8276 Chem. Commun., 2010, 46, 8276–8278 This journal is c The Royal Society of Chemistry 2010

Decarboxylative homocoupling of (hetero)aromatic carboxylic acidsw

Josep Cornella, Hicham Lahlali and Igor Larrosa*

Received 17th June 2010, Accepted 9th September 2010

DOI: 10.1039/c0cc01943g

A variety of hetero(aromatic) carboxylic acids are shown to

undergo decarboxylative homocoupling, mediated by a Pd/Ag

system. This novel methodology for the synthesis of symmetrical

biaryls avoids the use of haloarenes and organometallic

compounds as starting materials.

Substituted symmetrical biaryl subunits constitute an important

motif in chiral ligands,1 monomers for conductive polymers,2

liquid crystal precursors,3 natural products,4 pharmaceuticals

and pesticides.5 These structures are traditionally synthesised

via the transition metal-mediated coupling of suitably

functionalised arene precursors, usually haloarenes or organo-

metallic compounds (Scheme 1, eqn 1 and 2).6,7 However, the

need for pre-functionalisation together with the generation of

undesired and often toxic by-products arise as main drawbacks

for both of these approaches. A strategy involving the oxidative

homocoupling of arenes via C–H bond activation has been

shown to provide a greener alternative with increased atom and

step economy (eqn 3).8 However, due to current limitations in

the control of regio- and chemo-selectivity of C–H activation

processes this approach is limited to a narrow range of arenes.

Therefore, the development of a methodology that uses

inexpensive starting materials yet allows a precise control in

regio- and chemo-selectivity for the homocoupling of a wide

variety of arenes is still highly desirable.

Since the pioneering work of Myers and Goossen et al.,9 the

activation of C–CO2H bonds has emerged as an alternative to

C–H activation where the regioselectivity is controlled by the

position of the carboxylic acid functionality, while still

retaining the advantages of ready availability of starting

materials and innocuous by-product formation (CO2).10,11

To the best of our knowledge, the use of this mode of

activation for the homocoupling of arenes has not been

reported (eqn 4). Such methodology would provide easy access

to a variety of symmetric biaryls starting from inexpensive and

stable aromatic carboxylic acids.

During the course of our previous work on the decarboxyl-

ative C–H arylation of indoles with benzoic acids, small

amounts of the homocoupled product of the latter partner

were observed.12 Consequently, we explored the application of

this protocol for the synthesis of symmetrical biaryls. Herein,

we report the first decarboxylative homocoupling of aromatic

and heteroaromatic acids mediated by Pd and Ag salts.

Initially, we studied the homocoupling of 2-chloro-5-nitro-

benzoic acid (1a) to afford biaryl 2a in the presence of Ag2CO3,

Scheme 1 Strategies for the metal-mediated homocoupling of arenes.

Table 1 Optimisation of the decarboxylative homocoupling of2-chloro-5-nitrobenzoic acid

EntryPd cat.(mol%) Pd cat. T/1C

Ag2CO3/equiv. Solvent

Yielda

(%)

1 10 Pd(TFA)2 110 1.0 DMSO 582 10 Pd(TFA)2 110 1.0 DMF 683 10 Pd(TFA)2 110 1.0 DMA 464 10 Pd(TFA)2 110 1.0 Dioxane 05 10 Pd(TFA)2 110 1.0 DMF/DMSO

95 : 574

6 10 Pd(TFA)2 110 0.25 DMF/DMSO95 : 5

5

7 10 Pd(TFA)2 110 0.5 DMF/DMSO95 : 5

64

8 10 Pd(TFA)2 110 1.5 DMF/DMSO95 : 5

72

9 10 Pd(OAc)2 110 1.0 DMF/DMSO95 : 5

73

10 10 Pd(ACN)2Cl2 110 1.0 DMF/DMSO95 : 5

71

11 10 Pd(PPh3)2Cl2 110 1.0 DMF/DMSO95 : 5

37

12 5 Pd(TFA)2 110 1.0 DMF/DMSO95 : 5

64

13 7.5 Pd(TFA)2 110 1.0 DMF/DMSO95 : 5

79

14 7.5 Pd(TFA)2 120 1.0 DMF/DMSO95 : 5

84

15 0 Pd(TFA)2 120 1.0 DMF/DMSO95 : 5

0b

16 100 Pd(TFA)2 120 — DMF/DMSO95 : 5

0

a Yields were determined by 1H NMR using an internal standard.b 100% protodecarboxylation of 1a to 3a was observed by 1H NMR.

Queen Mary University of London, School of Biological and ChemicalSciences, Joseph Priestley Building, Mile End Road, E1 4NS, London,UK. E-mail: i.larrosa@qmul.ac.uk; Fax: +44 (0)20 7882 7427;Tel: +44 (0)20 7882 8404w Electronic supplementary information (ESI) available: Experimentalprocedures and analytical data are provided. See DOI: 10.1039/c0cc01943g

COMMUNICATION www.rsc.org/chemcomm | ChemComm

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This journal is c The Royal Society of Chemistry 2010 Chem. Commun., 2010, 46, 8276–8278 8277

different solvent systems and catalytic amounts of a Pd salt

(Table 1). The use of highly polar solvents was found essential

for the reaction to proceed, a mixture of DMF : DMSO 95 : 5

being optimal (entries 1–5). The only observed by-product

corresponded to the proto-decarboxylation of 1a, leading to

p-chloronitrobenzene (3a). Optimisation of the amount of

Ag2CO3 showed that an excess of this oxidant (1.0 equiv.) is

necessary to achieve high yields (entries 6–8). Further

optimization of the nature of the Pd catalyst (entries 9–11)

and its stoichiometry (entries 12 and 13), highlighted the use of

7.5 mol% of Pd(TFA)2, with a 79% yield of the homocoupling

product 2a. Finally, raising the temperature to 120 1C led to

biaryl 2a in 84% yield (entry 14). It is noteworthy that in the

absence of the Pd catalyst (entry 15) protodecarboxylation was

observed exclusively. Similarly, in the absence of Ag2CO3 but

with 1.0 equiv. of Pd(TFA)2 (entry 16) no dimerisation was

detected. This indicates that both metals are essential for the

reaction and that the role of the Ag salt is not just as the

terminal oxidant.

A plausible mechanism for this transformation is outlined in

Scheme 2. Since Ag(I) salts have been shown to mediate the

decarboxylation of ortho substituted benzoic and hetero-

aromatic acids,13 the formation of Ag(I)–arene I from benzoic

acid 1 was envisaged as the initial step in the reaction. I would

then undergo transmetalation to Pd(II) affording intermediate

II. A second transmetalation with another Ag(I)–arene, I,

would generate bisaryl–Pd species III. Subsequent reductive

elimination would then afford the biaryl 2. Finally, two

equiv. of Ag(I) would reoxidise Pd(0) to Pd(II), regenerating

the catalyst. The observation of small amounts of proto-

decarboxylated product 3 is consistent with the formation of

Ag(I)–arene I, which has been reported to be highly reactive

towards proto-demetalation.14

We next explored the scope of this novel decarboxylative

homocoupling reaction (Table 2). Benzoic acids bearing the

electron-withdrawing groups Cl or NO2 in ortho, underwent

homocoupling to produce the desired biaryls 2a–c in excellent

yields (entries 1–3), even in the presence of an electron-

donating para MeO substituent (entry 3).

Pleasingly, oxygen and sulfur based heteroarenes, such as

furans (1d), benzofurans (1e), benzothiophenes (1f) and

thiophenes (1g), containing a carboxylic acid in C-2 reacted

smoothly under the reaction conditions to afford biaryls 2d–g

in good yields (entries 4–8). The dimerisation of thiophene 1h

Scheme 2 Proposed mechanism for the decarboxylative homocoupling

of benzoic acids.

Table 2 Substrate scope for the decarboxylative homocoupling ofaromatic acidsa

Entry Acid Product Yieldb (%)

1 79

2c 94

3c 76

4 56

5 78

6c 57

7 66

8 64

a Conditions: 7.5 mol% Pd(TFA)2 and 1.0 equiv. of Ag2CO3 in 95 : 5

DMF/DMSO at 120 1C. b Yields of isolated pure material. c Reaction

carried out at 130 1C.

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8278 Chem. Commun., 2010, 46, 8276–8278 This journal is c The Royal Society of Chemistry 2010

bearing the carboxylic acid functionality in C-3 and an

ortho Cl also afforded good yields of the corresponding biaryl,

2h. On the other hand, m- and p-nitrobenzoic acids failed to

react. This underscores our previous observations on the

requirements for Ag(I)-mediated decarboxylation: namely,

the presence of an ortho electron-withdrawing substituent or

an a heteroatom.12,13 The main side reaction observed was in

all cases protodecarboxylation to arene 3, accounting for the

remainder of the mass balance. Unfortunately, when benzoic

acids ortho substituted with Br, OMe, or F were tested under

these conditions decarboxylation to 3 was the main product

observed, with only small amounts (10–20%) of dimer

detected by 1H NMR analysis. These results suggest that the

relative rates of protodemetallation of I versus transmetallation

to Pd are highly affected by the nature of the group in ortho.

The addition of molecular sieves did not improve the result.

Further studies to overcome this problem and extend the

substrate scope are underway.

In summary, we have developed the first decarboxylative

homocoupling of aromatic and heteroaromatic carboxylic

acids. This protocol, based on a Pd(II)/Ag(I) system allows

the preparation of a variety of biaryls in good to excellent

yields.

We gratefully acknowledge EPSRC and the Royal Society

for generous funding, QMUL for a scholarship (JC), Conseil

regional de Picardie for a travel bursary (HL), and Dr Goldup

(QMUL) for discussions.

Notes and references

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