Imidazole synthesis using 2-aminopyridines

Irnidazo[ 1,2-tf ]py ridines were covered in CHEC(1984) <1984CHEC(6)613> along with others imidazoles fused to six-membered rings and they were reviewed together with imidazo[l,5- ]pyridines in CHEC-II(1996) <1996CHEC-II(8)249>. The chemical literature on this heterocycle is very abundant, due to its easy synthesis (most of the preparations use readily available 2-aminopyridines) and to the very broad spectrum of bioactivities displayed by many derivatives. A simple Beilstein search on the fully conjugated heterocycle (free sites everywhere) disclosed ca. 3000 hits for the past decade. Therefore, this chapter cannot be exhaustive in view of space limitations, but will mainly focus on the original synthetic methods that have appeared in the last decade. 

The classical synthesis of IPs consisted in cyclization of o-DAP with carboxylic acids, their derivatives and precursors. This method was used to prepare the majority of IP derivatives with various substituents in the imidazole and pyridine rings. However, it should be mentioned that cyclization of o-diaminopyridines with carboxylic acids and their derivatives occurs less readily than that of o-phenylenedia-mines. Whereas the latter are cyclized into benzimidazoles when heated with carboxylic acid for a short time (51CRV397), boiling a 2,3-DAP and an acetic anhydride mixture for 2h affords only 2,3-diacetylaminopyridine, and fusion of this diamine with benzoic anhydride resulted only in the formation of 2,3-dibenzoyl-aminopyridine (64JOC3403). 

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