Modular access to bicyclo[1.1.1]pentyl alkylamines enabled by dual photoredox and tether-tunable distonic radical anion catalysis

Abstract

Bicyclo[1.1.1]pentane (BCP) motifs are valuable three-dimensional bioisosteres of para-disubstituted benzenes and the tert-butyl group, but their incorporation into drug candidates is hampered by a lack of concise and modular syntheses. Here we report a dual photoredox and tether-tunable distonic radical anion (TDRA) catalyzed multicomponent difunctionalization of [1.1.1]propellane with alkyl carboxylic acids and imines, delivering diverse BCP alkylamines in one-pot operations. This mild, redox-neutral transformation accommodates primary, secondary, and tertiary carboxylic acids, as well as a broad range of acyclic aromatic imines and a representative N-sulfinylamine. Photoredox-induced single-electron oxidation of catalytic phthalate salts generates TDRAs, which then engage in polarity-matched proton-coupled electron transfer (PCET) with the O–H bond of carboxylic acids to forge C-centered radicals. This mechanistic rationale, wherein the TDRA acts as a key hydrogen-atom abstractor in a redox-neutral radical relay, is supported by radical trapping and radical clock experiments, while the initial photoinduced electron-transfer step is corroborated by Stern–Volmer luminescence quenching studies. The synthetic utility and sustainability of this dual catalytic system are further demonstrated by gram-scale reactions, late-stage functionalization of complex natural products and pharmaceuticals, favorable green chemistry metrics, and biocompatibility with biologically relevant macromolecules. This modular platform thus provides expedient access to functionalized BCP-containing bioisosteres, constituting a practical and general strategy for incorporating sp3-rich scaffolds into drug discovery.