Sterically Facilitated Intramolecular Nucleophilic NMe(2) Group Substitution in the Synthesis of Fused Isoxazoles: Theoretical Study

The influence of steric repulsion between the NMe(2) group and a second ortho-(peri-)substituent in the series of 1-dimethylaminonaphthalene and N,N-dimethylanilene ortho-oximes on the ease of the NMe(2) group’s intramolecular nucleophilic substitution is studied. Possible reaction intermediates for three mechanisms are calculated (ωB97xd/def-2-TZVP), and their free Gibbs energies are compared to model reaction profiles. Supporting experiments have proved the absence of studied reactivity in the case of simple 2-dimethylaminobenzaldoxime, which allowed us to establish reactivity limits. The significant facilitation of NMe(2) group displacement in the presence of bulky substituents is demonstrated. The possibility of fused isoxazoles synthesis via the intramolecular nucleophilic substitution of a protonated NMe(2) group in the aniline and naphthalene series is predicted.