tert-butyl 2-cyanopropanoate

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

Procedure: 60.4 g (2.02 mol) of 80% strength sodium hydride in white oil are suspended in 2 liters of tetrahydrofuran and 311.8 g (2.02 mol) of tert.-butyl 2-cyanopropionate are added dropwise at 20°-30° C. During the course of 45 minutes this clear solution is added dropwise to a solution of 298 g (2.0 mol) of 3,6-dichloropyridazine and the mixture is heated under reflux for 2 hours. 317 ml of acetic acid are then added and the solvent is removed in vacuo. The residue is taken up in a mixture of 6,400 ml of acetic acid, 250 ml of acetic anhydride and 32 g of p-toluenesulfonic acid monohydrate, heated under reflux for 3 hours and again brought to dryness in vacuo. The residue is suspended in a little water, adjusted to pH 5 with sodium hydroxide solution and the water removed by evaporation. The residue is extracted hot using ethyl acetate. 99.7 g (33% of theory) of crude product are thus obtained, which can be employed for the following reaction without further processing. the mixture is heated under reflux for 2 hours the solvent is removed in vacuo The residue is taken up in a mixture of 6,400 ml of acetic acid, 250 ml of acetic anhydride and 32 g of p-toluenesulfonic acid monohydrate heated under reflux for 3 hours the water removed by evaporation The residue is extracted hot 99.7 g (33% of theory) of crude product are thus obtained which can be employed for the following reaction without further processing

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

Procedure: To a stirred slurry of sodium hydride (60% in mineral oil, 880 mg, 22 mmol) in dry N,N-dimethylformamide (100 mL) at 0° C., under nitrogen, was added dropwise cyano-methyl-acetic acid tert-butyl ester (prepared as in J. Am. Chem. Soc. 2011, 133, 8165, 3.10 g, 20 mmol). Any residual cyano-methyl-acetic acid tert-butyl ester was transferred by washing its original vessel with a little N,N-dimethylformamide and transferring to the reaction mixture. The reaction mixture was allowed to warm to ambient temperature for 40 minutes and then cooled to 0° C. 1,2-Dibromoethane (3.95 g, 1.81 mL, 21 mmol) was added dropwise via syringe pump over 30 minutes. The reaction mixture was stirred at 0° C. for a further 3 h and then allowed to warm to ambient temperature for 1 h. The mixture was poured into water and extracted with ethyl acetate (3×) and the combined organic extracts were washed with water (3×), dried over anhydrous magnesium sulfate, filtered and evaporated. To the residue was added 1,8-diazabicyclo[5.4.0]undec-7-ene (3.14 g, 3.07 mL, 20.6 mmol) and the mixture stirred and heated to 80° C. for 30 minutes and then allowed to cool. Saturated ammonium chloride solution was added and the mixture extracted with diethyl ether (2×). The organic extracts were washed with 0.5 M Hydrochloric acid, saturated sodium bicarbonate solution, saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using iso-hexanes/ethyl acetate 19:1 to afford the title compound (3.15 g, 87%) as a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 1.52 (s, 9H), 1.68 (s, 3H), 5.37 (d, J=10.0 Hz, 1H), 5.63 (d, J=17.0 Hz, 1H), 5.89 (dd, J=17.0, 10.0 Hz, 1H). by washing its original vessel with a little N,N-dimethylformamide and transferring to the reaction mixture cooled to 0° C to warm to ambient temperature for 1 h extracted with ethyl acetate (3×) the combined organic extracts were washed with water (3×) dried over anhydrous magnesium sulfate filtered evaporated the mixture stirred heated to 80° C. for 30 minutes to cool the mixture extracted with diethyl ether (2×) The organic extracts were washed with 0.5 M Hydrochloric acid, saturated sodium bicarbonate solution, saturated brine dried over anhydrous magnesium sulfate filtered evaporated The residue was purified by silica gel chromatography

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

Procedure: To a stirred slurry of sodium hydride (60% in mineral oil, 880 mg, 22 mmol) in dry N,N-dimethylformamide (100 mL) at 0° C., under nitrogen, was added dropwise cyano-methyl-acetic acid tert-butyl ester (prepared as in J. Am. Chem. Soc. 2011, 133, 8165, 3.10 g, 20 mmol). Any residual cyano-methyl-acetic acid tert-butyl ester was transferred by washing its original vessel with a little N,N-dimethylformamide and transferring to the reaction mixture. The reaction mixture was allowed to warm to ambient temperature for 40 minutes and then cooled to 0° C. 1,2-Dibromoethane (3.95 g, 1.81 mL, 21 mmol) was added dropwise via syringe pump over 30 minutes. The reaction mixture was stirred at 0° C. for a further 3 h and then allowed to warm to ambient temperature for 1 h. The mixture was poured into water and extracted with ethyl acetate (3×) and the combined organic extracts were washed with water (3×), dried over anhydrous magnesium sulfate, filtered and evaporated. To the residue was added 1,8-diazabicyclo[5.4.0]undec-7-ene (3.14 g, 3.07 mL, 20.6 mmol) and the mixture stirred and heated to 80° C. for 30 minutes and then allowed to cool. Saturated ammonium chloride solution was added and the mixture extracted with diethyl ether (2×). The organic extracts were washed with 0.5 M Hydrochloric acid, saturated sodium bicarbonate solution, saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using iso-hexanes/ethyl acetate 19:1 to afford the title compound (3.15 g, 87%) as a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 1.52 (s, 9H), 1.68 (s, 3H), 5.37 (d, J=10.0 Hz, 1H), 5.63 (d, J=17.0 Hz, 1H), 5.89 (dd, J=17.0, 10.0 Hz, 1H). by washing its original vessel with a little N,N-dimethylformamide and transferring to the reaction mixture cooled to 0° C to warm to ambient temperature for 1 h extracted with ethyl acetate (3×) the combined organic extracts were washed with water (3×) dried over anhydrous magnesium sulfate filtered evaporated the mixture stirred heated to 80° C. for 30 minutes to cool the mixture extracted with diethyl ether (2×) The organic extracts were washed with 0.5 M Hydrochloric acid, saturated sodium bicarbonate solution, saturated brine dried over anhydrous magnesium sulfate filtered evaporated The residue was purified by silica gel chromatography

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

Procedure: 60.4 g (2.02 mol) of 80% strength sodium hydride in white oil are suspended in 2 liters of tetrahydrofuran and 311.8 g (2.02 mol) of tert.-butyl 2-cyanopropionate are added dropwise at 20°-30° C. During the course of 45 minutes this clear solution is added dropwise to a solution of 298 g (2.0 mol) of 3,6-dichloropyridazine and the mixture is heated under reflux for 2 hours. 317 ml of acetic acid are then added and the solvent is removed in vacuo. The residue is taken up in a mixture of 6,400 ml of acetic acid, 250 ml of acetic anhydride and 32 g of p-toluenesulfonic acid monohydrate, heated under reflux for 3 hours and again brought to dryness in vacuo. The residue is suspended in a little water, adjusted to pH 5 with sodium hydroxide solution and the water removed by evaporation. The residue is extracted hot using ethyl acetate. 99.7 g (33% of theory) of crude product are thus obtained, which can be employed for the following reaction without further processing. the mixture is heated under reflux for 2 hours the solvent is removed in vacuo The residue is taken up in a mixture of 6,400 ml of acetic acid, 250 ml of acetic anhydride and 32 g of p-toluenesulfonic acid monohydrate heated under reflux for 3 hours the water removed by evaporation The residue is extracted hot 99.7 g (33% of theory) of crude product are thus obtained which can be employed for the following reaction without further processing