2,2,2-trifluoroethylhydrazine

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,2,2-Trifluoroethylhydrazine (70% solution in water, 35.0 g, 0.307 mol) was treated with mucochloric acid (51.88 g, 0.307 mol) in ethanol (300 mL) and refluxed for 5 hours. The solvent was concentrated in vacuo. The crystals obtained were washed with water and air dried (yield: 50 g; 67.5%). 1H NMR (300 MHz, CDCl3) δ 4.8 (q, J=9 Hz, 2H), 7.85 (s, 1H). MS (DCl-NH3) m/z 264 (M+NH4)+. refluxed for 5 hours The solvent was concentrated in vacuo The crystals obtained were washed with water and air dried (yield: 50 g; 67.5%)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-(4-Chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (1000 mg, 3.02 mmol; CAN 1018782-82-5) and (2,2,2-trifluoroethyl)hydrazine (380 mg, 3.33 mmol; CAN 5042-30-8) were combined with DMF (10 mL) to give a colorless solution. TBTU (1.06 g, 3.32 mmol) and DIPEA (1.56 g, 2.05 mL, 12.1 mmol) were added. The reaction mixture was stirred for 15 h at room temperature. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layers were combined and washed with water (1×50 mL) and brine (1×50 mL). The organic layers were dried with MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 50 g, 0% to 50% EtOAc in hexane) to give the title compound (0.35 g, 27%) as white solid; LC-MS (UV peak area/ESI) 100%, 426.0451 (M−H)−. to give a colorless solution extracted with ethyl acetate (2×50 mL) washed with water (1×50 mL) and brine (1×50 mL) The organic layers were dried with MgSO4 concentrated in vacuo The residue was purified by flash chromatography (silica gel, 50 g, 0% to 50% EtOAc in hexane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-(4-Chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (1000 mg, 3.02 mmol; CAN 1018782-82-5) and (2,2,2-trifluoroethyl)hydrazine (380 mg, 3.33 mmol; CAN 5042-30-8) were combined with DMF (10 mL) to give a colorless solution. TBTU (1.06 g, 3.32 mmol) and DIPEA (1.56 g, 2.05 mL, 12.1 mmol) were added. The reaction mixture was stirred for 15 h at room temperature. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layers were combined and washed with water (1×50 mL) and brine (1×50 mL). The organic layers were dried with MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 50 g, 0% to 50% EtOAc in hexane) to give the title compound (0.35 g, 27%) as white solid; LC-MS (UV peak area/ESI) 100%, 426.0451 (M−H)−. to give a colorless solution extracted with ethyl acetate (2×50 mL) washed with water (1×50 mL) and brine (1×50 mL) The organic layers were dried with MgSO4 concentrated in vacuo The residue was purified by flash chromatography (silica gel, 50 g, 0% to 50% EtOAc in hexane)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (Z)-methyl N-3-methylbut-2-enoylpyrrolidine-1-carbimidothioate (2.515 g, 11.1 mmol, Eq: 1.00) and (2,2,2-trifluoroethyl)hydrazine (5 g, 30.7 mmol, Eq: 2.76) was stirred for 1 hour at 100° C. The mixture was dissolved in ethyl acetate and washed with water 3 times and once with brine. The organic layer was separated, dried over magnesium sulfate, filtrated and evaporated affording 5-(2-methyl-prop enyl)-3-pyrrolidin-1-yl-1-(2,2,2-trifluoro-ethyl)-1H-[1,2,4]triazole (1.599 g/52.5%) as an off-white waxy solid. MS: m/e=275.4 (M+H+) washed with water 3 times and once with brine The organic layer was separated dried over magnesium sulfate filtrated evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1.38 g of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one boiled under reflux for 0.5 h with 1.6 of 2,2,2-trifluorethylhydrazine in 20 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from methanol/water. After drying, 3,5-bis(2-hydroxyphenyl)-1-(2,2,2-trifluoroethyl)-1H-[1,2,4]triazole remains as colorless crystals of m.p. 154-156° C. The mixture is cooled poured onto water extracted with ethyl acetate The combined organic phases are dried over sodium sulfate concentrated on a rotary evaporator The residue is crystallized from methanol/water After drying

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1.38 g of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one boiled under reflux for 0.5 h with 1.6 of 2,2,2-trifluorethylhydrazine in 20 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from methanol/water. After drying, 3,5-bis(2-hydroxyphenyl)-1-(2,2,2-trifluoroethyl)-1H-[1,2,4]triazole remains as colorless crystals of m.p. 154-156° C. The mixture is cooled poured onto water extracted with ethyl acetate The combined organic phases are dried over sodium sulfate concentrated on a rotary evaporator The residue is crystallized from methanol/water After drying

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 70% aqueous solution of CF3CH2NHNH2 (325 mL, 1.986 mol) (obtained from Aldrich) was extracted with toluene (3×1200 mL). To a solution of the product from step A (600 g, 1.655 mol) in toluene (900 mL) was first added the combined toluene extracts containing the anhydrous 2,2,2-trifluoroethyl hydrazine, followed by acetic acid (121.4 g, 1.986 mol). The reaction mixture was heated at about 70° C. for about 2 hours, then another toluene extraction of 70% aqueous 2,2,2-trifluoroethyl hydrazine (50 g) was added. The reaction mixture was heated at about 80° C. for about 3.5 hours, cooled to room temperature and diluted with saturated aqueous NaHCO3 (2 L). The toluene layer was separated and washed with saturated aqueous NaCl, dried over Na2SO4 and concentrated in vacuo to give an oil (754.8 g). Crystallization from methanol/water afforded the desired product as a white solid (609.5 g). 1H-NMR (CDCl3) δ 1.50 (s, 9H), 2.53 (d, 1H), 2.70 (br s, 2H), 2.88 (br s, 1H), 3.31 (m, 2H), 3.97 (m, 1H), 4.19 (m, 1H), 4.46 (br s, 1H), 4.63 (br s, 1H), 7.06 (m, 2H), 7.51 (m, 1H), 8.34 (m, 1H). another toluene extraction of 70% aqueous 2,2,2-trifluoroethyl hydrazine (50 g) was added The reaction mixture was heated at about 80° C. for about 3.5 hours cooled to room temperature diluted with saturated aqueous NaHCO3 (2 L) The toluene layer was separated washed with saturated aqueous NaCl dried over Na2SO4 concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,2,2-Trifluoroethylhydrazine (70% solution in water, 35.0 g, 0.307 mol) was treated with mucochloric acid (51.88 g, 0.307 mol) in ethanol (300 mL) and refluxed for 5 hours. The solvent was concentrated in vacuo. The crystals obtained were washed with water and air dried (yield: 50 g; 67.5%). 1H NMR (300 MHz, CDCl3) δ 4.8 (q, J=9 Hz, 2H), 7.85 (s, 1H). MS (DCl—NH3) m/z 264 (M+NH4)+. refluxed for 5 hours The solvent was concentrated in vacuo The crystals obtained were washed with water and air dried (yield: 50 g; 67.5%)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following the procedure for 9-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene, 9-bromo-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-2-carboxylic acid 1-dimethylaminomethylideneamide was reacted with trifluoroethyl hydrazine (70% aqueous) to give 9-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene as a white solid. LCMS RT=4.49 min, M+H+=414/416.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following the procedure for 9-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene, 9-bromo-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-2-carboxylic acid 1-dimethylaminomethylideneamide was reacted with trifluoroethyl hydrazine (70% aqueous) to give 9-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene as a white solid. LCMS RT=4.49 min, M+H+=414/416.