Efficient approach for regioselective synthesis of new trifluoromethyl-substituted spirotetracyclic isoxazolines and isoxazoles

Abstract

This paper describes firstly an effective protocol for the synthesis of a new series of five examples of 3-(trifluoromethyl)-3,3a-dihydrospiro[chromeno[4,3-c]isoxazole-4,1′-cycloalkan]-3-ols (4), in which the cycloalkanes — cyclopentane, cyclohexane, cycloheptane, and 4′-methyl- and 4′-t-butyl-cyclohexane — were isolated at yields of 65–84%. The dihydro-isoxazolinols 4 were obtained regioselectively from the reactions of 2,2,2-trifluoro-1-[4-methoxy-spiro(2H-chromen-2,1′-cycloalkane)-3-yl]ethanones (3) with hydroxylamine hydrochloride, in the presence of sodium bicarbonate and methanol as solvent, for 24h at 60°C. The ethanone precursors 3 were synthesized by trifluoroacetylation reaction, employing trifluoroacetic anhydride and mixtures of enolethers and/or acetals derived from spiro[chroman-2,1′-cycloalkan]-4-ones (2) (Kabbe’s adducts), which were obtained beforehand from the reaction of cycloalkanones 1 with 2-hydroxyacetophenone and pyrrolidine. Subsequently, dehydration reactions of isoxazolinols 4, employing thionyl chloride and pyridine, enabled the isolation of another series of five novel spiro-isoxazoles 5 (76–95% yield). The structural features of the two series of new spiro heterocycles (4 and 5) were unequivocally determined with the aid of: one-dimensional 1H, 13C, and 19F NMR spectroscopy; two-dimensional 1H and 13C NMR spectroscopy (NOESY, gHMBC, and gHMQC); single crystal X-ray diffraction; and GC–MS.