Periodic acid-promoted methylenation of imidazoheteroarenes: a green approach using ethylene glycol as a C1 source

Abstract

Herein, we describe an environmentally sustainable methodology for the methylenation of C3(sp²) imidazoheteroarenes, employing formaldehyde (C1) generated in situ via oxidative cleavage of ethylene glycol—a renewable feedstock. The protocol utilizes water as a non-toxic solvent and stoichiometric reagents, aligning with green chemistry principles by ensuring high atomic economy and minimal waste. Optimized conditions enable regioselective bis-heterocycle formation with yields up to 97%. The reaction proceeds through a Malaprade oxidation-mediated ionic pathway mediated by 0.5 molar equiv. of periodic acid, and demonstrates broad substrate scope, including imidazo[1,2-a]pyridines and imidazo[2,1-b]thiazoles. Scalability was validated (70% yield at 5.5 mmol scale), highlighting its potential for industrial applications. This method offers a robust, metal-free alternative for C–H functionalization.