ethyl 3-(2-fluorophenyl)-3-oxopropanoate

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:; See reaction.notes.procedure_details.

Procedure: Under nitrogen atmosphere, 30 mL of THF was added to 6.09 g (10 mmol, 1.0 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 1.21 g (10 mmol) of 2-fluorobenzonitrile in 5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20° C.˜25° C. for 46 hours. 15 mL of 10% hydrochloric acid added dropwise at 20° C. or lower, and the mixture was stirred at 20˜25° C. for 1. hour, followed by dilution with 50 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 15 mL of 1N hydrochloric acid, 20 mL of an aqueous saturated sodium chloride solution, 20 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 20 mL of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.94 g of the desired product (yield 92%). The mixture was stirred at 20° C.˜25° C. for 46 hours lower, and the mixture was stirred at 20˜25° C. for 1 Then, the layers were separated The organic layer was washed successively with 15 mL of 1N hydrochloric acid, 20 mL of an aqueous saturated sodium chloride solution, 20 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 20 mL of an aqueous saturated sodium chloride solution After washing the organic layer was dried with anhydrous magnesium sulfate Concentration under reduced pressure

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

Procedure: 2-Fluorophenyl hydrazine (1.26 g, 9.99 mmol) and ethyl 3-(2-fluorophenyl)-3-oxopropanoate (2.10 g, 9.99 mmol, 1 equiv) were combined in acetic acid (20 mL) and placed into an oil bath preheated at 120° C. for 3 hours. The mixture was cooled of ambient temperature and concentrated in vacuo. The residue was concentrated from toluene (3×50 mL), providing the titled compound. placed into an oil bath concentrated in vacuo The residue was concentrated from toluene (3×50 mL)

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

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

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

Procedure: Ethyl 3-(2-fluorophenyl)-3-oxopropanoate (1.00 g, 4.76 mmol) was dissolved in acetonitrile (14 mL) and treated with triethylamine (0.760 ml, 5.47 mmol, 1.15 equiv). The mixture was cooled to 0° C., treated with 4-acetamidobenzenesulfonylazide (1.26 g, 5.23 mmol, 1.1 equiv) and warmed to ambient temperature over 1.5 hours. The mixture was partially concentrated in vacuo, cooled to 0° C., treated with sodium hydroxide (50 mL, 1 N aqueous) and extracted with chloroform (3×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel gradient chromatography (100:0 to 85:15; hexanes:ethyl acetate) providing the titled compound as a yellow oil. warmed to ambient temperature over 1.5 hours The mixture was partially concentrated in vacuo cooled to 0° C. treated with sodium hydroxide (50 mL, 1 N aqueous) extracted with chloroform (3×50 mL) The combined organic extracts were dried with sodium sulfate filtered concentrated in vacuo The residue was purified via silica gel gradient chromatography (100:0 to 85:15; hexanes:ethyl acetate)

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

Procedure: Ethyl 3-(2-fluorophenyl)-3-oxopropanoate (1.00 g, 4.76 mmol) was dissolved in acetonitrile (14 mL) and treated with triethylamine (0.760 ml, 5.47 mmol, 1.15 equiv). The mixture was cooled to 0° C., treated with 4-acetamidobenzenesulfonylazide (1.26 g, 5.23 mmol, 1.1 equiv) and warmed to ambient temperature over 1.5 hours. The mixture was partially concentrated in vacuo, cooled to 0° C., treated with sodium hydroxide (50 mL, 1 N aqueous) and extracted with chloroform (3×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel gradient chromatography (100:0 to 85:15; hexanes:ethyl acetate) providing the titled compound as a yellow oil. warmed to ambient temperature over 1.5 hours The mixture was partially concentrated in vacuo cooled to 0° C. treated with sodium hydroxide (50 mL, 1 N aqueous) extracted with chloroform (3×50 mL) The combined organic extracts were dried with sodium sulfate filtered concentrated in vacuo The residue was purified via silica gel gradient chromatography (100:0 to 85:15; hexanes:ethyl acetate)

Conditions: temp:135.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 3-(2-fluorophenyl)-3-oxopropanoate (2.5 g, 12 mmol) and 2-fluorophenyl hydrazine hydrochloride (1.5 g, 12 mmol, 1.0 equiv) were dissolved in acetic acid (24 mL) and placed into a preheated oil bath at 120° C. for 3 hours and then heated for an additional 2 hours at 135° C. The mixture was cooled to ambient temperature, concentrated in vacuo and then concentrated once from toluene (1×25 mL). The residue was suspended in dichloromethane, filtered and the solid was washed once with dichloromethane and dried in vacuo, providing the titled compound. The resulting filtrate was concentrated in vacuo and purified by silica gel gradient chromatography (100:0 to 65:35; hexanes:ethyl acetate), providing additional titled compound as a light brown solid. The mixture was cooled to ambient temperature concentrated in vacuo concentrated once from toluene (1×25 mL) filtered the solid was washed once with dichloromethane dried in vacuo

Conditions: temp:135.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 3-(2-fluorophenyl)-3-oxopropanoate (2.5 g, 12 mmol) and 2-fluorophenyl hydrazine hydrochloride (1.5 g, 12 mmol, 1.0 equiv) were dissolved in acetic acid (24 mL) and placed into a preheated oil bath at 120° C. for 3 hours and then heated for an additional 2 hours at 135° C. The mixture was cooled to ambient temperature, concentrated in vacuo and then concentrated once from toluene (1×25 mL). The residue was suspended in dichloromethane, filtered and the solid was washed once with dichloromethane and dried in vacuo, providing the titled compound. The resulting filtrate was concentrated in vacuo and purified by silica gel gradient chromatography (100:0 to 65:35; hexanes:ethyl acetate), providing additional titled compound as a light brown solid. The mixture was cooled to ambient temperature concentrated in vacuo concentrated once from toluene (1×25 mL) filtered the solid was washed once with dichloromethane dried in vacuo

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

Procedure: A mixture of ethyl 3-(2-fluorophenyl)-3-oxopropanoate (14.29 g, 68.0 mmol) and DMF-DMA (12.15 g, 0.102 mol, 1.5 eq.) in toluene (50 mL) was refluxed for 2 hours and concentrated to give 3-dimethylamino-2-(2-fluoro-benzoyl)-acrylic acid ethyl ester as a red oil in quantitative yield. was refluxed for 2 hours concentrated