4-(Trifluoromethoxy)phenylhydrazine hydrochloride → 4-[(4-Bromophenyl)methyl]-5-cyclohexyl-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazole

Participants

Reaction Steps

To a solution of 3.17 g 2-(4-bromobenzyl)-3-cyclohexyl-3-oxopropanal from Step C above and 2.47 g 4-trifluoromethoxyphenylhydrazine hydrochloride in 100 mL methanol was added 21.6 mL 0.5 M sodium methoxide in methanol. The resulting mixture was refluxed under nitrogen for two days. The solvent was removed under reduced pressure. The resulting crude product was subjected to repeated chromatography on silica gel using 0˜10% MeCN in methylene chloride, 0˜2% MeCN in methylene chloride, or 7˜10% EtOAc in hexanes. Pure 4-(4-bromobenzyl)-5-cyclohexyl-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazole was obtained as the major product by recrystallization of chromatographic fractions from methanol. 1H NMR (CDCl3, 500 MHz) δ 7.64˜7.67 (m, 2H), 7.43˜7.46 (m, 2H), 7.44 (s, 1H), 7.23˜7.27 (m, 2H), 7.10˜7.13 (m, 2H), 3.82 (s, 2H), 2.63 (tt, J=3.3 & 11.8 Hz, 1H), 1.83˜1.89 (m, 4H), 1.72˜1.76 (m, 1H), 1.60˜1.69 (m, 2H), 1.27˜1.40 (m, 3H). LC-MS: 2.91 min. (M+H=479). Pure 4-(4-bromobenzyl)-3-cyclohexyl-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazole was obtained as the minor product following preparative HPLC of the silica gel chromatography fractions. 1H NMR (CDCl3, 500 MHz) δ 7.59˜7.63 (m, 2H), 7.44˜7.47 (m, 2H), 7.41 (s, 1H), 7.25˜7.28 (m, 2H), 7.10˜7.13 (m, 2H), 3.82 (s, 2H), 2.64 (tt, J=3.2 & 12.1 Hz, 1H), 1.83˜1.89 (m, 4H), 1.72˜1.76 (m, 1H), 1.57˜1.66 (m, 2H), 1.27˜1.39 (m, 3H). LC-MS: 2.70 min. (M+H=479.1/481). The identity of the isomers were confirmed by NOE difference spectra.

Provenance & Evidence