arene boronic acids, which could even, in certain cases, be
difficult to prepare. Because carboxylic acids are widely
available, they could represent an interesting alternative to
the arene boronic acids. Their use for this reaction, which is
related to the Suzuki-Miyaura process, has recently been
described by two groups.10-13 This prompts us to disclose
herein our own results. Goossen et al. reported the prepara-
tion of biaryls via a Pd-catalyzed decarboxylative coupling
reaction in the presence of a bimetallic Pd/Cu catalyst.10
Good yields have been obtained, but mostly for carboxylic
acids bearing electron-withdrawing groups. This procedure
is somewhat tedious and often has to be adapted to the nature
of the arene carboxylic acid. The Boehringer Ingelheim group
reported a Pd-catalyzed arylation reaction of heteroaromatic
carboxylic acids with aryl halides.11 Herein, we report a
versatile one-step synthesis of biaryls via a Pd-catalyzed
cross-coupling reaction of both electron-rich and electron-
deficient arene carboxylic acids with various aryl iodides.
This method can also be used for the preparation of sterically
hindered biaryls.
Table 1. Determination of the Reaction Conditions
yield
(%)a
entry
Pd catalyst
ligand
1b PdCl2
-
-
-
-
51
2b PdCl2(MeCN)2
3b Pd(O2CCF3)2
4b Pd(CN)2
49
<40
<40
<40
<40
-
5b Pd(OAc)2
6b Pd(dppf)2Cl2(CH2Cl2)2
7b Pd(PPh3)4
8b Pd2(dba)3
9b PdCl2
-
-
-
-
c
c
-
The determination of the reaction conditions was per-
formed with 2,6-dimethoxybenzoic acid, 4-iodoanisole, and
Ag2CO3 in DMSO (Table 1).13b It turned out that PdCl2 was
the most active catalyst, and the desired biaryl 3a was
obtained in 51% yield (entry 1).14 Apart from PdCl2(MeCN)2
which gave almost identical results (entry 2), other Pd(II)
or Pd(0) catalysts (entries 3-8) or Ni(II) derivatives [NiCl2-
(PPh3)2 or Ni(acac)2] were unsuccessful. Modifications of
the nature of the base (Li2CO3, Na2CO3, K2CO3, Cs2CO3,
AgOAc, or TMSOK) or of the solvent (sulfolane, DMA,
DMF, or DMSO/DMF mixtures13b), addition of various salts
(LiBF4, LiCl, MgCl2, CaCl2, CsCl, BiCl3, or CuI10), or
decrease of the amount of Ag2CO3 afforded only much lower
yields of 3a. Despite the fact that Pd catalysts containing
phosphine ligands were less efficient than PdCl2 (see above),
we carried out the reaction with PdCl2 in the presence of
additional Ph3P (entry 9) or numerous other phosphines (e.g.,
PCy3, DavePhos, xanthphos, or BINAP), and as expected,
3a was obtained in lower yields. Interestingly, the addition
of AsPh3 was much more beneficial, with 3a being isolated
in 71% yield (entry 10) and even in 90% yield if a slight
excess (1.3 equiv) of carboxylic acid 1 was used. Surpris-
ingly, only complex mixtures were obtained in the presence
PPh3
AsPh3
AsPh3
Ph2As-(CH2)2-AsPh2
SbPh3
37
71 (90)d
10b PdCl2
11e PdCl2
<60
12b PdCl2
-
-
c
13b PdCl2
c
a
Isolated yields after flash chromatography of the crude reaction mixture
on silica gel. b Reagents and reaction conditions: 4-iodoanisole (1.0 equiv),
2,6-dimethoxybenzoic acid (1.1 equiv), Ag2CO3 (3.0 equiv), ligand (0.6
c
equiv), and Pd catalyst (0.3 equiv). Complex reaction mixtures were
obtained. d The reaction was performed using 1.3 equiv of 2,6-dimethoxy-
e
benzoic acid. The reaction was performed using 0.1 equiv of PdCl2.
of other arsine or stibine ligands such as 1,2-bis(diphenyl-
arsino)ethane (entry 12) and triphenylstibine (entry 13).
Using either 0.3 equiv of PdCl2 and 0.1 equiv of AsPh3 or
0.3 equiv of PdCl2 and 0.1 equiv of AsPh3 afforded 3a in
only 50% and 66% yields, respectively. In the presence of
AsPh3 (0.6 equiv), attempts to lower the temperature to 100
°C or to decrease the amount of PdCl2 to 0.1 equiv afforded
3a in much lower yields, whereas replacing 4-iodoanisole
by 4-bromoanisole gave no biaryl 3a. Additionally, use of
microwave irradiation (150 °C, 10 min) yielded almost
identical results and was therefore not pursued.
With these reaction conditions in hand, we evaluated the
scope and limitation of the reaction using various arene
carboxylic acids and aryl iodides (Table 2).15 The use of the
electron-rich 2,6-dimethoxybenzoic acid, 2,4,6-trimethoxy-
benzoic acid, or 3-bromo-2,6-dimethoxybenzoic acid gave
the desired biaryls in good yields (entries 1-3). Interestingly,
the sterically more hindered 2,6-diisopropoxybenzoic acid16
(10) Goossen, L. J.; Deng, G.; Levy, L. M. Science 2006, 313, 662.
(11) Forgione, P.; Brochu, M.-C.; St-Onge, M.; Thesen, K. H.; Bailey,
M. D.; Bilodeau, F. J. Am. Chem. Soc. 2006, 128, 11350.
(12) Baudoin, O. Angew. Chem., Int. Ed. 2007, 46, 1373.
(13) Carboxylic acids and derivatives have also been used in Pd- or Rh-
catalyzed couplings to replace the aryl halides. For an example in a Rh-
catalyzed Suzuki-Miyaura-type reaction, see: (a) Goossen, L. J.; Paetzold,
J. AdV. Synth. Catal. 2004, 346, 1665. For examples in Pd-catalyzed Heck-
type reactions, see: (b) Myers, A. G.; Tanaka, D.; Mannion, M. R. J. Am.
Chem. Soc. 2002, 124, 11250. (c) Tanaka, D.; Romeril, S. P.; Myers, A. G.
J. Am. Chem. Soc. 2005, 127, 10323. (d) Tanaka, D.; Myers, A. G. Org.
Lett. 2004, 6, 433. (e) Goossen, L. J.; Paetzold, J. Angew. Chem., Int. Ed.
2002, 41, 1237. (f) Goossen, L. J.; Paetzold, J. Angew. Chem., Int. Ed.
2004, 43, 1095. (g) Goossen, L. J.; Paetzold, J.; Winkel, L. Synlett 2002,
10, 1721. (h) Carmichael, A. J.; Earle, M. J.; Holbrey, J. D.; McCormac,
P. B.; Seddon, K. R. Org. Lett. 1999, 1, 997. (i) Stephan, M. S.; Teunissen,
A. J. J. M.; Verzijl, G. K. M.; de Vries, J. G. Angew. Chem., Int. Ed. 1998,
37, 662. (j) Mo, J.; Xiao, J. Angew. Chem., Int. Ed. 2006, 45, 4152.
(14) No starting material 1 or 2 was recovered. In addition to 3a, 1,3-
dimethoxybenzene, anisole, and 4,4′-dimethoxybiphenyl were isolated.
(15) Typical experimental procedure: DMSO (6 mL) was added to a
mixture of the aryl iodide (0.50 mmol, 1.0 equiv), the arene carboxylic
acid (0.65 mmol, 1.3 equiv), Ag2CO3 (1.50 mmol, 414 mg, 3.0 equiv),
AsPh3 (0.30 mmol, 91.9 mg, 0.6 equiv), and PdCl2 (0.15 mmol, 26.6 mg,
0.3 equiv). The reaction mixture was degased twice with argon and directly
heated at 150 °C for 6 h. After cooling to rt, the reaction mixture was filtered
with Celite and AcOEt (100 mL) was added to the filtrate. The organic
phase was washed with saturated NH4Cl (70 mL), dried with MgSO4,
filtered, and concentrated under a vacuum. The residue was purified by
flash chromatography on silica gel to afford pure biaryls after drying under
a vacuum (0.1 mbar).
1782
Org. Lett., Vol. 9, No. 9, 2007