1

ABIKOMASAMUNE Asymmetric Aldol Reaction

Asymmetric aldol reaction between propionate esters e.g. 1 and aldehydes 2 using () or () norepinephrine (or norephedrine) as a chiral auxiliary; proceeds via ester boron enolates 4. Formation of preferentially syn3 or anti2 products depends on the bulkiness of alkyl in the dialkylboron triflate, as well as on the chiral auxiliary, the tert amine and temp (lower temp favors kinetic anti product); the large dicyclohexylboron triflate 4 leads predominantly to anti products 3 via E-boron ester enolates, while dibutylboron triflate and DIPEA give more syn aldols.10 Double aldol reaction of acetate esters is possible.6 Methoxyacetates give syn-glycolate derivatives with high selectivity.8 Compare with Evans syn-aldol and Crimmins anti-aldol (via ketone enolates).
Bn N Ph O 1 O Et3N, 78
oC

O R c-Hex2BOTf MeO2S 2 B(c-Hex)2 H

MeO2S

Bn N

Ph O 3

OH R

O c-Hex2BOTf, Et3N Ph Me R2O2S N R1 O 1 Bu2BOTf, iPr2NEt R1 = Me, R2 = OHA R*O 5 O

1 2 O R = Bn, R = Mes

O R*O

OH R

RCHO R*O 4 BBu2 RCHO 2 2

3-anti, 87% (R=iPr) O R*O OH R 3-syn, 98%5

anti Selective aldol (3).5 To a solution of norepinephrine ester (1R, 2S)-1 (4.80 g, 10 mmol) (R1 Bn, R2 Mes) in CH2Cl2 (50 mL) in an oven-dried 500 mL flask under nitrogen was added via syringe TEA (3.40 mL, 24 mmol). A solution of dicyclohexylboron triflate (1.0 M in hexane, 22 mL) was added over 20 min at 78  C and stirring was continued for 30 min. IBA 2 (R iPr, 1.08 mL, 12 mmol) was then added dropwise and the mixture was stirred at 78  C for 30 min and then brought to r.t. (1 h). After quenching with a pH 7 buffer (40 mL), MeOH (200 mL) and 30% H2O2 (20 mL) were added slowly. After stirring overnight at r.t. and usual workup and evaporation a solid was obtained which was crystallized from hexane (150 mL) to give crude 3 (4.4 g). Removal of cyclohexanol from the mother liquor and chromatography provided an additional product (0.6 g). Crystallization from EAhexane (1:5) afforded 4.77 g (87%) of pure anti ()-3. syn Aldol (3).5 As above, reaction of ester (1R, 2S)-1 (R1 Me, R2 octahydroanthracenyl(OHA), 0.4 mmol) with n-Bu2BOTf (0.8 mmol) and iPr2NEt afforded 3-syn (98%). 1 2 3 4 5 6 7 8 9R 10 Brown HC Abiko A, Masamune Abiko A, Masamune Abiko A, Masamune Abiko A, Masamune Abiko A Abiko A, Masamune Andrus MB Abiko A Dai W-M Tet Lett J Org Chem J Am Chem Soc J Am Chem Soc J Org Chem Org Syn J Am Chem Soc Org Lett Acc Chem Res Tetrahedron 1992 1996 1997 2001 2002 2002 2002 2002 2004 2010 33 61 119 123 67 79 124 4 37 66 3421 2590 2586 4605 5250 103,116 10759 3549 387 187

S S S S S

ABRAMOV Asymmetric Phosphonylation

Stereoselective phosphonylation of aldehydes by means of chiral phosphoro diamidates 2 or with BINAP catalysts, leading to chiral hydroxyalkyl phosphonates 7.
O=CH-Ph N P Cl O 1 LiHMDS Ph Me3Si N P N O Me3Si 2 Ph PhCHO 3

Ph Me3SiO

N SiMe3 4

N P O

Ph

O Ph 5 H P(OEt)3 6

OH (S)-BINAPO SiCl4 , iPrNEt CH2Cl2, 78 oC OEt Ph O P OEt POPh2 POPh2

7, 73%,10 31% ee (S)-BINAPO

Diethyl hydroxybenzyl phosphonate (7).10 Phosphite 6 (1.50 mmol) was added to benzaldehyde 5 (1.0 mmol), iPr2NEt (1.50 mmol), and (S)-BINAPO (10 mol %) in DCM (4 mL) at 78  C. SiCl4 (0.75 M DCM solution, 2.0 mL) was added over 2 h with a syringe pump. Water (4 mL, deionized), sat aq NaHCO3 (10 mL), and EA (10 mL) were added, the mixture was stirred for 1 h and filtered through celite. Extraction with EA (3 10 mL), usual workup, and chromatography (silica gel 15 g, hexane:acetone 2:1 and 1:1) gave 7 (73%, 35% ee).

1 2 3 4 5 6R 7 8 9 10*

Abramov VS Evans DA Kee TP Devitt PG Devitt PG Kee TP Hanessian S Shingare MS Klimovitskii EN Nakajima M

Dockl Akad NauKSSR J Am Chem Soc J Chem Soc Perkin 1 J Chem Soc Perkin 1 Tetrahedron Coord Chem Rev J Org Chem ARKIVOC Russ J Org Chem Tetrahedron

1954 1978 1994 1994 1995 1997 2000 2006 2007 2008

95 100

51 65 11 43 64

991 3467 3183 3169 10987 359 2667 196 911 6415

ACHMATOWICZ Furanylcarbinol Rearrangement

Rearrangement of 2-hydroxyalkylfurans 1, 7 (or 2-aminoalkylfurans)4 to pyranose derivatives 4, 8 (or to 7-membered rings) by reaction with Br22 2MeOH,1 NBS,5 m-CPBA4 or TBHP-VO 6 2 (acac)2. Also by anodic oxidation in MeOH.
+ OMe OH
3

HO O TBSO 1

NBS MeOH

MeO HO TBSO

OMe O 2

O TBSO

H 2O

O O 4, 95%5

OH

TBSO

O O CH3COCl, CH3CN (NH4)2Ce(NO3)6, r.t. 5 O

OH BH3.SMe2 toluene, r.t. O Cl 7, 84%

m-CPBA CH2Cl2, 0 oC HO

O O Cl

Cl 6, 85%

8, 70%8

2-(Chloromethyl)-6-hydroxy-2H-pyran-3(6H)-one (8).8 Freshly distilled acetyl chloride (5.64 g, 72.4 mmol) was added to a solution of 5 (7.96 g, 72.4 mmol) in CH3CN (20 mL) followed by ammonium ceric nitrate (1.94 g, 3.56 mmol) in CH3CN (20 mL). After usual workup and flash chromatography over silica gel (n-hexane/EA 3:1), product 6 was isolated as a yellow oil. To a solution of 6 (0.954 g, 6.624 mmol) in PhCH3 (20 mL) was added BH3SMe2 (2M in THF, 0.504 g, 6.624 mmol) in PhCH3 (10 mL), the mixture was stirred for 3 h at r.t. and then quenched with sat NH4Cl solution. After usual workup and flash chromatography over silica gel (n-hexane/EA 3:1), pure 7 was isolated as a pale yellow oil. Compound 7 (0.292 g, 2 mmol) was added to a solution of m-CPBA (0.344 g, 2 mmol) in CH2Cl2 (2 mL) at 0  C and the mixture was stirred for 3 h till a ppt was formed. The precipitated m-chlorobenzoic acid was filtered and the filtrate was concentrated in vacuo to afford the crude product which was purified by flash chromatography over silica gel (n-hexane/EA 3:1) to afford 8 as a colorless liquid, 70%.

1 2 3 4 5 6 7 8 9 10

Achmatowicz O Shono T Georgiadis MP Zhou W-S ODoherty GA Schreiber SL Schreiber SL Zuhal G Boger DL Nicolaou KC

Tetrahedron Chem Lett J Org Chem J Chem Soc Chem Comm Tet Lett Angew Chem Int J Am Chem Soc Turk J Chem J Am Chem Soc J Am Chem Soc

1971 1981 1986 1997 2000 2004 2004 2007 2010 2010

27 51 41 43 126 31 132 132

1973 1121 2725 317 183 57 14096 491 2157 6855, 8219

ACYLOIN Rearrangement
Rearrangement of O-silylacyloins (a-siloxyketones) catalyzed by strong bases (e.g. KHMDS 2); occurs with silyl transfer (1 4).
O MeN O 1 OSiMe2tBu SMe [KN(SiMe3) 2 2 O 50 oC OSiMe2tBu O MeN O OSiMe2tBu SMe O t 3 O-SiMe2 Bu O MeN O OSiMe2tBu SMe O OSiMe2tBu

4, 64%7

(1b,2S*,6S*,7b,11S*)-7,11-Di-t-butyldimethylsilyloxy-4-methyl-11-(methylsulfanyl)methyl-4azatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione (4).7 To a solution of 1 (2 mmol) in THF (10 mL) was added KHMDS 2 (15% in PhCH3, 4 mL, 3 mmol) at 50  C under Ar and the mixture was stirred for 3h, then 3% HCl was added at 0  C. Workup and chromatography (silica gel, PhH/hexane) afforded 4 (64%), mp 187189.5  C. 1 2 3 4 5 6 7 Herz W, Baburao V Iriye R Gokel GW Hall AJ McIntos J Sato T Katayama S J Org Chem Agri Biol Chem Tet Lett J Chem Soc Perkin 1 Can J Chem Tet Lett Chem Pharm Bull 1971 1978 1979 1980 1991 1994 2005 36 42 20 69 35 53 3899 1495 3379 1025 1315 5027 666

ADLER Phenol Oxidation

Also known as AdlerSingh. Oxidation of o-alkoxyphenols with sodium metaperiodate to afford 6,6-spiro-2,4-cyclohexadienones, e.g. 2, 5 which dimerize spontaneously to a Diels Alder adducts 3, 6.
O NaIO4 CH2OH OH 1 4 C O O I O O O O 2 O -NaIO3 1/2 O 3, 74% 4 O O

O OH OH 4 NaIO4 O 5 O O O 6 O

Spirooxirane (3).4 NaIO4 (47 g, 0.22 mol) in water (1 L) was added to a stirred solution of 2-hydroxybenzyl alcohol 1 (n = 1, 24.83 g, 0.2 mol) in water (1.5 L). After 10 min, colorless crystals appear. The mixture was kept for 24 h at 4  C in the dark. The crystalline product was filtered, washed (water) and dried in vacuum over P2O5 to afford 18.05 g of 3 (74%), mp 194195  C.

5
1 2 3 4 5 6 7 8 9 Adler E Adler E Adler E Adler E Singh V Waldmann H Singh V Castet F, Quideau S Singh V Acta Chem Scand Acta Chem Scand Acta Chem Scand Acta Chem Scand J Chem Soc Chem Comm Tet Lett Acc Chem Res Tetrahedron Org Biomol Chem 1959 1960 1962 1971 1992 1996 1999 2007 2010 13 14 16 25 37 32 63 8 505 1261, 1580 529 2055 1212 3833 324 6493 4472

ALDER (Ene) Reaction

Thermal or Lewis acid catalyzed sigmatropic rearrangement with H-transfer and C2 bond 2C formation 3, either inter or intramolecular, and with chiral induction 8.

CO2Me + Et 1
H LiClO 4 (cat)

O CO2Me 2

140 oC 16 h Et

H 3, 62%5
O

CO2Me CO2Me OH

O O Ph Me O 8

o CO 2Et 5 h, 20 C

CO 2Et EtO 2C 5, 100% 7

+ Ph H Me 6

O O 7

EtO 2C 4

Methyl 2-hydroxy-2-carbomethoxy-4-E-heptenoate (3).5 2 (2.92 g, 20 mmol) and 1-pentene 1 (1.4 g, 20 mmol) in DCM were heated at 140  C for 16 h. Evaporation and distillation gave a fraction boiling at 90105  C (0.5 torr) which was treated with 20 mL ether, worked up and distilled to afford 3 (62%). Diethyl (2-isopropenyl-4,4-dimethyl cyclopentyl)-1-malonate (5).7 The catalyst was prepared by stirring 4 g LiClO4 in 20 mL Et2O with silica gel for 30 min, evaporated and dried the catalyst at 150 C, 0.1 torr for 24 h. The catalyst (100 mg) was stirred with 4 (596 mg, 2 mmol) in 4 mL DCM for 5 h under Ar at r.t. Filtration and evaporation afforded 5 in quantitative yield. 1 2 3 4 5 6 7 8 9 10 11 Alder K Hill RK Usieli V Oppolzer W Achmatowicz O Snider BB Sarkar TK Chen H Naruse Y Hilt G Shen R Chem Ber J Am Chem Soc J Org Chem Angew Chem J Org Chem J Org Chem Synlett Organomet Tet Lett Angew Chem Int J Org Chem 1943 1964 1973 1978 1980 1982 1996 2005 2005 2007 2009 76B 86 38 90 45 47 24 46 46 74 27 965 1703 506 1228 745 97 872 6937 8500 4118

ALDERRICKERT Acetylene Cycloaddition

Synthesis of polysubstituted benzenes 5 via DielsAlder reaction of cyclohexadienes, e.g. 2 with acetylenes 3, via bicyclooctadienes 4.
Cl LDA O 1 Me3SiCl Cl + OTMS 2, 79% 4 CO 2Me
70140 C

Cl E Cl E E 5, 53% OH

CO 2Me 3

OTMS 4, E = CO2Me

Dimethyl 3-chloro-5-hydroxy-6-methyl-4-(2-propenyl)-phthalate (5). A solution of 2 (12 g, 47 mmol, prepared from cyclohexenone 1 with LDA and TMSCl at 70  C), and DMAD 3 (9 mL, 73 mmol) in xylene (45 mL) was heated at 70  C for 2 h and then at 145  C for 4 h. Evaporation of the solvent in vacuuo followed by routine work-up and silica gel chromatography afforded 9.48 g of 5 (53%) as an oil. 1 2 3 4 5 6 7 8 Alder K, Rickert HF Birch AJ Danishefsky S Winterfeldt E Patterson JW Labadie SS Kuwahara S White JM Liebigs Ann Aust J Chem J Am Chem Soc Tet Lett J Org Chem Syn Comm Tetrahedron J Org Chem 1936 1969 1974 1985 1995 1998 2008 2007 524 22 96 26 60 28 64 72 180 2635 7807 1705 560 2531 9073 2929

ALDOL Reactions
Base or acid activated condensation between aldehydes and/or ketones to afford a b-hydroxy aldehyde (aldol) or b-hydroxyketone (ketol) 4. First examples by Claisen2 and Schmidt.1 Reaction proceeds by attack of an enolate 2 (or an enol) as nucleophile on an aldehyde 3 or other carbonyl compound or on an iminium ion. Many base catalysts can be employed; the most common bases leading to enolates are KOH, K2CO3, KCN, NaOAc, CaO, amines, KOtBu, KHMDS, LDA (at low temp affords preferentially kinetic enolate 2), Amberlite. Acid catalysts include HCl, H2SO4, H3PO4, and Lewis acids like BF3, POCl3, ZnCl2, FeCl3, TiCl4, InCl3. Retroaldol reactions (4 1 + 3) are possible. E-enolates lead preferentially to anti aldol 6, while Z-enolates afford syn aldols 7, via 6-membered ring transition states. Many aldol type reactions, depending on carbonyl nucleophile or electrophile substrate (e.g. aldehyde, ketone, ester, amide, iminium ion), are known by name, e.g. Claisen, Evans, Knoevenagel, Mannich, Mukaiyama, Stork etc, as well as corresponding asymmetric aldols.47

7
O O LDA 1 -78 oC 2 O Ph 3 H Ph 4 OH O

A
OH O Ph O Me Me N Me SMe

O Me O

Ph Me N SMe 1. (i) LDA- Cp2ZrCl2 Ph (ii) Cp2ZrCl2 2. PhCHO

OH O O Me Me

Ph Me N SMe Ph +

Me

6, anti 90%

98%

7, syn 10%

Aldol product (6).5 To a stirred solution of iPr2NH (0.380 mL) in THF (7 mL), n-BuLi (1.5 M, 1.806 mL) was added at 0  C. The LDA solution was cooled to 78  C and a THF solution of Cp2ZrCl2 (118.6 mg, 0.406 mmol) was added to the reaction mixture. After 15 min, ester 5 (600 mg, 1.354 mmol) in THF (2 mL) was added and the mixture was stirred for 90 min. Then Cp2ZrCl2 (990 mg, 3.38 mmol) was added and the mixture was stirred at 78  C for another 10 min. PhCHO (158.2 mg, 1.490 mmol) in THF (3 mL) was added and the mixture was stirred at 78  C for 30 min and quenched with 1N HCl. After usual workup and concentration, the residue obtained was purified by silica gel chromatography (hexanes:EA:DCM 12:1:1 and hexanes:EA 10:1) to give the product as a mixture of 6 (major) and 7 in 98% yield. 1 2 3R 4R 5R 6R 7* 8R Schmidt JG Claisen L Heathcock CH Mukaiyama T Mukaiyama T Abiko A Michio K Moyano A, Rios R Ber Ber Science Org React Aldrichim Acta Aldrichim Acta J Org Chem Chem Rev 1880 1881 1981 1982 1996 1997 2001 2011 13 14 214 28 29 37 66 111 2342 349 395 187 59 387 1205 4703

ALLEN Phosphonium Rearrangement

Also known as AllenMillarTrippett. Ring enlargement of cyclic phosphonium salts 2,5 obtained by alkylation or acylation of cyclic phosphines 1, 4 in the presence of base.
CH2I2 P R 1
PhCOCl P Ph 4 TEA Ph 5 O P

PhH

P R CH2I 2

KOH reflux

R P O 3, 71%1

H2O reflux Ph OH Ph 6 O P Ph H O P Ph 7 Ph O

Ph OH P O Ph 8, 87%6

8
9-Methyl-9,10-dihydro-9-phosphaphenanthrene-9-oxide (3).1 The phosphonium salt 2 (R Me, 0.7 g, 1.5 mmol) in aq acetone containing KOH solution was heated to reflux for 2 h. Extraction of the cold mixture with CHCl3, evaporation of the solvent and silica gel chromatography via elution with EA:EtOH (7:3) afforded 0.24 g, 71% of 3. Hydroxyphosphine oxide (8).6 Benzoyl chloride (10 g, 71.1 mmol) was added to 4 (7.53 g, 40 mmol) and Et3N (20 mL) in Et2O (300 mL). After 3 h stirring under reflux 5 was hydrolyzed with water (150 mL) for 2 h. The precipitates thus formed were removed by filtration and the resulting filtrate dried over MgSO4. Evaporation of the solvent and recrystallization from PhCH3 afforded 10.8 g of 8 (87%). 1 2 3 4 5 6 7 8 9 10 11R 12 13 Allen DW, Millar IT Trippett S Allen DW, Millar IT Tebby JC Mathey F Mathey F Allen DW Markl G Keglevich Gy Keglevich Gy Savignac P Mapp AK Vignolle J Chem Ind Chem Comm J Chem Soc C J Chem Soc C Tetrahedron Tetrahedron J Chem Soc Perkin 1 Angew Chem Int J Org Chem Synthesis Eur J Org Chem J Am Chem Soc Tet Lett 1967 1967 1969 1971 1972 1973 1976 1987 1990 1993 2000 2006 2007 2178 1113 252 1064 4171 707 2050 1134 6361 931 3103 4576 685

28 29 26 55

128 48

ALPER Carbonylation
Carbonylation of cyclic amines 4, hydroformylation (CO2 2) of amino olefins 6, 2H carbonylation of alkenyl epoxides8 and allenyl alcohols10 or amines catalyzed by metal (Pd, Ru, Rh) complexes. Also dimerisation is possible with aziridine.
O R R 1
Bu CO Pd(Ph3P)4 or N 4 Pd(OAc)2/PPh3 Bu N NH O 5, 79%2 6

O
Pd I + N R1

R1

1. Pd(OAc)2 PPh3

R R (EtO2C)2HC

R Pd(0) base R

R1

R2 2. CO CH(CO2Et)2

R2 2

R2 CO2Et 311

CO HRh(CO)(Ph3P)3 NaBH4, 100 oC, 34 atm 7, 78%3

N O

N-(n-Butyl)-a-methylene-b-lactam (5).2 CO was bubbled through Pd(OAc)2 or Pd(PPh3)4 (0.136 mmol) in DCM (4 mL). After 2 min, PPh3 (0.54 mmol) in DCM (2 mL) was added followed by aziridine 4 in DCM. The mixture was stirred for 40 h at r.t., the solvent was removed in vacuo and the residue was purified by preparative TLC (silica gel, hexane:EA, 8:1) to give product 5 (79%). 1 2 3 4R 5 Alper Alper Alper Alper Alper H H H H H J Chem Soc Chem Comm Tet Lett J Am Chem Soc Aldrichim Acta J Org Chem 1983 1987 1990 1991 1992 1270 3237 2803 3 3328

28 112 24 57

9
6 7 8 9 10 11 Alper H Alper H Alper H Alper H Toros S Alper H J Am Chem Soc J Am Chem Soc J Org Chem Org Lett Steroids Org Lett 1992 1996 1997 2000 2004 2008 114 118 62 2 69 10 7018 111 8484 441 271 4903

AMADORI Glucosamine Rearrangement

Acid catalyzed rearrangement of aldoses 1, 3 via N-aldoglycosides to aminoglycosides of ketoses 2, 4 in the presence of amines. Apparently proceeds via ring opening (I), imine to enamine tautomerization and re-ring closure of aminoketone (II) to 2.
OH HO HO 1 O TolNH2 100 C OH OH HO HO I OH HO HO OH NHTol II +
Amberlite-H+ R = Cyl O3 S HO

OH

OH OH O NHTol

HO HO

O OH OH 2, 60% 3

NHPhMe

OH SO K 3 O HO OH OH 3

CH2NH2R OH

OH 4, 94%

1-Deoxy-1-p-tolylamino-D-fructose (2).3 A mixture of a-D-glucose 1 (100 g, 555 mmol), p-toluidine (80 g, 533 mmol), water (25 mL) and 2N AcOH (5 mL) was heated to 100  C for 30 min and to the cooled mixture was added anh EtOH (100 mL) and after 24 h the ppt was filtered, washed with EtOH:Et2O (2:3), to give 94 g of 2 (60%), mp 152153  C. 1-Cyclohexylamino-1,6-dideoxy-a-D-tagatofuranose-6-C-sulfonic acid (4).10 Amberlite IR-120 (H) cation exchange resin was added to a solution of 3 (131 mg, 0.465 mmol) in water (2.5 mL) up to pH 01. The resin was filtered and washed and the combined filtrate was brought to pH 6 using cyclohexylamine and concentrated to dryness several times by co-evaporating with abs EtOH. Crystallization from H2O/EtOH 1:1 afforded 4, 150 mg (94%). 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Amadori M Weygand F Hixon RM Hodge JE Ames GR Gyorgydeak Z Horvat S Mioduszewski JZ Peters JA Fernandez-Bolanos JG Jalbout AF Jakas A Wrodnigg TM Maugard T Atti Accad Nazl Lincei Chem Ber J Am Chem Soc J Agric Food Chem J Org Chem Carbohydrate Res J Chem Soc Perkin Trans 1 US Pat Eur J Org Chem Tet Asymm Food Chem Carbohyd Res Carbohyd Res Tetrahedron 1925 1940 1944 1953 1962 1997 1998 1998 2001 2003 2007 2008 2008 2009 2 73 66 1 27 302 337 (6) 1259 483 928 390 229 909 5723,504 3899 1009 919 2475 2057 531

14 103 343 343 65

10

ANGELIRIMINI Hydroxamic Acid Synthesis

Synthesis of hydroxamic acids 5 from aldehydes 1 and N-sulfonylhydroxylamines 2; also used as a color test for aldehydes.

CH=O O 2S + Cl 1

NHOH NaOMe MeOH 020 C 2 Ar

OH N O 3 SO2 Ph Ar

O C-NHOH OH N 4 O Cl 5, 68%

p-Chlorobenzene hydroxamic acid (5).6 To an ice-cold solution of N-hydroxybenzene sulfonamide 2 (730 mg, 4.2 mmol) in MeOH was added dropwise NaOMe-MeOH solution (4.36 mL, 8.4 mmol, 1.93 M). p-Chlorobenzaldehyde 1 (562 mg, 4 mmol) in MeOH (4 mL) was then added and the reaction mixture was warmed to r.t. MeOH was removed in vacuo, the residue was dissolved in ether (200 mL) and the organic layer was extracted with 2M NaOH. The aq layer was acidified with conc HCl and extracted with EA. The solution was concentrated to give product 5 (68%). 1 2 3 4 5 6 7 8 9 Angeli A Rimini E Balbiano L Yale HL Lwowski W Hassner A Stoyaoysky DA Porecheddu A King SB Gazz Chim Ital Gazz Chim Ital Att Accad Lincei Chem Rev Angew Chem Int J Org Chem J Am Chem Soc J Org Chem Org Lett 1896 1901 1913 1943 1967 1970 1999 2006 2009 26 31 22 33 6 35 121 71 11 17 84 575 228 897 1962 5093 7057 4580

APPEL Displacement Reagent

Formed from Ph3P and CCl4 (or CBr4) 1, a reagent for chlorine (also bromine or iodine) displacement of OH (2+1 to 3, often with inversion) or for dehydration of amides 6 to nitriles 7, or in Beckmann rearrangement (8 to 9). Sometimes used in the presence of imidazole. One can also use Ph3P and NCS.14
R Ph3P CCl4 (Ph3PCl) CCl3 1 2 OH + (Ph3P)

Cl R 3 Cl + Ph3PO

OH

OH CCl4, 1 Cl 5, 88%5 6 R R R

I CONH2

1 Reflux R = OMe

CN O

OH MeCN, Reflux 4

7, 89%2

R1 N OH R2 8

R Cl

N R2 9

Ph3PO

CHCl3

11
trans-2-Chlorocyclohexanol (5).5 trans-1,2-Cyclohexanediol 4 (3.82 g, 33 mmol) was added to a solution of 1, prepared from Ph3P (9.86 g, 33 mmol) in anh CCl4 (60 mL) and MeCN (20 mL). After 24 h reflux, 1.95 g of 5 (88%) was isolated. Retention of configuration here is probably due to epoxide intermediate. 2-Cyano-adamantan-4,8-dione (7).2 To a solution of 6 (600 mg, 2 mmol), Ph3P (786 mg, 3 mmol) and Et3N (202 mg, 2 mmol) in anh DCM (60 mL) was added CCl4 (308 mg, 2 mmol). After 15 h reflux, the solvent was removed by distillation and the residue was chromatographed on silica gel (100 g) (PE/Me2CO increasing the polarity). The product in Me2CO:H2O 1:1 (40 mL) and conc HCl (5 drops) was refluxed for 5 h. Recrystallization from PE (bp 6095  C)/Me2CO afforded 168 mg of 7 (89%), mp 255257  C. 1 2 3 4 5 6R 7 8 9 10 11 12 13 14 15 16 Rabinowitz R, Marcus R Appel R Appel R Appel R Evans SAJr Castro BR Brinkman HR Lee KJ Barrett AGM Nishida Y Wagener KB Iranpoor N Bergin E Baran P S Das B Soltani RMN J Am Chem Soc Chem Ber Chem Ber Angew Chem Int J Org Chem Org React Synthesis Synthesis Org Lett Org Lett Tetrahedron Tet Lett J Am Chem Soc J Am Chem Soc Tet Lett Synthesis 1962 1971 1975 1975 1981 1983 1992 1997 2002 2003 2004 2006 2007 2008 2009 2010 84 104 108 14 46 29 1312 1030 2680 801 3361 1 1093 1461 1975 2377 10943 5531 9566 17938 2072 1724

4 5 60 47 129 130 50

ARBUZOV Phosphonate Synthesis

Also known as MichaelisArbuzov. Synthesis of phosphonates 8 by heating of alkyl halides 5 with trialkyl phosphites. Ni catalyzed conversion of aryl halides 3 to aryl phosphonates 4 by reaction with phosphites 1, via phosphite-Ni complex 2.
I (EtO)3P 1
O Br (MeO)3 P N CH 2Ph CH(Me)Ph 5

NiCl2 150 oC

3 [(EtO)3P]4Ni 2 160 oC
OMe O Me O P MeO Br 7 R N CH 2Ph

O P

(OEt)2

4, 94%3
O O MeO P CH(Me)Ph N MeO CH 2Ph 8, 98%10

(MeO)3 P 6 110 oC

Diethyl phenylphosphonate (4).3 To 2 (2 mg) and PhI 3 (1 g, 4.9 mmol) was slowly added 1 (0.93 g, 5.64 mmol) at 160  C. The solution (red upon each addition of 1) faded to yellow and EtI was distilled. Vacuum distillation afforded 4 (94%), bp 94101  C, 0.1 mm. Dimethyl (N-benzyl-N-(1-phenylethyl)carbamoyl)methylphosphonate (8).10 Phosphite 6 (0.725 g, 0.69 mL, 5.85 mmol) and bromide 5 (0.65 g, 1.95 mmol) were heated at 110  C for 5 h. Volatile impurities were removed in a Kugelrohr in vacuum and the residue was purified by flash chromatography (silica gel, EA/hexanes/MeOH) to afford 8 (98%).

12
1 2 3 4 5 6 7 8 9 10* 11 12 Michaelis A Arbuzov AE Balthazor TM Lebeau L Hudson HR Klausmeyer KK Reddy CS Matveeva EV Pakulski Z Ordonez M Michalski J Mohanakrishnan AK Chem Ber J Russ Phys Chem Soc J Org Chem Tet Lett ARKIVOC Inorg Chem Comm ARKIVOC Tet Lett Tet Lett Tet Asymm Chem Eur J Org Lett 1898 1906 1980 1995 2004 2006 2006 2006 2007 2007 2009 2011 31 38 45 36 ix 9 xvi 47 48 18 15 13 1048 687 5425 5183 19 418 128 7645 8482 2427 1747 1270

ARNDTEISTERT RCOOH Homologation

Homologation of carboxylic acids, e.g. 1 to 4, via reaction of their acid chlorides with diazomethane and subsequent thermal or photochemical Wolff-rearrangement of the intermediate diazoketones 2 via trapping of ketenes 3 with nucleophiles. Water leads to carboxylic acids 4, alcohols afford esters while amines produce amides. Also ring enlargement of ketones (8 9/10), sometimes Lewis acid catalyzed. Compare with Kowalski. For conversion of aldehydes to ketones see Schlotterbeck.
O CO2H 1. SOCl2 1 2. CH2N2 2 N2 h, Ag+ H2O 3 H C C O CH2CO2H

H2O 4

Cl CH 2N 2 , Et3 N Et2O, 0 oC

CHN2 PhCO2Ag, Et 3N EtOH, heat

CO 2Et

7, 84% 3

CH2N2 O 8 9 O

+ 10

Ethyl 1-naphthylacetate (7).3 Diazoketone 6 (7.85 g, 0.04 mol) in abs EtOH (25 mL) was refluxed and freshly prepared catalyst (0.5 mL) made by dissolving silver benzoate (0.5 g) in Et3N (5 mL) was added. More catalyst (0.5 mL) was added to the black mixture till N2 evolution stopped. After the mixture was refluxed for 1 h, cooled, and filtered, the solvent was evaporated and 38 mL of ether was added. After washing (10% Na2CO3, water, and brine) and drying, the organic layer was evaporated in vacuum to afford ester 7 (84%). 1 2 3 4 Eistert B, Arndt F Barbier H Newman MS Shiori T Chem Ber Helv Chim Acta Org Synth Chem Pharm Bull 1927 1940 1970 1981 60 23 50 29 1364 523 77 3249

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5 6 7R 8 9 10 11 12 13 14 Smith AB Katritzky AR Wolfgang K Mazaleyrat J-P Albericio F Seebach D Hughes AB Perlmutter P Hoffmann-Roeder A Reisman SE J Am Chem Soc J Org Chem Eur J Org Chem Tet Asymm Tet Lett Helv Chim Acta Aus J Org Chem Tet Asymm Beil J Org Chem J Am Chem Soc 1986 2001 2002 2005 2006 2007 2008 2008 2010 2011 108 66 16 47 90 61 19 6 133 3110 5606 2193 857 4557 1651 131 2861 47 774

ASINGER Thiazoline Synthesis

Synthesis of thiazolines from ketones, sulfur and NH3 (1 to 2) or from a-thioaldehydes or a-thioketones and ammonia or imines (5 to 8).6 Also from aminothiols and aldehydes (3 to 4).
2 N 1 O S8 NH3, 40 C N N S 2, 97%
5

SH RO2C NH3 Cl
O O Cl 5 O O 6 O H O O

1. KOAc/R1CHO, EtOH, 20 C 2. MnO2, CH3CN RO2C

S N 4

R1 H
O

NH 3, NaSH 0 C, 12 h SH 7

NH

H O

O O

S H O

8, 71%, dr >95:57

10 ,6-Dimethyl-20 ,40 ,50 ,60 ,70 ,70 a-hexahydrospiropiperidine-4,2-thiazolo-[5,4-c]-pyridine 2HCl (2).5 A stirred and ice cooled suspension of sulfur (6.0 g, 187 mmol) in 1-methyl-4-piperidone 1 (40 g, 354 mmol) was treated with a flow of NH3 maintaining the temperature between 4050  C until all traces of sulfur disappeared. The excess of NH3 was removed in vacuo, the mixture was diluted with 50% K2CO3 solution (200 mL) and extracted with ether (5 100 mL). The dried solution was treated with dry HCl. The solid was filtered, washed (Et2O) and dried in vacuo to give 53.5 g of 2.2HCl (97%), mp 200205  C, after crystallization mp 240  C. 1 2 3 4 5 6 7* 8* 9R Asinger F Asinger F Asinger F Asinger F Lyle RE Domling A Martens J Dunach E Offermanns H Liebigs Ann Liebigs Ann Angew Chem Liebigs Ann J Org Chem Tetrahedron Tet Lett Tet Asymm Angew Chem Int 1957 1957 1958 1964 1965 1995 2000 2001 2007 602 606 70 674 30 51 41 12 46 37 67 372 57 293 755 7289 1279 6010

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ATHERTONTODD Phosphoramidate Synthesis

Synthesis of phosphoramidates 4, 5, 7 from formamides 1 and phosphites 2 or from iodoform, amines and dialkyl phosphites (2 to 7).
EtO 30% NaOH EtO P O R4N+Br , CCl4 H 2 3 O

H + N H 1 O

O OEt P OEt N H OH

O OEt P OEt N H 4 4, 60%

O P EtO NH 2 OEt 5, 83%9 CHI 3 , NH 3 CHCl3, r.t.

O P H EtO OEt 2 CHI 3 , PhNH2 Toluene, r.t.

O P I EtO OEt 6 EtO

O P NHPh OEt 7, 82%

Diethyl N-phenylphosphoramide (4).4 To an ice cold stirred suspension of formylanilide 1 (605 mg, 5 mmol) in CCl4 (25 mL) was added 30% NaOH (10 mL) and TEBAB (0.2 g). Diethyl phosphite 2 (828 mg, 6 mmol) in CCl4 (5 mL) was added dropwise. After 1 h at 0  C and 4 h at 20  C, the organic layer gave 4, after crystallization, 0.687 g (60%), mp 9697  C. Diethyl phophoramide (5).9 Into vigorously stirred liquid NH3 (1520 mL), 1.0 mmol of iodoform and 1.1 equiv of dialkyl phosphite 2 were added simultaneously at 33  C. After 510 min of stirring at 33  C, the cooling bath was removed and stirring was continued until NH3 was distilled off. The product was dissolved in dry chloroform and the mixture was filtered through Celite. After evaporation of the solvent, crystallization or distillation afforded 5 (83%).

1 2 3 4 5 6 7 8 9 10 11 12

Atherton FR, Todd AR Wadsworth WS Zwierzak A Lukanow LK Hovalla D Garrigue B Liu LZ Zhao YF Mielniczak G Zhao YF Ju Y Donghi M

J Chem Soc J Am Chem Soc Synthesis Synthesis Tet Lett Syn Comm Org Prep Proc Int J Chem Res S Syn Comm Synlett Synthesis Bioorg Med Chem Lett

1945 1962 1982 1985 1992 1995 1996 2003 2003 2005 2007 2009

64

33 25 28 33

19

660 1316 922 671 2817 871 490 262 3851 1927 407 1392

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AUWERS Flavone Synthesis

Synthesis of benzopyran-4-ones 4, 8 (flavones) from o-hydroxychalcones 5 or from benzofuran-3-ones 1.
O 1. PhCHO 36% HCl EtOH, 60 oC 2. Br2, 20 oC CHCl3 O Br Ph O Cl 2 0.1 N KOH, EtOH O Cl 3

O OHPh Br Cl Br reflux, 10 min

O OH O 4 Ph

O Cl 1

NO2 Ph + OH O 5

O EtOH dry HCl, 0 oC reflux, H2O Cl 6 O2 N

Ph CHO O2 N

Ph

O 6 Cl

O 8, 30% 5 Cl

6-Nitroflavanone (8).5 A mixture of chalcone 5 (1.35 g, 5 mmol) and 4-chlorobenzaldehyde 6 (1.45 g, 10 mmol) in EtOH (65 mL) was saturated with dry HCl, in an ice bath and allowed to stand for 1 h. It was then refluxed for 5 h. The unreacted chalcone was separated by cooling, the mother liquor was treated with H2O (30 mL) to afford a pale yellow solid which was recrystallized from CCl4 to afford 8 (30%).

1 2 3 4 5 6 7 8

Auwers K Minton TH Ingham BH Acharya BG Szell T Dorofeenko GN Gupta R Pawar RP

Chem Ber J Chem Soc J Chem Soc J Chem Soc J Org Chem Chem Heterocycl Comp Org Prep Proc Int ARKIVOC

1908 1922 1931 1940 1963 1977 2000 2006

41 121

28 13 32 xvi

4233 1598 895 817 1146 149 280 43

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AUWERSINHOFFEN Dienone-Phenol Rearrangement

Acid catalyzed rearrangement of dienones 1 or bromo substituted dienones5 3 to phenols (phenol acetates) via carbocations.
H+ O TsOH Ac2 O O H+ 1 AcO 2 Ph 3 Ph Br PTSA Ac 2 O reflux Ph 4 Ac 2 O OH Br + Ph OAc Br Ph Ph 5, 38%5

2-Bromo-3,4-diphenylphenylacetate (5).5 A solution of 3 (2.804 g, 8.62 mmol) and PTSAH2O (0.294 g) in Ac2O (60 mL) was refluxed for 1.75 h and then poured into water. The unreacted Ac2O was removed by addition of NaHCO3 and the mixture was extracted with ether (1.2 L). The solid that separated was dissolved in benzene (400 mL). The combined benzeneether fractions were dried and concentrated in vacuo to afford an oily solid, which was washed thoroughly with ether to afford 5 (38%).

1 2 3 4 5 6 7 8 9

Auwers KV Inhoffen C Djerassi C Winstein S Bordwell FG Uneyama K McPhail AT Li YL Fujioka H

Liebigs Ann Angew Chem Int J Am Chem Soc J Am Chem Soc J Org Chem J Org Chem Steroids Chin Chem Lett Chem Comm

1921 1940 1951 1957 1964 1995 1998 2003 2010

425 53 73 79 29 60 63 14 46

217 473 990 3109 509 6402 135 689 797