ethyl 3-methylbutanoate

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

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

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

Procedure: The material undergoes smooth pyrolysis when injected into a gas chromatography column (at about 230° C.) to generate acetophenone and ethyl isovalerate. injected into a gas chromatography column (at about 230° C.)

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Tetrahydrofuran (100 ml) and 1,3-dimethyl-3,4,5,6-tetrahydro 2 (1H)-pyrimidinone (140 ml) were mixed at −20° C. and lithium bis (trimethylsilyl) amide (1M in tetrahydrofuran, 100 ml) was added. The mixture was cooled to −70° C., ethyl isovalerate (18.75 ml) added and stirred for ½ hour at −70° C. Triisopropylsilyl trifluoromethane sulfonate was added and the mixture left to stir at −75° C. for ½ hour before warming to room temperature and stirring for 3 hours. The reaction mixture was quenched with aqueous sodium bicarbonate (8%, 150 ml) and extracted with hexane (1000 ml). The hexane extract was washed with water (4×500 ml), dried (MgSO4), filtered and concentrated in vacuo to afford a crude yellow oil containing the title compound. the mixture left to stir at −75° C. for ½ hour before warming to room temperature stirring for 3 hours The reaction mixture was quenched with aqueous sodium bicarbonate (8%, 150 ml) extracted with hexane (1000 ml) The hexane extract was washed with water (4×500 ml) dried (MgSO4) filtered concentrated in vacuo to afford a crude yellow oil

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 diisopropylamine (2.53 g, 25 mmol) in THF (25 mL) was treated with n-butyllithium (1.6M in hexane, 16 mL, 25.6 mmol) at room temperature under N2. The resulting pale yellow solution was cooled to −78° C. A solution of 3-methyl-butyric acid ethyl ester (2.91 g, 22.31 mmol) in THF (7 mL) was added. Stirring was continued for a half hour at −78° C., after which ethyl formate (5.5 g, 75 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for three hours under N2. The reaction mixture was quenched with acetic acid (4.5 ml), diluted with diethyl ether, washed with water, brine, and dried (Na2SO4). Silica gel chromatography (methyl acetate/hexane) provided 3.2 g of the title compound as a mixture of isomers. was continued for a half hour at −78° C. to warm to room temperature stirred for three hours under N2 The reaction mixture was quenched with acetic acid (4.5 ml) diluted with diethyl ether washed with water, brine dried (Na2SO4)

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Tetrahydrofuran (100 ml) and 1,3-dimethyl-3,4,5,6-tetrahydro 2 (1H)-pyrimidinone (140 ml) were mixed at -20° C. and lithium bis (trimethylsilyl) amide (1M in tetrahydrofuran, 100 ml) was added. The mixture was cooled to -70° C., ethyl isovalerate (18.75 ml) added and stirred for 1/2 hour at -70° C. Triisopropylsilyl trifluoromethane sulfonate was added and the mixture left to stir at -75° C. for 1/2 hour before warming to room temperature and stirring for 3 hours. The reaction mixture was quenched with aqueous sodium bicarbonate (8%, 150 ml) and extracted with hexane (1000 ml). The hexane extract was washed with water (4×500 ml), dried (MgSO4), filtered and concentrated in vacuo to afford a crude yellow oil containing the title compound. the mixture left to stir at -75° C. for 1/2 hour before warming to room temperature stirring for 3 hours The reaction mixture was quenched with aqueous sodium bicarbonate (8%, 150 ml) extracted with hexane (1000 ml) The hexane extract was washed with water (4×500 ml) dried (MgSO4) filtered concentrated in vacuo to afford a crude yellow oil

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Tetrahydrofuran (100 ml) and 1,3-dimethyl-3,4,5,6-tetrahydro 2 (1H)-pyrimidinone (140 ml) were mixed at -20° C. and lithium bis (trimethylsilyl) amide (1M in tetrahydrofuran, 100 ml) was added. The mixture was cooled to -70° C., ethyl isovalerate (18.75 ml) added and stirred for 1/2 hour at -70° C. Triisopropylsilyl trifluoromethane sulfonate was added and the mixture left to stir at -75° C. for 1/2 hour before warming to room temperature and stirring for 3 hours. The reaction mixture was quenched with aqueous sodium bicarbonate (8%, 150 ml) and extracted with hexane (1000 ml). The hexane extract was washed with water (4×500 ml), dried (MgSO4), filtered and concentrated in vacuo to afford a crude yellow oil containing the title compound. the mixture left to stir at -75° C. for 1/2 hour before warming to room temperature stirring for 3 hours The reaction mixture was quenched with aqueous sodium bicarbonate (8%, 150 ml) extracted with hexane (1000 ml) The hexane extract was washed with water (4×500 ml) dried (MgSO4) filtered concentrated in vacuo to afford a crude yellow oil

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Lithium diisopropylamide (22.2mL of 1.8M solution, 40 mmol) was added to a solution of ethyl isovalerate (5.2g, 40 mmol) in 40 mL of tetrahydrofuran at -40° C. After stirring for 0.5 hours and cooling to -70° C., 4,4'-difluorobenzophenone (4.36 g, 20 mmol) was added and the mixture stirred for 3 hours during which time the temperature was allowed to warm to -20° C. The reaction was quenched with 1N hydrochloric acid and the mixture extracted with diethyl ether. The extracts were dried with magnesium sulfate and concentrated in vacuo. The residue was crystallized from hexane to give 5.3 g of the title product; m.p. =118°-120° C. the mixture stirred for 3 hours during which time the temperature to warm to -20° C The reaction was quenched with 1N hydrochloric acid the mixture extracted with diethyl ether The extracts were dried with magnesium sulfate concentrated in vacuo The residue was crystallized from hexane

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

Procedure: Lithium diisopropylamide (1.5 M solution in cyclohexane/THF/ethylbenzene) (113 mL, 169 mmol, 1.1 equiv) was syringed into a 1000 mL round-bottom flask under a blanket of Ar. Dry THF (150 mL) was added and the mixture was cooled to −78° C. with a dry-ice/acetone bath. 3-Methyl-butanoic acid ethyl ester (20 g, 23 mL, 154 mmol, 1.0 equiv) was added dropwise from a syringe over a 10 min period followed by stirring at −78° C. for 1 h. Methyl iodide (10.5 mL, 169 mmol, 1.1 equiv) was added dropwise from a syringe over a 10 min period and the creamy mixture was stirred for 1 h at −78° C., resulting in a very thick mixture. The dry-ice bath was removed and replaced with an ice bath at 0° C. Another 150 mL of dry THF was added followed by another addition of LDA (113 mL, 169 mmol, 1.1 equiv). The resulting mixture was stirred for 10 min and then the flask was re-immersed in a dry-ice/acetone bath. Stirring was continued for another 50 min and then methyl iodide was added dropwise (10.5 mL, 169 mmol, 1.1 equiv) and the dry-ice/acetone bath was removed and the resulting mixture was stirred at ambient temperature for 14 h. The reaction mixture was quenched with 3 mL of conc. HCl and 2 N HCl was added until the pH was adjusted to <1. The mixture was further diluted with 150 mL water and 500 mL Et2O. The layers were separated and the organic layer was washed with 1×100 mL 2 N HCl, 1×100 mL saturated NaHCO3, and 1×200 mL brine. The organic layer was dried over Na2SO4 and then concentrated in vacuo to provide 2,2,3-trimethylbutanoic acid ethyl ester as an orange oil mixed with ethyl benzene (36.4 g of which 22.1 g was product by NMR). The mixture was used without further purification. the creamy mixture was stirred for 1 h at −78° C. resulting in a very thick mixture The dry-ice bath was removed replaced with an ice bath at 0° C Another 150 mL of dry THF was added The resulting mixture was stirred for 10 min the flask was re-immersed in a dry-ice/acetone bath Stirring was continued for another 50 min the dry-ice/acetone bath was removed the resulting mixture was stirred at ambient temperature for 14 h The reaction mixture was quenched with 3 mL of conc. HCl and 2 N HCl was added until the pH The mixture was further diluted with 150 mL water and 500 mL Et2O The layers were separated the organic layer was washed with 1×100 mL 2 N HCl, 1×100 mL saturated NaHCO3, and 1×200 mL brine The organic layer was dried over Na2SO4 concentrated in vacuo

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

Procedure: Lithium diisopropylamide (1.5 M solution in cyclohexane/THF/ethylbenzene) (113 mL, 169 mmol, 1.1 equiv) was syringed into a 1000 mL round-bottom flask under a blanket of Ar. Dry THF (150 mL) was added and the mixture was cooled to −78° C. with a dry-ice/acetone bath. 3-Methyl-butanoic acid ethyl ester (20 g, 23 mL, 154 mmol, 1.0 equiv) was added dropwise from a syringe over a 10 min period followed by stirring at −78° C. for 1 h. Methyl iodide (10.5 mL, 169 mmol, 1.1 equiv) was added dropwise from a syringe over a 10 min period and the creamy mixture was stirred for 1 h at −78° C., resulting in a very thick mixture. The dry-ice bath was removed and replaced with an ice bath at 0° C. Another 150 mL of dry THF was added followed by another addition of LDA (113 mL, 169 mmol, 1.1 equiv). The resulting mixture was stirred for 10 min and then the flask was re-immersed in a dry-ice/acetone bath. Stirring was continued for another 50 min and then methyl iodide was added dropwise (10.5 mL, 169 mmol, 1.1 equiv) and the dry-ice/acetone bath was removed and the resulting mixture was stirred at ambient temperature for 14 h. The reaction mixture was quenched with 3 mL of conc. HCl and 2 N HCl was added until the pH was adjusted to <1. The mixture was further diluted with 150 mL water and 500 mL Et2O. The layers were separated and the organic layer was washed with 1×100 mL 2 N HCl, 1×100 mL saturated NaHCO3, and 1×200 mL brine. The organic layer was dried over Na2SO4 and then concentrated in vacuo to provide 2,2,3-trimethylbutanoic acid ethyl ester as an orange oil mixed with ethyl benzene (36.4 g of which 22.1 g was product by NMR). The mixture was used without further purification. the creamy mixture was stirred for 1 h at −78° C. resulting in a very thick mixture The dry-ice bath was removed replaced with an ice bath at 0° C Another 150 mL of dry THF was added The resulting mixture was stirred for 10 min the flask was re-immersed in a dry-ice/acetone bath Stirring was continued for another 50 min the dry-ice/acetone bath was removed the resulting mixture was stirred at ambient temperature for 14 h The reaction mixture was quenched with 3 mL of conc. HCl and 2 N HCl was added until the pH The mixture was further diluted with 150 mL water and 500 mL Et2O The layers were separated the organic layer was washed with 1×100 mL 2 N HCl, 1×100 mL saturated NaHCO3, and 1×200 mL brine The organic layer was dried over Na2SO4 concentrated in vacuo