Combinatorial liquid-phase synthesis of structurally diverse benzimidazole libraries

An expedient liquid-phase synthesis for construction of the diverse benzimidazole libraries is described. Nucleophilic aryl substitution of poly(ethylene glycol)-supported 4-fluoro-3-nitrobenzoic acid 3 with several primary amines under basic conditions, followed by Zn/NH(4)Cl mediated nitro group reduction, gave the PEG bound diamines 5. Subsequent cyclization of immobilized o-phenylenediamine 5 using thiocarbonyldiimidazole (TCD) or thiophosgene in dichloromethane furnished benzimidazole-2-thiones 6. Treatment of 6 with alkyl halides and benzylic halides in the presence of triethylamine provided 1-substituted-2-alkylthio-5-carbamoylbenzimidazoles on the support. The desired products 8 were severed from the PEG under mild conditions in high yield and high purity.