General procedure for the synthesis of 2-methoxy-4-fluorobenzonitrile from 2-bromo-5-fluoroanisole and cuprous cyanide: to a solution of N-methylpyrrolidone (100 mL, Sure Seal; Aldrich) containing 1-bromo-4-fluoro-2-methoxybenzene (9.0 g) was added cuprous cyanide (6.6 g, 73.7 mmol, 1.8 equiv. Aldrich). The reaction mixture was stirred at 180 °C for 5.5 h in an anhydrous nitrogen atmosphere. After completion of the reaction, it was cooled to room temperature, a 14% aqueous ammonia solution (330 mL) was added, and stirring was continued at room temperature for 45 min. The reaction mixture was extracted with ether (100 mL x 3), and the organic phases were combined, washed sequentially with dilute ammonia, dilute hydrochloric acid and brine, and then dried with anhydrous magnesium sulfate, and concentrated to give 2-methoxy-4-fluorobenzonitrile (5.2 g, 85% yield in two steps). The product was a white solid with the following 1H NMR (CDCl3,500MHz) data: δ 3.91 (3H, s, OMe), 6.69 (1H, dd, J = 2.3Hz, J = 10.5Hz, Ar-H), 6.72 (1H, dt, J = 2.5Hz, J = 8.0Hz, Ar-H), 7.55 (1H, dd, J = 6.5 Hz, J = 8.5 Hz, Ar-H); 13C NMR (CDCl3,125.8 Hz) data as follows: δ 56.49, 98.16, 100.06, 100.27, 108.31, 108.50, 115.83, 135.37, 135.46, 163.25, 163.34, 165.47, 167.50. 167.50. analytical samples were obtained by ether milling. Calculated values for elemental analysis (C8H6FNO): C, 63.57; H, 4.00; N, 9.26; measured values: C, 63.36; H, 3.91; N, 9.16.
