Sterically Facilitated Intramolecular Nucleophilic NMe2 Group Substitution in the Synthesis of Fused Isoxazoles: Theoretical Study

Abstract

The influence of steric repulsion between the NMe2 group and a second ortho-(peri-)substituent in the series of 1-dimethylaminonaphthalene and N,N-dimethylanilene ortho-oximes on the ease of the NMe2 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 NMe2 group displacement in the presence of bulky substituents is demonstrated. The possibility of fused isoxazoles synthesis via the intramolecular nucleophilic substitution of a protonated NMe2 group in the aniline and naphthalene series is predicted.

Synthesis of Fused Isoxazoles: A Comprehensive Review

“…It is a SNAr aromatic nucleophilic substitution reaction. The compound 1,8-bis(dimethylamino)-2naphthaldehyde oxime (57) was converted at 120 • C, and the substitution of the NMe 2 group yielded the fused isoxazole N,N-dimethylnaphtho [2,1-d]isoxazole-9-amine (58) [28]. Mansour and co-workers studied the oxidative conversion of oximes (55) into 3-aryl isoxazoles (56) (Scheme 21).…”

“…It is a SNAr aromatic nucleophilic substitution reaction. The compound 1,8bis(dimethylamino)-2-naphthaldehyde oxime (57) was converted at 120 °C, and the substitution of the NMe2 group yielded the fused isoxazole N,N-dimethylnaphtho [2,1d]isoxazole-9-amine (58) [28]. Overall, the synthetic methods employed for the synthesis of fused isoxazoles possess advantages such as the use of easily available starting materials, feasible reaction conditions, short reaction time, simple cyclization reactions, easy scale-up, and high yield.…”