Manganese-catalysed benzylic C(sp3)–H amination for late-stage functionalization

Reactions that directly install nitrogen into C–H bonds of complex molecules are significant because of their potential to change the chemical and biological properties of a given compound. Although selective intramolecular C–H amination reactions are known, achieving high levels of reactivity while maintaining excellent site selectivity and functional-group tolerance remains a challenge for intermolecular C–H amination. Here, we report a manganese perchlorophthalocyanine catalyst [MnIII(ClPc)] for intermolecular benzylic C–H amination of bioactive molecules and natural products that proceeds with unprecedented levels of reactivity and site selectivity. In the presence of a Brønsted or Lewis acid, the [MnIII(ClPc)]-catalysed C–H amination demonstrates unique tolerance for tertiary amine, pyridine and benzimidazole functionalities. Mechanistic studies suggest that C–H amination likely proceeds through an electrophilic metallonitrene intermediate via a stepwise pathway where C–H cleavage is the rate-determining step of the reaction. Collectively, these mechanistic features contrast with previous base–metal-catalysed C–H aminations and provide new opportunities for tunable selectivities. A manganese phthalocyanine has been shown to catalyse intermolecular C–H amination reactions—proceeding through an electrophilic metallonitrene intermediate—with high levels of reactivity and site selectivity. Demonstrating good tolerance for tertiary amine, pyridine and benzimidazole moieties, nitrogen functionality can be selectively installed at electron-rich, sterically exposed benzylic sites in bioactive molecules.