Functional Group Transpositional Trimolecular Cross-Coupling via Interrupted Homolytic Substitution.

Abstract

Constitutional isomers are of great importance in drug discovery, yet their synthesis often requires individual synthetic planning and substrate-specific reaction design. Functional group reposition (FGR) offers an attractive alternative by enabling efficient access to constitutionally isomeric analogues. Here we introduce a strategy that leverages interrupted homolytic substitution (int-SH2) to enable FGR, specifically redirecting allylamine reactivity toward modular trimolecular cross-coupling via nickel/photoredox dual catalysis. This transformation is enabled by a cascade of electronic and steric radical sorting, which orchestrates selective amino migration and controlled bond formation to generate highly functionalized alkylamines from simple feedstock building blocks. The method exhibits broad functional-group tolerance, high chemo- and regioselectivity, and compatibility with a diverse range of electrophilic and nucleophilic radical partners, providing more than 60 structurally varied alkylamine products. The strategy was further applied to the facile and modular synthesis of diverse pharmaceutically relevant skeletons, opening up new opportunities for the rapid construction of compound libraries for drug discovery.