Solvent effects on the chemo- and site-selectivity of transition metal-catalyzed heterogeneous nitrene transfer reactions: Alternatives to chlorinated solvents.

Transition metal-catalyzed, non-enzymatic nitrene transfer (NT) reactions that selectively transform C-H and C=C bonds to new C-N bonds represent a powerful strategy to streamline the preparation of valuable amine building blocks. Our group has been engaged in the development of silver-catalyzed NT reactions, where the nature of the ligand can be used to tune the chemo-, site- and enantioselectivity of the amination event in a predictable manner. However, the majority of solvents employed for these reactions are environmentally unfriendly and typically include dichloromethane, chloroform, 1,2-dichloroethane and benzene. In addition, the need for PhIO as the oxidant in our system gives heterogenous mixtures that have limited reaction throughput to date. In this work, a high-throughput experimentation (HTE) protocol for heterogeneous NT reaction mixtures is coupled with the American Chemical Society Pharmaceutical Roundtable (ACSPR) solvent tool to identify suitable replacements for chlorinated solvents and to better understand how the solvent affects chemo- and site-selectivity in NT. Silver catalysts were compared and contrasted other popular catalysts for NT using our HTE protocol, including dinuclear Rh and Fe/Mn phthalocyanine catalysts, to highlight key differences between these systems. Several unexpected solvents were identified that gave both high conversions and selectivities in diverse NT reactions, providing alternatives to traditional chlorinated solvents. We hope these insights will encourage the community to: (1) consider more diverse solvent selections when developing new synthetic methods, (2) employ solvent tools to identify favorable solvent characteristics/parameters and (3) consider SHE impacts in reaction design.