transition-metal-catalyzed decarboxylative coupling november 13, 2007 dino alberico
TRANSCRIPT
Transition-Metal-Catalyzed Decarboxylative Coupling Transition-Metal-Catalyzed Decarboxylative Coupling
November 13, 2007
Dino Alberico
Decarboxylative CouplingDecarboxylative Coupling
Decarboxylative Biaryl Coupling
Decarboxylative Heck-Type Coupling
OH
O
X = I, Br
RR
R'X
R'
+ transition-metal catalyst
OH
O
R R
+ transition-metal catalystR'
R'
Biaryl CompoundsBiaryl Compounds
cavicularin
O
HOHO
HO
NH
Me
Me
OH
OH
HO
korupensamine A
OMe
OMe
MeO
MeO
CO2Me
NHAc
allocolchicine
N
NH
O
rhazinilam
Cl
NH
O
NCl
CO2H
O
NN
N NH
N
N
N
N
CO2H
NF
HN
O
OH
OH
HO2C
C8H17OCN
C7H15
N
PPh2
OH
OH PCy2
Me2N
Diovan (Valsartan, Novartis) Micardis (Telmisartan, Boehringer) Boscalid (BASF)
NCB 807 (Merck)
Lipitor (Atorvastatin, Pfizer)
Natural Products
Pharmaceuticals Agrochemicals
LigandsPAHLiquid Crystals
Biaryl Formation Using Transition MetalsBiaryl Formation Using Transition Metals
X, Y: I, Br, Cl, OTf, ONs, B, Sn, Si, Zn, Mg, H
Transition Metal (either stoichiometric or catalytic): Cu, Ni, Pd, Pt, Ru, Rh, Ir
XR
YR' R R'
+transition metal
Hassan, J.; Sévignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359.
XR
XR R R
+Cu (stoichiometric or excess)
MeO
MOMO
I
CONHiPr
Cu-bronze, 200 oCCONHPr
OMOM
MOMO
PrHNOC
OMe
MeO
66%
O
O
O
O
OMe
MeO NMe2
Taspine
Ullmann CouplingUllmann Coupling
Kelly, T. R.; Xie, R. L. J. Org. Chem. 1998, 63, 8045.
Ullmann, F.; Bielecki, J. Chem. Ber. 1901, 34, 2174.
Example:
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-CouplingTransition-Metal-Catalyzed Cross-Coupling
Lin, S.; Danishefsky, S. J. Org. Lett. 2000, 2, 2575.
Suzuki Coupling
Stille Coupling
Sauer, J.; Heldmann, D. K.; Pabst, R. Eur. J. Org. Chem. 1999, 1, 313.
OBn
BO
O
CO2Me
NHCbz NH
O
I
O
BocN
BnO
CO2Me
NHCbz
NH
O
O
BocNPdCl2(dppf)2, CH2Cl2,
K2CO3, DME, 80 oC, 2h
75%+
N
N
SnBu3
N
Br
N
N
N
+
Pd(PPh3)4, toluene, 110 oC
72%
XR'
YR R R'
+transition metal catalyst
aryl halide
X: I, Br, Cl, OTf
organometallic
Y: B, Sn, Si, Zn, Mg
Transition-Metal-Catalyzed Cross-CouplingTransition-Metal-Catalyzed Cross-Coupling
Amatore, C.; Jutand, A.; Negri, S.; Fauvarque, J.-F. J. Organomet. Chem. 1990, 390, 389.
Bumagin, N. A.; Sokolova, A. F.; Beletskaya, I. P. Russ. Chem. Bull. 1993, 42, 1926.
Hatanaka, Y.; Hiyama, T. Synlett 1991, 845.
Negishi Coupling
Hiyama Coupling
Kumada Coupling
Me Si(Me)2F2 TfOH
O
H
OMe
Pd(PPh3)4,
n-Bu4NF, THF,
50 oC, 5 h
92%
+
S
N
MeMeO
MeO
S
N
MeMeO
MeO ZnCl Br
PdCl2(dppf),THF, rt, 1.5 h
97%+
CNIS MgBr
Pd(PPh3)4,THF, rt, 2 h
73%CN
S+
Direct ArylationDirect Arylation
X: I, Br, Cl, OTf B, Sn, Si, Mg, Zn
XR'
YR R R'
+transition metal catalyst
aryl halide
X: I, Br, Cl, OTf
organometallic
Y: B, Sn, Si, Zn, Mg
XR'
HR R R'
+transition metal catalyst
Cross-Coupling
Direct Arylation
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 ArylationDirect Arylation
Bringmann, G.; Ochse, M.; Götz, R. J. Org. Chem. 2000, 65, 2069.
Intramolecular Direct Arylation
Examples:
Julie Côté, Shawn K. Collins
Y
X
Y
HR1
R2
R1 R2
transition metal catalyst
O
OBr
N
Oi-Pr
Oi-Pr
Me
Me
Bn
NaOAc, DMA, 140 °C O
O
N
Me
Me
Bn
Oi-Pr
Oi-Pr
NH
Me
Me
OH
OH
HOP
korupensamine A
5'
OPd
OOPd
O
P
P
Meo-Tol o-Tol
o-Tolo-Tol
Me(10 mol%)
74%
OMe
O
O
Cl
NO2
Cl
O
O
NO2
O2N
O2N
Pd catalyst
Direct ArylationDirect Arylation
Oi, S.; Aizawa, E.; Ogino, Y.; Inoue, Y. J. Org. Chem. 2005, 70, 3113.
Intermolecular Direct Arylation – Using a Directing Group
Examples:
Alexandre Larivée, James Mousseau, André Charette
XR'
HR R R'
+transition metal catalyst
DG DG
OH NHROROH
O O
H
NR
NN
O
N
RN
NN
NHR
OHN R
O
Directin Group (DG):
N+
N-
O
BrN+
N-
O
Pd(OAc)2, P(tBu)3, K2CO3, M.S., toluene, 125 °C
80%
+
N
O [RuCl2(6-C6H6)]2, (2.5 mol%),
PPh3, K2CO3, NMP, 120 °C
100%
N
OPh
Ph
Br
+
(2.5 equiv)
Direct ArylationDirect Arylation
Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71, 467.
Intermolecular Direct Arylation – Electronic Bias of Heterocycles
Examples:
Ohta, A.; Akita, Y.; Ohkuwa, T.; Chiba, M.; Fukunaga, R.; Miyafuji, A.; Nakata, T.; Tani, N.; Aoyagi, Y. Heterocycles, 1990, 31, 1951.
YX+ transition metal catalyst
Y
N
NR
NR
NN
O O
NN
S
S
N
NR
NO
N
N
O
R
N
N
O
R
N N
N
N
N N
NN
N N
N
Pd(OAc)2 (5 mol%), PPh3, Cs2CO3,DMF, 140 °C
83%
N
N
N
NI+
S
Pd(PPh3)4 (5 mol%), KOAc, DMA, 150 °C
66% SNO2
Br NO2+
NR
NR
Cross-Coupling of Aromatic C-H SubstratesCross-Coupling of Aromatic C-H Substrates
Li, X.; Hewgley, B.; Mulrooney, C.A.; Yang, J.; Kozlowski, M.C. J. Org. Chem. 2003, 68, 5500.
Stuart, D. S.; Fagnou, K. Science 2007, 316, 1172.Stuart, D. S.; Villemure, E.; Fagnou, K. J. Am. Chem. Soc. 2007, 129, 12072.
Dwight, T. A.; Rue, N. R.; Charyk, D.; Josselyn, R.; DeBoef, B.Org. Lett. 2007, 9, 3137.
Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 11904.
OH
OH
OH
NH
NH
10 mol%
CuI (10 mol%), O2,
Cl(CH2)2Cl, 40 °C
85%
CO2Me
CO2Me
CO2Me
NAc
MeO
NAc
MeO
Pd(TFA)2 (10 mol%),
Cu(OAc)2 (3 equiv),
CsOPiv (40 mol%),
pivalic acid, MW, 140 °C
84%
+
O
O
Pd(OAc)2 (10 mol%),
H4PMo11VO40 (10 mol%),
AcOH/benzene (3:2),
O2 (3 atm), 120 °C
98%
+
(30 equiv)
excess
N
+
(100 equiv)
Pd(OAc)2 (10 mol%),
benzoquinone (0.5 equiv),
Ag2CO3 ( 2equiv),
DMSO (4 equiv),
130 °C, 12 h
89%
N
HR'
HR R R'
+transition metal catalyst
Limitations to Aforementioned Transition-Metal Catalyzed MethodsLimitations to Aforementioned Transition-Metal Catalyzed Methods
X: I, Br, Cl, OTf
XR'
HR R R'
+transition metal catalyst
-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
- 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
- challenging to control regioselectivity
- large excess of one arene is needed
- an excess of oxidant is needed (sometimes an organometallic reagent is used)
HR'
HR R R'
+transition metal catalyst
XR'
YR R R'
+transition metal catalyst
aryl halideX: I, Br, Cl, OTf
organometallicY: B, Sn, Si, Zn, Mg
R
protections,
lithiations,
halogenations,
metallations, etc.
organometallic by-product
+
Aryl-Aryl Bond Formation via Decarboxylative CouplingAryl-Aryl Bond Formation via Decarboxylative Coupling
X: I, Br, Cl, OTf
XR'
CO2HR R R'
+transition metal catalyst + CO2
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) Albert Arnold (Al) Gore Jr.
Nobel Peace Prize 2007Academy Award Winner 2007
CO2 Sucks!
Baudoin, O. Angew. Chem. Int. Ed. 2007, 46, 1373.
Disadvantages:
It’s Done in NatureIt’s Done in Nature
HN
N
O
O
R O
O
NH2
H O
O
HN
N
O
O
R O
O
NH2
HO
O
HN
N
O
O
R
H
NH2
O
OOC
O
Enzymatic decarboxylation of orotidine monophosphate (OMP), followed by protonation of the carbanion
Begley, T. P.; Ealick, S. E. Curr. Opin. Chem. Biol. 2004, 8, 508.
Earlier Work – Stoichiometric Transition MetalEarlier Work – Stoichiometric Transition Metal
Peschko, C.; Winklhofer, C.; Steglich, W. Chem. Eur. J. 2000, 6, 1147.
Nilsson, M. Acta Chem. Scand. 1966, 20, 423.
N
O
OiPrO
MeO
iPrO
MeO MeOOiPr
Lamellarin L triisopropyl ether
N
O
O
iPrO
MeO MeOOiPr
Br
OiPr
OMe
HO2CPd(OAc)2 (1 equiv), PPh3 (2 equiv),
CH3CN / Et3N (3:1), 150 °C, 80 min
97%
NO2 O
OHBr
NO2
+
MeO
OMe
(1 equiv)(1.2 equiv)
Cu2O (0.8 equiv),
quinoline, 240 °C 15 min
50%
NO2 O
OHI
NO2
+
(1 equiv)(1.2 equiv)
Cu2O (0.8 equiv),
quinoline, 240 °C 15 min
"The yield of crystalline product was 10%, but can probably be improved to ca. 30%"
Effect of the Additive:
NHOH
O Pd[P(tBu)3]2 (5 mol%), additive (1 equiv),
Cs2CO3 (1.5 equiv),
DMF, MW, 170 °C, 8 min
N
Br
+
NH
Me MeMe
none
nBu4NOAc
nBu4NI
nBu4NBr
nBu4NCl
nBu4NCl H2O
nBu4NF
77%
64%
76%
86%
74%
88%
77%
9%
18%
8%
5%
trace
trace
11%
(2 equiv) 1 (equiv)
N
OHOH
O
Me
Pd[P(tBu)3]2, nBu4NBr, DMF, MW, 170 °C, 8 min
N
OOH
O
Me
Br
+N
OH
Me
Catalytic Decarboxylative Coupling of Heteroaryl CarboxylatesCatalytic Decarboxylative Coupling of Heteroaryl Carboxylates
X
Forgione, P.; Brochu, M.-C.; St-Onge, M.; Thesen, K. H.; Bailey, M. D.; Bilodeau, F. J. Am. Chem. Soc. 2006, 128, 11350.
Y
XOH
O Pd[P(tBu)3]2 (5 mol%), nBu4NCl H2O (1 equiv),
Cs2CO3 (1.5 equiv),
DMF, MW, 170 °C, 8 min Y
X
Br
+
(2 equiv) 1 (equiv)
N
OOH
O
Me
NOH
OMe
OOH
OO
OH
O
MeN
SOH
O
MeN
SOH
OO
OH
O
O
Me
OH
O
N
O
Me
N
Me
O O
MeN
S
MeN
S O
O
Me
Ph Ph Ph Ph Ph Ph Ph
Ph
R R
53% 88% 86% 41% 74% 23% 63%
SOH
O
Me
S
Me
Ph
86%
Pd[P(tBu)3]2 (5 mol%), nBu4NCl H2O (1 equiv),
Cs2CO3 (1.5 equiv),
DMF, MW, 170 °C, 8 min
no reaction
St-Onge Decarboxylative Coupling ReactionSt-Onge Decarboxylative Coupling Reaction
Starting Materials:
Products:
Scope of the Aryl BromideScope of the Aryl Bromide
NOH
O Pd[P(tBu)3]2 (5 mol%), nBu4NCl H2O (1 equiv),
Cs2CO3 (1.5 equiv),
DMF, MW, 170 °C, 8 min
N Ar+
(2 equiv) 1 (equiv)
N
Me
77%
Me Me
OMeN
Me NO2
Ar Br
N
Me
S MeN
Me N
66% 78% 85%
Proposed MechanismProposed Mechanism
OOH
O
Ar
PdL2 O Ar
R
O PdLAr
R
Ar Br
Ar PdL Br
OOH
O
R
OOH
O
PdLArR
CO2
OOH
O
PdLAr
If R = H
C2
C3
C3 to C2 migration and decarboxylation
reductive elimination
oxidative addition
coordination to carboxylatefollowed by
electrophilic palladation at C3
deprotanation
reductive elimination
O
Ar
Ar
side-product in some cases
Comparison of Regioselectivity with Direct ArylationComparison 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
SOH
O
Me
S
Me
O
HO
S
Me
Br
S
Me
S
Me
S
Me
S
Me
63%only product
19%only product
+
3.3:139%
Pd[P(tBu)3]2 (5 mol%), nBu4NCl H2O (1 equiv),
Cs2CO3 (1.5 equiv),DMF, MW, 170 °C, 8 min
Br
Pd[P(tBu)3]2 (5 mol%), nBu4NCl H2O (1 equiv),
Cs2CO3 (1.5 equiv),DMF, MW, 170 °C, 8 min
Br
Decarboxylative Coupling of Aromatic CarboxylatesDecarboxylative Coupling of Aromatic Carboxylates
NO2 O
OH Br Cl
NO2Cl
+ conditions
NO2
HNO2
O2N
Cl Cl Cl
These substrates were selected for optimization for two reasons:
1. Reactants, products, and by-products can be detected by GC
2. The product is a precursor to Boscalid (BASF)
Cl
NH
O
NCl
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.
OptimizationOptimization
Other Notable Reagents: Pd Source: PdCl2 Ligands: BINAP, P(Cy)3
Additives: KBr, NaF Base: Ag2CO3
Solvents: DMSO, DMPU, diglyme
NO2 O
OH Br Cl
NO2Cl
+ conditions
Catalyst
Pd(acac)2 (2 mol%)
none
Pd(acac)2 (2 mol%)
Pd(acac)2 (2 mol%)
Pd(acac)2 (2 mol%)Pd(acac)2 (2 mol%)
Pd(acac)2 (2 mol%), CuI (30 mol%)
Pd(acac)2 (2 mol%), CuI (1 mol%)
Catalyst
PPh3 (6 mol%)
PPh3 (6 mol%)
PPh3 (6 mol%)
PPh3 (6 mol%)
PPh3 (6 mol%)P(iPr)Ph2 (6 mol%)
bipyridine (30 mol%)
1,10-phenanthroline (3 mol%)
Base (1.5 equiv)
K2CO3
CuCO3
CuCO3
CuCO3
CuCO3
CuCO3
K2CO3
K2CO3
Additives (1.5 equiv)
none
none
none
KF
KF / 3 A mol sievesKF / 3 A mol sieves
3 A mol sieves
3 A mol sieves
Solvent
NMP
NMP
NMP
NMP
NMPNMP
NMP
NMP
Temperature ( °C)
120
120
120
120
120120
160
160
Yields
0
0
5%
32%
84%98%
78%
98%
(1.5 equiv) (1 equiv)
Proposed MechanismProposed Mechanism
XR'L2Pd
R'
X
L2PdR'
R'
R
Pd(0)L2
O
O [Cu]+X-
R R
[Cu]+
O
O
R
R
[Cu]CO2oxidativeaddition
reductiveelimination
transmetallation
decarboxylation
anionexchange
Scope of Aryl HalideScope of Aryl Halide
Br BrBr Br
OMe
Cl Cl I
Cl CN
N
Br
N
Br
A: 93%B: 23%
A: 80%B: 30%
A: 94%B: 94%
A: 88%B: 97%
A: 13%B: 53%
A: 14%B: 98%
A: 0B: 66%
A: 12%B: 96%
A: 84%B: 38%
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
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
NO2 O
OH
NO2
Ar+
(1.5 equiv) (1 equiv)
Ar X
Br
R
R = H, Me, nPr, OMe, SMe, F, CN, C(O)Me, C(O)Ph, CHO, CO2Et, NO2, CF3
A: 67-97%
B: 62-98%
stoichiometric Cu
catalytic Cu
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
Pd(acac)2 (2 mol%), CuI (1 mol%),
1,10-phenanthroline (3 mol%), K2CO3 (1.5 equiv),
mol sieves, NMP, 160 °C, 24 h
+
(1.5 equiv) (1 equiv)
Ar X
stoichiometric Cu
catalytic Cu
O
OH
R R
Ar
Except for R = 2-NO2
X
Scope of Aryl CarboxylateScope of Aryl Carboxylate
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 DecarboxylationExamining the Decarboxylation
O
OH
Cu2O, (7.5 mol%),
1,10-phenanthroline (15 mol%),NMP / quinoline, 170 °C, 6 h
R R
H
NO2
H
CN
H HH H
F
H
O2N
O iPrO OOMe
H HNC
100% 40% 79% 70% 75% 28% 52% 23%
NO2
CO2H
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.
Aryl-Aryl Coupling - Stoichiometric Cu: excellent yield
Aryl-Aryl Coupling - Catalytic Cu: excellent yield
Protodecarboxylation - Catalytic Cu: excellent yield
Discrepancies:CN
CO2H
Aryl-Aryl Coupling - Stoichiometric Cu: modest yield
Aryl-Aryl Coupling - Catalytic Cu: no reaction
Protodecarboxylation - Catalytic Cu: modest yield
Examining the DecarboxylationExamining the Decarboxylation
O
OH
Cu2O, (7.5 mol%),
1,10-phenanthroline (15 mol%),
NMP / quinoline, 170 °C, 6 h
(KBr)
H
NO2
H
CN
H
No KBr:
15 mol% KBr
100 mol% KBr
with 1,10-phenanthroline: 100%no 1,10-phenanthroline: 95%
with 1,10-phenanthroline: 40%no 1,10-phenanthroline: 15%
with 1,10-phenanthroline: 100%no 1,10-phenanthroline: 95%
with 1,10-phenanthroline: 25%no 1,10-phenanthroline: 10%
with 1,10-phenanthroline: 95%no 1,10-phenanthroline: 60%
with 1,10-phenanthroline: 10%no 1,10-phenanthroline: 0
R R
More General Catalytic Copper ConditionsMore General Catalytic Copper Conditions
PdBr2 (3 mol%), CuBr (10 mol%),
1,10-phenanthroline (10 mol%), K2CO3 (1 equiv),
mol sieves, NMP, 160 °C, 24 h+
(1 equiv) (1.2 equiv)
Br
O
OH
R R
CO2H CO2H CO2H CO2H CO2H S CO2HCO2H
F OMe CF3OH O
61% 69% 76% 46% 31% 62% 79%
CO2H CO2H CO2H CO2HCO2H
CN SO2Me NH NHAc
34%55%
42%97%
091%
042%
041%
MeO
catalytic Cu:stoichiometric Cu:
Application – Synthesis of ValsartanApplication – Synthesis of Valsartan
Cl
NC
B(OH)2
NC
H2N CO2Me
1. NBS2.
+Pd cat., K2CO3,
H2O, TBAB, , 2 d
NC
HN CO2Me
B
NC
Br
NC
+ Pd cat., K2CO3
1. nBuCOCl, Et3N2. NaN3, nBu3SnCl3. NaOH
O
O
H
O
H2N CO2Me
NaCNBH3H
O
N CO2H
NN
N NH
O
nBu
Valsartan (Diovan, Novartis)
69% 70-90%
73% no yield reported
60-85%
Buhlmayer, P.; Furet, P.; Criscione, L.; de Gasparo, M.; Whitebread, S.; Schmidlin, T.; Lattmann, R.; Wood, J. Bioorg. Med. Chem. Lett. 1994, 4, 29.
Application – Synthesis of ValsartanApplication – Synthesis of Valsartan
Goossen, L. J.; Melzer, B. J. Org. Chem. 2007, 72, 7473.
N CO2H
NN
N NH
O
nBu
Valsartan (Diovan, Novartis)
R
NC
HO2C
NC
R
Br+
HO2C
NC
R
Br+
PdBr2 (2 mol%), CuO (15 mol%),
PPh3 (20 mol%), KF (0.5 equiv), K2CO3 (1 equiv),
mol sieves, quinoline, 170 °C, 24 h
(1 equiv) (1.2 equiv)
NC
R
NC NC NC NC
O
H
O
O
OMe
MeO
71% 51% 81% 80%
Application – Synthesis of ValsartanApplication – Synthesis of Valsartan
1. NaN3, nBu3SnCl
TBAB
2. NaOH
NCBr
O
HO
O
81%
HO2C
NC
+
1. PdBr2, CuO, PPh3, KF,
K2CO3, mol sieves,
quinoline, 170 °C, 24 h
2. HCl
H2N CO2Me
NaCNBH3
NC
HN CO2Me
nBuCOCl, pyridine
NC
N CO2Me
O
N CO2H
NN
N NH
O
90%
98%
55%
Valsartan39% yield over 4 steps
Decarboxylative Coupling of Electron-Rich Aryl CarboxylatesDecarboxylative Coupling of Electron-Rich Aryl Carboxylates
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
OMe
OMe
CO2HI OMe
OMe
OMe
OMe
+
(1 equiv)(1.3 equiv)
PdCl2 (30 mol%), AsPh3 (60 mol%),Ag2CO3, (3 equiv), DMSO, 150 °C, 6 h
90%
Becht, J.-M.; Catala, C.; Le Drain, C.; Wagner, A. Org. Lett. 2007, 9, 1781.
Optimization:
Scope of Aryl CarboxylateScope of Aryl Carboxylate
CO2HI OMe
OMe
+
PdCl2 (30 mol%), AsPh3 (60 mol%),
Ag2CO3, (3 equiv), DMSO, 150 °C, 6 h
OMe
OMe
OMe OMe
OMe
OMe
MeO
OiPr
OiPr
OMe NO2OMe
NO2OMe F
F
OMeF
Cl
OMe
Br OMe
MeO
F
F
F
75% 65% 65% 79%
63% 92% 82%
RR
OOMe
65%
Scope of Aryl IodideScope of Aryl Iodide
CO2HI+
PdCl2 (30 mol%), AsPh3 (60 mol%),
Ag2CO3, (3 equiv), DMSO, 150 °C, 6 h
OMe
OMe
OMe
OMe
MeOMe
OMe
ClOMe
Br
OMe
OMe
OMe
OMe
Ac
OMe
OMe
89% 62% 76% 78% 58%
84% 77% 70%
OMe
OMe
OMe
OMeR
R
OMe
OMe
OMe
OMe
OMe
CF3
OMe
OMe
71%
NO2
OMe
OMe
59%
CO2Et
Decarboxylative Heck-Type CouplingDecarboxylative Heck-Type Coupling
OH
O
R R
+ transition-metal catalystR'
R'
Heck-Mizoroki ReactionHeck-Mizoroki Reaction
I R+
Pd catalyst
R
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:
Larson, R. D. et. al. J. Org. Chem. 1996, 61, 3398.
NCl OH
CO2Me
I+
NCl O CO2MeNCl S
CO2H
OH
singulair
Pd(OAc)2 (1 mol%),Et3N, MeCN, 85°C NCl OH CO2Me
tautomerization
83%
Mechanism of the Heck Reaction of Aryl HalidesMechanism of the Heck Reaction of Aryl Halides
Pd0L2 X
PdIIL2X
R
R
RPdIIL2H
base oxidativeaddition
insertion
ß-hydrideelimination
PdIIL
L
PdIIL
R
HH
PdIIL2XH
R
X = I, Br, Cl, OTf
XX
X
internalrotation
base.HX
Decarboxylative Heck-Type CouplingDecarboxylative Heck-Type Coupling
Optimized Conditions:
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
O
OH MeO
MeO OMe
Pd(O2CCF3)2 (20 mol%),
AgCO3 (3 equiv),
5% DMSO-DMF,
80 °C, 1 h(1.5 equiv)
+
91%
O
OH R'
Pd(O2CCF3)2 (20 mol%),
AgCO3 (3 equiv),
5% DMSO-DMF,
80 - 120°C, 0.5 - 3 h(1.5 equiv)
+
42 - 99%18 examples
R'
R R
R''
R''
CO2H CO2H CO2H CO2H CO2H
OMe
MeO
MeO
OMe
OMe OMe
CO2H CO2H
CO2H CO2H CO2H
Me
Me Me
F
F
F
F
F
F
F
Cl
Cl
OMe
OMe
Br
NO2 NO2
MeO
MeO
OOS
F3C
CO2H
Me
CO2HCO2H
Me N OMeMeO
CO2H
CO2Et CO2tBu
Me
ScopeScope
Scope of Aryl Carboxylic Acid:
Scope Of Alkene:
Side ReactionsSide Reactions
MeO
O
OH MeO
OMe
Pd(O2CCF3)2, AgCO3,
5% DMSO-DMF, 120 °C, 3 h+
MeO
OMe
O
OH
Pd(O2CCF3)2, AgCO3,
DMF, 120 °C, 3 h+
major product
MeO
O
OH
MeO
Pd(O2CCF3)2, AgCO3,
5% DMSO-DMF, 120 °C, 3 h+
major product
O
O
OMe
MeO
O
OOMe
71%
Importance of 5% DMSO-DMF
Importance of ortho substituent
These side reactions probably occur by a C-H insertion or ortho-palladation reaction
Arylation of 2-Cycloalken-1-onesArylation of 2-Cycloalken-1-ones
O
OH
Pd(O2CCF3)2 (20 mol%),
AgCO3 (2 equiv),
5% DMSO-DMF,
80 - 120°C, 0.5 - 3 h(1.5 equiv)
+
R R
O
R R'
( )nO
( )nRR'
O
OMe
O
Me
O
OMe
O
NO2 N
O
OMe
OMe Me
Me
OMe
Br
MeO
MeO MeO
89% 61% 58% 49% 63%
OMeO
MeO OMeO
OMeMeO
O
OMeMeO
30%
O
OMeMeO
86%
O
64%
O
81% 65%
Tanaka, D.; Myers, A. G. Org. Lett. 2004, 6, 433.
Reaction of 2-Methyl-cyclopenten-1-oneReaction of 2-Methyl-cyclopenten-1-one
O
OH
Pd(O2CCF3)2 (20 mol%),
AgCO3 (2 equiv),
5% DMSO-DMF,
80 - 120°C, 0.5 - 3 h
+
O
MeO MeO
O
MeOOMe
OMeOMe
MeO
O
OMeMeO
24% 5%
OMe
MeO
OOMe
Heck Reactions of Aryl Carboxylates vs Aryl HalidesHeck Reactions of Aryl Carboxylates vs Aryl Halides
ineffective in decarboxylative Heck-type coupling
O
OH
Pd(O2CCF3)2 (20 mol%),
AgCO3 (2 equiv),
5% DMSO-DMF, 80 °C, 0.5
92%
+
MeO OMe
O
I+
MeO OMe
O
MeO OMe
O
Pd(OAc)2, NaHCO3,
Bu4NCl, DMF, 80 °C, 17 h
57% MeO OMe
O
I
Me
Pd(OAc)2, NaHCO3,
Bu4NCl, DMF, 80 °C, 21 h
100% (HPLC)
+
O
Me
O
O
OH
Me
7 reported reactions yields range 3% - 57%
Mechanistic Studies – Insight into the Decarboxylation StepMechanistic Studies – Insight into the Decarboxylation Step
Heck Reaction with Aryl Halides – Oxidative Addition Occurs
Heck Reaction with Aryl Carboxylic Acids – What Happens?
Pd(0)
Pd(0)
I Pd(II)
O
OH
I
L
Loxidative addition
Pd(II) X
L
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 StepMechanistic Studies – Insight into the Decarboxylation Step
Pd
OMe
MeO
OMe
OCF3
O
C
1H NMR Studies
At 80 oC, A and B start disappearing and C forms.
After 15 min at 80 oC, only C is observed.
OMeMeO
MeO CO2Na DMSO-d6, rt
Pd OO
OCF3F3C
O
(1.2 equiv)
O
O
PdO
O
O
O
PdO CF3
OOMe
MeO
OMe
OMe
MeO
OMe
OMe
OMe
OMe
A:B ratio = 6:1
+
A
B
+
Mechanistic Studies – Insight into the Decarboxylation StepMechanistic Studies – Insight into the Decarboxylation Step
OMeMeO
MeO CO2Na DMSO-d6, room temperature
Pd OO
OCF3F3C
O
(1.2 equiv)O
O
PdO
O
O
O
PdO CF3
OOMe
MeO
OMe
OMe
MeO
OMe
OMe
OMe
OMe
+
A B
13C
13C NMR Studies
After 8 min at 60 oC, C and 13CO2 observed
Pd
OMe
MeO
OMe
OCF3
O
C
13CO2+
X-Ray of Palladium IntermediateX-Ray of Palladium Intermediate
Proposed Mechanism for the Decarboxylation StepProposed Mechanism for the Decarboxylation 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
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
Pd(O2CCF3)2DMSO-d6,
23 °CMeO
MeO OMe
O
ONaMeO
MeO OMe
O
O Pd O2CCF3
DMSO
DMSO
80 °COPd
O
DMSO
F3CCO2
MeOOMe
MeOPd O2CCF3
DMSO
DMSO
OMe
MeO
MeO
CO2
rate-determining step
- Conclusion: electron-deficient Pd center is needed for decarboxylative palladation
Final Steps: Alkene Insertion and Final Steps: Alkene Insertion and ββ-Hydride Elimination-Hydride Elimination
R alkene insertion
ß-hydrideeliminationPd O2CCF3
DMSO
DMSO
MeOMeO
R
Pd(II)
H
MeO
R
+
OMe
OMe OMe
OMe
OMe
MeO
NMR, X-ray, and deuterium experiments indicate the final steps are alkene insertion and
β-hydride elimination (similar to Heck reactions involving aryl halide)
However, NMR studies indicate a reactivity pattern opposite to that of Heck reactions of aryl halides,
that is:
CNCO2tBu> >
Competition ExperimentsCompetition Experiments
CO2H
OMeMeO
I
OMeMeO
I
OMeMeO
Pd(O2CCF3)2 (20 mol%), AgCO3,
5% DMSO-DMF, 80 °C, 24 h
OMeMeO
R
+
+
+
OMeMeO
R
OMeMeO
R
Pd(OAc)2 (10 mol%), NaHCO3,
nBu4NBr, DMF, 110 °C, 30 h
Pd(PPh3)4 (10 mol%), Et3N, DMF, 110 °C, 30 h
CN CO2tBu Ph+ +
(1 equiv) (1 equiv) (1 equiv)
CN CO2tBu Ph+ +
(1 equiv) (1 equiv) (1 equiv)
CN CO2tBu Ph+ +
(1 equiv) (1 equiv) (1 equiv)
R = CN < CO2tBu < Ph
1 : 2 : 2.7
R = CN < CO2tBu < Ph
17 : 7 : 1
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 CouplingsOther Interesting Transition-Metal Catalyzed Decarboxylative Couplings
OMe
OMe
CO2H
R
Pd(O2CCF3)2 (20 mol%),
CF3CO2H (10 equiv),
5% DMSO-DMF, 70 °C
OMe
OMe
H
R
Dickstein, J. S.; Mulrooney, C. A.; O'Brien, E. M.; Morgan, B. J.; Kozlowski, M. C. Org. Lett. 2007, 9, 2441.
CO2H
R
ArAr
R
Ar
Ar
Ar
Ar
[Cp*IrCl2]2 (2 mol%), Ag2CO3,
o-xylene, 160 °C, 6h+
Ueura, K.; Satoh, T.; Miura, M. J. Org. Chem. 2007
BnS OH
O O
H R
O
Cu(2-ethylhexanoate)2(20 mol%),
wet THF, air, 23 °C
NH
NMeO
+
(22 mol%)
BnS R
O OH
Lalic, G.; Aloise, A. D.; Shair, M. D. J. Am. Chem. 2003, 125, 2852.
The EndThe End
I Love CO2!
Albert Arnold (Al) Gore Jr.Nobel Peace Prize 2007 and future CO2 lover