You are on page 1of 1386

Chemistry of Heterocyclic Compounds

vol.22

OxO- and thioxo-1,3-thiazines (review)


1-13
Mass-spectrometric study of the cyclization reactions of diazoketones. 8. 1-Diazo-3,4-epoxy-4-
arylbutan-2-ones
13-18
Synthesis of 2-, 6-, and 7-aminomethyl derivatives in the 4,5-dihydroxybenzofuran series
18-22
Conversion of trans, trans-1-methoxy-3,5-diaryl-2-oxabicyclo[4.4.0]dec-3-enes into
hemidithioacetals and 4H-thiopyrans. Structure of trans, trans-1-mercapto-3-phenyl-5-(4-
methoxyphenyl)-2-thiabicyclo[4.4.0] dec-3-ene
23-28
Study of kinetics and mechanism of sulfonation of thiophene and its derivatives by complex
compounds of sulfuric anhydride
28-33
Synthesis of heterocyclic analogs of prostaglandins from pyrrole and indole
33-36
New synthesis of indole-7-carboxylic acid
36-37
Synthesis of heterocycles from 1,5-diketones. 3. Alicyclic 1,5-diketones in reaction with
phenylhydrazine
38-44
Synthesis of derivatives of 4-imino-2-amino-2-imidazoline. New example of a multicomponent
condensation involving isonitriles
45-51
New derivatives of imidazoline 3-oxide and thiazoline with 2,6-dialkylphenol fragments
52-56
Spectroscopic study of the structure of N-(2-benzimidazolyl)-O-methylcarbamate
57-63
Reactivity of methyl derivatives of nitrogenous heterocycles in vapor-phase catalytic oxidation
63-66
Synthesis and ring-chain isomerism of n-monosubstituted 4-benzoylnicotinamides and 3-
benzoylisonicotinamides
67-70
Acetals of lactams and acid amides. 46. Unusual reactions of -cyano--
dimethylaminocrotonamide with anthranilic acid derivatives
70-73
Synthesis of 5-oxoindeno[1,2-b]pyridinium salts
73-76
Azaindole derivatives. 67. Synthesis of N-substituted 1-benzyl-4-methyl-5-cyano-6-amino-7-
azaindoles
76-80
Synthesis and some reactions of 4-nitro derivatives of imidazo[4,5-c]pyridin-2-ones
80-85
Synthesis of N6-substituted adeninyl-9--D-glucofuranuronosides
85-88
Synthesis and properties of symm-triazine derivatives. 4. Synthesis of 2,4,6-trisubstituted symm-
triazines containing sterically-hindered phenol fragments
89-94
Structure and some properties of tetrazole 5-methylpyrimido[4,5-e]-[1,2,4]triazine-6,8-dione and
its azide in different phase states
95-100
10-Alkenylphenothiazines. 1. Synthesis and cis,trans-isomerization of 10-propenylphenothiazines
100-103
New type of recyclization of 2-benzopyrylium salts
104-105
Reaction of flavylium perchlorate with carbon monoxide
105
Unusual reaction of N,N-dimethylacetamide diethyl acetal with 2-aminomethylene-5,5-
dimethylcyclohexane-1,3-dione. Synthesis of coumarin and carbostyril derivatives
106-107
1-Thiocarbamoyl-5-oxy- and 5-thiosemicarbazido-2-pyrazolines
107-108
Methods for the synthesis of azoles containing indole substituents (review)
109-133
Quantum-chemical treatment of recyclization reactions. 9. Photoisomerization of five-membered
heterocycles
133-140
Synthesis of 5-substituted cyanofurans and their reaction with hydrazine
140-145
Chlorination of 1,3-dioxolan-4-ones
145-147
Reaction of 2-methyl-5,6-dihydro-2H-pyran with dichlorocarbene
147-148
Chemistry of isoflavone heteroanalogs. 11. Benzodioxane analogs of chalcone, flavone, and
isoflavone
149-154
An unusual product of the reaction of 1-phenyl-3-(3,4-dimethoxyphenyl)-3-(2-oxocyclohexyl)-1-
propanone with hydrogen sulfide and acids: 2-phenyl-2,4-ortho-(14,15-dimethoxybenzo)-cis-1-
thiadecalin
155-161
Reactions of azirines with sulfur nucleophiles. 4. Treatment of 2H-azirine with
mercaptosubstituted acids. reactions of aziridinyl alkyl sulfides with carboxylic acids and acyl
chloride derivatives
161-166
New derivatives of meso-(tetra-4-pyridyl)porphine and their reactions
167-171
Tetracyanoethylation and fischer rearrangement of some 4-oxo-4,5,6,7-tetrahydroindoles
172-175
Chemistry of the pyrazolidines. 26. Alkylation of 4-benzyliden-1-phenyl-3.5-dioxopyrazolidines
176-180
Reaction of 4-aminoimadazo[4.5-c]pyridin-2-ones with -bromomethylketones
180-186
Effects of acids on orientation in the reaction of 5-formyl-4-(1-pyridino)azole 2-oxides with
aromatic amines
186-192
Reaction of pyrido[1,2-a]benzimidazole and tetrahydropyrido[1,2-a]benzimidazole with
acetylenedicarboxylic ester
192-194
Mass spectrometric study of the stereoisomers of 2-furyl- and 2-phenyldecahydro-4-quinolinone
and their tertiary alcohols
195-199
Arylidenehydrazono-2(4)-azafluorenes
200-205
Synthesis and dynamic stereochemistry of 1,5-disubstituted 2,3,4,5-tetrahydro-1H-1,5-
benzodiazepin-2-ones
206-210
Homolytic addition of 1,3-oxathiolane to unsaturated hydrocarbons
210-214
Effect of substituents on the relative stability of furoxan isomers
214-217
Mass spectra and 13C NMR spectra of the adducts of epoxyenamines with sulfene
217-221
Fragmentation of substituted 2-sila-1,3-dioxacycloalkanes under electron impact
221-224
Synthesis of 2-(diazomethyl)-3-methyl-5H-furan-4-one from 1,5-bis(diazo)-3-methylpentane-2,4-
dione
225
Thermal isomerization of -arylideneisochromenes into -naphthols
226
Addition of isocyanates and isothiocyanates to 2-amino-3-phenylcarbamoylazirines
227-228
First synthesis of ethylenebisporphyrins
228-229
Synthesis of N-heterocyclic analogues of 2,5-diaryloxazoles
229
Synthesis of 2-benzoyl(thenoyl)benzo-1,4-thiazines
230
Electrophilic heterocyclization of unsaturated sulfur and phosphorus compounds (review)
231-242
Hydrogenation of furfural on polymer-containing catalysts
243-246
Interaction of ethoxyacetaldehyde with 1,3-dicarbonyl compounds
247-250
Acid-base properties and stability of pyrylium polymethine dyes in chlorohydrocarbon solutions
250-253
Electrochemical reduction of N-vinylazoles
253-257
Studies of 1-azabicyclics. 23. Nitration of 1,2-dihydropyrrolizine and its homologs
257-261
Synthesis of derivatives of indole and quinoline by the intramolecular catalytic cyclization of
allylanilines
262-264
Nucleophilic substitution reactions in 4-halonitro-pyrazolecarboxylic acids
265-267
Reaction of 1,2-hydroxylaminooximes with 1,2-diketones. Conversion of 2-acyl-1-hydroxy-3-
imidazoline 3-oxides to pyrazine 1,4-dioxides
268-275
Studies of imidazo[1,2-a]benzimidazole derivatives. 21. Synthesis of haloketones in the
imidazo[1,2-a] benzimidazole series
275-282
Reaction of N-aminobenzimidazolium cations with aromatic aldehydes. Synthesis of 2,4-diaryl-as-
triazino[1,6-a] benzimidazoles
282-287
Formation of 4,5-dihydro-1,2,4-triazoles during rearrangement of O-acetyl derivatives of 1,2-
hydroxylaminohydrazones and thiosemicarbazones
287-291
Quantum-chemical interpretation of recyclization reactions. 10. Photoisomerization of six-
membered heterocycles
291-297
Reaction of 5-bromo-6-amino-3-(4-methylaminobutyl)pyridine with potassamide
297-300
Rearrangement of 2-hetarylalkylpyridinium salts
300-303
New method of synthesis of 3-alkyl-4-piperidones
304-306
Mass spectrometry of stereoisomeric 3-hydroxy-4-piperidones
306-310
Synthesis of 5-arylpyrimidine-2-carboxylic acids and the liquid-crystal characteristics of their aryl
esters
310-318
Reactions of azinium ions. 4. Reactions of quinoxalinium salts with nitroalkanes Single-stage
path to tetraazaheterocycles with bridged and framework structures
318-328
Preparation of some substituted 1,2,4-triazines
328-330
Purinenucleoside analogs. 2. 9-(1-Alkoxyethyl-1)-6-substituted purines
331-334
Configuration of 2-(4-pyridyl)-5-aryloxazole molecules in various states of aggregation
334-339
Macroheterocycles. 24. Synthesis of new derivatives of diaza-18-crown-6
340-342
Reaction of phthalimide with diethylene triamine and triethylene tetramine
343
5-Amino-6-mercaptopyrimidines in the synthesis of derivatives of 5-amino-1,2,3-thiadiazole
344-345
2-Selenoxoquinazolones-4, a new kind of quinazolone
345-346
Alkylation of 6-substituted purines in conditions of interphase catalysis
346-347
Synthesis of condensed tetrahydropteridines by the cyclization of the 8-ethylpteridinium cation
with dinucleophiles
348-349
Synthesis of 2,3-diphenyl-5,6-dihydro-1,3-oxazinium hexachloroantimonate from 2-phenyl-1,3-
dioxane
349-350
Acidic transformation of 2-(2-hydroxyphenylamino)-1,4-naphthoquinone-4-phenylimines into N-
phenylbenzo[a]-phenoxazimes
350-351
Synthesis of heterocycles on the basis of aliphatic nitro compounds (review)
353-370
Some reactions of 3,7-dimethyl-2,3-epoxyoctanal and its derivatives
370-372
Synthesis of the diastereomeric 2-aryl-1-cyclohexyl-3-(2,3-epoxypropionyl)aziridines
372-375
Quantum-chemical treatment of recyclization and cyclization reactions. 11. Formation of a
pyrylium ring
376-380
Synthesis of 4-methyl-2,3,4-trichlorotetrahydropyran and several features of the stereochemistry
of the nucleophilic substitution of the -chlorine atom
380-386
Structure of the products of the o-monoalkylation of pyrocatechol by -bromoketones
386-389
X-ray structural investigation of novel azabicyclic systems containing aziridine rings
390-393
New examples of the vinylation of NH-heterocycles with acetylene at atmospheric pressure in the
KOH-DMSO system
393-396
Synthesis of tetraphenylporphins with reactive groups in the benzene rings. 3. Use of
diazotization for the preparation of substituted tetraphenylporphins
397-401
Ethyl 1,4-dihydropyridinecarbodithioates and the electronic effects of sulfur-containing ester
substituents
401-410
Formation of a derivative of 3,3,5-tricarbonyl-1,2,3,4-tetrahydropyridine under the conditions of
the hantzsch synthesis
410-414
Synthesis and reactions of 8-benzylidene-2-methyl-5,6,7,8-tetrahydroquinoline-3-carboxylic acid
arylamides
415-416
Preparation of derivatives of 1,2-dihydro- and 1,2,3,6-tetrahydropyrazinones from acylated 1,2-
hydroxylamino ketones
417-421
Synthesis of 1-alkyl(aralkyl)-4-acyl-2-piperazinones
421-424
Analogs of purine nucleosides. 3. Alkoxyalkylation of hypoxanthine by the silyl method
425-431
Alkyliminomalonic acid and 2-alkyloxaziridine-3, 3-dicarboxylic acid esters
431-437
Oxazolidines. 1. Basic catalytic disproportionation of cyclohexanospiro-2-oxazolidines: Synthesis
of N-substituted 4,5,6,7-tetrahydroindoles
437-439
Oxazolidines. 2. Synthesis of 2-methyloxazolidines by cyclization of vinyl ethers of 1, 2-amino
alcohols
440-442
Mass spectrometric study of 1,2,4- and 1,3,4-oxadiazoles containing indole substituents
442-446
NMR spectral study of the structure of 2-amino-4-thiazolinones
447-451
Synthesis of isomeric 4- and 5-hydroxylaminothiazolidin-2-thiones
451-455
Benzazolin-2-thiones in the michael reaction. 1. Reaction of benzothiazolin- and benzoxazolin-2-
thiones with acrylonitrile, acrylamide, and methylacrylate in the presence of acid catalysts
456-459
PMR study of the conformational behavior of 2,5,5-trisubstituted 1,3,2-dioxaborinanes
459-462
Synthesis of furan derivatives from 1,3-alkadiynes
463
A new reaction in the series of 4,5,5-trimethyl-3-butenolides
464
Addition of indole to fervenulin-3-one and its 4-N-oxide
465-466
New synthesis of pyrrolo[1,2-a] pyrrole derivatives
466-467
Homolytic alkylation of 2-methylquinoline by benzodioxolane and benzodioxane
467-468
Reaction of 4-methoxy(methylthio)-5-amino-6-mercaptopyrimidines with , -
dibromoacetophenone
468-469
New synthesis of 1-vinyl- and 1,3-divinyluracils
469-470
Reaction of 8-bromo-3-methylxanthine with amines in DMFA
470
Analogues of prostacyclin (PGI2) modified in the 2-oxabicyclo[3.3.0]octane fragment (review)
471-485
Reaction of 1-alkyl-2-aryl-3-(2-methyl-2,3-epoxypropionyl)aziridines with boron trifluoride etherate
in methanol
485-489
Formation of 2-phenyl--benzpyrone (flavone) in nucleophilic thiylation of 1-(2-hydroxyphenyl)-3-
phenylprop-1-yn-1-one by potassium p-thiocresolate
490-491
Synthesis of tetra(1,4-dithiacyclohexene)porphyrazine and its metal complexes
492-494
Asymmetrical alkylation of 1-[(s)--phenylethyl]-azethidinone-2
495-499
Azo coupling and aminomethylation of 2,5-diphenylpyrrole and its derivatives
499-503
Kinetics of the cycloaddition of maleic anhydride to arylaminomethylene derivatives of 3-methyl-1-
phenylpyrazole-5-thione
503-507
Recyclization of 1-amino-3.5-diaryl-2.6,6-tricyanocyclohexa-1,3,-dienes to pyridine derivatives
508-512
Electrochemical reduction of bipyridinium salts
513-516
Preparation and properties of betaines of 4-pyridyl-3,4-dihydropyridine-2-thiones(1H)
517-521
Acid deuterium exchange in methoxyquinolines and their N-oxides
522-529
-phenylisocinchomeronic and 4-azafluorenone 3-carboxylic acids
529-532
Reaction of 1-methyluracil with phenylbenzhydrazonoyl chloride
532-538
Reaction of diaroylethylenes with ortho-phenylenediamine and its derivatives
538-542
Nitroazines. 5. Use of the japp-klingemann reaction for the synthesis of nitrotriazines
543-546
Reaction of 3,4-diaminofurazan with carbonyl compounds and their metal complexes
546-549
Crown ethers bound to sulfanilamide preparations
549-551
2-Hydroxymethylamino-4-thiazolinone. Confirmation and chelate formation
551-557
Acid deuterium exchange in benzazoles
557-564
Benzazolin-2-thiones in the michael reaction. 2. Reaction of benzothiazolin- and benzoxazolin-2-
thiones with acrylonitrile, acrylamide, and methyl acrylate in the presence of basic catalysts
564-567
Heterocyclization of compounds containing diazo and cyano groups. 2. Synthesis and
recyclization of 4-substituted 5-amino-1,2,3-thiadiazoles
567-571
Divinyl sulfide. 15. Cycloaddition of divinyl sulfide and its 2-methyl derivatives to thiourea and N-
monoalkyl- and N-monoarylthioureas
572-577
Mass-spectrometric study of benzopyridosilaazepines and -azepinones
577-580
Electrochemical preparation of pyridinyl radicals, substituted by electron acceptors in the -
position
581-582
Synthesis of 4-aryl-5-thioxo-4,5-dihydroindeno[1,2-b]pyridines
582
Reaction of O-aryl-N-di(2-chloroethyl)amidoguanidyl phosphates with acetoacetic ester
583
Pyrimidinetetrasulfonic acid
584
Addition of trichloroacetonitrile to vinyltetrazoles
585
Effect of the acid-base properties of heteroaromatic compounds on their electrophilic substitution
reactions (review)
587-608
Condensed heterocycles. 45. Synthesis and structures of imines of 2-selenolo-3-benzo [b]
furanaldehyde and 3-selenolo-2-benzo [b] furanaldehyde and their derivatives
608-612
Condensed heterocycles. 46. Crystal structure of 3-mercapto-2-benzo[b]-furylidene-(p-
methylphenyl) amine
613-616
Mass-spectrometric behavior of benzo-substituted dibenzo-18-crown-6 ethers
616-619
Catalytic properties of rhodium hydridocarbonyl trithienyl-phosphine complexes in the
homogeneous hydrogenation and isomerization of unsaturated compounds
620-624
Reactions of aromatic and heteroaromatic compounds carrying electron-acceptor substituents.
26. Acylaminomethylation of 2-acylthiophenes, 2-thiophenecarboxylic acid, and its esters
625-629
Improved method for synthesis of substituted tetraphenylporphins
629-632
Tautomerism of azine derivatives. 11.14N-NMR and17O-NMR investigation of intrachelate
tautomerism of acylmethylpyridines
633-639
Condensation of 4-azafluorene with -butylene glycol and glycerin
640-642
Synthesis starting from 3-methyl-2-phenyl-5-(3-methyl-2-phenyl-3,4-dehydropiperidyl-6)pyridine.
2-phenyldinicotinic and 4-azafluorenone-2-carboxylic acids
642-646
Synthesis of methyl esters of 6-dialkylamino-2-(carbethoxy)-methylthiopyrimidine-4-carboxylic
acids
647-650
Synthesis of 2-aryl- and 2-hetaryloxazoles from the oxazolines and oxazolidines
650-653
Synthesis, structure, and spectral properties of some bioxazoles
654-663
Course of bromination of thiazole and 2-methylthiazole
663-666
Synthesis of macrocyclic compounds containing thiophene and thiazole nuclei
666-669
Synthesis and structure of methyl-substituted 1,3-Dioxa-2-Silacylohexanes
670-675
Synthesis of dibenzofuran and its nitro-substituted derivatives
676
Furo[2,3-c]pyrylium A new heteroaromatic system
677
Alkylation of furan and thiophene with tert-butanol in the presence of the strongly acid cation
exchanger amberlyst 15
678-679
New method of isolating N-substituted 3-aminomethylenethiol-4-en-2-ones
679
Synthesis of bis(o-xylylenedithio)tetrathiafulvalene
680
Reactions of copper and silver acetylides with hydrazone bromides A new route to 1,3,5-
substituted pyrazoles
681
New synthesisof imidazo[4,5-f]quinoline derivatives
682
Reaction of 2-aminobenzothiazoles with glycidyl phenyl ether
683
Ion-radical and redox transformations of cyclic acetals (review)
685-695
Effect of the heteroatom of a benzo[b]-annelated five-membered heteroring on the structure and
properties of an aminovinyl ketone fragment included in the ring
695-699
Condensation of 3-methyl-3-buten-1-ol with some ketones
700-702
Pyrylocyanines. 22. Styrils derived from methoxy-substituted 4-methylflavylium salts
703-707
Reactivity of cyclic sulfides in reactions with quinones
707-710
Preparation of spiroaziridinefluorene, spiroindoxyl-fluorene, and -aminopropionic acid ester with
a 4-azafluorene fragment
710-713
Mechanism of the Fischer indole synthesis. Quantum-chemical interpretation of the
rearrangement of substituted cyclohexanone arylhydrazones to tetrahydrocarbazoles
713-722
Thermal heterocyclization of methyl aryl ketazines. 2. Reactions of the tautomeric enehydrazine
form
723-732
Research on imidazo[1,2-a]benzimidazole derivatives. 22. Synthesis of 2,3-dihydroimidazo[1,2-
a]benzimidazoles starting from 2-imino-3-(2-hydroxyethyl)benzimidazolines
732-739
Heterocyclization of compounds containing diazo and cyano groups. 3. Two pathways in the
cyclization of 2-diazo-2-cyanoacetic acid derivatives under the influence of bases
740-745
Reactions of 4-nitro-1,2,3-triazole with alkylating agents and compounds with activated multiple
bonds
745-748
Chemistry of heterocyclic N-oxides and related compounds 13. Acylamination of pyridine N-oxide
by aniline, p-anisidine, and their N-p-tosyl derivatives
749-751
Synthesis of substituted 2-pyridones and 4-aza-3-fluoridones
751-754
Condensation of N-(piperidylidene-4)arylamines with acetylenedicarboxylic esters
755-758
Synthesis and luminescence of benzo[f]quinoline derivatives with fused alicyclic rings
759-762
Quantitative determination of the electronic effects of 3- and 4-pyridazinyl groups from NMR
spectral data for isomeric aminophenyl- and phenylpyridazines
763-770
Synthesis of condensed pyrazines from N-substituted amino-o-quinones and ethylenediamine
771-774
Chemical properties of ylidene derivatives of azines. 3. Synthesis and reactions of ylidene
derivatives of halopyrimidines
774-779
Free radicals in the perimidine series. 2-Tert-butylperimidyl radicals
780-782
Fluorine-containing azoles. 4. 2-Perfluoropolyoxaalkyl-substituted perimidines
783-785
Electronic structure and mass spectra of substituted hexahydro-1,3,5-triazine-2-thiones
786-790
Condensed imidazo-1,2,4-azines. 14. Synthesis and reactivity of 3-chlorine-substituted
imidazo[1,2-b]-1,2,4-triazines
791-795
Reaction of 2-alkylaminobenzothiazoles with acrylic acid
795-799
Investigation of nitrogen- and sulfur-containing heterocycles. 44. New heterocyclic systems.
Derivatives of imidazolidino-[3,2-f]pyrido[2,3-b]-and imidazolidino[3,2-f]pyrimido[4,5-b]-1,4-
thiazines. Synthesis and structure
800-805
Synthesis of bromo-substituted 2-formylpyrroles
806-807
Recyclization of 4-cyanobenzo[c]pyrylium salts upon reaction with hydrazine
807
1,1Azobenzimidazoles
808
Synthesis of benzopyrano[3,4-c]-and benzothiopyrano[3,4-c]-[2,1,3]selenadiazol-4-ones
809
Structures synthesis, and properties of 1,2,3-thiadiazoles (review)
811-827
Synthesis of acetylenic derivatives of 1,4-dioxane
828-829
Homolytic telomerization of vinyltrimethylsilane with 5,5-dimethyl-1,3-dioxane
830-834
Mechanism of amination of aziridines and oxiranes. 3. Quantum-chemical investigation of the
effects of specific solvation
834-839
Mechanism of amination of aziridines and oxiranes. 4. Quantum-chemical investigation of the
effect of the polar solvent
839-844
Crystal and molecular structure of 6-methyl-2,7-diphenyl-1,3-diformylindolizine
844-848
Mass-spectrometric behavior of isatin oximes
848-851
Reaction of 2,3,3-trimethyl-3H-indole salts with acrylamide. Synthesis of 1,2,3,4,10,10a-
hexahydropyrimido[1,2-a]indol-2-one derivatives
852-855
Formation of 2-imidazoline derivatives in the reaction of 1,2-hydroxyamino oximes with phenyl-
and methylglyoxal
856-860
The NMR spectra of cyclic nitrones. 3. Effect of protonation and a hydrogen bond on the chemical
shifts in the13c NMR spectra of derivatives of 3-imidazoline 3-oxide
861-868
Organolithium and organosodium compounds of n-substituted 2-alkylbenzimidazoles
868-872
Chemistry of 2-hetarylbenimidazoles. 7. Transformations of trans-1-methyl-2-[-(2-furyl)vinyl]
benzimidazole
872-875
Derivatives of imidazo[4,5-e]-2,1-benzisoxazole and synthesis of substituted benzimidazoles from
them
876-879
Tetrazoles. 21. Reaction of benzonitrile with salts of hydrazoic acid
880-883
Reaction of salts of nitroaminotetrazoles with alkyl iodides
883-886
Twofold reactivity of 1,2-disubstituted dihydro-n-heteroaromatic systems. 10. Synthesis and
aromatization of ferrocene-containing hantzsch esters
886-893
Synthesis and spectral characteristics of acenaphthene derivatives of benzo[f]quinoline
894-898
Three-dimensional structures of stereoisomers of 2-phenyl-4-ethynyldecahydro-4-quinolinol
899-902
Investigation of the acid- and base-induced transformations of nitrogen heterocycles by NMR
spectroscopy. 1. Substituted pyridines and pyrimidines
903-908
Acetals of lactams and acid amides. 47. Investigation of the behavior of substituted 6-(-
dimethylamino) vinyl-4-pyrimidinones in acidic media. Synthesis of 3-cyano-4-anilino-5-formyl-2-
pyridone and 3-chloro-4-cyanobenzo[b] [1,6]-naphthyridine
909-914
Synthesis and catalytic oxidation of 2,5-dimethylpyrazine
915-917
3-Aryl-1,2-dihydroquinoxalines
918-922
Reaction of 7-acylmethyl-8-bromo-3-methylxanthines with formamide
923-925
Reaction of 3-nitro- and 3,5-dinitro-derivatives of 2-pyridone with hydrazine hydrate
926
Formation of pyrimido[1,2-a]benzimidazoles in reaction of 1,2-diaminobenzimidazole with
chalcones
927
Direct introduction of azoloazine residues into resorcinol
928
1,2,3-Seleniumdiazolo[4,5-d]pyrimidine-5,7(4h,6h)dione A new condensed hetero system
929
Synthesis and properties of 1,6-dioxaspiro[4.4]nonane and its derivatives (review)
931-943
Synthesis and three-dimensional structures of 2-(2-furyl)-acrylonitriles
943-945
Conformations of isomeric 2,3,4-trisubstituted tetrahydrothiophenes
945-950
Synthesis and structure of derivatives of 7-aminobenzo[b]thiophene
951-953
13C and 15N NMR spectra of 2,3-substituted 2H-azirines
953-955
13C NMR spectra of N-substituted carbazoles. Transmission of the electronic effects of
substituents through the nitrogen atom to the carbazole ring
956-959
Nitration of tetrabenzoporphins
960-964
Electrochemical behavior of metal complexes of derivatives of dibenzo[c,j]dipyrazolo[3,4-f 3,4-
m][1,2,5,8,9,12]-hexaazacyclotetradecynes on a pyrographite electrode
965-970
Synthesis and structure of 1-benzoyl-2,5-dimethyl- and 1,2,5-trimethyl-4-arylpiperideins
970-976
Synthesis of stereoisomeric alkyl- and phenyl-substituted 5-cyanopiperidine-3,4-diols
976-980
Arylation, alkylation, reduction, and pyrolysis of 1h-1-methylindeno[2,1-b]pyridine
980-982
Investigation of stereoisomers of 4-alkenyl-trans-decahydroquinol-4-ols in mixtures by the method
of reaction chromato-mass spectrometry
983-985
Naphthyridines in hetarylation reactions
986-990
Synthesis and properties of derivatives of 1,4-dihydropyrimidine-5-carboxylic acid
990-994
Synthesis and mesomorphic properties of aryl 5-alkyl-(and alkoxy) pyrimidine-2-carboxylates
994-1001
Synthesis and spectral examination of the position of tautomeric equilibrium in 2-thioxo-4-
quinazolone
1001-1003
Diazabicycloalkanes with nitrogen atoms in nodal positions. 13. Reactions of benzo[b]-1,4-
diazabicyclo[2.2.2]octene with electrophiles
1004-1009
Cyclotrimerization of thiocyanic acid in organic solvents
1009-1010
Stereoisomerism in macrocyclic bis(piperidones)
1011-1016
Investigation of substituted 1,3-oxazolidines using 1H and 13C NMR spectroscopy
1017-1022
Synthesis and spectral and luminescent properties of 4-(5-aryloxazoyl-2)benzoic acids and their
derivatives
1022-1025
2-(4-Cyanophenyl)-5-aryloxazoles
1026-1027
Hetarylethylene derivatives of 2,5-diaryloxazoles and 2,5-diarloxadiazoles and their luminescence
and scintillation properties
1028-1031
Polynuclear heterocyclic compounds based on the adduct of o-cinnamoylbenzoic acid and
cyclohexanone
1031-1035
Optical and electrophysical properties of metal complexes of tetra(1,4-
dithiacyclohexeno)porphyrazine
1036-1039
Synthesis, structure, and transformations of 1-aza-3-oxa-7-thiabicyclo[3.4.0]nonan-2-one
1039-1044
Efficient method for the hydrolysis of 4-chlorotetrahydropyrans
1045
New reaction of malononitrile and arylidene- and 1-arylethylidenemalononitriles
1046-1047
1H-isobenzofurylium (phthalylium) salts (a review)
1049-1058
Mass spectrometric decomposition of -phenyloxiranecarboxylic esters
1058-1063
Photochemistry of unsaturated lactones. 2. Photoannelation of 2-acetyl-3,4,4-trimethyl-2-buten-4-
olide by terminal alkynes
1063-1068
The chemistry of 1,5-diketone derivatives. 2. Preparation of 2-hydroxy-1,3,5-triphenyl-1,5-
pentanedione and some heterocycle derivatives
1068-1071
2,2-Dimethyl-5-(5-r-2-furfurylidene)-1,3-dioxan-4,6-diones. 1. Synthesis, properties, and structure
1072-1075
Isomerization of 5-acyl-6-halo-1,6-diazabicyclo[3.1.0]hexanes, a case of inversion rather than 1,2-
acyl migration
1076-1079
Mass spectrometric study of ring-chain tautomers of 3-amino(hydroxy)pyrazolidines
1080-1083
Nitrosochlorination reaction of substituted imidazolin-2-ones
1084-1087
Mass-spectrometric study of the cyclization of diazo compounds. 9. 2-Diazo-2-cyanoacetamides
1087-1093
Synthesis and conversions of 2-aryl derivatives of s-triazolo[4,3-a]pyrimidine
1093-1096
Synthesis of acid-base transformations of 3-aroyl-6-methyl-2-oxopyridines
1097-1099
Synthesis and acid-base transformations of (4-styrylpyridinio)-alkanesulfonates
1099-1104
Acid hydrolysis of N-methyl derivatives of 4-phenyl-5-oxo-4,5-dehydroindeno[1,2-b]pyridine
1104-1107
1,2,5-Trimethyl-4-(p-hydroxyaryl)-3-tetrahydropyridines and their spatial structure
1107-1110
Synthesis of 1,5-methano-2-benzazocines from 3-hydroxy-1,3-dimethyl-6-phenyl-4-piperidone
1110-1113
Alkylation of quindoline and quindoline-11-carboxylic acid
1114-1117
Reaction of azinium cations. 5. Addition of water and methanol to 1,4-diazinium cations in the
presence of bases. equilibrium constants and PMR spectra of the mono- and diadducts
1118-1125
Heterocyclic analogs of pleiadiene. 59. Reaction of 1-acetonyl- and 1-phenacylperimidinium salts
with hydrazine and ammonium acetate
1126-1131
Reaction of vinyl ethers of the pyridine series with bromine and iodine
1132-1134
Structure of the alkaline salts of 2-phenyl- and 2-p-methoxyphenylimino-4-thiazolidinones
1134-1139
Synthesis and spectrometric investigation of the thioamides of thiazole- and benzothiazole-2-
carboxylic acids
1139-1144
Synthesis of substituted 1,3-thiazinoazoles
1145-1148
Synthesis and mass-spectrometric study of 2-amino- and 2-chloro-5-aryl-1,3,4-thiadiazoles
1148-1152
10-Alkenylphenothiazines. 2. Synthesis and mechanism of acidic hydrolysis of cis- and trans-10-
2-phenylvinyl)phenothiazines
1152-1157
Photodimerization of 2,6-diphenyl-4-(5-bromofuryl-2)-pyrylium and pyridinium perchlorates
1158
Formation of heterospirans, containing a -lactone ring, upon treatment of dialkylacetylcarbinols
with malonic ester
1159
Novel polyfunctional spiroheterocyclics based on acetylenic hydroxyacids
1160
Synthesis of benzothiazepines (review)
1161-1170
Reaction of furan compounds with hydrogen sulfide and aspects of its application
1170-1173
Synthesis and three-dimensional structure of 4-hydroxy-4-methyl-3-chloro-6-
alkyltetrahydropyrans
1174-1177
Alkylation of benzo- and dibenzocrown ethers by various alcohols
1178-1185
Synthesis and properties of bis(vinylenedithio)- and bis(dimethylvinylenedithio)tetrathiafulvalenes
1186-1189
5-Substituted 2-methyl- and 2-methyleneindolines
1189-1192
Heterogenous-catalytic synthesis of 2,3-dihydroselenophene and 3,4-dihydro-2H-selenopyran
1193-1195
Benzindoles. 24. Reduction of nitro-2,3-dimethyl[4,5]- and nitro-2,3-dimethyl[6,7]benzindoles
1195-1198
Synthesis of 1-substituted 1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-ones
1198-1202
Mass spectra of piperidine dicarboxylic acids and their esters
1203-1207
Conformation of the piperidine ring in isomeric 1,2,5-trimethyl-4-phenyl(triorganosilyl)piperidin-4-
ols from the PMR spectra
1208-1213
The 13C NMR spectra, isomerism, and conformational analysis of substituted piperidin-4-ones
1214-1225
Dual type of reactivity op 1,2-disubstituted dihydro-N-heteroaromatic systems. 11. Aromatization
of N-sulfonyl-1,2-dihydroquinolines and isoquinolines containing an -indolyl or pyrrolyl
substituent
1226-1228
Reaction of N-arylidene-2-naphthylamines with allylacetone
1229-1231
Synthesis of substituted 2- and 4-hydroxyaminopyrimidines
1232-1236
6-Aminopyrimidine 1-oxides. Acylation and methylation
1236-1241
Reactions of azinium cations. 6. N(1)-alkyl-1,2,4-triazinium salts. Reactions with indoles The
first case of the double addition of nucleophiles to a triazine ring
1242-1249
Nitroazines. 6. Direct introduction of indole residues into 6-nitroazolo[1,5-a]pyrimidines
1250-1255
Polarographic examination of 5-aryl-2-(2-thienyl)-oxazoles and -1,3,4-oxadiazoles
1255-1258
Conversion of 2-amino-5-R-phenyl-1,3,4-oxadiazoles into 3-R-phenyl-5-alkoxy-1,2,4-triazoles
1258-1261
Synthesis of arylazoles and their luminescent properties
1262-1266
1,4-Dihydrobenzothieno[3,2-b]pyridine-5,5-dioxides
1267-1271
Photochemical rearrangement of 4,5-ethylenedithio-1,3-dithiol-2-thione to 4,5-ethylenedithio-1,2-
dithiol-3-thione
1272
Stereospecificity of direct 13C-1H spin-spin coupling constants of vinylpyridines
1273-1274
Photochromic fulgides of the indole series
1274
Replacement of bromine by hydrogen in bromo derivatives of tetrahydropyrimido[4,5-
b][1,4]benzthiazine under conditions of electron-impact ionization
1275-1276
1-Tellurachromylium perchlorate
1276
Phosphorylated pyridines and their benzo-homologs (review)
1277-1291
Alkylation of -dicarbonyl compounds by 1,2,3-trihalopropanes as a method for the preparation of
-substituted furans
1291-1295
Pyrylocyanines. 23. 2-Pyrylocarbocyanines with substituents in hetero residues
1295-1300
Thermal hydrothiolysis of di(2-thienyl)sulfide in the gaseous and liquid phase
1301-1306
Structure of the intermediate particles in the radiolysis of indolinespiropyran
1307-1310
Indole derivatives. 128. Synthesis and properties of 5,6- and 4,5-ethylenedioxyindoles
1311-1315
Electronic and photoelectron spectra of amino-1-methylnitropyrazoles and their quantum-
chemical interpretation
1316-1321
Reactions of heterocyclic cations with n-containing nucleophiles. 15. Reaction of 2,6-
diphenylpyrylium perchlorate with semi- and thiosemicarbazides
1322-1326
Asymmetric synthesis and absolute configuration of 1--phenylethyl-2,5-dimethyl-4-piperidone
isomers
1327-1333
Synthesis of 2,3-polymethylenepyridines from 3-aminoacrolein and cyclic ketones
1334-1336
N-glycosides. 7. Synthesis of 4,5-anhydro-3-(2,2-O-isopropylidene--D-ribofuranosyl)-4-
hydroxyhexahydropyrimidine-2-thiones
1336-1341
Diazabicycloalkanes with nitrogen atoms in nodal positions. 14. Synthesis of dibenzo[1,2-b,e]-
1,4-diazabicyclo[2.2.2]octadienes containing a tertiary amino group in the aromatic ring
1342-1345
-Dimethylaminomethylene derivatives of succinimide and glutarimide in the Fischer reaction
1345-1349
Cyclizations with hydrazones of nitroglyoxalic acid. Synthesis and structure of tetrazolo[5,1-
b][1,2,4]triazines
1350-1354
Synthesis and properties of 1,4,9-triazaspiro[5,5]undecane and 3,7,11-triazaspiro[5,6]dodecane
1354-1357
Acid-base interaction of tetraazaporphin in organic solvents
1358-1362
Unusual reaction between 6H-6-oxo-5-haloanthra[1,9-cd]-isoxazoles and quinoline
1363-1366
Formation of derivatives of thiazoline by the reaction of thiourea with 2-bromo-3-aminopropionic
acid
1367-1369
Reaction of 2-thiopyrrolidones with monochloroacetic acid and its methyl ester
1370-1372
Condensed heterocyclic compounds containing a thiazole ring. 12. Derivatives of thiazolo[3,4-
b][1,2,4]triazine
1373-1376
OXO- AND THIOXO-I,3-THIAZINES (REVIEW)

G. A. Mironova, V. N. Kuklin, UDC 547.869.1(047)


E. N. Kirillova, and B. A. Ivin

Literature reports on the methods of synthesis, chemical properties, and tauto-


merism of oxo- and thioxo-l,3-thiazines have been summarized.

1,3-Thiazines, interest in which has increased steadily over the last decade, remain
relatively little-known compounds in comparison with pyrimidines and 1,3-oxazines. It has
nevertheless been established that a number of oxo- and thioxo-l,3-thiazines possess useful
properties, in particular high biological activity. The object of the present review is to
summarize the available information on the synthesis, chemical properties, and tautomerism
of 2-, 4-, and 6-oxo-l,3-thiazines, their sulfur analogs, and other derivatives.
It is preferable to divide the methods of preparation of these compounds into the four
general methods of synthesis of six-membered heterocycles, depending on the number of atoms
present in the fragments destined to form the ring [i]. Methods of synthesis which involve
modifications of compounds already containing the 1,3-tiazine ring will be considered in
the section devoted to the chemical properties of these compounds.

N C~ C N'~C"c NIC'C N/C"c N"C"c


] I I i I J [ I
Cxs/C C..S C C S C C"S C C S ''C
type A type B
(8+0) (s+x)

N/C'C N C--.C N/C C N C"C


I r l f i f I
C C- C C C S C C
~S S" r
type C type D
(4+~) (o+:0

(6 + O) CONDENSATION
Reactions of this type have been relatively little used for the synthesis of 2-, 4-,
and 6-oxo-l,3-thiazines. However, many reactions of types B-D occur via intermediates simi-
lar to those formed in type A reactions. The closure of six-membered fragments to form the
ring usually occurs by nucleophilic addition of nitrogen or sulfur to the carbonyl carbon
atom or the more reactive carbon of the protonated carbonyl group.
There have been no reports in the literature on the use of reactions of this type for
the synthesis of 2-oxo-l,3-thiazines, but there are a few examples of their use for the pre-
paration of 4- and 6-oxo-l,3-thiazines [2-5]. Condensation of the 2-thiocyanatocarbonyl
chlorides (I) in the presence of dry hydrogen chloride gives substituted 4-oxo-l,3-thiazines
(II) [2, 3]. The reaction must be carried out at O=C as a result of the high reactivity of
the carbonyl carbon. The reaction is assumed to proceed as follows [4]:

R ~. .SeN 2HCl ~i.. S>, ICI Cl- R S. ~.CI]c]" l~ - s. cl


"cii ~'~ ,cl[ ..'(:I ~- ....... |'--~,- I
c el / 2 c ~INH~ ! 9 R~/J" ./

II
1 RI=R2 II.CH:~: R I .R2=(_ r

Leningrad Institute for Pharmaceutical Chemistry, Leningrad 197022. Translated from


Khimiya Geterotsiklicheskikh Soedinenii, No. i, pp. 3-16, January, 1986. Original article
submitted May 2, 1984.

0009-3122/86/2201-0001512.50 9 1986 Plenum Publishing Corporation 1


The condensation of the 3-thioureidobutyrate (ili) in methanolic sodium methoxide at 80~
has been used to obtain 6-oxo-l,3-thiazines [5]. The unusual nucleophilic attack on the car-
bonyl carbon by sulfur is explained by the authors [5] as being due to the formation of the
anion (IV) in an alkaline medium. In this case, the electron density at the sulfur atom must
be increased to a greater extent than that at the amino-group, while simultaneously the posi-
tive charge on the carbonyl carbon is reduced by conjugation. These factors result in the
preferential formation of the C-S bond.

0 O CH~
" r ~i I
CH3"C~CH't:--OC2H~'
I NaOCli4]_
I CH 3,
"r "
CH-I.-OC.~H~ Na+ N' "b~
,.
9 t I ---- [I /
HN..C.NH 2 N:. /~2 ,-b,,
9" - ~{'. ] NH~ 'S" '~O
II S' NH 2 J '

II[ IV

A general method for the synthesis of 2,4-dioxo-l,3-thiazines and their thio-analogs,


which permits the introduction of substituents into the 5- and 6-positions, is based on in-
tramolecular nucleophilic attack on the carbonyl group or the more reactive corresponding
enol ether by the sulfur atom in acyldithiourethanes [i, 6]. For example, acetoacetyldi-
thiourethane slowly cyclizes to2-ethylthio-4-oxo-6-methyl-l,3-thiazine on treatment with cold
concentrated sulfuric acid [6]. Reaction of the acyl chloride (V) with the S-ethyldithio-
carbamate (VI) affords the unstable acryloyldithiourethane (VII), which on cyclization gives
2-ethylthio-4-oxo-5-methyl-l,3-thiazine (VIII) [6].
O O

il + ml~cssc~H~ - - - - | li I , I
9 - [ 4'~11 ~c" [
.c Ic.~o s" "sc,,z~ ] s%.~
V VI L. " Vll / Vlll

The isomerization of 2-thio-4-oxo-6-methyl-l,3-oxazine to the more stable 2,4-dioxo-l,


3-thiazine on treatment with concentrated sulfuric acid [7] may be regarded as a reaction of
this type.

(5 + i) CONDENSATION
Type B reactions comprize the condensation of five- and one-membered fragments, in the
course of which bonds are formed between the heteroatoms and a carbon atom, or between two
carbon atoms. The five-membered fragment is frequently an acyl isothiocyanate [8, 9], an
unsaturated acid [10-13], or an acyldithiourethane, which condense readily with amines,
thiols [8], aromatic carboxylic acid derivatives [11-13], or orthoesters [i, 14]. The reac-
tion is normally carried out in aprotic nonPolar solvents in the presence of acetic anhydride
[14] or polyphosphate ester [11-13]. This type of condensation is not used for the prepara-
tion of 2-oxo-l,3-thiazines. An example of its use for the synthesis of 4-oxo-l,3-thiazines
is the reaction of 3-chloro-3-phenylpropenoyl isothiocyanate (IX) with amines to give the
substituted thioureas (X), which then cyclize to 2-alkylamino-4-oxo-l,3-thiazines (XI) [8].

/0 HNRIR 2 .~0
C H--C=CH C / . . . C H--C~--CH-C~"
. . . . . . . |fN I
6 5 CII "NCS 6 ,5 CII *'NHCSNR R ~ R1RZN / CsH5
IX X gI
R~ =H,Alk,Ar.; R2~AIk,Ar

The condensation of the 3-acylamino-2-butenoate (XII) with 2,4-bis(4-methoxyphenyl)-l,


3,2,4-dithiaphosphetane 2,4-disulfide (XIII) has been used to prepare the 2-substituted 6-
thio-4-methyl-l,3-thiazines (XIV) [I0]. In the first step, the 3-(2-thioacylamino)-2-buten-
oate (Xlla) is formed, and on boiling in xylene this cyclizes by nucleophilic addition of
the sulfur to the carbonyl carbon. Simultaneously, the oxygen atom at C(6) is replaced b y
sulfur.
S
jS\ll
P-CH~OC.H~ - - P ~ ~P--C.H..-OCI.I.-p
" " - II--S . . . . cH~C:_: c
C113~C ~:CII-COOC21I~, S 3"111 - / t~C--OC2H s
RCONH" - ................................. NX\

XII
R'\
C--SI~

Xlla
B=Clia,CH(CH s)z,c(cll~) ~ coil s

Clt 3
XIY

This type of condensation is used rather more extensively for the synthesis of 2~4-di-
oxo-l,3-thiazines and their sulfur analogs, Condensation of the acyldithiourethanes (XV),
which contain a reactive methylene group, with the orthoesters (XVI) gives the intermediate
N-B-ethoxyacryloyldithiourethanes (SVII), which cyclize in the presence of acetic anhydride
to the corresponding 1,3-thiazines (SVIII) [i, 14]. Triethyl orthoformate is the most re-
active in the reaction. It appears that the use of triethyl orthoacetate or orthopropion-
ate increases the electron density at the electrophilic site, thus hindering the formation
of the C--S bond.

o o

~ OHC~.' ~ ~ s 2 9 1~:~ 'S""sC~H5


XV! XVll . XVIiI
R1 ~CN,COCH~; R2=H,CHs,CaH~.

The acyldithiourethanes (XIX), obtained by reacting the isothiocyanate (IX) with thiols,
cyclize to 2-alkylthio-4-oxo-6-phenyl-l,3-thiazines (XX) by intramolecular nucleophilic re-
placement of halogen by sulfur [8]. Reaction of the isothiocyanate (IX) with sodium hydro-
sulfide occurs via the unstable dithiocarbamate (XXI) to give 2-thio-4-oxo-6-phenyl-l,3-
thiazine (XXII) [8]. This compound (XXII) has previously been obtained from sodium hydro-
sulfide and 3-phenylpropionyl isocyanate [9].

0 0

HC I C ' - N t !

,>" co,,;,,
lX XT~ XX

Cl ...?N+ ~ ,C~
~S Coli 8
C6H5
x ~ r

R=C2H~,C3H?,CoHsCH 2

The condensation of substituted acrylamides (XXIII) with aromatic carboxylic acids has
been the subject of several studies [11-13]. Varying the reaction conditions and the reac-
tants affords differing reaction products. When benzoic acid or its anhydride i~ used, the
principal cyclization products are 6-thioxo-l,3-oxazines (XXIV), which isomerize quantita-
tively on heating in protic solvents to give the 6-oxo-l,3-thiazines (XXV) [12. The driving
force in this reaction is the greater stability of the 1,3-thiazine ring in comparison with
the 1,3-oxazine ring [7, 12]. It is noteworthy that condensation only occurs in the presence
of polyphosphate ester.

i 0 ~ir ~CII
NC NC II
(
r h c o , ~: l ~
i " R i '
"'l-
['.. "~'I ~'-H~
PhCOC|N" .CC
[]. . "INH
. z. . " ". ( p('!H'"5"
h ( T O ) 2 0. . . . . . (I IIN .E',)II- - .] "~" tlN
tlSCS ~ ' t'h " "' II~CS" :';H CII(.i5 .~ "" (I |eh 0 "" "'S Ph
~Xll[ X.XIV ~V
R:,;CH,(;ONtl 2
(4 + 2) CONDENSATION
Type C reactions, which comprize the condensation of a four-membered unit (8-diimines,
8-iminopropionitriles, isothiocyanates, or thioacylketenes) with a two-membered unit contain-
ing a multiple bond, are quite widely used for the synthesis of oxo- and thioxo-l,3-thiazines.

1 ~ C .. /NHAr CS 2 ..-"
1 C ~NHAr \

~'\,, S

N' 'S

XXVIIItc ~ d

XXVI--XXVIII a Ar=p-OCH~C~H~, b, e Ar=C~H~, d Ar=p-CI-tsC~H~; a-d R~=C~H~;


a,e~d R~=C~I-t~, b R~=CH~

The condensation of 8-diimines [15] or ~-iminonitriles [16] with carbon disulfide has
been employed to obtain 2-thioxo-l,3-thiazines. In the case of the diimine (XXVI), nucleo-
philic addition of the diimine to the CS2 carbon first takes place. The subsequent course
of the reaction depends on the electronic effects of the substituents in (XXVI), Electron-
donating substituents R2 at the electrophilic center hinder the formation of the C--S bond,
and in this case the reaction products are the pyrimidines (XXVII). The absence of a sub-
stituent with a +M effect in the benzene ring attached to nitrogen results in a decrease in
the yields of pyrimidines (XXVlI), the thiazines (XXVlII) being formed in yields which are
largely independent of the type of substituent present [15].
The activating effect of the cyano-group in ~-imino-B-arylpropionitriles (XXIX) together
with basic catalysis favor the addition of sulfur to the methylene group. When the reaction
is carried out in dimethylformamide at 2~ addition of a further molecule of sulfur occurs
with the formation of 5-substituted-2,6-dioxo-4-aryl-l,3-thiazlnes (XXX) [16].

H
I
NH N.~ R .
.--~-'CH~CU
X~3X US2'~-CsHI
'ON"r-- E ' ~ S~

s
R=Ar~M~; RI=CN,CO2CH~ XXX

4-Oxo-l,3-thiazines are most frequently obtained by (4 + 2)-cycloaddition. Usually,


thioacyl isocyanates [17, 18] or isocyanates [18-20] are condensed with alkenes [17], al-
kynes [17], ketenimines [19], or phosphacumulidenes [18]. The reactions are normally carried
out in nonpolar aprotic solvents, the temperature used being dependent on the reactivity of
the reactants. The condensation of thiobenzoyl isocyanate (XEXI) with nucleophilic alkenes
and alkynes [17] has received especially close attention. The rate of this reaction is great-
er with alkynes than alkenes, and increases as the electron-donor properties of the substitu-
ents at the multiple bond of the nucleophile are increased.
O
CsHs__C_N~C= 0 NaCH(CN)C%C2H s , li 9 i ~o N
[r - ~" C'H'--C-:IO~C--CH'C~ --~" II II

-~.~c
o " - ~R ~ . . ~-.~, o ~ . o

N N

cs. ~ "s ~ c6~ ~ "s" "c6H5 c~H~ "s" "N(C2Rs)~


The lower reactivity of the ketenimines (EXXII) in t h e i r reactions with isothiocyanates
(XXXIII) requires the use of more severe reaction conditions [9], The condensation is sen-
sitive to the electronic effects of the substituents. The yield of the 1,3-thiazinethione
(XXXIV) decreases as the electron density of the isothiocyanate (XXXIII) is increased, and
when electron-acceptor substituents are introduced into the keteneimines (XXXII).

S t~ -- . ~ 1
, II =
RIR=--~-C=C~.NR:s + ]~ 2,NC--NC8 CsHsCH
3- R42N/ ~ ' S ~ N R 3

X]ODI 13[XIII XX~V.

XXXIV a,b I~=R2=CHs, e RI=R~=C6Hs; a,b Ra=p.CH3CsH4,c RS=p.OCH3CsH4; a


R~=C~H~, b,c R4=i-CaHr

The cycloaddition of the isothiQcyanates (XXXV) to the phosphacumylidenes (XXXVI) af-


fords products with a zwitterionic structure (XXXVII) [18] in yields which are highly depend-
ent on steric factors (as the volume of R is increased, the yield of the thiazinethione
(XXXVII) decreases).

x
(Ph)3P
S
R--C--N--C~-~.g + (Ph)3--P--C=C=C-.~X
II
S S R
XXXV XXX'~ ]OtXVll
R=N(A.I.k)2; X=O,S,Nph

The four-membered unit can be thioacylketene (XXXVIII), which reacts with diisopropyl-
carbodiimide [ 2 1 ] .

f (Me)2HC% N ~ , - / R
Ph-- C--C..~-C=O I-C3H? --N~-C =-N-- C3ST-i
S (Me)2HC--N S 'Pb
XXXVIII R=CN,CO2C2H~

An interesting route to 4-oxo- or 4-thioxo-l,3-thiazines is by the reaction between 3-


substituted-2-oxo- or 2-thioxo-4-tosylimino-l,3-thiazetidines (XXXIX) and diethylaminopropyne
[22, 23]. Attack on the carbonyl or thiocarbonyl carbon by the ynamine appears to result in
recyclization of the four-membered to the six-membered ring.

X
R\ ~/CH 3
R N"C'~'S + CH3--CmC--N(C2Hm)2 ~ N [~
- - \CJl / TaN
~.~J \N(C2Hs)~
NTs
R=II.C~H~; X=O,S 9

The (4 + 2)-cycloaddition reaction has rarely been used to obtain 6-oxo-l,3-thiazines.


The only example known to the authors is the condensation of N-thioaroyl-N'N'-dimethylformi-
dines (XL) with ketches [24, 25]. Phenylketene is less reactive than its unsubstituted ana-
log.

~=c..(u,)2 R-c~c=o ---- 9 ]!


XL Ar '5 0
ll::.lt,l'rSl{~

Type C reactions have not been used for the preparation of 1,4-dioxo-l,3-thiazines.
They have, however, been used extensively in the synthesis of 4,6-dioxo-l,3-thiazines and
their sulfur analogs. The previously-mentioned isothiocyanate (XXXI) reacts with diethyl
sodiomalonate to give the straight-chain adduct (XLI), which cyclizes in the presence of c~-
pyridone to the 1,3-thiazine (XLII) [17].
,0
N,i /C02C2l[5
XXXI + NaC[4(CO~C~IIs)2 ...... ~m- C~Hb-CSNHCOCH(C02C,~H3) ~ . . . . -D- I1 ]I
CSI[~"~"'~S "~ " O H
XLI XLII

The rate of condensation with nucleophilic alkenes and alkynes increases when gem-electron-
donor substituents are present:

i
Ce~f~"' "~ S'
9

~R
T.
r
'='~
xxxx
,
CH3CmCOC~H5 ~ C6H 5 S 0 C 2H~t
110 e
R--OC2H~,SCH ~

The isothiocyanates (XXXIII) condense readily with reactive ketenes to give 5-substitu-
ted-2-alkylamino-4-thioxo-6-oxo-l,3-thiazines (XLIII) [19].
S

XXXIII + R~R2C--C-----O J~- R2


R42N ~S / ~'~0
R ! =R2=Ar;R4=Alk kqlII

One of the few examples of the condensation of a C3N fragment with the CS unit is the
reaction of 2-imino-4-oxothiazolidine l,l-dioxide (XLIV) with potassium tert-butoxide, car-
bon disulfide, and iodomethane in dimethyl-formamide solution [26].
0

~I RI SC 13
0 z "O
XMV R ~,R2::Ar XLV

(3 + 3) CONDENSATION
This reaction (type D) is that most frequently used for the preparation of the 1,3-thi-
azine ring. The most frequently-used method for the synthesis of oxo-l,3-thiazines is the
condensation of acetylenecarboxyli c acid derivatives with thioureas or dlthiocarbamic acid
derivatives, and for the preparation of 4,6-dioxo-l,3-thiazines, condensation of the appro-
priate thioamides with 'malonating' agents. Despite the extensive use of this type of syn-
thesis, there have been no reports of its use to prepare 2-oxo-l,3-thiazines or their thio-
analogs.
1,3-Thiazines with an oxo-group in the 4-position are formed by the condensation of B-
substituted acetylenecarboxylic acids (XLVI) with thiourea or its N-alkyl derivatives [27-36].

2 Jk R1
"'N"
1~
~
3
R=tl
C
II
NHR ~
I R ~=H
" -X
C-
I
R "..N + I -.i----- C + C ::S --~ S ---d~-
~C~ 3 RI/IN~/~'S X
R IN >" NR2R
XJ.NI XLVII XLVIII

RI=H, Alk,Ar; R2=H, Alk,At; R3=H, Alk; X=CO2CHs, Ar, 2-furyl


The mechanism of ring closure has unfortunately received little attention, and it is
not possible to provide an unambiguous explanation of the effects of substltuents on the
course of the reaction. The condensation is carried out in both protic and aprotic polar
solvents. It appears that initially ~-addition of the thiourea sulfur atom to the sp-hy-
bridized carbon takes place preferentially, and in several instances [35] the products of
such a reaction (XLVII) have been isolated. The NCS fragment can also be provided by 4-sub-
stituted thiosemicarbazides, which condense with acetylenedicarboxylic ester to give 2-imino-
3-amino-4-oxo-67alkoxycarbonyl-l,3-tbiazines [37]. The thiazine structure was assigned to
the product of the reaction of ethyl propiolate with thiobenzamide [38], but regrettably
these authors failed to provide any confirmation of this structure.
1,3-Thiazines with an oxo- or thioxo-group in the 6-position have been obtained by con-
densing substituted thiobenzamideswitb cyanoacetlc acid in the presence of PC1, or POCIs [39,
40]. The introduction of electron-acceptor substituents into the thioamide, and electron-
donor substituents in the a - p o s i t i o n of the c y a n o a c e t i c a c i d , reduce the y i e l d s of c y c l i z a -
tion products.
NIl 2

ArCSNH 2 + CN--CHqCOOH ~-- ~-


E At" "" "co ~ " 0
R=H.AIk

Reaction of B,B-dichlorovinyl ketones (XLIX) with thioamides or thioureas affords 6-


thioxo-l, 3-thiazines [41-43]
R' t H N .3 ~ N R3
" C .>0
I
.tt~/C.~ ,CI ~i ~ R2 I C ~ C / S R2 ~ S .
C~-CI I el
C! S

XLIX L
Rr=ph, Alk; R2=CI, H; R3=NH2; NHAlk, NAlk2, Alk. Ar
2,4-Dioxo-l,3-thiazines and their sulfur analogs are formed by condensing dithiocarbamic
acid [i, 44, 45] or its N-alkyl derivatives [44, 46] with propiolic [i, 44, 46] or y-hydroxy-
tetrolic acid [45].
The condensation of dithiocarbamic acid derivatives with propiolic acid in the presence
of PCIs had been studied previously [46]. Subsequently, acetic anhydride with traces of sul-
furic acid was used in place of PCIs [i, 44], the yields of 1,3-thiazines being considerably
increased. The reaction proceeds via the formation of the product of the nucleophilic attack
on the ~-carbon by sulfur. In several cases these compounds (LI) could be isolated [46].
O
ii. <'~~176162 .-lit-. ~3
It'CtCCOORz .+ ~'biiiCSSil ._._~ ,, NltR" ..... ! i

LI LI,
RI=~H,Cit20[I; R2=II; R3;-iI,Alk

It is preferable to use the free acetylencarboxylic acids in this reaction, since the
use of esters results in the cyclization giving low yields and requiring more severe condi-
tions [i].
(3 + 3)-Cyclocondensation is most frequently used to obtain 2-substituted 4,6-dioxo-l,3,
thiazines. These methods are based on the reaction of thioamides with a variety of 'malonat-
ing' agents, namely, malonyl chloride, malonic acid, and carbon suboxide [47-67].
In a study of the condensation of thiobenzamides (LIII) with malonyl chloride, it was
suggested that initially the sulfur atom of the thioamide (LIII) was acylated to give the
intermediate (LV), which is either converted into the 4,6-dioxothiazine (LVI), and reacts
with a second molecule of the thioamide (LIII) [47].

N .!L..,
.rcsN~ 2 + cH..(cocl) 2 ..... Arc(=Ns.)~eOc.2coct ....... ~
MI! LV Ar ~ S
I L~,'I

LIII
ArCSNHCOCII2COCI ------,.... ArCSNHCOCH2CONHCSA~

It has been found that the dichloride (LIV) or carbon suboxide react with S-alkyldith-
iocarbamates (LVII) or thioacetamides to give both cyclic (VLIII) and straight-chain (LIX)
products [48-50].
~-_r176
LIX . LVI[ LVII[
There have been several studies of the reaction of n~alonyi chloride (LIV) with alkane-
thiocarboxyllc acids or N-substituted thioamides to give 2-arylidene-or 2-alkyiidene-4,6-
dioxo-l,3-thiazines [51, 52].
,i~ O
hiV R~ N - ,\" ~:H,~
,R ~~zGHt-'SNH~" ....... ~ El , C - : : S'~3 ;'~i Clfz
O
Rl~ H,AIk: R :=:~lt~;Ar

Disubstituted maionyl dichlorides react with NNt-disubsLituted thioureas to give 3,5,5-


substituted 2-a!ky!imino-4,6-dioxo-l,3-thiazines [53, 54].
R3 , , O

R~ =Alk; R'?,t*,~D, lk ,A r

When O-alkylthiocarbamates react with the acid chloride (LIV), in addition to 2-alkoxy-
4,6-dioxo-l,3-thiazines there is also formed 2,4,6-trioxo-i,3-thiazine, apparently as a re-
sult of the reaction of the former with the hydrogen chloride liberated [55].
.OH OH

s --~:o s --~"o
Malonic acid and its derivatives react with thiobenzamides in the presence of condens-
ing agents (PCI3) to give 5-substituted-2-aryl-4,6-dioxo-l,3-thiazines [56]. A drawback of
this method is the partial resinification of the cyclization products. This reaction takes
place in acetic anhydride with O-ethyldithiocarbamates or N-acetylthiourea [56, 57], but in
this case further acylation of the 1,3-thiazines formed takes place to give the 4-acetoxy-
compounds [57].
A highly efficient 'malonating' agent is carbon suboxide, which reacts with thioamides
to give 2-substituted-4,6-dioxo,l,3-thiazines (LX) [57-60]. The reaction may be complicated
by the addition of C30= to the thiazine (LX) with the formation of hi- (LXI) and polycyclic
derivatives [57, 61].
OH X N O OH
X-CSNH 2 + C302 )=- J
X~- %o,._ TT-T
0 0
l ~X LXI

The reaction of carbon suboxide with N-acetylthiourea has received the closest attention.
It has been found that acylation reduces the electron density at one of the thiourea nitro-
gens, facilitating NS-cycloaddition of the carbon suboxide [49, 55, 57]. The use of thiourea
or N-arylthioureas results in the formation of 2-thiobarbituric acids [58, 62, 63]. Unsym-
metrical NN'-dialkyl(or aryl)thioureas are converted to 2-dialkylamino-4,6-dioxo-l,3-thia-
zones [63, 64].

CHEMICAL PROPERTIES
The chemical properties of oxo- and thioxo-l,3-thiazines have received much less atten-
tion than the condensation reactions used in their preparation. The majority of studies have
examined alkylation, acylation, and electrophilic and nucleophilic substitution. It is worthy
to note that several reactions have been used to modify compounds already containing the 1,3-
thizaine ring. For example, alkoxy-, alkylthio-, and alkylimino-l,3-thiazines are frequently
obtained by alkylating the appropriate thiazines with diazomethane [i, 6, 28, 45, 65], dimeth-
yl sulfate [i, 6, 41], or iodomethane [29, 41]. The use of dimethyl sulfate is complicated
by the possibility of the opening of the thiazine ring in the presence of caustic alkali.
Alkylation takes place both at the ring nitrogen [i, 6, 28] and at the nueleophilic centers
of the substituents [i, 29, 41, 45, 65]. Methylation of 2-substituted 4,6-dioxo-l,3-thiazines
w i t h diazomethane in ether affords only O-methylation products, which were originally regarded
as 6-methoxy-l,3-thiazines [60]. Subsequently, however, quantum-chemical calculations and the
~3C NMR spectra of *SN-phenyl-4,6-dioxo-l,3-thiazine and its O-methylation product showed that
the latter was 2-phenyl-4-methoxy-6-oxo-l,3-thiazine [68]. Acylation has been closely examined
in the case of 2-substituted-4,6-dioxo-l,3, thiazines (LX). The use of acetic anhydride gave
the O-acetyl derivatives [69]. Another method of preparation of O-acyl derivatives is by acyl-
ating the sodium salt of the thiazlne (LX) with aromatic carbonyl and sulfonyl halides [70,
71]. In addition to O-acylation, examples are known of the N-acylation of amino-groups in
the 2-position of the aminooxothiazines (XLVIII, L) [28, 35, 41].
The 1,3-thiazinediones (LX), which comprize a heteroaromatic system in which C(s) is ac-
tivated to electrophilic attack, react with great ease withelectrophilic reagents. For in-
stance, reaction with phenyldiazonium chloride gives 2-substituted-5-phenylazo-4-hydroxy-6-
oxo-l,3-thiazines [56, 65, 72]. Reaction of (LX) with disubstituted aminomethanols affords
the Mannich bases (LXII~ [73]. Nitration, halogenation, and sulfonation of 2-aryl-4,6-diox O-
1,3-thiazines, even under mild conditions with equimolar proportions of the reactants takes
place exclusively at C(s) of the thiazine ring [72]. Nitration has been effected in nitric
acid (d 1.42) in acetic acid in the presence of acetic anhydride, and halogenation with bro-
mine in organic solvents (preferably acetic acid), lodination has been accomplished only
with iodine chloride. When sulfonation of the thiazine (LX) was carried out with sulfuric
acid of SO~ in pyridine, no product could be isolated, However, sulfonation takes place
readily with SOa in dichloroethane.

I
OH q'J~|
I
N'"":::'~:',/CH:~NR:z N
I
":- '
NO~

9 .,v,~ ~OJ' "/x .....s ""o


I ! o,,

LXH ",'-'. 1 Br

~" C~ . IX
"':'
: .................. ""
3 I
01[ ~-- .d- X S "'0
.I . . . N:::N--Ph ~,, J) so,J!
N.

l~III

It is interesting that the nitration of 6-(2-furyl)-l,3-thiazines (XLVIII) takes place


in the s-position of the furan ring [35].
Reactions with nucleophilic reagents occupy an important place in studies of the chemi-
cal properties of oxo- and thioxo-l,3-thiazines. For example, the hydrolysis of 2-alkylimino-
[i, 34, 35] or 2-alkylthio-4-oxothiazines [i, 6] is frequently employed for the preparation
of 5- and 6-substituted-2,4-dioxo-l,3-thiazines~ The reaction is usually carried out with
acid catalysis [I]. In alkaline media, cleavage of the thiazine ring often takes place [72].
One of the most interesting of the chemical properties of substituted 2,4-dioxo-13,-thiazines
is their reaction with ammonia [6, 44] and primary amines [14, 44] when the thiazines are con-
verted into the corresponding pyrimidines. The first step in this reaction appears to be
cleavage of the ring by the nucleophile, and in several cases aeyclic reaction products (LXIV)
have been isolated [14].

q) 0

N ~ ' -

II " "
EtS "- "" S "" CH NIIR S ~" ~N"'
ux.]v I
R

Acyclic products have also been obtained in the reaction of 6-substituted 2-amino-4-oxo-
1,3-thiazines or the thiazines (LX) with secondary amines [28, 74-76]. It is interesting
that in the case of the thiazines (LX) the intermediate ammonium salts (LXV) have been iso-
lated, these undergoing cleavage on heating in organic solvents,

ItNR, N ~ I~
i,x: ---"" ]I I" ~"J . ~(' . - ....
. . X(::SNII~:Oe~.,('ONR,
r

J
1:-%

The reaction between 4,6-dioxo-l,3-thiazines and sodium a!koxides may follow two routes,
since 2-aryl-4,6-dioxo-l,3-thiazines form stable salts with sodium ethoxide [71], whereas 2-
alkylidiene-4,6-dioxo-l,3-thiazines rearrange to the piperidones [51].
Nucleophilic replacement o~ the halogen atom in 2-chloro-4-oxo-l,3-thiazines (II) has
been examined using amines [3]. Depending on the amine taken and on the reaction conditions
either the 2-alkylaminothiazines are obtained, or acyclic compounds, but cleavage always pre-
cedes replacement [3].

o
Jl
RaRIN ~S #
L\"VI I.XVII

It has been shown to be possible to convert oxo-l,3-thiazines into their thioxo-analogs


by treatment with P~S~o [24, 25, 77]. The reverse transformation has been effected with mer-
curic acetate (ii), and in the case of the 6-thioxo-l,3-thizaine (L), the 6-oxo-compound is
obtained [41].
The structures of the reduction products of oxo-l,3-thiazines are dependent on the re-
action conditions. For example, when sodium borohydride is used only the C=N bond of the
thiazine (XXV) is reduced [12], whereas the catalytic hydrogenation of methyl 3-methyl-2-
imino-40oxo-l,3-thiazine-6-carboxylate gives N-methylsuceinimide [28],
Less general chemical properties are the conversion of the carboxamide group in (XXV)
(R = CONH=) into the nitrile by treatment with trimethylsilyl polyphosphate [78] and the di-
merization of 2-alkyl-6-methyl-4-oxo-l,3-thiazines on heating with a catalytic amount of tri-
fluoroacetic acid in dimethylformamide [79].
Oxo-l,3-thiazines are potentially tautomeric. It is unfortunate that up to the present
only the ~automerism of 2-substituted-4,6-dioxo-l,3-thiazines (LX) has been studied. These
thiazines can exist in at least four tautomeric forms (LEa-d).

N.--./" 011 / 0 ' 0

ix a Lx b LX'c LXd

On the basis of the IR, PMR, and UV spectra, Beilin et al., [60, 68] have shown that
when the substituent in the 2-position of the thiazine ring is varied, the structure of the
fl-dicarbonyl fragment also changes, in the opinion of these workers owing to the "differing
contributions of the substituent to the conjugation of the thiazine ring." For instance,
crystalline 2-(p-chlorophenyl)- and 2-phenyl-4,6-dioxo-l,3-thiazine were assigned a zwitter-
ionic structure (LXd) on the basis of the similarity of the IR spectra to the spectra o f
their salts, and the absence of absorption above 1600 cm -~. In solution~ these compounds
already exist in the enol forms (LXa) of (LXc), since their IR spectra correspond to that of
4-methoxy-2-phenyl-6-oxo-l,3-thiazine. The enol form was confirmed by the PMR spectra, since
in DMSO solution they showed signals for olefinic (5-H, ~ 5.4-5.8 ppm), hydroxylic (12.0-
12.6 ppm), and phenyl (7.5-8.3 ppm) protons. The spectra showed no signals for the methylene
group with 6 = 3.5 ppm, as observed for compounds with structure (LXb) and an olefinic proton
for the anionic form with 6 = 4.7 ppm such as is present in the spectra of the salts. In or-
der to determine the relative stabilities of the tautomers (LEa) and (LXb) s the atomization
energies of these forms of 2-phenyl-4-hydroxy-6-oxo-l,3-thiazine were calculated by the PPP
method in Dewar's o, ~-parameterization. It was found that the tautomer (LXa) was the more
stable. From the IR spectra of crystalline samples and of solutions, 2-alkylthio-4,6-dioxo-
1,3-thiazines were assigned the diketonic form (LXb)o 2-Methyl- and 2-alkoxy-4,6-dioxo-l,3-
thiazines display an interesting structural feature. The IR spectra of crystalline samples
of these compounds shown characteristic C=O absorption at 1650-1628 cm -~, showing that they
exist in the enol form. However, solutions of these compounds in DMSO solution (from their
IR and PMR spectra) contain both the keto- and enol-forms [60]. It is difficult to arrive .
at any conclusions concerning the structure of 2-amino-4,6-dioxo-l,3-thiazines in the ab-
sence of adequate spectral data. In the opinion of Baranova, Dashkevich, et al., [6].
63], the PMR spectra of these compounds in DMSO indicate the presence of two tautomeric forms
(enol and diketonic).

i0
SUMMARY
This review has shown that the attention of workers has been concentrated for the most
part on the synthesis of 4-oxo-, 2,4-dioxo-, and 4,6-dioxo-l,3-thiazines. These compounds
are most commonly obtained by condensing acetylenecarboxylic acids with thioureas or dithi-
ocarbamic acids, or by reacting thioamides with malonic acid derivatives or carbon suboxide.
The chemical properties of this interesting group of heterocycles have received relatively
little attention, and it is not possible to arrive at any firm conclusions as to the effects
of variations in the ring heteroatoms on their chemical properties, and the position of these
compounds amongst their hetero-analogs. The available information does enable novel, pre-
viously inaccessible compounds to be prepared. It hardly needs to be mentioned that the 1,3-
thiazine ring is present in naturally-occurring biologically active compounds such as cephal-
osporins and antibiotics. Oxo-and thioxo-i,3,-thiazines possess properties which are valuable
from the practical point of view, such as antiinflammatory [54], analgetic [80], tranquiliz-
ing [81], antipyretic [39], diuretic [39, 70, 71], fungicidal [80], and antimicrobial [43]
activity.

LITERATURE CITED
I. E. N. Cain and R. N. Warrener, Austral. J. Chem., 23, 51 (1970).
2. G. Simchen and G. Entenmann, East German Pat. No. 2 010 558; Chem. Abstr., 76, 3181
(1972).
3 G. Simchem and G. Entenmann, Liebigs Ann., 8, 1249 (1977).
4 G. Simchem and J. Wenzelburger, Chem. Ber.. 103, 413 (1970).
5 J. Kav~lek, S. EI-Bahaie, V. Machacek, and V. Sterba, Coll., 45, 732 (1980).
6 R . N . Warrener and E. N. Cain, Tetrah. Lett., 28, 3225 (1966).
7 R . N . Warrener and E. N. Cain, Tetrah. Lett., 28, 3231 (1966).
8 J. Imrich and P. Kristain, Coil, 47, 3268 (1962).
9 M. Dzurilla and P. Kristian, Coll., 41, 1388 (1976).
i0. R. Shabana, J. B. Rasmussen, and S.-O. Lawesson, Bull. Soc. Chim. Belges, 90, 75 (1981).
ii. M. Yukoyama, Y. Sawachi, and T. Isso, J. Org. Chem., 38, 802 (1973).
12. M. Yokoyama, M. Nakamura, H. Otheki, T. Imamoto, and K. Yamagushi, J. Org. Chem., 47,
1090 (1982).
13. M. Yukoyama, M. Nakamura, T. Imamoto, and K. Yamagushi, Chem. Commun., No. ii, 560
(1981).
14. M. R. Atkinson, G. Shaw, K. Schaffner, and R. N. Warrener, J. Chem. Soc., No. I0, 3847
(1956).
15. T. Nishio and Y. Omote, J. Chem. Soc., Perkin I, No. 9, 2149 (1982).
16. M. Muraoke, T. Yamamoto, S. Yamagushi, F. Tonosaki, T. Takeshima, and N. Fukada, J. Chem.
Soc., Perkin I, No. ii, 1273 (1977).
17. J. Goerdeler, M.-L. Tiedt, and K. Nandi, Chem. Ber., i14, 2713 (1981).
18. H. J. Bestmann and I. Schmidt, Tetrah. Lett., No. 21, 2401 (1980).
19. J. Goerdeler and H. Luedke, Chem. Ber., iO3, 3393 (1970).
20. K. Seifert, S. Johne, and A. Shaks, East German Pat. No. 149 807; Chem. Abstr., 96,
52326 (1982).
21. I. Goerdeler and K. H. Koehler, Tetrah. Lett., No. 34, 2961 (1976).
22. G. L'Abbe, J.-P. Dekerk, and M. De Ketele, Bull. Soc. Chim. Belges, 91, 243 (]982).
23. G. L'Abbe, P. Vangheluwe, and S. Topper, Bull. Soc. Chim. Beiges, 92, 61 (1983).
24. J. S. Meslin and H. Quiniou, Synthesis, No. 4, 298 (1974).
25. J. C. Meslin and H. Quiniou, Tetrahedron, 31, 3055 (1975).
26. E. Fisher, I. Hartmann, and H. Priebs, Z. Chem., 15, 480 (1975).
27. J. W. Lown and J. C. N. Ma, Canad. J. Chem., 45, 939 (1967).
28. E. Winterfeldt and J. M. Nelke, Chem. Bet., i00, 3671 (1967).
29. L. I. Giannola, S. Palazzo, P. Agozzino, L. Lamartina, and L. Cerualo, J. Chem. Soc.,
Perkin I~ No~ Ii. 1428 (1978).
30. U. Voegeli, W. Von Philipsborn, K. Nagarajan, and M. D. Nair, Helv. Chim, Acta, 61, 607
(1978).
31 G. Dallas, J. W. Lown, and J. C. N. Ma, J. Chem. Soc., C, No. 20, 2510 (1968).
32 H. Tanaka and A. Yikoyama, Chem. Pharm. Bull, iO, 13 (1962).
33 A. Yokoyama and H. Tanaka, Chem. Pharm. Bull.~ 12, 683 (1964).
34 Y. Kishida and T. Atsusuke, Chem. Pharm. Bull., 16, 1351 (1968).
35 E. Akerblom, Chem. Ser., 6, 35 (1974).
36 E. G. Kataev, L. K. Konovalova, and E. G. Yarkova, Zh. Org. Khim., ~, 621 (]969).

II
37. J. W. Lown aud J. C. N. Ma, Canad. J. Chem., 45, 953 (1967).
38. A. K. Mushkalo and G Ya. Yangol' Ukr Khim. Zh., 21, 732 (1955)
39. E. Ziegler, US Pat. No. 3,062,816; Chem. Abstr., 58, 6841 (1963).
40. E. Steiner and E. Ziegler, Monatsh. Chem., 95, 1550 (1964).
41. W. Schroth, G. Dill, Nguyen Thi Kim Dung, Nguyen Thi Mai Khoi, Phan Thi Binh, H9 J.
Waskiewicz, and A~ Z. Hildebrandt, Z. Chem9 14, 52 (1974).
42. W. Schroth, G. Dill, and A. Hildebrandt, East German Pat. No. 106 650; Chem. Abstr., 82,
73011 (1975).
43. A. N. Mirskova, A. S. Atavin, G. G. Levkovskaya, and P. V. Lidina, in: Abstr. Reports,
13th Scientific Session on the Chemistry and Technology of Organic Sulfur Compounds and
Sulfur-Containing Petroleum [in Russian], Zinatne, Riga (1974), p. 1969
44. R. N. Warrener and E. N. Cain, Chem. Ind., 48, 1989 (1964).
45. R. N. Warrener and E. N. Cain, Austral. J. Chem., 21, 785 (1971).
46. J. L. Garraway, J. Chem. Sot., No. i0, 4077 (1962)9
479 G. Goerde!er and H. Horstmann, Chem. Ber., 93, 663 (1960).
48. L. B. Dashkevich, V. G. Beilin, N. A. Baranova, E. N. Kirillova, S. P. Saenchuk, and
G. G. Verga, in: The Chemistry of Dicarbonyl Compounds9 Abstr. Reports, 3rd All-Union
Conference on the Occasion of the 80th Birthday of Academician of the Academy of Sciences
of the Latvian SSR Gustav Vanag [in Russian], Riga (1971), p. 54.
49. V. G. Beilin, L. B. Dashkevich, and E. N. Kirillova, Zh. Org. Khim., ~, 2609 (1970).
50. L. B. Dashkevich, V. G. Beilin, and E. N. Kirillova, Inventor's Cert. (USSR) No. 291,920;
Publ. in Byull. Izobret., No. 4, 70 (1971).
51. J. C. Martin, K. C. Bronnock, and R. C. Menn, J. Org. Chem., 31, 2966 (1966).
52. W. Zankowska-Jasinka and J. Eiimes, Roczn. Chem., 50, 1059 (1976).
53. T. Zawisza, E. Wagner, J. Matczakova, andT. Jacobiec, Arch. Immunol. Ther. Exp., 26, 943
(1978).
54. T. Zawisza, J. Matczak, S. H. Kowalczyk-Bronisz, and T. Jacobiec, Arch. In~nunol. Ther.
Exp., 2_~9, 235 (1981).
55. L. I. Khirul'kova, V. G. Beilin, and L. B. Dashkevich, in: Results and Prospects in
the Search for New Drugs at the Leningrad Institute for Pharmeceutical Chemistry. Abstr.
Reports [in Russian], Leningrad (1979), p. 27.
56. E. Ziegler and E. Steiner, Monatsh. Chem., 95, 495 (1964).
57. E. Ziegler and E. Steiner, Monatsh. Chem., 96, 548 (1962).
58. E. Ziegler and H. Biemann, Monatsh. Chem., 93, 34 (1962).
59. E. Ziegler and R. Wolf, Monatsh. Chem., 95, 1061 (1964).
60. V. G. Beilin, V. A. Gindin, E. N. Kirillova, and L. B. Dashkevich, Khim. Geterotsikl.
Soedin, No. 8, 1042 (1976).
61. N. A. Baranova, V. G. Beilin, L. B. Dashkevich, and L. I. Khitul'kova, in: Results and
Prospects in the Search for New Drugs at the Leningrad Institute for Pharmaceutical
Chemistry. Abstr. Reports [in Russian], Leningrad (1979), p. 28.
62. T. Kappe, G. Lang, and E. Ziegler, Naturforschung, 29B, 258 (1974).
63. L. B. Dashkevich and V. M. Siraya, Zh. Obshch. Khim., 32, 2330 (1960).
64. V. G. Beilin, V. A. Gindin, L. B. Dashkevich, V. N. Kuklin, and L. I. Khirul'kova, in:
Results and Prospects in the Search for New Drugs at the Leningrad Institute for Phar-
maceutical Chemistry. Abstr, Reports [in Russian], Leningrad (1979), p. 31.
65. E. Ziegler and E. Steiner, Monatsh. Chem., 95, 495 (1964).
66. J. C. Martin and R. N. Meen, US Pat. No 3 408 348; Chem. Abstr., 70, 11709 (1969),
67. J. C. Martin and K. C. Bronnock, US Pat. No. 3 373 159; Chem. Abstr., 69, 59254 (1968).
68, V. G. Beilin, V. A, Gindin, and B. Ya, Simkin, Khim. Geterotsikl. Soedin., No. 4, 481
(1979).
69. H. C. Scarborough and C. A. Hanning, US Pat, No 3 336 305; Chem. Abstr., 68, 12968 (1968).
70. V, G. Beilin, E. N. Kirillova, L. B. Dashkevich, A. A. Lebdev. and N. S. Ma!achevskaya,
Khim.-farm. Zh., No. i, 20 (1980).
71. V. G. Beilin, E. N. Kirillova, and L. B. Dashkevich, Inventor's Cert. (USSR) No. 596,583;
Publ. in Byull. Izobret., No. 9, 107 (1978).
72. V. G. Beilin, V. A. Gindin, V. N. Kuklin, and L. B. Dashkevich, Khim. Geterotsikl. Soe-
din., No. i, 44 (1979).
73. E. Ziegler and E. Kiesewetter, Monatsh. Chem., 96, 659 (1965).
74. L. M. Manoilova, E. N. Kirillova, V. G. Beilin, T. N. Zozulya, and L. B. Dashkevich,
Khim.-farm. Zh., No. i0, 89 (1976).
75. V. G. Beilin, E. N. Kirillova, and L. B. Dashkevich, Inventor's Cert. (USSR) No. 412,186;
Publ. in Byull Izobret., No. 3, 96 (1974).

12
76. V. G. Beilin, I. M. Ginzburg, E. N. Kirillova, and L. B. Dashkevich, Zh. Org. Khim., 13,
1333 (1977).
77. R. N. Warrener and E. N. Cain, Chem. Ind., No. 7, 591 (1982).
78. M. Yokoyama, S. Yoshida, and T. Imamoto, Synthesis, No. 7, 591 (1982).
79. Y. Yamamoto, S. Ohnishi, A. Moroi, and A. Yoshida, Chem. Commun., No. i, 56 (1983).
80. K. Tomito and T. Murakami, Jap. Pat. No. 7 920 504; Chem. Abstr., 91, 157 755 (1979).
81. H. M. Blather and G. Stevens, US Pat. No. 3 098 071; Chem. Abstr., 60, 1766 (1964).

MASS-SPECTROMETRIC STUDY OF THE CYCLIZATION REACTIONS OF DIAZOKETONES.


8.* I-DIAZO-3,4-EPOXY-4-ARYLBUTAN-2-ONES

A. T. Lebedev, P. A. Sharbatyan, A. G. Kazaryan, UDC 543.51:547.537'


T. P. Pokidova, V. G. Kartsev, and V. S. Petrosyan 284.4'235.2

An analysis of the mass spectra of l-diazo-3,4-epoxy-4-arylbutanones has shown


that the molecular ions of these compounds lose a molecule of nitrogen and that
the [M-- N2] + ions formed cyclize to form hydroxyfuran structures, whose fur-
ther fragmentation determines the whole picture of the dissociative ionization
of the compounds investigated under electron impact. The majority of the [M --
N2] + ions have the form of the cyclic intermediate formed in the first step of
the cyclization process. It cannot, however, be ruled out that a certain por-
tion of the [M -- N2] + ions are stabilized as a result of a Wolff rearrangement
and do not cyclize at all.

We previously [2] showed that under electron impact in the gaseous phase diazoketones
which contain a heteroatom or a heteroatomic grouping in their chain eliminate a nitrogen
molecule and cyclize to form heterocyclic systems owing to the practicable cooperation of the
heteroatom, rather than decompose according to a mechanism involving a Wolff rearrangement
[3, 4]. Since the action of acids on diazoketones in solutions produces similar products [5,
6], it was concluded that it would be possible to predict the direction of this reaction on
the basis of mass-spectrometric data. The results of the treatment of phthaloyldipeptide
derivatives of diazomethane with acidic reagents completely correspond to the predictions
made on the basis of the mass spectra of these compounds [2, 7].
Continuing this investigation, we studied the mass spectra of a series of arylepoxydia-
zoketones I, whose conversions in solutions were not previously investigated.

H I!

s2~ O R ~

sa-h
I a RI=H, b RI=CH3, c h RI=OCH3, d RI=NO2, e RI=F, f, g Rs=CI;
a--f R~=R3=H, g R2=}I, R~=D; h I{~=OCH:~,l~:'~=l!

The first step of the fragmentation of these compounds under electron impact, as would
be expected [I, 2], is the elimination of a nitrogen molecule. This results in the formation
of [M -- N2] + ions, whose structure makes it possible to draw a conclusion regarding the direc-
tion of the reactions of diazoketones with acidic reagents, which is the main goal of the
present work. The possible structures of the [M -- N2] + ions (see Scheme I) can be suggested
on the basis of the preceding investigations [i, 2] and the data in [3, 4].

*For report 7 see [i].

M. V. Lomonosov Moscow State University, Moscow 117234. Translated from Khimiya Getero-
tsiklicheskikh Soedinenii, No. i, pp. 17-22, January, 1986. Original article submitted Decem-
bet 4, 1984.

0009-3122/86/2201-0013512.50 9 1986 Plenum Publishing Corporation 13


TABLE i. Intensities of the Peaks of the Characteristic Frag-
ment Ions in the Mass Spectra of Diazoketones I in the Total Ion
Current
,e,

Corn-
pond
M~ [M-N~I' F~ F'2 F3 F~ Fs F~ Flo 105169
i
!a -- 0,6 1,1 2,0 4,3 -- 3,5 0,9 3,2 : 7,0 0,5 7,1 21,6 6,0
lb 0,1 1,3 1,1 1,4 4,2 0,1 2,8 0,5 2,0 i 6,6 0,9 17,0 20,1 3,2
Ic 0,4 1,45 1,2 0,9 4,2 0,4 1,8 0,3 1,4 6,2 1,3 15,9 18,5 --
Id -- 4,0 0,3 1,1 1,5 0,7 1,4 3,5 0,7 -- 7,7 1,1 0,6
le 2,1 4,0 1,1 3,1 0,1 2,7 1,0 6,7 10,7 0,6 5,9 2,1 10,2
If ~ 0,5 0,5 0,4 1,6 - - 1,2 0,2 3,5 5,6 0,2 11,6 9,9 6,6
lg 0,4 0,8 0,4 1,1 4,6 0,4 1,3 0,7 1,0 3,6 0,8 15,8 5,7 0,8
lh 0,3 7,9 2,5 3,4 0,2 6,5 1,5 1,6 8,5 0,8 5,8 7,1 5,0

The ions of type A with a linear structure are unstable and are stabilized either as a
result of a Wolff rearrangement (ion B) or as a result of intramolecular cyclization (inter-
mediate D' and ions of type D). Ketene B can also cyclize to form ion C [8]. It should be
noted that both intramolecular cyclization and a Wolff rearrangement can take place simul-
taneously with the elimination of a molecule of nitrogen and can, in fact, initiate this pro-
cess.

Scheme i
]+"
H H H H
i I - I I
~_c<_pc_co CnN2 -N~ \ /
Ar --C--C--C0- CH +" Ar - - C ~ - - ~ C - - C H : C = 0
o o 0
M+ A B

A~ I IJ"
0 + ~C,~ 0 ~C / CIt
"CH "~0
II
/ D'
o
c
+"

Ar "/C~'o/CH2

D D

The molecular ions (M+ of compounds I, like M + of the previously studied diazoketones
[2], are unstable. The intensity of the peaks for M + does not exceed 0.5% of the total ion
current,* and the presence of electron-acceptor substituents in the benzene ring (NO~, F)
results in the complete disappearance of the peak of this ion. Nevertheless, the formation
of [M -- CHN ]+ fragments with an intensity of 0.1-0.2% and of [COCHN2] + which has a mass-to-
charge ratio equal to 69# (see Table i), proves that diazo compounds I form M +, i.e., ioni-
zation of the diazo compounds, rather than the products of their thermal decomposition, par-
ticularly the ketenes, occurs under the conditions of our experiment [3, 4].
An analysis of the fragmentation paths of the [M -- N=] + ions allows us to conclude that
they mainly have a cyclic structure (form D, see Scheme i). Some of the [M -- N ]+ ions de-
compose prior to the migration of the hydrogen ion (the D'-D transition) and the formation
of the hydroxyfuran pseudomolecular ion. Ion D can exist in two principal tautomeric forms:
a keto and an enol form. In the case of 4-isopropyl-3-hydroxy-4,5-dihydrofuran, the enol
form is predominant in the gaseous phase [9]; therefore, it may be postulated that in the
case of diazo compounds I, the majority of the ions of type D will have the enol form, since
additional stabilization of such a structure is caused by the formation of the aromatic furan
system.

*The fraction of the ions of a particular type in the total ion current is given in percent.
#The formation of this ion form M + in the case of compound I is confirmed by the peak of the
metastable ion with an apparent mass of 21.4. Here and in the following, the numbers char-
acterizing an ion determine the value of m/z.

14
The main directions of the fragmentation of the [M-- Na] + ions of diazoketones I may be
represented by the general scheme

Scheme 2

A~"c~.TSa
09 ArCllO-]+ " [ M - N ~ -C01+'
Fs Fz o --2

_]+. ~ --cHco I I +'


Ar ~CII----CII ~ I ---C..~O J --I!.,CO "~" "~ CH~

-uco' j-'" ,c .' ..I o.~ ,c~ \ \

ArCtl2+ A~CH=CH --,~--- IM_N2 _CHO]+ ..... ~. Ar-C~C~ I+"


F8 F5 F6
(ArCO+)
I05

"The genetic relationship of these ions was not established.

The structures of ions F~, Fz, Fa, Fa, and F9 may be represented differently, if it is
postulated that the first step in the transformation of the [ M , N=] + ions is a Wolff rear-
rangement [3, 4]. However, other experimental findings attest to the fact that the majority
of the [M -- N=] ~ ions (and possibly all of them) are stabilized as a result of intramolecular
cyclization.
First, the Wolff rearrangement does not result in the destruction of the epoxy ring;
therefore, peaks of ions characteristic of the decomposition of aromatic epoxy compounds
should be observed in the mass spectra of diazoketones I. In the mass spectra of pheny!
epoxides the peaks of the ArCH + and ArC + ions have the maximum intensities [I0]. In the case
of diazoketones I, the peaks of these ions have intensities below 0.5%,* attesting to the
destruction of the epoxy ring in the initial steps of the fragmentation. On the other hand,
the peak of the ArCHO +" ions (F~o), which has the maximum intensity in the mass spectra of
the compounds investigated, is practically absent in the mass spectra of aryl epoxides [10]
and arylepoxyketones [ii]. The proves the impossibility of its formation from linear ions
A and B (see Scheme i), while the decomposition of intermediate D' with the formation of such
an ion is very favorable.
Second, the Wolff rearrangement does not account for the formation of ion F~ (see Scheme
2), while its appearance from intermediate D' as a result of the elimination of a COCHO par-
ticle or from ion Fa (elimination of a CO molecule) is not impeded. In addition, the forma-
tion of ions of type F6 as a result of the elimination of a COCH=O particle from the [M -- N=] "+
ion in one or two steps, as was observed in the mass spectra of 1,3-oxazin-5-ones [12] and
4,5-dihydro-3-oxofurans [9], confirms the cyclic structure of D for these ions.
Third, an additional mass-spectroscopic finding which confirms the cyclization of the
[M -- Na] + ion is the formation of the fragments of type FT. As a result of the attack of
the oxygen atom of the epoxy ring at the methine group, which bears a positive charge and a
free electron, the lone pair of the oxygen atom can form a bond either with the carbon atom
(the electrophilic center) (this results in the formation of intermediate D') or with the
acidic proton of the methine group with the subsequent cleavage of a C--C bond and the forma-
tion of fragment FT.

" c ~ ~ -%o Ar .
CH-- c~ Ar ~ C H ~ C H ~ + "
,.,+. . . . . . . \/
0:~ .' 0 O

*An e x c e p t i o n i s compound I e , f o r w h i c h t h e i n t e n s i t i e s of the peaks of these fragments are


5 . 5 and 4 . 5 % , r e s p e c t i v e l y . They a r e a l s o s u f f i c i e n t l y intense in the mass spectra of un-
substituted diazoketone I a ( 1 . 7 and 2.2%, r e s p e c t i v e l y ) .

15
Electro1~-acceptor substituents in the aromatic ring increase the acidity of the methine
group. This is reflected in the increases in the relative intensities of the peaks of the
F7 ions in the mass spectra of compounds Id-f (see Table i).
In order to refine the fragmentation scheme, we synthesized compound Ig with deuteration
at the diazo group. The calculation of the intensities of the peaks in the mass spectrum of
this compound showed that the deuterium label is completely retained in ion FI, while 30% of
it is lost in F~. Therefore, the [M -- N2] + ions eliminate the benzyl hydrogen atom, and such
elimination can occur either from intermediate D' or from linear forms A and B of the [M -- N] +
ion [i0, ii].
The Fs ions apparently form along several paths. The successive elimination of a hydro-
gen atom and a molecule of CO from the [M -- N2] + ion does not result in the loss of the deu-
terium label. The elimination of an HCO" radical is the main process in the fragmentation of
furans [13, i4]. The fragmentation of diazoketone Ig according to such a mechanism should
result in the complete loss of the deuterium label in the case of the existence of ion D ex-
clusively in the enol form and in its partial loss when the keto form of this ion is present.
The partial loss of the deuterium label may also be the result of the elimination of a hydro-
gen atom from ion F2. It is not possible to evaluate the contribution of each of these paths
to the formation of ion F3; however, the experimental findings presented can be explained only
when the [M-- N2] + ions are assumed to have a cyclic structure. In this case, the structure
of fragment F~ can vary as a function of the mechanism for its formation and is, therefore,
not presented in the scheme.
It is known 14 that substituents in positions 2 and 5 of the furan ring (R) can result
in the appearance of an alternative direction of fragmentation~ An RCO" radical is eliminated
along with an HCO" radical. In the case of diazoketones I, position 5 in the furan ring
formed is occupied by an aryl substituent. The electronic properties of the substituents
in the benzene ring play an important role in the competitive elimination of the HCO' and
RCO" radicals. For example, in the mass spectra of compounds Ia-c with electron-donor sub-
stituents, the peak of the [M -- N2 -- RCO] ion is not observed at all. Electron-acceptor sub-
stituents (compounds Id-f) make this fragmentation path competitive. The mass spectra of
these compounds display peaks for the corresponding ion 55 with relative intensities equal
to 4.6, 1.0, and 1.0%, respectively. As was shown in [13, 14], this ion has a cyclic cyclo-
propane structure.
Tile cyclic structure of the [M --N2] + ions is also confirmed by the formation of the F~
fragments as a result of the elimination of a molecule of formaldehyde from the keto form of
ion D or an HCO" radical from ion F:.
Nevertheless, all the mass-spectrometric findings described do not allow us to completely
discount the possibility of a Wolff rearrangement; therefore, it should be assumed that the
formation of ketene ions of type B according to a mechanism involving a Wolff rearrangement
[3, 4] may be a process which competes with the intramolecular cyclization and takes place
for some of the [M-- N2] + ions.
Cleavage of the C(2)--C(s) bond in M + results in the formation of ions F9 and 69, and
the mass spectra of diazoketones I display peaks for both these ions (see Table i), i.e.,
these fragments have similar ionization energies [15, 16].
Substituents in the benzene ring do not alter the principal fragmentation paths. The
behavior of fluorinated derivative le is anomalous. The peaks of ions Fa and 69 have the
maximum intensities in the mass spectrum of this compound; the peaks of the ArCH +. and ArC +
fragments (5.5 and 4.1%), which are characteristic of the fragmentation of aryl epoxides
[i0], are also intense. The intensity of the peak of ion F7 is alsoincreased (see Table I).
Such a sharp increase in the number of ~ ions decomposing along paths not associated with
the initial formation of a furan ring indisputably reduces the proportion of [M -- N=] + ions
in form D to the total number of ionized molecules of this compound in comparison to the
other compounds of type I.

_/--CH--CH-
S \ /
0
CO- CH-X

I i X=~r z

16
TABLE 2. Mass Spectra of Compounds la-i

Values of m/z:'~
Co m - (relative intensities of ion peaks as percentages of the maximum)
pound

|a 131 (19,4), 120 (15,0), 106 (36,2), 105 (100), 103 (16,3), 91 (32,2), 78
(12,5), 77 (54,0), 69 (30,1), 51 (25,0)
Ib 145 (21.3). 120 (84.2). 119 (I00), 117 (13.3), 105 (33,0), 92 (19.4), 91
(63,8), 69 (17.0), 65 (51,4). 41 (16.4)
Ic 161 (24.9), 159 (10,8), 137 (13,1), 136 (85.7). 135 (100). 121 (33.3), 91
(13.9), 78 (10.1), 77 (31,7), 51 (19,9)
Id 205 (51,6), 165 (45.7). 151 (lO0). 118 (33.8). 105 (70.4), 102 (37,3), 89
(38,3), 90 (36,9), 77 (36.9), 55 (59,6)
le 177 (40,3), 149 (30,8), 138 (66,7). 124 (55,0), 109 (100), 108 (61,8), 107
(33,0). 101 (49.0). 95 (68.9), 69 (95.5)
If 159 (30,5). 154 (28,2). 142 (62.9), 141 (80,t), 140 (100), 139 (85,0), 125
(48,1). 110 (27,6), 89 (43.4), 69 (67,1)
Ig't" 160 (14.2), 142 (30.4), 141 (43,2), 140 (87,8). 139 (100), 138 (27,0), 125
(33,1), 111 (21,6), 89 (28,3), 70 (14,8)
Ill 191 (28.9), 189 (15,9), 166 (100), 165 (36,4). 151 (23,0), 95 (23.8). 79
(13,4), 77 (21.9), 63 (11,3), 51 (16,7)
li 166 (91,9), 138 (29,5), 137 (39,6). 112 (68,4). 111 (83,2), I10 (26,2). 109
(76,5). 97 (I00), 69 (57.7), 65 (22,8)

i
*The i0 most intense peaks are given.
tThe spectrum was obtained on an MKh-1303 mass spectrometer.

The behavior of epoxythiophene li is similar to that of the compounds described. The


mass spectrum of this compound differs significantly from the spectrum of epoxyketone lli,
which has a similar structure [17], and all the fragments are described well by the general
scheme for the fragmentation of diazoketones I presented, i.e., in this case, too, the epoxy
ring opens and a cyclic furan ion forms.
Thus, an analysis of the mass spectra of diazoketones I showed that the M + ions of
these compounds lose a molecule of nitrogen and the [M -- N=] + ions formed undergo cyclization
with the formation of hydroxy furan structures, whose further fragmentation determines the
entire picture of the dissociative ionization of the compounds investigated under electron
impact. The majority of the [M -- N~] + ions have the form of the cyclic intermediate formed
in the first step of the cyclization process. It cannot, however, be ruled out that a cer-
tain portion of the [M -- N2] + ions are stabilized as a result of a Wolff rearrangement and
do not cyclize at all. On the basis of the investigation carried out, it may be postulated
that cyclic furan systems will form when the diazoketones studied are reacted with solutions
of acids. In the case of fluorinated derivative le, secondary reactions with the formation
of other products are possible.

EXPERIMENTAL
All the compounds investigated were synthesized at the Chernogolovka Branch of the In-
stitute of Chemical Physics of the Academy of Sciences of the USSR. The mass spectra of
diazoketones la-h were obtained on an LKB-2091 mass spectrometer (Sweden) with the use of a
system for the direct admission of the sample into the ion source. The temperature of the
samples was 60-140~ and the energy of the ionizing electrons was 70eV. The mass spectra
of compounds If and Ig were additionally recorded under identical conditions (the temperature
was 100~ and the energy of the ionizing electrons was 50 eV) on an MKh-1303 mass spectro-
meter with a similar admission system. The deuterated form of compound Ig was obtained by
holding diazoketone If in deuteromethanol (CD3OD) for 24 h with further evaporation of the
solvent and recrystallization of the deuterated derivative f~om deuteromethanol.

LITERATURE CITED
i. A. T. Lebedev, P. A. Sharbatyan, A. G. Kazaryan, V. G. Karsev, A. M. Sipyagin, and V.
S. Petrosyan, Khim. Geterotsikl. Soedin., No. 6, 788 (1985).
2. A. T. Lebedev. Dissertation for the Degree of Candidate of Chemical Sciences, M. V,
Lomonosov Moscow State Univeristy (MGU), Moscow (1982).
3. P. Kinson and B. Trost, Tetrah. Lett., 14, 1075 (1969).
4. K.-P. Zeller, H. Meier, and E. Muller, Tetrahedron, 28, 5831 (1972).
5. V. G. Kartsev and A. M. Sipyagin, Khim. Geterotsikl. Soedin., No. I0, 1324 (1980).
6. V. G. Kartsev, A. M. Sipyagin, N. F. Sepetov, and L. A. Sibel'dina, Khim. Geterotsikl.
Soedin., No. I0, 1327 (1980).
17
7. A. T. Lebedev, P. A. Sharbatyan~ A. M. Sipyagin, V. G. Kartsev, and V. S. Petrosyan,
Khim. Geterotsikl. Soedin., No.5, 623 (1983).
8. K. K~gu, Helv. Chim. Acta, 24, 141 (1941).
9. M. Anteunis and M. Vandewall, Spectrochim. Acta, ~7A, 2119 (1971).
i0~ H. E. Audier, J. F. Dupin, M. Fetizon, and J. Hoppiliard, Tetrah. Lett., No. 19, 2077
(1966).
ii. S. Sasaki, H. Abe, and K. Nakanishi, Bull. Chem. Soc., Japan, 41, 522 (1968).
12. A. T. Lebedev, P. A. Sharbatyan, A. M. Sipyagin, V. G. Kartsev, and V. S. Petrosyan,
Khim. Geterotsikl. Soedin, No. i0, 1332 (1983).
13. R. I. Reed and W. K. Reed, J. Chem. Soc., 12, 5933 (1963).
14. K. Heyns, R. Stute, and H. Scharmann, Tetrahedron, 22, 2223 (1966).
15. D. P. Stevenson, Disc. Faraday Soc., i0, 35 (1951).
16. H. E. Audier, Org. Mass Spectrom., ~, 283 (1969).
17. F. P. Ballistreri, G. Musumara, and S. Occhipinti, Ann. Chim. (Rome), 71, 269 (1981).

SYNTHESIS OF 2-, 6-, AND 7-AMINOMETHYL DERIVATIVES


IN THE 4,5-DIHYDROXYBENZOFURAN SERIES

A. N. Grinev,* V. M. Lyubchanskaya, L. S. Sarkisova, UDC 547.728.1.07:


L. M. Alekseeva, and Yu. N. Sheinker 543.422.25

The 2-, 6-, and 7-aminomethyl derivatives have been synthesized from derivatives
of 4-hydroxy-5-methoxy- and 4-methoxy-4-hydroxybenzofuran. 2-Methyl-3-carbeth-
oxy-5-methoxy-7-dimethylaminomethylbenzofuran has been Converted into the 7-cyan-
omethyl derivative.

Aminomethyl derivatives of benzofuran are of definite interest in the area of the search
for drugs. One of them, viz., 2-phenyl-3-carbethoxy-4-dimethylaminomethyl-5-hydroxybenzofur-
an hydrochloride (phenykoberan), has found application in the practice of medicine [i]. We
recently synthesized derivatives of 4-hydroxy-5-methoxy- and 4-methoxy-5-hydroxybenzofuran
[2]. In the present work, we have used them as a basis for obtaining various, primarily the
2-, 6-, and 7-aminomethyl, derivatives.
The bromination of 2-methyl-3-carbethoxy-4-acetoxy-5-methoxybenzofuran (II) by N-bromo-
succinimide in the presence of benzoyl peroxide gives 2-bromomethyl derivative III, and 2-
dimethylaminomethyl-2-piperidinomethyl-, and 2-isopropylaminomethyl-4-hydroxy-5-methoxybenzo-
furan (IVa-c) are obtained by reacting the corresponding amines with III. When III is re-
acted with an excess of the amines, elimination of the acetyl group is observed along with
the replacement of bromine by the residue of the amine.
OH OCOCH3

%"~ Ao o J[ 'il
'%. / -.. ...~.
v 0 "CH~
I II
OCOCH3 OH

', CH3 C00C2H 5 HNRR I H3 C00C2H 5

~//" ~0 / ~ CH2Br ~//~ OA CH2NRR I


III IVa-s

IV a R=R'=CHa, b R-kRI=(CH2)~,c R=H, R~=CH(CH3)z


*Deceased.

S. Ordzhonikidze All-Union Scientific-Research Institute for Pharmeceutical Chemistry,


Moscow 119021. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. i, pp. 23-27,
January, 1986. Original article submitted December 18, 1984.

18 0009-3122/86/2201-0018512.50 9 1986 Plenum Publishing Corporation


TABLE i. Carbon-13 Chemical Shifts of Compounds Va, Vlla, and
VIII

, ppm in CDCI3
Compound
C,2) I C,3) Ci3a) C~4) C(5) C(7) [ C(TR)

Va
Vlla
I
16~,6 I 108,8
161,5 I 109.4
113,8
119,0
138,9
139,7
143,0
147,5
1132
190,4
Ilia
105,4
I 147,7
147,5
VIll 162,6 109,1 113,6 143,! 140,6 112,9 119,2 149,6

The aminomethylation of 2-methyl-3-carbethoxy-4-hydroxy-5-methoxybenzofuran (I) by bis-


(dimethylamino)methane and a mixture of formalin with piperidine gives 7-aminomethyl deriva-
tives Va and b, and the aminomethylation of isomeric 2-methyl-3-carbethoxy-4-methoxy-5-hy-
droxybenzofuran (VI) by bis(dimethylamino)methane and dimorpholinomethane gives 6-aminomethyl
derivaties Vlla and b.

OH OCH~ OH

. ~[~ 0 -CH, R'RNCH~0 %CH~ Br TOLCI%


CH2NRR~ CH2N(CH~)2
va, b VIIa, b Vlll

Va, Vlla RffiRIfCH3; Vb R+RI=(CH2)~, VII bR+RJffi(CH2)20(CH2)2

In order to determine the positions of the substituents i n compounds Va, Vb, V I I a and
V I I b , we c o m p a r e d t h e Z3C s p e c t r a o f compounds Va and V l I a and t h e s p e c t r a o f V I I I , w h i c h
was p r e v i o u s l y o b t a i n e d i n [ 3 ] .
The s i g n a l s i n t h e X3C s p e c t r u m of u n s u b s t i t u t e d benzofuran for the C(3), C(3a), C(.),
C ( 5 ) , C ( s ) , and C(7) a t o m s and f o r t h e C ( a ) a n d C ( T a ) a t o m s a r e known t o be o b s e r v e d i n t h e
106-127 and 145-155 ppm r a n g e s , r e s p e c t i v e l y [4]. An e v a l u a t i o n o f t h e c h e m i c a l s h i f t s o f
the aromatic carbon atoms with the-use of the increments of the substituents f o r b e n z e n e [5]
r e v e a l s t h a t i n t h e s p e c t r u m o f V I I I t h e C ( . ) a n d C(5) s i g n a l s s h o u l d f a l l i n t h e w e a k e r - f i e l d
g r o u p a l o n g w i t h t h e s i g n a l s o f t h e C ( a ) a n d C(Ta) a t o m s . To a s s i g n t h e s i g n a l s h a v i n g s i m i -
l a r c h e m i c a l s h i f t s and t h e same m u l t i p l i c i t y , we a l s o t o o k i n t o a c c o u n t t h e d e p e n d e n c e o f
t h e v a l u e s o f t h e s p i n - - s p i n c o u p l i n g c o n s t a n t s o f t h e c a r b o n a t o m s of b e n z o f u r a n w i t h t h e p r o -
tons of the substituents on t h e number o f b o n d s [ 6 ] . On t h e b a s i s o f a l l t h e c o n s i d e r a t i o n s
just enumerated, the signals at 162.6 162.6 (q, 2Jc~2~' 2-CHa = 7.5 Hz, 109.1 (q, 37c~ 2CH , =
2.5 HZ), 112.9 (t, aJc(~a~.7-CH~ = 4.5 Hz) 119.2 (t, 2J~7 7-CH~ = 6 HZ), and 149.6 (t, 3Jci.~ 7CH~
=4.5) were assigned to the C(=), C(3 ), C(6); C(7), and C(7a) atoms, respectively.' It
should be noted that the spectrum ot compound VIII in CDCL3 displays additional splitting of
the signals of C(,) (2JG<~v4OH = 4 Hz), as well as of C(3a) and C(5) (3Jq~v4OH = S.[Cs;4OH
= 2.5 Hz), by the proton of the OH group, which participates in a chelating hydrogen bond
with the oxygen atom of the carbethoxy group at C(3) [3]. This splitting is absent in the
spectrum of VIII in CD3OD, where at singlet at 112.9, the signlet at 142.5, and the quartet
at 139.4 ppm (3Jcc~'~ocH~ = 4 HZ) belong to the C(3a), C(4), and C(5) atoms.
The spectrum of compound Va is similar in many ways to the spectrum of VIII. Here we
also observe additional splitting of the signals of the C(3a), C(,), and C(5) atoms due to
the proton of the hydroxyl group, which vanishes in the spectrum recorded in CD3OD. The
chemical shifts of the signals of most of the carbon atoms of the benzene fragment change
only slightly upon the transition from Va to VIII (Table i). The multiplicity*, of these
signals is consistent exclusively with placement of the aminomethyl group at C(7). The
signal of C(3a) is a singlet, the signal of C(,) is a doublet (fc~4~.6-H 8 HZ), the signal =

of C(~) is a quartet (~fC,~rSOCH~ = 4, =7C(~;O-H = 4 Hz), the signal of C(~) is a doublet of


triplets (~Jc~H = 158, ~Jq~l.;eH~ = 5 Hz), the signal of C(~) is a sextet (~7c,7
~ 7cu~ =

*The splitting of the signals in CD~OD is given.

19
4.5, ~]c,;~o.l~ = 1.5 Hz;, and the signal of C(~a) is a sextet (sJc(7=vG.~l= 11,5, ~]~(7~,,.7.cij~
4:5 Hz). The spectrum of compound VIIa differs significantly from the spectrum of
Va with respect to the values of the chemical shifts (Table i) and especially with respect
to the character of the multiplicity of the signals of the carbon atom of the benzene frag-
ment, ~ i c h can be unequivocally attributed only to the presence of an aminomethyl substiuent
iu position 6 in compound Vlla. The splitting of the signals of C(7) , C(~a), and C(s),
which are observed, respectively, in the form of a doublet (2]C(7~),7.H= 3 Hz) at 147.5, a
doublet (~Jc,3~v~.a 5.5 Hz) at 119, and a quartet
= (3/C(~),G-CH~4, = s/c<~>:H = 8 Hz) at
147.5 ppm, are the most characteristic from this point of view.
We also carried out the chloromethylation of 2-methyl-3-carbethoxy-4,5-dimethoxybenzo-
furan (IX) and obtained 7-chloromethylated derivative Vc and bis(benzofurnanyl)methane der-
ivative X. Demethylation of the methoxy group in position 4 by hydrogen chloride was ob-
served during the reaction.

OCII3
/
OCH3 OH CH~0 ~ _ .~COOC2H 5

z ""~''~Y-- i] ~ '" ~ ( H e l l o ) ' ~"~F:Y'~ ...... ,(~ '~ s

"-- O {-:It~ "~'i~ " 0 . . . . CH 3 CH 2

" (' k%,.~)~k . - {.>H:~CI , CH3


Oft z :-

CII30." , : ' . \ COOC21I 5 CHsO / "']~ C00C2H 5

1. CIl :~I
"CII 5 Va ....... =-~ - ~ V e X
; " 2. N a C N
CII2R

Vd, e vd R=o%iis;e R~CN

According to the literature data, the chloromethylation of derivatives of 4-methoxy-


and 5-methoxybenzofuran produces derivatives of bis(benzofuranyl)methane exclusively [7].
Compound Vc reacts with nucleophilic reagents, viz., ethanol and sodium cyanide. These
reactions result in the formation of 2-methyl-3-carbethoxy-4-hydroxy-5-methoxy-7-ethoxymethyl-
benzofuran (Vd) and 2-methyl-3-carbethoxy-4-hydroxy-5-methoxy-7-cyanomethylbenzofuran (Ve)
with high yields.
We also obtained 7-cyanomethylbenzofuran derivative Ve from 7-dimethylaminomethyl de-
rivative Va. Compound Va reacts with methyl iodide in dioxane to form a methiodide, which
is converted without isolation under the action of sodium cyanide into compound Ve.
The structures of the compounds synthesized were confirmed by the data from ~H NMR
spectra (Table 3).

EXPERIMENTAL
The ~H and :3C NMR spectra were obtained on Varian XL-200 and XL-100 spectrometers,
respectively, in CDCI3 with TMS as an internal reference. The course of the reaction was
monitored chromatographically on Silufol-254 plates in a 9:1 benzene'methanol system with
development in UV light.
The characteristics and yields of the compounds obtained are presented in Tables 1-3.
2-Methyl-3=carbethoxy-4-acetoxy75-methoxybenzof~ran (II~. A mixture of 2.5 g (I0 mmole)
of methoxybenzofuran I, I0 ml of acetic anhydride, and 0.01 ml of concentrated H2SO, was
heated at 60~ with stirring for 2.5 h. The reaction mixture was diluted by I00 ml of water,
and the precipitate was filtered out, washed with water, and dried. This gave 2.15 g (73.6%)
of II.
2-Bromomethyl-3-carbethoxy-4-acetoxy-5-methoxybenzofuran (III). A mixture of 5.45 g
(19 mmole) of acetoxybenzofuran II, 3.4 g (19 mmmole) of N-bromosuccinimide, ll ml of car-
bon tetrachloride, and i mg of benzoyl peroxide was boiled for i0 h. The hot reaction mix-
ture was filtered, the mother solution was evaporated to dryness, and the residue was re-
crystallized from ethanol. This gave 6.1 g (88%) of compound III.
2-Dimethylamingmethyl-3-carbethoxy-4-hydroxy-5-methoxybenzofuran (IVa). A solution of
1.85 g (5 m m o l e ) o f derivative III in 15 ml of dry benzene was given an addition of a solu-
tion of 0.68 g (15 nunole) of dimethylamine in i0 ml of benzene with stirring. The reaction

20
TABLE 2. Characteristics of Compounds II, III, IVa-c, Va-e,
VZIa, Vllb, and X

Found, % Calculated, %
Com- mp/~ ~ Empirical Yield, %
pound formula l-
H [CI(Br) N c H [Cl(Br) N

II 129--131 61,9 5,5 C,5H1606 61,6 5,5 73,6


III 96--97 48,4 4,1 C~sHlsBrO6 48,5 4,1 '2~,5 88,0
IVa 170--173" 54,4 6,2 10,8 C,sH2oCINO5 54oE 6,1 '10,8 ~,2 51,0
IVb 181--1824 58,7 6,6 9,3 CIsH24CINOs 58,5 6,5 9.6 3,8 60,0
IVc 180--182 56,0 6,3 9,9 CIsH~2CINO5 55,9 6,4 10,3 4,0 45,0
Va 205---207 55,8 6,7 10,3 C,sH22CINO5 55,9 6,4 10,3 4,0 69,5
Vb 220--221: 59,7 6,9 9,4 CIgHmCINO~ 59,5 6,8 9,2 3,7 49,5
Vc 126--128 56,9 5,0 11,3 C14HIsCIOs 56,3 5,1 11,8 16,8
Vr 85--86 62,8 6,3 CisH2006 62,3 6,5 -- 87,5
Ve 174--176 52,3 5,3 C,sH,sNOs 62,3 5,2 ~,8 77,0
Vlla
Vllb
175--176~"
136--138
55,7
51,5
6,4
6,6
1;3 CI6H2~CINO6 55,9 6,4 10,,3 4,0 48,0
C,sH~3NO6 51,9 6,6 4,0 25,0
X 257--259 54,2 5,7 C2~H32Oto 54,4 6,0 18,5

*Compounds II, III, Va, Vb, and Vllb were recrystallized from
ethanol; IVa-c, Ve, and Vlla were recrystallized from acetone;
Vc and Vd were recrystallized from hexane; X was recrystallized
from ethyl acetate. Compounds IVa_c, Va, Vb, and Vlla were
characterized in the form of the hydrochlorides, and Vllb was
characterized in the form of the base.
~Decomposition.

TABLE 3. Proton Chemical Shifts of Compounds III, Vc, Vd, and


Ve

6 , ppm, in CDCI3
Com-
2-CH~, 7-H, 7-CH2CI. 7-CH2CN,
pound 2-CH2Br,S 3-COOC2Hs 5-OCH3, S 6.H 7-CH2OC2Hs

III 4,82 4,40 q 3,87 7,33 d, 7,10d (~rUao8 m.)


1,42 t
Vc 2,73 4,42 tq 3,92 6,94 s 4,79 s
1,45
Vd 2,70 4,42 q. 3,92 6,95 s 4,66 s 3,55q , 1,25t
1,44 t
Ve 2,72 4,42 q 3,92 6,92 s 3,87 s
1,45 t

mixture was left to stand for 24 h at 20=C and then washed with water (two 50-ml portions,
and the benzene) layer was separated, dried over magnesium sulfate, and evaporated to dryness.
The residue was dissolved in 20 ml of acetone and given an addition of concentrated hydro-
chloric acid to pH 3. The precipitate isolated was filtered, washed with acetone, and dried.
This gave 0.84 g (51%) of the hydrochloride of IVa.
Compounds IV and IVc were obtained in a similar manner.
2-Methyl-3-carbethoxy-4-hydroxy-t-methoxy-7-dimethylaminomethylbenzofuran (Va). A so-
lution of 15.0 g (60 mmole) of methoxybenzofuran I in 250 ml of dioxane was given an addition
of 24.5 g (240 mmole) of bis(dimethylamino)methane and boiled for 20 h. The reaction mixture
was diluted with 1 liter of water, and the precipitate formed was filtered out, washed with
water, dried, and recrystallized from acetone. The base obtained was dissolved in i00 ml
of acetone, and the pH was adjusted to 3 with concentrated hydrochloric acid. The precipi-
tate formed was filtered out, washed with acetone, and dried. This gave 14.3 g (69.5%) of
the hydrochloride of compound Va.
Compounds Vlla and Vllb were obtained in a similar manner from 2-methyl-3-carbethoxy-4-
hydroxy-5-methoxy-7-piperidinomethylbenzofuran (VI).
2-Methyl-3-carbethoxy-4-hydroxy-5-metboxv-7-piperidin0methylbenzofuran (Vb). A solution
of 2.75 g (llmmole) of compound I in 50 ml of dioxane was given an addition Of 1.72 g (21

21
mmole of piperidine and 0.7 ml of formalin and boiled for 25 h. The reaction mixture was
diluted with 200 ml of water, and the precipitate isolated was filtered out, washed with
water, and dried. The precipitate was dissolved in 20 ml of acetone, the pH was adjusted to
3 with concentrated hydrochloric acid, and the precipitated substance was filtered out, washed
with acetone, and dried. This gave 2.1 g (49.5%) of the hydrochloride of compound Vb.
2-Methyl-3-carbethoxy-4-hydroxy-5-methoxy-7-chloromethylbenzofuran (Vc) and Bis(2-methyl-
3-carbethoxy-4,5-dimethoxybenzofuran-7-yl)methane (X). A solution of 2.64 g (i0 rgnole) of
dimethoxybenzofuran IX in i0 ml of dry benzene was saturated with dry hydrogen chloride and
given an addition of 0.4 g (13 mmole) of paraformaldehyde at 5~ with stirring. The passage
of hydrogen chloride through the reaction mixture was continued for i h at 5-I0~ The pre-
cipitate formed was filtered out, washed with 30 ml of benzene, and dried. This gave 1.0 g
(18.5%) of compound X. The mother solution was washed with water (five i00 ml portions), and
the benzene layer was separated, dried, and evaporated to dryness. The residue was recrystal-
lized from hexane. This gave 0.5 g (16.8%) of Vc.
2-Methyl-3-carbethoxy-4-hydroxy-5-methoxy-7-ethoxymethylbenzofuran (Vd). A solution of
1.0 g (3 mmole) of chloromethyl derivative Vc in 30 ml of ethanol was boiled for 2 h. The
alcohol was evaporated to dryness, and the residue was recrystallized from hexane. This gave
0.9 g (87.5%) of Vd.
2-Methyl-3-carbethoxy-4-hydroxy-5-methoxy-7-cyanomethylbenzofuran (Ve). A. A solution
of 1.48 g (5 mmole of Vc in 30 ml of dioxane was given an addition of a solution of 0.245 g
(4 mmole) of sodium cyanide in 3 ml of water, and the mixture was boiled for 14 h. The re-
action solution was diluted with 200 ml of water, and the precipitate formed was filtered
out, washed with water, dried, and recrystallized from acetone. This gave 0.9 g (63%) of
compound Ve.
B. A solution of 6.6 g (21 mmole) of Va in 40 ml of dioxane was given an addition of
6.1 g (42 mmole) of methyl iodide with stirring. The precipitated methiodide was filtered
out, washed with dioxane, dissolved in 75 ml of dioxane, and given an addition of a solution
of 1.03 g (21 mmole) of sodium cyanide in 7.5 ml of water. The mixture was boiled for 3.5
h. Then the reaction mixture was diluted with water (300 ml), and the precipitate formed
was filtered out, washed with water, dried, and recrystallized from acetone. This gave 4.8
g (77%) of Ve. A mixed sample with the product obtained according to method A does not dis-
play any melting-point depression.

LITERATURE CITED
I. A . N . Grinev, A. A. Stolyarchuk, K. S. Shadurskii, N. I. Ivanova, N, K. Venevtseva, V.
I. Shevdov, V. K. Vasil'eva, and E. K. Panisheva, USSR Patent (Inventor's Certificate)
No. 530,683; Byul. Izobr., No. 37 (1976).
2. A . N . Grinev, L. S. Sarkisova, and V. M. Lyubchanskaya, Khim. Geterotsikl. Soedin., No.
i0, 1322 (1984).
3. A . N . Grinev, L. S. Sarkisova, V. M. Lyubchanskaya, Yu. N. Sheinker, and L. M. Alekseeva,
Khim. Geterotsikl. Soedin., No. 9, 1181 (1983).
4. P . D . Clark, Org. Magn. Reson., No. 8, 252 (1976).
5. G . C . Levy and G. L. Nelson, Carbon-13 Nuclear Magnetic Resonance for Organic Chemists,
Wiley-lnterscience, New York (1972).
6. P . F . Hansen, Progress in Nuclear Magnetic Resonance Spectroscopy, Vol. 14 (1981), p.
216.
7. R. Royer, J. Guillaumei, P. Demerseman, N. Platzer, and J.-P. Buisson, Bull. Soc. Chim.
France, No. Ii, 4201 (1972).

22
CONVERSION OF trans,trans-I-METHOXY-3,5-DIARYL-2-OXABICYCLO[4.4.0]DEC-
3-ENES INTO HEMIDITHIOACETALS AND 4H-THIOPYRANS.
STRUCTURE OF trans,trans-I-MERCAPTO-3-PHENYL-5-(4-METHOXYPHENYL)-2-
THIABICYCLO[4.4.0]DEC-3-ENE

S. K. Klimenko, T. I. Tyrina, N. N. Sorokin, UDC 547.81:543.422:


L. V. Vlasova, A. A. Shcherbakov, G. A. Aleksandrov, 548.737
Yu. T. Struchkov, and V. G. Kharchenko

The conversion of trans,trans-l-methoxy-3,5-diaryl-2-oxabicyclo[4.4.0]dec-3-enes


into trans,trans-l-mercapto-3,5-diaryl-thiabicyclo[4.4.0]dec-3-enes or 2~4-diaryl-
5,6-tetramethylene-4H-thiopyrans, which takes place when hydrogen sulfide
is reacted with the acetals in acetic acid with the use of gaseous hydro-
gen chloride as a catalyst, has been described. A mechanism for the reaction has
been proposed. The structure and confirmations of the molecules have been deter-
mined by x-ray diffraction analysis and I~C NMR.

According to the data in [i], the reactions of 1,3-diaryl-3-(2-oxocyclohexyl)-l-propan-


ones with hydrogen sulfide in methanol in the presence of hydrogen chloride result in the
formation of either trans,trans-3,5-diaryl-2-thiabicyclo[4.4.0]dec-3-enes or trans,trans-
l-methoxy-3,5-diaryl-2-oxabicyclo[4.4.0]dec-3-enes (I). In the latter case, an interaction with
one of thenucleophiles, i.e., with methanol, takes place. It was noted that the conversion of oxy-
gen analogs of I into sulfur analogs of type II is not observed in methanol. At the same
time, it is known that acetals are split under the action of hydrogen chloride. In this con-
text it seemed to be of interest to study the reactions of bicyclic acetals la-c with hydro-
gen sulfide and hydrogen chloride in a polar solvent.
For this purpose we studied the reactions of trans,trans-acetals la-c with hydrogen sul-
fide in acetic acid under the conditions of acid catalysis. It was established that the re-
action of hydrogen chloride with a suspension of trans,trans-acetals la-c in acetic acid
which had been saturated to the limit with hydrogen sulfide at I0-15~ results in the forma-
tion of trans,trans-hemithioacetals IVa and IVc. If the reaction mixture is subjected to
the simultaneous action of hydrogen sulfide and hydrogen chloride, 4H-thiopyrans lllb and
lllc are recovered as the reaction products. Thioacetals lla-c were not detected.
The openin~ of the acetal ring in compounds la-c should produce a carbonium ion (A),
which is structurally similar to the protonated form of 1,3-diaryl-3-(2-oxocyclohexyl)-l-
propanones. Since the equatorial attack of ions of such a type is sterically hindered, as
was shown in [i], the preferential axial attack of ion A should produce intermediate B. The
absence of trans,trans-thioacetals lla-c in the reaction products attests to the fact that
intermediate C with a configuration which is most favorable for the intramolecular interac-
tion of the mercapto group with the carbonyl group clearly does not form. The intramolecular
interaction of the mercapto and carbonyl groups which occupy axial and equatorial positions
in hemithioacetal B is impeded by the rigidity of the acyclic chain, and the formation of
cis,trans isomers of type II is also not observed. The elimination of methanol from intermed-
iate B gives carboniumion D and then either 4H-thiopyrans lllb and lllc, if the concentration
of hydrogen sulfide is small, of trans,trans-hemidithioacetals IVa and IVc via gem-dithiol E.

N. G. Chernyshevskii Saratov State University, Saratov 410601. Translated from K h i m i y a


Geterotsiklicheskikh Soedinenii, No. I, pp. 28-33, January, 1986. Original article submitted
August 2, 1984.

0009-3122/86/2201-0023512.50 9 1986 Plenum Publishing Corporation 23


~:[t + ......tI2S/ttC!.~ 0 <.~r..._ R
V
/_..-_ /_.#. /
0C}'I3 I 1 1It

la- C A
SH
. ~}~
/

H H '\" l " "'R


B C
0CH 3
CH3OH] IIa-C
+ .SH H~> ,,,R~

H (~H S R
D H+
lllb, c
I H.aS
~, ~ .,,,,R
' ~ .,,,,,,R
I

"~./* .' Z -H20 \S ~'R


SH" ~ .'
SFI
E IVa, C

a, cR=C611s, b R=CoH~OCI|3-4;a,b Rl=CoHa, c R~=C6H4OCHs-4


A necessary condition for the formation of gem-diothiolsof type E and then of trans,
trans compounds IVa and c as intermediates is the limiting saturation of the reaction mix-
ture at I0-15~ with hydrogen sulfide. When hydrogen sulfide and hydrogen chloride are sim-
ultaneously reacted with acetals Ib and Ic, the dissolution of the original compounds Ib and
Ic and the precipitation of 4H-thiopyrans lllb and c are observed after 30-40 min.
When there is a shortage of hydrogen sulfide in the mixture, ion A can be subjected to
the attack of another nucleophile, viz., water, which is evolved when 4H-thiopyrans of type
III are formed. This results in the formation of the products of the intramolecular cyclo-
dehydration of 1,5-diketones of type V, i.e., 2,4-diarylbicyclo[3.3.1]non-2-en-9-ones of
type VI.
The intramolecular cyclodehydration process E + IVa,c is stereospecific and results in
the formation of substances with a trans,trans configuration. The trans-diequatorial arrange-
ment of the interacting parts in gem-dithiol E is most favorable for cyclization.. This is
consistent with the results in [i].

" . . . . . . . . . . . . :g r
-CH~OH /" , ( ~'R '"R
V C VIc

When the experiment is conducted in the absence of acetic anhydride, a small quantity
(9.5%) of compound Vlc is recovered along with 4H-thiopyran lllc.
For the purpose of confirming the proposed mechanism for the conversion of trans,trans-
acetals of type I into hemidithioacetals of type IV, we determined the crystal and molecular
structure of l--mercapto-3-phenyl-5-(4-meth0xyphenyl)-2-thiabicyclo[4.4.0]dec-3-ene (IVc).
The crystals of compound IVc are monoclinic: a = 12.575(1), b = 10.2942(8), c = 16.425(1)
~, ~ = 115.71(1) ~ , V = 1915.7 ~3, M = 368, d c a l = 1.28 g/cm 3, z = 4, space group P2~/c, v(Cu
Ka) = 24.7 cm -~. The coordinates of the atoms are listed in Table i, and the equations of
t h e planar fragments in the molecule and the deviations of the atoms from them are given in
TabZe 2. The stereochemistry of the molecule with the principal bond lengths and bond ang-
les is shown in Fig. i, and the torsion angles are presented in Fig. 2.
The geometry of dihydrothiopyran ring A is close to that found in the molecules of
trans,trans--methxy-3-(4-methxypheny)-5-pheny-2-thiabicyc[4.4.]dec-3-ene [2] and cis-
3,5-diphenyl-2-thiabicyclo[4.4.0]decene-A ~'6 [3]. The geometry of the methoxy group is close

24
/X'16(6 "

P117,9(3)

Fig. 1 Fig. 2
Fig. i. Bond lengths and bond angles in compound IVc. S(,)-C(,)= 1.835(4);
S(~)C(,)S(2) =108.6(2); S(,)C(~)C(,o) = 109.4(3); S(2)C(,)C(,o) = 105.6(3);
C(~)--C(6) = 1.546(6); S(,)C(~)C(6)= 112.7(3).
Fig. 2. Torsion angles in compound IVc.

to that found in the structure of 4-methoxybenzoic acid [4], where O-C(Me) = 1.443, O-C(Ph) =
1.360 A, and the C-O-~ angle is equal to 116.8 ~ . The length of the S(,)-C(,) bond in the mer-
capto group, which is equal to 1.835(4) ~, does not coincide with the standard value of 1.817(5)
[5].
The bicyclic system has trans annelation. Dihydrothiopyran ring A has a "half-chair"
conformation, the C(i) and C(,) atoms deviate in opposite directions from the planar S(2)C(3)-
C(~)C(5) fragment; cyclohexane ring B has a "chair" conformation. Phenyl rings C (in position
3) and D (in position 5) are planar. The dihedral angles between rings C and D and the planar
fragment of the heterocycle are 46.7 and 99.4 ~ , respectively. Phenyl substituent D is found
in a pseudoequatorial position.
l-Mercapto-3,5-diphenyl-2-thiabicyclo[4.4.0]dec-3-ene (IVa), like hemidithioacetal IVc,
has a trans,trans configuration, which was established on the basis of an analysis of their
'3C NMR spectra* (see Experimental section).
4H-Thiopyrans IIIb and IIlc were identified on the basis of the characteristic signals of
the vinyl and 4-H protons in the PMR spectra [6].

EXPERIMENTAL
The unit-cell parameters and the intensities of 1772 independent reflections with I > 30
were measured on a Hilger--Watts automatic four-circle diffractometer, which was controlled by
a PDP 8/1 computer, in Cu Ka radiation with a graphite monochromator, 0/20 scanning, and I <
e < 57 ~ . The structure was solved by the direct method according to the MULTAN program and--
re~ined by the least-squares method in the full-matrix anisotropic approximation. All the hy-
drogen atoms were revealed by a difference synthesis and taken into account in the concluding
steps of the refinement with fixed positional and thermal parameters (it was assumed that
Bis o = 5.0 ~2). The final values of the R factors were R = 0.0514 and Rw = 0.0641.

*A detailed discussion of the ~3C NMR spectra of hemidithioacetals of type IV and related he-
terocyclic systems will be presented in a separate report.

25
TABLE i, Coord,ina~:es o f At:oms ( ~)

S(i) 4214 (I) 3376 (1) 8061 fl) FI/,q I 3187 3518 7729
Sc~ 5612 (i) 1777 tl) 9676 (1) 11(4~ 4195 3772 I0735
0 - 5 4 8 (2) 2234 3) 10602 (2) FI(81 2891 3689 9074
C(1) 4231 (3) 1866 13 8661 (2) |IIfll 3293 956 9267
C(s) 5319 (3) 2820 41 10409 (2) ||fT~ 1370 1435 8225
C~ 4245 (3) 3203 (41 10261 (3) |I ~7Q 1863 2401 7677
C(~ 3096 (3) 2903 (3] 9475 (2) ;l[~h 1308 442 6883
3167 (3) 1756 (3; 8893 (2) 2118 -383 7791
2023 (3) 1585 (4; 8042 (3) ;Iig~ 2988 1325 6831
C(e) 2050 (3) 445 (4) 7454 (2) 3137 -253 6898
C(9) 3097 (4) 547 (41 7225 fl(lO~ 4903 8O5 7907
C(~o) 4238 (3) 695 (3) ~]flo,) 4367 - I13 8451
C(,;~ 6393 (3) ]092 (3) 1126O (2) ll(12i 7490 3556 I0667
C(m) 7451 (3) ]445 (4) 11259 (3) 9200 3903 12027
8442 (4) 3648 (4) 12047 (3) llfI4~ 9114 3622 13453
Coo 8392 (4) ~491 (4) 12872 (3) /][iR~ 7298 3059 13470
C(~5) 7346 (4} H54 (4) 12881 (3) zL(f6) 5592 2685 12106
C~m) 6362!3) }945 (4) 12090 (3) H(,8) I075 4220 9067
C(17) 2129 t3) ~694 (3) i 9784 (2) H(191 -398 3941 9583
C(18) 1154 (3) L500 (4) i 9499 (3) H~21) 1409 796 II096
C(m) 291 (3) ;334 (4) 9789 (3) H ~22~ 2911 1123 I0607
C(~o) 368 (3) !331 (4) 10369 (2) HI~3~ -1389 Illl lllll
Cim) -1335 (3) 520 (4) 10667 (2) H (~B,) 56 1049 I1771
C(~2) 2210 (3) :715 (4) 10378 (2) -442 35O I0763
C(~) -596 (4) 123 (4) 11093 (3)

*The numbers of the H atoms coincide with the numbers of the


corresponding nonhydrogen atoms (with single and double prime
signs for the second and third H atoms), and the hydrogen atom
of the mercapto group is denoted by H(S ).

The *H and X3C NMR spectra were recorded on a Varian FT-80A spectrometer (80 MHz) with
HMDS (for XH) and CDCI3 (for '3C) as internal references. The course of the reactions was
monitored by TLC on Silufol UV-254 plates with a 6:1 hexane-ether mixture as the eluent.
The original acetals la-c were obtained in analogy to [7].
Conversion of trans,trans-l-Methoxy-3,5-diaryl-2-oxabicyclo[4.4.0]-dec-3-enes (la, c)
into trans,trans--Mercapt-3-pheny-5-(4-methxypheny)-2-thiabicyc[4.4.]de-3-ene (IVc)
and trans,trans-l-Mercapto-3,5-diphenyl-2-thiabicyclo[4.4.0]dec-3-ene (IVa). A suspension of
3.6 g (15 mmole) of acetal Ic in 40 ml of glacial acetic acid (with an addition of 2 ml of
acetic anhydride) is saturated with hydrogen sulfide for 1.5 h at !0-15~ and then with a
mixture of hydrogen sulfide and hydrogen Chloride for i h. After 0.5 h has elapsed from the
beginning of the passage of HCI, initial acetal Ic is dissolved, and crystallization of re-
action product IVc is observed. The mixture is left to stand for 17 h in a refrigerator,
and then compound IVc is filtered out, washed with water, and dried in air. This gives 2.05
g of hemidithioacetal IVc with Tm = 139.5-140.5 ~ (from petroleum ether). The mother solution
is poured onto ice, and another 1.5 g of IVc are recovered; the total yield is 94%. *SC NMR
spectrum (CDCI3): 57.32 (C(z)), 130.76 (C(s)), 123.09 (C(4)), 47.02 (C(5)), 49.56 (C(6)),
25.69 (C(7)), 27.13 (C(s)), 22.22 (C(9)), 40.98 (C(~o)), 139.06, 128.13, 126.32, 127.93 (phen-
yl), 134.96, 129.63, 113.83, 158.37 (p-methoxyphenyl), 55.03 ppm (the CHsO group in the aryl
radical at C(~)). In the case of the aromatic substituents, the signals of the quaternary,
ortho, meta, and para carbon atoms were given in that order. Found: C, 71.6; H, 6.9; S,
16.9%. Calculated for C==HzsOS=: C, 71.7; H, 6.6; S, 17.4%.
The treatment of 20 mmole of trans,trans acetal Ia according to the method just de-
scribed gives 5.9 g (87%) of hemidithioacetal IVa with Tm = I07-I09~ (from a 1:3 ethanol--
acetone mixture); according to the data in [8], Tm = I07-I09~ :3C NMR spectrum (CDCIs):
57.20 (C(:)), 130.82 (C(s)), 122.54 (C(4)), 47.72 (C(5)), 49.23 (C(6)), 22.50 (C(7)), 26.92
(C(s)), 22.06 (C(9)), 40.78 (C(xo)), 138.28, 128.26, 126.32, 127,87 (phenyl at C(s)), 142.88,
128.66, 128.04, 126.49 ppm (phenyl at C(5)).
Conversion of trans,trans-l-Methoxy-3-5-diaryl-2-oxabiqyclo[4.4.0]dec-3-enes (Ibp c)
into 2-(4-Methoxyphenyl)-4-phenyl-5,6-tetramethylene-4H-thiopyran (IIIb) and 2-Phenyl~4 -
(

26
TABLE 2. Equations of the Planar Fragments in the Molecule
Ax + By + Cz = D* and Deviations of Atoms from Them in
0,352x + 0797y + 0,490z = - 5.503

S(2) C(3) C[4) C(5) C(D* C(6)* I S(1)*


Plane I - 0,003 0,009 - 0,009 0,004 0,450 -0,339 I 2,267
(ring A)

C(7)* C(1o)* I C(H)* I C~lT)* H(s)* H(6)* I

O:118x+ 0 , 8 2 7 y - 0:549z = - 5.781


c,,, c,o, ic., c,s, c,o, I c.o, ls,,,*l S/'-"* ICr H(6)*

- 0.261x + 0.9659 - 0.018z= 2.768


C(ll) C(121 I C1131 C~14) C(15) C1161 C131"~
Plane 3
(ring C)
--0,001 O,OOl I 0,003 -0,006 0,005 --0,002 --0,054
L
--0,169x--0.60gg- 0.756z= - 12,19
c )ic o) c,=,, i.c ),lo
Plane
4(ringD) 1o,oo6Io,oo2I-o,oosI o,oo6 0,002-0,009 i --0,012 10,022

1/2 1/3 1/4 2/3 2/4 3/4


Angles between 14,0 9 [ 46,7 99,4 39,0 95,6 121,9
planes in deg

*Atoms not involved in the calculation of the equations of the


corresponding planes.

methoxyphenyl)-5,6-tetramethTlene-4H-thiopyran (lllc). A suspension of 20 mmole of acetal


IB in 35 ml of glacial acetic acid with an addition of 2.5 ml of acetic anhydride is satur-
ated by a mixture of hydrogen sulfide and hydrogen chloride at I0-15~ After 0.5 h, dis-
solution of original acetal Ib is observed, and after 1.5 h the reaction mixture is poured
onto ice, and the precipitate formed is filtered out, washed with water, and dried in a
desiccator. The precipitate is dissolved in ether and filtered, and 4H-thiopyran lllb is
precipitated from the etheral extract by ethanol. The yield is 4.6 g (69%), and Tm = 107-
I08~ (ethanol--ether). PMR spectrum (CDCI~): 1.65-2.20 (8H, m, methylene protons), 3.68
(3H, s, CH30), 3.95 (IH, d, 4-H), 5.81 (IH, d, 4-H, 3Js,~ = 5.9 Hz), 6.69-7.20 ppm (9H, aro-
matic protons). Found: C, 79.3; H, 6.4; S, 9.6%. Calculated for C22H22OS: C, 79.0; H,
6.6; S, 9.6%.
4H-Thiopyran lllc is obtained in analogy to the method just described from 20 mmole of
acetal Ic. The yield is 4.8 g (72%), and T m = I19-120~ (ethanol--ether). PMR spectrum
(CDCI3): 1.61-2.20(8H, m, methylene protons), 3.67 (3H, s, CH30), 3.95 (IH, d, 4-H), 5.96
(IH, d, 3-H, 3J~,4 = 5.9 Hz), 6.72-7.40 ppm (9H, m, aromatic protons. Found: C, 78.9; H,
6.4; S, 9.6%. Calculated for C2=H22OS: C, 79.0; H, 6.6; S. 9.6%.
If the reaction is carried out in the absence of acetic anhydride, 0.6 ~ (9.5%) of 2-
phenyl-4-(4-methoxyphenyl)bicyclo[3.3.1]non-2-en-9-one (~Ic) with Tm = 174-1757 (ethanol)
is recovered from the residue which does not dissolve in ether. According to [9], Tm = 174-
175~ A mixed sample with a known preparation of the compound does not show melting-point
depression~

27
LITERATURE CITED
I. S . K . Klimenko, T. I. Tyrina, T. V. Stolbova, N. N. Sorokin, and V. G. Kharchenko, Khim.
Geterotsikl. Soedin., No. 9, 1194 (1985).
2. S . V . Soboleva, O. A. D'yachenko, L. O. Atovmyan, V. G. Kharchenko, and S. K. Klimenko,
Zh. Strukt. Khim., 19, 499 (1978).
3. T . V . Stolbova, S. K. Klimenko, A. A. Shcherbakov, G. G. Aleksandrov, Yu. T. Struchkov~
and V. G. Kharchenko, Khim. Geterotsikl. Soedin., No. 8, 1056 (1980).
4. R . F . Bryan, J. Chem. Soc., B, No. 12, 1311 (1967).
5. L . E . Sutton, Tables of Interatomic Distances and Configuration in Molecules and Ions.
Supplement 1956-1959. Special Publication No. 18, The Chemical Society, London (1965).
6. I. Ya. Evtushenko, V. I. Ionin, S. K. Klimenko, and V. G. Kharchenko, Zh. Org. Khim.,
ii, 435 (1975).
7. L . V . V!asova, T. I. Tyrina, S. K. Klimenko, and V. G. Kharchenko, Khim. Geterotsikl.
Soedin., No. 4, 470 (1979).
8. I. Ya. Evtushenko, S. K. Klimenko, V. G. Kharchenko, and B. I. lonin, Zh. Org. Khim.,
13, 193 (1977).
9. J . R . Merchant, J~ B. Mehta, and V. B. Desai, Indian J. Chem., !, 561 (1965).

STUDY OF KINETICS AND MECHANISM OF SULFONATION OF THIOPHENE


AND ITS DERIVATIVES BY COMPLEX COMPOUNDS OF SULFURIC ANHYDRIDE

T. K. Shustareva, and V. E. Druzhinina UDC 541.127:547.732.07(088.8):


541.49:546.226.31

By quantitatively studying the sulfonation of thiophene and its homologs by com-


plexes of sulfuric anhydride with ethers, amides, and trialkyl phosphates it was
possible to determine kinetic and thermodynamic parameters of the process, to
propose a SE2 type reactionmechanism and also to reveal a quantitative depend-
ence of the rate constant of the sulfonation reaction of thiophene on the basic-
ity of the complex-forming agent: The sulfonating activity of the complexes
studied increases in the series ~ amides < trialkyl phosphates < ethers, which
is the reverse of the increase in the basicity series of a donor.

Despite the large amount of quantitative information of the electrophilic substitution


in the heteroaromatic ring [i, 2], no quantitative data are available in the literature*
on the sulfonation reaction of 5-membered heteroaromatic compounds, including thiophenes,
which are widely used in fine organic synthesis [3], and in particular for the preparation
of medicinal compounds, where thiophene sulfonic acid and its homologs are intermediate pro-
ducts in the synthesis of sulfamide and sulfanilamide derivatives [4, 5].
On the other hand, in recent years great attention has been paid to the study of the
structure and reactivity of complex compounds of S03, which are of interest as mild sulfona-
ting reagents for the sulfonation of acidophobic compounds (heterocyclic compounds, alcohols,
polysaccharides, steroids, etc) [6, 7].
Therefore, besides the study of kinetics and mechanism of sulfonation of thiophene and
its homologs, it was also of interest to study and quantitatively compare the reactivity of
complex compounds of SO3 with different organic donors.
*We have made a preliminary report on this problem in coauthorship with B. V. Passet in 1979
at the XVth Scientific Session of Chemistry and Technology of Organic Compounds and Sulfur-
Containing Oils in Ufa.

North-West Correspondence Polytechnical Institute, Leningrad 191041. Translated from


Khimiya Geterotsiklicheskikh Soedinenii, No. i, pp. 34-39, January, 1986. Original article
submitted November 21, 1984.

28 0009-3122/86/2201-0028512.50 9 1986 Plenum Publishing Corporation


9 C, mole/m3

3
3o Fig. I. Time-dependent change in con-
centrations of reaction compounds and
reaction products during sulfonation of
20 21` thiophene by a DMFA.SOs complex in a i,
2-dichloroethane medium at 20~ 30~
(2), 400C (3) and 50 ~ (4). 1-4) con-
1o , centration of sulfonic acid, I'-4') con-
centration of sulfonating agent.

0 I0 2o 30 c0 50 60 70 80 90 I00~, rain

In the present work, we quantitatively studied the sulfonation reaction of thiophene by


complexes of S03 with various organic donors: ethers [diethyl ether (E.S03), dioxane (DO.
S03), tetrahydrofuran (THF.S03)], amides [dimethylformamide (DMFA.S0s)], and trialkyl phos-
phates [tributyl phosphate (TBpoS03)], which are more active than the known agent [8, 9], the
pyridine.S03 complex (Py.S03). As the initial substrates, we chose thiophene, 2-methylthio-
phene (more active than thiophene), and 2-bromothiophene (less active in electrophilic sub-
stitution reactions).
Depending on the activity of the corresponding complexes and the reactivity of the het-
erocyclic compound, the sulfonation reaction is carried out in an inert solvent (l,2-dichlor-
oethane) or in the complex-forming agent medium.
In the benzene series, which is less active than thiophene, similar studies could not be
carried out, since the sulfonation of benzene proceeds very slowly (DO-SOs, THF.S03, TBP.S03),
or there is practically no reaction (DMFA.SOs).
In all the experiments, the change in the concentration of the initial sulfonation agent
(the SO3 complex) and the sulfonic acid formed in the reaction was quantitatively recorded by
the method of differential nonaqueous potentiometric titration of an aliquot portion by an
alcoholic solution of diphenylguanidine in mixed solvent medium (acetone--isopropanol--glycer-
in). It was thus possible to determine the overall amount of sulfonic acid and of the unre-
acted sulfonating agent for each experimental point over the whole kinetic curve. This amount
was the same and equal to the initial concentration of the complex or the corresponding thio-
phene, w h i c h p r o v e s t h e absence of stable by-products in analytically determinable amounts,
during the transformation of the heterocycle into a monosulfonic acid according to equation:

where D is a donor.
The UV spectra of the reaction mixture taken after the end of each experiment confirmed
the formation of monosulfonic acids only.
The nature of the kinetic curves obtained for the sulfonation reaction of thiophene and
its homologs was shown for the example of a sulfonation reaction of thiophene by the DMFA.SO~
complex at different temperatures (see Fig. i).
To determine the order of reaction with respect to the SOs complex, thiophene was sul-
fonated under pseudomonomolecular reaction conditions, i.e., at a considerable excess (>60:1)
of the heterocyclic compound with respect to the sulfonating agent (the SOs complex). The
experimental data thus obtained obey the kinetic equation for a pseudomonomolecular processes,
which shows a first order of the sulfonation reaction with respect to the SOs complex. As has
already been shown in [7, 10], the order of the reaction with respect to the substrate is also
equal to i.
As in the sulfonation of benzene homologs by SOs and its complexes [7, ii], during the
reaction of thiophene and its derivatives with complexes of SOs with different organic donors,

29
and l~s Derivatives by Sulfurlc Anhydride Complexes

k'lOS~ 5~, mS/ k'lOS~5%, mS/


System T,~C kmole,sec System 7',"C kmole'sec
stage 1 ~ ;tage llstage Z
lhiophene and 5,495 0,330 Thiophene and 19,1c
Z'SOs, (i. -15 1,545
e~ner) 15,53 1,279 THF,SOs (in
37,85 4,141 DCE)
Thiophene and 2-Bromothiophene
DO'SO~(~n di- 314,3 ~6,48 I0 0,01
oxane) 17,87 1,551 and DMFA.S~ 50 2,13
29,17 2,657 (in- DCE), 60 5,7~
61,72 7,425
2-Bcomothiphene 70 14,6E
Thiophene and 93,77 3,59 and DO" S03 (in 30 6,58
TBP'SO S (in 155,2 7,285 dioxane)
DCE) ~63,0 ,9,60 2-Methylthio-
595,6 9,4 phene and DMFA, I0 ;0,53 4,285
Thiophene and
1053 ;6,9 SO 3 (im DCE)
0,106 0,008
DMFA.SO 3 '(in 1,789 0,183
DCE) 5,174 0,576
13,29 1,689
31,17 4,528
70,55 2,94

*In dichloroethane (DCE).

a stage which in general ends at 40-50% conversion of the initial reagents is first observed,
and then monosulfonic acids are further slowly formed, until a final yield of 85-100% is
reached (after 2-5 h). The fairly sharp change in the rate of sulfonation, leads us to as-
sume the existence of at least two sulfonating agents in the reaction mixture, of which one
should be considerably more active than the other.
For the reaction of each of the two sulfonating agents with one and the same substrate,
each has a characteristic rate, which is determined by means of a differential kinetic extra-
polation method, proposed in [12, 13], and successfully used previously for the determination
of the kinetic parameters of the sulfonation of benzene derivatives by complexes of SOs with
ethers [7]. By using this method fn the case of the sulfonation of thiophenes it is possible
to determine the values of kinetic parameters given in Table I.
In general, the sulfonation reaction of thiophenes comprises two stages. The first
stage is characterized by a rate constant kz, and the second by k=. Since slowing down of
the reaction rate begins after ~50% conversion of the initial compounds, it can be assumed
that in this case, a deactivation of the sulfonating complex by the sulfonic acid takes place
(see scheme).
According to the data in [7], and from our results it could be assumed that there exists
in the reaction mixture a complex of sulfonic acid with SOs, which is the presence of the
complex forming agent probably has the structure of Het,SOsH ... SOs ... D (Het is hetero-
cyclic radical), i.e., the donors in this case are the sulfonic acid formed during the reac-
tion and the complex forming agent (organic base) bound into a complex with SOs at the begin-
ning of the reaction. The formation of the intermediate complex as the result of the reac-
tion of the sulfonicacidwiththe SOs complex, and not with SOs itself is confirmed by the fact
that during the sulfonation in the complex forming agent medium, or in the presence of an ap-
preciable excess of the latter, when the dissociation of SOs complex is suppressed, there are
two sections on the anomorphosis of the kinetic dependence, as during the sulfonation by the
SOs complex in an inert solvent medium.
It is clear that the sulfonating activity of the intermediate complex is lower than
that of the D.SOs complex, which also leads to the slowing down of the rate of reaction.
To prove this supposition, the sulfonation of thiophene was carried out with a threefold
excess of D.SOs complex. In this case, the formation of the Het-SOsH ... SOs ... D complex
does not limit the rate of reaction, the sulfonating agent is the D,SOs complex, while the
reaction rate obeys a kinetic equation of the second order up to complete transformation of
the heterocycle into the sulfonic acid, i.e., the anamorphosis of the kinetic dependence is
in the form of a straight line. An excess of substrate does not lead to this result, i.e.,
in this case the anamorphosis of the kinetic dependence has two sections.

30
Our data and the results of the other authors on the absence of a kinetic isotopic ef-
fect in sulfonation reactions of aromatic compounds by sulfuric anhydride [Ii] or its com-
plexes [7], and also the fact that stages 1 and 2 of the reaction obey a second order kinetic
equation, lead us to conclude that the sulfonation of thiophenes by SOs complexes proceeds in
accordance with a bimolecular electrophilic substitution mechanism of the SE2 type (see scheme
below):

Scheme of reaction mechanism

+ Ds% ~ - ~ ~%'" D ~ ip~.~+//


S so~..D
Complex

e- complexSO~ ~s ~s%n

so..
o o--- 7~i__-~__ s%"'D~etc.
~'H "~S03H'-SOs'"D ,i

The first stage, limited by formation of a o-sulfonation complex, is concluded by the


formation of an intermediate complex Ret*SOsH ... SO3 ... D. At the second (slow) stage, as
the result of the interaction of the intermediate complex with the substrate with rate con-
stant k2, the further formation of the sulfonic acid takes place in a similar way.
It should be noted that when a sample is poured into water (to stop the reaction), the
intermediate complex formed in the reaction mixture immediately decomposes, and therefore,
the data of the material balance for the sulfonating agent at each point of the kinetic
curve indicate the absence of intermediate products.
The study of the influence of substituents at the 2-position of the heteroaromatic ring
on the rate of sulfonation in the thiophene series shows that in the case of substitution
into the 5-position, the log k, values satisfactorily correlate with Hammet's o n constants
in accordance with the equation (~ = 0.99):

Jgkt= -2.75-8.75o..
According to the value of the rate constant obtained p = --8.75, the increase in the el-
ectron denisty of the reaction center (electron-donor substituents) favors the acceleration
of the sulfonation reaction, while decrease in the electron density (electron-acceptor sub-
stituents) favors a decrease in the reaction rate. Thus, introduction of a methyl group in-
to the 2-position of thiophene considerably increases the rate of reaction at both the first
and second stages. For example, in the case of sulfonation by DMFA.SO3 complex at i0 ~ in
dichloroethane, the activity of thiophene at the first stage is -30 times lower than in the
case of 2-methylthiophene, but it is ~i00 times higher than in the case of 2-bromothiophene
(Table I).
The high value of O in absolute terms (8.75) indicates the great sensitivity of this
reaction to structural changes in the substrate molecule and the high polarity of the tran-
sition state of the sulfonation reaction that fully corresponds to the o-complex during el-
ectrophilic substitution. The determined value of 0 =--8.75 fully correlates with the con-
stants 0 of other electrophilic substitution reactions in the heteroaromatic ring [I, 2] and
of the sulfonation reaction of benzene homologs by sulfuric acid [i0], which proves a common
mechanism for the benzene and thiophene series.
The values of the kinetic and thermodynamic parameters that we calculated for the sul-
fonation process, confirm our supposition on the mechanism of this theoretically interesting
and practically important reaction (Table 2).
We carried out a comparative study of the reactivity of the complex SO3 compounds on
the example of the sulfonation of thiophene at --15~ in 1,2-dichloroethane. From the results
obtained (Table i), the SO3 complexes can be arranged into the following series according to
their sulfonating activity:
E.SO~ > DO.S03 > TBp.SO3 > THF.SO3 > DMFA-SO3,

31
TABLE 2. Values of Kinetic and Thermodynamic Parameters of
Sulfonation of Thiophene Derivatives by Sulfuric Anhydride
Complexes

Stag_e_l Stage _ _
System AW ~ 5 ~ A S ~ 5 ~ K 0, m3/ A H ~ 5 ~ A S ~ 5 % K0, m 3 /
kJ/mol4 J/mole" k~ole" ~J/molel~egree /mole" kmole"see
|de~ree sec
Thiophene and E~SO3 61,94 60,67 5,62. I0'c 81,97 10,71 4,46.1012
(im ether)
Thiophene and DO-SO3 (in 56,02 83,40 7,46. lOs 76,89 32,11 3,53. ION
dioxane)
Thiophene and TBP,SO3 (in 26,72 157,0 1,08. 105 50,74 8%02 3,80. lOs
DCE) 1,64.1011
Thiophene and DMFA~SO 65,~J6 63,86 8,33. 109 78,75 3%05
(in DCE)
2-Bromothiophene and 85,89 31,24 4,46- 10"
D~A,SO 3 (in DCE)

which is the reverse of the relationship of the basicity series (pK~) of the complex-forming
agent [14]: E < DO < TBP < THF < DMFA, i.e., the lower the basicity, the higher is the sul-
fonating activity of the corresponding complexes. This dependence is expressed by correla-
tion equations (z = 0.99).

lgkl=O:35--1.11pK~;lgk2=- 0 , 7 0 - - 1 , 1 4 pK=.

Thus, the rate of sulfonation of thiophenes depends on the nucleophilicity of both the
substrate and the complex-forming agent.

EXPERIMENTAL
All the reagentsused in the investigation were thoroughly purified and dried. The char-
acteristics of the solvents, complex-forming agents and thiophenes corresponded to handbook
data.
Preparation of Solutions of Sulfuric Anhydride, Complex-Forming Agents and Substrates.
Sulfuric anahydride was obtained by conventional methods [8, 9] from 65% oleum. Before car-
rying out the experiment, a given amount of S03 was distilled at Tbp (44.8~ into a weighed
flask with 1,2-dichloroethane. The concentration of the solution was determined from the dif-
fernece in weights or by titration of aliquots with an alcoholic solution of diphenylguanidine.
The amounts of the complex-forming agent and the substrate required in the reaction were cal-
culated from the known concentration of SO3.
Method of Kinetic Investigations. A calculated amount of a solution of the complex-form-
ing agent in 1,2-dichloroethane is charged into a 150 cm 3 four-necked glass reactor with a
jacket, fitted with a thermometer, reflux condenser, a tube filled with P~Os, a sealed stir-
rer, and a sampler, and a calculated amount of SOs in l,2-dichloroethane at a known concentra-
tion is added by means of a hermetic microburette. After thermostating for 50-60 min, a sam-
ple (3-5 cm 3) is withdrawn from the reactor, and poured into 3-5 cm s of cold water. The mixture
is vigorously shaken. Then, an aliquot is withdrawn for analysis to determine the concentra-
tion of the corresponding complex. A c a l c u l a t e d amount of the substrate solution, thermostat-
ed at the same temperature is added to the reactor. The temperature is maintained with an
accuracy of 176 The number of samples withdrawn in the experiments is 14-17. The rela-
tive error of the determination of the concentration of the sulfonating agent and the sulfonic
acid is 0.1-3.0%.
For the determination of k, each experiment was repeated not less than 3 times, and the
mean value of k was found. The relative deviations from the mean value for k are -1-3%.
Finally, the values of k and the activation energies Ea were determined by the method of
least squares on an Odra-1204 compus

LITERATURE CITED
i. Dzh. Marino, Khim. Geterotsikl. Soedin., No. 5, 579 (1973).
2. A. N. Kost and V. A. Budylin, Zh. Vses. Khim. Ob-va, 22, 3151 (1977).
3. New Trends in Thiophene Chemistry [in Russian], Nauka, Moscow (1976), p. 424.

32
4. P. I. Buchin and A. E. Lipkin, T h i o p h e n e and Bithiophene Derivatives a s Prospective New
Group of Antiseptics [in Russian], Izd-vo Sarat. Un-ta (1974), p. 102,
5. G. A. Carter, G. W. Dawson, and J. L. Garraway, Pestic. Sci., ~, 43 (1975).
6. E. E. Gilbert, Sulfonatlon of Organic Compounds [Russian translation], Khimiya, Moscow
(1969), p. 416.
7. A. P. Mel'nik, B. V. Passer, and G. M. Gaevoi, in: Proceedings of VIIth International
Congress of Surface Active Agents, Vol. 1 [in Russian], Moscow (1976), p. 262.
8. A. P. Terent'ev and L. A. Kazitsyna, Zh. Obshch. Khim., 18, 723 (1948).
9. A. P. Terent'ev and G. M. Kadatskii, Zh. Obshch. Khim., 21, 1524 (1951).
i0. A. W. Kaanderp, H. Cerfontain, and F. L. Sixma, Rec. Tray. Chim., 81, 969 (1962).
ii. J. K. Bosscher and H. Cerfontain, Tetrahedron, 24, 6543 (1968).
12. S. Siggia and J. Hanna, Anal. Chem., 33, 896 (1961).
13. C. Reillej and L. Papa, Anal. Chem., 34, 801 (1962).
14. A. Gordon and R. Ford, Chemist's Guide [Russian translation], Mir, Moscow (1976), p. 541.

SYNTHESIS OF HETEROCYCLIC ANALOGS OF PROSTAGLANDINS


FROM PYRROLE AND INDOLE

V. A. Dombrovskii, E. V. Gracheva, UDC 547.741'754'295'361.07


and P. M. Kochergin

Heterocyclic analogs of prostaglandin, dl-2-(trans-3-hydroxyocten-lyl)-N-(6-eth-


oxycarbonylhexyl)pyrrole and -indole were obtained by the condensation of 2-for-
mylpyrrole and 2-formylindole with 2-oxoheptylidenetriphenylphosphorane, followed
by alkylation with ethyl 7-iodoheptanoate and reduction of the keto group by sod-
ium borohydride.

In recent years, studies on the preparation of prostaglandin analogs, which are synthe-
tically more accessible than the natural prostaglandins and have the same or comparable bio-
logical activity, received great impetus [i, 2]. Special attention is paid at present to the
synthesis of analogs of prostaglandins in which the cyclopentane ring is replaced by a nitro-
gen-containing heterocycle, for example, derivatives of indole, pyrrolidine, oxazole, and
others [i, 3-5]. This is mostly due to the fact that some of the azacyclic analogs of pro-
staglandin are strong inhibitors of the thrombocyte aggregation [6].
In search for new potential thrombocyte aggregation inhibitors, we were first to synthe-
aize dl-2-(trans-3-hydroxyocten-l-yl)-N-(6-ethoxycarbonylhexyl)pyrrole (la) and dl-2-(trans-
3-hydroxyocten-l-yl)-N-(6-ethoxycarbonylhexyl)indole (Ib), in which the side chains corres-
pond to the side chains of natural prostaglandins. Commercially available 2-formylpyrrole
(lla) and 2-formylindole (lib) served as the starting materials for the synthesis of these
compounds. The synthesis of compounds la, b is shown by the following scheme:

RI ~ ~N" ~CHO I~~ "" " ' N ' / ~ C H = C | I C O - C ~ I I 1 1 - n


H 9 lI
lla.b Ilia, b
R~ R

R1/ -N / " CII=CtI-CO:CbH ~,~-n R1 "N


( ~C112)6~-C00C2iI~ ( ]CI|2)g-'COOC2I| 5
Iva,b la, b

I,ll a R~RI=}I; fi R4.RI=-CH=CH-~CII=CH --

All-Union Scientific-Research Institute of Technology of Blood Substitutes and Hormonal


Preparations, Moscow 109044. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. i,
pp. 40-43, January, 1986. Original article submitted December 4, 1984.

0009-3122/86/2201-0033512.50 9 1986 Plenum Publishing Corporation 33


The condensation of aldehydes ila, b by the Wlttig condensation with 2-oxoheptylidene-
triphenylphosphorane was carried out in carbon tetrachiorlde by boiling for several hours.
2-(trans-3-oxoocten-l-yl)pyrrole (Ilia) and -idole (lllb) thus obtained had the required E-
configuration of the double bond protons (the SSCC of olefinic protons is 16 Hz). Treatment
of ketones file, b by ethyl 7-1odoheptanoate in DMFA in the presence of NaH at 70-80~ leads
to 2-(trans-3-octoocten-l-yl)-N-(6-ethoxyearbonylhexyl)pyrrole (IVA) and -indole (IV5). Re-
duction of the carbonyl group in ketones IVa,b by sodium borohydride in 70% aqueous isopro-
panol at room temperature took place nonselectively, but without the side-processes of 1,4-
addition, and led to dl-la and lb. The individual compounds dl-la and -Ib were isolated
chromatographically on silica gel. Attempts to saponify the ester group in compounds la, b
by alkaline or acid hydrolysis led to resinification.
The structure of the intermediate and final compounds was confirmed by IR, ~3C NMR and
PMR spectroscopy. Some of the spectral characteristics of compounds Is, b, Ilia, b, IVa,b
are shown in Table i.
Thus, a simple, three-step synthesis of nitrogen-containing prostaglandin analogs has
been proposed, enabling obtention of dl-2-(trans-3-hydroxyocten-l-yl)-N)a(6-ethoxycarbonyl-
hexyl)pyrrole and dl-2-(trans-3-hydroxocten-l-yl)-N-(6-ethoxycarbonylhexyl)indole, whose ac-
tivity in the thrombocyte inhibition test in a rabbit is equal to 40% of a standard (ara-
chidonic acid).

EXPERIMENTAL
The I R s p e c t r a w e r e r e c o r d e d on a UR-20 spectrometer, the PMR spectra of a BS-27 spec-
trometer (60 MHz) with reference to TMS as internal standard. The '3C NMR spectra were re-
corded on a Bruker WP-80DS spectrometer. A qualitative analysis of the mixtures was carried
out by TLC of Siiufoi UV-254 plates in the following systems of solvents: ethyl acetate--
hexane, 2:3 (system A), acetone--chloroform, 1:19 (system B), ethyl acetate--heptane, i:i (sys-
tem C). Brand LI00/160, 40/100 silica gel was used for column chromatography.
2v(trans-3-Oxooeten-l-yl)p~rrole (Ilia). A 0.42 g (4 mmole) portion of 2-formylpyrrole
was added with stfrring to a solution of 3 g (8 mmoles) of 2-oxo,heptylidenetriphenylphos-
phorane in 25 ml of CCI~. The reaction mixture was boiled for 6 h. The solvent was evapor-
ated, and the yellow oil obtained was dissolved in 5 ml of ethyl acetate, and the solution
was deposited on a column with silica gel (d 2.5 cm, I 20 cm) LI00/160, with elution by a
2:8 ethyl acetate--hexane mixture. The yield of ketone Ilia was 0.68 g (80%), mp 94-95~ Rf
0.63 (B).
2-(trans-3-Oxoocten-l-yl)indole (lllb) was obtained and isolated in the same way as com-
pound Ilia. A 0.2 g (18 mmole) portion of 2-formylindole was added to 1.4 g (3.7 mmoles) of
2-oxoheptylidenetriphenylphosphorane. After chromatographic purification, 0.37 g of ketone
lllb (88%) was obtained; mp 146-147~ RfI0.78 (B).
2-(trans-3-Oxoocten-l-yl)-N-(6-ethoxycarb@nylhexyl)pyrrole (IVa). A mixture of 0.i g
(4 mmoles) of NaH and 0.3 g (1.5 mmoles) of 2-(trans-3-oxoocten-l~yl)pyrrole in 5 ml of ab-
solute DMFA was stirred for 1 h at room temperature. A solution of 0.6 g (2 mmoles) of
ethyl 7-iodoheptanoate in 5 ml of absolute DMFA was added dropwise to the reaction mixture,
with stirring, for i h at 70-80~ followed by cooling, dilution with water, and acidifica-
tion with i N H2S0~ to pH 5. The aqueous solution was extracted with ether (5 x 50 ml), and
dried over Na2SO~. After distillation of the solvent, a yellow oil was obtained, which was
deposited on a column (d 2.5 cm, I 20 cm) with silica gel L40/100) with elution by a 2:8
ethyl acetate--hexane mixture. The yield of pure ketone was 0.51 g (94%), oil, Rf 0.73 (A).
2-(trans-3-Oxoocten-l-yl)-N-(6-ethoxycarbonylhexyl)indole (IVb) was obtained in a sim-
ilar way as compound IVa. A 0.6 g (2 mmole) portiona ofethylT-iodoheptanoatewasadded toe
mixture of 0.I g (4 mmoles) of NaH and 0.36 g (1.5 mmoles) of ketone lllb. After chromato-
graphic purification, 0.6 g of ketone IVb (77%) was obtailed. Oil, Rf 0.64 (B).
dl-2-(trans-3-Hydroxyocten-l-yl)-N-(6-ethoxycarbonylhexyl)pyrrole (la). A suspension
of 0.05 g (10.25 mmoles) of NaBH~ in 3 ml of water was added to a solution of 0.14 g (0.41
mmole) of 2-(trans-3-oxoocten-l-yl)-N-(ethoxycarbonylhexyl)pyrrole in 7 ml of 2-propanol,
and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted
with water, extracted by ethyl acetate (4 50 ml), the extract was washed with water, and
dried over Na2SO~. After a chromatographic purification on a column with silica gel (d 2.5

34
TABLE i. Spectral Characteristics of Compounds la,b, Ilia,b, IVa,b
I IR spectrum,V , cm- ~ PMR s p e c t r u m , 6, ppta ( j , HZ), ~ Cilia
Compound CH-CH N--CH2 EH3 i n sid~
trans C=C c=o coo NH OH CH~CH OH CO~--CH2--CH3 CO--CH2 chain NH COOCHz--CHa

Ilia 975 16t0 1670 3290 6,8 d (IH); 5,8 d , d 2,60 t (2H) 0,90 t 8,70 s
(IH); I = 1 6 Hz
IIIb 960 1610 1650 3320 7,01 (IH); 6,85 d , d 2,65 t (2H) 0,93 t 8,20s
(IH); 1 = 1 6 Hz
IV a 970 1600 1680 1740 7,53 (IH); 6,35 (1H) 3,97 m (4H) 2,28 m (4H) 0,92 t 1,20 t (3H)
IVb 970 1600 1680 1740
la 96O 1650 1740 3200--3700 7,37 d (IH); 6,22 d,d 3,27 M (IH) 4,16m (4H) 2,28 t (2H) 0,86 t 1,22t (3H)
(IH)
lb 96O 1620 1740 3180--3600

ZSC ~ spectrum, 6 , ppm. i n CCI~


C(t) C~2) C(3) C(4~ C(5)' C(6)' C(7)"C(8)'C(22) I C(9) C(to) . C(H) Cil2) C(13)

I
IV b 14,33 59,71 172,38 41,97 24,70; 26,60; 28,70; 29,70; I 33,88 125,28 121,46 127,55 129,55
30,42
Ib 13,20 59,25 172,76 42,05 23,75; 25,75; 27,75; 29,03;[
I 33,21 119,88 118,69 120,42 120,88
30,76
I

t c(14)I C(l~)I c(m)I C(17)I C{,a)I c(19)I c(-oo) I C(21) I C(2a) I C{24) I c(25)

I 136,26 134,53 117,78 119,42 108,32 100,58 71,81 42,59 31,49 21,56 13,01

~o
~n
cm, ~ 25 cm) L40/IO0 with elution by a 1:19 acetone--chloroform mixture, 0.08 g (52%) of com-
pound la was isolated. Oil, Rf 0.78 (B).
dl-2-(trans-3-Hydroxyocten-l-yl)-N-(6-ethoxycarbonylhexyl)indole (Ib) was obtained and
isolated in the same way as la. A 0.i g (20 mmole) portion of NaBH~ and 20 ml of 70% 2-pro-
panoi were added to 0.32 g (0.8 mmole) of ketone IVb. After chromatographic purification,
0.18 g (56%) of compound Ib was obtained. Oil, Rf 0.73 (B).

LITERATURE CITED
i. E. I. Levkoeva and L. N. Yakhontov, Usp. Khim., 44, 1074 (1975).
2. V. A. Dombrovskii, D. Yu. Fonskii, V. A. Mironov, and P. M. Kochergin, Usp. Khim., 53,
689 (1984).
3. V. G. Avramenko, N. N. Levinova, V. D. Nazina, and N. I. Suvorov, Khim. Geterotsikl.
Soedin., No. 2, 204 (1975).
4. I. Barta, G. Ambrus, Gg. Horvath, M. Sdti, and P. S6har, Acta Chim. Sci. Hung., 98, 463
(1978).
5. G. Ambrus and I. Barta, Prostaglandins, i0, 661 (1975).
6. P. Parraclough, C. J. Harris, and A. G. Caldwell, U. K. Patent No. 2094793; Ref. Zh.
Khim., 12060P (1983).

NEW SYNTHESIS OF INDOLE-7-CARBOXYLIC ACID

V. I. Dulenko and Yu. A. Nikolyukin UDC 547.757.07

A new preparative method for the synthesis of indole-7-carboxylic acid has been
developed, consisting in reductive cyclization of ~-(dimethylamino)-3-carbo-
methoxy-2-nitrostyrene by the action of iron in acetic acid.

Indole-7-carboxylic acid is used in the synthesis of optical filter dyes, used for the
protection of an exposed light-sensitive material fogging during its treatment in light [i,
2]. The known methods for the preparation of this compound are multistep and proceed with a
low overall yield, which does not exceed 20% [3, 4].
In developing a new variant of the synthesis of indole-7-carboxylic acid [5], free of
the above drawbacks, we used the method of constructing the indole ring, consisting in a re-
ductive cyclization of B-(dialkylamino)-2-nitrostyrenes [6]. The latter compounds are most
conveniently obtained by the condensation of substituted o-nitrotoluenes with DMFA dialkyl
acetals [7]. In accordance with this, we selected 2-nitro-m-toluic acid (I) as the starting
compound.

+ (CH.~)='N-CH(OCI%)z J. Fe,Cl..I~COOH
..... ~7 ~-~" "
~'N% I1 NOz
COOt,I COOCH~ COOH

When acid I is heated with dimethyl acetal (II) in DMFA, an esterification of the car-
boxyl group takes place together with the formation of an enamine grouping. Reduction of
enamine III by iron in acetic acid gives methyl indole-7-carboxylate, which, without purifi-
cation, is hydrolyzed by boiling with an aqueous solution of sodium hydroxide. The overall
yield of indole-7-carboxylic acid is thus 60%.

Institute of Physical Organic Chemistry and Carbon Chemistry, Academy of Sciences of the
Ukrainian SSR, Donetsk 340114. Translated from Khimiya Geterotsiklicheskikh Soedlnenii, No~ I~
pp. 44-45, January, 1986. Original article submitted December 4, 1984.

36 0009-3122/86/2201-0036512.50 9 1986 Plenum Publishing Corporation


EXPERIMENTAL
The IR spectra were run in mineral oil on a UR-20 spectrophotometer.
B-(Dimethylamino)-3-carbomethoxy-2-nitrostyrene. A mixture of 9 g (0.05 mole) of 2-
nitro-m-toluic acid [8], 32.5 ml (0.25 mole) of DMFA dimethyl acetgl [9] and 50 ml of DMFA
is heated in an argon atmosphere to 130-140~ for 24 h. The red solution formed is evapor-
ated under vacuum, using an aspirator, and water is added to the residue. The precipitate
is filtered, washed with water, and dried. Yield, 9.3 g (74%), mp 131~ (from isopropano!).
IR spectrum: 1720 (C=O), 1635 (C=C), 1530, 1290 cm -~ (NO2). Found: C 57.4; H 5.8; N 11.2%.
C12HI~N=O~. Calculated: C 57.6; H 5.6; N 11.2%.
Indole-7-carboxylic acid. A mixture of 75 g of B-(diethylamino)-3-carbomethoxy-2-nit-
rostyrene, 180 g of iron powder, 800 ml of ethanol, and 80 ml of acetic acid is heated, with
vigorous stirring, on a water bath. When the temperature in the flask reaches 50~ the
bath is removed, and the mixture spontaneously heats up to 80~ This temperature is main-
tained by a cold water bath until the end of the exothermal reaction, after which the flask
contents are heated for another 30 min. The reaction mixture is cooled, 4.5 liters of water
are added, and the unreacted iron is filtered off. The residue on the filter is washed thor-
oughly with benzene, and the aqueous filtrate is extracted 3 times with benzene. The com-
bined organic extracts are washed with water and saturated sodium carbonate solution, and
dried over sodium sulfate. Benzene is distilled off, and a solution of 35 g of sodium hy-
droxidd in 310 ml of water is added to the residue. The mixture is boiled for 5.5 h, then
cooled, filtered, and acidified with hydrochloric acid to pH 2. The precipitate of indole-
7-carboxylic acid is filtered, washed with water, and dried. Yield 38.5 g (80%), mp 205-
206~ (from an ethanol-water mixture). IR spectrum: 3420 (N--H), 1670 cm -~ (C=O).

LITERATURE CITED
S. Bloom, A. Borror, and P. Hayffer, US Patent No. 4124592; Ref. Zh. Khim., 13N223P
(1979).
2. A. Borror, US Patent No. 3954799; Ref. Zh. Khim., 2N224P (1966); US Patent No. 3941807;
Ref. Zh. Khim., 23N238P (1976).
3. R. Ikan and E. Rapaport, Tetrahedron, 23, 3823 (1967).
4. H. Singer and W. Shiwe, J. Amer. Chem. Soc., 77, 5700 (1955).
5. Yu. A. Nikolyukin, Yu. A. Vasil'ev, A. V. Kazymov, K. M. Kirillova, V. N. Chepurko, and
V. I. Dulenko, Inventor's Certificate No. 1097619 (USSR~; published in Byul. Ozobr., No.
22, 76 (1984).
0 R. Clark and D. Repke, Heterocycles, 22, 195 (1984).
7. R. Abdulla and R. Brinkmeyer, Tetrahedron, 35, 1699 (1979).
8. E. M~ller, Bet., 42, 423 (1909).
9. H. Bredeck, G. Simchen, and S. Rebsdat, Chem. Ber., !0!, 41 (1968).

37
SYNTHESIS OF HETEROCYCLES FROM 1,5-DIKETONES.
3.* ALICYCLIC 1,5-DIKETONES IN REACTION WITH PHENYLHYDRAZINE

T. V. Moskovkina and M. N. Tilichenko UDC 547.594.3'556.8'759.3'


812.5'.816'835.9:543.422

8-R-7aH-5,6,7,8,9,10,11,12-Octahydroindolo[3.2.l-d,e]acridines, 1,2,3,4-tetra-
hydrocarbazole, 9-R-sym-octahydroacridines, and 9-R,10-phenyl-sym-octahydroac-
ridinium salts are formed by the action of phenyl-hydrazine on alkylidene-2,2'-
dicyclohexanone or the corresponding 8-R-tricyclo(7.3.1.02'7)tridecan-2-ol-13-
ones in an acid medium. Postulations were made for the paths of formation of
these compounds.
2,2-Dimethyl-3-oxa-4a-(2',2'-dimethyltetrahydropyran-4'-on-5'yl-methyl)-4aH-l,
2,3,4-tetrahydrocarbazole, 3,3,14,14-tetramethyl-2-oxa-ba,10b-(methanoxyisobu,
tane)-l,2,3,4,5a,10b,ll,lla-octahydroquinindoline.2,2-dimethyl-3-oxa-l,2,3.4 -
tetrahydrocarbazole and 3,3,6,6-tetramethyl-2,7-dioxa-sym-octahydroacridine were
obtained by the reaction of methylene-3,3'-di(6,6-dimethyltetrahydropyran-4-one)
with phenylhydrazine in acetic acid. The quinindoline structure was confirmed
by the synthesis of this compound from 2,2-dimethyi-3-oxa-4a-(2',2'-dimethyl-
tetrahydropyran-4'-on-5'-ylmethyl)-4aH-l,2,3,4-tetrahydrocarbazole by the ac-
tion of ammonia.

In a continuation [i, 2] of the study of the reaction of 1,5-diketones with phenylhydra-


zone, we studied the transformations taking place during the reaction of methylene-2-2'dicy-
clohexanone (I) with phenylhydrazine in the presence of acids. As the result, the previously
unknown heterocyclic compound, indoloacridine (Va), whose A, B, C, D rings are analogous to
the corresponding structural fragment of strychnine, and also the already known tetrahydro-
carbazole (VI), acridine (Villa) [3] and acridinium salt (iXa) [4] were isolated fmom the re-
action mixture. The. paths of the reaction of diketone I with phenylhydrazine are represented
by the scheme given below (following page).
The data obtained show that diketone I reacts with an equimolar amount of phenylhydra-
zine in acid medium with no clear-cut results - together with the indolization processes
(paths A, B) leading to indoloacridine Va and tetrahydrocarbazole VI, pyridination process
(path C) also takes place, as the result of which compounds Villa and IXa are formed.
Indoloacridine Va is formed as the result of the indolization of monohydrazone II with
the participation of the ~-CH2 group of the hydrazone fragment, followed by dehydration of
compound III. The appearance of tetrahydrocarbazole VI in the reaction mixture can be ex-
plained as occurring by splitting of a substituent from the position 4a of the intermediate
carbazolenine IV. A similar splitting was observed [5, 6] during the indolization of 2-R-
substituted derivatives of cyclohexanone.
The formation of acridine VIII is explainable b y t h e possible splitting of aniline from
the intermediate decahydroacridine VII. These data conform with previous reports on the re-
action of I with phenylhydrazine in the presence of CH3COOH and KBH~ [7]. The acridinium
salt IXa can be considered to be a product of the reaction of I with aniline, similarly to
that described in [4].

*For article 2, see [i].

Far East State University, Vladivostok 690600. Translated from Khimiya Geterotsiklich-
eskikh Soedinenii. No. i. pp. 46-52. January, 1986. Original article submitted December
26, 1984.

38 0009-3122/86/2201-0038512.50 ~ 1986 Plenum Publishing Corporation


R R

~ ~5 .'

1 RffiH

I CetlsNHNII2 Ill V

I
NIIC,H~ IV Vl
II

\,
R R

NHC~II5 VIII a-d


VII +
R

o~ OH I
x a-d xla-d NHC~a5 [ ClO 4 -
IX'a
V~ X a R = H ; b R=CH3; c R=CeHs; d R=p.CH~O_C6H~

The structure of indoloacridine Va particularly follows from the analysis of its spec-
tral characteristics. Thus, in the mass spectrum, a peak of the molecular ion is observed
at m/z 263. In the IR spectrum, there is no absorption of the C=O and NH groups and absorp-
tion bands are observed at 1660 cm -x (C=C), while in the UV spectrum there is a long-wave
maximum at 312 nm, indicating a conjugation of the tetrahydrocarbazole ring with the C=C bond
(in the UV spectrum of tetrahydrocarbazole, a long-wave maximum is observed at 282 nm [5]).
The structure of other reaction products (VI, Vllla, IXa) was confirmed by comparison
with the corresponding standard samples (comparison of constants, spectra, mixed melting
point) [3-5].
It should be noted that the preparation of indoloacridine (Va) and its 8-R-substituted
derivatives (obtained from other alicyclic 1,5-diketones) proceeds in low yield and is im-
peded by the necessity for the chromatographic separation of the mixture of compounds ob-
tained. Another variant of the synthesis of indoloacridines that we have developed is to
some extent free of these drawbacks. It involves the use of tricyclohexanolones Xa-d as the
starting materials, which are the products of an intramolecular adolization of the corres-
ponding 1,5-diketones [8-10], During the reaction of compounds Xa-d with phenylhydrazine, we
obtained phenylhydrazones Xla-d in good yields. Heating of these compounds in concentrated
acetic acid led to the formation of indoloacridines Va-d, after which compounds Vb-d were
isolated by crystallization (Table i).
3,3'-Methylenedi(6,6-dimethyltetrahydropyran-4-one) (XII) [II] considerably differed in
its behavior in the reaction with phenylhydrazine in acetic acid from other alicyclic 1,5-
diketones. When the corresponding monophenylhydrazone XIII was treated with glacial acetic
acid at room temperature, we also obtained new heterocyclic compounds: 2,2-dimethyl-3-oxa-
4-a-(2',2'-dimethylpyran-4'~on-5'-ylmethyl)-4aH-l,2,3,4-tetrahydrocarbazole (XIV), 3,3,14,14-
tetramethy-2-xa-5a,b-(methanxyisbutane)-,2,3,4,5a,,,a-ctahydrquinindine (XV),
and 2,2,-dimethyl-3-oxa-l,2,3,4-tetrahydrocarbazole (XVI), as well as the known 3,3,6,6-tet-
ramethyl-2,7-dioxa-sym-octahydroacridine (XVII) [ii].

39
o-"y"-~o
o
XqI

i CsHsNHNH2
lo ~'~._ 11 , 2 "~
0/'"7/~7/A" 0 H+ ,::~;"-I~" ~o,'~.~"'~..J~" o 0 / ~ - ~ - . . . . . . . "'~":.~

NItC6H5
XV XVI
Xlll

O~ -~ -.=.,.i "0

""J "~N

X",qI

Tile formation of compound XIV is explainable by the occurrence of indolization of mono-


phenylhydrazone XIII with the participation of a -CH group ~ with respect to the hydrazone
fragment. The absence in the reaction mixture of indolization products with the participa-
tion of the ~-CH= group clearly results from its being screened.
Compounds XV and XVI can be regarded as products of further transformations of carba-
zolenine XIV under the reaction conditions. 3-Oxatetrahydrocarbazole (XVI) was probably
formed by splitting a substituent from the 4a-position of compound XIV, while quinindoline
XV by the addition of NH3 to the C=N bond, followed by the closing of the six-membered ring
during the reaction of the carbonyl group and the NH2 group. It is known that indolenines
are capable of adding ammonia, amines, and phenylhydrazine at the C=N bond [12]. According
to the Fischer reaction mechanism, ammonia is liberated during the indolization of hydrazone
XIII.
We obtained confirmation for the formation of compound XV by this path by carrying out
the reaction XIV with ammonia in ethanol at room temperature. As the result, quinindoline
XI was obtained in a yield of 50%.
The structure of compound XIV is confirmed by the IR spectrum, with an absorption band
of the C=O group at 1713 cm -t. In the mass spectrum of this compound, a peak of a molecular
ion (m/z 341) and characteristic peaks of fragmentary ions with m/z 201 and 143 are present.
The latter indicate a splitting of a y-pyranonylmethyl fragment from the molecular ion, and
a molecule of acetone from the ion with m/z 201. In the PMR spectrum, signals of three iso-
lated methylene groups (AB system) and the CH=-'CH--CHa fragment were revealed by the spin-
decoupling and differential spectroscopy methods, as well as the signals of four aromatic
protons and four methyl groups. The C(~) methylene group protons appear as doublets at 4.0
and 3.11 ppm (J = 11.5 Hz). Irradiation of the signal at 4.0 ppm leads to degeneration of
the signal at 3.11 into a singlet. Similar experiments were carried out for signals of the
methylene group protons at C(t) (doublets at 3.01 and 2,69 ppmj J = 13.0 Hz) and at C(s)
(doublets at 2.28 and 2.10 ppm, J = 13.5 Hz). The CH=--CH--CH= fragment is revealed as a four-
proton multiplet at 3.25 ppm and one-proton multiplet at 1.55 ppm.
In the IR spectrum of quinindoline XV, there are absorption bands of NH and C=N groups
at 3370 and 1660 cm-t. In the mass spectrum, a peak of the molecular ion is observed with
m/z 340.
In the t3C NMR spectrum, in the absorption region of the aromatic carbon atoms (ii0-
128 ppm), there are four signals giving doublets under the off-resonance conditions. This
indicates the presence of a disubstituted phenyl ring in compound XV. Two other signals of
this ring are displayed as signlets at 130~0 and 164.4 ppm. The shift of one of these sig-
nals into a weak field shows that the'carbon atom is bound to the hetero atom. The signal
at 148.7 ppm (s) confirms the presence of the C=N fragment in the quinindoline structure.
The three singlet signals (72.7, 74.8, 80.5 ppm) indicate the presence of a further three
quaternary carbon atoms (C(3), C ( ~ ) , C(tsa)), having a hereto atom as one of the substitu-
ents. The signal at 42.2 ppm is characteristic of a quaternary alkyl-substituted carbon
atom (C(1ob)). In the spectrum, signals of carbon atoms belonging to four methyl groups

40
TABLE i. Characteristics of Phenylhydrazones of 8-R-Tricyclo(7.3.1.0a'7)tridecan-2-ol-13-ones (Xla-d) and 8-R-7aH-5,
6,7,8,9,10,11,12-Octahydroindolo[3.2.l-d, d,e]acridines (Va d)
UV spectrum '" Calculated
Foun~
Compound~ Mp~ ~ IR spectrtun, cm- i %"max( log Empirical formula [ !
c,% H,% N,% M c,% [ H,% N,%

132---133 1650 (C=N), 3000, 3342 (NH, OH) * 67,85 7 , 9 8 8,17 CmH26N~O"HCI 68.10 J 7,77 8,37 63
Hydrochloride XI~
several peaks 70
153--154 ]655 (C=~N), 3000--3400 (NH, OH) $, 68,60 8,30 7,83 CuoH28N~O"HCI 68.86 I 8,33 8,03
Hydrochleride XII
several Desks 80,20 I 8,0 7,40 374 78
XI c 158--159 1602 (C=N), 3330 (NH), 3600 (OH) i 80,0 8,40 7,90 I 374 C25H~oN~O
XId 159--160 1602 (C=N), 3440 (NH), 3580 (OH) 77,11 7,92 6,73 Z 404 C27I-I~N202 77.20 J 7,70 6,90 404 41
Va 1660 (C=C) 312 (4,24) 87,30 7,79 5,40 263 CtgH21N 87.60 ] 7,98 5,32 263 7(15)
Vb 99--100 1~0 (C=C) 314 (3,90) 86,92t 8,90 5,15 277 C20H=3N 86,60 [ 8,30 5,10 277 ;5
V c 160--161 165o (c=c) 318 (4,40) 88,06 7,62 4.10 339 C2sH=sN 88,5 [ 7,38 4,12 333 40
Vd 195--196 1655 (c=c) 318 (4,40) 84,78 7.75 3,75 369 C26H~zNO 84,55 [ 7,30 3,80 369 25

*V, Xla, R = H; b R = CHs; c R = C6H5; d R = p-CH30-C6H..


+The compounds were crystallized: Xla from a 1:3 ethanol--ethyl acetate mixture, Xlb from a 1:4 ethanol-ethyl acetate
mixture, Xlc, d from methanol, Vb, c from ethanol, Vd from ethyl acetate.
~The spectra were run in mineral oii.
~,4~ 23~5, 30.5~ ~ , 6 ppm) and live metilylene groups ~23.5, 42.5, 48.1, 66.4, 69.3 ppm)
are also observed.
In the PMR spectrum of compound XV, signals are observed of protons of four methyl
groups (1.16, 1.25, 1.29, 1.49 ppm), four protons of a disubstituted benzene ring,.6.7-7.1
ppm#, and a signal of an NH group proton (which disappears during a deutero exchange) at
4.37 ppm. The presence of three isolated methylene groups (at the 4, 12, 15-positions) was
revealed by double resonance. For the corresponding AB systems, the following chemical
shifts and SSCC were found: C~ (2H) A part 2.15, B 2.03 ppm (J = 13.5 Hz); C12 (2H) A 2.57,
B 3.37 ppm (J = 12.5 Hz); C:5 (2H) A 1.4, B 2.13 ppm (J = 14.5 Hz). There is also a CH2-CH--
CH2 fragment. The only nonaromatic methine proton is displayed as a multiplet at 2.38 ppm.
It interacts with two methylene groups. One of them at C ~ (2H) is represented by a doublet
of doublets at 1.83 ppm (J = 14; ii Hz) and a broadened doublet at 2.03 ppm (J = 14 Hz),
while the other at C= (2H) is in the form of a doublet of doublets at 3.95 ppm (J = 11.3;
7.5 Hz) and a broadened doublet at 3.46 ppm (J = 11.3 Hz).
The structure of 2,2'dimethyl-3-oxa-l,2,3,4-tetrahydrocarbazole (XVI) was confirmed by
elemental analysis, mass spectrum [a molecular ion is observed at m/z 201 and a fragmentary
ion at m/z 143, due to splitting of (CHs)2CO] and by IR spectrum (3473 cm -~, the NH group).

EXPERIMENTAL
The course of the reaction and the identification of individual compounds were control-
led by the TLC method [Silufol UV-254; petroleum ether-ethyl acetate 5:2 (system i, the spots
on the chromatograms were developed by iodine vapors]. The preparative TLC was carried on
plates (20 > 35 cm) with nonstationary A1203 layer (grade II of activity) in a i0:i petroleum
ether--ethyl acetate mixture (system 2) and in a 5-1 heptane--ethyl acetate mixture (system 3).
The IR spectra were obtained on a Specord IR-75 spectrophotometer (in CHCI3), the NMR
spectra (in CDCI3) on spectrometers Bruker WH-250 for IH, Bruker HX-90-E for 13C, at 250 and
22.63 MHz, respectively. The chemical shifts are given with reference to TMS. The mass spec-
tra were determined on LKV 9000 mass spectrometer at 70 eV, and the UV spectra on Specord UV-
vis in methanol.
The initial 1,5-diketones I, XII and ketones Xa-d were obtained by methods described in
[8-11, 13], respectively.
The characteristics of compounds Va-d and XIa-d are listed in Table i.
Reaction of Methylene-2,2'~Dicyclohexanone (I) with Phenylhydrazine~ A__~. A 5.18 g (48
mmole) portion of phenylhydrazine is added to a solution of i0 g (48 mmoles) of diketone I
in i00 ml of glacial acetic acid. The mixture heats up to 60~ and is left to stand for
24 h at room temperature. It is then diluted by 150 ml of water, and the oil that separates
is extracted by ether (3 30 ml). The extract is washed with water (2 30 ml) and a NA~C03
solution to a neutral reaction. The aqueous layer and the wash waters are combined. The
ether extract is dried over MgSO~, and evaporated to yield 3.2 g of reaction products. The
mixture is separated by preparative TLC in system 3. From the zone with Rf 0.74, 0.88 g (7%)
2O
of 7aH-5,6,7,8,9,10,11,12-octahydroindolo[3,2,l-d,3]acridine (Va), bp 167-1700C (i mm), n D
1.6319, is obtained.
From the zone with Rf 0.40, 0.58 g (7%) of tetrahydrocarbazole (VI), mp I14-I160C is iso-
lated; according to the data in [5], mp I15-I16~
The aqueous solution is made alkaline with potassium carbonate to pH 9. The oil that
separated is extracted by ether (3 25 ml). The extract is dried over MgSO~, the solvent
is distilled off to yield 6.5 g of a mixture of products, which are separated by distillation
2O
in vacuo. Two fractions are c o l l e c t e d : the first, aniline, i.I g, bp 48-500C (10 mm), n D
1.5863; the second, sym-octahydroacridine, 4.1 g, 46%, bp 151-153~ (5 mm), mp 72-73=C (pet-
roleum ether), according to the data in [3], mp 74~
B__~. A mixture of 6.2 g (30 mmoles) of diketone I and 4.3 g (30 mmoles) of phenylhydra-
zinc hydrochloride in 25 ml of dry dioxane is boiled for 6 h. When cool, the NH~CI precipi-
tate is filtered. Dioxane is evaporated, and the residue is dissolved in ether. The ether
solution is washed with a dilute hydrochloric acid, 1:3 (2 20 ml), and water to neutral
reaction. The aqueous layer is combined with wash waters (aqueous solution i). The ether
extract is dried over MgSO4 and ether is distilled to yield 2.3 g of a mixture of compounds
in the form of a partially crystallized mass. A 20 ml portion of petroleum is added, and

42
crystals of compound Vl are filtered, mp i15-i16~ From the filtrate, 0.3 g (3%) of indo-
loacridine Va and in addition, 0.2 g (3%) of tetrahydrocarbazole VI are obtained by prepara-
tive TLC.
The aqueous solution of I is made alkaline with sodium carbonate to pH 9. The oil that
is obtained is extracted by ether and separated from the equeous layer (aqueous solution 2).
The extract is evaporated to yield 3.5 g of a mixture of products, from which 2.2 g (40%) of
acridine Villa and 0.5 g of aniline are obtained, as described under A. Ammonium perchlor-
ate is added to aqueous solution 2, and the precipitate of N-phenyloctahydroacridinium per-
chlorate IXa is filtered. Yield l.l g (i0%), mp 198-199~ (from ethanol); according to the
data in [4], mp 199-200~
C. A 2 g portion of polyphosphoric acid is added to 2.08 g (i0 mmoles) of 2.08 g (i0
mmoles) of diketone I in l0 ml of absolute dioxane. A solution of 1.08 g (i0 mmoles) of
phenylhydrazine in 6 ml of dioxane is added, with stirring, to this mixture, which is then
stirred at room temperature for 6 h. Dioxane is evaporated, 50 ml of water are added to the
residue, and the oil is extracted by ether. From the extract, indoloacridine Va (0.13 g, 5%)
and tetrahydrocarbazole VI (0.2 g, 14%) are isolated, as described under A. From the aqueous
solution, compounds Villa (0.7 g, 35%) and IXa (0.2g, 5%) were isolated.
Phenylhydrazones of 8-R-Tricyclo(7.3.1.0217)tridecan-2-ol-13-ones (IXa-d). A 4.3 g (40
mmole) portion of phenylhydrazine is added to 40 mmoles of the corresponding ketone Xa-d in
150 ml of absolute benzene. The reaction mixture is boiled in a flask fitted with a Dean--
Stark trap up to the end of separation of water (5 h). Benzene is evaporated, and the resi-
due obtained in the form of a glass-like mass, crystallized under ethanol only in the case
of Xlc,d. Hydrazones Xla,b could not be crystallized and they were obtained as hydrochlor-
ides.
Transformation of Phenylhydrazones of 8-R-Tricyclo(7.3.1.0='7)tridecan-2-ol-13-ones
(Xla-d) by the Action of CH3COOH and Polyphosphoric Acid. A. A 20 g portion of polyphos-
phoric acid is added to 6.6 g (20 n~noles) of hydrochloride of phenylhydrazone Xla. The re-
action mixture is heated on a boiling water bath for 2 h, then cooled, and poured into 50 ml
of H20. The oil is extracted by ether (3 x 30 ml), the extract is washed with water to neu-
tral reaction, dried, and evaporated to yield 2.5 g of an oily product. From this product,
0.82 g (15%) of indoloacridine Va and l.l g (30%) of tetrahydrocarbazole VI are isolated by
preparative TLC. From the aqueous solution, I g (27%) of acridine Villa and 0.4 g (10%) of
acridinium salt IXa are isolated in a similar way as described above.
B_~. A corresponding phenylhydrazone Xlb-d (30 mmoles) is heated in CH3COOH for 2 h.
The hydrazone thus dissolves and a new crystalline precipitate separates. The mixture is
cooled, the precipitate is filtered, washed on the filter with CH3COOH (2 5 ml) and alco-
hol, and dried to yield indoloacridines Vb-d.
The mother liquor from the isolation of compounds Vb-d is neutralized with sodium car-
bonate to pH 7. The oily products are extracted by ether. After evaporation of ether, the
residue is separated by preparative TLC. Additional amounts of indoloacridine Vb-d and tet-
rahydrocarbazole VI (10-15%) are thus isolated. The aqueous layer is made alkaline with sod-
ium carbonate to pH 9 to give the corresponding acridines: 9-methyl-sym-octahydroacridine
(Vlllb 20%, 9-phenyl-sum-octahydroacridine (Vlllc) 22%, and 9-p-methoxyphenyl-sum-octahydro-
acridine (Vllld) 20%. Acridines Vlllb,c were identified by direct comparison with the cor-
responding samples [3]. Acridine Vllld has been prepared by us for the first time, mp 230-
231~ (from ethanol). IR spectrum: 1580, 1608 cm -I (vibrations of the aromatic ring).
Found: C 81.83; H 7.68; N 4.90%. M 293. C2oH23NO. Calculated: C 81.90; H 7.80; N 4.70%;
M 293.
3,3-Methylenedi(6,6-dimethyltetrahydropyran-4-one)monophenylhydrazone (XIII). A 16.1 g
(60 mmole) portion of diketone XII is dissolved in 40 ml of ethanol with heating and 6.5 g
(60 mmoles) of phenylhydrazine in 30 ml of ethanol are added to this solution in the course
of 2 h. The reaction mixture is heated for another hour, and left to stand at room tempera-
ture for 18 h. The precipitate is filtered, washed with ethanol (2 20 ml), and dried.
Yield, 4.3 g (20%) of hydrazone XIII, mp 142-143~ (from ethanol). IR spectrum~ 1705 (C=O),
3315 cm -I (NH). Found: C 69.97; H 8.41; N 7.73%; M 358. C21H3oN203. Calculated: C 70.39;
H 8.39; N 7.82%; M 358.
Transformation of 3,3'-Methylenedi(6,6-Dimethyltetrahydropyran-4-one)monophenylhydrazone
(XIII) by the Action of CH3COOH. A 7.16 g (20 mmole) portion of hydrazone XIII is dissolved

43
in JO mi of CH~CO{~H~ The reaction mixture is left to stand for 24 h, and then is diluted
by an equal volume of water, and neutralized by a Na=COs solution to pH 7. The reaction
products that separate are extracted by diethyl ~ther (4 50 ml). The extract is dried
over MgSO~, the ether is evaporated, and 30 ml of ethanol are added to the residue weighing
7 g. The precipitate is filtered to yield 1.8 g (26%) of quinindoline XV, mp. 174-176~
IR spectrum: 1660 (C=N), 3380 cm -~ (N--H). Found: C 74.27; H 8.47; N 8.21%; M 340. C2~H2s-
N=O2. Calculated: C 74.11; H 8.23; N 8.23%; M 340. The compounds remaining in the mother
liquor after the isolation of quinindoline XV, are separated by column chromatography: 5 g
of the mixture separated on a column (42 2.5 cm) with 300 g of silica gel 40/100 ;i. A
gradual elution is used (systems: petroleum ether--ethyl acetate, 6:1.3, 3:1, i:!, 0:I, 500
ml in each case and fractions of 50 ml are collected. The following compounds are isolated:
3-oxatetrahydrocarbazole (XVI) [0.56 g (14%), mp 150-160~ (petroleum ether). IR spectrum:
3473 cm -: (NH). Found: C 77.32; H 7.26; N 7.01%; M 201. CIsHIsNO. Calculated: C 77.61;
H 7.16; N 6.96%; M 201], 2,2-dimethyl-4a-(2',2'-dimethyltetrahydropyran-4'-on-5'-ylmethylo-
3-oxa-4~H-l,2,3,4-tetrahydrocarbazole (XIV) [0.8 g (12%), mp 161-1620C (ethanol). IR spec-
trum: 1713 cm -~ (C=O). Found: C 73.70; H 8.10; N 4.25%; M 341. C2~H=TNO3. Calculated:
C 73.90; H 7.91; N 4.10%; M 341], and 3,3,6,6-tetramethyl-2,7-dioxa-sym-octahydroacridine
(XVIII) [0.6 g (11%), mp I19-120~ (from petroleum ether), according to the data in [ii],
mp I18~ (from water)].
Preparation of Quinindoline XV from Compound XIV by the Action of Ammonia. A 2 ml por-
tion of 25% NH~OH is added to a solution of 0.7 g (2 mmoles) of compound XIV in I0 ml of
ethanol. The mixture is left to stand at room temperature for 5 h, then evaporated to half
its volume, and the precipitate that separates is filtered to yield 0.35 g (50%) of quinin-
doline XV, which was identified from TLC, IR spectrum and melting point of a previously iso-
lated sample.

LITERATURE CITED
i. T. 9. Moskovkina and M. N. Tilichenko, Khim. Geterotsikl. Soedin., No. 6, 821 (1983).
2. M. N. Tilichenko and T. V. Moskovkina, Khim. Geterotsikl. Soedin., No. 5, 645 (1976).
3. N. S. Berbulesku, G. Beditse, and M. N. Tilichenko, Zh. Obshch. Khim., 33, 645 (1963).
4. V. I. Vysotskii and M. N. Tilichenko, Khim. Geterotsikl. Soedin., No. 3, 376 (1971).
5. A. N. Kost, L. G. Yudin and Y. Ch'iu, Zh. Obshch. Khim., 34, 3444 (1964).
6. I. I. Grandberg, A. N. Kost, and L. S. Yaguzhinskii, Zh. Obshch. Khim., 30, 3108 (1960).
7. T. V. Moskovkina, V. A. Kaminskii, V. I. Vysotskii, and M. N. Tilichenko, Khim. Geter-
otsikl. Soedin., No. 6, 826 (1973).
8. M. N. Tilichenko, in: Yearbook of Saratov University [in Russian] (1954), p. 500.
9. V. Barbulescu, Rev. Chim., ~, 45 (1956).
i0. V. I. Vysotskii, N. V. Vershinina, and M. N. Tilichenko, Khim. Geterotsikl. Soedin.,
No. 7, 898 (1975).
li. M. N. Tilichenko, Izv. Vyssh. Uch. Zav., Khim. Khim. Teknol., ~, 96 (1961).
12. Heterocyclic Compounds [Russian translation], Vol. 3, R. Elderfield (ed.), Izd-vo Inostr.
Lit., Moscow (1954), p. 80.
13. M. N. Tilichenko and T. I. Akimova, Zh. Org. Khim., ~, 976 (1970).

44
SYNTHESIS OF DERIVATIVES OF 4-1MINO-2-AMINO-2-1MIDAZOLINE.
NEW EXAMPLE OF A MULTICOMPONENT CONDENSATION INVOLVING ISONITRILES

A. I. Polyakov, L. A. Medvedeva, O. A. D'yachenko, UDC 547.239'233.1'783'


A. B. Zolotoi, and L. O. Atovmyan 789.1:543.422'51

!sonitriles have been found to react with ketones and ammonium and methylammonium
thiocyanates in methanol or ethyleneglycol at 20~ to form derivatives of 4-imino-
2-amino-2-imidazoline and 2,4-diaminoimidazolium salts.

Ugi [i] has shown the possibility of preparing 2-thiohydantoin-4-imines by the conden-
sation of amines I and ketones II with isonitriles III and thiocyanic acid by the scheme

+
RIMH2 + R2-C0-R ~ + R4-N~C + I|SCN ~ ~ R v - N H .-C(RZR3)--C=~N'-R4 ] -~-------a"
I II If! IV NC3- -J
-- R 1 ~. /.R2

L ~CZ S~%'-N-"~N_LR~
H
VI

Upon using this reaction for the preparation of hydantoins VI with Rx = H and CH3j we
found an unusual multicomponent condensation leading to imidazole derivatives VII and VIII,
which were more complex than previously assumed [2].

I R2"C/R~ A IRZ" C ~'I~3


"'N" "CS-NH-R ~, R--.N/ -.CS_NI~R4
\ \
I + II + III + H$CN c-~ Ncs- _ =. f_--N
9 /! \\ - mCN
T '
J'"C / "NH E "r 1 .-*'N'-.c/C~.~. / R4
I R ~"/ \R 3 - R R2/-..R 3 ..--

VIIa-k vm a-k

The condensation products are, as a rule, imidazolium salts Vll, have strong IR bands
for the S-CEN group at 2030-2080 cm-* and give a positive test for the thiocyanate ion with
FeC13 solution.
Compounds such as VIIa and VIIe formed from acetone, p-tolylisonitrile and benzylisoni-
trile contain two molecules of bound HSCN, apparently as a result of the reaction 2 VII +
VII.HSCN + VIII. This is supported by the elemental analysis and IR spectral data (Table i).
The site of the addition of the second HSCN molecule could not be determined but is most
likely N(2) of the imidazole ring.
Imidazole derivatives VII and VIII are readily interconverted upon the corresponding
change in solution pH. Their structures were established finally only by x-ray diffraction
structural analysis. The x-ray diffraction structural data for model compounds VIIi and VIIIe
are given in Fig. 1 and in the Experimental.
Since the conditions for the reaction studied are identical to those for a well-investi-
gated four-component condensation, we assume, that differences in the reaction mechanism be-
tween them may arise only in the step involving stabilization of intermediates IV and V. As-
suming the formation of aziridinimine IX as an intermediate, the preparation of VII and VIII
may, in our opinion he explained by the following scheme:

#
All-Union Scientific-Research Institute for Chemical Means for the Protection of Plants,
Moscow 109088. Institute of Chemical Physics, Academy of Sciences of the USSR, Moscow 117334.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. i, pp. 53-61, January, 1986. Ori-
ginal article submitted August 7, 1984; revision submitted January 22, 1985.

0009-3122/86/2201-0045512.50 9 1986 Plenum Publishing Corporation 45


| }~', Nc:~" ' : R' ../C.,.~--R
W,V
9" ' " ' : ' " , >'--%_,: ,, : - '~%._,,. I'/:-~
SCN
IX

R ~ ,. ,,R'~ ,, " R2NI "r R~


" (: '' R ' "'~:/ rN__.~ ~' I
R*N,..C,C.;N L e~r I '-N" c r.'

_M//C ......S I I
.,C, N--R t ,<C .N r 1
X R'--N "/ "C~., --N;, :C..R, '

XI XI!

+H+ +IlSCN
.....
~ VIII ------~"

The reaction of thiazolidine X with IV or V may be presented analogously to the forma-


tion of VII and VIII.
The rate of consumption of X in the abovementioned reactions is apparently rather high
and, as a result, the corresponding 2,5-dilmino-l,3-thiazolidines are not found among the
products.
Thus, the key compound controlling the condensation is aziridinimine IX. Conformations
of the reaction site close to eclipsed must precede the formation of both IX and VI from in-
termediate IV or V. These conformations for IV and V may be represented along the C--N bond
as follows,

R I R2 R ~ R2
I ,
.... J_:: .L~

:~.::,jz r, c, C-: R
R4 / NR4 ,
IV V

The steric hindrance which is important for realization of the conformation leading to
the formation of aziridinimine IX is minimal for R* = H and CH3. Thus, the steric factor
apparently determines the nature of the reaction such that multicomponent condensation is
found upon slight repulsion between R*, R 2 and R 3, while four-component condensation is found
in the case of strong repulsion of these substituents.
The IR spectra of all imidazolium salts VII and imino-2-imidazolines VIII taken in KBr
pellets are in full accord with the x-ray diffraction structural data. An increase in the
intensity of the C=N band at 1620-1660 cm-* by almost a factor of 2 in going from VII to VIII
is characteristic for the IR spectra of these compounds. T h i s increase is probably a conse-
quence of the extension of the conjugation chain involving the two azomethlne groups.
This conclusion is in accord with the x-ray diffraction structural data. The delocali-
zation of the ~-electron density leads to the levelling out of the lengths of the C-N double
and single bonds (Fig. i).
The bond lengths found indicate a definite contribution, for example, of the following
resonance forms of imidazolium salts VII:

I
---NIl / ----" [ tl / "----" t I_ +/
N_ ~---N --N N --- " --

VIIa %'II b ~Ic

Special interest is found in the results of the spectral studies of solutions of these
two groups of compounds (Tables 1 and 2). This is related, especially for iminoimidazolines
VIII, to the expectation of a tautomeric equilibrium involving at least two forms; thioamide
(A) and thiolimide (B). The formation of tautomer VIIIB, although this form was not found
in the usual state for thioamides [3], might have been expected due to the possible stabili-
zation of the thiol form by the nitrogen atoms of the guanidine group.

46
c :J it~ 84

$7 CI22)
C(23)

%
Vllle
Vllj " 9 $12 )

Fig. i. Structure of the products of the multicomponent condensation, imidazolium salt


Vllj and imino-2-imidazoline Vllle.

According to the spectral data, derivatives Vll in media of different polarity such as
CHCI3 and DMSO are virtually in a single tautomeric form A, containing an NH group in either
the free or bound state. The IR spectra of solutions of salts VII in CHCI3 do not contain
a band characteristic for the SH group.
We should note the absence of coupling of the NH-CH3 group protons in the PMR spectra
of Vlla, c, h-j, which indicates that the azomethine group nitrogen atom is also protonated
in solution.
The spectral data for iminoimidazolines VIII are rather complex in nature. Thus, the
IR spectra of Vllle, f, h, j in CHCI3 show weak bands for a bound SH group at 2400-2600 cm -~,
signals for a free NH group at 3440-3490 cm -I and lack the absorption characteristic for a
bound NH group.
Some support for the equilibrium proposed above for solutions of VIII was obtained in
the ~3C NMR spectrum of VIlli. In addition to the signals for the carbon atoms of the thio-
amide, guanidine and amidine groups at 203.9 and 170.2 (double signal), in contrast to salt
VIIi, there is a broad signal at 140.2 ppm for the base, which is apparently a result of the
overla p of the signal for the thiolimide group S - - ~ bond and of the aromatic carbon atoms.
To support this assignment, we studied the possibility of the synthesis of a model compound
with fixed tautomeric structure B. On the basis of elemental analysis and PMR spectral data,
the iodomethylate obtained from VIlli is a monoalkylated compound whose *SC NMR spectrum
lacks a thioamide group signal. Thee these findings indicate that reaction according to the
scheme

~C(S)NH_CH2C6H 5 - - -Cliff
-.~ ---C = N ~ - C H ~ s H s
I 'HI
~II j ~CH~

The s p e c t r u m h a s a s i g n a l a t 1 4 5 . 4 ppm a s s i g n e d t o t h e t h i o l i m i d e g r o u p . The somewhat


u p f i e l d s h i f t o f t h i s s i g n a l i s due t o t h e s a l t c h a r a c t e r o f t h i s compound.
The iodomethylate thereby obtained has a structure analogous to imidazolium salts VII.
As in compounds such as VII, it contains two similar NH--CH2 group doublets in the PMR spect-
rum (see Experimental) and two C=N bond signals in the ~3C NMR spectrum.

47
~1 I~1 I~1 ~~1~ i a~l
I I l,.,c~,.

zzzzzz~zzzz~zzz~z

~1 ~ I I~ ~ ~

,..M
I
I-4
I-4
I-4
:>

'1:1
Itl
.M
I
i-4
I-4 ~1 I I I I~1. I I I
:> r~

I.i
0
1.1-1

ol-4 .co
"el .co 00 r./3

I-.I o~c~ o~o ~ o o c~ ~ o


o
,-4
Itl

m
4.1

0 o
.r.t

48
TABLE 2. PMR Spectra of Vll and Vlll

Compound Chemical shift, 6, ppm

VII a 1,31; 1,44; 1,62; 1,65 (4 4 s, CHs); 2.28~ 2,49 (d2 9s, Ar--CHs);
3,10 (6H, b r . s N--CH3); 6,97:7,13 (2 2 ,, C~'H~); 9,01; 10,28
(NH, b r . s )
VIII a 0,48; 1,24 (2 2 s, CHz); 1,44 (6H, b r . s CH3); 2,14; 2,36 (2
2 a N--CH3); 2,21 (6H, b r . s . Ar--CHs); 7,14 (8H, m, C6H~); 8,48 (NH,
br.s )
VII r 1,69 (20H, m-, cyclo-C6Hlo); 2,25 (6H, b r . s , Ar--CHz); 7,39 (8H, ra
C6H4); 7,87; 9,41; 10,90 (NH,b r . s j
VII h A t 250 Mtlz 1,43--2,26 (20H, M, cyclo-C~,H,o); 4,40; 4,75 {2X2H, 2 d.
CH_~N); 7,18; 7,27 (10H, m, CnH~); 7,80; 9,16; 10,05 (NH, b r . s )
VIII h ( At 250MHz ) 1.05--1.84 (20H. m, cyclo-C.H,o); 4,45; b4~ys(2X2H, 2 d,
CH=N); 7,21; 7,28 (10H, m C6H5)_; 6,32; 8,19; 9,56 (NH, )
VII i 1,91 (16H, m cyclo-CsH~); 3,13; 3,22 (2 2 s CH~--N); 4,36 (2tt, br.s.
, CH~--N); 4,73 (2H, d, CH.~--N); 7,15; 7,24 (2 2 s, C~Hs); 9,72;
10,02 (NH, b r . s )
V i l l i . {~(CDs)?CO] 1,72 (16H, n~ cyclo-CsHs);The NCBa :signals f a l l i n the region
of the solvent siBnals4,25; 4,33 (2}t, 2 d CH2N)j 4,42; 4,67 (2H. 2 s,
CHIN); 7,17 {10H, br.s CoHs);6.15;9,26 (NH, ~
v i i J 1,48--2,06 (20H,m. cyclo-C6H,o): 3,07; 3,26 (2X3H, 2 s, CHIN); 4,27 (2H,
b r . d . CH.~N); 4,70 (2H, d, CH.~N); 7,21 (10H, b r . s . C~Hs); 7,75; 9,72
(NH, or-s_L
ibr.d250 MHZ ) 1,13--2,41 (20H, r~ cyclo-CsH,o); 3,17; 3,32 (2 2s,
CH~--N); 4,37 (2H, br.d CH2N); 4,82 (2H, d, CH2N); 7,04--7,20 (10H,
m C6Hs); 9,68; 9,83 (NH, br. t )
(,HCL s a l t , 80~ 1,12~1,92 (20H, m cgclo-C~H~o); 3,07; 3,26 (2 s,
CHIN); 4,26 (2H, b r . d , CH2N); 4,70 (2H, d CH2N); 7,19 (10H, m,
C~H~); 9,96; 10,4 (NH b~.s )
VIII 1,61 (20H, m. cyclo-C~H,o); 1,88; 2,06 (2 2 sCHzN); 4,21; 4,27 (2>(2H,
2inCH~N); 7,12; 7,17 (10H, 2 s C6H~); 8,53 (NH, b r . s )
[in(CD~)~CO] 1,65 (20H, m cyclo-C6H,o); The NCHa s i g n a l s f a l l i n the
,~egionofLhesolventsignals4.77,;4,35 (2H, 2 d CH.~N); 4,50; 4,76 (2H,
2S, CHIN); 7,12; 7,16 (10H, 2s, C~H~); 8,62 (NH, b r . s )

The PMR spectra of solutions of Vlllg and VIlli in DMSO-d6 show a significant downfield
shift of the N--H and N-CH3 group signals in comparison with Vllg and VIIi. This difference
is attributed to the lack of the deshielding effect of the positive charge of the quanidine
fragment upon going to the free base. The broadening of the NH signals in the PMR spectra
of these compounds is also more pronounced relative to the salts, which complicates the de-
tection of the thiolimide group.
Imidazolidines VIII are stable upon heating, but gradually decompose upon heating at
reflux in water-ethanol solutions of KOH with~;the release of H=S and formation of unidenti-
fied compounds.
Upon brief heating at reflux in benzene or toluene, salt VII is converted to thiazoli-
dine XIII. On the whole, we propose the following scheme for this reaction:

I R2 ~ ~R:N--F.4

[ R~ /~ xN--R
VII ~ - Till --.,-e=,.- lq__,!. SI][ --r { {
I { R' -N-~ b,q' : R nN*"
+zC N~ 1 " -

H -S -C-=N

The conversion of VII to 2 XIII in the case of R ~ = p-CH3C6Ha proceeds more rapidly
than in the case of R 4 = CH=C6Hs. Thus, one of the steps of this conversion presumably in-
volves the thiolimide form, whose formation is especially facilitated in the case of R ~ =
p-CHsC6H4 by the conjugation of the aromatic ring electrons with the C----Nbond.
Pseudoanalogs of thiazolidinimines XIII, namely, iminothiohydantoins VI, were not found
among the reaction products.
A mass spectrometric study of Vlllh-j and Xllla showed that Villi and VIlli do not give
molecular ion peaks, even at 15 eV, while the (M + i) peak is present in these spectra. On

49
the other hand, the presence of peaks for the (M -- C2H4) and (M -- C2Hs) ions (487 and 486
for VIlli and 459 and 458 for Villi) in these spectra indicates their molecular mass (515
for VIlli and 487 for Villi) in accord with the structures p~oposed for these compounds on
the basis of the above results.
As expected, the mass spectra of these compounds have ion peaks* 91 (C6HbCH2 +) while
the (M + i) peaks are 3"5 times stronger at 15 eV than at 70 eV. In addition, Villi and
VIlli give strong peaks for ions 272 and 286 , which apparently, are formed as a result of
M -- [CH3--N-C(CH2)n-C-NHCH~C6Hb], where n = 4 and 5, respectively, for Vllli and VIlli. The
mass spectrum of Vlllh, in contrast to VIlli , contains not only an M+ peak (487) but also a
greater number of strong peaks for ions with high mass numbers. The effect of structure of
these similar compounds on the mass spectral intensity distribution clearly requires a sepa-
rate discussion.

EXPERIMENTAL
The IR spectra were taken on a Perkin-Elmer 457 spectrometer in KBr pellets and CHCIs
and CCI~ solutions. The PMR and '3C NMR spectra were taken on Bruker HX-90E (90MHz), Varian,
and WM-250 (250 MHz) spectrometers for solutions in (CDs)2SO with TMS as the internal stand-
ard. The mass spectra were taken on an LKB-2091 mass spectrometer at 70 eV.
The reaction course and compound purities were monitored by thin-layer chromatography
on Silufol UV-254 plates in 1:5 acetone--benzene and 1:2 acetone-hexane solvent systems.
The isoitriles were obtained according to ~gi [i]. The x-ray diffraction structural an-
alyses were carried out for monocrystals of Vllj and Vllle. The major crystallographic data
for Vllj, C32H~N6S2, M = 574.54 are a = 14.899(5), b = 18.875(8), c = 12.247(3) A, a = 90,
8 = 90, y = 65.23(2) ~ , V = 3127.22 ~3, deal c = 1.22 g/cm s, z = 4, space group P2,/b. The
major crystall~graphic data for Vllle, Cs,H4,NsS, M = 515.76 are a = 10.743(5), b = 11.185(6),
c = 12.052(3) A, a = 79.98(4), 8 = 80.88(3), y = 89.62(4) ~ V = 1407.77 ~a, d c a l c = 1.22 g/
cm ~, z = 2, space group PI. Sets of 2846 reflections for VIIi and 2914 reflections for Vllle
with I > 2o were measured on DAR-UM (for VIIi) and Syntex P1 (for Vllle) diffractometers. Ab-
sorption was not taken into account.
The structures were determined by the direct method according to Andrianov et al. [4].
The hydrogen atoms were localized from the R maps. The refinement was carried out by the
method of least squares in the full-ma~rixapproximation according to Andrianov et al. [4]
assuming anisotropy for the S, N, and C atoms and isotropy for the hydrogen atoms to R =
0.056-0.055. Molecular representations were obtained using the ELLIDS program [5].
Structural parameters for the hydrogen bonds: VIIi, bond lengths: N(4)...H(,)2.04 (3);
N(~)...N(~) 2.891 (3); N(,)...H(5) 1.93 (4); N(,)...N(,) 2.814 (4) ~; angle N(~)H(,)N(,) 156
(3), C(,)N(~)H(,) 99.3 (9),-C(~7)N(~)H(~) 146.7 (8), N(,)H(5)N(,) 146 (3), C(,,)N(,)H(,) 161
(i)~ VlIIe, N(~)...H(,) 1.92 (3);oN(4)...N(*) 2.809 (3); N(~)H(,)N(,) 160 (3); C(,)N(4)H(,)
103.7 (9); C(,7)N(4)H(,) 146.3 (9) 9 VII, Vlla, d-f, i-k R* = CH,, b, c, g, h R* = H; a, f
R 2 + R a = 2CH3, b, d, g, i R = + R a = (CH,)~, c, e, h, j, k R 2 + R = = (CH=)s, a-e R 4 = p-CH,-
C,H~, f-j R ~ = C6HbCH2, k R ~ = C2H,O,CCH2.
2-4-Diaminoimidazolium Derivatives Vlla, d-f, i-k. A sample of 0.01 mole isonitrile was
added dropwise with stirring to an equimolar mixture of 0.01 mole ketone, CHsNHa,HCl + KSCN
(NH~SCN was ~sed in the case of VIlb, c, g, h) in 8 ml ethyleneglycol or methanol at 20~
The reaction mixture was stirred for 6 h and left overnight to yield a single, chromatograph-
ically-pure product as lightly colored crystals, which were washed with hexane and dried. In
the preparation of VIld, the reaction mixture contained VIlld, which was isolated upon evap-
oration of the solution and lwashing of the residue with water (0.8 g).
The condensation with acetone and p-tolylisonitrile has several special features: only
Villa is formed in ethyleneglycol while both VIIa and VlIla are obtained in methanol. In the
latter case, 0.65 g VllIa in the precipitate was filtered off and VIIa was obtained by pre-
cipitation from water. This precipitate was extracted with three 20 ml portions of chloro-
form and the extract was dried over MgSO~. The solvent was evaporated and the precipitate
was filtered off and dried with 5 ml acetone and then hexane to yield 1.46 g (53%) Vlla. By
analogy, 1.53 g (55%) Vllf and 0.7 g VIllf were obtained in the reaction with benzylisonit-
rile in methanol.
9Here and subsequently, the ion peaks are given in units of m/z.

50
These compounds are insoluble in water, benzene, ether, and most organic solvents but
are partially soluble in acetone, CHCI3, dimethylsulfoxide, and DMF. 13C NMR spectrum of
Vllj: 204.3 (C=S), 181.3 (guanidine C=N), 170.0 (amidine (C=N), 130.3 (SCN), 137.1, 136.8,
128.5, 128.2, 127.4, 126.9 (C6H5), 72,9, 72.0 (Cspiro), 48.7, 46.3 (N--CH2C6H~), 37.9, 36.8
(N--CH3), 34.7, 33.0, 24.6, 22.7, 21.9, 20.4 (cyclo-C~H1o).
2-Amino-4-imino-2-imidazoline Derivatives (Vllla-k (Table i). A sample of i0 ml 0.015
mmole 10% aqueous NaOH was added to a solution of 0.01 mmole VII in chloroform and stirred
for 0.5 h. The chloroform solution of VIII was separated, dried over Na2SO~ and evaporated.
These compounds are soluble in acetone, ethanol and chloroform.
~3C NMR spectrum of VIIi: 203.9 (C=S), 170.2 (double signal as a result of overlap of
the guanidine and amidine C=N signals), 140.1 br, 136.9, 127.9, 127.3, 127.1, 126.4, 125.9,
117.3 (C6H5), 68.3, 63.5 (Cspiro), 45.5, 45.1 (N--CH2C6Hs), 38.5, 38.1 (N-CH3), 35.6, 35.3,
31.4, 31.0, 27.7, 26.9, 24.8, 23.9, 22.2, 22.0, 21.8 (cyclo-C6H1o). Mass spectra*: Vlllh,
91 (98), 92 (9), 98 (i0), 107 (7),.215 (9), 245 (8), 257 (i00), 258 (19), 281 (91), 336 (19),
337 (56), 338 (20), 354 (9), 362 (17), 453 (301, 454 (10~,M + 487 (16); Villi, 65 (6), 68 (9),
91 (55), 92 (7), 96 (i0), 98 (14), 125 (5), 176 (7), 230 (21), 271 (141, 272 (i00), 273 (14),
380 (9), 381 (ii), (M + i) + 488 (13). VIlli, 34 (6), 68 (5), iii (14), 117 (16), 232 (5), 286
(100),365 (9), 405 (7), (M + i) + 516 (18).
The iodomethylate of VIIIj was obtained by treating VIIIj with a five-fold excess of
CH31 for 48 h. The product was obtained in 70% yield, mp 87~ Found: C, C, 58.2; H, 69;
N, i0.3; S, 4.9%. Calculated for C32H~INsS: C, 58.4; H, 6.7; N, 10.7; S, 4.9%. IR spect-
rum (KBr): 16.0, 1640 (C=N), 3160-3650 cm -~ (br. NH). PMR spectrum: 1.46-1.74 (20H, m, cy-
clo-C6HIo), 2.22 (3H, s, S-CHs), 3.24 (6H, br. s, NCH3), 4.29 (2H, d, (NHCH2), 4.68 (2H, br.
d, NHCH2), 7.13 (10H, br. s, C6H5), 9.62 ppm (NH, br. s). 13C NMR spectrum: 178.7 (quanidine
C=N), 166.0 (amidine C=N), 145.4 (S--C=N), 135.6, 134.6, 132.3, 129.4 (br. s), 121.8, 118.7
(hr. s, C6H5), 71.49, 71.24 (Cspiro), 37.4, 36.3 (NCHs), 32.8-20.47 (cyclo-C6H1o), 13.20,
12.95 ppm (SCHs).
1.3-Thiazolidin-5-imines (XXXa,e,j) were obtained from VIIa,e,j by heating at reflux
in 2% toluene solution. The reaction was monitored by thin-layer chromatography. Products
XIIIa and XIIIe were isolated from the oil obtained after solvent removal. XIIIa was dis-
solved in a minimum amount of acetone and separated by thin-layer chromatography using 1:3
acetone-benzene as eluent. XIIIe was obtained by crystallization of the oil from hexane.
Thiazolidinimine XIIIj was crystallized from toluene upon cooling.
Thiazolidinimine XIIIa was obtained in 65% yield, mp 185~ Found: N, 16.8; S, 13.3%.
Calculated for C13HITNsS: N, 17.0; S, 13.5%. Mass spectrum: 41 (7), 56 (i00), 57 (7), 65
(7), 70 (7), 91 (14), 116 (27), 118 (7), 132 (14), 159 (9), 173 (7), 232 (33), M + 247 (99).
IR spectrum (KBr): 1610, 1640 (C=N), 3435 cm -I (NH).
Thiazolidinimine XIIIe was obtained in 70% yield, mp 155~ Found: N, 14.8; S, 11.2%.
Calculated for C16H21N3S: N, 14.7; S, 11.2%. IR spectrum (KBr): 3415 (NH), 1695 cm -~ (br,
C=N). ~ C NMR spectrum, 179.2, 178.7 (NC=NH), 157.8, 157.3 (C=N--Ar), 145.8, 138.6, 136,3,
133.4, 131.6, 129.5, 120.8, 119.0 (C6H~), 70.1, 65.5 (Cspiro), 37.9, 37.1 (NCH3), 31.4-19.8
(cyclo-C6H~o, CH3--Ar).
Thiazolidinimine XIIIj was obtained in 100% yield, mp 205~ Found: C, 66.4; H, 7.4;
N, 14o4; S, 11.2%. Calculated for C16H2~N3S: C, 66.7; H, 7.3; N, 14.6; S, 11.2%. IR spect-
rum (KBr): 1585-1600 (C=C, C=N), 3420 cm -l (NH). PMR spectrum: 1.66 (1OH. m, cyclo-C6H~o),
3.01, 3.15 (3H, 2 s, CH3N), 4.29, 4.48 (2H, 2 s, CH=N), 7.03-7.14 (5H, 2 s, C6H5), 8.33 ppm
(NH, br. s). The ratio of the E and Z isomers was 1:5.

LITERATURE CITED
I. I. Ugi, Isonitrile Chemistry, Academic Press, New York (1971), p. 145.
2. I. Ugi, F. K. Rosendahl, and F. Bodesheim, Ann., 666, 54 (1963).
3. W. Walter and E. Schaumann, Chem. Ber., iO4, 3361 (1971).
4. V . I . Andrianov, D. Sh. Safina, and B. L. Tarnapol'skii, Rentgen-75. An Automatic Prog-
ram System for The Solution of Crystal Structures [in Russian], Div~son of the Institute
of Chemical Physics, Academy of Sciences of the USSR, Chernogolovka (1975), p. 82.
5. A . N . Chekhlov, Kristallografiya, 26, 596 (1981).
*Here and subsequently, the ion peaks with intensity greater than 5% of the strongest peak
are given; the intensities are given in parentheses.

51
NEW DERIVATIVES OF IMIDAZOLINE 3-OXIDE AND THIAZOLINE
WITH 2,6-DIALKYLPHENOL FRAGMENTS

T. F. Titova, A. P. Krysin, and V. V. Martin UDC 547.563.4:781.3'789.1:


541.124:678.048

(2,6-Dialkyl-4-hydroxyphenyl)-2-butanones and aminooxides were used to obtain the


corresponding 3-imidazoline 3-oxides. Nitrosylation of 3-imidazoline 3-oxide con-
taining a phenol substituent proceeds either at the imidazoline ring amino group
or at the phenol fragment. Intermolecular cyclization of (2,6-di-tert-butyl-4-
hydroxyphenyl)-2-butanone with sulfur and ammonia gave a 3-thiazoline as two dia'
stereomers.

A promising area of research in the chemistry of polymer stabilizers lies in the creation
of additives with a broad action range which protect the polymer from the action of light,
heat and atmospheric oxygen. The structure of such compounds consists, as a rule, of two
functional fragments, specifically, a sterically-hindered phenol and heterocycle such as pi-
per idine [i, 2]and hydantoin [3].
In the present work, we synthesized new imidazoline and thiazoline derivatives contain-
ing a phenol moiety. Interest in such heterocyclic compounds is related to the use of sever-
al 4-thiazolines as light stabilizers for polyolefins [4]. Compositions of 3-thiazolines and
thiurams act as thermal stabilizers [5], while benzimidazoline-2-thiones have been proposed
for use as oil and rubber antioxidants [6].
Imidazoline derivatives h a v e b e e n synthesized by the acid-catalyzed condensation of ke-
tones with aminooximes [7], while thiazoline derivatives have been prepared by the reaction
of ketones with sulfur and gaseous ammonia [8]. Readily available 4-(3,5-dialkyl-4-hydr0xy-
phenyl)-2-butanones I and II prepared by the alkylation of 2,6-dialkylphenols by methyl vinyl
ketone in the presence of bases [9] were used as the starting materials.
Heating butanones I and II with 3-amino-3-methyl-2-oximinobutane (III) and I with amino-
oxime IV in the presence of p-toluenesulfonic acid leads to the corresponding 3-imidazoline
3-oxides V-VII.
0It OII
~, / R~

R2 /Ott R 2 "~ ..O


-3~]~"--~:I N r --N R1
CH .--i-- C H 3 ; ~ -CH3 ----~/ +

! !
C~-O C~N--OH
[ Ill,IV Y,YI,YII I
CH~ CH 3
I,II VIII,IX

I, V, VII, IX R'=t-C4Hg; II, VI, VIII RI=CHz III, V, VI R2=CH~;


IV, VII R~=C6H5

The condensation of ketones I and II with aminooxime III proceeds rather smoothly to give
high yields of 3-imidazoline 3-oxides (~80%). The use of a 2.5-fold excess of aminooxime III
in the reaction with ketone II leads to a side reaction involving the formation of butanone
oxime VIII in 62% yield. A similar conversion was observed in the condensation of ketone I
with aminooxime IV; the yield of the product, oxime IX, was 5% in this case.

Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Academy of Sciences


of the USSR, Novosibirsk 630090. Translated from Khimiya Geterotsiklicheskikh Soedinenii,
No. I, pp. 62-67, January, 1986. Original article submitted October 31, 1984.

52 0009-3122/86/2201-0052512.50 9 1986 Plenum Publishing Corporation


3-1midazoline3-oxidesreadily underg o nitrosylation [7] to give sterically-hindered
nitrosoamines, which have not been extensively studied. The reaction of V with NaNOa was
carried out in order to study the effect of the phenol substituent on the nucleophilic pro-
perties of 3-imidazolines.

OB
7 O
.... N
V"
"/"Nz ~'CIl:,CII~(( ~ ' ~ - - O H ....'-' +

NO2
X~ XlI

The PMR and elemental analysis data (Tables i and 2) permit the unequivocal assignment
of structure X to one of the reaction products. N-Nitroso compounds are known to exist in
solution as two stereomeric forms [7]. The signal for such forms XA and XB in the PMR spect-
rum were assigned taking account of the anisotropic effect of the N-nitroso group on the B-
methyl group protons [i0] of the imidazoline fragment and the aromatic ring protons.

11
~J~q/2
H ~ CH2CH2-~(/("
. . , \ . -"~')
j , --0H "~" CH2-C.H~( )f)--- OH

XA XB

In addition to substitution in the imidazoline ring, the phenol fragment in nitrosylated


leading to the formation of 4-nitro-2,6-di-tert-butylphenol (XI)and XII. The IR spectrum of
XII shows bands at 1680 and 1655 (C=O and C=C),, 1625 (heterocyclic nitrone ~ ) and 3610 cm-z
(OH). The PMR spectrum indicates cyclohexadiene and imidazoline 3-oxide fragments in XII
(Table i). Further proof for the structure was obtained in the Z3C NMR spectrum in CDCI3
which shows signals at 186.9 and 89.8 ppm related to the carbonyl carbon atom and carbon atom
attached to the OH group. Hence, XII was assigned the structure of 2,4,5,5-tetramethyl-2-[2-
(~-hydr~xy-3,5-di-tert-butylcyc~hexadien-2,5-~ny~)-~-ethy~]-3-imidaz~ine-3-~xide.
The formation of XI and XII may be represented by a scheme beginning with the attack of
the para positive relative to the benzene ring hydroxyl group by a nitrosium cation [ii] and
oxidation of intermediate XIII and quinonitrile XIV [12]. Due to its instability [13], XIV
is rapidly converted by two independent pathways. Pathway A involves the loss of an alkyl-
eneheterocyclic substituent from the geminal unit [14]. Pathway B involves substitution of
the nitro group by a hydroxy group and the formation of quinol XII [14, 15].
Thus, the presence of the 2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethyl fragment in the
structure of 3-imidazoline-3-oxide V sharply reduces the selectivity of the nitrosylation at
the amino group due to the appearance of an additional reaction site in the phenol substitu-
ent.

CII~r --01] ~ "N


HI / "CII~Ctf~
" \ ~ ' ~4~:=0H .....
V
"-. r r w o ~,o -
H
--A---~- Xl

XIII XIV
9 .__~o i~~
HO-

53
The in~ermolecular cycllza~ion of ke~ones by the action of sulfur and a~unonia with the
formation of 3-thiazolines has been studied by Asinger [8], Various aliphat~c, alicyclic
and heterocyr ketones with at least one hydrogen atom in the ~-position relative to the
carhonyl group undergo this reaction, Such conversions for carbonyl derivatives of 2,6-
dialkylphenols have not been reported. We have prepared 3-thiazoline XVI by heating ketone
I with sulfur and gaseous ammonia for 7 h at 120~
Thiazoline XVI is a i:I mixture of diastereomers XVIA and XVIB wh:[ch may be separated
by crystallization. The iR spectra of these compounds show a band at 1660 cm -l (O,:N) char-
acteristic for thiazolines [16]. Further proof of the product structure was obtai~led from
the PMR and ,3 C NMR spectral data (Tables 2 and 3).

OH

S
;If
, ~,,~cH a s ;'"~crI 2' ,
CII-SII
]
C ==0
[
CH3
O~I
XY

Preliminary experiments of the compounds synthesized showed that some of them have both
thermal and light stabilizing action. The results of these tests will be published separately.

EXPERIMENTAL
The IR spectr 9 were taken on a UR-20 spectrometer in CCI~ and KBr pellets. The UV spec-
tra were taken on a Specord UV-VIS spectrometer in ethanol. The PMR spectra were taken on a
Varian A-56/60A spectrometer for V, VII, and IX in CCI~, for VI, X, and XII in CDCIs and for
VII in CD3OD. The *SC NMR spectra were taken in CDCI3 on Bruker HX-90 and WP-200SY at 22.63
MHz.
The yields, melting points and elemental analysis data for V-XII and XVl in Table 4.
2,4,5,5-Tetramethy~-2-[2-(3,5-di-tert-buty~-4-hydr~xypheny~)-~-ethy~]-3-imidaz~$ne 3-
oxide (V). A mixture of 29 g (105 mmoles) ketone I, 12 g (103 mmoles) aminooxime lll-and
0.05 g p-toluenesulfonic acid was heated in an argon stream for 2 h at 80~ and 8 h at 130~
The cooled glassy mass was treated with hexane. The precipitate was filtered off, washed
with hexane and dried to yield 31 g V.
2,4,5,5-Tetramethyl-2-[2-(3,5-dimethyl-4-bydroxyphenvl)-l-ethvl]-3-imidazoline 3-oxide
(Vl). A. A mixture of O. 3 g (1.56 mmole) ketone II, 0.177 g (1.53 mmoles) aminooxime III
and 1.5 mg p-toluenesulfonic acid was maintained in an argon stream for 2 h at 80~ and for
8 h at 130~ After cooling, the glassy mass was separated by column chromatography of sil-
ica gel with gradient elution using chloroform-ethanol to yield 0.076 g starting ketone II
and 0.346 g VI.
B__=Heating and subsequent treatment of a mixture of 5.5 g (29 mmoles) ketone II, 8.4 g
(72 mmoles) aminooxime III and 20 mg p-toluenesulfonic acid under the conditions described
in A gave 3.7 g 2-oximino-4-(3,5-dimethyl-4-hydroxyphenyl)butane (VIII) and 2.2 g imidazol-
ine 3-oxide VI.
2,5,5-Trimethy-4-pheny-2-[2-di-tert-buty-4-hydrxypheny--ethy]-3-imidazine 3-
oxide (VII) was obtained analogously under conditions described in procedure A from 5.52 g
(20 mmoles) ketone I, 3.5 g (19.7 mmoles) aminooxime IV and 15 mg p-toluenesulfonic acid.
Column chromatography gave 2.3 g starting ketone I, 0.3 g 2-oximino-4-(3,5-di-tert-butyl-4-
hydroxyphenyl~butane (IX), and 4 g 3-imidazoline 3-oxide VII.
Nitrosylation of 3-imidazoline 3-oxide (V). A sample of 62 ml 5% hydrochloric acid (pH
2-3) and 50 ml 10% aqueous NaNO2 was added to a solution of 11.5 g (30 m~oles) V in 200 ml
50% aqueous ethanol and maintained for 3 h at room temperature. The oil separated was ex-
tracted with chloroform, dried over MgSO~ and evaporated to give 12 g product, which was
subjected to column chromatography on silica gel with gradient elution using chloroform-
ethanol to give five fractions containing 0.5 g (7%) 4-nitro-2,6-di-tert-butylphenol XI '~

54
TABLE i. Spectral Indices for V-X and Xll

IR spectrum, .cm~l UV spee- l PMR spectruma,6 , ppm


[solvent] trum, Xmax.
I [ CH3 CH~--CI-12 H&roi I OH

V 1610 [CCI,] (C=N); 228 (4,20) 1,2C 1,3~ 2,12C 6,7; 1,34i 4,99
3650 (OH) 278 (3,30) 1,26
VI 1655 [KBr] (C=N) 224,2 (4,23); 1,27 1,5J 2,28c 6,7~ 1,I( 6,27
277,8 (3,27) 1,30
VII 1540 [CCI,] (C=N); 284 (3,96) 1,57 1,4~ 2,28 c 6,86 1,3~ 4,96
3650 (OH) 1,54
VIII 1610 [KBr] (C=N) 281 (3,76) ! -- 2,52c 6,67 2,14
IX 1635 [KBr] (C=N); 278 (3,29) 2,55c 6,84 1,34 4,84
3635 (OH)
Xt 1625 [KBr] (C=N) 229 (4,32); 1,64 }(a) 2,o~ 2,54 7,00 1,39 5,14
~278 (3,41); 1,66 (b) (a)
304 (3,00) 1,89 (b) 1,7{~ 6,94
1,84 (a)
XII 1625 [CC14] (C=N); 233 (4,38) 1,32 1,51 1,77 6,56 1,17
1655 (C=C);
1680 (C=O);
3610 (OH)

ai.81 ppm for VIII and IX ( C H z ~ H ) . bSlight predominance


of the B form. CMultiplet center.

TABLE 2. Spectral Indices for XVIA and SVIB

~R spectrum, UV spec PMR spectrum (in CDCI3), ~, ppm


Com- ":m-I':[solvent] trum,
Ama~
pound
~
[ log !-C4H9
L ore 6-CH.. 17-CH2 10-CH2aI CH 8-CHa J9-CHa OH
I

XVIA 1660 [CHCI3] I278 (3,6O) 1,42 7,00;1 2,47b 12,04c 3,05 [4,58( 1,65 2,15 5,08;
(C=N); 5,12
3640 (OH)
XVI B 1660 [CCI4]
I
[278 (3,57) 1,42 6,94;I 2,39 b[2,04c 3,05 14,53c 1,42 2,!7 5,01;
(C=N); 7,00 [ 2,66c[ 5,08
3640 (OH) I
aMultiplet center (ABX system) for XVlA, JAB = 14, JAX = 4,
JBX = 12 Hz; for XVlB, JAB = 14, JAX = 4, JBX = 8 Hz.
bcenter of triplet of doublets, J = 12, J = 4 Hz. CMultiplet
center.

TABLE 3. Chemical Shifts (ppm) in the ~aC NMR Spectra of XVIA


and XVIB

Carbon atom XVIA XvIB Carbon atom XVIA XVIB

C(2) s, 89,1 s. 89,4 C(]2) q, 30,2 :q, 30,3


C(4) 168,2 s. 167,6 C (]') s, 129,3 s, 129,6
C~s) 65,0 q 65,2 C(w) s, 132,4 s, 131,1
C(6) b 46,4 t~ 46,8 C(2,6,) d, 124,7 d, 124,6
C~z) b 31,9 31,4 C (2",6") d, 125,2 d, 125,8
32,3 ~1 32,0 C (3',3",5t ~5") s, 135,7 $, 135,4
C(9~ qq, 18,3 9 18,3 C (~') s' 151,6 s, 151,6
Cr t, 41,2 g, 41,1 C (4") s' 152,4 s' 152,4
Coo s, 34,1 s, 34,2

(identified by comparison with the PMR and IR spectra of an authentic sample), 3.7 g 1-nitro-
so-2-[2-(3,5-di-tert-butyl-4-hydroxyphenvl)-l-ethyl]-3_imidazoline 3-oxide (X), 3.8 g 3-imi-
dazoline 3-oxide V, and 2.2 g 2,4,5,5-tetramethyl-2-[2-(l-hydroxy-3,5-di-tert-butylcylohex-
adien-2,5-onyl)-l-ethyl]-3-imidazoline 3-oxide (XII). X3C NMR spectrum: 186.2 (C(xs)),
176.3 (C(,)), 145.9 (C(~,,~6)), 142.4 (C(~a,~7)), 89.8 (C(x2)), 68.5 (C(2)), 61.6 (C(5)),
35.7 (C(x~)), 34.5 (C(~a)), 32.9 (C(xo)), 29.3 (C({9)), 28.0, 27.7 (C(s,9)), 26.3 (C(6)), 9.2
ppm (C(7)).

55
TABLE 4. Indices for the Compounds Synthesized

Com- [~) ~ Found, % Chemical Calculated, % Yield, %


pound formula
C H N(S) c H N(S)
i

V 175--177 73,80 ' 10,3I 7,48 CzJ]3~N202 73,75 [0,23


7,48 78
VI 129--13s 70,39 9,07 9,62 C17112,;N~O2 70,31 ,(},02
9,64 76
VII 133--13~ 77,13 9,11 6,39 C~114(,N,2C)2 77,02 (,},23
6,41 47
VIII ~00--201 69,4,q 8,30 6,75 C,~lllTN()2 69,54 8,27
6,75 62
IX 126--128 74,23 10,00 4,80 C,~1-t2~)NO2 74,19 [0,03 4,80 5
X 159--161 68,57 9,53 10,41 C2~1t3,N~O2 68,55 9,57 10,41 30
XlI [62--t64 70,69 9,85 7,16 C,J~I3~N203 ,70,739,81 7,17 18
XVI.a [34--135 76,35 9,71 2,47 C36Hs~=NO2S 6,42 9,80 2,47 25
{5,64) (5,67)
XVI b 85--87 76,37 9,77 2,47 C3sHs~NO2S 76,42 9,80 2,47 25
(5,63) (5,67)

av, VII, IX, XVIA and XVIB were crystallized from hexane, VI,
VIII, X, and XII were crystallized from 1:2 ethyl acetate--
hexane, bRelative to the starting ketone.

2-4-Dimethy-2-[2-(3,5-ditert-buty-4-hydrxyheny)--ethy]-5-(3,5-di-tertbuty-4-
hydroxybenzyl)-3-thiazoline (XVI). A mixture of i0 g (36 mmoles) ketone I and 0.864 g (27
mmoles) sulfur was heated for 7 h at 120~ in a stream of ammonia. After cooling, the glas-
sy, dark red mass crystallized upon the addition of hexane to yield 5 g 3-thiazoline XVI as
diastereomers XVIA and XVIB. Three-fold washing with hot hexane gave 2.5 g of insoluble
diastereomer XVIA as a colorless precipitate. Evaporation of the filtrate gave 2.5 g color-
less diastereomer XVIB which turns pink upon exposure to light.

LITERATURE CITED
i. L. A. Skripko, Z. B. Popova, T. A. Pankova, V. M. Levin, E. N. Matveeva, E. V. Merkur'
eva, and E. I. Kirillova, USSR Inventor's Certificate; Byul. Izobr., No. 17, 87 (1980).
2. D. Randell and M. Smith, British Patent No. 1,395,159; Ref. Zh. Khim., 5N210 (1976).
3. US Patent No. 4,162,246; Ref. Zh. Khim., 3NI9OP (1980).
4. M. Bloom and G. Newland, US Patent No. 3,391,i06; Chem. Abstr., P36758S (1968).
5. C. Heuck, O. Mauz, and F. Rochlitz, West German Patent No. 1,096,599; Chem. Abstr.,
24116B (1961).
6. A. Amery, J. Crook, and V. Sharma, British Patent No. 1,363,233; Ref. Zh. Khim., 24N188
(1975).
7. V. V. Martin and L. B. Volodarskii, Khim. Geterotsikl. Soedin., No. i, 103 (1979).
8. K. V. Vatsuro and G. L. Mishchenko, Name Reactions in Organic Chemistry [in Russian],
Izd. Khimiya, Moscow (1976), p. 8.
9. T. F. Titova, A. P. Krysin, M. M. Shakirov, and V. I. Mamatyuk, Zh. Org., Khim., 20,
331 (1984).
i0. D, R. Battiste and J. G. Traynham, J. Org. Chem., 40, 1239 (1975).
ii. V. V. Ershov and G. A. Zlobina, Izv. Akad. Nauk SSSR, Ser. Khim., 2082 (1964).
12. R. Henry, J. Org. Chem., 23, 648 (1958).
13. V. V. Ershov, A. A. Volod'kin, and G. I. Bogdanov, Usp. Khim., 32, 154 (1963).
14. V. V. Ershov and G. A. Zlobina, Zh. Org. Khim., ii, 299 (1966).
15. K. Ley and E. Mfiller, Chem. Ber., 89, 1402 (1956).
16. L. Bellamy, The Infrared Spectra of Complex Molecules [Russian translation], Izd. Inostr.
Lit., Moscow (1963), p. 388.

56
SPECTROSCOPIC STUDY OF THE STRUCTURE OF
N-(2-BENZIMIDAZOLYL)-O-METHYLCARBAMATE

B. Eo Zaitsev, M. V. Palishkin, UDC 541.62:543.42:547,785.5


S. S. Kukalenko, and V. P. Brysova

X-ray electronic, IR, and electronic spectroscopy were used to determine that
N-(2-benzimidazolyl)-O-carbamate in the crystalline state and in organic sol-
vents exists predominantly in the benzimidazole carbamate form. The acid--base
characteristics of N-(2-benzimidazolyl)-O-methylcarbamate were evaluated. The
spectra of this compound were interpreted using quantum chemical calculations
and experimental data.

Benzimidazole derivatives have a set of biological properties which permit their use as
pesticides and drugs. N-(2-Benzimidazolyl)-O-methylcarbamate (BMC) occupies a special posi-
tion among these compounes [I, 2]. However, the structure and properties of this compound
have not been studied. In the present work, we carried out a detailed study of the structure
and physicochemical properties of BMC in the polycrystalline state and in various media.
The structure of BMC may be represented as tautomers I-III

~\ /c-oc~ 3 \ / - \

~-..o n H...o ~---o


i . ~F. III

Since monocrystals of BMC could not be grown, x-ray electronic spectra (XES), IR and UV spec-
tra as well as quantum chemical calculations were used to establish the predominant tautomer.
The x-ray electronic spectra were taken on a Kratos ES-100 spectrometer by pressing the
compound into a copper lattice. The Cls line at 285.0 eV obtained from the vapor of diffu-
sion oil condensed on the sample was used as the standard. Since the bond energy of the in-
ternal electrons in atoms within molecules depends on the electron density of their outer
shells, the XES method permits the qualitative differentiation Of the valence states of atoms
in molecules. Thus, one of the oxygen atoms is in a C=O double bond and the other is in an
OCH3 group. Of the three nitrogen atoms, one is a C=N double bond, and the other two have
three o-bonds and supply Pz electrons of the unshared pair to the ~-bond system. In struc-
ture II, both oxygen atoms are of the same bridging type while the three nitrogen atoms are
divided among two nitrogen atoms in double bonds and one atom supplying Pz electrons to the
T-system. In accord with the valence state types for the oxygen and nitrogen atoms in the
XES of tautomers I and III, we should expect the appearance of two Ols lines with i:i inten-
sity ratio and two Nls lines with 1:2 intensity ratio. In the XES of tautomer II, there
should be one Ols line and two Nls lines with inverse intensity relative to the intensity of
the Nls lines in tautomers I and III.
The XES of BMC shows two Ols lines with energies 531.4 and 533.2 eV and I.'i intensity
ratio (Table i). The assignments of these values to oxygen atom types were carried out using
literature data for the XES of compounds containing oxygen atoms of a determined type. Table
1 shows that the Ols bond energy of the oxygen atom within a double bond is 1.5-2 eV lower
than the Ols line for the oxygen atom in the bridging bond. Thus~ the BMC molecule has car-
bonyl and bridging oxygen atoms, which correspond to structures I and III and excludes struc-
ture II." The Ols values in the XES of BMC hydrochloride are higher by 0.3-0.5 eV (Fig. i).
The XES of BMC shows two Nls lines. The intensity of the line with higher energy is twice

P. Lumumba International Friendship University, Moscow 117923. Translated from Khimiya


Geterotsiklicheskikh Soedinenii, No. i, pp. 68-74, January, 1986. Original article submitted
August 21, 1984, revision submitted December 28, 1984.

0009-3122/86/2201-0057512.50 9 1986 Plenum Publishing Corporation 57


TABLE i. Bond Energies of Internal Electrons

Eb, eV
0Is NIs

Compound
.... OCII~, N~C

[" 0 ~ 0 -I 531,0 532,7

J
OCtt. N .... S
533,5 399,4
I "11 ~ [4]

531,4 533,2 398,5 400,2


..BHC. HCI 531,9 533,5 398,9 400,6
Benomil (V) 531,6 533,4 398,7 400,4

that of the low-energy line. According to XES data, the Nls bond energy in a,a'-dipyridine
is 399.1 eV [4], while for the Nls values for pyridines in the solid state lie in the range
from 388 to 399 eV [5]. In five-membered aromatic rings such as imidazole, the Nls line
atom of a double bond nitrogen atom is 399.1 eV and the corresponding value for a hydrogen
atom in p, ~-conjugation is 1.5 eV higher [6]. Finally, two Nls energies of 400.5 and 399.1
eV are observed in phthalocyanine for the eight nitrogen atoms with signal halfwidth d~/2 =
1.7 eV and 1:3 intensity ratio. The Nls value of 400.5 eV is related to the six "pyrroiic"
..

nitrogen atoms N while the value of 399.1 eV is related to two "pyridinic" nitrogen
/l\
atoms (N=C) [7]. Hence, the Nls energy of 400.2 eV in the XES of BMC was assigned to two
NH group nitrogen atoms and the line at 398.5 eV was assigned to the C==N bond nitrogen atom.
The Nls values in BMC.HCI are higher by 0.4 eV due to the induction effect of the proton.
The XES of benomil shows two Nls lines close to the Nls values in BMC (Table i) but with 1:3
intensity ratio.
Thus, the examination of the XES indicates that BMC in the crystalline state exists
predominantly as tautomer I or Ill.
Pariser--Parr--Pople quantum chemical calculations [8, 9] were carried out using a var-
iable ~ [10] according to the program of Kosobutskii [ii]. The energy characteristics of
tautomers I-III were calculated in order to determine the existence of tautomers in the gas
phase, the effect of the electrostatic interaction with the medium and evaluation of the con-
tribution of the ~- and o-energies to the total energy of BMC (Table 2). According to the
heats of atomization of tautomers I-III, these compounds have similar stability with some
preference for tautomer I in the gas phase due to the gain in H-bond energy in the tautomer
series 1-Ill. The similarity in the atomization energies of tautomers I and III and the en-
hanced solvation coefficient in tautomer III relative to I indicate that, the facile tauto-
merle transition between these forms is possible depending on the solvent.
The electronic absorption spectra were taken on Specord UV-VIS spectrometer in ethanol
and CHCI3. The electronic spectrum of BMC tautomer I has three absorption regions (Fig. 2).
According to the calculation, the first absorption region is related to the complex electron-
ir transition from the highest occupied molecular orbital (HOMO) ~n to the lowest unoccupied
molecular orbital (LUMO) ~m (41%), from ~n-~ to ~m (33%) and from ~n to ~m+1 (10%). The
transition is polarized at an angle of --13~ relative to the long molecular axis (x-axis).
The redistribution of H-charge in the molecule upon going from the ground state to the first
excited state indicates that the electron-donor fragment in this transition is the carbamate
group, while the electron-withdrawing fragment is the benzimidazole ring (Fig. 3). The ob-
served fine structure of the long-wavelength band with difference in frequency between the
components A~ = 800 cm-* is a consequence of electronic-vibrational transitions (Fig. 2).

58
AI
I
1,2

7
--Z0~---Z;0
/\ -

~imEb,eV '?'-s!~--g3*3-g-3iEb, eV
0,8#.

0,4
I \EU~, ~il ,i

0
z,oz r :~98Eb, eV b3b 5a3 531 gb, eV 50 42 34 9.10 ~ c ~

Fig. 1 Fig. 2
Fig. i. X ray electronic spectra: a) Nls for BMC, b) Ols for BMC,
c) Nls for BMC-HCI and d) Ols for BMC-HCI.
Fig. 2. Electronic absorption spectra of BMC in ethanol (i) and of
BMC in alkaline ethanolic solutions (2-4).

TABLE 2. Energy Characteristics of Tautomers and lonic Forms


of BMC

",'-Bond O -Bond ne~t of ~olvation "


~nergy~, energy ~tomiza-~oefficient,
Compound ?~ ~ ev
EO , eV tion, L~4,~ M

I 23,92 49,26 I03.78 4,10


Ill 23,73 49,30 I03.62 4,70
II 23,50 49,27 I03.60 3,24
24,44 49,30 I08.67 4,38
J-:%
OH
IA 24.78 49,29 I08.77 5.17

The second n-electron transition is also complex: ~n + ~m (48%), ~n + ~m+, (19%), and
~n-~ + ~'m (17%) This transition is polarized by --32~ relative to the x-axis and is local-
ized predominantly in the benzimidazole system (C(I), C(~), C(5) and N(9) are electron-
withdrawing while C(a), C(a), C(6) and N(7) are electron donating). The band with two re-
solved vibrational components (Av = 950 cm-*) corresponds to this transition in the observed
spectrum.
The third complex electronic transition appears in the experimental spectrum as a shoul-
der kTabie 3) and is localized in the benzene ring (C(2) and C(3) are electron-withdrawing
and C(~) and C(6) are electron-donating) and in the carbamatoimidazole fragment (the imida-
zole ring is electron-donating and the carbamate group is electron-withdrawing).
The fourth transition is given in Table 3.
A bathochromic shift is observed in the spectra for BMC in alkaline ethanolic solutions
relative to the spectra in ethanol for all bands. The existence of isobestic points indi-
cates the existence of an ionized form of the molecule in solution (Fig. 2). According to
the calculation, the anionic form IIA of tautomer II is formed in alkaline solution (Table 3):

H / ." / C - - ,fJCH.3 , /
/ O- /

59
%012 ,00~ ",3,~,~

-,oi~ -;,,~'~ "~","'r'~,~o~' 4,~' ,o~ /,27s


.Ie. ---I . ~%,/ 1,387 "~-" 18&

a -,o,, '~
, 0'8LAI ,
~%/%:,I
37 no I -,377

000 " " \ ' 6 ~" 004 /342


o.,,.. (.,"x,"':' A'/
j'
,od.... L:: x4. /Z"
9@ ' - - 4 Nx " ,,t@ . . . .
-IZ4 " 035 \x ~/
b " ,~B H (~ o L...li .............
%584 43 :.;3
C]II -

Fig. 3 Fig. 4
Fig. 3. Molecular diagrams of tautomer I: a) in the ground state,
and b) in the first excited state.
Fig. 4. Electronic absorption spectra for i) BMC in CHCI~; 2, 3) BMC
in CHCl~ after the passage of gaseous HCI; and 4) calculated spectrum
for protonated tautomer IA.

The long-wavelength band is attributed to the extent of 87% to the transition ~n(HOMO)
Tm(LUMO) and the intensity (f = 0.621) is 2.6 times greater than for the neutral form (f =
0.238). The calculated fneutr/fanion = 0.4 and experimental Cneutr/eanio n = 0.3 ratios for
the long-wavelength transitions are in satisfactory accord (Table 3). This transition is
polarized along the long molecular axis. The oxide anion is electron-donating while the
henzimidazole system is electron-withdrawing. The doublet nature of the band is due to the
appearance of vibrational structure in the electronic transition.
The spectra of the solutions of BMC in acidic ethanol media and in CHCI3 through which
gaseous HCI was introduced show that the BMC molecules are protonated as indicated by the ob-
servation of isosbestic points (Fig. 4). This protonation leads to a significant change in
the absorption spectrum (Table 3). The intensities of the bands at 212 and 228 nm undergo
inversion and a hypsochromic shift of 4 nm. T h e intensity of the 250/245 nm band is very re-
duced. According to the calculation, this band is shifted hypsochromically, which prevents
its observation due to overlap with the adjacent strong band. The long-wavelength band re-
tains its fine structure and undergoes hypsochromic shift by 4 nm. The calculated spectrum
of protonated tautomer IA is in satisfactory accord with the experimental spectrum (Fig. 4).

V2"b......~K
.

C--O~

The acidity and basicity constants of BMC in 50% ethanol were determined spectrophoto-
metrically using Na2B~O~,I0~20 (pH 9.18) and KH~PO~ (pH 6.86) buffer solutions, respectively.
The pK a value of 11,64 and pkb value of 5.60 fall withing the pK ranges for reported benzim-
idazole derivatives: pK a 13.2 and pKb 5.53 for benzimidazole and pK a 12.0 for 2-phenylbenz-
imidazole [12].
The IR absorption spectra were taken on a Specord IR-75 spectrometer. The IR spectrum
of BMC in vaseline oil at 3700-2100 cm -I shows a diffuse band with a set of maxima at 2555,
2675, 2755, and 2810 cm-* which we assigned to the stretching vibrations of the NH group
bound hy a strong intramolecular bond to the carbonyl group. This assignment is in accord
with the lack of this band in the IR spectra of polycrystalline benomil (Fig. 5) and in di-
lute solutions of BMC in CHC13. The band at 3330 cm-* is assigned to vibrations of the ex-
ocyclic NH bond forming strong intermolecular hydrogen bonds. The bands at 1640-1655 cm-*
were assigned to the C=O bonds since the vC==N band of benzimidazole is observed at 1620 cm-*
while the vC-_~ band of iminoesters are observed at 1615-1575 cm-* [13, 14]. The strong shift

60
TABLE 3. Experimental and Calculated Absorption Spectra for
BMC Tautomer I in Ethanol (7 <_ pH < 7)

~max, rim Intensity Transition I


~olarization[ MKV eigen
Form of tautomer I exp "~]calc"'IExP 9, - direction9 I vectors
I' caxc. (~), deg.l

y pH----7 "
294' 278 5333,7 0,238 '-13 -0,64 (8--9);
7 287 14142,3 0,57 (7--9);
281 13360,9 0,32 (8--10)
276 11159,7
~',/5 "N C--OCH3 25O 249 9273,3 0,397 -32 0,69 (8--9);
6 9~]t I~//11 12 245 12520,7 0,43 (8--10);
-o
0,41 (7--9)
228 227 14318,8 0,308 10 0,59 (8--I0);
-0,54 (7--9);
0,42 (7--11)
212 197 23483,5 0,287 6O 0,79 (8--11);
--0,39 (7--9);
-0,27 (7--10)
y~ pH>7 304 301 18446,6 0,621 - 12 0,93 (8--9)
i ~(oc] 296 18203,9
26l 266 11650,5 0,140 -19 0,69 (8--10);
253 11407,8 0,46 (7--9);
0,35 (7--11)
II r 9~}1 J~111 12 "~ 226 237 66504,9 0,239 -64 0,59 (7--9);
0,54 (8--11);
-0,35 (8--1o);
.0,32 (7--10)
208 0,429 -41 0,76 (8--11);
--0,52 (7--9)
204 0,224 71 -0,60 (8--1o);
0,51 (6--9);
0,46 (7--11)
y~ pH<7 283 280 14508,9 0,339 9 -13 0,81 (8--9);
277 14508,9 -0,35 (7--11);
266 8816,9 -0,34 (7--9)
242 0,256 -35 0,57 (7--9);
0,50 (8--9);
0,41 (8--10);
0,38 (8--11)
225 231 21316,9 0,276 I0 -0,61 (7--9);
0,50 (8--10);
0,47 (7--11)
2O8 199 12276,8 0,083 -84 -0,62 (8--11);
0,57 (7--1o);
0,32 (7--9)

*Experimentally not distinguished since the solvent has strong


absorption in this region.
r by a broad band in the region 210-250 nm in the ex-
perimental spectrum.

of the vC= 0 band is a result of strong hydrogen bonding. The existence of a C=O bond in BMC
in the polycrystalline state is also indicated by the sharp bands at 1276 and 1292 (doublet)
and 1198 cm -x characteristic for vibrations of ester C-O--bonds [15, 16]. The low-intensity
band at 1712 cm -x in the IR spectrum of BMC is related to rotational isomer i':

~"" ----N O.::C_. 9

This hypothesis i s s u p p o r t e d b y ttle f i n d i n g o f a v e r y s t r o n g b a n d a t 1712 cm - x i n t h e


spectrum of benomil, The r e p l a c e m e n t of a hydrogen atom at the ring nitrogen a t o m by a n
amide group destroys the intramo]ecular hydrogen bond with the carbamate group in isomer I
and ]eads to the formation of a new bond:

61
6O
&

2O

i 8O ~ Fig. 5. IR spectra in the crystalline


state and in vaseline oil for BMC (a),
BMC.HCI (b), and benomil (c),
~o 60

s0~ ~0
20
<0

w - - ~ - b.,< i _ , i ~-~ 0
20 16 12 B 6 37 33 29 25 21..l
"7,!O~' cIB

i
~:~
....
,~ . . . .
r, . ~ I 9
_:~
bl ,'~C
i l

)cll~

i iJ: o<:lI. "'~" ]I


O'.'(\N,+IJ~ ,'O tI. .C"-I"
I "N
('411~ . C4H~
IY "r

Since an eight-membered ring is formed in isomer IV, while a six-membered ring is formed in
V, the latter is favored energetically. This is in accord with the assignment of the band
at 1712 cm-* to the vibration for the free carbamate group of V since the vibrational fre-
quency of the free amide group does not exceed 1680 cm -I [15]. The ~NC=O frequency of the
amide group is strongly shifted toward lower values due to intramolecular hydrogen bonding
and is 1635 cm-Z.
The carbamate and am!de group C=O bands in the spectra of dilute solutions of benomil
in CCI~ are higher by 19 cm -I. The form and number of bands in the NH stretching band re-
gion in the spectra of benomil in vaseline oil and in CC14 solution are the same but are
shifted toward higher frequencies in solution by 20 cm -i. This behavior indicates that the
structures of the benzimidazole ring and the carbamate group in BMC and benomil are the same.
The IR spectra of BMC,HCI in the crystalline state shows a strong band at 1753 cm -~,
which was assigned to C=O group vibrations. The increase in vC==O relative to the frequency
of this band in BMC is attributed to a strong inductive effect. This is in accord with the
XES data which indicate that the energy of the C=O group increases upon protonation of BMC.

LITERATURE CITED
i. S. S. Kukalenko and E. A. Dvoichenkova, Khim. Sel'sk. Khoz., No. ii, 36 (1970).
2. G. P. Clemons and H. D. Sisler, Pesticide Biochem. Physiol,, ~, 32 (1971).
3. D. Clark, Proceedings of the Sixth Conference on Molecular Spectroscopy, Durham, 1976,
London (1977), p. 339.
4. B. E. Zaltsev, T. M. Ivanova, V. V. Davydov, and A. K, Molodkin, Zh, Neorg. Khim., 25~
No. Ii, 3031 (1977).
5. V, I. Nefedov, The Application of X-Ray Electronic Spectroscopy in Chemistry [in Rus-
sian], VINITI, Chemical Bond and Molecular Structure, Vol, i, Moscow (1973), p. 64.
6. Yu. A. Teterln, A. N. Baranov, V. M. Kulakov; L. N. Nikolenko, and N. S. Tolmacheva,
Koord. Khlm., ~, 1860 (1978).
7. M. Barker and D. T. Clark, Chem. Co~mun., 22, 24 (1970).
8. R. Pariser and R. G. Parr, J. Chem. Phys., 21, 466 (1953),
9. J. A, Pople, Trans. Faraday Soc., 49, 1375 (1953).
i0. K. Nishimoto and L. S. Forster, Theoret. Chim. Acta., ~, 407 (1965).
ii. V. A. Kosobutskii, Author's Abstract of Chemical Sciences Candidate's Dissertation, A l l -
Union Glass Research Institute, Vladimir (1974).

62
12. A. R. Katritsky (ed.), Physical Methods in Heterocyclic Chemistry [Russian translation],
Izd. Khimiya, Moscow--Leningrad (1966), p. 112.
13. K. J. Morgan, J. Chem. Soc., 2343 (1961).
14. B. Baccar, R. Mathis, A. Secches, J. Barrans, and F. Mathis, J. Mol. Struct., ~, Nos.
3-4, 369 (1971).
15. L. Bellamy, The Infrared Spectra of Complex Molecules, Izd. Inostr. Lit., Moscow (1963),
p. 275.
16. L. A. Kazitsina and N. B. Kupletskaya, The Application of UV, IR and N'MR Spectroscopy in
Organic Chemistry, Izd. Vyssh. Shkola, Moscow (1971), p. 122.

REACTIVITY OF METHYL DERIVATIVES OF NITROGENOUS HETEROCYCLES


IN VAPOR-PHASE CATALYTIC OXIDATION

L. Ya. Leitis, R. A. Skolmeistere, L. O. Golender, UDC 547.8:542.943.7


D. P. Yansone, P. A. Meksh, and M. V. Shimanskaya

A study has been made of the reactivity of methylpyridines, methylpyrazines,


and methylquinolines in oxidation in the vapor phase in the presence of B-VO
(P03)2. Relationships have been found between the overall reaction rates of
heterocyclic compounds and the charge on the ring nitrogen, and between the
partial oxidation rate and the charge on the ring carbon atom adjacent to the
methyl group. The partial oxidation rate of methylpyridines is given to a
first approximation by the Hammet-type expression InWa = --3.5 + 4.6 Eo, with
a correlation coefficient of 0.93.

The vapor phase oxidation of methylheterocycles with atmospheric oxygen over vanadium
catalysts forms the basis of the industrial production of heteryl aldehydes, which are inter-
mediates in the synthesis of biologically active compounds. In order to establish the most
important structural features governing the reactivity of heterocyclic compounds in oxidation,
and to obtain further information on the reaction mechanisms under comparable conditions, the
oxidation of representatives of three classes of nitrogen heterocycles has been studied, name-
ly pyridines, diazines, and quinolines. In the pulsed vapor-phase oxidation of these com-
pounds (Table i) in the presence of vanadyl ~-polyphosphate at 400~ the principal reaction
products are the monoa~dehyde and oxides of carbon. Under these conditions, 4-MP, 2,3-DMP,
2,5-DMP, 3,4-DMP, 2-MQ, and 4-MQ give predominantly the partial oxidation products, whereas
oxidation of 3-MP, 3,5-DMP, and DMPZ results in extensive oxidation. The rates of total and
partial oxidation W a of the remaining compounds are similar. Comparison of the total oxida-
tion rates (Wtot) of the pyridine bases shows that introduction of methyl substituents into
the pyridine ring increases the overall reaction rate, but there is not clear relationship
between the reactivity of the pyridines and the number of methyl groups present.
Under impulse conditions, the total conversion rate of monomethylpyridines and the
amounts of aldehydes formed on oxidation over B-VO(POs)2 decreases in the isomer sequence ~
4- > 2- > 3-, just as when vanadium oxide catalysts are used [i].
It is noteworthy that the sequence of reactivities of 2-, 3-, and 4-MP obtained under
conditions which restrict the occurrence of subsequent reactions is similar to the rate of
deuteration of the methyl groups in these compounds [2], and also to their reactivity in pro-
totropic reactions, for example with sodamide [3]. In the quinoline series, 4-MQ also under-
goes vapor phase oxidation more readily than 2-MQ both in total and partial oxidation (Table
i). These facts lead to the conclusion that the limiting step in the heterogeneous catalytic

Institute of Organic Chemistry, Academy of Sciences'of the Latvian SSR, Riga 226006.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. i, pp. 75-79, January, 1986.
Original article submitted May 7, 1985.

0009-3122/86/2201-0063512.50 9 1986 Plenum Publishing Corporation 63


TABLE i. Rates and Selectlvity of Oxidation and Methylhetero-
cyclic Compounds over Vanadyl Polyphosphate

Con%"
pond 2 seC) I v i np ridineal-
Compound oxidized Idehy~es, %
J Wtot ~l J
I Pyridne (P).,
2-Methylpyridine (2-MP) 2,9
2 4,8 3,0 60
;3 3-Meuhylpyridine (3-MP) 3,0
4-Methylpyridin~ (4-MP) 0,3 8
4 5,0 3,:3
,5 2,3-Dime~ylpyridine (2,3-DHP) 3,9 3,2 81
6 2,4-Dimethylpyridine (2,4-DMP) 4,8 2,2 48
7 2,5-Dimethylpyridine (2,5-DMP) 3,9 1,7 44
8 2,6-Dimethylpyridine(2,6-DMP) 4,8 3,2 86
9 3,4-Dimethylpyridine (3,4-DMP) ,%6 3,7 65
I0 3~5-~imethylpyridine (b,5-DMP) 2,6 0,3 8
11 2,4,6-Trimethylpyridine(2,4,6-TMP) 3,7 1,8 47
12 2-Me~lyl-5-ethylpyridine(MEP) 3,0 1,6 56
13 Methylpyrazine (MP) 1,3 1,3 I O0
14 2,5-Dimethylpyrazine (DS~Z) 2,0 0,5 "~7
15 2-Hethylquinoline (Z-MQ) 2,4 2,1 89
16 4-Methylquinoline (4-~) 8,9 3,1 80

oxidation of nitrogen heterocycles has an ionic mechanism, and the rate of this step is de-
pendent on the mobility of hydrogen in the methyl group.
The variations in the reactivity of monomethylpyridines in vapor phase catalytic oxida-
tion are usually regarded as being due to the superimposition of r and inductive
effects. With methyl groups in the 3-position, there is no +M effect (the increased basic-
ity of pyridine consequent upon the introduction of a methyl group into this position is at-
tributed mainly to the +I effect), and the reactivity of 3-MP is similar to that of toluene.
However, in 2- and 4-MP conjugation is increased to such an extent that some authors have
assumed that the formation of quinoid structures is possible [3], the hydrogen of the methyl
group thereby becoming highly mobile. However, as a result of the high electronegative in-
ductive effect of the heteroatom at the 2-position, the shift in electron density at this
position is reduced, and reactivity of the 2-CH3 group is less than that of the 4-CH3 group.
Furthermore, according to nonempirical quantum chemical calculations [4], 2-MP should also
be more stable overall then 4-MP.
In the oxidation of di- and trimethylpyridines over a vanadium phosphate catalyst, this
sequence of reactivities of the methyl groups is maintained, i.e., the rates of conversion
of the CH3 group to CHO decrease in the sequence 4- > 2- and 6- > 3- and 5-. Similar behav-
ior has been found in the oxidation of pyridine bases over vanadium oxide catalysts [5].
Since, in nitrogen heterocycles, interaction with acidic sites on the catalyst surface
is most likely, to a first approximation it is desirable in assessing the effects of adsorp-
tive interactions on reactivity to compare the reactivities of these compounds with their
basicity.
An experimental measure of the basic properties of molecules in the vapor base is pro-
ton affinity (PA). However, the literature data on the PA of nitrogen heterocycles is high-
ly ambiguous [6, 7]. For example, even using the same method of measurement, for pyridine
the values vary from 908.7-943.0, and for 2-MP from 922.5-961.4 kJ/mole. We therefore re-
sorted to a theoretical measure of basicity, namely the value of the negative charge on the
nitrogen atom (qN), as calculated by the MO LCAO PPDP/2 method, which provides a good de-
scription of the electron density distribution in organic molecules [8].
For all the compounds examined, as qN is increased, the overall reaction rate increases
(Fig. i). For compounds 1-14, this relationship may be described by a trinomial equation,
with a correlation coefficient of 0.89:
lnWcot = -2,4-21.TqN+O.TEEs~
S=0.18; F=345,
where EEs ~ is the sum of the steric coefficients [9], which characterize steric hindrance in
the reaction of the N-heterocycle with the catalyst, involving the nitrogen atom. The points
for 2- and 4-MQ do not lie on this plot.

64
1,8 In V~ot

1,5 9
1~" ~ 5 o16
1,0 I~ Wa
075
a "0" /
~'5~2"/ ~,
1,5 lnw,,
1,0
b
'Z 9/

IO/'
0 11 7
I(I 12"~ "3 7 12
-0,5 In Wa=3,0+0,9 tnqc(cH3)
o15 X 0
-1 - 0,5 r=0,93; S=q23; F=56,2
0
0,7 1~13 -1,0
,, L i X6 .... 3" /'~0 I i itrtqcccH3)
I 0,9 1,1 -5 -4 -3 -2
- 0,20 -0,16 -0,12 -0,08 O,5 0,7
Fig. 1 Fig. 2
Fig. i. Plot of Wto t against the charge on the nitrogen atom.
Fig. 2. Plots of inW a against the induction contant (a) and the charge on the carbon
adjacent to the methyl group (b).

As is well known, the heteroatom in pyridine may be regarded as a substituent introduced


into the benzene ring in place of the CH fragment. In this case, the rate of formation of
monoaldehydes in the oxidation of compounds 2-12 is satisfactorily approximated by a Hammet-
type equation with o-constants describing the electron-acceptor properties of the he teroatom
(Fig. 2a):

In W.= -3.5+4.6Eo; r=0.93; S=0.41.

In the case of 2,3- and 2,4-DMP, the sigma constants used were the sums ON2 + on-CH 3 and
(ON~ + On_CH3) , as in [ii].
Since these o-constants were calculated [12] from the rate of replacement of chlorine
by alkoxy-groups in pyridines, it may be that their use here indicates a similarity in the
transmission of electronic effects in nucleophilic substitution and in vapor-phase catalytic
oxidation at the stage of interaction with the catalyst.
From the values of the reaction constant s, obtained from the inWa-o plots, two conclu-
sions may be drawn with respect to the mechanism of the partial oxidation of methylhetero-
cycles: i) Oxidation of the CH3 group to CHO is a nucleophilic reaction, and 2) the surface
complex in the transition state is largely ionic in character.
These features of the mechanism of the oxidation of methylpyridines appear to hold true
both for vanadyl phosphate and vanadium-molybdenum oxide systems.
The description of oxidative reactions of other methylheterocycles in a single series
with methylpyridines by a Hammet-type equation has not so far been possible as a result of
the absence from the literature of o-constants which take fully into account electronic in-
teractions in these compounds.
The positive values of the parameter p obtained for the partial oxidation of methylpy-
ridines lead to the conclusion that the reaction proceeds the more readily as the electron
density at the ring carbon adjacent to the methyl group is reduced. It has in fact been
found that an adequately linear in Wa--ln qC(CH)s plot is obtained for methylpyridines (Fig.
2b).
Correlational analysis shows that the principal features determining the overall reac-
tivity of methylheterocycles in vapor-phase catalytic oxidation are the basic properties of
the heteroatom, and in partial oxidation to the aldehydes, tile most important factor is the
electron density at the ring carbon atom attached to the methyl group, which is dependent on
the electron-acceptor properties of the heteroatom.
Taking some diazines and quino]ines as examples, we have shown that the incorporation
of methylheterocyclic compounds of different types into an overall reaction series appears
to require the use of multifactorial correlational relationships which take into account the
basic properties and the structural features of the compounds to be oxidized, which have a
considerable influence on the mechanism of the oxidation reaction.

65
Since such information is not atpresent available to us, a quantitative description of
the rates of catalytic oxidative reactions using the approaches developed here has been ob-
tained for pyridine derivatives only.

EXPERIMENTAL
Oxidations were carried out in a microreactor (3 ~:m ~ ].2 ~m) in the pulsed mode. The
catalyst volume was 0.5 ml, and the free volume of the reacLor was packed with quartz. The
preparation and properties of the catalyst have been described previously [13].*
The grain size of the catalyst and the inert packing w~th 0.25-0.5 mm. The impulse vol-
ume was 0.4 ~i, and the air flow 40 ml/min. The reaction products were analyzed chromato-
graphically on a column with a stationary phase containing 2.5% of Reoplex 400 and 10% SE-301
on Chromosorb W-AW (40-60 mesh), The column temperature was 120-160~
Before use, the compounds were dried over KOH and redistilled over CaH2. 2-MP, 4-MP,
and 1,6-DMP were first purified by crystallization of their complexes with Mn(CNS)2, CaCI2,
and urea, respectively.

LITERATURE CITED
i. L. Ya. Leitis, M. V. Shimanskaya, and V. A. Slavinskaya, Khim. Geterotsikl. Soedin., No.
6, 1061 (1968).
2. N. N. Zatsepina and I. F. Tupitsyn, Advances in Heterocyclic Chemistry [in Russian],
Zinatne, Riga (1976), p. 32.
3. H. C. Brown and W. A. Marphey, J. Amer. Chem. Soc., 73, 3308 (1951).
4. J. E. Del Bane, J. Amer. Chem. Soc., I01, 6184 (1979).
5. Yu. Sh. Gol'dberg and M. V. Shimanskaya, Izv. Akad. Nauk Latv. SSSR, Ser. Khim., No. 6,
731 (1977).
6. R. Welder and J. L. Franklin, J. Mass Spectrom. and Ion Physics, 36, 85 (1980).
7. D. H. Aue and M. T. Bowers, in: Gas-Phase Ion Chemistry, Vol. 2, M. T. Bowers (ed.),
Academic Press, New York (1979), p. 2.
8. G. Klopman and R. Ivens, in: Semiempirical Methods for the Calculation of Electronic
Structures [Russian translation], Mir, Moscow (1980), p. 47.
9. V. A. Pal'm, Fundamentals of the Quantitative Theory of Organic Reactions [in Russian],
Khimiya, Leningrad (1977).
lO. I. F. Tupitsyn, N. N. gatsepina, N, S. Kolodina, and A. A. Kane, Reakts. Sposob. Org.
Soedin., ~, 931 (1969).
Ii. N. N. Zatsepina, I. F. Tupitsyn, and A. V. Kirova, ibid., ~, 195 (1972).
12. M. Liveris and J. Miller, J. Chem. Soc., 3486 (1963).
13. R. A. Skolmeistere, L. Ya. Leitis, M. V. Shlmanskaya, Ya. Ya. Gedrovits, and Z. A. Kon-
stant, in: The Mechanisms of Organic Reactions. proceedings of the 3rd All-Union Con-
ference [in Russian], Novosibirsk, part 2, p. 1664 (1982).
*We thank our colleague at the Institute of Inorganic Chemistry of the Academy of Sciences of
the Latvian SSR u Ya, Gedrovits for the gift of catalyst samples.

66
SYNTHESIS AND RING-CHAIN ISOMERISM OF N-MONOSUBSTITUTED
4-BENZOYLNiCOTINAMIDES AND 3-BENZOYLISONICOTINAMIDES

R. E. Valter, and A. E. Batse, and M. V. Petrova UDC 541.62:547.824'826.1'298.1

4-Benzoylnicotinoyl and 3-benzoylisonicotinoyl chlorides have been found to ex-


ist in cyclic forms (3-chloro-3-phenyl-6(or 5)-azaphthalides), and their benzyl-
amides also occur as the cyclic forms (azaisoindolinones). The tert-butylamides
of both acids are obtained in the open amide forms. It has been shown by PMR
that N-tert-butyl-4-benzoylnicotinamide displays a greater tendency to undergo
closure of the isoindolinone ring (KT = 0.24 in CDsOD) than does N-tert-butyl-3-
benzoylisonicotinamide (KT = 0).

Ring-chain isomerism in 2-acylbenzoic acids has been the subject of thorough study [i],
but in the case of heterocyclic o-carboxylic acids this phenomenon has received little atten-
tion [2].
The object of this investigation was to synthesize and examine the ring-chain isomeric
interconversions of N-monosubstituted 4-benzoylnicotinamides and 3-benzoylisonicotin~mides,
and of their protonated forms. According to their IR spectra, both acids (I, III) resemble
2-aroylbenzoic acids [i] in the crystalline state, whereas in solution in dioxane they exist
in the open (ketocarboxylic) forms.

I I =--_ so=,,
Y COC~s Cell5 B O H C6H ~ "el
A
I-IV I-IV 'V.VI

, _ _

Y ~" Y .-.. N..


CeH s Oil A
VII=X ~-XIV X~-XIY

[, VII, XI X=N; II, V, VIII, XII X=N+H CI-; llI, IV, VI, IX, X, XIII, XIV X=CH;
I, II, V, VII, VIII, XI, XII Y=CH; III, VI, IX, XIII Y=N; IV, X, XIV Y=N+HCI -

Their hydrochlorides (II, IV) also possess the open structure, although in the IR spect-
rum of 3-benzoylisonicotinic acid hydrochloride (IV) there is weak absorption at 1805 cm -I,
indicating the presence of small amounts of the lactol form (IVB).
Treatment of the acids ( I ) a n d (III) with thionyl chloride affords the acid chlorides,
which exist in the cyclic chlorolactone form (V, VI), which is also characteristic of 2-
acylbenzoyl chlorides [i]. This is confirmed by the presence in their IR spectra of one,
and only one C=O band at -1800 cm -I. The chlorolactone (V~ was isolated as its hydrochlor L-
ide, and (VI) as the free base.
Acylation of benzylamine with the chlorolact0nes (V) and (Vl) gave the cyclic isomeric
amides (2-benzyl-3-hydroxy-3-phenyl-6-(or 5)-azaindolinones VII and IX), the IR spectra of
which showed broad OH absorption typical of intermolecularly associated hydroxyl groups (O--
H...O=C or O--H...N ) together with C=O absorption for the isoindolinone at 1703-1685 cm-*
(in Nujol). On passing from the crystalline state to the dioxane solution, there is a char-
acteristic shift in this absorption towards higher frequencies as a result of fission of the

A. Ya. Pel'she Polytechnic Institute, Riga 226355. Translated f r o m Khimiya Gerero-


tsiklicheskikh Soedinenii, No. i, pp. 80-83, January, 1986. Original article submitted
November 23, 1984.

0009-3122/86/2201-0067512.50 9 1986 Plenum Publishing Corporation 67


x111

~k

Fig. i. IR spectra of crys-


talline N-tert-butylamides
W and their hydroch!orides.

O-H...O=C hydrogen bonds.


chlorides (Vlll, X).
I
700 1600 1500
#, cm'
The cyclic isoindolinone structure is retained in their hydro-

It is known [3] that cyclization of 2-acylbenzamides is prevented by the presence of a


tert-alkyl substituent on the nitrogen atom, and it has now been found that acylation of
tert-butylamine by the chlorolactones (V) and (VI) affords the N-tert-butylamides (XI) and
(XIII). Their IR spectra, obtained in Nujol, show absorption for N--H, C=O, amide-l, and
amide-ll. In the spectra obtained in dioxane solution, the absorption for the ketone C=O
and amide-I overlap, and a single band is seen at 1670 cm-*. This, together with the pre-
sence of the amide-ll band, confirms the open structure of amides (XI) and (XIII) in dioxane
solution.
The PMR spectrum of the amide (XI), obtained in CD3OD, shows two signals for the pro-
tons of the tert-butyl group (6 = 1.12, form A, and 1.43 ppm, form B), which is characteris-
tic of the ring-chain equilibrium XIA $ XIB [4]. The ratio of intensities gives the equili-
brium constant, K T = [XIB]/[XIA] = 0.24. In the PMR spectrum of the amide (XIII), there is
only one signal for the tert-butyl group at 1.13 ppm, confirming that this amide exists only
in the open form (XIIIA) in solution in CDsOD, within the limits of sensitivity of the PMR
method.
The same capacity to exist in the cyclic form is also seen in the crystalling hydro-
chlorides (XII) and (EIV). The IR spectrum of the hydrochloride (XIV), over the range 1800-
1480 cm -~, differs little from that of the base (XIII). The appearance of a low-intensity
band at 1698 cm-* (Fig. I) could be due to the presence of small amounts of the protonated
cyclic form (EIVB). The IR spectrum of the hydrochloride (XII) shows a strong, broad band
for the isoindolinone C = C at 1707 cm-*, and generally speaking the spectrum at 1800-1480 and
3600-2400 cm-* is similar to that of 2-benzyl-3-hydroxy-3-phenyl-6-azaindolinone (VIII), thus
confirming the cyclic structure of 2-tert-butyl-3-hydroxy-3-phenyl-6-azaindolinone hydrochlor-
ide (XIIB).
It has thus been shown, taking the N-tert-butylamides as examples, that 4-benzolnicotin-
amide shows a sreater tendency to exist in cyclic forms as a result of intramolecular addi-
tlon of the amide N--H to the C = O bond than does 3-benzoylisonicotinamlde. This behavior also
holds true for the hydrochlorides.

EXPERIMENTAL
IR spectra were obtained on IKS-14A and Specord 75-IR instruments, as suspensions in
Nujol and as solutions in dioxane (c = (2.5-5).10 -2 mole). PMR spectra were obtained on a
Tesla BS-487C (80 MHz) in solution in CD,OD at 25~
4-Benzolnicotinic acid (I) was obtained as described in [5], mp 215-219~ IR spectrum
(Nujol): 2400 (broad band, COOH), 1706 (COOH), 1669 (C=O), 1592, 1577, 1552; (dioxane):
1721 (COOH), 1680 (C=O), 1595, 1581, 1551 cm -~.

68
Hydrochloride (II). To a solution of 0.i g of the acid (I) in 2 ml of anhydrous diox-
ane was added 5 ml of ether saturated with dry hydrogen chloride. There was obtained 0.i g
(86%) of colorless cyrstals, mp 238-242~ (decomposed) IR spectrum (Nujol): 3353, 3282,
3097, 2955, 2858, 2727 br. 2578 br., 2457 br., 1805, 1721, 1680, 1634, 1595 cm -z. Found:
C1 13.0%. C13HIoCINOs. Calculated: C1 13.4%. e

3-Benzoylisonicotinic acid (III) was obtained as described in [5], mp 272~ (decomposed).


IR spectrum (Nujol): 2417 (br., COOH), 1722 (COOH), 1670 (C=O), 1594, 1563; (dioxane): 1730
(COOH), 1676 (C=O), 1595, 1580, 1551 cm -~
Hydrochloride (IV) was obtained similarly to the above. IR spectrum (Nujol): 3369 br.,
3098, 3071, 2690, 2580, 2352 hr., 1722, 1677, 1635, 1588, 1507 cm -l. Found: C1 13.0%.
C~3HIoCINO3. Calculated: C1 13.4%.
3-Chloro-3-phenyl-6-azaphthalide Hydrochloride (V~. A solution of 0.46 g (2 mmole) of
the acid (I) and 1.4 ml (20 mmole) of thionyl chloride in 15 ml of benzene was boiled for 4
h. After 24 h, 0.51 g (90%) of colorless crystals of (V) were isolated, mp 171-173~ (de-
composed). IR spectrum (Nujol): 3095, 3066, 2869 br., 1814 (C---O), 1644, 1606, 1506 cm -~.
Found: C1 24.6%. C~3HgCI~NO2. Calculated: C1 25.1%.
3-Chloro-3-phenyl-5-azaphthalide (VI) was obtained as in the foregoing example, mp 174-
176~ IR spectrum (Nujol): 3044, 3017, 2698, 2931, 1799 (C=O), 1618, 1549 cm -I. Found:
C1 14.90%. C~3HeCINO2. Calculated: C1 14.43%.
2-Benzyl-3-hydroxy~3-phenyl-6-azaindolinone (VII). The hydrochloride (V) (2.5 mmole)
was suspended in i0 ml of dioxane, and added to a solution of 2.5 mmole of benzylamine and
5 mmole of triethylamine in 5 ml of dioxane. The mixture was kept for 12 h at 20~ then
diluted with i00 ml of water, the solution saturated with sodium chloride, and 0.74 g (94%)
of (VII) isolated, mp 183~ Two recrystallizations from ethanol gave 0.36 g (46%) of color-
less crystals, mp 205-206~ IR spectrum (Nujol): 3390, 3057 br., 2920, 2830 br., 1703 (C=
O), 1609; (dioxane): 1711 (C=O), 1603, 1409 cm -I. Found: C 76.1; H 5.3~ N 90%. C2oH~6N202.
Calculated: C 75.9; H 5.1; N 8.9%.
Compounds (IX), (XI), and (XIII) were obtained similarly from the chlorophthalides (V)
for (XI) and (VI) for (IX and XIII), and benzylamine for (IX) or tert-butylamine for (XI) and
(XIII with the addition of triethylamine.
HYdrochloride (VIII). To a solution of 0.14 g of the isoindolinone (VII) in 2.5 ml of
dioxane was added 15 ml of ether saturated with dry hydrogen chloride. There was obtained
0.16 g (100%) of colorless cyrstals of the hydrochloride (VIII), mp. 234-236~ (decomposed).
!R spectrum (Nujol): 3412 hr., 3051, 2584 br., 1716 (C=O), 1646, 1613, 1536 cm -~. Found:
C 69.3; H 5.1; C1 10.3; N 8.0%. C2oH~TCIN202. Calculated: C 68.1; H 4.9; C1 i0.0; N 7.9%.
Hydrochiorides (X), (XII), and (XIV) were obtained similarly.
2-Benzyl-3-hydroxy-3-phenyl-5-azaindolinone (IX). Yield 94%, mp 95-98~ After three-
fold recrystallization from benzene--hexane, mp I03-I06~ (decomposed). IR spectrum (Nujol):
3410 br., 3357 pl., 3157 br., 3067 sh., 2845, 1685 (C=O), 1591; (dioxane): 1714 (C=~O), 1590
cm -~. Found: C 75.3; H 5.1; N 8.3%: C2oHI6N202: Calculated: C 75.9; H 5.1; N 8.9%.
Hydrochloride CX). Mp 220-222~ (decomposed). IR spectrum (Nujol): 3352 hr., 3126,
3080, 3030, 2483 br., 1720 sh., 1706 (C=O), 1619 cm -2. Found: C 67.9; H 4.6; C1 10.9; N
8.0%. C2oHITCIN202. Calculated: C 68.1; H 4.9%; C1 I0.0; N 7.9%.
N-tert-Butyl-4-benzoylnicotinamide (XI). After two recrystallizations from benzene--
hexane, yield 36%, mp I19-i20~ IR spectrum (Nujol): 3269 (N--H), 3068, 2979, 1674 (C~O),
1632 (amide-I), 1596, 1581, 1556 (amide-II); (dioxane): 1671 (C=O + amide-l), 1594, 1581,
1552, 1531 cm -I (amide-II). Found: C 71.7; H 6.8; N 9.9%. C17HIsN202. Calculated: C
72.3; H 6.4; N 9.9%.
Hydrochloride (XII). Mp 224~ (decomposed). iR spectrum (Nu~ol): 3393, 3100, 3058,
2954, 2508 br., ]707 (C=O), 1643, !619, 1543 cm -~. Found: C 64.1; H 6.0; C! 11.4; N 8.7%.
C~TH~gCIN20=. Calculated: C 64.0; H 6.0; C1 ii.i; N 8.8%.
N-tert-Butyl-3-benzoylisonicotinamide (XIII). After two recrystallizations from ben-
zene--hexane, yield 56%, mp IIO-III~ IR spectrum (Nujol): 3390 (N--H), 3211 (N-H), 3066,
3043, 2989, 2968, 2931, 2902, 1671 (C=O), 1642 (amide-I, 1593, 1578, 1544 (amide-II); (diox-
ane): 1668 (C~O + amide-I), 1594, 1579, 1540 sh., 1529 cm -~ (amide-II). Found: C 71.6; H
6~6; N ]0.0%. C~THIsN202. Calculated: C 72.3; H 6.4; N 9.9%.

69
Hydrochloride (XIV). Mp 220-222~ (decomposed). IR spectrum (Nujol): 3361 (O--H),
3096 (N-H), 3062, 2976, 2923, 2501 br., 1698 (isoindolinone C=O), 1668 (C=O + amide-I),
1657 sh., 1634, 1595, 1551 cm -~ (amide-II). Found: C 63.8; H 6.2; C1 11.3; N 8.7%. C~TH~9-
CINa02. Calculated: C 64.0; H 6.0; C1 ii.i; N 8.8%.

LITERATURE CITED
i. R . E . Valter, Ring-Chain Isomerism in Organic Chemistry [in Rusdian], Zinatne, Riga
(1978).
2. B. Paul and B. Korytnyk, J. Heterocyc. Chem., 13, 701 (1976).
3. G . A . Karlivan, R. E. Valter, and S. P. Valter, Zh. Org. Khim., 13, 805 (1977).
4. R . B . Kampare, R. ~. Valter, E. E. Liepin'sh, and G. A. Karlivan~-Izv. Akad. Nauk. Latv.
SSR, Ser. Khim., No. 2, 244 (1981).
5. A . A . Artamonov, T. Shneider, and N. V. Baranova, Khim. Geterotsikl. Soedin., No. 4,
514 (1980).

ACETALS OF LACTAMS AND ACID AMIDES.


46.* UNUSUAL REACTIONS OF ~-CYANO-B-DIMETHYLAMINOCROTONAMIDE
WITH ANTHRANILIC ACID DERIVATIVES

N. Z. Yalysheva, V. V. Chistyakov, and V. G. Granik UDC 547.391.3'398.1'583.5'


856.1'831:543.51'422

It has been shown that the reaction of the enaminoamide a-cyano-8-dimethylamino-


crotonamide with anthranilic acid and its ethyl ester unexpectedly gives quina-
zoline-2,4-dione and 2-methyl-3-cyano-4-quinolone, respectively. The structures
of the products were confirmed by their spectra and by direct synthesis.

It has been shown [2] that tertiary enaminoamides react with aromatic amines, the trans-
amination being best effected in acetic acid. For this reason, it was attempted to carry out
this reaction with ~-cyano-B-dimethylaminocrotonamide (I) and ethyl anthranilate (II) in or-
der to obtain the secondary N-arylenemonoamlde (III), which has a functional substituent (the
ethoxycarbonyl group) in the ortho-position in the benzene ring. The product obtained was
the compound (IV), the mass spectrum of which contained three main peaks%, viz., the molecu-
lar peak (162), 119 (M -- CONH) +, and 92, The IR spectrum of the compound showed absorption
at 1670 and 1700 cm -~ (CO), 3160 and 3250 cm -~ (NH). These findings, together with the ele-
mental analysis, lead to the conclusion that the reaction of (I) and (II) follows an unexpec-
ted route to give quinazoline-2,4-dione (IV). The structure of (IV) was confirmed by compar-
ison with an authentic sample synthesized by a literature method [3].

*For communication 45, see [i].


%Here and subsequently, the m/z values for the peaks are given (with the intensity relative
to the maximum ion peak, %, in parentheses.

S. 0rdzhonikidze All-Union Scientific-Research Institute for Pharmaceutical Chemistry,


Moscow 119021. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. I, pp. 84-87,
January, 1986. Original article submitted November 27, 1984.

70 0009-3122/86/2201-0070512.50 9 1986 Plenum Publishing Corporation


Me CONII 2 /.~.. .COOEL
,:::_.= ...../.t.. ~ "-'" " Me
. . . . ., ,.. J->. / CONII~
(Me).,N CN "'"-/ "N '~' " "
U "x'CN

.., cooer
ri/>] o
hie CN "/ "NIl.. "~ .
: + HN,'o ...................... &.~!
(Me)2N
)-~<, ,
l~ 11 " <>-"
,~.
i"
, :-:" 0
"N "
H
I), iv
NH 2 o

11 CN
"~~ q Oi~ O " Oil "
..... j. li .... ~ ...... I. )1 ...... ? il
M,a" " "[" " Me
CN
~~ ' ) ..... "~
CN
~~ 1CN '~ "~ "~'i
CN
''~ ~" T
CN
'~
v

The f o r m a t i o n o f the q u i n a z o l i n e d i o n e (IV) may be r a t i o n a l i z e d as follows. On h e a t i n g i n


acetic acid the enaminoamide (I) undergoes reversible c l e a v a g e o f HNCO, f o l l o w e d by c y c ! i z a -
tion. A s i m i l a r c l e a v a g e o f HNCO h a s b e e n p o s t u l a t e d p r e v i o u s l y i n t h e c a s e of N - c a r b a m o y l -
amidines [4]. Heating the enaminoamide (I) in acetic acid in the absence of ethyl anthrani-
l a t e ( I I ) a f f o r d s a complex mixture, from which 4 , 6 - d i m e n t y l - 5 - c y a n o - 2 - p y r i d o n e (V~ wa~ i s o -
lated [5]. The PMR s p e c t r u m o f t h i s compound (DMF-D6) showed s i g n a l s f o r t h e 4 - and 6 - m e t h -
y l g r o u p s a t 2 . 2 5 and 2 . 4 8 , r e s p e c t i v e l y , and s i g n a l s a t 6 . 1 2 (3-H) and 7.95 ppm (NH). The
mass spectrum of (V) contained a strong molecular ion peak at 148 (78). The principal mode
of mass spectral fragmentation was elimination of CO (as in unsubstituted u-pyridone) to
give a fragment of mass 120 (51), from which a hydrogen atom is eliminated to give a stable
fragment 119 (i00). The formation of the quinazolinedione (IV) and the pyridone (V) is
shown by the scheme above.
It is noteworthy that (V) was previously synthesized from 8-aminocrotononitrile [5].
The IR spectrum of (V) shows absorption at 720, 870, 1370, 1410, 1615, 1660, 2210, and 3400
cm -~, in full agreement with the data reported in [5]. The next step in this investigation
was to attempt to carry out the transamination reaction with anthranilic acid (VI) rather
than with ethyl anthranilate (II). Heating (I) and (VI) in acetic acid gave a complex mix-
ture (which contained no starting materials), from which it was possible to isolate 2-methyl-
3-cyano-4-quinolone (VII) [6] in low yield. The structure of the quinolone (VII) was con-
formed by its mass spectrum, in which the strongest peak was for the molecular ion, 184 (i00).
One of the main routes of mass spectrometric fragmentation, as in the case of unsubstituted
7-pyridone [7]) is elimination of carbon monoxide from M +" to give the indole ion-radical 156
(15), which in turn decomposes in the well-known way with loss of a hydrogen atom and HCN to
give the ion 128 (5). The spectrum also contains ion peaks at 130 (4), 129 (6), and 92 (ii).
The quinolone (VII) was also obtained by direct synthesis from a-ethoxycarbonyl-B-anilino-
crotononitrile (VIII) by the literature method [6]. The formation of the quinolone (VII) ap-
pears to be also due to the conversion of the enaminoamide (I) into fl-dimethylaminocrotono-
nitrile (IX), which then undergoes deamination to (X) and cyclization, since under these con-
ditions (heating in acetic acid) ~-cyano-fl-anilinocrotonamide (XI) does not cyclize to (VII).
A likely scheme for the formation of the latter is shown below.

~ COOH COOH CN
Me Me
,~.)~N J-.
/ ">11"
CN L ~ T
CONH a
(Me)2N /
T
"V
H
LX
CN + Lc )1
VI
......
.~.'"
L
t
H

X
J
/ IJ ~ CN I|2NOI~.
i~/":'-)'[ "" " , , / A (CH,COOH) ,} :~ ~. CN

"'" "" ~ ' N "Me ""~ "'N'" ''Me


I[ H
VII X[

According to this scheme, the B-monosubstituted enamine (IX) reacts with anthranilic
acid (VI). It was of interest to examine this reaction in another case, namely the reaction
of the acid (VI) with 8-aminocroton~c ester (XII). On heating these compounds in acetic acid,

71
a mixture of two compounds was obtained, which was separated by treatment with caustic alk-
ali. Using this method, it was possible to isolate the previously-described 2-methyl-4-
quinolone-3-carboxylic acid (XIII) [8] and the pyranoquinolone (XIV), into whicl~ it is sub-
sequently converted under these conditions. The mass spectrum of (XIII) contained a strong
peak for the molecular ion at 203 (75), and peaks for [M - CH3] + at 188 (i00), 120 (35), at-
tributed to the fragment H2NC6H~C~O +, 92 (C6H,NH= +, 25) and 77 (Ph+, 11). The (X!V) mole ~
cule is stable to electron impact. The spectrum shows a strong molecular ion peak, M+" 227
(81), [M-- CO] + 199 (I00), and probably [M -- CH~COCH3] + 170 (59). The IR spectrum of (XIV)
shows absorption at 3160 (NH), 1750 (lactone CO), and 1670 cm "t (quinolone CO), confirming
the presence of the pyran ring. The PMR spectrum in DMSO-D6 also corresponds to the proposed
structure, signals being present for CH3 at 2.61, CH at 6.26, and Ph at 7.21-8.10 ppm.

~.~ . o 9
L', 9 "cooI-t
[.. CtPOEt -~Nl:ia,-H20 ~ .-J" .' . . . .
'-" "~NH~ /
NH ~
"" /
i
" : " "N'"
1t
""Me "N" " ' ~
It
.Me
H
VI Xll Xlll XIV '

To conclude this investigation, it was found that when the enaminoamide (XV) (which does
not contain a CHa group in the ~-position of the enamine) reacts with ethyl anthranilate or
anthranilic acid, the normal transamination products (XVIa, b) are formed.

~COOR ~ (COOR
H
+ I
~"" ~NH2 NH2 "!'Nt~ "~ "N-
11
CH:=C""
~CONH z

ILVI XY .V,'~ a ~ : : - ~ t ; b g ~ H
II R = E t ; VI R = H

EXPERIMENTAL
Mass spectra were obtained on a Varian MAT-II2 spectrometer with direct introduction of
the sample into the ion source. The ionization chamber temperature was 180~ and the energy
of the ionizing electrons 70 eV. IR spectra were obtained on a Perkin-Elmer 457 in vaseline
oil.
quinazoline-2,4-dione (IV). A mixture of 1.53 g (I0 mmole) of the enamine (I) and 4.95
g (30 mmole) of the ester (II) in 15 ml of glacial acetic acid was boiled for 5 h, then
cooled, the solid filtered off, and washed with water and alcohol to give 0.9 g (50%) of (IV)
mp 350~ (from DMF). Found: C 59.0; H 4.1; N 17.4%. CaH6NaO~. Calculated: C 59.3; H 3.7;
N 17.3%.
4,6-Dimethyl-5-cyano-2-pyridone (V). A solution of 0.5 g (3.3 mmole) of the enamine
(I) in i0 ml of glacial acetic acid was boiled for 2.5 h, evaporated, filtered, and washed
wit b alcohol to give 0.05 g (10%) of (V), mp 294-2960C (from methanol) [5]. Found: C 64.8;
H 5~6; N 19.2%. CaHeN20. Calculated: C 64.9; H 5.4; N 18.9%.
2-Methyl-3-cyano-4-quinolone (VII). A mixture of i g (6.5 mmole) of the enamine (I)
and 2.74 g (20 mmole) of the acid (VI) in i0 ml of glacial acetic acid was boiled for 7 h.
The solid which separated was filtered off and washed with water and alcohol to give 0.i g
(8%) of (VII), mp 360-368~ (from DMF) [6]. Found: C 71.7; H 4,4; N 15.2%. CttHeN=O.
Calculated: C 71.9;H 4.3; N 15.5%.
2-Methyl-4-quinolone-3-carboxylic Acid (XVIII and 3-Methyl-!,2,5,10-tetrahydropyrano
[4,3-b]quinoline-l,lO-dione (XIV). A mixture of 1.26 g (i0 mmole) of 'the ester (XII) and
4.11 g (30 mmole) Of the acid (Vl) in i0 ml of glacial acetic acid was boiled for i0 h, eva-
porated, filtered, and washed with alcohol to give 0.32 g of a mixture of (XIII) and XIV).
The mixture was dissolved in 0.02 N NaOH, and the insoluble solid filtered off and washed
with water and alcohol to give 0.08 g (4%) of (XIV), mp 300~ (from DMF). Found: C 68.4;
H 3.8; N 5.9%. CIaH3NO3. Calculated: C 68.7; H 4,0; N. 6.2%.
The mother liquors were acidified with HCI to pH 3-4, and the solid which separated
was filtered off, and washed with water and alcohol to give 0.09 g (4%) of (XIII), rap 239-
243~ (from DMF)[8].

72
~-Cyano-~-(o-ethoxycarbonylphenyl)aminoacrylamide (XVIa). A mixture of 0.6 g (4.3
mmole) of the enamine (XV) and 2.5 g (15 mmole) of the ester (II) in i0 ml of glacial acetic
acid was boiled for 6 h, cooled, and the solid filtered off and washed with water and alco-
hol to give 0.24 g (19%) of (XVIa), mp 227-229~ (from DMF). M +" 259. Found: C 60.3; H
5.2; N 16.5%. C~HI3N30~. Calculated: C 60.2; H 5.0; N 16.2%.
a-Cyano-~-(o-carboxyphenyl)aminoacrylamide (XVIb). A mixture of 0.6 g (4.3 mmole) of
the enamine (XV) and 2 g (15 mmole) of the ester (II) in i0 ml of glacial acetic acid was
boiled for 6 h, cooled, and the solid filtered off and washed with water and alcohol to give
0.24 g (19%) of (XVIa), mp 227-229~ (from DMF). M +" 259. Found; C 57.0; H 3.9; N 18.1%.
Calculated: C 57.1; H 3.9; N 18.2%.

LITERATURE CITED
l~ L. V. Ershov and V. G. Granik, Khim. Geterotsikl. Soedin., No. 7, 929 (1985).
2. L. V. Ershov, S. S. Kiselev, and V. G. Granik, Khim. Geterotsikl. Soedin., No. 4, 538
(1984).
. Organic Synthesis, A. H. Blatt (ed.), Wiley, New York; Chapman and Hall, London (1946),
Coll. Vol. 2, p. 79.
. S. I. Kaimanakova, E. A. Kuleshova, N. P. Solov'eva, and V. G. Granik, Khim. Getero-
tsiklo Soedin.,No. Ii, 1553 (1982).
. K. Sato, M. Ohashi, T. Amakasu, and K. Takeda, Bull. Chem. Soc. Japan, 42, 2319 (1969).
6. R. J. Grout, B. M. Hynam, and M. W. Partridge, J. Chem. Soc., C, 1590 (1969).
7. G. Budzikevich, K. Djerassi, and D. Williams, Interpretation of the Mass Spectra of Or-
ganic Compounds [Russian translation], Mir, Moscow (1966).
. R. T. Coutts and D. G. Wiberley, J. Chem. Soc., No. 6, 2518 (1962).

SYNTHESIS OF 5-OXOINDENO[I,2-b]PYRIDINIUM SALTS

A. Z. Zandersons, V. K. Lusis, UDC 547.821.3'665.07


D. Kh. Mutsenietse, and G. Ya. Dubur

When N-methylated 4-aryl-5-oxo-4,5-dihydroindeno[l,2-b]pyridines are oxidized


with hydrogen peroxide in the presence of perchloric acid, in addition to the
formation of the indenopyridinium perchlorates, cleavage of the dihydropyri-
dine ring occurs, giving the 2-arylideneindan-l,3-dione.

We have previously converted the 1,4-dihydro-isomers of cyclic pyridine derivatives into


the corresponding 1,2-isomers by reducing pyridinium salts [i, 2]. Similar conversions of
polycyclic dihydropyridines such as dihydroindeno[l,2-b]pyridines have not been described.
The aim of this investigation was to develop methods for the synthesis of N-methyl-5-oxoin-
deno[l,2-b]pyridinium salts. The starting materials were 5-oxoindeno[l,2-b]pyridines (I) or
the N-methylated 5-oxo-4,5-dihydroindeno[l,2-b]pyridines (II) [3, 4]. In the case of pyr i-
dines (I), these were heated with methyl toluene-p-sulfonate or dimethyl sulfate. The use
of this classical method for the synthesis of the salts was restricted by preparative diffi-
culties, namely, resinification and the hygroscopicity of the products. When the salts (III)
were obtained as the monosulfates or tosylates, therefore, they were converted into the per-
chlorates by ion exchange by treatment with NaCIO4, since pyridinium perchlorates are read-
ily crystallizable compounds. A method used by us previously [I, 2] for the preparation of
pyridinium salts by the oxidation of N-methylated 1,4-dihydropyridines with hydrogen perox-
ide in the presence of perchloric acid was complicated in the indenopyridine series by the
occurrence of side reactions, i.e., in addition to salt formation, cleavage of the dihydro-

Institute of Organic Synthesis, Academy of Sciences of the Latvian SSR, Riga 226006.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. i, pp. 88-90. January, 1986.
Original article submitted December 3, 1984.

0009-3122/86/2201-0073512.50 9 1986 Plenum Publishing Corporation 73


TABLE I. Properties of Indenopyridinium Perchlorates (III)

Found, % ~Iculated, %
:om- Np, ~ Empirical Yield; %
,ound
C H N
formula

Ilia 272--273 60,0 4,1 3,5 C2aH2oCINOz 60,3 4,4 3,1 55


lllb 210--213 58,8 4,5 3,1 C24H22CINO8 59,1 4,6 2,9 42
Illc 188--190 51,0 3,2 2,1 CmH,gBrCINO7 51,5 3,6 2,6 28
llld 237--240 54,5 3,8 5,.2 CmH I~C1N20~ 54,9 3,8 5,6 19
Ille 184--187 56,0 3,5 3,1 C23H19CI2NO7 56,1 3,9 2,9 27
Illf 230--232 54,5 3,5 3,0 C~4tt2oCIF~NO8 55,0 3,9 2,7 38
lllg 268--270 61,3 4,2 3,6 C~:Hz~ClNO~ 61,8 4,2 3,3 14
Illh 171--174 61,0 4,0 6,5 CmHIaCINaO5 61,4 3,7 6,8 48
llli 208~210 64,7 4,7 5,5 C~HmCIN~O~ 64,2 4,2 5,6 35

pyridine ring took place, which will be the subject of a further communication. Preparative-
ly, in addition to the salts (III), from the reaction mixture there were also isolated ti~e
acid hydrolysis products of (II) (in the case of (lla), 3%, (lib), 32%, and (llc), 10%). In
the oxidation of (lid), in addition to the expected 2-(p-nitrobenzylidene)indan-l,3-dione
(IVd) there was isolated 2-spiro-(2'-indan-l',3'-dione)-3-(4'-nitrophenyl)oxirane (V).
/ (I O Ar
II II ~Ar
~! "- I{ I1 ! .
V :} ....
<iT-" N' cl~_
i(. )i ti
N" CII~
t
II I
H:~%l ,
a-i I;113 c,O~
"HCI04 y] \" ,-4~ '
q,, ,

O s~r

0 / ~ ~O
o ,9
b _ / ~ ....... i,. j ; + i ~, ~; !. ~ ..:' . %;-::7---<( )? --N%
~"/ " " N" "" clI3 " ~' : : CH-Ar
i
IIIa-i Cl-la cPo. 0 V

II, llI a - f R=COOC2Hs, g R=COCH3, h R=CN, i R=CONHC6H~; a , g - - i Ar=C6H~,


b Ar=4-CH~OC6H4,c Ar=4-BrCeH4, d Ar=4-NO.~C6H4, e Ar=2-CIC6H4,f Ar=2-F2CHOC~H4

Clearly, the electron acceptor group in the 2-arylideneindan-l-3-dione activates the


>C=CH group, as a result of which addition of oxygen to this bond takes place under the
reaction conditions, giving the oxirane (V). The structure of (V) was confirmed by ~H and
ZaC NMR, IR, and mass spectroscopy, as well as by direct synthesis. It is noteworthy that
the synthesis of indan-l,3-dione derivatives of oxirane has hitherto been effected in basic
media only [5].
N-Methyl derivatives of 5-oxo-4,5-dihydroindeno[l,2-b]pyridine (II) are fairly readily
oxidized by atmospheric oxygen, since the salt (Ilia) was obtained in 55% yield on prolonged
boiling of (lla) in alcoholic solution acidified with HCIO4 (similarly, 28% of lllb was ob-
tained from lib). The 4-(p-nitrophenyl) derivative of the indenopyridine (lid) did not af-
ford the corresponding salt under these conditions, the reaction product being 2-(p-nitro-
benzylidene)indan-l,3-dione (IVd) (yields 40-60%).
The IR spectra of the 5-oxoindenopyridinium salts (III) show strong absorption for the
5-C0 group at 1735 cm-*. The absorption due to the CO at C(a) in the esters (Ilia-f) merges
with that for the 5-CO group, but in the 3-COCHa derivative (lllg) the absorption at 1712
cm-* is clearly separated. In the IR spectrum of (lllh), two amide bands are seen at 1694
and 1668 cm -I The type of anion in the salts (III) has no effect on these IR bands.

EXPERIMENTAL
PMR spectra were obtained on a Bruker WH-90 spectrometer in DMSO-D6, internal standard
TMS, and IR spectra on a PE 580 B. The compounds (II) were synthesized as described in [4].
The properties of the indenopyridinium perchlorates are given in Tables I and 2.
Synthesis of 1,2-Dimethyl-4-aryl-5-oxolndeno[l,2-b]pyridinium Salts (III). A. The in-
denopyridine (I) (i0 mmole) was heated with 2 ml of dimethyl sulfate (until a neutral reac-

74
TABLE 2. PMR Spectra of 1,2-Dimethyl-4-aryl-5-oxoindeno[l,2-b]
pyridinium Perchlorates (III)

Compound 1-c[-I, 2-cH, iProtons at :.


(~3z~l (s,3m 3-. ,~-A~ ic(6,~_ c(9)
Ill a 4,47 2,84 0,86 ( t 31f}; 7,27--7,60 (m, 5H) 7,78--7,60 (m, 3H);
4,06 (q 2H) 8,32--8.52 (m, IH)
[IIb 4,51 2,88 ,,0l lq~ 3H}; 3,88 (s 3H); 7,79--8,10 (m, 3H);
4,19 ,2H) 7,12 (d 2H); 8,38--8,60 (m IH)
7,42 (d 2H)
IIIc 4,55 2,9l 0,93 (t 3H); 7,71 ~1,, 2H) 7,87--8,12 (r~ 3H)
4,12 !q, 2H} 8,36--8,61 (m, 3H)
IIId 4,52 2,90 0,99 (t 3H): 7,38 (d 2H); 17,87--8,09(m, 3H);
4,17 ~/q, 2H) 7,80 (,d, 2H) 18,42--8,58(m, 1H)
Ill e 4,55 2,94 0,89 ( t 3H); 7,18--7,71 (m, 4H) [7,83--8,09 (m, 3H);
,128 (o. 21]) ]8,42--8,60 (m, IH)
I!If 4,53 2,92 0,89 (~ 3H); 7,18 ('t; IH) /8,40--8,57 (m, IH)
4,10 (q, 2[t) IJh_ f=72,0 Hz] /
7,24--8,09 (m, 7H)
Illg 4,54 2,80 2,09 (s 3I-]) 7,31--7,68 (m, 5H) 7,83--8,03 (m, 3H);
8,40--8,58 (m, IH)
Illh 4,51 3,10 7,57 (s, 5H) 7,69--8,03 (m, 3H);
8,38--8,53 (ra, IH)
llli 4,62 2,94 7,49 ( s 5H): 7,07--7,43 (m, 5H) 7,84--8,31 (m, 3H);
10,79 (s IH) 8,44--8,60 (m, IH)

tion was obtained) for 6-8 h at 60-80~ The mixture was cooled, treated with ether, and
the solid separated and dissolved in the minimum amount of water. The aqueous solution was
saturated with NaCIO~, and the colorless or pale yellow indenopyridinium perchlorate which
separated was filtered off and recrystallized from propan-2-ol. Yield 35-60%. (In the case
of 1,2-dimethyl-3-acetyl-4-phenyl-5-oxoindeno[l,2-b]pyridinium monomethylsulfate, mp 250-
253~ yield 65%).
B. The indenopyridine (I) (3 mmole) and 1.5 g (8 mmole) of methyl toluene-p-sulfonate
were heated at 130-140~ for 12 h. The cooled reaction mixture was treated with dry dioxane,
filtered, and the tosylate recrystallized from chloroform-hexane. (In the case of 1,2-di-
methyl-3-cyano-4-phenyl-5-oxoindeno[l,2-b]pyridinium tosylate, mp 220-223~ yield 69%).
Exchange of the anion for CIO~- in the remaining tosylates was carried out by method A,
yields 40-65%.
C. The N-methyl compound (II) (i0 mmole) was boiled in 80 ml of ethanol with 20 mmole
of hydrogen peroxide (30% aqueous solution) and i0 mmole of perchloric acid (57% aqueous so-
lution) until the red color disappeared (1-4 h). The solvent was removed in vacuo, and the
residue cooled and treated with ether. The perchlorate (III) which separated was filtered
off and recrystallized. The ethereal solution was evaporated to give the 2-arylidene~ndan-
1,3-dione (IV), which was recrystallized from acetic acid. The compound (IVa) was identical
in its physicochemical properties with the authentic indan-l,3-dione derivative [6]. Follow-
ing oxidation of (Ild), the oxirane (V) was isolated from the ether solution (yield 35%).
2-Spiro-(2'-indan-l',3'-dione)-3-(4'-nitrophenyl)oxirane (V). 2-(4'-Nitrobenzylidene)-
indan-l,3-dione (2.8 g, i0 mmole) was boiled for 4 h in 50 ml of ethanol with 2.3 ml of 30%
H202 and 1.3 ml of 57% perchloric acid. The reaction mixture was diluted with water, and
the colorless solid which separated was filtered off and recrystallized from ethanol. The
yield of the oxirane (V) was 1.19 g (65%), mp 217-219~ IR spectrum: 1756, 1723 cm -I (CO).
PMR spectrum: 5.16 (s, IH, 3-H), 7.67-8.11 (m, 6H) and 8.33 ppm (d, 2H) -- aromatic protons.
~ C N~IR spectrum: 63.1 (C(~), 65.7 (C(2)), 192.1 (CO), 190.7 ppm (CO). Mass spectrum:
295 (6) [M] +', 278 (15) [M --)OH]+ , 182 (18) [M -- CO] + , 104 (i00). Found: C 64.9; H 3.2; N
4.5%. CI6HgN05. Calculated: C 65.1; H 3.1; N 4.7%; M 295.

LITERATURE CITED
i* D. Kh. Mutsenietse, V. K. Lusis, and G. Ya. Dubur, Khim. Geterotsikl. Soedin., No. 9,
1225 (1982).
2. V. K. Lusis, A. Z. Zandersons, D. Kh. Mutsenietse, and G. Ya. Dubur, Khim. Geterotsikl.
Soedin., No. 4, 508 (1983).
3. V. Petrov, I. Saper, and B. Sturgeon, J. Chem. Soc., No. 9, 2134 (1949).
4. V. K. Lusis, D. Kh. Mutsenientse, A. Z. Zandersons, I. V. Mazheika, and G. Ya. Dubur,
Khim. Geterotsikl. Soedin., No. 3, 393 (1984).

75
5. M. Weigele, J. P. Tengi, S. De Bernado, R. Czajkowski, and W. Leimgruber, J. Org. Chem,,
41, 388 (1976).
6. A . K . Aren, B. ~. Arch, and G. Ya. Vanag, Dokl. Akad. Nauk SSSR, 13_55, 320 (1960).

AZAINDOLE DERIVATIVES.
67.* SYNTHESIS OF N-SUBSTITUTED
I-BENZYL-4-METHYL-5-CYANO-6-AMINO-7-AZAINDOLES

T. V. Sycheva, O. S. Anisimova, UDC 547.759:543.87:543.51


and L. N. Yakhontov

N-substituted l-benzyl-4-methyl-5-cyano-6-amino-7-azaindoles have been synthe-


sized from the respective l-benzyl-4-methyl-5-cyano-6-chloro(and 6-hydroxy)-7-
azaindoles. The effect of the 5-cyano group on the oxidation-reduction proces-
ses accompanying nucleophilic replacement of chlorine in 6-chloro-7-azaindoles
by primary and secondary amines has been considered. 7-Azaindoline compounds
were dehydrogenated by chloranil to N-substituted l-benzyl-4-methyl-5-cyano-6-
amino-7-azaindoles.

The selective effect of various 6-amino derivatives of l-benzyl-7-cyano-azaindoles on


central serotoninergic systems has been described in [2]. In order to broaden the study of
the antiserotonin effects of isomeric azaindoles it was of interest to obtain the hitherto
unknown 6-amino derivatives of l-benzyl-5-cyano-7-azaindoles (I). The starting material for
the synthesis of compounds la-g was l-benzyl-4-methyl-5-cyano-6-chloro-7-azaindoline (II)
[i].
We have shown [3, 4] that the nucleophilic replacement of chlorine at position 6 in the
7-azaindoline system is a serious problem. For these reactions in such a system, because of
the electron density distribution extremely severe conditions are needed, e.g., 6-chloro-7-
azaindolines that do not contain a r group react with amines only at temperatures of at
least 250~ , Under such severe conditions, normal nucleophilic replacement is accompanied by
redox processes, so that along with the 6-amino-7-azindolines there are formed the respective
6-amino-7~azaindoles and 7-azaindoles unsubstituted at position 6. The amounts of the latter
are determined by the nucleophilicity of the amine and the redox potential of the azoindoline
compound [3, 4].
The presence of a cyano group ortho to chlorine in l-benzyl-6-chloro-7-cyano-5-azaindol-
ine,/,~hich is distinguished b y a higher redox potential than would be expected, increased the
reactivity of the chlorine, and enabled it to undergo nucleophilic substitution by various
other amines at lower temperature (180-185 ~ without the occurrence of redox reactions [2].
An analogous effect of an ortho-cyano group was observed in our case. The chlorine in
compound II undergoes nucleophilic substitution with most primary and secondary aliphatic
and heterocyclic amines at 180-185 ~ to form N-substituted l-benzyl-4-methyl~5-cyano-6-amino-
7-azaindolines (IIIa-e) in high yield (77-87%). Only in the case of the sterically more
hindered di-n-butylamine is the substitution less complete (55%) under these conditions, and
about 35% of the starting chloroderivative II is recovered unchanged. With still weaker nu-
cleophiles -- aromatic amines of the aniline type -- compound II does not react at all, not
only at 180-185 ~ but is recovered practically unchanged even at 250 ~ Raising the temper-
ature to 280-290 ~ causes significant thermal decomposition of II. However with a stronger
nucleophile -- viz., hydrazine -- II reacts already at 110-120 ~ to form l-benzyl-4-methyl-5-
cyano-6-hydrazino-7-azaindoline (IV).
*For communication66, see [i].

S. Ordzhonokidze All-Union Scientific-Research Institute for Pharmaceutical Chemistry,


Moscow 119021. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. i, pp, 91-96,
January, 1986. Original article submitted February 21, 1985.

76 0009-312286/2201-0076512.50 9 1986 Plenum Publishing Corporation


1t 3 Ctlj

N C -.
7
'.. NC.
!
~-~
,7. .

0" " N N N
It ! E ~ "' I
C H ~C'6H ~ (ll.CeH ~
VI III
,r
Cli 3 CII~ 9 " CIt~E CIi3

NC ;~ NC. .~ I

H N ' " - e~. -- "'~- i" CI N N . "N ~ "~'N/ ' N " "N ~ "N
I I I 1~ I" I I
NH 2 Cii..Cr CH.2CJ|. a CIIZ(T6TT~ {!ti~C~II~
IV 11 1 V

I, III a) RR'N = morpholino; b) RR"N = piperidino; c) RR~N = pyrolidino;


d) RR'N = (C2H 5)2N- ; e) RR'N = n - C ~ H g N H ; f) RR'N = (n-C~Hg)2N_; g)
RR'N = CsH 5 CH2NH.

Moreover, in the reaction of chloroazaindoline II with benzylamine the previously noted


[5] lower redox potentials of 7-azaindoline compounds as compared with the 5-azindoline ana-
logs caused the formation not of 5-cyano-6-benzylamino-7-azaindoline derivative lllg, but of
the corresponding oxidized compound, viz., l-benzy!-4-methyl-5-cyano-6-benzylamino-7-azai n_
dole (Ig). In contrast to these previously described redox reactions between a 6-chloro-7-
azaindoline without a cyano group and an amine, where along with a 6-amino-7-azaindole an
azaindoline compound dehalogenated at position 6 is always obtained [3, 4], in the reaction
of compound II (5-cyano-6-chloro-7-azaindoline derivative) with benzylamine not even traces
of l-benzyl-4-methyl-5-cyano-7-azaindoline (V) could be detected in the reaction mixture.
The corresponding 6-benzylamino-7-azaindoline lllg was also entirely absent, but the amino-
azaindole Ig was separated in 81% yield. Evidently in this case the redox process is dif-
ferent from that previously observed [3, 4], and needs further intensive study.
In connection with publications on the direct replacement of the oxo group in azine sys-
tems by secondary amine residues [6, 7] we studied the analogous reaction as exemplified by
the reaction of l-benzyl-4-methyl-5-cyano-6-hydroxy-7-azaindoline (VI) with piperidine and
phosphorus pentoxide. The yield of the 5-cyano-6-piperidino-7-azaindoline compound lllb was
]0%; this is substantially lower than the overall conversion of VI to the aminoitrile lllb
via the corresponding 6-chloro derivative II. The 7-azaindoline compounds llla-f were de-
hydrogenated to the 7-azaindoies llla-f by chloranil in boiling xylene in 78-88% yield.
Study of these N-substituted compounds la-g* showed that only compound Id shows weak
central antiserotonin activity in 50 and i00 mg/kg doses (internal) in mouse tests, reducing
the number of head agitations caused by administration of 300 mg/kg of 5-hydroxytryptophane.
The mass spectra of compounds la-g and llla-f showed molecular ions, the mass numbers
of which confirmed the proposed structures. For all these compounds the most characteristic
decomposition is the formation of benzyl cation (m/z 91), to which the peak of maximum in-
tensity in the spectra of Ib-f and Ilia, c, e, f corresponds. The other decomposition route
of the molecular ions is the stepwise detachment of the RR'N substituent, as a result of
which the following ion peaks appear: [M-- CH=OH] +, [M -- C2H~OH]+, [M -- C3H50] + (la, Ilia);
[M -- C2H,] +, [M-- C4H,] + (Ib, lllb); [M-- C2H~] +, [M-- C,HT] + (Ic, lllc); IN-- CH,] +, [M --
C21I,]+, [M-- NC2H,] + (Id, llld); [M-- C3H7] +, [M-- C~Hg] + (le, f, llle, f).
The spectra of Ib, c and lllb, c in which NRR' are pyrolidine and piperidine residues,
show ion peaks with m/z 70 and 84 that correspond to fragments of the respective cyclic a-
mines.
The characteristic feature of the decomposition of the azaindoles la-f is a certain de-
crease in the peak intensity of the molecular ions as compared with the respective substi-
tuted azaindoline llla-f. The increase in peak intensity of benzyl cation observed here
causes the IM/ICHzC6H 5 ratio to decrease. These data, which are shown in Table i, show that
the N-benzyl group is easier to detach in the azaindole compounds I than in the azaindoline
compounds III.
*Carried out in the pharmacology laboratory of the All-Union Scientific-Research Institute
for Pharmaceutical Chemistry (Academician M. D. Mashkovskii, manager) by Canad. Med. Sci.
N. I. Andreeva, to whom the authors express sincerest thanks).

77
-,4
co

TABLE i. N-Substituted l-Benzyl-4-methyl-5-cyano-6-amino-7-azalndolines and Azaindoles

Com- [.t~_, ~ Found, % Empirical Calculated, % IR soectrum,[c{a_


1 ) Imax I
I UV spectrum,( Mass spectr~n
pound (solvent) formula ,,[ Inn l o g e Yield, %
i mlz
C H N C H N CN NH [ [ (intensity, %) IM/I CH~Cnl'I~
I
Ilia 136--137 ~2,7 5,2 17,0 C2oH=N40 72,3 6,0 16,9 2190 -- 335 (0,8), 334 (100), 303 (21), 162 81
(hexane- 255 (0,74), 289 (17), 277 (34),
benzene) 205 (0.79) 276 (21). 91 (62)
IIIb 85--86 T6,O 7,2 17,1 CmH24N4 75.9 7.2 16.9 2190 -- 339 (0,75), 332 (100), 303 (11). 430 87
312 (0,54), 277 (8), 276 (17),
(hexane) 257 (0.85) 91 (23). 84 (9)
IIIc 121--122 ~5,7 7,0 17,8 C2oH=N4 75,5 0,9 17,5 2180 -- 347 (0,8l). 318 (100), 290 (43). 100 76
hexane 296 (0.51), 289 (59). 275 (12).
244 (0.74), 263 (~ 91 (100),
240 (0,73) 70 (25)
IIId 75--76 ~5,2 7,6 17,8 C~oH24N4 75 7,5 17,5 2190 -- 346 (0,81), 320 (1O0), 305 (90), 250 81
(hexane) 297 (0.57), 291 (50). 277 (70),
258 (0,80), 91 (40)
24O (O,77)
Ilia 145--146 ~'5,0 7,7 17,5 C2oH24N4 75,0 7.5 17.5 2180 335O 347 (1,03), 32O (97), 291 (17), 97 86
hexane 292 (0,47), 278 (23), 277 (87),
benzene 247 (0.61) 263 (14), 91 (100)
Ill" f 39 40* 76.8 7,8 14,6 C24H32N4 76.6 8.5 14,9 2180 -- 348 (0.75), 376 (14), 334 (23), 14 55
298 (0,51), 333 (41), 319 (14),
259 (0,76) 291 (55), 277 (36),
91 (10o)
la 118--119 72,7 6,2 16,8 C2olqzoN40 72,3 6,0 16,9 2210 -- 334 (0,26), 332(100), 3Ol (23), 137 78
(hexane): 266 (I,20), 275 (42), 91 (73)
248 (I,27)
Ib 114--115 76,6 6,~ 16,9 C~tII~2N4 76,4 6,7 17,0 2210 -- 338 (0,25), 330 (31), 301 (12), 31 83
(hexane) 270 (I,II), 274 (7). 262 (7).
248 (I,10) 91 (100), 84 (27)
Ic !04--105 76,1 6,4 17,7 C2oH2oN4 76,0 6,3 17,7 2200 -- 3.58 (0,36), 316 (90), 287 (72), 90 88
hexane 270 (1,39). 273 (8), 261 (14),
244 (I,05) 91 (100), 77 (31)
Id 48--49 75,6 7,(: 17.5 C2oH2~N4 75,5 6,9 17,6 2200 -- 353 (0,29), 318 (19), 303 (38), 19 86
(hexane) 272 (1,28), 290 (19), 275 (17),
244 (I,07) 91 (100)
ie 98--99 75,4 6,8 17.6 C2oH.22N4 75,5 6,9 17,6 2190 3380 349 (0,41), 318 (25), 289 (17), 25 88
(hexane) 262 (I,36), 275 (6{}), 262 (13),
242 (I,08) 91 (100)
If 60--61" 77,1 8,(~ 14.9 C24H3oN4 77.0 8.0 15,0 2180 -- 354 (0,28), 374 (4), 331 (18), 86
272 (I,05), 289 (16), 275 (14),
244 (0,93) 91 (100)
Ig 186--187 78.4 5,7 15,7 C~3H2oN4 78,4 5.7 15,9 2200 3380 350 (0.38), 352 (100), 275 (11), 81
265 (1,01) 261 (20), 106 (22),
91 (65)

WPurified by chromatography,
EXPERIMENTAL
Mass spectra were obtained on a Varian MAT-II2 instrument with direct introduction of
sample into the source. The energy of the ionizing electrons was 70 eV, the temperature of
the ionizing chamber was 180 ~ PMR spectra were obtained on a JNM-4H-IO0 instrument, with
TMS internal standard; IR spectra, on a Perkin-Elmer 457 spectrometer in mineral oil; UV
spectra, on a Carl Zeiss (Jena) Specord M-40 spectrophotometer in chloroform.
The properties of compounds la-g and llla-f are shown in Table I.
General Synthesis of N-Substituted l-Benzyl-4-methyl-5-cyano-6-amino-7-azaindolines
(Ilia-e). A mixture of 3 g (10.6 mmole) of azaindoline II and 15 ml of amine was heated in
a 55 ml steel autoclave for i0 h at 180-185 ~ The reaction product was treated with i00 ml
of water and 30 ml of 50% aqueous potassium hydroxide and extracted with chloroform. The
chloroform extract was dried with magnesium sulfate and evaporated in vacuum, and excess
amine was removed by addition of toluene and vacuum evaporation. The residue was recrystal-
lized from hexane or a 3:1 hexane--benzene mixture.
l-Benzyl-4-methyl-5-cyano-6-(di-n-butylamino)-7-azaindoline (lllf) is synthesized as
described in the preceding test. After removal of chloroform and excess di-n-butylamine the
residue was ground with hexane, and the residue of chloroazaindoline II was filtered off.
The material did not depress the melting point of an authentic sample, and has an identical
IR spectrum. The hexane filtrate was evaporated and the residue was placed on a column (d
30 mm, h 50 cm) with i00 g of 40/100 ~ silica gel. The column was washed with 200 ml of 9:1
hexane--benzene, then with 1.5 liters of 7:3 hexane--benzene which eluted 2.1 g (53%) of aza-
indoline lllf; then with 500 ml of i:i hexane--benzene which eluted 0.06 g of chlorozazindol-
ine !I. Total yield of II, 1.06 g (35.3%).
l-Benzyl-4-methyl-5-cyano-6-hydrazino-7-azaindoline (IV). To a solution of 3 g (Ii
mmole) of II in 45 ml of butanol at 110-112 ~ was added four i.I ml portions of hydrazine hy-
drate over i h. The reaction mixture was stirred at 110-112 ~ for i h and cooled to room
temperature. The precipitate was filtered off and washed with 40 ml of benzene. There was
obtained 1.3 g (44%) of IV. Colorless crystals, mp 256-257 ~ (from methanol). The material
was soluble in DMFA and hot alcohols; insoluble in water, acetone, ether. PMR spectrum in
DMSO D~: 2.33 (s, 3H, 4-CH3)~ 2.86 (t, 2H, 3-CH2)~ 3.44 (t, 2H, 2-CH2); 4.53 (s, 2H, CH2-
C~Hs); 4.68 (br. s., 2H, NH2NH); 7.25-7.35 (m, 5H, CH2C~Hs); 11.23 ppm (s, IH, NH2-NH. Mass
spectrum: 279 [M] +" (I00); 263 [M--NH2] + (9); 202 [M-- Ph] + (45); 91 [PhCH2] + (i00). Found:
C 68.6; H 6.3; N 24.7%: C~H27Ns. Calculated: C 68.8; H 6.1; N 25.1%.
l-Benzyl-4-methyl-5-cyano-6-piperidino-7-azaindoline (lllb). A mixture of 0.4 g (1.5
mmole) of hydroxyazaindoline VI, 0.21 g (1.5 mmole) of phosphorus pentoxide, and 2 ml of
piperidine was held for i0 h at 170-180 ~ in a steel autoclave. The reaction product was
treated with 50 ml of water and 20 ml of 50% potassium hydroxide solution, and extracted
with chloroform. The chloroform ~xtract was dried with magnesium sulfate and evaporated in
vacuum. The residue was treated with 40 ml of boiling benzene, and the residue thereof was
filtered off to give 0.22 g (55%) of starting VI. The benzene solution was evaporated and
the residue was recrystallized from 3:1 hexane--benzene. There was obtained 0.05 g (10%) of
lllb, which did not depress the melting point of an authentic sample obtained by the method
described above. Rf values of the two materials were identical in chloroform (0.66) and
benzene (0.13).
i-Benzy!-4-methyl-5-cyano-6-benzylamino-7-azaindole (Ig). A mixture of 1.7 g (6 mmo!e)
of compound II and 9 ml of benzylamine was stirred for i0 h at 180-185 ~ in a flask with a
reflux condenser. The cooled reaction mixture was treated with 50 ml of water and 20 ml
of 50% aqueous potassium hydroxide and extracted with chloroform. The chloroform extract
was dried with magnesium sulfate and evaporated in vaduum; excess benzylamine was removed by
addition of toluene and evaporation in vacuum. The residue was recrystallized from i:i hex-
ane--benzene. There was obtained 1.71 g (81%) of azalndole Ig.
General Method for Synthesizing N-Substituted l-Benzyl-4-methyl-5-cyano-6-amino-7-aza-
indoles (ia-e). A mixture of 6.5 mmole of azaindoline IIIa-f and an equal weight of chlora-
nil in 50 ml of xylene was boiled for 1.5 h. After cooling the xylene solution was washed
successively with 150 ml of 10% sodium hydroxide solution and three 150 ml portions of wa-
ter, dried with magnesium sulfate, and evaporated in vacuum. The residue was recrystallized
from hexane.

79
l-Benzyl-4-me~hyl-5-cyano-6-(di-n-butylamino)-7-azaindole (If) was synthesized as de-
scribed in the preceding experiment. The residue after evaporation of xylene was placed on
a column (30 mm diameter, 20 cm high) with 90 g of 40/100 ~ silica gel. The column was
washed with 100 ml of hexane and 300 ml of 9:1 hexane-benzene, and 1.6 g of If was eluted.

LITERATURE CITED
l, T. V. Sycheva and L. N. Yakhontov, Khim. Geterotsikl. Soedin., No. I, 84 (1985).
2. V. A. Azimov, N. N. Bychikhina, A. I. Polezhaeva, M. D. Mashkovskii, and L. N. Yakhon-
toy, Khim.-farm. Zh., No. 5, 40 (1980).
3. L. N. Yakhontov, D. M. Krasnokutskaya, and A. N. Akalaev, Dokl. Akad. Nuak SSSR, 192,
119 (1970).
4. L. N. Yakhontov, D. M. Krasnokutskaya, A. N. Akalaev, I. N. Palant, and Yu. I. Vainsh-
rein, Khim, Geterotsikl. Soedin,, No. 6, 789 (1971).
5. I. N. Palant, Yu. I. Vainshtein, D. M, Krasnokutskaya, and L. N. Yakhontov, Khim. Geter-
otsikl. Soedin., No. 6, 773 (1973),
6. E. A. Arutinyan, V. I. Gunar, E. P. Gracheva, and S. I. Zav'yalov, Izv. Akad. Nauk SSSR,
Set. Khim., No. 2, 445 (1968).
7. E. A. Arutinyan, V. I. Gunar, and S, I. Zav'yalov, Izv. Akad. Nauk SSSR, Ser. Khim., No.
4, 953 (1970).

SYNTHESIS AND SOME REACTIONS OF 4-NITRO DERIVATIVES


OF IMIDAZO[4,5-e]PYRIDIN-2-ONES

Yu. M. Yutilov and I. A. Svertilova UDC 547.783'821:542.958.1:543.422.25

Imidazo[4,5-c]pyridine and its N-methyl derivatives do not undergo nitration,


but the 2-oxo derivatives of these compounds are easily nitrated when heated.
Some properties of the resulting 4-nitroimidazo[4,5-c]pyridin-2-ones have been
studied.

The introduction of a nitro group into the imidazo[4,5-c]pyridine molecule has not been
previously studied. However, work in this direction is of considerable importance in devel-
oping the chemistry of this heterocycle.
We have shown that imidazo[4,5-c]pyridine (I) and its i- and 3-methyl substituted deriv-
atives (II, III) are inert to nitrating mixtures. These compounds do not change when treated
with nitric acid or potassium nitrate in concentrated sulfuric acid and high-strength oleum
at temperatures up to 200 ~ The same result was obtained after heating the dinitrate of base
I with gaseous sulfur trioxide at I00 ~ For this reason it was of interest to carry out the
nitration of 2-oxo derivatives of compounds I-III, especially because with the analogous sub-
stituted imidazo[4,5-b]pyridines the strong activating effect of the oxo group appears in
this reaction [i].
Nitration of 1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (IVa) with nitrating mixture
proceeds at about i00 ~ to form the mononitro derivative in almost quantitative yield. For
example, the PMR spectrum of the product in CF3COOH solution (Table i) has two doublets of
aromatic protons (8.03 and 8.63 ppm), the spin--spin coupling constants (SSCC) of which, at
6.5 Hz, unambiguously demonstrate their vicinal location; this is possible only in 4-nitro-
1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (Va). In the spectrum of 7-nitroimidazo[4,5-c]-
pyridin-2-one (VI) the pyridine ring protons do not show spin-spin coupling.

Institute of Physical Organic Chemistry and Coal Chemistry, Academy of Sciences of the
Ukrainian SSR, Donetsk 340114. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No.
I, pp. 97-102, January, 1986. Original article submitted December i0, 1984.

80 0009-3122/86/2201-0080512.50 9 1986 Plenum Publishing Corporation


TABLE i. PMR Spectra of N e w l y Synthesized Compounds
,,,,,

Com- Chmeical shift, 6 , ppm


SSCC,
pound So ivent Hz
C(? ) N- and O-alky!
C(4) C(6)
groups
va CF6COOH -- 8,63 (d, 1H) S,03 (d, 1H) ,/67=6,5
J DMSO .D6 -- 8,47 (d 1H) 7,87 (d., IH) Ja;=5,0
Vb CFaCOOH -- 8,73 ~d, IH) 7,97 3s Is, 3H, N~)--CHz)
(d,, IH) I67=5,4
DMPA - D r -- 8,19 (d, IH) 7,56 3,43 s. 3I-1, N(,)--CH3)
Id, I H) J67 =- 5,2
ve CFaCOOH -- 8,68 (d, IH) 8,t5 (d, 1H)4,02 (s, 3H, N(3)--CHa) ,/67=5,0
DMSO - D -- 8,08 (d,IN) 7,38 (d. 1H)3,33 (s, 3H, N~3~--CH3) J67=5,2
Vd CFaCOOH -- 8,63 ( d , 1H) 7,87 3,95 ,,,@,3H,
(d, 1}1) ,/67=6,3
Nr
3,77 is, 3H, N~I)--CtI3)
9 DMSO -D,3 -- 8,20 (d, ltI) 7,63 (d, I H) 3,42 ~ 3H, Joy=5,2
Nm--CHa);
3,38 s, 31-1, N(3)--CI-Ia)
w [5] CFaCOOH 9,40 ( , IH) 9,00 ts. IH) ,/4G~ 0
VII a CFaCOOH -- 7,86 d,
IH) 7,09 d, lit) ,/67 = 6,9
VII b CF3COOH -- 7,74 d,IH) !6,94 (d, IH) 3,60 r 3H, N,l)--CI-1a) ,/67= 7,0
VII c CFaCOOH -- 7,76 (d,
1H) 7,04 (d, 1}t) 3,87 (s, 3H, N,3i--CHz) ,/67=6,9
VII d CFaCOOH -- 7,78 (d.
IH) 7,03 (d, IH) 3,89 ~, 3H, 167=6,9
Nr
3,63 ~, 3H, N~I)--CH3)
VIII b CFaCOOH -- 8,02 (d, ltI) 7,34 (d, IH) 3,80 s , 3I-t, IG7=7,0
N,31--CHa) ;
1,65 {s, 3H,
N(I)--CHa) ;
4,49 ~S. 311, O--CH3)
VIII e CFaCOOH -- 7,98 (d, 1H) 7,31 (d, lit) 3.82 s. 3H, ,/67-- 7, l
N(3)--CH3); I<~ = 6,8
3,66 ts, 31-1,
N~--Clta);
4,76 ( q, 21t,
O- -CH~--);
1,70 {t 3II,C--CHa)
VIII d CFaCOOH -- 7,98td, 1H) 7,31 (d, Ill) ~,85 ~s 3H, JGr= 6,6
N(a~--CHa); ,/~ = 6,4
3,65 S~ 31-t, J~v = 7,4
N, ,~--CHa);
4,63 (t, 2H,
O--CH2--) ;
2,06 (m, 2H,
C--CIt~--C) ;
1,17 it, 3H, C--CI-{a)
VIII e CFaCOOH -- 8,01 (d, IH) 7,31 (d, lil) 3,77 s, 3H); ,/87=6,8
N,3~----CH~) ; 1~=5,6
3.60 (s, 3H, lv~ = 6,0
No )--s ;
4.67 I% 21-I,
O--CH2--) ;
2,13--1,40 (ra, 4H,
C---CH_~--CH2--C) ;
1,01 it, 3H, C--CHa)

Analogously to the formation of Vb, the 1-methyl derivative of base Iva also nitrates
(iVb) [2]. But the introduction of a nitro group into 3-methylimidazopyridin-2-one (IVc)
requires more severe conditions; the reaction goes at 125-130 ~ to give 4-nitro-l,3-dihydro-
2H-imidazo[4,5-c]pyridin-2-one (Vc) in good yield. The PMR spectra of Vb, c resemble that
of Va, and are distinguished from it by the N-methyl signals (Table i). It is important to
note that aside from the substances mentioned, no nitro derivatives of other structure could
be detected in the nitration products of bases IVa-c. All this indicates that the reaction
under consideration is highly selective. Of tile two free a-positions in the pyridine ring
of IVa-c, only C(,) undergoes attack by a nitrating agent. Even in the case of IVc, where
the N(3)-methyl group shields the reaction center, the 4-nitro derivative forms. Further
increase in the shielding effect of the N(3) substituent, e.g., in 3-ethylimidazo[4,5-c]-
pyridin-2-one (IVe), stops the reaction at position 4 completely, but it does not promote
the entrance of the nitro group at the other unoccupied e-position of the pyridine ring,
viz., at C(6).

81
TABLE 2. 4-Substituted Imldazo[4,5-c]pyridin-2-ones
, i,,

I Cas

] C H
!

Va ,lO0 J 39,8 2,5 31,0 C~li~NoO~ 40.0, 2,2 3LJ 9~ (A).99 (B)
Vb 309--,3101 43,6 3,3 29,1 C~H~N4Os 43,3 3,1 28,9 9:3{A),96 (~)
Vc 274~275 [ 43,1 2,9 28,7 C71{eN4OII 43,3 3. I 28,9 77 [B)
Vd 225 46, I 4,0 27,1 Cal'lsN~Os 46,21 3.9 26,9 90(A),98{ )
Vlla 309--31( 47,8 3,9 37,2 C~I'IBN~O 48,0 4,0 :37,3 99,9 (B)
vIIb 360 50,9 5,2 33,8 Cyt'i~N40 51,2 4,9 34,1 99,9
VIIc 242--24~, 51,0 5,3 33,7 CrHaN40 51,2 4,9 34, l 9fi
Vlr" 240 53,8 5,8 31,1 Csl,i.iN40 53,9 5,7 31,4 92 (A),82 ( )
Villa 310--311 53,9 5,2 23,3 C~I-19N,~O2 53,6 5,1 23,5 80
VllIb 144-~145 55,9 5,8 21.7 C91'1,N302 55,9 5,7 21,8 99,9
Vllle 78--79 58,1 6,4 20,2 Clot-I~sNsO~ 58,0 6,3 20,3 95
Vllld 75--76 59,8 6,8 18.9 C.HIsNaO~ 59,7 6,8 19,0 94
VIIle 50--51 61,2 7,2 18.0 CI2H=rN~O~ 61,3 7,3 17,9 85

*Compounds Vlla,c recrystallized from water, Va from DMPA, Vb


from water or ethanol, Vc from nitromethane, Vd, Vlld from eth-
anol, Villa from water or nitromethane, Vlllb-e from hexane,
Vllb was reprecipitated from weak acid solution by ammonia.

The nitro compounds Va-c (Table 2) are high melting and insoluble in many solvents.
Since they are weak acids, however, they dissolve readily in aqueous alkali to give yellow
solutions. When such solutions are treated with dimethyl sulfate at room temperature, a
compound forms with mp 224-225 ~ in high yield that is insoluble in alkali but soluble in
alcohol; its PMR spectrum contains methyl signals (3.78 and 3.96 ppm in CF3COOH). This
material is also obtained with bases Vb, c are methylated with diazomethane in nitromethane
medium. We therefore assign this compound the structure of 4-nitro-l,3-dimethyl-l,3-dihy-
dro-2H-imidazo[4,5-c]pyridin-2-one (Vd).

1.. F. r ' -- N .R .yfi~. ......... N . R " 1- CtI=


.~" \, ___N ~

iv, a-e v a-d vlla-d VIII a-fi~

IV, V, VII a, h e R=H, b, d R=CHa; g b R'=H, e .d R'=CHo, e RI=C2Hb;


VIII aR=H, b R=CHa, e R=C2H6, dR=nCaHT, e R=n.C4H9

All the nitro compounds V are easily converted to the respective amines Vlla-d by such
reducing agents as iron, sodium sulfide, hydrazine, and hydroiodic acid. The two latter re-
agents give especially good results. Moreover when Va-d are reduced by hydrazine hydrate no
catalyst is needed and the amine yields approach quantitative [3].
4-Nitro-l,3-dimethylimidazo[4,5-c]pyridin-2-one, Vd, can replace the nitro group by a
hydroxy or alkoxy group, similar to what occurs with 2- and 4-nitropyridines [4], Such a
conversion is easily carried out by heating Vd with water or the appropriate alcohol in the
presence of alkali. The properties of the resulting 4-hydroxy- and 4-alkoxy-l,3,-dimethyl-
1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-ones (VII) are shown in Table 2. In the PMR spectra
of bases VIIIb-e, besides the coublets of the aromatic protons at positions 6 and 7 and the
N-methyl singlets, the signals of the O-alkyl hydrogens also appear (Table I),

EXPERIMENTAL
PMR standards were obtained on Tesla BS-467 (60 MHz) and Varian XL-IO0/15 (I00 MHz) in-
struments; internal standard, TMS.
The properties of V, VII, and VIII are shown in Table 2.
Reaction of Nitrating Mixture with Imidazo[4,5-c]pyridine (I) [6] and Its i- and 3-
Methyl Derivatives (II, I!I ) [7]' A. A mixture of 0.36 g (3 mmole) of compound I, 2.1 g
of U=SO4 (d 1.86) and 0.6 g (9.5 mmole) of HNO~ (d 1.50) was heated in a sealed glass tube
at 170-180 ~ for 5 h. The contents of the tube were poured on ice and neutralized with po-

82
tassium hydroxide to pR 6-7. The colorless precipitate was filtered off, dried, and recyrs-
tallized from dioxane. There was isolated 0.3 g (85%) of the starting compound, mp 167-168 ~
B_~. A mixture of 2.38 g (20 mmole) of base I and 2.2 ml of HNOs (d 1.35) was evaporated
on a boiling water bath, and the residue was recrystallized from 2 N HNO,. There was ob-
tained 4.4 g (90%) of the dinitrate of I (prisms), mp 220-221 ~ (with decomposition). Found:
C 29.3; H 3.0; N 28.6%. C6HbN3.2HN03. Calculated: C 29.4; H 2.9; N 28.6%.
A mixture of 2.5 g (i0 mmole) of I dinitrate and 6 g of 60% oleum, prepared at 2-5 ~
was heated in a sealed tube at 100 ~ for 2 h. After cooling the contents of the tube were
poured on ice and neutralized to pH 6 with sodium carbonate solution. The precipitate was
filtered off, dried, and recrystallized from dioxane to give 0.8 g (67%) of imidazopyridine
I, mp 167-168 ~ The mother-salt solution was evaporated almost to dryness and washed with
boiling alcohol (3 20 ml). The aqueous alcohol solution was evaporated to dryness, the
residue was washed twice with hot alcohol, and the extract was evaporated. Recrystalliza-
tion from dioxane gave an additional 0.30g (25%)of I, mp 165-167 ~
C_:. Into the inner tube of a straight Liebig condenser held horizontal was placed 1 g
(4 mmole) of imidazo[4,5-c]pyridinium dinitrate, and gaseous sulfur trioxide was introduced
while water vapor at i00 ~ was passed through the jacket. After 2 h heating the tube contents
were dissolved in 5 ml of water, and the solution was neutralized to pH 6 and evaporated to
dryness. The solid residue was washed with alcohol (3 5 ml), the solution was evaporated
to dryness, and the residue was recrystallized from dioxane. There was obtained 0.44 g (94%)
of compound I, mp 168-169 ~ (according to [6], mp 169,170~
In all the experiments the isolated base samples did not depress the mp in a mixture
with an authentic sample of I.
The ability of 7-nitroimidazo[4,5-c]pyridine (IX) [8] and similar nitro compounds to
give an intense yellow color in alkaline medium was used for the qualitative detection of
small amounts of nitration products of compound I. In no test did alkalization of reaction
mixture, mother liquors, or unpurified unreacted I give a yellow color, or give reason to
speak of the presence of nitro compounds.
D. A mixture of 0.27 g (2 m/Role) of base If, 1.80 ml of H~SO~ (d 1.86), and 0.33 ml of
HNO3 (d 1.50) was heated in a sealed tube at 200 ~ for 4 h. After cooling the mixture was
poured on ice and made strongly alkaline with 40% sodium hydroxide solution. The oil that
separated crystallized when cooled. The precipitate was filtered off and dried. Reerys-
tallization from i:i benzene-hexane gave 0.22 g (81%) of starting compound II, mp 111-112 ~
(according to [7], mp 111.5-112.5~
Nitration of 3-methylimidazopyridine III was attempted under similar conditions. After
the mixture was heated, 88% of the starting compound was separated, mp 101-102 ~ (from ben-
zene) (according to [7], mp 101-101.5~
4-Nitro-3,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (Va). A. To a solution of 2.0 g
(14.8 mmole) of base IVa [5] in 8 ml of concentrated H2SO~ was a-dded 1.50 g (14.8 mmole) of
potassium nitrate in 8 ml of concentrated H2SO~ with cooling in ice, and the mixture was
heated for 3 h at 100 ~ . The mixture was cooled, poured on ice, and neutralized with aqueous
ammonia. The precipitate was filtered off, washed with water and dried. Yield, 2.6 g.
B_z. To a solution of 60.0 g (440 mmole) of base IVa in 220 ml of concentrated H=SO~ was
added a mixture of 52 ml of HNO3 (d 1.50) and 52 ml of concentrated H2SO~ dropwise at 4-5 ~ .
After being held at room temperature for 0.5 h the reaction mixture was heated for 2 h in a
boiling water bath. The cooled mixture was poured on 1 kg of ice and neutralized with dry
ammonium carbonate, and finally w~th ammonia to pH 5. The precipitate was filtered off,
washed with cold water, and dried. Yield, 79.2 g,
4-Nitro-l-methyl- and 4-nitro-3-methvl-l,3,-dihydro-2H-imidazopyr2dines (Vb and Vc)
were obtained similarly, but in [5] compound IV was nitrated at 125-130 ~ .
4-Nitro-l,3,-dimethyl-l,3-dihYdro-2H-imidazo[4,5-c]pyridin-2-one (Vd). A. To a mix-
ture of 1.0 g (5.5 mmole) of compound Va and 0.8 g (14.3 mmole) of potassium hydroxide in
13.5 ml of water was added ].3 ml (13.4 mmole) of d:[methyl sulfate dropwise with vigorous
stirring, at such a rate that the temperature of the reaction mixture did not exceed 30-32 ~ .
After 10-15 m2n a precipitate formed. The mixture was stirred another 0.5 h at room temper-
ature, 1 ml of 8% KOH solution and 0.6 ml (6.2 mmole) of dimethyl sulfate were added, and

83
the mixture was kept for i h. Then another 1 ml of 8% KOH was added, and the mixture was
left overnight. The precipitate was filtered off, washed with water, and dried. Yield,
1.04 g.
B._.. To a suspension of 0.32 g (1.65 mmole) of compound Vb in a solution of 0.16 g (4.0
mmole) of NaOH in 30 ml of water was added 0.40 ml (4 mmole) of dimethyl sulfate dropwise
with stirring, After holding for 0.5 h, a solution of 0.2 g of sodium hydroxide in 2 ml of
water, and 0.40 ml of dimethyl sulfate were added and the mixture was left overnight. The
bright yellow precipitate was filtered off, washed with water, and dried. Yield, 0.!7 g
(50~).
C__~. Into a suspension of 0.20 g (i mmole) of compound Vb in 1.5 ml of nitromethane was
poured 1.2 ml of a 4% ether solution of diazomethane and the mixture was held for 1 day at
10-15 ~ . After the ether was distilled off the residue was recrystallized from alcohol.
Yield, 0.16 g (76%).
D. A suspension of 0.20 g (i mmole) of nitro compound Vc in 1 ml of nitromethane was
methylated with 1.3 ml of 4% ether solution of diazomethane as described in method C.
Yield, 0.18 g (84%).
Et To a solution of 0.40 g (2 mmole) of compound Vc in 4.2 ml of 6% NaOH solution was
added 0.65 ml (6.9 mmole) of dimethyl sulfate dropwise with stirring. After holding for i
h at room temperature, 1 ml of 8% NaOH was added and the mixture was stirred another 3 h.
The precipitate was filtered off, washed with 5% NaOH, and dried. Yield, 0.41 g. The mat-
erial did not depress the melting points of the methylation products obtained by the methods
described above.
4-Amino-l,3-dihydro-2HTimidazo[4,5-c]pyridin-2-0ne (VIIa). A. A solution of 0.50 g
(2.8 m_mole) of compound Va in a mixture of 4 ml of alcohol, 2 ml of water, and 5 drops of
concentrated HCI was heated to boiling; 1.0 g (18 mmole) of pulverized carbonyl iron was
added in portions with vigorous stirring, and the mixture was boiled for 6 h. The precipi-
tate was filtered off and washed with hot water (3 x 2 ml), and the filtrate was evaporated
to half its volume and alkalized with 20% NaOH solution. The precipitate was filtered off,
washed with water, and dried. Yield, 0.25 g (60%).
B. A mixture of 1.0 g (5.5 mmole) of Va, i0 ml of hydroiodic acid (d 1.7), and 1.0 g
(32 mmole) of red phosphorus was boiled for 4 h. The phosphorus was filtered off, and the
filtrate was evaporated to 1/3 its starting volume and alkalized with aqueous ammonia to pH
8. The precipitate was filtered off, washed with a minimal amount of cold water, and dried.
Yield, 0.75 g (91%).
C~ A mixture of 1.80 g of Va and i0 ml (200 mmole) of hydrazine hydrate was heated at
the boiling point for 2 h. The solution was evaporated to dryness and the residue was re-
crystallized from water. Yield, 1.50 g. This amine did not depress the melting point of
samples obtained by methods A and B.
4-Amino-l-methyl-l,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (VIIIB) was obtained hy
method C from 1.95 g (i0 mmole) of Vb and 15 ml (300 ml) of hydrazine hydrate. Yield, 1.64
g.
4-Amino-3-methyl-l,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (Vile) was obtained by
boiling a mixture of 1.95 g (i0 mmole) of Vc and 20 ml of hydrazine hydrate. Yield, 1.58 g.
4-Amino-l,3-dimethyl-l,3-dihydro-2H-imidazo 4,5-c pyridin-2-one (Vlld). A. It was ob-
tained similarly to amine VIIa by method C from 2.08 g (i0 mmole) of Vd and 15 ml of hydra-
zinc hydrate. Yield, 1.64 g.
B~. A mixture of 1.0 g (4.8 mole) of Vd, 20 ml of 45% hydroiodicacid, and 1.0 g (32
mmole) of red phosphorus was boiled for 4 h. The phosphorus was filtered off, and the fil-
trate was evaporated to 1/3 its original volume and alkalized with 20% NaOH solution. The
reaction product was extracted with chloroform (3 x 5 ml). Yield, 0.71 g.
4-Hydroxy-l,3-dimethyl-l,3-dihydro-2H-imidazp[4,57c]pyridin-2-one (VIIIa)~ A mixture
of 2.i g (10 mmole) of Vd and 70 ml of 5% NaOH solution was heated at the boiling point for
4 h. After cooling the solution was neutralized with concentrated HCI and evaporated to
dryness. The reaction product was extracted from the residue by methanol (3 8 ml) and
the solvent was evaporated. Yield, 1.54 g.

84
4-Alkoxy-l,3-dimethyl-l,3-dihydro-2H-imidazo[4,5-c]pyridin-2-ones (Vlllb-e). To the
solution obtained by heating 0.15 mole of NaOH ~o~KOH)~ini.@-2.O mole of the appropriate
alcohol was added 0.I mole of Vd, and the mixture was boiled for 2-4 h. The sodium (or po-
tassium) nitrate precipitate was filtered off, excess alcohol was distilled from the filtrate
the reaction product was extracted with hot chloroform (50-60 ml) and the solvent was evapo-
rated.

LITERATURE CITED
i. R . M . Bystrova and Yu. M. Yutilov, Khim. Geterotsikl. Soedin., No. 2, 378 (1969).
2. Yu. M. Yutilov and I. A. Svertilova, Khim. Geterotsikl. Soedin., No. i, 138 (1973).
3. I . A . Svertilova and Yu. M. Yutilov, USSR Inventor's Certificate 521,277; Byull. Izo-
bret., No. 26, 80 (1976).
4. R . H . Mizzoni, in: Pyridine and Its Derivatives, E. Klingsbert (ed.), New York, London
(1961), Part 2, p. 479.
5. Yu. M. Yutilov and I. A. Svertilova, Khim. Geterotsikl. Soedin., No. 9, 1277 (1976).
6. Yu. M. Yutilov, A. G. Ignatenko, O. G. Eilazyan, and I. A. Svertilova, USSR Inventor's
Certificate 717,055; Byull. Izobret., No. 7, 121 (1980).
7. Y. Mizuno, M. Ikehara, T. Itoh, and K. Saito, J. Org. Chem., 28, 1837 (1963).
8. N . S . Miroshnichenko, I. G. Ryabokon', and A. V. Stetsenko, Ukr. Khim. Zh., 39, No. 4,
350 (1973).

SYNTHESIS OF N~-SUBSTITUTED ADENINYL-9-~-D-GLUCOFURANURONOSIDES

Yu. A. Maurin'sh, R. A. Pa~gle, UDC 547.857.7'483:


I. Ya. Zhola, and M. Yu. Lidak 577.113.3:631.8

N6-substituted adeninyl-9-~-D-glucofuranuronosides have been obtained by the conden-


sation of trimethylsilylated 6-aminopurines with 1,2,5-tri-O-acetyl-B-D-glucofur-
ano-6,3-1actone. The structure of the glucuronides was demonstrated by the UV,
IR 9 and PMR spectra.

For the synthesis of nucleosidic derivatives of kinetine (6-furfurylaminopurine) and


other 6-substituted adenines, mainly the amination of 6-chloro- and 6-methylmercaptopurine
nucleosides has been used [1-4]; only in individual cases [5] has glycosylation of a 6-sub-
stituted adenine with a carbohydrate fragment been used.
The purpose of the present work was to synthesize potential cytokinines in the 6-sub-
stituted adenine glucuronide series. Attempts to use l-(6-chloro- or 6-methylmercaptopurin-
yl-9)-~-D-glucofuranosides that we had previously synthesized [6] to obtain these compounds
were unsuccessful, due to the instability of the glycoside bond and the lactone ring under
the reaction conditions. We therefore synthesized the compounds by condensation of the tri-
methylsilyl derivatives of 6-methylamino- (IIa), 6-butylamino- (IIb), 6-cyclohexylamino-
(IIc), 6-benzylamino- (IId), 6-morpholino- (IIe), and 6-furfurylaminopurine (IIf) with 1,2,5-
tri-O-acetyl-~-D-glucofurano-6,3-1actone (III) [7] in 1,2-dichloroethane in the presence of
the condensing agent trimethylsilyltrifluoromethanesulfonic acid (TMS-TF), which is more re-
active than SnCI~ which we used previously [6, 8].
When the reaction was carried out at 80 ~ for 12 h (II:III:TMS-TF 1.1:1.0:1.2 moles), the
principal product was the Ng-~-D-glucofuranoside of N~-substituted purines (IVa-f). The TLC
data bear witness that other nucleosidic products are formed in the reaction (not more than

Institute of Organic Synthesis, Academy of Sciences of the Latvian SSR, Riga 226006;
"Meristemnye Kul'tury" Agricultural Plant, Ogre 228300. Translated from Khimiya Getero-
tsiklicheskikh Soedinenii, No. i, pp. 103-106, January, 1986. Original article submitted
April 29, 1985.

0009-3122/86/2201-0085512.50 9 1986 Plenum Publishing Corporation 85


TABLE I. Parameters of PMR S p e c t : r a o f Co.:~pound~ i V a ~
- ca~'mlc,'i" ...................

o. o . , otoo, I'-"1" P"I2


I
IVa 8,23, !6,34 6,13rid ' 0,7~ 3,8]5,4
8,15 i (311, (~.Xc), 2,97, m (3H
CI.I:~), ,,84, m (IH, lILt
IVb 8,20, ! 6,31 6,11 dd , 5,27 dd 'i5,13 5,8~] 2,1t,s (311, OAt), 2,06,s 4,0 l,O 3,414,8
836! (3H, OAc), 0,~8, t (3H,
EI I~), 1,37-- 1,70 (4H,
J
2CI12), 3,48, m (2H, CH,.,),
I L58, ra (Ill,tlil) i
IVe 8,21, 6,32 6,11 d 5,29dd e. 5; 5,91 2,12, s (3H, OAt), 2,09,s 3,8
o,l,., 0,78 3,4 4,8
8,17 i (3I'|, OAt), 1,17--1,95
(101 I, 5CH,.,), 4,13,m (lit,
CH),7,67, a ( l i i , Ill{)
IVd 8,20, 6,321(5,11 d 5,26 d 5,12 5,86 2,10, s(3li,-OAc), 2,07,s 4,0 ,L,O 3,6 5,0
8,18 I (3H, OAc), 4,74, m (2H.
CH.2), 7,24, m (5H, Ph).
,~,47, m (Ill. lilt)
IVO 8,28, 6,37 6,11 dd 5,2.9 d 5,17 5,84 ]2,!2, s (3H, OAc), 2,09.s 3,6 0,75 3,4 5,0
8,22 (3{I. OAt). 3,73, m (4]-t,
2CH.,), 4,22,m (4[{, 2CH2)
IVf 8,26, 6,33 6,13 dd 5,28 d 5,16 5,0012;10, s (3t[, OAc), 2,06,s 3,8 0,75 3,8 5,0
8,20 131i, OAc). 4,75, m (2H,
CI4!!), 6 26--6 38 (3H.
3CH). 7.5.t, t (IH. NH)

5-10% of the total); these could not be separated in pure form for identification. Appar-
ently they are isomers of nucleosides IVa-f. Furthermore, unreacted lactone III and 6-am-
inopurines la-f are left in the reaction mixture. Changing the proportions of reagents or
raising the reaction temperature to boiling did not increase the yield of nucleosides IVa-f.
The glucuronide of 6-dimethylaminopurine could not be synthesized by this method, because
the silyl derivative of 6-dimethylaminopurine does not react with lactone III even at the
boiling point of the solvent. Analytically pure samples of IVa-f were obtained by column
chromatography of the reaction products on silica gel.
The structure and configuration of the synthesized nucleosides were established on the
basis of spectral data.
The properties of the UV absorption spectra of the 6-aminopurine nucleosides IVa-f are
identical with those of the Ng-alkyl derivatives [9, I0] and the Ng-ribofuranosides [2-5,
ii, 12] of the related heterocyclic bases, and are significantly different from those of the
N7 derivatives [5, 13].
The IR spectra of IVa-f contain absorption bands at 1595-1615 (purine C=N), and in the
1800-1805 (7-1actone C=O) and 1750-1760 cm-* (acetate C=~) regions.

.'.co..--!"\o,. OAc n

N~'r------N

............. P"Ac 0
II sJi(cH=)
=
Za- f nL-
OA~
IVa-f

l-llI a R = N H C H a ; b r R = HNC~H's; c R = H N C e H x l i d R = HNCH2CeHs;


i R = morphlino - ; f R = furfurylamino -

The PMR spectral data (Table i) confirm the 8-anomeric configuration and the presence
of a hexafuranose ring in these compounds [14]. The spin-spin coupling constant (SSCC)
values of the carbohydrate protons of IVa-f (at least 6 Hz) are typical of furanose deriva-
tives. This enables us to confirm that during the glycosylation of the purine bases the

86
furanose form is not converted to pyranose. The SSCC value J,,~, = 3.6-4.0 Hz is evidence
for the 8-anomeric configuration of the lactones IVa-f.
Cytokinine properties were studied for IVd,f by the tissue culture method in synthetic
culture media, for the growth of plants from m eristem. The tests were carried out on the
growth of Dianthus from meristem in a modified culture medium. To compare the action of
glucuronides IVd and f, kinetin was added to the medium. The tests show that at concentra-
tions of 0.125 and 0.250 ml/g, IVd and IVf act approximately at the level of kinetine.
Another experiment was carried out to study lactones IVd,f as stimulators of sprout
formation in the growth of cuttings from meristem. In this case 6-benzylaminopurine (BAP)
was added to the culture medium to stimulate sprout formation. It was determined that the
activities of IVd and IVf are lower than that of BAP.

EXPERIMENTAL
UV spectra were recorded in methanol on a Spectromom-204 spectrophotometer; IR spectra
in mineral oil on a Perkin--Elmer spectrometer; PMR spectra in DMSO-D6 on a Bruker WH-90 in-
strument, with HMDS internal standard. Specific rotation w a s determined on a Perkin--Elmer
241 spectropolarimeter.
The course of the reaction and the identity of the reaction products were monitored
by TLC on Silufol-254plates in a 9:1 chloroform-methanol system. The chromatograms were
developed by spraying with a i:i mixture of 0.2% naphthoresocinol in ethanol and dilute
(I:i0) phosphoric acid followed by heating at 110-115 ~ for 15 min. Column chromatography
was carried out on a LKB (Switzerland) column (2.5 60 cm) with LI00/250 silica gel (Czech-
oslovak SSR).
6-Aminopurines la-f were synthesized by the procedures of [15, 16] from 6-chloropurine
or 6-methylmercaptopurine.
Silylation of 6-aminopurines la-f was carried out by boiling the purine in hexamethyl-
enedisilazane (20 ml per g of purine) (for Ib-d), with addition of 2 ml of trimethylchloro-
silane (for le, f) or 2 ml of pyridine (for la) until complete dissolution. The solution
was evaporated in vacuum, 20-30 ml of p-xylene was added, and the solution was again evapor-
ated. The silylated purines lla-f were used without further purification.
l-(6-Methylaminopurinyl-9)-2,5-di-O-acetyl-B-D-glucofuranurono-3,6-1actone (~ya). To a
solution of 1.48 g (6.71 mmole) of 9-trimethylsilyl-6-methylaminopurine (lla) in i00 ml of
1,2-dichloroethane was added 1.84 g (6.1 mmole) of lactone III and 1.71 g (1.38 ml; 7.32
mmole) of TMS-TF and the mixture was heated in an oil bath for 12 h at 80 ~ . After cooling
to 20 ~ the solution was poured into a vigorously stirred suspension of sodium bicarbonate
in 300 ml of chloroform and 50 ml of acetonitrile. The mixture was stirred for i h, the
precipitate was filtered off and washed with 2 i00 ml of chloroform, and the combined fil-
trates were evaporated in vacuum. The residue was dissolved in a minimal amount of chloro-
form, transferred to a column of i00 cm 3 of silica gel with chloroform, and eluted succes-
siveiy with 500 ml of chloroform and 300 ml each of 99:1 (by volume), 98:2, and 97:3 chloro-
form-ethanol, until all lactone IVa had come off the column. The fractions containing IVa
were combined and evaporated to dryness in vacuum. The yield of analytically pure IVa was
0.35 g (15%); mp 204-205; Rf 0.42;[~]D~U 89.2 ~ (c 0.56,DMFA). UV spectrum: %max 265 nm (log
4.24). Found: C 49.6; H 4.2; N 17.6%. CI~HITNsOT. Calculated: C 49.1; H 4.4; N 17.9%.
l-(6-Butylaminopurinyl-9)-2,5-di-O-acetyl-8-D-~glucofuranurono_3,6-1acton (IVb) was obtained
condensation of 9-trimethyl-silyi-6-butylaminopurine (lib) with lactone III, similarly to
IVa. After solvent was evaporated the residue was dissolved in 20 ml of chloroform, i0 cm 3
of silica gel was added, the mixture was evaporated to dryness and transferred with hexane
to a column of I00 cm 3 of silica gel. Material was eluted with 500 ml of hexane, then by
linear gradient elution with 500 ml each of hexane and ethyl acetate. The fractions con-
taining IVb were combined and evaporated. The yellow oily residue was dissolved in the min-
imal volume of chloroform and repeatedly chromatographed on a column of i00 cm s silica gel
with chloroform. Elution was carried out with chloroform. The fractions containing IVb
were evaporated to give a frothy residue. Yield, 17%; Rf 0.54; [a]D =~ 69.3 ~ (c 0.53, DMFA).
UV spectrum: Amax 267 nm (log c 4.21). Found: C 52.6; H 5.3; N 16.1%. C,gH23Ns07. Cal-
culated: C 52.6; H 5.4; N 16.2%.

87
l-(6-Cyclohexylaminopuri~yl-9)-2,5-di-O-acetyl-8-D-glucofuranurono-6,3-1actone (!Vc) was
synthesized similarly to IVa from 9-trimethylsilyl-6-cyclohexylaminopurine (IIc) and lactone
2o
IIl, and was isolated similarly to glucuronide IVb. Yield, 39%, mp 175-177~ Rf 0.53; [aiD
77.1 ~ (c 0.54; DMFA). UV spectrum: Imax 267 nm (log e 4.30). Found: C 54.8; H 5.6; N
15.0%. C=IH25N~OT. Calculated: C 54.9; H 5.5; N 15.2%.
l-(6-Benzylaminopurinyl-9)-2,5-di-O-acetyl-8-D-glucofuranurono-6,3-1actone (IVd) was synthe-
sized from 9-trimethylsilyl-6-benzylaminopurine (IId) and lactone III and isolated similarly
to IVa. Yield, 41%; mp 11-113~ Rf 0.54; [a]D 2~ 70.2 ~ (c 0.56, DMFA). UV spectrum: Ima x
266 nm (log e 4.27). Found: C 56.7; H 4.4, N 14.8%. C22H2,NsOT. Calculated: C 56.5; H
4.5; N 15.0%.
l_(6_Morpholinopurinyl_9)_2,5~di-O-acetyl-8-D-glucofuranurono-6,3-1actone (IVe) was synthe-
sized and isolated similarly to IVa from 9-trimethylsilyl-6-morpholinopurine (lie) and lac-
tone III. Yield 26%. Mp 99-101~ Rf 0.56; [a]D 2~ 83.8 ~ (c 0.56, DMFA). UV spectrum: imax
277 nm (log e 4.28). Found: C 50.7; H 4.7; N 15.6%. CliH2,NsOs. Calculated: C 51.0; H
4.7; N 15.6%.
l-(6-Furfurylaminopurinyl-9)-2,5-di-O-acetyl-B-D-zlucofuranurono-6,3-1actone (IVf)was syn-
thesized similarly to IVa from 9-trimethylsilyl-6-furfurylaminopurine (llf) and lactone I!I,
and isolated similarly to IVb. Yield 23%; mp 175-176~ Rf 0.54; [a]D 2~ 85.0 ~ (c 0.40, DMFA).
UV spectrum: imax 266 nm (log e 4.26). Found: C 52.4; H 4.1; N 15.4%. C2oH,gNsO,. Calcu-
lated: C 52.5; H 4.2; N 15.3%.

LITERATURE CITED
i. A. Hampton, J. J. Biesele, A. E. Moore, and G. B. Brown, J. Amer. Chem. Soc., 78, 5695
(1956).
2. J. A. Johnson, J. J. Thomas, and H. J. Shaeffer, J. Amer. Chem. Soc., 80, 700 (1958).
3. M. Ikehara and H. Uno, Chem. Pharm. Bull., 13, 221 (1965).
oV
4. J. Zemllcka and F. Sorm, Coll., 30, 1880 (1965).
5. H. M. Kissman, C. Pidacks, and B. R. Baker, J. Amer. Chem. Soc., 77, 18 (1955).
6. J. A. Maurin~, R. A. Pa~gle, A. A. Zidermane, M. J. Lidaks, E. I. Kvasyuk, and I. A.
Mikhailopulo, Nucleosides and Nucleotides, ~, 147 (1984).
7. D. B. Davies, Studia Biophys., 55, 29 (1976).
8. M. K. Kilevitsa, Yu. A, Maurin'sh, R. A. Pa~gle, E. E. Liepin'sh, A. A. Zidermane, and
M. Yu. Lidak, Khim. Geterotsikl. Soedln., No. ii, 1532 (1981).
9. R. K. Robins and H. H. Lin, J. Amer. Chem. Soc., 79, 490 (1957).
i0. J. A. Montgomery and C. J. Temple, J. Amer. Chem. Soc., 79, 5238 (1957).
ii. H. M. Kissman and M. J. Weiss, J. Org. Chem., 21, 1053 (1956).
12. G. M. Blackburn and A. W. Johnson, J. Chem. Soc., No. Ii, 4347 (1960).
13. N. Prasad and R. K. Robins, J. Amer. Chem. Soc., 79, 6401 (1957).
14. A. A. Akhrem, V. A. Timoshchuk, L. N. Kulinkovich, and I. A. Mikhailopulo, Bioorg. Khim.,
~, 513 (1976).
15. J. W. Daly and B. E. Christensen, J. Org. Chem., 21, 177 (1956).
16. G. B. Elion, E. Burgi, and G. H. Hitchings, J. Amer. Chem. Sor 74, 411 (1952).

88
SYNTHESIS AND PROPERTIES OF symm-TRIAZINE DERIVATIVES.
4.* SYNTHESIS OF 2,4,6-TRIS~BSTITUTED symm-TRIAZINES
CONTAINING STERICALLY-HINDERED PHENOL FRAGMENTS

V. I. Kelarev, F. Laawad Yakhya, R. A. Karakhanov, UDC 547.491.07:543.422


A. F. Lunin, and O. V. Malova

2,4,6-Trisubstituted symm-triazines containing sterically-hindered phenol frag-


ments were synthesized by the cyclotrimerization of ethyl iminoesters. 2,4,6-
Trimercapto-symm-triazine derivatives containing shielded phenol residues may
be formed by the cyclotrimerization of the corresponding thiocyanates in acidic
medium.

The introduction of sterically-hindered phenol groups into symm-triazines permits the


preparation of antioxidants and thermal and light stabilizers for polymer materials and lub-
ricating oils [2-4]. In our previous work [5], we demonstrated the feasibility of preparing
such sym~-triazine derivatives by the reaction of chloro-symm-triazines with 4-hydroxy-3,5-di-
tert-butylaniline. In a continuation of this investigation, we synthesized 2,4,6-trisubsti-
tuted symm-triazines, in which shielded phenol fragments are attached to the heterocyclic
ring by means of C--C or C--S bonds.
Derivatives of symm-triazine may be obtained by the cyclotrimerization of the iminoes-
ters of carboxylic esters in the presence of their hydrochloride salts [6, 7] or other acid
agents [8, 9]. In the present work, we studiedthe use of this method for the preparative
synthesis of 2,4,6-trisubstituted summ-triazines containing 2,6-di-tert-butylphenol fragments
(VII) and (VIII).
Iminoesters V and VI required for the preparation of this type of heterocyclic compounds
were synthesized by the ordinary scheme from the corresponding nitriles I and II.
(~H2)~Ar

Ar--(CIIT)C~N C?'HsOtt"" NH'Itr .INH H N:~:'I~


- ........
Hc~ A~ - ~+ ,+.). Cc-+-oc...~. --- .c,'-^ ~ " ~':~';~" ':~;oco:o " I [
1-xt~-e mw. ~ v.vt,,-- c " ~,-~c. i "'N ff.H~) Ar
Vll--Vllle. - C
C(ClI~ s -C(('H.~)a
la.-.C)lllo- ~m42 .VIIa CAr +~
/z / Oil ; Ha C.IVa. ~Vla C.VIIIa CAI'==+ S --O11 ;

1 VI]I a , O; b .. I;C +~ .~
The hydrochtoride salts of ethyl iminoesters III and IV were prepared by the Pinner re-
action by passing dry HCI into a mixture of the corresponding nitrile I or II and absolute
ethanol in a suitable solvent. In the case of 4-hydroxy-3,5-di-tert-butylbenzonitrile (la),
the reaction was carried out in an excess of ethanol at I0-15~ with subsequent maintenance
of the reaction mixture for four days [I0]. The iminoester hydrochlorides lllb, lllc, and
IVa-c were formed in good yield upon carrying out the reaction at 0-5"C using equimolar
amounts of the corresponding nitrile and ethanol with subsequent maintenance of the reaction
mixture for 10-12 h at 20~ Iminoester salts III and IV are rather stable compounds and may
be stored for prolonged periods avoiding moisture.

*For communication 3, see [i].

I. M. Gubkin Moscow Petroleum Chemistry and Gas Industry Institute. Translated from ......
Khimiya Geterosiklicheskikh Soedinenii, No. i, pp. 107-113, January, 1986. Original article
submitted November 20, 1984.

0009-3122/86/2201-0089512.50 9 1986 Plenum Publishing Corporation 89


TABLE i, Characteristic of Ethyl Im~noesters V, V~ and 'l'iies
Hydrochlortde Salts Iii and IV
~ , L : . . . . . . . . . . ~ .......... ~: . . . . . . . . . . . . . . . . . . . . .

~ ~ Found, ~ r
C Che~aical Yield, %
Corn-
pound

IIla 258~260 - ,- 65,3 8,9 4.(~1 1,5 1 CI71127NO,~. 1IC1 65,1 8,9 4,5 t,3 67
(260 [2H)
]V~ [54--155,5 O,42 73,5 9.8 5.2 1 .... CI,;It~TNO2 73.6 9,7 5,0 -- 89
172--174 {16,0O,l 4.2 1113) (iml I~,jNO2 9I ICI 55,9 9.2 4,3 0,8 74
Vb 80.--8 I 0,30 74,4 :J,9 5.0 I -- C,~I'12~NO~ 74,'2 0,0 4,8 -- 92
lllc 116--118 - - 86,6 9,3 :[.2 IlO, l C,ol'hlNO2" I ICI 86.8 9,4 4,1 0,4 93
Vc Macro 0,25 74,5 0,2 4,8 1 -- CI91"13INO:~ 74,7 0.2 4,6 -- 88
IVa 16,5.-166 -- 58,9 8.2 4,2 ii0,0 I CITI'I~TNO,.,S. 11C1 59,0 8,1 4,0 0,3 68
Via 133--135 0,67 66,2 8,6 4,31 -- CITH27NO2S 66,(] 8,7 4,5 -- 75
IVb 233--235 -- 60,0 8,3 4~0J10,2 I CLaI-I~oNO2S. HCI 50,1 8,3 3,9 9,9 76
V|b I05--I06,5 0,62 57,0 9,1 ~,5 - - C,~]-I~oNO2S ~6.9 9,0 4,3 -- 91
IVc 134.--136 -- 60,8 8,7 l~,91 ~,3 CmI-I3tNO2S. HCI 61.0 8,6 i3,7 9,5 86
Vlc Macro -~
"6"
0,51 57,7 CIgH~,NO2S 57,6 9,2 i4,2 - - 92
9 2 i4,4l -

*III and IV were purified by reprecipitation from glacial acetic


acid in dry ether, V and Via were purified by recrystallization
from aqueous ethanol, Vb, Vc, Vlb, and Vlc were purified by chro-
matography on alumina columns with elution by i0:i benzene--metha-
nol. Salts llla-c and IVa-c melted with decomposition.
tThin-layer chromatography on alumina with heptane eluent.
SnD 2~ 1.4864
Ethyl iminoester bases V and VI were obtained by treatment of suspensions of the imino-
ester salts in ether or methylene chloride at 0-5 ~ by 10% aqueous KOH or saturated aqueous
K2COa. However, heavy tar forumtion was noted using this method in the case of iminoesters
Vb and Via and thus, hydrochloride salts lllb and IVa were converted to the corresponding
iminoesters by treatment with triethylamine in dry ether.
The IR spectra of iminoester salts III and IV show strong bands at 1670-1655 cm-* char-
acteristic for C=N + stretching vibrations [i0, ii]. This band in the IR spectra of imino-
ester bases V and VI appear at lower frequencies (1635-1615 cm-'). The C=N+--H stretching vib-
rations in the spectra of salts III and IV are found at 3155-3100 cm -~, which is characteris-
tic for NH vibrations in imine salts [12]. T h e NH group vibrations in the IR spectra of im-
inoesters V and VI are seen as medium-intensity bands at 3370-3340 cm -~.
A study of the cyclotrimerization of ethyl iminoesters V and VI showed that these com-
pounds, with the exception of ethyl iminoester 4-hydroxy-3,5-di-tert-butylbenzoic acid (Va)
are smoothly converted to the corresponding 2,4,6-trisubstituted symm-triazines VII and VIII.
The cyclotrimerization of iminoesters Vb, Vc and Vla-c was carried out at 90-95~ for 20-25
h in the presence of iminoester hydrochlorides III and IV (3-5 mass % relative to iminoesters
V and Vl). The yields of symm-triazines Vllb, Vllc, and Vllla-c were 80-88% (Table 2).
The cyclotrimerization of iminoester Va proceeded with much more difficulty. Thus, 2,4,
6-tris(4-hydroxy-3,5-di-tert-butylphenyl)-symm-triazines (Vlla) was isolated in only 12%
yield after carrying out the reaction under the above conditions (90=C, 24 h) and the start-
ing iminoester Va was also isolated. Despite varying the reaction conditions by using other
acid catalysts, increasing the reaction time to I00 h and increasing the temperature to 120-
125*C, the yield of symm-triazine Vlla could not be markedly increased. We should note that
the major reaction products upon carrying out the cyclotrimerization of Va at 145-150~ for
15 h are 4-hydroxy-3,5-di-tert-butylbenzamide and nitrile In.
This difference in the behavior of iminoester Va is realted to the reduced reactivity of
the iminoester group as a consequence of its conjugation with the hydroxy group [i0]. In ad-
dition, the steric hindrance due to the tert-butyl groups in the vicinity of the reaction site
undoubtedly play a definite role.
Dexter et al., [13] have reported the preparation of symm-triazine Vlla by the direct
alkylation of 2,6,di-tert-butylphenol with cyanogen chloride (3:1 mole ratio) in the presence
of AICI3 in tetrachloroethylene. However, all our attempts to reproduce this procedure were
unsuccessful and only tar formation was noted; individual compounds could not be isolated.

90
TABLE 2. Characteristics of 2,4,6-Trisubstituted symm-Triazines

77
919,11
,1
VII-VIII and X

Found, % Calculated, % Yield, %=~'/


Chemical (prepara-
~OIR- i~, ~ Ry.'~"
formula
potmd tive ree-
C H N s d H N S t.hod )

VII !' 310--3tl,5 0 92 78,0 CasH63N30~


~,0 B,3 -- -- 15 (A)
VII 161--162,5 0:54 78,6 C4sFI69N30~
9,4 15,0 78,8 9,4 5,7 84 (A)
VII 209--210 0,46 178,9 C511-ITsNaO3 178,8 9,6 5,4 ~z-,2 88(.A)
~,5 15,6
VIII 211--212 (I,42 [38,3 ',9 ]5,1 12,3
C4sI-I6aN303S3 58,4 8,0 5,3 81(A},
45(B),
67 (B)
VllI b 102--104 0,82 139,3 ~,8 i~,2 I 1,2 C48H~N303S3 1~9,4 8,3 5,0 11,5 80(A)
VIII c 57--59 0,66 170,0 8,7 5,0 10,9 CsII-175N303S3 170,1 86 4-8 I1,0 86(A)
X 195--196
( 197---198 [261)
0,50lB9,5
B,4 4,9 11,7 C481-1~9N303S3 [59,4 813 510 11,5 37(B,
69(B )

*The recrystallization solvents were aqueous DMF (Vlla and Vllb),


glacial acetic acid (Vllc), ethanol (Villa), aqueous ethanol
(VIII b and Vlllc), and i:i toluene--hexane (X).
*In 20:1 benzene-methanol.
SA) Cyclotrimerization of iminoesters, B) cyclotrimerization of
thiocyanates, C) convergent synthesis.

Martin et al, [14] have reported that 2,4,6-trialkyl- and 2,4,6-triarylthio-symm-tria-


zincs may be obtained by the cyclotrimerization of alkyl- and arylthiocyanates in the pres-
ence of acids. We attempted to use this method for the synthesis of derivatives of 2,4,6-
trimercapto-symm-triazine containing shielded phenol residues. Upon heating in DMF in the
presence of catalytic amounts of HaSO4, 4-hydroxy-3,5-di-tert-butylphenylthiocyanate (lla)
and 4-hydroxy-3,5-di-tert-butylbenzylthiocyanate (IX) were converted in good yield to the
corresponding symm-triazines Villa and X.

s(cn~)A,
li ~ N/
7 "N
lIa.IX Ar(C|I2) S N "~(C][.? Ar

VIIla.X

.... C(CII3} 5

IIa.VHIa,L':,X Ar . . . . . . f"(" ")")/-Oil ; IIu,VIHa i,-:O; IX,X .... l

c(ciI:) 3

In the present work, 2,4,6-trimercapto-symm-triazine derivatives Villa and X were also


obtained by convergent synthesis. The condensation of 4-mercapto-2,6-di-tert-butylphenol
with cyanogen chloride gave Villa, while X was obtained by the reaction of 2,4,6-trimercapto-
sym-triazine with 2,6-di-tert-butylphenol and formaldehyde.
I
The IR spectra of symm-triazines VII, VIII and X have a narrow band at 3650-3635 cm-
corresponding to the stretching vibrations of the nonassociated OH group in the hindred
phenols [15]. The spectra of these compounds show bands of different intensity characteris-
tic for the stretching and deformation bands of the symm-triazine ring (Table 3) [7, 16-18].
The bands at 885-880 and 825-820 cm -~ are characteristic for the 4-substituted benzene ring
while tile two bands at 1265-1210 cm-* are characteristic for the Ar--OH bonds [19].
The PMR spectra of s3~m-triazines VII, VIII and X show signals for the hydroxyl group
protons as singlets at 5.12-5.22 ppm, which is characteristic for sterically-hindered phenols
[20]. The signals for the tert-butyl group protons are seen as singlets at 1.62-1.75 ppm.
The aromatic ring protons give rise to singlets with intensity 2H at 7.14-7.30 ppm.

EXPERIMENTAL
The IR spectra were taken on a UR-20 spectrometer as a suspension in vaseline oil (III
and IV), in CCI, (V and VI) or in KBr pellets (VII, VIII and X). The PMR spectra were taken
on a Tesla BS-487C spectrometer at 80 MHz using the 6 scale with HMDS as the internal stand-

91
TABLE 3. Spectral Data for 2,4,6-Trisubstituted summ-Triazines
VII, VIII and X

IRspectrum, cm"I
'Vs' ~"a s triazine ring Vc-o PMR spectrum,~, ppm
G--H vibrations % 6~ 8a~
%'0-II (CHa,
C[la)
; V-rl ; f-
VII,

VII 1,72 (541t, a terl-C4H~); 3,56 (6H,


s CH,,); 5,12 (3tJ, a OH); 7,25 (5!t,
s, arom.protons )

VII ~ i,75 (541t, s lert-C4Ho); 4,46--4,68


(12}t, m CI-12--CH.~); 5,18 (3tl, s ,
OH); 7,28 (6H,s, arom.protons)
VIII,

VIII t,74 (54H, H lert-C41Ig); 4,22 (6H,


H CH2); 5,14 (3H, c, OH); 7,18 (6H,
s,, a r o m . protons)
VIII, 1,66 (54H, s, ferl-C4|tg); 4,58--4,74
(12H, m CH2--CH2); 5,22 (3H, s,
OH); 7,18 (6H, s. atom.protons)
1,62 (54H, s, tert-C4Hg); 4,42 (6H,
s, CH2'); 5.20 (3H, s OH); 7,14 (6H,
atom.protons)

*The PMR spectra of Vllb, Vllc and X were taken in DMSO-D6,


while the spectra of Vlllb and Vlllc were taken in deuterometh-
anol.
%~) In-plane ring deformation vibrations, ~) out-of plane ring
deformation vibrations.
SRing "breathing" bands.

ard. The reaction was monitored and the purity of the compounds obtained was checked by thin-
layter chromatography of Brockman grade II alumina with iodine vapor development or on Silufol
UV-254 plates with development in UV light.
4-Hydroxy-3,5-di-tert-butylbenzonitrile (la) [21] and 4-hydroxy-3,5-di-tert-butylphenyl-
acetonitrile (IV [22] as well as 4-hydroxy-3,5-di-tert-butylphenylthiocyanate (lla) [23] were
obtained according to published procedures.
~_(4_Hydr0xy_3,5_di_tert_butylphenyl)propionitrile (It). A sample of 14.8 g (279 mmoles)
freshly prepared acrylonltrile was added dropwise with stirring in an inert gas stream over
l0 mln to a mixture of 51.0 g (246 mmoles) 2,6-di-tert-butylphenol and 6.0 g (120 mmoles) KOH
in 150 ml dry DMSO. The reaction mixture was stirred for 8 h at 60-65~ and then DMSO and
unreacted 2,6-di-tert-butylphenol were removed at reduced pressure. A sample of 15 ml 15%
aqueous HCl was added to the residue and the organic layer was extrated with two 150 ml por-
tions of benzene. The benzene solution was washed with 150 ml waterj dried over CuSO, and
evaporated to dryness. The residue was crystallized from hexane to give 19.7 g (13%) nitrile
Ic, mp 110-112~ Rf 0.95 (20:1 benzene--ethanol), mp i13-114~ [24].
4_Cyanomethylthio_2,6_di-tert-but71phenol (llb~. A solution of 3.1 g (55 mmoles) KOH
in 45 ml absolute ethanol was added dropwise in an inert gas stream to a stirred solution of
12.9 g (50 mmoles) 4-mercapto-2,6-di-tert-butylphenol [25] in 35 ml absolute ethanol at 5-10~
The reaction mixture was stirred for 30 min at 5~ and then 7.75 g (50 mmoles) chloroacetoni-
trile was added dropwise in an inert gas stream at 5~ The mixture was stirred for 3 h at
65-70~ cooled to 10~ poured into 200 ml cold water, and acidified by dilute HCI to pH 6.5.
The organic layer was extracted with three 50 ml portions of ether. The extract was washed
with water, dried over CuSO,, and evaporated to dryness. The oil was crystallized from 20:1
hexane--benzene to give 6.57 g (51%) nitrile lib, rap 60.5-62~ Rf 0.18 (heptane). Found:
C 73.6;~H 7.0; N 4.4; S 10.0%. Calculated for CaoH2sNOS: C 73.8; H 7.1; N 4.3; S 9.8%.

92
4-(B-Cyanoethyl)thio-2,6-di-tert-butylphenol(I~Ic). Three drops of concentrated aque-
ous KOH was added to a stirred solution of Ii.0 g (46 mmoles> 4-mercapto-2,6-di-tert-butyl -
phenol in 60 ml dioxane and then, 7.3 g (138 mmoles) acrylonitrile was added dropwise at 20-
25~ The reaction mixture was stirred at 70~ for 5 h, cooled to 20~ poured into 200 ml
cold water and neutralized with dilute hydrochloric acid to pH 7.0. The organic layers was
extracted with three 50-ml portions of ether. The extract was washed with water, dried over
CuSO~ and evaporated to dryness. The residue was crystallized from heptane to yield 10.9 g
(70%) nitrile llc, mp 97-990C, Rf 0.24 (heptane). Found: C 74.1; H 7.3; N 4.3; S 93%.
Calculated for C=~H25NOS: C 74.3; H 7.4; N 4.1; S 9.4%.
Hydrochloride Salt of the Ethyl Iminoester of 4-Hydroxy-3,5-di-tert-butylbenzoic Acid
(IIIa). A stream of dry HCI was passed for 2 h at I0-15~ through a stirred mixture of 4.6
g (12 mmoles) Ia in 40 ml absolute ethanol and 20 ml dry ether. The reaction mixture was
maintained for 72 h at 20~ and evaporated to dryness at reduced pressure. The residue was
treated with dry ether. The precipitate was filtered and dried in vacuum over KOH.
Hydrochloride Salts of Ethyl Iminoesters IIIb~ IIIc~ IVa-c. A stream of dry HCI was
passed for 1 h through a stirred mixture of i0 mmole nitrile Ib, Ic, IIa-c and 12 mmole ab-
solute ethanol in 30 ml dry ether at 0~ The reaction mixture was maintained for 4-5 h
at 200C and cooled to --15~ The hydrochloride precipitate of IIIb, IIIc, IVa-c was filter-
ed off and dried in vacuum over KOH (Table i).
Ethyl Iminoester of 4-Hydroxy-3,5-di-tert-butylphenylacetic Acid (Vb). A sample of
1.12 g (12 mmoles) triethylamine in i0 ml ether was added dropwise to a stirred suspension
of 3.27 g (i0 mmoles) hydrochloride IIIb in 120 ml dry ether at 0~ and stirred for 1 h at
O~ T h e precipitate was filtered off. The solvent was removed at a water pump and the
residue was subjected to chromatography on a 3.5 50 cm alumina column with i0:i benzene--
methanol as the eluent.
Ethyl iminoester Via was obtained analogously. The PMR spectrum of Via in deuterometh-
ano!: 1.34 (3H, t, CH~), 18.2 (18H, s, tert-C~Hg), 4.52 (2H, q, OCH2), 5.20 (IH, s, OH),
7.12 (2H, s, aromatic protons), 8.18 ppm (IH, s, NH).
Ethyl Iminoesters of Acids Va, Vc, VIb and Vlc. A sample of 35 ml 10% aqueous KOH was
added dropwise to a stirred suspension of 25 mmole ethyl iminoester hydrochloride IIa, IIIc,
IVb or IVc in 300 m! ether or methylene chloride at 0.5~ The ethereal layer was separated,
washed with 120 ml water and dried over CuSO~. The solvent was removed at a water pump.
The residue was either crystallized from aqueous ethanol (Va) or subjected to chromatography
on a 3.5 75 ml alumina column with I0:I benzene-methanol as eluent (Table i). PMR spectrum
of iminoester Vc (in CCI~): 1.22 (3H, t CH3), 1,66 (18H, s, tert-C~Hg), 4.24 (2H, q, OCH2),
4.48-4.72 (4H, m. CH2CH=), 5.65 (IH, s, OH), 7.34 (2H, s, aromatic protons), 8.12 ppm (IH,
s, NH).
2,4,6-Trisubstituted symm-T~iazines (Vlla-c, Villa-c). A mixture of 30 mmoles ethyl
iminoester Va-c or Vla'c and 3 mmoles of the corresponding iminoester hydrochloride was heat-
ed at 90-95~ for 20-25 h with protection from atmospheric moisture. The reaction mixture was
maintained for 1 h in vacuum created by a water pump on a steam bath. The residue was sub-
jected to chromatography on a 3.5 80 ml alumina column with 30:1 benzene-methanol as the
eluent (Table 2).
4-Hydroxy-3,5-di-tert-butylbenzylthiocyanate (IX). A solution of 34.3 g (135 mmoles)
4-hydroxy-3,5-di-tert-butylbenzyl chloride in 50~ml ethanol was added dropwise to a stirred
suspension of 19.4 g (200 mmoles) potassium thiocyanate in i00 ml ethanol. The reaction mix-
ture was heated at reflux with stirring for 2 h and then, 80-85 ml solvent was distilled off.
A sample of 150 ml cold water was added to the residue. The organic layer was extracted with
three 75 ml portions of ether. The extract was washed with i00 ml water, dried over CaCI2
and evaporated to dryness. The residue was crystallized from aqueous ethanol with activated
charcoal to yield 20.2 g (54%) thiocyanate IX, mp 42-43.5~ Rf 0.52 (20:1 benzene-methanol).
Found: C 69.2; H 8.2; N 4.9; S 11.7%. Calculated for C~6H=3NOS: C 69.3; H 8.3; N 5.0; S
]1.5%.
2,4,6-Tris(4-hydroxy-3,5-di-tert-butylphenylthio)-symm-triazine (VIIIa). B~ Five
drops of concentrated sulfuric acid was heated to a solution of 4.0 g (15 mmoles) thiocyan-
ate IIa in 15 ml dry DMF and heated at reflux for 8 h. The reaction mixture was cooled to
20~ and poured into !00 ml cold water. The dark oil isolated was extracted with I00 ml
ether. The extract was washed with 50 ml water, dried over CuSO~, and evaporated in vacuum.

93
The residue was subjected to chromatography on a 3.5 50 ml alumina column with 10:1 ben-
zene-methanol as eluent to yield 1.8 g (45%) symm-triazlne Villa, mp 210-2]I~ (from ethanol).
C__~. An ethanolic solution of potassium mercaptide obtained from 8.14 g (30 mmoles) 4-
mercRpto-2,6-di-tert-butylphenol and 1.68 g (30 mmoles) KOH in 30 ml absolute ethanol was
added dropwise to a solution of 1.84 g (i0 mmoles) cyanogen chloride in 25 ml acetone. The
reaction mixture was heated at reflux for 3 h, cooled to IO~ and the KCI formed was filter-
ed off. The filtrate was poured into 100 ml water. The organic layer was extracted with
three 50 ml portions of ether and dried over CuSO~. The solvent was distilled off and the
residue was crystallized from ethanol to yield 5.2 g (67%) symm-triazine VIIIa.
2,4,6-Tris(4THydroxy-3,5-di-tert-butylbenzylthio)-s,vmm-triazine(X ) . B~ This compound
was obtained by analogy to symm-triazine Villa from thiocyanate IX in 37% yield, mp 195-196~
C__z A solution of 27.8 (130 mmoles) 2,6-di-tert-butylphenol in 80 ml glacial acetic
acid was added with stirring to a suspension of 7.14 g (40 mmoles) 2,4,6-trimercapto-symm-
triazine and 7.25 paraformaldehyde in 30 ml glacial acetic acid, and then 13 ml 20% hydro-
chloric acid was added. The reaction mixture was stirred for 6 h at 45~ The precipitate
was filtered off, washed with 150 ml water and then with 100 ml 2:1 ethanol--acetone to yield
23.1 g (69.5%) symm-triazine X, mp 194-195~

LITERATURE CITED
i. V. I. Kelarev, A~mar Dibi, and A. F. Lunin, Khim. Geterotsikl. Soedin., No. ii, 1557
(1985).
2. H. Brunetti, West German Patent No. 2,155,453; Chem. Abstr., 77, 62782 (1972).
3. P. Klemehuk, US Patent No. 3, 81,006; Chem. Abstr., 81, 105575 (1974).
4. G. Gaspari, US Patent No. 4,038,197; Chem. Abstr., 88, 52833 (1978).
5. O. V. Malova, T. P. Vishnyakova, I. A. Golubeva, V. I. Kelarev, and A. F. Lunin, Khim.
Geterotsikl. Soedin., No. 12, 1678 (1984).
6. A. Ya. Yakubovich, E. L. Zaitseva, G. I. Braz, and V. P. Bazov, Khim. Obshch. Khim., 32,
3409 (1962).
7. V. I. Kelarev, Ammar Dibi, A. F. Lunin, R. L. Ushakova, A. I. Mikaya, N. V. Petrova,
and S. M.-G. Shvekhgeimer, Zh. Org. Khim., 19, 2401 (1983).
8. F. C. Schaefter and P. Grace, J. Org. Chem., 26, 2778 (1961).
9. V. G. Ostroverkhov, L. M. Goncharenko, and A. A. Kornienko, Ukr. Khim. Zh., 37, 1129
(1971).
I0. V. I. Kelarev, S. M.-G. Shvekhgeimer, V, N. Koshelev, A. F. Lunin, and G. A. Shvekhgei-
mer, Zh. Vses, Khim. Obshch. im. D. I. Mendeleeva, 27, 582 (1982).
ii. V. I. Kelarev and G. A. Shvekhgeimer, Khim. Geterotsikl. Soedin., No. 5, 645 (1980).
12. K. Nakanishi, IR Spectra and the Structure of Organic Compounds [Russian translation],
lzd. Mir, Moscow (1965), p. 46.
13. M. Dexter, B. Manor, and M. Knell, US Patent No. 3,905,939; Ref. Zh. Khim., 12NI82P
(1976).
14. D. Martin, M. Bauer, and V. A. Pankratov, Usp. Khim., 47, 1814 (1978).
15. V. V. Ershov, G. A. Nikiforov, and A. A. Volod'kin, Sterically-Hindered Phenols [in Rus-
sian], Izd. Khimiya, Moscow (1972), p. 38.
16. A. I. Finkel'shtein and E. N. Boitsov, Usp. Khim., 31, 1496 (1962).
17. V. E. Allenstein, W. Rodzum, and J. Weidhein, Z. Anorg. Chem., 53, 408 (1974).
18. A. R. Katritzky (ed.), Physical Methods in Heterocyclic Chemistry [Russian translation],
Izd, Mir, Moscow (1966), p. 594.
19. M. Avram and G. Hattescu, Infrared Spectroscopy, Wiley-lnterscience (1970), p. 527.
20. T. N. Pliev, Zh. Prikl. Spektroskopii, 13, 124 (1970).
21. L. A. Cohen, J. Org. Chem., 22, 1333 (1957).
22. V. V. Ershov and I. S. Belostotskaya, Izv. Akad. Nauk SSSR, Ser. Khim., No. 2, 376 (1965).
23. E. Muller, H. B. Stegmann, and K. Scheffler, Ann., 645, 79 (1961).
24. E. V. Glebova and T. P. Vishnyakova, Izv. VUZov. Khim. i Khim. Teknol., 20, 1076 (1977).
25. E. B. Hotelling, R. J. Windgassen, E. P. Previc, and M. B. Neuwort, J. Org. Chem., 24,
1598 (1959).
26. J. Grilles, US Patent No. 3,862,942; Ref. Zh. Khim., 22N243P (1975).

94
STRUCTURE AND SOME PROPERTIES OF TETRAZOLE 5-METHYLPYRIMIDO[4,5-e]-
[I,2,4]TRIAZINE-6,8-DIONE AND ITS AZIDE IN DIFFERENT PHASE STATES

N. A. Klyuev, G. G. Aleksandrov, Yu. A. Azev, UDC 539.26:547.859.2'866o796.1


E. O. Sidorov, and S. E. Esipov

The structure of the tetrazole, 5-methylpyrimido[4,5-e][l,2,4]triazine-6,8-dione


was established by x-ray structural analysis. The tautomeric equilibrium with
its azide isomer in solution was examined. The effect of bases on this equili-
brium was discovered. Analytical criteria were proposed which permit identifica-
tion of the tetrazole and the azlde forms in the gas phase.

The present study is a continuation of our previous work [1-3] on the physicochemical
properties of pyrimido-as-triazine antibiotics including rheumacine, fervenuline, and xantho-
tricine and their structural analogs [4-6] having antiviral activity [7].
In the present work, we established the nature of the ring fusion in the tetrazole, py-
rimido[4,5-e][l,2,4]triazine-6,8-dione (la or Ib) in the crystalline state and elucidated the
differences between the cyclic form (la or Ib) and its isomer (Ic) in the aizde form relate
to dissociative ionization upon electron impact. The structural results were compared for
isomers la-c (taking account of possible tautomerism) for different aggregate states.

0"" N ~ ' N "N 0 "N "N >:N 0 N N N-=N=rN


I I I I i
CHI CIII N :n-~:N CH 3
la I b IC

I n o u r p r e v i o u s w o r k , by a n a l o g y t o t h e s t u d i e s o f Messmer [8] and B o g a t s k i i [9] f o r t h e


c y c l i c f o r m , we a d o p t e d t h e a n g u l a r s t r u c t u r e (Ib) for both the crystalline and g a s e o u s s t a t e s
of this molecule. T h e r e i s no common o p i n i o n p r e s e n t l y i n t h e l i t e r a t u r e concerning the na-
ture of the cyclization of the 3-azido group in 1,2,4-triazine derivatives. Thus, x - r a y d i f -
fraction structural a n a l y s i s h a s shown t h a t t h e t e t r a z o l e isomer of 3-azido-5-p-chlorophenyl-
1,2,4-triazine exists in crystals as the linear analog, 5-p-chlorophenyltetrazolo[l,5-b]-l,2,
4-triazine [i0]. On the other hand, Messmer et al. [8] have shown that 3-azido derivitives
of benzotriazine cyclize in solution mainly to give the angular tetrazolo[5,l-c]benzo-as-tri-
azine and only a small amount of linear tetrazolo[l,5,-b]benzo-as-triazine is observed in
highly polar aprotic solutions. Recently, Nishigaki et al. [Ii] studied the UV spectra of
model azolopyrimidopyridazines and found that 3-azido-6,8-dimethylpyrimido[5,4-3][l,2,4]tri-
a zine-5,7-dione cycl izes to linear i, 3-dimethyl te trazolo [4,5-b ]pyrimido [5,4-e ]-a s-triazine-
2,4-dione but they did not present melting point or elemental analysis data for this compound.
In addition, no data were given on the state of the azido--tetrazole equilibrium for this iso-
mer pair or for the PMR and UV spectra of the azido derivative.
Thus, the lack of reliable data on th~ nature of the ring fusion of the tetrazole ring
in 1,2,4-triazines requires a special study in each specific case.
In order to determine the nature of the condensation of the tetrazole system in pyrimido-
[4,5-e][l,2,4]triazine-6,8-dione, we studied the molecular and crystal structure of this com-
pound by x-ray diffraction structural analysis and established that the tetrazole ring is
fused with the as-triazine ring at the C(~)--N(4) bond (structure la) and not at the C(~)--N(8)
bond (structure Ib, Fig. i). Dione la consists of three planar condensed heterocyclic rings,
namely, a uracil ring (A), as-triazine ring (B) and tetrazole ring (C, Table I), and has a

All-Union Scientific-Research Institute of Antibiotics, Moscow 113105. S. M. Kirov


Urals Polytechnical Institute, Sverdlovsk 620002. Translated from Khimiya Geterotsikliche-
skikh Soedinenii, No. i, pp. 114-120, January, 1986. Original article submitted November 20,
1984.

0009-3122/86/2201-0095512.50 9 1986 Plenum Publishing Corporation 95


%~ 7~.--.:. ,~, ~ :L ~ BO }

,~%3,0L'3~
9 , co ~ ' ,
Fig. i. Bond lengths and angles in la~
:. _ +

-+ ,+

,,,,,,+-?:+.+

TABLE I. Coefficients of the Plane Equations Az + By + Cz --


D = 0 of Several Planar F~agments of la and Deviation of the
Atoms from These Planes, A

Plane Atoms

A N(u C(,) N~2) Ct2) C~3) 0,908 -0,0324 -0,4160 2,0077


- 0,002 --0,010 0,021--0,035 0,020
C(s) O*(1) 0*(2) C*(8)
-0,005-0,021-0,109 -0,043
0,91C -0,0017 -0,4126 2,2999
-0,010 0,001 0,006-0,010 0,0000,009
N(4) N(5~ Nt6) N(z) C(~) 0,907 0,0228 -0,4193 2,4839
-0,008 0,007 0,000-0,006 0,013
Nu) C(,) N(~) C(2) C~3, N~a) 0,90~ --0,0092 -0,4161 2,2103
0,028 0,001--0,001 --0,071 0,007 0,070
N(4) N(5) N(6) N(7) C(4) N(8)
0,011 0,038-0,007-0,047 -0,014 -0,004
C(s) O*(i) 0"(2) C*(m
0,016 0,000-0,170 0,020

*Atoms not included in the calculation of the corresponding plane.


Planes A, B, and C form the dihedral angles: A/B = 1.8; A/C =
3.2; B/C = 1.5 ~ .

highly compressed boat conformation. The plane of the central ring B forms dihedral angles
of 1.8 and 1.5 ~ with rings A and C, respectively.
The bond length distribution in Ia (Fig. i) indicates the electron delocalization usual
for such conjugated nitrogen-containing heterocycles: All the formal single C--N and N-N
bonds are shortened while the double bonds are extended relative to the standard values: C-N,
1.474| N--N, 1.451; N=-N, 1.25; C~N, 1.29 ~ [12].
Each molecule of la in the crystal participates in the formation of two intermolecular
hydrogen bonds: N(a)--H...O(a) (*/= -- x, i -- y, */s + z) and O(a)...H--N a (I/a -- x, i - y,
*/a + z) [N--H0.91(5);N.o.O, 2.819(7), H...O, 1.91(5) ~, <[N--H...O, 168(2)~ which leads
to the formation of spirals of la molecules about 2, axes parallel to the c-axis. The some-
what greater C(z)-O(a) bond length [1.219(7) ~] relative to C(,)-O(~) [1.186(8) ~] is a con-
sequence of the participation of O(a) in hydrogen bonding.
Crystalline azide and tetrazole isomers are sometimes capable of interconversion. Thus,
Messmer et al. [13] noted that solid 3-azidopyrido[2,3-3]-as-triazine spontaneously converts
to solid pyrido[2,3-3]tetrazole[5,l-e]-as-triazine. Equilibrium between these isomers is es-
tablished in dimethylsulfoxide solution. Irreversible conversion to the tetrazole isomer
occurs upon heating crystals of 3,3'-diazido-5,5'-bis-as-triazine [14]. The reverse process
of the conversion of solid tetrazole derivatives of quinazoline to azide derivatives has also
been noted [15]. A unique case of the conversion of the tetrazole isomer of naphthothiazole
upon heating to the aizde isomer and the reverse process upon cooling were noted by Postovskii
et al. [16].
96
3 o.
/3max 9+o
100 93 la M
41
8O
6O
40 ]3 67 81 94 ] [ 192 l
2O 121 164 1
100(0) . . . . . . . ,, I,a ..lll ,I . , , ,,,.,. ,.... , , ~..-i .,l , . . . . ,...............

80
60 192
M+"
4O
2O
0
40 60 80 100 120 140 160 180 200 220
Fig. 2. Mass spectra of isomers Ia and Ic.

TABLE 2. Elemental Composition of Ions Indicated by the High-Resolution Mass Spectra of


Tetrazole (Ia) and Azide (Ic) of Pyrimido[4,5-e][l,2,4]triazine-6,8-dione and Their Met-
astable Ion Mass Spectra

Measured
Ion Calculated Mass spectra of metastable ions [de-
Ions
composition flecting voltage of the electrostatic
la 1C sector (E0 and El, V)]

M 220,0449 220,0462 C,;H4NsO2 220,0457


[ ( M - N~) +2HI +" 194,0538 C6fI6N602 194,0552
[ M - N21+" I{l},) 192,0388 192,0399 CstI4N~O~ 192.0395 506 (220)* +441 (191,7)
[(d},-N2) +21tl ~" 166,0455 C611sN402 166,0491 506 (192) - - +433 (164,3)
[ q h - N d +" (~.,) 164,0364 161,0351 C~I14N402 164,0351 --~-320 (121,4)
leD2-I!NCO] +" (OOa) 121,0290 121,0292 CslIaN30 121,0270 ---+248 (94,1)
[qba - I ICNp !)1,0174 94,0143 C4H2N~O 94,0167 5o5(~64) - - + 3 7 3 (121,1)
[ { P a - CO] ~" 93,0340 93,0333 C4H~N3 93,0326 504 (t21) - -+392 (94,1)
81,0308 CaI't3Na 81,0326 [--~387 (92,9)

*Parent peak (m/z).


#Calculated mass of the daughter ion (m/z).

Hence, prior to examining the analytical aspects of the mass spectrometric fragmentation of
isomers Ia and Ic, we must study the possible interconversion of these compounds in the gas
phase. Precedents exist for such isomerization [17, 18].
However, there are no isomerizational processes for azide Ic and tetrazole Ia under the
conditions of direct inlet to the ion source (150-170~ injector temperature) as indicated
by the different values of the IE a n d P E of the [M-- N2] + ions upon photoionization [3]~
This finding indicates definite differences in the nature of the fragmentation of isomers
Ia and Ic and requires detailed examination of their mass spectra (Fig. 2).
The fragmentation sequence of the molecular (M+) and major fragment ions for Ia and Ic
was established relative to the mass spectra of the metastable ions obtained in the secondary
fieldless space on a "reverse geometry" spectrometer (DADI/MIKES technique [19]). The ion
composition was found by high-resolution mass spectrometry (Table 2).
Figure 2 indicates that the major difference in the nature of the fragmentation of azide
Ic relative to tetrazole isomer la lies in the detection of ions with m/a 194 and 166 (the
difference in the ratio of the intensities of the peaks of ions M+/[M -- N2] + was discussed
in our previous work [3]). The appearance of these ions is probably not dictated by ion--
molecule reactions (1-10 -7 tort vacuum) although some workers have made such conclusions [20].
In our opinion, it is more realistic to assume the addition of a hydrogen atom to the nitrene

*The lack of interconversions upon heating crystals of I and Ic was indicated in a thermo-
gravimetric study. The DTA curves for each compound differ and there are no peaks for ther-
mal isomerization effects which should be observed in temperature ranges excluding change in
the sample mass (TG and DTG curves).

97
TABLE 3 . Atomic Coordinates (xl0 ~, xl0 ~ for H) and Their
Anisotropic Temperature Factors T = exp[-i/4(B**h~a*~+.,.
+2B=~klb*c~)]
,,,i ,,,

Atom B. B=~ B~=


I
Oql) 1902 (5 7724 (3ti-2219 (6 5,2 (2: 3,8 (2) 3,8 (2 0,2 (2)',- 1,1 (21 0,8 (2)
O{2~ 2980 (5 4871 (311 1365 (ff 6,4 (2: 2,5 (2) 3,9 (2 o,1 (2}1-o,2 (2) 0,2 (2)
N,I} 2924 (5 8139 (4)1 448 (6', 4,0 (2 2,5 (2) 3,2 (2 0,2 (2)1 0,[ (2j 0,4 (2)
N{~ 2534 (5 6309 (4~1 -454 (71 3,6 (21 2,9 (2) 3J (2 0,0 (2)i-0,3 (2) -0,5 (2)
N~s) 4137 (5 6237 (4)1 3856 (6: 3,4 (2' 3,7 (2) 3,4 (2 0,4 (2)1-o,o (2) 02 (2)
N(4) 4558 (5 7010 (5)I 4995 {6] 3,1 (21 4,6 (3) 3,1 (21 0,4 (2)]-0,3 (21 0,2 (2)
N(5 5177 (61 6811 (5)I 6599(7) i 4,5 (3', 6,3 (3) 3,8 (31 0,0 (2)I-0,6 (3 o,7 (3)
N,~ 5391 (6' 7804 (5)] 7290(8) i 4,0 (31 6,8 (3) 4,4 (31 0,3 (3)]-0,3 (2! 1,9 (3)
N(7 4951 (if, 8605 (4)I 6190 (41 5,3 {3', 4,7 (3) 3,7 (31 03 (3) I o8(21 ' - 0 8 (3)
N~8 391l (51 8533 (4~1 3225 (7} 4,0 (2', 3,2 (2) 3,5 (31 03 (2)1-0,2 (2) I-<3 I2)
C(~ 2404 (61 7417 (5)1 -847 (8) 3,3 {3} 3,3 (3) 3,5 (3: 0,3 (2) I o,0 (2) o,o (2)
3oo8 (71 5850 (5}1 I079(8) 3,9 (3) 3,3. (3) 3,2 (31 o,3 (2)] 0,7 (3) o,o (2)
C~3 3898 (6) 5637 (4)1 2405 (8) 3,0 (3) 3,o (3) 3,0 (3~, 0,2 (2)1 0,3 (2) 0,2 (2)
C~4 4447 (71 8131 (5)I 4730 (8) i.l{3) 3,6 (3) 3,7 (31 0,4 (3)j 0,4 (3) -0,3 (3)
C~5 3495 (6} 7810 (4)1 2054 {8) 3,6 (3) '2,7 (2) 3,1 (3) 0,2 (2)I o,3 (2) -0,2 (2)
C~6 2794 (8) 9316 (5}1 78 (9) 5,9 (4) 2,8 (3) 5,0 (3) 0,6 (3L-0,8 (4) 0,3 (3)
HN<~ 241 (5) 586 14~I-142 (7) $
H(~2) 227 (5) 971 (4)1 107 (7)
H{~) 223 (5) 948 (5)1 -107 (7)
377 (5) 962 (4)1 --5 (7) $

~Value of B.

[17, 18, 21] formed exclusively from the azide form upon the loss of an N2 molecule as a re-
sult of thermolysis. This hypothesis is supported by the increase of the peak intensities
of the ions with m/z 192 and 194 over time and the lack of me(as(able transition from M + for
the ion with m/z (Table 2). The addition of hydrogen to the nitrene in this specific case
is apparently accomplished by migration of hydrogen atoms upon the thermal decomposition of
the dimeric or trimeric aggregate of Ic existing in the gas phase. The possible existence
of such aggregates was noted previously for derivatives of tetrazole [22] and pyrazole [23].
Thus, in azide Ic, the [M -- Na] + (~i) arises both due to dissociative ionization and
thermolysis leading finally to ionization of the nitrene and its amine addition product
[(M-- N=) + 2H] +. The formation of amines was observed in the thermolysis of tetrazoles [17].
The appearance of the other fragment ions is related to the decomposition of the ~ ion.
The #s ion and ions with m/z 94 and 93 (Table 2) arise as the result of one-, or two- and
three-step reactions. The metastable ion mass spectra obtained for isomers la and Ic coin-
cide fully, which proves the identity in structure and energy parameters (release of the same
kinetic energy) for ions ~,, ~=, and %3. The following decomposition scheme illustrates the
formation of the major ions:
o

-N2 ~HN ~ 2 ~ . ~ -N2'-HNCO'-HCN


M + (la,IO ----~ j ~i- |C4H2N20]+"
220 0 N N N +' ~ 94
l "" /
CIt3 ~ /-HCN
/
t _N2,_ItNco
:+'" "" L ~ --- I < +.;
i H
Ctt3 @~ 93
@2

These results indicate that la and Ic in the gas phase have structures analogous to
those in the crystalline state (Ic is apparently associated in pairs).
Information on the azide--tetrazole equilibrium in solution was obtained by PMR spectro-
scopy. Thus, the PMR spectrum of la in DMSO-d6 has two singlets with ~ 3.37 and 3.57 ppm
a n d a broad signal with 6 14.00 ppm. Upon the addition of a few drops of CF3COaH, the in-
tensity of the signal at 3.37 ppm increases and that of signal at 3.57 ppm decreases (the
signal at 14.00 ppm disappears). The downfield signal apparently is related to the NH group

98
proton in the uracil fragment, while the interconversion of the intensities of the signals
at 3.37 and 3.57 ppm upon acidification reflects the conversion Of the tetrazole isomer to
the azide isomer. Upon increasing the temperature of the solution of la, there is a shift
in the tautomeric equilibrium toward the azide. Thus, at 35~ we find 91% la and 9% Ic.
At 60~ we find 89% la and 11% Ic. At 100~ we find 77% la and 23% Ic, while at 140~
we find 67% la and 33% Ic. In aqueous solution, the equilibrium is shifted toward the azide;
at 35~ we find 32% la and 68% Ic. The tetrazole isomer predominantes in pyridine; at 35~
we find 65% la and 35% Ic. It is interesting that in the case of 3-azido-5,7-dimethylpyrimido-
[4,5-e][l,2,4]triazine-6,8-dione, the fraction of the tetrazole isomer [4] in pyridine is 15%
less than for the monomethyl derivative la. A significant shift in the Ic la equilibrium
toward tetrazole la (A = 15%) is also observed in aqeuous solution upon the addition of an
equimolar amount of sodium azide.
The azide--tetrazole equilibrium is established most slowly in dimethylsulfoxide solution
(4-5 h). PMR spectroscopy may be used to observe the formation of azide form Ic from an auth-
entic sample of linear tetrazole la. Since only signals for la and Ic are seen in the PMR
spectrum, we may conclude that angular tetrazole Ib does not exist in solution.

EXPERIMENTAL
The electron impact mass spectra were taken on a Varian MAT-311A mass spectrometer under
standard conditions with 70 eV ionization energy and 1.0 mA cathode emission current. The
accelerating voltage was 3 kV and the injector temperature was 150-170~ The high-resolution
mass spectra and the mass spectra of the metastable ions were measured on the same instrument.
The M/AM resolution was 15,000, PFC standard and 0.01 V error in the measurement of the peaks
on a digital voltmeter.
The x-ray diffraction structural analysis was carried out on a Syntex P1 four-circle dif-
fractometer using ~CuKa radiation, graphite monochromator, 8/2e scanning (2 ~ ~ 2e < 120~ A
total of 614 reflections with F 2 > 2o were recorded. The unit cell parameters of ~rthorhombic
crystals of la are a = 9.288(2), ~ = 12.254(3), c = 7.456(2) ~, d c a l c = 1.72 g/cm 3, z = 4,
space group P2,2,2~. The structure was solved by the direct method and refined by the method
of least squares in the anisotropic full-matrix approximation* to R = 0.049, Rw = 0.056. The
atomic coordinates and temperature factors are given in Table 3.
The thermal analysis was carried out on an MOM derivatograph under the conditions de-
scribed in our previous work [18].
The PMR spectra were taken on a Perkin--Elmer R-12B spectrometer at 60 MHz with TMS as the
internal standard using the 6 scale.

LITERATURE CITED
i. V. M. Adanin, S. E. Esipov, A. M. Zyakun, N. A. Klyuev, L. A. Saburova, and V. A. Bondar',
Khim. Geterotsikl. Soedin., No. 9, 1270 (1979).
2. V. M. Kazakova, S. E. Esipov, I. G. Makarov, N. E. Minina, and A. I. Chernyshev, in: Ab-
stracts of the All-Union Symposium on Magnetic Resonance in Biology and Medicine [in Rus-
sian], Moscow (1981), p. 16.
3. N. A. Klyuev, V. M. Adanin, I. Ya. Postovskii, and Yu. A. Azev, Khim. Geterotsikl. Soe-
din., No. 4, 547 (1983).
4. Yu. A. Azev, I. Ya. Postovskii, E. L. Pid~mskii, and A, F. Goleneva, Khim.-farm. Zh.,
14, 39 (1980).
5. Yu. A. Azev, N. N. Verreshchagin, I. Ya. Postovskii, E. L. Pid~mskii, and A. F. Goleneva,
Khim.-farm. Zh., 15, 50 (1981).
6. Yu. A. Azev, N. N. Verreshchagina, E. L. Pid4mskii, A. F. Goleneva, and G. A. Aleksand-
rova, Khim.-farm. Zh., 18, 573 (1984).
7. C. Kuechler, W. Kuech]er, and L. Heinisch, Arzneimit. Forsch., 16, 1122 (1966).
8. A. Messmer, G. Hajos, J. Tamas, and A. Nessmelyi, J. Org. Chem., 44, 1823 (1979).
9. A. V. Bogatskii, S. A. Andronati, Z. I. Zhilina, and N. I, Danilina, Zh. 0rg, Khim., 13,
]773 (1977).
i0. M. M. Goodman, J. L~ Atwood, R. Carlin, W. Hunter, and W. Paudler, J. 0rg. Chem., 41,
2860 (1976).
*Only the positional parameters were refined for the hydrogen atoms found in the difference
map with fixed Bis O = 5.0 A=.

99
ii. S. Nishigaki, M. Ichiba, and K. Senga, J. Org. Chem., 48, 1628 (1983).
12. Tables of Interatomic Distances and Configuration in Molecules and lons, Special Publi-
cation No. 18, London (1965).
13. A, Messmer, G. Hajos, P. Benko, and L. Benko, J. Heterocycl. Chem., i0, 575 (1973).
14. Yu. A. Azev and N. P. Lobanova, i n : Abstracts of the All-Union Conference on Aromatic
Nucleophilic Substitution [in Russian], Novosihirsk (1982), p. 85.
15. I. Ya. Postovskii and I. N. Goncharova, Zh. Obshch. Khim., 33, 2334 (1963).
16. I. Ya. Postovskii, G. N. Tyurenkova, and L. F. Lipatova, Dokl. Akad. Nauk SSSR, 179, I!I
(1968).
17. C. Wentrup, Tetradedron, 26, 4969 (1970).
18. Yu. V. Shurukhin, N. A. Klyuev, I. I. Gradnberg, and V. A. Konchits, Khim. Geterotsikl.
Soedin., No. 19, 1422 (1984).
19. N. A. Klyuev, E. N. Istratov, R. A. Khmel'nitskii, V. A. Zyrayanov, V. L. Rusinov, and
I. Ya. Postovskii, Zh. Org. Khim., 13, 2218 (1977).
20. D. M. Forkey and W. R. Carpenter, Org. Mass Spectrom., ~, 433 (1969).
21. c. Wentrup, A. Mmquestiau, and R. Flammang, Org. Mass Spectrom., 16, 115 (1981).
22. R. R. Fraser and G. K. E. Maque, J. Org. Chem., 34, 4118 (1969).
23. A. N. Kost and I. I. Grandberg, Advances in Heterocyclic Chemistry, Vol. 6, New York
(1966), p. 347.

10-ALKENYLPHENOTHIAZINES.
I. SYNTHESIS AND CIS,TRANS-ISOMERIZATION OF 10-PROPENYLPHENOTHIAZINES

V. A. Anfinogenov, O. A. Napilkova, E. E. Sirotkina, UDC 547.869.2:542.952.4:


V. D. Filimonov, and V. D. Ogorodnikov 541.634

A study was carried out on the isomerization of lO-allylphenothiazine (I)in


DMSO by the action of t-BuOK, KOH and NaOH. The isomerization proceeds stereo-
specifically at room temperature by the action of t-BuOK at an elevated temper-
ature by the action of KOH and NaOH to give cis-10-propenylphenothiazine (II).
The effect of the t-BuOK concentration, temperature and reaction time on the
isomeric composition of the 10-propenylphenothiazines formed was studied. Un-
der conditions of kinetic control, I gives II, which Isomerizes under the re-
action conditions to give an equilibrium mixture of cis- and trans-10-propenyl-
phenothiazine with 44-45% trans isomer III. The isomerization temperature has
virtually no effect on the II/III isomer ratio.

Of the N-akenylphenothiazines, only N-vinylphenothiazine has been studied in considerable


detail [1-3], while the homologs of this compodnd have not been described in the literature.
There has only been mention of 10-propenylphenothiazine obtained by the multistep procedure
in the proof of the structure of the product of the alkylation of phenothiazine by l-chloro-
2-dimethylaminopropane [4].
The base-catalyzed isomerization of N-allylamines is commonly employed in preparative or-
ganic chemistry to obtain N-allylamines [5] but this reaction has not been studied for thia-
zlnes.
In order to obtain lO-propenylphenothiazine, we studied the isomerization of 10-allyl-
phenothiazine (I) in DMSO by the action of t-BuOK, KOH and NaOH.

i. I. Polzunov Altai Polytechnical Institute, Barnaul 656099. Tomsk Institute of Petro-


leum Chemistry, Siberian Division, Academy of Sciences of the USSR, Tomsk 634055 and S. M.
Kirov Tomsk Polytechnical Institute, Tomsk 634004. Translated from Khimiya Geterotsikliches-
kikh Soedinenii, No. i, pp. 121-124, January, 1986. Original article submitted November 21,
1984.

I00 0009-3122/86/2201-0100512.50 9 1986 Plenum Publishing Corporation


TABLE i. Dependence of the
Composition of the Isomer
Mixture of Propenylpheno-
thiazines II/III on Time
and Temperature Upon the
Isomerizationofl([l]o =
Tempera:' II/III
ture, ~ Time, isomer
min ratio, %

5O 300 l oo/o
7O I0 84/16
60 69/3 l
180 62/38
300 61/39
10 77/23
120 59/41
300 56/44
100 10 71/29
180 56/44
300 57/43
150 10 60/40
180 54/46
300 54/46

*Here and subsequently,


0.717 N solution in
t-BuOH.
..... s \
i, i~ ~ '~ , /.. U. z~

"~" ~ " "N "


I i s ~ ! II
Cl~2Ci'Ia CH a C~-C~ . . . . .
ll" "H 11 ( . - - C ~ C l t a
I 11 1II

The isomerization both by the action of t-BuOK and KOH or NaOH gives the complete con-
version of phenothiazine I to a mixture of isomers II and III; other products were not de-
tected. In the presence of t-BuOK, the reaction rate reaches a maximum at a catalyst con-
centration of 0.15 mole/liter and the reaction is complete in this case in 15 min. The ef-
fect of the amount of catalyst on the time required for total conversion of phenothiazine I
at room temperature as determined by thin-layer chromatography is given below. The time for
total conversion is 4320, 75(65) and 15 min for 0.049, 0.083, and 0.15 mole/liter t-BuOK.
PMR spectroscopy at room temperature indicates that the reaction proceeds with high
steric specificity to form exclusively cis isomer II. This finding distinguishes this reac-
tion in the phenothiazine series from the isomerization of dialylallyamines [6] and 9-allyl-
carbazoles [7], in which the isomeric purity of the cis-isomers is not greater than 90%. As
shall be shown below, this is apparently related to the greater thermodynamic stability of cis-
isomer II relative to the trans isomer III.
The effect of temperature and reaction time on the ratio of isomers II and III was eval-
ulated relative to the integral intensities of the methyl group signals in the PMR spectra
(Table I). The trans isomer III appears in the reaction mixture at 70~ and its content after
5 h reaches 39%. A further increase in the reaction temperature to 150~ increases the con-
tent of III to 44-46%. The II ~ III equilibrium is reached 3-5 h after the onset of the iso-
merization and, within experimental error, temperature has virtually no effect on the equili-
brium constant (K) which was found to be 0.82 0.03 (AG,oo = 0.62 0.Ii kJ/mole). We note
that thin-layer chromatography indicates the absence of starting compound I in the reaction
solution. Under analogous conditions, pure cis isomer Ii gives a mixture of cis and trans
isomers II and III with approximately the same composition. Hence, under kinetically con-
trolled conditions, ally]phenothiazine forms II which isomerizes under the reaction conditions
to an equilibrium mixture of the cis and trans isomers, II and III.
The high thermodynamic stability of cis isomer II relative to trans isomer III distin-
guishes lO-propenylphenothiazine from previously studied 9-propenylcarbazoles, for which the
cis isomer is less stable than the trans isomer due to steric interaction of the methyl
group and the planar carbazole ring [7] Our results indicate that the steric interaction

i01
TABLE 2. Conditions for the Preparation of cis-10-P~openyl-
phenothiazine II

l*,mole Catalyst(mole) Temperature, Time,t Yield


~ min % of II,

0,063 t-BuOK (1,6.10 -~) 25 15 89


0,0l t-BuOK (4,9 10-4) 50 I0
0,002 KOH (8,9.10 -~) 25 3600
0,002 KOH (8,9. l0 -4) I00 270
0,251 KOH (2.1.l0 -2) 60 30 68
0,013 NaOH (1,5.10 -2) 60 60 64

*5 ml DMSO per g I.
%Reaction time corresponding to complete conversion of I.

TABLE 3. Spectral Characteristics of 10-Propenylphenothiazines


PMR spectrum (CCl~)* IR spectrum ~, cm
Compound I' '"

II
III
[
H~

6,16,d
6,29,d
Chemical shifts,~, ppm t, j, Hz

5,6,m ],55.d
i

[ 7,0
I 1657
I
i

I 945
."I
5,6, m 1,68, d I 13,0 -- [ --

eFor compounds II and III, the SSCC are: J HB, CHs = 7.0, J
Ha, CHa = 1.5 ~z"
%The signals of the phenothiazine protons form a multiplet at
6.5-7.1 ppm.
%The IR spectrum of II is completely identical to the spectrum
of the mixture of II and III.

of the methyl group and the phenothiazine system in cis-i0-propenylphenothiazine is absent


or very weak compared to cis-9-propenylcarbazole.
This decrease in the steric strain in II is likely a consequence, firstly, of the non-
planar structure of the phenothiazine system [8] and the quasiaxial orientation of the sub-
stituent at the nitrogen atom (extra configuration [9]). It is quite obvious that the ster-
ic interaction in the extra configuration between the cis-methylgroup and the hydrogen atom
at C(,) of the nonplanar heterocyclic fragment in isomer II is less pronounced than in planar
cis-9-propenylcarbazole. Secondly, we should recall that the participation of the nitrogen
unshared electron pair in the extra configuration to the total z-electron conjugation is re-
duced [I0] and, thus, some twisting of the phenothiazine system in II about the C--N bond
leads to a significant suppression of p--, conjugation [7, ii].
The high thermodynamic stability of cis isomer II relative to the trans isomer of 10-
propenylphenothiazine permits us to categorize 10-propenylphenothiazlnes as "anomalous"
olefins, whose cls isomers are more stable than their trans isomers despite steric strain
[12-15]. Unfortunately, we are not able to give an unequivocal explanation for this inter-
esting finding.
This reaction is efficiently catalyzed by KOH and NaOH in DMSO. We should note that, in
contrast to t-BuOK, the isomerization of phenothiazine I in the presence of KOH and NaOH
proceeds stereospecifically both at room temperature and at IO0~ Although the catalytic
activity of KOH and NaOH is much less than that of t-BuOK (Table 2), these hydroxides are
conveniently used for the preparation of cis-10-propenylphenothiazine II to their availability
and ease in handling.
The structures of 10-propenylphenothiazines II and III were demonstrated using IR and
PMR spectroscopy. The spectral parameters are given in Table 3.

EXPERIMENTAL
The IR spectra were taken neat on a IKS-29 spectrometer. The PMR spectra were taken on
a BS-487C spectrometer in CCI~. In the study of the effect of the reaction conditions for

102
the isomerization of I on the ratio of isomers II and III, the spectra were taken in benzene.
Phenothiazine I was prepared according to the method of Simov and Kamenov [16].
cis-10,Propenylphenothiazine (II). A sample of 31 ml 0.51 N t-BuOK in t-BuOH was added
to a solution of 15 g (63 mmoles) 10-allylphenothiazine I in 75 ml dry DMSO and the mixture
was maintained at room temperature for 15 min. The reaction was monitored using thin-layer
chromatography on Silufol plates with 6:1 hexane-ether as the eluent. After the complete
conversion of I, the solution was poured into water. The precipitated oil was extracted with
benzene. The benzene layer was washed with water and dried over potassium carbonate. PMR
spectroscopy indicated that the solution contained cis isomer II. Vacuum distillation and
crystallization from ethanol give 13.4 g (89%) cis-lO-pr0penylphenothiazine as white needles
with mp 34-35~ bp 182-184~ (4 hPa). Found: C 75.4; H 5.3; N 6.0; S 13.2%. Calculated
for C:sHI3NS: C 75.2; H 5.4; N 5.9; S 13.4%.
Mixture of cis-10-propenylphenothiazine (II) and trans-lO-Propenylphenothiazine: (III).
A sample of 5 g (21 mmoles) I and 7 ml 0.69 N t-BuOK in t-BuOH in 25 ml dry DMSO was m a i n -
tained at 100~ for 1 h. T h e isolation of the products was carried out by analogy to the pre-
vious procedure. Vacuum distillation at 191-193~ (5-7 hPa) gave 3.9 g (78%) of a yellow
oil. PMR spectroscopy indicated that the mixture of isomers II and III was 54:46. Isomer
III could not be isolated from the mixture.
The reaction in the presence of KOH and NaOH was carried out by analogy to the above
procedure under the conditions indicated in Table 2. Samples of powdered KOH and NaOH were
used.

LITERATURE CITED
I. G. N. Kurov, L. I. Svyatkina, E. G. Pal'chuk, I. P. Naumova, and G. G. Skvortsova, Zh.
Obshch. Khim., 54, 178 (1984).
2. V. K. Turchaninov, A. G. Gorshkov, M. F. Larin, and G. G. Skvortsov, Vysokomol. Soedin.,
25A, 1892 (1983).
3. G. G. Skvortsova, M. F. Shostakovskii, and G. N. Kurov, Zh. Org. Khim., 8, 382 (1972).
4. P. Charpentier, Comptes Rendus, 225, 306 (1947).
5. M. Ju!ia, A. Schouteeten, and M. Bailerge, Tetrah. Lett., No. 38, 3433 (1974).
6. T. Sauer and H. Prahl, Chem. Ber., 102, 1917 (1969).
7. V. D. Filimonov, S. G. Gorbachev, and E. E. Sirotkina, Khim. Geterotsikl. Soedin., No.
3, 340 (1980).
8. I. I. H. McDowell, Acta Crystogr., 832, 5 (1976).
9. G. Fronsa, R. Mondelli, and G. Scapini, J. Magn. Reson., 23, 437 (1976).
i0. D. Simov, L. Kamenov, and S. Stoyanov, Khim. Geterotsikl. Soedin., No. 4, 497 (1973).
ii. V. D. Fi!imonov, V. A. Anfinogenov, and S. G. Gorbachev, Khim. Geterotsikl. Soedin., No.
12, 1640 (1982).
12. J. Huet, Tetrahedron, 34, 2473 (1978).
13. E. Tasinen and P. Liukas, Acta Chem. Scand., 28, 114 (1974).
14. V. A. Rodionov and V. D. Filimonov, Zh. Org. Khim., 18, 1094 (1982).
15. N. D. Epiotis, D. Bjorkquist, L. Bjorkquist, and S. Sarkanen, J. Am. Chem. Soc., 95,
7558 (1973).
16. D. Simov and L. Kamenov, Godishnik Sof. Univ., 60, 247 (1965/66).

103
LETTERS TO THE EDITOR

NEW TYPE OF RECYCLIZATION OF 2-BENZOPYRYLIUM SALTS

V. G. Brovchenko and E, V. Kuznstsov UDC 547.812+546.137

Decarboxylation of monocyclic a-carboxy-substltuted pyrylium [i], pyridinium salts [2],


pyridine and its bezologs [3] proceeds with the retention of the heterocyclic structure.
We found that when heated with a twofold excess of morpholine in benzene for 2.5 h, l-
aryl-3-carboxy-2-benzopyrylium salts la, b convert into ketols llla, b. It is probable that
the formation of ketols Ilia, b takes place as the result of opening the heterocyclic ring
in adduct II, decarboxylatlon of the intermediate enamine, in a similar way as described in
[4], an attack by the anion formed on the benzophenone carbonyl group carbon atom, and sub-
sequent hydrolysis of the enamine.

CH30 ' //~, ~/-<~ ~COOH

9 -[- f :ooo,,
1

/11

tl i:"
0(:]]3 ocll.s OCII3
la,b II
a R=OClI~;bR=I! H
C 1I.sO -~ /~.. N" CH~O . . ,;.

, CII O" "):" " "~'~'OH

9 OCH3 OCll 3 _ Ilia ~ b ~

Ketols llla,b were isolated after column chromatography on aluminum oxide (eluent--chlor-
oform).
Ketol IIIa. mp 97-98~ (from benzene); yield 68%. IR spectrum (CHCI3): 35.25, 1755,
1590, 1240 cm-*. PMR spectrum (CDCI,): 3.70, quart., JAB = 5 Hz, CH2); 3.82 (s, 30CH3);
3.92 (s, 0CH3); 6.42-7.42 ppm (m, 5H); M + 344.
Ketol IIIb. mp 150-152~ (from benzene); yield 46%. IR spectrum (CHCI,): 3545, 1755,
1600, 1235 cm-*. PMR spectrum (CDCIs): 3.31 and 3.36 (Ch, 2s, CRy); 3.62 (s, OCH~); 3.72
(s, OCH,); 3.80 (s, OCK3); 6.52-7.20 ppm (m, 6H).
The initial, previously unknown salts la,b were obtained by the reaction of 3,4-dimeth-
oxyphenylpyruvic acid with veratraldehyde or anisaldehyde in polyphosphoric acid.
Salt la. mp 296~ (from acetic acid); yield 20%. IR spectrum: 3500, 1725, 1600, lllO
cm-*. PMR spectrum (CF3COOH): 3.55 (s, 30CHs); 3.80 (s, OCHa); 6.95 (d, IH); 7.30 (s, 2H),
7.50 (d, iH); 7.70 (s, IH); 8.20 ppm (s, IH).
Salt lb. mp 290-291~ yield 23%. IR spectrum: 3500, 1715, 1600, 1095 cm-*.
For all the compounds studied, the elemental analysis corresponds to the calculated val-
ues.

Scientific-Research Institute of Physical and Organic Chemistry of the M. A. Suslov


Rostov-on-Don State University, Rostov-on-Don 344090. Translated from Khimiya Geterotsikich-
eskikh Soedinenii, No~ i, pp. 125-126, January, 1986. Original article submitted July iO,
1985.

104 0009-3122/86/2201-0104512.50 9 1986 Plenum Publishing Corporation


LITERATURE CITED
i. Yu. P. Andreichikov, N. V. Kholodova, and G. N. Dorofeenko, Dokl. Akad. Nauk SSSR, 236,
1364 (1977).
2. A . R . Katritzky, R. Awartani, and R. C. Patel, J. Org. Chem., 47, 498 (1982).
3. L. Pakett, Principles of Modern Chemistry of Heterocyclic Compounds [Russian translation],
Mir, Moscow (1971), p. 260.
4. J . K . Stamos, Tetrahedron Lett., 23, 459 (1982).

REACTION OF FLAVYLIUMPERCHLORATE WITH CARBON MONOXIDE

I. M. Gavrilyuk UDC 546.262:547.814

It is known that pyrylium and benzopyrylium salts, unsubstituted at the 4-position, react
with nucleophilic reagents, such as triphenylphosphine [i], or for example malonodinitrile in
the presence of triethylamine [2]. It could be expected that a similar reaction will proceed
also with carbon monoxide, although such examples were not reported in the literature. In
fact, it was found that when CO is passed for a long time into a hot solution of flavylium
perchlorate I in glacial acetic acid, a small amount of blue dye is formed. The latter was
isolated in individual state, and was identified as flavylomonomethinecyanine II, previously
described in [3] (6% after heating for 6 h and passing CO). T h e initial salt I, contaminated
by unidentified impurities, was also isolated from the reaction mixture.
The above described reaction is a new reaction in the series of pyrylium salts, a complex
redox process, whose mechanism is still unknown. However, it can possibly be stated that at
the first stage a nucleophilic addition of CO takes place at the 4-position of salt I, and the
following mechanism can be suggested for this reaction:

~ 5 clo4- %H5["c,~o,- c~.~ zo,


I

c'-o
-CO 2
! ~ t ~ ~ o
o J
| -HCIO 4

1 I 2clo~.- !
Cell~ Cell s _1 C6H5 C6H5
H

LITERATURE CITED
io S. V. Krivun, Dokl. Akad. Nauk SSSR, 182, 347 (1968).
2. F. Kr~nke and K. Dickore, Chem. Bet., 92, 46 (1959).
3. R. Wizinger and H. Tobel, Helv. Chim. Acta, 40, 1305 (1957).

" Institute!of Organic Chemistry of the Ukrainian $SR, Kiev, 252660. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. i, p. 126, January, 1986. Original article sub-
mitted April 15, 1985.

0009-3122/86/2201-0105512.50 9 1986 Plenum Publishing Corporation 105


UNUSUAL REACTION OF N,N-DIMETHYLACETAMIDE DIETHYL ACETAL WITH
2-AMINOMETHYLENE-5,5-DIMETHYLCYCLOHEXANE-I,3~DIONE.
SYNTHESIS OF COUMARIN AND CARBOSTYRIL DERIVATIVES

A. K. Shanazarov, V. V. Chistyakov, UDC 547.814:547.824


and V. G. Granik

It is known that amide acetals react with primary enamines to form enamidines [i]. In
contrast to this, we found that in the reaction of N,N-dimethylacetamide diethyl acetal (I)
with 2-aminomethylene-5,5-dimethylcyclohexane-l,3-dione (II) [2], unexpectedly, not the enam-
idinodiketone II is formed, but a mixture of l,l-bisdimethylamino-3-(2,6-dioxo-4,4-dimethyl)-
cyclohexylidene-l-propene (IV) and l-dimethylamino-l-(a-dimethylamino)ethylideneamino-3-(2,6-
dioxo-4,4-dimethyl)cyclohexylidene-l-propene (V), 3:7 (PMR spectrum) is obtained in an over-
all yield of 90%. Compounds IV and V were separated by fractional crystallization from ethyl
acetate. When the diene-diamine IV was boiled in a 10% aqueous HCI, 5-oxo-7,7-dimethyl-5,6,
7,8-tetrahydrocoumarin (IV) was obtained. Under the same comditions, amidine V, or a mixture
of compounds IV and V give a mixture of courmarin VI and 5-oxo-7,7-dimethyl-5,6,7,8-tetrahydro-
carbostyril (VII). The following compounds were synthesized: IV {yield 38%, mp 163~ (from
ethyl acetate). PMR spectrum (CDCI,): 1.05 (s, 6H, 4', 4'-CH,), 2.35 (s, 4H, 3',5'-CH2),
3.09 (s, 12H, I,I'-Me2N), 6.86 (d, IH, J = 14.7 Hz, 2CH), 7.92 ppm (d, iH, J = 14.7 Hz, 3-CH).
Mass spectrum, m/z: M +" 264, [M -- Me2N] + 220}, V {yield 9%, mp 183~ (from ethyl acetate).
PMR spectrum (CDCIs): 1.03 (s, 6H, 4',4'-CH3), 1.96 (s, 3H, a-CH3), 2.32 (s, 4H, 3',5'-CH2),
3.08 and 3.25 (two s, 3H, u-Me2N in each case), 3.16 (s, 6H, I-Me2N), 7.46 (d, IH, J = 14.4 Hz,
2-CH), 7.63 ppm (d, IH, J = 14.4 Hz, 3-C~). Mass spectrum, m/z: M +" 305, [M-- CH3] + 290;
[M--NMe2] + 261 and [M--NMe2 -- H -- CH3] ~245},VI {yield 96; (from IV), mp 88-900C (from hep-
tane), according to the data in [3], mp 89-92~ and VII {yield 45% (from V, together with
51% of VI), mp 276~ (from ethyl acetate) according to the data in [4], mp 276~

C!I 3
_

CH3~CH 3 + ~ 2' I 0E~ +


CH3" "C}I~ CH s" "CH 1
II ~ iV Y
A IHCI A IICI 0
N.~:_n<~Ctl3
.NMe2 %'I 0
0... 7'<. //0
CH~ + CH
CH 3 v "0 0 CH 3- v "N" "0
H
UI
The results of the elemental analysis of compounds IV and V for C, H, and N correspond
to the calculated data.
Information on the possible mechanism of this unexpected reaction and additional examples
will be submitted later on.

LITERATURE CITED
i. V. G. Granik, N. B. Marchenko, E, O. Sochneva, T. F. Vlasova, A. B. Grigor'ev, M. K.
Poliektov, and R. G. Glushkov, Khim. Geterotsikl. Soedin., No. ii, 1505 (1976).

S. Ordzhonikidze All-Union Scientific-Research Institute for Pharmaceutical Chemistry,


Moscow 119021. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. i, p. 127, Jan-
uary, 1986. Original article submitted August 20, 1985.

106 0009-3122/86/2201-0106512.50 9 1986 Plenum Publishing Corporation


. A. Ya. Strakhov, D. V. Brutane, S. P. Valter, and M. T, Shul'tsa, Izv. Akad. Nuak Latv.
SSR, No. 2, 141 (1971).
3. J. H. Sellstedt, J. Org. Chem., 37, 1337 (1972).
4. A. Roegig, R. Manger, and S. Sch~del, Chem. Ber., iO, 2294 (1960).

I-THIOCARBAMOYL-5-OXY- AND 5-THIOSEMICARBAZIDO-2-PYRAZOLINES

K. N. Zelenin, A. B. Tomchin, UDC 547.772.2'497.1'422:04


O. V. Sol,d, and M. Yu. Malov

Products of the condensation of 1,3-diketones with thiosemicarbazide and its N3-substi -


tuted homologs in a 1:2 ratio have an antitumorigenic activity. These compounds I were as-
sumed to be bisthiosemicarbazones A [1-3], but their structure has not yet been studied.
We found that compounds I have actually a cyclic pyrazoline structure B, and not the
linear structure A. We shall add that also the condensation products of these reagents in a
ratio of i:i (II) are not monohydrazones A, as assumed in [3, 4], but the corresponding 5-
hydroxypyrazolines B.

It .^ R R

NNIIC.~N HIe T IlO" ~N


HA S ~ ::C- - N I I R I
lIB
-" R NNHCSNHR I

............. )~ N ' II
R ! I I N C S N I I N~II N ' - R~ HNC.~NHN
f" = I
S ~-~-C - .-NItR

IB IA

la-c, lla R = CH3, lib R = C6Hs; la, lib R I = H, Ib, lla R I = CH3, Ic R I = C2Hs.
Compound la [3]. PMR spectrum (Py-Ds): 1.58 (3H, t, J = 0.6 Hz, 3-CHs), 1.75 (3H, s,
5-CH3), 2.53 and 3.15 (AB system, JAB I = 18 Hz, j2 = 0.6 Hz, 2H, CH2), 7.30 (IH, s, NHa), 7.96,
8.20 (2H, s, CSNH2), 8.90, 9.17 (2H, s, CSNH2), 9.45 ppm (IH, s, NHB).
Derivative Ib [3]. PMR spectrum (CDCIs): 1.72 (3H, s, 5-CH3), 1.91 (3H, t, J = 0.6 Hz,
3-CH3), 2.58 and 2.92 (AB system, JAB x = 18 Hz, j2 = 0.6 Hz, 2H, CH2), 3.01 (3H, d, 5Hz, N--
CH3), 3.09 (3H, d, 5 Hz, N--CH3), b.65, 6.91 (2H, s, 2NH), 7.35 ppm (2H, m, 2NHCH3).
Compound Ic [3]. PMR spectrum (CDCI3): 1.15 (6H, t, J = 7 Hz, 2C=Hs), 1.73 (3H, s, 5-
CH3), 1.93 (3H, t, J = 0.8 Hz, 3-CH3), 2.61 and 2.91 (AB system, JAB ~ = 18 Hz, j2 = 0.8 Hz,
2H, CH2), 3.3-3.8 (4H, m, 2C2Hs), 6.61, 6.85 (2H, s, 2NH), 7.3 ppm (2H, m 2NHC2Hs). 13C NMR
spectrum (DMSO-D6): 14.5 and 14.6 (q, CH3CH2N), 15.9 (q, 3-CH3), 23.5 (q, 5-CHs), 37.7 (t,
CH3CH2N), 47.1 (t, 4-C), 84.6 (s, 5-C), 154.4 (s, C==N), 174.0 and 181.8 ppm (s, 2C==S).
Derivative lla was obtained by condensation of acetylacetone with N3-methylthiosemicar -
bazide in aqueous acetic acid. Mp 95-97~ PMR spectrum (CDCI3)" 1.87 (3H, s, 5-CH3), 1.94
(3H, t, JH--CH = i Hz, 2-CH3), 2.79 and 3.07 (AB system, JAB 2 = 18 Hz, J= = i Hz, 2H, CH2),
3.00 (3H, d, J = 4 Hz, NCH3), 6.30 (IH, s, OH), 7.25 (1H, m, NH). Foundi C 44.7; H 7.2; N
22.3%. CTH~3N~OS. Calculated: C 44.9; H 7.0; N 22.4%.
Compound llb [4]. PMR spectrum (DMSO-D6): 4.16 and 3.84 (AB system, J = 19 Hz, 2H, CH2),
6.80 (IH, s, OH), 7.5-8.2 (10H, m Harom) , 8.45, 8.65 ppm (2H, s, NH=). ~3C NMR spectrum
(DMSO-D6): 51.4 (4-CH2), 95.4 (5-C, 151.8 (C==N), 175.4 (C==S), 124.0-145.1 ppm (Carom' 8 sig-
nals) .

S. M. Kirov Military Medical Academy, Leningrad 194175. Translated ~rom Khimiya Geter-
otsiklicheskikh Soedinenii, No. i, p. 128, January, 1986. Original article submitted June
25, 1985.

0009-3122/86/2201-0107512.50 9 1986 Plenum Publishing Corporation 107


Our data agree with those known on the structure of malonodialdehyde bisthiosemicarba-
zone [5]. The pyrazoline structure of the above described compounds is interesting in con-
nection with the search for antitumorigenic preparations, which in their activity sre not
inferior to bisthiosemicarbazones of 1,2- and 1,4-dioxo compounds [i],

LITERATURE CITED
i. V. C. Barry, M. L. Conalty, C. N. O'Callaghan, and D. Twomey, Proc. Roy. Irish Acad.,
65B, 309 (1967).
21 G. Losse, W. Hessler, and A. Berth, Chem. Bet., 91, 150 (1958).
3. C. N. O'Callaghan and D. Twomey, J. Chem. Soc., No. 22, 2400 (1967).
4. B. A. Gingras, T. Suprunchuk, and C. H. Bayley, Canad. J. Chem., 40, No. 6, 1053 (1962).
5. H. Buttkus and R. Bose, J. Org. Chem., 36, 3895 (1971).

108
METHODS FOR THE SYNTHESIS OF AZOLES CONTAINING INDOLE SUBSTITUENTS (REVIEW)

V. I. Kelarev and G. A. Shvekhgeimer UDC 547.751:547.77:324.7

A systematic review is given for advances in the synthesis of various azoles (im-
idazoles, oxazoles, thiazoles, pyrazoles, oxadiazoles, and triazoles) containing
indole fragments. A significant number of biologically active compounds have
been found among these bisheterocyclic compounds.

An enormous amount of experimental data has now accumulated in the literature on the syn-
thesis and application of heterocyclic compounds containing indole substituents. However,
only a few indolylazoles were very briefly considered among other bisheterocyclic compounds in
a single review [I].
In compiling this review of the literature data, we preferred to organize the subjects
not according to the indolylazole types but rather according to the means of their preparation
from specific classes of compounds. In our opinion, this approach to the systematization of
the vast literature data gives a clearer concept of the synthetic possibilities of the speci-
fic methods, which may be useful in selecting approaches for further studies on the prepara-
tion of new indolylazoles.
In the present review, we have limited ourselves to noncondensed indolylazoles, in which
the residues of the two heterocycles are joined either directly to each other or by carbon
chains.

i. PREPARATION OF INDOLYLAZOLES
BY THE FISCHER--ARBUZOV REACTION
The Fischer--Arbuzov reaction is the most general and common method for the synthesis of
indole derivatives. However, this method has not yet found extensive use for the synthesis
of indolylazoles since azole carbonyl derivatives and arylhydrazines containing azole residues
have generally been difficult to prepare.
The condensation of N(,)-hetaryl-4-methoxyphenylhydrazines with levulinic acidwas carried
out in order to synthesize structural analogs of the drug indomethacin, [l-(4-chlorobenzoyl)-
2-methyl-5-methoxyindolyl-3-acetic acid] [2, 3].

,- CH O ~ - - CHz-COOH

!
Hei

Het = 2-chlorothiazolyl-4-carbonyl, benzthiazolyl-2


The indomethacin analogs I synthesized display analgesic, anti-inflammatory and high fe-
ver-reducing activity.
The condensation of N(,)-aroyl-N(,)-(4-methoxyphenyl)hydrazines with 1,2-diphenyl-4-(3-
oxobutyl)-3,5-pyrazolinedione [4] or with <l-(2-oxopropyl)-2-methyl-4-nitroimidazoles [5-7]
was used to prepare another type of indomethacin analogs containing heterocyclic fragments
at C(3) of the indole ring.

I. M. Gubkin Moscow Institute of Petroleum Chemistry and Gas Industry, Moscow 117296.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 147-172, February, 1986.
Original article submitted January 4, 1984; revision submitted August 3, 1984.

0009-3122/86/2202-0109512.50 9 1986 Plenum Publishing Corporation 109


CO-At CHj
CO,Ar
I!

n = i, Her = 1,2-diphenyl-3,5-pyrazolidinedione-4-yl; n = 0,
Her = 4-nitro-2-methy!-l-imidazolyl
Compounds containing high analgesic activity were found among indolylazoles If.
A patent has been issued for the preparation of 5-(indolyl-3-methyl)hydantoin (Ill) en-
tailing Fischer--Arbuzov cyclizatlon of the phenylhydrazone of ~-(5-hydantoyl)propionaldehyde
upon heating in hydrochloric acid [8].
0
~ . ---NH

0 ~ . ........
Nll

C6Hs_NII-N:CH-(CIL~)2 --. ~.N/~--O


II
H
III

Tatevosyan et al. [9, i0] synthesized indolybenzlmidazoles IV, which display strong an-
tiviral activity [ill, by heating 2-(3-oxobutyZ)- or 2-(4-oxopentyl)benzimidazoles with phen-
ylhydrazine in the presence of sulfuric acid.

IV CH3/ ~ N ~ ~ / J
H

R = H, alkyl; n = 0, i
2-Alkyl-3-(2-benzoxazolon-3-yl)indoles (V) were obtained in 65-70% yield upon heating
3- (2-oxopropyl)- or 3- (2-oxobutyl)-l, 3-benzoxazol-2-ones with phenylhydrazine in polyphos-
phoric acid [12].

R H
V

R = CHs, CaHs; R l = H, 5-CH3, 5-Ci, 6-SO2NH2


2-(l-Methyl-2-R-imidazol-5-yl)indoles (R = H, SC2H5) [13] and 2-(3-methylisothiazol-4-
yl)indole [14] were prepared by the cyclocondensation of l-methyl-2-R-5-acetylimidazoles and
3-methyl-4-acetylisothiazole with phenylhydrazines in the presence of zinc chloride. How-
ever, the yield of these indolylazoles did not exceed 25-40%.
The phenylhydrazones of 4- or 5-acetylthiazoles were converted by the Fischer-Arbuzov
reaction to indolythiazoles VI or VII, respectively [15]. High pesticide activity was n o t e d
for these compounds.

VI VII

R = H, CH3, Ph, COOH, COOC2Hs; R 1 = H, CHs


A patent was i s s u e d i n 1981 f o r the synthesis of 2-(5-R-3-R~-isoxazol-4-yl)indoles (R =
H, alkyl; R z = H, alkyl, aryl), which were obtained in high yield by the cyclization of 4-
aeetyl-5-R-3-RZ-isoxazole phenylhydrazone in polyphosphoric acid. These indole derivatives

ii0
are key compounds in the preparation of biologically active tryptamine analogs containing
isoxazole fragments.

2. PREPARATION OF INDOLYLAZOLES BY THE ALKYLATION


OR ACYLATION OF INDOLE AND ITS DERIVATIVES
l-(Imidazolinyl-2-methyl)indoles (VIII) are formed upon the alkylation of 2-arylindoles
by 2-chloromethylimidazoline in the presence of sodium hydride [17, 18].

-NaCl ~../'~.N/~-.Ar
~/~N H Ar H ! N--

N--...J
VIII H

R = H, CHs, C1; R x -- H, CHa; Ar = Ph) 4-ClC6H4, 4-CHs0CaHa

Hocker and Merten [19, 20] found that the alkylation of indole and 2-substituted indoles
by bis(l,3-diphenyl-2-imidazolidinylidene), which is a cyclic analog of tetraminoethylene,
proceeds at C(s) with the formation of 3-(1,3-diphenylimidazolidin-2-yl) indoles (IX).

~ sH5 COCH 3

9 N-,

H
ix_ x kl
R = H, CHs, Ph
Bergman [21] in an attempt to acylate indole with N-acetylimidazole in acetic anhydride
isolated the indole hetarylation product, 1,3-diacetyl-2-(indol-3-yl)-4-imidazoline (X) in-
stead of the expected N-acetylindole. This author considered that (X) is formed by electro-
philic attack at C(s) in indole by the 1,3-diacetylimidazolinium cation generated from N-ace-
tylimidazole. Also, heating indole with thiazole in acetic anhydride gave l-acetyl-2-(l-
acetylindol-3-yl)-4-thiazo!ine (Xl) [21].
D detailed study was carried out on the hetarylation of indoles not substituted at C(s)
by N-acylimidazolinium or N-acylhenzimidazolinium salts (XII) in situ. Sheinkman et al.
[22-24] reported that the reaction of indoles with imidazole or benzimidazole in the presence
of the acid chlorides or aliphatic, aromatic, or heterocyclic acids gave 3-(l,3-diacylimida-
zolin-2-yl)- or 3-(l,3-dfacylbenzimidazolin-2-yl)indoles (XII).

N" It;' i-. ~'Ol:


. COR

+ RCOCI - ~- , CI
I ;
i !
'N
i ("OR I~;'" " N
i.. (,OR
Xlll
XII

R = CHs, Ph, thienyl-2; R* = H, CHs; R ~ = H, CHs


The formation of salts Xll as intermediates was confirmed by the preparation of XIII un-
der analogous conditions using N-acylimidazoles instead of imldazole.
The benzoxazole fragment could not be introduced into the indole ring by the reaction
of indole with benzoxazole in the presence of acylating reagents in an inert solvent or by
using benzoxazole salts, which resulted only in N-acyl-o-aminophenols and tris(indol-3-yl)-
methane [25].
The reaction of indole with 4-ethoxymethylene-2-phenyl-5-oxazoline in acid medium gave
4-(indol-3-ylmethyl)-2-phenyl-5-oxazolone, which is an important intermediate in the synthe-
sis of tryptophan [26].

Iii
Heating a mixture of indole or i~s derivatives not substituted at C(z) with 2-chioro-
ethyl Iso~hiocyanate in 1,2-dlmethoxyethane in the presence of sodium hydride at reflux gave
l-(Aa-thiazolin-2-yl)indoles (XZV), which are intermediates in the preparation of anti-in-
flammatory agents [27-30].

' " 1r " "R


" 1
S.+~ % N

XIV

R = H, thiazolyl-4; R z = H, (CHa)aNCHa; R a = H, CHaO, NOa

3. PREPARATION OF INDOLYLAZOLE$ FROM INDOLE C~BONYL DERIVATIVES


1,3-Disubstituted 2-(indol-3-yl)imidazolidlnes (XV) were synthesized by the cyclocon-
densation of l-acetyl-3-formyllndole with N,N'-dlarylethylenediamines with subsequent hydro-
lysis of the N-acetyl derivatives formed [31].

Ar Ar

< .:'+ . +

A ..o.o+ +"~"i"'.";- i ii Ii'~'i;m " ~i 'I , "~.m,~


ArlIN CI[ z N Ar ', "N" Ar
I 11
]
COCII3 ~,
(:(>r X','

Ar = Ph, 4-CHa0CeH4, 4-BrC6H~, C6HsCH2


3-Formylindole does not undergo this reaction, apparently due to insufficient electro-
philicity of the carbonyl group carbon atom. The introduction of electron-donor groups in
the benzene ring of the amines leads to increased yields of indolylimidazolidines XV. On
the other hand, electron-withdrawing substituents hinder the cyclocondensation. For example,
indolylimidazolidines could not be prepared from N,N'-di(4-nitrophenyl)- or N,N'-di(4-ethoxy-
carbonylphenyl)ethylenediamine.
3-Formylindole reacts readily with 2-mercaptoethylamine, which is a stronger nucleophile,
to give 2-(indol-3-yl)thiazolidine in high yield [32].
Heating Schiff bases XVI with acetic anhydride gives both acylation and cyclization to form
l-acetyl-2-(l-acetylindol-3-yl)oxazolidines (XVII) [33].

0--- P~

,.... , , _ + +

++

XWI
h + + +
+ , +

i
COCH 3

XVI1
oi!
R = H, CHs, C2H~, Ph, 4-CHsC6H~
The reaction of 3-formylindole hydrazones with 2,4-dinitrophenyl azide proceeds anomal-
ously with the formation of 2,5-disubstituted tetrazoles XVIII [34].

111
N ~ f~ ..... N Nh2
.... II + l
+~ ii-+ -i[ + [+~
~..~j .... L~. i[........+~
I + '~%
N" "r ~" ~:" N'
( I t J
R NO 2 R NO2
X"~'III

R = H, C6HsCH2; R ~ = Ph, 4-BrC6H~, 2,4-(NO2)=C6Ha, CONH=


4-(Indol-3-ylmethylene)-5-oxazolones (XIX), which are important intermediates in the
synthesis of tryptamine, tryptophan, and other biologically active indoles are readily formed

112
from 3-formylindole and N-acyl derivatives of glycine in the presence of potassium acetate
in acetic anhydride [35-38].

O,

H H
~X

R = H, COOCaHs; R x ffi CHs, Ph


The reaction of 3-formylindole with nitroacetate esters in the presence of sodium ace-
tate gives esters of the N-oxides of 4-(indol-3-yl)-3,5-dicarboxyisoxazolines (XXI) [39].
The extremely reactive nitroalkene X X w a s proposed as an intermediate, which rapidly reacts
with the starting nitroesters. The treatment of N-oxides XXI by aqueous ammonia gives the
diams of 4-(indol-3-yl)isoxazole-3,5-dicarboxylic acid (XXII).

1"-'*d--CliO + 02NCH2C00R ~ Ind--CH(OH)CH(NO2)COOR ~ Ind --CH:C--COOR -~---m.-


. -H20 I
N0 2

Ind C00R NH~_.Ind ~-~:--':- I~


02NCH2COOR ~02 "-~
--'- Ind--CtI-CH--COOB I
_lIND2
CONII2

CH(NO2)COOR ROOC H2NOC/k~N/0


O
X~ XXII

R = CHs, CeHsCHa; here and subsequently, Ind = 3-indolyl


4,5-Diaryl-2-(indol-3-yl)imidazoles were isolated in 60-67% yields as a result of the
cyclocondensation of 3-formylindole or its N-methyl derivative with aromatic a-diketones
[40, 41].
Indole aldehydes may undergo condensation with some azoles containing active methylene
or methyl groups. Thus, cyanine dyes XXIII were synthesized from substituted 3-formylin-
doles and the corresponding 2-alkylbenzazole salts. These dyes have been proposed for use
in photographic films [42-46].
.Y
X ...... 7

B" ~3 " R B-

XXIII
R, R x, R a, R s = H, alkyl, aryl; R ~ = H, CN; X = O, S, Se; Y =
CH, N; B - = I-, Ts-, ClO~-
Dyes obtained by the condensation of l-methyl-2-phenyl-3-formylindole with 3-substituted
derivatives of 5-pyrazolone and 5-isoxazolone have been used for the same purposes [47, 48].
IndolylmethyldenazolesXXIV which display strong anti-inflammatory action are formed by
the condensation of 3-formylindoles with derivatives of imidazolidine, isoxazoline, pyrazol-
ine, pyrazoline and thiazolidine containing the --CHaCO--group i ~ t h e ring [49-53].

(X h

I I
R R

X = --NH--CO-RNH--, --C(CHs) = N-O-, -CO--NPh--NR*--, --CRs = N--NRa-,


--NH--CO--S--; R, R*, R 2 = H, aryl~ R s = CHs, NHa
The Knoevenagel reaction of 3-acetylindole with 5-formyl-3-phenylisoxazoline gave the
corresponding ~,8-unsatumated ketone XXV [54].

113
In6--CO-CH~ + OHC--- ~,. . ."HaO
.. ~ I~d- C0-CH=: C l l ~ 0 1 N
XXV
a,8-Unsaturated aldehydes and ketones, a-epoxyketones, 8-diketones, and a,8-diketoesters
of the indole series are convenient starting compounds for the synthesis of various indolyl-
pyrazoles.
Heating 8-(l-acetylindol-3-yl)acroleln (XXVI, R = Ar with hydrazine hydrate or phenyl-
hydrazine in acetic acid at reflux gave 1-substltuted 5-(l-acetylindol-3-yl)pyrazolines
(XXVII), which upon treatment with ethanolic alkali are converted to l-substituted 5-(indol-
3-yl)pyrazolines (XXVIII) [55].
The phenylhydrazone of 8-(indol-3-yl)acrolein (XXV, R = H) upon heating at reflux in
acetic acid is slowly cyclized to l-phenyl-5-(indol-3-yl)pyrazoline (XXVII, R: = Ph). The
phenylhydrazone of N-substituted aldehyde XXVI (R = Ac) undergoes more rapid cyclization un-
der the same conditions to give pyrazoline derivative XXVII (R = Ac, R: = Ph) and, upon de-
acylation, pyrazoline XXVIII (R = H, R ~ = Ph).
These authors consider that nucleophilic addition at the -CH=CH - double bond is diffi-
cult in ~-(indol-3-yl)acrolein due to the strong electron-donor effect of the indolyl group.
The introduction of an acetylgroup at N(z) in the indole system reduces the electron-donor
effect of the indole group and increases the reactivity of aldehyde XXVl (R = Ac) relative to
nucleophilic reagents.
Suvorov et al. [55] have proposed the following method for the synthesis of l-phenyl-5-
(indol-3-yl)pyrazole (XXIX).

] I n
COClI~ COCH a
~VI X~X

The reaction of l-(indol-3-yl)-3-aryl-3-propenones (XXX), which are the products of the


Knoevenagel reaction of 3-formylindole and methyl aryl ketones, with arylhydrazines lead to
the formation of 1,3-disubstituted 5-(indol-3-yl)pyrazolines (XXXI) [56-59].

//-~. ,~_..... /CHInCH-CO-At ~ ~ .- ] ~N..i~l ~Ar

H H
XX.-X XX~I
R=H, Ar
Indolypyrazolines EXXI have valuable properties and are central nervous system depres-
sants [57], anticonvulsants, monoamine oxidase inhibitors [58], and anti-inflammatory agents
[59]. These compounds also have strong luminescence both in the solid state and in solution
[561.
Indolylpyrazolines XXXIII which contain indolyl fragments at C(s) of the pyrazoline ring
were synthesized by heating l-(indol,3-yl)-3-aryl-l-propenones (XXXII) with a large excess of
hydrazine hydrate [60, 61].

Ind

Ind ~ CO-CH=CIt-A~ + N~lt4'tI~O .... !~ ~N~7s Ar


I
R
X.~XII .XD~XIII
R = H, Ac
Pyrazolines XXXIII w h i c h a r e n o t s u b s t i t u t e d at N(,) of the pyrazoline ring (R = H) a r e
rather unstable compounds which decompose upon purification. However, carrying out the re-
action in acetic acid leads to the formation of 1-acetyl derivatives of p y r a z o l i n e s XXX!II
(R = Ac) which are completely stable compounds [61].

114
Unsaturated indole ketones may also be used to prepare indolylisoxazollnes. For exam-
ple, the heating Df ketones XXXWIth hydroxylamine gave 3-aryl-5-(indol-3-yl)isoxazollnes
(XXXIV) [62].

.At

Ind

Piozzi and Fuganti [60] studied the reaction of vinyl 3-indolyl ketone with hydroxylam-
ine to give 3-~indol-3-yl)isoxazoline and noted the inability to synthesize analogous isox-
azoline derivatives from l-(indol-3-yl)-3-phenyl-l-propenone (XXXll).lerivatives from l-(in-
dol-3-yl)-3-phenyl-l-propenone (XXXII),
Considerable interest is found in the reaction of indole ~-epoxyketones with hydrazine
hydrate, which, depending on the reaction conditions, leads to the formation of either 3-(in-
dol-3-yl)-4-hydroxy-5-arylpyrazolines (XXXV) [54, 63, 64] or 3-(indol-3-yl)-4-arylpyrazoles
(XXXVI, R = H) [60]. Pyrazolines XXXV are obtained upon carrying out the cyclocondensation
in alcohol using catalytic amounts of acetic acid, while pyrazoles XXXVI are obtained in eth-
er in the presence of BF3"0(CIHs),.

[rid ~I"

had 01f .~g~,'.. ~ "'N"


I} ' I N7114" 1f:~0 ;:--~.% ,{
CO CIi CII A r - -~
" " ~2~/A~,x x:kx v I
H

f" Ar
i
coil b
"%'<>{!'i l

R = H i Ph
Carrying out this reaction in acetic acid gives l-phenyl-3-(indol-3-yl)-5-arylpyrazoles
(XEXVII) [63, 64], while l-phenyl-3-(indol-3-yl)-4-arylpyrazoles (XXXVl, R = Ph) were ob-
tained in e:her in the presence of BF3 etherate [60]~
The reaction of ~-diketones XEXVIII with hydroxylamlne gave 3-aryliS-(indol-3-yl)isoxa-
zolines (XXXIX) [66], while the action of hydrazine hydrate or phenylhydrazine gave 3-aryl-5-
(indol-3-yl)pyrazoles (XL) [64, 67].

.At .At
........ hid C 0 Ctl ,CO A r I N
Ind ]C<XVlll hid N"

~D~LE XL
R=H, Ph
The ethyl ester of 4-(indol-3-yl)-2,4-butanedionoic acid (XLI) reacts with hydrazine
hydrate or phenylhydrazine in acetic acid to form the ethyl esters of l-R-5-(indol-3-yl)py-
razole-3-carboxylic acids (XLII), which were converted to l-R-5-(indol-3-yl)pyrazoles (XLIII)
upon subsequent hydrolysis to the acid and decarboxylation; these pyrazoles have high anti-
inflammatory activity [68, 69].

115
,COOC, LI,,
.... )I h
~" ,<,,,N,, N
lnd
i I
~,+,~,,~' R
ELl[ XLIII

Ind CO' f)H,~(IO9 COOC,!I] ~ : ,~'~t

coo('Jl:~

~0
[t)d '
XLIV

R=H, Ph

Treatment of 8-diketoester XLI with hydroxylamine in the presence of pyridine gives a


high yield of the ethyl ester of 5-(indol-3-yl)isoxazole-3-carboxylic acid (XLIV) [70]. An
interesting transformation occurs in the reaction of ester XLIV with hydrazine hydrate in
ethanol at reflux which gives the hydrazide of 5-(indol-3-yl)pyrazole-3-carboxylic acid.
Indole a-haloketones have been used in the synthesis of indolylimidazoles and indolyl-
thiazoles. Thus, heating 3-chloroacetylindole with a large excess of formamide gives 4(5)-
(indol-3-yl)imidazole [71], while heating with a stoichiometric amount of formamide and phos-
phorus pentasulfide gives 4-(indol-3-yl)thiazole [72]. Suvorov et al. [71] noted the inabil-
ity to extend this method for the preparation of indolylimidazoles from the amides of other
acids. For example, the reaction of 3-chloroacetyllndole with acetamide proceeds with heavy
tar formation and 2-methyl-4-(indol-3-yl)imldazole was isolated from the reaction mixture in
only a 4% yield.
The cyclocondensation of 3-chlbroacetylindoles with acid thioamides gives 2-substituted
4-(indol-3-yl)thiazoles (XLV) [14, 73], while this reaction with thiourea or N-substituted
thioureas gives 2-amino-4-(indol-3-yl)thiazoles (XLVI) or their N-substituted derivatives
[14, 72].
.,. ~ COCH.CI

"'~'/ ".'N'" ~'R ~'S"-"'R 1 - -" . . . . .


'~ N "~ ~ "~<." " N ~ R \s N~m2
II II H
XLV XLVl

R = H, CHs; R ~ = CHs, aryl, pyridyl-3! R 2 = H, CHs, NH2,


C(=NH)NHz
Significant interest is found in the condensation of 3-chloroacetylindoles with the func-
tional derivatives of several azoles in the synthesis of indolylazoles. For example, the re-
action of ~-chloroketones with 2-imidazolidinethione gives 5,6-dihydro-3-(2-R-indol-3-yl)-
thiazolo[3,2-a]imidazoles (XLVlI) while this reaction with 2-amino-Aa-thiazoline gives 2-
imino-3-[l-oxo-l-(2-R-indol-3-yl)ethyl]thiazolidines (XLVIII) [14].

H H It
~NI! XLVIII

R = H, CHs

Indolylthiazoles XLV-XLVIII have a broad range of pharmaceutical activity and are cen-
tralnervous system depressants, analgesics, and antibacterial agents as well as substances
used for lowering arterial pressure [14, 72, 73].
3-Aminoacetylindole hydrochloride was used in the synthesis of indolylimidazoles [71, 74].
The reaction of this hydrochloride with molten potassium thiocyanate gives a 16% yield of 5-
(indol-3-yl)-2-imidazolethione (XLIX). Heating this hydrochloride with an equivalent amount
of isothiocyanates gives 1-substituted 5-(indol-3-yl)-2-imidazolethiones (L) in 30-50% yield.
The desulfurization of 2-imidazolethiones XLIX and L by nancy nickel in ethanol leads to the
corresponding indolylimidazoles LI and LII which display tuberculostatic activity [71, 74].

116
lnd Ind
KSCN NH
II J =- I r7
L N ~S
N
li It
lnd--I;0CH~.NHT. IICI XIJX LI
lnd Ind R
RNCS Ni N

It
L I.II

The antibiotic pimprinine was isolated from several natural products and identified in
1960 as 2-methyl-5-(indol-3-yl)oxazole (LIII) [75]. The structure of pimprinine was confirmed
by its synthesis from 3-aminoacetylindole hydrobromide [76-78].

9 1-Ac,aO + CsHsN CH3 D" C


2.POCIa "-~
it I H
C0CH3 LIII

In 1981, Houwing et al. [79, 80] reported the preparation of pimprinine analogs (LIV)
by the condensation of substituted 3-formylindoles with ~-tosylisocyanide or with dimethoxy-
N-tosylmethylimine; these analogs display antihistiminic activity [80].

R2 .

I~1 ~, CHO R~ It "N

+ Ts CH N ::C ~ ~
k . -" "N 1~'~ "P'" "- "
l.t R LIV

R ffiCHs,(CHs)2NCO; R x ffiH, CHsO, NO2; R a = H, CHs; R s ffiH,


CHsO
There has been a report of the use of l-acetylindoxyl (LV) as the starting agent for the
preparation of some indolylazoles. For example, the condensation of indoxyl LV with 1,2-
diphenyl-3,5-pyrazolidinedione gives a quantitative yield of I, 2-diphenyl-4- (1-acetylindol-3-
yl)-3,5-pyrazolidinedione (LVI) [81].
o~ -N C e H s
..~. .0 O~ C6H 5

I 0>" ~'C6115 !
COCI[~ CCCH3
LV Lvl

Heating carboethoxyisopropylidene hydrazone with l-acetylindoxyl in polyphosphoric acid


at 90~ gives intramolecular cyclizationwith the formation of 3-methyl-l-(l-acetylindol-3-
yl)-5-pyrazolinone [82].

4. PREPARATION OF INDOLYLAZOLES FROM INDOLE


CARBOXYLIC ACIDS AND THEIR FUNCTIONAL DERIVATIVES
Indole acids themselves have rarely been used for the preparation of indolylazoles until
recently. The condensation of derivatives of indol-3-ylacetic acids with o-phenylenediamine
leading to the corresponding 2-(indol-3-ylmethyl)benzimidazoles (IV) [9] has been described
in [9],

~ ,:. 11 ~
.~ CII COOII NH2~- . " ' k
. 4.~ H

" ~ ' / ' " ~z'"ctt~i} NI,, ": L. ~ IIN CH~


IV

R = H, C~H9

117
The reaction was carried out by heating the corresponding acids with a large excess of
o-phenylenediamine in 4 N hydrochloric acid at reflux, However, the yields of indolylbenzim-
idazoles did not exceed 30%.
The reaction of ~-(indol-3-yl)alkanoie acids with tris(hydroxymethyl)methylamine gave
4-di(hydroxymethyl)-2-~-[(indol-3-yl)alkyl]-A'-oxazolines (LVII) [64].

Ind-(CH2)n-C00lI + NII2C(ClI20H)-~ ..... ~ Ind-(CII2),V-


N----~-CH20H
C}I20H
Lu
n=l-4
5-[a-(Indol-3-yl)ethyl]oxazole (LVIII) is an important intermediate in the synthesis of
the alkaloid, ellipticine, which stimulates brain activity and was prepared by the reaction
of the methyl ester of 2-(indol-3-yl)propionic acid with lithium methyl isocyanide at --50~
[83].

Ind-C[{(CII3)-COOCIl ~ + LiCII=N=C ~ Ind-'CH(CII'~).... "O 1

LVIII

Suvorov et al. [84] used the condensation of ethyl (indol-3-ylmethyl)malonate with hy-
drazobenzene in ethanol in the presence of sodium ethylate to obtain 1,2-dlphenyl-4-(indol-
3-ylmethyl)pyrazolidine-3,5-dione.
S-[~-Carbomethoxy-B-(indol-3-yl)ethyl]thiuroniumhydrobromide obtained from the methyl
ester of ~-bromo-8-(indol-3-yl)proplonic acid and thiourea is cycllzed upon heating in water
to give 5-(indol-3-ylmethyl)thiazolidine-2,4-dlonewhich has tuberculostatic activity [85].
Of all the functional derivatives of indolecarboxylic acids used as starting materials
in the preparation of indolylazoles, the nitriles of indole acids have been studied most ex-
tensively.
The hydrogenation of 3-indoly!acetonitriles or their N-acetyl derivatives over Raney
nickel in the presence of N,N'-diphenylethylenediamine leads to 1,3-diphenyl-2-(indol-3-yl-
methyl)imidazolidines (LIX) [86, 87].

~sH5
~\ c.~-cN Co%HN-~., H~ F" it- il~ ~_t
/ " C6HsHN-CH 2 Ni '~"
, ,J c' .o
I
LIX
R=H, Ac
Great interest has been found in the reaction of 3-indolylacetonitriles with ethylene-
diamine which gives indolylimidazoline s [88-94]. Thus, heating these nitriles with anhy-
drous ethylenediamine in the presence of sulfur compounds gives 2-(indol-3-ylmethyl)-A=-imi -
dazoles (LX). Hydrogen sulfide, carbon disulfide, phosphorus pentasulflde, aluminum sulfide
[88] and p-toluenesulfonic acid have been used as catalysts for this reaction [89, 94].

H H
LX
R : H, C1, Br, F, CHsO
Indolylimidazolines LX which may be formally considered as tryptamine derivatives have
various biological activities and are antidepressants, vasoconstrictors [91], repellants
[92], and serotonin antimetabolites [90].
Analogously, l-cyanomethyl-3-alkylindoles and ethylenediamine give 3-alkyl-l-(imidazol-
inyl-2-methyl~indoles (LXI), which display strong vasoconstrictor activity [93].

118
CI{, ':/ ! ~"~" N
N ! It
1II H LXll

The cyclocondensation of indol-3-ylacetonitrile with B-mercaptoethylamine gives good


yield of 2-(indol-3-ylmethyl)-Al-thiazoline (LXII), which combines significant bacteriosta-
tic activity with low toxicity [95].
In the search for effective anti-inflammatory agents, a series of indomethacine analogs
LXIV has been prepared containing a tetrazole residue instead of the carboxyl group. The
synthesis of these compounds is carried out by the prolonged heating of 3-indolylacetic ac-
ids with sodium azide and aluminum chloride [96] or ammonium chloride [97] in DMF or THF.
These tetrazoles (LXIII) were subsequently acylated at the nitrogen a t o m of the indole frag-
ment in the presence of sodium hydride [97-100].

N -N N .....

~/ " N/
COCJ14CI
i).~ii IXIV

R = H, Cl, Br, CH30; R* ffi H, CHs


Of all the compounds synthesized, greatest activity was found for 5-(l-p-chlorobenzoyl-
indol-3-ylmethyl) tetrazole (LIV, R = R* = H) [97]. This compound also has antiserotonin and
antihistimine activities [98, i00].
The reaction of ethyl ester of 3-cyano-3-(indol-3-yl)propionic acid with sodium azide
and ammonium chloride gives the ester of 3-(tetrazol-5-yl)-3-(indol-3-yl)propionic a c i d (LXV),
which upon hydrazinolysis and subsequent Curtius rearrangement in the presence of ethanol is
converted to the corresponding urethane LXVI. Upon alkaline hydrolysis and decarboxylation,
LXVI gives 8-(tetrazol-5-yl)tryptamine (LXVlI) which displays antidepressant and hypotensive
activities [i01].

N N N ~ N -N

indl -C}I-CN -
N.N~
.' h)d I CH
[I i, 9
t:~ m.- l n ( ] '
9
t:H ,
]L hi
,:" - ~ h~d ! CH
[i
,.
INI
l i " N ] N - C2Hso 11
CH2COOC~II 5 }I i I{ I "N
H
. CII2COOC.2H5 (;[I,zNtICO0~2 H 5 "CO 7 CIt2NIt 2
I LK'r 12/', I L x~WII

Ind* = 4-chloroindol-3-yl, 4-chloro-5-methoxyindol-B-yl, 6-


chloro-5-me thoxyindo l-3-yl
N-Acetyl-~-cyano-8-carboethoxy-6-chlorotryptamine reacts with sodium azide in the pre-
sence of AICIs to give the corresponding tetrazole LXVIII, which upon alkaline hydrolysis is
converted to ~-(tetrazol-5-yl)-6-chlorotryptamine (LXIX) [102].

NHAa
NIIAe i N N N - N
N~'I~ , ~ ]I i! l)
1.d' e.T i: cN NtI~ r t ),,,l '.":<.;,"~ N ~ - t~,,,' e . , i H JP" N .~
COOCIH~ :i 1[ NI," 2 1{
COOC ,li >
L:.V[H ,>:,X
2nd ~ = 6-chioroindol-B-yl
Taborsky [103] obtained an unusual result upon the prolonged heating of indol-3-ylace-
tonitrile with anhydrous hydrazine (in 2:1 mole ratio), which yielded 4-amino-3,5-bis(indol-
3-ylme thyl) -i, 2,4-t riazole.
Indol-3-ylacetonitrile has been used in the Knoevenagel reaction with several hetero-
cyclic aldehydes to give trisubstituted ethylenes LXX [104].

119
{~N
lnd*~ClI~*CN + [Iot,=(~llO ~ h~d {!~,C|I* llot

Bet = s 1-benzylimidazolin-2-yZ, 4-meth-


ylthiazol-2-yt
A convenient method f o r the p r e p a r a t i o n of indolyZoxadiazoles e n t a i l s ~he s
cycloaddition of indole nitriles with nitrile N-oxldes [105]. Thus, 3-cyanoindole, Indol-3-
ylacetonitrile and B-(indol-3-yl)propionitrile and aromatic nltrlle N-oxldes, generated ~n
s~r from the corresponding arylhydroxamic acid chlorides, gave 3-aryl-5-[(Indol-3-yl)alkyl]-
1,2,4-oxadiazoles (LXXI).

A~
i . l[Id ~-(CH~)n'~CN N 0~

,4.............................................................................
-HCI

n = 0, i, 2~ Ar = Ph, 4-OaNC6Hd, 4-ClCsHd, 3-CHsC6H~


Dyankova et el. [106, 107] have found that the best yleld of adducts LXXI is achieved
upon carrying out this reaction in the presence of boron trifluoride etherate, which enhances
the dipolarophilic activity of the nitrile group due to complexation. Oxadiazoles LXXI were
also obtained upon heating of these nltriles and arylhydroxamic acid chlorides in an inert
solvent for >48 h.
These authors [105-107] have noted that the yields of adducts LXEI synthesized by the
thermal condensation of nitriles with arylhydroxemic acid chlorldes are signlficantly higher
than in the reaction with nitrile N-oxldes.
Carboxylic acid iminoester hydrochlorides may be used as convenient starting materials
in the synthesis of various azoles. However~ only limited information is available on the
use of indole acid iminoester hydrochlorides for these purposes.
The condensation of indolylalkanoic acid imlnoester hydrochlorides with ethylenediamine
has been described [108-110]. This reaction proceeds rapidly under mild conditions and gives
a high yield of 2-substituted A2-imidazolines (LXXII).

R',
"r:<~.}1 .......I'",C[{R'(CH2).C"
" "oc~% l~- S)'~". . . . . . . . . . CIIR_(CII2)n_.~/~" I

Zl " -NIIdCt It
L~XII
R = H, Ph, 3-CHsOC~H~; R x = II, Clls; R 2 = H, CI, CHs0; n = 0, i
2-[B-(lndol-3-yl)phenethyl]-A2-1midazoline hydrochloride (LXXs163 R = Ph, R z = R 2 = H,
n = l) displays strong sympatholytic activity [108]. We should also note that 2-(indol-3-
yZalkyl)-AZ-imidazolines (LXXZZ, n = l) have recently been found to possess pronounced ra-
dioprotective activity [5, ii0].
Fel'dman e t a l . [111] have synthesized 5-imidazolones (LXXIIs which are unstable under
ordinary conditions, from the ethyl iminoester of 3-indolylacid and a-amino acids according
to the scheme:

Ind --CHI-C ~NH


~ + tI2N-CHR-COOH ........... ~
/~
Ind --CIIz-C~ NH
~2H50H
OC2H5 -C2}Is0|I NHCftRC00H HCI

.... ~ Ind ~-CIt2--c~NIt'HC1 0H~ N~ ~F ~0


~NIICHRC00C2H5 ~_C2Hs0H ~ Ind --CH2~ ~ '

12~III

R = H, i-CsH~, i-C4Hg, s-C4Hg~ indol-3-ylmethyl


In our previous work [112-116], we have shown that the cyclocondensation of carboxylic
acid iminoester hydrochlorides with 1,2-bifunctional compounds yields a large number of var-

120
ious azoles. Thus, the reactions of 3-indolecarboxylic and 3-indolylacetic a c i d ethyl hy-
drochlorides with N-monosubstituted ethylenediamines, monoethanolamine, o-phenylenediamine,
o-aminophenol, hydrazides, and acid amidoximes lead to the corresponding 2-substituted A=-
imidazolines (LXXIV, X = NR), A2-oxazolines (LXXIV, X = O), benzimldazoles (LXXV, X = NH),
benzoxazoles (LXXV, X = 0), 2,5-disubstituted 1,3,4-oxadiazoles (LXXVI), and 3,5-disubsti-
tuted ],2,4-oxadiazoles (LXXI).

I n d ' - ( C H 2 ) dX- f - ] | ~HXCH2CH2NH2 R1CONHNH2 N---N


- r------- Ji.
X--J ] Ind--(CH2).l" "~o~ --Ri

LXXIV "NH2 lad --(CH2)~--Cz~'0C2115


NH'HCI-~[ 2 ~NOH
R'-C~I~i2_ N ~/R"o

N--]~ ~ -:~ :~ o~
n = O, i; X = NH, NR, O; R = H, C6HsCHI, CHICH=CN, 2-thien-
ylmethyl; R z = H, CH3, Ph, 4-OiNC~H4, 4-CIC~H4, 5-nitro-2-
furyl, indol-3-yl, indol-3-ylmethyl; R= = CHs, CHIC1, Ph,
5-nitro-2-furyl
The use of indole acid thioamides for the preparation of indolylazoles has been indi-
cated only in a report of the cyclocondensation of l-methyl-2-indolcarboxylic and 3-indole-
carboxylic acid thioamides with halomethyl ketones to give 2-indolyl-4-substituted thiazoles
(LXXVII) [117, 118].

N ~
Ind1---c~S + R-C0-CH2X
NH2 -H20
-I~ IndI S
LXXVII

Ind I = l - m e t h y l i n d o l - 2 - y l ,i n d o l - 3 - y l , R = CH3, CHIC1, Ph,


4-CHsOC6H~, 2-thienyl, X = CI, Br
Indole acid hydrazides have found as yet only limited use for the preparation of 1,3,4-
oxadiazoles, 1,3,4-thiadiazoles, and 1,2,4-triazoles containing indole fragments.
Heating N-acyl derivatives of 2-indolecarboxylic acid hydrazides (LXXVIII) with POCI3
gave 2-substituted 5-(indol-2-yl)-l,3i4-oxadiazoles (LXXIX) [119, 120].

Rt R~

H H
LXXVII!
R = H, CH3, CHIC1, CHCI2; Ph; R' = H, C1
5-(Indol-2-yl)-l,3,4-oxadiazole (LXXIX, R = R z = H) was also synthesized by the reaction
of 2-indolecarboxylic acid hydrozide with ethyl orthoformate [119, 121]. Robba [119] and
Ainsworth [121] have noted that heating N-acyl derivatives LXXVll with phosphorus pentasul-
fide gives low yields of 2,5-disubstituted 1,3,4-thiadiazoles.
Hydrazides of substituted 2-indolylacetic acids upon treatment with cyanogen bromide in
an inert solvent give 2-amino-l,3,4-oxadiazoles (LXXX) [122].

R R
~'~ .__./"CH3 ~- /CH 3
- N---N

LXXX

Treatment of benzylidene derivatives of substituted 3-indolecarboxylic acid hydrazides


with bromine in the presence of sodium acetate in acetic acid or iron chloride in ethanol
gives a 38-40% yield of 2-phenyl-l,3,4-oxadiazoles (LXXXI) containing indole fragments at
C(,) [123].

121
....... N
R~O' 7 . . / , /CONHN=CHCeH" "'///'"I]...... i]/''''0''~-
C~H$

%-'""~'N....... cH~ I .......


R R'

R = H, C6HsCO; R I = H, CHs
Hiremath et al. [123] also showed that the reaction of 5-hydroxy-2-methylbenz[g]indole-
3-carboxylic acid (LXXXII) with carbon disulfide and base in ethanol gives the corresponding
1,3,4-oxazole-5-thione LXXXIII, which upon the action of formaldehyde and 2-aminothiazoles
is converted to Mannich bases LXXXIV, which display antimicrobic activity.

HNHet
I
N--NH N--N/CH2

~S H ~ ~N~ ~CH3 CH2-~-~O~ N ~'~CH~

T.XXX.II IXXXIII
Her ffi 4-phenylthiazol-2-yl, 4-ethyl-S-methylthiazol-2-yl,
benzthiazol-2-yl
Upon heating at reflux in alkaline solution, l-(2-methylindol-3-ylacetyl)-4-R-thiosemi-
carbazides (LXXXV) cyclize to give high yields of 4-R-3-(2-methylindol-3-ylmethyl)-l,2,4-
triazoline-5-thiones (LXXXVI) which are cardiac activity stimulators [124].

N--NH

CH~ -r L~N~CH 3 ~
LXXXV H
LXXXVl

R = CHs, CH2 : CH-CH~, Ph, 4-CIC~H,


Hiremath et al. [125] in 1981 reported the synthesis of various types of indolylazoles
using thiosemicarbazides LXXXVII. The oxidative cyclization of LXXXVII by iodine in an al-
kaline solution of potassium iodide gives N-substituted 2-amino-l,3,4-oxadiazoles (LXXXVIII).
Heating LXXXVll with orthophosphoric acid gives 40-45%yields of N-substituted 2-amino-l,3,4-
thiadiazoles (LXEXIX), while heating of this compoundwith aqueous alkali gives 4-R-I,2,4-
triazoline-5-thiones (XC);

H~PO4 ~ N--N
Ind 2 /~['S ~/~NHk
N.--N l. + KI | I.XXXlX
"~ --~" Ind :~'~CONHNHCSNHR
Ind2 / ~ O ~ N H R LXXXV]I
NaOH N--NH
Ind2 N S
R
XC
[nd 2 = 5-hydroxy-2-methylbenzo[g]indol-3-ylD R ffi C H s , Ph

Indolylisoxazolidines XCl are formed in 50-60% yield upon the treatment of potassium
salts of indol-3-ylalkylhydroxamic acids by 1-chloro-3-bromopropane in the presence of base
[1261.

Ind --(CH2)n-'C~NHOK+CI-(CH2)3-Br Na2CO~ CI CO"


Ind ~-( 12)n- / ~0"
n=l,3 XCI

The reaction of methyl thioesters of substituted indole-3-dithiocarboxylic acids with


aminoacetaldehyde diethylacetal has been used to prepare 3-(5-ethoxy-A2-thiazolin-2-yl)in -
doles (XCII) [127].

122
J3C2H 5

~ ~
C~scH3 + 'H2NCHaCH(CCzHs)2
_._

XCII

R = H, CH,; R* = H, CH,, Ph
Tominada et al. [128] have described the preparation of indole derivatives of A~-imida -
zolines XCIV or Aa-oxazolines XCV from the iodomethylate of 1,2-dimethyl-3-indolcarboxylic
acid thiomorphilide (XCIII) and ethylenediamine or ethanolamine, respectively.
H

,%~~,,. "</ "iN" "CH~


/--.,, /C-----N 0 /,~. .,5C- -N
"~ .... +"
-
J -- < ~S~.+ \ ? . . . . . . .
"r "~'"

~>'~" "" " N'" " Cli~


I
CH3
XCV

However, the starting sulfur-containing compounds are not readily prepared due to dis-
advantages of the latter two synthetic methods.
Harris [129] has proposed using indol-3-yltrimethylthioformamidinium perchlorate (XCVI)
obtained from indole and chlorotrimethylthioformamidinium chloride as the key compound for
the synthesis of indolylazoles.

H
XC;I

Salt XCVI has high reactivity in reactions with bifunctional nucleophilic reagents and
thus various hetarylindoles may be prepared using this ~ompound [130].
N--N

N-q Ind S NH2


I n d -- // i .,=H~NCII?CH>XH ~ N H 2
XCVI
~x-J
X=O,S
.Ind

However, in using this method, we encounter great difficulties due to the extremely hy-
groscopicity and instability of the starting chlorotrimethylthioformamidinium chloride and
perchlorate, which require special care in their use.
Indole amino acids and hydroxyacids and their derivatives have also been used for the
synthesis of several types of indolylazoles.
Thus, tryptophan and ammonium thiocyanate in acetic anhydride gave l-acetyl-5-(indol-3-
ylmethyl)-2-thio-4-imidazolone [131, 132]. The use of phenyl isocyanate instead of ammonium
thiocyanate gives 3-phenyl-5-(indol-3-ylmethyl)-2-thio-4-imidazolone [133~ 134].
2-Methyl-4-(indol-3-ylmethylen)-5-oxazolone (XlX) was synthesized by the Bergman method
involving treatment of N-chloroacetyltryptophan by acetic anhydride in pyridine [37].
Oki and Nagasaka [135, 136] have synthesized 4-(l-acetylindol-3-ylmethyl)-2,5-oxasolid-
inedione which displays strong anti-inflammatory activity and is a central nervous system
stimulant by the action of phosgene on l-acetyltryptophan.

123
Considerable interest is found in the method of Oikawa et el. [137, 138] for the pre-
paration of analogs of the pyrlmidine antibiotic, 2-methyl-5-(indol-3-yl)oxazole (LIII)
which entails the oxidation of the methyl ester of N-acyltryptophan by dichlorodicyanoben-
zoquinone in anhydrous TRF to give a high yield of 2-substltuted 4-carbomethoxy-5-(indol-3-
yl)oxazoles (XCVIZ).

0
CI. L~ CN CH,~OOC,.,...........
N
Ind CLT~Cli C,OOCIi.~ + ...... .........
NHCOR CI "~ "'CN Ind " "0 "R

o ,XCVll
R = CHs, Ph, 4-CHs0C,H4
The reaction of tryptophan amide with acetone gave 4-(indol-3-ylmethyl)-5-imino-2,2-
dimethyloxazolidine, which is converted upon hydrolysis to the corresponding 5-oxasolidinone,
which is an inhibitor of tyrosine and hlstldlne decarboxylases [139].
In 1960, Rao [140] isolated the antibiotic indolemycln from natural substances and iden-
tified it as 2-methylamino-5-[a-(indol-3-yl)ethyl]-4-oxazollnone. In 1963, this antibiotic
was prepared as a mixture of two isomers XCVIZI and XCIX by the scheme of Shach et al. [141].

II. .,,C00C2]IS
"~011

+ CH .--.,r.~-j.-~-CO0 CzH ~ ..... ~ N "' CH~ (CH3NH)'C=NH.,

H H

_NHCH~ CH~HN

-~ .....~ * H"I"

II H
XCVIII XCIX

In addition to indolemycin XCVIII itself, the condensation of the ethyl ester of a-hy-
droxy-B-(indol-3-yl)butyric acid (a-indolemycinic acid) with N,N'-dimethylguanidine gives
some amount of isoindolemycin XCIX as a result of the ready stereoisomerization of indole-
mycin under alkaline conditions [141].
Preobrazhenskaya et al. [142-144] have shown that, in addition to N,N'-dimethylguanidine,
N-methylthiourea may be used as the second component of the reaction for the preparation of
indolemycin.
The cyclocondensation of the esters of racemic indolemycinic acids with guanidine or
urea and several other compounds was studied in order to prepare indolemycin analogs and de-
termine their biological activity [145].
The reaction of indolymycinic acid esters with guanidine or thiourea gives a mixture of
racemic 2-amino-5-[a-(indol-3-yl)ethyl]-A2-oxazolin-4-ones (C) [145]. The condensation of
these esters with urea leads to a mixture of diastereomeric 5-[a-(indol-3-yl)ethyl]- A2-oxa -
zolidine-2,4-diones (CI), while this reaction with methyl isocyanate leads to diastereomeric
3-methyl-5-[u-(indol-3-yl)ethyl]-A2-oxazolidine-2,4.diones (CII), which are also formed upon
the methylation of 2,4-oxazolidinediones CI, which, in turn, may be obtained by the hydroly-
sis of 2-amino-A2-4-oxazolinones C [145].

I (H2N)2C=S Ind --C 0


I NIl 2
/CH~ [
CH~ C
_ _ -.-.N CH~NCO lnd --CIt-CH(OH)~OOC2H5
Ind --C
I 0 CH3
CH~
CII Ind -- CH 0--O
I
CH~ CI

124
The methyl esters of racemic a-hydroxy-8-(indol-3-yl)propionic acids serve as starting
materials for the preparation of thiazoline analogs of indolemycin. Upon the action of meth-
anesulfonyl chloride, these esters are converted to O-mesylates CIII. The condensation of
CIII with thiourea or its derivatives gives a mixture of 2-imino-3-R-5-(indol-3-ylalkyl)-4-
thiazolinone (CIV) and 2-amino-5-(indol-3-ylalkyl)-A2-thiazolin-4-one (CV) [146-148].

Ind --CH-CH-COOC2H 5 + H2 NCSNHR~ .... ~ O NH _ _~_ N 0.. N

R O--S02CH 3 Ind --C S NIl Ind - C S NHR'


cm )
R R
I
ely CV
R, R* = H, CH3
Diastereomeric 2-methyl-5-[a-(indol-3-yl)ethyl]-~-thiazolin-4-ones (CV, R = R* = CH,)
and their derivatives obtained upon acylation of the indole ring at the nitrogen atom are
effective antiviral compounds [148].

5. SYNTHESIS OF INDOLYLAZOLES FROM INDOLE AMINES


The N-alkylation of azoles of indole Mannich bases, 3-(N,N-dimethylaminomethyl)indole
(gramine), 3-(N-piperidinomethyl)indole [149-151] and substituted gramines [152-154] has been
used rather commonly for the preparation of indolylazoles.
With the exception of benzimidazole, heterocyclic substrates are alkylated only in apro-
tic media such as upon heating in xylene at reflux [150, 151].

R
CVl

R, R* = H, alkyl, alkenyl, acyl, CtH~CH2; R 2 = H, alkyl,


alkoxy, HO, CF,, NH2; R 3 ffiCH3; R2' = (CH2)5 ; Her = imida-
zol-l-yl, pyrazol-l-yl, benzimidazol-l-yl, benztriazol-l-yl
It is noteworthy that in addition to the direct alkylation product in the alkylation of
indole by l-(N-piperidinomethyl)benzimidazole, namely, l-(indol-3-ylmethyl)benzimidazole
(CVI, R =R~ = R 2 = H), 3-(N-piperidinomethyl)indole is formed as the result of a transamination
reaction and benzimidazole is also obtained [149]. On the other hand, the action of indole
Mannich bases on azoles does not yield transamination products.
Greatest interest among indolylazoles CVI is found for substituted l-(indol-3-ylmethyl)-
imidazoles which may be used as drugs in cardiac disease, thromboses, and diabetes-related
vascular problems [153-156].
As noted above, the condensation of ethyl 3-indolylmethylmalonate with hydrazobenzene
leads to 1,2-diphenyl-4-(indol-3-ylmethyl)-3,5-pyrazolidinedione [84]. Subsequently, this
compound was obtained in higher yield by treating the sodium salt of 1,2-diphenyl-3,5-pyra-
zolidinedione by the methylsulfomethylate of gramine in DMF [157].

O~__N/Ce~5

Ind CH2"-NICH3) 3 "~" a~


,. -CH~OSO3Na
CH3OSO s O~ ~CeH s [

Vampilova [157] also indicated that the reaction of gramine itself with 1,2-diphenyl-3,
5-pyrazolidinedione gives exclusively the dialkylation product CVII. The dialkylation reac-
tion is facilitated by an increase in temperature to 160~ and the use of polar aprotic sol-
vents.
O C61L o~ N td~lt~

Ind- CH2N(CII3) 2 4 << I - + -- ,nd-CH2. / ]

O" Cell 5 0<" XC6115


CYI!

125
The synthesis of 2-amino-4-(indol-3-ylmethyl)-Aa-thiazoline (CVlll) from a-chloromeChyl-
tryptamine hydrochloride and thiourea was carried out in a search for radioprotectlve indole
derivatives [158].

N ' ~ "~ll~
NH~' HCI CVlII

6. THE PREPARATION OF INDOLYLAZOLES FROM OTHER INDOLE DERIVATIVES


Presently, one of the most general methods for the synthesis of various heterocyclic
systems is the 1,3-dipolar cycloaddltion reaction. Despite extensive studies in this area,
the information of the participation of indole derivatives in these reactions has been lim-
ited. The use of indole acid nltriles as dipolarophiles in 1,3-dipolar cycloaddition with
nitrile N-oxides has already been discussed above [i05-i07].
Piozzi and Fuganti [60] have synthesized the corresponding indolylisoxazolines ClX and
CX in the reaction of vinyl 3-indolyl ketone or the ethyl ester of 8-(indol-3-yl)acrylic acid
with benzonitrile N-oxide.
,/CsH 5 C2H500C ~ ./Celts

Ind-"CO~ 0 I d'
r CX

Dyankova [106] has d e s c r i b e d the c y c l o c o n d e n s a t i o n of s e v e r a l s u b s t i t u t e d i n d o l e a l k e n e s


with aromatic n i t r i t e N-oxides to give 4 - s u b s t i t u t e d 3 - a r y l - 5 - ( i n d o l - 3 - y l ) - A 2 - i s o x a z o l i n e s
(CXI) in 17-53% yield.

Ar ~ ...... / R I
Ind'-CH=CRR I + [Ar,-C~N-*Ot D- ~1- [ ' ~ R
N~ 0/'~-..hl d

CXl

R = NO2, CN, COCHs; R I = H, COOCaHs; Ar = Ph, 4-O~NCsH~


A series of indolylisoxazolineswith interesting pharmacological properties was obtained
upon the introduction of the isoxazoline fragment into known indole drugs, namely, dimecar-
bine (5-hydroxy-3-ethoxycarbonyl-l,2-dimethylindole) and oxyfemedol (5-hydroxy-3-ethoxycar-
bonyl-l-phenyl-2-methylindole) [106, 159]. The alkylation of these derivatives at C(,)
yielded the corresponding allyl derivatives CXII. These dipolarophiles were used in the 1,3-
dipolar cycloaddition with aromatic nitrile N-oxides.

CH2~II:CH2 CIt2~Het
H0 I COOC2H5 HO ~" C0VC2H ~
HO.\s~___ [ ~ cOO%H~ " ~" , ....... , ~ [Ar-C~.N-PO] " ~ 2 "~I....... ' ] /

R R R
CXII CXIII

R = CHs, Ph; Ar ffi Ph, 4-02NC~H4, 4-ClC6H~| H e t = 3 - a r y l -


a~-isoxazolin-5-yl
The adducts synthesized in this reaction CXIII inhibit chollnesterase activity and act
as central nervous system stimulators and hypotensive agents.
The cyclocondensation of esters of u-nitro-~-(indol-3-yl)acrylic acid or 2-nitro-1-
phenyl-3-(indol-3-yi)-2-propen-l-one with sodium azide gives 4-substituted 5-(indol-3-yl)-
1,2,3-triazoles (CXIV) [160]. These authors also noted that the presence of electron-with-
drawin~ substituents in the indole ring (5-N02 or I-COCH3) enhances the reaction rate and
the presence of a methoxy group reduces the reaction rate.

126
ROC~
I i

CXIV

R = CHs0, C2HsO, Ph; R* = H, COCHs; R ~ = H, CHs| R 3 = H, CHsO,


NO2
The 1,3-dipolar cycloaddition reaction of indole aldimines with aromatic nitrile N-ox-
ides was used to synthesize 4-alkyl-3-aryl-5-(indol-3-yl)-A2-oxadiazolines (CXV) [106].
These adducts display pronounced anti-inflammatory activity comparable to that of indometh-
acin.

r~
Ind-CH~-R [Ar-C~.N-~OJ ---~,11- "i-----

CXV

R = CHs, C2Hs, n-CsHT, i = CsHT; Ar = Ph, 4-02NC6H,, 4-C1C6H4


S i g n i f i c a n t i n t e r e s t i s found i n the 1 , 3 - d i p o l a r c y c l o a d d i t i o n i n v o l v i n g i n d o l e n i t r i l e
N-oxides [106, 161, 162]. These N-oxides are r e a d i l y formed i n the d e h y d r a t i o n of the c o r -
r e s p o n d i n g p r i m a r y n i t r o ~ompounds u s i n g p h e n y l i s o c y a n a t e i n the p r e s e n c e of t r i e t h y l a m i n e .
These r e a c t i o n s give good y i e l d s of 3 , 5 - d i s u b s t i t u t e d A 2 - i s o x a z o l i n e s CXVI, among which com-
pounds have been found w i t h a n t i b a c t e r i a l and a n t i f u n g a l a c t i v i t y .

Ar
f
I n d --CH-CHzNO 2 + R--CH:CH 2
%HsNCo md- C H ~
I
ar (CaHs)~N
N'-O./~'-R
c X~,-I

Ar = Ph, 3,4-(CHsO)2C~Hs; R = Ph, 4-CHsC6H., 4-pyridyl, CN,


C00CHs
N-(Indol-3-yl)alkylthiazolines (CXVII) displaying antiactinic activity were synthesized
by the reaction of 2-[ (indol-3-yl)alkylamino]ethanethiols with Rongalite (formaldehyde sod-
ium sulfoxylate) [163].

F--~--
, I ]
ind-,(CH2 ) _NHCH2CH2SH + HOCH2SO3Na ---.p ~d--(CH2)" - - N ~ / ~ S

CX~I

n=2-5
Zhungietu e t a l . [164-167] used i n d o l y l p y r i l i u m s a l t s f o r the s y n t h e s i s of i n d o l a z o l e s .
The r e a c t i o n of 2 , 6 - d i a r y l - 4 - ( 1 - R - i n d o l - 3 - y l ) p y r i l i u m p e r c h l o r a t e (CXVIII) with hydroxylamine
or p h e n y l h y d r a z i n e gave monooxime CXIX or monophenylhydrazone CXX, which upon h e a t i n g in a c e -
t i c a c i d c y c l i z e to give 5 - p h e n a c y l - 5 - ( 1 - R - i n d o l - 3 - y l ) - A 2 - i s o x a z o l i n e s (CXXI) or 5 - p h e n a c y l -
5 - ( 1 - R - i n d o l - 3 - y l ) - A 2 - p y r a z o l i n e s (CXXII). H e a t i n g CXXI or CXXII with a l k a l i in w a t e r - ~ t h -
anol a t r e f l u x gave 3 - a r y l - 5 - ( 1 - R - i n d o l - 3 - y l ) i s o x a z o l e s (XXXIX) or 1 - p h e n y l - 3 - a r y l - 5 - ( 1 - R -
i n d o l - 3 - y l ) p y r a z o l e s (LX), r e s p e c t i v e l y [164, 165].

127
Ar

........ -ArCOCll~ / .N

XXXIX
Ax Ar
Indl._~x~ 0+ _ CX~X
CXX!
ClO~ Ar Ar
' ' ,l NHCsH~ Ar Ar

/~ ,N
OH . . . .
..........
-ArCOCH~ /~'N"
IIL
~"
CsH5 ma Csl[
I ~
Ar ~'-"0
C~ Ar
CXXI!
Ind ~ = l-methylindol-3-yl, l-benzylindol-3-yl; Ar = Ph, 4-CH~CIH.
Heating hydrazlne hydrate with 4-(l-methylindol-3-yl)flavinlum perchlorate gave 3-phen-
yl-5-(l-methylindol-3-yl)pyrazole (CXXIV) as the flnal product [166].

CsH 9
~CeH5 ._._J~_NHNH 2 CeH~ j.CsH 5

Ind ~ + ~ InclI ---(' 0 ~ ~'N/~" -CsH~OH I


CIO 4 -
/ /OH CXXIV

CXXIII ~._J/
In~ ~ = l-methylindolyl-3
Stupnikova et al. [168-170] have recently established that treatment of the iodomethyl-
ate of 4-(indol-3-yl)pyrimidine (CXXV) under mild conditions with ethanolic KOH gives a quan-
titative yield of the completely stable anhydrobase, l-methyl-4-(3-1ndolinylidene)-l,4-di-
hydropyrlmidlne (CXXVl).

H
CXXV CXXVI

This anhydrobase holds considerable interest as an intermediate in the synthesis of var-


ious heterocyclic indole derivatives including indolylazoles [168-171].
The treatment of CXXVI with hydrazine hydrate in ethanol gave 3(5)-(indol-3-yl)pyrazole
(XXIX), whose formation apparently proceeds by the following scheme [170].

NHNH2 NHNH 2

~ _._~ / , ~ / ~ N - - CH3

It

-CH~N=CHN_"2
11 ,,_/ H
XXlX

The reaction of CXXVI with hydroxylamine in acetonitrile gives a low yield of 3-(indol-
3-yl)isoxazole [171].
In conclusion, we note that two new indolylazoles were recently isolated from natural
substances, whose structures were established by chemical and spectral methods. One of these
compounds was identified as 2-imino-l,3-dimethyl-5-(indol-3-ylmethylene)-4-pyrazolidinone
(CXXVlI) [172], while the other was identified as 3-dimethylamino-5-(indol-3-ylcarbonyl)-l,
2,4-thiadiazole (CXXVIII) [173].

128
, ~ -N(CH~)2

f lnd-CO' S

CH~ CXX~'II!
C~'VII

However, information on the synthesis of these compounds has not appeared in the liter-
a ture.

LITERATURE CITED
i. G. I. Zhungietu and G. N. Dorofeenko, Usp. Khim., 41, 1627 (1972).
2. G. Toth, G. Szabo, G. Eibel, and E. Somfai, West German Patent 2,135,145; Chem. Abstr.,
77, 5329 (1972).
3. G. R. Birchall, W. Hepmorth, and S. S. Smith, West German Patent 2,253,927; Chem. Abstr.,
79, 31865 (1973).
4. L. Fishnerowa, V. Kakac, and O. Nemecek, Coll. Czech. Chem. Comm., 39, 624 (1974).
5. J. K. Sughenand T. Yoloye, Pharm. Acta Helv., 58, 65 (1978).
6. M. Michalik, V. Sunjic, F. Kajfez, V. Caplar, and T. Kovac, Croat. Chem. Acta, 51~ 81
(1978).
7. F. Kajfez and M. Michalik, Swiss Patent No. 605,742; Chem. Abstr., 80, 72049 (1979).
8. Y. Suzuki, S. Komachiya, and S. Sakurai, US Patent No. 3,419,551; Ref. Zh. Khim.,
12N659R (1970).
9. E. V. Esayan and G. T. Tatevosyan, Arm. Khim. Zh., 25, 969 (1972).
10. K. S. Karagezyan, R. T. Grigoryan, and G. T. Tatevosyan, USSR Inventor's Certificate No.
455,104; Chem. Abstr., 82, 170945 (1975).
i!. Tsung-Ying Shen, V. J. Grenda, and R. F. Czaja, West German Patent No. 2,219,408; Chem.
Abstr., 78, 29771 (1973).
12. D. Simov, V. Kalcheva, and C. Roycheva, FECS: First International Conference on the
Chemistry and Biotechnology of Biologically Active Natural Products (Sofia), Vol. 3/2
(1981), p. 582; Ref. Zh. Khim., 21Zh291 (1982).
13. A. Jordan and R. Arndt, J. Heterocycl. Chem., 5, 723 (1968).
14. V. P. Arya, J. David, R. S. Grewall, C. L. Kaul, R. H. Modoni, S. Rajappa,and S. J. Shenoy,
Indian J. Chem., 15B, 473 (1977).
15. G. Sarodnick and G. Kempter, Z. Chem., 19, 21 (1979).
16. L. J. Brand and J. Nadelson, Europ. Patent No. 32,298; Chem. Abstr., 96, 52291 (1982).
17. W. Schingler and F. Haflinger, US Patent No. 2,751,393; Chem. Abstr., 51, 4440 (1957).
18. H. L. Kung and W. Schingler, Experientia, 15, 66 (1959).
19. J. Hocker and R. Merten, Chem. Ber., !05, 1651 (1972).
20. J. Hocker and R. Merten, West German Patent No. 2r Chem. Abstr., 81, 105510
(1974).
21. J. Bergman, Tetrahedron Lett., No. 46, 4723 (1972).
22. A. K. Sheinkman, T. V. Stupnikova, N. A. Klyuev, L. Yu. Petrovskaya, and V. G. Zhil'-
nikov, Khim. Geterotsikl. Soedin., No. 2, 238 (1977).
23. A. K. Sheinkman, T. V. Stupnikova, and L. A. Rybenko, Khim. Geterotsikl. Soedin., No.
4, 561 (1978).
24. A. K. Sheinkman, T. V. Stupnikova, L. M. Kaplan~ A. Yu. Chervinskii, and G. I. Makhlai,
USSR Inventor's Certificate No. 504,765; Byul. Izobr., No. 53, 55 (1976).
25. A. K. Sheinkman, T. V. Stupnikova, V. I. Zherebchenko, L. A. Rybenko, and N. A. Klyuev,
Khim. Geterotsikl. Soedin., No. 7, 904 (1978).
26. K. Takeo, O. Kijoshi, and K. Hakuji, J. Chem. Soc. Japan, Pure Chem. Sec., 79, 91 (1958).
27. V. Narayanan and R. D. Huagwitz, West German Patent No. 2,248,959; Chem. Abstr., 79,
32072 (1973).
28. R. D. Haugwitz, B. V. Maurer, A. J. Martinez, G. Jacobs, and V. Narayanan, Synthesis,
No. 5, 336 (1976).
29. V. Narayanan and R. D. Haugwitz, West German Patent No. 2,415,351; Chem. Abstr., 82,
4241 (1975).
30. V. Narayanan and R. D. Haugwitz, US Patent No. 3,853,857; Chem. Abstr., 82, 112060
(1975).
31. Yu. I. Smuskevich, N.N. Mar'yanovskaya, and N. N. Suvorov, Trudy Moskovsk. Khim. Tek-
nol. Inst. im. D. I. Mendeleeva, No. 61, 155 (1969).
32. T. P. Johnston and A. Gallagher, J. Org. Chem., 27, 2452 (1962).
33. G. H. Walker and M. A. Moore, J. Org. Chem., 26, 432 (1961).

129
34. Nguyen Dinh Trlen, Ha Trl Diep, Luong Thu Huong, and Le Thi Thauh Vinh, Tap Chi Hoa Hoc,
18, 22 (1980); Chem. Abstr., 94, 121415 (1981).
35. H. King and E. Stiller, d. Chem. Sot., No. 2, 466 (1937),
36. L. H o m e r and H. Schwahn, Ann., Sgl, 99 (1955).
37. K. Shaw, A. McMillan, A. Gundmundson, and M. Armstrong, J. Org. Chem., 23, 1171 (1958).
38. O. Tsude, M. Noguchi, and H. Moriyama, Heterocycles, 16, 209 (1981).
39. L. Kh. Vinograd and N, N. Suvorov, Khim. Geterotsikl, Soedln., No. ii, 1505 (1970).
40. A. P. Bhaduri and N. M. Khanna, Indian J. Chem., ~, 419 (1966).
41. B, S. Tanaseichuk and V. N. Belyamov, Uch. Zap, Mordovsk. Univ., No. 81, 95 (1971).
42. L. C. Brooker, R. H. Sprague, C. P. Smyth, and C. L, Lewis, J. Am. Chem. Soc., 62, ii16
(1940).
43. W. S. Gaugh, US Patent No. 3,687,675; Chem. Abstr,, 78, 73667 (1973).
44. P. Beretta and L. Val Busa, West German Patent No. 2,429,230; Chem. Abstr., 83, 12227
(1977).
45. J. Mee, French Patent No. 1,599,796; Chem. Abstr., 74, i00,619 (1971).
46. O. Reister and H. Oecheshlaeger, West German Patent No. 2,165,915; Chem. Abstr., 79,
99215 (1973).
47. L. Brooker and F. Webster, US Patent No. 3,539,349; Chem. Abstr., 75, 7444 (1971).
48. Mitsubishi Paper Mills, Ltd.,Japanese Patent No. 80-96941; Chem. Abstr., 94, 112466
(1981).
49. F. Eiden and H. Kucklaender, Arch. Pharm. (Weinheim), 304, 523 (1981).
50. F. Eiden and H. Kucklaender, West German Patent No. 1,944,419; Chem. Abstr., 75, 5691
(1971).
51. V. M. Kotlyareskaya and I. M. Gubenko, Methods for the Preparation of Chemical Reagents
and Preparations [in Russian], No. 26 (1974), p. 273.
52. C. Wen~rup and H. W. Winter, Aagew. Chem., 90, 643 (1978).
53. V. S. Velezheva, Yu. V. Erofeev, N. S. Yares'ko, A. G. Balbushevich, and N. N. Suvorov,
Khim. Geterotsikl. Soedin., No. i0, 1343 (1978).
54. F. Piozzi and C. Fuganti, Ann. Chim. (Rome), 56, 1248 (1966).
55. V. P. Gorbunova, K. F. Turchin, and N. N. Suvorov, Khim. Geterotsikl. Soedin., No. Ii,
1508 (1970).
56. S. V. Tsukerman, V. M. Nikitchenko, A. I. Bugai, and V. F. Lavrushin, Khim. Geterotsikl.
Soedin., No. 2, 268 (1969).
57. B. R. Pandey, K. Raman, J. P. Barthwall, and S. S. Parmar, Natl. Acad. Sci. Left. (India),
2, 98 (1979).
58. S. Tripathi, B. R. Pandey, J. P. Barthwall, K, Kishor, and K. P. Bhargawa, Indian J.
Physiol. Pharmacol., 24, 155 (1980).
59. K. Raman, B. R. Pandey, J. P. Barthwall, and S. S. Parmar, Eur. J. Med. Chem.-Chim. Ther.,
15, 567 (1980).
60. F. Piozzi and C. Fuganti, Ann. Chim. (Rome), 57, 486 (1967).
61. A. Sammour and H. H. Zoorob, Acta Chim. Acad. Sci. Hung., 86, 53 (1975).
62. E. Roeder and J. Pigulla, Arch. Pharm. (Weinheim), 311, 817 (1978).
63. V. E. Zhigachev, Yu. I. Smushkevich, N. A. Mel'nikov, and N. N. Suvorov, Trudy Moskovsk.
Khim. Tekhnol. Inst. im. D. I. Mendeleeva, No. 66, 120 (1970).
64. Yu. I. Smushkevich, Chemical Sciences Doctoral Dissertation, Moscow (1982).
65. V. E, Zhigachev, Yu. I. Smushkevich, and N. N. Suvorov, Zh. Vses. Khim. Obshch., 18,
348 (1973).
66. G. Sanna, Gazz. Chim. Ital., 52, 170 (1982).
67. J. Bergman, Acta Chem. Scand., 22, 1063 (1968).
68. V. P. Gorbunova and N. N. Suvorov, Khim. Geterotsikl. Soedin,, No. ii, 1519 (1973).
69. N. N. Suvorov, V. P. Gorbunova, M. D. Mashkovskii, S. S. Liberman, and S. P. Kushchak,
USSR Inventor's Certificate No. 271,523; Byul. Izobr., No. 18, 23 (1970).
70. V. P. Gorbunova and N. N. Suvorov, Khim. Geterotsikl. Soedin.,~No. 7, 936 (1978).
71. N. N. Suvorov, Yu. I. Smushkevich, N. N. Mar'yanovskaya, and A. V. Sulima, Khim.-farm.
Zh., ~, i0 (1970).
72. Yu. I. Smushkevich, Ts. M. Babueva, and N. N. Suvorov, Khim. Geterotsikl. Soedin., No.
i, 91 (1969).
73. G.Y. Sarkis and S. Ai-Azawe, J. Chem. Eng. Data, 17, 516 (1972).
74. N. N. Gireva, Chemical Sciences Candidate's Dissertation, Moscow (1969), p. 73.
75. D. S. Bhate, R. K. Hulgalkar, and S. Menon, Experientia, 16, 504 (1960).
76. B. S. Joshi, W. R. Taylor, D. S. Bhate, and S. Karmarkar, Tetrahedron, 19, 1437 (1963).
77. K. Bodendorf and A. Walk, Arch. Pharm. (Weinheim), 294, 484 (1961).

130
78. T. J. Turchi and M. J. S. Dewar, Chem. Rev., 75, 389 (1975).
79. H. Houwing and A. M. van Luesen, J. Heterocycl. Chem., 18, 1127 (1981).
80. H. Houwing, J. Wildeman, and A. M, van Leusen, J. He~erocycl. Chem., 18, 1133 (1981).
81. V. V. Vampilova, N. N. Suvorov, and V. S. Velezheva, Trudy Moskovsk. Khim. Tekhnol.
Inst. im. D. I. Mendeleeva, No. 80, 150 (1974).
82. A. N. Grinev and O. Yu. Ryabova, Khim. Geterotsikl. Soedin., No. 2, 201 (1982).
83. A. P. Kozikowski and N. M. Hasan, J. Org. Chem., 42, 2039 (1977).
84. N. N. Suvorov, V. S. Velezheva, V. V. Vampilova, and E. I. Gordeev, Khim. Geterotsikl.
Soedin., No. 4, 515 (1974).
85. N. N. Suvorov and B. I. Buyanov, Khim. Geterotsikl. Soedin., No. 3, 377 (1970).
86. H. Plieninger and G. West, Chem. Ber., 88, 1956 (1955).
87. H. Plieninger and G. West, Chem. Bet., 89, 2783 (1956).
88. H. Islet, US Patent No. 2,505,247; Chem. Abstr., 44, 6888 (1950).
89. D. V. Wysong and H. C. White, US Patent No. 3,586,695; Chem. Abstr., 75, 76789 (1971).
90. C. W. Schneider, S. K. Ewans, M. B. Chenoweth, and F. L. Bewan, Proc. Soc. Exp. Biol.
Med., 140, 1221 (1972).
91. J. Eble, US Patent No. 3,377,247; Chem. Abstr., 69, 5206 (1968).
92. F. J. Rosenberg and J. G. Miller, US Patent No. 3,689,655; Chem. Abstr., 78, 12704
(1973).
93. S. Archer, US Patent No. 3,404,156; Ref Zh. Khim., 5N499 (1970).
94. V. I . Kelarev and G. A. Shvekhgeimer, Izv. Muzov. Khim. Khim. Tekhnol., 24, 1354 (1981).
95. R. Kuhn and F. Drawent, West German Patent No. 937,231; Chem. Abstr., 53, 409 (1959).
96. J. M. McManus and R. M. Herbst, J. Org. Chem., 24, 1464 (1959).
97. P. F. Juby and T. W. Hudyma, J. Med. Chem., 12, 396 (1969).
98. Bristol-Myers Co., Dutch Patent No. 6,609,235; Chem. Abstr., 67, 82215 (1967).
99. W. G. Finnegan, R. A. Henry, and R. Letquist, J. Am. Chem. Soc., 80, 3908 (1958).
i00. H. J. Bisher, D. F. Bruley, and M. H. Knisely, Adv. Exp. Med. B i o l . , 37B, 657 (1973).
i01. M. E. Safdy, E. Kurchacova, R. N. Schut, H. Vidrio, and E. Hong, J. Med. Chem., 25,
723 (1982).
102. E. Kornfeld, South African Patent No. 6,904,486; Chem. Abstr., 75, 76800 (1971).
103. R. S. Taborsky, J. Med. Chem., iO, 880 (1967).
104. T. M. Efremova, K. N. Kuchkova, A. A. Semenov, Khim. :Geterotsikl. Soedin., No. i0,
1382 (1974).
105. G. A. Shvekhgeimer, V. I. Shvedov, L. A. Kyankova, D. I. Stefanova, and M. P. Nikolova,
Bulgarian Inventor's Certificate No. 31,238.
106. L. A. Kyankova, Chemical Sciences Candidate's Disseration, Moscow (1979).
107. G. Shvekhgeimer, V. Shvedov, L. Dyankova, D. Stefanova, and M. Nikolova, Tr. Nauchn.-
Issled. Khim.-farm. Inst. (Sofia), Ii, 70 (1981).
108, G. Ehrhart and H. Leditschke, US Patent No. 2,752,358; Chem. Abstr., 51, 2873 (1957).
109. H. Piotrowska, B. Serafin, and K. Wejroch-Matacz, Pol. J. Pharmacol. Pharm., 27, 297
(1975).
II0. S. Bithy-Szlahto, S. Kweiek, H. Piotrowska, B. Serafin, and K. Wejroch-Matacz, Acta
Pol. Pharm., 34, 527 (1977).
iii. I. Kh. Fel'dman, N. A. Kogan, and E. S. Voikhanskaya, Khim.-farm. Zh., No. 9, 21 (1967).
112. V. I. Kelarev and G. A. Shvekhgeimer, Khim. Geterotsikl. Soedin., No. 5, 645 (1980).
113. V. I. Kelarev and G. A. Shvekhgeimer, Zh. Vses. Khim. Ohshch., 26, 457 (1981).
114. V. I. Kelarev and G. A. Shvekhgeimer, Khim. Geterotsikl. Soedin., No. 3, 343 (1982).
115. V. I. Kelarev and G. A. Shvekhgeimer, Izv. Vuzov. Khim. Khim. Tekhnol., 25, 1458 (1982).
116. G. A. Shvekhgeimer, V. I. Kelarev, and L. A. Dyankova, Khim. Geterotsikl. Soedin., No.
12, 1609 (1984).
117. N. A. Kogan, Khim. Geterotsikl. Soedin., No. 10, 1327 (1977).
118. V. I. Kelarev and G. A. Shvekhgeimer, Khim. Geterotsikl. Soedin., No. 6, 761 (1984).
119. M. Robba and D. Maume, Tetrahedron Lett., No. 23, 2333 (1972).
120. M. Robba, D. Maume, and J. C. Lancelot, Bull. Chim. Soc. France, Nos. 3-4, Part 2, 333
(1977).
121. C. Ainsworth, J. Am. Chem. Soc., 77, 1148 (1955).
122. H. M. Stroh and H. Beitz, Ann., 700, 78 (1966).
123. S. P. Hiremath, N. N. Goudar, and M. G. Purohit, Indian J. Chem., 19B, 1031 (1980).
124. V. K. Rastogi, V. K. Agarwall, J. N. Sinha, A. Chandhari, and S. Rarmar, Canad. J.
Pharm. Sci., 9, 107 (1974).
125. S. P. Hiremath, N. N. Goudar, and M. G. Purohit, Indian J. Chem., 20B, 388 (1981).
126. Yu. I. Smushkevich, V. Kayumov, and N. N. Suvorov, Trudy Moskovsk. Khim. Tekhnol. Inst.
im. D. I. Mendeleeva, No. 74, 65 (1973).

131
127. G. Kobayashi, J, Matsuda, R. Natsuki, and Y. Tominada, J. Pharm. Soc. Japan, 90, 1251
(1970).
128. Y. Tominada, J. Matsuda, and G. Kobayashi, J. Pharm. Soc., Japan, 95, 1073 (1975).
129. R. L. M. Harris, Tetrahedron Lett., 5217 (1970).
130. R. L. M. Harris, Austral. J. Chem., 27, 2635 (1974).
131. J. K. Kuck, J. J. Herba, W. E. Kowac, and J. V. Karabinos, J. Am. Chem. Soc., 73, 5470
(1951).
132. J. M. Swan, Austral. J, Chem., A5, 711 (1952).
133. L. K. Ramachahdran, A. Epp, and W. McConnel, Anal. Chem., 27, 1734 (1955).
134. J. Sj~quist, Acta Chem. Scand,, ~, 447 (1953).
135. S. Oki and T. Nagasaka, Chem. Pharm. Bull., 19, 1734 (1971).
136. S. Oki and T. Nagasaka, Japanese Patent No. 73-14668; Chem. Abstr., 78, 124573 (1973).
137. Y. Oikawa and O. Yonemitsu, J. Org. Chem., 42, 1213 (1977).
138. T. Yoshioka, K. Nohri, Y. Oikawa, and O. Yonemitsu, J. Chem. Res. Synops., No. 7, 194
(1981).
139. E. E. Smisman, R. L. Inloes, S. Ei-Antably, and P. Shaffer, J. Med. Chem., 19, 161
(1976).
140. K. V. Rao, Antibiotic Chemotherapy , iO, 3121 (1960).
141. V. Shach, M. Wittenan, and H. Els, J. Am. Chem. Soc., 85, 3425 ( 1 9 6 3 ) .
142. M. N. Preobrazhenskaya, L. M. Orlova, and N. N. Suvorov, Zh. Obshch. Khim., 33, 1378
(1963).
143. M. N. Preobrazhenskaya, L. M. Orlova, L. A. Savel'eva, A. V. Kisin, N. N. Yaretskii,
N. S, Vul'fson, and N. N. Suvorov, Dokl. Akad. Nauk SSSR, 166, 611 (1966).
144. M. N. Preobrazhenskaya, N. V. Uvarova, E. N. Padieskaya, G. N. Pershin, and N. N. Suv-
orov, Dokl. Akad. Nauk SSSR, 172, 870 (1967).
145. M. N, Preobrazhenskaya, E, G~ Balash0va, K. F. Turchin, E. N. Padeiskaya, N. V. Uvar-
ova, G. N. Pershin, and N. N. Suvorov, Tetrahedron, 24, 1631 (1968~.
146. M. R. Harden and N. D. Wright, West German Patent No. 2,611,089; Chem. Abstr., 86,
43694 (1977).
147. M. R. Harden and N. D. Wright, J. Chem. Soc. Perkin Trans. i, No. 9, 1012 (1977).
148. M. R. Harden, S. Bailey, M. R. Boyd, I. B. Wilkinson, and N. D. Wright, J. Med. Chem.,
22, 191 (1979).
149. T. Ocuda, J. Chem. Pharm. Soc. Japan, 80, 208 (1960).
150. F. Andreani, R. Andrisano, and C. Della Casa, J. Chem. Soc., No. 8, 1157 (1970).
151. G. Decordts and M. C. Wakselman, Comptes Rendus Acad. Sci. Paris, C, 266, 1168 (1968).
152. P. Gross and R. Dickinson, European Patent No. 3901; Chem. Abstr., 92, 94394 (1980).
153. Pfizer Corp., Dutch Patent No. 80-0351; Chem. Abstr., 94, 156925 (1981).
154. P. Gross and R. Dickinson, British Patent No. 2,045,244; Ref. Zh. Khim., 6094P (1981).
155. S. Heptinstall, I. Bevan, S. R. Cockbill, S. Hauley, and M. Parry, Throm. Res., 20,
219 (1980).
156. P. Gross, R. P. Dickinson, M. I. Parry, and M. I. Raundall, Agents Actions, Ii, 274
(1981).
157. V. V. Vampilova, Chemical Sciences Candidate's Dissertation, Moscow (1976).
158. T. Hino, K. Hoji, and S. Acaboshi, Chem. Pharm. Bull., 18, 384 (1970).
159. G. A. Shvekhgeimer, V. I. Shvedov, L. A. Kyankova, and V. I. Apostolova, Bulgarian In-
ventor's Certificate No. 42858.
160. V. S. Velezheva, Yu. V. Erofeev, and N. N. Suvorov, Zh. Org., Khim., 16, 2157 (1980).
161. G. A. Shvekhgeimer, V. I. Shvedov, and L. A. Dyankova, Tr. Nauchn.-Issled. Khim.-farm.
Inst. (Sofia), 12, 57 (1982).
162. G. A. Shvekhgeimer, V. I. Shvedov, L. A. Dyankova, and V. I. Apostolova, Bulgarian In-
ventor's Certificate No. 42857.
163. N. N. Suvorov, L. Kh. Vinograd, L. N. Lavrishcheva, V. M. Bondarenko, M. V. Vasin, and
N. V. Gorelova, Trudy Mokovsk Khim. Tekhnol. Inst. im. D. I. Mendeleeva, No. 94, 9
(1977).
164. G. N. Zhungietu, I. V. Shantsevoi, and V. I. Sukhanyui, Zh. Vses. Khim. Obshch., No. 2,
232 (1971).
165. G. N. Zhungietu and I. V. Shantsevoi, Abstracts of the Third All-Union Colloquium on
the Chemistry and Pharmacology of Indole Compounds [in Russian], Izd. Stinitsa, Kish-
inev (1971), p. 32.
166. G.N. Zhungietu, I. V. Shantsevoi, and D. D. Buburuz, Khim. Geterotsikl. Soedin.,, No.
2, 281 (1971).
167. B. I. Sskhanyuk, Chemical Sciences Candidate's Dissertation, Kishinev (1977).

132
168. T. V. Stupnikova and Kh. Ya. Lopatinskaya, Khlm. Geterotslkl. Soedin., No. ii, 1566
(1980).
169. T. V. Stupnikova, T. V. Nuzhnaya, G. A. Zaritovskaya, and S. N. Baranov, Dokl. Akad.
Nauk UkrSSR, Set. B., No. 8, 51 (1980).
170. T. V. Stupnikova, T. V. Nuzhnaya, N. A. Klyuev, and L. Yu. Chervinskii, Khim. Getero-
tsikl. Soedin., No. 2, 212 (1982).
171 9 T. V. Stupnikova, T. V. Nuzhnaya, N. A. Klyuev, S. N. Baranov, and S. M. Klyuev, Dokl.
Akad. Nauk UkrSSR, Ser. B., No. 6, 53 (1982).
172. R. Kazlanskas, P. Murphy, R. J. Quinn, and R. J. Wells, Tetrahedron Lett., No. I, 61
(1977).
173. S. Heitz, M. Durgeat, M. Guyot, C. Brassy, and B. Backef, Tetrahedron Lett., No. 15,
1457 (1980).

QUANTUM-CHEMICAL TREATMENT OF RECYCLIZATION REACTIONS.


9.* PHOTOISOMERIZATION OF FIVE-MEMBERED HETEROCYCLES

Yu. B. Vysotskii and L. N. Sivyakova UDC 541.141:539.196:547.72'77'78

The pho~oisomerization of a number of five-membered heterocycles has been con-


sidered in the framework of the coupled variant of perturbation theory for a
one-electron transition density matrix in the n-electronic approximation of the
MO--LCAO-SCF method.

A method for describing photochemical reactions of the X type in Dougherty's terminology


[3], one of whose main steps is photoelectrocyclic contraction or ring formation, we developed
in [2]. In such reactions the energy of the light is utilized only for bringing the reactant
into an excited state and is not converted into the thermal energy needed for overcoming the
activation barrier, spent on light-induced electron transfer, etc. In this case, the reactiv-
ity is determined mainly by the changes in the electronic structure of the molecule upon ex-
citation and is, therefore, more easily subjected to quantum-chemical treatment.
Without dwelling in detail on the problem of using the index approach for the description
of the reactivity of molecules in electronically excite~ states (see, for example, [4, 5]), as
well as on the alternative method of correlation diagrams (see [3, 6-8], etc.) in the case of
electrocyclic reactions, we note only that expressions for the reactivity indices of such re-
actions, wfiich were obtained on the basis of the coupled variant of perturbation theory for a
transition density matrix in the PPP method [9], were presented in [2]. Here the perturbation
may be characterized as intramolecular coupling (see [3]), and the perturbation matrix is rep-
resented by the following matrix elements:

(H~)~= ( ~ 6 ~ + 6 ~ h ~ ) ~ . (1)
Then from the expression for the change in the n-electronic energy of the ground state in
first-order perturbation theory with respect to ASik

6Eih ~ = 2 P ~hA~ik (2)

it follows that in the ground state the bond orders between the not directly bonded atoms
Pik can serve as the reactivity indices in intramolecular recyclization and cyclization re-
actions.

*For report 8 see [i].

Institute of Physical Organic Chemistry and Carbon Chemistry, Academy of Sciences of the
Ukrainian SSR, Donetsk 3 4 0 1 1 4 . Translated from Khimiya Geterotsiklicheskikh Soedinenii, No.
2, pp. 173-180, February, 1986. Original article submitted July 31, 1984.

0009-3122/86/2202-0133512.50 9 1986 Plenum Publishing Corporation 133


When a molecule undergoes a transition to an excited state, the change in the ~-elec-
tronic excitation energy in first-order perturbation theory with respect to ABik may be writ-
ten for the slnglet states in the form [9] (Eq. 15.88)

6Ei: = 2, Tr {Hm YD 2+ O (Yik) Y D~+ [ D, O (D) ] _ Y r~h} = 2 K~:A,~h, (3)


and for triplet transitions calculated in the Tamm-Dankov approximation, in a similar manner
we obtain
6E~,J= Tr {2ItmYD2+2G (r~h) YD2+ [O, O ( D ) ] _.YY~,, + [G ( D r ) , D]_.Yr = 2K~,TA,~m, (4)

where D is the unperturbed transition density matrix corresponding to the excited state un-
der consideration, Yik is the matrix of bond--bond mutual polarizabilities, which reflects
the change in the electronic structure in the ground state under the action of perturbation
(i), and supermatrix G describes the interelectronic interaction.
In [2] it was shown in the example of the photochemical ring-contraction reaction of
furan that the main contribution to the indices Kik is made by the changes in the long-range
bond orders AP*ik upon excitation of the molecule. The latter were used for the treatment
of photochemical, particularly, di-~-methane, rearrangements [10, ii]. The arguments in sup-
port of the use of AP*ik are based on the correspondence between these quantitites (see [ii])
and the location of the excitation energy in a molecule, its redistribution during a reaction,
and its conversion into the vibrational energy of the ground state. The bond orders in elec-
tronically excited states, which are generally calculated according to the HUckel method,
served as photoelectrocyclization indices in [12, 13]. Several quantities whichare directly
or indirectly related to them were used in [13-15]. The use of the sum of the free valences
of the positions at which cyclizatlon occurs, Mulliken populations~ including transition pop-
ulations, or localization energies ~of course, in a given excited state) as reactivity in-
dices is less substantiated and gives a poorer description than do AP*ik (see~ for example,
[16, 17]).
In the present work we examined the relationship between the indices Kik and the occur-
rence of the photoisomerization of several five-membered heterocycles in the PPP approxima-
tion.
i. Table 1 presents the indices for the four lowest singlet and triplet states of fur-
an, pyrrole, and thiophene. From the data presented it follows that the transition of a
molecule to the excited states is generally accompanied by weakening of the bonds between
the directly bonded atoms and strengthening of some of the bonds between the not chemically
bonded atoms. In the cases in which this strengthening (increase in the coefficients Kik)
is so great that the sum of the indices Pik and Kik becomes positive (see [2]), photoelectro-
cyclic contraction of the heterocycle, which is the first step in its further conversions,
should occur at positions i and k.
For example, from the data in Table 1 (see also [2]) it follows that the photorecycli-
zation of the furan molecule in the S, and T2 states should take place with the formation of
acylcyclopropene intermediate Ill, and in states $2 and T, it should involve the formation
of intermediate IIa followed by its isomerization to IIb, etc.
Scheme 1
L 2

s '>: ';: x ' 2 ,,


"o'( ". . . . . . . " . . . . . . "%o~ ' ' ...... "o~
I III i ~ + CO

,:-,.i:>--, "i,,
Ila II b II C II d

- . /
"o[ "O] o I

134
The occurrence of a reaction along path a, especially in the T= state, has been thor-
oughly studied [6, 18-22]. Sensitization by mercury [Hg(SPz)] gives a steady yield of CO
and C3H4, which is large in comparison to the direct irradiation of furan. The latter find-
ing is consistent with the fact that K=,4 S < K=,4 T. There are still no experimental data on
the photoisomerization of furan in the $3 and Tz states (path b).
2. An analysis of the values of Kik for the pyrrole molecule (Table i) reveals that
in the Sx state, in contrast to the case of furan, isomerization should not occur owing to
the fact that IK=,4SI < [P=i4J and IK=,,Sl < IP=,sI. In the second triplet state iK=,4TI >
IP=,~I; however, the 2--3 (4--5) bonds are weaker than the 1--2 (i--5) bonds (see Table i). This
circumstance should result in the photolytic cleavage of these bonds with the evolution of
acetylene as the reaction product. In fact, when unsubstituted pyrrole was irradiated in the
gaseous phase (Sz), decomposition products, in particular, acetylene, were discovered [23].
It should, however, be stressed, that the presence of strong electron-donor or acceptor
substituents in a molecule can cause changes in the relationship between the Pik and the Kik
and, as a consequence, the corresponding photoisomerization [19, 22, 24]. In this case, the
direct participation of the atoms of functional groups, for example, of the nitro group [25],
in the isomerization process is possible. A radical mechanism with subsequent recombination
of the radicals has likewise not been ruled out [26].
According to the data from the calculation, the photoisomerization of pyrrole in the
second singlet and first triplet states should be similar to that of furan (path b).

Scheme 2
2 3 4
5
5
@ 3

I 5 _.

I x\C, /
9 "-3 4 . f,,~_ 2 ..J
1 \~ //
[, 4
Ya ~'b vc

(%)

"s~ S2(TI) * VI

,v -sit

fr i "2

st" \ sli

3. As follows from the data in Table i, the photoisomerization of the thiophene mole-
cule (IV) in the T= state should involve the formation of 1--3 and 2--4 (or i--4 and 3--5) bonds
(paths a and b in Scheme 2), i.e., the intermediate formation of a Weinberg zwitterionic tri-
cyclic intermediate [27]. A similar picture is also observed in the SI state. A structure
of type V implies the active participation of the d orbitals of the sulfur atom [18, 19, 22],
and, in fact, without consideration of the d orbitals the positive long-range orders of the
I--3 (i--4) bonds do not appear.
We note that, in contrast to the case of furan, cyclopropene was not discovered either
upon the direct irradiation (Sz state) or upon the sensitization (Tz) of thiophene vapor [28].
Finally, as follows from Table l, in the case of the S= and Ti states, recyclization
should involve the intermediate formation of a structure of type VI along path d in Scheme 2.

135
TABLE i. Reactivity Indices in Photoisomerization Reactions
of Five-Membered lieterocycles

Compound State K*I,2 K2,3 K3,4 A'L,3 A'2,4 h'2 ,~

Furan So 0,442 0,763 0,5% 0,205 0,105 - 0,459


S, - 0,075 -- 0,386 -0,270 0,117 0,t31 0,254
$2 -- 0,205 - 0,205 0,070 0,058 0,032 0,864
Tt -0,187 -0,370 0,189 0,088 0,033 0,747
T~ -0,021 -0,474 -0,666 0,078 0,i70 0,16I
Pyrrole So 0,501 0,740 0,60.9 0,227 0,128 - 0,424
S, -O, lOI -0,354 -0,284 0,165 0,101 0,262
$2 -0,223 -0,314 0,091 0,071 0,036 0,849
T, - 0,196 - 0,356 0,107 0,090 0,024 0,757
T2 0,001 - 0,541 - 0,07 l 0,052 0,401 0,075
Thiophene So 0,627 0,715 0,635 0,315 0,028 - 0,400

St -0,101 -0,275 -0,211 0,344 0,001 0,348


$2 - 0,241 - 0,282 --0,180 0,122 0,011 0,732
Ti -0.243 9 0,102 0,112 0,003 0,736
7'2 -0,018 -0,070 -0,831 0,375 0,064 0,092

*The corresponding Pik are given for the ground state So.

TABLE 2. Reactivity Indices in Photoisomerization Reactions


of Azoles

Compound State A'*I,3 K,,4 /(2,4 K2,~ Ks~

Oxazole So -0,201 -0,184 -0,167 - 0,446 -0,108


S, 0,209 -0,008 0,460 0,365 -0,131
$2 -0,005 0,155 -0,111 0,713 0,280
TL 0,087 0,082 0,076 0,762 - 0,030

T~ 0,035 0.052 0.465 0,036 0,367


Imidazole So -0,223 -0,204 -0,188 -0,409 -O,131
S, 0,208 0,018 0,431 0,356 -O, IIO
S~ 9 0,007 0,175 -0.079 0,686 0,256
Tt 0,094 0,096 0.079 0,750 -0,025
T2 0.028 0.052 0,500 0,043 0,372
Thiazole So -0.312 - 0.274 --0,094 --0,4O0 --0,040
St 0,326 0.292 0.212 0,348 -- 0,056
$2 0,195 0.230 0,054 0,544 0,037
Tz 0,128 0,146 0,061 0,726 -0,050
T2 0,361 0,252 0,497 0,175 -0,175
Isodazole So -0.190 -0,240 -D,136 -0,390 " 0,051
St 0,26 I 0.158 0,257 0,489 - 0,478
-- 0,045 0.201 - 0,064 0,493 0,347
T, 0,086 0.184 0,070 0,763 -0,150
T2 0,059 0,176 0,302 0,039 0,II0
Pyrazole So --0,241 - 0,238 --0,179 --0,378 --0,014
St 0,358 0,208 0,189 0,352 --0,456
$2 --0,153 0,282 --0,024 0,559 0,355
Tt 0,092 0.058 0,180 0,758 - 0,064

T2 0,305 0,125 0,535 0,047 -0,102


Isothia- So -0,291 -0,350 -0,058 - 0.386 0,065
zole St 0,514 0,500 0,067 0,344 -0,3t0
$2 - 0,068 0,207 --0.107 0.672 0,201
T~ 0,070 0.196 0.055 0,742 - 0,080
T2 0,332 0,604 --0,127 0.144 -- 0,035

*The corresponding Pik are given for the So ground state.

There are still no experimental data on the reactions of thiophene derivatives in these
states. Nevertheless, in the case of the $I and T2 states, Scheme 2 is confirmed by all the
data available in the literature (see monographs [19, 22, 29] etc.).
4. Table 2 presents the indices Kik and Pik for photoisomerization reactions of azoles.
It is seen that the isoxazole molecule (VII) should readily isomerize to oxazole, the value
of Pik + Kik in the S, state being greater than 0 for both the 2--4 bond and for the 2--5 and
1--3 bonds. When the weakness of the i--2 bond is taken into account, this implies the pos-
sibility of the occurrence of a reaction both along the ring-openinE-contraction--formation

136
path and along the path of intramolecular cyclization with isomerization (with the intermed-
iate formation of IX and X) or isomerization with the formation of a zwitterionic tricyclic
intermediate. However, as follows from the calculation, the main reaction path should in-
volve the intermediate formation of azirine VIII (path b, Scheme 3).
Path b should also be predominant in the T2 state, although there is already another
isomerization path with cyclization at positions 3 and 5, which, incidentally, does not re-
sult in isomerization to oxazole.
Since the values of Pik + Kik for the S, state of molecule VII are significantly greater
than zero, the introduction of suhstituents should not alter the predominant direction of the
reaction. Experimental data confirming the conclusions drawn are found in monographs and re-
views [19, 22, 29, 30] and the literature cited therein.
The isomerization of isoxazole (VII) to oxazole (XI) is reversible, photoisomerization
through azirine intermediate VIII (Scheme 4, path a) being preferable for the oxazole mole-
cule in the S, and T2 states, according to the data from the calculation.
As is seen from Table 2, in contrast to the case of the $2 and T, states, bonding be-
tween positions 2 and 5 (the formation of intermediate Xlll) should not occur in this reac-
tion, in agreement with the data from the experiment and the nonempirical calculations with
consideration of the configuration interaction in [31]. In the second triplet state the re-
action can follow path b in Scheme 4 with the intermediate formation of XII.
The influence of the functional groups on lthe direction of the photoisomerization of ox-
azole is more pronounced than in the case of isoxazole, although the value of P2~ + Ka~ in
the S, state is fairly high. From the calculation in [22] it follows that the introduction
of phenyl and/or methyl groups into positions 2 and/or 5 of the oxazole ring results in in-
itial electrocyclization at positions 2-5 (intermediate XIII). it is curious that not only
substituents, but also the reaction conditions, particularly the solvent, have a significant
influence. For the experimental data on this reaction see [19, 22, 29, 30, etc.].
Scheme 3
%_._N 2 -, 5
);,
Oi OT O1

i,, ..~ . . . . %
"F--:r~"
.....
0

:_ J
IXa LX, b 'IX C md
a I $1{$2'T1)
. O

o'1 ~ s~(r2)
N'% ''~ -"; " o~
VII VIII

"1 '~ ('r:t)

Xa
i --~o
x~b
~/---~
xc xd

4/___N2 4 N Z /
2
o~ o %(

The photoisomerization of pyrazole XIV is distinguished from the isomerization of isox-


azole by the fact that in this case, according to the data in Table 2, electrocyclization at
positions 1 and 3 (intermediate XV), rather than at 2 and 4 (intermediate XVI), is predomin-
ant in the S, state, while the reaction should proceed predominantly by means of bonding be-
tween positions 2 and 4 in the T2 state. We stress that, although this mechanism differs
somewhat from that adopted in [22], it gives the same products, as is seen from Scheme 5.

137
The photoisomerlzatlon paths of pyrazole in the S= and T, states are not presented in
the scheme, since there are no experimental data on these reactions. With respect to the
reverse isomerlzation of imidazole to pyrazole, it follows from the calculated data that it
should be completely analogous to the isomerization of oxazole.
Scheme 4

3
2 3 01
xx .... . b vm

i
c, s2(r,), ~
..........
"" ~
If
o~
~ ..N3

4 'o'i

7 .._N 3
2 ..... m.,,.
-- OI
9......... N
......
. . . . . . e,,.. # %,

5 4
F %__!.~

Scheme 5
3
---~?/N r=(s~) ~ N2
5 ab-
It 5 ~ 5 C~,~3
M Ht ~I
X]V X~

blS~(rD
'" ~' '~N"1 4" N2 3

2 It
L s ,j

L N2
-<>3 N~
4 __N? 4 5

1t 1t It

As was noted in [22], at the present time 95% of all the isomerization products of iso-
thiazole and thiazole in the lowest singlet state (see [19, 22, 29, 32, 33]) can be explained
either by a tricyclic zwitterionic mechanism or by an intramolecular cyclization-isomerization
mechanism. In the framework of the scheme developed here, this is manifested by the presence
of large positive values of Kik S for the 1--3, 1-4, and 2-4 positions of thiazole and isothia-
zole in the lowest singlet state (see Table 2). The possible photorecyclization paths of the
S, state of isothiazole (XVlI) under the assumption of a bicyclic transition complex are pre-
sented in Scheme 6. As we have already stated above, the predominance of a particular tran-
sition state is greatly dependent on the nature of the substituents and the reaction condi-
tions.

138
Scheme 6

,, ~ 3 -N 2

~'~/:' s~(T2) sl
XWI[

bi ,N~(T2 )

4 --N ?

According to the calculated data, in the $2 and T, states this reaction should involve
bonding between positions 2 and 5. We note that the existence of large positive values of
K,,~ s for the S, state is also an indication of the possibility of the elimination of an HCN
fragment with the formation of a potentially antiaromatic C=H2S system. Photoreactions of
this type were studied in [34].

LITERATURE CITED
i. Yu. B. Vysotskii, B. P. Zemskii, T. V. Stupnikova, V. N. Kalafat, R. S. Sagitullin, and
B. P. Marshtupa, Khim. Geterotsikl. Soedin., No. 9, 1277 (1982).
2. Yu. B. Vysotskii and L. N. Sivyakova, Zh. Strukt. Khim., 21, 164 (1980).
3. M. J. S. Dewar and R. C. Dougherty, The PMO Theory of Organic Chemistry, Plenum Press,
New York (1975).
4. G. M. Zhidomirov, A. A. Bagatur'yants, and I. A. Abronin, Applied Quantum Chemistry [in
Russian], Khimiya, Moscow (1979).
5. R. Zagradnik and R. Polak, Zaklady Kvantove Chemie (Principles of Quantum Chemistry),
XNTL, Prague (1976).
6. J. A. Barltrop and J. D. Coyle, Excited States in Organic Chemistry, Wiley, London (1975).
7. J. Michl, in: Chemical Reactivity and Reaction Paths, G. Klopman (ed.), Wiley, New York
(1974), Chap. 8.
8. D. O. Cowan and R. L. Drisko, Elements of Organic Photochemistry, Plenum Press, New York--
London (1976).
9. M. M. Mestechkin, Density Matrix Method in Molecular Theory [in Russian], Naukova Dumka,
Kiev (1977).
i0. H. E. Zimmerman and T. R. Welter, J. Am. Chem. Soc., i00, 4131 (1978).
ii. H. E. Zimmerman and R. I. Pasteris, J. Org. Chem., 45, 4876 (1980).
12. E. E. Weltin, J. Am. Chem. Soc., 95, 7650 (1973).
13. C. Minor, P. Roland-Gosselin, and C. Thai, Tetrahedron, 36, 1209 (1980).
14. K. A. Muszkat, G. Seger, and S. Sharafi-Ozeri, J. Chem. Soc., Faraday II, No. 9, 1529
(1975).
15. S. El-Basil and R. Hilal, Bull. Chem. Soc. Japan, 51, 2749 (1978).
16. J. Sauer, U. Ladhoff, and H.-G. Henning, Ztschr. Chem., 16, 370 (1976).
17. M. Scholz, F. Dietz, and M. M~hlstadt, Usp. Khim., 38, 93 (1969); Z. Chem., 7, 329 (1967).
18. A. Lablache-Combier and M.-A. Remy, Bull. Soc. Chim. France, No. 2, 679 (197~).
19. A. Lablache-Combier, in: Photochemistry of Heterocyclic Compounds, O. Buchardt (ed.),
Interscience, New York--London-Sidney (1976), p. 123.
20. H. Hiraoka, J. Phys. Chem., 74, 574 (1970).
21. E. Poquet, A. Dardelog, and M. Chaillet, Tetrahedron, 32, 1729 (1976).
22. A. Padwa, in: Rearrangements in Ground and Excited States, Vol. 3, P. de Mayo (ed.),
Academic Press, New York (1980), p. 501.
23. E. C. Wu, J. Am. Chem. Soc., 93, 3432 (1971).
24. H. Hiraoka, Chem. Comm., No. 24, 1610 (1971).
25. R. Hunt and S. T. Ried, Chem. Comm., No. 22, 1576 (1970).
26. H. Hiraoka, Chem. Comm., No. 20, 1306 (1970).
27. H. Wynberg, R. M. Kellogg, H. van Driel, and G. E. Beekhuis, J. Am. Chem. Soc., 89,
3501 (1967).

139
28. H. A. Wiebe and J. Heicklen, Canad. J. Chem., 47, 2965 (1969).
29. H. C. Van der Plas, Ring Transformations of Heterocycles, Vol. i, Academic Press, London--
New York (1973).
30. S. T. Reid, Adv. Heterocycl. Chem., ii, i (1970).
31. H. Tanaka, T. Matsushita, and K. Nishimoto, J. Am. Chem. Soc., i05, 1753 (1983).
32. M. Kojima and M. Marda, Chem. Comm., No. 6, 386 (1970).
33. M. Ohashi, A. Jio, and T. Yonezawa, Chem. Comm., No. 8, 1148 (1970).
34. A. Krantz and J. Lanreni, J. Am. Chem. Soc., 99, 4842 (1977).

SYNTHESIS OF 5-SUBSTITUTED CYANOFURANS AND THEIR REACTION WITH HYDRAZINE

P. A. Pavlov and V. G. Kul'nevich UDC 547.72:543.422.25+547.792.1'


722.2+547.882'722.2

Based on the Schmidt reaction, a new method has been developed for the prepara-
tion of nitriles in furan series from the corresponding furfural derivatives.
Depending on conditions, the reaction of 5-substituted cyanofurans with hydra-
zinc leads to amidrazones, N-aminotriazoles, or 1,2,4,5-dihydrotetrazines.

The known methods for the preparation of cyanofurans from furancarboxaldehydes [1-6]
have several disadvantages: multiplicity of stages, difficulties related to the regeneration
of the reagents, limited number of suitable methods, because of scarcity of starting mater-
ials, as well as impossibility of their use for the preparation of individual compounds, for
example, 5-nitro-2-cyanofuran [5].
For this purpose we used the Schmidt reaction [7], considered to be unsuitable for the
preparation of nitriles of the furan series. Instead of sulfuric, phosphoric, hydrochloric
and other mineral acids, and also Lewis acids [7], we used 72% perchloric acid, with which it
was possible to avoid resinification of furancarboxaldehydes, but the yield of the nitrile did
not exceed 50%. When anhydrous magnesium perchlorate was introduced, it was possible to re-
duce the amount of perchloric acid to catalytic quantities, and thus the yield of products
I-XXI increased to 76-96%, while the time of the reaction was shortened.

S
R O C ~NH R ~* .... ~/ ~-- ~R
~NHNH2 H H
XXII,XXIII ~"VII - X ~

I, XXIV, XXVll R = H, II, XXV, XXVll R = CHs, III R = C6Hs, IV


R = --C -~ CC~Hb, V, XXII, XXVl, XXIX R = Br, VI R = I, VII, XXIII
R = NO2, VIII R = CH2CI, IX R = 4-C6H~NO~, X R = 4-OC6H~CHs, XI
R = OC6H4CI, XII R = SCHs, XIII R = SCHzCOOC2Hb, XIV R = 2,4-
SC~Ha(NOa)z, XV R = 5-thio-2-cyanofuran, XVl R = 5-thio-2-oxo-
furan, XWll R = S~-C,Hs, XVIII R = 3-S~-C,H4Br, XIX R = thio -

furo-5-yl, XX R -- SO2C6Hs, XXI R = 4-SO2C,H~CHs

Krasnodar Poiytechnical Institute, Krasnodar 350700. Translated from Khimiya G e t e r o -


tsiklicheskikhSoedinenii, No. 2, pp. 181-186, February, 1986. Original article submitted
July 13, 1984; revlsion submitted April 16, 1985.

140 0009-3122/86/2202-0140512.50 9 1986 Plenum Publishing Corporation


28. H. A. Wiebe and J. Heicklen, Canad. J. Chem., 47, 2965 (1969).
29. H. C. Van der Plas, Ring Transformations of Heterocycles, Vol. i, Academic Press, London--
New York (1973).
30. S. T. Reid, Adv. Heterocycl. Chem., ii, i (1970).
31. H. Tanaka, T. Matsushita, and K. Nishimoto, J. Am. Chem. Soc., i05, 1753 (1983).
32. M. Kojima and M. Marda, Chem. Comm., No. 6, 386 (1970).
33. M. Ohashi, A. Jio, and T. Yonezawa, Chem. Comm., No. 8, 1148 (1970).
34. A. Krantz and J. Lanreni, J. Am. Chem. Soc., 99, 4842 (1977).

SYNTHESIS OF 5-SUBSTITUTED CYANOFURANS AND THEIR REACTION WITH HYDRAZINE

P. A. Pavlov and V. G. Kul'nevich UDC 547.72:543.422.25+547.792.1'


722.2+547.882'722.2

Based on the Schmidt reaction, a new method has been developed for the prepara-
tion of nitriles in furan series from the corresponding furfural derivatives.
Depending on conditions, the reaction of 5-substituted cyanofurans with hydra-
zinc leads to amidrazones, N-aminotriazoles, or 1,2,4,5-dihydrotetrazines.

The known methods for the preparation of cyanofurans from furancarboxaldehydes [1-6]
have several disadvantages: multiplicity of stages, difficulties related to the regeneration
of the reagents, limited number of suitable methods, because of scarcity of starting mater-
ials, as well as impossibility of their use for the preparation of individual compounds, for
example, 5-nitro-2-cyanofuran [5].
For this purpose we used the Schmidt reaction [7], considered to be unsuitable for the
preparation of nitriles of the furan series. Instead of sulfuric, phosphoric, hydrochloric
and other mineral acids, and also Lewis acids [7], we used 72% perchloric acid, with which it
was possible to avoid resinification of furancarboxaldehydes, but the yield of the nitrile did
not exceed 50%. When anhydrous magnesium perchlorate was introduced, it was possible to re-
duce the amount of perchloric acid to catalytic quantities, and thus the yield of products
I-XXI increased to 76-96%, while the time of the reaction was shortened.

S
R O C ~NH R ~* .... ~/ ~-- ~R
~NHNH2 H H
XXII,XXIII ~"VII - X ~

I, XXIV, XXVll R = H, II, XXV, XXVll R = CHs, III R = C6Hs, IV


R = --C -~ CC~Hb, V, XXII, XXVl, XXIX R = Br, VI R = I, VII, XXIII
R = NO2, VIII R = CH2CI, IX R = 4-C6H~NO~, X R = 4-OC6H~CHs, XI
R = OC6H4CI, XII R = SCHs, XIII R = SCHzCOOC2Hb, XIV R = 2,4-
SC~Ha(NOa)z, XV R = 5-thio-2-cyanofuran, XVl R = 5-thio-2-oxo-
furan, XWll R = S~-C,Hs, XVIII R = 3-S~-C,H4Br, XIX R = thio -

furo-5-yl, XX R -- SO2C6Hs, XXI R = 4-SO2C,H~CHs

Krasnodar Poiytechnical Institute, Krasnodar 350700. Translated from Khimiya G e t e r o -


tsiklicheskikhSoedinenii, No. 2, pp. 181-186, February, 1986. Original article submitted
July 13, 1984; revlsion submitted April 16, 1985.

140 0009-3122/86/2202-0140512.50 9 1986 Plenum Publishing Corporation


In the preparation of compounds X and XI, the use of perchloric acid as the catalyst led
to the resinification of the reaction mixture, but when HCIO4 was used in the form of diox-
anium perchlorate, they could be obtained in a yield of 69-76%. The characteristics of the
previously known compounds I-III, V, VII, IX, XX, XXI correspond to those described in [1-6],
but their yields are 10-15% higher, and the yield of 5-nitro-2-cyanofuran even increased from
50 to 92%.
In the IR spectra of the compounds synthesized, the characteristic absorption bands of
the stretching vibrations of the CN group are present in the region of 2244-2205 (I-XXI),
C=O at 1780-1680 cm -I (XIII-XIX) the COC grouping (X, XI) absorbs at 1260, 1230, and S02 at
1340, 1150, and 1130 cm -I (XX, XXI). Compounds IV, VIII, X-XIX were synthesized for the
first time, and their characteristics are given in Table i.
The reaction of different nitriles with hydrazine with the formation of amidrazones,
aminotriazoles, and tetrazines has been discussed fairly comprehensively in [8-10], but there
is no information on the reaction of furan nitriles.
Our studies showed that the direction of the reaction depends on the conditions under which
it is being carried out, while the stability of the desired end products depends on the nature of
the substituent at the 5-position of the furan ring (Table 2). The reaction of 5-bromo- and
5-nitrocyanofurans with an alcoholic solution of hydrazine leads to the corresponding amidra-
zones, and that 2-cyanofuran and 5-methyl-2-cyanofUran, to unstable products, which could not
be isolated.
Heating of 5-R-2-cyanofurans with an excess of hydrazine hydrate gave 4-amino-3,5-di(5-
R-2-furyl)-l,2,4-triazoles (XXIV-XXVI) in a high yield. In boiling alcohol in the presence
of sulfur, 3,6-di(5-R-2-furyl)-l,2-dihydro-l,2,4,5-tetrazines (XXVII-XXIX) are formed. 5-
Nitro-2-cyanofuran, which resinifies under the above conditions, is an exception.
In the IR spectra of triazoles XXIV-XXVI there are two stretching vibration absorption
bands at 3350-3325 and 3150 cm-* of the primary amino group, and two deformational vibration
bands at 1665-1645 and 1610 cm-*. The IR spectra of dehydrotetrazines XXVII-XXIX are char-
acterized by the presence of one single stretching vibration band of the secondary amino
group in the 3320-3330 cm-* region, and one deformational vibration band at 1740-1770 cm -I.
In the PMR spectra of compounds XXIV-XXIX, the signals of the NH and NH2 group protons
are recorded as a broadened singlet, which disappears during deuteration.
When 3,6-di(2-furyl)-l,2-dihydro-l,2,4,5-tetrazine (XXVII) is heated in pyridine in
the presence of copper sulfate, 3,6-di(2-furyl)-l,2,4,5-tetrazine (XXX) is formed in 81%
yield, while the corresponding 4-amino-3,5-di(2-furyl)-l,2,4-triazole (XXIV) is isolated un-
changed.

EXPERIMENTAL
The IR spectra were run on a UR-20 spectrophotometer in mineral oil. The PMR spectra
were recorded on a Tesla BS-467 spectrometer (60 MHz) for compounds I, II, V, VII, X, XI in
(CD3)2CO; for III-VI, VIII, IX, XII-XXI in CCI~, and for XXV and XXVIII in CDCI3, using
HMDS as internal standard. The spectra of the remaining compounds were recorded in DMSO-D6,
using t-BuOHas internal standard. The purity of the compounds synthesized was checked by
chromatography of Silufol in a 3:20 ethanol--toluene system.
The benzene solution of hydrazoic acid was in all cases prepared by the method described
in [7].
5-Substituted-2-cyanofurans (I-XXI). A 6.7 g (0.03 mole) portion of anhydrous magnesium
perchlorate is added to a mixture of 0.i mole of furancarboxaldehyde and 0.ii mmole of a ben-
zene solution of hydrazoic acid, and then 1.4 ml (0.01 mole) of 72% perchloric acid is added
dropwise, with stirring, at 35~ The rate of addition is controlled by the current of lib-
erated nitrogen, which should be rapid, but not violent. At the end of the evolution of nit-
rogen, the mixture is treated with water, the benzene layer is separated, washed once more
with water, and dried over sodium sulfate. Benzene is removed under reduced pressure, and
the residue is distilled in vacuo or recrystallized from alcohol. Compound XVI is recrystal-
lized from CCI~ and VII from a mixture of chloroform and cyclohexane.
Compounds X and XI are prepared in a similar way, but instead of perchloric acid, a
previously prepared dioxaniumperchlorate is used [5 ml of 1,4-dioxane and 1.4 ml (0.01 mole)
of 72% perchloric acid].

141
TABLE i. Cyanofurans I-XXI

Com- oMPc[Bp]j PMR spectrum, ppm SSCC) Hz


pound" (Ira) .,,, d,,0 .....
8-H 4-H " R J R:' ,t R4 Ja4

7,82 d ),75 1,8


I 2,32 s
II 7,47 m.
I% 7,33 m
%
V:
Vl!
VII: 4,48 s
8,05 m

H'H" = I 0 , 0

7,03 ',
XI 6,97 (d, H');
7,27 (d, H") j.--,., i 9,0
XII 2,45 (s)
XIII 1,02 it, CH~);
4,08 (,q,, CH~O)
-I:
J CH,~CHa-- 7,0
3,51 (s, C H 2S)
XIV 7,60 O )
XV
XVI H
wt
H
f -- I --
! 'H'"N = 1,75
O It m J.H,. H =2,00
6,40 It, H'"); I.H... u = 5,50
6,10 (dd, H");
7,67 (dd , H')
XVII 7,68 (m)
XVIII 6,60 (m)
XlX ,,"
H~'H4' : 37
HJHs' = 2,0
I H~'H~'= 0,75

-j-
7,44 (d, H~');
6,55 (q , H4') ;
7,58 (d, 1{5')
XX ,7,55 (q. 7,85 (m)
an r i n g
tern pro-
H,,~H~ S02

XXI 7,51 ( q, 2,38 ~, CH3);


m ring 7,40 ~, H); =8,o
i~m pro- 7,85 (d, H)

Amidrazones XXlI, XXIII. A 0.5 ml (0.01 mole) portion of hydrazine hydrate is added to
a mixture of 0.01 mole of cyanofuran V, VII in 10 ml of alcohol. The mixture is stirred,
and left to stand overnight. The alcohol is distilled off under reduced pressure, and the
residue is recrystallized from CCl~ (XXiI) and CHCl, (XXIII).
4-Amino-3~5-di(5-K-2-furyl)-l,2,4-triazole (XXlV-XXVI). A mixture of 0.i mole of 5-R-
2-cyanofuran and 40 ml (0,8 mole) of hydrazine hydrate is boiled for 3 h in a nitrogen cur-
rent, then cooled, the crystals are filtered, washed with water and recrystallized from CHCI3,
3-6-Di(5-R-2-furyl)-l)2-dihydro-l)2,4,5-tetrazines (XXVII-XXIX). A mixture of 0.i
mole of 5-R-2-cyanofuran, 30 ml of ethanol, 30 ml (0.6 mole) of hydrazine hydrate

142
Calculated, %
Found, % Empirical Yield, %
formula
S H N (2al)
H N (Hal)

34,5 %3 15,0 CsH3NO M,5 %3 5,0 -- 76


77,0 5,3 14,8 -- CsHsNO Z7,0 5,2 4,8 -- 82

70,0 8,3 -- C,,HzNO r8,0 f,2 8,3 -- 84


~0,2 3,5 7,1- -- C,3HzNO ~0,2 3,6 7,8 94
34,8 1,2 8,4 16.5) CsH~BrNO 34,8 I,l 8,3 16,5 78
27,3 ~,9 6,3 i7,7) CsH=INO .)7,4 %9 6,4 i7,7 85
43,5 1,4 20,3 -- CsH~N~O~ 13,5 1,4 !0,3 -- 92
50,6 2,7 9,8 ~5.2) C6H,CINO ~0,7 2,8 9,8 -)5,3 96
52,8 2,8 13,3 -- C,tH6N20~ i2,8 2,7 :3,3 -- 80

72,2 4,5 C,2HgNO2 72,4 4,5 7,0 -- 69

50,0 2,6 6,4 16.4) CItH,CINO2 60.0 2,7 6,4 16,4 76

51,7 3,5 10,0 23,0 CsHsNOS 51,8 3,6 [0,0 23,0 79


53,4 4,3 6,8 15,8 CgH~NO3S 53,4 4,4 6,9 15,8 78

45,3 1,7 14,4 10,9 C,,HsN3OsS 45,3 1,7 4,4 10,9 93


55,4 1,7 12,8 14,8 C,oH4N202S. 55,5 1,8 [2,9 14,8 92
52,1 2.3 6,7 15,4 CgHsNO.S 52,2 2,4 6,7 15,4 89

62,8 2,(. 6,1 13,9 C,~HTNO2S 62,9 3,0 6,1 14,0 90


46,7 1,~ 4,5 10,3 CI~HsBrNO~S 46,7 1,9 4,5 10,4 91
25,9: - 26,0)
54,7 2fi 6,4 14,5 C,oHsNO3S 54,7 2,3 6,4 14,6 90

58,4 2,4 6,0 13,6 C.HTNOsS 58,6 3,C 6,0 13,7 98

59,0 2,~ 5,7 13,0 Cj~H6NOaS 59,( 2,4 5,7 13,1 98

and 2 g of sulfur is boiled in a nitrogen current. After 2 h, crystals begin to sep-


arate. After heating for 1 more hour, the mixture is treated as described above. Compounds
XXVII, XXVIII are recrystallized from chloroform, XXIX from toluene.
3,6-Di(2-furyl)-l,2,4,5-tetrazine (XXX). A mixture of 1.92 g (0.01 mole) of 1,2,dihy-
drotetrazine XXVlI, 2.5 g (0.01 mole) of CuS04 and i0 ml of pyridine is heated with stir-
ring for 5 h at 50~ It is then cooled and filtered. The filtrate is poured into I00 ml
of ice water, the crystals are filtered with suction, washed with cold alcohol, and recrys-
tallized from CHCIa. The yield of compound XXX is 1.54 g (81%).

143
i-d
$-

TABLE 2. Characteristics of C o m p o u n d s Synthess


IR spectrum, cm-~ H~R spectrum Found
SSCC, Hz Empirica] Calculated, %
Com- .~ ! Yield, %
pound |'14
fgrmula
VNH 6N~I / NH R Hs . ]2,3 13,4 12,4 C N (Hal) C H N (Hal)

XXII 108 3500 1600 4,41 (1~r~) 6,33 (d,) 6,66 (d) -- 4,0 -- 29,4 2,8 20,5 CsH6BrNaO 29,4i 2.9 20.6 92
3300 (39,1) (39.2)
3200
XXIII '160 ~ 3555 1600 4,57 ( b r . s ) , 5,80 (d) 6,50 .~.) -- 4,0 -- 35,3 3,4 32,9 CsH6N403 35,3 3,5 32,9 89
3325 3,39 (br. s)
32O0
XXIV 240 3350 1645 5,10 ( b r . $) 6,70 ,~d) 5,55 ldd ) 6,]8 (d) 0,7 3,5 2,0 49,9 4,1 29,2 CsHsN402 50,0 4,2 29,2 87
XXV 242 3325 t665, 5,05 ( b r . s) 2,35 (CH~C) 6,08 (d) 7,03 (a) - - 3,9 - - 54,4 5,4 25,4 CIoH,2N402 54,5 5,5 25.5 90
3150 1610
XXVI 244: 3325 1665, 7,83 ( b r . s ) 5,66 (d) 6,11 (dl - - 3,8 -- 35,5 2f 20,5 8 5
CsHeBrN~O. 35,5 2,2 20.7
3180 1620 (29,5) (29,6)
XXVII 208 3330 1770 7 8 3 ~br.s) 6,66 (d) 5,50 ~dd ) 6,03 (d) 0,7 3,5 2,0 50,0 4,0 29,0 CsHsN40~ 50,0 4.2 29.2 88
XXVIII 189' 3320 1740 7,05 , Dr.s~ 2,26 (CHzC) 6,00 (d~ 6,55 (d) - - 4,0 -- 54.5 5,3 25,5 CIoHt2N40~ 54,5 5,5 25,5 87
XXIX 1255 3325 1760 7,91 (.hr. s) 5,6o ~d) 6.04 (d) - - 4,0 - - 35,3 2,1 20,6 CsH~BrN40 35,5 2,2 20,7 83
(29,3) (29,6)
XXX 195 1600 6,95 (@ 5,88 ( d d ) 6,54 (d) 0,9 3,8 2,5 50,3 3,0 29,4 CsH~N402 50,5 3,1 29,5 81

*With decomposition.
LITERATURE CITED
i. A. L. Mndzhoyan, V. G. Afrikyan, and E. A Grigoryan, Dokl. Akad. Nauk Arm.SSR, 301 (1958).
2. G. Sosnovsky, J. A. Krogh, and S. G. Jmhofer, Synthesis, ~, 722 (1979).
3. P. Andove and A. Gaset, J. Chim., 237, 167 (1983).
4. A. P. Dunlop and F. N. Peters, The Furans, Reinhold Publ. Corp., New York (1953), p. 447.
5. Y. Kovac, Coll., 41, No. 6, 1692 (1976).
6. D. R. Shridhar, M. Ioglbhukta, and P. Gopalreddy, Indian. J. Chem. Sect..B, 1 9 No. 5, 386
(1980).
7. G. V. Wolf, in: Organic Reactions [Russian translation], Izd-vo Inostr. Lit. (1951), p.
291.
8. E. N. Zil'berman, Reactions of Nitriles [in Russian], Khimiya, Moscow (1972), p. 429.
9. Yu. P. Kitaev, and B. I. Buzykin, Hydrazones [in Russian], Nauka, Moscow (1974), p. 162.
i0. General Organic Chemistry, Vol. 8, D. Barton and W. D. Ollis (eds.), Nitrogen-Containing
Heterocycles, P. G. Simms (ed.), [Russian translations], Khimiya, Moscow (1985).

CHLORINATION OF 1,3-DIOXOLAN-4-ONES

V. R. Likhterov and V. S. ~tlis UDC 547.729.7:542.944

It is shown that the direction of chlorination of 1,3-dioxolan-4-ones in the pre-


sence of benzoyl peroxide is determined by the nature of the substituent at the
5-position of the ring. In this case a chloromethyl group, having a --I effect,
promotes a selective replacement of hydrogen at the 2-position, while a methyl
group mainly causes replacement of hydrogen at the 5-position.

The present work is devoted to the reaction of 1,3-dioxolan-4-ones with chlorine and aims
to establish the effect of the substituent at the 5-position of the ring on the direction of
chlorination.
5-Methyl- (I) and 5-chloromethyl-l,3-dioxolan-4-one'(II) underwent chlorination. Re-
placement of hydrogen by chlorine proceeds only at an increased temperature (80-I00~ and in
the presence of free-radical initiators. In the case of dioxolanone I on chlorination to an
increase in weight equal to the replacement of one atom %f hydrogen by chlorine, determination
of the composition of the reaction mixture was not achieved. In the second case chlorination
proceeds selectively and leads to 2-chloro-5-chloromethyl-l,3-dioxolan-4-one (III). This,
evidently, can be accounted for by the influence of the substituent with a --I effect, which to
a large extent lowers the reactivity of the C--H bond at the 5-position of the ring to attack
by an electrophilic chlorine radical.

C I C H 2 . ........ ..0
~:~'" C I C H 2 \. .0
'~ i c ~/r tlJ:%b
O. O O. /O

&
II
Ill

It was established (GLC) that the compound synthesized was a mixture of cis and trans
isomers; it showed thermal stability and was readily distilled, but was unstable on hydroly-
sis. Among the products of hydrolysis were identified 3-chloro-2-hydroxypropionic, formic,
and hydrochloric acids.

III - H--20~" C IC H ~ C H C O O H + HCO011 + HCl


-l
Oil

Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 187-189, February,


1986. Original article submitted November 13, 1984; revision submitted February 26, 1985.

0009-3122/86/2202-0145512.50 9 1986 Plenum Publishing corporation 145


It could be supposed that in the case of dioxolanone I, chlorine would, on the contrary,
replace hydrogen at the 5-position, forming a thermally unstable compound. For proof of this
hypothesis we chlorinated 5-methylene-l,3-dioxolan-4-one (IV). The reaction proceeded smooth-
ly at 0-5~ The 5-chloro-5-chloromethyl-lj3-dioxolan-4-one (V) obtained was a substance of
low thermal stability, and it was not possible for us to isolate it by vacuum distillation.

C! ~ 0
C H ~ O ._Cl---,
.2-~. CICt'2,'~--'-'~
O~.~/O 0~/~O
IV V

The dioxolanones III and V synthesized are isomers, being at the same time both lactones
and ~-chlorethers. It is well known that such compounds display exceptionally high reactiv-
ity in reactions with various nucleophilic reagents. We established that in the presence of
triethylamine as a base, in both cases splitting off of hydrogen chloride occurred and 2-
chloro-5-methylene-l,3-dioxolan-4-one (VI) and 5-chloromethylene-l,3-dioxolan-4-one (VII),
respectively, were obtained in high yield. ,.

4=

9 CH2.~ .O :~ CIHC ~ ~O
,H,~ .... ~ 5 ~ _ . . "l ..........~ .: "~--~S ~
O......0 0 ~,~.,0

C1
VI VII
The properties of the unsaturated compounds obtained were dependent on the nature of
the substituents at the 2- and 5-positlons. The first was a mobile, colorless liquid with
an odor similar to that of acid chlorides! it could be distilled under vacuum and hydrolyzed
with the formation of pyruvic, formic, andhydrochloric acids. The second was a stable,
crystalline substance. Their composition and structure were confirmed from the data of el-
emental analysis and IR spectroscopy.

EXPERIMENTAL
1R spectra were recorded on a UR-20 instrument using a thin film between KBr plates.
Chromatographic analysis was carried out on a Tsvet series chromatograph, with flame ioniza-
tion detector, and 3% neopentyl glycol succinate on cellite 545 as adsorbent. Dioxolanone I
was obtained according to a standard method [1].
.2-Chloro-5-chloromethyl-3-dioxolan-4-one (III). Into a reaction vessel fitted with
bubbler, thermometer, and reflux condenser with calcium chloride tube were inserted 136.5 g
(i mole)dioxolanone II [2] and 0.0014 g (0.001 wt. %)benzoyl peroxide; and this was heated
to 90-95~ Chlorine dried with sulfuric acid was passed through until there was a gain in
weight of 35 g and the mixture was distilled under vacuum, i0 g (7%) initial product was ob-
tained as well as 120 g (75% based on initial reactant) cis,trans-dioxolanone III, mp 57-58~
(1.33 hPa), nD 2~ 1.4680, d42~ 1.4740. IR spectrum: 1831 cm-* (C=O). Found: C 28.0; H 2.3;
C1 41.7%; MW 169. C~H~CI2Os. Calculated: C 27.5; H 2.3; Cl 42.0%; MW 171.
Hydrolysis of dioxolanone III was carried out on a boiling water bath, and after the
suspension was dissolved vacuum evaporation was carried out at 50~ The residue was 3-
chloro-2-hydroxypropionic acid, mp 77-78=C (from an ether-chloroform mixture), according to
[3]: rap 78-79~ A test mixture with a known sample melted without depression.
2-Chloro-5-methylene-l,3-dioxolan-4-one (VI). Into a reaction vessel fitted with stir-
rer, thermometer, dropping funnel, and reflux condenser with calcium chloride tube were in-
serted 20 g (0.118 mole) dioxolanone III, 50 ml ether, and free-radical polymerization inhib-
itors (p-methoxyphenol and phenothiazine); and at --5~ over the course of 0.5 h was added
dropwise a solution of 12 g (0.119 mole) triethylamine in 40 ml ether. Stirring was contin-
ued for a further 2 h at the temperature indicated. The triethylamine salt was filtered off,
the solvent was removed, and the residue was distilled under vacuum. 12.5 g (77%) was ob-
tained, mp 40~ (5.32 hPa), nD 2~ 1,4724, d~ 2~ 1.4579. IR spectrum: 1830 cm-* (C=O), 1680
cm -I (C=C). Found: C 35,5; H 2.3; Cl 26.4%; MW 135.0. C4H,CIO,. Calculated: C 35.7; H
2.2; C1 26.4%; MW 134.5. The product was easily hydrolyzed by water, undergoing quantitative
conversion to pyruvic acid (determined by polarography), formic and hydrochloric acids.

146
5-Chloro-5-chloromethyl-3,3-dioxolan-4-one (V). Into a reaction vessel with stirrer,
thermometer, bubbler, and calcium chloride tube were inserted i0 g (0.i mole) of compound IV
[4], 20 ml carbon tetrachloride, and free-radical polymerization inhibitors. At--5~ 7.5 g
(0.107 mole) chlorine was passed in, and the mixture was maintained with stirring at room
temperature for 4 h. Completion of reaction was determined chromatographically according to
the disappearance of initial dioxolanone IV. The solvent was removed under vacuum, and 16.3
g (95%) crude dioxolanone V was obtained, which on heating decomposed with the formation of
tarry products. In a subsequent synthesis it was used without purification.
5-Chloromethylene-l,3-dioxolan-4-one (VII). Into a reaction vessel with stirrer, drop-
ping funnel, thermometer, and calcium chloride tube were inserted 10.6 g (0.105 mole) tri-
ethylamine and 20 ml benzene. At 20-250C a solution of 17.1 g (0.i mole) dioxolanone V in
30 ml benzene was further added. The mixture was maintained for 5 h; then triethylamine hy-
drochloride salt was filtered off, and the filtrate was washed successively with 5% solutions
of hydrochloric acid and sodium carbonate, and then with water. The solvent was removed,
and 9.5 g (71%) was obtained, mp 7.52-73.0~ (from an ether--n-hexane mixture in the presence
of grade A activated carbon). IR spectrum, 1817, 1805 cm-* (C=O), 1680 cm -2 (C=C). Found:
C 35.9; H 2.3; C1 26.5%; MW 138.5. C~HaCIO3. Calculated: C 35.7; H 2.2; C1 26.4%; MW 134.5.

LITERATURE CITED
i. P. Salomaa and S. Laiho, Acta Chem. Scand.~ 17, 103 (1963).
2. M . I . Khramushina, V. R. Likhterov, V. S. Etlis, and D. K. Chuprov, USSR Inventor's
CertificateNo. 609,290; Byull. Izobret., No. 6, 215 (1984).
3. E. Bear and H. Fischer, J. Biol. Chem., 180, 145 (1949).
4. V . R . Likhterov, V. S. Etlis, L. A. Balandina, and S. A. Arzhakov, USSR Inventor's Cer-
tificate No. 606,313; Byull. Izobret., No. 6, 215 (1984).

REACTION OF 2-METHYL-5,6-DIHYDRO-2H-PYRAN WITH DICHLOROCARBENE

U. G. Ibatullin, T. F. Petrushina, UDC 547.811.542.955:


R. R. Gataullin, and M. G. Safarov 543.422:541.634

Upon treatment of 2-methyl-5,6-dihydro-2H-pyran with dichlorocarbene there are


formed products of addition to the double bond a~d insertion at the C--H bond
giving cis- and trans-7,7-dichloro-2-methyl-3-oxabicyclo[4.1.0]heptane and 2-
dichloromethyl-2-methyl-5,6-dihydro-2H-pyran.

The reactionof dihalocarbenes with alkenes usually yields the corresponding adduct via
addition to the double bond (including 5- and 6-membered cyclic vinyl ethers [i, 2]).
We have found that three compounds are formed from 2-methyl-5,6-dihydro-2H-pyran (I) in
37% overall yield: cis- (III) and trans- (IV) 7,7-dichloro-2-methyl-3-oxabicyclo[4.1.0]-
heptane and 2-dichloromethyl-5,6-dihydro-2H-pyran (V) in the ratio 1.0:5.7:3.3.

i :'~- i~ i ~' ~ i I!
i
i c,~, I'~: CH~:l~
I:H~ t'H~
[ I!I,IV V

It can be proposed that the C--H insertion product appearing together with the adducts
III and IV is due to the allyl structure of I, the same course of reaction having earlier
been observed in the case of 2,5-dihydrofuran [3].

Bashkir State University, Ufa 450074. Translated from Khimiya Geterotsiklicheskikh


Soedinenii, No. 2, pp. 190-191, February, 1986. Original article submitted October 8, 1984;
revision submitted May 16, 1985.

0009-3122/86/2202-0147512.50 9 1986 Plenum Publishing Corporation 147


TABLE i. Mass Spectra of the Products of Reaction of Di-
chlorocarbene with 2-Methyl-5,6-dlhydro-2H-pyran*
L , ,i , |,,, , i It, r HI 7

Compound m/z value (~ of maximum ion)

Ill 180 (0,3), 138 (5,8), 136 (9,8), 125 (I0,4), 124 (t6,2), 123 (16,5), 122 (265),
lC}3 (5,6), lOl (21,0), 97 (6,3), 89 (5,4.), 87 (18,7), 79 (6,6), 77 (7,0), 65
(20,8), 53 (5,0), 5l (9,6), 43 ([00,0), 4[ 12[,0)
IV 180 (0,2), 145 (6,6), 138 (19,5), 1'36 131,0), 125 (30,8)~ 124 (17,0). 1~3
(,16,5), 122 (24,4), 115 (6,3), 103 (10,5), ]01 (34,9), 89 (10,1), 87 (30,6),
79 (14,0), 77 (15,3), 71 (10,5), 65 (31,7), 53 (8,9), 51 (15,9), 43 (100,0),
4[ (30,9)
V 167 (3,2), ]65 (5,5), 98 (6,4), 97 (lOO,O), 79 (5,9), 77 (6,[), 65 16,0), ,53
(6,5), 43 157,7), 41 (19,4)

*Ion peaks greater than 5% given.

It is known, however, that another allyl isomer (4-methyl-5,6-dlhydro-2H-pyran (VI))


gives only the corresponding adduct in ~70% yield under the same conditions. I n all proba-
bility the different behavior of dihydropyrans I and VI is due to the high lability of the
2H in pyran I as well as the lower reactivity of the di-substituted double bond when com-
pared with the trisubstituted one in pyran VI.
The elemental composition of the mixture of IIl and IV agrees well with the empirical
formula CTH,oCI=O. In the PMR spectrum there are signals charaeterlstlc of the tetrahydro-
pyran ring together with signals for the protons of the double bond 15,81 ppm) and the di-
chloromethyl group (5.52 ppm). The'lll/V mixture contains 35% of oleflne (ozonolysls)
pointing to the dihydropyran V,
Compounds III and IV are extremely unstable towards electron impact (molecular ion In-
tensity 0,2-0.3%) and they break down by several routes. On the whole their mass spectra
are very similar. The spectrum of dihydropyran V is significantly simpler and markedly dif-
ferent from Ill and IV. The molecular ion is absent but there are fragments at M--CH= (m/z
165 and 167) and for CHCI= (m/z 83 and 85). The most intensive peak is seen for M-CHC1,
(m/z 97) (see Table 1).
In connection with the difficulty of separating III-V the stereochemlstrles are not es-
tablished. However, as is known for norbornene [5], dichlorocarbene adds to six-membered
olefines with a preferred formation of the trans isomer. Hence, in our case we can propose
that the predominant product is trans-7,7-dichloro-2-methyl-3-oxablcyclo[4.1.O]heptane (IV)

EXPERIMENTAL
GCMS analysis was carried out on a Finnegan-4021 instrument with glass capillary column
(30 m x 0.25 mm, SE-30) with temperature programming from 50 to 180~ (5~ at 68-70 eV
and a scan velocity of 1 spectrum/second. PMR spectra were recorded in a Tesla BS-467C (80
MHz) instrument in CC14. Double bond analysis was performed o n a n ADS-4M,
The reaction was carried out using the method [4] of generating diehlorocarbene from
CHCIs under phase transfer catalyticconditions to give an isomer mixture in 37% yield with
mp 97~ nD 2~ 1.5010. Found: C 46.2; H 5.2; C1 39.2%. C,H,oCI=O. Calculated: C 46.6; H
5.5; C1 39.2%.
When the system potassium tert-butylate/chloroform was used the yield of products fell
to 2%.

LITERATURE CITED
i. E.E. Schweizer and W. E. Parham, J. Amer. Chem. Soc., 82, 4085 11960).
2. J.C. Anderson and D. J. Lindsay, Tetrahedron, 20, 2021 11964).
3. J.C. Anderson and C. B. Reese, Chem. Ind., No. 3, 575 11963).
4. A.A. Gevorkyan, N. M. Khizantsyan, P. I. Kazaryan, and G. A. Panosyan, Khim. Getero-
tsikl Soedin., No. 2, 167 11981).
5. V. Kirmse, Chemistry of Carbenes [Russian translation], Mir, Moscow, 11966), p. 201.

148
CHEMISTRY OF ISOFLAVONE HETEROANALOGS.
ii.* BENZODIOXANE ANALOGS OF CHALCONE, FLAVONE, AND ISOFLAVONE

V, P. Khilya, A. Aitmambetov, A. V. Turov, UDC 547.814.5'841.07:


A. M. Kornilov, D. Litkei, and T. Patonai 543.422.25:615.272.4

Benzodioxane analogs of chalcones and their epoxides have been prepared. Dif-
ferent types of analogs of natural flavonolignan -- silibin -- have been synthe-
sized from these compounds. The PMR spectra of the new compounds and the re-
sults of the preliminary biological testings are reported and discussed.

A complex flavanoid (sibilin [2]) and its related compounds (for example, hydrocarplne [3]),
in which the chromone or chromanone nucleus is bound to 2,3-disubstituted 1,4-benzodioxane
have been isolated from different types of plant material. The structure of silibin has been
established and confirmed by synthesis [4-7].

/o..~H ~O~/CH20H

Of} 0 OH 0

Silibin Hydrocarpine
The increased interest in this group of compounds is due to their biological activity.
Thus, silihln has hepato-protectlve [2, 8], antiphalloidine [9], antiperoxide [i0] activi-
ties and inhibits prostaglandin synthetase [ii].
Natural sillblnhas a 3-hydroxy-3',4'-ethylenedioxyflavanoid structure. Hydrocarpine, which
has been isolated later [3], is a derivative of 2-(6-benzodioxan-l,4-yl)chromone and has a
similar structure. Since compounds of this type and those with other degrees of oxidation
have not yet been prepared, we decided to synthesize structurally more simple benzodioxane
analogs of isoflavones (VI) and flavones (VII) and to study their chemical and biological prop-
erties. The key materials for the synthesis of these 6ompounds were substituted 3,4-ethyl-
enedioxychalcones III and IV, obtained by an alkaline condensation of the corresponding o-
hydroxyacetophenones with 6-formyl-l,4-benzodioxane by a known method [12].
The benzodioxane analogs of chalcones III and IV are fairly high-melting crystalline sub-
stances with a yellow or orange color, which are readily soluble in organic solvents (Table
i). There are intense absorption bands in the 1636-1656 cm-* region in the IR spectra of
these compounds, corresponding to the stretching vibrations of the chalcone carbonyl group.
In the reaction of chalcones IV with hydrogen peroxide in an alkaline medium, epoxides
V are formed in good yields, which in contrast to the initial chalcones, are colorless crys-
talline substances, while stretching vibrations of the carhonyl in the molecules are shifted
to the 1664-1687 cm-* region

*For article i0, see [i].

T. G. Shevchenko Kiev State University, Kiev 252017. L. Koshut Debrecen University,


Hungarian People's Republic, Debrecen N-4010. Translated from Khimiya Geterotsiklicheskikh
Soedinenii, No. 2, pp. 192-198, February, 1986. Original article submitted January 14, 1985.

0009-3122/86/2202-0149512.50 9 1986 Plenum Publishing Corporation 149


TABLE 2. Physicochemical Constants of BenzodloxaneAna!ogs
of Isoflavones and Flavones Via, d-ks Va, l
] !R spec-
3ore- rap,~ ~trum~ Foun.'d, % Empirical Calculated, ~ Yield

7.1, Ioo
~.C=O, " Formula
,o~d [cm. 1 C l'l Ital C H llal

VI a [96-- 197 1634 C,;H,204


vld 189.,~. 19(I 1638 C18H1404 73,5 I 42
V,e 192 :..,193 1634 C,sHi4Os 6a
\qf 168 169 1638 C,rH.Br04 69'7 I ~,3 37
VI g 171-172 1638 II,5 C,7H.CIO4 64,8 ] II,3 41
V Ih 209----21(I 1640 6,7 CtTHHFO4 6,8 43
Vii 205.---.21)6 1639 C,yH,604 74,0 I 61

Vlj 19(~.--197 1637 ClsHl405 57


VIk 189--19'0 1639 CmI-11404 45
VIIa 184-..185 1646 C,:H,=O4 52
VIIb 205---206 1646 10i8 C,TH,~Cl04
Vile 213.--214 165O I 1,3 C,rHhCD4 [ 6!
Vlkl 168-.-169 1644 Ci,H*~O4 55
vI[e 170---171 1643 C*,H,40~ 3!
VII f 239..- 240 1633 22,1 ClTH~tBrO4 43
VII g 22&.. 227 1641, I 1,5 C,rH.CIO4 50
1633
V [ l h 213214 1634, 6,8 C,rHnFO4 68
1630
VII i 207---208 1639 CmHI604 64
v!I j 194----,195 C,eHNO5 28
VII k 195--196 C,eH1404 64
VII 1 216-..217 9-O,3 C,7HIoC1204 95

*Compounds Via, i, j, k, and Vile were crystallized from an


ethyl acetate-petroleum ether mixture; VId and Vlla from an
alcohol-octane mixture; Vlf, g, and VIlc, i from alcohol; Vllf,
g, h, j-i from ethyl acetate; Vlld from aqueous alcohol.

isoflavones Vl are preferentially high-melting colorlesscrystalline substances. The


stretching vibrations of the carbonyl group in their molecules are present in the 1637-1650
cm-: region. The physical constants, spectral and analytical characteristics of compounds
VI, VII are listed in Table 2.
To confirm the structure and 9 the configuration of cha!coneslll, IV, epoxides
V, flavones VII and isoflavones VI we used the PMR method in the presence of a lanthanlde
shifting reagent (LSR), as well as the above indicated methods. In the spectra of chalcones
Ilia-l, the signal of the hydroxyl proton is observed in the weakest field (13.4-14.2 ppm).
The type of the functional groups located in the vicinity has only slight influence on the
position of this signal. In several cases, the signals of aromatic protons of these com-
pounds form an unresolved multiplet in the 7.0-8.3 ppm region, In all the compounds, there
is a somewhat detached signal of a proton aligned with the carbonyl group (see Table 3). The
chemical shift (CS) for this proton is 8-8.3 ppm. The signals of the aromatic protons of
the benzodioxane ring form a multiplet with a center at 7.52-7.57 ppm, while the methylene
group signals give a singlet at 4.52-4.54 ppm. Attempts to simplify the spectrum by means
of LSR, europium-III tris-l,l,l,2,2,3,3-heptafluoro-7,7-dlmehtyloctane-4,6-dlonate [Eu(fOd)s]
were unsuccessful, because of strong signal broadenings in the presence of LSR, which are
clearly due to the decomposition of the LSR by the action of strongly acidic phenol proton
of products IIIa-l.
The spectra of the benzyl derivatives IVa, d-i are also difficult to interpret. The
aromatic and olefinic protons give an unresolved multiplet in the 7-8 ppm region (see Table
3), but they can be simplified by the action of [Eu(fod),]. When this LSR is added, con-
siderable paramagnetic lanthanide-induced shifts (LIS) of the NMR signals are observed.
Thus, the highest LIS are characteristic for the methylene proton signals of the benzyl
group, signals of the olefinic protons and the signal of the aromatic proton located at the
o-position with respect to the carbonyl group (see Table 3). From the shift values it fol-
lows that the coordination of LSR is brought about at two centers: at the ether oxygen atom
of the O-benzyl and at the carbonyl group (cf. [15-17]). The benzodioxane ring oxygen atoms
do not participate in the complexation with LSR, as follows from the absence of noticeable

150
TABLE i. Physicochemical Constants of Benzodioxane Analogs of
Chalcones and Epoxides lllaUl, IVa, d-l, Va, d-k

Calculated, %
Co~l- rap,~'C IR spec-' Found ~ Fapirical !Yield,
pound trum, I " formula
~0 C = O ~ c m - c H Hal C [ H Hal

Illa 126--12; 1638 72A 5,( - - Ct7Ht;O4 72,3 5,0 59


IIlb 172--1~ 1636 64,~ 4,~ 11,~ CjzH,3C104 64,5 4,1 II,2 25
IIIC 152--15~ 1642 64,~ 4,~ 11,,r CI7H],CIO4 64,5 4,1 11,2 97
Illd 127--12~ 1637 72,8 5,{ -- CIsHI~O4 72,9 5,4 8()
rile 140--141 1639 69,9 5,C C~sHlaO5 69,3 5,1 57
IIIf 140--141 1638 22,4 C17HI3BrO4 ~,l 96
IlI g 135--13~ 1638 64,7 4,3 i 1,~ CITH,3CIO~ 64,5 4,1 11,2 6O
lllh 173--174 1643 6,4 C~TH~FO; 6,3 78
/lli 145--14~ 1640 73,6 5,6 C,gH,~O~ 73,5 5,8 -- I 80
IIIj 80--81 69,5 5,3 -- CISHI~O~ 69,3 5,1 58
IIIK 138--!3~ 72,5 5,4 -- C18HlaO4 72,9 5,4 -- I 90
IILI 187--188 20,2 C~HmCI~O~ 20,2 85
1Va 111--112 1658 76,9 5,3 -- C,~H,oO~ 77,4 5,4 96
IV4 I10--111: 1659 78,1 5.9 -- C,~H=~O~ 77,7 5,7 83
IVe 113--115 1644 74,7 5,4 -- C=~H=~O~ 74,6 5,5 94
lVf 124--125 91648 18,0 C~H~oBrO4 17,8 I 96
IV, g 119--121~ 1645 70,5 4,7 8,9 C~4H~9CIO~ 70,8 4,7 8,7 95
IVh 118--119 1643 4,8 C~H,~FO~ 5,1 96
IVi 98--99 I 1649 77,6 6,1 -- C~6H2404 78,0 B,6 95
IVj 85--86 1648 74,6 5,5 -- C~sH~Os 74,6' 5,5 79
IVk 113--114 1645 77,9 5,7 1-6,0 C~H~O, 77,7 5.7 82
IV i 125--126 C~H,~CI~O~ 16,1 94
ya 120--121 1677 ?'4,4 5,3 -- C~H2oOs 74,2 5,2 82
143--144 1672 ?'4,5 5,5 -- C~H~Os 74,6 $,5 81
Vie 101--I02 1665 ?'1,8 5.3 lv~.9 C~sH~2Os T1,8 ~,3 72
y f 142--143 1682 C~,HI~BrOs 17,1 79
V g 147--149 1687 ~8,3 4,5 8,4 C~4HtgCIOs ~8,7 t,5 8,4 65
y h 142--143 1678 4,7 C~HIoFOs 4,7 8,t
vi. 134--135 1669 r5,3 5,6 -- C~H2405 ~5,0 87
V J: 129--130 1665 ~2.0 5,4 -- C~sH~O~ ~1,8 $,3 84
V k 120--121 1667 r4,4 5,7 ~- C~H~O~ q ,6 $,5 75

*Compounds Ilia, b and Vf, g, h were crystallized from an al-


cohol-ethyl acetate mixture; lllc, e, h from acetic acid; llld,
e, g, i, k, IVa-h, i, j, and Va, d, e, i-k from alcohol; lllj
from hexane; IVk from aqueous alcohol; IV1 from ethyl acetate.

0 ' 0
~ra-I ina-I

R2 OR + H/C .... ~ RI CH2C6H5


~'-~/~- ICH~ "~.2 ! ol o

l,ll R~ ~ ~ x ~ , ~ O/
I R=H; II R=CH2CsH ~
o Ira,d-1
RI I I{202/0}{-
R2 ~ 0 RI CH2C6H5

E3 C ~ CH~--~C 0

Vla,d-k II
o va,d-k
l'Vll a, c-k R* = H, b, 1 R* = CI; a, b, f-h, j-i R 2 = H, c
R = = CI, d, i R 2 = CH3, e R 2 OCH3; a-e R s = H, f R ~ = Br,
g, 1 R 3 = CI, h R 3 = F, i, k R 3 = CH3, j R s = OCH3
As the result of the rearrangement [13] of opoxides V under the influence of boron tri-
fluoride etherate, benzodioxane analogs of isoflavones VI were obtained in good yields.
Their isomers VII are formed from chalcones III by oxidative cyclization with selenium diox-
ide in amyl alcohol [14]. In contrast to the colored initial chalcones, flavones VII and

151
TABLE 3. PMR Spectra* of Benzodioxane Analogs of Chalcones
Ilia, c-l, Ira, d-k and Their Epoxides Va, d-k

I [ Protons of t h e ~ diOxaale pax-t


, .... [ ' ......
I , o,,
S~ or --C--C~=CH ,L,
Z-OR, ~" 3-H 4-R 2 5-R ~ 6-H d). or
--C'CH- CH--, 7-, I-OCH~CH:O~,
5-,8.H S
s II x /
0 0 9 I
. y,,., .

Ilia 4,52
IIlc 4,54
llld 4,53
Ille 4,51
IIlf 9
IIIg 4,54
IIIh : 4,38
IIli 4,54
u)j 4,32
IIlk 4,33
fill 4,32
IVa 4,48
(o,o)
IXa 4.48
(0,3)
IVe 4,45
(0,2)
Iu 4,50
(0,2)
IVg 4,54
(o,0)
I~h 4,33
(o,3)
IVi 4,52
lo, i)
IVj 4.51
(o2)
lVk 4.45
(o,!)
va 4,r
Vd 4,,46
Ve 4A5
Vf 4,49
Vg 4,46
Vh 4,25
Vi 4,45
vj 4,47
Vk 4,37

*Units of measurement: 6, ppm; the values of the specific


LIS are given in brackets; absence of a letter, multlplet.
%CS of 2-OCHsC6Hs group protons.
%CS of 8-H proton.

LIS for the methylene proton signals of the benzodioxane ring. At a 0,2-0.3 molar ratio be-
tween LSR and the substrata, doublets of the two olefinic protons can beobserved separately
in the PMR spectra of products IVa, d-l. The SSCC [spin-spln coupling con~ant] for these
protons, equal to 15 Hz, indicates a trans structure of all the chalcones obtained.

In the PMR spectra of epoxides Va, d-k, the most characterlstleslgnals are the peaks
of methine protons of the oxirane ring in the form of doublets with a small SSCC (1-1.5 Hz).
One of the peaks is located at 4,55-4.70, and the other at 4,0-4.1 ppm. Changes in the na-
ture of the substituents in the molecules of the epoxides Va, d-k influence the disposition
of these signals in the spectrum very slightly (see Table 3). We assigned the signals of
oxirane protons on the basis of study of the interaction of LSR with compound Vl. The LIS
values found are shown in Table 3. It is seen that the maximal shifts are observed for sig-
nals of the epoxide ring protons, whereby one of the signals i$ shifted more strongly than
the other. At one side of the oxirane ring there is a carbonyl group~ which, as also the
epoxide oxygen atom, is capable of undergoing complexation with LSR. We therefore ascribed
the signal for which a higher value of LIS is observed, to the methine proton located in the

152
TABLE 4. PMR Spectra* of Benzodioxane Analogs of Isoflav-
ones Vla,. d-k and Flavones Vlla, c-i

Compound[ Chromonerlng protons 8enzodioxane ring protons


I
s,I 5.
7-H
187, -OC~Ca20- ,
S
4

VIa 8,31 ~,04, dd : 7,2--7,7 7,2--7,7 7,2---7,7 6,9--7,2 4,29


Via'I" 7,95 B,29, dd 7,3--7,6 7,3--7,6 7,3--7,6 6,9--7,2 4,31
VId 8,34 7,94, d 6,7--7,4 2,49, s 6,T--7,4 6,7--7,4 4,25
vl d f 7,83 ~,09, d 6,7--7,4 2,48, s 6,7--7,4 6,7--7,4 4,27
VI e 8,25 7,94, d 6,7--7,2 3,92, s 6,7--7 o, 6,7--7,2 4,30
VI s 8,42 ~,13, d 7,88, dd 7,54,d , 6,8--7,2 4,32
VI g 8,50 B,03, d~ 7,77, s 7,77,s 6,8--7,3 4,34
VI 8,40 7,4--7,7 - - 7,4--7,7 7,4--7,7 6,7--7,2 4,31
w ~q" 7,91 3,04, s 2,42, s 2,42, s 6,9--7,3 6,9--7,3 4,32
VI' ].I. : 8,39 7,47 3,89, s 7,47 7,47 6,7--7,2 4,30
VI . 7,92 7,63, d 3,93, s 6,7--7,4 6,7---7,4 6,7--7,4 4,31
VI k 8,32 7 83 d 2,09, s 7,46, s 7,46, s 6,7---7, I 4,22
vL k f 7,87 S:O0: d_ 2,49, S 7,33, s 7,33, s 6,7--7,2 4,30
VII a 6,87' 05 d d 7,3--7,8 7,3--7,8 7,3---7,8 7,3--7,8 7,01 4,37
VII a% (6,71' dd 7,3--7,7 7,3--7,7 7,3--7,7 7,3--7,7 6,97 4,36
VII e 6,8oi 7,97, d 7,3--7,7 7,83, d 7,3--7,7 6,99 4,36
VII d 6,75' 7,88 d 7,3--7,7 2,49, s 7,3--7,7 7,3--7,7 6,97 4,36
VII ed-I- (6,591 7,97: d 7,0--7,4 2,51, s 7,0--7,4 ~,0--7,4 6,85 4,33
VII (6,79' 7,93 d 7,58 3,95, s 7,58 r,26, 0 7,00 4,37
Vll et (6,61', 7,36 3,92, s 7,36 i,8--7,1 6,8--7,1 4,36
Vlr ~-t (6,791 ~02 a -- 7,84, dd 7,60, d ',46 6,95 4,36
VI1 (6,65] ~,30, d 7,33, dd 7,2--7,5 ',2--7,5 6,94 4,33
VII (6,83; r,90, d 7,75, s 7,75, s ~,49 6,98 4,37
VII ~'!'. (6,66) ~,14, d 7,2--7,7 7,2--7,7 ',2--7,7 6,93 4,35
VII ~'l" (6,83) r,4--7,9 -- 7,4--7,9 7,4--7,9 ',4--7,9 6,98 4,35
VII (6,63) r,80 7,2--7,6 7,2--7,6 ',2--7,6 6,94 4,33
VII i (6,74) ~,74, s .>,38, .>,38, s 7,46 ',46 7,00 4,36
VII i S (6,66) ~,95, s .>,40, s ~,40, s 7,29, s ',37, dd 6,95 4,34
VII j (6,64) ',51, d 3,91, s 7,32, dd 7,28, d ',32 fi,91 4,33
VII k (6,77) ',79, d !,46, s 7,53 7,53 ',53 5,98 4,33
(6,66) ',96, d !,47, s ~,40 7,40 ',40 6,93 4,31
VII (7,82) 1,30, d -- 3,15, d ',82 7,20 4,53

*Absence of a letter) multiplet.


%The spectra of the compounds were measured in CDCIa, in
unmarked cases, the PMR spectra of the same compounds were
measured in DMSO-D6.
~The PMR spectrum was measured in CFaCOOH.

vicinity of the carbonyl group. The CS of signals of other protons of epoxides Va, d-k are
similar to the CS of the corresponding signals of chalcones IVa, d-k.
In the PMR spectra of isoflavones Vlaj d-k, the 2-H proton, located in the vicinity of
the heterocyclic oxygen atom, absorbs in the weakest field (8.2-8.4 ppm, in DMSO). The na-
ture of substituents R ~, R 2, and R a practically does not influence its CS. It is of interest
that when the spectra are run in deuterochloroform, the CS of the 2-H proton is located 0.5
ppm in a stronger field than when the spectra are run in a DMSO solution (see Table 4). It
is possible that this effect is caused by the stabilization of the bipolar form of the chrom-
one ring due to solvation by DMSO, and as a result, by a greater pramagnetic influence of
the heterocyclic oxygen atom on the position of the 2-H proton signal. The signal of the
5-H proton aligned with the carbonyl oxygen atom is present in a somewhat stronger field
(7.4-8.1 ppm). The signals of the remaining aromatic protons of compounds Via, d-k in most
cases form a multiplet in the 6.7-7.4 ppm region, from which signals corresponding to in-
dividual protons cannot be isolated. The signals of the methylene groups of the benzodiox-
ane ring appear in the form of a singlet at 4.2-4.35 ppm.
In the spectra of flavones Vlla-l, besides the signals of the chromone ring protons 3-H
and 5-H located at 6.5-6.9 and 7.7-5.9 ppm, respectively, the signal of the 8-H proton of the
benzodioxane ring is characteristic. It is located at 6.9-7.0 ppm and does not coincide with
the multiplet of the remaining protons. As in the case of 3-(6-benzodioxan-l,4-yl)chromones,
the signal of the methylene protons of the benzodioxane fragment is located at 4.3-4.4 ppm.
The results of biological tests showed that the compounds with flavone structure obtained
exhibited a weakly pronounced hepato-protective action, while compounds with an isoflavone

153
structure have an appreciable hypolipidemic activity, and in their pharmacological effect
are not inferior to the antlatherosclerotic preparation cetamlphen.

EXPERIMENTAL
The purity of the compounds was checked by TLC on Silufol UV-254 plates in a 9:1 benz-
ene-ethanol mixture. The IR spectra were run on a UR-20 spectrophotometer in potassium brom-
ide tablets. The PMR spectra were measured on a ZKR-60 spectrometer in CDCI~ with reference
to TMS (internal standard).
l%(2-Hydroxyphenyl)-3-(6-benzodioxan-l,4-yl)propenones (Ilia-l) and l-(2-Benzyloxyphen-
.yl)-3-(6-benzodioxan-l,4-yl)propenones (IVa~ d-l). A 20 mmole portion of 6-formyl-l,4-benz-
odioxane and 4.7 ml of a 50% solution of sodium hydroxide are added to a solution of 20
mmoles of the corresponding 2-hydroxy-l) or 2-benzyloxyacetophenone (II) in alcohol. The
reaction mixture is held at room temperature for 20-40 h. The precipitate is suspended in
water and the mixture is acidified with acetic acid to a neutral reaction. The product is
filtered, and crystallized from a suitable solvent.
l-(2-Benzyloxyphenyl)-3-(6-benzodioxan-l,4-yl)-2,3-epoxypropan-l-ones (Va, d-k). A 30
ml portion of 30% hydrogen peroxide and 30 ml of 2 N sodium hydroxide are added to a solution
of 6 mmoles of compound IVa, d-k in a minimal amount of a 15:4 acetone-methanol mixture. Af-
ter complete decoloration of the solution (12 h), the reaction mixture is diluted with water,
the precipitate that separates is filtered and crystallized.
3',4'-Ethylenedioxyisoflavones (Vla, d-k). A 0.6 ml portion of boron trifluoride ether-
ate is added to a solution of 3 mmoles of compound Va, d-k in 50 ml of absolute benzene, and
the mixture is boiled for 1-3.5 h (the end of the reaction is determined from the TLC data).
The solution is washed with water and benzene is evaporated under an aspirator. The precipi-
tate is crystallized from a suitable solvent.
3',4'-Ethylenedioxyflavones (VIIa-l). A 6.65 g (60 mmole) portion of a finely divided
selenium dioxide is added to a solution of 20 mmoles of IIa-1 in a minimal amount of a fresh-
ly distilled amyl alcohol, and the mixture is boiled for 18-50 h, with the course of the re-
action being controlled by TLC. Metallic seleniumis filtered off and amyl alcohol is evap-
orated under an aspirator. The residue is recrystallized several times from a suitable sol-
vent.

LITERATURE CITED
i. V. P. Khilya, M. Yu. Kornilov, N. V. Gorbulenko, G. M. Golubushina, E. N. Kovtun, N. V.
Kolotusha, and G. V. Panasenko, Khim. Geterotsikl. Soedin., No. ii, 1542 (1985).
2. A. Pelter and R. Hansel, Tetrahedron Lett., No. 25, 2911 (1968).
3. K. R. Rangenathan and T. R. Seshadri, Tetrahedron Lett., No. 36, 3481 (1973).
4. R. Hansel, J. Schulz, A. Pelter, and H. Rimpler, Tetrahedron Lett., No. 51, 44i7 (1969).
5. R. Hansel, J. Schulz, and A. Pelter, J. Chem. Soc. Chem. Commun., No. 3, 195 (1972).
6. L. Merlini, A. Zanarotti, A. Pelter, M. P. Rochefort, and R. Hansel, J. Chem. Soc.,
Perkin Trans., No. 3, 775 (1980).
7. A. Pelter and R. Hansel, Chem. Ber., 108, 790 (1975).
8. L. Cavallini and G. Lucchetti, Gazz. Med, Ital., 135, 365 (1976).
9. G. Vogel and W. Trost, Arzneim.-Forsch., 25, 392 (1975).
i0. L. Cavallini, A. Bindoli, and N. Siliprandi, Pharmacol. Res, Cormn., i0, 133 (1978).
ii. F. Fiebrich and H. Koch, Experientia, 35, 1550 (1979).
12. R. Bogn~r and Gy. Litkei, Acta Chim. Acad, Sci. Hung., 67, 83 (1971).
13. Gy. Litkei, R. Bogn~r, and Z. Dinya, Acta Chim. Acad. Sei. Hung., 71, 403 (1972).
14. H.S. Mahal, H. S. Rai,and K. Venkataraman, J. Chem. Soc., 866 (1935).
15. I. G. Marchenko, A. V, Turov~ and V. P. Khilya, Dokl. Akad. Nauk UkrSSR, Ser. B., No.
l, 43 (1979).
16. L. G. Grishko, A. V. Turov, M. G. Spasenov, and V. P. Khilya, Khim. Geterotsikl. Soedin.,
No. 9, 1202 (1981).
17. L. G. Grishko, A. V. Turov., I. A. Potrusaeva, and V. P. Khilya, Ukr. Khim. Zh., 49, 174
(1983).

154
AN UNUSUAL PRODUCT OF THE REACTION OF I-PHENYL-3-(3,4-DIMETHOXYPHENYL)-
3-(2-OXOCYCLOHEXYL)-I-PROPANONE WITH HYDROGEN SULFIDE AND ACIDS:
2a-PHENYL-2,4-ortho-(14,15-DIMETHOXYBENEO)-cls-I-THIADECALIN

S. K. Klimenko, T. I. Tyrina, UDC 547.81:543.422


N. N. Sorokin, and V. G. Kharchenko

The reaction of l-phenyl-3-(3,4,dimethoxyphenyl)-3-(2-oxocyclohexyl)-l-propan-


one with hydrogen sulfide and acids gives an intramolecular rearrangement pro-
duct, 2u-phenyl-2,4-ortho-(14,15-dimethoxybenzo)-cis-l-thiadecalin in addition
to the usual products of disproportionation of intermediate 2-phenyl-4-(3,4rdi-
methoxyphenyl)-5,6-tetramethylene-4H-thiopyran, namely , 5,6-tetramethylenethio-
pyrilium salts and 2a-phenyl-4u-(3,4-dimethoxyphenyl)-cis-l-thiadecalin. The
configurational and conformational assignments for the sulfides, their sulfox-
ides, and sulfones were made by *SC NMR spectroscopy.

l-Aryl- and 1,3-diaryl-3-(2-oxocyclohexyl)-l-propanones are converted by the action of


hydrogen s u l f i d e i n acid media initially to the corresponding 5,6-polymethylene-4H-thiopyrans
[i], which then, by the action of a strong mineral or organic acid, undergo disproportiona-
tion to give 5,6-polymethylenethiopyrilium salts and 2-thiabicycloalkenes or 2-thiabicycloalkanes
[2-4].
We have studied the reaction of l-phenyl-3-(3,4-dimethoxyphenyl)-3-(2-oxocyclohexyl)-l-
propanone (I) at room temperature with hydrogen sulfide and trifluoroacetic acid. In contrast
to other "seven-membered" 1,5-diketones, diketone I forms the tetracyclic intramolecular re-
arrangement product, 2a-phenyl-2,4-ortho-(14,15-dimethoxybenzo)-cis-l-thiadecalin (V) along
with the usual reaction products, namely, thiopyriliumtrifluoroacetate III and cis-l-thiade-

TABLE i. Conditions and Products of the Reactions of 1,5-


Diketone I with Hydrogen Sulfide and Acids
r ,,] .
Reaction conditions Reactionproducts Yield,g IV/V or Vl~V
starting acid solvent (rap, ~ sulfide ratios
compound (amount,ml) (amount,m in the mixtUreb
(mmoles)
I (30) CF3COOH III (166~-168) 7,0 (50)
(30) 1V 042.5--143,5)
v (180--181) !3,1 (28) 1:8
I (40) 70% HCI04 Ctt3COOH V (180--181)
(17,4) (75) VI (145---146) I 59 (40) 1:1
VII (183--184) 9,1 (49)
I (30) BF3 (30) CH3COOH V (180--181)
(7o) V1 (145--146) : 4,6 (44) 3:1
VIII (191--193) 5,8 (45)
1I (12) CFaCOOH tV (142,5--143,5
(30) V (180--181) 1,3 (29) 5:l
(III), VII (183--184)' 12,8 (52)

aproducts IV, Vl, and Vll were identified by mixing melting


points with authentic samples [2, 4, 5]. bThe sulfide ratio
in the:mixture was determined relative to the '3C NMR spec-
tra of the crude mixtures, eTrifluoroacetate III was con-
verted to perchlorate VII.

N. G. Chernyshevskii Saratov State University, Saratow410601. Translated from Khimiya


Geterotsiklicheskikh Soedinenii, No. 2, pp. 199-205, February, 1986. Original article sub-
mitred December i0, 1984.

0009-3122/86/2202-0155512.50 9 1986 Plenum Publishing Corporation 155


calin IV. The dimethoxyphenyl group in V is bound both to C(2) and C(4) of the heterocycle.
This led us also to study the reactions of 1,5-dlketone lwith hydrogen sulfide and 70% perchlo-
tic acid or boron trifluoride etherate. The experimental conditions and reaction products
are given in Table i. In both cases, tetracyclic product V was found in addition to the cor-
responding perchlorate or tetrafluoroborate VII and VIII and 2-thiabicyclo[4~
VI. All these compounds are given in Table 2. The configurational and conformationa! assign-
ments for IV-VI and IX-XII were carried out by laC NMR spectroscopy (Table 3). Sulfides V and
VI were oxidized by hydrogen peroxide to sulfoxides IX and X and sulfones XI and XII, respec-
tively.
CsH3(OMe) 2

V + I + VII(VIII)
(BF~) ~" / " ~ S ....."Ph
Ph Ph

I ] II VI

CsHs(OMe)2 CsHs(OMe)2 ,~./OMe

Ph
y-
Ill,VII,VIII IV
V
Me0,~ /0Me
15 ~4 ,

- ~3 r
10 f .....'X

6
V,IX,X IV.XI,XI~

III Y = CF~COO; VII Y = C104; VIII Y = BF~; IV, V X = S; IX,


XI X = SO; X, X I I X = S02
The formation of trifluoroacetate III and sulfide IV with cis,cis,cis configuration is
in accord with the usual concepts concerning the cyclization of 1,5-diketones and 4H-thiopy-
tans [i] and the mechanism for the disproportionation with acids [3] including the steric
specificity of hydride transfer in these systems [5]. Thus, we shall not treat these ques-
tions in the present work.
The sterically less hindered double bond (C(~)=C(s)) is initially protonated in the dis-
proportionation of condensed 4H-thiopyrans with acids [3]. Carbonium ion a which is generat-
ed in this step may be a hydride ion acceptor. The loss of a hydride ion from a second 5,6-
tetramethylene-4H-thiopyran molecule leads to reestablishment of the C(2)=C(3) double bond.
In our case, this ordinary process is accompanied by the reaction of the electrophilic site
in carbonium ion a with the dimethoxyphenyl group at C(~). Electrophilic substitution in
the aromatic ring apparently leads to intermediate XIII and then to product V due to the re-
duction of second double bond upon disproportionation.

GMe
~O~

/'- .I",.. if+ ~.~\ . . ; " \ .... ~ "~. ~(,>---OMe

"~/ " s / '"Ph


tI (o0 XIII

In our previous work [6], we have established that the heterocycle in 2,4-disubstituted
5,6-polymethylene-4H-thiopyrans is in boat form, while the substituent in the y-position is
pseudoaxial and, thus, close to C(2), which facilitates attack on C(a) upon formation of the
carbonium ion. The dimethoxyphenyl group itself is extremely active relative to electrophilic
attack, thereby facilitating its reaction with the carbonium site.

156
TABLE 2. Characteristics of Compounds Obtained

Found, % Calculated
Chemical Yield,
&] rap, ~ IR spectrum, cm" i formula %
81 c H S C H S

III 166--168 [680--1660 (COO-), 1600, 63,1 5,2 6,9 C26H~31::304S 63,0 50--52
1585, 1525, 1495 (C=C),
1270, 1075 (C--O--C) I
V 180--181 1605, 1495 (C=C arom.i !75,2 7,4 8,7 C23H2802S 75,4 , 8,8 22
1265, 1070 (C--O--C)
VIII 191--193 1600, 1540, 1495 (C=C), 61,4 5,3 7,3 C23H23BF402S 61,4 [7,1 45
126% 1o3o (c--o--c),
1040 (BF4-)
1265, 1070 (C--O--C), i
IX 172--173 1600, 1500 (C=C ~.om~ 72,6 7,2 8,6 C23H28OaS 72,2 71
1045 (S--O)
X 221--222, 1600, 1500 (C=C arom. 69,5 !6,9 8,4 C2aH2oO4S 69,3 6,6 87
1300, 1130 (S--O), 1270,
1065 (C--O--C)
XI 156--158 1600, 1500 (C=C atom. 71,6 ,0 8,5 C23H28OaS 71,8 7,3 , 73
125o, 1o2o ( o - - o - - c ) ,
lO45 ( s - - o )

*The recrystallization solvents were i:I ethanol-acetone for


sulfide V and sulfone X and 2:1:0.5 hexane--ether--acetone for
sulfoxides IX and XI. Salts III and VIII were reprecipitated
from chloroform by the addition of ether.

The structure of tetracyclic sulfide V indicates that the reduction of the'angular dou-
ble bond as a result of protonation at C(~o) and transfer of a hydride ion from 5,6-tetra-
methylene-4H-thiopyran II to the carbonium site at C(9) proceeds by cis addition although
the approach of the hydride ion donor from the side of the condensed aromatic ring is ster-
ically hindered.*
The formation of t~iabicyclo[4.4.0]-A1'6-decene VI in addition to the intramolecular con-
densation product V in the reactions of 1,5-diketone I with hydrogen sulfide and perchloric
acid or boron trifluoride etherate supports our mechanism for the formation of V.
The reaction products did not contain 2a-phenyl-2,4-ortho-(14,15-dimethoxybenzo)-trans-
l-thiadecalin or 28-phenyl-2,4-ortho-(14,15-dimethoxybenzo)-cis-lrthiadecalin , which are iso-
mers of sulfide V.
Table 1 also gives the results of the disproportionation of thiopyran II in trifluoro-
acetic acid. The relative yield of tetracyclic sulfide V in this case is significantly lower
than in the reaction of 1,5-diketone I with H2S/CF3C02~. The higher yield of sulfide V in
this experiment indicates that the dimethoxyphenyl group apparently also reacts with carbon-
ium ions directly preceding the formation of 5,6-tetramethylene-4H-thiopyran II from the bi-
cyclic semithioacetal.
There have been reports of the intramolecular rearrangement of 9-benzyl-symm-octahydro-
thioxanthenes upon the action of hydrogen chloride, perchloric acid, and trifluoroacetic acid
to give 3,4-benzo-5,9-7,8-bis(tetramethylene)-6-thiabicyclo[3.3.1]-7-nonene as a result of
intramolecular electrophilic reaction of the benzyl group with the carbocation site with re-
duction of the double bond and formation of disproportionation products [7].
The formation of thiadecalin V in the reactions considered in the present work is the
first example of an intramolecular rearrangement during a disproportionation reaction. We
should note the finding that intermediate XIII is reduced in this reaction while the angular
double bond is retained in dihydro product VI.
The configurational and conformational assignments for 2~-phenyl-4u-(3,4-dimethoxyphenyl)-
cis-l-thiadecalin (IV) were carried out in our previous work [5]. The *SC--{H} and double het-
eronuclear resonance spectra permitted examination of the change in the multiplicity of two
signals in the rearrangement product V relative to thiadecaline IV. The aliphatic part of the
spectrum of V shows a singlet at 57.70 ppm while the aromatic part shows a singlet at 134.64
instead of doublets at 48.70 and 119.33 ppm in IV. These data indicate an intramolecular re-
action of a dimethoxyphenyl group with one of the u-carbon atoms of the heterocycle.

*Assuming that the transfer of the hydride ion from the donor molecule to the acceptor mole-
cule occurs in a ~imolecular complex.
157
oo

TABLE 3. "aC NMR Spectra of IV, V, and IX-XII, d, ppm

2-Ph 2,4-At or 4-Ar


Com- c,~ C(3) C(3) C(5) C(6) C(7) C(8) C(9) CHo) OCHa
pound c(~) II ortho meta para C(12) C(I~)
C(n) c.4) Ic~5) [c(~6)

V 57,70:s 39,20 57,50d 24,709 28,60 22,20 i 30,70 46,63,d 44,54, d 55,80 140,~7 127,71 127,71 126,60 136,64 134,64 104,84 148,321148,791107.28
(135}? (138) ~ (137)~
IX 70,43 s 35,46 49,92p 23,71 27,41 21,24 [ 27,27t 63,83,d 46,06, u 55,74 135,86 128,93 128,14 127,69 136,93 127,91 107,20 148,601149,331107,60
(130, (146)* (139)~,
X 75,78,s 35,08 51,61,d 23,33' 27,23 20,52:t I 19,54t 61,08, d 45,07, 55,85, 129r63 130,22 127,97 128,51 137,94 128,37 107,60 148,821150,241107,79
(13o) (133)* (138)* 55,76
C(I) C(6) C(5) c(,) Ic(,) It(,)

IV 48,70 33,50 48,20 21,10 126,50 19,20 i31,60 46,50 43,10 55,68, 142,29 127,12 128,23 126,93 136,88 119,33 110,86 148,481147,141111,20
55,59
XI 68,93 30,98 46,94 22,11 [ 25,93 20,86 [ 25,65 . 66,22 46,81 55,66, 136,77 128,62 128,13 128,05 134,25 118,29 110,76 148,45 148,53II 10.76
55,58
XII 67,39 31,02 46,67 21,12 /25,26 19,16 [ 23,12 60,72 44,94 55,78, 130,28 129,84 128,38 128,79 134,39 119,30 110,95 147,71 148,741110,95
55,67

*The XJc_ H coupling constants are given in parentheses. *Tentative signal assignment.
TABLE 4. Difference in the Chemical Shifts of the y-Carbon
Atoms in Sulfoxides IX and XI and Sulfones X and XII Rela-
tive to the Corresponding Sulfides V and IV, ppm

Iv v
Atom
SO 802 SO SO~

-- 2,52 -2,48 --3,74 -4,12


t,~s) --5,95 -8,48 -- 3,43 -11,16
C([o) +3,61 + 1,84 + 1,52 +0,53

The complete interpretation of the '3C NMR spectrum of sulfide V became possible due to
analysis of two series of sulfide-sulfoxide--sulfone spectra for V, IX, X and IV, XI, XII tak-
ing account of the characteristic effects of the sulfinyl and sulfonyl groups in going from
sulfides to the corresponding sulfoxides and sulfones. Table 4 gives the y-effects of the SO
and SO= groups in IX-XII, which are in good accord with the data for thiadecaline derivatives
[i0]. The use of the SO and SOs group y-effects in IX-XII permitted the identification of
the signals for C(s), C(o), and C(,o). The C(e) signals in both series IV + XI + XII and V
IX + X are more shielded than the C(s) signals.
The signals for C(o) and C(zo) in sulfides IV and V (Table 3) do not differ significant-
ly, while the C(s) signal in V is shifted downfield by 5.7 ppm, perhaps as a consequence of
anisotropy of the condensed dimethoxyphenyl group and the presence of this atom in a five-
membered ring. Hence, we have assumed that the intramolecular cyclization proceeds at C(=).
The presence of an upfield signal at 22.20 ppm indicates cis ring fusion according to
the accepted criterion for condensed cyclohexanes [ii].
In addition, analysis of the theoretical Chemical shifts of the alicyclic carbon atoms
for conformations A and B or 2~-phenyl-cis-l-thiadecalin~[5] and the chemical shifts of C(5),
C(6), C(7), and C(e) in IV and V indicates that the cis-l-thiadecalin system is in conforma-
tion A in both IV and V (Table 5).
The orientation of the sulfinyl groups in IX and XI is equatorial. The '3C NMR spec-
tra of the sulfoxides and sulfones of 2-aryl- and 2,4-diaryl-cis-l-thiadecalins will be con-
sidered in a subsequent communication.

EXPERIMENTAL
The IR spectra were taken on a UR-20 spectrometer ~n vaseline oil and hexachlorobuta-
diene. The *H and '3C NMR spectra were taken on a Varian FT-80A fourier-transform spectrom-
eter using HMDS (for *H) and CDCI3 solvent (for *SC) as internal standards. The 13C NMR
spectra were taken with broad-field suppression of the spin-spin coupling of the '3C and *H
nuclei with incomplete proton decoupling. The spectra for V, IX, and X were taken with gated
decoupling with retention of the *Jc-H values. The data of various workers [5, 8, 9] were
taken to calculate the chemical shifts of some alicyclic and aryl group carbon atoms with
subsequent comparison of the experimental and theoretical parameters.
The reaction course and product purity were monitored by thin-layer chromatography on
Silufol UV-254 plates with 6:1 hexane--ether as the eluent. Sulfides IV and V or V and VI
were separated by preparative column chromatography on alumina with hexane as the eluent.
The characteristics of the compounds synthesized for the first time are given in Tables
2 and 3.
Reaction of l-Phenyl-3-(3,4-dimethoxyphenyl)-3-(2-oxocyclohexyl)-l-propanone (I) with
~ydrogen Sulfide and Trifluoroacetic Acid. A sample of 30 ml absolute trifluoroacetic acid
was saturated with hydrogen sulfide for 1 h at 20-25~ A sample of 10.96 g (30 mmoles) di-
ketone I was added in portions over 1 h and saturation with hydrogen sulfide was continued
for an additional 3 h. The reaction mixture was maintained for three days until the inter-
mediate 4H-thiopyran had completely disappeared and then repeatedly extracted with a total
of 350 ml hexane. The extract was washed with water and dried over MgS04. Partial evapora-
tion of the hexane in vacuum gave crystallization of sulfide V, mp 180-181~ (from 1:2 etha-
nol--acetone) in 22% yield. Complete evaporation of the hexane from the residue gave a i:I

159
TABLE 5. Comparison of Theoretical a and Experimental Chemical
Shifts of Alicyclic Carbon Atoms in IV and V, ppm
Configuratio~
Compound and confir- Nature of
[nation the data G{5) C~7) C(B)

2~ -phenyl-cis- cis-A calc. 24,40 26,69 2(I,88 31,86


l-thiadecalina cis-B talc. 34,22 19,61 . 28,28 27,34
IV cis-A exp. 21,10 26,50 19,20 31,60
V cis-A exp. 24,70 28,60 22,20 30,70

aData for the theoretical spectra of 2e-phenyl-cis-l-thiadeca-


fin from our previous work [5] are given for comparison.

mixture of sulfides IV and V in 6% yield. Trifluoroacetate II crystallized upon dilution of


the acid mother liquor of the reaction mixture by ether, mp 166-168~ (from chloroform-ether).
Reaction of 1,5-Diketone I with HTdrogen Sulfide and Boron Trifluoride Etherate. A sam-
ple of 70 ml glacial acetic acid was saturated with hydrogen sulfide for i h at 20~ and then
30 mmoles 1,5-diketone I was added in smallportlons along with the dropwise addition of 30 ml
boron trifluoride etherate over 1.5 h. The reaction mixture was maintained at room tempera-
ture for 72 h and diluted with 350 ml ether. Tetrafluoroborate VIII was filtered off, mp
191-193~ (from chloroform-ether) in 45% yield. The mother liquor was washed with water and
dried over MgS04. Removal of the solvent and chromatography permitted the separation of V
and Vl in 12 and 33% yield, respectively.
Reaction of l~5-Diketone I wit~ Hydrogen Sulfide and Perchloric Acid. The reaction was
carried out as in our previous work [2]. The experimental conditions and results a r e g i v e n
in Table i. Perchlorate VII and a mixture of sulfides V and VI were obtained.
2e-Phenyl-4e-(3,4-dimethoxyphenyl)-cis-l-thiadecalin 1-Oxide (XI). A sample of 0.6 g
(1.63 mmole) sulfide IV was dissolved in 21 ml glacial acetic acid and l.65 mmole 30% hydro-
gen peroxide was added dropwise. The mixture was left for 24 h at room temperature and then
poured onto chopped ice. Sulfoxide XI was filtered off.
2e-Phenyl-2,4-ortho-(14,15-dimethoxybenzo)-cis-l-thiadecalin 1-oxide (IX) was obtained
according to the procedure described above.
2u-Phenyl-4u-(3,4-dimethoxyphenyl)-cis-l-thiadecaline l,l-dioxide (Xil) and 2a-phenyl-
2,4-ortho-(14,15-dimethoxybenzo)-cis-l-thiadecalin l,l-dioxide (X) were obtained from the
corresponding sulfides by oxidation with excess hydrogen peroxide as described in our previ-
ous work [12]. Sulfone XII was obtained in 90% yield, mp 166-167=C (from ethanol). A mixed
probe of this sample with an authentic sample gave an undepressed melting point.

LITERATURE CITED
i. S. K. Klimenko, M. N. Berezhnaya, and V. G. Kharchenko, Zh. Org. Khim., i0, 2425 (1974).
2. S. K. Klimenko, T. V. Stolbova, M. N. Berezhnaya, N. S. Smirnova, I. Ya. Evtushenko, and
V. G. Kharchenko, Zh. Org. Khlm., iO, 1942 (1974).
3. T. V. Stolbova, S. K. Klimenko, and V. G. Kharchenk0, Zh. Org. Khim., 16, 178 (1980).
4. S. K. Klimenko, T. V. Stolbova, and V. G. Kharchenko, Khim. Geterotsikl. Soedin,, No.
i0, 1338 (1981).
5. S. K. Klimenko, T. V. Stolbova~ T. I. Tyrina, N. N. Sorokin, I. F. Leshcheva, N. M.
Sergeev, and V. G. Kharchenko, Khim. Geterotsikl. Soedin., No. 7, 898 (1984).
6. I. Ya. Evtushenko, S. K. Klimenk0, B. I. lonin, and V. G. Kharchenko, Zh. Org. Khim.,
ll, 2417 (1975).
7. A. A. Shcherbakov, G. G. Aleksandrov, Yu. T. Struchkov, and V. G. Kharchenko, Khim.
Geterotsikl. Soedin., No. ii, 1470 (1979).
8. R. Kh. Freidlina, V. I. Dostovalova, N. A. Kuz'mina, and E. C, Chukovskaya, Org. Magn.
Reson., 15, 133 (1981).
9. A. M. Krapivin and L. I. Perepelitchenko, Izv. Akad. Nauk SSSR, Ser. Khim., No. 2, 452
(1982).
i0. R. P. Rooney and S. A. Evans, J. Org. Chem., 45, 180 (1980).
ii. E. R. Eliel and F. W. Vierhapper, J. Org. Chem., 41, 199 (1976).

160
12. N. S. Smirnova, S. K. Klimenko, M. N. Berezhnaya, T. V. Stolbova, and V. G. Kharchenko,
Zh. 0rg. Khim., ii, 440 (1975).

REACTIONS OF AZIRINES WITH SULFUR NUCLEOPHILES.


4.* TREATMENT OF 2H-AZIRINE WITH MERCAPTOSUBSTITUTED ACIDS.
REACTIONS OF AZIRIDINYL ALKYL SULFIDES WITH CARBOXYLIC ACIDS
AND ACYL CHLORIDE DERIVATIVES

R. S. El'kinson and A. V. Eremeev UDC 547.717'279.104

Treatment of 2H-azirines with mercaptosubstituted acids and their derivatives


leads to B-ketoamides and 2-aziridinyl alkyl sulfides, respectively. 2-Aziri-
dinyl alkyl sulfides, in turn, react with carboxylic acids to give B-ketoamides
and substituted ethanethiol derivatives. Acylation of 2-aziridinyl alkyl sul-
fides with acyl halides generates a variety of products, depending on the reac-
tion conditions; either products derived from cleavage and isomerization of the
aziridinyl ring or (l-acylaziridinyl-2) alkyl sulfides are obtained.

Electrophilic addition of carboxylic acids to the C=N bond of 2H-azirines gives the cor-
responding B-ketoamides as a result of ~somerization and 1,2-cleavage of the aziridine ring
in the initially formed 2-acyloxyaziridine derivatives [2]. At the same time, 2,2-dimethyl-
3-phenylazirine (I) reacts with B-substituted ethanethiols to give a new type of functional
aziridine derivative, namely, aziridinyl alkyl sulfides [3].
It was of interest to us to study the reactions of azirine (I) with mercaptosubstituted
acids, i.e., bifunctional reagents which should be capable of entering into both nucleophilic
and electrophilic addition reactions to ~ bond of azirine (I). We have found that reaction
of azirine I with mercaptoacetic and mercaptopropionicacids occurs at the carboxyl group to
generate the corresponding u-(mercaptoacylamino)isobutyrophenones II and III:

Ce.Hs-~." -CH 3
~'~.~'-. CH 5 + [[S(CII2)COOH ....... C~IIsCOC(CkI5)2NHC0(CII2)sSH
N If,Ill
I

II n = i; III n = 2
The formation of products II and III from the reactions of azirine I with mercaptosub-
stutited acids should be anticipated based on a comparison of the ionization constants of
these acids (pKa 3.68; 10.40 and 4.32; 10.47, respectively) with those of unsubstituted car-
boxylic acids, which are known to react with 2H-azirines to give the corresponding B-ketoam-
ides.
In cases where protonation of azirine ring and subsequent nucleophilic addition of a
carboxylate anion are impossible, such as, for instance, during esterification or salt for-
mation, themercapto group of the carboxylic acid is the only reactive site, and as a result,
nucleophilic addition of the mercapto group to the C=N bond of azirine I occurs, and the cor-
respondin~ aziridinyl alkyl sulfides are formed, in analogy with the results reported in [3].
For instance, treatment of azirine I with the ethyl ester of mercaptoacetic acid for the sod-
ium salts of N-acetylcysteine or cysteine yields the aziridinyl alkyl sulfides IV-VI as the
only reaction products (Table i):

*For communication 3, see [i].

Institute of Organic Synthesis, Academy of Sciences of the Latvian SSR, Riga 226006.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 206-211, February, 1986.
Original article submitted November 30, 1984.

0009-3122/86/2202-0161512.50 9 1986 Plenum Publishing Corporation 161


CY~
tJ

TABLE 1. Physical Chemical Properties of Su.lfides IV-VI, XV-XVII, XIX, and XXI

Com- Found, % Calculated, %


pound IR spectrum, cm- 1 Molecular formula Yield, %
fl N
I S(Cl) 1t N S (Cl )

IV [68~9 1080, 1260, 1730, 3280 63.3 7,2 5,0 ii.8 C,4H ,,lqO2S' 63,4 7,2 5,3 12,1 72
(2,6 hPa)]
V 178--180 1410, 1560, 1650, 1690, 3250, 3300 54,3 5,6 8,7 9,4 C,sH,gNaN~OsS 54.5 5,8 8,5 9,7 57
VI 120--121 1600, 3200, 3260, 3350 54,1 5,7 9,9 10,9 C,aHjzNaN202S 54,2 5,9 9,7 11,1 51
XV 46---48 1640, 3300 63, I 7, I 5,5 11,9 C,4HvjNO2S 63,4 7,2 5,3 12,1 61
XVI 119--120 1650, 3350 69,6 6,1 4,5 9,6 C~gH~tNO2S 69.7 6.4 4,3 9,8 58
XVII 15---18 900, 980, 1430, 1650, 3330 65,2 6,6 5,3 11.3 C,sH,9NO2S 65,0 6.9 5.1 11.6 37
XIX 37--39 1050. 1250, 1640, 1720 62,4 6,5 4,4 t03 C u;H~ NOaS 62.5 6.8 4.5 10.4 45
XX! 183--185 825, 1540, t650, 2It0, 2210, 3300 49,6 6,3 8,4 9.3 C,4H2ICIN2OS. HC[ 49,9 6.5 8,3 9.5 64
(2o,9) (21,1)
I

%19/'~-}
.6- ...... | IIRCII/CI[(NI1COCtI3.)COONa -\\',,

CSII5 CII3 C6II%>~. . . . ~/CH3


S~'~/'CHs /S" ~ .,, "-CH~ ,S'~/// CH.~
Ha HN CH2 HN ~H2 HN
COOC2H5 CII(NHCOCII3)COONa CII(NfI2)COONa
IV ~, VI
The azirldinyl alkyl sulfides were of considerable research interest, inasmuch as their
structural characteristics, namely, the presence of both aziridinyl and sulfide functional
groups, would seem to imply a wide spectrum of chemical reactivity, encompassing the chem-
istry of the aziridine ring as well as that of sulfides. We have therefore studied the re-
activity of these sulfides in reactions involving both retention and cleavage of the aziri-
dine ring, which are characteristic of aziridines. It is known, for example, that heteroly-
tic cleavage of the aziridlne ring occurs upon treatment with organic acids to give the cor-
responding 2-acyloxyethylamines [4]. However, our experiments concerning the reactions of
2-hydroxyethyl- and 2-dimethylaminoethylaziridinyl sulfides VII and VIII [3] with either sat-
urated or unsaturated carboxylic acids unexpectedly revealed some unusual product structures.
Instead of generating the expected 2-acyloxyethylamines, treatment of sulfides VII and VIII
with carboxylic acids led to the formation of the corresponding 8-ketoamides X-XIII and a
substituted ethanethiol derivative (Tables 2 and 3). 2-Alkoxyaziridines react in a similar
manner to aziridinyl alkyl sulfides with carboxylic acids. For instance, t r e a t m e n t of 2-
ethoxy-3,3-dimethyl-2-phenylaziridine (IX) [5] with carboxylic acids gave the same 8-keto-
amides as prepared above, and the compounds X-XIII were identical with respect to all physi-
cal chemical and spectral characteristics with these compounds. It should be noted, however,
that the reactions of aziridine IX with carboxylic acids require both longer reaction times
(6 h) and higher reaction temperatures (80=C) than the analogous reactions of sulfides VII
and VIII (3 h, 50 ~

RCH2CH2~q~CH3 R~C00H C6Hb~CH3


C6H5' N/ CH3 ":RCH2CHzS~- C6HsCOC(CH3)2NHCOR1 ~C2HsoHR1COOHC2H5~~ / ~CH~
H X-~II HN
3I,~II IX
Vll R = OH; VIII R = N ( C H s ) a ; X R* = C 6 H 5 ; X l R* = C 6 H ~ C H = CH;
R* = CeH=C-C; XIII R x = CHa,= CH
We cannot exclude the possibility that these reactions occur via intermediate 2-acyloxy-
ethylamines, since the rearrangement of 2-acyloxyethylamines to 2-hydroxyethylamides is known
[6]. One observation supporting this assumption is the fact that reaction of aziridine IX
with carboxylic acids requires harsher conditions than the analogous reactions of aziridinyl
alkyl sulfides; the sulfide group is, of course, a better leaving group than an alkoxy group.
It is known that acylation of aziridines with acyl halides to give N-acylaziridines oc-
curs only in the case of acceptor acids [7]. Treatment of the aziridinyl alkyl sulfides VII

TABLE 2. Physicochemical Properties of 8-Ketoamides X-Xlll

Com- / Found, % Molecular C,a l c . %


pound " rap, oC | R! IR spectrum, cm- i formula
0)
ther C H[N el.IN
X 153--155 0,71 1535, 1635, 1690, 3080, 76,2 6,3;5,4 CIzHITNO2 76,416,4 5,2 78
3250
XI 218--220 0,59 1540, 1620, 1655, 1680, 77,7 6,3 i4,9 CI9HIgNO2 77,816,5 4,8 56
3280 !
XII 118--120 0,75 1530, 1620, 1660, 1685, 78,1 5,6 4,7 CioHlTNO2 78,415,8 4,8 78
2210,3210,3315
XIII 158--160 0,44 1530, 1620, 1655, 1680, 71,7 6,6 6,3 CI~HIsNO2 71,915,9 6,41 53
3290, 3310

163
TABLE 3. PHR Spectral Parameters of 8-Ketoamides X-Xll (CDCIs)

Com- ~, ppm
pound C0H~ C1% NH H.Rt (J, Hz)

X 7,91 (Ho); 7,11--7,33 (H., an~ 1,72 7,58 (H~), 7,11--7,33 (H.,and[.{~)*
Hp)
XI 7,93 (Ho); 7,4 (H.,andHv) 1,78 6,56 7,4 (C6H~); 6,25~'d6,51 (CH=CH,
16)
XII 7,89 .~[-Io); 7,11--,7,58 (Hr~and 1,71 7,02 7,1 I--7,58 (C6H~)t
H~)
XIII 7,91 (Ho); 7,42 (H,.andH~) 1,76 6,67 5,58 (CH; 5,4; 6,6), 6,r
(=CH2; 14,1; 5,4; 6,6)

*Multiplet, including both the aromatic ring proton signals and


the NH group signal.
tMultiplet consisting of all of the aromatic ring proton signals.

and ElY [3] with acyl halides in the presence of triethylamine readily gave the corresponding
N-acylaziridinyl alkyl sulfides XV-XVII (Tables 1 and4):

RCH2CII~S .CH3 RCII2CIt2S,. _ ...... _~CH3


%.(~:,+-)~"c% .el .- co.,~ I c,+

C(IR

X'V-.,X~'I! XVIII

9 R1COC1 =611; (C~Its)~N

C{CH3)2NH2'HCI RCH2CH2S ' CH RI C00CH2CH2S CH


........................... "" c H ~ \ / ~CH
C=H=
~~ SI , ~ / - 9 .R=OH
... C6['15/ ~ C INI 3 R=0H; (C2Hs)3N
" 6 5 \ N/ 3

H COR 1
X~ VII,XIV XIX

" RICOCII R=NH2. HCI CH3

CaHsC(Cl )C(CH3 )2NItCOR 1 H2_O_... C6HsCO~NIICOR


I 1 + IISCII2CH2R
!
SCI]2CII2R CH3
XXI

Vll R = OH; X I V R = NH2~ R* = CHs, C6H5, CH2 = CH


The rearrangement of N-acylaziridines in the presence of acid to give ring-enlarged pro-
ducts, namely, 2-oxazolines [8] is characteristic of N-acylaziridines; we have demonstrated this
reaction using sulfide XV, which gave the hydrochloride salt of 2,4,4-trimethyl-5-phenyl-5-
(2-hydroxyethylthio)-2-oxazoline XVlII.
When 1 mole of the aziridinyl alkyl sulfide VII was treated with 2 moles of acylating
agent in the presence of base, the hydroxy group of the sulfide also underwent acylation, and
the corresponding (l-acylaziridinyl-2-)-2-acylhydroxyethyl sulfide XIX was obtained.
In the absence of base the N-acylaziridines generated in these reactions undergo further
conversions involving ring opening and formation of B-halosubstituted N-acylethylamines [9].
Our experiments have shown, however, that, depending on the nature of the substituent in the
B-position to the sulfide group, a variety of products can be obtained from the reactions of
the aziridinyl alkyl sulfides VII and XlVwith acyl halides in the absence of base. For in-
stance, treatment of sulfide VII with acetyl chloride in the absence of base gave an almost
quantitative yield of a substituted 1,3-oxathiolane, which was isolated in the form of its
hydrochloride salt XX [i0]. Apparently, hydrogen chloride, which is generated in the begin-
ning of the reaction, induces heterolytic cleavage of the aziridine ring, which leads to in-
tramolecular rearrangement of sulfide VII to the 1,3-oxathiolane ring system, as has been
demonstrated previously [I0].
In contrast, workup of the hydrochloride salt of 2-aminoethyl aziridinyl sulfide XIV
with acetyl chloride under analogous reaction conditions generates the sulfide XXI; the struc-
ture of the latter was verified by spectroscopic analysis, as well as by hydrolysis to give
the known compounds [ii] ~-(acetylamino)isobutyrophenone and 2-aminoethanethioi hydrochloride.

164
TABLE 4. PMR SpectralParameters o f Sulfides XV-XVII, XIX
(r
RCH2CII~S'~_ CH3

N
I ,
COR

8, ppm
tom- " R'
pound C6H5 CH~ CH2--S CH2--R Ha HRt (I, Hz)

XV OH CH3 7,49 (Ho); 7,29 0;62 and 2,44 3,49 2,88 2,02
(H,,,~ndH p) 1,56
XVI OH CsHs 7,99 (Ho); 7,29-- 0,78 and 2,58" 3,56 2,13 7,62 (Ho);
7,56 (H.,and Hp)* 1,73 - 7,29--7.56 (Hm
andHp )*
XVII OH CH2=CI-I 7,33 (Ho); 7,56 (Hr~ 0,71 and 2,51 3,40 2,51] 5,78 (CH; 3,44;
and Hp) 1,64 - 8,1); 6,17and
6,35 (=CH2;
7,92 (Ho); 7,48 18,1; 8,1; 3,44)
XIX CH3COO CHa (H~ and H~) 0,76 and 3,06 4,44 2,18 2,03
1,77

*Multiple, corresponding to all of the protons of the aro-


matic ring.

EXPERIMENTAL
IR spectra were recorded on a Perkin-Elmer 580B spectrophotometer using thin films. PMR
spectra were obtained on a Bruker WH-90 spectrometer using 5% solutions and TMS as internal
standard. Melting points of the compounds prepared in this paper were determined on a Boeth-
ius microheating apparatus.
2-(Mercaptoacetylamino)-2-methyl-l-phenylpropanone (II). A solution of 2.61 g (18 mmole)
of azirine I [5] in 20 ml of acetone was treated dropwise with 1.66 g (18 mmole) of mercapto-
acetic acid. The mixture was stirred 15 h at 70~ and the acetone was evaporated. The resi-
due was recrystallized from 1:3 chloroform--hexane. Yield 2 g (47%), mp 183-185~ Rf 0.18
(Silufol UV-254, ether). IR spectrum (nujol): 1550, 1645, 1690 (amide bands, C--O), 2500-2680
(SH), 3330 cm-* (NH)~ PMR spectrum (DMSO-D6): 8.57 (IH, s, N'H), 7.92 (2H, m, Ho), 7.46 (3H,
m, Hm, and Hp), 3.21 (2H, s, CH2). 1.46 ppm (6H, s, CH3). Found: C 60.4; H 6.0; N 5.7; S
13.4%. C,2H, sNO2S. Calculatedt C 60.7; H 6.3; N 5.9; S 13.5%.
2-(3-Mercaptopropionylamino)-2-methyl-l-phenyl-l-propanone (III). This was prepared in
an analogous manner; mp I18-120~C. IR spectrum (nujol): 1545, 1650, 1685 (amide I and II
b a n d s , CzO), 2530-2600 (SH), 3300 cm-* (Nil). PMR spectrum (DMSO-D6): 8.77 (IH, s, NH), 7.90
(2H, m, Ho), 7.46 (3H, m, Hm, and H p ), 2.89 (2H, m, 2-CH=) , 2.62 (3H, m, 3-CH2 and SH) , 1.46
ppm (6H, s, CH3). Found: C 61.9; H 6.7; N 5.3; S 12.5%. CI3HtTN02S. Calculated: C 62.2;
H 6.8; N 5.6; S 12.7%.
Ethyl (3,3-Dimethyl-2-phenylaziridinyl-2-thio)acetate (IV). A solution of 2.9 g (20
mmole) of azirine I in I0 ml of ethanol was treated dropwise with a solution of 2.5 g (20
mmole) of ethyl mercaptoacetate in i0 ml of ethanol. The reaction mixture was stirred 12 h
at 50~ the alcohol was evaporated, and the residue was distilled. Yield 3.8 g (72%); bp
68-69~ (2.6 hPa) PMR spectrum (CDCXs): 7.94 (2H, m, Ho), 7.39 (3H, m, H m and Hp), 4.21
(2H, q, O-CH2), 3158 (3H, s, S--CH= and NH), 1.29 (3H, t, CH3), 0.89 and 1.69 ppm (3H and 3H,
s, CH3).
Sodium 2-Acetylamino-3-(3,3-dimethyl-2-phenylaziridinyl-2-thio)propanoate (V). This
was prepared in a similar manner and was purified by washing twice with 20 ml of acetone.
PMR spectrum (D20): 7.34 (SH, 2, C6Hs), 4.33 (IH, t, J = 5 Hz, CH), 2.89 (2H, d, J = 5 Hz,
CH2), 2.03 (3H, s, CH3CO), 0.87 and 1.59 ppm (3H and 3H, s, CH3).
Sodium 2-Amino-3-(3,3-dimethyl-2-phenylaziridinyl-2-thio)propanoate (VI). This compound
was also prepared analogously to the manner described for compound (IV) and was purified by
recrystallization from a 1:3 chloroform--hexane mixture. PMR spectrum (CDCI3): 7.22 (5H, m,
C6H5), 3.26-2.71 (6H, m, S--CHa, CH, NH2 and NH), 0.83 and 1.53 ppm (3H and 3H, s, CH3).
The physicochemical properties of compounds IV-Vl are recorded in Table i.

165
2-Benzoylamino-2-methyl'l-phenyl-l-propanone (X; Tables 2 and 3) A solution of 0.7 g
(3 mmole) of sulfide VII or VIII [3] in 30 ml of acetone was treated dropwise with a solution
of 0.37 g (3 mmole) of benzoic acid in i0 ml of acetone. The mixture was stirred 3 h at 50~
and the acetone was evaporated. The residue was recrystallized from 1:3 ethanol--ether. Yield
0.62 g (77.5%); mp 153-155~
Compounds XI-XIII were prepared in a similar manner (Tables 2 and 3).
l-(Acetyl-3,3-dimethyl-2-phenylaziridinyl-2)2- (hydroxyethyl) Sulfide (XV; Tables i and 4)~
A solution of 0.75 g (3.3 mmole) of sulfide VII and 0.34 g (3.3 mmole) of triethylamine in 20
ml of dry tetrahydrofuran was treated dropwise with a solution of 0.27 g (3.3 mmole) of acetyl
chloride in i0 ml of dry tetrahydrofuran. The mixture was stirred 3 h at 20~ and the triethyl-
ammonium chloride precipitate was removed by filtration. The filtrate was concentrated and the
residue was recrystallized from 1:3 ether-petroleum ether. Yield 0.53 g (60.9%); mp 46-48~
Sulfides XVI and XVII were obtained analogously (the latter was purified by recrystalliza-
tion from hexane).
2,4,4-Trimethyl-5-phenyl-5-(2-hydroxyethylthlo)-2-oxazoline Hydroch!oride (XVIII) o A so-
lution of 0.53 g (3 mmoles) of sulfide XV in i0 ml of acetone was treated dropwise with a solu-
tion of 0.Ii ml of concentrated hydrochloric acid in 5 ml of ethanol. The mixture was stirred
3 h at 20~ and the solvent was evaporated. The residue was recrystallized from 1:3 acetone--
ether. Yield 0.76 g (84.4%); mp i18-120~ IR spectrum (nujol): 1660 (C=~-~), 18i0 (imine
salt band), 2420 (ammonium band), 3300 cm-* (OK). PMR spectrum (DMSO-D~): 8.08 (2H, br s,
NH + and OK), 7.46 (5H, m, C~Hs), 3.33 (2E, t, O-CH2), 2.39 (SH, m, S-CH~ and 2-CH3), 0.78 and
1.64ppm (3Hand3H, s, 4.4-CH3). Found: C 55.5; H 6.4; N 4.3; S 10.8%. CI~HIgNO2S "HCI. Cal-
culated: C 55.7; H 6.6; N 4.6; S 10.6%.
(l-Acetyl-3,3-dimethyl-2-phenyla~iridinyl-2) 2-Acetoxyethyl Sulfide (XIX). This compound
was prepared similarly to compound XV. See Tables 1 and 4.
Hydrochloride Salt of (l-Chloro-2-acetylamino-2-methyl-l-phenylpropyl) 2-Aminoethyl Sul-
fide (XXI; Table i). A solution of 0.52 g (2 mmole) of sulfide XIV [3] in 20 ml of ethanol
was treated dropwise with a solution of 0.24 g (3 mmole) of acetyl chloride in l0 ml of ethanol.
The mixture was stirred i0 h at 20~ the alcohol was evaporated, and the residue was recrysta!-
lized from 1:3 alcohol--ether. Yield 0.43 g (64%); mp 183-185~ P~[R spectrum (DMSO-D6): 9.77
(IH, br s, NH), 8.94 (3H, br s, NHs+), 7.96 (2H, m, Ho), 7.55 (3H, m, E m and Hp), 3.56 (2H= t,
N--CH2), 3.29 (2H, t, S--CH2), 2.03 (3H, s, CH3CO), 1.76 ppm (6H, s, CH3).

LITERATURE CITED
i. R. S. El'kinson, A. V. Eremeev, Ya. Ya. Bleidelis, A. F. Mishnev, and S. V. Belyakov,
Khim. Geterotsikl. Soedin., No. 12, 1633 (1985).
2. A. V. Eremeev and R. S. El'kinson, Khim. Geterotsikl. Soedin,, No. 6, 736 (1984).
3. R. S. El'kinson, A. V. Eremeev, A. F. Mishnev, Ya. Ya. Bieidelis, and V. G. Semenikhina,
Khim. Geterotsikl. Soedin., No. I, 53 (1985).
4. J. Yukawa and S. Kimura, Patent No. 4,973 (Japan); Chem. Absto, 58, 1032 (1963).
5. R. F. Parcell, Chem. Ind., 33, 1396 (1963).
6. O. C. Dermer and G. E. Ham, Ethyleneimine and Other Aziridines, Academic Press, New York
(1969).
7. H. C. Brown and A. Tsukamoto, J. Am. Chem. Soc., 83, 2016 (i961).
8. H. W. Heine, M. E. Fetter, and E. M. Nicholson, J. Am. Chem. Soc., 81, 2202 (1959).
9. H. Bestian, Ann., 566, 210 (1950).
i0. R. S. El'kinson, A. V. Eremeev, and ~. ~. Liepin'sh, Khim. Geterotsikl. Soedin., No~ 5,
623 (1985). r

ii. A. Hassner, S. S. Burke, and I. Cheng-fan, J. Am. Chem. Soc., 97 , 4692 (1975).

166
NEW DERIVATIVES OF meso-(TETRA-4-PYRIDYL)PORPHINE AND THEIR REACTIONS

V. N. Madakyan, R. K. Kazaryan, Mo A. Khachatryan, UDC 547.979.733.07:


A. S. Stepanyan, T. S. Kurtikyan, and M. B. Ordyan 543.422

Some reactions of Co-meso(tetra-4-pyridyl)porphine were carried out, and a cyan-


opyridine complex was isolated. New water-soluble complexesbased on Co-meso-
(tetra-4-N-hydroxyethylpyridyl)porphine were obtained. Aliphatic, aromatic, and
heterocyclic amines were examined as ligands.

The effect of the structure and functional substituents of the porphyrine molecule on
its biological activity can be examined by studying a large number of different synthetic por-
phyrines.
The purpose of the present work is to synthesize some cyanamine cobalt complexes of meso-
(tetra-4-pyridyl)porphine (TPyP), a structural analog of vitamin B,2, and to prepare water-
soluble analogs of some previously described unsymmetric cobalt complexes [I]. Aliphatic,
aromatic, and heterocyclic amines were used as ligands on the central cobalt atom.
The reaction of a chlorofozmrnnethanol solution of CoTPyP (2) with 48% hydrobromic acid
gave meso-(tetra-4-pyridyl)porphinobromocobalt (III) (3) CoBrTPyP. Treatment of the latter
with cyclohexylamine gave the complex4, also obtained directly from CoTPyP in solution by
reaction with cyclohexylamine hydrobromide in cyclohexylamine [i].
Treatment of CoBrTPyP 3 or the complex 4 with excess KCN in methanol gave the complex 5,
in which cobalt is present as an anion. By refluxing in glacial acetic acid, followed by
chromatography on AI20~ (Brockmann activity grade II), the dicyano complex 5 was converted to
the monocyano derivative 6, which with pyridine gave a quantitative yield of the cyanopyridine
complex 7.
Attempts to synthesize the imidazole and benzimidazole cyano-derivatives of CoTPyP were
not successful; in neither case was the complex isolated.
The reaction of meso-(tetra-4-pyridyl)porphine (TPyP) i [3] with excess ethylene chloro-
hydrin gave the tetrachloride of meso-(tetra-4-N-hydroxyethylpyridyl)porphine (THEtPyP) (8)
in quantitative yield. The central cobalt atom was introduced by treating THEtPyP in aqueous
medium with a tenfold excess of cobalt chloride followed by concentrated hydrochloric acid;
the course of the reaction was monitored spectrophotometrically. The reaction of an aqueous
solution of the complex 9 with excess of the corresponding amine yielded the amino derivatives
10a-d.
All the compounds synthesized (8-10) were readily soluble in water at any pH.
In the infrared spectra of compounds 5-7, the cyano group absorbs in the region 2100-
2200 cm -I. The two cyano groups of complex 5 give rise to only one absorption band (at 2170
cm -I) indicating that they are equivalent. It can be assumed that both cyano groups are co-
ordinated to the cobalt atom and are situated symmetrically relative to the plane of the por-
phyrine molecule. This structure consists of two normal oscillations: inphase and antiphase.
These oscillations include the valency oscillations of the cyano group. Such a structure
is unique since only one of the oscillation, i.e. the antiphase oscillation, is IR-aetive.

Erevan State Medical Institute, Erevan 375025. Translated from Khimiya Geterotsikliche-
skikh Soedinenii, No. 2, pp. 212-216, February, 1986. Original article submitted January 23,
1985; revision submitted April 8, 1985.

0009-3122/86/2202-0167512.50 9 1986 Plenum Publishing Corporation 167


CfI2CH201i
,~< c :

C ] " +/'t:'-::'x / NI'| N ,.[. /. " { k + C1


N. N
UOCU.,CH=
. .
,iN~ ,'~,
//
.-#'
\
~:.... ~i ; N-.
N" COfI.N .,.t ....... --. | ' f " :'=" N. IINI "[;r ,
" "":'=
C;I ~C.~zOH
"
9 '~ " "~" " ':':. ' 8
' t

N "~'~ %../' -" CltzCH20H ~,~. t


ieaA~.~
ne
/ i II / / / / l

.... '-<, /o._ 2 - \ :


.......

d + - J ...... 1 ;
N / I "N f ~'N:

.... N/Cq,N Br-


/ 3
/
4 //
CN

/~ N" I "N
CN .N
N..N,~.NI
.NIC ---.- N, .N
N;C~.~:~ ........ O
CN
5 8
Note. a~ n-butylamine, b) cyclohexylamine, c) piperidine, d) pyridine
Infrared spectral data and elemental analysis, show that the conversion of the complex 3
to the complex 5 is accompanied by the dehydrobromlnation of the peripheral pyridine groups,
so that in compound 5 the pyridine groups occur as free bases. Thus, in going from complex 3
to 5 there is a shift of the pyridine ring absorption band from 1640 to 1595 cm-*. Analogous
shifts in the absorption for the transition from a pyridine salt to a free base have been re-
ported in the literature [4].
In compound 6, stretching vibrations of the C-N group absorb at 2148 cm -~, while the free
C=_N- ion absorbs at 2080 cm -~ . An appreciable change in the frequency indicates that the cyano-
group is located in the inner sphere as in the complex 6, where the cyano group is covalently
bonded, and not in a structure with separated charges, as was proposed in [5] for etioporph-
r ine (cobalt) cyanide.
The infrared spectra of compounds 10a-d contain more absorption bands than that of the
complex 9; the frequencies of the additional bands are similar to the vibration frequencies of
the coordinated ligands (see Table i). It should be noted, however, that axial coordination
in the test compounds shows up less sharply in the infrared than in previously obtained com-
plexes of CoTPyP with a numher of amines [i]. This is to be expected, since the porphyrines
which we studied contain hydroxyethyl groups, the vibrations of which partially overlap the
region of absorption of the coordinated amines. Thus, some of the bands given in Table i, ap-
pear as shoulders on porphyrin absorption bands, and in several cases bands in the spectrum
of the complex are stronger and (or) half as wide as the corresponding bands in complex 9.
This is particularly the case for bands due to the stretching vibrations of the NH(NH~) group,
which indicate axial coordination. Bands corresponding to these vibrations, are small peaks
in the same region as the broad OH stretching absorption band with maximum at 3400 cm -~ . How-
ever, in all cases these bands are at lower frequencies than in the free amines. This pro-
vides evidence for ligand-coordination, since it is known [6] that the coordination of amines
is accompanied by a decrease in the frequency of the stretching vibrations of the N(NH2) groups.

168
TABLE i. Aminoderivatives of meso-(Tetra-4-N-hydroxyethylpyridyl)porphinochlorocobalt (III) Tetrachloride lOa-d

UV spectrum.X , nm Found, % Calculated, % Yield,


Coln- Empirical
pound Amine (~ -zo-~ F, IR s p e c t r u m , cm- 1 % I I
C It CI I formula II CI

10a Butylamine 436 (115), 548 (10,8), 575 V~ZI-L), 745, 1078 VtCN~, 1375, 56,7 1 4,8 16,0 I 11,4 C~2H5504CI~,CoN,j 56,4 5,0 16,1 11,4 93
585 sh (4,4) 1465 6(CH~ ' all:,), ' 2968 V,,,~(CH:,) ' 3200
Y (N H,.,)
I I
16b Cyclohexyl- 436 (114), 548 (10,3), 557 s h v~,~1.-To, 705, 898, 1385 5(Ci ), 57,5 5,2 15,8 ] 11,1 Cs4HszO4CIsCoN9 57.3 5,0 15,7 ql,l 91
amine 587 sh, (3,9) 2868 v,~ccH~) , 2945 V.~(CHA, 32',30
I
V.~(NH: ), 3300 %'"~(NHz)
16c Piperidine 439 (91,2), 552 (10,4), 555 V~--L), 1088 V~CN~, 1385 8(CH~) , 56,8 4,7 15,8 11,4 Cs3H,~O4CI.~CoN.a 56,9 4, 9 15.9 11,3 92
591 sh, (4,5) 1452 s h 8(dH~ ) , 2750, 2800, 2950
~'.S(CH:0 , 3200 VtNIt)
10d Pyridine 57,6 4,3 15,9 11,3 C~H4904CI~CoN9 57,2 4.4 16,0 11,3 93
440 (116), 562 (10,1), 696 pt~:u), 1440, 1598 vtcc~, [~cc.~
6Ol (4) i

*For complex 9 the corresponding bands were at 435, 546, and 584 nm, and at 412, 530, and 560 nm for Co(II)TPyP.
TWave numbers for bands not present in the spectrum of complex 9 are given.

O~
%0
For the pyridine ligand, there is no N-H bond and this criterium cannot be used. How-
ever, two new bands at 696 and 1598 cm-* in the spectrum can reasonably be attributed to a
displacement of the ~*~b(CH), ~ea(CC), and 8(CCH) vibrations on coordination, In free pyri-
dine, the3e absorptions occur at 702 and 1580 cm-*; similar displacements have previously been
reported for pyridlne complexes [4].
The frequencies of the porphyrine ring vibrations change little on axial coordination.
The strongest bands from the macroring are at 800 and i000 cm-x, and are out-of-plane and in-
plane deformation vibrations of the pyrrole CH bonds [7], shifted by 6 cm-*. The greatest
shift is observed for the complex with pyridlne. Ultraviolet spectral data (see Table i) also
show the greatest bathochromic shift in the spectrum of the complex 10d. Apparently, increased
coordination of Co(Ill) with an aromatic system, which may also involve the dative component
of the metal-ligand bond, disturbs the electron system of the macrorlng more strongly, although
~udging from the small frequency shift, these disturbances are small.
The ultraviolet spectra of the compounds show a small bathochromic shift compared with
the complex 9 because of additional coordination. Examples of such bathochromic [8], and also
hypsochromic shifts [9] have been reported for absorption bands as a result of axial coordina-
tion.
Attempts were made to cleave the axial ligand from the complex at elevated temperatures
(70-80~ and reduced pressure (10-4 tort). The eliminated llgands were directly precipitated
onto a KBr substrate cooled with liquid nitrogen inside a vacuum cryostat, enabling the infra-
red spectra of the cleaved particles to be taken. In all cases they were found to be starting
amines, which, therefore, did not undergo any chemical change during the course of the reaction.

EXPERIMENTAL
Infrared spectra in the range 400-3600 cm -l were taken on a UR-20; samples were prepared
as KBr pellets or as suspensions in mineral oil. Ultraviolet spectra over the range 350-800
nm were obtained on a Specord UV-vis using anhydrous chloroform ~n a 4:1 mixture of chloroform
and methanol, or distilled water.
Chromatography was carried out on AlaO, (Brockman activity grade If).
Tetrahydrobromide of meso-(Tetra-4-pyridyl)porphinobromocobalt (llI) (3). To 4.25 g (6.28
mmoles) of CoTPyP (2) was added 500 ml of methanol, 500 ml of chloroform, and 12.5 ml of 48%
hydrobromic acid. The mixture was vigorously stirred at room temperature for 4 h. evapor-
ated to dryness, and the residue recrystallized from chloroform and ether, and dried for 1 h
in a vacuum desiccator at 40 ~ The violet crystals were carefully washed with dry ether and
dried in air to give 6.7 g (99%) of compound 3. Found: C 44.6; H 2.6; Br 37.2; N 10.0%.
CdoH~sBrsCoN,. Calculated: C 44.5; H 2.6: Br 37.1; N 10.4%.
Potassium Salt of meso-(Tetra-4-pyridyl)porphinodic[anobromocobalt (III) (5). A. To a
solution of 0.3 g (0.36 mmole) of the complex 4 in 300 ml of methanol was added 1.5 g (23
mmoles) of KCN. The reaction mixture was heated at 40~ with periodic stirring for 20 mln
and then allowed to stand overnight. A further 600 ml of chloroform was added, and after
3 h the mixture was chrommtographed on an A1203 column and evaporated to dryness. Recrys-
tallization from dry ether gave 0.13 g (48%) of 5, Rf 0.12 (AI~O3; chloroform-methanol, 5:3).
Found: C 65.5; H 2.9; N 18.5%. C~H2~CoKN,o. Calculated: C 65.8; H 3.1; N 18.3%.
B. To a solution of 0.3 g (0.28 mmole) of compound 3 in 200 ml of methanol was added 1.5
g (23 mmoles) of KCN. The reaction mixture was heated at 40~ for 0.5 h and 400 ml of
chloroform added. After standing overnight, the mixture was chromatographed on an A1203 col-
umn and then evaporated to dryness. T h e residue was recrystallized from dry ether to give 0.2
g (95%) of the salt, 5, Rf 0.12 (AlaO~; chloroform-methanol, 5:3). Found: C 65.8; H 3.0; N
18.4%. C~2EadCoKN,o. Calculated: C 65.8; H 3.1; N 18.3%.
meso-(Tetra-4-pyridyl)porphinocyanocobalt (III) (6). A solution of 0.15 g (0.17 mmole)
of the complex 5 in 50 ml of glacial acetic acid was refluxed for 0.5 h. When cool, the
reaction mixture was passed through an A120s column (chloroform-methanol 5:3). After evapor-
ation of the eluate, the residue was recrystalllzed from dry ether to give 0.i g (83%) of com-
pound 6, Rf 0.85 (Al~Os; chloroform-methanol, 5:3). Found: C 70.2| H 3.2; N 17.6%. Cd,H24-
CON,. Calculated: C 70.2; H 3.4; N 18.0%.
meso-(Tetra-4-pyridyl)porphinocyanopyridlnocobalt (III) (7). The complex 6 (0.05 g; 0,07
mmole) was dissolved in 20 ml of pyrldine by heating at 70~ for i0 min. The solution was

170
chromatographed on an Al2Os column and eluted with a chloroform-methanol-pyridlne (10:l:3)+mix-
ture. The eluate was evaporated to dryness and the residue recrystallized from dry ether to
+

give 0.055 g (99%) of the complex 7, Rf 0.75 (Alz 0 s,9 chloroform-methanol, 8:1) +Found: .C 70.9;
H 3.5; N 18.0%. C46H29CoN,o. Calculated: C 70.8; H 3.7; N 17.9%,
Tetrachloride of meso-(Tetra-4-N-hydroxyethylpyridyl)porphine (8). A mixture of 1 g (16
mmoles) of the TPyP i in I00 g (1.24 moles) of ethylenechlorhydrin was refluxed +for 2 h
(course of the reaction monitored by chromatography). The reaction mixture was evaporated to
dryness ~n Vucuo and the dry residue recrystallizedfrom ether. The crystalline material was
washed with chloroform and recrystallized from a mixture of water and propanol (i:i0)to give
1.5 g (99%). Found: C 61.0; H 4.9; CI 14.7; N 11.9%. C~,H~CI4N,04. Calculated: C 61.3;
H 4.9; C1 15.1; N 11.9%.
Tetrachloride of meso(Tetra-4-N-hydroxyethylpyridyl)porphinochlorocobalt (III) (9). To
a solution of 8 g (8.5 mmoles) of compound 8 in 500 ml of distilled water was added 8 g (61
mmoles) of COC12 in i0 ml of distilled water. The solution was refluxed for 2 h with
simultaneous distillation of+water until the volume was reduced to i00 ml (course of reaction
was monitored spectrophotometrically). After the addition of 12 ml of concentrated HCI, the
reaction mixture was evaporated to dryness ~n vaouo, recrystallized from ether, washed with
9 acetone, and recrystallized from a mixture of water and ethanol (i:i0) to give 8.5 g (97%) of
the complex 9. Found: C 55.5; H 4.7; C1 17.4; N 10.8%. C~eH~4CIsCoN.O~ Calculated: C
55.8; H 4.3; CI 17.2; N 10.8%.
Aminoderivatives of meso-(Tetra-4-N-hydroxyethylpyridyl)porphinochlorocobalt (III) T e t r a -
chlori~e (10a-d, Table i). To a solution of 0.i mmole of compound 9 in i0 ml of distilled
water was added 0.4 mmole of the corresponding amine. After I0 minutes the reaction mixture
was evaporated to dryness, the dry residue recrystallized from absolute ether and then further
recrystallized from a mixture of water and the corresponding amine (i:i0). The crystalline
material was filtered off and washed with the corresponding amine and absolute ether.

LITERATURE CITED
i. V . N . Madakyan, R. K. Kazaryan, M. A. Khachatryan, T. S. Kurt~kyan, M. B. Ordyan, and N.
S. Enikolopyan, Khim. Geterotsikl. Soedin., No. I, 82 (1984).
2. E . B . Fleischer, Inorg. Chem., ~, 493 (1962).
3. S. Sugata, S. Yamanouchi, and Y. Matsushima, Chem. Pharm. Bull., 25, 884 (1977).
4. N . S . Gill, R. H. Nuttal, D. F. Scaife, and D. W. A. Sharp, J. Inorg. Nucl. Chem., 18, 79
(1961).
5. A . W . Johnson and J. T. Kay, J. Chem. Soc., No. 7, 2979 (1960).
6. K. Nakomoto, Infrared Spectra of Inorganic and Coordination Compounds [Russian transla-
tion], Mir, Moscow (1966).
7. G . P . Gurinovich, A. N. Sevchenko, and K. N. Solov'ev, Spectroscopy of Chlorophyll and Re-
lated Compounds [in Russian], Nauka i Tekhnika, Minsk (1968), p. 397.
8. D . V . Stynes, H. C. Stynes, and B. R. James, J. Amer. Chem. Soc., 95, 1786 (1973).
9. T . J . Bengelsdiyk and R. S. Drago, J. Amer. Chem. Soc., 97, 6466 (1975).

171
TETRACYANOETHYLATION AND FISCHER REARRANGEMENT
OF SOME 4-OXO-4,5,6,7-TETRAHYDROINDOLES

K. Dagher, P. B. Terent'ev, UDC 547.754.04'339.2:543.422


and N. S. Kulikov

The reaction of the 1,2-diaryl-4-oxo-4,5,6,7-tetrahydroindoles, and 3-methy[-4-


oxo-4,5,6,7-tetrahydroindole with tetracyanoethylene occurred at the 5 position
of the tetrahydroindole ring. A Fischer rearrangement of the phenylhydrazones
of these 4-oxotetrahydroindoles gave pyrrolo[2,3-c]carbazoles.

Pyrroles and indoles react readily with tetracyanoethylene (TCE) with electrophilic at-
tack by the latter at position 3 of the pyrrole ring [1-3]. However, it is known that TCE,
like acrylonitrile [4], can react with alicyclic ketones by the Michael reaction to give u-
tetracyanoethyl derivatives [5], while tetracyanoethane reacts with carbonyl compounds to form
furan derivatives [7].
In a continuation of work on the reactions of the 1,2-diaryl-4-oxo-4,5,6,7-tetrahydroin-
doles, which have both a pyrrole ring and an alicyclic ketone fragment [8, 9], we have studied
the reaction of the indoles la-f with TCE.
II
NC. ~,.CN O
NC ~N
NC / "CN ! .CN~ 'R~

O I" "'" " N "'R 2


I

~zN ~ /f ~ ~ R3 ...... ti6H~ lla- f

"" g i CsHsN21I 3, IICI. .... i It"


CI|~COOH i.... ii ........ i[ i
""//'"N" " R2 !
- R" 2

r '1 i
"'~'f;"" N.
", ] R~ ,oi 'X L, .R~
, il .tl "J II ....... II
" ' "N"'R z i <~ N " R2
L_ R .
]]10:t,d~ f~ g

g:R* = R s = H, R 2 = C,H5
It was found that by mild heating (40-60=C) in ethyl acetate solution, the reaction was
complete in two to four mi.nutes and gave 62-88% of the tetracyanoethyl-substituted indoles
lla-f, as white or light-colored crystals, which quickly darkened in air (Table I). When
heated to I00-150~ they decomposed, so that satisfactory elemental analysis data could not
be obtained.
Even on ionization by electron bombardment in the mass spectrometer, the molecular ion
(M+) of compounds lla-f* could not always be recorded, and only the use of field desorption
(FD) enabled their molecular weight to be established. Primary decay of the M + ion of com-
mA peak corresponding to [M--HCN]+ is observed in the region of greatest m/z values.

M. V. Lomonosov Moscow State University, Moscow 117234. LebaneseUniversity, Beirut,


Lebanon. Translated from Khimiya Geterotsiklichesklkh Soedinenii, No. 2, pp. 217-221, Feb-
ruary, 1986. Original article submitted February 15, 1985.

172 0009-3122/86/2202.0172512.50 9 1986 Plenum Publishing Corporation


TABLE 1. Properties of 5 - T e t r a c y a n o ethyl-4-oxo-4,5,6,7-tetra-
hydroindoles lla-f

u tmethanol~-] IR spec-,j
[.~ I ~ "l tvam, cm'~l Mass spectrum,# m/z
(relative intensity, %)
u

LIa C8H5 248 (4,44), FD . 415 (23), 389 (32), 388 82


278 (4,23), (1oo)
474 (4,02)
lib 2-CHzC6Ii4 245 (4,32), 429 (78), 402 (38), 375 (20), 88
282 (4,35), 365 (33), 364 (100), 301 (100),
474 (4,44) 245 (55), 244 (60), 230 (44),
149 (84), 91 (25)
lic 3-C ['IaC,~]-I4 250 (4,60), 429 (25), 402 (100), 400 (50), 64
278 (4,38), 375 (85), 364 (100), 301 (50),
475 (4,52) 273 (37), 245 (40), 244 (42),
230 (37), 115 (37)
lid 4-CH3C~H4 217 (4,60), 402 # (5)~ 375 (9), 299 (16), 62
250 (4,60), 149 (]8), 145 (12), 135 (19),
472 (4,50) 131 (18), if5 (20), I07 (30),
105 (50), 91 (100)
lie 4-BrC~I-[4 248 (4,4t), 460'~(27), 439 (21), 365 (60), 62
286 (4,19), 363 (53), 244 (26), 165 (67),
468 (4,45) 149 (73), 121 (100), 119 (87),
{05 (80)
IIf 202 (4,22), 277 (23), 250 (15), 168 (10), 85
234 (4,30), 150 (10), 149 (20), 129 (14),
440 (4,38) 128 (100), III (20), 109 (15),
]05 (13), ]03 (100)

*lla-e R 2 = C6H5, R" = H; llf R 2 = H, R 3 = CH3.


tThe M + peak and the I0 most intense peaks are given. Ion peaks
for 79Br are given in italics.
~FD: 430 [M + i] + (15), 429 M + (19), 404 (10), 403 (16), 402
(i00), 400 (21).
*eFD: 493 (i00), 467 (28), 466 (25), 489 (59).

pounds lla-f occurs primarily by the successive elimination of two molecules of HCN, or with
the loss of a molecule of TCE or tetracyanoethane by a McLafferty rearrangement. This type of
decay indicates the presence of a tetracyanoethyl residue at position 5 of the heterocyclic
nucleus (ring system). This conclusion is supported by the fact that the 3-methyl-4-oxo-4,5,
6,7-tetrahydroindole If also reacts with TCE to give the tetracyanoethyl derivative of llf,
whereas when TCE is mixed with the previously reported 6,6-dimethyl substituted derivative of
these ketones [i0], the reaction does not take place, possibly because of steric hindrance,
and only starting compounds are isolated from the reaction mixtures.
In the UV spectra of compounds lla-f were observed two short-wave bands at 250 and 280
nm, characteristic of aryl pyrroles [I, ii], and one long-wave band at 468-475 nm, which is
probably due to the partially ionized particle formed by strong hydrogen bonding between the
acidic proton of the terminal dicyanomethyl group and the earbonyl oxygen atom. Consequently,
the C=O group stretching vibrations absorb at lower frequencies (1640-1645 cm-*) than those of
the ketones la-f (1660-1650 cm-*) [i0].
Conclusive proof of the position of the tetracyanoethyl group was obtained from an analy-
sis of the NMR spectra of compounds lid and e. In addition to a multiplet from the five pro-
tons of the 2-C6H~ group at 7.1-7.3 ppm and, partly superimposed on this, two 2-proton doub-
lets from the para-substituted l-phenyl residue at 7.2-7.7 ppm in the upfield region, there
was a singlet from the 3-H proton at 6.71-6.72 ppm, a three proton multiplet from the two pro-
tons of the methyl group (C(I))and one equatorial proton on the C(6) atom at 2.7-2.9 ppm and
a multiplet from one proton (6-Ha), centered at 3.30 ppm. Furthermore, in both PMR spectra
there was a sharp single-proton doublet of doublets from the 5-Ha proton, since the coupling
constants are 5 (axial-equatorial) and 15 Hz (axial-axial). These data confirm that the tet-
racyanoethyl residue in these compounds in on the 5-C atom and in the equatorial position.
It was found that the presence of methyl groups at position 6 of the 4-oxo-4,5,6,7-tetra-
hydroindole ring had a significant effect on reactivity, not only at position 5, but also at

173
TABLE 2. Proper=ies of the Pyrrolocarbazoles lllc, d, f,
and g
. . . . . . . . . . . . . . . . .

p ~m
I t .o
111r I75~,~177 200 (4,22), 228 sh 3420 ;~72 (iO0), 371 (iT), 356 (i7), 9-54 34
(4,12), 248 (4,28), (20), 186 (rT), 17,q (~0), LTB(37),
253 (4,28), 29O 149 (33), III (33), I09 (30), I05
(4,19), 350 gh (2o)
(8,33), 432 (4,06)
IIld 220-~223 210 (4,33), 228 $h 3115 ;72 (I00), 371 ([2), 357 (5), 356 31
(4,19), 256 (4,40), [3), 254 (i?), 253 (9), 186 (12),
290 (4,28), 351 sh 49 (9), 105 (5), 91 (I00),77(3)
(3,37), 440 (3,08)
Ili f 240--242 202 (4,22), 229 3505 .~20 (100), 219 (82), 218 (36),205 21
(4,07), 255 (4,28),
295 (4,36), 328
(4,38)
3420
I(17), 191 (27), 190 (16), 179(II),
I78 (12), 165 (9), 164 (10), 152
(9)
Illg * 285--287 202 (4,40), 229 3460 282 (lO0), 281 (23), 280 (13), 254 55
(4,27), 256 (4,41), 3420 1(9), 253 (6) 179 (6) ]78
295 (4,45), 328 151 (7), 141 (20), 140 02) (8),
(4,26)

*The M + p e a k and the l0 most intense peaks are given.


#For the reacting ketone l.
~Found: C 84.9; H 5.0%. C2oH~N2. Calculated: C 85.1; H
5.0%.

the carbonyl group. Thus, compounds Ic, d, f, and g, which have no substituent at position 6,
when heated with phenylhydrazine hydrochloride, gave, apparently, normal hydrazones (confirmed
by the Fischer rearrangement to give the corresponding 1,2-dihydropyrrolo[2,3-c]carbazoles),
which are readily oxidized by atmospheric oxygen to the aromatic compounds lllc, d, f, g, iso-
lated in yields of 21-55%(Table 2). However, the reaction mixture always contains the start-
ing ketones, and the use of excess phenylhydrazone, or an increased reaction time does not in-
crease the yield of the final heterocyclic compounds III. Their UV spectra were very similar
to one another; in the IR spectra, there is an N--H stretching band at 3420-3415 cm -x, and in
the IR spectra of compounds !llf and g, an additional band at 3460-3505 cm -x. In the mass
spectra of the pyrrolocarbazoles III, there are strong peaks corresponding to M + and [M -- HI +
ions, which are typical for aryl- and methylindoles [ii].

O i- ]IN ' N -l', N 4-N

--~~.......... ' --Lc)~.-c113.. i i! I


~v;oo. ~c,L'"- ~-.~o >..... ,.. 9...
CH~ C611s
[
~ ' h call5 C6H5 ~ '-j IV ('6H5

Thus, 4-oxo-4,5,6,7-tetrahydroindoles can serve as suitable starting compounds for the


preparative single-stage synthesis of a number of pyrrolo[2,3-c]carbazoles. However, our at-
tempts to carry out an analogous Fischer rearrangement starting from 6,6-dimethyl-substituted
4-oxo-4,5,6,7-tetrahydroindoles were not successful. On prolonged heating in glacial acetic
acid, a mixture of phenylhydrazlne hydrochloride and 6,6-dimethyl-l, 2-diphenyl-4-oxo-4,5,6,7-
tetrahydroindole (Ig) gave an 88% yield (based on reacting ketone), of a yellow crystalline
material; in the UV, this material absorbed at 402 nm, and in the IR, there was a strong con-
jugated C=C stretching band, and a band at 1420 cm -~ which we attributed to the azo group. In
the mass spectrum of this compound was observed an M + peak with m/z 403; further decay of this
ion corresponds well with an enazo structure for IV (see reaction scheme), and leads to the
formation of [M-CH~] +, [M-CH~--C~HsN2] +, and [M-CHs--C6H~N~--H]+. The formation of
the enazo compound IV, instead of the usual Fischer rearrangement, is also apparently due to
steric factors, caused by the geminal methyl groups at the 6 position.

174
EXPERIMENTAL
UV spectra were obtained on a Varian Cary (in methanol), IR spectra on a UR-20 (in mineral
oil), PMR spectra on a Varlan XL-100 (in deuterochloroform), using TMS as a standard. Mass
spectra were run on a Varian MAT-f12 at an ionization energy of 70 eV with direct introduction
of the compound into the ion source. Field desorptlon mass spectra were obtained on a Varlan
MAT-212, voltage of emitter 6 kV. Preparative chromatographic separation of the compounds was
carried out on Silufol UV-254 plates in ethyl acetate-hexane, 3:7; compounds were visualized
in UV light.
Characteristics of compounds lla-f and lllc, d, f, g are given in Tables 1 and 2.
5-Tetracyanoethyl-4-oxo-4,5,6,7-tetrahydroindoles (lla-f). To a solution of 0.7 mmoles
of the ketone I and 90 mg (0.7 mmole> of TCE in 15 ml of dry ethyl acetate was added 1 drop of
concentrated HCI, and the mixture stirred and heated on a water bath (40-45~ for 2-4 min.
The resulting solution was concentrated to 3-4 ml and the precipitate of II filtered off.
Pyrrolo[2,3-c]carbazoles (lllc, d, f, g). A solution of 0.3 m~mole of ketone I and 0.3
mmole of phenylhydrazine hydrochloride in 4 ml of glacial acetic acid was refluxed for 8 h,
poured onto 40 g of ice, and the precipitated material separated and washed with water followed
9 by 5% sodium hydroxide solution. After again washing with water, the produce was dried and
chromatographed, the bands with Rf 0.45-0.5 yielded the starting ketone, and bands with Rf
0.8-0.9, the pyrrolocarb@zole III. The latter was recrystallized from a mixture of ether and
hexane (i:i).
6,6-Dimethyl-l,2-diphenyl-4-phenylazo-6,7-dihydroindole (IV) was obtained analogously from
1 0 0 m g ( O . 3 2 ~ m o l e ) of ketone lh and 46 g (0.32 n~nole) of phenylhydrazine hydrochloride by re-
fluxing for i0 h. Bands with Rf 0.9 yielded 56mg (88%, based on the ketone) of the azo compound
IV, with mp 230-232 ~ (from a mixture of ether and hex~ne, I:I). UV spectrum, %max (log e): 250
(3.97); 296 (4.04), 402 nm (4.03). IR spectrum (CCI~): 1420 (~N==N), 1620 cm-* (~C=~). Mass
spectrum, m/z (%): 403 (33) M +, 402 (8), 388 (20), 298 (6), 283 (18), 180 (5), 165 (8), 149
(ll), 105 (38), 91 (70), 77 (i00).

LITERATURE CITED
1. R. I. Sunberg, The Chemistry of Indoles, Academic Press, New York (1970), p. 488.
2. W. E. Noland, W. C. Kuryla, and R. F. Lange, J. Am. Chemc_. Soc., 81, 6010 (1959).
3. Y. Shirota, S. Ezaki, S. Kusabayashi, and H. Mikawa, Bull Chem. Soc. Japan, 4 5 8 3 6 (1972).
4. A. P. Terent'ev and A. N. Kost, Reactions and Methods of Studying Organic Compounds [in
Russian], 2nd Edn., GNTI Chemical Literature, Moscow-Leningrad (1952), p. 47.
5. O. E. Nasakin, V. A. Kukhtin, G. I. Petrov, E. G. Nikolaev, V. V. Alekseev, and S. Yu.
Sil'vestrova, USSR Inventor's Cert. No. 759607; Byull. Izobr., No. 38, 38 (1980).
6. W. J. Middleton, R. E. Heckert, E. Z. Little, and C. G. Krespan, J. Am. Chem. Soc., 8~,
2783 (1958).
7. O. E. Nasakin, V. V. Alekseev, P. B. Terent'ev, A. Kh. Bulai, and V. A. Shmorgunov, Khim.
Geterotsikl. Soedin., No. 12, 1605 (1982).
8. K. Dagher, P. B. Terent'ev (Terentiev), Yu. G. Bundel, R. Hanna, and B. I. Maximov, J.
Heterocycl. Chem., 20, 989 (1983).
9. K. Dagher andP. B. Terent'ev, Khim. Geterotsikl. Soedin., 12, 1462 (1984).
i0. K. Dagher and P. B. Terent'ev (Terentiev), A. N. Kost, Yu. G. Bundel, B. I. Maxlmov, and
R. Hanna, J. Heterocycl. Chem., 19, 645 (1982).
il. R. A. Khmel'nitskii, Khim. Geterotsikl Soedin., No. 3, 291 (1984).

175
CHEMISTRY OF THE PYRAZOLIDINES.
26.* ALKYLATION OF 4-BENZYLIDEN-1-PHENYL-3,5-DIOXOPYRAZOLIDINES

B. L. Moldarev, M. E. Aronzon, UDC 547.722.2'775'778'542.953


V. M. Adanin, and A. M. Zyakun

The reaction of 4-benzyliden-l-phenyl-3,5-dioxopyrazolidines with alkyl halides


in the presence of sodium alkoxide gave l-phenyl-2-alkyl-4-benzyliden- and l-
phenyl-2,4-dialkyl-4-(a-alkoxybenzyl)-3,4-dioxopyrazolines. The structures of
these compounds were confirmed by UV, IR, and PMR spectroscopy, and by mass-
spectrometry.

Previously, it was shown [ 2 ] that 4-benzyliden-l,2-diphenyl-3,5-dioxopyrazolidines react


with sodium alkoxides to give sodium salts of the 4-(a-alkoxybenzyl) compounds B, which do
not show the characteristic long-wave UV absorption bands present in the spectrum of A. The
enolates B react with methyl iodide to give 4-methyl derivatives C.

0:~,7-- N/Cells 0%,, ...C~:I{


s,. O~ N C~IIs
~,-~.~ j _A,~o~. X --~, ~.,. ~.~. , ...., "
- ~-?"-~"- I +- ........... A~-cH-\ I
0 "C6H5 O'" C~;IIs 0 ' Cell.~
A B C

It was of interest to perform this reaction with the 4-benzyliden-l-phenyl-3,5-dioxopy-


razolidines (la-c), since there are two possible reaction products -- the product of the reac-
tion with alkoxide, and the alkylation product.

0 ~ Cell 5 0 "

" '\k_"iY.,/ .'. N|] "" N


;" ".
O" O -- Na+
I a-c lla

0~ Call 5 0, 9 .Ceil 5

c,,j t
ORO.~X----N,.R
1 2 I ' ' ~---
/ , ~-~, -' N,
OR~/"-~'~L- ......... \___y Ob._.i~ RI
O- Na + R ~
va,b, c iv a ma-d

Ia-Va X = H, tb, lllb, Vb, e X = NO~; Ic, Illc, d X ffiOCHs;


Ilia-c, IVa, Va, b, e R l = CHs; Ilia, R x = C2H~; IVa, Va, b
R ~ = CHs; Ve R ~ = C2H5; Va, b, e R s = CHs
In the UV spectra of compounds la-c in alkaline ethanol, the position and intensity of
the long-wave band do not change significantly (experimental section). From this it can be
concluded that these compounds, unlike the 1,2-disubstituted analogs (A), react with sodium
alkoxide not as Lewis acids, but as Nil-acids, which form the enolates II. For compounds B,
as a result of bonding with the alkoxy-anion, the benzyl proton signal9 is shifted upfield to
5.2-5.4 ppm [2], however, in the PMR spectrum of compound la in CDsONa, there is no signal
in this region, confirming that the exocyclic double bond has been retained (Table i). In
the IR spectrum of compound lla, obtained by the reaction of la with sodium methoxide and
isolated by a precipitation with absolute ether, both the C=O absorption band at 1670 cm-* and
*For communication 25 see [I].
Leningrad Institute of Pharmaceutical Chemistry, Leningrad197022. Institute of Bio-
chemistry and Physiology of Microorganisms, Academy of Sciences of the USSR, Pushchino-on-Oka,
142292. Translated from Khimiya Geterosiklicheskikh Soedinenii, No. 2, pp. 222-226, February,
1986. Original article submitted February 26, 1985.

176 0009-3122/86/2202-0176512.50 ~ 1986 Plenum Publishing Corporation


TABLE i. PMR Spectra of the Starting Compounds and Their
Alkylation Products

0 N--C~Hs -- C ~ I I 4 - - X , R' C~
(IH) I R2 R~
r~

la 7,11--7,78 (m 8H); 8,32--8,65 (q,2tt) 7,80 (~} ;


!7,93 {~'
It 7,11.--7,58 (m,3H); 8,21 (d,2tI, 17,81 (s);
7,71 (d 2 1 1 , J=8Hz}; 7,93 {s}
J = 4 Hz) . 18,45--8,76 {q, 2H)
It 7,20--7,68 (In, 5[-I) 6,94--7,17 (m 2tt); !7,79 (s};I
8,42--8,72 ( q2H); 7,92 (s)
3,81 (s 31t)
Ilia 7,01--7,48 (m, 8H); 7,98--8,45 ~a ,2H) 3,07 (s 3H) 7,82 (s)
I l l t 7,15--7,62 (m, 5H) 18,15--8,52 ( m .~'II); 3,18 (s, 3tt) 7,90(s)
(8,52-8,81 (-~2n} 7,94 (s)
lllc 7,22--7,65 (m, 5Hi 16,83--7,15 ( ~ 2H); 3,18 (s, 3H) 7,91(s)
18,63 (d, 2H, 7,95(s)
11=9 Hz);
[3,87 (~ 3H)
IVa 6,9--7,3 (m, 81-1); 7,3--7,58 ~n, 21t) 2,81 Is ,3H) 5,13 @) 3,23 ( s 3H)
Va 6,65--7,38 (m 10H) 2,83 {s, 3H) 4,33 (s, 3,16 (s 3H) 1,27 ~s,3H)
Vt 7,08--7,42 (m,5H) 7,42--7,68 (m 2H); 2,85 {s 3H) 4,55 (s) 3,18 (s 3H) 1,25 (s 3H)
8,02--8,32 (m, 2H)
vd 7,25--7,65 ~., 5H) 7,65--7,82 (m 21t}; 3,05 .s,, 3H) 4,65 (s) 3,28 (ra, 2H}; 1,21 (s, 3H}
8,15--8,42 (m, 21-t) 1,01 (Ill,3H)

*Spectrum of I was taken in DMSO, III-V in CDCI3.

the C=C band at 1625 cm -x are retained, in agreement with the proposed structure; in this it
differs from compound B. The dual character of the products of the reaction of la-c with sod-
ium alkoxide, and the previously reported [2] course of the alkylation of compound A indicates
that alkylation of compounds la-c with alkyl halides in the presence of excess sodium alkoxide
can occur at either the N or O atom.
The reaction with excess sodium alkoxide and alkyl halides was carried out with compound
la, (without a substituent at position 4), and also compounds with electron-acceptor (Ib) and
electron-donor (Ic) substituents. Under the conditions employed, the N-alkylation products
llla-d, and also the products of further alkylation of the latter, V, were obtained (Table 2).
No O-alkylation products could be detected.
The alkylation of compounds la-c occurs in a step-wise manner, as shown in the reaction
scheme; this was confirmed by the formation of compound IVa from the N-methyl derivative Ilia
and sodium methoxide, and by the formation of complete alkylation products Va and b from 4-
benzyliden- (Ilia) and 4-p-nitrobenzyliden- (lllb) derivatives from methyl iodide in the pre-
sence of sodium methoxide, and of the 4-methyl-4-(a-ethoxy-p-nitrobenzyl)- (Ve) derivative
from methyl iodide and sodium ethoxide.
Evidence for the structure proposed for III comes from infrared spectra,