Synthesis of 2-Substituted Benzimidazoles by Reaction of o-Phenylenediamine with Aldehydes in the Presence of Sc(OTf)3

Abstract

2-Substituted benzimidazoles were synthesised under mild conditions by reaction of o-phenylenediamine with aldehydes in the presence of Sc(OTf) 3 as a Lewis acid catalyst.Benzimidazole nucleus has recently received interest in the field of medicinal chemistry, 2 and some solid-phase syntheses have been applied to their synthesis. 3A conventional method for the synthesis of benzimidazoles is the reaction of o-phenylenediamine with carboxylic acids or their derivatives under harsh conditions. 4In recent literatures, some methods using transition metal catalyzed coupling reactions to construct benzimidazole nucleus were reported.Those involved palladium-catalyzed carbonylation reaction of an o-phenylenediamine followed by cyclodehydration, 5 palladium-catalyzed intramolecular N-arylation reaction of (o-bromophenyl)amidines, 6 and rhodium-catalyzed hydroformylation of N-alkenyl-o-phenylenediamines. 7In the course of our studies on the synthesis of heteroaromatics using Sc(OTf) 3 , which acts as a Lewis acid catalyst even in the presence of water, we found that the reaction of 2-aminobenzenethiol with aqueous HCHO gives benzothiazole in a high yield. 8In the reaction, initial formation of an imine followed by intramolecular nucleophilic attack of the sulfanyl group afforded benzothiazoline which was then oxidized to give benzothiazole.Thus, we applied this type of reaction to the synthesis of benzimidazoles by use of o-phenylenediamine instead of 2-aminobenzenethiol, and found a new method for the synthesis of 2-substituted benzimidazoles.We describe these results in this paper.When o-phenylenediamine was allowed to react with 37% aqueous solution of HCHO in the presence of Sc(OTf) 3 (1 mol%), benzimidazole was obtained in 24% yield and 1-methylbenzimidazole was also produced in 27% yield.The latter compound was produced when both of two amino groups of ophenylenediamine and HCHO reacted before imidazoline ring was formed.The reaction using benzaldehyde, however, exclusively gave 2-phenylbenzimidazole in 97% yield.Therefore, we investigated the scope of the synthesis of 2-substituted benzimidazloes from o-phenylenediamine and HETEROCYCLES, Vol.61, 2003