Coupling of α-bromoamides and unactivated alkenes to form γ-lactams through EDA and photocatalysis

gamma-Lactams are prevalent in small-molecule pharmaceuticals and provide useful precursors to highly substituted pyrrolidines. Despite numerous methods for the synthesis of this valuable motif, previous redox approaches to gamma-lactam synthesis from alpha-haloamides and olefins require additional electron withdrawing functionality as well as N-aryl substitution to promote electrophilicity of the intermediate radical and prevent competitive O-nucleophilicity about the amide. Using alpha-bromo imides and alpha-olefins, our strategy enables the synthesis of monosubstituted protected gamma-lactams in a formal [3 + 2] fashion. These species are poised for further derivatization into more complex heterocyclic scaffolds, complementing existing methods. C-Br bond scission occurs through two complementary approaches, the formation of an electron donor-acceptor complex between the bromoimide and a nitrogenous base which undergoes photoinduced electron transfer, or triplet sensitization with photocatalyst, to furnish an electrophilic carbon-centered radical. The addition of Lewis acids allows for further increased electrophilicity of the intermediate carbon-centered radical, enabling tertiary substituted alpha-Br-imides to be used as coupling partners as well as internal olefins.

Automated summary

gamma-Lactams, which are commonly found in small-molecule pharmaceuticals, can be used as precursors for highly substituted pyrrolidines. Previously, redox approaches to gamma-Lactam synthesis required additional electron withdrawing functionality and N-aryl substitution to promote electrophilicity and prevent undesired reactions. However, a new strategy using alpha-bromo imides and alpha-olefins enables the synthesis of monosubstituted protected gamma-Lactams in a formal [3 + 2] fashion, offering opportunities for further derivatization.