Synthesis of a series of trifluoromethylazoles and determination of pKa of acidic and basic trifluoromethyl heterocycles by 19F NMR spectroscopy

Abstract

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)propanol and 2-(3-trifluoromethyl-1H-pyrazol-4-yl)ethanol, respectively. In the latter case, an intermediate 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-benzyloxypropylamine with 2,5-bis(trifluoromethyl)-1,3,4-oxadiazole, followed by deprotection, afforded 3-[3,5-bis(trifluoromethyl)-4H-1,2,4-triazol-4-yl]propanol. A series of 2-trifluoromethyl-1H-benzimidazoles and 2-trifluoromethyl-3H-imidazopyridines were prepared by condensation of the appropriate ortho-arenediamine with trifluoroacetic acid. Analysis of the ¹⁹F NMR spectra of the trifluoromethylazoles and of 3-trifluoromethylpyridine in aqueous solution at different pHs enabled determination of pK_a values. All the compounds evaluated had one or more pK_a between 1 and 13, except the triazole. Several compounds were identified as having potential use in measuring pH in biological media by ¹⁹F NMR spectroscopy.