Transition-Metal-Catalyzed Decarboxylative Coupling
November 13, 2007
Dino Alberico
Decarboxylative Coupling
Decarboxylative Biaryl Coupling
O
OH
X
R'
transition-metal catalyst
+
R
R'
R
X = I, Br
Decarboxylative Heck-Type Coupling
R'
O
OH
R
R'
+
transition-metal catalyst
R
Biaryl Compounds
Natural Products
OH OMe
HO
MeO
N
O
NHAc
MeO
HO
OMe
CO2Me
Me
N
H
NH
HO
HO
allocolchicine
cavicularin
O
OH Me
korupensamine A
rhazinilam
Agrochemicals
Pharmaceuticals
O
N
CO2H
OH
HO2C
Cl
OH
N
N
CO2H
F
N
N
NH
HN
O
O
N
N
N NH
Diovan (Valsartan, Novartis)
Micardis (Telmisartan, Boehringer)
Cl
Lipitor (Atorvastatin, Pfizer)
PAH
Liquid Crystals
N
Boscalid (BASF)
Ligands
C7H15
C8H17O
CN
NCB 807 (Merck)
OH
OH
N
Me2N
PPh2
PCy2
Biaryl Formation Using Transition Metals
X
R
+
transition metal
Y
R'
R
Transition Metal (either stoichiometric or catalytic):
Cu, Ni, Pd, Pt, Ru, Rh, Ir
X, Y:
I, Br, Cl, OTf, ONs, B, Sn, Si, Zn, Mg, H
Hassan, J.; Sévignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359.
R'
Ullmann Coupling
X
+
Cu (stoichiometric or excess)
X
R
R
R
R
Ullmann, F.; Bielecki, J. Chem. Ber. 1901, 34, 2174.
Example:
MeO
MeO
Cu-bronze, 200 oC
MOMO
CONHiPr
MeO
MOMO
PrHNOC
CONHPr
OMOM
I
NMe2
O
O
O
O
OMe
66%
OMe
Taspine
Kelly, T. R.; Xie, R. L. J. Org. Chem. 1998, 63, 8045.
Drawbacks:
- stoichiometric amount of copper
- high reaction temperatures
- limited to symmetrical biaryls
- unsymmetrical biaryl can be formed by using aryl halides of different reactivity
but require a large excess of the activated aryl halide
Transition-Metal-Catalyzed Cross-Coupling
Y
+
transition metal catalyst
X
R
organometallic
Y: B, Sn, Si, Zn, Mg
R'
R
R'
aryl halide
X: I, Br, Cl, OTf
Suzuki Coupling
OBn O
B
O
BocN
O
PdCl2(dppf)2, CH2Cl2,
K2CO3, DME, 80 oC, 2h
BocN
O
O
+
O
NHCbz
I
CO2Me
N
H
75%
BnO
N
H
NHCbz
CO2Me
Lin, S.; Danishefsky, S. J. Org. Lett. 2000, 2, 2575.
Stille Coupling
N
SnBu3
+
Pd(PPh3)4,
toluene, 110 oC
Br
N
N
N
72%
N
N
Sauer, J.; Heldmann, D. K.; Pabst, R. Eur. J. Org. Chem. 1999, 1, 313.
Transition-Metal-Catalyzed Cross-Coupling
Hiyama Coupling
O
Me
Si(Me)2F2
+
TfO
Pd(PPh3)4,
n-Bu4NF, THF,
50 oC, 5 h
O
Me
H
H
92%
Hatanaka, Y.; Hiyama, T. Synlett 1991, 845.
Negishi Coupling
MeO
Me
S
ZnCl + Br
MeO
PdCl2(dppf),
THF, rt, 1.5 h
N
97%
MeO
Me
S
N
MeO
Bumagin, N. A.; Sokolova, A. F.; Beletskaya, I. P. Russ. Chem. Bull. 1993, 42, 1926.
Kumada Coupling
Pd(PPh3)4,
THF, rt, 2 h
S
MgBr
+
I
CN
CN
73%
S
Amatore, C.; Jutand, A.; Negri, S.; Fauvarque, J.-F. J. Organomet. Chem. 1990, 390, 389.
Direct Arylation
Cross-Coupling
Y
+
transition metal catalyst
X
R
R'
organometallic
Y: B, Sn, Si, Zn, Mg
R
R'
R
R'
aryl halide
X: I, Br, Cl, OTf
Direct Arylation
H
R
+
transition metal catalyst
X
R'
X: I, Br, Cl, OTf
B, Sn, Si, Mg, Zn
Challenge:
- how to arylate a typically unreactive aryl C-H bond
- how to selectively arylate an aryl C-H bond
1. Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174. (Shameless Promotion)
2. Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173.
Direct Arylation
Intramolecular Direct Arylation
X
R2
transition metal catalyst
Y
R1
Y
R1
H
R2
Examples:
Me
o-Tol o-Tol
O
P O
Pd
Pd
O P
O
Oi-Pr
o-Tol
Me o-Tol
O
O
Br
Me
(10 mol%)
NaOAc, DMA, 140 °C
5'
N
OH OMe
Oi-Pr
O
O
HO
Me
74%
N
Bn
Me
NH
Bn
OH Me
Oi-Pr Me
Oi-Pr Me
P
korupensamine A
Bringmann, G.; Ochse, M.; Götz, R. J. Org. Chem. 2000, 65, 2069.
NO2
O2N
Cl
O
O
O
O
Pd catalyst
Cl
NO2
Julie Côté, Shawn K. Collins
O2N
Direct Arylation
Intermolecular Direct Arylation – Using a Directing Group
DG
DG
H
transition metal catalyst
X
+
R
Directin Group (DG):
OR
OH
O
H
N
NHR
OH
R'
R
R'
O
O
R
H
NHR
O
O
NR
RN
N
N
N
N
N
Examples:
O
Br
N
[RuCl2(6-C6H6)]2, (2.5 mol%),
PPh3, K2CO3, NMP, 120 °C
Ph
O
N
+
100%
Ph
(2.5 equiv)
Oi, S.; Aizawa, E.; Ogino, Y.; Inoue, Y. J. Org. Chem. 2005, 70, 3113.
N+
N-
+
Pd(OAc)2, P(tBu)3, K2CO3,
M.S., toluene, 125 °C
N+
N-
Br
O
Alexandre Larivée, James Mousseau, André Charette
80%
O
Direct Arylation
Intermolecular Direct Arylation – Electronic Bias of Heterocycles
transition metal catalyst
X
+
Y
Y
N
N
R
N
N
R
N
O
S
N
R
N
O
N
N
R
N
N
N
R
O
O
N
S
N
N
N
N
N
N
N
N
N
N
O
N
R
N
Examples:
Pd(OAc)2 (5 mol%),
PPh3, Cs2CO3,
DMF, 140 °C
N
I
+
N
N
N
83%
Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71, 467.
+
Pd(PPh3)4 (5 mol%),
KOAc, DMA, 150 °C
S
Br
NO2
66%
S
NO2
Ohta, A.; Akita, Y.; Ohkuwa, T.; Chiba, M.; Fukunaga, R.; Miyafuji, A.; Nakata, T.; Tani, N.; Aoyagi, Y.
Heterocycles, 1990, 31, 1951.
N
N
R
Cross-Coupling of Aromatic C-H Substrates
H
+
transition metal catalyst
H
R
H
N
CO2Me
CO2Me
10 mol%
NH
CuI (10 mol%), O2,
Cl(CH2)2Cl, 40 °C
R'
R
R'
MeO
OH
OH
+
N
Ac
Pd(TFA)2 (10 mol%),
Cu(OAc)2 (3 equiv),
CsOPiv (40 mol%),
MeO
pivalic acid, MW, 140 °C
N
Ac
OH
85%
84%
CO2Me
(30 equiv)
Li, X.; Hewgley, B.; Mulrooney, C.A.; Yang, J.; Kozlowski, M.C.
J. Org. Chem. 2003, 68, 5500.
O
+
Pd(OAc)2 (10 mol%),
H4PMo11VO40 (10 mol%),
AcOH/benzene (3:2),
O2 (3 atm), 120 °C
98%
Stuart, D. S.; Fagnou, K. Science 2007, 316, 1172.
Stuart, D. S.; Villemure, E.; Fagnou, K.
J. Am. Chem. Soc. 2007, 129, 12072.
N
+
Pd(OAc)2 (10 mol%),
benzoquinone (0.5 equiv),
Ag2CO3 ( 2equiv),
DMSO (4 equiv),
130 °C, 12 h
N
O
excess
Dwight, T. A.; Rue, N. R.; Charyk, D.; Josselyn, R.; DeBoef, B.
Org. Lett. 2007, 9, 3137.
89%
(100 equiv)
Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 11904.
Limitations to Aforementioned Transition-Metal Catalyzed Methods
protections,
lithiations,
Y
R
+
R
halogenations,
metallations, etc.
transition metal catalyst
X
+
organometallic
Y: B, Sn, Si, Zn, Mg
organometallic by-product
aryl halide
X: I, Br, Cl, OTf
-preparation of organometallic partner can require several synthetic steps
- more solvents, more purifications, more time, higher costs, more harmful to the enviroment
- a stoichiometric amount of undesired, and sometimes toxic, organometallic by-product is produced
H
+
transition metal catalyst
X
R
R
R'
R'
X: I, Br, Cl, OTf
- challenging to control regioselectivity
- for intermolecular direct arylation reactions of arenes, a directing group is needed;
which may take several steps to introduce and then remove if not desired in the final product
H
R
R'
R
R'
+
transition metal catalyst
H
R'
R
- challenging to control regioselectivity
- large excess of one arene is needed
- an excess of oxidant is needed (sometimes an organometallic reagent is used)
R'
Aryl-Aryl Bond Formation via Decarboxylative Coupling
CO2H
+
transition metal catalyst
X
R
R'
+ CO2
R
R'
X: I, Br, Cl, OTf
Advantages (for best case scenario):
- aryl carboxylic acids are ubiquitous in nature
- many are commercially available and inexpensive
- easier to control regioselectivity
- no extra steps are needed to introduce the acid moiety
- fewer purifications
- use of less solvent
- less time
- less energy wasted www.carbonfootprint.com
- lower costs
- more environmentally friendly
- more environmentally friendly CO2 by-product
(compared to toxic organometallic reagents)
Baudoin, O. Angew. Chem. Int. Ed. 2007, 46, 1373.
Disadvantages:
CO2 Sucks!
Albert Arnold (Al) Gore Jr.
Nobel Peace Prize 2007
Academy Award Winner 2007
It’s Done in Nature
Enzymatic decarboxylation of orotidine monophosphate (OMP), followed by protonation of the carbanion
O
O
O
O
HN
HN
N
R
O
O
O
O
H
NH2

N
R
H
O
HN
O
O
O
N
R
C
O
NH2

O
H
O
O
Begley, T. P.; Ealick, S. E. Curr. Opin. Chem. Biol. 2004, 8, 508.

O
O
NH2
Earlier Work – Stoichiometric Transition Metal
NO2 O
MeO
OH
+
Cu2O (0.8 equiv),
quinoline, 240 °C 15 min
NO2
Br
OMe
50%
(1.2 equiv)
(1 equiv)
NO2 O
OH
(1.2 equiv)
+
NO2
Cu2O (0.8 equiv),
quinoline, 240 °C 15 min
I
(1 equiv)
"The yield of crystalline product was 10%, but can probably be improved to ca. 30%"
Nilsson, M. Acta Chem. Scand. 1966, 20, 423.
OMe
OiPr
Br
iPrO
N
HO2C
N
Pd(OAc)2 (1 equiv), PPh3 (2 equiv),
CH3CN / Et3N (3:1), 150 °C, 80 min
O
O
MeO
O
O
iPrO
97%
iPrO
MeO
MeO
MeO
OiPr
MeO
OiPr
Lamellarin L triisopropyl ether
Peschko, C.; Winklhofer, C.; Steglich, W. Chem. Eur. J. 2000, 6, 1147.
Catalytic Decarboxylative Coupling of Heteroaryl Carboxylates
Br
O
H
O
OH
N
+
Pd[P(tBu)3]2, nBu4NBr,
DMF, MW, 170 °C, 8 min
X
O
O
N
Me
H
OH
O
N
Me
Me
Effect of the Additive:
H
Me
N
Br
O
OH
+
Pd[P(tBu)3]2 (5 mol%),
additive (1 equiv),
Cs2CO3 (1.5 equiv),
Me
N
H
Me
N
DMF, MW, 170 °C, 8 min
(2 equiv)
1 (equiv)
none
nBu4NOAc
nBu4NI
nBu4NBr
nBu4NCl
nBu4NCl H2O
nBu4NF
77%
64%
76%
86%
74%
88%
77%
9%
18%
8%
5%
trace
trace
11%
Forgione, P.; Brochu, M.-C.; St-Onge, M.; Thesen, K. H.; Bailey, M. D.; Bilodeau, F. J. Am. Chem. Soc. 2006, 128, 11350.
St-Onge Decarboxylative Coupling Reaction
Pd[P(tBu)3]2 (5 mol%),
nBu4NCl H2O (1 equiv),
Cs2CO3 (1.5 equiv),
Br
O
X
Y
OH
+
X
Y
DMF, MW, 170 °C, 8 min
R
(2 equiv)
R
1 (equiv)
Starting Materials:
O
O
Me
N
O
O
S
S
OH
OH
Me
O
O
O
O
OH
OH
N
O
OH
N
Me
O
S
OH
N
O
O
OH
Me
Me
OH
Me
Products:
O
Ph
Me
N
Ph
O
O
Ph
N
S
Ph
S
Ph
53%
Me
88%
Me
86%
41%
O
OH
O
DMF, MW, 170 °C, 8 min
Ph
Me
74%
Pd[P(tBu)3]2 (5 mol%),
nBu4NCl H2O (1 equiv),
Cs2CO3 (1.5 equiv),
S
O
Ph
N
N
Me
Ph
23%
O
Ph
no reaction
63%
Me
86%
Scope of the Aryl Bromide
Me
N
O
OH
+
Ar Br
Pd[P(tBu)3]2 (5 mol%),
nBu4NCl H2O (1 equiv),
Cs2CO3 (1.5 equiv),
Me
N
Ar
DMF, MW, 170 °C, 8 min
(2 equiv)
Me
N
OMe
1 (equiv)
Me
N
NO2
Me
N
S
77%
66%
78%
Me
Me
N
85%
N
Proposed Mechanism
O
O
Ar
PdL2
O
O
Ar
OH
Ar
side-product
in some cases
Ar
reductive
elimination
R
Ar Br
oxidative
addition
reductive
elimination
O
O
O
Ar
OH
PdL
PdL
R
O
Ar
PdLAr
Br
O
coordination to carboxylate
followed by
electrophilic palladation at C3
C2
OH
C3
R
deprotanation
O
O
OH
If R = H
R
PdLAr
CO2
C3 to C2 migration
and decarboxylation
Comparison of Regioselectivity with Direct Arylation
Pd[P(tBu)3]2 (5 mol%),
nBu4NCl H2O (1 equiv),
Cs2CO3 (1.5 equiv),
DMF, MW, 170 °C, 8 min
O
S
S
OH
Me
Me
63%
only product
Br
Pd[P(tBu)3]2 (5 mol%),
nBu4NCl H2O (1 equiv),
Cs2CO3 (1.5 equiv),
DMF, MW, 170 °C, 8 min
O
S
HO
S
Me
19%
only product
Br
Pd[P(tBu)3]2 (5 mol%),
nBu4NCl H2O (1 equiv),
Cs2CO3 (1.5 equiv),
DMF, MW, 170 °C, 8 min
S
Me
Br
+
S
Me
Me
S
Me
3.3:1
39%
Decarboxylative Coupling of Aromatic Carboxylates
NO2 O
Cl
NO2
OH
+
Br
Cl
conditions
These substrates were selected for optimization for two reasons:
1. Reactants, products, and by-products can be detected by GC
NO2
H
NO2
Cl
Cl
Cl
O2N
2. The product is a precursor to Boscalid (BASF)
Cl
NH
O
Cl
N
Boscalid (BASF)
Goossen, L. J.; Deng, G.; Levy, L. M. Science 2006, 13, 662.
Goossen, L. J.; Rodriguez, N.; Melzer, B.; Linder, C.; Deng, G.; Levy, L. M. J. Am. Chem. Soc. 2007, 129, 4824.
Optimization
NO2 O
NO2
OH
(1.5 equiv)
+
Br
Cl
Cl
conditions
(1 equiv)
Catalyst
Catalyst
Base (1.5 equiv)
Pd(acac)2 (2 mol%)
PPh3 (6 mol%)
K2CO3
none
PPh3 (6 mol%)
CuCO3
Pd(acac)2 (2 mol%)
PPh3 (6 mol%)
CuCO3
Pd(acac)2 (2 mol%)
PPh3 (6 mol%)
CuCO3
Pd(acac)2 (2 mol%)
PPh3 (6 mol%)
CuCO3
Pd(acac)2 (2 mol%)
P(iPr)Ph2 (6 mol%)
CuCO3
Pd(acac)2 (2 mol%), CuI (30 mol%)
bipyridine (30 mol%)
K2CO3
Pd(acac)2 (2 mol%), CuI (1 mol%) 1,10-phenanthroline (3 mol%)
K2CO3
Additives (1.5 equiv) Temperature ( °C)
none
120
none
120
none
120
KF
120
KF / 3 A mol sieves
120
KF / 3 A mol sieves
120
3 A mol sieves
160
3 A mol sieves
160
Other Notable Reagents:
Pd Source: PdCl2
Ligands: BINAP, P(Cy)3
Additives: KBr, NaF
Base: Ag2CO3
Solvents: DMSO, DMPU, diglyme
Solvent
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
Yields
0
0
5%
32%
84%
98%
78%
98%
Proposed Mechanism
R'
[Cu]
CO2
L2Pd
X
decarboxylation
oxidative
addition
R'
X
R
[Cu]+
O
transmetallation
O
Pd(0)L2
R'
R
anion
exchange
[Cu]+X-
O
R'
L2Pd
reductive
elimination
O
R
R
R
Scope of Aryl Halide
A
Pd(acac)2 (2 mol%), P(iPr)Ph2 (6 mol%),
CuCO3 (1.5 equiv), KF (1.5 equiv),
mol sieves, NMP, 120 °C, 24 h
stoichiometric Cu
NO2 O
OH
(1.5 equiv)
+
NO2
Ar
Ar X
(1 equiv)
catalytic Cu
B
Pd(acac)2 (2 mol%), CuI (1 mol%),
1,10-phenanthroline (3 mol%), K2CO3 (1.5 equiv),
mol sieves, NMP, 160 °C, 24 h
Br
R = H, Me, nPr, OMe, SMe, F, CN, C(O)Me, C(O)Ph, CHO, CO2Et, NO2, CF3
A: 67-97%
B: 62-98%
R
Br
Br
Br
Br
Br
OMe
Br
Cl
Cl
Cl
CN
I
N
N
A: 94%
B: 94%
A: 88%
B: 97%
A: 93%
B: 23%
A: 80%
B: 30%
A: 13%
B: 53%
A: 14%
B: 98%
A: 0
B: 66%
A: 12%
B: 96%
A: 84%
B: 38%
Scope of Aryl Carboxylate
Pd(acac)2 (2 mol%), P(iPr)Ph2 (6 mol%),
CuCO3 (1.5 equiv), KF (1.5 equiv),
mol sieves, NMP, 120 °C, 24 h
O
stoichiometric Cu
OH
+
Ar
Ar X
R
(1.5 equiv)
R
(1 equiv)
catalytic Cu
X
Pd(acac)2 (2 mol%), CuI (1 mol%),
1,10-phenanthroline (3 mol%), K2CO3 (1.5 equiv),
mol sieves, NMP, 160 °C, 24 h
Except for R = 2-NO2
Stoichiometric Cu Conditions: Works well for a wide range of aryl carboxylic acids.
Catalytic Cu Conditions: Only works with 2-nitro substituted aryl carboxylic acid.
Examining the Decarboxylation
In order to design an effective catalyst for a range of carboxylic acids, they examined
the relative reactivity toward decarboxylation compared to 2-nitrobenzoic acid.
O
OH
Cu2O, (7.5 mol%),
1,10-phenanthroline (15 mol%),
NMP / quinoline, 170 °C, 6 h
H
R
NO2
R
O
CN
H
H
iPrO
O
H
F
H
OMe
H
H
H
NC
H
O2N
100%
40%
79%
70%
75%
28%
52%
23%
Discrepancies:
CN
NO2
CO2H
Aryl-Aryl Coupling - Stoichiometric Cu: excellent yield
Aryl-Aryl Coupling - Catalytic Cu: excellent yield
Protodecarboxylation - Catalytic Cu: excellent yield
CO2H
Aryl-Aryl Coupling - Stoichiometric Cu: modest yield
Aryl-Aryl Coupling - Catalytic Cu: no reaction
Protodecarboxylation - Catalytic Cu: modest yield
Examining the Decarboxylation
R
O
OH
Cu2O, (7.5 mol%),
1,10-phenanthroline (15 mol%),
NMP / quinoline, 170 °C, 6 h
R
H
(KBr)
NO2
CN
H
H
No KBr:
with 1,10-phenanthroline: 100%
no 1,10-phenanthroline: 95%
with 1,10-phenanthroline: 40%
no 1,10-phenanthroline: 15%
15 mol% KBr
with 1,10-phenanthroline: 100%
no 1,10-phenanthroline: 95%
with 1,10-phenanthroline: 25%
no 1,10-phenanthroline: 10%
100 mol% KBr
with 1,10-phenanthroline: 95%
no 1,10-phenanthroline: 60%
with 1,10-phenanthroline: 10%
no 1,10-phenanthroline: 0
More General Catalytic Copper Conditions
O
OH
+
PdBr2 (3 mol%), CuBr (10 mol%),
1,10-phenanthroline (10 mol%), K2CO3 (1 equiv),
mol sieves, NMP, 160 °C, 24 h
Br
R
R
(1 equiv)
H
O
(1.2 equiv)
O
CO2H
61%
F
CO2H
69%
CN
CO2H
OMe
CO2H
76%
SO2Me
CO2H
CF3
CO2H
46%
NH
CO2H
CO2H
31%
S
62%
NHAc
CO2H
catalytic Cu:
stoichiometric Cu:
34%
55%
42%
97%
0
91%
0
42%
79%
CO2H
MeO
0
41%
CO2H
CO2H
Application – Synthesis of Valsartan
1. NBS
2.
B(OH)2
+
Cl
Pd cat., K2CO3,
H2O, TBAB, , 2 d
H2N
CO2Me
70-90%
69%
NC
NC
O
nBu
HN
CO2Me
NC
H
O
Br
+
O
O
B
Pd cat., K2CO3
H2N
CO2Me
NaCNBH3
H
73%
CO2H
1. nBuCOCl, Et3N
2. NaN3, nBu3SnCl
3. NaOH
60-85%
O
N
no yield reported
NC
NC
Buhlmayer, P.; Furet, P.; Criscione, L.; de Gasparo, M.; Whitebread, S.; Schmidlin, T.; Lattmann, R.; Wood, J.
Bioorg. Med. Chem. Lett. 1994, 4, 29.
N
N
N NH
Valsartan (Diovan, Novartis)
Application – Synthesis of Valsartan
O
nBu
N
CO2H
R
R
HO2C
+
Br
N
NC
NC
N
N NH
Valsartan (Diovan, Novartis)
R
PdBr2 (2 mol%), CuO (15 mol%),
PPh3 (20 mol%), KF (0.5 equiv), K2CO3 (1 equiv),
mol sieves, quinoline, 170 °C, 24 h
HO2C
+
Br
(1 equiv)
R
NC
NC
(1.2 equiv)
O
O
O
H
NC
71%
OMe
NC
51%
Goossen, L. J.; Melzer, B. J. Org. Chem. 2007, 72, 7473.
MeO
NC
81%
NC
80%
Application – Synthesis of Valsartan
1. PdBr2, CuO, PPh3, KF,
K2CO3, mol sieves,
quinoline, 170 °C, 24 h
2. HCl
O
HO2C
O
+
Br
O
HN
H2N
H
90%
NC
NC
nBuCOCl,
pyridine
98%
O
N
CO2H
1. NaN3, nBu3SnCl
TBAB
2. NaOH
O
N
CO2Me
55%
N
N
N NH
Valsartan
39% yield over 4 steps
CO2Me
NaCNBH3
81%
NC
CO2Me
NC
Decarboxylative Coupling of Electron-Rich Aryl Carboxylates
Optimization:
OMe
CO2H
+
I
OMe
90%
OMe
(1.3 equiv)
PdCl2 (30 mol%), AsPh3 (60 mol%),
Ag2CO3, (3 equiv), DMSO, 150 °C, 6 h
OMe
OMe
OMe
(1 equiv)
Other Reagents Examined:
Catalyst Source: PdCl2(MeCN)2, Pd(O2CCF3)2, Pd(CN)2, Pd(OAc)2,
Pd(dppf)2Cl2(CH2Cl2)2, Pd(PPh3)4, Pd2(dba)3,
NiCl2(PPh3)2, Ni(acac)2
Ligands: BINAP, P(Cy)3, DavePhos, xanthphos
Additives: LiBH4, LiCl, MgCl, CaCl2, CsCl, BiCl3, CuI
Base: Li2CO3, Na2CO3, K2CO3, Cs2CO3, AgOAc, TMSOK
Solvents: DMA, DMF, DMSO/DMF mixtures, sulfolane
Becht, J.-M.; Catala, C.; Le Drain, C.; Wagner, A. Org. Lett. 2007, 9, 1781.
Scope of Aryl Carboxylate
CO2H
+
I
OMe
R
R
OMe
OMe
MeO
OMe
OMe
OMe
OiPr
OMe
OMe
75%
65%
OMe
OMe
F
F
OMe
OMe
79%
65%
F
OMe
NO2
MeO
OiPr
Br
NO2
OMe
PdCl2 (30 mol%), AsPh3 (60 mol%),
Ag2CO3, (3 equiv), DMSO, 150 °C, 6 h
OMe
F
63%
F
F
92%
Cl
82%
O
65%
Scope of Aryl Iodide
OMe
PdCl2 (30 mol%), AsPh3 (60 mol%),
Ag2CO3, (3 equiv), DMSO, 150 °C, 6 h
CO2H
+
I
OMe
R
R
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
89%
Me
OMe
62%
Cl
OMe
OMe
OMe
76%
78%
Br
OMe
OMe
58%
CF3
OMe
OMe
OMe
84%
OMe
77%
Ac
OMe
OMe
CO2Et
OMe
NO2
OMe
OMe
70%
OMe
71%
59%
Decarboxylative Heck-Type Coupling
R'
O
OH
R
R'
+
transition-metal catalyst
R
Heck-Mizoroki Reaction
R
I
R
Pd catalyst
+
Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971, 44, 581.
Heck, R. F.; Nolley, J. P., Jr. J. Org. Chem. 1972, 37, 2320.
Review: Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009.
Example:
CO2Me
Cl
N
OH
+
Pd(OAc)2 (1 mol%),
Et3N, MeCN, 85°C
I
Cl
N
OH
CO2Me
tautomerization
CO2H
Cl
N
S
OH
singulair
Larson, R. D. et. al. J. Org. Chem. 1996, 61, 3398.
Cl
N
O
83%
CO2Me
Mechanism of the Heck Reaction of Aryl Halides
base.HX
Pd0L2
X
base
R
oxidative
addition
L
PdII X
L
H PdIIL2 X
R
ß-hydride
elimination
H
PdIIL2X
L
PdII X
R
R
X = I, Br, Cl, OTf
internal
rotation
PdIIL2X
H
H
R
insertion
Decarboxylative Heck-Type Coupling
Optimized Conditions:
O
MeO
MeO
Pd(O2CCF3)2 (20 mol%),
AgCO3 (3 equiv),
OH +
OMe
(1.5 equiv)
5% DMSO-DMF,
80 °C, 1 h
Notes:
- 5:95 DMSO/DMF is important
- DMF alone or DMSO alone gave lower yields
- at least one ortho substitutent is needed
Myers, A. G.; Tanaka, D.; Mannion, M. R. J. Am. Chem. Soc. 2002, 124, 11250.
MeO
MeO
OMe
91%
Scope
O
Pd(O2CCF3)2 (20 mol%),
AgCO3 (3 equiv),
R'
OH
+
R''
R''
R'
5% DMSO-DMF,
80 - 120°C, 0.5 - 3 h
R
R
(1.5 equiv)
42 - 99%
18 examples
Scope of Aryl Carboxylic Acid:
OMe
Me
MeO
CO2H
CO2H
CO2H
MeO
OMe
OMe
OMe
Me
F
F
Cl
CO2H
F
CO2H
CO2H
CO2H
Me
F
F
F
Cl
F
OMe
CO2H
CO2H
MeO
OMe
NO2
MeO
CO2H
NO2
S
CO2H
Me
O
CO2H
Me
Br
Scope Of Alkene:
CO2Et
Me
CO2tBu
O
F3C
CO2H
CO2H
MeO
N
OMe
Side Reactions
Importance of ortho substituent
O
O
OH +
Pd(O2CCF3)2, AgCO3,
5% DMSO-DMF, 120 °C, 3 h
O
MeO
MeO
major product
Importance of 5% DMSO-DMF
O
MeO
OH +
Pd(O2CCF3)2, AgCO3,
5% DMSO-DMF, 120 °C, 3 h
MeO
OMe
OMe
71%
OMe O
O
MeO
OH +
OMe
Pd(O2CCF3)2, AgCO3,
DMF, 120 °C, 3 h
O
MeO
major product
These side reactions probably occur by a C-H insertion or ortho-palladation reaction
Arylation of 2-Cycloalken-1-ones
O
O
OH
+
( )n
R
R'
R
Pd(O2CCF3)2 (20 mol%),
AgCO3 (2 equiv),
5% DMSO-DMF,
80 - 120°C, 0.5 - 3 h
R R'
( )n
O
R
(1.5 equiv)
OMe
Me
OMe
O
O
O
Me
OMe
OMe
Me
MeO
O
MeO
NO2
O
MeO
N
OMe
Br
89%
61%
58%
49%
63%
O
MeO
O
O
MeO
OMe
81%
MeO
OMe
65%
Tanaka, D.; Myers, A. G. Org. Lett. 2004, 6, 433.
MeO
O
MeO
OMe
86%
O
O
64%
OMe
30%
Reaction of 2-Methyl-cyclopenten-1-one
O
OMe O
OH
MeO
OMe
OMe
Pd(O2CCF3)2 (20 mol%),
AgCO3 (2 equiv),
O
O
+
MeO
MeO
5% DMSO-DMF,
80 - 120°C, 0.5 - 3 h
OMe
MeO
24%
OMe
O
MeO
OMe
MeO
5%
Heck Reactions of Aryl Carboxylates vs Aryl Halides
O
O
OH
MeO
Pd(O2CCF3)2 (20 mol%),
AgCO3 (2 equiv),
5% DMSO-DMF, 80 °C, 0.5
OMe
MeO
92%
O
I
+
MeO
O
+
OMe
OMe
Pd(OAc)2, NaHCO3,
Bu4NCl, DMF, 80 °C, 17 h
57%
O
MeO
OMe
7 reported reactions
yields range 3% - 57%
O
OH
ineffective in decarboxylative Heck-type coupling
Me
O
I
Pd(OAc)2, NaHCO3,
Bu4NCl, DMF, 80 °C, 21 h
O
+
Me
100% (HPLC)
Me
Mechanistic Studies – Insight into the Decarboxylation Step
Heck Reaction with Aryl Halides – Oxidative Addition Occurs
L
Pd(II)
L
Pd(0)
I
oxidative addition
I
Heck Reaction with Aryl Carboxylic Acids – What Happens?
O
OH
Pd(0)
L
Pd(II) X
L
Does this intermediate form.
If so, how does it form and what are X and L.
Tanaka, D.; Romeril, S. P.; Myers, A. G. J. Am. Chem. Soc. 2005, 127, 10323.
Mechanistic Studies – Insight into the Decarboxylation Step
1H
NMR Studies
OMe O
O
O
MeO
OMe
MeO
CO2Na
O
CF3
MeO
OMe
+
O
Pd
DMSO-d6, rt
A
+
OMe O
O
F3C
CF3
O
O
Pd
OMe
O
O Pd O
MeO
(1.2 equiv)
OMe
OMe
B
OMe
A:B ratio = 6:1
At 80 oC, A and B start disappearing and C forms.
O
OMe
CF3
Pd O
MeO
OMe
C
After 15 min at 80 oC, only C is observed.
Mechanistic Studies – Insight into the Decarboxylation Step
13C
NMR Studies
O
O
F3C
CF3
O Pd O
MeO
OMe
13
OMe O
(1.2 equiv)
O
C
MeO
DMSO-d6,
room temperature
CO2Na
MeO
After 8 min at 60 oC, C and 13CO2 observed
O
CF3
Pd O
+
MeO
OMe
C
13
CO2
O
OMe O
CF3
O
O
+
Pd
OMe
O
MeO
OMe
A
OMe
O
Pd
OMe
OMe
OMe
B
X-Ray of Palladium Intermediate
Proposed Mechanism for the Decarboxylation Step
O
MeO
MeO
ONa
OMe
Pd(O2CCF3)2
DMSO-d6,
23 °C
DMSO
O
MeO
MeO
DMSO
O Pd O2CCF3
DMSO
OMe
80 °C
F3CCO2
MeO
MeO
Pd O
MeO
O
OMe
DMSO
Pd O2CCF3
DMSO
MeO
OMe
CO2
rate-determining step
Importance of DMSO:
- rate of decarboxylation is dependent on the solvent
- 19:1 DMF-d7 : DMSO-d6 was 2-fold greater than DMSO-d6 alone
- this is consistent with the dissociation of DMSO occurring prior to or during the rate-determining step
Trifluoroacetate Plays a Key Role in the Decarboxylative Palladation
- an excess of NaO2CCF3 only slightly slowed the rate of decarboxylative palladation
- addition of 1.1 equiv of LiBr or nBu4NBr results in no decarboxylative palladation
- Pd(OAc)2, PdCl2, PdO2, Pd(OTf)2 were ineffective
- electron-donating phosphine or trialkyl amine ligands inhibit the reaction
- Conclusion: electron-deficient Pd center is needed for decarboxylative palladation
Final Steps: Alkene Insertion and β-Hydride Elimination
NMR, X-ray, and deuterium experiments indicate the final steps are alkene insertion and
β-hydride elimination (similar to Heck reactions involving aryl halide)
MeO
MeO
DMSO
Pd O2CCF3
DMSO
OMe
R
+
OMe
OMe
alkene
insertion
MeO
Pd(II)
ß-hydride
elimination
MeO
R
R
OMe
OMe H
However, NMR studies indicate a reactivity pattern opposite to that of Heck reactions of aryl halides,
that is:
CO2tBu
>
CN
>
Competition Experiments
CO2H
CO2tBu
CN
+
MeO
Ph
+
+
Pd(O2CCF3)2 (20 mol%), AgCO3,
5% DMSO-DMF, 80 °C, 24 h
R
MeO
OMe
(1 equiv)
(1 equiv)
OMe
(1 equiv)
R = CN < CO2tBu < Ph
1 : 2 : 2.7
I
MeO
CO2tBu
CN
+
Ph
+
+
R
Pd(OAc)2 (10 mol%), NaHCO3,
nBu4NBr, DMF, 110 °C, 30 h
OMe
MeO
(1 equiv)
(1 equiv)
OMe
(1 equiv)
R = CN < CO2tBu < Ph
17 : 7 :
1
I
+
MeO
CO2tBu
CN
Ph
+
+
R
Pd(PPh3)4 (10 mol%),
Et3N, DMF, 110 °C, 30 h
MeO
OMe
(1 equiv)
(1 equiv)
(1 equiv)
OMe
R = CN < CO2tBu < Ph
17 : 6 :
1
Conclusions: These differences are due to the electron-deficient nature of the Pd(II) species
Other Interesting Transition-Metal Catalyzed Decarboxylative Couplings
Pd(O2CCF3)2 (20 mol%),
CF3CO2H (10 equiv),
5% DMSO-DMF, 70 °C
OMe
CO2H
OMe
H
OMe
R
R
OMe
Dickstein, J. S.; Mulrooney, C. A.; O'Brien, E. M.; Morgan, B. J.; Kozlowski, M. C. Org. Lett. 2007, 9, 2441.
CO2H
+
Ar
Ar
Ar
[Cp*IrCl2]2 (2 mol%), Ag2CO3,
o-xylene, 160 °C, 6h
Ar
R
Ar
R
Ar
Ueura, K.; Satoh, T.; Miura, M. J. Org. Chem. 2007
O
BnS
O
OH
Cu(2-ethylhexanoate)2
(20 mol%),
wet THF, air, 23 °C
O
+
H
R
MeO
N
N
H
(22 mol%)
Lalic, G.; Aloise, A. D.; Shair, M. D. J. Am. Chem. 2003, 125, 2852.
O
BnS
OH
R
The End
I Love CO2!
Albert Arnold (Al) Gore Jr.
Nobel Peace Prize 2007 and future CO2 lover