Wenjun Zhao Department of Chemistry Michigan State University Nov. 24 th , 2010 S S RECENT DEVELOPMENTS IN DECARBOXYLATIVE COUPLING REACTIONS
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Wenjun Zhao Department of Chemistry Michigan State University
Nov. 24th, 2010
S S
RECENT DEVELOPMENTS IN DECARBOXYLATIVE COUPLING REACTIONS
OUTLINE
• Introduction of Decarboxylative Coupling Reactions
• Different Types of Decarboxylative Coupling Reactions
• Applications in Organic Synthesis
I. Intra-molecular Couplings
II. Inter-molecular Couplings
CO2
R2X R1 R2R1 OH(M)
O
• Intra-molecular couplings
• Inter-molecular couplings
R1 O
OR2 R1 R2
CO2
CLASSIFICATION OF COUPLING REACTIONS
CO2
R2X
R1 R2
R1 OH
O
R1 O
OR2
or
DECARBOXYLATIVE COUPLING REACTIONS
Stable, easy to make and store
Formally neutral conditions
Functional group compatibility
SOO
PhR1 R2
R
Generally inexpensive
ArR1
Ar Ar
NEWG
R2
R1
R1
O
R2 R3
Ar R
O
Goossen, L. J.; Rodriguez, N.; Goossen, K. Angew. Chem. Int. Ed. 2008, 47, 3100-3120 Fang, P.; Li, M.; Ge, H. J. Am. Chem. Soc. 2010, 132, 11898-11899
OUTLINE
• Introduction of Decarboxylative Coupling Reactions
• Different Types of Decarboxylative Coupling Reactions
• Applications in Organic Synthesis
I. Intra-molecular Couplings
II. Inter-molecular Couplings
1980 2004 recent
Tsuji :
Saegusa :
INTRA-MOLECULAR DECARBOXYLATIVE COUPLING REACTIONS
Tsuda, T.; Chujo, Y.; Nishi, S.; Tawara, K.; Saegusa, T. J. Am. Chem. Soc. 1980, 102, 6381-6384
Discovery of Pd-catalyzed Decarboxylative Allylic Alkylation (DAA)
O
OO O5 mol % Pd(OAc)2
20 mol % PPh3THF, reflux
O
OO O5 mol % Pd(PPh3)4
DMF, rt
96 %
Shimizu, I.; Yamada, T.; Tsuji, J. Tetrahedron. Lett. 1980, 21, 3199-3202
Quantitative yield
96%
2004 1980 recent
INTRA-MOLECULAR DECARBOXYLATIVE COUPLING REACTIONS
Tunge :
Stoltz :
Burger, E. C.; Tunge, J. A. Org. Lett. 2004, 6, 4113-4115
Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044-15045
PPh2 N
O
Decarboxylative Asymmetric Allylic Alkylation (DAAA)
Ph2P
HNO
PPh2
NHO
96% yield 88% ee
81% yield 98% ee
Ligand A
Ligand B
Me O
O O5 mol % Pd2(dba)310 mol % Ligand A
25 °C, C6H6- CO2
Me
O
O O
OO 5 mol % Pd2(dba)3
12.5 mol % Ligand B
THF, 25 °C- CO2
1980 Recent
INTRA-MOLECULAR DECARBOXYLATIVE COUPLING REACTIONS
Tunge :
Stoltz :
Burger, E. C.; Tunge, J. A. Org. Lett. 2004, 6, 4113-4115
Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044-15045
Decarboxylative Asymmetric Allylic Alkylation
Improvement on selectivity
Extended substrate scope
Mechanistic study
2004
96% yield 88% ee
81% yield 98% ee
INTRA-MOLECULAR DECARBOXYLATIVE COUPLING REACTIONS
A. sp3_ sp3 C-C Bond Formation
• Decarboxylative Allylation of Enolates
• Decarboxylative Allylation with Sulfones
B. sp3_ sp C-C Bond Formation
C. Decarboxylative Allylation Cascade
O O
O
O2.5 mol % Pd2(dba)3 CHCl35.5 mol % Ligand
Toluene, 23 °C+
O
PALLADIUM-CATALYZED DAAA OF ENOL CARBONATES
Trost, B. M.; Xu, J.; Schmidt, T. J. Am. Chem. Soc. 2009, 131, 18343-18357
PhPh
HNNHOO
PPh2 Ph2P
HNNHOO
PPh2 Ph2P
HNNHOO
PPh2 Ph2P
HNNHOO
PPh2 Ph2P
Entry Ligand ee % Yield % 1 (R,R)-L1 31 73 2 (R,R)-L2 61 73 3 (R,R)-L3 60 85 4 (R,R)-L4 85 88
(R,R)-L1 (R,R)-L4 (R,R)-L2 (R,R)-L3
b
MECHANISM OF DECARBOXYLATIVE ALLYLIC ALKYLATION
O
R1R2
R3
PdLn
CO2
Decarboxylation
R1
O
R2 R3
Recombination
O O
O
R2
R3
R1
O O
O
R2
R3
R1
PdLn
Pd(0)Ln
Coordination& Ionization
Trost, B. M.; Xu, J.; Schmidt, T. J. Am. Chem. Soc. 2009, 131, 18343-18357
enantioselectivity-determining step
O O
O
2.5 mol % Pd2(dba)3 CHCl3
5.5 mol % L4, Dioxane, rt
O
Favored
ORIGIN OF ENANTIOSELECTIVITY OF DAAA
Trost, B. M.; Xu, J.; Schmidt, T. J. Am. Chem. Soc. 2009, 131, 18343-18357
HNNHOO
PPh2 Ph2P89% yield 99% ee
Case A Case B
O O
ReRe
PdP P
Linker Linker
Chiral Scaffold
Disfavored
SUBSTRATE SCOPE OF DAAA
88% 99% ee
94% 91% ee
99% 95% ee
99% 93% ee
78% 94% ee
80% 94% ee
95% 73% ee
89% 88% ee
Trost, B. M.; Xu, J.; Schmidt, T. J. Am. Chem. Soc. 2009, 131, 18343-18357
OMe
OBn
BnO
OMe
F
O
Ph
O
N
OMe
O
Ph
O
OMe
O
HNNHOO
PPh2 Ph2P
(R,R)-L4
R1
O O
O
2.5 mol % Pd2(dba)3 CHCl3
5.5 mol % L4, Dioxane, rt R1
O
R2 R2
R4
R4
O O
O
O
Ar
O O
ArH
RO O
ArMe
2 mol %Pd(PPh3)4
toluene, rtR = Me
2 mol %Pd(PPh3)4
toluene, rtR = H
X X X
STEREODIVERGENCE IN DECARBOXYLATIVE ALLYLATION
Complete reversal in stereochemical outcome of the allylation
Product Yield % trans:cis Product Yield % trans:cis
90 20:1 72 1:18
90 20:1 90 1:13
Chattopadhyay, K.; Jana, R.; Day, V. W.; Douglas, J. T.; Tunge, J. A. Org. Lett. 2010, 12, 3042-3045
trans cis
O O
HOMe
MeO
Ph
O O
HOMe
MeO
CF3
O O
MeOMe
MeO
Ph
O O
Me
MeO
OMe
OMe
Potential explanation: Base-catalyzed epimerization causes the product to form the more stable cis compound.
Chattopadhyay, K.; Jana, R.; Day, V. W.; Douglas, J. T.; Tunge, J. A. Org. Lett. 2010, 12, 3042-3045
O OMeO
OMe
OMe
0.015 mmol 1a2 mol % Pd(PPh3)4
toluene, rt
O OMeO
OMe
OMetrans
0.057 mmol, dr = 6.7:1trans
0.057 mmol, dr = 5.6:1
1a
INITIAL EXPLANATION FOR THE SELECTIVITY
1a
O OMeO
OMe
OMe
H
O OMeO
OMe
2 mol % Pd(PPh3)4
toluene, rtO
OH
OMe
O OMeO
OMe
OMe
H
O O
Ar
O
O
HO O
Ar
O
O
H
Pd
protontransfer
X X
O O
Ar
O
OH
PdX
PROPOSED MECHANISM FOR THE DIASTEREOSELECTIVITY
Chattopadhyay, K.; Jana, R.; Day, V. W.; Douglas, J. T.; Tunge, J. A. Org. Lett. 2010, 12, 3042-3045
Carboxylic acid
Cat.
allylation O O
ArO
OH
X
B
H
- CO2O OH
Ar
X
O O
Ar
HOO
Ar
H Protonation
X
X
H HB
Chattopadhyay, K.; Jana, R.; Day, V. W.; Douglas, J. T.; Tunge, J. A. Org. Lett. 2010, 12, 3042-3045
OBSERVATION OF INTERMEDIATE CARBOXYLIC ACID O OMeO
OMe
2 mol % Pd(PPh3)4
toluene-d8, rtPh O
OH
O OMeO
PhOMe
O
OH
O OMeO
OMe
O O
Ar
O
O
MeO O
Ar
O
O
Me
Pd
- CO2O O
ArMe
PdX X X
O O
Ar
MeOO Me
Ar
H allylation
Pd
X
X
PROPOSED MECHANISM FOR THE DIASTEREOSELECTIVITY
Chattopadhyay, K.; Jana, R.; Day, V. W.; Douglas, J. T.; Tunge, J. A. Org. Lett. 2010, 12, 3042-3045
Cat.
INTRA-MOLECULAR DECARBOXYLATIVE COUPLING REACTIONS
A. sp3_ sp3 C-C bond formation
• Decarboxylative allylation of enolates
• Decarboxylative allylation with sulfones
B. sp3_ sp C-C bond formation
C. Decarboxylative Allylation Cascade
Entry Reactant ee(%) Product Yield(%) ee(%) cee(%)
1 94 95 92 98
2 80 99 80 99
3 94 82 92 99
4 98 85 95 97
PhO2S
MeO O
PhO2S
MeO
O
O O
STEREOSPECIFIC DECARBOXYLATIVE ALLYLATION OF SULFONES
Weaver, J. D.; Ka, B. J.; Morris, D. K.; Thompson, W.; Tunge, J. A. J. Am. Chem. Soc. 2010, 132, 12179-12181
conservation of enantiomeric excess(cee) = 100% × (product ee)/(reactant ee)
O
OS
Ar Me
OO
PhS
Ar Me
OO
Ph2 mol % Pd(PPh3)4
toluene, rtR1
R2 R2
R1
PhO2S
MeOSiMe2tBu
PhO2S
MeO
O
OSiMe2tBu
PhO2S
Bn MeO
OPhO2S
Bn Me
PhO2S
MeO
O
Br
PhO2S
Me
Br
PROPOSED PATHWAYS
Weaver, J. D.; Ka, B. J.; Morris, D. K.; Thompson, W.; Tunge, J. A. J. Am. Chem. Soc. 2010, 132, 12179-12181
O
OHS
R R'
OO
PhCO2S
R R'
OO
Ph
conditions
toluene - d8
S
R R'
OO
PhH
R R’ Conditions Pd source time % Conv. Me Bn 95 °C, Et3N none 45min 25 Me Bn 95 °C, Et3N 10 mol % Pd(OAc)2 45min 27 Me H 23 °C, Cs2CO3 none 36h 59
Me H 23 °C, Cs2CO3 10 mol % Pd(OAc)2 36h 59
Experiment 1 Is Pd involved in Decarboxylation step?
O
OS
Ph Me
OO
PhPdLn
S
Ph Me
OO
PhPdLn
path 2
- CO2
O
OS
Ph Me
OO
Ph O
OS
Ph Me
OO
PhPdLn S
Ph Me
OO
PhPdLn
path 1
- CO2
PdLnPath 1
Path 2
Pd
CO2CH3
OSO2Ph
Cl Ph
O
Pd
CO2CH3
SO2Ph
Cl Ph
CO2CH3
Cl Ph
SO2Ph- CO2
Pd
CO2CH3
OSO2Ph
Cl Ph
O
Pd
CO2CH3
SO2Ph
Cl Ph
CO2CH3
SO2Ph
Cl Ph
- CO2
Weaver, J. D.; Ka, B. J.; Morris, D. K.; Thompson, W.; Tunge, J. A. J. Am. Chem. Soc. 2010, 132, 12179-12181
Path 2
Not observed
49 %
PROPOSED PATHWAYS
CO2CH3
OSO2Ph
Cl Ph
O PdLn Path 1
Experiment 2 Double SN2 or single SN2 ?
EXPLANATION OF THE STEREOCHEMISTRY
Weaver, J. D.; Ka, B. J.; Morris, D. K.; Thompson, W.; Tunge, J. A. J. Am. Chem. Soc. 2010, 132, 12179-12181
Product enantiomer enantiomer
S
Ph Me
OO
Phinvertion
SPhMe
OO
Ph
PdLn
S PhMe
OO
Ph
PdLn
S
Me Ph
OO
Ph
PdLn
S
Ph Me
OO
Ph
O
OS
Ph Me
OO
Ph - CO2
PdLn S
Ph Me
OO
Ph PdLn
S
Me Ph
OO
Phrotation
Barrier > 9.9 kcal/mol Barrier < 2 kcal/mol
INTRA-MOLECULAR DECARBOXYLATIVE COUPLING REACTIONS
A. sp3_ sp3 C-C bond formation
• Decarboxylative allylation of enolates
• Decarboxylative allylation with sulfones
B. sp3_ sp C-C bond formation
C. Decarboxylative Allylation Cascade
Pd
ReductiveElimination
R
R
Ln
Rayabarapu, D. K.; Tunge, J. A. J. Am. Chem. Soc. 2005, 127, 13510-13511
O
O
RR
10 mol % Pd(PPh3)4
toluene, 75 °C, 2h
O
O
O
PdLn
CO2
Pd(0)Ln
Coordination& Ionization
Decarboxylation
R
OR
PdLn
R
sp-sp3 COUPLING SYNTHESIS OF 1,4-ENYNES
R
Rayabarapu, D. K.; Tunge, J. A. J. Am. Chem. Soc. 2005, 127, 13510-13511
O
O
RR
10 mol % Pd(PPh3)4
toluene, 75 °C, 2h
CO2CH3
OPh
O 10 mol % Pd(PPh3)4
toluene, 75 °C, 6h
CO2CH3
Ph
sp-sp3 COUPLING SYNTHESIS OF 1,4-ENYNES
Pd
ReductiveElimination
R
R
Ln
Rayabarapu, D. K.; Tunge, J. A. J. Am. Chem. Soc. 2005, 127, 13510-13511
Acetylide is bound to Pd prior to reductive elimination
O
O
RR
10 mol % Pd(PPh3)4
toluene, 75 °C, 2h
O
O
O
PdLn
CO2
Pd(0)Ln
Coordination& Ionization
Decarboxylation
R
OR
PdLn
R
sp-sp3 COUPLING SYNTHESIS OF 1,4-ENYNES
sp-sp3 COUPLING SYNTHESIS OF 1,4-ENYNES
Entry R1 R2 Product Yield %
1 77
2 84
3 82
4 70
5 81
Rayabarapu, D. K.; Tunge, J. A. J. Am. Chem. Soc. 2005, 127, 13510-13511
10 mol % Pd(PPh3)4
toluene, 75 °C, 2hOR2
O
R1R1 R2
PhOMe
PhMe
Me
PhPh
PhCl
TMSPh
Cl
OMe
Ph
Me Me
Ph
Ph
TMS
Ph
Ph
Ph
Me4
O
O
RAr
5 mol % Pd(PPh3)4
toluene, 110 °C, 15hAr
R
sp-sp3 COUPLING BENZYLATION
78 % 79 % 75 %
89 % 93 % (10 mol % Ph(PPh)4)
78 % 74 %
Torregrosa, R. R. P.; Ariyarathna, Y., Chattopadhyay, K.; Tunge, J. A. J. Am. Chem. Soc. 2010, 132, 9280-9282
81 % (10 mol % Ph(PPh)4)
TMS
NPhPh
Ph NBoc
NMe
NMe
PhOMe
Pd
INTRA-MOLECULAR DECARBOXYLATIVE COUPLING REACTIONS
A. sp3_ sp3 C-C bond formation
• Decarboxylative allylation of enolates
• Decarboxylative allylation with sulfones
B. sp3_ sp C-C bond formation
C. Decarboxylative Allylation Cascade
GENERAL MECHANISM OF DECARBOXYLATIVE ALLYLIC ALKYLATION
Trost, B. M.; Xu, J.; Schmidt, T. J. Am. Chem. Soc. 2009, 131, 18343-18357
O
O
R1
CO2
Pd(0)Ln
Decarboxylation
R1
O
O
R1
CoordinationIonizationAllylation
PdLnR1PdLn
PLAUSIBLE CATALITIC CYCLE FOR THE CASCADE
Streuff, J.; White, D. E.; Virgil, S. C.; Stoltz, B. M. Nat. Chem. 2010, 2, 191-196.
O
O
CO2
RO
PdN P
L L
*O
RR'
NC CN
OR
R'
CN
CN PdPH2N
*
RO
PdN P
*
R'CN
CN
conjugate addition
oxidative additiondecarboxylation
reductiveelimination
OR
R'CN
CN
5 mol % Pd2(dba)3
12.5 mol % (s)-Ligand1,4-dioxane, 40 °C
ORR'
NC CN+
ORR'
NC CN+
O
O
X
OR
PhCN
CN
5 mol % Pd2(dba)3
12.5 mol % (s)-Ligand1,4-dioxane, 40 °C X
OR
Ph
NC CN+
X
OR
Ph
NC CN+
O
O
OBnPh
NC CN
OEtPh
NC CN
OMePh
NC CN
ONC CN
Ph
CO2Et
Streuff, J.; White, D. E.; Virgil, S. C.; Stoltz, B. M. Nat. Chem. 2010, 2, 191-196.
Substrate Scope of the R group
A PALLADIUM-CATALYSED ENOLATE ALKYLATION CASCADE
a b
99% yield 87% ee
dr = 6.1:1
91% yield 99% ee
dr = 3.5:1
49% yield 88% ee
dr = 1.9:1
56% yield 89% ee
dr = 3.3:1
X = ,CH2 N(Bn)
97% yield 89% ee
dr = >20:1
NBn
OMePh
NC CN
O
NC CN
OO
NC CN
Me
O
NC CN
O
NC CN
OMe
O
NC CN
OO
O
NC CN
OMe
Substrate Scope of the R’ group
Streuff, J.; White, D. E.; Virgil, S. C.; Stoltz, B. M. Nat. Chem. 2010, 2, 191-196.
87% yield 88% ee
dr = 7.8:1
A PALLADIUM-CATALYSED ENOLATE ALKYLATION CASCADE
a b
78% yield 86% ee
dr = 8.2:1
99% yield 95% ee
dr = 14:1
76% yield 87% ee
dr = 6.2:1
83% yield 82% ee
dr = 9.4:1
92% yield 81% ee
dr = 3.5:1
OR
R'CN
CN
5 mol % Pd2(dba)3
12.5 mol % (s)-Ligand1,4-dioxane, 40 °C
ORR'
NC CN+
ORR'
NC CN+
O
O
OUTLINE
• Introduction of Decarboxylative Coupling Reactions
• Different Types of Decarboxylative Coupling Reactions
• Applications in Organic Synthesis
I. Intra-molecular Couplings
II. Inter-molecular Couplings
INTER-MOLECULAR DECARBOXYLATIVE COUPLING REACTIONS
1966 2006 Recent
Not practical: low yield, large amount of Cu2O, high temperature & limited reaction scope.
Seminal study
Nilsson, M. Acta Chem. Scand. 1966, 20, 423-426
2002
CO2H
NO2 OMe
80 mol % Cu2O
quinoline, 240 °CNO2
50 %
I
MeO
INTER-MOLECULAR DECARBOXYLATIVE COUPLING REACTIONS
Discovery of decarboxylative Heck-Type reaction
2006 Recent 2002 1966
High catalyst loading. 3 equiv. Ag2CO3 was used.
Myers, A. G.; Tanaka, D.; Mannion, M. R. J. Am. Chem. Soc. 2002, 124, 11250-11251
MeO
MeO OMe
O
OH20 mol % Pd(O2CCF3)2
3 equiv. Ag2CO35 % DMSO - DMF, 120 °C
MeO
MeO OMe91 %
+
CO2H
NO2 CF3
1 mol % Pd(acac)23 mol % CuI
1.2 equiv. K2CO3NMP, 160 °C NO2
93%
Br CF3
INTER-MOLECULAR DECARBOXYLATIVE COUPLING REACTIONS
Practical large scale biaryl synthesis
2002 Recent 2006
1966
Bimetallic catalyst system – Pd/Cu Lower temperature Higher yield
Gooβen, L. J.; Deng, G.; Levy, L. M. Science 2006, 313, 662–664
INTER-MOLECULAR DECARBOXYLATIVE COUPLING REACTIONS
Practical large scale biaryl synthesis by Goossen
2002 2006 1966
Bimetallic catalyst system – Pd/Cu Lower temperature High yield.
Recent
Improvement on reaction efficiency.
Extended substrate scope
Mechanistic study
Gooβen, L. J.; Deng, G.; Levy, L. M. Science 2006, 313, 662–664
A. sp2_ sp2 C-C bond formation
• Olefination of arene
• Biaryl synthesis
• Acylation of arene
B. sp2_ sp C-C bond formation
C. sp2_ sp3 C-C bond formation
D. Carbon-heteroatom bond formation
INTER-MOLECULAR DECARBOXYLATIVE COUPLING REACTIONS
A. sp2_ sp2 C-C bond formation
• Olefination of arene
• Biaryl synthesis
• Acylation of arene
B. sp2_ sp C-C bond formation
C. sp2_ sp3 C-C bond formation
D. Carbon-heteroatom bond formation
INTER-MOLECULAR DECARBOXYLATIVE COUPLING REACTIONS
Goossen, L. J.; Rodriguez, N.; Goossen, K. Angew. Chem. Int. Ed. 2008, 47, 3100-3120
DECARBOXYLATIVE OLEFINATION OF ARENES
L2PdX2
R
O
OPdL
XL
PdL
XL R
R1
Pd LX
L
R
HPdL2X
PdL2
R1R
HX
Ag salt
AgR
O
HO
HX
CO2
R1
Anion exchange
Insertion
b-hydrideelimination
Oxidation
Myers, A. G.; Tanaka, D.; Mannion, M. R. J. Am. Chem. Soc. 2002, 124, 11250-11251
Anion exchange
Insertion
β-Hydride elimination
Oxidation
MeO
MeO OMe
O
OH20 mol % Pd(O2CCF3)2
3 equiv. Ag2CO35 % DMSO - DMF, 120 °C
MeO
MeO OMe91 %
+
Entry Cat. Loading Oxidation condition Yield %
1 10 mol % O2 (1 atm) 90
2 5 mol % O2 (1 atm) 73
3 5 mol % O2 (1.8 atm) 89
4 10 mol % air (1 atm) 34
5 10 mol % air (1.8 atm) 36
O2 as TERMINAL OXIDANT IN DECARBOXYLATIVE HECK COUPLING
Oxygen as the terminal oxidant: Pd(0) Pd(II)
Fu, Z.; Huang, S.; Su W.; Hong, M. Org. Lett. 2010, 12, 4992-4995
O2
OMeCOOH
MeO+
O
OMe
OMe
MeO
OMe
OPd(OAc)2O2 or air
5 % DMSO-DMF120 °C, 10h
OMe
OMe
O
BrOMe
OMe
OMe
O
H2NCl
OMe
OMe
OMe
O
MeO OMe
O
OtBu
MeO OMe MeO OMe
F F
F
F
F
SUBSTRATE SCOPE OF THE HECK-TYPE COUPLING
64 % 36 %
(O2 3.2atm 85% ) 88 %
94 % 90 % 93 %
Fu, Z.; Huang, S.; Su W.; Hong, M. Org. Lett. 2010, 12, 4992-4995
COOH+
10 mol % Pd(OAc)2, O2 (1 atm)
5% DMSO-DMF120 °C, 10h
OMe
OOMe
O
R1 R1
COOH
MeO+
OMeR2
10 mol % Pd(OAc)2, O2 (1 atm)
5% DMSO-DMF120 °C, 10h
MeO OMe
R2
A. sp2_ sp2 C-C bond formation
• Olefination of arene
• Biaryl synthesis
• Acylation of arene
B. sp2_ sp C-C bond formation
C. sp2_ sp3 C-C bond formation
D. Carbon-heteroatom bond formation
INTER-MOLECULAR DECARBOXYLATIVE COUPLING REACTIONS
EXAMPLES OF DRUGS CONTAINING BIARYL MOTIFS
Goossen, L. J.; Deng, G.; Levy, L. M. Science 2006, 313, 662–664
Biphenomycin B Valsartan
Telmisartan
Ar1COOH + Ar2Br(or Ar2Cl)
1 mol % Pd(acac)23 mol % CuI
1.2 equiv. K2CO3NMP, 160 °C, 24h
Ar1 Ar2
DECARBOXYLATIVE BIARYL SYNTHESIS
entry ArCOOH ArBr (orArCl) product Yield %
1 99
2 96
3 72
4 66
Goossen, L. J.; Deng, G.; Levy, L. M. Science 2006, 313, 662–664
NO2
COOH
NO2
COOH
NO2
COOH
ClBr
CNCl
CH3Br
COOH
O O
CH3Br
[Cu]+X-
C
R
OO
[Cu]+
CO2
decarboxylation
R
[Cu]
C
R
OO
anionexchage
CATALYTIC CYCLE OF THE BIMETALLIC SYSTEM
Ar1COOH + Ar2Br(or Ar2Cl)
Pd/Cu catalystK2CO3
- CO2, -H2O, -KBrAr1 Ar2
L2PdR'
X
L2Pd(0)
R'X
oxidativeaddition
L2PdR'
R
trans-metallation
R'
R
reductiveelimination
[Cu]+ = [Cu(II)X- ]+, [Cu(I)L2]+, ... ; X = I, Br, Cl
Goossen, L. J.; Deng, G.; Levy, L. M. Science 2006, 313, 662–664
SYNTHESIS OF BIARYLS USING ARYL TOSYLATES INSTEAD OF ARYL HALIDES
RCO2K
+ TsOAr RAr
2.5-7.5 mol % Cu2O5 mol % Pd(acac)2
7.5 mol % XPhos, NMPiPriPr
iPr
PCy2
NO2 NO2
CHO
NO2
NMe2
NO2
O
OEt
NC
NC
MeO
NO2
73 %
74 % 89 % 96%
75 % 83 % 85 %
Goossen, L. J.; Rodriguez, N.; Lange, P. P.; Linder, C. Angew. Chem. Int. Ed. 2008, 47, 3100-3120
XPhos
A. sp2_ sp2 C-C bond formation
• Olefination of arene
• Biary synthesis
• Acylation of arene
B. sp2_ sp carbon bond formation
C. sp2_ sp3 carbon bond formation
D. Carbon-heteroatom bond formation
INTER-MOLECULAR DECARBOXYLATIVE COUPLING REACTIONS
NH OO NH OO
Ac
NH OO
F
NH OO
CO2H
NH OO
OMe
NH OO NH OO
F
NH OO
ROOM TEMPERATURE DECARBOXYLATIVE ACYLATION OF ARENES via C-H ACITIVATION
96% 79% 83% 89%
90% 71% 76% 94%
Fang, P.; Li, M.; Ge, H. J. Am. Chem. Soc. 2010, 132, 11898-11899
HN OH R2
OHR2
OO
O
NHO
+
10 mol % Pd(O2CCF3)22 equiv. (NH4)2S2O8
Diglyme, rtR1 R1
PROPOSED MECHANISM OF DECARBOXYLATIVE ACYLATION OF ARENES
Fang, P.; Li, M.; Ge, H. J. Am. Chem. Soc. 2010, 132, 11898-11899
Pd(II)
Pd(0)
HNR1
HX
CO2
Oxidation
O
Pd(II)X2
NHAc
NHAc
O
R1Pd(II)
X
O
O
R2HO
OR2
O
Pd(II)NHAc
R2
O
NHAcO
R2
R1
R1
R1
A. sp2_ sp2 C-C bond formation
• Biary synthesis
• Olefination of arene
• Acylation of arene
B. sp2_ sp C-C bond formation
C. sp2_ sp3 C-C bond formation
D. Carbon-heteroatom bond formation
INTER-MOLECULAR DECARBOXYLATIVE COUPLING REACTIONS
SYNTHESIS OF SYMMETRICAL DIARYLALKYNES
Park, K.; Bae, G.; Moon, J.; Choe, J.; Song, K. H.; Lee, S. J. Org. Chem. 2010, 75, 6244-6251
Method A:
Method B:
Entry ArX Product Yield % (method A)
Yield % (method B)
1 95 93
3 95 91
4 88 84
5 97 83
OTf
I
OMe OMe MeO
Br
O
H
O
H
O
HBr
+ HO
OHAr1 Ar1
5 mol % Pd(PPh3)2Cl210 mol % dppb
DBU, DMSO, 80°C
Ar1X
+O
OHAr2 Ar2
5 mol % Pd(PPh3)2Cl210 mol % dppb
DBU, DMSO, 110°C
O
HOAr2X
Sonogashira
I
R1
Br
R2
+ + HO
OH
5 mol % Pd(PPh3)Cl210 mol % dppb
DBU, DMSO50 °C, 5h
80 °C 6h
R1 R2
SYNTHESIS OF UNSYMMETRICAL DIARYLALKYNES
-CO2
One pot--The combination of Sonogashira coupling and decarboxylative coupling
Sonogashira coupling
Decarboxylative coupling
Park, K.; Bae, G.; Moon, J.; Choe, J.; Song, K. H., Lee, S. J. Org. Chem. 2010, 75, 6244-6251
HO
OH
O
OHR1
I
R1
+
5 mol % Pd(PPh3)Cl210 mol % dppb
DBU, DMSO50 °C, 5h
Br
+
R2
O
OHR1 R1 R280 °C, 6h
Entry ArI ArBr Product Yield %
1 68
2 75
3 73
4 65
5 89
SUBSTRATE SCOPE
I
I
I
I
Br
Cl Cl
SBr
S
O
Me
O
MeBr
I
Me
NMeBr
N
Park, K.; Bae, G.; Moon, J.; Choe, J.; Song, K. H., Lee, S. J. Org. Chem. 2010, 75, 6244-6251
One pot--The combination of Sonogashira coupling and decarboxylative coupling
I
R1
Br
R2
+ + HO
OH
5 mol % Pd(PPh3)Cl210 mol % dppb
DBU, DMSO50 °C, 5h
80 °C 6h
R1 R2
N
BrN
A. sp2_ sp2 C-C bond formation
• Biary synthesis
• Olefination of arene
• Acylation of arene
B. sp2_ sp C-C bond formation
C. sp2_ sp3 C-C bond formation
D. Carbon-heteroatom bond formation
INTER-MOLECULAR DECARBOXYLATIVE COUPLING REACTIONS
DECARBOXYLATIVE sp2-sp3 COUPLING O
PPh2PPh2
Xant-Phos
Shang, R.; Yang, Z.; Zhang, S.; Liu, L. J. Am. Chem. Soc. 2010, 132 , 14391–14393
NN
N O
O
N
OMe
N
OTs
79% 88% 73% (X = OTf 76%)
72%
N
SMe
89% 84%
NCl
S
N
OMeO
N
F
86%
N
61% 85% 78%
Substrate scope of carboxylate
Substrate scope of Aryl Halide
NCOOK + ArX
NAr
X = Br, OTf
0.5-2 mol % Pd2(dba)3
1.5-6 mol % Xant-Phos150 °C, diglyme
R
N
CF3
LnPd(0)
PdL
XL
PdL
ArL
NPd LAr
L
Ar-X
NCO2
RAr
O
K
KX
O
N
RO
OCO2
NPd LAr
LCH2
CH2
Pd LAr
LN
NAr
PROPOSED MECHANISM FOR THE sp2-sp3 COUPLING
Shang, R.; Yang, Z.; Zhang, S.; Liu, L. J. Am. Chem. Soc., 2010, 132 , 14391–14393
A. sp2_ sp2 carbon bond formation
• Biary synthesis
• Olefination of arene
• Acylation of arene
B. sp2_ sp carbon bond formation
C. sp2_ sp3 carbon bond formation
D. Carbon-heteroatom bond formation
INTER-MOLECULAR DECARBOXYLATIVE COUPLING REACTIONS
Jia, W.; Jiao, N. Org. Lett. 2010, 12, 2000-2003
The first intermolecular Csp-heteroatom bond formation via decarboxylation
CARBON-HETEROATOM BOND FORMATION
84 %
76 %
68 % 75 %
68 % 75 %
R1 COOH +
CuCl2 2H2O(10 mol %)Na2CO3 (2.0 equiv)
toluene, 100 °Cunder air
R2
NHR3
Ph NR3
R2
PROPOSED MECHANISM FOR C-N BOND FORMATION
Jia, W.; Jiao, N. Org. Lett. 2010, 12, 2000-2003
R1
O
OXCuII
CuIIX2
BH+X-R1 COOH
CO2
XCuII
R1base
BH+X-H NR2R3
CuII
R1
R2R3N
R1 NR3
R2Cu(0)
2BH+X- + 1/2 O2
2B + H2O
R1 COOH +R2
NHR3
R1 NR3
R210 mol % CuCl2 2H2O
2.0 equiv. Na2CO3
toluene, 100 °Cunder air
OUTLINE
• Introduction of Decarboxylative Coupling
• Classifications of Decarboxylative Coupling
• Applications in Organic Synthesis
I. Intra-molecular Coupling
II. Inter-molecular Coupling
THE SYNTHESIS OF (-)-CYANTHIWIGIN F
O
O
+
O
O
O
OO
O
1. Allyl alcohol NaH, toluene reflux
2. K2CO3, MeI acetone, reflux 51%
O
O
O
O
O
O
Pd(dmdba)2Et2O, 25 °C
78%
PPh2 N
O
O
H
99% ee meso dr = 4.4 : 1
6 steps
O
O
1:1 mixture of racemic : meso
Enquist, J. A., Jr; Stoltz, B. M. Nature 2008, 453, 1228-1231
(-)-Cyanthiwigin F
1.2% overall yield
SYNTHESIS OF TELMISARTAN
O
CO2iPr
+N
N
NH2
NH
iPrO
4 steps
OHON
NN
N n-Pr
Goossen, L. J.; Knauber, T. J. Org. Chem. 2008, 73, 8631-8634
Synthesis of Telmisartan via Decarboxylative cross-coupling
Telmisartan
1. Cu2O, 1,10-phenanthroline Pd2(dba)3, 2-(biphenyl)P(tBu)2 NMP/quinoline, 170 °C, 24h
2. HCl, H2O/iPrOH, 80 °C, 3h 83%
O
CO2iPr
CO2K+
Cl
O
OiPrO2C
35% overall yield
SUMMARY • Decarboxylative Coupling Reactions are powerful synthetic tools for constructing C-C or C-heteroatom bonds.
Starting materials are easy to make and handle
Lowered catalyst loadings make large scale synthesis practical
Wide functional group compatibility
The diversity of the methods allows for various bond-forming processes: sp3-sp3, sp2-sp3, sp-sp3, sp2-sp2, sp2-sp C-C bond formation & C-X bond formation
Lower the temperatures in some inter-molecular reactions will allow for broader reaction scopes.
Increase the activities of catalyst and thus to exploit less activated substrates.
• Further improvements are necessary.
Acknowledgement
• Dr. Wulff
• Dr. Maleczka
• Dr. Jackson
• Dr. Smith
• Hong, Li, Yong, Anil, Munmun, Nilanjana, Wynter, Dima, Xin, Victor
• Li, Yimeng, Family
Thank you all
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