Context <p>(3 + 2) Cycloaddition reactions are foundational in the synthesis of biologically and industrially relevant heterocycles, including isoxazolidine and spirocyclic frameworks. In this work, we investigated the reactivity of <i>C</i>-substituted-<i>N</i>-phenyl nitrones with 3,5-bis-(arylidene)-1-methylpiperidine-4-one toward the synthesis of isoxazolidine derivatives. The study revealed how structural modifications of the nitrone substituents influence reaction dynamics, with emphasis on chemo-, regio-, and stereoselectivity. Two possible reaction pathways were identified: selective addition of the nitrone to the olefinic bond of the bis-arylidene piperidine and alternative addition across the carbonyl group. Energy profiles and kinetic data indicate that the second step responsible for generating the bis-products is unfavorable relative to the mono-products. Global electron density transfer (GEDT) values indicated that the processes are highly polar, and reactivity indices correlated well with the observed activation energies and selectivity trends.</p> Methods <p>All computations were performed using density functional theory at the M06-2X/6-311G(d,p) level. Solvent effect was included with the integral equation formalism polarizable continuum model (IEFPCM). Transition structures were verified by frequency analysis and intrinsic reaction coordinate (IRC) calculations. Global and local reactivity indices, together with GEDT values, were calculated to characterize electron density transfer and reactivity. All computations were carried out with Gaussian 09.</p> Graphical abstract <p></p>