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

ABSTRACT We report herein the first copper‐mediated three‐component modular synthesis of N ‐fluoroalkyl amides from fluoroalkylcopper species ([Cu I ─CF 3 ], [Cu I ─CF 2 CO 2 Et], and [Cu I ─C 2 F 5 ]), a nitrene precursor (dioxazolone), and an electrophile, featuring broad substrate scope and the unprecedented construction of acyclic N ‐C 2 F 5 and N ‐CF 2 CO 2 Et 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 I N(CF 3 )(COAr)] 5c and [Cu I (N(CF 3 )(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.