4-bromo-2,6-dichlorophenol

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

Procedure: To a solution of 4-bromo-2,6-dichlorophenol (11.9 g, 49.2 mmol, H. Joyce et al., J. Amer. Chem. Soc., 39, 2644 (1917)) in DMF (100 mL) imidazole (5.0 g, 74 mmol) and tert-butyldimethylsilylchloride (8.9 g, 59 mmol) was added at room temperature and the mixture was stirred for 1 h. The mixture was poured into water (300 mL) and extracted with diethyl ether (100 mL×2) and washed with water (50 mL×2), dried over MgSO4 and concentrated in vacuo gave pale yellow oil. (15.3 g, 87%) extracted with diethyl ether (100 mL×2) washed with water (50 mL×2) dried over MgSO4 concentrated in vacuo gave pale yellow oil

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

Procedure: Methyl iodide (467 TL, 8.12 mmol) and K2CO3 (2.24 g, 16.24 mmol) were added to a solution of 4-bromo-2,6-dichlorophenol (982 mg, 4.06 mmol) in DMF (10 mL) and stirred at rt under Ar for 40 min. 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-dichloroanisole (768 mg, 74%) as a white solid. See, for example, Li, J.; et al. J. Med. Chem. 1996, 39, 1846-1856, which is incorporated by reference in its entirety. 1H NMR (DMSO-d6, 400 MHz) δ 7.75 (s, 2H), 3.81 (s, 3H). 13C NMR (DMSO-d6, 100 MHz) δ 151.3, 131.5, 129.6, 116.5, 60.6. HREIMS calculated for C7H5BrCl2O (M+) 253.8905, found 253.8901. 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 (467 TL, 8.12 mmol) and K2CO3 (2.24 g, 16.24 mmol) were added to a solution of 4-bromo-2,6-dichlorophenol (982 mg, 4.06 mmol) in DMF (10 mL) and stirred at rt under Ar for 40 min. 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-dichloroanisole (768 mg, 74%) as a white solid. See, for example, Li, J.; et al. J. Med. Chem. 1996, 39, 1846-1856, which is incorporated by reference in its entirety. 1H NMR (DMSO-d6, 400 MHz) δ 7.75 (s, 2H), 3.81 (s, 3H). 13C NMR (DMSO-d6, 100 MHz) δ 151.3, 131.5, 129.6, 116.5, 60.6. HREIMS calculated for C7H5BrCl2O (M+) 253.8905, found 253.8901. 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: A solution of 4-bromo-2,6-dichlorophenol (1.24 g, 6.02 mmol), methyl (2S)-2-hydroxy-3-phenylpropanoate (1.30 g, 7.22 mmol) and triphenylphosphine (2.05 g, 7.83 mmol) in THF (13 mL) at room temperature was treated with DEAD (1.28 mL, 8.13 mmol), stirred for 2 hours, and concentrated. The concentrate was triturated with 10% ethyl acetate/hexanes, filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5% ethyl acetate/hexanes to provide 1.90 g (78%) of the desired product. concentrated The concentrate was triturated with 10% ethyl acetate/hexanes filtered concentrated The concentrate was purified by flash column chromatography on silica gel with 5% ethyl acetate/hexanes

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

Procedure: To a solution of 4-bromo-2,6-dichlorophenol (11.9 g, 49.2 mmol, H. Joyce et al., J. Amer. Chem. Soc., 39, 2644 (1917)) in DMF (100 mL) imidazole (5.0 g, 74 mmol) and tert-butyldimethylsilylchloride (8.9 g, 59 mmol) was added at room temperature and the mixture was stirred for 1 h. The mixture was poured into water (300 mL) and extracted with diethyl ether (100 mL×2) and washed with water (50 mL×2), dried over MgSO4 and concentrated in vacuo gave pale yellow oil. (15.3 g, 87%) extracted with diethyl ether (100 mL×2) washed with water (50 mL×2) dried over MgSO4 concentrated in vacuo gave pale yellow oil

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

Procedure: To a solution of 4-bromo-2,6-dichlorophenol (11.9 g, 49.2 mmol, H. Joyce et al., J. Amer. Chem. Soc., 39, 2644 (1917)) in DMF (100 mL) imidazole (5.0 g, 74 mmol) and tert-butyldimethylsilylchloride (8.9 g, 59 mmol) was added at room temperature and the mixture was stirred for 1 h. The mixture was poured into water (300 mL) and extracted with diethyl ether (100 mL×2) and washed with water (50 mL×2), dried over MgSO4 and concentrated in vacuo gave pale yellow oil. (15.3 g, 87%) extracted with diethyl ether (100 mL×2) washed with water (50 mL×2) dried over MgSO4 concentrated in vacuo gave pale yellow oil

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

Procedure: To a stirred solution of 4-bromo-2,6-dichlorophenol (2.3 g) in acetonitrile (25 mL) was added potassium carbonate (1.3 g) and ethyl bromodifluoroacetate (3.8 g). The mixture was heated to reflux for 4 hours and then cooled to room temperature. The resulting mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL×1). The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography on silica gel eluted with ethyl acetate-hexane (1:4) to afford the title compound as yellow oil (2.4 g). The mixture was heated to reflux for 4 hours extracted with ethyl acetate (100 mL×1) The organic layer was washed with water and brine dried over anhydrous sodium sulfate concentrated under reduced pressure to provide a residue The residue was purified by column chromatography on silica gel eluted with ethyl acetate-hexane (1:4)

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

Procedure: The title compound was prepared analogously to Step 1 in Example A(52), where iodoethane was substituted instead of methyl α-bromobutyrate and 4-Bromo-2,6-dichloro-phenol was substituted instead of 4-Bromo-2-fluorophenol of that example.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mechanically stirred solution of 2,6-dichlorophenol (100 g) in acetonitrile (400 mL) was cooled to 0° C. and bromine (108 g) in acetonitrile (100 mL) was added dropwise. The red solution was stirred at 0° C. for an additional two hours and an saturated aqueous solution of sodium sulphite was added until the red color disappeared. The phases were separated and the aqueous phase was extracted three times with ethyl acetate. Concentration of the combined organic phases gave 4-bromo-2,6-dichlorophenol as a yellow oil, which crystallized on standing. The crystalline material was washed with water and dried to give 126 g (85%) of colorless crystals. The phases were separated the aqueous phase was extracted three times with ethyl acetate

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

Procedure: To a stirred solution of 4-bromo-2,6-dichlorophenol (2.3 g) in acetonitrile (25 mL) was added potassium carbonate (1.3 g) and ethyl bromodifluoroacetate (3.8 g). The mixture was heated to reflux for 4 hours and then cooled to room temperature. The resulting mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL×1). The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography on silica gel eluted with ethyl acetate-hexane (1:4) to afford the title compound as yellow oil (2.4 g). The mixture was heated to reflux for 4 hours extracted with ethyl acetate (100 mL×1) The organic layer was washed with water and brine dried over anhydrous sodium sulfate concentrated under reduced pressure to provide a residue The residue was purified by column chromatography on silica gel eluted with ethyl acetate-hexane (1:4)

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

Procedure: To a stirred solution of 4-bromo-2,6-dichlorophenol (2.3 g) in acetonitrile (25 mL) was added potassium carbonate (1.3 g) and ethyl bromodifluoroacetate (3.8 g). The mixture was heated to reflux for 4 hours and then cooled to room temperature. The resulting mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL×1). The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography on silica gel eluted with ethyl acetate-hexane (1:4) to afford the title compound as yellow oil (2.4 g). The mixture was heated to reflux for 4 hours extracted with ethyl acetate (100 mL×1) The organic layer was washed with water and brine dried over anhydrous sodium sulfate concentrated under reduced pressure to provide a residue The residue was purified by column chromatography on silica gel eluted with ethyl acetate-hexane (1:4)

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

Procedure: A mixture of 4-bromo-2,6-dichlorophenol (10 g, 41.67 mmol), K2CO3 (11.5 g, 83.3 mmol) and CH3I (8.88 g, 62.5 mmol) in DMF (100 mL) was stirred at rt for 16 h. TLC (EtOAc/petroleum ether=1:2) indicated complete consumption of 4-bromo-2,6-dichlorophenol. The reaction mixture was poured into water (300 mL). The aqueous phase was extracted with EtOAc (2×100 mL). The combined organic phases were dried over anhydrous Na2SO4, and concentrated in vacuo to give crude 5-bromo-1,3-dichloro-2-methoxybenzene, which was purified by column chromatography (silica gel, EtOAc/petroleum ether=1:5) to yield the ether product (9 g, yield 84.9%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.45 (s, H), 3.91 (s, 3H) ppm. consumption of 4-bromo-2,6-dichlorophenol The reaction mixture was poured into water (300 mL) The aqueous phase was extracted with EtOAc (2×100 mL) The combined organic phases were dried over anhydrous Na2SO4 concentrated in vacuo to give crude 5-bromo-1,3-dichloro-2-methoxybenzene, which was purified by column chromatography (silica gel, EtOAc/petroleum ether=1:5)