Buchwald-Hartwig C-C Bond Formation

39 Pages·2010·1.73 MB·English

Buchwald-Hartwig C-C Bond Formation
Ar-X
L Pd(0)
n
O
R1
R2
Ar
Ar
L Pd
n
X
O
O R1 + base
R2
R1
R2
PdL base•HX
n
Ar
L
n
Pd
O Ar
R
1 R2
Group Meeting Presentation
Andrew Dilger
April 21st, 2010
3 2
Csp -Csp C-C Bond Formation
X Pd cat.
unactivated sp3 C-H R-H
aryl halide
H
Pd cat.
aryl C-H
R-M
alkyl metals
H Au or Pd R
aryl C-H R-X
alkyl halide
M i. Pd
unactivated sp3 C-H
R-H
aryl metals ii. Pr, Ru, or Cu
and O
2
H
dehydrogenation Cu, H-acceptor or
aryl C-H/sp3 C-H R-H
Pd cat., base, air
W
X Z
Z Pd, Ni, or Cu
aryl halide
R R
acidic sp3 C-H W
base
Z, W = electron withdrawing group
Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082.
Scope of This Presentation
Z
W
R
O O
R1 R1 !-arylated nitriles, amides
R2(H) OR2(H)
lactams, dicarbonyls
Ar Ar
ketone enolates ester enolates
silyl enol ethers silyl ketene acetals
aldehydes
enol esters
ketimines
Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082.
Buchwald-Hartwig C-C Bond Formation
Presentation Outline
! Introduction
! !-Arylated ketones
• Discovery and optimization studies
• Direct arylations of ketones and enones; including asymmetric variants
• Arylation of silyl enol ethers
! !-Arylated aldehydes, esters, and carboxylic acids
• Intra- and intermolecular arylation of aldehydes
! Conclusions
Relevant review articles:
Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082.
Burtoloso, A. C. B. Synlett 2009, 320.
Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234.
Lloyd-Jones, G. C. Angew. Chem. Int. Ed. 2002, 41, 953.
Synthetic Interest in !-Arylated Carbonyls
! Natural products and pharmaceuticals
O
O
R1 O
HO N
O
OMe
N O R
R2 O Ar Ph
OMe
O NH R = H = deoxychilenine
2
rocaglaols
R = OH = chilenine
Trileptal
OMe
CHO
OH
N H
Me Me
Me CO H
O O 2
H Me
Me
nominine Me
O
NH
HO
MeO CO2H
Me
Naproxen
polimastamide A
Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082.
Selected Methods for !-Arylation of Carbonyls
! Stoichiometric, pre-activated aryl and/or carbonyl substrates
O O
Ph
CO2Et Ph3BiCO3 CO2Et
73%
TsHN O
N THF-Et O, -60 °C
Cu 2
Ph
Br +
then; BF •OEt ,
3 2
wet acetone
75%
O
OTMS NO
2 F
CH Cl /DMSO
I 2 2
+
-40 °C NO
2
89%
Aryl bismuth:Abramovitch, R. A.; Barton, D. H. R.; Finet, J.-P. Tetrahedron, 1988, 44, 3039.
Aryl copper: Sacks, C. E.; Fuchs, P. L. J. Am. Chem. Soc. 1975, 97, 7372.
Diaryl iodonium: Iwama, T.; Birma, V. B.; Kozmin, S. A.; Rawal, V.H; Org. Lett. 1999, 1, 673.
Selected Methods for !-Arylation of Carbonyls
! Photoinduced electron transfer
1,4-dicyanonapthalene
CH CN:H O, h"
3 2 Pandey, G.; Krishna, A.; Girija, K.; Karthlkeyan, M.
Tetrahedron Lett, 1993, 34, 6631.
MeO OTBS MeO O
74%
! Acyl anion addition to o-quinone methide
Me I OTES Cl
OTBS OH
Me N-F
N 4
Br + Me Mattson, A. E.; Scheidt, K. A. J. Am. Chem. Soc.
2007, 129, 4508.
S CH Cl
2 2
Cl O
Me
72%
! Ni-catalyzed coupling of enolate with aryl halide
O
N
N 1. LiCPh , THF, -78 °C
O 3
O
H
2. Ni(COD) , rt
O 2
I
OMe 28% O
O
OMe
Semmelhack, M. F.; Chong, B. P.; Stauffer, R. D.; Rogerson, T. D.; Chong, A.;
Jones, L. D. J. Am. Chem. Soc. 1975, 97, 2507
Transition Metal-Catalyzed !-Arylation of Carbonyls
"The observation of phenylacetone as a side product of an aryl
halide amination in acetone solvent inspired the development of
a practical synthetic method for the !-arylation of a variety of
ketones and carboxylic acid derivatives."
Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234.
Simultaneous Reports of Practical Pd-Catalyzed !-Arylations
! Buchwald's initial conditions
Pd (dba) (1.5 mol%)
2 3
O ligand (3.6 mol%) O
Ar-Br + R R' R R' 63-93% yield
NaOt-Bu, THF, 70 °C
Ar
ligand = BINAP or Tol-BINAP
Me
Me Me O
Fe
O
O Me Me O
NC
O
76% 93% 75%
O
t-Bu
n-Bu Me
O O
Ph
O O
Ph N Me
83% 64% 84% (3% Pd)
Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108.
Simultaneous Reports of Practical Pd-Catalyzed !-Arylations
! Hartwig's initial conditions
Pd (dba) (7.5 mol%)
2 3
O DTPF (9.0 mol%) O
Ar-Br + R R R' 51-94% yield
R' NaOt-Bu or LiHMDS
THF, 70 °C Ar
O O O Me
N
Me Me
Me
55% (10% Pd) 94% 79%
MeO
O O P(Tol)
2
DTPF = Fe
CN P(Tol)
2
73% (NaOt-Bu) 69% (LiHMDS)
Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 12382.