4-bromo-2,6-difluorophenol

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:

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

Procedure: A solution of bromine (1.6 g) in dry carbon disulphide (10 cm3) was added over 5 minutes to a solution of 2,6-difluorophenol (1.3 g) in dry carbon disulphide (10 cm3). To the stirred reaction mixture was added 5 drops of 48% hydrogen bromide solution. The mixture was heated for 2 hours at the reflux temperature, then allowed to stand at the ambient temperature (ca 22° C.) for 16 hours. After a further period of heating (4 hours) the mixture was allowed to stand for 24 hours before being poured onto water (20 cm3). To the mixture was added saturated sodium metabisulphite solution (30 cm3). The layers were separated, and the organic phase was washed with saturated sodium hydrogen carbonate solution (20 cm3) and water (20 cm3). The organic layer was dried over anhydrous sodium sulphate then evaporated under reduced pressure to given an oil which solidified. The crude product was distilled in a Kugelrohr apparatus at an oven temperature of 100° C. under reduced pressure (ca. 20 mmHg). The distillate crystallised to give 4-bromo-2,6-difluorophenol as a white solid (0.48 g). To the stirred reaction mixture The mixture was heated for 2 hours at the reflux temperature After a further period of heating (4 hours) the mixture to stand for 24 hours before being poured onto water (20 cm3) The layers were separated the organic phase was washed with saturated sodium hydrogen carbonate solution (20 cm3) and water (20 cm3) The organic layer was dried over anhydrous sodium sulphate then evaporated under reduced pressure The crude product was distilled in a Kugelrohr apparatus at an oven temperature of 100° C. under reduced pressure (ca. 20 mmHg) The distillate crystallised

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

Procedure: The title compound was prepared from 4-bromo-2,6-difluorophenol and tetrahydro-4H-pyran-4-ol in analogy to Example 9c): MS (EI): 292 and 294 M+.

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

Procedure: 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)

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

Procedure: 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)

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

Procedure: To a solution of 2,6-Difluorophenol (10.0 g, 76.86 mmoles) in DMF (60 mll), N-bromosuccinimide (13.68 g, 76.86 mmoles) was added at 0° C. and stirred at RT for 20 h. The reaction mixture was concentrated, diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as light yellow liquid (15.1 g, 93% yield). 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 10.49(s,1H), 7.35 (d, J=6.2 Hz, 2H). The reaction mixture was concentrated diluted with water extracted with ethyl acetate The organic layer was dried over sodium sulphate concentrated under reduced pressure

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

Procedure: 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