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Synthesis 2005(1): 47-56  
DOI: 10.1055/s-2004-834926
PAPER
© Georg Thieme Verlag Stuttgart · New York

A Versatile Method for the Synthesis of Benzimidazoles from o-Nitroanilines and Aldehydes in One Step via a Reductive Cyclization

Donglai Yang*, Demosthenes Fokas*, Jingzhou Li, Libing Yu, Carmen M. Baldino
Department of Chemistry, ArQule Inc, 19 Presidential Way, Woburn, MA 01801, USA
Fax: +1(781)3766019; e-Mail: dfokas@arqule.com;
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Publication History

Received 26 April 2004
Publication Date:
24 November 2004 (online)

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Abstract

A highly efficient and versatile method for the synthesis of benzimidazoles was achieved in one step via the Na2S2O4 reduction of o-nitroanilines in the presence of aldehydes. Heating a solution of o-nitroaniline (1c) and an aldehyde in EtOH or another appropriate solvent, in the presence of aqueous or solid Na2S2O4, provided facile access to a series of 2-substituted N-H benzimidazoles 5a-m containing a wide range of functional groups not always compatible with the existing synthetic methods. This methodology has also been applied to the regioselective synthesis of N-alkyl and N-aryl benzimidazoles 6a-f via the cyclization of the corresponding N-substituted nitroanilines 13a-e, respectively. In addition, the method was applied successfully to the synthesis of other imidazole containing heterocyclic ring systems such as 1H-imidazo[4,5-b]pyridines 14a,b and 1H-imidazo[4,5-f]quinoline 15.

Key words

benzimidazoles - reductive cyclization - sodium dithionite - imidazopyridines - imidazoquinolines

    References

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    Disubstituted benzimidazoles were also formed as by-products.

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1

Current address: Donglai Yang, SSCI, Inc., 3065 Kent Avenue, West Lafayette, IN 47906, USA. E-mail: dyang@ssci-inc.com.

13

For oxidative methods, see ref. 14 and references cited therein.

23

Old solutions were ineffective. A fresh solution of sodium dithionite was used each time as it gradually decomposes in water.

24

Reaction with solid sodium dithionite was found to work as well as an aqueous solution of the reagent. However, better results were obtained in some cases utilizing solid sodium dithionite rather than an aqueous solution.

31

We observed that the presence of the aldehyde had a dramatic effect on the reduction of the starting o-nitroaniline as shown in Scheme [3] .
Imine formation could facilitate the aryl nitro group reduction because of electronic effects. Indeed, the fact that the corresponding benzimidazole (rather than the arylene diamine) is captured in high yield as the end product could indicate that the thermodynamically formed benzimidazole might be the one driving the nitro reduction.

33

This method has been routinely applied in our AMAPTM (Automated Molecular Assembly Plant) for the high throughput solution phase synthesis of benzimidazole containing structures. More details will be communicated in due course.