Despite significant advances in hydrogen atom transfer (HAT) catalysis,1–5 there are currently no molecular HAT catalysts capable of homolyzing the strong N-H bonds of N-alkyl amides (Figure 1a). 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 amination6–11 and directed C-H bond functionalization.12–16 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 (Figure 1b).17–21 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 (Figure 1c). 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.

Here we describe a dual catalyst system comprised of an iridium photocatalyst and weak phosphate base that is capable of both selectively homolyzing the N–H bonds of N-arylamides (bond dissociation free energies ~ 100 kcal/mol) via concerted proton-coupled electron transfer (PCET) and mediating efficient carboamination reactions of the resulting amidyl radicals. This manner of PCET activation, which finds its basis in numerous biological redox processes, enables the formal homolysis of a stronger amide N–H bond in the presence of weaker allylic C–H bonds, a selectivity that is uncommon in conventional molecular H atom acceptors. Moreover, this transformation affords access to a broad range of structurally complex heterocycles from simple amide starting materials. The design, synthetic scope, and mechanistic evaluation of the PCET process are described.

Here we report a ternary catalyst system for the intramolecular hydroamidation of unactivated olefins using simple N-aryl amide derivatives. Amide activation in these reactions occurs via concerted proton-coupled electron transfer (PCET) mediated by an excited state iridium complex and weak phosphate base to furnish a reactive amidyl radical that readily adds to pendant alkenes. A series of H-atom, electron, and proton transfer events with a thiophenol cocatalyst furnish the product and regenerate the active forms of the photocatalyst and base. Mechanistic studies indicate that the amide substrate can be selectively homolyzed via PCET in the presence of the thiophenol, despite a large difference in bond dissociation free energies between these functional groups.

Catalytic Alkene Carboaminations Enabled by Oxidative Proton-Coupled Electron Transfer. -A catalytic system comprising an iridium photocatalyst and a weak phosphate base is efficiently applied for intramolecular alkene carboamination reactions (25 examples). -(CHOI, G. J.; KNOWLES*, R. R.; J. Am. Chem. Soc. 137 (2015) 29, 9226-9229, http://dx.

A broad spectrum of unactivated olefins bearing a terminal amide function is subjected to the optimized conditions A) which include a catalyst system of 3 components.