Michel Addition

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Organic Name reaction

JAYANTA SAHAMSc

Asymmetric Michael Additions: Advancements in Organocatalysis

Michael Additions

Arthur Michael

“the way how this combination (of malonateester with unsaturated acid ester) resulted was clearly knownby Mr. Claisen and correctly described. Mr. Michael contributed to make the reaction remarkably practical by the use ofsodium compounds of malonate and acetoacetate esters andto have substantially generalized.”- Ernst Von Meyer

Mechanism Of Micheal addition:

O

O

O

ONa

O

O

Br

CO2Et

CO2EtO

O

Br

Michael, A. J.Prakt.Chem. 1887, 35, 349;

“On the Addition of Sodioacetoacetic and Sodiomalonic Ester to Unsaturated Acid Esters,”

1,2 - Addition

1,4 - Addition

OPh

Ph OMgBr

MgBrPh OH

racemic

H

Nu Me

Nu

Me

NuO

Me

O OR

R RH

Me

Nu OH

R

R = H, alkyl

Classical Reaction Challenges

Nu Me

Nu

Me

NuO

Me

O OR

R RH

Me

Nu OH

R

Me

Nu O

RE

E

(electrophile)

R = H, alkyl

• Scope of Nucleophiles (formation of C–C, N, O, S, P Bonds)

• Alkene Substitution Patterns

• Scope of Electrophile

• Control Stereochemistry Catalytically

• Outline

• Enamine/Iminium Catalysts• Michael Cascades• Reductive Michael• Hetero-Michael

Enamine / Iminium Catalysis

NH

NO Me

t-BuAr

Imidazolidinone= HNR2

·TFA

O

O

N

N

R

R

R

R

±H2O

±H2O

Enamine (En)

Iminium (Im)

MacMillan, D. et.al. J. Am. Chem. Soc. 2005, 127, 15051-15053

I

• Imidazolidinone Catalyst

Me

NH

NOMe

t-Bu

Ph

N

N

O

NH

NOMe

Ph

Me

Me

H

HHHH

H

H

H

MeN

N

O H

HHHH

H

H

MeNR

MeN

N

O Me

Me

Me

H

MeN

N

O Me

Me

Me

MeNR

HH

HH

MacMillan, D. and Austin, J. J. Am. Chem. Soc. 2002, 124, 1172-1173

Aromatic Nucleophiles

Me O

Ar (Nu)

(E)

OCl

Cl

ClCl

Cl

Cl

Im En

20 mol% cat.EtOAc

NBn

OTMSOMe

71% yield, d.r. >25:1, >99% ee

75% yield, d.r.=12:1, 99% ee

86% yield, d.r.=14:1, 99% ee

NBn

OMe OMe

NH

NOMe

t-BuBnN

catalyst

OCl

Me

OCl

Ar

Me

OCl

Me

OCl

Me

OO

Me

MacMillan, D. et.al. J. Am. Chem. Soc. 2005, 127, 15051-15053.

Catalytic Cycle

NH

NO Me

t-BuAr

N

NO Me

t-BuAr

N

NO Me

t-BuAr

R

X

RNu

+HX

N

NO Me

t-BuAr

RNu

+H2O

X

E

Me O

Nu

E

+H2O

O

NuE

Cascade Product

Iminium (Im)

Enamine (En)

MacMillan, D. et.al. J. Am. Chem. Soc. 2005, 127, 15051-15053.

Mukaiyama-Michael ReactionO CO2MeO

t-BuO2C

OO

CO2MeO

CO2t-Bu20 mol%·TFA

THF-H2O, 4°C

N

N O

Me

t-Bu

Ph

90% yield, 89% ee,11:1 syn :anti

TIPS

t-BuO2C O

H2ONH

NOt-Bu

Me

Ph

O CO2MeOTIPS

MacMillan, D. et.al. J. Am. Chem. Soc. 2003, 125, 1192-1194.

Chem. Soc. Rev., 2014, 43, 7430

Aza-Michael reaction

Catalytic Cycle

Chem. Soc. Rev., 2014, 43, 7430

Asymmetric Aza-Michaels

Chem. Soc. Rev., 2014, 43, 7430

Catalytic Cycle

Chem. Soc. Rev., 2014, 43, 7430

• Outline

• Enamine/Iminium Catalysts• Michael Cascades• Reductive Michael• Hetero-Michael

Michael-Aldol Cascade

Ar

O

PhCO2Bn

O NH

HN

CO2HBn

10 mol%

EtOH, 25°C

O

Ph ArHO

CO2Bn

Ar = Ph80% yield, 95% ee

97:3 d.r.

Ar yield (%) ee (%)4-Cl-Ph 60 97

2-NO2-Ph 56 962-furyl 40 85

2-thiophene 52 83

Jorgensen, K. et.al. Angew. Chem. Int. Ed. 2004, 43, 1272-1277

Michael Cascades

Ph

O

Ph PhHO

CO2Bn

O

Ph PhHO

CO2Bn

O

OPh

Ph

O

Ph

Ph

O

CO2Bn

CO2Bn

anti

syn

cis

equatorial

Ph

O

PhCO2Bn

O

NH

HN

CO2HBn

Iminium-catalyzedMichael

OPh

CO2BnPh

O

OPh

CO2Bn

O

Base-catalyzed Aldol

Jorgensen, K. et.al. Angew. Chem. Int. Ed. 2004, 43, 1272-1277

Chiral Cyclopentanes

O

H

R

CO2EtCO2Me

MeO2C NH

PhPh

OTMSN

R

PhPh

OTMS

N

R

PhPh

OTMS

MeO2C CO2Me

CO2Et

1st Michael 2nd Michael

H2O catalystR

CHO

MeO2C CO2Me

CO2Et

10 mol%

EtOH, 25°CMeO2C

CO2Me

CO2Et

Wang, W. et.al. Angew. Chem. Int. Ed. 2007, 46, 3732-3734.

Triple Cascade

NH

PhOTMS

Ph

O

PhNO2

O

Ph

(S)-1

A B

C

3

4

5

2

(S)-1

Enamine catalysis

O

NO2

Ph

(S)-1

H2O

H2O

H2O

Iminium catalysis

CASCADECYCLEN

NO2

Ph Ph

PhOTMS

Ph

O N

NO2

Ph Ph

PhOTMS

Ph

O

O

PhPhNO2

TBSO

TBSO

TBSO

TBSO

TBSO

Enders, D. et.al. Nature 2006, 441, 861-863

• Outline

• Enamine/Iminium Catalysts• Michael Cascades• Reductive Michael• Hetero-Michael

Reductive Michael Additions

CHCl3, -30 50°C

O

R2

R1 O

R2NH

MeMe

EtO2C CO2EtN

NH

MeO

t-Bu

Ph O

Et

c-hex O

Et

t-Bu O

Me

MeO2C O

Me

20 mol% ·TFAR1

74% yield, 94% ee 95% yield, 97% ee83% yield, 91% ee 95% yield, 91% ee

MacMillan, D. et.al. J. Am. Chem. Soc. 2004, 127, 32-33

Reductive Michael Cyclization

COPh

CHO

COPh

CHO

CHO

CHO

COPh

COPh

95% yield72% ee, 24:1 d.r.

85% yield,95% ee,12:1 d.r.

NH

MeMe

EtO2C CO2EtNH

NOMe

Bn ·HCl

dioxane25°C

COR

CHOCHO

CORt-Bu

20 mol%

R = Ph, 98% yield, 96% ee, 15:1 d.r.

R = Me, 91% yield, 91% ee, 50:1 d.r.

List, B. et.al. J. Am. Chem. Soc. 2005, 127, 15036-15037

Reductive Michael Cascade

-H2ONH

MeMe

EtO2C CO2Et

N MeMe

EtO2C CO2Et

H

+H2O

NH

NOMe

Bn ·HCl

t-Bu

N

NOMe

Bn Clt-Bu

OO

O

N

NOMe

Bn

Cl

t-BuO

Cl

N

NOMe

Bnt-Bu

HO

O

O

List, B. et.al. J. Am. Chem. Soc. 2005, 127, 15036-15037.

Cyclic Reduction

MacMillan, D. et.al. J. Am. Chem. Soc. 2006, 128, 12662-12663.

O

R

O

RNH

NMe

O

Ph

O Me

NH

Me

t-Bu t-Bu

Me

20mol%

O

R

O

REt2O, 0°C

O O O

n-Bu MeO

82% yield90% ee

71% yield88% ee

81% yield96% ee

78% yield91% ee

O

c -hex

• Outline

• Enamine/Iminium Catalysts• Michael Cascades• Reductive Michael• Hetero-Michael

Asymmetric Hetero-MichaelO

XX O

X = S, O, N, P

Michael

retro-Michael

Sulfa-Michael

Ph O t-Bu SH

NH

OTMS

ArAr

10 mol%Ar=3,5-(CF3)2C6H3

PhCO2H (10 mol%)toluene, -24°C

Ph O

St-Bu

Ph OH

St-Bu

NaBH4

80% yield, 90% ee

Me OH

SBn

80% yield, 89% ee

Jørgensen, K. et.al. J. Am. Chem. Soc. 2005, 127, 15710-15711.

Tetrahydrothiophenes

Jørgensen, K. et.al. J. Am. Chem. Soc. 2006, 128, 14986-14991.

PhSH

R

O

O

NH

ArAr

OTMS

10 mol%, PhCO2H

R

N

R S

PhO

N

S

Ph

R

HO

Michael

Aldol

Hydrolysis

CHO

S

Ph

R

HO

tetrahydrothiophenes

N

ArAr

OTMS

ArAr

OTMS

ArAr

OTMS

R = alkyl44-74% yield90-95% ee

Oxa-Michael

O

OHX

NH

PhPh

OTMS

20 mol% cat.20 mol% o-NO2PhCO2H

O

CHO

X

O

Rtoluene, 25°C

O Ph

CHO

O

CHO

O CO2Et

CHO

O

CHO

O CO2Et

CHO

O CO2Et

CHO

81% yield, 88% ee

57% yield, 87% eeNO2

95% yield, 90% ee

92% yield, 93% ee

MeO

F

Me

65% yield, 97% ee

72% yield, 98% ee

R

Chromenes = privileged structure

Cordova, A. et.al. Chem. Eur. J. 2007, 13, 574-581; Nicolaou, K.C. et.al. J. Am. Chem. Soc. 2000, 122, 9968.

Oxa-Michael

RSC Adv., 2015, 5, 88133,L.-Y. Cui,ab Y.-H. Wang,ab S.-R. Chen,ab Y.-M. Wangab and Z.-H. Zhou

PROPOSED TRANSITION STATE

RSC Adv., 2015, 5, 88133,L.-Y. Cui,ab Y.-H. Wang,ab S.-R. Chen,ab Y.-M. Wangab and Z.-H. Zhou

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