Non-catalytic regioselective synthesis of trans bis-pyrrolo isoxazole cycloadducts in water

Abstract

Pyrrolo isoxazoles are key structural motifs of many drugs and pharmacologically active compounds and are often synthesized by one-pot cycloaddition reactions under thermal conditions. In the present study, a series of new symmetric bis-pyrrolo isoxazole cycloadducts have been synthesized by cycloaddition of bis-nitrones of glyoxal with N-substituted maleimides in water under non-catalytic conditions. The thermal cycloaddition reactions conducted in an aqueous medium at 70 °C afforded a single regioisomer of symmetric bis-pyrrolo isoxazoles in a shorter reaction period of 10–15 minutes. The formation of only the trans diastereoisomer, as confirmed by ¹H-NMR spectral analysis, was attributed to the involvement of endo-transition mode, where a succinimide moiety and N-phenyl ring of the nitrone being on the same side stabilized the transition state by maximum π–π overlap. Several pyrrolo isoxazole derivatives have been synthesized using this methodology. The present approach for pyrrolo isoxazole synthesis, being one-pot, facile, non-catalytic, and conducted at low temperature and under aqueous conditions, can be counted as a step towards sustainable and green synthetic chemistry.