General procedure for the synthesis of 4-chloro-2-methoxypyridine from 4-iodo-2-methoxypyridine:
(d) 50.6 mL of isopropylmagnesium chloride (2 mol/L tetrahydrofuran solution) was mixed with 19.8 g (84.3 mmol) of the crude product of 4-iodo-2-methoxypyridine made in step (c) dissolved in 80 mL of tetrahydrofuran under ice bath cooling conditions. The reaction mixture was stirred at 0 °C for 1 hour, followed by continued stirring at room temperature for 1 hour. Then, 16.9 g (127 mmol) of N-chlorosuccinimide was slowly added and stirring was continued for 1 hour at room temperature. Upon completion of the reaction, the reaction was quenched by the addition of 100 mL of water and the tetrahydrofuran was removed by distillation under reduced pressure. The reaction mixture was extracted with ether and the organic layer was dried with sodium sulfate, filtered and the solvent was removed by decompression distillation to give 11.0 g (91% crude yield) of 4-chloro-2-methoxypyridine crude product.
1H-NMR (CDCl3, 400 MHz): δ (ppm) = 3.91 (s, 3H), 6.70 (d, 1H, J = 2.0 Hz), 6.81 (dd, 1H, J = 6.0 Hz, 2.0 Hz), 7.99 (d, 1H, J = 6.0 Hz).
