General procedure for the synthesis of ethyl 2-(4-bromopyridin-2-yl)acetate from 4-bromo-2-methylpyridine and diethyl carbonate:
Step 1: Synthesis of ethyl 2-(4-bromopyridin-2-yl)acetate
Under nitrogen protection, 4-bromo-2-methylpyridine (2.00 g) and diethyl carbonate (1.8 mL) were dissolved in anhydrous tetrahydrofuran (30 mL) and cooled to -70°C. Lithium diisopropylammonium (2 mol/L in tetrahydrofuran/heptane/ethylbenzene, 3.00 mL) was slowly added and the reaction was stirred by keeping the temperature at -70°C for 1 hour. Subsequently, lithium diisopropylammonium (2 mol/L in tetrahydrofuran/heptane/ethylbenzene, 3.00 mL) was added again and stirring was continued at -70°C for 1 hour. Upon completion of the reaction, the reaction was quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and the resulting crude product was purified by silica gel column chromatography (eluent: cyclohexane/ethyl acetate, 95:5→1:1) to give ethyl 2-(4-bromopyridin-2-yl)acetate. Yield: 2.35 g (83% yield).
LC (Method 3): tR = 2.86 min; MS (ESI+): m/z = 244/246 (Br)[M + H]+.
