Visible-Light-Induced N-Radical Directed Remote Functionalization of sp3 C-H Bonds

Abstract

The selective functionalization of unactivated sp3 carbon-hydrogen (C-H) bond is an attractive strategy in modern organic transformation. The hydrogen atom transfer (HAT) catalysis has recently shown its advances in remotely selective activation of an inert C-H bond with great functional group compatibility, generating new carbon-carbon (C-C) bonds and carbon-heteroatom (C-O, C-N, C-X) bonds. Therefore, the remote sp3 C-H functionalization has become an intensively investigated research area, drawing extensive attention in synthetic community. Particularly, the 1,5-hydrogen atom abstraction of nitrogen radicals, the key step of the Hoffman-Löffler-Freytag (HLF) reaction, has been widely applied in the preparation of heterocycles. Comparing to the well-studied area of nucleophilic N-species, N-centered radical based reactions are still underdeveloped. The limited utility is partially due to the required use of hazardous radical initiators, elevated temperatures, or high-energy UV irradiation for the generation of N-radicals. Recently, visible-light photoredox catalysis has been leading efficient accesses to Nitrogen-radicals under mild conditions. The visible-light-induced nitrogen radical formation has also stimulated the development of the remote sp3 C-H functionalization by photoredox catalysis. The classic HLF reaction requires pre-functionalization at N-center in the substrate to promote the formation of N-radical. Recently, a direct N-H single electron transfer (SET) oxidation was realized by photoredox catalysis in Knowles and Rovis's group, generating N-radicals efficiently. The processes significantly simplified the preparation of the HLF reaction substrates and broaden the application of this classic reaction. In addition, the visible-light-induced nitrogen radical-directed reaction on modified imines provided possibilities for the remote sp3 C-H functionalization of ketones, as ketone is the product of imine hydrolysis. Moreover, the application of chiral Lewis acid catalysis combined with visible-light photoredox catalysis enabled the asymmetric alkylation of the unactivated remote sp3 C-H position, which achieves both regioselective and stereoselective functionalization. In conclusion, this strategy takes advantage of mild generation of N-radicals upon visible-light excitation. Subsequent 1,5-hydrogen atom transfer (1,5-HAT) and intermolecular radical coupling would realize the remote functionalization of unactivated sp3 C-H bonds. The strategies have been successfully applied in remote C(sp3)-H amidation, fluorination, chlorination, iodination, alkylation, vinylation, allylation, oxygenation, thioetherification, cyanation and alkynylation. In this review, we focus on visible-light-induced nitrogen radical directed functionalization of remote sp3 C-H bonds, summarized the methodologies, and briefly reviewed their synthetic applications in pharmaceuticals and natural products.