diaminoarene derivatives with carbonyl compounds is perhaps
the most common.6 Substituted o-nitroanilines can also be used
in the place of the 1,2-diaminoarene derivatives under reducing
conditions.7 However, the preparation of benzimidazoles with
these methods depends on the availability of the requisite 1,2-
diaminoarene or o-nitroaniline derivatives, and some of them
are sometimes difficult to prepare.8 Recently, considerable
progress has been made in the area of copper-catalyzed Ullmann
N-arylations,9 with some research groups10-12 and ourselves13
having developed highly efficient copper catalyst systems to
N-arylate amines, and therefore construct N-heterocycles.14
Copper15 and palladium-catalyzed16 couplings of o-haloacetoa-
nilides with amines to form N-aryl benzimidazoles have been
reported. Herein, we report a novel and efficient copper-
catalyzed cascade reaction of o-haloacetoanilide derivatives with
amidine hydrochlorides to synthesize 2-substituted benzimidazoles.
Copper-Catalyzed Synthesis of Benzimidazoles
via Cascade Reactions of o-Haloacetanilide
Derivatives with Amidine Hydrochlorides
Daoshan Yang,†,‡ Hua Fu,*,† Liming Hu,*,‡ Yuyang Jiang,†,¶
and Yufen Zhao†
Key Laboratory of Bioorganic Phosphorus Chemistry and
Chemical Biology (Ministry of Education), Department of
Chemistry, Tsinghua UniVersity, Beijing 100084, People’s
Republic of China, College of Life Sciences and
Bioengineering, Beijing UniVersity of Technology, Beijing
100124, People’s Republic of China, and Key Laboratory of
Chemical Biology (Guangdong ProVince), Graduate School
of Shenzhen, Tsinghua UniVersity, Shenzhen 518057,
People’s Republic of China
fuhua@mail.tsinghua.edu.cn; huliming@bjut.edu.cn
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(9) For recent reviews on copper-catalyzed Ullmann N-arylation, see: (a)
Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 15, 2428. (b) Ley, S. V.; Thomas,
A. W. Angew. Chem., Int. Ed. 2003, 42, 5400. (c) Beletskaya, I. P.; Cheprakov,
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We have developed an efficient method for the synthesis of
benzimidazoles via cascade reactions of o-haloacetoanilide
derivatives with amidine hydrochlorides. The protocol uses
10 mol % CuBr as the catalyst, Cs2CO3 as the base, and
DMSO as the solvent, and no ligand is required. The
procedure proceeds via the sequential coupling of o-
haloacetoanilide derivatives with amidines, hydrolysis of the
intermediates (amides), and intramolecular cyclization with
the loss of NH3 to give 2-substituted 1H-benzimidazoles.
Benzimidazoles have attracted much attention for their wide
applications as enzyme inhibitors,1 drugs,2 dyes,3 and polymers.4
Among the previous methods,5 the condensation of 1,2-
* To whom correspondence should be addressed. Fax: 86-10-62781695.
† Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology
(Ministry of Education), Tsinghua University.
‡ College of Life Sciences and Bioengineering, Beijing University of
Technology.
¶ Key Laboratory of Chemical Biology (Guangdong Province), Tsinghua
University.
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10.1021/jo8014984 CCC: $40.75
Published on Web 08/28/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7841–7844 7841