Mechanistic Insights into Fe Catalyzed α-C-H Oxidations of Tertiary Amines

Abstract

We report detailed mechanistic investigations of an iron-based catalyst system, which allows the α-C-H oxidation of a wide variety of amines, including acyclic tertiary aliphatic amines, to afford dealkylated or amide products. In contrast to other catalysts that affect α-C-H oxidations of tertiary amines, the system under investigation employs exclusively peroxy esters as oxidants. More common oxidants (e.g. tBuOOH) previously reported to affect amine oxidations via free radical pathways do not provide amine α-C-H oxidation products in combination with the herein described catalyst system. Motivated by this difference in reactivity to more common free radical systems, the investigations described herein employ initial rate kinetics, kinetic profiling, Eyring studies, kinetic isotope effect studies, Hammett studies, ligand coordination studies, and EPR studies to shed light on the Fe catalyst system. The obtained data suggest that the catalytic mechanism proceeds through C-H abstraction at a coordinated substrate molecule. This rate-determining step occurs either at an Fe(IV) oxo pathway or a 2-electron pathway at a Fe(II) intermediate with bound oxidant. We further show via kinetic profiling and EPR studies that catalyst activation follows a radical pathway, which is initiated by hydrolysis of PhCO3 tBu to tBuOOH in the reaction mixture. Overall, the obtained mechanistic data support a non-classical, Fe catalyzed pathway that requires substrate binding, thus inducing selectivity for α-C-H functionalization.<br>

Iron-Catalyzed α-C–H Cyanation of Simple and Complex Tertiary Amines

“…Recent mechanistic work in the Fe-catalyzed α-C–H oxidation of tertiary amines has uncovered a radical rebound (instead of a free radical) mechanism by which tertiary aliphatic amines can undergo α-C–H functionalization. − We speculated that this reaction manifold could enable α-C–H cyanations with greater functional group tolerance than methods mediated by free radicals and thus be valuable for late-stage functionalization approaches in complex molecular settings (Scheme C). This manuscript details reaction optimizations and substrate scope studies employing this approach to establish a general catalyst system for the late-stage functionalization of tertiary amine substrates.…”