abiko masamune asymmetric aldol reaction a -...

ABIKO–MASAMUNE Asymmetric Aldol Reaction

Asymmetric aldol reaction between propionate esters e.g. 1 and aldehydes 2 using (þ) or (�) nor-

epinephrine (or norephedrine) as a chiral auxiliary; proceeds via ester boron enolates 4. Formation

ofpreferentially syn3 oranti2 productsdependson thebulkiness 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).

c-Hex2BOTf

Et3N, –78 oC R

O

H

2

NO

Bn

MeO2S

Ph O

NO

Bn

MeO2S

Ph O

R

OH

1 3

NR1

O

Ph

Me

R2O2S

O

c-Hex2BOTf, Et3NR*O

OB(c-Hex)2

R*O

OBBu2

RCHOR*O

O OH

R

R*O

O OH

R1 Bu2BOTf, iPr2NEt

3-anti, 87% (R=iPr)

RCHO

3-syn, 98%5

R1 = Bn, R2 = Mes

R1 = Me, R2 = OHA

4

5

2

2

anti Selective aldol (3).5 To a solution of norepinephrine ester (1R, 2S)-1 (4.80 g, 10 mmol) (R1¼ Bn,

R2 ¼ 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 ¼ 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 cyclohex-

anol from the mother liquor and chromatography provided an additional product (0.6 g). Crystalliza-

tion from EA–hexane (1:5) afforded 4.77 g (87%) of pure anti (þ)-3.

syn Aldol (3).5 As above, reaction of ester (1R, 2S)-1 (R1 ¼ Me, R2 ¼ octahydroanthracenyl(OHA),

0.4 mmol) with n-Bu2BOTf (0.8 mmol) and iPr2NEt afforded 3-syn (98%).

1 Brown HC Tet Lett 1992 33 3421

2 Abiko A, Masamune S J Org Chem 1996 61 2590

3 Abiko A, Masamune S J Am Chem Soc 1997 119 2586


5 Abiko A, Masamune S J Org Chem 2002 67 5250

6 Abiko A Org Syn 2002 79 103,116


8 Andrus MB Org Lett 2002 4 3549

9R Abiko A Acc Chem Res 2004 37 387

10 Dai W-M Tetrahedron 2010 66 187

A

1

ABRAMOV Asymmetric Phosphonylation

Stereoselective phosphonylation of aldehydes by means of chiral phosphoro diamidates 2 or with

BINAP catalysts, leading to chiral hydroxyalkyl phosphonates 7.

NP

O PhCl

NP

O PhN

NP

O PhLiHMDS

Me3Si

Me3Si

N

SiMe3

Me3SiO

Ph

421

PhCHO3

O=CH-Ph

O

POPh2

POPh2H

O OH

POEt

OEtP(OEt)3

CH2Cl2, –78 oC

iPrNEt

5 6 7, 73%,10 31% ee

Ph Ph,

(S)-BINAPO

SiCl4

(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 Abramov VS Dockl Akad NauKSSR 1954 95 991

2 Evans DA J Am Chem Soc 1978 100 3467

3 Kee TP J Chem Soc Perkin 1 1994 3183

4 Devitt PG J Chem Soc Perkin 1 1994 3169

5 Devitt PG Tetrahedron 1995 51 10987

6R Kee TP Coord Chem Rev 1997 359

7 Hanessian S J Org Chem 2000 65 2667

8 Shingare MS ARKIVOC 2006 11 196

9 Klimovitskii EN Russ J Org Chem 2007 43 911

10* Nakajima M Tetrahedron 2008 64 6415

2

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 Br222MeOH,1 NBS,5 m-CPBA4 or TBHP-VO

(acac)2.6 Also by anodic oxidation in MeOH.2

O O

O

O

Cl

HO

CH3COCl, CH3CN

(NH4)2Ce(NO3)6, r.t. toluene, r.t.

m-CPBACH2Cl2, 0 oC

5 7, 84% 8, 70%8

O

Cl

OHO

6, 85%

O

Cl

BH3.SMe2

NBS

MeOHOMeO

OHOHO OMe

MeO+

5

OHO

OO OH

1

H2O

2 3 4, 95%TBSO TBSO

TBSO TBSO

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 BH3�SMe2 (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 ofm-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 productwhich was purified by flash chromatography over silica gel (n-hexane/EA 3:1) to afford 8 as a colorless

liquid, 70%.

1 Achmatowicz O Tetrahedron 1971 27 1973

2 Shono T Chem Lett 1981 1121

3 Georgiadis MP J Org Chem 1986 51 2725

4 Zhou W-S J Chem Soc Chem Comm 1997 317

5 O’Doherty GA Tet Lett 2000 41 183

6 Schreiber SL Angew Chem Int 2004 43 57

7 Schreiber SL J Am Chem Soc 2004 126 14096

8 Zuhal G Turk J Chem 2007 31 491

9 Boger DL J Am Chem Soc 2010 132 2157

10 Nicolaou KC J Am Chem Soc 2010 132 6855, 8219

A

3

ACYLOIN Rearrangement

Rearrangement of O-silylacyloins (a-siloxyketones) catalyzed by strong bases (e.g. KHMDS

2); occurs with silyl transfer (1 Æ 4).

OSiMe2tBu

OOSiMe2

tBu

OSiMe2tBu

SMe

O

[KN(SiMe3)2

–50 oC

1 4, 64% 7

OSiMe2tBu

OO-SiMe2

tBu3

MeN

O

O

MeN

O

OMeN

O

OOSiMe2

tBu

2 SMeSMe

(1b,2S*,6S*,7b,11S*)-7,11-Di-t-butyldimethylsilyloxy-4-methyl-11-(methylsulfanyl)methyl-4-

azatricyclo[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 187–189.5 �C.

1 Herz W, Baburao V J Org Chem 1971 36 3899

2 Iriye R Agri Biol Chem 1978 42 1495

3 Gokel GW Tet Lett 1979 20 3379

4 Hall AJ J Chem Soc Perkin 1 1980 1025

5 McIntos J Can J Chem 1991 69 1315

6 Sato T Tet Lett 1994 35 5027

7 Katayama S Chem Pharm Bull 2005 53 666

ADLER Phenol Oxidation

Also known as Adler–Singh. 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.

OH

OH

O

ONaIO4O

O

O

O

4 5 6

OH

CH2OH

NaIO4

4 °CO

IO O

O

OO

OO

1/2

1 2 3, 74%4O

OO

-NaIO3

Spirooxirane (3).4NaIO4(47 g,0.22 mol) inwater (1 L)wasadded toastirredsolutionof2-hydroxybenzyl

alcohol1 (n=1, 24.83 g, 0.2 mol) inwater (1.5 L).After 10 min, colorless crystals appear.Themixturewas

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 194–195 �C.

4

1 Adler E Acta Chem Scand 1959 13 505

2 Adler E Acta Chem Scand 1960 14 1261, 1580



5 Singh V J Chem Soc Chem Comm 1992 1212

6 Waldmann H Tet Lett 1996 37 3833

7 Singh V Acc Chem Res 1999 32 324

8 Castet F, Quideau S Tetrahedron 2007 63 6493

9 Singh V Org Biomol Chem 2010 8 4472

ALDER (Ene) Reaction

Thermal or Lewis acid catalyzed sigmatropic rearrangement with H-transfer and C22C bond

formation 3, either inter or intramolecular, and with chiral induction 8.

HEt+ O

CO2Me

CO2Me 16 h

140 oC

HEt

CO2Me

OH

CO2Me

1 2 3, 62%5

EtO2C

CO2Et

LiClO4 (cat)

5 h, 20 oC

EtO2C

CO2Et∗

Ph HMe

+ O

O

OMePh

∗O

O

O

4 5, 100%7 6 7 8

H

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 90–105 �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 Alder K Chem Ber 1943 76B 27

2 Hill RK J Am Chem Soc 1964 86 965

3 Usieli V J Org Chem 1973 38 1703

4 Oppolzer W Angew Chem 1978 90 506

5 Achmatowicz O J Org Chem 1980 45 1228

6 Snider BB J Org Chem 1982 47 745

7 Sarkar TK Synlett 1996 97

8 Chen H Organomet 2005 24 872

9 Naruse Y Tet Lett 2005 46 6937

10 Hilt G Angew Chem Int 2007 46 8500

11 Shen R J Org Chem 2009 74 4118

A

5

ALDER–RICKERT Acetylene Cycloaddition

Synthesis of polysubstituted benzenes 5 via Diels–Alder reaction of cyclohexadienes, e.g. 2

with acetylenes 3, via bicyclooctadienes 4.

Cl

O

Cl

OTMS

LDA

Me3SiCl+

CO2Me

CO2Me

70–140 °C

Cl

E

E OH

ClE

E OTMS

5, 53%2, 79%41 3 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 Alder K, Rickert HF Liebigs Ann 1936 524 180

2 Birch AJ Aust J Chem 1969 22 2635

3 Danishefsky S J Am Chem Soc 1974 96 7807

4 Winterfeldt E Tet Lett 1985 26 1705

5 Patterson JW J Org Chem 1995 60 560

6 Labadie SS Syn Comm 1998 28 2531

7 Kuwahara S Tetrahedron 2008 64 9073

8 White JM J Org Chem 2007 72 2929

ALDOL Reactions

Base or acid activated condensation between aldehydes and/or ketones to afford a b-hydroxyaldehyde (aldol) or b-hydroxyketone (ketol) 4. First examples by Claisen2 and Schmidt.1 Re-

action 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 com-

mon 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 Æ 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.4–7

6

MeO

N

O

SMe

Me

Ph

1. (i) LDA- Cp2ZrCl2(ii) Cp2ZrCl2

2. PhCHO

O

N

O

SMe

MePh

OH

O

N

O

SMe

MePh

OH

+

6, anti 90% 7, syn 10%5

Me Me Me

Me Me

Ph Ph

98%

O OO

OLDA

-78 oCPh H

Ph

1 23

4

OH

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 Schmidt JG Ber 1880 13 2342

2 Claisen L Ber 1881 14 349

3R Heathcock CH Science 1981 214 395

4R Mukaiyama T Org React 1982 28 187

5R Mukaiyama T Aldrichim Acta 1996 29 59

6R Abiko A Aldrichim Acta 1997 37 387

7* Michio K J Org Chem 2001 66 1205

8R Moyano A, Rios R Chem Rev 2011 111 4703

ALLEN Phosphonium Rearrangement

Also known as Allen–Millar–Trippett. Ring enlargement of cyclic phosphonium salts 2,5

obtained by alkylation or acylation of cyclic phosphines 1, 4 in the presence of base.

P

RP

R CH2I

KOHCH2I2

PhH reflux P

O

R

1 2 3, 71%1

P

PhP

PhPh

O

TEA

H2O

refluxP

PhPh

O

P

PhOH

O

PhOH PO Ph

OHPh

4 5 8, 87%6

PhCOCl

6 7

A

7

9-Methyl-9,10-dihydro-9-phosphaphenanthrene-9-oxide (3).1 The phosphonium salt 2 (R ¼ 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 Allen DW, Millar IT Chem Ind 1967 2178

2 Trippett S Chem Comm 1967 1113

3 Allen DW, Millar IT J Chem Soc C 1969 252

4 Tebby JC J Chem Soc C 1971 1064

5 Mathey F Tetrahedron 1972 28 4171

6 Mathey F Tetrahedron 1973 29 707

7 Allen DW J Chem Soc Perkin 1 1976 2050

8 Markl G Angew Chem Int 1987 26 1134

9 Keglevich Gy J Org Chem 1990 55 6361

10 Keglevich Gy Synthesis 1993 931

11R Savignac P Eur J Org Chem 2000 3103

12 Mapp AK J Am Chem Soc 2006 128 4576

13 Vignolle J Tet Lett 2007 48 685

ALPER Carbonylation

Carbonylation of cyclic amines 4, hydroformylation (CO22H2) of amino olefins 6,

carbonylation of alkenyl epoxides8 and allenyl alcohols10 or amines catalyzed by metal (Pd,

Ru, Rh) complexes. Also dimerisation is possible with aziridine.

R

R R2

NR1

CH(CO2Et)2

I 1. Pd(OAc)2PPh3

2. CO

R

R

NPd

O

R1

R2(EtO2C)2HC

I–

+ –Pd(0)R

R R2

NR1

CO2Et

O

base

21 311

Pd(Ph3P)4

5, 79%2

NHNN

BuBu

O

CO HRh(CO)(Ph3P)3

NaBH4, 100 oC, 34 atm

N

O6 7, 78%3Pd(OAc)2/PPh3

or

4

CO

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 andthe residue was purified by preparative TLC (silica gel, hexane:EA, 8:1) to give product 5 (79%).

1 Alper H J Chem Soc Chem Comm 1983 1270

2 Alper H Tet Lett 1987 28 3237

3 Alper H J Am Chem Soc 1990 112 2803

4R Alper H Aldrichim Acta 1991 24 3

5 Alper H J Org Chem 1992 57 3328

8



8 Alper H J Org Chem 1997 62 8484

9 Alper H Org Lett 2000 2 441

10 Toros S Steroids 2004 69 271

11 Alper H Org Lett 2008 10 4903

AMADORI Glucosamine Rearrangement

Acid catalyzed rearrangement of aldoses 1, 3 viaN-aldoglycosides to aminoglycosides of ketoses

2, 4 in the presence of amines. Apparently proceeds via ring opening (I), imine to enamine tau-

tomerization and re-ring closure of aminoketone (II) to 2.

O

OH

HOHO

OH OH

OHO

HO

OH OH

NH–PhMe

1 2, 60%3

Tol–NH2

100 °COH

OH

HOHO

OH NHTol+

OH

HOHO

O NHTolI II

OH

O

OH

HO

SO3

OHOH

K O

OHHO

O3S

CH2NH2R

OH

4, 94%3

Amberlite-H+

R = Cyl

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 152–153 �C.1-Cyclohexylamino-1,6-dideoxy-a-D-tagatofuranose-6-C-sulfonic acid (4).

10 Amberlite IR-120

(Hþ) cation exchange resin was added to a solution of 3 (131 mg, 0.465 mmol) in water (2.5 mL)

up to pH 0–1. 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 Amadori M Atti Accad Nazl Lincei 1925 2 337 (6)

2 Weygand F Chem Ber 1940 73 1259

3 Hixon RM J Am Chem Soc 1944 66 483

4 Hodge JE J Agric Food Chem 1953 1 928

5 Ames GR J Org Chem 1962 27 390

6 Gyorgydeak Z Carbohydrate Res 1997 302 2297 Horvat S J Chem Soc Perkin Trans 1 1998 909

8 Mioduszewski JZ US Pat 1998 5723,504

9 Peters JA Eur J Org Chem 2001 3899

10 Fernandez-Bolanos JG Tet Asymm 2003 14 1009

11 Jalbout AF Food Chem 2007 103 919

12 Jakas A Carbohyd Res 2008 343 2475

13 Wrodnigg TM Carbohyd Res 2008 343 2057

14 Maugard T Tetrahedron 2009 65 531

A

9

ANGELI–RIMINI Hydroxamic Acid Synthesis

Synthesis of hydroxamic acids 5 from aldehydes 1 and N-sulfonylhydroxylamines 2; also used

as a color test for aldehydes.

Cl

C-NHOH

NaOMe

0–20 °C+

O2S

Cl1 2 5, 68%

MeOH

CH=O NHOH O

Ar

OH

N

O

SO2PhAr

OH

N

O3 4

p-Chlorobenzene hydroxamic acid (5).6 To an ice-cold solution ofN-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) inMeOH (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 Angeli A Gazz Chim Ital 1896 26 17

2 Rimini E Gazz Chim Ital 1901 31 84

3 Balbiano L Att Accad Lincei 1913 22 575

4 Yale HL Chem Rev 1943 33 228

5 Lwowski W Angew Chem Int 1967 6 897

6 Hassner A J Org Chem 1970 35 1962

7 Stoyaoysky DA J Am Chem Soc 1999 121 5093

8 Porecheddu A J Org Chem 2006 71 7057

9 King SB Org Lett 2009 11 4580

APPEL Displacement Reagent

Formed from Ph3P and CCl4 (or CBr4) 1, a reagent for chlorine (also bromine or iodine) dis-

placement 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

Ph3P CCl4 (Ph3PCl) CCl3

R OHO R(Ph3P)

+ Cl–

R Cl Ph3PO

I1

+2

3

OH

OH

OH

Cl R

RR

R

CONH2 CNO

O

CCl4, 1

MeCN

1

4 5, 88%5 6 7, 89%2R = OMe

Reflux

Reflux,

NR2

R1

OH NCl

R1

R2 Ph3PO CHCl31

8 9

10

trans-2-Chlorocyclohexanol (5).5 trans-1,2-Cyclohexanediol 4 (3.82 g, 33 mmol) was added to a solu-

tion 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 re-

flux, 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 60–95 �C)/Me2CO afforded 168 mg of 7 (89%),

mp 255–257 �C.

1 Rabinowitz R, Marcus R J Am Chem Soc 1962 84 1312

2 Appel R Chem Ber 1971 104 1030

3 Appel R Chem Ber 1975 108 2680

4 Appel R Angew Chem Int 1975 14 801

5 Evans SAJr J Org Chem 1981 46 3361

6R Castro BR Org React 1983 29 1

7 Brinkman HR Synthesis 1992 1093

8 Lee KJ Synthesis 1997 1461

9 Barrett AGM Org Lett 2002 4 1975

10 Nishida Y Org Lett 2003 5 2377

11 Wagener KB Tetrahedron 2004 60 10943

12 Iranpoor N Tet Lett 2006 47 5531

13 Bergin E J Am Chem Soc 2007 129 9566

14 Baran P S J Am Chem Soc 2008 130 17938

15 Das B Tet Lett 2009 50 2072

16 Soltani RMN Synthesis 2010 1724

ARBUZOV Phosphonate Synthesis

Also known asMichaelis–Arbuzov. 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.

NiCl2[(EtO)3P]4Ni

P

O

(OEt)2

I

(EtO)3P150 oC 160 oC

1 2

3

4, 94%3

BrN

O

CH2Ph

CH(Me)Ph PN

O

CH2Ph

O

MeOCH(Me)PhMeO

(MeO)3P

110 oC8, 98%10

6

5(MeO)3P

PN

O

CH2Ph

OMe

MeORO

Br

Me

7

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 Et–I was dis-

tilled. Vacuum distillation afforded 4 (94%), bp 94–101 �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 im-

purities were removed in a Kugelrohr in vacuum and the residue was purified by flash chromatography

(silica gel, EA/hexanes/MeOH) to afford 8 (98%).

A

11

1 Michaelis A Chem Ber 1898 31 1048

2 Arbuzov AE J Russ Phys Chem Soc 1906 38 687

3 Balthazor TM J Org Chem 1980 45 5425

4 Lebeau L Tet Lett 1995 36 5183

5 Hudson HR ARKIVOC 2004 ix 19

6 Klausmeyer KK Inorg Chem Comm 2006 9 418

7 Reddy CS ARKIVOC 2006 xvi 128

8 Matveeva EV Tet Lett 2006 47 7645

9 Pakulski Z Tet Lett 2007 48 8482

10* Ordonez M Tet Asymm 2007 18 2427

11 Michalski J Chem Eur J 2009 15 1747

12 Mohanakrishnan AK Org Lett 2011 13 1270

ARNDT–EISTERT 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 interme-

diate 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 Æ 9/10), sometimes Lewis acid catalyzed. Compare with Kowalski. For conversion of

aldehydes to ketones see Schlotterbeck.

1 42

CO2HCH2CO2H

O

N21. SOCl2hυ, Ag+

H2O2. CH2N2

CC

OH

H2O

3

OO O

CH2N2+

8 9 10

5 6 7, 84%3

ClO

CH2N2, Et3N

Et2O, 0 oC

CHN2O

PhCO2Ag, Et3N

EtOH, heat

CO2Et

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 mix-

ture 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 Eistert B, Arndt F Chem Ber 1927 60 1364

2 Barbier H Helv Chim Acta 1940 23 523

3 Newman MS Org Synth 1970 50 77

4 Shiori T Chem Pharm Bull 1981 29 3249

12

5 Smith AB J Am Chem Soc 1986 108 3110

6 Katritzky AR J Org Chem 2001 66 5606

7R Wolfgang K Eur J Org Chem 2002 2193

8 Mazaleyrat J-P Tet Asymm 2005 16 857

9 Albericio F Tet Lett 2006 47 4557

10 Seebach D Helv Chim Acta 2007 90 1651

11 Hughes AB Aus J Org Chem 2008 61 131

12 Perlmutter P Tet Asymm 2008 19 2861

13 Hoffmann-Roeder A Beil J Org Chem 2010 6 47

14 Reisman SE J Am Chem Soc 2011 133 774

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).

N O NS

N

N

S8

NH3, 40 °C

2, 97%1 5

2

NH3

SH

RO2C Cl

1. KOAc/R1CHO, EtOH, 20 °C

2. MnO2, CH3CN3 4N

S

RO2C

R1

H

Cl

O

O O

OO O

OH

O O

OO

OH

N

S H

8, 71%, dr >95:57

NH3, NaSH

0 °C, 12 h

5 6

SH

NH

7

10,6-Dimethyl-20,40,50,60,70,70a-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 40–50 �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 200–205 �C, after crystallization mp 240 �C.

1 Asinger F Liebigs Ann 1957 602 37


3 Asinger F Angew Chem 1958 70 372


5 Lyle RE J Org Chem 1965 30 293

6 Domling A Tetrahedron 1995 51 755

7* Martens J Tet Lett 2000 41 7289

8* Dunach E Tet Asymm 2001 12 1279

9R Offermanns H Angew Chem Int 2007 46 6010

A

13

ATHERTON–TODD Phosphoramidate Synthesis

Synthesis of phosphoramidates 4, 5, 7 from formamides 1 and phosphites 2 or from iodoform,

amines and dialkyl phosphites (2 to 7).

ONH

HP O

H

EtOEtO+ P

N OEt

OOEt

30% NaOH

R4N+Br–, CCl4

1 2

PNH

OEt

OOEt

4, 60%4O H OH–3

CHI3, NH3

CHCl3, r.t.

25, 83%9

EtOP H

O

EtOP

NH2

O

CHI3, PhNH2

Toluene, r.t. EtOP

NHPh

O

7, 82%6

EtOP

I

O

OEt OEt OEt OEt

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 organiclayer gave 4, after crystallization, 0.687 g (60%), mp 96–97 �C.Diethyl phophoramide (5).9 Into vigorously stirred liquid NH3 (15–20 mL), 1.0 mmol of iodoform

and 1.1 equiv of dialkyl phosphite 2 were added simultaneously at�33 �C. After 5–10 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 Atherton FR, Todd AR J Chem Soc 1945 660

2 Wadsworth WS J Am Chem Soc 1962 64 1316

3 Zwierzak A Synthesis 1982 922

4 Lukanow LK Synthesis 1985 671

5 Hovalla D Tet Lett 1992 33 2817

6 Garrigue B Syn Comm 1995 25 871

7 Liu LZ Org Prep Proc Int 1996 28 490

8 Zhao YF J Chem Res S 2003 262

9 Mielniczak G Syn Comm 2003 33 3851

10 Zhao YF Synlett 2005 1927

11 Ju Y Synthesis 2007 407

12 Donghi M Bioorg Med Chem Lett 2009 19 1392

14

AUWERS Flavone Synthesis

Synthesis of benzopyran-4-ones 4, 8 (flavones) from o-hydroxychalcones 5 or from benzo-

furan-3-ones 1.

O

Cl

O 1. PhCHO36% HCl

EtOH, 60 oC

21

2. Br2, 20 oCCHCl3

O

Cl

OBr Ph

Br

4

0.1 N KOH, EtOH

reflux, 10 min O

O

OH

Ph

Cl3

O–

Cl

OOHPh

Br

O

O Ph

O2N

Cl

O

Ph

OH

NO2

+

O

Cl

HEtOH

dry HCl, 0 oC

5 6 8, 30%5

reflux, H2O O

O Ph

O2N CHO

Cl

7

6

6-Nitroflavanone (8).5Amixture 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 Auwers K Chem Ber 1908 41 4233

2 Minton TH J Chem Soc 1922 121 1598

3 Ingham BH J Chem Soc 1931 895

4 Acharya BG J Chem Soc 1940 817

5 Szell T J Org Chem 1963 28 1146

6 Dorofeenko GN Chem Heterocycl Comp 1977 13 149

7 Gupta R Org Prep Proc Int 2000 32 280

8 Pawar RP ARKIVOC 2006 xvi 43

A

15

AUWERS–INHOFFEN Dienone-Phenol Rearrangement

Acid catalyzed rearrangement of dienones 1 or bromo substituted dienones5 3 to phenols (phenol

acetates) via carbocations.

O AcO

TsOH

Ac2O

O

Br

PhPh

PTSA

reflux

OAc

Br

Ph

Ph

OH

Br

PhPh

+

1 2 3 5, 38%5

Ac2O

4H+

H+ Ac2O

–

2-Bromo-3,4-diphenylphenylacetate (5).5 A solution of 3 (2.804 g, 8.62 mmol) and PTSA�H2O

(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 benzene–ether fractions were dried

and concentrated in vacuo to afford an oily solid, which was washed thoroughly with ether to afford

5 (38%).

1 Auwers KV Liebigs Ann 1921 425 217

2 Inhoffen C Angew Chem Int 1940 53 473

3 Djerassi C J Am Chem Soc 1951 73 990

4 Winstein S J Am Chem Soc 1957 79 3109

5 Bordwell FG J Org Chem 1964 29 509

6 Uneyama K J Org Chem 1995 60 6402

7 McPhail AT Steroids 1998 63 135

8 Li YL Chin Chem Lett 2003 14 689

9 Fujioka H Chem Comm 2010 46 797

16

abiko masamune asymmetric aldol reaction a -...

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