Copper-catalyzed regiospecific synthesis of N-alkylbenzimidazoles

Article abstract of DOI:10.1021/ol7020737

(Chemical Equation Presented) A copper-catalyzed method is described for the preparation of N-alkylbenzimidazoles in regioisomerically pure form starting from o-haloanilines. The method utilizing CuI and trans-N,N′-dimethyl-1, 2-cyclohexanediamine allows the preparation of N-alkylbenzimidazoles in good to excellent yields.

Full text of DOI:10.1021/ol7020737

ORGANIC
LETTERS
2007
Vol. 9, No. 23
4749-4751
Copper-Catalyzed Regiospecific
Synthesis of N-Alkylbenzimidazoles
Nan Zheng and Stephen L. Buchwald*
Department of Chemistry, Room 18-490, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
sbuchwal@mit.edu
Received August 22, 2007
ABSTRACT
A copper-catalyzed method is described for the preparation of N-alkylbenzimidazoles in regioisomerically pure form starting from o-haloanilines.
The method utilizing CuI and trans-N,N′-dimethyl-1,2-cyclohexanediamine allows the preparation of N-alkylbenzimidazoles in good to excellent
yields.
Benzimidazoles are an important class of heterocycles with
a wide range of applications.1-4 Although numerous methods
for their synthesis have been disclosed,5 it remains difficult
to access regioisomerically pure N-substituted benzimid-
azoles. We have recently disclosed a palladium-catalyzed
method that allows access to N-arylbenzimidazoles in regio-
isomerically pure form.6 However, the catalyst system used
in the method failed to provide N-alkylbenzimidazoles (e.g.,
2) in acceptable yield when primary aliphatic amines were
used as substrates (Scheme 1). Despite extensive effort made
in the screening of ligands, bases, and solvents, only a modest
yield of the product (2) could be realized. The desired
coupling reaction was plagued by competing reduction of 1
to acetanilide. The problem was traced to a â-hydride
elimination process from the intermediate Pd(aryl)amide
through the use of 2,2-dideuterohexylamine (Scheme 1). This
result demonstrates a major difference in the efficiency of
the Pd-catalyzed coupling of o-haloanilides with primary
aliphatic amines and with anilines. We reasoned that an
analogous copper-catalyzed transformation might be more
effective with amines possessing â-hydrogen atoms. Herein
we describe a complementary copper-based catalytic method
Scheme 1. Pd-Catalyzed Amination with Aliphatic Amines
(1) Morphy, R.; Rankovic, Z. J. Med. Chem. 2005, 48, 6523-6543.
(2) Velik, J.; Baliharova, V.; Fink-Gremmels, J.; Bull, S.; Lamka, J.;
Skalova, L. Res. Vet. Sci. 2004, 76, 95-108.
(3) Carella, A.; Centore, R.; Fort, A.; Peluso, A.; Sirigu, A.; Tuzi, A.
Eur. J. Org. Chem. 2004, 2620-2626.
(4) Kim, J. D.; Mori, T.; Hayashi, S.; Honma, I. J. Electrochem. Soc.
2007, 154, A290-A294.
(5) Grimmett, M. R. In Imidazole and Benzimidazole Synthesis; Meth-
Cohn, O., Ed.; Best Synthetic Methods; Academic: London, 1997.
(6) Zheng, N.; Anderson, K. W.; Huang, X.; Nguyen, H. N.; Buchwald,
S. L. Angew. Chem., Int. Ed. 2007, 46, 7509-7512.
10.1021/ol7020737 CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/19/2007

that enables us to prepare N-alkylbenzimidazoles in regio-
isomerically pure form.7
Retrosynthetically, there are two clear carbon-nitrogen
bond disconnections for the synthesis of 5, the precursor to
N-alkylbenzimidazoles 4 (Scheme 2). Each requires a dif-
provide benzimidazole 9 in 82% yield.7 Unfortunately, the
process only worked well for trifluoroacetamide substrates
(5, R ) CF3) and hence lacked generality.
We next turned our focus to a route based on bond
disconnection B (Scheme 4). Using conditions for the copper-
Scheme 2. Possible Bond Disconnections for the Synthesis of
N-Alkylbenzimidazoles
Scheme 4. Scope for Copper-Catalyzed Synthesis of
N-Alkylbenzimidazoles
ferent type of coupling reaction (the amination or amidation
of an aryl bromide or iodide). Using copper catalysts, both
processes are well precedented in the literature.8
Bond disconnection A was investigated first using the
model reaction that combined aryl iodide 6 and n-hexylamine
(Scheme 3). Under the conditions screened, none of the
Scheme 3. Synthesis of N-Alkylbenzimidazoles via Bond
Disconnection A
catalyzed amidation (5 mol % of CuI, 20 mol % of diamine
ligand, 1.5 equiv of Cs2CO3 in 1,4-dioxane) previously
reported by our group, aryl iodide 10 was allowed to react
with benzamide to provide the desired amidation product
11a; these coupling conditions proved to be quite general.
In addition to benzamide, hexanamide, cyclohexanecarbox-
amide, and (E)-cinnamamide were all successfully coupled
with 10. In contrast to the synthesis of N-arylbenzimidazoles,
the amidation products 11a-d did not spontaneously cyclize
to provide N-alkylbenzimidazoles 12a-d under the coupling
conditions. Depending on the substrate, two protocols were
developed to accomplish the dehydration process. Amides
such as 11a,b were converted to N-alkylbenzimidazoles
12a,b by treatment with 1.5 equiv of K3PO4 in t-BuOH at
110 °C (8 h). The amidation and cyclodehydration steps were
performed in a single reaction vessel. The cyclodehydration
of amides 11c,d to N-alkylbenzimidazoles 12c,d was ac-
complished by heating the former in AcOH at 90 °C for 2
h. We were also able to extend this chemistry to an aryl
bromide substrate, 13, as shown for the preparation of 15.
ligands provided amination product 7 in acceptable yield.
Considering that the acidity of the amide proton is known
to have a substantial effect on the rate of amination,9 we
examined the combination of aryl iodide 8 and n-hexylamine,
which proceeded smoothly at room temperature, not neces-
sitating the use of added ligand. The nascent coupling product
spontaneously cyclized under the reaction conditions to
(7) During the preparation of this manuscript, Ma et al. published a related
Cu-catalyzed process for the preparation of N-alkylbenzimidazoles: Zou,
B.; Yuan, Q.; Ma, D. Angew. Chem., Int. Ed. 2007, 46, 2598-2601.
(8) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. ReV. 2004, 248,
2337-2364.
To address the issue of preparing regioisomerically pure
N-alkylbenzimidazoles, the coupling reactions of two pairs
(9) Cai, D.; Zou, B.; Ma, D. Angew. Chem., Int. Ed. 2006, 45, 1276-
1279.
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Org. Lett., Vol. 9, No. 23, 2007

of isomeric aryl iodides 16a-d and two amides (benzamide
and hexanamide) were carried out (Scheme 5). Four pairs
of regioisomeric N-alkylbenzimidazoles 18a-h were syn-
thesized in good yields using the conditions described above
without need for further optimization. Compared to the
palladium-catalyzed synthesis of N-arylbenzimidazoles,6 this
method appeared to be less sensitive to the substitution
pattern of the aryl iodide substrates.
Scheme 5. Copper-Catalyzed Synthesis of Regioisomeric
N-Alkylbenzimidazoles
In summary, we have developed a copper-catalyzed
method for the synthesis of N-alkylbenzimidazoles. In
conjunction with our palladium-catalyzed method for the
synthesis of N-arylbenzimidazoles, these two complementary
methods allow the synthesis of N-substituted benzimidazoles
in regioisomerically pure form, an unmet need in the
synthesis of benzimidazoles.
Acknowledgment. We thank the National Institutes of
Health (GM 58160) and the National Cancer Institute (Cancer
Training Grant CA09112) for support of this work. Ad-
ditional support provided by unrestricted funds from Merck,
Amgen, and Boehringer Ingelheim is gratefully acknowl-
edged. N.Z. thanks the National Institutes of Health for a
postdoctoral fellowship (F32-GM074407). The Varian 300
and 500 MHz instruments used in this study were purchased
with funding from the National Science Foundation (CHE
9808061 and DBI 9729592). We are indebted to Chemetall
for a generous gift of Cs2CO3.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL7020737
Org. Lett., Vol. 9, No. 23, 2007
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