Carbene-Mediated C-H Activation and Insertion
Presentation outline
! Introduction
" Classification of carbene precursors: diazocarbonyls
" Synthesis of diazocarbonyls
" Decomposition of diazocarbonyl to metal-carbenoids
! Intermolecular C-H activation
" Acceptor-Substituted Carbenoids
" Acceptor/Acceptor-Substituted Carbenoids
" Donor/Acceptor-Substitued Carbenoids
! Catalysts and models for asymmetric induction
! Conclusions
Interesting Reviews:
" Davies, H. M. L.; Øystein, L. Synthesis 2004, 16, 2595.
" Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861.
" Bourissou, D.; Guerret, O.; Gabbai, F. P.; Bertrand, G. Chem. Rev. 2000, 100, 39.
Introduction to Carbene-Mediated C-H Activation
! Activation through insertion of highly reactive metal complex
H
C
MLn
X
C
MLn
H
C
XH
Regeneration of the metal complex can be difficult
! Activation using a metal-carbenoid complex
X
MLn
N2
C
H
Y
X
MLn
N2
Y
H
C
X
Y
No direct interaction between the metal and alkane C-H bond
Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861.
Classification of the Carbene Precursor
Most commonly used diazo compounds
! The carbenes used for C-H activation can be divided into three groups
N2
Acceptor-Substututed
X
H
X= EWG: COR, CO2R, NO2, PO(OR)2, SO2R
N2
Acceptor/Acceptor-Substituted X
X
X= EWG: COR, CO2R, SO2R, CN
N2
Donor/Acceptor-Substituted
X
Y
X= EWG: COR, CO2R
Y= EDG: aryl, vinyl, alkynyl, heteroaryl
Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861.
Synthesis of Diazocarbonyls
A Brief Look
Curtius 1883
EtO2C
KNO2
NH2•HCl
EtO2C
2 H2O
KCl
N2
Acyl transfer
O
R
O
OH
O
Cl
Cl
or Cl
1.
OEt
N2
R
CH2N2
2.
O
O
Et3N
Diazo transfer
O
O
O
O
TsN3, Et3N
R
R
R'
R'
R,R' = alkyl, alkoxy
N2
Deformylating diazo transfer
O
O
O
R
R'
H
OEt
Base
OH
R
H
R'
O
TsN3
N2
R
R'
TsNHCHO
R = alkyl, alkoxy
R'= alkyl, aryl
Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091.
Decomposition of Diazocarbonyls to Metal-Carbenoids
RO
O
Rh
Rh
RO
RO
N2
R
N
Rh
N
O
N2
CH2
N
Rh
N
O
–N2
O
Rh2
R
CH2
RO
Rh2
R
N
N
CH2
R
N
N
CH2
Acceptor-Substituted Carbenoids
Intermolecular C-H activation
! C-H Activation of Alkanes
CO2Et
H
CO2Et
N2
EtO2C
CO2Et
CO2Et
Rh(II) catalyst
A
catalyst
Rh2(OAc)4
Rh2(9-trp)4a
Rh2(TFA)4
aDirhodium(II)
B
C
D
ratio
A:B:C:D
1:8:90:1
18:18:27:37
5:25:66:4
tetrakis(9-triptycenecarboxylate).
Carbene dimerization is also a major side reaction.
Other Rh(II) catalysts did not improve selectivity.
Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861.
Acceptor-Substituted Carbenoids
Intermolecular C-H activation
! C-H Activation of Functionalized Organic Substrates
H
H
CO2Et
N2
EtO2C
CO2Et
Rh2(OAc)4
CH2Cl2, 25˚C
H
16% yield
64% yield
Cyclopropanation out competes C-H insertion.
H
N2
OEt
EtO2C
Rh(II) catalyst
CH2Cl2
OEt
EtO2C
OEt
CO2Et
Only products obtained are from cyclopropanation and ylide rearrangement.
Doyle, M. P.; Hu, W. J. Org. Chem. 2000, 65, 8839.
Muller, P.; Tohill, S. Tetrahedron 2000, 56, 1725.
Davies, H. M. L.; Hansen, T. J. Am. Chem. Soc. 1997, 119, 9075.
Acceptor-Substituted Carbenoids
Intermolecular C-H activation
! C-H Activation of Functionalized Organic Substrates
OTIPS
H
N2
CO2Et
TIPSO
OTIPS
EtO2C
Rh2(II) catalyst
catalyst
Rh2(OOct)4
Rh2(S-DOSP)4
CO2Et
yield, A+B
ratio, A:B
66
54
96:4
76:24
R
H
N2
R
EtO2C
O
Cu(I) catalyst
O
98% yield
N
R
N
B
N
CO2Et
R
N
R
H
Cu
R
N
R
N
R
R
R= 2,4,6-Me3C6H2
Diaz-Requejo, M. M.; Belderrain, T. R.; Nicasio, M. C.;
Trofimenko, S.; Perez, P. J. J. Am. Chem. Soc. 2002, 124, 896.
Davies, H. M. L.; Ren, P. J. Am. Chem. Soc. 2001, 123, 2070.
Acceptor/Acceptor-Substituted Carbenoids
Intermolecular C-H activation
! C-H Activation of Functionalized Organic Substrates
MeO2C
MeO2C
CO2Me
N2
MeO2C
CO2Me
Rh(II) catalyst
CH2Cl2, 25˚C
CO2Me
catalyst
A
B
yield, A+B
ratio, A:B
ee B, %
96
86
30
38:62
24:76
49:51
24
7
Rh2(OAc)4
Rh2(S-PTPA)4
Rh2(R-BPN)4
MeO2C
MeO2C
CO2Me
N2
MeO2C
CO2Me
Rh(OAc)4
CH2Cl2, 25˚C
CO2Me
42%
21%
Müller, P.; Tohill, S. Tetrahedron 2000, 56, 1725.
Donor/Acceptor-Substituted Carbenoids
Intermolecular C-H activation
! C-H Activation of cycloalkanes
Ar
CO2Me
N2
MeO2C
n
n
1
1
2
2
2
2
2
2
Ar
Rh(S-DOSP)4
10˚C
Ar
yeild, %
C6H5
p-ClC6H4
C6H5
p-BrC6H4
p-ClC6H4
p-MeOC6H4
p-C3C6H4
o-ClC6H4
aConfigurational
n
72
70
80
64
76
23
78
81
ee, %a
96(R)
95(R)
95(R)
95(R)
94(R)
88(R)
94(R)
90(R)
assignment in parentheses.
Davies, H. M. L.; Hansen, T. J. Am. Chem. Soc. 1997, 119, 9075.
Donor/Acceptor-Substituted Carbenoids
Intermolecular C-H activation
! C-H Activation of cycloalkanes
Ar
CO2R
N2
MeO2C
Ph
Rh(S-DOSP)4
10˚C
R
CH3
CH(CH3)2
C(CH3)3
yeild, %
80
39
45
ee, %
92
86
20
We can see the delicate balance between steric and electronic effects in these systems
Davies, H. M. L.; Hansen, T.; Churchill, M. R. J. Am. Chem. Soc. 2000, 122, 3063.
Donor/Acceptor-Substituted Carbenoids
Intermolecular C-H activation
! C-H Activation of alkanes
Relative reactivity of alkyl C-H bonds 3˚ ! 2˚ >> 1˚
Ph
N2
Ph
Ph
MeO2C
Rh(II) catalyst
MeO2C
MeO2C
31% yield
86% ee
44% yield
26% ee
Ph
Ph
Ph
MeO2C
MeO2C
CO2Me
27% yield
66% ee
67% yield
90% ee
60% yield
68% ee
Davies, H. M. L.; Hansen, T.; Churchill, M. R. J. Am. Chem. Soc. 2000, 122, 3063.
Donor/Acceptor-Substituted Carbenoids
Intermolecular C-H activation
! Allylic C-H Activation
N2
R2
p-BrPh
Rh2(S-DOSP)4
2,2-DMB, 23˚C
R1
R1
C2H5
CH3
C6H5
R2
H
CH3
C6H5
R2
CO2Me
yeild, %
56
67
33
R2
CO2Me
R1
CO2Me
R1
Php-Br
de, %
ee A, % ee B, %
92
86
96
12
50
70
Php-Br
80
66
30
No cyclopropanation products were observed
!,"-Unsaturated esters with two stereocenters are analagous
to typical products from Claisen rearrangements
OMe
Johnson-Claisen
O
OMe
R1
O
R2
R1
R2
O
OMe
R2
R1
Davies, H. M. L.; Ren, P.; Jin, Q. Org.Lett. 2001, 3, 3587
Donor/Acceptor-Substituted Carbenoids
Intermolecular C-H activation
! Allylic C-H Activation
N2
R
p-BrPh
R
R
CO2Me
H
Rh2(S-DOSP)4
2,2-DMB, 23˚C
H
CO2Me
A
CO2Me
Php-Br
B
Php-Br
Reactions are highly regioselective.
R1
CH3
C2H5a
CH(CH3)2
C(CH3)3
C6H5
Cl
TMS
TBDPS
a
yeild, %
53
46
65
46
65
58
48
64
ratio, A:B
17:83
25:75
36:64
62:38
23:77
65:35
70:30
94:6
ee A, % ee B, %
94
90
90
91
90
96
88
95
98
94
93
81
95
91
–
–
Also isolated 2% yield from insertion into pendant ethyl group.
Davies, H. M. L.; Ren, P.; Jin, Q. Org.Lett. 2001, 3, 3587
Donor/Acceptor-Substituted Carbenoids
Intermolecular C-H activation
! Allylic C-H Activation of Cyclic and Acyclic Silyl Enol Ethers
N2
OTIPS
R2
p-R1Ph
OTIPS
R2
CO2Me
Rh2(S-DOSP)4
0 to -30˚C
R1 = H, Br
R2 = H, CH3
OTIPS
R2
CO2Me
H
CO2Me
H
Php-R1
Php-R1
Yields from86–90% and up to 96%ee
N2
OSiR3
Ph
p-BrPh
OSiR3 Me
CO2Me
Rh2(S-DOSP)4
2,2-DMB, -30˚C
CO2Me
Ph
Ph
SiR3=TIPS, TBDPS
65% yield
>90% de
up to 84%ee
Products are comparable to those obtained from asymmetric Michael additions
But can these reactions be applied to the
synthesis of useful targets?
Davies, H. M. L.; Ren, P. J. Am. Chem. Soc. 2001, 123, 2070.
Donor/Acceptor-Substituted Carbenoids
Intermolecular C-H activation
! Application Toward Pharmaceutically Relevant Targets
N2
Cl
CO2Me
Cl
Cl
Rh2(S-DOSP)4
-20˚C
CO2Me
Cl
NHCH3•HCl
Cl
Cl
(+)-indatraline
83% yield, 93% ee
N2
O
S
Cl
O
Rh2(R-DOSP)4
hexane, 23˚C
O
S
O
55% yield, 88% ee
O
Cl
S
N
O
(+)-cetiedil
Davies, H. M. L.; Gregg, T. M. Tetrahedron Lett. 2002, 43, 4951.
Davies, H. M. L.; Walji, A. M. Townsend, R. J. Tetrahedron Lett. 2002, 43, 4981.
Donor/Acceptor-Substituted Carbenoids
Intermolecular C-H activation
! Benzylic C-H Activation
N2
p-BrPh
Me
CO2Me
CO2Me
Rh2(S-DOSP)4
2,2-DMB, 50˚C
CO2Me
Php-Br
Me
MeO2C
H
H
p-BrPh
Php-Br
H
A
H
CO2Me
Php-Br
H
B
CO2Me
Php-Br
C
50% combined yield
A:(B+C) = 28:72
Complex mixtures of products can be avoid using substituted
rings or by C-H activation of secondary benzylic sites.
N2
p-BrPh
R
CO2Me
Rh2(S-DOSP)4
2,2-DMB, 50˚C
R=H, alkyl, alkoxy, halogen,
Acetoxy, Acetate
Me
Me
CO2Me
CO2Me
R
Php-Br
50-86% yield
up to 5.25:1 d.r.
up to 89% ee
R
Php-Br
No cyclopropanation products
Davies, H. M. L.; Jin, Q.; Ren, P.; Kovalevsky, A. Y. J. Org. Chem. 2002, 67, 4165.
Donor/Acceptor-Substituted Carbenoids
Intermolecular C-H activation
! Benzylic C-H Activation
N2
Ph
MeO
CO2Me
Rh2(S-DOSP)4
50˚C
CO2Me
Ph
MeO
74% ee
CO2Me
CO2Me
Ph
MeO
94% ee
Ph
OMe
78% combined yield
19:79:2
An electron donating group helps stabilize the
positive charge that builds-up in the transition state
at the site of carbene insertion
Davies, H. M. L.; Jin, Q.; Ren, P.; Kovalevsky, A. Y. J. Org. Chem. 2002, 67, 4165.
Donor/Acceptor-Substituted Carbenoids
Intermolecular C-H activation
! C-H Activation ! to Nitrogen
N2
1) Ar
N
Boc
H
CO2Me
Rh2(S-DOSP)4
-50˚C
N
H
Route to "-amino acids.
Products comparable to Mannich reaction
products.
Ar
CO2Me
2) TFA
yeild, %
Ar
C6H5
p-ClC6H4
p-MeC6H4
2-naphthyl
3-thiophenyla
a
1) Ph
Boc
ee, %
92
94
93
93
91
94
94
93
93
67
Reaction conducted at 23˚C
N2
N
72
70
67
49
64
de, %
(6 equiv.)
CO2Me
Rh2(S-DOSP)4
-50˚C to 58˚C
Ph
MeO2C
H
H
N
H
Ph
CO2Me
2) TFA
Davies, H. M. L.; Walji, A. M. Townsend, R. J. Tetrahedron Lett. 2002, 43, 4981.
Davies, H. M. L.; Hansen, T.; Hopper, D. W.; Panaro, S. A. J. Am. Chem. Soc. 1999, 121, 6509.
Donor/Acceptor-Substituted Carbenoids
Intermolecular C-H activation
! C-H Activation ! to Oxygen
N2
Ar
CO2Me
H Ar
Rh2(S-DOSP)4
hexane, -50˚C
O
yeild, %
Ar
p-ClC6H4
p-MeC6H4
p-MeOC6H4
74
60
56
O
CO2Me
de, %
41
60
55
ee, %
98
97
96
! C-H Activation ! to Oxygen
N2
Php-Cl
TBSO
R
p-ClPh
CO2Me
Rh2(R-DOSP)4
hexane, 23˚C
R= H, alkyl, vinyl, aryl
R
MeO2C
Aldol-like syn-"-hydroxy esters
OTBS
35–70% yield
up to 98% de, 90%ee
Davies, H. M. L.; Hansen, T.; Churchill, M. R. J. Am. Chem. Soc. 2000, 122, 3063.
Davies, H. M. L.; Hansen, T. J. Am. Chem. Soc. 1997, 119, 9075.
Donor/Acceptor-Substituted Carbenoids
Intermolecular C-H activation
! Carbenoids Derived from Vinyldiazoacetates
Ph
N2
Ph
CO2Me
CO2Me
CO2Me
Rh2(S-DOSP)4
hexane, 23˚C
H
Ph
63% yield, 98% ee
12% yield
This reaction gave an unexpected major product in addition to a product arising from a well known
cyclopropanation/Cope pathway. Athough it appears to come from C-H insertion followed by a Cope
rearrangement, this is not the case.
Ph
Ph
CO2Me
Rh(II) catalyst
hexane, reflux
CO2Me
The 1,3 diene undergoes a retro-Cope to the
thermodynamic product.
Proposed mechanisms include a one-step C-H activation/Cope or the vinylcarbenoid
may react as a 2!-system analgous to an ene reaction.
Davies, H. M. L.; Stafford, D. G.; Hansen, T. Org. Lett. 1999, 1, 233.
Donor/Acceptor-Substituted Carbenoids
Intermolecular C-H activation
! The C-H Insertion/Cope Tolerates Various Substituents on the Vinyldiazoacetate
R1
N2
R1
CO2Me
CO2Me
Rh2(S-DOSP)4
hexane, 23˚C
R
yeild, %
C6H5
p -MeOC6H4
3,4-Cl2C6H3
2-naphthyl
o -MeOC6H4
1-naphthyl
(E)-CH=CHC6H5
–(CH2)4–
63
58
59
50
17
22
60
73
ee, %
96
99
99
99
86
84
99
97
Davies, H. M. L.; Stafford, D. G.; Hansen, T. Org. Lett. 1999, 1, 233.
Donor/Acceptor-Substituted Carbenoids
Intermolecular C-H activation
! C-H Insertion/Cope Utilized in the Synthesis of (+)-Imperaene and (–)-Conidendrin
OH
N2
CO2Me
CO2Me
MeO
MeO
TBSO
1) LAH
TBSO
OMe
MeO
Me
HO
2) TBAF
Rh2(R-DOSP)4
2,2DMB, 23˚C
OMe
OTBS
OMe
OTBS
OH
43% yield, 91% ee
(+)-imperanene
O
N2
CO2Me
MeO
MeO
CO2Me
MeO
Me
O
HO
TBSO
TBSO
OMe
OTBS
Rh2(S-DOSP)4
2,2DMB, 23˚C
OMe
OMe
OTBS
44% yield, 92% ee
OH
(–)-conidendrin
Davies, H. M. L.; Jin, Q. Tetrahedron: Asymmetry 2003, 14, 941.
Donor/Acceptor-Substituted Carbenoids
Intermolecular C-H activation
! Synthons Accesible Through Asymmetric C-H Activation
R2
O–
O
O
R1
R2
X
Claisen
rearrangement
R
X
R1
R
Michael
R2
R1
O
O
O
OTBS
R2
R1
R1
R2
X
R1
X
R2
R
R
N2
X
R
O
NHR O
R1
OH
NR2
X
R1
OTBS
R1
R1
X
R
R
Aldol
Mannich
NR
R1
O
O
O–
H
X
R
R1
O–
H
Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861.
X
R
Donor/Acceptor-Substituted Carbenoids
Intermolecular C-H activation
! Relative Reactivity
BOC
N
0.66
1
0.078
0.011
1700
O
Ph2tBuSi
Ph
2700
24,000
H
24,000
28,000
O
Reactions with
Ph
MeO
and Rh2(S-DOSP)4.
N2
Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861.
Catalytic Asymmetric C-H Activation
Mechanistic Considerations
! The Mechanism is not Well Understood and a Source of Dispute
Taber: four-centered
H
E
H
E
Rh
Me
H
E
Rh
H
Me
H
E
Rh
H
H
Me
E
Rh
Me
H
Me
Doyle: three-centered concerted
BA
B
A
H
H
D
H
E
A
Rh2L4
D
H
E
B
H
D
Rh2L4
H E
Taber, D. F.; You, K. K.; Rheingold, A. L. J. Am. Chem. Soc. 1996, 118, 547.
Doyle, M.P.; Westrum, L.J.; Wolthuis, W.N.E.; See, M.M.; Boone, W.P.;
Bagheri, V.; Pearson, M.M. J. Am. Chem. Soc. 1993, 115, 958.
Catalytic Asymmetric C-H Activation
Mechanistic Considerations
! The Mechanism is not Well Understood and a Source of Dispute
Davies: three-centered concerted yet nonsynchronous process
B
A
B
D
MeO2C
H
Ar
A
D
MeO2C
Rh2L4
B
D
H
Ar
MeO2C
A
Ar
H
Rh2L4
Pirrung: stepwise approach
O
O
O
R
R
Rh
Rh
Rh
H
Rh
H
C
Rh
Rh
H
R
C
C
! complex
Davies, H.M.L.; Hansen, T.; Churchill, M.R. J. Am. Chem. Soc. 2000, 122, 3063.
Pirrung, M.C.; Morehead Jr, A.T.; J. Am. Chem. Soc. 1994, 116, 8991.
Catalytic Asymmetric C-H Activation
Mechanistic Considerations
! Stereochemical Rationale for the Catalysts that Give the Highest ee's.
These simplified models of the catalyst systems help rationalize stereoselectivity.
H
CO2Me
CO2Me
H
ester groups
N
N
O
O
O
Rh
O
Rh
N
N
Rh2(5R-MEPY)4
phthalimide groups
Rh
Hashimoto's catalysts
Rh
Doyle's catalysts
arylsulfonyl
groups
Rh
Davies/McKervey's
prolinate catalysts
Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861.
Catalytic Asymmetric C-H Activation
Mechanistic Considerations
! Stereochemical Rationale
!-Lactam formation with Hashimoto's catalyst.
O
O
O
N
MeO2C
Rh
tBu
H
O
MeO2C
tBu
N
R
R
approach
from front
Rh
Rh2(S-PTPA)4
O
Me
O
Hb
Rh
O
O
N
R
Ha
Me
O
Hb
Rh
O
N
R
Ha
O
MeO2C
N
Ha
Hb
R
Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861.
Catalytic Asymmetric C-H Activation
Mechanistic Considerations
! Stereochemical Rationale
Cyclopentanone formation with Hashimoto's catalyst.
O
O
O
O
OCHiPr2
OCHiPr2
Rh
R
R
R
approach
from front
H
O
Rh2(S-PTPA)4
H
O
O
H
OCHiPr2
O
Rh
R
H
Rh
CO2CHiPr2
OCHiPr2
O
Rh
R
(3R)
Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861.
Catalytic Asymmetric C-H Activation
Mechanistic Considerations
! Stereochemical Rationale
Asymmetric induction with Doyle's catalyst.
O
H
O
O
O
N2
R
R
approach
from front
Rh
Rh2(5R-MEPY)4
R
H
H
R
H
O
H
O
Rh
O
O
HH
O
Rh
O
R
(4R)
Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861.
Catalytic Asymmetric C-H Activation
Mechanistic Considerations
! Stereochemical Rationale
Asymmetric induction with dirhodium tetraprolinates.
MeO2C
Ar
N2
S
M
S L
M H
approach
from front
MeO2C
Rh
Ar
Rh
H Ar
L
L
CO2Me
H
SM
L
S !+
H
M
MeO2C
Ar
!"
Rh
S
M
MeO2C
L
Ar
H
Rh2(S-DOSP)4
Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861.