1-(3-bromo-4-fluorophenyl)ethanone

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:

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

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

Procedure: To a suspension of sodium hydride (1.1 g of 60% suspension in mineral oil, hexane-washed, 27.6 mmol) in 50 mL of tetrahydrofuran was added dimethyl carbonate (2.3 mL, 27.6 mmol) and 3′-bromo-4′-fluoroacetophenone (3.0 g, 13.8 mmol).

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

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

Procedure: Methyl-5-hydroxynicotinate (1.0 g, 6.53 mmol), 3′-bromo-4′-fluoroacetophenone (1.42 g, 6.53 mmol), 18-crown-6 (155.3 mg, 0.59 mmol) and potassium fluoride (40 wt. % on alumina, 996 mg, 6.86 mmol) were dissolved in ACN (10 mL). The reaction was refluxed for three days. After cooling the mixture was quenched with 2N aqueous potassium carbonate solution, extracted with ether, dried with sodium sulphate, filtered, evaporated and purified by silica gel chromatography (ethyl acetate:n-heptane 1:4). 635 mg (yield: 28%) of the pure compound was obtained. The reaction was refluxed for three days After cooling the mixture was quenched with 2N aqueous potassium carbonate solution extracted with ether dried with sodium sulphate filtered evaporated purified by silica gel chromatography (ethyl acetate:n-heptane 1:4)

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

Procedure: To 3-bromo-4-fluoroacetophenone (11.0 g) in 1,4-dioxane (160 ml) and water (15 ml) was added selenium dioxide (8.8 g). The mixture was heated at reflux for 10 h, cooled to room temperature, and the solvent then removed at reduced pressure. The residue was suspended in 50% diethyl ether in isohexane, and residual solid removed by filtration. The filtrate was dried over Na2SO4, and solvent then evaporated to give (3-bromo-4-fluorophenyl)oxoacetaldehyde as a yellow oil, which was used without further purification in the next step. The mixture was heated at reflux for 10 h the solvent then removed at reduced pressure residual solid removed by filtration The filtrate was dried over Na2SO4, and solvent then evaporated

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

Procedure: A solution of 1.09 gm (5 mMol) 3-bromo-4-fluoroacetophenone and 3.45 gm (20 mMol) m-chloroperbenzoic acid (70%) in 15 mL dichloromethane was heated at reflux for 18 hours. An additional 3.45 gm m-chloroperbenzoic acid were added and reflux continued for about 12 hours. At this point an additional 1.4 gm m-chloroperbenzoic acid were added and reflux continued for 18 hours. The reaction mixture was cooled to room temperature and was then diluted with 50 mL diethyl ether. The resulting mixture was cooled to 0° C. and was then treated with 15 mL 20% aqueous sodium thiosulfate. The resulting slurry was stirred for about 1 hour and then the phases separated. The organic phase was washed sequentially with 3×20 mL 20% aqueous sodium thiosulfate followed by 3×20 mL saturated aqueous sodium chloride. The organic phase was then dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 10:1 hexane:diethyl ether. Fractions containing product were combined and concentrated under reduced pressure to provide 68% of the desired compound. at reflux for 18 hours reflux reflux continued for 18 hours The resulting mixture was cooled to 0° C. the phases separated The organic phase was washed sequentially with 3×20 mL 20% aqueous sodium thiosulfate The organic phase was then dried over sodium sulfate concentrated under reduced pressure eluting with 10:1 hexane Fractions containing product concentrated under reduced pressure

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of sodium hydride (1.1 g of 60% suspension in mineral oil, hexane-washed, 27.6 mmol) in 50 mL of tetrahydrofuran was added dimethyl carbonate (2.3 mL, 27.6 inmol) and 3'-bromo-4'-fluoroacetophenone (3.0 g, 13.8 mmol). The resulting suspension was stirred at 65° C. for 1 h and then was cooled to room temperature. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (elution with 3:1 hexane/ethyl acetate) to afford 1.0 g (26%) of the title compound. 1H NMR (CDCl3) (data for keto tautomer) δ8.15 (dd, 1H), 7.87 (m, 1H), 7.2 (m, 1H), 3.95 (s, 2H), 3.73 (s, 3H). was cooled to room temperature washed with water and brine dried (MgSO4) concentrated in vacuo The residue was purified by flash chromatography (elution with 3:1 hexane/ethyl acetate)

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

Procedure: 1-(3-Bromo-4-fluorophenyl)ethanone (5.0 g, 23.0 mmol) was dissolved in toluene (100 mL), a 3.0 M methylmagnesium chloride-tetrahydrofuran solution (11.5 mL, 34.6 mmol) was added dropwise with stirring under ice cooling, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. Subsequently, acetic acid (1 mL) was added with stirring under ice cooling, and the mixture was stirred with heating to reflux for 4 hours. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added with stirring under ice cooling, and ethyl acetate was further added to separate the layers. The resulting organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1, v/v) to give the title compound (2.06 g; yield, 42%) as a colorless oily substance. the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour with stirring under ice cooling the mixture was stirred with heating to reflux for 4 hours with stirring under ice cooling to separate the layers The resulting organic layer was separated washed with saturated sodium chloride solution dried with anhydrous sodium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (hexane