diethyl 2-methyl-2-(3-methylbut-2-enyl)propanedioate

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Palladium on carbon (4.26 g, 5%, “50% wet”, Alfa) was added to a solution of rac-2-methyl-2-(3-methyl-but-2-enyl)-malonic acid diethyl ester (12.15 g, 50.1 mmol) in ethyl acetate (225 mL) at 25° C. The atmosphere above the reaction mixture was evacuated and replaced with hydrogen from a balloon (3 cycles). The reaction mixture was then stirred under an atmosphere of hydrogen (3 balloons) at 25° C. for 21 h, and then was filtered through Celite. The filtrate was concentrated in vacuo to afford rac-2-methyl-2-(3-methyl-butyl)-malonic acid diethyl ester (11.91 g, 48.7 mmol, 98%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 0.89 (6H, d, J=7.0 Hz), 1.07-1.13 (2H, m), 1.25 (6H, t, J=6.9 Hz), 1.39 (1H, s), 1.48-1.57 (1H, m), 1.84-1.88 (1H, m), 4.13-4.21 (2H, m). The atmosphere above the reaction mixture was evacuated was filtered through Celite The filtrate was concentrated in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-methyl-malonic acid diethyl ester (20.0 g, 115 mmol) in tetrahydrofuran (50 mL) was added dropwise over 15 min to a suspension of sodium hydride (2.89 g, 120 mmol) in tetrahydrofuran (100 mL) at 0° C. The clear reaction mixture was stirred for 5 min at 0° C., then a solution of 1-bromo-3-methyl-but-2-ene (18.8 g, 126 mmol) in tetrahydrofuran (30 mL) was added over 10 min. The reaction mixture was allowed to warm to 25° C. and was stirred at that temperature for 22 h. After quenching with 1.0 M aqueous hydrochloric acid solution (20 mL), the mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash chromatography (self packed glass column, gradient elution: 5-20% ethyl acetate in hexanes) to afford rac-2-methyl-2-(3-methyl-but-2-enyl)-malonic acid diethyl ester (22.15 g, 91.4 mmol, 79%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 1.25 (6H, t, J=7.0 Hz), 1.37 (3H, s), 1.62 (3H, s), 1.69 (3H, s), 2.57 (2H, d, J=7.0 Hz), 4.17 (4H, q, J=7.0 Hz), 4.99-5.03 (1H, m). to warm to 25° C. was stirred at that temperature for 22 h After quenching with 1.0 M aqueous hydrochloric acid solution (20 mL) the mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL) The organic layers were dried over sodium sulfate were concentrated in vacuo The residue was purified by flash chromatography (self packed glass column, gradient elution: 5-20% ethyl acetate in hexanes)

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

Procedure: 85.3 g of 2-ethoxycarbonyl-2,5-dimethyl-4-hexenoic acid ethyl ester is dissolved in 645 ml of dimethyl sulfoxide and combined in succession with 29.7 g of lithium chloride and 6.3 ml of distilled water. Then the reaction mixture is heated for a total of 13 hours to 200° C. and then--after having been allowed to cool down--is poured on 1 liter of ice water. The aqueous phase is extracted three times with respectively 500 ml of methylene chloride. The combined organic extracts are then washed twice with water, dried over magnesium sulfate, concentrated with the aid of a forced-circulation evaporator, and distilled under vacuum, thus isolating 53.1 g, bp13 75°-78° C. Then the reaction mixture is heated for a total of 13 hours to 200° C. to cool down The aqueous phase is extracted three times with respectively 500 ml of methylene chloride The combined organic extracts are then washed twice with water dried over magnesium sulfate concentrated with the aid of a forced-circulation evaporator distilled under vacuum thus isolating 53.1 g, bp13 75°-78° C.

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 36.1 g of sodium (cut into small pieces) is introduced into a three-necked flask equipped with reflux condenser, dropping funnel, and agitator. To this is added 800 ml of absolute ethanol dropwise so quickly that the solution keeps boiling vigorously. To the hot alcoholate solution is added dropwise 269.6 g of freshly distilled methylmalonic acid diethyl ester, the mixture is stirred for 0.5 hour at 60° C. and then--likewise in droplet form--241.7 g of dimethylallyl bromide is added thereto. After one hour of agitation with heating, the thus-precipitated sodium bromide is removed by filtering, the precipitate is washed, and the filtrate is concentrated. The residue is taken up in ether, washed neutral with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated with the use of a forced-circulation evaporator. The evaporation residue is fractionated on an oil pump. *Yield: 266 g of the title compound, bp7 97°-112° C. equipped with reflux condenser After one hour of agitation with heating the thus-precipitated sodium bromide is removed by filtering the precipitate is washed the filtrate is concentrated washed neutral with saturated sodium chloride solution dried over magnesium sulfate concentrated with the use of a forced-circulation evaporator *Yield: 266 g of the title compound, bp7 97°-112° C.

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

Procedure: 85.3 g of 2-ethoxycarbonyl-2,5-dimethyl-4-hexenoic acid ethyl ester was dissolved in 645 ml of dimethyl sulfoxide and combined in succession with 29.7 g of lithium chloride and 6.3 ml of distilled water. The reaction mixture was thereafter heated a total of 13 hours to 200° C. and subsequently--after cooling--poured on 1 liter of ice water. The aqueous phase was extracted three times with respectively 500 ml of methylene chloride. The combined organic extracts then were washed twice with water, dried over magnesium sulfate, concentrated on a forced circulation evaporator, and distilled under vacuum, thus isolating 53.1 g, bp13 75°-78° C. The reaction mixture was thereafter heated a total of 13 hours to 200° C. subsequently--after cooling The aqueous phase was extracted three times with respectively 500 ml of methylene chloride The combined organic extracts then were washed twice with water dried over magnesium sulfate concentrated on a forced circulation evaporator distilled under vacuum thus isolating 53.1 g, bp13 75°-78° C.

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 36.1 g of sodium (cut into small pieces) was introduced into a three-necked flask equipped with reflux condenser, dropping funnel, and agitator. To this mixture was added 800 ml of absolute ethanol so quickly that the solution continued to boil vigorously. The hot alcoholate solution was combined dropwise with 269.6 g of freshly distilled methylmalonic acid diethyl ester, the mixture was stirred for 1/2 hour at 60° C. and then 241.7 g of dimethylallyl bromide was also added dropwise thereto. After one hour of agitation under heating, the thus-precipitated sodium bromide was filtered off, the precipitate was washed, and the filtrate was concentrated. The remainder was taken up in ether, washed neutral with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated on a forced circulation evaporator. The evaporation residue was fractionated on an oil pump, yielding 266 g of the title compound, bp7 97°-112° C. equipped with reflux condenser After one hour of agitation under heating the thus-precipitated sodium bromide was filtered off the precipitate was washed the filtrate was concentrated washed neutral with saturated sodium chloride solution dried over magnesium sulfate concentrated on a forced circulation evaporator

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Palladium on carbon (4.26 g, 5%, “50% wet”, Alfa) was added to a solution of rac-2-methyl-2-(3-methyl-but-2-enyl)-malonic acid diethyl ester (12.15 g, 50.1 mmol) in ethyl acetate (225 mL) at 25° C. The atmosphere above the reaction mixture was evacuated and replaced with hydrogen from a balloon (3 cycles). The reaction mixture was then stirred under an atmosphere of hydrogen (3 balloons) at 25° C. for 21 h, and then was filtered through Celite. The filtrate was concentrated in vacuo to afford rac-2-methyl-2-(3-methyl-butyl)-malonic acid diethyl ester (11.91 g, 48.7 mmol, 98%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 0.89 (6H, d, J=7.0 Hz), 1.07-1.13 (2H, m), 1.25 (6H, t, J=6.9 Hz), 1.39 (1H, s), 1.48-1.57 (1H, m), 1.84-1.88 (1H, m), 4.13-4.21 (2H, m). The atmosphere above the reaction mixture was evacuated was filtered through Celite The filtrate was concentrated in vacuo

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Palladium on carbon (4.26 g, 5%, “50% wet”, Alfa) was added to a solution of rac-2-methyl-2-(3-methyl-but-2-enyl)-malonic acid diethyl ester (12.15 g, 50.1 mmol) in ethyl acetate (225 mL) at 25° C. The atmosphere above the reaction mixture was evacuated and replaced with hydrogen from a balloon (3 cycles). The reaction mixture was then stirred under an atmosphere of hydrogen (3 balloons) at 25° C. for 21 h, and then was filtered through Celite. The filtrate was concentrated in vacuo to afford rac-2-methyl-2-(3-methyl-butyl)-malonic acid diethyl ester (11.91 g, 48.7 mmol, 98%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 0.89 (6H, d, J=7.0 Hz), 1.07-1.13 (2H, m), 1.25 (6H, t, J=6.9 Hz), 1.39 (1H, s), 1.48-1.57 (1H, m), 1.84-1.88 (1H, m), 4.13-4.21 (2H, m). The atmosphere above the reaction mixture was evacuated was filtered through Celite The filtrate was concentrated in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-methyl-malonic acid diethyl ester (20.0 g, 115 mmol) in tetrahydrofuran (50 mL) was added dropwise over 15 min to a suspension of sodium hydride (2.89 g, 120 mmol) in tetrahydrofuran (100 mL) at 0° C. The clear reaction mixture was stirred for 5 min at 0° C., then a solution of 1-bromo-3-methyl-but-2-ene (18.8 g, 126 mmol) in tetrahydrofuran (30 mL) was added over 10 min. The reaction mixture was allowed to warm to 25° C. and was stirred at that temperature for 22 h. After quenching with 1.0 M aqueous hydrochloric acid solution (20 mL), the mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash chromatography (self packed glass column, gradient elution: 5-20% ethyl acetate in hexanes) to afford rac-2-methyl-2-(3-methyl-but-2-enyl)-malonic acid diethyl ester (22.15 g, 91.4 mmol, 79%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 1.25 (6H, t, J=7.0 Hz), 1.37 (3H, s), 1.62 (3H, s), 1.69 (3H, s), 2.57 (2H, d, J=7.0 Hz), 4.17 (4H, q, J=7.0 Hz), 4.99-5.03 (1H, m). to warm to 25° C. was stirred at that temperature for 22 h After quenching with 1.0 M aqueous hydrochloric acid solution (20 mL) the mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL) The organic layers were dried over sodium sulfate were concentrated in vacuo The residue was purified by flash chromatography (self packed glass column, gradient elution: 5-20% ethyl acetate in hexanes)

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

Procedure: 85.3 g of 2-ethoxycarbonyl-2,5-dimethyl-4-hexenoic acid ethyl ester is dissolved in 645 ml of dimethyl sulfoxide and combined in succession with 29.7 g of lithium chloride and 6.3 ml of distilled water. Then the reaction mixture is heated for a total of 13 hours to 200° C. and then--after having been allowed to cool down--is poured on 1 liter of ice water. The aqueous phase is extracted three times with respectively 500 ml of methylene chloride. The combined organic extracts are then washed twice with water, dried over magnesium sulfate, concentrated with the aid of a forced-circulation evaporator, and distilled under vacuum, thus isolating 53.1 g, bp13 75°-78° C. Then the reaction mixture is heated for a total of 13 hours to 200° C. to cool down The aqueous phase is extracted three times with respectively 500 ml of methylene chloride The combined organic extracts are then washed twice with water dried over magnesium sulfate concentrated with the aid of a forced-circulation evaporator distilled under vacuum thus isolating 53.1 g, bp13 75°-78° C.

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

Procedure: 85.3 g of 2-ethoxycarbonyl-2,5-dimethyl-4-hexenoic acid ethyl ester is dissolved in 645 ml of dimethyl sulfoxide and combined in succession with 29.7 g of lithium chloride and 6.3 ml of distilled water. Then the reaction mixture is heated for a total of 13 hours to 200° C. and then--after having been allowed to cool down--is poured on 1 liter of ice water. The aqueous phase is extracted three times with respectively 500 ml of methylene chloride. The combined organic extracts are then washed twice with water, dried over magnesium sulfate, concentrated with the aid of a forced-circulation evaporator, and distilled under vacuum, thus isolating 53.1 g, bp13 75°-78° C. Then the reaction mixture is heated for a total of 13 hours to 200° C. to cool down The aqueous phase is extracted three times with respectively 500 ml of methylene chloride The combined organic extracts are then washed twice with water dried over magnesium sulfate concentrated with the aid of a forced-circulation evaporator distilled under vacuum thus isolating 53.1 g, bp13 75°-78° C.

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 36.1 g of sodium (cut into small pieces) is introduced into a three-necked flask equipped with reflux condenser, dropping funnel, and agitator. To this is added 800 ml of absolute ethanol dropwise so quickly that the solution keeps boiling vigorously. To the hot alcoholate solution is added dropwise 269.6 g of freshly distilled methylmalonic acid diethyl ester, the mixture is stirred for 0.5 hour at 60° C. and then--likewise in droplet form--241.7 g of dimethylallyl bromide is added thereto. After one hour of agitation with heating, the thus-precipitated sodium bromide is removed by filtering, the precipitate is washed, and the filtrate is concentrated. The residue is taken up in ether, washed neutral with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated with the use of a forced-circulation evaporator. The evaporation residue is fractionated on an oil pump. *Yield: 266 g of the title compound, bp7 97°-112° C. equipped with reflux condenser After one hour of agitation with heating the thus-precipitated sodium bromide is removed by filtering the precipitate is washed the filtrate is concentrated washed neutral with saturated sodium chloride solution dried over magnesium sulfate concentrated with the use of a forced-circulation evaporator *Yield: 266 g of the title compound, bp7 97°-112° C.