pubs.acs.org/joc
During our drug discovery efforts, we became interested
CuI-Catalyzed Amination of Arylhalides with
Guanidines or Amidines: A Facile Synthesis of
1-H-2-Substituted Benzimidazoles
in the facile assembly of 1-H-2-amino-benzimidazoles,
molecules that have exhibited antihistamine,4 immunosup-
pressive,5 anti-inflammatory,6 analgesic,7 antiviral,8 and
antibacterial9 activities. The prevailing synthetic strategy
for this class of compounds is through a three-step sequence,
starting from a 1,2-diaminobenzene (Scheme 1). 1,3-Dihy-
dro-benzoimidazol-2-one formation is followed by activa-
tion of the ketone to chloride or sulfur derivatives10 and then
the displacement with an amine to provide the desired 1-H-2-
amino-benzimidazole. Depending on the nucleophilicity of
the amine, protection of the NH proton is often required
prior to the amination step, which adds two steps to the
overall sequence. In addition, 1,2-diaminobenzenes with the
desired substitution pattern are often unstable and difficult
to prepare. Apparently, there is a need for a more concise
synthesis. Herein, we report our results on a one-step synth-
esis of 1-H-2-amino-benzimidazoles through tandem amina-
tion of 1,2-dihalobenzenes with substituted guanidines. This
methodology is also quite general in preparing other
2-substituted benzimidazoles.
Xiaohu Deng,* Heather McAllister, and
Neelakandha S. Mani
Johnson & Johnson Pharmaceutical Research & Development,
LLC 3210 Merryfield Row, San Diego, California 92121
Received May 1, 2009
We envisioned that a direct metal-catalyzed double ami-
nation of 1,2-dihalobenzenes with substituted guanidines
might offer one-step access to 1-H-2-amino-benzimidazole
(Scheme 2). In pursuit of this goal, we recognized two
potential obstacles. First, despite extensive studies on the
metal-catalyzed Buchwald-Hartwig amination reaction,11
amination of arylhalides with guanidines has rarely been
found in the literature. Although a few intramolecular cases
exist,12 to the best of our knowledge, the intermolecular
catalytic amination of nonactivated arylhalides with guani-
dines has not been reported.13 The relative paucity of exam-
ples might result from the proclivity of guanidine to strongly
bind many transition metals.14 Alternatively, guanidines or
CuI/L5 (N,N0-dimethylethylenediamine) proves to be an
efficient catalyst system for the amination of arylhalides
with guanidines. The same catalyst system is then success-
fully applied to the one-step synthesis of 1-H-2-amino-
benzimidazoles through tandem aminations of 1,2-diha-
loarenes in modest yields. This methodology is also
applicable for the preparation of 1-H or 1-substutituted
2-aryl- or 2-alkyl-benzimidazoles.
Benzimidazoles, a “privileged” structure, is a hugely impor-
tant class of compounds for the pharmaceutical industry.1 The
benzimidazole core structure can be found in many commer-
cial drugs such as Prilosec, Nexium, Protonix, Atacand,
Famvir, and Vermox, as well as numerous experimental drug
candidates in a wide range of therapeutic areas.2 Therefore, it
is not surprising that the synthesis of benzimidazoles has
always been of great interest to organic chemists.3
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(13) A recent paper described the synthesis of quinazolinones from 2-
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5742 J. Org. Chem. 2009, 74, 5742–5745
Published on Web 06/15/2009
DOI: 10.1021/jo900912h
r
2009 American Chemical Society