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, circumventing the typical catalytic transfer hydrogenation of N-heteroarenes and formic acid for the construction of these compounds, thus avoiding potential non-green issues remains a challenge. Herein, we present the first catalyst- and solvent-free system that takes advantage of radical-mediated pathways for the transfer hydrogenation synthesis of N-formyl-heterocycles via reductive formylation of N-heteroarenes with formic acid, which exhibited applicable to a wide variety of substrates and gave the desired products with moderate to excellent yields. Furthermore, key intermediate capture, control reactions exploration, isotopic tracing, black-box simulation and theoretical calculations were conducted, and a plausible reaction mechanism was proposed. It was revealed that the thermal cleavage of formic acid to generate •CHO and •OH radicals occur in the presence of protonated N-heteroarenes that has been proved to have an indispensable role in the process.