Titanium-Catalyzed Divergent Deoxycyclization for Synthesizing Semisaturated Nitrogen Heterocycles

Abstract Semisaturated nitrogen heterocycles, such as 3-pyrrolines and unsaturated azepanes, possess highly prized three-dimensional geometries for drug discovery. However, their divergent synthesis from simple, unactivated feedstocks remains a formidable challenge. Herein, we report a highly selective, titanium-catalyzed divergent radical deoxycyclization coupling of nitrosoarenes and 1,3-dienes. Following an initial aza-Diels–Alder cycloaddition, an in situ generated low-valent titanium(III) species mediates single-electron homolytic cleavage of the robust oxazine N–O bond, yielding a transient nitrogen-centered aminyl radical. By rationally tuning the solvent coordination sphere and chlorosilane dissociation kinetics, this radical’s trajectory is selectively directed down two orthogonal pathways: a 5-exo-tet cyclization to afford 3-pyrrolines (formal [4 + 1]) and a highly strained vinylaziridine-mediated aza-Claisen rearrangement to yield unsaturated azepanes (formal [4 + 3]). This radical-polar crossover protocol features broad functional group tolerance and enables a streamlined, cyanide-free synthesis of the antiarrhythmic drug candidate SU-13197. Comprehensive mechanistic studies, including EPR spin-trapping, support the crucial aminyl radical intermediacy and the important role of titanium coordination in orchestrating cascade divergence.