Strained exo-Methylene Heterocycles as Dipolarophiles: Synthesis of Unexplored Spiroisoxazolines

Key words

2-methyleneoxetanes - spiroisoxazolines - thietanes - azetidines

Significance

Spiroheterocycles have been of significant interest in medicinal chemistry due to their non-planar topology (M. Rogers-Evans et al. Chimia 2014, 68, 492) and there have been considerable efforts towards the synthesis of these compounds. Syntheses of spirocycles with four-membered heterocycles such as spirooxetane and spiroazetidine pose additional challenges, as these rings are more strained than their five- or six-membered counterparts. However, their compactness and three-dimensional properties make them desirable scaffolds in drug discovery. The current report details a regio- and diastereoselective [3+2] cycloaddition of strained alkenes 1 and nitrile oxides 4 to provide previously unreported spiroisoxazolines 3 bearing four-membered oxetanes, azetidines and thietanes.

Comment

The authors report that when the precursor to nitrile oxide 2 was added slowly to the dipolarophile 1 and base, improved yields were observed. A variety of aliphatic, aromatic and N-substituents on the 2- and 3-positions of the heterocycle were tolerated (3a–d). In contrast, 3,3-bis-substituted 2-methylene oxetanes gave lower yield (3g) or no product (3f). Azetidine and thiophene dipolarophiles gave moderate yields of the spiroisoxazolines (3h–i). Different aromatic and aliphatic groups were tolerated on the dipole precursor (3j–m). In certain cases, the desired isoxazolines were converted into ring-opened products either readily (3e) or over time (3i). Further studies on the stability and reactivity of these compounds would help to expand the scope and applications of these heterocycles.

Publication History

Article published online:
14 February 2024