3,5-二氟-4-叔丁基苯酚

反应条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 3,5-difluorophenol (TCI, 14 g, 107 mmol), tert-butyl methyl ether (12.8 ml, 108 mmol) and zirconium(IV) chloride (25 g, 107 mmol) was stirred for 12 hours at 55° C., followed by addition of tert-butyl methyl ether (6.4 ml, 54 mmol). The additional injection of tert-butyl methyl ether (6.4 ml, 54 mmol), was repeated 8 times at intervals of 24 hours and then the reaction was quenched with saturated ammonium chloride aqueous solution and 2 M HCl aqueous solution. The whole was extracted with DCM, washed with brine, and dried over magnesium sulfate. The organic layer was evaporated to give a crude residue which was purified by silica gel column chromatography, eluting with gradually from hexane only to hexane/EtOAc (10:1), to give the title compound (10.8 g, 54%) as white solids. at intervals of 24 hours the reaction was quenched with saturated ammonium chloride aqueous solution and 2 M HCl aqueous solution The whole was extracted with DCM washed with brine dried over magnesium sulfate The organic layer was evaporated to give a crude residue which was purified by silica gel column chromatography eluting with gradually from hexane only to hexane/EtOAc (10:1)

反应条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 3,5-difluorophenol (TCI, 14 g, 107 mmol), tert-butyl methyl ether (12.8 ml, 108 mmol) and zirconium(IV) chloride (25 g, 107 mmol) was stirred for 12 hours at 55° C., followed by addition of tert-butyl methyl ether (6.4 ml, 54 mmol). The additional injection of tert-butyl methyl ether (6.4 ml, 54 mmol), was repeated 8 times at intervals of 24 hours and then the reaction was quenched with saturated ammonium chloride aqueous solution and 2 M HCl aqueous solution. The whole was extracted with DCM, washed with brine, and dried over magnesium sulfate. The organic layer was evaporated to give a crude residue which was purified by silica gel column chromatography, eluting with gradually from hexane only to hexane/EtOAc (10:1), to give the title compound (10.8 g, 54%) as white solids. at intervals of 24 hours the reaction was quenched with saturated ammonium chloride aqueous solution and 2 M HCl aqueous solution The whole was extracted with DCM washed with brine dried over magnesium sulfate The organic layer was evaporated to give a crude residue which was purified by silica gel column chromatography eluting with gradually from hexane only to hexane/EtOAc (10:1)

反应条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a suspension of sodium hydride (75 mg, 1.9 mmol) in THF (5 ml) was added 4-tert-butyl-3,5-difluorophenol (290 mg, 1.6 mmol) at 0° C., followed by stirring for 30 minutes. Then, tert-butyl bromoacetate (370 mg, 1.9 mmol) was added and the mixture was refluxed at 90° C. for 1 hour. The reaction was quenched with saturated ammonium chloride aqueous solution and the product was extracted with EtOAc, washed with brine, dried over magnesium sulfate. Then, filtration, evaporation, and purification through silica gel column chromatography eluting with hexane/EtOAc (20:1 to 4:1) gave the tert-butyl(4-tert-butyl-3,5-difluorophenoxy)acetate (403 mg, 86%). The DCM (2.0 ml) solution of tert-butyl(4-tert-butyl-3,5-difluorophenoxy)acetate (400 mg, 1.34 mmol) and TFA (2.0 ml), was stirred for 1 hour at room temperature. Evaporation gave the residue which was triturated with Hexane to furnish the title compound as a white solid (253 mg, 77%). 1H NMR (300 MHz, CDCl3): δ 1.42 (9H, t, J=2.2 Hz), 4.63 (2H, s), 6.39 (2H, d, J=12.1 Hz). MS (ESI) m/z 243 (M−H)−. The reaction was quenched with saturated ammonium chloride aqueous solution the product was extracted with EtOAc washed with brine dried over magnesium sulfate Then, filtration, evaporation, and purification through silica gel column chromatography eluting with hexane/EtOAc (20:1 to 4:1)

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a suspension of zirconium tetrachloride (1.17 g, 5 mmol) in DCM (10 ml) was added tert-butyl methyl ether (0.44 g, 5 mmol) at 0° C. After stirring for 30 minutes at 0° C., 3,5-difluorophenol (0.65 g, 5 mmol) in DCM was placed there and the mixture was stirred for 8 hours at 60° C. The reaction was quenched with saturated sodiumbicarbonate aqueous solution followed by addition of DCM. Then, organic layer was separated, dried over magnesium sulfate, evaporated in vacuo to give the residue which was purified through silica gel column chromatography eluting with hexane/EtOAc (20:1 to 4:1) to furnish 4-tert-butyl-3,5-difluorophenol as colorless oil (293 mg, 31%). 1H NMR (300 MHz, CDCl3): δ 1.42 (9H, t, J=2.2 Hz), 5.22 (1H, bs), 6.32 (2H, d, J=11.9 Hz). the mixture was stirred for 8 hours at 60° C The reaction was quenched with saturated sodiumbicarbonate aqueous solution followed by addition of DCM Then, organic layer was separated dried over magnesium sulfate evaporated in vacuo to give the residue which was purified through silica gel column chromatography eluting with hexane/EtOAc (20:1 to 4:1)

反应条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 3,5-difluorophenol (TCl, 14 g, 107 mmol), tert-butyl methyl ether (12.8 ml, 108 mmol) and zirconium(IV) chloride (25 g, 107 mmol) was stirred for 12 hours at 55 ° C., followed by addition of tert-butyl methyl ether (6.4 ml, 54 mmol). The additional injection of tert-butyl methyl ether (6.4 ml, 54 mmol), was repeated 8 times at intervals of 24 hours and then the reaction was quenched with saturated ammonium chloride aqueous solution and 2 M HCl aqueous solution. The whole was extracted with DCM, washed with brine, and dried over magnesium sulfate. The organic layer was evaporated to give a crude residue which was purified by silica gel column chromatography, eluting with gradually from hexane only to hexane/EtOAc (10:1), to give the title compound (10.8 g, 54%) as white solids. at intervals of 24 hours the reaction was quenched with saturated ammonium chloride aqueous solution and 2 M HCl aqueous solution The whole was extracted with DCM washed with brine dried over magnesium sulfate The organic layer was evaporated to give a crude residue which was purified by silica gel column chromatography eluting with gradually from hexane only to hexane/EtOAc (10:1)

反应条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 3,5-difluorophenol (TCI, 14 g, 107 mmol), tert-butyl methyl ether (12.8 ml, 108 mmol) and zirconium(IV) chloride (25 g, 107 mmol) was stirred for 12 hours at 55° C., followed by addition of tert-butyl methyl ether (6.4 ml, 54 mmol). The additional injection of tert-butyl methyl ether (6.4 ml, 54 mmol), was repeated 8 times at intervals of 24 hours and then the reaction was quenched with saturated ammonium chloride aqueous solution and 2 M HCl aqueous solution. The whole was extracted with DCM, washed with brine, and dried over magnesium sulfate. The organic layer was evaporated to give a crude residue which was purified by silica gel column chromatography, eluting with gradually from hexane only to hexane/EtOAc (10:1), to give the title compound (10.8 g, 54%) as white solids. at intervals of 24 hours the reaction was quenched with saturated ammonium chloride aqueous solution and 2 M HCl aqueous solution The whole was extracted with DCM washed with brine dried over magnesium sulfate The organic layer was evaporated to give a crude residue which was purified by silica gel column chromatography eluting with gradually from hexane only to hexane/EtOAc (10:1)