Freshly titrated n-butyl lithium (27.0 ml, 1.39 M in hexanes) is added slowly (over about 30 minutes) to a -78°C solution of diethyl ether (90 ml) containing 1,4-dibromo-2,5-difluorobenzene (10.22 g, 0.038 mol). The resulting yellow solution is stirred at -78°C for 2 hours to give a yellow suspension. Several pellets (~10) of dry ice are added to the suspension, which is then allowed to warm slowly to room temperature as it degasses (approximately 40 minutes). The resulting suspension is acidified with a 1 M aqueous solution of hydrochloric acid (500 ml), and the product extracted with diethyl ether (5 x 200 ml). The combined organics are washed with water (4 x 100 ml) and filtered. The ether solution is concentrated to approximately 200 ml under reduced pressure, and the product extracted into a saturated aqueous solution of sodium bicarbonate (3 x 200 ml). The combined aqueous extracts are washed with methylene chloride (3 x 100 ml) and acidified with hydrochloric acid. The product is extracted with diethyl ether (3 x 200 ml), and the combined organic extracts washed with water (2 x 200 ml), dried over magnesium sulfate, and concentrated under reduced pressure to give 4-Bromo-2,5-difluorobenzoic acid as a pale yellow solid.
Figure Synthesis of 4-Bromo-2,5-difluorobenzoic acid
