Copper Catalyzed sp3 C‐H Amidation: Sterically Driven Primary and Secondary C‐H Site‐Selectivity

Undirected sp3 C−H functionalization reactions often follow site‐selectivity patterns that mirror the corresponding C−H bond dissociation energies (BDEs). This often results in the functionalization of weaker 3° C−H bonds in the presence of stronger 2° and 1° bonds. An important, contemporary challenge is the development of catalyst systems capable of selectively functionalizing stronger 1° and 2° C−H bonds over 3° and benzylic C−H sites. Herein, we report a Cu catalyst that exhibits a high degree of 1° and 2° over 3° C‐H bond selectivity in the amidation of linear and cyclic hydrocarbons with aroyl azides ArC(O)N3. Mechanistic and DFT studies indicate that C−H amidation involves H−atom abstraction from R−H substrates by nitrene intermediates [Cu](κ2−N,O−NC(O)Ar) to provide carbon−based radicals R• and copper(II)−amide intermediates [CuII]−NHC(O)Ar that subsequently capture radicals R• to form products R−NHC(O)Ar. These studies reveal important catalyst features required to achieve 1° and 2° C‐H amidation selectivity in the absence of directing groups.

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