Step A: Preparation of (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine: To a 2L round bottom flask was added (R)-3-isopropylpiperazine-2,5-dione (20.7 g, 133 mmol), trimethine oxonium tetrafluoroborate (49.0 g, 331 mmol), and dichloromethane (500 mL). The reaction mixture was stirred vigorously at room temperature and protected by nitrogen.After 18 h, the reaction mixture changed to a clarified solution and formed a very viscous yellow oil at the bottom of the flask. Trimethyloxonium tetrafluoroborate (19.6 g, 133 mmol) was added additionally and stirring was continued at room temperature.After 23 h, the reaction mixture was cooled in an ice bath and 200 g of ice and 100 mL of concentrated ammonium hydroxide solution (28%) were added slowly. Stirring was continued in the ice bath for 1 hr. The organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane (2 x 50 mL). The organic layers were combined, washed sequentially with saturated sodium bicarbonate solution (2 x 100 mL) and brine (100 mL), dried with anhydrous potassium carbonate, filtered through a pad of diatomaceous earth, and concentrated under reduced pressure to give 25.9 g of light brown oil. The crude product was purified by column chromatography (eluent: ether/pentane=1:4) to afford 17.464 g of the target compound (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine as a colorless oil in 71.5% yield.1H NMR (400 MHz, CDCl3) δ 4.08-3.94 (m, 3H), 2.95 (s, 3H) , 2.87 (s, 3H), 2.30-2.18 (m, 1H), 1.04 (d, J=7.03Hz, 3H), 0.76 (d, J=6.64Hz, 3H).
