1-dimethoxyphosphoryl-3-methylhept-5-yn-2-one

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

Procedure: A solution of dimethyl methylphosphonate (22.47 g, 181.24 mmol) in 260 ml of tetrahydrofuran is cooled to -78° C. and treated dropwise with n-butyllithium (113 ml, 181.24 mmol), 1.6M in hexane) over a 25-minute period. The mixture is stirred an additional 30 minutes at -78° C., then treated dropwise with 2-methyl-4-hexynoic acid methyl ester (7.25 g, 51.78 mmols) in 65 ml of tetrahydrofuran over a period of 10 minutes. The contents are stirred for another 3 hours at -78° C. and then 17 hours at ambient temperature. The reaction mixture is cooled to 8° C., treated with 14 ml of acetic acid, stirred at ambient temperature for 30 minutes, then concentrated in vacuo. The residue is treated with 100 ml of saturated brine and 100 ml of ice water to form a slurry and extracted 3 times with ether (1400 ml total) and once with 250 ml of ethyl acetate-ether (1:1). The combined organic extracts are washed with saturated brine (2×75 ml), the combined aqueous washings extracted with ethyl acetate-ether (1:1, 1×100 ml) and dried over anhydrous sodium sulfate, and concentrated at reduced pressure. Vacuum distillation gives 10.21 g of the title product, m.p. 121°-125° C., 0.15 mmHg. The contents are stirred for another 3 hours at -78° C. 17 hours at ambient temperature The reaction mixture is cooled to 8° C. stirred at ambient temperature for 30 minutes concentrated in vacuo The residue is treated with 100 ml of saturated brine and 100 ml of ice water to form a slurry extracted 3 times with ether (1400 ml total) The combined organic extracts are washed with saturated brine (2×75 ml) the combined aqueous washings extracted with ethyl acetate-ether (1:1, 1×100 ml) dried over anhydrous sodium sulfate concentrated at reduced pressure Vacuum distillation

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

Procedure: A solution of dimethyl methylphosphonate (22.47 g, 181.24 mmol) in 260 ml of tetrahydrofuran is cooled to -78° C. and treated dropwise with n-butyllithium (113 ml, 181.24 mmol), 1.6M in hexane) over a 25-minute period. The mixture is stirred an additional 30 minutes at -78° C., then treated dropwise with 2-methyl-4-hexynoic acid methyl ester (7.25 g, 51.78 mmols) in 65 ml of tetrahydrofuran over a period of 10 minutes. The contents are stirred for another 3 hours at -78° C. and then 17 hours at ambient temperature. The reaction mixture is cooled to 8° C., treated with 14 ml of acetic acid, stirred at ambient temperature for 30 minutes, then concentrated in vacuo. The residue is treated with 100 ml of saturated brine and 100 ml of ice water to form a slurry and extracted 3 times with ether (1400 ml total) and once with 250 ml of ethyl acetate-ether (1:1). The combined organic extracts are washed with saturated brine (2×75 ml), the combined aqueous washings extracted with ethyl acetate-ether (1:1, 1×100 ml) and dried over anhydrous sodium sulfate, and concentrated at reduced pressure. Vacuum distillation gives 10.21 g of the title product, m.p. 121°-125° C., 0.15 mmHg. The contents are stirred for another 3 hours at -78° C. 17 hours at ambient temperature The reaction mixture is cooled to 8° C. stirred at ambient temperature for 30 minutes concentrated in vacuo The residue is treated with 100 ml of saturated brine and 100 ml of ice water to form a slurry extracted 3 times with ether (1400 ml total) The combined organic extracts are washed with saturated brine (2×75 ml) the combined aqueous washings extracted with ethyl acetate-ether (1:1, 1×100 ml) dried over anhydrous sodium sulfate concentrated at reduced pressure Vacuum distillation

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

Procedure: To a solution of dimethyl 3-methyl-2-oxo-5-heptynylphosphonate (10.0 g, 0.043 mol) in ethyl acetate (100 ml) was added 10% palladium on active carbon (5.0 g) and the mixture was stirred under hydrogen atmosphere for one hour. The reaction mixture was filtered and the filtrate was concentrated. The residue was distilled under reduced pressure to give colorless oily product dimethyl 3-methyl-2-oxo-heptylphosphonate (8.12 g, 0.034 mol, 80%, b.p. 90°-92° C./0.05 mmHg). The structure was identified by the following data. The reaction mixture was filtered the filtrate was concentrated The residue was distilled under reduced pressure

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

Procedure: A solution of dimethyl methylphosphonate (22.47 g, 181.24 mmol) in 260 ml of tetrahydrofuran is cooled to -78° C. and treated dropwise with n-butyllithium (113 ml, 181.24 mmol), 1.6 M in hexane) over a 25-minute period. The mixture is stirred an additional 30 minutes at -78° C., then treated dropwise with 2-methyl-4-hexynoic acid methyl ester (7.25 g, 51.78 mmols) in 65 ml of tetrahydrofuran over a period of 10 minutes. The contents are stirred for another 3 hours at -78° C. and then 17 hours at ambient temperature. The reaction mixture is cooled to 8° C., treated with 14 ml of acetic acid, stirred at ambient temperature for 30 minutes, then concentrated in vacuo. The residue is treated with 100 ml of saturated brine and 100 ml of ice water to form a slurry and extracted 3 times with ether (1400 ml total) and once with 250 ml of ethyl acetate-ether (1:1). The combined organic extracts are washed with saturated brine (2×75 ml), the combined aqueous washings extracted with ethyl acetate-ether (1:1, 1×100 ml) and dried over anhydrous sodium sulfate, and concentrated at reduced pressure. Vacuum distillation gives 10.21 g of the title product, m.p. 121°-125° C., 0.15 mmHg. The contents are stirred for another 3 hours at -78° C. 17 hours at ambient temperature The reaction mixture is cooled to 8° C. stirred at ambient temperature for 30 minutes concentrated in vacuo The residue is treated with 100 ml of saturated brine and 100 ml of ice water to form a slurry extracted 3 times with ether (1400 ml total) The combined organic extracts are washed with saturated brine (2×75 ml) the combined aqueous washings extracted with ethyl acetate-ether (1:1, 1×100 ml) dried over anhydrous sodium sulfate concentrated at reduced pressure Vacuum distillation

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

Procedure: A solution of dimethyl methylphosphonate (22.47 g, 181.24 mmol) in 260 ml of tetrahydrofuran is cooled to -78° C. and treated dropwise with n-butyllithium (113 ml, 181.24 mmol), 1.6 M in hexane) over a 25-minute period. The mixture is stirred an additional 30 minutes at -78° C., then treated dropwise with 2-methyl-4-hexynoic acid methyl ester (7.25 g, 51.78 mmols) in 65 ml of tetrahydrofuran over a period of 10 minutes. The contents are stirred for another 3 hours at -78° C. and then 17 hours at ambient temperature. The reaction mixture is cooled to 8° C., treated with 14 ml of acetic acid, stirred at ambient temperature for 30 minutes, then concentrated in vacuo. The residue is treated with 100 ml of saturated brine and 100 ml of ice water to form a slurry and extracted 3 times with ether (1400 ml total) and once with 250 ml of ethyl acetate-ether (1:1). The combined organic extracts are washed with saturated brine (2×75 ml), the combined aqueous washings extracted with ethyl acetate-ether (1:1, 1×100 ml) and dried over anhydrous sodium sulfate, and concentrated at reduced pressure. Vacuum distillation gives 10.21 g of the title product, m.p. 121°-125° C., 0.15 mmHg. The contents are stirred for another 3 hours at -78° C. 17 hours at ambient temperature The reaction mixture is cooled to 8° C. stirred at ambient temperature for 30 minutes concentrated in vacuo The residue is treated with 100 ml of saturated brine and 100 ml of ice water to form a slurry extracted 3 times with ether (1400 ml total) The combined organic extracts are washed with saturated brine (2×75 ml) the combined aqueous washings extracted with ethyl acetate-ether (1:1, 1×100 ml) dried over anhydrous sodium sulfate concentrated at reduced pressure Vacuum distillation

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

Procedure: At 0° C., a solution of 10.5 g of 3-methyl-2-oxohept-5-ynephosphonic acid dimethyl ester in 70 ml of dimethoxyethane is added dropwise to a suspension of 1.81 g of sodium hydride in 180 ml of dimethoxyethane; the mixture is stirred for one hour at 0° C. and then 7.4 g of finely pulverized N-bromosuccinimide is added thereto. The mixture is agitated for 30 minutes at 0° C., combined with a solution of 11.4 g of (1R,5S,6R,7R)-3,3-ethylenedioxy-7-benzoyloxy-6-formylbicyclo[3.3.0]octane in 90 ml of dimethoxyethane, and agitated for 2 hours at 0° C. The reaction mixture is poured on saturated ammonium chloride solution and extracted with ether. The organic extract is washed neutral with water, dried over magnesium sulfate, and evaporated under vacuum. Chromatography of the residue on silica gel yields, with hexane/ether (3+2), 8.2 g of the unsaturated ketone as a colorless oil. The mixture is agitated for 30 minutes at 0° C. agitated for 2 hours at 0° C extracted with ether The organic extract is washed neutral with water dried over magnesium sulfate evaporated under vacuum

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

Procedure: At 0° C., a solution of 10.5 g of 3-methyl-2-oxohept-5-ynephosphonic acid dimethyl ester in 70 ml of dimethoxyethane is added dropwise to a suspension of 1.81 g of sodium hydride in 180 ml of dimethoxyethane; the mixture is stirred for one hour at 0° C. and then 7.4 g of finely pulverized N-bromosuccinimide is added thereto. The mixture is agitated for 30 minutes at 0° C., combined with a solution of 11.4 g of (1R,5S,6R,7R)-3,3-ethylenedioxy-7-benzoyloxy-6-formylbicyclo[3.3.0]octane in 90 ml of dimethoxyethane, and agitated for 2 hours at 0° C. The reaction mixture is poured on saturated ammonium chloride solution and extracted with ether. The organic extract is washed neutral with water, dried over magnesium sulfate, and evaporated under vacuum. Chromatography of the residue on silica gel yields, with hexane/ether (3+2), 8.2 g of the unsaturated ketone as a colorless oil. The mixture is agitated for 30 minutes at 0° C. agitated for 2 hours at 0° C extracted with ether The organic extract is washed neutral with water dried over magnesium sulfate evaporated under vacuum

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

Procedure: A solution of dimethyl methylphosphonate (22.47 g, 181.24 mmol) in 260 ml of tetrahydrofuran is cooled to -78° C. and treated dropwise with n-butyllithium (113 ml, 181.24 mmol), 1.6M in hexane) over a 25-minute period. The mixture is stirred an additional 30 minutes at -78° C., then treated dropwise with 2-methyl-4-hexynoic acid methyl ester (7.25 g, 51.78 mmols) in 65 ml of tetrahydrofuran over a period of 10 minutes. The contents are stirred for another 3 hours at -78° C. and then 17 hours at ambient temperature. The reaction mixture is cooled to 8° C., treated with 14 ml of acetic acid, stirred at ambient temperature for 30 minutes, then concentrated in vacuo. The residue is treated with 100 ml of saturated brine and 100 ml of ice water to form a slurry and extracted 3 times with ether (1400 ml total) and once with 250 ml of ethyl acetate-ether (1:1). The combined organic extracts are washed with saturated brine (2×75 ml), the combined aqueous washings extracted with ethyl acetate-ether (1:1, 1×100 ml) and dried over anhydrous sodium sulfate, and concentrated at reduced pressure. Vacuum distillation gives 10.21 g of the title product, m.p. 121°-125° C., 0.15 mmHg. The contents are stirred for another 3 hours at -78° C. 17 hours at ambient temperature The reaction mixture is cooled to 8° C. stirred at ambient temperature for 30 minutes concentrated in vacuo The residue is treated with 100 ml of saturated brine and 100 ml of ice water to form a slurry extracted 3 times with ether (1400 ml total) The combined organic extracts are washed with saturated brine (2×75 ml) the combined aqueous washings extracted with ethyl acetate-ether (1:1, 1×100 ml) dried over anhydrous sodium sulfate concentrated at reduced pressure Vacuum distillation

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

Procedure: At 0° C., a solution of 10.5 g of 3-methyl-2-oxohept-5-ynephosphonic acid dimethyl ester in 70 ml dimethoxyethane is added dropwise to a suspension of 1.81 g of sodium hydride in 180 ml of dimethoxyethane; the mixture is stirred for one hour at 0° C. and then 7.4 g of finely pulverized N-bromosuccinimide is added. The mixture is stirred for 30 minutes at 0° C., combined with a solution of 11.4 g of (lR,5S,6R,7R)-3,3-ethylenedioxy-7-benzoyloxy-6formylbicyclo [3.3.0]octane in 90 ml of dimethoxyethane, and agitated for 2 hours at 0° C. The reaction mixture is poured on saturated ammonium chloride solution and extracted with ether. The organic extract is washed neutral with water, dried over magnesium sulfate and evaporated under vacuum. After chromatographing the residue on silica gel, 8.2 g of the unsatura-ted ketone is obtained as a colorless oil with hexane/ether (3+2). The mixture is stirred for 30 minutes at 0° C. agitated for 2 hours at 0° C extracted with ether The organic extract is washed neutral with water dried over magnesium sulfate evaporated under vacuum

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

Procedure: Next, to a solution of 18 g of dimethyl methanephosphonate in 294 ml of anhydrous tetrahydrofuran was added at -78° C. 86 ml of n-butyl lithium (1.5N), and the mixture was stirred for 20 mins. To the thus prepared reaction mixture was added a solution of 10.4 g of the above-mentioned ester in 20 ml of anhydrous tetrahydrofuran. Then, the mixture was stirred for 15 mins at -78° C. and for 1 hour at room temperature, and 300 ml of ether was added. The solution was washed with 150 ml of aqueous saturated solution of oxalic acid, 150 ml of water and 50 ml of aqueous saturated solution of sodium chloride and condensed. The residue was distilled under a reduced pressure to give 14.7 g of dimethyl 3-methyl-2-oxo-hept-5-yne-phosphonate (138° to 142° C./0.62 mmHg). To the thus prepared reaction mixture The solution was washed with 150 ml of aqueous saturated solution of oxalic acid, 150 ml of water and 50 ml of aqueous saturated solution of sodium chloride and condensed The residue was distilled under a reduced pressure

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

Procedure: A solution of dimethyl methylphosphonate (22.47 g, 181.24 mmol) in 260 ml of tetrahydrofuran is cooled to -78° C. and treated dropwise with n-butyllithium (113 ml, 181.24 mmol), 1.6M in hexane) over a 25-minute period. The mixture is stirred an additional 30 minutes at -78° C., then treated dropwise with 2-methyl-4-hexynoic acid methyl ester (7.25 g, 51.78 mmols) in 65 ml of tetrahydrofuran over a period of 10 minutes. The contents are stirred for another 3 hours at -78° C. and then 17 hours at ambient temperature. The reaction mixture is cooled to 8° C., treated with 14 ml of acetic acid, stirred at ambient temperature for 30 minutes, then concentrated in vacuo. The residue is treated with 100 ml of saturated brine and 100 ml of ice water to form a slurry and extracted 3 times with ether (1400 ml total) and once with 250 ml of ethyl acetate-ether (1:1). The combined organic extracts are washed with saturated brine (2×75 ml), the combined aqueous washings extracted with ethyl acetate-ether (1:1, 1×100 ml) and dried over anhydrous sodium sulfate, and concentrated at reduced pressure. Vacuum distillation gives 10.21 g of the title product, m.p. 121°-125° C., 0.15 mmHg. The contents are stirred for another 3 hours at -78° C. 17 hours at ambient temperature The reaction mixture is cooled to 8° C. stirred at ambient temperature for 30 minutes concentrated in vacuo The residue is treated with 100 ml of saturated brine and 100 ml of ice water to form a slurry extracted 3 times with ether (1400 ml total) The combined organic extracts are washed with saturated brine (2×75 ml) the combined aqueous washings extracted with ethyl acetate-ether (1:1, 1×100 ml) dried over anhydrous sodium sulfate concentrated at reduced pressure Vacuum distillation

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

Procedure: A solution of dimethyl methylphosphonate (22.47 g, 181.24 mmol) in 260 ml of tetrahydrofuran is cooled to -78° C. and treated dropwise with n-butyllithium (113 ml, 181.24 mmol), 1.6M in hexane) over a 25-minute period. The mixture is stirred an additional 30 minutes at -78° C., then treated dropwise with 2-methyl-4-hexynoic acid methyl ester (7.25 g, 51.78 mmols) in 65 ml of tetrahydrofuran over a period of 10 minutes. The contents are stirred for another 3 hours at 31 78° C. and then 17 hours at ambient temperature. The reaction mixture is cooled to 8° C., treated with 14 ml of acetic acid, stirred at ambient temperature for 30 minutes, then concentrated in vacuo. The residue is treated with 100 ml of saturated brine and 100 ml of ice water to form a slurry and extracted 3 times with ether (1400 ml total) and once with 250 ml of ethyl acetate-ether (1:1). The combined organic extracts are washed with saturated brine (2×75 ml), the combined aqueous washings extracted with ethyl acetate-ether (1:1, 1×100 ml) and dried over anhydrous sodium sulfate, and concentrated at reduced pressure. Vacuum distillation gives 10.21 g of the title product, m.p. 121°-125° C., 0.15 mmHg. The contents are stirred for another 3 hours at 31 78° C. 17 hours at ambient temperature The reaction mixture is cooled to 8° C. stirred at ambient temperature for 30 minutes concentrated in vacuo The residue is treated with 100 ml of saturated brine and 100 ml of ice water to form a slurry extracted 3 times with ether (1400 ml total) The combined organic extracts are washed with saturated brine (2×75 ml) the combined aqueous washings extracted with ethyl acetate-ether (1:1, 1×100 ml) dried over anhydrous sodium sulfate concentrated at reduced pressure Vacuum distillation