The Essence in Selectivity of Copper-Mediated Intermolecular Nucleophilic Substitution of a C-H Bond in 2-Methyl--methoxyaniline: A Theoretical Study.

The detailed mechanism for NHC-Cu(I)catalyzed intermolecular nucleophilic substitution of the C-H bonds at aniline (2-methyl--methoxyaniline) was studied via DFT methods to reveal the essence of the selectivity. Calculations revealed that the C-H functionalization proceeds via two nucleophilic attacks on the aromatic ring rather than a one-step C-H substitution to give the experimentally observed major product. The reaction is initiated by activation of the substrate via oxidative addition with an NHC-Cu(I) catalyst, through which an umpolung occurs at the ring. From the activated intermediate, methoxyl group transfer to benzyl forms a resting state, while a nucleophile can attack the position of benzyl to form a more stable intermediate. The nucleophile group can then transfer to the position by a 1,2-Wagner-Meerwein rearrangement to form the final product through a proton shuttle. In contrast, other transfer processes affording or substituted products encounter higher activation barriers. This work investigates the relationship of product selectivity with the umpolung of the aromatic ring, as well as the priority of a nucleophilic attack at the position of the aromatic, 1,2-Wagner-Meerwein rearrangement from the substituted intermediate, and proton shuttle from the substituted intermediate.