At room temperature, 2-chloro-4-methoxypyridine (0.5 g, 3.48 mmol) was dissolved in sulfuric acid (2.5 mL), followed by batchwise addition of N-iodosuccinimide (0.825 g, 3.48 mmol). The reaction mixture was stirred at 55 °C for 2 hours. After completion of the reaction, the mixture was slowly poured into ice water (10 mL) and 8 M NaOH solution (20 mL) was added dropwise, at which time the color of the solution changed from dark brown to light yellow. The aqueous layer was extracted with water (2 x 20 mL) and dichloromethane (CH2Cl2). The organic layers were combined and washed with brine (10 mL), followed by adsorption of the organic phase onto silica gel by vacuum concentration. Purification by fast column chromatography using a solvent mixture of 25% ethyl acetate (EtOAc) and cyclohexane (c-Hex) as eluent resulted in 2-chloro-5-iodo-4-methoxypyridine as a white crystalline solid (0.169 g, 0.760 mmol, 22% yield). The product was characterized by 1H NMR (500 MHz, d6-DMSO): δ 8.52 (s, 1H), 7.19 (s, 1H), 3.96 (s, 3H); LC-MS (LCT, 4 min) retention time (Rt) = 2.56 min; mass spectrometry (ESI) m/z 270 ([M+H]+).
