2,2-difluorocyclopropane-1-carbaldehyde

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: At −78° C., 1.87 ml (1.87 mmol) of bis(trimethylsilyl)lithium amide (1M in THF) were added dropwise to a solution of 500 mg (1.33 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in 10 ml of THF, and the mixture was stirred for another 10 min 488 mg (4.60 mmol) of 2,2-difluorocyclopropanecarbaldehyde were then added, and after a further 10 min the mixture was warmed to −20° C. After 3 h at −20° C., the reaction was terminated by addition of 30 ml of saturated aqueous ammonium chloride solution and the reaction mixture was extracted three times with 20 ml of ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The residue was taken up in a little dichloromethane and purified by flash chromatography (24 g silica cartridge, 35 ml/min, cyclohexane/ethyl acetate gradient). Yield: 240 mg (purity 78%, 30% of theory) were then added the reaction was terminated by addition of 30 ml of saturated aqueous ammonium chloride solution the reaction mixture was extracted three times with 20 ml of ethyl acetate The combined organic phases were washed with saturated aqueous sodium chloride solution dried over magnesium sulphate filtered the solvent was removed under reduced pressure purified by flash chromatography (24 g silica cartridge, 35 ml/min, cyclohexane/ethyl acetate gradient)

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: At −78° C., 1.87 ml (1.87 mmol) of bis(trimethylsilyl)lithium amide (1M in THF) were added dropwise to a solution of 500 mg (1.33 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in 10 ml of THF, and the mixture was stirred for another 10 min 488 mg (4.60 mmol) of 2,2-difluorocyclopropanecarbaldehyde were then added, and after a further 10 min the mixture was warmed to −20° C. After 3 h at −20° C., the reaction was terminated by addition of 30 ml of saturated aqueous ammonium chloride solution and the reaction mixture was extracted three times with 20 ml of ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The residue was taken up in a little dichloromethane and purified by flash chromatography (24 g silica cartridge, 35 ml/min, cyclohexane/ethyl acetate gradient). Yield: 240 mg (purity 78%, 30% of theory) were then added the reaction was terminated by addition of 30 ml of saturated aqueous ammonium chloride solution the reaction mixture was extracted three times with 20 ml of ethyl acetate The combined organic phases were washed with saturated aqueous sodium chloride solution dried over magnesium sulphate filtered the solvent was removed under reduced pressure purified by flash chromatography (24 g silica cartridge, 35 ml/min, cyclohexane/ethyl acetate gradient)

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

Procedure: To a solution of diethyl cyanomethylphosphonate (4.09 g; 23.1 mmol) in dry THF (200 mL) at 0° C. under nitrogen was added potassium t-butoxide (23.1 mmol; 1M solution in THF). The mixture was stirred for 1 hour. The solution of 2,2-difluorocyclopropanecarbaldehyde from Step A was added and the mixture was stirred while allowing to warm to ambient temperature. A portion of the solvent was removed under reduced pressure and the remaining solution was diluted with ammonium chloride solution (50 mL). The mixture was extracted into ethyl acetate (2×50 mL). The combined extracts were dried (magnesium sulfate and sodium sulfate), filtered and evaporated under reduced pressure. The material was purified by chromatography on silica gel, eluting with hexane/ethyl acetate (3:1) to give 3-(2,2-difluorocyclopropyl)acrylonitrile (0.50 g) as a pale yellow oil (containing some ethyl acetate). the mixture was stirred A portion of the solvent was removed under reduced pressure the remaining solution was diluted with ammonium chloride solution (50 mL) The mixture was extracted into ethyl acetate (2×50 mL) The combined extracts were dried (magnesium sulfate and sodium sulfate) filtered evaporated under reduced pressure The material was purified by chromatography on silica gel eluting with hexane/ethyl acetate (3:1)

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: At −78° C., 1.87 ml (1.87 mmol) of bis(trimethylsilyl)lithium amide (1M in THF) were added dropwise to a solution of 500 mg (1.33 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in 10 ml of THF, and the mixture was stirred for another 10 min 488 mg (4.60 mmol) of 2,2-difluorocyclopropanecarbaldehyde were then added, and after a further 10 min the mixture was warmed to −20° C. After 3 h at −20° C., the reaction was terminated by addition of 30 ml of saturated aqueous ammonium chloride solution and the reaction mixture was extracted three times with 20 ml of ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The residue was taken up in a little dichloromethane and purified by flash chromatography (24 g silica cartridge, 35 ml/min, cyclohexane/ethyl acetate gradient). Yield: 240 mg (purity 78%, 30% of theory) were then added the reaction was terminated by addition of 30 ml of saturated aqueous ammonium chloride solution the reaction mixture was extracted three times with 20 ml of ethyl acetate The combined organic phases were washed with saturated aqueous sodium chloride solution dried over magnesium sulphate filtered the solvent was removed under reduced pressure purified by flash chromatography (24 g silica cartridge, 35 ml/min, cyclohexane/ethyl acetate gradient)