Electrochemical Selective C ₂ –H Hydroxymethylation of Pyridines via a Zinc Single-Atom Cathode and Anodic Iodide Relay-Mediated Strategy

Pyridines are ubiquitous scaffolds in pharmaceutical chemistry and appear in approximately 90% of pyridine-derived drugs as C 2 -substituted motifs. Nevertheless, direct C–H bond molecular editing remains limited by stringent reaction conditions and low metal atom efficiency. Here, we report the first site-selective aryl-substituted 2-hydroxymethylation at the C 2 position of pyridines, enabled by relay mediation between a single-atom zinc-modified cathode and iodide ions. The protocol shows broad substrate tolerance, low metal loading, operational simplicity, negligible overpotential, and high regioselectivity. Direct molecular modification of drugs is achieved, and gram-scale synthesis of Bisacodyl is demonstrated. Mechanistic studies indicate that anodic iodide oxidation suppresses the intrinsic C 4 reactivity preference of pyridine radicals. Coupled with a relay sequence comprising adsorption, activation, electroreduction, coupling, and electrooxidation, this effect enables efficient formation of the target products. By integrating single-atom catalysis with relay paired electrolysis, this work provides a new framework for the electrocatalytic transformation of inert chemical bonds.