Example 6 (Scheme 1) Preparation of 3,5-dichloro-4-methylpyridine (4): diisopropylamine (70 mL, 500 mmol) was dissolved in anhydrous tetrahydrofuran (500 mL) under nitrogen protection, and the resultant solution was cooled to -10 °C and n-butyllithium (2.5 M hexane solution, 210 mL, 525 mmol) was added slowly dropwise under stirring. After the dropwise addition, stirring was continued for 30 min at -10 °C. Subsequently, the reaction system was further cooled to -20 °C and a tetrahydrofuran (200 mL) solution of 3,5-dichloropyridine (66.6 g, 450 mmol) was slowly added dropwise. After the dropwise addition was completed, the reaction mixture was stirred at -10 °C for 30 min. Next, the reaction system was cooled to -70 °C and a tetrahydrofuran (100 mL) solution of iodomethane (50 mL, 1.6 mol) was added dropwise. After the dropwise addition, the reaction mixture was slowly warmed up to room temperature. Upon completion of the reaction, the reaction was quenched with deionized water (100 mL) and extracted with ether (3 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate (5 g), filtered and concentrated to dryness under reduced pressure. The crude product was recrystallized by two recrystallizations from aqueous ethanol followed by hexane to give 3,5-dichloro-4-methylpyridine (49.9 g, 306 mmol, 68% yield) as a white solid.
