A Modular Approach to <i>N</i> ‐Fluoroalkyl Amides via Nitrene Insertion Into Fluoroalkylcopper(I)

We report herein the first copper-mediated three-component modular synthesis of N-fluoroalkyl amides from fluoroalkylcopper species ([Cu^I─CF₃], [Cu^I─CF₂CO₂Et], and [Cu^I─C₂F₅]), a nitrene precursor (dioxazolone), and an electrophile, featuring broad substrate scope and the unprecedented construction of acyclic N-C₂F₅ and N-CF₂CO₂Et structures. The reaction proceeds via reaction of the dioxazolone with the fluoroalkylcopper complex to generate a nitrene/Cu intermediate, followed by nitrene migratory insertion into the [Cu^I─C_Rf] bond as the pivotal step that directly forges the N-fluoroalkyl bond. Such a key step was supported by isolation and single-crystal x-ray characterization of intermediates [(L1)Cu^IN(CF₃)(COAr)] 5c and [Cu^I(N(CF₃)(COAr))₂]^- 5d. Leveraging the versatile reactivity of copper, these intermediates react with various electrophiles to access a wide range of N-fluoroalkyl-N-alkyl(aryl)amides, and the derivatization of several drug molecules further demonstrates the synthetic utility of this approach.