Iron catalyzed intramolecular Csp³-H amination of aliphatic azides

This thesis explores the development of chiral iron catalysts for intramolecular C(sp³)–H amination of aliphatic azides and provides mechanistic insight into the factors controlling reactivity, selectivity, and catalyst stability. Iron-catalyzed C–H amination is an attractive, sustainable route to nitrogen-containing heterocycles, as iron is abundant, inexpensive, and biocompatible, while alkyl azides release only N₂. Current systems, however, are limited by low reactivity, poor stereocontrol, and incomplete mechanistic understanding.
To address these challenges, novel tetradentate chiral diamine-bisoxazoline Fe(II) complexes were designed and tested for asymmetric intramolecular C–H amination. Catalyst deactivation via intramolecular ligand dehydrogenation during nitrene transfer was identified and mitigated by introducing gem-dialkyl substituents at the oxazoline moieties. This modification enabled efficient room-temperature amination of 4-phenylbutyl azide to 2-phenylpyrrolidine. Further optimization with long-chain gem-dialkyl substituents enhanced stereocontrol, raising enantioselectivity from 33% to 81% ee under additive-free conditions. The methodology was applied to the synthesis of pyrrolidine intermediates for bioactive compounds including larotrectinib and crispine A.
Mechanistic studies combining kinetics, isotopic labeling, Mössbauer and EPR spectroscopy, mass spectrometry, and DFT calculations revealed a high-spin iron(III)-nitrene radical intermediate on the quintet spin surface. Azide activation is turnover-limiting, followed by stereodetermining radical-type hydrogen atom transfer. This work establishes mechanistic principles for designing efficient, selective, and robust iron-catalyzed C–H amination systems, providing a foundation for sustainable nitrene-transfer catalysis.