Molecular Electron Density Theory Study of Fused Regioselectivity in the Intramolecular [3+2] Cycloaddition Reaction of Cyclic Nitrones

Abstract

AbstractThe intramolecular [3+2] cycloaddition (IM32CA) reactions of cyclic nitrones Z‐7 and E‐7 have been studied within the Molecular Electron Density Theory at the MPWB1K/6‐311G(d) computational level. For these IM32CA reactions, which take place through a one–step mechanism, two regioisomeric reaction paths associated with the formation of the 6,6,5‐ring fused and 6,5,5‐ring bridged isoxazolidines have been considered. Analysis of the relative Gibbs free energies indicates that under thermodynamic control, these IM32CA reactions are completely regioselective, stereoselective and stereospecific, cyclic nitrones Z‐7 and E‐7 yielding the fused isoxazolidines 8 and 9, respectively, as the only product, in complete agreement with the experimental outcomes. The low electrophilic character of nitrones Z‐7 and E‐7 together with the strain caused by the chain along these intramolecular processes are responsible for the high activation energies found in these IM32CA reactions. An ELF topological analysis of the asynchronous TSs associated with the IM32CA reaction of cyclic nitrone Z‐7 indicates that along the more favourable fused reaction path, the IM32CA reaction begins with the formation of the C−O single bond involving the most nucleophilic and electrophilic centers of the molecule.