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

HRID 2102227Notes

Reaction equation

HRID 2102227 reaction equation
[Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]([C:10]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=O)[CH:8]=O)=[CH:4][CH:3]=1.Cl.[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1.C[O-].[Na+]>CO>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[CH:8]=[N:31][N:30]([C:27]3[CH:28]=[CH:29][C:24]([O:23][C:22]([F:21])([F:33])[F:32])=[CH:25][CH:26]=3)[C:10]=2[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1

Participants

5

Reactant 3

HCID 27773284-(Trifluoromethoxy)phenylhydrazine hydrochlorideHCID 10942334Sodium MethoxideHCID 86604612HCID 86604612, compound

Product 1

HCID 673347364-[(4-Bromophenyl)methyl]-5-cyclohexyl-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazole

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent2×

Procedure

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.

Workup

  1. temperatureThe resulting mixture was refluxed under nitrogen for two days
  2. customThe solvent was removed under reduced pressure

Sources & evidence

ORD record
ord-c660e4673ced48e2a3bbb99748931a6a
Source dataset
uspto-grants-2009_08
Patent number
US07572922B2

Reaction notes

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