Programmable remodelling of carbon-nitrogen connectivity in amines

Tertiary amines are ubiquitous motifs in biologically active molecules, where they play central roles in molecular recognition and function^1,2. Among these, tertiary benzylamines are particularly prominent in discovery chemistry as readily assembled starting points for lead generation from abundant building blocks^3,4, with favourable physicochemical and binding properties. However, despite their accessibility, the core C-N connectivity of these frameworks remains effectively locked^5,6, confining diversification to benzylamine derivatives and preventing direct access to structurally distinct aryl-alkylamine architectures. Overcoming this limitation requires direct and selective reconfiguration of C-N connectivity within fully elaborated amine scaffolds. Here we show that tertiary benzylamines can be transformed from static scaffolds into programmable platforms for molecular diversification through catalytic remodeling of their C-N bonds^7-9. N-alkylation with a bifunctional electrophile generates a quaternary ammonium intermediate that encodes palladium-catalyzed disassembly and reconfiguration of C-N connectivity. This concept is first exemplified through one-carbon homologation of tertiary benzylamines and, more significantly, establishes a general strategy for programmable insertion of modular units-ranging from single carbon atoms to complex molecular fragments, including hydrocarbon chains, heterocycles and aryl groups-directly across the C-N bond on fully elaborated amine scaffolds. This capability opens a route to programmable diversification of amine frameworks, enabling systematic exploration of amine connectivity and molecular architecture.