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

• Published in: Journal of the American Chemical Society 2022-03, Vol.144 (9), p.3776-3781
• Main Authors: Maust, Mark C, Hendy, Cecilia M, Jui, Nathan T, Blakey, Simon B
• Format: Article
• Language: English
• Subjects: Catalysis; Cyclization; Hydrogen; Molecular Structure
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.2c00192

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.