Decarboxylative Cross-Coupling (NTJ) - Princeton University · The First Example of a Decarboxylative Cross-Coupling Reaction! In 1958, Nilsson reported his findings regarding an

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."



! 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.


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


PdX2

PdX

Ar

Pd

R

Pd Ar

X

ArCO2H

CO2 + HXAg2CO3

2 Ag(0) + HCO3

RRAr

HX

Myers: Mechanistic Studies


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



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



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



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


OMeMeOn n

O O O

O

MeMe

O

Me Me

81% 92% 65% 30% 86%



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


OMeMeOn n

O O O

O

MeMe

O

Me Me

81% 92% 65% 30% 86%



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%



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


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]


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




R R

OH

O

BrK2CO3, MS-3Å

NMP, 160 ˚C, 24 h

1 mol% Pd(acac)2

3% CuI / 5% phen


Cl

CO2H CO2H

CO2H

NHAC

Cl

57% 79% 42%

0%

CO2H CO2H CO2H

34% 0% 0%

CO2H

SO2Me

CN NHPh

MeO

62%

S

CO2H



! 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


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




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




! 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




! 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


! 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


! The optimized reaction conditions are useful for many heteroaromatic acids.

Y

X

Y

X Ph

BrR R

CO2H


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


! Biproduct of reaction using 2-furancarboxylic acid could shed light on the mechanism.

O

Br

CO2H


Bu4NCl ! H2O, CsCO3

DMF, µW, 170 ˚C

8 minutes

+

O OPh Ph

Ph

41% main biproduct

Proposed Mechanism of Heteroaromatic Acid Coupling


! Biproduct of reaction using 2-furancarboxylic acid could shed light on the mechanism.

O

Br

CO2H


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


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


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



! 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




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)




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

Decarboxylative Cross-Coupling (NTJ) - Princeton University · The First Example of a Decarboxylative Cross-Coupling Reaction! In 1958, Nilsson reported his findings regarding an

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