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

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 24 h at 60 degrees 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 H-1, C-13, and F-19 NMR spectroscopy; two-dimensiona H-1 and C-13 NMR spectroscopy (NOESY, gHMBC, and gHMQC); single crystal X-ray diffraction; and GC -MS. (C) 2017 Elsevier B.V. All rights reserved.