methyl 2,2-dimethylhexanoate

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

Procedure: To a solution of 2,2-Dimethyl-hexanoic acid (10.15 g, 0.07 mol) in ether (150 mL) was added (trimethylsilyl)diazomethane (46 ml, 2M in hexanes, 0.092 mol) drop wise. The mixture was stirred for 3 h, and ether was evaporated without applying reduced pressure. Fractional distillation of the residue provided the title ester 11.12 g (b.p. 90-95° C./1 mmHg). 1H NMR (CDCl3): δ 0.85 (t, J=7.0 Hz, 3H), 1.1-1.2 (m, 2H), 1.13 (s, 6H), 1.21-1.31 (m, 2H), 1.44-1.51 (m, 2H), 3.72 (s, 3H). ether was evaporated Fractional distillation of the residue

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: 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

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

Conditions: temp:-50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Anhydrous diisopropylamine (14.8 g, 0.146 mol) was dissolved in anhydrous THF (90 ml) under argon atmosphere. To the mixture stirred at -50° C. was added dropwise n-butyl lithium (1.62N, 90 ml, 0.146 mol) over a period of 30 minutes, and then a solution of isobutyric acid (6.4 g, 0.073 mol) in anhydrous THF (10 ml) was added over a period of 30 minutes. After the mixture was warmed to -5° C., n-butyl bromide (15.0 g, 0.11 mol) dissolved in 10 ml anhydrous THF was added dropwise. After 30 minutes, the mixture was acidified to pH2 with 6N aqueous hydrogen chloride. The mixture was extracted with ethyl acetate (60 ml33 2). The ethyl acetate layers were washed with water (30 ml×1) and with brine (20 ml×1), dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in 50 ml ether, and treated with an excess of ethereal solution of diazomethane. After concentration, distillation of the residue gave 2,2-dimethyl-hexanoic acid methyl ester (8.2 g, 0.052 mol, 71%, b.p.=69°-70° C./25 mmHg) as a colorless clear liquid. The structure of this product was confirmed by the following data. After the mixture was warmed to -5° C. was added dropwise The mixture was extracted with ethyl acetate (60 ml33 2) The ethyl acetate layers were washed with water (30 ml×1) and with brine (20 ml×1) dried over anhydrous sodium sulfate concentrated The residue was dissolved in 50 ml ether treated with an excess of ethereal solution of diazomethane After concentration, distillation of the residue

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

Procedure: To a solution of 2,2-Dimethyl-hexanoic acid (10.15 g, 0.07 mol) in ether (150 mL) was added (trimethylsilyl)diazomethane (46 ml, 2M in hexanes, 0.092 mol) drop wise. The mixture was stirred for 3 h, and ether was evaporated without applying reduced pressure. Fractional distillation of the residue provided the title ester 11.12 g (b.p. 90-95° C./1 mmHg). 1H NMR (CDCl3): δ 0.85 (t, J=7.0 Hz, 3H), 1.1-1.2 (m, 2H), 1.13 (s, 6H), 1.21-1.31 (m, 2H), 1.44-1.51 (m, 2H), 3.72 (s, 3H). ether was evaporated Fractional distillation of the residue

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

Procedure: To a solution of 2,2-Dimethyl-hexanoic acid (10.15 g, 0.07 mol) in ether (150 mL) was added (trimethylsilyl)diazomethane (46 ml, 2M in hexanes, 0.092 mol) drop wise. The mixture was stirred for 3 h, and ether was evaporated without applying reduced pressure. Fractional distillation of the residue provided the title ester 11.12 g (b.p. 90-95° C./1 mmHg). 1H NMR (CDCl3): δ 0.85 (t, J=7.0 Hz, 3H), 1.1-1.2 (m, 2H), 1.13 (s, 6H), 1.21-1.31 (m, 2H), 1.44-1.51 (m, 2H), 3.72 (s, 3H). ether was evaporated Fractional distillation of the residue

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

Procedure: Dimethyl methylphosphonate (14.88 g) is dissolved in dry tetrahydrofuran (THF, 34 ml) under a nitrogen atmosphere. The solution is cooled to -78° C. Butyllithium (7.68 g, 52 ml of 2.3 molar solution, 3 equiv.) is added very slowly during 1 hour. The mixture is stirred at -78° C for 15 minutes. A solution of 2,2-dimethylhexanoic acid methyl ester (6.32 g) in dry THF (16 ml) is added to the cold solution over a period of 1 hour. The mixture is stirred for 30 minutes and then allowed to warm up to room temperature. The reaction mixture is diluted with ether. Dilute (10%) hydrochloric acid (30 ml) is added and the reaction mixture shaken well. The organic phase is separated and washed several times with water, dried (MgSO4) and the solvent removed. The residue is distilled under reduced pressure to give the title compound, b.p. 110° - 120° C/0.1mm, γmaxfilm 1700, 1250, 1020 cm-1. The mixture is stirred for 30 minutes to warm up to room temperature is added the reaction mixture shaken well The organic phase is separated washed several times with water dried (MgSO4) the solvent removed The residue is distilled under reduced pressure

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 atmosphere. To the stirred phosphonate solution is added 67.3 ml. 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 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 (3×), 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. the reaction temperature less than -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: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: 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

Conditions: temp:-50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Anhydrous diisopropylamine (14.8 g, 0.146 mol) was dissolved in anhydrous THF (90 ml) under argon atmosphere. To the mixture stirred at -50° C. was added dropwise n-butyl lithium (1.62N, 90 ml, 0.146 mol) over a period of 30 minutes, and then a solution of isobutyric acid (6.4 g, 0.073 mol) in anhydrous THF (10 ml) was added over a period of 30 minutes. After the mixture was warmed to -5° C., n-butyl bromide (15.0 g, 0.11 mol) dissolved in 10 ml anhydrous THF was added dropwise. After 30 minutes, the mixture was acidified to pH2 with 6N aqueous hydrogen chloride. The mixture was extracted with ethyl acetate (60 ml33 2). The ethyl acetate layers were washed with water (30 ml×1) and with brine (20 ml×1), dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in 50 ml ether, and treated with an excess of ethereal solution of diazomethane. After concentration, distillation of the residue gave 2,2-dimethyl-hexanoic acid methyl ester (8.2 g, 0.052 mol, 71%, b.p.=69°-70° C./25 mmHg) as a colorless clear liquid. The structure of this product was confirmed by the following data. After the mixture was warmed to -5° C. was added dropwise The mixture was extracted with ethyl acetate (60 ml33 2) The ethyl acetate layers were washed with water (30 ml×1) and with brine (20 ml×1) dried over anhydrous sodium sulfate concentrated The residue was dissolved in 50 ml ether treated with an excess of ethereal solution of diazomethane After concentration, distillation of the residue