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

• Type of Material: Article
• Authors: Mark C Maust, Emory University; Cecilia M Hendy, Emory University; Nathan Jui, Emory University; Simon Blakey, Emory University
• Language: English
• Date: 2022-03-09
• Publisher: American Chemical Society
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2022 American Chemical Society
• Final Published Version (URL): http://dx.doi.org/10.1021/jacs.2c00192
• Title of Journal or Parent Work: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• Volume: 144
• Issue: 9
• Start Page: 3776
• End Page: 3781
• Keywords: photoredox; Redox reactions; catalysis; pyridine; radical cyclization

Abstract

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.