Mechanism of the Acid-Mediated Thermal Fragmentation of 5-Spirocyclobutane-isoxazolidines

Protonation at the nitrogen of 5-spirocyclopropane-isoxazolidines induces clean thermal rearrangement/fragmentation to beta-lactams and ethylene. Under the same conditions, homologous 5-spirocyclobutane-isoxazolidines undergo unselective fragmentation to give cyclobutyl derivatives through a completely different mechanism. Experimental data and DFT calculations show that the process is initiated with less-favored protonation at the isoxazolidine oxygen rather than nitrogen. Highly energetic O-protonated isoxazolidines undergo N-O cleavage with concomitant endo- or exocyclic deprotonation to give iminium ions that, in the presence of trifluoroacetate, evolve into 2-(1-hydroxycyclobutyl)ethanones and N-[2-(1-hydroxycyclobutyl)ethyl]trifluoroacetamides, respectively. DFT data validate protonation at oxygen of 5-spirocyclobutane-isoxazolidines, which requires higher energy than protonation at nitrogen, but can trigger the proposed process without any energy barrier. The N-protonated derivatives could rearrange to give oxazaspirooctane, with enlargement of the spirocyclobutane ring, but this process, owing to its high energy barrier, cannot compete with the reaction channel promoted by oxygen protonation and, in fact, is not experimentally observed. Being independent of the presence of a strained spirofused ring, acid-catalyzed fragmentation was also demonstrated to occur in normal isoxazolidines, such as those derived from cycloaddition of C-Ph-N-Me-nitrone to norbornene, suggesting that isoxazolidines, widely used in organic synthesis, should not be heated in the presence of protic acids.