Α-(三甲基硅氧基)苯乙腈

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of phenyl[(trimethylsilyl)-oxy]aceto-nitrile (13.7 g, 60.7 mmol) in anhydrous THF (140 mL) cooled in a dry ice/acetone bath, was added a THF solution of lithium bis(trimethylsilyl)amide (62 mL 1.0M) slowly over 15 minutes. The reaction mixture was stirred for 45 minutes cooling at −78° C., then a solution of 5-(bromomethyl)-1,3-difluoro-2-(methylthio)benzene (14.7 g, 58 mmol) in anhydrous THF (20 mL) was added over 10 minutes. The reaction mixture was allowed to warm to room temperature, and stirred for 18 hours. To this mixture was added 5% HCl (300 mL) and the mixture stirred for one hour. The resulting oil was extracted with ethyl acetate (1×400 mL, 2×100 mL). To the combined extracts was added 5% sodium hydroxide (200 mL), and the mixture stirred for one hour. Additional water (200 mL) was added, the organic phase was separated, and the aqueous phase extracted with ethyl acetate (2×150 mL). The combined extracts were dried using magnesium sulfate, and concentrated. Chromatography on silica gel with 15% dichloromethane in hexanes initially and eluting the product with 30% gave 2-[3,5-difluoro-4-(methylthio)phenyl]-1-phenylethanone as light yellow solid (11.0 g, 68%). MP 71.8-71.9° C. 1H NMR (CDCl3/400 MHz) 7.96-7.99 (m, 2H), 7.57-7.61 (m, 1H), 7.24-7.50 (m, 2H), 6.80-6.85 (m, 2H), 4.24 (s, 2H), 2.42 (s, 3H). HRMS m/z 279.0667 (M+H+, calcd 279.0655). Anal. Calcd for C15H12F2OS: C, 64.73; H, 4.35. Found: C, 64.70; H, 4.38. to warm to room temperature stirred for 18 hours the mixture stirred for one hour The resulting oil was extracted with ethyl acetate (1×400 mL, 2×100 mL) To the combined extracts was added 5% sodium hydroxide (200 mL) the mixture stirred for one hour Additional water (200 mL) was added the organic phase was separated the aqueous phase extracted with ethyl acetate (2×150 mL) The combined extracts were dried concentrated Chromatography on silica gel with 15% dichloromethane in hexanes initially and eluting the product with 30%

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of phenyl[(trimethylsilyl)-oxy]aceto-nitrile (13.7 g, 60.7 mmol) in anhydrous THF (140 mL) cooled in a dry ice/acetone bath, was added a THF solution of lithium bis(trimethylsilyl)amide (62 mL 1.0M) slowly over 15 minutes. The reaction mixture was stirred for 45 minutes cooling at −78° C., then a solution of 5-(bromomethyl)-1,3-difluoro-2-(methylthio)benzene (14.7 g, 58 mmol) in anhydrous THF (20 mL) was added over 10 minutes. The reaction mixture was allowed to warm to room temperature, and stirred for 18 hours. To this mixture was added 5% HCl (300 mL) and the mixture stirred for one hour. The resulting oil was extracted with ethyl acetate (1×400 mL, 2×100 mL). To the combined extracts was added 5% sodium hydroxide (200 mL), and the mixture stirred for one hour. Additional water (200 mL) was added, the organic phase was separated, and the aqueous phase extracted with ethyl acetate (2×150 mL). The combined extracts were dried using magnesium sulfate, and concentrated. Chromatography on silica gel with 15% dichloromethane in hexanes initially and eluting the product with 30% gave 2-[3,5-difluoro-4-(methylthio)phenyl]-1-phenylethanone as light yellow solid (11.0 g, 68%). MP 71.8-71.9° C. 1H NMR (CDCl3/400 MHz) 7.96-7.99 (m, 2H), 7.57-7.61 (m, 1H), 7.24-7.50 (m, 2H), 6.80-6.85 (m, 2H), 4.24 (s, 2H), 2.42 (s, 3H). HRMS m/z 279.0667 (M+H+, calcd 279.0655). Anal. Calcd for C15H12F2OS: C, 64.73; H, 4.35. Found: C, 64.70; H, 4.38. to warm to room temperature stirred for 18 hours the mixture stirred for one hour The resulting oil was extracted with ethyl acetate (1×400 mL, 2×100 mL) To the combined extracts was added 5% sodium hydroxide (200 mL) the mixture stirred for one hour Additional water (200 mL) was added the organic phase was separated the aqueous phase extracted with ethyl acetate (2×150 mL) The combined extracts were dried concentrated Chromatography on silica gel with 15% dichloromethane in hexanes initially and eluting the product with 30%

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a cold (−78° C.) freshly-prepared solution of lithium diisopropylamide (2.62 mmol) in THF (5 mL) was added a solution of 2-phenyl-2-(trimethylsilyloxy)acetonitrile (0.5 ml, 2.382 mmol) in THF (4 mL). The solution was stirred for 2 hours, and a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (554 mg, 2.382 mmol) in THF (3 mL) was added dropwise. The cold bath was removed, and the reaction warmed to room temperature. The reaction mixture was quenched by the addition of saturated sodium bicarbonate solution (15 mL) and ethyl acetate (15 mL). The layers were separated, and the aqueous extracted with addition ethyl acetate. The combined organics were dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in THF (15 mL), and a solution of tetrabutyl ammonium fluoride (3.0 mmol, 3.0 mL, 1 M in THF) was added. The reaction mixture was stirred for 1 hour, and quenched by the addition of saturated sodium bicarbonate solution (15 mL) and ethyl acetate (15 mL). The layers were separated, and the aqueous layer extracted with addition ethyl acetate. The combined organics were dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with a gradient of hexane to 30% ethyl acetate in hexane, to give the title compound. MS ESI(+) m/z 302.9 [M+H]+. The cold bath was removed The reaction mixture was quenched by the addition of saturated sodium bicarbonate solution (15 mL) and ethyl acetate (15 mL) The layers were separated the aqueous extracted with addition ethyl acetate The combined organics were dried with anhydrous sodium sulfate filtered concentrated under reduced pressure The residue was dissolved in THF (15 mL) The reaction mixture was stirred for 1 hour quenched by the addition of saturated sodium bicarbonate solution (15 mL) and ethyl acetate (15 mL) The layers were separated the aqueous layer extracted with addition ethyl acetate The combined organics were dried with anhydrous sodium sulfate filtered concentrated under reduced pressure The residue was purified by chromatography on silica gel eluting with a gradient of hexane to 30% ethyl acetate in hexane

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a cold (−78° C.) freshly-prepared solution of lithium diisopropylamide (2.62 mmol) in THF (5 mL) was added a solution of 2-phenyl-2-(trimethylsilyloxy)acetonitrile (0.5 ml, 2.382 mmol) in THF (4 mL). The solution was stirred for 2 hours, and a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (554 mg, 2.382 mmol) in THF (3 mL) was added dropwise. The cold bath was removed, and the reaction warmed to room temperature. The reaction mixture was quenched by the addition of saturated sodium bicarbonate solution (15 mL) and ethyl acetate (15 mL). The layers were separated, and the aqueous extracted with addition ethyl acetate. The combined organics were dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in THF (15 mL), and a solution of tetrabutyl ammonium fluoride (3.0 mmol, 3.0 mL, 1 M in THF) was added. The reaction mixture was stirred for 1 hour, and quenched by the addition of saturated sodium bicarbonate solution (15 mL) and ethyl acetate (15 mL). The layers were separated, and the aqueous layer extracted with addition ethyl acetate. The combined organics were dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with a gradient of hexane to 30% ethyl acetate in hexane, to give the title compound. MS ESI(+) m/z 302.9 [M+H]+. The cold bath was removed The reaction mixture was quenched by the addition of saturated sodium bicarbonate solution (15 mL) and ethyl acetate (15 mL) The layers were separated the aqueous extracted with addition ethyl acetate The combined organics were dried with anhydrous sodium sulfate filtered concentrated under reduced pressure The residue was dissolved in THF (15 mL) The reaction mixture was stirred for 1 hour quenched by the addition of saturated sodium bicarbonate solution (15 mL) and ethyl acetate (15 mL) The layers were separated the aqueous layer extracted with addition ethyl acetate The combined organics were dried with anhydrous sodium sulfate filtered concentrated under reduced pressure The residue was purified by chromatography on silica gel eluting with a gradient of hexane to 30% ethyl acetate in hexane

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a cold (−78° C.) freshly-prepared solution of lithium diisopropylamide (2.62 mmol) in THF (5 mL) was added a solution of 2-phenyl-2-(trimethylsilyloxy)acetonitrile (0.5 ml, 2.382 mmol) in THF (4 mL). The solution was stirred for 2 hours, and a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (554 mg, 2.382 mmol) in THF (3 mL) was added dropwise. The cold bath was removed, and the reaction warmed to room temperature. The reaction mixture was quenched by the addition of saturated sodium bicarbonate solution (15 mL) and ethyl acetate (15 mL). The layers were separated, and the aqueous extracted with addition ethyl acetate. The combined organics were dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in THF (15 mL), and a solution of tetrabutyl ammonium fluoride (3.0 mmol, 3.0 mL, 1 M in THF) was added. The reaction mixture was stirred for 1 hour, and quenched by the addition of saturated sodium bicarbonate solution (15 mL) and ethyl acetate (15 mL). The layers were separated, and the aqueous layer extracted with addition ethyl acetate. The combined organics were dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with a gradient of hexane to 30% ethyl acetate in hexane, to give the title compound. MS ESI(+) m/z 302.9 [M+H]+. The cold bath was removed The reaction mixture was quenched by the addition of saturated sodium bicarbonate solution (15 mL) and ethyl acetate (15 mL) The layers were separated the aqueous extracted with addition ethyl acetate The combined organics were dried with anhydrous sodium sulfate filtered concentrated under reduced pressure The residue was dissolved in THF (15 mL) The reaction mixture was stirred for 1 hour quenched by the addition of saturated sodium bicarbonate solution (15 mL) and ethyl acetate (15 mL) The layers were separated the aqueous layer extracted with addition ethyl acetate The combined organics were dried with anhydrous sodium sulfate filtered concentrated under reduced pressure The residue was purified by chromatography on silica gel eluting with a gradient of hexane to 30% ethyl acetate in hexane

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of phenyl[(trimethylsilyl)-oxy]aceto-nitrile (13.7 g, 60.7 mmol) in anhydrous THF (140 mL) cooled in a dry ice/acetone bath, was added a ThF solution of lithium bis(trimethylsilyl)amide(62 mL 1.0 M) slowly over 15 minutes. The reaction mixture was stirred for 45 minutes cooling at −78° C., then a solution of 5-(bromomethyl)-1,3-difluoro-2-(methylthio)benzene (14.7 g, 58 mmol) in anhydrous THF (20 mL) was added over 10 minutes. The reaction mixture was allowed to warm to room temperature, and stirred for 18 hours. To this mixture was added 5% HCl (300 mL) and the mixture stirred for one hour. The resulting oil was extracted with ethyl acetate (1×400 mL, 2×100 mL). To the combined extracts was added 5% sodium hydroxide (200 mL), and the mixture stirred for one hour. Additional water (200 mL) was added, the organic phase was separated, and the aqueous phase extracted with ethyl acetate (2×150 mL). The combined extracts were dried using magnesium sulfate, and concentrated. Chromatography on silica gel with 15% dichloromethane in hexanes initially and eluting the product with 30% gave 2-[3,5-difluoro-4-(methylthio)phenyl]-1-phenylethanone as light yelow solid (11.0 g, 68%). MP 71.8-71.9° C. 1H NMR (CDCl3/400 MHz) 7.96-7.99 (m, 2H), 7.57-7.61 (m, 1H), 7.24-7.50 (m, 2H), 6.80-6.85 (m, 2H), 4.24 (s, 2H), 2.42 (s, 3H). HRMS m/z 279.0667 (M+H+, calcd 279.0655). Anal. Calcd for C15H12F2OS: C, 64.73; H, 4.35; Found: C, 64.70; H, 4.38. to warm to room temperature stirred for 18 hours the mixture stirred for one hour The resulting oil was extracted with ethyl acetate (1×400 mL, 2×100 mL) To the combined extracts was added 5% sodium hydroxide (200 mL) the mixture stirred for one hour Additional water (200 mL) was added the organic phase was separated the aqueous phase extracted with ethyl acetate (2×150 mL) The combined extracts were dried concentrated Chromatography on silica gel with 15% dichloromethane in hexanes initially and eluting the product with 30%

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of phenyl[(trimethylsilyl)-oxy]aceto-nitrile (13.7 g, 60.7 mmol) in anhydrous THF (140 mL) cooled in a dry ice/acetone bath, was added a THF solution of lithium bis(trimethylsilyl)amide (62 mL 1.0M) slowly over 15 minutes. The reaction mixture was stirred for 45 minutes cooling at −78° C., then a solution of 5-(bromomethyl)-1,3-difluoro-2-(methylthio)benzene (14.7 g, 58 mmol) in anhydrous THF (20 mL) was added over 10 minutes. The reaction mixture was allowed to warm to room temperature, and stirred for 18 hours. To this mixture was added 5% HCl (300 mL) and the mixture stirred for one hour. The resulting oil was extracted with ethyl acetate (1×400 mL, 2×100 mL). To the combined extracts was added 5% sodium hydroxide (200 mL), and the mixture stirred for one hour. Additional water (200 mL) was added, the organic phase was separated, and the aqueous phase extracted with ethyl acetate (2×150 mL). The combined extracts were dried using magnesium sulfate, and concentrated. Chromatography on silica gel with 15% dichloromethane in hexanes initially and eluting the product with 30% gave 2-[3,5-difluoro-4-(methylthio)phenyl]-1-phenylethanone as light yellow solid (11.0 g, 68%). MP 71.8-71.9° C. 1H NMR (CDCl3/400 MHz) 7.96-7.99 (m, 2H), 7.57-7.61 (m, 1H), 7.24-7.50 (m, 2H), 6.80-6.85 (m, 2H), 4.24 (s, 2H), 2.42 (s, 3H). HRMS m/z 279.0667 (M+H+, calcd 279.0655). Anal. Calcd for C15H12F2OS: C, 64.73; H, 4.35. Found: C, 64.70; H, 4.38. to warm to room temperature stirred for 18 hours the mixture stirred for one hour The resulting oil was extracted with ethyl acetate (1×400 mL, 2×100 mL) To the combined extracts was added 5% sodium hydroxide (200 mL) the mixture stirred for one hour Additional water (200 mL) was added the organic phase was separated the aqueous phase extracted with ethyl acetate (2×150 mL) The combined extracts were dried concentrated Chromatography on silica gel with 15% dichloromethane in hexanes initially and eluting the product with 30%