2-Bromo-5-fluoroanisole

Colorless liquid to pale yellow liquid

To a pre-cooled suspension of 2-bromo-5-fluorophenol (5 g, 26.18 mmol) and potassium carbonate (10.84 g, 78.54 mmol) in DMF (15 mL) at 0-5° C., was added methyl iodide (4.75 mL, 39.27 mmol) and the resulting reaction mixture was stirred at room temperature for 16 hours. In a 1L four-necked flask, 48percent hydrobromic acid 660 g was added, stirred, and slowly poured into 4-fluoro-2-methoxyaniline 195 g (1.38 mol), stirred for 30 min, and large number of solids were precipitated. The mixture was cooled to -5°C, 300 g (1.45 mol) of a 33percent aqueous solution of sodium nitrite was added dropwise, the temperature was controlled to below -5 ° C for 1 hour. The temperature was maintained at 0 ° C for 15-30 minutes to obtain diazo solution. In another 2L four-necked flask, 48 g of hydrobromic acid was added, water 200 g, cuprous bromide 80 g were added, heated to boil for about 105°C. The diazo liquid was began to drop through the dropping funnel for about 30-60 min. After completion of dropping, steam distillation was carried out, the product was distilled out. Diazo liquid was dropped, steam distillation was carried out for 5 hours, until the distillate does not have oil beads. The layer separation was carried out, the oil layer was separated to obtain 263 g of 4-fluoro-2-methoxybromobenzene, light yellow oily liquid. GC content of 98.30percent, yield 93percent.a) 2-Bromo-5-fluoroanisole To a suspension of 2-bromo-5-fluorophenol (20.0 g, 104.7 mmol) and potassium carbonate (21.71 g, 157.1 mmol) in acetone (200 mL) was added dimethyl sulphate (10. 90 ML, 115.2 mmol). The resulting suspension was allowed to stir at 60C for 2 h before being allowed to cool and then concentrated in vacuo. The residue was dissolved in ether (200 mL) and water (100 mL). The organic phase was washed with aqueous hydrochloric acid (2 N, 50 mL), saturated sodium bicarbonate solution (50 mL) with the resulting organic phase being dried (MGS04) and the solvent evaporated in vacuo to give a pale yellow oil (21.46 g, 100percent). ON (300 MHz, CDC13) 7.45 (1H, dd, Ar), 6.70-6. 55 (2H, m, Ar), 3. 90 (3H, s, OCH3)3-FLUORO-2-METHOXVBENZALDEHYDE To a suspension of 3-fluoro-2-hydroxybenzaldehyde (5.328 g, 38.02 mmol) and potassium carbonate (7.88 g, 57.03 mmol) in acetone (60 mL) was added dimethyl sulphate (3.96 ML, 41.83 mmol). The resulting suspension was stirred at 60C for 2 h before being allowed to cool and then concentrated in vacuo. The residue was dissolved in dichloromethane (100 mL) and water (50 mL). The organic phase was washed with saturated sodium bicarbonate (50 mL) with the resulting organic phase being dried (MGS04) and the solvent evaporated in vacuo to give a pale yellow oil (6.262 g, 38.02 mmol, 100percent). OH (300 MHz, CDC13) 10.40 (1H, s, CHO), 7.60 (1H, d, Ar), 7.30 (1H, m, Ar), 7.10 (1H, m, Ar), 4.10 (3H, s, OCH3).a) 2-Bromo-5-fluoroanisole To a suspension of 2-bromo-5-fluorophenol (20.0 g, 104.7 mmol) and potassium carbonate (21.71 g, 157.1 mmol) in acetone (200 mL) was added dimethyl sulphate (10.90 ML, 115.2 mmol). The resulting suspension was allowed to stir at 60C for 2 h before being allowed to cool and then concentrated in vacuo. The residue was dissolved in ether (200 mL) and water (100 mL). The organic phase was washed with aqueous hydrochloric acid (2 N, 50 mL), saturated sodium bicarbonate solution (50 ML) with the resulting organic phase being dried (MgSO4) and the solvent evaporated in vacuo to give a pale yellow oil (21.46 g, 100percent). SN (300 MHz, CDCl3) 7.45 (1H, dd, Ar), 6.70-6. 55 (2H, m, Ar), 3.90 (3H, s, OCH3).A mixture of 1-bromo-2, 4-difluorobenzene 1 (Scheme 6) (75.6 g, 0.39 mol), KOMe (37 g, 0.5 mol) in THF (300 mL) was heated to 65 - 68°C and stirred at that temperature for 5 hours. The reaction mixture was cooled to room temperature and water (300 mL). The resulting mixture was extracted with DIPE and the organic layer was washed twice with water (2 x 150 mL) and brine (100 mL), dried over NaA mixture of 1-bromo-2, 4-difluorobenzene 1 (Scheme 6) (75.6 g, 0.39 mol), KOMe (37 g, 0.5 mol) in THF (300 mL) was heated to 65 - 68°C and stirred at that temperature for 5 hours. The reaction mixture was cooled to room temperature and water (300 mL). The resulting mixture was extracted with DIPE and the organic layer was washed twice with water (2 x 150 mL) and brine (100 mL), dried over NaTo tert-butyl (R)-3-methylpiperazine-1 -carboxylate (5.37 g, 26.8 mmol) and 1 - bromo-4-fluoro-2-methoxybenzene (5.00 g, 24.4 mmol) in toluene (50 ml.) was added sodium tert-butoxide (4.69 g, 48.8 mmol) followed by BrettPhos palladacycle G3 (66.4 mg, 0.0732 mmol). The mixture was sealed under nitrogen and stirred at 100 C and after 1 h the mixture was cooled to ambient temp, diluted with ethyl acetate and water. The organic layer was dried with sodium sulfate, filtered, and concentrated. Crude product was purified by column chromatography (0-40%, ethyl acetate/hexanes) to provide the product. MS(EI) for C; /H:FN;.C. found 325 [M+H]+.