Electrochemical Single-Carbon Insertion via Distonic Radical Cation Intermediates

Abstract

The synthesis of polysubstituted (hetero)aromatic compounds is essential in various fields, including pharmaceuticals, where such compounds are fundamental to many approved drugs. In this study, we present a novel electrochemical method for single-carbon insertion targeting various (hetero)aromatic compounds, with a particular focus on pyridines. In this process, the electrochemical oxidation of pyrrole derivatives produces a radical cation intermediate, which then undergoes nucleophilic attack by diazo compounds to yield polysubstituted pyridine derivatives. Notably, the insertion position is influenced by the electronic properties of N-protecting groups, allowing for unprecedented para-selective insertion through the introduction of electron-withdrawing groups. Insights from in situ spectroscopy and theoretical calculations suggest the involvement of distonic radical cation intermediates, facilitating carbon-atom migration on the aromatic ring and enabling insertion at different positions. This study expands the chemical toolkit for synthesizing polysubstituted (hetero)aromatic compounds and introduces a new concept for single-carbon insertion chemistry.