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

Article

关键词: CENTERED RADICALS;    ATOM-TRANSFER;    FUNCTIONALIZATION;    HYDROAMINATION;    CARBOXAMIDES;    ABSTRACTION;    CYCLIZATION;    GENERATION;    OXIDATION;    ENERGIES;   

DOI  :  10.1038/nature19811

来源: SCIE

【 摘 要 】

Despite advances in hydrogen atom transfer (HAT) catalysis(1-5), 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(6-11) and directed carbon-hydrogen (C-H) bond functionalization(12-16). In the latter process-a subset of the classical Hofmann-Loffler-Freytag reaction-amidyl radicals remove hydrogen atoms from unactivated aliphatic C-H bonds(17-21). 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-Loffler-Freytag reaction, using 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, this study demonstrates that concerted proton-coupled electron transfer can enable homolytic activation of common organic functional groups that are energetically inaccessible using traditional HAT-based approaches.

【 授权许可】

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