SYNTHESIS OF A SERIES OF TRIFLUOROMETHYLAZOLES AND DETERMINATION OF PK(A) OF ACIDIC AND BASIC TRIFLUOROMETHYL HETEROCYCLES BY F-19 NMR-SPECTROSCOPY

Trifluoroacetylation at the 5-position of 3,4-dihydro-2H-pyran and the 3-position of 4,5-dihydrofuran, followed by treatment with hydrazine, gave 3-(3-trifluoromethyl-1H-pyrazol-4-yl)prop and 2-(3-trifluorometh yl-1H-pyrazol-4-yl)ethanol, respectively, In the latter case, an inter mediate dimer was isolated. Isomeric 2-(3-trifluoromethyl-1H-pyrazol-5 -yl)ethanol was formed by reaction of hydrazine with 6-benzyloxy-1,1,1 -trifluorohex-3-yn-2-one and deprotection. Reaction of 3-benzyloxyprop ylamine with 2,5-bis(trifluoromethyl)-1,3,4-oxadiazole, followed by de protection, afforded s(trifluoromethyl)-4H-1,2,4-triazol-4-yl]propanol . A series of 2-trifluoromethyl-1H-benzimidazoles and 2-trifluoromethy l-3H-imidazopyridines were prepared by condensation of the appropriate ortho-arenediamine with trifluoroacetic acid, Analysis of the F-19 NM R spectra of the trifluoromethylazoles and of 3-trifluoromethylpyridin e in aqueous solution at different pHs enabled determination of pK(a) values. All the compounds evaluated had one or more pK(a) between 1 an d 13, except the triazole, Several compounds were identified as having potential use in measuring pH in biological media by F-19 NMR spectro scopy.