General procedure for the synthesis of 2-chloro-6-methoxypiperazine and 2-chloro-3-methoxypyrazine from 2-methoxypyrazine-4-oxide (CAS: 23902-69-4): 0.98 g (0.0078 mol) of 2-methoxypyrazine-4-oxide (Example P6) was mixed with 4 mL of phosphoryl chloride and heated to reflux and stirred for 2 hours. Prior to the start of the reaction, 1.25 mL (0.0078 mol) of N,N-diethylaniline was slowly added via syringe. After completion of the reaction, the solution was cooled to 20 °C and slowly poured into ice water. After adjusting the pH of the mixture to 9 with 30% aqueous sodium hydroxide, it was extracted four times with 10 mL of chloroform. The organic phases were combined, washed sequentially with 3N hydrochloric acid and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Separation by silica gel column chromatography (eluent: ethyl acetate/isohexane, 1:8) afforded the target product 2-chloro-3-methoxypyrazine and its isomer 2-chloro-6-methoxypyrazine. 2-chloro-3-methoxypyrazine was obtained in a yield of 0.29 g (25% of the theoretical value) with 1H NMR (300 MHz, CDCl3) δ: 8.143 ppm (s, 1H), 8.131 ppm (s, 1H), 3.988 ppm (s, 3H). The yield of the isomer 2-chloro-6-methoxypyrazine was 0.38 g (33% of the theoretical value), 1H NMR (300 MHz, CDCl3) δ: 8.031 ppm (d, J = 2.7 Hz, 1H), 7.937 ppm (d, J = 2.7 Hz, 1H), 4.057 ppm (s, 3H).
