reactions.6-8 In this regard, Fagnou6 and Daugulis7 have
successfully developed the direct arylation of electron-
deficient polyfluoroarenes or heterocycles for synthesis of
fluorobiaryl or heterocycle-containing biaryl compounds.
Recently, efforts made by Yu,9 Shi,10 and others11 have
led to the development of palladium-catalyzed C-H bond
arylation with organoboron reagents, and Murai and Kakiuchi
disclosed a ruthenium-catalyzed ortho C-H arylation of
acetophenones with boronic esters.12 Copper-13 and iron-
based catalysts14 have successfully been exploited as a cost-
efficient replacement for palladium-based catalysts for the
direct arylation of arenes with arylboronic acids. These
reported reactions are limited to directing group-containing
or electron-rich arenes. However, to date, no example has
been reported that involves the direct arylation of electron-
deficient arenes with organoboron reagents, except for a few
substrates bearing directing groups.9b In view of the impor-
tance of electron-deficient fluorobiaryls in medicinal15 and
materials chemistry,16 the discovery of new reactions for the
synthesis of these valuable compounds remains highly
desirable. Herein, we report a palladium-catalyzed method
for the direct arylation of electron-deficient polyfluoroarenes
with organoboron reagents and also present the result of the
preliminary mechanistic study on this reaction.
the transmetalation between the arylboronic acid and the
Pd(II) species, whereas the fast transmetalation would readily
lead to the undesired homocoupling of arylboronic acid if
the C-H bond cleavage is relatively slow,17 thus hampering
the generation of the desired cross-coupling product. Our
strategy to solve this problem is to simultaneously add a weak
base, which we believe promotes the C-H bond cleavage,
and a weak acid, which we believe reduces the transmeta-
lation rate of arylboronic acid, and therefore suppresses the
undesired homocoupling.10b
A variety of reaction parameters were screened with the
reaction of pentafluorobenzene (1) with 1.5 equiv of phe-
nylboronic acid (2) as a model reaction system. Selected
results that illustrate the effect of acid and base on this
reaction are listed in Table 1. In the presence of 5 mol % of
Table 1. Selected Screening Results for Pd-Catalyzed Direct
Arylation of Pentafluorobenzene with Phenylboronic Acida
entry
base (equiv)
acid (0.3 equiv)
yield (%)b
To achieve the direct arylation of fluoroarenes with
arylboronic acids, we need to address the following issue:
the cleavage of the C-H bond of electron-deficient fluoro-
arene generally requires basic conditions that also accelerate
1
2
3
4
5
6
7
8
trace
75
70
7
K2CO3 (2)
Na2CO3 (2)
Cs2CO3 (2)
K3PO4 (2)
80
69
71
55
72
84
80
79
77
88
89
85
90c
(7) (a) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404.
(b) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 1128. (c) Do,
H.-Q.; Kashif Khan, R. M.; Daugulis, O. J. Am. Chem. Soc. 2008, 130,
KOAc (2)
K2HPO4 (2)
p-Me-C6H4-CO2K (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
KF (2.5)
K3PO4 (2)
15185
.
9
tBuCO2H
(8) Cho, S. H.; Hwang, S. J.; Chang, S. J. Am. Chem. Soc. 2008, 130,
9254
.
10
11
12
13
14
15
16
17
p-Me-C6H4-CO2H
o-MeO-C6H4-CO2H
o-O2N-C6H4-CO2H
p-Me-C6H4-CO2H
p-Me-C6H4-CO2H
p-Me-C6H4-CO2H
p-Me-C6H4-CO2H
p-Me-C6H4-CO2H
(9) (a) Giri, R.; Maugel, N.; Li, J.-J.; Wang, D.-H.; Breazzano, S. P.;
Saunders, L. B.; Yu, J.-Q. J. Am. Chem. Soc. 2007, 129, 3510. (b) Wang,
D.-H.; Mei, T.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 17676. (c) Wang,
D.-H.; Wasa, M.; Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 7190.
(10) (a) Shi, Z.; Li, B.; Wan, X.; Cheng, J.; Fang, Z.; Cao, B.; Qin, C.;
Wang, Y. Angew. Chem., Int. Ed. 2007, 46, 5554. (b) Yang, S.; Sun, C.;
Fang, Z.; Li, B.; Li, Y.; Shi, Z. Angew. Chem., Int. Ed. 2008, 47, 1473. (c)
Li, B.-J.; Yang, S.-D.; Shi, Z.-J. Synlett 2008, 949.
K2CO3 (0.5)
K3PO4 (0.5)
K2CO3 (0.5)
(11) (a) Kirchberg, S.; Vogler, T.; Studer, A. Synlett 2008, 2841. (b)
Kirchberg, S.; Fro¨hlich, R.; Studer, A. Angew. Chem., Int. Ed. 2009, 48,
4235. (c) Ge, H.; Niphakis, M. J.; Georg, G. J. J. Am. Chem. Soc. 2008,
130, 3708. (d) Deicamp, J. H.; White, M. C. J. Am. Chem. Soc. 2006, 128,
15076.
a 0.2 mmol scale, 2 mL of DMA (0.1 M). b Isolated yields. c Pd(OAc)2
(2 mol %) and phenylboronic acid (1.2 equiv).
(12) (a) Kakiuchi, F.; Usui, M.; Ueno, S.; Chatani, N.; Murai, S. J. Am.
Chem. Soc. 2004, 126, 2706. (b) Kakiuchi, F.; Kan, S.; Igi, K.; Chatani,
N.; Murai, S. J. Am. Chem. Soc. 2003, 125, 1698. (c) Kakiuchi, F.; Matsuura,
Y.; Kan, S.; Chatani, N. J. Am. Chem. Soc. 2005, 127, 5936.
(13) Ban, I.; Sudo, T.; Taniguchi, T.; Itami, K. Org. Lett. 2008, 10,
3607.
Pd(OAc)2 as a catalyst and 2 equiv of Ag2CO3 as an oxidant,
the reaction carried out in dimethylacetamide (DMA) at 110
°C in the absence of any additive did not afford the desired
product in appreciable quantities. Instead, it produced the
undesired biphenyl from homocoupling of phenylboronic
acid (entry 1, Table 1). The addition of 2 equiv of K2CO3
led to the formation of the desired arylation product in 75%
yield (entry 2, Table 1). Both Na2CO3 and KOAc gave a
slightly lower yield (entries 3 and 6, Table 1), but Cs2CO3
was almost ineffective for this reaction (entry 4, Table 1).
K3PO4 was found to be superior to K2CO3 (entry 5, Table
1). As expected, the addition of carboxylic acids efficiently
(14) Wen, J.; Zhang, J.; Chen, S.-Y.; Li, J.; Yu, X.-Q. Angew. Chem.,
Int. Ed. 2008, 47, 8897.
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S.-A.; Wafford, K. A.; Castro, J. L. J. Med. Chem. 2005, 48, 1367.
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N.; Suzuki, T.; Tokito, S. AdV. Mater. 2003, 15, 1455. (e) Kitamura, T.;
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R. H. Angew. Chem., Int. Ed. 1999, 38, 2741. (g) Nitschke, J. R.; Tilley,
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