1-dimethoxyphosphoryl-3,3-dimethylheptan-2-one

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of dimethyl methylphosphonate (35.0 ml) in THF (300 ml) was cooled to -78° C., to which n-butyllithium (1.6-M, 196 ml) was added dropwise. After stirring at -78° C. for one hour, a solution of ethyl 2,2-dimethylcaproate (27 g) in dry THF was added. The reaction solution was stirred at -78° C. for one hour, and then at room temperature for additional 2 hours. The reaction solution was cooled to 0° C. and acetic acid (18 ml) was added thereto. The crude product obtained after the conventional work-up was distilled under reduced pressure and the resulting fraction (>130° C.) was chromatographed to give dimethyl (3,3-dimethyl-2-oxoheptyl)phosphonate. Yield, 9.72 g (26%) was added dropwise The reaction solution was stirred at -78° C. for one hour at room temperature for additional 2 hours The reaction solution was cooled to 0° C. The crude product obtained after the conventional work-up was distilled under reduced pressure the resulting fraction (>130° C.) was chromatographed

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

Procedure: n-Butyllithium (400 ml.) is slowly added to a solution of dimethyl methylphosphonate (73.7 g.) in 1.3 l. of THF at about -66° C. To the mixture is added a solution of ethyl 2,2-dimethylhexanoate (53 g.) in 150 ml. of THF, and the resulting mixture is stirred at -70° C. for 2 hrs. Then, 46 ml. of acetic acid is added, and the mixture is concentrated under reduced pressure. The residue is mixed with portions of dichloromethane (about 1.2 l.) and water (about 150 ml.), shaken, and separated. The organic phase is dried over magnesium sulfate and concentrated. Distillation yields the title compound, 41.6 g., b.p. 117°-120° C./1 mm. at about -66° C the mixture is concentrated under reduced pressure The residue is mixed with portions of dichloromethane (about 1.2 l.) and water (about 150 ml.) separated The organic phase is dried over magnesium sulfate concentrated Distillation

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

Procedure: A solution of 18.4 g. (0.116 moles) dimethyl methylphosphonate (Aldrich) in 200 ml. dry tetrahydrofuran is cooled to -78° in a dry nitrogen at atmosphere. To the stirred phosphonate solution is added 67.3 ml. (127.8 mmoles) of 1.90 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 40 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes stirring at -78°, 10.2 g. (58.1 mmoles) methyl 2,2-dimethylhexanoate in 10 ml. of tetrahydrofuran is added dropwise at a rate that kept the reaction temperature less than - 70° (20 minutes). After 1.0 hour at -78° the reaction mixture is allowed to warm to ambient temperature, neutralized with 10 ml. acetic acid and rotary evaporated to a white gel. The gelatinous material is taken up in 75 ml. water, the aqueous phase extracted with 100 ml. portions of chloroform (3x), the combined organic extracts are backwashed (50 cc H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled (b.p. 80°-85° at 0.05 mm) to give dimethyl 2-oxo-3,3-dimethylheptylphosphonate. 70° (20 minutes) After 1.0 hour at -78° the reaction mixture is allowed acetic acid and rotary evaporated to a white gel water, the aqueous phase extracted with 100 ml dried (MgSO4) concentrated (water aspirator) to a crude residue distilled (b.p. 80°-85° at 0.05 mm)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of dimethyl methylphosphonate (35.0 ml) in THF (300 ml) was cooled to -78° C., to which n-butyllithium (1.6 -M, 196 ml) was added dropwise. After stirring at -78° C. for one hour, a solution of ethyl 2,2-dimethylcaproate (27 g) in dry THF was added. The reaction solution was stirred at -78° C. for one hour, and then at room temperature for additional 2 hours. The reaction solution was cooled to 0° C. and acetic acid (18 ml) was added thereto. The crude product obtained after the conventional work-up was distilled under reduced pressure and the resulting fraction (>130° C.) was chromatographed to give dimethyl (3,3-dimethyl-2-oxoheptyl)phosphonate. Yield, 9.72 g (26%) was added dropwise The reaction solution was stirred at -78° C. for one hour at room temperature for additional 2 hours The reaction solution was cooled to 0° C. The crude product obtained after the conventional work-up was distilled under reduced pressure the resulting fraction (>130° C.) was chromatographed

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of dimethyl methylphosphonate (35.0 ml) in THF (300 ml) was cooled to -78° C., to which n-butyllithium (1.6 -M, 196 ml) was added dropwise. After stirring at -78° C. for one hour, a solution of ethyl 2,2-dimethylcaproate (27 g) in dry THF was added. The reaction solution was stirred at -78° C. for one hour, and then at room temperature for additional 2 hours. The reaction solution was cooled to 0° C. and acetic acid (18 ml) was added thereto. The crude product obtained after the conventional work-up was distilled under reduced pressure and the resulting fraction (>130° C.) was chromatographed to give dimethyl (3,3-dimethyl-2-oxoheptyl)phosphonate. Yield, 9.72 g (26%) was added dropwise The reaction solution was stirred at -78° C. for one hour at room temperature for additional 2 hours The reaction solution was cooled to 0° C. The crude product obtained after the conventional work-up was distilled under reduced pressure the resulting fraction (>130° C.) was chromatographed

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of dimethyl methylphosphonate (35.0 ml) in THF (300 ml) was cooled to -78° C., to which n-butyllithium (1.6 - M, 196 ml) was added dropwise. After stirring at -78° C. for one hour, a solution of ethyl 2,2-dimethylcaproate (27 g) in dry TEF was added. The reaction solution was stirred at -78° C. for one hour, and then at room temperature for additional 2 hours. The reaction solution was cooled to 0° C. and acetic acid (18 ml) was added thereto. The crude product obtained after the conventional work-up was distilled under reduced pressure and the resulting fraction (>130° C.) was chromatographed to give dimethyl (3,3-dimethyl-2-oxoheptyl)phosphonate. Yield, 9.72g (26%) was added dropwise The reaction solution was stirred at -78° C. for one hour at room temperature for additional 2 hours The reaction solution was cooled to 0° C. The crude product obtained after the conventional work-up was distilled under reduced pressure the resulting fraction (>130° C.) was chromatographed

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

Procedure: n-Butyllithium (400 ml.) is added slowly to a solution of dimethyl methylphosphonate (73.7 g.) in 1.3 l. of THF at about -66° C. To the mixture is added a solution of ethyl 2,2-dimethylhexanoate (53 g.) in 150 ml. of THF, and the resulting mixture is stirred at -70° C. for 2 hrs. Then, 46 ml. of acetic acid is added, and the mixture is concentrated under reduced pressure. The residue is mixed with portions of dichloromethane (about 1.2 l.) and water (about 150 ml.), shaken, and separated. The organic phase is dried over magnesium sulfate and concentrated. Distillation yields the title compound, 41.6 g., b.p. 117°-120° C./1 mm. at about -66° C the mixture is concentrated under reduced pressure The residue is mixed with portions of dichloromethane (about 1.2 l.) and water (about 150 ml.) separated The organic phase is dried over magnesium sulfate concentrated Distillation

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dimethyl methylphosphonate (9.92 g, 0.08 mol) was dissolved in 60 ml anhydrous THF under argon atmosphere. To the mixture stirred at -78° C. was added drowise n-butyl lithium 1.62N, 49.5 ml, 0.08 mol) over a period of 30 minutes, and then a solution of 2,2-dimethylhexanoic acid methyl ester (5.0 g, 0.032 mol) in 10 ml anhydrous THF was added over a period of 30 minutes. The reaction mixture was warmed to room temperature. Acetic acid (5 ml) and water (10 ml) were added to the reaction mixture cooled with ice bath. After concentration, 20 ml water was added to the residue and the mixture was extracted with ethyl acetate (50 ml×2). The ethyl acetate layers were washed with water (20 ml×1) and with brine (20 ml×1), dried over anhydrous sodium sulfate, and concentrated. Distillation of the residue gave dimethyl 3,3-dimethyl-2-oxoheptylphosphonate (4.74 g, 0.019 mol, yield 59.3%, b.p.=108°-111° C./0.2 mmHg) as a colorless clear oil. The structure of this product was confirmed by the following data. The reaction mixture was warmed to room temperature cooled with ice bath After concentration, 20 ml water was added to the residue the mixture was extracted with ethyl acetate (50 ml×2) The ethyl acetate layers were washed with water (20 ml×1) and with brine (20 ml×1) dried over anhydrous sodium sulfate concentrated Distillation of the residue