Anti-Markovnikov radical hydroxychlorination of alkenes enabled by amine-promoted chlorine radical generation

Abstract

A transition-metal-free protocol for the regioselective synthesis of β-chlorohydrins from alkenes, 1,1,2,2-tetrachloroethane (TCE) and TBHP was developed under mild conditions. This method employs TCE as a chlorine atom donor and TBHP as a hydroxyl radical source under mild conditions. This protocol features reversed regioselectivity (anti-Markovnikov addition of OH) compared to conventional electrophilic hydroxychlorination, achieved through a synergistic radical process involving amine-assisted generation of chlorine radicals. The reaction exhibits broad substrate tolerance, including aryl alkenes with diverse electronic and steric properties, and demonstrates practical utility in the late-stage functionalization of drug-like molecules. Mechanistic studies support a radical pathway involving hydroxyl and chlorine radicals, offering an operationally simple alternative to traditional methods for β-chlorohydrin synthesis.