<i>Endo</i>-Selective Intramolecular Alkyne Hydroamidation Enabled by NiH Catalysis Incorporating Alkenylnickel Isomerization

Abstract

Intramolecular alkyne hydroamidation represents a straightforward approach for the access to synthetically valuable cyclic enamides. Despite some advances made in this realm, the ability to attain a precise regiocontrol still remains challenging, especially for <i>endo</i> cyclization that leads to six-membered and larger azacyclic rings. Herein, we report a NiH-catalyzed intramolecular hydroamidation of alkynyl dioxazolones that allows for an excellent <i>endo</i> selectivity, thus affording a range of six- to eight-membered endocyclic enamides with a broad scope. Mechanistic investigations revealed that Ni(I) catalysis is operative in the current system, proceeding via regioselective <i>syn</i>-hydronickelation, alkenylnickel <i>E</i>/<i>Z</i> isomerization, and Ni-centered inner-sphere nitrenoid transfer. In particular, the key alkenylnickel isomerization step, which previously lacked mechanistic understandings, was found to take place through the η²-vinyl transition state. The synthetic value of this protocol was demonstrated by diastereoselective modifications of the obtained endocyclic enamides to highly functionalized δ-lactam scaffolds.