Mechanistic and Computational Insights into Asymmetric Intramolecular Iron-Catalyzed Nitrene Transfer into Benzylic C-H Bonds

Chiral, nonracemic amines are valuable synthetic building blocks for diverse bioactive molecules. Asymmetric C-H amination via transition metal-catalyzed nitrene transfer (NT) is a popular strategy to access enantioenriched benzylamines, but many useful chemocatalysts for this transformation are based on precious metals or require elaborate ligands. Iron catalysts supported by simple ligands capable of asymmetric aminations of diverse sulfamates would be valuable but are surprisingly rare. Herein, we study features of the asymmetric iron-catalyzed NT of homo- and bis-homobenzylic sulfamates to better understand why the development of such reactions has proven challenging. Diverse parameters were examined, including ligand, iron source, oxidant, additive, and solvent. Reactions of the preoxidized iminoiodinane revealed some unexpected relationships between the pK a of acid additives and the enantiomeric ratio (er). Computational models show that radical rebound is the enantiodetermining step and highlight noncovalent interactions (NCIs) between the ligand and aryl ring of the substrate that drive the er. These insights, combined with experimental data, provide a foundation for the design of second-generation chemocatalysts for iron-catalyzed asymmetric C-H amidation via NT.