1017
References and Notes
1
not observed even using L2 at 85 °C to afford 3e-3g in good
yields (Entries 7-9). Besides bromobenzenes, 2-bromonaphtha-
lene (2h) and 2-bromo-5-methylthiophene (2i) also underwent
the reaction with 1a in the presence of L1 (Entries 10 and 11).
A plausible mechanism for the arylation of 1a with 2 is
illustrated in Scheme 3, in which neutral ligands are omitted.
First, oxidative addition of 2 toward Pd0 species generated in
situ followed by ligand exchange with 1a gives an arylpalladium
carboxylate intermediate A. Then, directed palladation8 on the
thiophene ring may occur to form an aryl(thienyl)palladium
species B. Final reductive elimination affords a C2-arylated
product and regenerates Pd0 species. It should be noted that
treatment of methyl thiophene-3-acetate with 2a gave 3a only in
a low yield (Scheme 4). Therefore, coordination of the carbox-
ylic group of 1a appears to be the key for the effective
palladation in A.9
Benzo[b]thiophene-3-acetic acid (1b) also underwent the
phenylation upon treatment with 2a in the presence of the
Pd(OAc)2/L2 catalyst system at 120 °C to afford the corre-
sponding C2-phenylated product 5a in 94% yield (Entry 1 in
Table 2). At 100 °C, 5a was obtained quantitatively (Entry 2). In
the reactions of 2b-2d with 1b, L1 was used in place of L2 to
avoid the contamination as in the reaction with 1a (Entries 4-6).
In the cases using 2b and 2c, addition of the increased amount of
L1 improved the product yields. The reaction of 1b with 2e took
place efficiently in the presence of the Pd(OAc)2/L2 catalyst
system at 100 °C, rather than at 85 °C (Entry 7 vs. 8).
For example, see: a) W. F. Fobare, W. R. Solvibile, A. J. Robichaud,
M. S. Malamas, E. Manas, J. Turner, Y. Hu, E. Wagner, R. Chopra,
5353. b) N. Floquet, C. Richez, P. Durand, B. Maigret, B. Badet,
J. G. Park, P. C. Sill, E. F. Makiyi, A. T. Garcia-Sosa, C. B. Millard,
2
For selected recent reviews concerning direct C-H functionalization,
3
4
2002, 124, 5286. See also: b) L. Lavenot, C. Gozzi, K. Ilg, I. Orlova,
Nitrogen-containing analogs, 2-arylindole-3-acetic acids,
have also attracted attention because of their interesting bio-
logical properties.10 Therefore, we next examined their synthesis
through the direct arylation of readily available indole-3-acetic
acids. Treatment of N-methylindole-3-acetic acid (1c) (0.4
mmol) with 2a (0.5 mmol) in the presence of Pd(OAc)2 (0.008
mmol), L1 (0.016 mmol), and K2CO3 (0.9 mmol) in DMF at
120 °C for 8 h under N2 and subsequent methyl esterification
gave a C2-phenylated product 6a in a quantitative yield (Entry 1
in Table 3). Under the same conditions, a number of 4-
substituted bromobenzenes 2b-2k reacted with 1c efficiently
to produce the corresponding 2-arylindole derivatives (Entries
2-9). Similarly, 2-bromotoluene (2l), 2-bromonaphthalene (2h),
2-bromo-5-methylthiophene (2i), and ¢-bromostyrene (2m,
E:Z = 6.5:1) underwent the reaction at 120-140 °C (Entries
10-13). In the case with 2m, the product yield was decreased by
the addition of L1 or L2. The arylation of N-unsubstituted and
N-phenylated indole-3-acetic acids, 1d and 1e, with bromides
2a, 2n, and 2o took place effectively to form products 6n-6q in
74-84% yields (Entries 14-17).
5
6
B. Glover, K. A. Harvey, B. Liu, M. J. Sharp, M. F. Tymoschenko,
a) T. Ueyama, S. Mochida, T. Fukutani, K. Hirano, T. Satoh, M.
2010, 49, 2202. g) M. Yamashita, H. Horiguchi, K. Hirano, T. Satoh,
7
8
9
M. Miura, S. Pivsa-Art, T. Satoh, M. Nomura, M. Miura, G. Dyker,
Pd-Catalyzed oxidative ortho-arylation of phenylacetic acids with
arylborates has been reported: D.-H. Wang, T.-S. Mei, J.-Q. Yu,
10 For example, see: a) K. D. Dykstra, L. Guo, E. T. Birzin, W. Chan,
Y. T. Yang, E. C. Hayes, C. A. DaSilva, L.-Y. Pai, R. T. Mosley, B.
Kraker, P. M. D. Fitzgerald, F. DiNinno, S. P. Rohrer, J. M.
2322. b) B. W. Trotter, A. G. Quigley, W. C. Lumma, J. T. Sisko,
E. S. Walsh, C. S. Hamann, R. G. Robinson, H. Bhimnathwala,
D. G. Kolodin, W. Zheng, C. A. Buser, H. E. Huber, R. B. Lobell,
N. E. Kohl, T. M. Williams, S. L. Graham, C. J. Dinsmore, Bioorg.
Ishiguro, Y. Ichihara, H. Oomura, Jpn. Kokai Tokkyo Koho JP
55151505 (A), 1980.
In summary, we have demonstrated that thiophene-3-,
benzothiophene-3-, and indole-3-acetic acids undergo regio-
selective arylation upon treatment with aryl bromides under
palladium catalysis to afford the corresponding C2-arylated
products of pharmaceutical interest.11
This work was partly supported by Grants-in-Aid from
MEXT and JSPS, Japan.
This paper is in celebration of the 2010 Nobel Prize
awarded to Professors Richard F. Heck, Akira Suzuki, and
Ei-ichi Negishi.
11 Supporting Information is available electronically on the CSJ-
Chem. Lett. 2011, 40, 1015-1017
© 2011 The Chemical Society of Japan