In a dry 250 mL three-necked round-bottomed flask equipped with a stir bar, thermometer and flushed with nitrogen, anhydrous THF (16 mL, Aldrich, no inhibitor) was added followed by N,N-diisopropylamine (0.895 g, 8.85 mmol, Aldrich, redistilled 99.95% pure). After cooling the stirred solution to -70 °C, n-butyllithium (3.54 mL of a 2.5 M hexane solution, 8.85 mmol) was added slowly and dropwise, keeping the reaction temperature below -60 °C. The resulting solution was continued to be stirred at -70 °C for 10 min, followed by warming to -20 °C and then rapidly cooled to -90 °C. A solution of 5-bromo-2-(trifluoromethyl)pyridine (2 g, 8.85 mmol) in anhydrous THF (8 mL, Aldrich, no inhibitor) was slowly added dropwise to ensure that the reaction temperature was below -85°C. The resulting orange solution was stirred at -90 °C for 40 min. In another dry 250 mL three-necked round-bottomed flask equipped with a stir bar, thermometer and flushed with nitrogen, anhydrous THF (5 mL, Aldrich, no inhibitor) was added, followed by iodomethane (5 mL, 80 mmol). After cooling the solution to -90 °C, the preformed lithiated pyridine solution was slowly added through a cannula, controlling the addition rate to keep the reaction temperature in the receiving flask below -80 °C. The resulting dark-colored solution was continued to be stirred at -90 °C for 15 min (LCMS showed completion of the reaction). The reaction mixture was quenched with saturated aqueous NaHCO3 followed by slow addition of NH4Cl solution (50 mL) and warmed to room temperature. The organic phase was extracted with EtOAc (2 x 50 mL) and the combined organic layers were washed sequentially with water (50 mL) and brine (50 mL), separated, dried with MgSO4 and filtered. Vacuum concentration afforded 1.68 g of brown oil, which was purified by short-range vacuum distillation (45-46 °C, ca. 5 mmHg) to give 5-bromo-4-methyl-2-(trifluoromethyl)pyridine (0.289 g, 14% yield) as a yellow oil (purity >97%). mS (M+H)+: 241.8, tR = 2.458 min (Method 1); 1H NMR (CDCl3) δ 8.74 (1H, s), 7.56 (1H, s), 2.50 (3H, s).
