Development of Novel Methods of C-H Functionalization Enabled by Proton-Coupled Electron Transfer Activation of Amides

Abstract

A fundamental objective in organic synthesis is to devise catalytic methods of activating common functional groups so that simple starting materials can be readily functionalized. Hydrogen atom transfer (HAT) catalysis can activate simple C-H bonds, but molecular HAT catalysts fall short of being able to homolyze the strong bonds of protic functional groups. Herein I report my studies of a novel oxidant-base catalyst system that activates the exceptionally stable nitrogen-hydrogen (N-H) bond in secondary N-alkyl amides by proton-coupled electron transfer (PCET); the resulting amidyl radical intermediate then directs the selective functionalization of remote aliphatic carbon-hydrogen (C-H) bonds in either the amide substrate or an exogenous alkane. Specifically, I investigated the ability of the catalyst system to support (1) distal C-H alkylation, (2) distal C-H fluorination, (3) distal C-H amination, and (4) intermolecular C-H alkylation. I was able to expand the substrate scope of the distal C-H alkylation protocol, make preliminary advances toward the development of distal C-H fluorination and amination protocols, and contribute to the optimization of the intermolecular C-H alkylation protocol. Overall, the results I obtained support the use of PCET activation as a versatile strategic tool to introduce molecular complexity to amide-containing targets.