89976-56-7

64113-84-4

127-06-0

89976-56-7

General procedure for the synthesis of 5-methylbenzo[d]isoxazol-3-amine from 2-fluoro-5-methylbenzonitrile and acetone oxime: potassium tert-butoxide (4.57 g, 40.8 mmol, 1.1 eq.) was suspended in tetrahydrofuran (THF, 40 mL). Acetone oxime (2.97 g, 40.7 mmol, 1.1 eq.) was added and the reaction mixture was stirred for 20 min at room temperature. Subsequently, a THF solution (30 mL) of 2-fluoro-5-methylbenzyl cyanide (5.00 g, 37 mmol, 1.0 eq.) was added slowly and dropwise. After continued stirring for 3 h at room temperature, the reaction mixture was refluxed overnight. Upon completion of the reaction, the reaction was quenched with deionized water (10 mL). The mixture was partitioned between saturated aqueous sodium bicarbonate (50 mL) and ethyl acetate (EA, 150 mL). The aqueous layer was further extracted with ethyl acetate (50 mL). All organic layers were combined, dried and concentrated with anhydrous sodium sulfate to give a brown oily crude product. The crude product was dissolved in ethanol (EtOH, 80 mL), deionized water (53 mL) and concentrated hydrochloric acid (27 mL) were added, and stirred at 90 °C for 2 hours. After cooling to room temperature, the pH was adjusted with aqueous sodium hydroxide to 10. The aqueous layer was extracted with ethyl acetate (100 mL × 3). The organic layers were combined, dried and concentrated with anhydrous sodium sulfate. The residue was purified by fast chromatography (petroleum ether/ethyl acetate = 5/1, v/v) to afford 5-methylbenzo[d]isoxazol-3-amine as a white solid (2.5 g, 45.6% yield).