Despite significant advances in hydrogen atom transfer (HAT) catalysis,– there are currently no molecular HAT catalysts capable of homolyzing the strong N-H bonds of N-alkyl amides (). The motivation to develop amide homolysis protocols stems from the synthetic utility of the resulting amidyl radicals, which engage in a variety of synthetically useful transformations, including olefin amination– and directed C-H bond functionalization.– The latter process, a subset of the well-known Hofmann-Löffler-Freytag (HLF) reaction, relies on a favorable bond strength differential to enable amidyls to abstract H• from unactivated aliphatic C-H bonds ().– While powerful, these transforms typically require oxidative N-prefunctionalization of the amide starting materials to achieve efficient amidyl generation. Moreover, as these N-activating groups are often incorporated into the final products, these methods are generally not amenable to the direct construction of C-C bonds. Here we report a new approach that overcomes these limitations by homolyzing the N-H bonds of N-alkyl amides through a proton-coupled electron transfer (PCET) event. 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 resulting amidyl radical intermediates are shown to be competent to promote subsequent C-H abstraction and radical alkylation steps (). As such, this C-H alkylation represents a novel catalytic variant of the HLF reaction that makes use of simple, unfunctionalized amides to direct the formation of new C-C bonds. Given the prevalence of amides in pharmaceuticals and natural products, we anticipate that this method will simplify the synthesis and structural elaboration of amine-containing targets. Moreover, these studies further demonstrate that concerted PCET can enable homolytic activation of common organic functional groups that are energetically inaccessible using traditional HAT-based approaches.>Design and development of a catalytic amidyl-mediated C-H alkylation>a, With bond dissociation free energies (BDFEs) of 107–110 kcal/mol, there are no reported molecular catalysts capable of homolyzing the N-H bonds of N-alkyl amides. >b, The classical Hofmann-Löffler-Freytag reaction enables the selective abstraction of C-H bonds at positions remote from the amidyl radical via hydrogen-atom transfer (HAT). >c, Proposed direct C-H alkylation of remote C-H bonds via the intermediacy of an amidyl radical generated by concerted oxidative proton-coupled electron transfer (PCET).
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