Room-temperature electrochemical hydroxyalkylation of pyridines.

Abstract

Direct and selective functionalization of ubiquitous pyridine scaffold is of paramount importance across numerous fields, yet remains challenging due to the inherent inertness of pyridines and the presence of competing reactive sites. Here, using an undivided cell equipped with a zinc cathode, a graphite anode, and a TEMPO mediator, we report a room-temperature electrochemical strategy that enables the direct hydroxyalkylation of diverse pyridines with readily available carbonyl compounds. This method features a broad substrate scope, operational simplicity, metal-free conditions, and high step/atom economy. It overcomes the limitations of conventional approaches requiring pre-functionalized substrates or stoichiometric activators, establishing a practical platform for direct access to C4- or C2-hydroxyalkyl pyridines, depending on the substitution pattern of the pyridine substrates. Mechanistic studies reveal that acetic acid activates both reactants, and the products are formed via cross-coupling of cathodic reduction-induced pyridyl radicals and hydroxy α-radicals followed by protonation and anodic oxidative aromatization.