N-Arylation of Benzimidazole
COMMUNICATIONS
Table 4. Coupling of benzimidazole 1 with various phenyl-
boronic acids.
ditions with Cu(OAc)2 (1.5 equivs.) gavep-tolylbenzimi-
dazole 3g in only a 69% yield after 4 days.[4b]
In conclusion, we have developed a novel procedure
for the N-arylation of imidazole with arylboronates, bor-
oxines and boronic acids. The presence of an optimal
amount of water plays a significant role to accelerate
the reaction. The effect of acceleration made the reac-
tion more than twice as fast as that under the hitherto
known anhydrous conditions with molecular sieves. Ow-
ing to this effect, N-arylation was achieved with a cata-
lytic amount of a simple copper salt under mild condi-
tions, and the desired compound was obtained in excel-
lent yield. On the other hand, the formation of phenols
as by-products did not depend on the amount of water,
and the formed phenols did not affect the yield of the de-
sired N-arylimidazoles. This finding is especially benefi-
cial for large-scale manufacture because there is no need
for commonly used dehydrating agents such as mo-
lecular sieves. Such reagents are unfavorable for a large
(or industrial) scale production. Further work and the
study on the mechanism are in progress.
Conditions: 1 (1 equiv.), boronic acid (2 equivs.), water
(1 equiv), Cu(OAc)2 ·H2O (30 mol %), dry pyridine
(2 equivs.), dry DMF, 308C, 24 h.
[a]
Experimental Section
Isolated yield.
Typical Procedure for the Cross Coupling Reaction
As with 2, the presence of water demonstrated the ef-
fect to accelerate the reaction using non-substituted tri-
phenylboroxine 4 and phenylboronic acid 5a (Table 3,
Figures 6 and 7). In this case, the desired N-phenylben-
zimidazole 3b was obtained in excellent yield within
24 hours. We also found that boronic acid 5a was more
reactive than boroxine 4 (Figure 6, entries 2 and 3).
On the other hand, as discussed above, the amount of
To
a 20-mL vial were added benzimidazole 1 (0.5 g,
4.23 mmol), boronate 2 (1.6 g, 8.46 mmol), Cu(OAc)2 monohy-
drate (84.6 mg, 0.42 mmol), dry DMF (4 mL), water (75 mL,
4.23 mmol) and then dry pyridine (0.68 mL, 8.46 mmol). The
reaction mixture was vigorously stirred under an atmosphere
of air at 308C for 24 h, poured into 12.5% aqueous NH3
(13 mL) and then extracted with toluene (50 mL, 2 times).
The combined organic layers were concentrated under re-
formed phenol did not depend on the amount of water duced pressure at 508C, and the residue was purified by flash
column chromatography on silica gel (hexane/ethyl acetate,
10/1 to 1/1) to give N-(2-cyano-1-phenyl)benzimidazole 3a;
yield: 0.87 g (93%); mp 107.88C (lit.[9] mp 106–107.58C); slight-
and did not exceed initial conversion. However, the
yield was approximately 50% to 2 equivs. of phenylbor-
onic acid at the start (after 2 hours). Benzene, in addi-
tion to other by-products, was observed in minor
amounts within 24 hours.
1
ly yellowish-white solid (Table 2, entry 3); HNMR (CDCl 3,
400 MHz): d¼7.36–7.41 (m, 3H), 7.63 (t, J¼7.22 Hz, 2H),
7.83 (td, J¼7.94 Hz, 1.48 Hz, 1H), 7.90–7.94 (m, 2H), 8.19 (s,
1H); MS (ESI): m/z¼220.4 [MH]þ.
Finally, several substituted boronic acids were evalu-
ated under the above-mentioned reaction conditions
(Table 4). We found that the reaction conditions tolerat-
ed both electron-donating and electron-withdrawing
substituents at the ortho-, meta- or para-positions of
the phenylboronic acid. However, we found that one
boronic acid derivative 5b (Table 4, Entry 1) was not
well tolerated by the reaction conditions. It is thought
that this particular boronic acid derivative is less stable
due to the presence of an electron-withdrawing substitu-
ent at the ortho-position.[8] However, the presently re-
ported reaction conditions allowed the coupling of ben-
zimidazole with p-tolylboronic acid to give p-tolylbenzi-
midazole 3g in 96% yield (Table 4, Entry 6). In contrast,
N-Phenylbenzimidazole (3b):1HNMR (CDCl 3, 400 MHz):
d¼7.33–7.36 (m, 2H), 7.46–7.61 (m, 6H), 7.88–7.90 (m,
1H), 8.13 (s, 1H); MS (ESI): m/z¼195.3 [MH]þ.
N-(2-Methyl-1-phenyl)benzimidazole
(3c):
1HNMR
(CD3OD, 400 MHz): d¼2.05 (s, 3H), 7.11–7.14 (m, 1H),
7.28–7.36 (m, 3H), 7.38–7.44 (m, 1H), 7.48–7.49 (m, 2H),
7.74–7.79 (m, 1H), 8.23 (s, 1H).
N-(3-Cyano-1-phenyl)benzimidazole
(3d):
1HNMR
(CDCl3, 400 MHz): d¼7.37–7.42 (m, 2H), 7.51–7.55 (m,
1H), 7.72–7.82 (m, 3H), 7.86 (t, J¼1.46 Hz, 1H), 7.89–7.93
(m, 1H), 8.12 (s, 1H); mp 104.48C (lit.[9] mp 98–1058C).
N-(3-Methyl-1-phenyl)benzimidazole
(3e):
1HNMR
(CD3OD, 400 MHz): d¼2.43 (s, 3H), 7.30–7.38 (m, 5H), 7.46
(t, J¼7.7 Hz, 1H), 7.50–7.55 (m, 1H), 7.71–7.76 (m, 1H),
the previously reported methods using anhydrous con- 8.33 (s, 1H).
Adv. Synth. Catal. 2004, 346, 1679–1684
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