A one-pot assembly of Δ2-isoxazolines from ketones, aryl acetylenes and hydroxylamine: Revisiting the mechanism in terms of quantum chemistry

Abstract

A mechanism of the sequential reaction of ketones with arylacetylenes and hydroxylamine in the presence of KOBut/DMSO followed by the treatment of the reaction mixture with H2O and KOH yielding Δ2-isoxazolines is investigated using a DFT approach by the example of the assembly of (4R,5S)-5-benzyl-4-ethyl-3-methyl-4,5-dihydroisoxazole from pentan-2-one, phenylacetylene and NH2OH·HCl. Activation energies were estimated for successive stages of nucleophilic addition of a ketone carbanion to a triple bond (vinylation), addition of hydroxylamine to a carbonyl group and subsequent dehydration of the carbinolamine formed (oximation), base-assisted E/Z-isomerization of the oxime group, probable prototropic rearrangement of the β,γ-unsaturated oxime to the α,β-unsaturated structure and) intramolecular nucleophilic attachment to a double bond of α,β- or β,γ-unsaturated oxime with the formation of a five-membered heterocycle. It was shown that it is not the α,β-unsaturated oxime that participates in the ring closure, as previously assumed, but the β,γ-unsaturated form.