Catalytic alkylation of remote C–H bonds enabled by proton-coupled electron transfer

Catalytic alkylation of C–H bonds is achieved via homolysis of N–H bonds of N -alkyl amides through proton-coupled electron transfer. Functionalizing unactivated aliphatic C–H bonds In two separate reports, Robert Knowles and colleagues, and John Chu and Tomislav Rovis report the selective homolysis of selected amidyl N–H bonds through a photocatalytic proton-coupled electron-transfer process. The resulting radical enables C–H abstraction and radical alkylation at the unactivated 5 position on the aliphatic chain of the N -alkyl amide. As this method does not rely on pre-activation of the amidyl N–H bond or the use of haloamides, it offers a potentially simpler solution than previous approaches to radical amidyls. Additionally, the subsequent 1,5-hydrogen-atom transfer offers a route to selective C–C bond formation in the presence of alkyl amides. Despite advances in hydrogen atom transfer (HAT) catalysis 1 , 2 , 3 , 4 , 5 , there are currently no molecular HAT catalysts that are capable of homolysing the strong nitrogen–hydrogen (N–H) bonds of N- alkyl amides. The motivation to develop amide homolysis protocols stems from the utility of the resultant amidyl radicals, which are involved in various synthetically useful transformations, including olefin amination 6 , 7 , 8 , 9 , 10 , 11 and directed carbon–hydrogen (C–H) bond functionalization 12 , 13 , 14 , 15 , 16 . In the latter process—a subset of the classical Hofmann–Löffler–Freytag reaction—amidyl radicals remove hydrogen atoms from unactivated aliphatic C–H bonds 17 , 18 , 19 , 20 , 21 . Although powerful, these transformations typically require oxidative N- prefunctionalization of the amide starting materials to achieve efficient amidyl generation. Moreover, because these N -activating groups are often incorporated into the final products, these methods are generally not amenable to the direct construction of carbon–carbon (C–C) bonds. Here we report an approach that overcomes these limitations by homolysing the N–H bonds of N -alkyl amides via proton-coupled electron transfer. In this protocol, an excited-state iridium photocatalyst and a weak phosphate base cooperatively serve to remove both a proton and an electron from an amide substrate in a concerted elementary step. The resultant amidyl radical intermediates are shown to promote subsequent C–H abstraction and radical alkylation steps. This C–H alkylation represents a catalytic variant of the Hofmann–Löffler–Freytag reaction, using simple, unf