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Switchable Regioselective 6- endo or 5- exo Radical Cyclization via Photoredox Catalysis

2022; American Chemical Society; Volume: 144; Issue: 9 Linguagem: Inglês

10.1021/jacs.2c00192

1943-2984

Mark C. Maust, Cecilia M. Hendy, Nathan T. Jui, Simon B. Blakey,

Catalytic C–H Functionalization Methods

Controlling the regioselectivity of radical cyclizations to favor the 6-endo mode over its kinetically preferred 5-exo 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 N-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-exo cyclization product. Conversely, limiting the solubility of the HAT reagent Hantzsch ester (HEH) leads to selective formation of the thermodynamically favored 6-endo product. This occurs through an initial 5-exo cyclization, with the resulting alkyl radical intermediate undergoing neophyl rearrangement to form the 6-endo product. Development of this switchable catalysis strategy allows for two modes of divergent reactivity to form either the 6-endo or 5-exo product, generating fused N-heteroaromatic/saturated ring systems.