General procedure for the synthesis of methyl 2-cyano-3-methylbenzoate from zinc cyanide and methyl 2-bromo-3-methylbenzoate:
Intermediate 8: 2-(bromomethyl)-6-methylbenzonitrile
Step 1: Synthesis of methyl 2-cyano-3-methylbenzoate
Methyl 2-bromo-3-methylbenzoate (5 g, 21.8 mmol), Zn(CN)2 (10.26 g, 87.3 mmol) and Pd(PPh3)4 (1.51 g, 1.3 mmol) were dissolved in DMF (60 mL) and the reaction was stirred at 80 °C under nitrogen protection overnight. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The residue was dissolved in dichloromethane (100 mL) and washed with water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by column chromatography (eluent: petroleum ether/ethyl acetate=10:1) to afford methyl 2-cyano-3-methylbenzoate (1.6 g, 43% yield) as a white solid.
Product Characterization:
1H NMR (400 MHz, CD3OD) δ 7.97-7.95 (m, 1H), 7.68-7.62 (m, 2H), 3.96 (s, 3H), 2.60 (s, 3H); ES-LCMS m/z: 176.1 (M + H).
