2,4,6-Trimethylpyridine → 3-Bromo-5-hydroxybenzonitrile

Participants

Reaction Conditions

Reaction Steps

A solution of 3-bromo-5-methoxybenzaldehyde (4.02 g, 18.7 mmol) and hydroxylamine hydrochloride (6.50 g, 93.5 mmol) in pyridine (50 mL) and EtOH (50 mL) was heated to 65° C. for 16 h. The solvent was removed, and the remaining materials were partitioned between 1:1 EtOAc/hexanes (150 mL) and H2O (75 mL). The organic layer was washed with brine (60 mL), and the solvents were evaporated. The remaining oil was dissolved in anhydrous dioxane (50 mL), and trifluoroacetic anhydride (5.1 mL, 37.4 mmol) and pyridine (9.07 mL, 112.2 mmol) were added. The mixture was heated to 60° C. for 3 h and then cooled to RT. CHCl3 (100 mL) was added, and the organic layer was washed with H2O (2×50 mL), 5% aqueous HCl solution (30 mL), brine (30 mL), and dried with anhydrous MgSO4. The solvents were removed to provide a white solid. This solid was placed in a 150 mL flask that was flushed with nitrogen. Collidine (40 mL) and LiI (7.92 g, 59.10 mmol) were added, and the mixture was heated to 180° C. for 5 h. The reaction mixture was cooled to RT, and partitioned between H2O (400 mL) and EtOAc (100 mL). The layers were separated, and the aqueous layer was acidified with 10% aqueous HCl solution, and extracted with 2:1 EtOAc/hexanes (3×125 mL). The combined organic layers were washed with H2O (100 mL), 10% aqueous HCl solution (2×50 mL), brine (75 mL), and dried with anhydrous MgSO4. The solvents were evaporated and the resulting solid was purified by flash chromatography on silica gel (10% to 40% EtOAc/hexanes) to provide 3.40 g (92%) of 3-bromo-5-hydroxybenzonitrile (116).

Provenance & Evidence