An in-depth study of the mechanism of the azidation of C(sp³)-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(sp³)-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(sp³)-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(sp³)-H bonds.

C(sp³ )-Cl bonds are present in numerous biologically active small molecules, and an ideal route for their preparation is by the chlorination of a C(sp³ )-H bond. However, most current methods for the chlorination of C(sp³ )-H bonds are insufficiently site selective and tolerant of functional groups to be applicable to the late-stage functionalization of complex molecules. We report a method for the highly selective chlorination of tertiary and benzylic C(sp³ )-H bonds to produce the corresponding chlorides, generally in high yields. The reaction occurs with a mixture of an azidoiodinane, which generates a selective H-atom abstractor under mild conditions, and a readily-accessible and inexpensive copper(II) chloride complex, which efficiently transfers a chlorine atom. The reaction's exceptional functional group tolerance is demonstrated by the chlorination of >30 diversely functionalized substrates and the late-stage chlorination of a dozen derivatives of natural products and active pharmaceutical ingredients.