Decarboxylative Cross-Coupling Chemistry
Nathan Jui
MacMillan Group Meeting
February 12, 2008
Boudoin, O. Angew., 2007, 46, 1373-1375.
OH
O
Br
N
HO2C
HO
HO
O
HN
F
N Cl
HO
S
HO2C
N
N
N
ON
NCF3
S
O
O
H2N
CelebrexAmbien
Singulair
Lipitor
Decarboxyative Cross-Coupling Chemistry
! By definition, decarboxylative cross-coupling extrudes CO2 and forms C-C (or C-R) bond.
! Tsuji-Trost type decarboxylative coupling / decarboxylative allylic alkylation.
R O
O
R'
MT catalyst
R'
PdO
R
O-CO2
oxid. add. red. elim.R'R
O
O
R'
MT catalyst
R'
PdOO
-CO2
oxid. add. nuc. add.R'
R
O
R
O R
O
Decarboxylative Tsuji-Trost Type Chemistry
! Initial report of reactivity Tsuji 1980 (palladium-catalyzed Carroll rearangement).
! Tunge.
Me O
Me O
Me
O Pd(OAc)2 / PPh3
THF, reflux, 1 h Me
Me
Me
O
! Stoltz.
100%
O O
O
Me Pd2(dba)3
(S)-t-Bu-PHOX
O
Ph
O
O
Ph
Pd(PPh3)4 Ph
Ph
77%
97%
92% ee
Stoltz JACS., 2004, 126, 15044-15045.
Tunge JACS., 2005, 127, 13510-13511.
Tsuji Tett. Lett., 1980, 21, 3199-3202.
Decarboxyative Cross-Coupling Chemistry
! Cross-coupling chemistry typically requires a stoiciometric organometallic reagent.
! Acids can function in place of organometallic reagents in cross-coupling chemistry.
R M X R'MT catalyst
R R'+ + M X
MT catalyst
-CO2
R CO2H X R' R R'+ + H X
MT catalyst
-CO2
R CO2HR'
R'
+ + H X
R
! Acids can also replace aryl halides in Heck chemistry.
The First Example of a Decarboxylative Cross-Coupling Reaction
! In 1958, Nilsson reported his findings regarding an Ullmann coupling.
I
Cl I
I
OMe
OMe
Cl
Cl
Cl
Cl
ClOMe
MeO
Quinoline, 220 ˚C
copper-bronze
"...The reactive intermediate in the Ullmann reaction is likely to be an arylcopper."
Nilsson, M. Acta Chem. Scand., 1958, 12, 537-546.
The First Example of a Decarboxylative Cross-Coupling Reaction
! In 1966, Nilsson reported the first decarboxylative Ullmann reaction.
OH
O
NO2
I
OMe
NO2
MeO
50 % Yield
0.8 Eq Cu(I) oxide
Quinoline, 240 ˚C
! In 1958, Nilsson reported his findings regarding an Ullmann coupling.
I
Cl I
I
OMe
OMe
Cl
Cl
Cl
Cl
ClOMe
MeO
Quinoline, 220 ˚C
copper-bronze
"...The reactive intermediate in the Ullmann reaction is likely to be an arylcopper."
Nilsson, M. Acta Chem. Scand., 1958, 12, 537-546.
Nilsson, M. Acta Chem. Scand., 1966, 20, 423-426.
! This finding remained unelaborated for 35 years.
Andy Myers' Decarboxylative Heck-Type Reaction
! Typical Heck reactions couple aryl- or vinyl-halides with olefins.
I Pd(0), ligandR
R
base
Andy Myers' Decarboxylative Heck-Type Reaction
! In 2002, the Myers group reported a Heck reaction using benzoic acids as halide surrogates.
! Typical Heck reactions couple aryl- or vinyl-halides with olefins.
I Pd(0), ligand
Myers, A. G. et al. JACS, 2002, 124, 11250-11251.
R
R
base
Ar OH
O PdX2
HX, CO2
ArPdX
R
XPdH
ArR
Myers Decarboxylative Heck-Type Reaction
! The palladium system developed my the Myers group.
Myers, A. G. et al. JACS, 2002, 124, 11250-11251.
OMe
MeO
MeO
Ar OH
O
R
0.2 Eq Pd(OTFA)2
3.0 Eq Ag2CO3
5% DMSO / DMF
120 ˚C, <3 h1.0 Eq 1.5 Eq
ArR
91% Yield
F
F
F
OnBu
O
F
F
66% Yield
O
Me
90% Yield
18 examples
! Electron-rich, -poor, and heteroaromatic acids are tolerated.
Me
Me Me
O
61% Yield
Myers: Proposed Mechanism of Decarboxylative Heck
Myers, A. G. et al. JACS, 2005, 127, 10323-10333.
PdX2
PdX
Ar
Pd
R
Pd Ar
X
ArCO2H
CO2 + HXAg2CO3
2 Ag(0) + HCO3
RRAr
HX
Myers: Mechanistic Studies
Myers, A. G. et al. JACS, 2005, 127, 10323-10333.
PdX2
PdX
Ar
Pd
R
Pd Ar
X
ArCO2H
CO2 + HXAg2CO3
2 Ag(0) + HCO3
RRAr
HX
CO2Na
OMe
MeO
MeO
1.0 Eq Pd(OTFA)2
5% DMSO / DMF
80 ˚C, 15 min.
O
Me
O
Me
O
Me
PdOF3C
O
S
S
O
CD3D3C
O CD3
CD3
Confirmed by crystal structure
Myers: Mechanistic Studies
Myers, A. G. et al. JACS, 2005, 127, 10323-10333.
PdX2
PdX
Ar
Pd
R
Pd Ar
X
ArCO2H
CO2 + HXAg2CO3
2 Ag(0) + HCO3
RRAr
HX
O
Me
O
Me
O
Me
PdOF3C
O
S
S
O
CD3D3C
O CD3
CD3
DMSO-d6, 0 ˚C
O
OtBu Ar
Pd
tBuO2C
OTFA
Characterized by NMR
Myers: Mechanistic Studies
Myers, A. G. et al. JACS, 2005, 127, 10323-10333.
PdX2
PdX
Ar
Pd
R
Pd Ar
X
ArCO2H
CO2 + HXAg2CO3
2 Ag(0) + HCO3
RRAr
HX
O
Me
O
Me
O
Me
PdOF3C
O
S
S
O
CD3D3C
O CD3
CD3
DMSO-d6, 23 ˚C
O
OtBu ArtBuO2C
90% NMR Yield
Myers: Heck-Type Arylation of Cyclic Enones
Myers, A. G. et al. Org. Lett., 2004, 6, 433-436.
Ar OH
O
Ar
0.2 Eq Pd(OTFA)2
2.0 Eq Ag2CO3
5% DMSO / DMF
80 ˚C, <3 h
! Scope of the aromatic acid
O O
! In 2004, the Myers group published a Heck paper using cyclic enone substrates.
OH
O
OMeMeO
OH
O
OMe
MeO
OH
O
Me
Me
Me
OH
O
F
F
OH
O
OMe
MeO
OH
O
NO2
MeO
MeO N
OH
O
OMeMeO
O
Me
O
OH
92% 89% 61% 52%
58% 49% 63% 66%
Br
Myers: Heck-Type Arylation of Cyclic Enones
Myers, A. G. et al. Org. Lett., 2004, 6, 433-436.
OH
O
Ar
0.2 Eq Pd(OTFA)2
2.0 Eq Ag2CO3
5% DMSO / DMF
80 ˚C, <3 h
! Scope of the cyclic !,"-unsaturated ketone.
O O
! In 2004, the Myers group published a Heck paper using cyclic enone substrates.
OMeMeOn n
O O O
O
MeMe
O
Me Me
81% 92% 65% 30% 86%
Myers: Heck-Type Arylation of Cyclic Enones
Myers, A. G. et al. Org. Lett., 2004, 6, 433-436.
OH
O
Ar
0.2 Eq Pd(OTFA)2
2.0 Eq Ag2CO3
5% DMSO / DMF
80 ˚C, <3 h
! Scope of the cyclic !,"-unsaturated ketone.
O O
! In 2004, the Myers group published a Heck paper using cyclic enone substrates.
OMeMeOn n
O O O
O
MeMe
O
Me Me
81% 92% 65% 30% 86%
Myers: Heck-Type Arylation of Cyclic Enones
Myers, A. G. et al. Org. Lett., 2004, 6, 433-436.
OH
O
Ar
0.2 Eq Pd(OTFA)2
2.0 Eq Ag2CO3
5% DMSO / DMF
80 ˚C, 0.5 h
O O
! Advantage of decarboxylative Heck: electron rich arene substrates.
OMeMeO
O
92 %
I
OMeMeO
conditions
Ar
O
! Same reaction using traditional conditions is challenging.
Pd(OAc)2 (0.1)
NaOAc (2.0), Bu4NCl (1.0)
DMF, 80 ˚C, 22 h
29%
Pd(OAc)2 (0.1)
NaHCO3 (3.0), Bu4NCl (1.0)
DMF, 80 ˚C, 17 h
55%
Pd(OAc)2 (0.2)
NaHCO3 (3.0), Bu4NCl (1.0)
DMF, 80 ˚C, 16 h
59%
Myers: Heck-Type Arylation of Cyclic Enones
Myers, A. G. et al. Org. Lett., 2004, 6, 433-436.
OH
O0.2 Eq Pd(OTFA)2
2.0 Eq Ag2CO3
5% DMSO / DMF
80 ˚C, 0.5 h
O
O
! Disadvantage of decarboxylative Heck: ortho-substitution is needed.
Me
OI
Me
! 'Traditional' Heck conditions form product in quantitative yield.
0.2 Eq Pd(OAc)2
3.0 Eq NaHCO3
1.0 Eq Bu4NCl
DMF, 80 ˚C, 21 h
O
0%
100%
Biaryl Synthesis via Decarboxylative Coupling
Baudoin, O. Angew., 2007, 46, 1373-1375.
! Traditional biaryl couplings use stoichiometric organometallic reagents.
Ar1 M
M = SnR3, BR3, ZnX...
X Ar2
X = halide, OTf...
MT cat.
Ar1 Ar2 M X
Biaryl Synthesis via Decarboxylative Coupling
Baudoin, O. Angew., 2007, 46, 1373-1375.
! Traditional biaryl couplings use stoichiometric organometallic reagents.
! Decarboxylative biaryl coupling reactions utilize aromatic acid as organometallic surrogate.
Ar1 M
M = SnR3, BR3, ZnX...
X Ar2
X = halide, OTf...
MT cat.
Ar1 Ar2 M X
Ar1 COOH X Ar2
X = halide, OTf...
MT cat.
Ar1 Ar2 H X
-CO2
Biaryl Synthesis via Decarboxylative Coupling: Gooßen
Gooßen, L. J. et al. Science., 2006, 313, 662-664.
! In 2006, Gooßen reported a bimetallic system for decarboxylative biaryl synthesis.
R R'R
R'OH
O
BrK2CO3, MS-3Å
NMP, 24 h
Pd(acac)2
CuI / phen
Biaryl Synthesis via Decarboxylative Coupling: Gooßen
Gooßen, L. J. et al. Science., 2006, 313, 662-664.
! In 2006, Gooßen reported a bimetallic system for decarboxylative biaryl synthesis.
R R'R
R'OH
O
BrK2CO3, MS-3Å
NMP, 24 h
Pd(acac)2
CuI / phen
R
R'
[Cu]+X!
[Cu]
O
O
O
O
R
R
R
L2Pd
R
R'
L2Pd(0)
X
L2Pd
R'
X
R'
CO2
! Proposed mechanism.
[Cu]
Biaryl Synthesis via Decarboxylative Coupling: Gooßen
Gooßen, L. J. et al. JACS., 2007, 129, 4824-4833.
! System catalytic in palladium and copper.
R R
OH
O
BrK2CO3, MS-3Å
NMP, 160 ˚C, 24 h
1 mol% Pd(acac)2
3% CuI / 5% phen
! Scope of the aromatic acid.
Cl
CO2H
NO2
CO2H CO2H CO2H
F
Cl
CO2H
OMe
Me
74%
Me
NO2
51% 77% 76% 46%
CO2H CO2H CO2H CO2H CO2H
CF3
OEt2NOiPrO
61% 69% 51% 45% 30%
OH
NO2
MeO
OMe
Biaryl Synthesis via Decarboxylative Coupling: Gooßen
Gooßen, L. J. et al. JACS., 2007, 129, 4824-4833.
! System catalytic in palladium and copper.
R R
OH
O
BrK2CO3, MS-3Å
NMP, 160 ˚C, 24 h
1 mol% Pd(acac)2
3% CuI / 5% phen
! Scope of the aromatic acid.
Cl
CO2H CO2H
CO2H
NHAC
Cl
57% 79% 42%
0%
CO2H CO2H CO2H
34% 0% 0%
CO2H
SO2Me
CN NHPh
MeO
62%
S
CO2H
Biaryl Synthesis via Decarboxylative Coupling: Gooßen
Gooßen, L. J. et al. JACS., 2007, 129, 4824-4833.
! System stoichiometric in copper.
R R
OH
O
BrK2CO3, MS-3Å
NMP, 160 ˚C, 24 h
2 mol% Pd(acac)2
1.2 Eq CuI / bipy
! Scope of the aromatic acid.
Cl
CO2H CO2H
CO2H
NHAC
Cl
57% 79% 97% (42)
42% (0)
CO2H CO2H CO2H
55% (34) 91% (0) 41% (0)
CO2H
SO2Me
CN NHPh
MeO
62%
S
CO2H
Biaryl Synthesis via Decarboxylative Coupling: Gooßen
Gooßen, L. J. et al. JACS., 2007, 129, 4824-4833.
! System catalytic in palladium and copper.
OH
O
BrK2CO3, MS-3Å
NMP, 160 ˚C, 24 h
1 mol% Pd(acac)2
3% CuI / 5% phen
! Summary of the aryl bromide scope.
ClNO2
NO2
R
R
24 examples
NO2
NO2NO2 NO2
OMe
N
NO2
77% 91% 68% 53%
Biaryl Synthesis via Decarboxylative Coupling: Forgione & Bilodeau
Forgione, P.; Bilodeau, F. et al. JACS., 2006, 128, 11350-11351.
! Boehringer Ingelheim group was trying to do C-H activation of oxazoles.
N
O
N
O
N
OPh Ph
+
Br
Pd(0)
Me Me Me
Biaryl Synthesis via Decarboxylative Coupling: Forgione & Bilodeau
Forgione, P.; Bilodeau, F. et al. JACS., 2006, 128, 11350-11351.
! Boehringer Ingelheim group was trying to do C-H activation of oxazoles.
! They postulated that regioselectivity would be dictated by the presence of a blocking group.
N
O
N
O
N
OPh Ph
+
Br
Pd(0)
N
O
O
OHN
OPh
OH
O
Pd(0)
Me Me Me
Me Me
Biaryl Synthesis via Decarboxylative Coupling: Forgione & Bilodeau
Forgione, P.; Bilodeau, F. et al. JACS., 2006, 128, 11350-11351.
! Boehringer Ingelheim group was trying to do C-H activation of oxazoles.
! They postulated that regioselectivity would be dictated by the presence of a blocking group.
N
O
N
O
N
OPh Ph
+
Br
Pd(0)
N
O
O
OHN
OPh
OH
O
N
OPhPd(0)Pd(0)
Me Me Me
MeMe Me
Forgione & Bilodeau: Heteroaromatic Decarboxylative Biaryl Synthesis
Forgione, P.; Bilodeau, F. et al. JACS., 2006, 128, 11350-11351.
! The optimized reaction conditions are useful for many heteroaromatic acids.
Y
X
Y
X Ph
BrR R
CO2H
5 mol% Pd[P(t-Bu)3]2
Bu4NCl ! H2O, CsCO3
DMF, µW, 170 ˚C
8 minutes2.0 Eq 1.0 Eq
N
O
Me
Ph
N
H
Ph
S
Me
Ph
74%
88%
63%
O
Me
Ph
O
R
Ph
N
S
R
Ph
86%
R = Me, 86%
R = H, 41%
R = Me, 74%
R = H, 23%
Forgione & Bilodeau: Heteroaromatic Decarboxylative Biaryl Synthesis
Forgione, P.; Bilodeau, F. et al. JACS., 2006, 128, 11350-11351.
! The optimized reaction conditions are useful for many heteroaromatic acids.
Y
X
Y
X Ph
BrR R
CO2H
5 mol% Pd[P(t-Bu)3]2
Bu4NCl ! H2O, CsCO3
DMF, µW, 170 ˚C
8 minutes2.0 Eq 1.0 Eq
N
O
Me
Ph
N
H
Ph
S
Me
Ph
74%
88%
63%
O
Me
Ph
O
R
Ph
N
S
R
Ph
86%
R = Me, 86%
R = H, 41%
R = Me, 74%
R = H, 23%
! Electron-rich, -poor, and heteroaromatic bromides also work (66-85% yield).
Proposed Mechanism of Heteroaromatic Acid Coupling
Forgione, P.; Bilodeau, F. et al. JACS., 2006, 128, 11350-11351.
! Biproduct of reaction using 2-furancarboxylic acid could shed light on the mechanism.
O
Br
CO2H
5 mol% Pd[P(t-Bu)3]2
Bu4NCl ! H2O, CsCO3
DMF, µW, 170 ˚C
8 minutes
+
O OPh Ph
Ph
41% main biproduct
Proposed Mechanism of Heteroaromatic Acid Coupling
Forgione, P.; Bilodeau, F. et al. JACS., 2006, 128, 11350-11351.
! Biproduct of reaction using 2-furancarboxylic acid could shed light on the mechanism.
O
Br
CO2H
5 mol% Pd[P(t-Bu)3]2
Bu4NCl ! H2O, CsCO3
DMF, µW, 170 ˚C
8 minutes
+
O OPh Ph
Ph
41% main biproduct
PdL2
ArPdLBrO PdLArO CO2H
OPh
R
R
CO2
ArBr
If R = H
O CO2H
OCO2H
Ar
PdArL
PdLAr
R
O CO2H
R
Synthesis of Lamellarin L
Steglich, W.; Peschko, C.; Winklhofer, C. Chem. Eur. J., 2000, 6, 1147-1151.
! In 2000, Steglich et al. used similar chemistry to forge the final bond in Lamellarin L.
NHO2C
O
iPrO
MeO
O
MeOOiPr
Br
OMe
OiPr
Pd(OAc)2, PPh3
CH3CN / NEt3 (3 : 1)
150 ˚C, 80 min.
N
O
iPrO
MeO
O
MeOOiPr
MeO
iPrO
97%
Biaryl Synthesis via Decarboxylative Coupling: Becht
Becht, J.-M. et al. Org.Lett., 2007, 9, 1781-1783.
! Optimized system uses 30 mol % palladium and arsine ligand.
RR
OH
O
3.0 Eq Ag2CO3
DMSO, 150 ˚C, 6 h
30 mol% Pd(Cl)2
60 mol% AsPh3
! Scope of the aromatic acid.
R'
R'I
CO2H
OMe
OMe
CO2H
OMe
OMeMeO
CO2H
OMe
OMe
CO2H
OiPr
OiPr
Br
90% 75% 65% 62%
CO2H
NO2
CO2H
NO2
CO2H CO2H
Cl
F
79% 63% 92% 82%
MeO
MeO
F
F
F
F
F
Summary of Decarboxylative Biaryl Syntheses
! Gooßen system is ideal for electron-poor benzoic acids.
OH
O
3.0 Eq Ag2CO3
DMSO, 150 ˚C, 6 h
30 mol% Pd(Cl)2
60 mol% AsPh3
I
O O
BrMe Me
CO2H
5 mol% Pd[P(t-Bu)3]2
Bu4NCl ! H2O, CsCO3
DMF, µW, 170 ˚C
8 minutes
OH
O
Br K2CO3, MS-3Å
NMP, 160 ˚C, 24 h
1 mol% Pd(acac)2
3% CuI / 5% phenNO2
OMe
OMeOMe
OMe
NO2
! Forgione / Bilodeau system for heteroaromatic acids.
91%
86%
84%
! Becht system is best for electron-rich benzoic acids.
Decarboxylative Non-Symmetrical Diaryl Alkyne Synthesis: Lee
Lee, S. et al. Org.Lett., ASAP.
! Standard syntheses of unsymmetrically substituted diaryl alkynes utilize protected acetylenes.
! Propiolic acid as TMS-acetylene substitute in a one-pot diaryl alkyne synthesis protocol.
M
M = SiR3, BR3...Sonogashira
ArX
Ar
M
cross-coupling
Ar'X
Ar
Ar'
cat. Pd
ArX
Ar
Ar'X
Ar
Ar'O
OHOH
O
-CO2
Decarboxylative Non-Symmetrical Diaryl Alkyne Synthesis: Lee
Lee, S. et al. Org.Lett., ASAP.
! Diaryl alkyne synthesis system developed by Lee group.
Ph IBr Ar'O
OH
Ph Ar'
90 ˚C, 12 h
5 mol% Pd2(dba)3
10 mol% dppf
6 Eq TBAF
NMP, rt, 12 h
+ H
Decarboxylative Non-Symmetrical Diaryl Alkyne Synthesis: Lee
Lee, S. et al. Org.Lett., ASAP.
! Diaryl alkyne synthesis system developed by Lee group.
Ph IBr Ar'O
OH
Ph Ar'
90 ˚C, 12 h
5 mol% Pd2(dba)3
10 mol% dppf
6 Eq TBAF
NMP, rt, 12 h
+ H
(o-,p-tol)
Decarboxylative Non-Symmetrical Diaryl Alkyne Synthesis: Lee
Lee, S. et al. Org.Lett., ASAP.
! Diaryl alkyne synthesis system developed by Lee group.
Ph IBr Ar'O
OH
Ph Ar'
90 ˚C, 12 h
5 mol% Pd2(dba)3
10 mol% dppf
6 Eq TBAF
NMP, rt, 12 h
+ H
! Aryl bromide scope.
Br
OMe
Br
Ph
Br
Me
Me
Me
48% 94% 91%
Br
70%
Br
N
Br
62% 70% 61%
Br
86%
Me NO2SBr
(o-,p-tol)
Summary of Decarboxylative Cross-Coupling Chemistry
! Acids can be used (in some cases) as organometallic reagent surrogates.
! Acids can also function as replacements for aryl (and potentially vinyl) halides.
M
OH
O
M
OH
O
R M R
OH
O
I
OH
O