5-iodo-2-methylbenzenecarbonitrile

50670-64-9

52107-68-3

General procedure for the synthesis of 5-iodo-2-methylbenzonitrile from 2-methyl-5-aminobenzonitrile: water (30 mL) and concentrated hydrochloric acid (37% w/v, 9 mL) were cooled to 0 °C in an ice bath. To this mixture was added 2-methyl-5-aminobenzonitrile (3.00 g, 22.7 mmol) followed by dropwise addition of a solution of sodium nitrite (1.72 g, 25.0 mmol) in water (7.5 mL). The reaction system was kept stirred at 0 °C until all ingredients were completely dissolved (about 30 min). Next, a solution of potassium iodide (5.65 g, 34.0 mmol) in water (7.5 mL) was slowly added and stirring was continued at 0°C for 30 minutes. After the reaction was completed, ether (20 mL) was added and stirring was continued for 30 min. The reaction mixture was transferred to a partition funnel and the organic layer was separated. The aqueous layer was extracted with ether for a second time, and the combined organic phases were washed sequentially with saturated aqueous sodium thiosulfate solution, saturated sodium bicarbonate solution, water, and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give an orange crystalline residue. Purification by fast column chromatography (eluent: 3-5% ethyl acetate/hexane) afforded 5-iodo-2-methylbenzonitrile as a white solid (3.86 g, 70% yield). A portion of the intermediate (3.5 g, 14.4 mmol) was taken and subjected to cyclization under similar conditions as those for the preparation of compound 16, and the target product 5-iodo-2-methylbenzonitrile was obtained as light yellow crystals (1.23 g, 16% overall yield in two steps) after purification by fast column chromatography (eluent: 0-15% ethyl acetate/hexane).