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

The detailed mechanism for NHC-Cu(I)-catalyzed intermolecular nucleophilic substitution of the C-H bonds at aniline (2-methyl-N-methoxyaniline) was studied via DFT methods to reveal the essence of the selectivity. Calculations revealed that the meta C-H functionalization proceeds via two nucleophilic attacks on the aromatic ring rather than a one-step meta 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 ortho position of benzyl to form a more stable intermediate. The nucleophile group can then transfer to the meta position by a 1,2-Wagner-Meerwein rearrangement to form the final product through a proton shuttle. In contrast, other transfer processes affording ortho- or para-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 ortho position of the aromatic, 1,2-Wagner-Meerwein rearrangement from the ortho-substituted intermediate, and proton shuttle from the meta-substituted intermediate.