1,1,1-trifluorobutan-2-one

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: To 1,1,1-trifluorobutan-2-one (5.0 g, 39.7 mmol, 1.0 equiv) was slowly added trimethylsilylcyanide (4.7 g, 47.6 mmol, 1.2 equiv) and the resulting mixture stirred overnight at ambient temperature. To the resulting mixture was added water (80 mL) followed by zinc chloride (5.4 g, 39.7 mmol, 1.0 equiv) and sodium azide (3.1 g, 47.1 mmol, 1.2 equiv) and the mixture was heated at 80° C. for three hours. The mixture was cooled to room temperature and the precipitate was filtered and dried in vacuo to afford 1,1,1-trifluoro-2-(2H-tetrazol-5-yl)butan-2-ol (3-3) as a white solid. LRMS m/z (M+H)+ 197.0 found, 197.1 required. the mixture was heated at 80° C. for three hours The mixture was cooled to room temperature the precipitate was filtered dried in vacuo

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

Procedure: To a solution of 1,1,1-trifluorobutan-2-one (5.0 g, 39.9 mmol) and hydroxylamine hydrochloride (3.22 g, 46.3 mmol) in water (28 mL) was added a solution of sodium hydroxide (1.84 g, 46.0 mmol) in water (14 mL), then the mixture was brought to reflux for 4 hr. After cooling to room temperature, the mixture was extracted with dichloromethane (3×50 mL) and the combined organic layers were washed with water, brine, then dried over anhydrous sodium sulfate. Filtration and concentration then distillation using a 10 cm Vigreux column (b.p. 123-124° C.) afforded (E)-1,1,1-trifluorobutan-2-one oxime (2.50 g, 44.5% yield) as a clear liquid. 1H NMR (400 MHz, CDCl3): 9.18 (br s, 1H), 2.52 (q, 2H), 1.21 (t, 3H). to reflux for 4 hr the mixture was extracted with dichloromethane (3×50 mL) the combined organic layers were washed with water, brine dried over anhydrous sodium sulfate Filtration and concentration distillation

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

Procedure: To a suspension of 5.6 g of sodium hydride (60% in oil) in 500 ml of tetrahydrofuran was added dropwise 31.6 g of ethyl diethylphosphonoacetate under ice-cooling. After the mixture was stirred at the same temperature for 10 minutes, the a solution of 1,1,1-trifluoro-2-butanone in diethyl ether obtained in Step 1 was added dropwise thereto. The mixture was stirred at the same temperature for 1 hour, and then warmed to nearly room temperature. To the reaction mixture was added 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain crude ethyl 3-trifluoromethyl-2-pentenoate. cooling The mixture was stirred at the same temperature for 1 hour extracted with ethyl acetate The organic layer was dried over anhydrous magnesium sulfate concentrated under reduced pressure

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

Procedure: To a suspension of 5.6 g of sodium hydride (60% in oil) in 500 ml of tetrahydrofuran was added dropwise 31.6 g of ethyl diethylphosphonoacetate under ice-cooling. After the mixture was stirred at the same temperature for 10 minutes, the a solution of 1,1,1-trifluoro-2-butanone in diethyl ether obtained in Step 1 was added dropwise thereto. The mixture was stirred at the same temperature for 1 hour, and then warmed to nearly room temperature. To the reaction mixture was added 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain crude ethyl 3-trifluoromethyl-2-pentenoate. cooling The mixture was stirred at the same temperature for 1 hour extracted with ethyl acetate The organic layer was dried over anhydrous magnesium sulfate concentrated under reduced pressure

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: To ethyl trifluoromethyl ketone (5.00 g, 40.0 mmol) in THF (20 ml) at room temperature was added 1-propynyl magnesium bromide (0.5 M in THF, 60 mL, 30.0 mmol). The reaction mixture was allowed to stand at rt 1 h, and concentrated in vacuo. The residue was partitioned between Et2O and aq. NH4OAc, the phases were separated, and the organic phase washed with brine, dried over MgSO4, filtered and concentrated (not to complete dryness), to afford a 50 wt. % solution (estimated by 1H NMR) of the title compound (remainder THF and Et2O), which was used without further purification. 1H NMR (400 MHz, DMSO-d6): 6.63 (s, 1H), 1.87 (s, 3H), 1.75-1.63 (m, 2H), 1.04 (t, 3H). concentrated in vacuo The residue was partitioned between Et2O and aq. NH4OAc the phases were separated the organic phase washed with brine dried over MgSO4 filtered concentrated (not to complete dryness),

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

Procedure: To ethyl trifluoromethyl ketone (5.00 g, 40.0 mmol) in THF (20 ml) at room temperature was added 1-propynyl magnesium bromide (0.5 M in THF, 60 mL, 30.0 mmol). The reaction mixture was allowed to stand at rt 1 h, and concentrated in vacuo. The residue was partitioned between Et2O and aq. NH4OAc, the phases were separated, and the organic phase washed with brine, dried over MgSO4, filtered and concentrated (not to complete dryness), to afford a 50 wt. % solution (estimated by 1H NMR) of the title compound (remainder THF and Et2O), which was used without further purification. 1H NMR (400 MHz, DMSO-d6): 6.63 (s, 1H), 1.87 (s, 3H), 1.75-1.63 (m, 2H), 1.04 (t, 3H). concentrated in vacuo The residue was partitioned between Et2O and aq. NH4OAc the phases were separated the organic phase washed with brine dried over MgSO4 filtered concentrated (not to complete dryness),

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

Procedure: To ethyl trifluoromethyl ketone (5.00 g, 40.0 mmol) in THF (20 ml) at room temperature was added 1-propynyl magnesium bromide (0.5 M in THF, 60 mL, 30.0 mmol). The reaction mixture was allowed to stand at rt 1 h, and concentrated in vacuo. The residue was partitioned between Et2O and aq. NH4OAc, the phases were separated, and the organic phase washed with brine, dried over MgSO4, filtered and concentrated (not to complete dryness), to afford a 50 wt. % solution (estimated by 1H NMR) of the title compound (remainder THF and Et2O), which was used without further purification. 1H NMR (400 MHz, DMSO-d6): 6.63 (s, 1H), 1.87 (s, 3H), 1.75-1.63 (m, 2H), 1.04 (t, 3H). concentrated in vacuo The residue was partitioned between Et2O and aq. NH4OAc the phases were separated the organic phase washed with brine dried over MgSO4 filtered concentrated (not to complete dryness),

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of trimethylsilylacetylene (6.0 g, 61.1 mmol) in THF (80 mL) cooled at −78° C., a 1.6M n-butyllithium in hexanes (38 mL, 61.1 mmol) was added dropwise. The solution was then stirred 1 hour, before a solution trifluoromethylethylketone (10 g, 79.4 mmol) in 25 mL of THF was added slowly. The reaction was stirred at −78° C. for 4 hours. The reaction was then poured into a saturated ammonium chloride solution and the aqueous layer was extracted (4×) with diethyl ether. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue obtained was used as such for the next step. 1H NMR (400 MHz, acetone-d6): 5.83 (s, 1H), 1.80 (q, 2H), 1.14 (t, 3H), 0.18 (s, 9H). was added slowly the aqueous layer was extracted (4×) with diethyl ether The combined organic layers were washed with brine dried over MgSO4 filtered concentrated under reduced pressure