recent developments in decarboxylative coupling reactions · wenjun zhao department of chemistry...

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






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


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


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


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


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


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


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.


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


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


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


Cat.


A.  sp3_ sp3 C-C bond formation

•  Decarboxylative allylation of enolates

•  Decarboxylative allylation with sulfones

B.  sp3_ sp C-C bond formation


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


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


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


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

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


Decarboxylation

R

OR

PdLn

R

sp-sp3 COUPLING SYNTHESIS OF 1,4-ENYNES

R


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


Pd

ReductiveElimination

R

R

Ln


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


Decarboxylation

R

OR

PdLn

R



Entry R1 R2 Product Yield %

1 77

2 84

3 82

4 70

5 81


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

GENERAL MECHANISM OF DECARBOXYLATIVE ALLYLIC ALKYLATION


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


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


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






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


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


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


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


•  Olefination of arene

•  Biaryl synthesis

•  Acylation of arene


C.  sp2_ sp3 C-C bond formation

D.  Carbon-heteroatom bond formation


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



•  Biaryl synthesis






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


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


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



•  Biary synthesis


B.  sp2_ sp carbon bond formation

C.  sp2_ sp3 carbon bond formation



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

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

+


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


DBU, DMSO50 °C, 5h

80 °C 6h

R1 R2

N

BrN

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




B.  sp2_ sp carbon bond formation

C.  sp2_ sp3 carbon bond formation



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


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

recent developments in decarboxylative coupling reactions · wenjun zhao department of chemistry...

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