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 function1,2. Among these, tertiary benzylamines are particularly prominent in discovery chemistry as readily assembled starting points for lead generation from abundant building blocks3,4, with favourable physicochemical and binding properties. However, despite their accessibility, the core C–N connectivity of these frameworks remains effectively locked5,6, 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 bonds7-9. 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.