Angewandte
Chemie
DOI: 10.1002/anie.201204710
Synthetic Method
Catalyst-Controlled Chemoselective Arylation of
2-Aminobenzimidazoles**
Satoshi Ueda and Stephen L. Buchwald*
Transition-metal-catalyzed heteroatom arylation reactions
are emerging as valuable tools in organic synthesis, fuelled
by the identification of more efficient catalyst systems with
increased substrate scopes.[1] The synthetic utility of these
transformations is increased if catalysts are both highly
reactive and selective. This is particularly important for
substrates with multiple heteroatom sites capable of under-
going reaction. Furthermore, the development of comple-
Scheme 1. Chemoselective arylation of 2-aminobenzimidazole.
mentary sets of catalysts or conditions for the selective
arylation of substrates possessing multiple nucleophilic sites
enables the rapid, protecting group-free generation of molec-
ular complexity with minimal synthetic manipulations. In this
context, we have developed sets of procedures for the Pd- and
Cu-catalyzed chemoselective arylation of aminobenzami-
des,[2a] 5-aminoindole,[2a] 4-(2-aminoethyl)aniline,[2a] amino
alcohols,[2b] oxindoles,[2c] and aminophenols.[2d]
report the successful development of an orthogonal set of Pd-
and Cu-catalyzed chemoselective conditions for the N-
arylation of unprotected 2-aminobenzimidazoles and related
aminoazoles.
We initiated our investigation by examining the Pd-
catalyzed coupling of 2-aminobenzimidazole and bromoben-
zene (Table 1). With [Pd2(dba)3] (0.1 mol%; dba = dibenzyli-
deneacetone), L1 (0.2 mol%), and K3PO4, the N-arylation
went smoothly to give 2-anilinobenzimidazole 1a in 92%
yield and without formation of regioisomer 1b or poly-
arylated products (entry 1). The use of other biaryl phosphine
ligands (L2–L4) provided low yields of product under these
conditions. Replacing K3PO4 with other bases also resulted in
lower yield of the product (entries 5 and 6).
During our work on the N-arylation of nitrogen-contain-
ing heterocycles,[3] we became interested in the use of 2-
aminobenzimidazoles as potential substrates for chemoselec-
tive N-arylation reactions. Both N1-aryl-2-aminobenzimida-
zoles and 2-arylaminobenzimidazoles are found in a variety of
medicinally important compounds including integrin a4b1
antagonists,[4] mTOR inhibitors,[5] aurora kinase inhibitors,[6]
Tie-2 kinase inhibitors,[7] Ca channel blockers,[8] and CXCR2
antagonists.[9] Thus, the selective syntheses of both of these
isomers from a common core structure represent attractive
alternatives to other previously employed routes[10,11] and
could provide rapid access to a diverse array of potentially
bioactive 2-aminobenzimidazole derivatives (Scheme 1).
While the efficient Cu-[12] and Pd-catalyzed[13] N1-aryla-
tions of some benzimidazole derivatives with aryl halides
have been described, the chemoselective N-arylation of
unprotected 2-aminobenzimidazoles with aryl halides has
received little attention.[14–16] Potential challenges of such an
approach include the formation of regioisomers and/or poly-
arylated products due to the presence of three adjacent
nucleophilic nitrogens (N1, N3 and C2-amino group), as well as
the tautomeric nature of 2-aminobenzimidazoles. Herein, we
Turning our attention to finding conditions for the
selective formation of the the N1-arylated product (2a), we
found that reactions with a Cu-catalyst system (iodobenzene/
bromobenzene, CuI, L5,[17] and Cs2CO3) were completely
chemoselective, providing no trace either of regioisomer 1a
or of any poly-arylated products (entries 7 and 8). The use of
other ligands (L6–L8) and bases did not alter this chemo-
selectivity, but rather gave lower yields of 1b (entries 9–13).
Thus, complete selectivity and complementarity can be
achieved by using Pd- and Cu-based catalyst systems.
We next explored the scope of the Pd-catalyzed selective
N-arylation of aminoazoles, and found that a variety of 2-
aminobenzimidazoles and 2-aminoimidazole could be cou-
pled chemoselectively with both electron-rich and electron-
poor aryl halides, as well as with an ortho-substituted aryl
halide (Table 2, 1b–1h).[18] For 3-amino-5-alkylpyrazoles the
primary amino groups were also selectively and efficiently
arylated by using 0.2–0.5 mol% catalyst. Though the selective
Pd-catalyzed N-arylation of 3-aminopyrazoles has been
previously reported, relatively high catalyst loadings
(5 mol% Pd and 10 mol% L4) and the use of a strong base
(NaOtBu) were required.[13a]
[*] Dr. S. Ueda, Prof. Dr. S. L. Buchwald
Department of Chemistry, Room 18-490
Massachusetts Institute of Technology
Cambridge MA 02139 (USA)
E-mail: sbuchwal@mit.edu
[**] This work is supported by National Institutes of Health (GM58160).
S.U. thanks the Japan Society for the Promotion of Sciences (JSPS)
for a Postdoctral Fellowship for Research Abroad. We thank Dr.
Meredeth A. McGowan for help with preparation of this manuscript.
The scope of the Cu-catalyzed N1-selective arylation was
also investigated (Table 3). Reactions of 2-aminobenzimid-
azoles and 2-aminoimidazole with a variety of functionalized
aryl iodides gave N1-arylated products 2b–2 f and 2i selec-
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!
Ueda, Satoshi
