Room-Temperature Direct C4-Hydroxyalkylation of Pyridines via Paired Electrolysis

Direct and selective functionalization of ubiquitous pyridine rings is of paramount importance across numerous fields, but it remains a challenge due to pyridine's inherent thermodynamic stability, kinetic inertness, and multiple competitive reaction sites. Herein, by using an undivided cell tolerant to ambient air and moisture, we report a room-temperature paired electrolysis strategy for C4-selective hydroxyalkylation of diverse inert pyridines with readily available carbonyl compounds. Employing a Zn cathode, graphite anode, and TEMPO mediator, 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-hydroxyalkyl pyridines. 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. In this work, the concept merging electroreduction-induced dearomatization followed by radical transformations will open a door to further develop useful transformations with inert chemical systems.