the o-, m- and p-tolylboronic acids were used, the corresponding N-
arylation products were obtained in almost quantitative yields
(Table 3, Entries 2, 3 and 4). Completed conversion was readily
obtained for naphthylboronic acid and to give N-naphthylimidazole
in 98% yield (Table 3, Entry 7). Although a slightly longer reaction
time compared with the phenylboronic acid was required, which is
consistent with the general trend that the latter is less steric
hindrance of the reaction center than the former. In particular with
the o-methoxyarylboronic acids, the coupling yields was only in
5% in previous work,6c but it was also obtained in excellent yields
in the catalytic system of simple copper salts. (Table 3, Entry 5,
8)
In recent years, many chemists devoted to the use of water as a
reaction medium for organic synthesis.9 However, very few
examples of N-arylation accomplished in aqueous media have been
reported.5b
We then set out to explore the coupling reaction in aqueous
solution, and found when water was used solely, the yields were
depressed (Table 4, Entry 1, 2). This may be attributed to the poor
solubility of reactants in water. In view of the excellent yield while
the coupling reaction was performed in CH3OH, we tried to study
this coupling in mixed protic solvent, as can be seen from Table 4,
a small quantity of CH3OH was added, the coupling yield was still
poor, and when a 1 : 1 ratio of H2O–CH3OH was used, the coupling
yield came to 90% (Table 4, Entry 3, 4). The results encouraged us
to study the coupling reaction in other mixed solvents such as
C2H5OH–H2O, THF–H2O or CH3COCH3–H2O in 1 : 1 ratio,
respectively, the coupling product was also obtained in the same
high yield (Table 4, Entreis 5, 6 and 7). Obviously, it can be
considered that solvent effect was one of the most important factors
in the coupling of arylboronic acids with imidazole. Protic solvents
were essential to the coupling reaction in the catalytic system of
simple copper salts.
In conclusion, we have developed a novel and highly efficient
catalytic system for preparing a variety of N-arylimidazoles in
excellent yields through the cross coupling of arylboronic acids
with imidazole in protic solvents and in the presence of a catalytic
amount of simple copper salts. In addition, this system also works
well with pyrazole, anilines, and imides. The further work and the
study on mechanism are being in progress.
This work was supported by the National Natural Science
Foundation of China (20172038, 20132020) and Doctoral Founda-
tion of Education Ministry of China.
Notes and references
Table 3 Synthesis of a variety of N-arylimidazolesa
1 (a) J. Ohmori, M. Shimizu-Sasamata, M. Okada and S. Sakamato, J. Med.
Chem., 1996, 39, 3971; (b) Y. S. Lo, J. C. Nolan, T. H. Maren, Jr., W. J.
Welstead, D. F. Gripshover and D. A. Shamblee, J. Med. Chem., 1992,
35, 4790.
2 (a) P. Cozzi, G. Carganico, D. Fusar, M. Grossoni, M. Menichincheri, V.
Pinciroli, R. Tonani, F. Vaghi and P. Salvati, J. Med. Chem., 1993, 36,
2964; (b) T. Güngör, A. Fouquet, J. M. Teulon, D. Provost, M. Cazes and
A. Cloarec, J. Med. Chem., 1992, 35, 4455; (c) G. R. Martinez, K. A. M.
Walker, D. R. Hirschfeld, J. J. Bruno, D. S. Yang and P. J. Moloney, J.
Med. Chem., 1992, 35, 620.
3 (a) H. M. Lee and S. P. Nolan, Org. Lett., 2000, 2, 2053; (b) W. A.
Herrman and C. Köcher, Angew. Chem., Int. Ed. Engl., 1997, 36,
2161.
4 (a) P. Y. S. Lam, S. Deudon, K. M. Averill, R. Li, M. Y. He, P. DeShong
and C. G. Clark, J. Am. Chem. Soc., 2000, 122, 7600; (b) G. I. Elliott and
J. P. Konopelski, Org. Lett., 2000, 2, 3055; (c) A. Kiyomori, J.-F.
Marcoux and S. L. Buchwald, Tetrahedron Lett., 1999, 40, 2657; (d) P.
López-Alvarado, C. Avendaño and J. C. Menéndez, J. Org. Chem., 1995,
60, 5678; (e) P. López-Alvarado, C. Avendaño and J. C. Menéndez,
Tetrahedron Lett., 1992, 33, 659.
Entry
1
1
N-arylimidazoles (3)
Yield (%)b
98
2
98
3
97
98
93
92
4
5c
6c
5 (a) P. Y. S. Lam, C. G. Clark, S. Saubern, J. Adams, K. M. Averill, D. M.
T. Chan and A. Combs, Synlett, 2000, 674; (b) A. P. Combs, S. Saubern,
M. Rafalski and P. Y. S. Lam, Tetrahedron Lett., 1999, 40, 1623; (c) P.
Y. S. Lam, C. G. Clark, S. Saubern, J. Adams, M. P. Winters, D. M. T.
Chan and A. Combs, Tetrahedron Lett., 1998, 39, 2941; (d) D. M. T.
Chan, K. L. Monaco, R.-P. Wang and M. P. Winters, Tetrahedron Lett.,
1998, 39, 2933.
7c
98
8c
92
6 (a) J. P. Collman, M. Zhong, C. Zhang and S. Costanzo, J. Org. Chem.,
2001, 66, 7892; (b) J. P. Collman, M. Zhong, L. Zeng and S. Costanzo,
J. Org. Chem., 2001, 66, 1528; (c) J. P. Collman and M. Zhong, Org.
Lett., 2000, 2, 1233.
a 5% mol of CuCl was used. b Isolated yield, purity confirmed by HPLC,
MS and 1H NMR. c Reflux 6 h.
7 (a) J. S. You, X. Q. Yu, G. L. Zhang, Q. X. Xiang, J. B. Lan and R. G.
Xie, Chem. Commun., 2001, 1816; (b) Y. Yuan, G. Gao, Z. L. Jiang, J. S.
You, Z. Y. Zhou, D. Q. Yuan and R. G. Xie, Tetrahedron, 2002, 58, 8993
and references cited therein.
Table 4 Coupling reaction in different aqueous solutiona
Entry
Solvent (V/V)
Yield (%)b
8 Typical procedure for the cross coupling reaction: a mixture of 2 mmol of
arylboronic acid (1 ), 2.4 mmol of imidazole (2), and a catalytic amount
of copper salt in 10 ml dry methanol was stirred under an atmosphere of
air and refluxed 3 h. The reaction mixture was concentrated and the
residue was purified by silica gel column chromatography using CH2Cl2–
C2H5OH as the eluent to give N-arylimidazole (3). N-(2-methoxyna-
phthyl)imidazole (3h) is a new compound and its spectral data: 1H NMR
(400 MHz, CDCl3): d 7.89 (s, 1H), 7.78–7.80 (m, 2H), 7.74 (s, 1H),
7.49–7.54 (m, 1H), 7.40–7.44 (m, 1H), 7.30–7.31 (d, 2H), 7.22 (s, 1H),
3.96 (s, 3H) ppm; M/S (m/z): 224(M+, 100), 196, 182, 169, 152, 139, 127,
113, 101, 84, 77, 58; elemental analysis calcd. (%) for C14H12N2O
(224.26): C 74.98, H 5.39, N 12.49; found C 74.62, H 5.32, N 12.35%.
9 (a) C. J. Li, Acc. Chem. Res., 2002, 35, 533; (b) N. Miyaura and A.
Suzuki, Chem. Rev., 1995, 95, 2457.
1
2c
3
4
5
6
7
8
H2O
H2O
22
10
22
90
90
92
88
58
H2O–CH3OH (10 : 1)
H2O–CH3OH (1 : 1)
H2O–C2H5OH (1 : 1)
H2O–THF (1 : 1)
H2O–CH3COCH3 (1 : 1)
H2O-CH3CN (1 : 1)
a 5% mol of Cu(OAc)2.H2O was used and refluxed 6 h. b Isolated yield,
purity confirmed by HPLC, MS and 1H NMR. c 5% mol of CuCl was
used.
C h e m . C o m m u n . , 2 0 0 4 , 1 8 8 – 1 8 9
189