TEMPO mediated oxidative annulation of aryl methyl ketones with amines/ammonium acetate for imidazole synthesis

A facile synthesis of 1H-imidazoles by direct oxidative annulation of aryl methyl ketones and primary amines has been developed in the presence of TEMPO under weakly acidic conditions. By replacing amines with ammonium acetate, 2H-imidazole skeletons were achieved for the first time from ketones. Substrates containing various functional groups, such as alkyl, aryl, naphthyl, halogen (F, Cl, Br, I), nitro, trifluoromethyl, sulfonyl ester, furyl, thienyl, and pyridyl groups, were readily transformed into the desired products. The application potential of this method was verified by the scale-up synthesis and Sonogashira coupling functionalization of imidazoles. Mechanistically, the alpha-TEMPO-enamine adduct may serve as the key reaction intermediate.

Automated summary

A facile synthesis of 1H-imidazoles has been developed through direct oxidative annulation of aryl methyl ketones and primary amines in the presence of TEMPO under weakly acidic conditions. This method enables the synthesis of 2H-imidazole skeletons from ketones for the first time by replacing amines with ammonium acetate. Various functional groups can be easily transformed into desired products, and the potential application of this method has been verified through scale-up synthesis and Sonogashira coupling functionalization of imidazoles.