N-(4-fluorophenyl)acetamide

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

Procedure: To a room temperature suspension of sodium hydride (33.4 mmol, 1.34 g of 60% in mineral oil) in 60 mL of THF was added a solution of the N-(4-fluorophenyl)acetamide (4.1 g, 26.8 mmol) in THF (30 mL) over a 5 minute period. After 30 minutes, a solution of 4-bromo-1-fluoro-2-nitrobenzene (3.2 mL, 26.8 mmol) in THF (10 mL) was added. After 15 hours, the reaction was concentrated in vacuo, the residue was diluted with 1 N sulfuric acid (300 mL) and extracted with three 100 mL portions of methylene chloride. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford a brownish oil. The residue was purified by column chromatography over silica gel eluting with 0-100% ethyl acetate in hexanes to afford 3.7 g of N-(4-bromo-2-nitrophenyl)-N-(4-fluorophenyl)acetamide as a thick yellow oil. MS m/z 353/355 (MH+). After 15 hours the reaction was concentrated in vacuo the residue was diluted with 1 N sulfuric acid (300 mL) extracted with three 100 mL portions of methylene chloride The combined organic layers were washed with water dried over anhydrous sodium sulfate concentrated in vacuo to afford a brownish oil The residue was purified by column chromatography over silica gel eluting with 0-100% ethyl acetate in hexanes

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

Procedure: To a room temperature suspension of sodium hydride (33.4 mmol, 1.34 g of 60% in mineral oil) in 60 mL of THF was added a solution of the N-(4-fluorophenyl)acetamide (4.1 g, 26.8 mmol) in THF (30 mL) over a 5 minute period. After 30 minutes, a solution of 4-bromo-1-fluoro-2-nitrobenzene (3.2 mL, 26.8 mmol) in THF (10 mL) was added. After 15 hours, the reaction was concentrated in vacuo, the residue was diluted with 1 N sulfuric acid (300 mL) and extracted with three 100 mL portions of methylene chloride. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford a brownish oil. The residue was purified by column chromatography over silica gel eluting with 0-100% ethyl acetate in hexanes to afford 3.7 g of N-(4-bromo-2-nitrophenyl)-N-(4-fluorophenyl)acetamide as a thick yellow oil. MS m/z 353/355 (MH+). After 15 hours the reaction was concentrated in vacuo the residue was diluted with 1 N sulfuric acid (300 mL) extracted with three 100 mL portions of methylene chloride The combined organic layers were washed with water dried over anhydrous sodium sulfate concentrated in vacuo to afford a brownish oil The residue was purified by column chromatography over silica gel eluting with 0-100% ethyl acetate in hexanes

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

Procedure: To a chilled (ice-bath) solution of 4-fluorophenylamine (2.9 mL, 30 mmol) and anhydrous pyridine (3.7 mL, 45 mmol) in methylene chloride (50 mL) was slowly added a solution of acetyl chloride (2.4 mL, 33 mmol) in methylene chloride (10 mL). After 15 minutes, the mixture was concentrated in vacuo and the residue was diluted with cold water. The resulting precipitate was filtered, washed with water and dried to afford 4.2 g of N-(4-fluorophenyl)acetamide as an off white solid. MS m/z 154 (MH+). the mixture was concentrated in vacuo the residue was diluted with cold water The resulting precipitate was filtered washed with water dried

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

Procedure: According to AVV A, (Z)-3-(4-fluorophenylamino)-but-2-enoic acid tert-butylester (251.3 mg, 1.0 mmol, 1.0 equiv.) was stirred with Cu(OAc)2 (544.9 mg, 3.0 mmol, 3.0 equiv.) into propionitrile (3.0 ml, 41.9 mmol, 41.9 equiv.) for 24 hours at 120° C. The dark-brown/blue raw product (295.9 mg) was analyzed by means of 1H and 19F-NMR-spectroscopy. The 19F-NMR spectra showed the desired product (δ=−112.7 ppm) and N-(4-fluorophenyl)-acetamide (δ=−118.0 ppm) in a ratio of 89:11. After purification by means of column chromatography (silica gel (50 g), pentane/EtOAc 98:2→70:30→0:100), the product was obtained in the form of a yellowish oil (222.9 mg, 0.73 mmol, 73%).

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

Procedure: To a room temperature suspension of sodium hydride (33.4 mmol, 1.34 g of 60% in mineral oil) in 60 mL of THF was added a solution of the N-(4-fluorophenyl)acetamide (4.1 g, 26.8 mmol) in THF (30 mL) over a 5 minute period. After 30 minutes, a solution of 4-bromo-1-fluoro-2-nitrobenzene (3.2 mL, 26.8 mmol) in THF (10 mL) was added. After 15 hours, the reaction was concentrated in vacuo, the residue was diluted with 1 N sulfuric acid (300 mL) and extracted with three 100 mL portions of methylene chloride. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford a brownish oil. The residue was purified by column chromatography over silica gel eluting with 0-100% ethyl acetate in hexanes to afford 3.7 g of N-(4-bromo-2-nitrophenyl)-N-(4-fluorophenyl)acetamide as a thick yellow oil. MS m/z 353/355 (MH+). After 15 hours the reaction was concentrated in vacuo the residue was diluted with 1 N sulfuric acid (300 mL) extracted with three 100 mL portions of methylene chloride The combined organic layers were washed with water dried over anhydrous sodium sulfate concentrated in vacuo to afford a brownish oil The residue was purified by column chromatography over silica gel eluting with 0-100% ethyl acetate in hexanes

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

Procedure: To a chilled (ice-bath) solution of 4-fluorophenylamine (2.9 mL, 30 mmol) and anhydrous pyridine (3.7 mL, 45 mmol) in methylene chloride (50 mL) was slowly added a solution of acetyl chloride (2.4 mL, 33 mmol) in methylene chloride (10 mL). After 15 minutes, the mixture was concentrated in vacuo and the residue was diluted with cold water. The resulting precipitate was filtered, washed with water and dried to afford 4.2 g of N-(4-fluorophenyl)acetamide as an off white solid. MS m/z 154 (MH+). the mixture was concentrated in vacuo the residue was diluted with cold water The resulting precipitate was filtered washed with water dried

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

Procedure: A solution of 67.5 parts of acetanilide in 22,200 parts of chloroform was cooled to 0° C. and maintained at that temperature for 2.5 hours while fluoroxytrifluoromethane was bubbled into the solution at a rate of 46 parts per hour. Analysis of the reaction product by gas chromatographic technique indicated a 91 percent conversion with a yield of 37% 2-fluoroacetanilide, 16% 4-fluoroacetanilide, 10% 2,4-difluoroacetanilide, 3% 2,6-difluoroacetanilide and about 25% higher molecular weight material. was bubbled into the solution at a rate of 46 parts per hour

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

Procedure: A solution of 67.5 parts of acetanilide in 22,200 parts of chloroform was cooled to 0° C. and maintained at that temperature for 2.5 hours while fluoroxytrifluoromethane was bubbled into the solution at a rate of 46 parts per hour. Analysis of the reaction product by gas chromatographic technique indicated a 91 percent conversion with a yield of 37% 2-fluoroacetanilide, 16% 4-fluoroacetanilide, 10% 2,4-difluoroacetanilide, 3% 2,6-difluoroacetanilide and about 25% higher molecular weight material. was bubbled into the solution at a rate of 46 parts per hour

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

Procedure: Triethylamine (31 ml) and acetyl chloride (15 ml) were added dropwise to a chloroform (100 ml) solution of 4-fluoroaniline (22.3 g) in this order under ice-cooling. The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The thus-obtained solid was washed with water, collected by filtration, and recrystallized from ethanol-water to obtain colorless crystals of 4-fluoroacetanilide (25.5 g; yield, 83%). cooling concentrated under reduced pressure The thus-obtained solid was washed with water collected by filtration recrystallized from ethanol-water

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

Procedure: A mixture of p-fluoroacetanilide (76.5 g, 0.5 mole), 4-bromofluorobenzene (262.5 g, 1.5 mole), K2CO3 (76 g, 0.55 mole), Cu2Br2 (157.8 g, 0.55 mole) and N-methylpyrrolidone (600 ml) were heated at 175°-180°. After allowing low boiling material to condense off, the mixture was heated at reflux for 7 days. The mixture was cooled to 60° and quenched into a mixture of 2 liters H2O, 600 ml ethylenediamine and 1.2 liters toluene, filtered and the toluene layer separated, back-washed 2×600 ml H2O, treated with activated carbon, dried over MgSO4 and concentrated to oily solids in vacuo. The latter were taken up in 1.5 liters 10% ethanolic KOH, refluxed 18 hours and concentrated in vacuo to an oil. The oil was partitioned between 750 ml H2O and 750 ml. ether. The water layer was washed 2× 200 ml ether. The organic layers were combined, back-washed 2×200 ml H2O, treated with activated carbon, dried over MgSO4, reconcentrated to an oil (60.3 g) and distilled to yield purified title product 41.6 g, b.p. 158°-160°/2 mm. were heated at 175°-180° to condense off, the mixture was heated at reflux for 7 days The mixture was cooled to 60° quenched into a mixture of 2 liters H2O, 600 ml ethylenediamine and 1.2 liters toluene filtered the toluene layer separated back-washed 2×600 ml H2O treated with activated carbon dried over MgSO4 concentrated to oily solids in vacuo refluxed 18 hours concentrated in vacuo to an oil The oil was partitioned between 750 ml H2O and 750 ml The water layer was washed 2× 200 ml ether back-washed 2×200 ml H2O treated with activated carbon dried over MgSO4 distilled to yield purified title product 41.6 g, b.p. 158°-160°/2 mm

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

Procedure: A mixture of p-fluoroacetanilide (76.5 g, 0.5 mole), 4-bromofluorobenzene (262.5 g, 1.5 mole), K2CO3 (76 g, 0.55 mole), Cu2Br2 (157.8 g, 0.55 mole) and N-methylpyrrolidone (600 ml) were heated at 175°-180°. After allowing low boiling material to condense off, the mixture was heated at reflux for 7 days. The mixture was cooled to 60° and quenched into a mixture of 2 liters H2O, 600 ml ethylenediamine and 1.2 liters toluene, filtered and the toluene layer separated, back-washed 2×600 ml H2O, treated with activated carbon, dried over MgSO4 and concentrated to oil solids in vacuo. The latter were taken up in 1.5 liters 10% ethanolic KOH, refluxed 18 hours and concentrated in vacuo to an oil. The oil was partitioned between 750 ml H2O and 750 ml. ether. The water layer was washed 2× 200 ml ether. The organic layers were combined, back-washed 2×200 ml H2O, treated with activated carbon, dried over MgSO4, reconcentrated to an oil (60.3 g) and distilled to yield purified title product 41.6 g, b.p. 158°-160°/2 mm. were heated at 175°-180° to condense off, the mixture was heated at reflux for 7 days The mixture was cooled to 60° quenched into a mixture of 2 liters H2O, 600 ml ethylenediamine and 1.2 liters toluene filtered the toluene layer separated back-washed 2×600 ml H2O treated with activated carbon dried over MgSO4 concentrated to oil solids in vacuo refluxed 18 hours concentrated in vacuo to an oil The oil was partitioned between 750 ml H2O and 750 ml The water layer was washed 2× 200 ml ether back-washed 2×200 ml H2O treated with activated carbon dried over MgSO4 distilled to yield purified title product 41.6 g, b.p. 158°-160°/2 mm

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

Procedure: A mixture of p-fluoroacetanilide (76.5 g, 0.5 mole), 4-bromofluorobenzene (262.5 g, 1.5 mole), K2CO3 (76 g, 0.55 mole), Cu2Br2 (157.8 g, 0.55 mole) and N-methylpyrrolidone (600 ml) were heated at 175°-180°. After allowing low boiling material to condense off, the mixture was heated at reflux for 7 days. The mixture was cooled to 60° and quenched into a mixture of 2 liters H2O, 600 ml ethylenediamine and 1.2 liters toluene, filtered and the toluene layer separated, back-washed 2×600 ml H2O, treated with activated carbon, dried over MgSO4 and concentrated to oily solids in vacuo. The latter were taken up in 1.5 liters 10% ethanolic KOH, refluxed 18 hours and concentrated in vacuo to an oil. The oil was partitioned between 750 ml H2O and 750 ml. ether. The water layer was washed 2× 200 ml ether. The organic layers were combined, back-washed 2×200 ml H2O, treated with activated carbon, dried over MgSO4, reconcentrated to an oil (60.3 g) and distilled to yield purified title product 41.6 g, b.p. 158°-160°/2 mm. were heated at 175°-180° to condense off, the mixture was heated at reflux for 7 days The mixture was cooled to 60° quenched into a mixture of 2 liters H2O, 600 ml ethylenediamine and 1.2 liters toluene filtered the toluene layer separated back-washed 2×600 ml H2O treated with activated carbon dried over MgSO4 concentrated to oily solids in vacuo refluxed 18 hours concentrated in vacuo to an oil The oil was partitioned between 750 ml H2O and 750 ml The water layer was washed 2× 200 ml ether back-washed 2×200 ml H2O treated with activated carbon dried over MgSO4 distilled to yield purified title product 41.6 g, b.p. 158°-160°/2 mm