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.