Copper-Mediated Amination of Aryl C–H Bonds with the Direct Use of Aqueous Ammonia via a Disproportionation Pathway

The direct amination
of C–H bonds with ammonia is a challenge
in synthetic chemistry. Herein, we present a copper-mediated approach
that enables a chelation-assisted aromatic C–H bond amination
using aqueous ammonia. A key strategy was to use soft low-valent Cu­(I)
species to avoid the strong coordination of ammonia. Mechanistic investigations
suggest that the catalysis is initiated by a facile deprotonation
of bound ammonia, and the C–N coupling is achieved by subsequent
reductive elimination of the resultant copper–amido intermediate
from a Cu­(III) intermediate that is readily generated by disproportionation
of low-valent copper analogues. This mechanistic postulate was supported
by a preliminary kinetic isotope effect study and computations. This
new chelation-assisted, copper-mediated C–H bond amination
with aqueous ammonia was successfully applied to a broad range of
substrates to deliver primary anilines. Moreover, the mild conditions
required for this transformation allowed the reaction to operate even
under substoichiometric conditions to enable a late-stage application
for the preparation of pharmaceutical agents.