by a low activation barrier, which also determines formation of the phosphorylated 1,3-oxazines 5.
EXPERIMENTAL The X-ray diffraction experiment was carried out at -80C on a Syntex P21 automatic 4-circle diffractometer (MoK radiation, graphite monochromator, /2 scanning). The crystals were triclinic, and at -80C: a = 8.985(4), b = 12.659(4), c = 12.706(3) ; = 89.85(2), = 71.07(3), = 71.07; V = 1337(1) 3; Z = 2; space group P1. Of the total 7259 measured reflections, in further calculations we used 5559 independent observed reflections with I 2(I). The structure was deciphered by the direct method and refined in the full-matrix anisotropic approximation (in the isotropic approximation for the hydrogen atoms). The final values were R = 0.049, Rw = 0.049, GOF = 1.87. All the calculations were carried out on an IBM PC/AT personal computer using the SHELXTL PLUS software package. The quantum-chemical calculations were carried out on a Pentium 200 MMX computer using the MOPAC 7.0 software package [13].
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. D. D. Nekrasov, Yu. S. Andreichikov, and O. A. Rakitin, Zh. Org. Khim., 28, 1319 (1992). A. G. Orpen, L. Brammer, F. H. Allen, O. Kennard, D. G. Watson, and R. Taylor, J. Chem. Soc., Dalton Trans., 83 (1989). A. N. Chernega, A. A. Korkin, M. Yu. Antipin, and Yu. T. Struchkov, Zh. Obshch. Khim., 9, 2045 (1988). F. H. Allen, O. Kennard, D. G. Watson, L. Brammer, A. G. Orpen, and R. Taylor, J. Chem. Soc., Perkin Trans. 2, 1 (1987). E. Bayer and G. Hofelinger, Chem. Ber., 99, 1 689 (1966). Yu. S. Andreichikov, Yu. A. Nalimova, A. P. Kozlov, and I. A. Rusakov, Zh. Org. Khim., 14, 2436 (1978). Yu. S. Andreichikov, G. Kollenz, C. P. Kappe, R. Lueng-Toung, and C. Wentrup, Acta Chem. Scand., 46, 683 (1992). Yu. S. Andreichikov, S. N. Shurov, V. V. Zalesov, and N. N. Shapet'ko, Zh. Org. Khim., 22, 857 (1986). M. J. P. Dewar and W. Thiel, J. Am. Chem. Soc., 99, 4899 (1977). M. J. P. Dewar, E. G. Zoebisch, E. F. Healy, and J. J. P. Stewart, J. Am. Chem. Soc., 107, 3902 (1985). J. J. P. Stewart, J. Comput. Chem., 10, 202 (1989). Yu. S. Andreichikov and D. D. Nekrasov, Zh. Org. Khim., 20, 1755 (1984). J. J. P. Stewart, MOPAC. Version 7.0, Frank J. Seiler Research Laboratory, US Air Force Academy, QCMP 175.
1625

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Chemistry of Heterocyclic Compounds vol.

Chemistry of Heterocyclic Compounds, Vol. 40, No. 1, 2004

PYRROLE OXIMES: SYNTHESIS, REACTIONS, AND BIOLOGICAL ACTIVITY. (REVIEW)

NH2OH .HCl MeONa

NOH Ph Ph NOH NOH

Br N H 28 CH=NOH EtONa, EtOH N H 67

COOEt PhSO2Cl, NaOH Me

HON HON N N (CH2)n O N O 77 R = H, Alk; n = 35 N R N F N Me O 78 N Ph

CR=NOCH2CH(OH)CH2NHCMe2R' 79 R = H, Alk, Ar; R' = H, Me

The O-lauroyl- and O-nicotinoyloximes of 1-methyl-2-acetylpyrrole possess anti-inflammatory activity [36].

Chemistry of Heterocyclic Compounds, Vol. 40, No. 1, 2004

OCOMe MeCOO OCOMe

Carbon atoms 2 3 3a 3b 5 6 7 7 8 9 9 1-CH2C6H5

15.3 193.4(CH3) 30.5 CH3

Chemistry of Heterocyclic Compounds, Vol. 40, No. 1, 2004

PREPARATIVE SYNTHESIS OF 7-CARBOXY-2-R-ISOINDOL-1-ONES

COOH O H3PO4 70100 oC

TABLE 2. The Spectral Characteristics of Compounds 2a-5

5-H d 3.07 d 2.84 d 3.07 d 3.15 d 3.14 d 2.89 d

9-H 6.64 d 6.54 d

5,6 9.1 9.2 9.2 9.1 9.2 9.2

12.15 br. s 4.55 d 3.89 d 4.52 d

4.58 d 12.25 br. s 4.64 d 9.41 br. s 4.23 d

3.84 d 4.05 d 3.91 d 3.96 d

3.82 d 3.62 d 3.46 d 3.78 d

2.86 s 2.74 d 2.46 d 3.20 d 2.80 d 2.79 d 2.50 d

5.32 s 4.96 d 4.97 d 5.35 d

6.48 s 6.42 dd 6.57 d 6.41 dd 6.50 dd 6.53 d 6.46 d

2.79 d 5.19 br. s 6.48 br. d 6.58 d

9.2 9.2 9.0

1.8 1.3 1.5

5.8 5.6 5.8

COOH 15.53 s 15.74 br. s

5.04 s 4.81 s 5.18 s 5.09 s 5.25 s 4.83 d 4.64 d

7.2 7.3 7.2

7.70-7.60 m 7.85 t 7.99 d 7.69 t 8.38 d

4.69 s 4.76 s 4.63 s 4.83 s

7.88 d 7.91 dd 7.86 br. d

7.79 t 7.81 t 7.79 t 7.60 br. s

8.16 d 8.16 dd 8.15 br. d

7.4 7.6 7.3

7.4 7.6 7.3

Jom = Jmp = 7.6; JCH2CH3 = 7.2

Chemistry of Heterocyclic Compounds, Vol. 40, No. 1, 2004

CH2C CCH2OH CH2C C

CH2OH _ OH + R2 N _ Hal 2af, 4af

TABLE 1. The Characteristics of the Salts 1a-f4a-f, 5a-e, and 6a-e

232(4.60),275 (3.62), 285(3.60), 327(2.65)

OH, s 4.63 4.68 4.66 4.91

_______ * The spectrum was recorded in CD3OD.

Chemistry of Heterocyclic Compounds, Vol. 40, No. 1, 2004

SYNTHESIS AND ANTI-HIV-1 ACTIVITY OF 2-[2-(3,5-DIMETHYLPHENOXY)ETHYLTHIO]PYRIMIDIN-4(3H)-ONES

TABLE 1. The Characteristics of the Synthesized Compounds

12. 13. 14. 15. 16.

Chemistry of Heterocyclic Compounds, Vol. 40, No. 1, 2004

MULTICOMPONENT SYNTHESIS OF 2,5-DIOXO- AND 4-ARYL-5-OXO-2-THIOXO1,2,3,4,5,6,7,8-OCTAHYDROQUINAZOLINES

TABLE 1. Characteristics of the Synthesized Compounds

TABLE 2. Spectral Characteristics of the Synthesized Compounds

NMR spectra, , ppm (coupling constant, J, Hz)

1628, 1572, 1510; 3260, 3200

7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

Chemistry of Heterocyclic Compounds, Vol. 40, No. 1, 2004

a r = Ph; b Ar = 4-MeC6H4 ; c Ar = 4-MeOC6H4