Radical reductive formylation of N-heteroarenes with formic acid under catalyst- and solvent-free conditions

Abstract

N-Formyl-heterocycles are commonly  found in pharmaceuticals and bioactive drugs. However, identifying green alternatives to the catalytic transfer hydrogenation of N-heteroarenes with formic acid, the typical method for constructing these compounds, remains a challenge. Herein, we present the first catalyst- and solvent-free system that utilizes radical-mediated pathways for the transfer-hydrogenation-mediated synthesis of N-formyl-heterocycles via reductive formylation of N-heteroarenes with formic acid. This method is applicable to a wide variety of substrates, affording the desired products in moderate to excellent yields. Furthermore, key intermediate capture, exploration of the control reactions, isotopic tracing, black-box simulation and theoretical calculations are conducted, based on which a plausible reaction mechanism is proposed. The mechanistic analysis reveals that the thermal cleavage of formic acid, in the presence of protonated N-heteroarenes that have been demonstrated to play an indispensable role in the process, generates ˙CHO and ˙OH radicals.