Iodoarene-directed photoredox β-C(sp3)-H arylation of 1-(o-iodoaryl)alkan-1-ones with cyanoarenes via halogen atom transfer and hydrogen atom transfer.

Abstract

Site selective functionalization of inert remote C(sp3)-H bonds to increase molecular complexity offers vital potential for chemical synthesis and new drug development, thus it has been attracting ongoing research interest. In particular, typical β-C(sp3)-H arylation methods using chelation-assisted metal catalysis or metal-catalyzed oxidative/photochemical in situ generated allyl C(sp3)-H bond processes have been well developed. However, radical-mediated direct β-C(sp3)-H arylation of carbonyls remains elusive. Herein, we describe an iodoarene-directed photoredox β-C(sp3)-H arylation of 1-(o-iodoaryl)alkan-1-ones with cyanoarenes via halogen atom transfer (XAT) and hydrogen atom transfer (HAT). The method involves diethylaminoethyl radical-mediated generation of an aryl radical intermediate via XAT, then directed 1,5-HAT to form the remote alkyl radical intermediate and radical-radical coupling with cyanoarenes, and is applicable to a broad scope of unactivated remote C(sp3)-H bonds like β-C(sp3)-H bonds of o-iodoaryl-substituted alkanones and α-C(sp3)-H bonds of o-iodoarylamides. Experimental findings are supported by computational studies (DFT calculations), revealing that this method operates via a radical-relay stepwise mechanism involving multiple SET, XAT, 1,5-HAT and radical-radical coupling processes.