Synthesis of 2-Azolylcycloalkanols

w -New 2-awlylcycloalkanol derivatives were synthesized stereoselectively by Grignard reaction of 2-awlylcyclohexanones (7, s), and particularly 2-awlylcycloheptanones (9.10) afforded one of the diastereomers of kawlylcycloalkanols stereospecifically because the reagent attacked the carbonyl group from the less hindered side of the magnesium complex intermediate.These azolylcycloalkanols (13-38) were tested for antifungal activities.Several new antifungal agents having imidazole and triazole structures have been developed in last few years.They are effective topically in the treatment of vaginal candidasis anddennatophytasis; one of them, ketoconawle is effective orally.1 Active research is underway on the synthesis of orally active and broad spectrum antimycotic azole compounds.Recently?l-(2,4-dichlorophenyl)-l-(4-fluorophenyl)-2-1,2,4-trial-l-ylethanol (ICI 153066) and l-(4-chlorophenoxy)-2-(t-butyl)-3-(1,2,4-triazol-l-yl-2-prpauol (Bay n-7133) were reported to show oral antifungal activity.3.4They have in common a free rotatable (1,2,4-triazol-1-y1)ethanol structure.This directed us to the synthesis of awlylcycloalkanols having a rigid awlylethanol segment and the study of their antifungal activities.In this paper> we report the synthesis of 2-awlylcycloalkanol derivatives uia the stereoselective Grignard reaction of 2-azolylcycloalkanones (7-10).Synthesis The synthetic route to the target compounds (13-38) is shown in Scheme I.The reaction of cycloalkene oxides (1, 2) with azoles in ethanol or propanol yielded 2-azolylcycloalkanols (3-6),whicb were oxidized by Swern oxidation6 to afford the 2-azolylcycloalkanones (7-10).2-(1H-1,2,4-Triazol-1-y1)cycloheptanone (10) was also obtained from the reaction of 2-bromocycloheptanone (12) with 1,2,4-triazole in the presence of potassium carbonate.Grignard reaction of 2-azolylcyclohexanones (7-8) with various Grignard reagents in tetrahydrofuran 1 "-2 3 " -2 , Y-N 5 n=3, Y=N 7 11=2, Y=N 9 n=3.Y-N 2 n=3 4 n=Z, Y 4 I 6 "-3, Y-CH 8 n=2.Y=CH 10 "-3, Y-CH 5.