Methyl 4-chloropyridinecarboxylate (CYD-1-1, 4.8 g, 27.9 mmol) was mixed with 57% hydriodic acid (26.6 mL, 232.2 mmol) and 50% aqueous hypophosphorous acid (1.32 mL, 12.0 mmol), and the reaction was stirred for 2 hr at 85 °C, and then warmed up to 107 °C to continue the reaction overnight. Upon completion of the reaction, the mixture was cooled to 95 °C and 8.4 mL of 10N aqueous sodium hydroxide solution was slowly added. The mixture was continued to cool to room temperature and stirred for 1 h. A yellow solid was precipitated. After filtration, washing with cold water and vacuum drying overnight, 4-iodopyridinecarboxylic acid (6.8 g, 89% yield) was obtained. The resulting 4-iodopyridinecarboxylic acid (6.73 g, 27.0 mmol) was dissolved in methanol (101 mL), concentrated sulfuric acid (508 μL) was added, and the reaction was refluxed at 80 °C for 2 days. After completion of the reaction, the solvent was evaporated and the residue was dissolved in saturated sodium bicarbonate solution and extracted with ethyl acetate (3 times). The organic layers were combined, washed with saturated brine, dried over anhydrous Na2SO4 and the solvent evaporated. The residue was purified by silica gel column chromatography with 1:3 ethyl acetate-hexane as eluent to afford methyl 4-iodopyridinecarboxylate (CYD-1-4, 2.88 g, 40% overall yield in two steps) as a yellow solid with a melting point of 73-74 °C.1H NMR (600 MHz, CDCl3) δ 8.50 (d, 1H, J=1.2 Hz), 8.39 (d, 1H, J = 5.4 Hz), 7.87 (dd, 1H, J = 1.8 Hz and 4.8 Hz), 4.02 (s, 3H).
