cyanomethyl diethyl phosphate

反应条件: temp:-14.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Diethyl cyanomethyl phosphate (745 g, 4.20 mol, 1.20 equiv) and anhydrous tetrahydrofuran (THF, 9 L) were added to a four-neck flask equipped with a thermowell, an addition funnel and the nitrogen protection tube at room temperature. The solution was cooled with an ice-methanol bath to −14° C. and a 1.0 M solution of potassium tert-butoxide (t-BuOK) in anhydrous tetrahydrofuran (THF, 3.85 L, 3.85 mol, 1.1 equiv) was added over 20 min keeping the reaction temperature below −5° C. The resulting reaction mixture was stirred for 3 h at −10° C. and a solution of 1-tert-butoxycarbonyl-3-azetidinone (600 g, 3.50 mol) in anhydrous tetrahydrofuran (THF, 2 L) was added over 2 h keeping the internal temperature below −5° C. The reaction mixture was stirred at −5 to −10° C. over 1 h and then slowly warmed up to room temperature and stirred at room temperature for overnight. The reaction mixture was then diluted with water (4.5 L) and saturated aqueous sodium chloride solution (NaCl, 4.5 L) and extracted with ethyl acetate (EtOAc, 2×9 L). The combined organic layers were washed with brine (6 L) and dried over anhydrous sodium sulfate (Na2SO4). The solvent was removed under reduced pressure and the residue was diluted with dichloromethane (CH2Cl2, 4 L) before being absorbed onto silica gel (SiO2, 1.5 Kg). The crude product, which was absorbed on silica gel, was purified by flash column chromatography (SiO2, 3.5 Kg, 0-25% EtOAc/hexanes gradient elution) to afford tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (2, 414.7 g, 679.8 g theoretical, 61% yield) as a white solid. For 2: 1H NMR (300 MHz, CDCl3) δ 5.40 (m, 1H), 4.70 (m, 2H), 4.61 (m, 2H), 1.46 (s, 9H) ppm; C10H14N2O2 (MW, 194.23), LCMS (EI) m/e 217 (M++Na). equipped with a thermowell, an addition funnel at room temperature the reaction temperature below −5° C The resulting reaction mixture the internal temperature below −5° C The reaction mixture was stirred at −5 to −10° C. over 1 h slowly warmed up to room temperature stirred at room temperature for overnight extracted with ethyl acetate (EtOAc, 2×9 L) The combined organic layers were washed with brine (6 L) dried over anhydrous sodium sulfate (Na2SO4) The solvent was removed under reduced pressure the residue was diluted with dichloromethane (CH2Cl2, 4 L) before being absorbed onto silica gel (SiO2, 1.5 Kg) The crude product, which was absorbed on silica gel was purified by flash column chromatography (SiO2, 3.5 Kg, 0-25% EtOAc/hexanes gradient elution)

反应条件: temp:-14.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Diethyl cyanomethyl phosphate (745 g, 4.20 mol, 1.20 equiv) and anhydrous tetrahydrofuran (THF, 9 L) were added to a four-neck flask equipped with a thermowell, an addition funnel and the nitrogen protection tube at room temperature. The solution was cooled with an ice-methanol bath to −14° C. and a 1.0 M solution of potassium tert-butoxide (t-BuOK) in anhydrous tetrahydrofuran (THF, 3.85 L, 3.85 mol, 1.1 equiv) was added over 20 min keeping the reaction temperature below −5° C. The resulting reaction mixture was stirred for 3 h at −10° C. and a solution of 1-tert-butoxycarbonyl-3-azetidinone (600 g, 3.50 mol) in anhydrous tetrahydrofuran (THF, 2 L) was added over 2 h keeping the internal temperature below −5° C. The reaction mixture was stirred at −5 to −10° C. over 1 h and then slowly warmed up to room temperature and stirred at room temperature for overnight. The reaction mixture was then diluted with water (4.5 L) and saturated aqueous sodium chloride solution (NaCl, 4.5 L) and extracted with ethyl acetate (EtOAc, 2×9 L). The combined organic layers were washed with brine (6 L) and dried over anhydrous sodium sulfate (Na2SO4). The solvent was removed under reduced pressure and the residue was diluted with dichloromethane (CH2Cl2, 4 L) before being absorbed onto silica gel (SiO2, 1.5 Kg). The crude product, which was absorbed on silica gel, was purified by flash column chromatography (SiO2, 3.5 Kg, 0-25% EtOAc/hexanes gradient elution) to afford tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (2, 414.7 g, 679.8 g theoretical, 61% yield) as a white solid. For 2: 1H NMR (300 MHz, CDCl3) δ 5.40 (m, 1H), 4.70 (m, 2H), 4.61 (m, 2H), 1.46 (s, 9H) ppm; C10H14N2O2 (MW, 194.23), LCMS (EI) m/e 217 (M++Na). equipped with a thermowell, an addition funnel at room temperature the reaction temperature below −5° C The resulting reaction mixture the internal temperature below −5° C The reaction mixture was stirred at −5 to −10° C. over 1 h slowly warmed up to room temperature stirred at room temperature for overnight extracted with ethyl acetate (EtOAc, 2×9 L) The combined organic layers were washed with brine (6 L) dried over anhydrous sodium sulfate (Na2SO4) The solvent was removed under reduced pressure the residue was diluted with dichloromethane (CH2Cl2, 4 L) before being absorbed onto silica gel (SiO2, 1.5 Kg) The crude product, which was absorbed on silica gel was purified by flash column chromatography (SiO2, 3.5 Kg, 0-25% EtOAc/hexanes gradient elution)

反应条件: temp:-14.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Diethyl cyanomethyl phosphate (745 g, 4.20 mol, 1.20 equiv) and anhydrous tetrahydrofuran (THF, 9 L) were added to a four-neck flask equipped with a thermowell, an addition funnel and the nitrogen protection tube at room temperature. The solution was cooled with an ice-methanol bath to −14° C. and a 1.0 M solution of potassium tert-butoxide (t-BuOK) in anhydrous tetrahydrofuran (THF, 3.85 L, 3.85 mol, 1.1 equiv) was added over 20 min keeping the reaction temperature below −5° C. The resulting reaction mixture was stirred for 3 h at −10° C. and a solution of 1-tert-butoxycarbonyl-3-azetidinone (600 g, 3.50 mol) in anhydrous tetrahydrofuran (THF, 2 L) was added over 2 h keeping the internal temperature below −5° C. The reaction mixture was stirred at −5 to −10° C. over 1 h and then slowly warmed up to room temperature and stirred at room temperature for overnight. The reaction mixture was then diluted with water (4.5 L) and saturated aqueous sodium chloride solution (NaCl, 4.5 L) and extracted with ethyl acetate (EtOAc, 2×9 L). The combined organic layers were washed with brine (6 L) and dried over anhydrous sodium sulfate (Na2SO4). The solvent was removed under reduced pressure and the residue was diluted with dichloromethane (CH2Cl2, 4 L) before being absorbed onto silica gel (SiO2, 1.5 Kg). The crude product, which was absorbed on silica gel, was purified by flash column chromatography (SiO2, 3.5 Kg, 0-25% EtOAc/hexanes gradient elution) to afford tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (2, 414.7 g, 679.8 g theoretical, 61% yield) as a white solid. For 2: 1H NMR (300 MHz, CDCl3) δ 5.40 (m, 1H), 4.70 (m, 2H), 4.61 (m, 2H), 1.46 (s, 9H) ppm; C10H14N2O2 (MW, 194.23), LCMS (EI) m/e 217 (M++Na). equipped with a thermowell, an addition funnel at room temperature the reaction temperature below −5° C The resulting reaction mixture the internal temperature below −5° C The reaction mixture was stirred at −5 to −10° C. over 1 h slowly warmed up to room temperature stirred at room temperature for overnight extracted with ethyl acetate (EtOAc, 2×9 L) The combined organic layers were washed with brine (6 L) dried over anhydrous sodium sulfate (Na2SO4) The solvent was removed under reduced pressure the residue was diluted with dichloromethane (CH2Cl2, 4 L) before being absorbed onto silica gel (SiO2, 1.5 Kg) The crude product, which was absorbed on silica gel was purified by flash column chromatography (SiO2, 3.5 Kg, 0-25% EtOAc/hexanes gradient elution)