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

Abstract

Despite advances in hydrogen atom transfer (HAT) catalysis, 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 and directed carbon-hydrogen (C-H) bond functionalization. In the latter process-a subset of the classical Hofmann-Löffler-Freytag reaction-amidyl radicals remove hydrogen atoms from unactivated aliphatic C-H bonds. 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, 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.

Figure 1. 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).

Figure 2. Proposed catalytic cycle

The catalytic cycle begins with an association of the phosphate base (B) via hydrogen bonding to the amide N-H bond of the substrate 1 (p-methoxyphenyl = PMP). Oxidative proton-coupled electron transfer generates a neutral amidyl radical. A 1,5 H-atom abstraction then occurs to generate the distal carbon-centered radical. This intermediate undergoes a conjugate addition with an olefin acceptor to furnish a new C-C bond and an α-carbonyl radical. Electron transfer from the reduced Ir(II) catalyst furnishes an enolate. Proton transfer from phosphoric acid produces the product 2 and returns the catalysts to their active forms.

Figure 3. Substrate Scope

a, A range of amide substrates can be alkylated in an intramolecular fashion. The olefin acceptor scope (electron withdrawing group = EWG) illustrates that a variety of common functional groups that can be incorporated into the final alkylated products. A number of structurally and electronically distinct benzamide derivatives can be accommodated, including aryl sulfonamides and N-Boc carbamates. ^a Photocatalyst D used in reactions to form products 13 and 27. b, Intermolecular C-H alkylations can also be effected with an excess of the alkane relative to the olefin acceptor. TBS = tert-butyldimethylsilyl. Boc = tert-butyl carbamate