Hypervalent iodine in synthesis 85: An efficient method for the synthesis of N-arylbenzimidazoles by the copper-catalyzed N-arylation of benzimidazole with diaryliodonium salts

Article abstract of DOI:10.1002/hc.10043

A method for the synthesis of N-arylbenzimidazoles by the copper catalyzed N-arylation of benzimidazole with diaryliodonium salts was described. The process had many advantages such as mild reaction conditions, simplicity of procedure, using nonpoisonous, accessible reagents and reasonable yields. It was found that all products gave satisfactory melting points, infrared and NMR spectra.

Full text of DOI:10.1002/hc.10043

Heteroatom Chemistry
Volume 13, Number 7, 2002
Hypervalent Iodine in Synthesis 85:
An Efficient Method for the Synthesis
of N-Arylbenzimidazoles by the Copper-
Catalyzed N-Arylation of Benzimidazole
with Diaryliodonium Salts
Tao Zhou and Zhen-Chu Chen
Department of Chemistry, Zhejiang University (Xixi Campus), Hangzhou 310028,
People’s Republic of China
Received 7 May 2001; revised 1 November 2001
of toxic or inaccessible reagents, and limitation
ABSTRACT: N-arylbenzimidazoles were prepared
of substrates. Therefore, the development of an
efficient and convenient method for the synthesis of
N-arylbenzimidazoles is still in demand.
in moderate yields by copper-catalyzed N-arylation
ꢀ
C
of benzimidazole with diaryliodonium salts.
2002
Wiley Periodicals, Inc. Heteroatom Chem 13:617–619,
2002; Published online in Wiley InterScience (www. inter-
science.wiley.com). DOI 10.1002/hc.10043
Recently, our research into synthetic applica-
tions of transition metal-catalyzed arylation reac-
tions with diaryliodonium salts [8] showed that they
are efficient arylation reagents. This prompted us
to investigate copper-catalyzed N-arylation of ben-
zimidazole to provide an efficient synthesis of N-
arylbenzimidazoles. Here, we report a convenient
method for the synthesis of N-arylbenzimidazoles by
copper-catalyzed N-arylation of benzimidazole with
diaryliodonium salts (Scheme 1).
INTRODUCTION
N-arylbenzimidazoles are important compounds
particularly in pharmaceutical research because
of their biological activities, such as spasmolytic
activity [1]. The method for the preparation of
N-arylbenzimidazoles mainly deals with the
Ullmann coupling reaction, which requires harsh
reaction conditions. Usually this coupling reaction
is carried out in nitrobenzene [2] or pyridine [3] and
very often gives low yields. Recently, other methods
have also been developed, such as N-arylation of ben-
zimidazole with aryllead triacetates [4], organobis-
muth reagents [5], arylboronic acids [6], or by
nucleophilic aromatic substitution [7]. These meth-
ods also have some disadvantages, such as the use
RESULTS AND DISCUSSION
We found that N-arylation of benzimidazole with
diaryliodonium salts could proceed smoothly in
the presence of a copper catalyst at 80◦C in DMF
and gave N-arylbenzimidazoles in moderate yields.
Among the tested copper catalysts, including CuI,
Cu(OAc)2, and Cu(acac)2, CuI is the most effective al-
though each of them can catalyze this reaction. Sev-
eral diaryliodonium salts with various substituents,
such as methyl, chloro, methoxy, bromo, and ni-
tro groups were tested. It was found that the reac-
tion is general for these substrates. The results are
Correspondence to: Zhen-Chu Chen; e-mail: zhenchuc@mail.
HZ.ZJ.CN.
c
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2002 Wiley Periodicals, Inc.
617

618 Zhou and Chen
and then aqueous H2S (40 ml) was added, and the
biphasic system was vigorously stirred for 1 h and fil-
tered to remove the insoluble inorganic species. The
CHCl3 layer was washed with brine (2 × 40 ml), dried
over anhydrous sodium sulfate and evaporated un-
der a vacuum. The residue was chromatographed on
a silica gel plate using cyclohexane/ethyl acetate (2:1)
as a developer to give pure product.
SCHEME 1
summarized in Table 1. All products gave satisfac-
tory m.p., IR, and 1H NMR spectra.
DATA OF PRODUCTS
In summary, we provide a convenient synthe-
sis for N-arylbenzimidazoles by copper-catalyzed
N-arylation of benzimidazole with diaryliodonium
salts. It has some advantages over the existing
methods such as mild reaction conditions, simplic-
ity of procedure, using nonpoisonous, accessible
reagents, and reasonable yields.
N-Phenylbenzimidazole (3a): m.p. 92–94◦C (lit.
[2(b)], m.p. 95–96◦C). 1H NMR δH 7.36 (m, 2H), 7.49–
7.61 (m, 6H), 7.91 (m, 1H), 8.25 (s, 1H). IR ꢀmax cm−1
3070, 1600, 1500, 1455, 1293, 1228.
N-(4-Methylphenyl) benzimidazole (3b): oil (lit.
[4], oil). 1H NMR δH 2.47 (s, 3H), 7.39–7.44 (m, 6H),
7.53 (m, 1H), 7.95 (m, 1H), 8.42 (m, 1H). IR ꢀmax cm−1
3060, 1520, 1485, 1455, 1290, 1230.
N-(4-Chlorophenyl) benzimidazole (3c): m.p.
89–91◦C (lit. [9], m.p. 92◦C). 1H NMR δH7.36 (m, 2H),
7.49 (m, 3H), 7.56 (m, 2H), 7.90 (m, 1H), 8.16 (s,
1H). IR νmax cm−1 3095, 3033, 1597, 1507, 1455, 1300,
1235, 1092, 897, 731.
EXPERIMENTAL
Melting points were uncorrected. 1H NMR data were
recorded on an Avance 400 spectrometer using CDCl3
as the solvent with TMS as an internal standard.
IR spectra were determined on a Vector 22 in-
frared spectrometer with KBr pellets. MS spectra
were recorded on an HP5859B mass spectrometer.
Elemental analyses were performed on an EA1110
instrument.
N-(4-Methoxyphenyl) benzimidazole (3d): m.p.
98–99◦C (lit. [9], m.p. 99◦C). 1H NMR δH 3.89 (s, 3H),
7.07 (m, 2H), 7.34 (m, 2H), 7.41 (m, 2H), 7.46 (m,
1H), 7.88 (m, 1H), 8.09 (m, 1H). IR νmax cm−1 3065,
1515, 1487, 1457, 1290, 1245, 1211, 1030, 848, 750.
N-(4-Bromophenyl) benzimidazole (3e): m.p.
General Procedure for Preparation
of N-Arylbenzimidazoles
1
112–113◦C. H NMR δH 7.36 (m, 2H), 7.42 (m, 2H),
7.51 (1H), 7.71 (m, 2H), 7.89 (m, 1H), 8,11 (s, 1H). IR
νmax cm−1 3053, 1590, 1498, 1457, 1315, 1291, 1231,
1208, 1071, 1012, 870, 841, 745. MS m/z 272 (M+,
100), 274 ( M++2, 99.17). Anal. Calcd. for C13H9BrN2:
C 57.17, H 3.32, N. 10.25. Found: C 57.12, H 3.31, N
10.17%.
A mixture of diaryliodonium salt 1 (1 mmol),
benzimidazole 2 (1 mmol), K2CO3 (2 mmol), CuI
(10 mol%), and DMF (5 ml) was stirred under a ni-
trogen atmosphere at 80◦C or 2.5–3 h. After cooling,
the reaction mixture was diluted with CHCl3 (30 ml),
N-(3-Nitrophenyl) benzimidazole (2f): m.p. 148–
150◦C (lit. [3], 151–152◦C). 1H NMR δH 7.41 (m, 2H),
7.55 (m, 1H), 7.82 (m, 1H), 7.91 (m, 2H), 8.22 (s, 1H),
8.35 (m, 1H), 8.45 (m, 1H). IR ꢀmax cm−1 3035, 1610,
1542, 1057, 1456, 1347, 1297, 1238, 1206, 1163, 894,
870, 812, 784, 734, 685.
TABLE 1 Copper-Catalyzed N-Arylation of Benzimidazole
Copper
Catalyst
Yield
Entry
Iodonium Salt
Product (%)(a)
−
1
2
3
4
5
Ph2 I+BF4 (1a)
Cu(OAc)2
Cu(acac)2
CuI
3a
3a
3a
3b
41
62
80
76
1a
1a
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Hypervalent Iodine in Synthesis 85: An Efficient Method for the Synthesis of N-Arylbenzimidazoles 619
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