ethyl 2-(3-chlorophenyl)-2-oxoacetate

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

Procedure: Diethyl oxalate (4.4 g, 30.2 mmol) was dissolved in dry ethyl ether (30 mL) and freshly distilled THF (30 mL) and cooled to −78° C. with stirring, under a nitrogen atmosphere. Then added 3-chlorophenylmagnesium bromide (0.5 M in THF, 72.5 mL, 36.2 mmol) dropwise, via an addition funnel, while keeping the temperature between −75 to −78° C. The addition took approximately 90 minutes. After 3 hours, the reaction was quenched by the dropwise addition of 2N sulfuric acid (50 mL, 91 mmol) at −78° C. and upon completion of the addition, the mixture was allowed to return to room temperature. The mixture was extracted with ethyl ether (3×) and the combined ether extracts were washed with brine (2×), dried over magnesium sulfate, filtered, evaporated in vacuo and vacuum-dried to yield ethyl-(3-chlorophenyl)(oxo)acetate (6.5 g, HPLC RT=3.46 min, Method A; LCMS m/z=213). between −75 to −78° C The addition After 3 hours to return to room temperature The mixture was extracted with ethyl ether (3×) the combined ether extracts were washed with brine (2×) dried over magnesium sulfate filtered evaporated in vacuo vacuum-dried

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

Procedure: An aqueous 2 mol/L NaOH solution (24 mL) was added to a solution of ethyl (3-chlorophenyl)(oxo)acetate (2.00 g) in THF/MeOH (1:1) (48 mL) in an ice bath, followed by stirring at room temperature overnight. The solvent was distilled off under reduced pressure, and an aqueous 3 mol/L HCl solution was added thereto in an ice bath. The precipitated solid was collected by filtration to yield the title compound (2.00 g, colorless solid). The solvent was distilled off under reduced pressure an aqueous 3 mol/L HCl solution was added The precipitated solid was collected by filtration

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

Procedure: An aqueous 2 mol/L NaOH solution (24 mL) was added to a solution of ethyl (3-chlorophenyl)(oxo)acetate (2.00 g) in THF/MeOH (1:1) (48 mL) in an ice bath, followed by stirring at room temperature overnight. The solvent was distilled off under reduced pressure, and an aqueous 3 mol/L HCl solution was added thereto in an ice bath. The precipitated solid was collected by filtration to yield the title compound (2.00 g, colorless solid). The solvent was distilled off under reduced pressure an aqueous 3 mol/L HCl solution was added The precipitated solid was collected by filtration

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

Procedure: To a flask was added ethyl 2-(3-chlorophenyl)-2-oxoacetate (1.8 g, 8.47 mmol) and acetic anhydride (1.60 ml, 16.93 mmol) in DCE (5 ml) at RT. To the resulting solution was added titanium(IV) chloride (16.93 ml, 16.93 mmol) and tributylamine (2.42 ml, 10.16 mmol). The solution was heated to reflux for 12 hours. The solution was then cooled in ice, and a solution of ammonium chloride was added. The mixture was stirred for 30 min. LC/MS indicated all starting material was gone. The solution was washed with 1×NH4Cl, 1N HCl, water, dried and concentrated in vacuo to provide 3-(3-chlorophenyl)furan-2,5-dione which was used as is in the next reaction. LC/MS, m/e 209 (M+1). HPLC Rt, 2.89 min. Waters Sunfire C18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min. hold at 100% B 1 min, flow rate 4 mL/min. The solution was heated to reflux for 12 hours The solution was then cooled in ice The solution was washed with 1×NH4Cl, 1N HCl, water dried concentrated in vacuo

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

Procedure: To a flask was added ethyl 2-(3-chlorophenyl)-2-oxoacetate (1.8 g, 8.47 mmol) and acetic anhydride (1.60 ml, 16.93 mmol) in DCE (5 ml) at RT. To the resulting solution was added titanium(IV) chloride (16.93 ml, 16.93 mmol) and tributylamine (2.42 ml, 10.16 mmol). The solution was heated to reflux for 12 hours. The solution was then cooled in ice, and a solution of ammonium chloride was added. The mixture was stirred for 30 min. LC/MS indicated all starting material was gone. The solution was washed with 1×NH4Cl, 1N HCl, water, dried and concentrated in vacuo to provide 3-(3-chlorophenyl)furan-2,5-dione which was used as is in the next reaction. LC/MS, m/e 209 (M+1). HPLC Rt, 2.89 min. Waters Sunfire C18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min. hold at 100% B 1 min, flow rate 4 mL/min. The solution was heated to reflux for 12 hours The solution was then cooled in ice The solution was washed with 1×NH4Cl, 1N HCl, water dried concentrated in vacuo

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

Procedure: To a flask was added ethyl 2-(3-chlorophenyl)-2-oxoacetate (1.8 g, 8.47 mmol) and acetic anhydride (1.60 ml, 16.93 mmol) in DCE (5 ml) at RT. To the resulting solution was added titanium(IV) chloride (16.93 ml, 16.93 mmol) and tributylamine (2.42 ml, 10.16 mmol). The solution was heated to reflux for 12 hours. The solution was then cooled in ice, and a solution of ammonium chloride was added. The mixture was stirred for 30 min. LC/MS indicated all starting material was gone. The solution was washed with 1×NH4Cl, 1N HCl, water, dried and concentrated in vacuo to provide 3-(3-chlorophenyl)furan-2,5-dione which was used as is in the next reaction. LC/MS, m/e 209 (M+1). HPLC Rt, 2.89 min. Waters Sunfire C18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min. hold at 100% B 1 min, flow rate 4 mL/min. The solution was heated to reflux for 12 hours The solution was then cooled in ice The solution was washed with 1×NH4Cl, 1N HCl, water dried concentrated in vacuo

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

Procedure: Diethyl oxalate (4.4 g, 30.2 mmol) was dissolved in dry ethyl ether (30 mL) and freshly distilled THF (30 mL) and cooled to −78° C. with stirring, under a nitrogen atmosphere. Then added 3-chlorophenylmagnesium bromide (0.5 M in THF, 72.5 mL, 36.2 mmol) dropwise, via an addition funnel, while keeping the temperature between −75 to −78° C. The addition took approximately 90 minutes. After 3 hours, the reaction was quenched by the dropwise addition of 2N sulfuric acid (50 mL, 91 mmol) at −78° C. and upon completion of the addition, the mixture was allowed to return to room temperature. The mixture was extracted with ethyl ether (3×) and the combined ether extracts were washed with brine (2×), dried over magnesium sulfate, filtered, evaporated in vacuo and vacuum-dried to yield ethyl-(3-chlorophenyl)(oxo)acetate (6.5 g, HPLC RT=3.46 min, Method A; LCMS m/z=213). between −75 to −78° C The addition After 3 hours to return to room temperature The mixture was extracted with ethyl ether (3×) the combined ether extracts were washed with brine (2×) dried over magnesium sulfate filtered evaporated in vacuo vacuum-dried

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

Procedure: An aqueous 2 mol/L NaOH solution (24 mL) was added to a solution of ethyl (3-chlorophenyl)(oxo)acetate (2.00 g) in THF/MeOH (1:1) (48 mL) in an ice bath, followed by stirring at room temperature overnight. The solvent was distilled off under reduced pressure, and an aqueous 3 mol/L HCl solution was added thereto in an ice bath. The precipitated solid was collected by filtration to yield the title compound (2.00 g, colorless solid). The solvent was distilled off under reduced pressure an aqueous 3 mol/L HCl solution was added The precipitated solid was collected by filtration