Michael Addition

Mechanism of the Michael Addition

Original publication	J. Prakt. Chem.. 1887, 35, 349. J. Org. Chem.. 2005, 70, 6757.
Reviews	Angew. Chem. Int. Ed.. 2003, 42, 1688. Arkivoc. 2002, 7, 167. Chem. Rev.. 1992, 92, 771. Chem. Rev.. 2003, 103, 2035. Chem. Rev.. 2005, 105, 933. Chem. Soc. Rev.. 2012, 41, 988. Eur. J. Org. Chem.. 2006, 0, 29. Org. React.. 1992, 41, 135. Tetrahedron. 2009, 65, 9657.

Sample reactions

Methyl Cyanoacetate

Cyclohexane, t-BuOH

RT, 48 h, 91%

NaSBn

MeOH

RT, 3 h, 77%

KOH

EtOH

100 °C, 5 h

"8 mg of strychnine was obtained from a mixture of 7 mg isostrychnine and 65 mg isostrychnine acetates."

t-BuOOH, Me3N+Bn HO-

THF

-15 °C, , 91%

BnSH, n-BuLi

THF

-50 °C, , 85% (4 steps)

Bz2O2, CuBr, MeLi

Et2O

-78 to 0 °C, 45 min, 75%

80 °C, 16 h

CuCN, t-BuLi, TMSCl

Et2O, Et3N

-78 to -10 °C, 3 h, 93%

Et3NBn+ i-PrO-, Ph3COOH

THF

-10 °C, 3 h, 72%

CuI, MeLi

THF

0 °C to RT, 45 min, 60%

CuI, MeLi, TMSCl

Et2O, Et3N

0 °C to RT, 3.5 h, 80%

CuI, (CH2NMe2)2, TMSCl, VinylMgBr

Et3N, THF

90%

TMS2NLi

DME, THF

-78 °C, 4.5 h, 71%

CuI, VinylMgBr

THF

KOt-Bu, NaOH, Ethyl vinyl ketone

H2O, t-BuOH

0 °C to RT, 10 h, 53%

Me3N+Bn HO-, VinylCN

H2O, PhH, t-BuOH

50 °C, 45 h

BF3.OEt2, CuCN, MeLi

THF

n-BuLi

THF

-78 °C to RT, 6 h, 67%

CuI, MeLi

Et2O

-78 °C to RT, ON, 97%

i-Pr2NLi, i-PrCO2Et

THF

-78 to 0 °C, 2.5 h

CuCN, t-BuLi

Et2O

-78 to 0 °C, 2 h, 92%

"99 % yield base on 93 % conversion."

i-Pr2NLi

THF

-78 °C to RT, 3 h, 64-85%

DBU, t-BuOOH

THF

RT, 72 h, 82%

CuCN, MeLi

Et2O

-78 °C, 2 h

Li, NH3

t-BuOH, THF

-78 to -5 °C, 75 min

KOt-Bu

t-BuOH

PhH

Reflux, 22 h, 76%

MeI, CuBr.Me2S

HMPA

66%

Me2CuLi, AllylCl

HMPA, THF

-78 °C to RT

Sc(OTf)3

Sealed tube

DCE, H2O

120 °C, 36 h, 73%

Et3N

CH2Cl2

RT, 12 h

n-BuLi, Ph3COOH

THF

-78 °C, 2 h

BnNHMe

RT, 16 h

Et3N, TMSCl, Vinyl2CuMgCl

THF

-78 °C to RT

K2CO3

THF

Reflux, 4 h, 98%

KOt-Bu, VinylCN

THF

0 °C, 20 min, 74%

CuI, Et3N, TMSCl, TMSCH2MgCl

HMPA, THF

-78 °C to RT, 2 h

TASF

CH2Cl2

-78 °C, 5 min, 79%

MeMgBr, TMSCl, CuBr.Me2S

HMPA, THF

-78 °C to RT, 2.5 h

"The starting material was 90:10 er."

HMPA, (n-Bu3PCuI)4

THF

-50 °C to RT, 3 h, 60%

Me2CuLi

Et2O

-78 °C, 30 min

Me2CuLi

Et2O

-78 °C, 30 min

CuBr.Me2S

THF, Me2S

-78 to 0 °C, 6 h

CuBr.Me2S

THF, Me2S

-78 to 0 °C, , 68%

Et3N

Sealed tube

Ethylene Glycol

225 °C, 24 h, 8-12%

"The yield was 10-15 % brsm."

Me2CuLi

Et2O

-20 °C, 40 min, 96%

AcCl, t-BuLi, (n-Bu3PCuI)4

Et2O

-78 to 0 °C, , 84%

VinylMgBr, (n-Bu3PCuI)4

HMPA, THF

-45 °C to RT, 3 h, 54%

TiCl4

CH2Cl2

-78 °C to RT, 40 min

"R = H, t-Bu."

TsOH, Morpholine

PhH

Reflux, , 92%

NaOH, t-BuOOH

H2O, MeOH

RT, , 89% (2 steps)

Tf2O, Et2AlCN, n-Bu4N+ Ph3SiF2-

PhH

0 °C to RT, 19.5 h, 81%

H2O2, NaOH

CH2Cl2, H2O, MeOH

0 °C, 2 h, 75%

"Also isolated was the TES-deprotected product (16 % yield)."

TMSCl, VinylMgBr, CuBr.Me2S

THF

-78 °C, 2 h, 92%

CuBr.Me2S

THF, Me2S

-78 to 0 °C, 24 h

VinylMgBr, CuBr.Me2S

50%

"Also isolate was the C3-epimer (15 % yield)."

Et2O

Reflux, , 13%

"Also isolated was the C3-epimer (40 % yield)."

i-Pr2NLi

THF

-100 to -78 °C, , 50%

"For the synthesis of this enone, see : J. Am. Chem. Soc. 1984, 106, 6690."

Et3N, K3Fe(CN)6, NCCH2CO2Et

EtOH, H2O

RT, 11 min, 84%

NaOCl

H2O, Pyr

0 °C, 60 min, 90%

HCl

EtOH, H2O

Reflux, 4 h, 50% (2 steps)

ClCH2CO2H

CH2Cl2

0 °C to RT, 3.5 h

p-MePhSH

EtOH

-15 °C, 36 h, 70% (2 steps)

Et3N, Methyl propynoate

THF

-20 to 0 °C, 3.5 h, 89%

TMS2NNa, CuBr.Me2S

NMP

0 to 65 °C, 95 min, 10%

NaH

THF

0 °C, 105 min, 98%

Dimethyl malonate, KOt-Bu

4Å MS

THF

4 °C to RT, 24 h, 91%

i-Pr2NEt, Tf2O

CH2Cl2

-78 °C, 90 min

Br3CCO2H

PhMe

-60 °C to RT, 23 h, 82%

CuBr.Me2S, Mg

THF

-50 °C to RT, 80 min, 58%

TiCl4

CH2Cl2

71%

TMS2NLi

THF

0 °C to RT, 100 min, 100%

BF3.OEt2, CuI, t-BuLi

Et2O, HMPT

-120 to -20 °C, 9 h, 60%

"The yield was 74 % brsm."

AcCl, i-Pr2NLi

HMPA, THF

-78 °C, 105 min, 86%

Li, CuI.Me2S

Et2O

-30 °C to RT, 2.5 h, 85%

"Also isolated was the C6'-epimer (5 % yield)."

AcOH

100 °C, 60 min, 63%

CuBr.Me2S

THF

-78 °C, 15 h

KOt-Bu

DMSO

RT to 100 °C, 10 h, 60%

NaOMe

MeOH

RT, 12 h, 58%

CuI, MeLi

-78 to -40 °C, 80 min, 93%

VinylMgBr

THF

-78 to 0 °C, 12.5 h, 90%

CuI, MeLi.LiBr

Et2O

0 °C, 30 min, 80%

CuI, VinylMgBr

THF

-78 °C to RT, 30 min, 55%

Et3N, Methyl vinyl ketone

MeOH

RT, 105 min, 74%

Me3N+Bn HO-

DME

-20 °C, 2.5 h, 44%

"Also isolated was the C2-epimer (14 % yield)."

K2CO3

MeCN

Reflux, 42 h, 95%

Me3N+Bn HO-, Methyl acrylate

Dioxane

50-70 °C, 60 min, 88%

Me2NH

H2O

0 °C, 2 h

CuCN, VinylMgBr

THF

-78 to -40 °C, 40 min, 98%

LDA

THF

-78 to -20 °C, 17.5 h, 79%

"another diastereomer was also isolated (6% yield)"

Me2CuLi

Et2O

-78 to -34 °C, , 99%

CuI, Et3N, TMSCl, VinylMgBr, HMPA

THF

-60 °C to RT, 3 h, 89%

AcOH, H2O, Methyl acrylate, Hydroquinone, THF

RT to 65 °C, 2 d, 78% (2 steps)

"94:06 e.r.; the enantiomeric purity was improved to >99:01 e.r. by crystallization of the corresponding semicarbazone."

LDA

THF

-78 °C to RT, 2 h, 75%

"66:33 dr"

H2O, HCl, NaOEt

EtOH

10 °C to Reflux, 20 min, 90%

TMSCl, AllylMgBr, CuBr.Me2S

THF

-78 °C, 2 h, 75%

KOt-Bu, VinylCO2t-Bu

t-BuOH, THF

-10 to 0 °C, 2 h, 62%

"91:09 dr"