(5-bromo-2,4-dimethoxyphenyl)methanol

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:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (5-bromo-2,4-dimethoxy-phenyl)-methanol (2.75 g, 11.13 mmol) in dimethylformamide (15 mL) at room temperature was added zinc cyanide (784 mg, 6.678 mmol). The reaction mixture was degassed by passing argon through for 2 h before tetrakis(triphenylphosphine)palladium (772 mg, 0.668 mmol) was added. The reaction mixture was heated at 90° C. for 12 h. After the reaction mixture was cooled to room temperature, it was diluted with diethyl ether (100 mL) and washed with sodium bicarbonate solution, brine and dried over anhydrous sodium sulfate. The solid was filtered off and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 40-50% ethyl acetate in hexanes yielded 5-hydroxymethyl-2,4-dimethoxy-benzonitrile as a white solid (1.089 g, 51%). The reaction mixture was degassed through for 2 h was added After the reaction mixture was cooled to room temperature washed with sodium bicarbonate solution, brine dried over anhydrous sodium sulfate The solid was filtered off the filtrate was concentrated in vacuo Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 40-50% ethyl acetate in hexanes

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

Procedure: To a solution of methyl 5-bromo-2,4-dimethoxy-benzoate (5.137 g, 22.05 mmol) in tetrahydrofuran (60 mL) cooled to 0° C. was added lithium aluminum hydride (863 mg, 22.05 mmol) in several portions. At the end of addition, the reaction mixture was stirred at 0° C. for 15 min before the icebath was removed. The reaction was continued at room temperature for 48 h. It was cooled to 0° C. and water (˜5 mL) was carefully added to quench the excess lithium aluminum hydride. Sodium hydroxide (5% solution, 20 mL) was then added and the layers were separated after 2 h of stirring. The product was extracted with diethyl ether (2×100 mL). The organic layers were washed with sodium bicarbonate solution (1×10 mL), brine (1×10 mL) and dried over anhydrous sodium sulfate. The solid was filtered off and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 40% ethyl acetate in hexanes yielded (5-bromo-2,4-dimethoxy-phenyl)-methanol as off-white solids (3.743 g, 81%). At the end of addition was removed The reaction was continued at room temperature for 48 h It was cooled to 0° C. water (˜5 mL) was carefully added to quench the excess lithium aluminum hydride Sodium hydroxide (5% solution, 20 mL) was then added the layers were separated after 2 h of stirring The product was extracted with diethyl ether (2×100 mL) The organic layers were washed with sodium bicarbonate solution (1×10 mL), brine (1×10 mL) dried over anhydrous sodium sulfate The solid was filtered off the filtrate was concentrated in vacuo Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 40% ethyl acetate in hexanes