Michel Addition

Organic Name reaction
JAYANTA SAHA
MSc
Asymmetric Michael Additions:
Advancements in Organocatalysis

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

Mechanism Of Micheal addition:
O
O
O
O
Na
O
O
Br
CO2Et
CO2Et
O
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
O
Ph
Ph O
MgBr
MgBr
Ph OH
racemic
H
Nu
Me
Nu
Me
Nu
O
Me
O OR
R R
H
Me
Nu OH
R
R = H, alkyl

Classical Reaction Challenges
Nu
Me
Nu
Me
Nu
O
Me
O OR
R R
H
Me
Nu OH
R
Me
Nu O
R
E
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
N
H
N
O Me
t-Bu
Ar
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
N
H
NO
Me
t-Bu
Ph
N
N
O
N
H
NO
Me
Ph
Me
Me
H
H
H
HH
H
H
H
MeN
N
O H
H
H
HH
H
H
Me
N
R
MeN
N
O Me
Me
Me
H
MeN
N
O Me
Me
Me
Me
N
R
HH
HH
MacMillan, D. and Austin, J. J. Am. Chem. Soc. 2002, 124, 1172-
1173

Aromatic Nucleophiles
Me O
Ar (Nu)
(E)
O
Cl
Cl
Cl
Cl
Cl
Cl
Im En
20 mol% cat.
EtOAc
N
Bn
OTMSO
Me
71% yield, d.r. >25:1,
>99% ee
75% yield, d.r.=12:1,
99% ee
86% yield, d.r.=14:1,
99% ee
N
Bn
O
Me OMe
N
H
NO
Me
t-BuBnN
catalyst
O
Cl
Me
O
Cl
Ar
Me
O
Cl
Me
O
Cl
Me
O
O
Me
MacMillan, D. et.al. J. Am. Chem. Soc. 2005, 127, 15051-15053.

Catalytic Cycle
N
H
N
O Me
t-Bu
Ar
N
N
O Me
t-Bu
Ar
N
N
O Me
t-Bu
Ar
R
X
RNu
+HX
N
N
O Me
t-Bu
Ar
RNu
+H2O
X
E
Me O
Nu
E
+H2O
O
Nu
E
Cascade Product
Iminium (Im)
Enamine
(En)

Mukaiyama-Michael Reaction
O CO2MeO
t-BuO2C
O
O
CO2Me
O
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
H2O
N
H
NO
t-Bu
Me
Ph
O CO2MeOTIPS

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

Michael-Aldol Cascade
Ar
O
Ph
CO2Bn
O N
H
H
N
CO2H
Bn
10 mol%
EtOH, 25°C
O
Ph
Ar
HO
CO2Bn
Ar = Ph
80% yield, 95% ee
97:3 d.r.
Ar yield (%) ee (%)
4-Cl-Ph 60 97
2-NO2-Ph 56 96
2-furyl 40 85
2-thiophene 52 83
Jorgensen, K. et.al. Angew. Chem. Int. Ed. 2004, 43, 1272-1277

Michael Cascades
Ph
O
Ph
Ph
HO
CO2Bn
O
Ph
Ph
HO
CO2Bn
O
OPh
Ph
O
Ph
Ph
O
CO2Bn
CO2Bn
anti
syn
cis
equatorial
Ph
O
Ph
CO2Bn
O
N
H
H
N
CO2H
Bn
Iminium-catalyzed
Michael
O
Ph
CO2Bn
Ph
O
O
Ph
CO2Bn
O
Base-catalyzed Aldol
Jorgensen, K. et.al. Angew. Chem. Int. Ed. 2004, 43, 1272-1277

Chiral Cyclopentanes
O
H
R
CO2Et
CO2Me
MeO2C N
H
Ph
Ph
OTMS
N
R
Ph
Ph
OTMS
N
R
Ph
Ph
OTMS
MeO2C CO2Me
CO2Et
1st Michael 2nd Michael
H2O catalyst
R
CHO
MeO2C CO2Me
CO2Et
10 mol%
EtOH, 25°C
MeO2C
CO2Me
CO2Et
Wang, W. et.al. Angew. Chem. Int. Ed. 2007, 46, 3732-3734.

Triple Cascade
N
H
Ph
OTMS
Ph
O
Ph
NO2
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
CASCADE
CYCLEN
NO2
Ph Ph
Ph
OTMS
Ph
O N
NO2
Ph Ph
Ph
OTMS
Ph
O
O
PhPh
NO2
TBSO
TBSO
TBSO
TBSO
TBSO
Enders, D. et.al. Nature 2006, 441, 861-863

Reductive Michael Additions
CHCl3, -30 50°C
O
R2
R1 O
R2N
H
MeMe
EtO2C CO2Et
N
N
H
Me
O
t-Bu
Ph O
Et
c-hex O
Et
t-Bu O
Me
MeO2C O
Me
20 mol% ·TFA
R1
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% yield
72% ee, 24:1 d.r.
85% yield,
95% ee,12:1 d.r.
N
H
MeMe
EtO2C CO2Et
N
H
NO
Me
Bn ·HCl
dioxane
25°C
COR
CHO
CHO
COR
t-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
-H2O
N
H
MeMe
EtO2C CO2Et
N MeMe
EtO2C CO2Et
H
+H2O
N
H
NO
Me
Bn ·HCl
t-Bu
N
NO
Me
Bn Cl
t-Bu
O
O
O
N
NO
Me
Bn
Cl
t-BuO
Cl
N
NO
Me
Bn
t-Bu
HO
O
O
List, B. et.al. J. Am. Chem. Soc. 2005, 127, 15036-15037.

Cyclic Reduction
O
R
O
R
N
H
N
Me
O
Ph
O
Me
N
H
Me
t-Bu t-Bu
Me
20mol%
O
R
O
REt2O, 0°C
O O O
n-Bu Me
O
82% yield
90% ee
71% yield
88% ee
81% yield
96% ee
78% yield
91% ee
O
c -hex

Asymmetric Hetero-Michael
O
X
X O
X = S, O, N, P
Michael
retro-Michael
Sulfa-Michael
Ph O t-Bu SH
N
H
OTMS
Ar
Ar
10 mol%
Ar=3,5-(CF3)2C6H3
PhCO2H (10 mol%)
toluene, -24°C
Ph O
S
t-Bu
Ph OH
S
t-Bu
NaBH4
80% yield, 90% ee
Me OH
S
Bn
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.
Ph
SH
R
O
O
N
H
Ar
Ar
OTMS
10 mol%, PhCO2H
R
N
R S
Ph
O
N
S
Ph
R
HO
Michael
Aldol
Hydrolysis
CHO
S
Ph
R
HO
tetrahydrothiophenes
N
Ar
Ar
OTMS
Ar
Ar
OTMS
Ar
Ar
OTMS
R = alkyl
44-74% yield
90-95% ee

Oxa-Michael
O
OH
X
N
H
Ph
Ph
OTMS
20 mol% cat.
20 mol% o-NO2PhCO2H
O
CHO
X
O
R
toluene, 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% ee
NO2
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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Editor's Notes