Charge-Transfer Complexes for Amine Synthesis

A method to generate α-amino radicals, via a photoinduced charge-transfer complex, is reported. A multicomponent radical fragmentation-cyclization reaction was developed, combining secondary amines, cyclopropyl carboxaldehydes and alkenes, to generate cyclopentyl methylamines. To initiate the fragmentation step, single-electron reduction of alkyliminium ions to α-amino radicals was achieved, using an aromatic thiol and visible light irradiation. Mechanistic and computational studies supported the formation of a transient, ion-pair charge-transfer complex between iminium and thiolate ions. DFT calculations indicated that irradiation of the complex with visible light could promote intra-complex electron transfer from the thiolate HOMO to the iminium LUMO. This method of α-amino radical formation was extended to acyclic aldehydes, by development of a radical reductive amination, using thiol as the single-electron reductant and hydrogen atom source. Subsequently, the chemoselective reductive amination of secondary amines over primary amines was attempted. Preliminary studies on a di-amine drug indicated that the radical reductive amination had high selectivity for primary aminothiazoles over secondary amines, contrasting with existing polar reductive amination techniques