2,2,2-trifluoroethyl trichloromethanesulfonate

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

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

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

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-(2-morpholinylmethyl)-5H-dibenz[b,f]azepine (0.23 g) in tetrahydrofuran was added sodium amide (0.063 g). The resulting mixture was stirred at 40° C for 30 minutes. To the reaction mixture was added trifluoroethyl trichloromethylsulfonate (0.265 g) in tetrahydrofuran at room temperature. The resulting mixture was stirred at 50° C for 5 hours. After cooling, the reaction mixture was admixed with water and extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over anhydrous sodium sulfate and evaporated to afford 5-(4-trifluoroethyl-2-morpholinylmethyl)-5H-dibenz[b,f]azepine. M.P. 97°-98° C. The resulting mixture was stirred at 50° C for 5 hours After cooling extracted with ethyl acetate The ethyl acetate extract was washed with water dried over anhydrous sodium sulfate evaporated

Conditions: temp:-35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (60% dispersion in mineral oil; 180 mg, 4.43 mmol) was added to a solution of benzyl 6-[(tert-butoxycarbonyl)amino]-5-oxo-1,4-diazepane-1-carboxylate (1.34 g, 3.69 mmol) in N,N-dimethylformamide (25 mL) at −35° C. After 15 min, 2,2,2-trifluoroethyl trichloromethanesulfonate (0.911 mL, 5.54 mmol) was added and the reaction was stirred at −35° C. After 2 h, an additional amount of sodium hydride (100 mg, 2.5 mmol) and trichloromethanesulfonate (0.500 mL, 3.04 mmol) were added. After 18 h, the reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was washed with water (3×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (hexanes→30% ethyl acetate/hexanes) gave the title compound (690 mg). MS 446 (M+1). After 2 h After 18 h the reaction was quenched with water the mixture was extracted with ethyl acetate The organic layer was washed with water (3×), saturated brine dried over magnesium sulfate filtered concentrated Purification by silica gel chromatography (hexanes→30% ethyl acetate/hexanes)

Conditions: temp:-35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (60% dispersion in mineral oil; 180 mg, 4.43 mmol) was added to a solution of benzyl 6-[(tert-butoxycarbonyl)amino]-5-oxo-1,4-diazepane-1-carboxylate (1.34 g, 3.69 mmol) in N,N-dimethylformamide (25 mL) at −35° C. After 15 min, 2,2,2-trifluoroethyl trichloromethanesulfonate (0.911 mL, 5.54 mmol) was added and the reaction was stirred at −35° C. After 2 h, an additional amount of sodium hydride (100 mg, 2.5 mmol) and trichloromethanesulfonate (0.500 mL, 3.04 mmol) were added. After 18 h, the reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was washed with water (3×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (hexanes→30% ethyl acetate/hexanes) gave the title compound (690 mg). MS 446 (M+1). After 2 h After 18 h the reaction was quenched with water the mixture was extracted with ethyl acetate The organic layer was washed with water (3×), saturated brine dried over magnesium sulfate filtered concentrated Purification by silica gel chromatography (hexanes→30% ethyl acetate/hexanes)

Conditions: temp:-35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (60% dispersion in mineral oil; 70.7 mg, 1.06 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxoazepan-3-ylcarbamate (301 mg, 0.884 mmol) in N,N-dimethylformamide (7 mL) at −35° C. After 15 min, 2,2,2-trifluoroethyl trichloromethanesulfonate (0.314 mL, 1.91 mmol) was added and the reaction was stirred at −35° C. After 30 min, an additional amount of sodium hydride (27 mg, 0.40 mmol) and 2,2,2-trifluoroethyl trichloromethanesulfonate (0.140 mL, 0.85 mmol) were added. After 2 h, the reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was washed with water (3×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (0% ethyl acetate/hexanes→30% ethyl acetate/hexanes) gave the title compound (306 mg). MS 423 (M+1). After 30 min After 2 h the reaction was quenched with water the mixture was extracted with ethyl acetate The organic layer was washed with water (3×), saturated brine dried over magnesium sulfate filtered concentrated Purification by silica gel chromatography (0% ethyl acetate/hexanes→30% ethyl acetate/hexanes)

Conditions: temp:-35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (60% dispersion in mineral oil; 70.7 mg, 1.06 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxoazepan-3-ylcarbamate (301 mg, 0.884 mmol) in N,N-dimethylformamide (7 mL) at −35° C. After 15 min, 2,2,2-trifluoroethyl trichloromethanesulfonate (0.314 mL, 1.91 mmol) was added and the reaction was stirred at −35° C. After 30 min, an additional amount of sodium hydride (27 mg, 0.40 mmol) and 2,2,2-trifluoroethyl trichloromethanesulfonate (0.140 mL, 0.85 mmol) were added. After 2 h, the reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was washed with water (3×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (0% ethyl acetate/hexanes→30% ethyl acetate/hexanes) gave the title compound (306 mg). MS 423 (M+1). After 30 min After 2 h the reaction was quenched with water the mixture was extracted with ethyl acetate The organic layer was washed with water (3×), saturated brine dried over magnesium sulfate filtered concentrated Purification by silica gel chromatography (0% ethyl acetate/hexanes→30% ethyl acetate/hexanes)

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

Procedure: A mixture of 15.6 (0.06 mole) of 6,7-methylenedioxy-4(1H)-quinolone-3-carboxylic acid, ethyl ester (J. Med. Chem. 11, 160 (1968)) and 1.5 g. (0.062 mole) of sodium hydride powder in 250 ml. of dimethyl formamide was heated with stirring for 0.5 hour at 80°-90° C. 2,2,2-Trifluoroethyl trichloromethanesulfonate (17.5 g. 0.62 mole) was then added dropwise. The temperature is maintained at 80°-90° for an additional 2 hours. The cooled mixture was poured into ice water and the solid product was isolated by filtration. It was recrystallized from ethanol. This product was identical to that obtained from Example 4. The temperature is maintained at 80°-90° for an additional 2 hours the solid product was isolated by filtration It was recrystallized from ethanol that obtained from Example 4

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

Procedure: A mixture of 15.6 (0.06 mole) of 6,7-methylenedioxy-4(1H)-quinolone-3-carboxylic acid, ethyl ester (J. Med. Chem. 11, 160 (1968)) and 1.5 g. (0.062 mole) of sodium hydride powder in 250 ml. of dimethyl formamide was heated with stirring for 0.5 hour at 80°-90° C. 2,2,2-Trifluoroethyl trichloromethanesulfonate (17.5 g. 0.62 mole) was then added dropwise. The temperature is maintained at 80°-90° for an additional 2 hours. The cooled mixture was poured into ice water and the solid product was isolated by filtration. It was recrystallized from ethanol. This product was identical to that obtained from Example 4. The temperature is maintained at 80°-90° for an additional 2 hours the solid product was isolated by filtration It was recrystallized from ethanol that obtained from Example 4

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

Procedure: A mixture of 7 g. (0.051 mole) of 3,4-methylenedioxyaniline, 14.5 g. (0.051 mole) 2,2,2-trifluoroethyl trichloromethanesulfonate, and 5.2 g. (0.052 mole) of triethylamine in 60 ml. of toluene was heated under reflux for 31/2 hours. The cooled mixture was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The oily residue is distilled (b.p. 1.9 mm. 103°-5°) to give pure 3,4-methylenedioxy-N-(2,2,2-trifluoroethyl)aniline. A mixture of 7 g under reflux for 31/2 hours The cooled mixture was washed with water dried over anhydrous magnesium sulfate concentrated under reduced pressure The oily residue is distilled (b.p. 1.9 mm. 103°-5°)

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

Procedure: A mixture of 7 g. (0.051 mole) of 3,4-methylenedioxyaniline, 14.5 g. (0.051 mole) 2,2,2-trifluoroethyl trichloromethanesulfonate, and 5.2 g. (0.052 mole) of triethylamine in 60 ml. of toluene was heated under reflux for 31/2 hours. The cooled mixture was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The oily residue is distilled (b.p. 1.9 mm. 103°-5°) to give pure 3,4-methylenedioxy-N-(2,2,2-trifluoroethyl)aniline. A mixture of 7 g under reflux for 31/2 hours The cooled mixture was washed with water dried over anhydrous magnesium sulfate concentrated under reduced pressure The oily residue is distilled (b.p. 1.9 mm. 103°-5°)