Synthesis
Step 1 - Synthesis of 1-(5-methyl-3-isoxazole)ethanone (1-a): sodium nitrite (100 g, 1.44 mol) was dissolved in 50 mL of ethanol to produce ethyl nitrite gas in situ. In another reaction vessel, 400 mL of water was slowly added to 50 mL of concentrated sulfuric acid mixed with 50 mL of ethanol and 400 mL of water. The resulting ethyl nitrite gas was passed into a reaction flask containing 2,5-hexanedione (80 g, 700.88 mmol) and concentrated hydrochloric acid (10 mL). The reaction solution was stirred at 50 °C for 6 hours. After completion of the reaction, it was cooled to room temperature, the reaction mixture was diluted with ether (600 mL) and washed sequentially with saturated sodium carbonate solution (2 x 500 mL) and brine (500 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by reduced pressure distillation (12 mmHg) and the fraction with a boiling point of 70 °C was collected to give 61 g (69% yield) of 1-(5-methyl-3-isoxazole)ethanone as a colorless liquid.1H NMR (300 MHz, CDCl3) δ 6.36 (s, 1H), 2.63 (s, 3H), 2.49 (s, 3H).
References
[1] Patent: US2012/214762, 2012, A1. Location in patent: Page/Page column 102
[2] Journal of Heterocyclic Chemistry, 2003, vol. 40, # 4, p. 655 - 658
[3] Journal of Medicinal Chemistry, 2017, vol. 60, # 2, p. 627 - 640
[4] Chemische Berichte, 1909, vol. 42, p. 1879
[5] Tetrahedron Letters, 1987, vol. 28, # 47, p. 5797 - 5800
