[Synthesis]
The general procedure for the synthesis of 3-iodo-4-fluorobenzoic acid from 3-amino-4-fluorobenzoic acid is as follows: to a concentrated aqueous hydrochloric acid solution (37%, w/w, 8 mL) of 3-amino-4-fluorobenzoic acid (5) (1.00 g, 6.45 mmol) was added dropwise an aqueous (10 mL) solution of sodium nitrite (667 mg, 9.67 mmol) at -15 °C, while maintaining the reaction temperature below -10°C. After continued stirring at -10 °C for 30 min, a solution of potassium iodide (3.21 g, 19.34 mmol) in water (10 mL) was slowly added, keeping the temperature below -5 °C. The reaction mixture was gradually warmed to 0 °C and stirred for 30 min, followed by standing for 3 h at room temperature. Upon completion of the reaction, the pH was adjusted to 3 by slow addition of 10 N aqueous sodium hydroxide solution and then the reaction was quenched with 1 M aqueous sodium thiosulfate solution (20 mL) at 0 °C. The reaction mixture was extracted with dichloromethane (3 x 50 mL), the organic layers were combined and washed with deionized water (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford 4-fluoro-3-iodobenzoic acid (6) (1.47 g, 5.53 mmol) as an orange solid in 86% yield. The product characterization data were as follows: melting point 169-171 °C (literature value [1]: 173-174 °C); IR (KBr) νmax 1039, 1291, 1426, 1484, 1585, 1686, 2500-3100 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.16 (t, 1H, J = 7.8 Hz. 3JH-F = 7.8 Hz, H-5), 8.10 (m, 1H, H-6), 8.54 (dd, 1H, 4JH-F = 6.0 Hz, J = 2.1 Hz, H-2); 13C NMR (50 MHz, DMSO-d6) δ 83.0 (d, 2JC-F = 27 Hz, C-3), 116.5 (d, 2JC-F = 25 Hz, C-5), 129.5 (C-1), 132.4 (d, 3JC-F = 9 Hz, C-6), 140.9 (C-2), 164.5 (d, 1JC-F = 249 Hz, C-4), 165.7 (CO); 19F NMR (470 MHz, CDCl3) δ -86.0; ESI-MS m/z 264.94 [M-H]-. |