Prof. Dr. Lukas J. GooßenFachbereich Chemie - Organische Chemie

Technische Universität Kaiserslautern

Decarboxylative Cross-Coupling Reactions

A Modern Strategy for C-C-Bond Formation

Catalytic Cross-Coupling Reactions

Reactions in which two molecules are connected at positions defined by leaving groups to give a target molecule and a byproduct

Selective bond formation at a given position A-MNo reaction at other functional groups B, C, D…

Cross-coupling reactions are indispensable tools in organic synthesis

A + M + A M

substrate 1 substrate 2 target molecule byproduct,often a salt

E

FG

B

D

E

FG

BCat.

CD

C

O NN

N NOH OH

NH2

I

OH

+ Bu3Sn

O NN

N NOH OH

NH2

OH

+ Bu3Sn IPd-cat.

DMF, RT

V. Nair et al., Chem. Commun. 1989, 878

C-Nucleophiles in catalytic cross-couplings

M. Kosugi,T. Migita, et al., Chem. Lett. 1977, 301; Chem. Lett. 1977, 1423; J. K. Stille, et al., J. Am. Chem. Soc. 1978, 100, 3636; J. Am. Chem. Soc. 1979, 101, 4992.

R1 = alkyl, alkynyl, aryl, vinylR2 = acyl, alkynyl, aryl, benzyl, vinylX = Br, Cl, I, OAc, OP(=O)(OR)2, OTf

R1 X R2 SnR3+ R1 R2Cat. [Pd0Ln]

K. Tamao, M. Kumada, et al., Organometallics 1982, 1, 542; A. Hallberg, et al., Chem. Lett. 1982,1993;Y. Hatanaka, T. Hiyama, J. Org. Chem. 1988, 53, 918; S. E. Denmark, et al., J. Am. Chem. Soc. 1999, 121, 5821.

R1 = alkenyl, aryl, allylR2 = silyl, alkyl, aryl, alkenyl, alkynylX = Cl, Br, I, OSO2CF3, OCO2EtY = Me, F, Cl, ...

R1 X R2 SiY3+ R1 R2Cat. [Pd0Ln]

activator

F−

δ−δ+

M. Nilsson, Acta Chem. Scand. 1966, 20, 423.

R2O

O-M+R2 M- CO2

R1 X R2 CY3+ R1 R2Cat. [Pd0Ln]

?R1 X +

Cat. [Pd0Ln]

R OH

O

R Ar

O RR'

R'

R'

R O

O

R'

cat.

cat.RR O

O

cat. cat.R

O

cat.R

R H

OR"

R'R HR Ar R Ar

ArB(OH)2ArB(OH)2

CO

δ−

CO2activation with coupling reagents

"H" for R = R"CH2CHR'H+

reactions via carboxyl-metal species reactions via acyl-metal species

+δ+

direct conversion

Ar-Hal

Carboxylic Acids as Substrates in Catalysis

Excellent availabilityHuge variety of carboxylic acids are commercially available and cheapMany natural products contain acid functionalitiesEnvironmentally benign syntheses of carboxylic acids by (air) oxidations

At least four reaction modes are conceivable:

Angew. Chem. 2001, 113, 3566JACS 2005, 127, 11102

Angew. Chem. 2002, 114, 1285Angew. Chem. 2004, 116, 1115

ChemComm. 2003, 706Angew. Chem. 2005, 117, 4110

Science 2006, 313, 662JACS 2007, 129, 4824

1st Reaction Mode

Reactions via metal carboxylate speciesAddition of carboxylic acids to multiple bond

R OH

O

R Ar

O RR'

R'

R'

R O

O

R'

cat.

cat.RR O

O

cat. cat.R

O

cat.R

R H

OR"

R'R HR Ar R Ar

ArB(OH)2ArB(OH)2

CO

δ−

CO2activation with coupling reagents

"H" for R = R"CH2CHR'H+

reactions via carboxyl-metal species reactions via acyl-metal species

+δ+

direct conversion

Ar-Hal

ChemComm 2003, 706Angew. Chem. 2005, 117, 4110

Ideal atom economy, extremely mild reaction conditionsHigh selectivities for the Markovnikov product (>20:1)

DMAP as the base: reversal of selectivity! >40:1 anti-Markovnikov!

OH

O

Ph

Heck !

Ru

Cl Cl

ClRu

Cl

O

OPh

O

OPh

+

2 mol% P(Fur)3, Na2CO3

DMAP

4 mol%

1 mol%, Toluol, 60 °C

2 mol% P(p-Cl-C6H4)3, 4 mol%

1st Reaction Mode: Additions to Multiple Bonds

Compare with: T. Mitsudo, Y. Hori, Y. Watanabe, J. Org. Chem. 1985, 50, 1566

O

O

O

O

OO

O

N+O

O

O

ONMe

O

O

O

OF

O

OOH

11

O

O

NHCbz91 % 76 % 99 %

61 %

82 %

87 % 95%72 %

L. Gooßen, J. Paetzold, D. Koley, Chem. Commun. 2003, 706-707

R OH

O

R Ar

O RR'

R'

R'

R O

O

R'

cat.

cat.RR O

O

cat. cat.R

O

cat.R

R H

OR"

R'R HR Ar R Ar

ArB(OH)2ArB(OH)2

CO

δ−

CO2activation with coupling reagents

"H" for R = R"CH2CHR'H+

reactions via carboxyl-metal species reactions via acyl-metal species

+δ+

direct conversion

Ar-Hal

2nd Reaction Mode

Reactions via acyl metalspecies:Carboxylic acids as synthetic equivalents of acyl halides

Angew. Chem. 2001, 113, 3566JACS 2005, 127, 11102

Equilibrium of possible anhydrides forms when mixing carboxylic acids with pivalic anhydridePivalic anhydride does not react, mixed anhydride reacts regiospecifically

O

OHPh O

O O

t-Bu t-Bu O

O O

t-BuPhO

O O

Ph Ph O

O O

t-Bu t-Bu

O

ArPh

ArB(OH)2

O

t-Bu Ar

THF, H2O+ + +

> 70 % < 2 %

55 %40 %5 %

Pd/PR360 °C, 16 h

2nd Reaction Mode: Arylation of Carboxylic Acids

Keya Ghosh

O

O

NO2

O

OH

O

S

OO

O

OO

OEt

ON

O

O

OOH

8

60 % 70 %

75 % 69 % 80 %

48 % 45 %

60 %

with K. Ghosh, Angew. Chem. 2001, 113, 3566

R OH

O

R Ar

O RR'

R'

R'

R O

O

R'

cat.

cat.RR O

O

cat. cat.R

O

cat.R

R H

OR"

R'R HR Ar R Ar

ArB(OH)2ArB(OH)2

CO

δ−

CO2activation with coupling reagents

"H" for R = R"CH2CHR'H+

reactions via carboxyl-metal species reactions via acyl-metal species

+δ+

direct conversion

Ar-Hal

3rd Reaction Mode

Reactions via the decarboxylation of acyl metal species:Carboxylic acids as synthetic equivalents of aryl or alkyl halides

Angew. Chem. 2002, 114, 1285Angew. Chem. 2004, 116, 1115

Decarbonylative olefination of p-nitrophenyl esters

Catalyst: PdCl2/LiCl, No phosphine; isoquinoline stabilizes the PdNitrophenol ester can be regenerated:vSalt-free olefination process is practicable

Alternative: Reaction via enol esters

Ph

O

ONO2

OH

NO2

CO+ +PdCl2 / LiClisoquinolineNMP, 4 h, 160 °C > 90 %

PhCOOH, cat. Sc(OTf)3

Decarbonylative Heck Reactions

O

Ar O

R

ArR

Pd-cat.

O

Ar OH Ru-cat.

acetoneCO+

4 CO2 + 3 H2O

+

+

CH3H

H H

HH

with J. Paetzold, Angew. Chem. 2002, 114, 1285

with J. Paetzold, Angew. Chem. 2004, 116, 1113

Jens Paetzold

4th Reaction Mode

Reactions via decarboxylation of metal carboxylatesCarboxylate salts as synthetic equivalents of aryl metal species

Science 2006, 313, 662JACS 2007, 129, 4824

R OH

O

R Ar

O RR'

R'

R'

R O

O

R'

cat.

cat.RR O

O

cat. cat.R

O

cat.R

R H

OR"

R'R HR Ar R Ar

ArB(OH)2ArB(OH)2

CO

δ−

CO2activation with coupling reagents

"H" for R = R"CH2CHR'H+

reactions via carboxyl-metal species reactions via acyl-metal species

+δ+

direct conversion

Ar-Hal

4th Reaction mode: Opportunities

Biaryls are a privileged motif in pharmaceuticals and functional materialsSyntheses via Suzuki couplings are troublesome in industrial production

N

O

n-Bu CO2H

NN

N NH

Diovan (Valsartan, Novartis)2004 sales: 2.6 bn €

NH

O

NCl

Cl

Boscalid (BASF)ca. 1000 t/a, ca. 150 mio €/a

N

N

OH ON

N

n-Pr

Micardis (Telmisartan, Boehringer)2004 sales: 789 mio €

Biphenomycin B

OHNH2

NH2

OH

O

NH

NH

O

O

OHOH

Synthesis of Biaryls from Carboxylic Acids

Method of choice for regiospecific arylations: Suzuki reactionThe problem in cross-couplings is the synthesis of the carbon nucleophiles

Alternative direct arylations are regioselective not for all arenes

Regiospecific decarboxylative coupling of carboxylatesGeneration of organometallic reagents from simple metal carboxylatesThe carboxylate group predefines the position of C-C-bond formation

NO2

COOH Cl

Cl

ClNO2

+catalyst

- KCl+ CO2

K2CO3

Cl

Cl

Cl

ClMg

Cl

(HO)2B

ClNO2

ClNO2

1) B(OMe)32) HCl

Pd

ClNHO

N

Cl

Boscalid

Mg

Rational Design of a Catalytic Process

Combination of a decarboxylation with a Pd-catalyzed cross-coupling

Key step: decarboxylation of a metal carboxylate to an aryl metal speciesInsertion of the metal into the aromatic C-C bond: Ag+, Cu+, Au+…

L2Pd Pd0-precursor

CO2

L2PdX

R'

R

[Cu]R R'

XR'

L2PdR

R'

X-[Cu]+OO

R

[Cu]+OO

R

1st System: Catalytic in Cu(I), Catalytic in Pd

Decarboxylation at a Cu(I)-phenanthroline complexRemoval of the reaction water via azeotropic distillation or molecular sieves avoids protodecarboxylationTransfer of the aryl group to a phosphine-free palladium co-catalyst

OH

ONO2

+Br

Cl NO2

Cl

0.5 % Pd(acac)2 1.5 % CuI

3 % phenanthroline

1.2 eq. K2CO3, MSNMP, 160 °C

+ CO2

1.5 1 99%

+ catalytic in Pd: 0.5 mol%+ catalytic in Cu: 1.5 mol%+ inexpensive bipyridine as ligand

Christophe Linder

with G. Deng, L. M. Levy, Science 2006, 313, 662;Guojun Deng

Smooth reaction of o-nitrobenzoic with a wealth of aryl bromides...

...and meanwhile also aryl chlorides!

Scope with Regard to the Aryl Halides

Cl

NO2 NO2

CN

NNO2

NO2

OMe

SCH3

NO2 NO2

NO2

NO2

COCH3

NO2

COOEt

NO2

CHO

NO2

NO2

CF3

NO2

97% 86%

98%

69%

62% 67% 99% 62%

87%

99%

80% 93%

Laura Levy

with G. Deng, L. M. Levy, Science 2006, 313, 662;

OH

OR

Cl

R

R'R'

+ + CO2

10% CuI, 1% PdI2,1,10-phenanthroline,(o-biphenyl)P(tBu)2

NMP/quin., 160 °C

69-95%

with B. Melzer, T. Knauber, Angew. Chem. 2008,120,

Scope with Regard to the Carboxylic Acids

„Double-catalytic“ protocol already works for many carboxylic acids, particularly when bearing a coordinating o-substituent

Fine tuning of the catalyst is required for every substrate

Some other carboxylates also work but still require stoichiometric amounts of Cu

MeO

O

41%

69%

43%

65%

S

Cl

CHO

F

NHNHO

82% 58%

76%

91%42%

CN

71%

Cl

COOiPr

51%

SO2Me70%

Nuria Rodriguez with N. Rodríguez, B. Melzer, C. Linder, G. Deng, L. M. Levy, J. Am. Chem. Soc. 2007, 129, 4824.

Application: Industrial Synthesis

O

ONO2

+Br

NO20.03 % Pd(acac)2

0.3 % Cu-complex 160 °C

+ CO2

1 1 > 80%

R'K+

R R

R'

Optimized protocol for a commercial substrate (pilot scale: 100 kg)1:1 substrate ratio, in situ deprotonation with KOHSmall amount (60%) mesitylene as solventOnly 0.03 mol% Pd, 0.3 % CuSimple workup: 80 % yield after crystallization

Compare with:

Christophe Linder

B(OH)2

R

X R'

R'

base, Pd cat.

Br MgBr2. B(OMe)3

RR3. HClaq

1. Mg

Preparative scale procedures: with N. Rodríguez, C. Linder, B. Melzer, T. Knauber, Org. Synth. 2008, 85, 196-204.

Are there Intrinsic Substrate Limitations ?

In the absence of halide salts, a broad variety of substrates decarboxylateThe presence of halide salts has little influence on the decarboxylation of some benzoates, mostly o-substituted derivatives, while for other benzoates, an excess ofhalide with regard to Cu inhibits decarboxylation

Modified Cu-catalysts give full conversion for most benzoic acidsL. J. Gooßen, W. R. Thiel, N. Rodríguez, C. Linder, B. Melzer, Adv. Synth. Catal. 2007, 349, 2241-2246

COOHNO2

55 %

COOH

MeO

42 %

COOH

O2N

50 %

COOH

CN

85 % cat. CuO+ LiBr 2 %63 % 6 %26 %

Conditions: 0.15 mmol CuO, 0.15 mmol 1,10-phenanthroline, 0.15 mmol quinoline, 0.15 mmol K2CO3, 3 mL NMP, 160 °C, 24 h

FN Cu

C

N

OO

C FN Cu

C

N

OO

C

Andreas Fromm

Limiting Step of the “Double-catalytic” Process

The ligand exchange between potassium carboxylate and copper halide is apparently more difficult for non-ortho-functionalized arene carboxlates

Improved Cu-catalyst with a higher preference for carboxylates over halides may lead to general reaction protocols for decarboxylative cross-couplings

L2Pd Pd0-precursor

CO2

L2PdX

R'

R

[Cu]R R'

XR'

L2PdR

R'

X-[Cu]+OO

R

[Cu]+OO

R

Coupling of non-Activated Arenecarboxylates

Aryl triflates as coupling partners preclude the formation of halide saltThe most recent systems allow the turnover of less costly tosylates

⇒ The biaryl synthesis is not intrinsically limited to o-substituted benzoates

with N. Rodriguez, C. Linder, J. Am. Chem. Soc. 2008,130, 15248-15249;L. J. Gooßen, C. Linder, N. Rodríguez, P. P. Lange, Chem. Eur. J. 2009, 15, 9336-9349.

Nuria Rodriguez

O-K+

O

Ar ArTfO R R

O2N SN

MeONC

F

O2N O2N COOEt NO2

N

+ CO2+

Cu2O, PdI21,10-phen., tol-Binap NMP, µW, 190°C, 10 min

∆T: 54%µW: 65%

∆T: 52%µW: 83%

∆T: 41%µW: 50%

∆T: 68%µW: 81%

∆T: 5%µW: 54%

µW: 64% µW: 40% ∆T: 80%

Microwave-Assisted Couplings of Aryl Tosylates

Microwave irradiation shortens reaction time to five minutes Sealed vessels, 1 mmol scale, 1 ml solvent, 50W (190°C), 5 minReduces thermal strain, simplifies reaction layout, ideal for parallel synthesisAdvantageous for all substrate combinations

Coupling of non-activated benzoates with tosylatesUse of microwave irradiation effectively suppresses side reactions

with N. Rodríguez, P. P. Lange, C. Linder, Angew. Chem. 2010, 122, 1129

O-K+

O

Ar + CO2Ar +TsO

Cu2O, Pd(acac)21,10-phen., Xphos

NMP, ∆T or µWR R

∆T: 84%µW: 97%

NO2 ∆T: 75%µW: 69%

NO2

O

OEtNC

µW: 59%

O2N

∆T: 68%µW: 81%

Paul Lange

with B. Zimmermann, C. Linder, N. Rodríguez, P. P. Lange, J. Hartung, Adv. Synth. Catal. 2009, 351, 2667

Towards low-temperature decarboxylations

Development of low-temperature catalysts guided by DFT calculations Modifications at the N-N-ligand will have only limited effect on the Cu-catalystdecarboxylations with silver or gold catalysts should be much faster

Low-temperature Pd/Ag-catalyzed decarboxylative cross-couplingThe new protodecarboxylation catalysts are also effective as co-catalysts

with P. P. Lange, N. Rodríguez, C. Linder, A. Fromm, Chem. Eur. J. 2010, 16, 3906.Christophe

Linder

with C. Linder, N. Rodríguez, P. P. Lange, A. Fromm, Chem. Comm. 2009, 7173.

ArO-K+

OTfO Ar

Cl

Cl

Cl

ClN N

ClS

ClN

S

R R+

10 mol% [Ag], 3 mol% PdCl29 mol% PPh3, 20 mol% 2,6-lutidine

∆T: NMP, 130 ºC, 16hµW: NMP, 130 ºC, 150W, 5min

+ CO2

∆T: 76%µW: 56% ∆T: 60% ∆T: 80%

10 mol% AgOAc/K2CO3COOH

OMe

80%

+ CO2NMP, 120 ºC, 16hH

OMe

Extension to New Substrate Classes

Synthesis of arylketones via decarboxylative coupling of α-ketocarboxylates– In situ generation of „acyl anions“ by decarboxylation and coupling with aryl halides

• Inverse approach to traditional ketone syntheses

O

O

O

RBr

O

RK

+

R' R'

O

CO2Et

O

CN

O OMe

O

S

O

N

O O

Me2N

O

+ + CO2NMP/Chinolin, 170 °C, 16 h

1 mol% Pd(F6-acac), 2 mol% P(o-Tol)315 mol% CuBr, 15 mol% 1,10-Phenanthrolin

90 %

73 %

69 %

70 % 99 % 57 %

50 %59 %

with F. Rudolphi, C. Oppel, N. Rodriguez, Angew. Chem. 2008, 120, 3085-3088.

Felix Rudolphi

imine condensation directly of the carboxylate saltdecarboxylative cross-couplingOptional: hydrolysis of the imine after the reaction is complete

PdL2

Ar

N

R1

R2

[Cu]

N

R1

R2

Br

PdL2

Br

Ar

N

R1 Ar

R2

N

R1

O

O

R2O

R1

O

O

O

R1 ArR2NH2

[Cu]+N

R1

O

O

R2

CO2

[Cu]+Br-

a

c

L2Pd(0)d

e

f

ArBr

+- H2O

H2O

+ H2O

b trans-metalation

decarboxy-lation

reductiveelimination

oxidativeaddition

salt metathesis

iminecondensation

Combining Organo- with Bimetallic Catalysis

One-Pot Three Component Azomethine Synthesis

R1

O

O

O K+

R1

N

Ar

R2

R2NH2R1

O

Ar+ Cu/Pd cat.

NMP 100-130 °C, 16 hArBr+H2O

NCy

OMe

Ph

NCy

SMe

Ph

NCy OMe

Ph

NCy

NMe2

Ph

NCy

Cl

Ph

NCy

NO2

Ph

NCy

CN

Ph

NCy

CO2Et

Ph

NCy

Ph

NCy

Ph

NCy

N

Ph

NCy

S

Ph

NCy

TolPh

NCy

Tol

N

Tol

-C5H11NCy

Tol

MeO

NCy

Tol

NC

NCy

Tol

Tol

NCy

O

N

TolPh

NMe2

N

Tol

MeO

Ph

OMe

N

H

Ph Tol

Ph

p

N

Tol

-C5H11

Ph p

n-

NPh

TolPh p

N

Tol

MeO

Ph p

p p

n-

pp

p p

p

pp

91% 66%

34% 45%

94% 43%

71%

87% 64%

94% 50%

53% 73%

90% 92% 93%

85% 86% 94%

57% 95% 83%

91% 85% 66%

with F. Rudolphi, B. Song, Adv. Synth. Catal. 2011, 353, 337

Synthesis of α,β-Unsaturated Ketones

Optimized decarboxylative/isomerization tandem reaction:

neutral conditions, no organometallic reagentsalternatively: in-situ generation of esters from carboxylate salts

O O

Cl

O

F3C

O

O OCF3OF

O

O

O

S

O

NC

O

98% 62% 78% 99%

94% 66% 82% 97%

88% 77% 97%

O

O

O

O

R R5% Pd-catalyst

toluene, 100 °C, 12 h− CO2

with N. Rodriguez, F. Manjolinho, M. F. Grünberg, 2011, manuscript in preparation.

M. F. Grünberg

F. Manjolinho

Alternatives to Friedel-Crafts Reactions

Friedel-Crafts chemistry is established but unselective and waste intensive– Acid chloride substrates, 4 equiv. waste salt, some isomers are inaccessible

Our Pd-catalyzed reactions are convenient but expensive for bulk chemicals

New discovery: high-temperature decarboxylative cross-ketonization

Cl

O

Alk+

O

AlkMCln

O

Alk

O

Alk+ +

Traces

O

O

O

Alk +

Cl+

- CO2

(OH)2B

K+

O

AlkPd/Cu Pd

OH

O

Alk

OH

O

Alk+

O

OH

- CO2

O

AlkCat.

- H2O∆

> 80%, > 95:5 sel

O

Alk Alk+

Decarboxylative Ketonizations

Pioneer work: pyrolysis of lead or calcium carboxylates

Homo-ketonization (Librarius, 1606) Cross-ketonization (Friedel, 1858)

stoichiometric processes, high temperatures, low yields and selectivity

O

O

2Pb

2+O

+ CO2 PbO+

OH

O ArOH

O

OH

O

Ar

OO

OHH

OH H

[M][M]+ CO2++CO2 +

„Kalksalzsynthese“, T = 270 – 430 °C [M] : Ca, Pb, Zr, Mg, K, Ba

T : 250 – 340 °C[M] : Mn, Co, Fe

a) T. H. Easterfield, C. M. Taylor, J. Chem. Soc. 1911, 99, 2298; b) D. M. Cowan, G. H. Jeffrey, A. I. Vogel, J. Chem. Soc.1940, 171; c) R. Davis, H. P. Schultz, J. Org. Chem. 1962, 27, 854; C. Granito, H. P. Schultz, J. Org. Chem. 1963, 28, 879; S. Gerchakov, H. P. Schultz, J. Org. Chem. 1967, 32, 1656; d) E. Müller-Erlwein, Chem. Ing. Tech. 1990, 62, 416; e) M. Renz, A. Corma, Eur. J. Org. Chem. 2004, 2036.

OM

a

c

2 ArOH

O

CO2H

RAr

O

ArOH

O

2

d

be

H2O

[M]

H2

OM

O

OOR

ArH

OM

O

OO Ar Ar

O

OR

HO

Ar

Ar

O

O

O

R

HM

OM

O+

ArOH

OOH

OR

Decarboxylative Cross-Ketonization

How could one achieve selectivity for the aryl alkyl ketone?Aromatic carboxylic acids are more acidic and thus bind preferentially Attack at b-position is possible only after exchange with alkyl derivatives

S. Rajadurai, Catal. Rev.-Sci. Eng. 1994, 36,385.

First Catalytic Protocol for Cross-Ketonizations

Selectivity for aryl alkyl ketones is observed with Fe, Co, MnFe is uniquely reactive, allows catalytic turnover at 250 °C

OH

O

Ar

O

OH

O

Ar

[Fe] (15 mol%)+

(1 eq) (1.2 eq)

20 nm magnetite

O

OF

OBr

80 %

78 % 65 %

OCl

80 %

OO

69 %

OOH

O

O

26 %

32 %

ON

41 %

O

65 %

OCF3

O O

S

81 %

77 % 64 %

P. Mamone

C. Oppel

with P. Mamone, C. Oppel, Adv. Synth. Catal. 2010, 353, 57

Scope Regarding Aliphatic Carboxylic Acids

Various aryl alkyl ketones were synthesized in good yields, many of them inaccessible via Friedel-Crafts-type chemistry :

OH

OR

OR

OH

O

+

(1 eq) (1.2 eq)

[Fe] (21 mol%)

O

2

78 %

O

7770 %

O

2

MeO

59 %

O

2

OH

41 %

OF

76 %

O

380 %

O

7

86 %

O

10

85 %

O

12

76 %

O

14

70 %

Related Decarboxylative Couplings

Many decarboxylative couplings are being disclosed by a rapidly growingnumber of scientists, e.g., Myers, Steglich,Toste, Stoltz, Crabtree, Forgione, Becht, Liu, Kanai, Moon, Larrosa, Glorius ….

Decarboxylative heteroarylation

Decarboxylative allylations

Decarboxylative 1,4-additions

+ CO2

5 mol% Pd(0) source5 mol% phosphine

O

OR toluene R

J. A. Tunge, et al., J. Am. Chem. Soc. 2005, 127, 13510.

P. Forgione, F. Bilodeau, et al., J. Am. Chem. Soc. 2006, 128, 11350.

+ + CO2

X

YR

CO2HArBr

X

YR

Ar

2 equiv

5 mol% Pd[P(tBu)3]21 equiv nBu4N+Cl− x H2O1.5 equiv Cs2CO3

DMF, µW, 170 °C, 8 min

+ + CO2

1.5 mol% Rh sourceCO2H

OnBu

O

base, toluene/H2O, 120 °C

OnBu

O

R R

P. Zhao, et al., Angew. Chem. Int. Ed. 2009, 121, 6854.

Heck-Reactions

Biaryl syntheses under C-H activation

Directed ortho-acylations

+ CO2O

CO2H10-15 mol% Pd source(20 mol% tBuXPhos)Ag2CO3

∆ or µW, DMSO or 5% DMSO/1,4-dioxane

O

Oxidative Decarboxylative Couplings

NHH

O

O

O

OH+

10 mol% Pd(TFA)2 2 equiv (NH4)2S2O8

diglyme, rt, 9-36h

O NH

O

+ CO2

P. Fang, M. Li, H. Ge, J. Am. Chem. Soc. 2010, 132, 11898.

R. H. Crabtree, et al., Chem. Commun., 2008, 6312;F. Glorius, et al., J. Am. Chem. Soc. 2009, 131, 4194.

+ + CO2

20 mol% Pd(O2CCF3)23 equiv Ag2CO3

CO2HR1

DMSO-DMF (1:20), 120 °C

R1

R R

A. G. Myers, et al., J. Am. Chem. Soc. 2002, 124, 11250.

The Reversal of Protodecarboxylations

Copper-Catalyzed Insertion of CO2 into the C–H Bond of Terminal Alkynes

Mild conditions: equilibrium on the side of the carboxylated products

R

O

R

I: R1= C6H5X: R1= p-F-C6H4

N

N

Ph

Ph

NO3Cu(PR13)2

O H (1-5 atm), Cs2CO3, 35-50 ºC, DMFCO2

O

5 95%

O

97%

O

2 73%

O

98%

O

O

81%

O

F3C

99%

O

Cl86%

O

O

Br63%

OH OH

OHOHOHOH

OH OH

with N. Rodriguez, F. Manjolinho, P. P. Lange, Adv. Synth. Catal. 2010, 352, 2913

F. Manjolinho

Catalytic Decarboxylation of Trifluoroacetates?

Stoichiometric reactions are known:Cu-mediated decarboxylative trifluoromethylation by Chambers et al.

– Large amounts of copper, varying yields, expensive aryl iodides

Dream Reaction: Pd/Cu catalyzed decarboxylative Trifluoromethylation

Key issues: generate CF3- using only catalytic amounts of metalTransfer the CF3-group to a cross-coupling catalyst (Pd)Find a way to reductively eliminate aryl-CF3 from Pd catalysts

I

CF3 CO2M

CF3

2 eq. CuINMP, 16 h+

ClCF3 CO2M

CF3

R R+Pd / Cu cat.

- CO2, - MCl

?

G. E. Carr, R. D. Chambers, T. F. Holmes, D. G. Parker, J. Chem. Soc. Perkin Trans. 1988, 921

Pd-Catalyzed Trifluoromethylation

Successful spot-checks using Ruppert’s reagent Jan. 2010

Fluoride free, more stable CF3-source required– Decarboxylations also involve fluoride additives– Idea: Potassium (trifluoromethyl)trimethoxyborate K+[CF3BOR3]−

Break-through by Buchwald et al. CF3SiEt3 as the reagent, aryl chlorides rather than triflates

reductive elimination of CF3-groups from Pd-complexes works!

OTf CF3

CF3 SiMe3

F2 eq. CsF2 mol% [(cinnamyl)PdCl2]2

6 mol% tBu-Brett-Phostoluene, 110 °C

12 h+ +

3% 96%

Cl CF3

R RCF3 SiEt3

2 eq. KF3 mol% [(allyl)PdCl]2

9 mol% BrettPhos +

R = 4-nBu 80%, 3-CO2Hex 83%, 4-CN 72%, 4-Ph 84%, 3-OBn 88%,

dioxane, 120 °C16 h

E. J. Cho, T. D. Senecal, T. Kinzel, Y. Zhang, D. A. Watson, S. L. Buchwald, Science 2010, 328, 1679.

K+[CF3BOMe3]−: A convenient CF3-Source

Transformation of volatile CF3SiMe3 into a crystalline saltCollaboration with G.-V. Röschenthaler, 2003:

Access to multigram quantities, potentially accessible via direct fluorinationEasy-to-handle, crystalline solidShelf-stable, mp. 116-118°C (decomposition) Stable in aprotic polar solvents (e.g. DMF) up to 80°CMeanwhile commercially available, ca 300 € / 100g

CF3 BOMe

OMeOMe

K+

CF3 SiMe3 +

KF-Me3SiFTHF, RT24-48 h

B(OMe)3

quant.

A. A. Kolomeitsev, A. A. Kadyrov, J. Szczepkowska-Sztolcman, M. Milewska, H. Koroniak, G. Bissky, J. A. Bartene, G.-V. Röschenthaler, Tetrahedron Lett. 2003, 44, 8273. Single crystall structure: thermal ellipsoids at 50 % probability level. Selected bond lengths [Å] and angles [°]: B3-O7 1.488(6), B3-O8 1.1.473(6), B3-O9 1.455(6), B3-C12 1.646(7); O7-B3-O8 115.1(4), O7-B3-O9 116.4(4), O9-B3-O8 101.2(4), O7-B3-C12 103.7(4), O8-B3-C12 110.0(4), O9-B3-C12 110.6(4).

Molecular structure of the anion

Cu-Catalyzed Trifluoromethylation

Development of a Cu-catalyzed protocol:chelating nitrogen containing ligands, DMSO as the solvent

K+

I

MeO

CF3

MeOCF3 B

O

O

O+

20 mol% CuI20 mol% 1,10-phenanthroline

DMSO60 °C, 16 h

3 equiv. 95%

Thomas Knauber

CF3

Et2N

O

O

O

CF3

CF3 CF3

OMeCF3

Br

CF3

SMe

CF3

CO2Me N CF3

Br

CF3CF3

O2N

N

CF3

CF3

NC

S CF3CF3

Me2N

CF3

CF3

CNF

CF3

CF3

N

O

83%93% 91%

96% 81% 82%

95%

85%

59%

76%

52%

97%

96% 92%

91%

81% 95%

84%

with T. Knauber, F Arikan, G.-V. Röschenthaler, Chem. Eur. J. 2011, 17, 2689

Trifluoromethylation of Carbonyl Compounds

Conversion of carbonyl compounds into trifluoromethylated alcohols Base-free conditions, good yields, easy workup

Research perspective: Use trifluoroacetate as source of CF3-groups

CF3

OH

MeO

CF3

OH

MeOOMe

MeOCF3

OH

MeS

CF3

OH

CF3

OH

CF3

OH

NC

CF3

OH

MeO2C

CF3

OH

Me2N

CF3

OH

Cl

CF3

OH

Me3SiO

CF3

OH OH CF3

85% 84% 79% 78% 92%

75% 92%

83%

74% 88% 77% 79%

R1

O

R2 CF3 BOMe

OMeOMe

K+

R1

OH

R2

CF3

THF, 60 °C5 h+

aqueous workup

Fonds der Chemischen Industrie, DFG, NanoKat, A.v.H.-StiftungSaltigo, Novartis, AstraZeneca, Cognis, Bayer CropScience, Umicore, Boehringer Ingelheim,

BASF, Pfizer

Nuria Rodriguez, Guojun Deng, Christophe Linder, Bettina Melzer, Thomas Knauber, Dominik OhlmannPaul Lange, Laura Levy, Kifah Salih, Andreas Fromm, Felix Rudolphi, Christoph Oppel, Patrizia

Mamone, Filipe Costa, Matthias Arndt, Bilal Ahmad Khan, Bingrui SongProfs. M. T. Reetz, Walter Thiel, Werner Thiel, G. Niedner-Schatteburg, V. Röschenthaler

Acknowledgements