5-bromo-1,3-difluoro-2-methoxybenzene

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl iodide (580 TL, 10.06 mmol) and K2CO3 (2.80 g, 20.12 mmol) were added to a solution of 4-bromo-2,6-difluorophenol (1.05 g, 5.03 mmol) in DMF (10 mL) and stirred at rt under Ar for 24 h. Upon completion, ethyl acetate was added and the reaction was washed with 1% HCl (2×20 mL), brine (1×), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (hexane) to afford 4-bromo-2,6-difluoroanisole (747 mg, 67%) as a white solid. See, for example, Chambers, R. D.; et al. J. Fluorine Chem. 2000, 102, 169-174, which is incorporated by reference in its entirety. 1H NMR (CDCl3, 400 MHz) δ 7.06 (m, 2H), 3.97 (q, 3H, J=1.1 Hz). 13C NMR (CDCl3, 100 MHz) δ 155.8, 136.3, 116.2, 113.8, 61.9. LREIMS found for C7H5F2OBr (M+) 223.0. the reaction was washed with 1% HCl (2×20 mL), brine (1×) dried over MgSO4 concentrated in vacuo The residue was purified by flash chromatography (hexane)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl iodide (580 TL, 10.06 mmol) and K2CO3 (2.80 g, 20.12 mmol) were added to a solution of 4-bromo-2,6-difluorophenol (1.05 g, 5.03 mmol) in DMF (10 mL) and stirred at rt under Ar for 24 h. Upon completion, ethyl acetate was added and the reaction was washed with 1% HCl (2×20 mL), brine (1×), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (hexane) to afford 4-bromo-2,6-difluoroanisole (747 mg, 67%) as a white solid. See, for example, Chambers, R. D.; et al. J. Fluorine Chem. 2000, 102, 169-174, which is incorporated by reference in its entirety. 1H NMR (CDCl3, 400 MHz) δ 7.06 (m, 2H), 3.97 (q, 3H, J=1.1 Hz). 13C NMR (CDCl3, 100 MHz) δ 155.8, 136.3, 116.2, 113.8, 61.9. LREIMS found for C7H5F2OBr (M+) 223.0. the reaction was washed with 1% HCl (2×20 mL), brine (1×) dried over MgSO4 concentrated in vacuo The residue was purified by flash chromatography (hexane)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Add n-butyl lithium 1.6N (22 ml, 35.2 mmol) to diisopropylamine (4.8 ml, 34.2 mmol) in anhydrous THF (7 ml) at 0° C. Stir the resulting yellow solution for 30 min at 0° C. Add this LDA solution dropwise via canula to a solution of 5-bromo-1,3-difluoro-2-methoxybenzene (5.83 g, 26.17 mmol) in anhydrous THF (40 ml) at −78° C. over 40 min. Stir the resulting bright yellow solution for 50 min at −78° C. Add anhydrous DMF (2.7 ml, 34.8 mmol) and stir the mixture for 1.5 h at −78° C. Quench the mixture with dilute sulfuric acid and extract the product with EtOAc (×3). Wash the combined organic layers with water (×3), saturated aq. sodium chloride and dry over anhydrous sodium sulfate. Filter and concentrate to yield the crude product. Purification by flash chromatography (Silica gel-hexane/EtOAc) yields the title compound. Stir the resulting bright yellow solution for 50 min at −78° C Quench the mixture with dilute sulfuric acid extract the product with EtOAc (×3) Wash the combined organic layers with water (×3), saturated aq. sodium chloride dry over anhydrous sodium sulfate Filter concentrate to yield the crude product Purification by flash chromatography (Silica gel-hexane/EtOAc)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Add n-butyl lithium 1.6N (22 ml, 35.2 mmol) to diisopropylamine (4.8 ml, 34.2 mmol) in anhydrous THF (7 ml) at 0° C. Stir the resulting yellow solution for 30 min at 0° C. Add this LDA solution dropwise via canula to a solution of 5-bromo-1,3-difluoro-2-methoxybenzene (5.83 g, 26.17 mmol) in anhydrous THF (40 ml) at −78° C. over 40 min. Stir the resulting bright yellow solution for 50 min at −78° C. Add anhydrous DMF (2.7 ml, 34.8 mmol) and stir the mixture for 1.5 h at −78° C. Quench the mixture with dilute sulfuric acid and extract the product with EtOAc (×3). Wash the combined organic layers with water (×3), saturated aq. sodium chloride and dry over anhydrous sodium sulfate. Filter and concentrate to yield the crude product. Purification by flash chromatography (Silica gel-hexane/EtOAc) yields the title compound. Stir the resulting bright yellow solution for 50 min at −78° C Quench the mixture with dilute sulfuric acid extract the product with EtOAc (×3) Wash the combined organic layers with water (×3), saturated aq. sodium chloride dry over anhydrous sodium sulfate Filter concentrate to yield the crude product Purification by flash chromatography (Silica gel-hexane/EtOAc)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Add iodomethane (2.0 ml, 32.1 mmol) dropwise to a suspension of 4-bromo-2,6-difluorophenol (5.90 g, 28.2 mmol) and potassium carbonate (4.40 g, 31.8 mmol) in acetone (50 ml) at room temperature while stirring vigorously. Heat the mixture under reflux overnight. Evaporate acetone and add dichloromethane. Filter through silica eluting the product with dichloromethane/EtOAc. Concentrate to yield the title compound. Heat the mixture under reflux overnight Filter through silica eluting the product with dichloromethane/EtOAc Concentrate

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Isopropyl magnesium chloride lithium chloride complex (22.0 mL, 28.02 mmol) was added dropwise to a stirred solution of 5-bromo-1,3-difluoro-2-methoxybenzene (5.0 g, 22.42 mmol) at −5° C. in THF (100 mL) and the reaction mixture was stirred at same temperature for 30 min. Methyl trifluoroacetate (3.67 g, 28.69 mmol) was added dropwise and the reaction mixture was stirred at ambient temperature for 2 h. A 2 N HCl solution (200 mL) was added to quench the reaction and then it was extracted with diethylether. The combined organic layers were washed with brine, dried (Na2SO4) filtered and concentrated to afford the title compound (5.4 g, crude) as a yellow liquid. The material was taken to next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.68-7.60 (m, 2H) 4.19 (s, 3H); ESIMS m/z 240.1 ([M]+). the reaction mixture was stirred at ambient temperature for 2 h to quench the reaction it was extracted with diethylether The combined organic layers were washed with brine dried (Na2SO4) filtered concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Isopropyl magnesium chloride lithium chloride complex (22.0 mL, 28.02 mmol) was added dropwise to a stirred solution of 5-bromo-1,3-difluoro-2-methoxybenzene (5.0 g, 22.42 mmol) at −5° C. in THF (100 mL) and the reaction mixture was stirred at same temperature for 30 min. Methyl trifluoroacetate (3.67 g, 28.69 mmol) was added dropwise and the reaction mixture was stirred at ambient temperature for 2 h. A 2 N HCl solution (200 mL) was added to quench the reaction and then it was extracted with diethylether. The combined organic layers were washed with brine, dried (Na2SO4) filtered and concentrated to afford the title compound (5.4 g, crude) as a yellow liquid. The material was taken to next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.68-7.60 (m, 2H) 4.19 (s, 3H); ESIMS m/z 240.1 ([M]+). the reaction mixture was stirred at ambient temperature for 2 h to quench the reaction it was extracted with diethylether The combined organic layers were washed with brine dried (Na2SO4) filtered concentrated