Hydrogen Bromide → 3-(5-Bromo-2-fluorophenyl)pyridine

Participants

Reaction Conditions

Reaction Steps

A solution of 3-(2-fluoro-5-aminophenyl)pyridine (22.4 g, 119 mmol) in 1,4-dioxane (40 ml) was treated with a solution of 48% aqueous hydrobromic acid (500 ml). The resulting suspension was cooled to 0° C. before being treated dropwise over 20 min with an aqueous solution of NaNO2 (9.5 g, 137 mmol) in water (30 ml) keeping the internal temperature <5° C. After stirring at 0° C. for 2 h, a cooled (0° C.) solution of CuBr (25.6 g, 179 mmol) in 48% aqueous hydrobromic acid (150 ml) was added to the reaction which was then stirred at 0° C. for 10 min before heating at 50° C. for 20 min. The reaction was cooled to ambient temperature, diluted with ice-cold water (500 ml), then treated with ice-cold aqueous 33% ammonium hydroxide solution until pH 8-9 (ca. 750 ml). After stirring for 20 min the product was extracted into EtOAc (600 ml), the organics were washed with water, brine (300 ml), dried over anhydrous NaSO4, filtered and pre-adsorbed onto silica. Purification by column chromatography [silica; 20-50% EtOAc/isohexane (containing 1% MeOH and 1% triethylamine)] gave 3-(5-bromo-2-fluorophenyl)pyridine as a white solid (22 g, 73% for sequence): 8H (360 MHz, CDCl3) 7.09 (1H, dd, J 9 and 1), 7.37-7.40 (1H, m), 7.46-7.51 (1H, m), 7.56-7.59 (1H, m), 7.83-7.86 (1H, m), 8.63-8.65 (1H, m), 8.77-8.79 (1H, m).

Provenance & Evidence