Transition-metal-, oxidant- and additive-free multi-component synthesis of alkyl heteroaryl BCPs enabled by visible-light-induced phosphine-catalyzed halogen-atom transfer

Abstract

Alkyl heteroaryl bicyclo[1.1.1]pentanes (BCPs) are an important class of bioisosteres, playing a crucial role in the realm of drug discovery. The quest for their synthesis, however, has been hindered by the limitations of existing protocols, which are characterized by the need for multiple reagents and a poor atom economy. This has prompted an urgent need for the development of more sustainable and efficient synthetic methodologies. Our contribution addresses this challenge by unveiling a novel, sustainable, and highly practical multi-component coupling reaction. This breakthrough process facilitates the direct alkylation/heteroarylation of [1.1.1]propellane through a photoinduced phosphine-catalyzed halogen-atom transfer mechanism. Notably, this innovative reaction is conducted under conditions devoid of transition metals, ligands, oxidants, and additives, thereby embodying the tenets of green chemistry. The versatility of our method is underscored by its remarkable tolerance towards a wide spectrum of heteroarenes and its seamless compatibility with diversely activated alkyl radical precursors, ranging from polyhalides to halides of tertiary, secondary, and primary alkyl groups. Moreover, the practicality of our protocol is further elaborated by its ability for late-stage functionalization of pharmaceutically relevant compounds, paving the way for large-scale synthesis and facile product derivatization. Our mechanistic studies have elucidated a radical-relay pathway, providing a solid foundation for the robustness of this synthetic strategy. We are confident that this sustainable and adaptable synthetic platform will significantly expand the toolkit available in drug discovery, offering a promising avenue for the development of novel therapeutic agents.