Photoinduced Palladium-Catalyzed Cross-Coupling of Chloroacetamides with Alkenes and Heteroarenes.

Abstract

A visible light-induced palladium catalyzed intramolecular and intermolecular C(sp3)-C(sp2) cross-coupling reaction has been established. This synthetic method exhibits broad functional group tolerance and a wide substrate scope including bioactive molecules, pharmaceutical scaffolds, and peptides, enabling access to structurally novel β,γ-unsaturated amides, benzazepine derivatives as bioisosteres of sedative-hypnotic 1,4-benzodiazepine drugs, and heterocyclic acetamides. Moreover, it offers a direct route to commercially relevant pharmaceuticals such as zolpidem and alpidem. Notably, the successful synthesis of key inhibitors─including those targeting KDM5B, JNK1, and PDE10A─highlights the practical significance and broad applicability of this method. The reaction mechanism was explored using control experiments, Stern-Volmer fluorescence quenching experiments, light on/off experiments, and density functional theory (DFT) calculations.