Switchable Regioselective 6-<i>endo</i> or 5-<i>exo</i> Radical Cyclization via Photoredox Catalysis

Abstract

Controlling the regioselectivity of radical cyclizations to favor the 6-<i>endo</i> mode over its kinetically preferred 5-<i>exo</i> counterpart is difficult without introducing substrate prefunctionalization. To address this challenge, we have developed a simple method for reagent controlled regioselective radical cyclization of halogenated <i>N-</i>heterocycles onto pendant olefins. Radical generation occurs under mild photoredox conditions with control of the regioselectivity governed by the rate of hydrogen atom transfer (HAT). Utilizing a polarity-matched thiol-based HAT agent promotes the highly selective formation of the 5-<i>exo</i> cyclization product. Conversely, limiting the solubility of the HAT reagent Hantzsch ester (HEH) leads to selective formation of the thermodynamically favored 6-<i>endo</i> product. This occurs through an initial 5-<i>exo</i> cyclization, with the resulting alkyl radical intermediate undergoing neophyl rearrangement to form the 6-<i>endo</i> product. Development of this switchable catalysis strategy allows for two modes of divergent reactivity to form either the 6-<i>endo</i> or 5-<i>exo</i> product, generating fused <i>N-</i>heteroaromatic/saturated ring systems.