2. 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
3. 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,”
4. 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
5. 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
7. 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
9. 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.
10. 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)
MacMillan, D. et.al. J. Am. Chem. Soc. 2005, 127, 15051-15053.
19. 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
24. 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
25. 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
26. 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.
27. Cyclic Reduction
MacMillan, D. et.al. J. Am. Chem. Soc. 2006, 128, 12662-12663.
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
29. 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.
30. 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
31. 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.
