Mechanistic Investigation of the Iron-Catalyzed Azidation of Alkyl C(sp 3)–H Bonds with Zhdankin’s λ3‑Azidoiodane

• Published in: Journal of the American Chemical Society Vol. 143; no. 39; pp. 16184 - 16196
• Main Authors: Day, Craig S, Fawcett, Alexander, Chatterjee, Ruchira, Hartwig, John F
• Format: Journal Article
• Language: English
• Published: American Chemical Society 06.10.2021
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.1c07330

An in-depth study of the mechanism of the azidation of C­(sp 3)–H bonds with Zhdankin’s λ3-azidoiodane reagent catalyzed by iron­(II)­(pybox) complexes is reported. Previously, it was shown that tertiary and benzylic C­(sp 3)–H bonds of a range of complex molecules underwent highly site-selective azidation by reaction with a λ3-azidoiodane reagent and an iron­(II)­(pybox) catalyst under mild conditions. However, the mechanism of this reaction was unclear. Here, a series of mechanistic experiments are presented that reveal critical features responsible for the high selectivity and broad scope of this reaction. These experiments demonstrate the ability of the λ3-azidoiodane reagent to undergo I–N bond homolysis under mild conditions to form λ2-iodanyl and azidyl radicals that undergo highly site-selective and rate-limiting abstraction of a hydrogen atom from the substrate. The resultant alkyl radical then combines rapidly with a resting state iron­(III)-azide complex, which is generated by the reaction of the λ3-azido­iodane with the iron­(II)­(pybox) complex, to form the C­(sp 3)–N3 bond. This mechanism is supported by the independent synthesis of well-defined iron complexes characterized by cyclic voltammetry, X-ray diffraction, and EPR spectroscopy, and by the reaction of the iron complexes with alkanes and the λ3-azido­iodane. Reaction monitoring and kinetic studies further reveal an unusual effect of the catalyst on the rate of formation of product and consumption of reactants and suggest a blueprint for the development of new processes leading to late-stage functionalization of C­(sp 3)–H bonds.