| 81% |
With ammonia;copper; In water; at 150℃; for 48h;Autoclave; |
a. 3,6-Dimethylpyrazin-2-amine A 100 mL autoclave vessel was charged with 3-chloro-2,5-dimethylpyrazine (25.0 g, 176 mmol), NH3 (aq. 25-28% w/w, 80 mL) and Cu powder (1.69 g, 26.4 mmol) and the autoclave vessel was sealed. The resulting mixture was heated to 150 C. and stirred vigorously for 48 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with brine (100 mL) and extracted with EtOAc (4*100 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was washed with PE to render the title compound as a light yellow solid (17.6 g, yield 81%). ESI MS: m/z 124 [M+H]+. |
| 73% |
With ammonium hydroxide; copper; at 150℃; for 22h;Sealed tube; |
In a pressure tube were placed 4 mL of 25% ammonia solution, 64 mg of powdered copper and 1.0 g (6.66 mmol) of 3-chloro-2,5-dimethylpyrazine. The whole was heated to 150 C for 18 hours. Further 1 mL of 25% ammonia solution was added and heating was continued for further 4 hours. The mixture was filtered through silica gel layer, washed with 10 mL of water and 10 mL of ethyl acetate. The filtrate was extracted with ethyl acetate (5 x 10 mL). Organic phase was dried over sodium sulphate and concentrated. Resulted solid was triturated with heptane and filtered-off (first crop). Second crop of the product crystallized from the filtrate. Combined solids were dried under reduced pressure to obtain 0.60 g of 2-amino-3,6-dimethyl- pyrazine as a solid (yield 73%). MR (300 MHz, DMSO-d6): delta 7.45 (s, 1H), 6.01 (s, broad, 2H), 2.22 (s, 3H), 2.10 (s, 3H). |
| 109 mg |
With ammonia; In water; at 165℃; for 23h;Microwave irradiation; |
Intermediate 18: 3,6-d imethyllyrazin-2-amineAmmonia in water (3 mL, 48.5 mmol) was added to 3-chloro-2,5-dimethylpyrazine (0.121 mL, 1 mmol) and the mixture heated by microwaves to 165 C for 7 hours. Following LCMS analysis, the reaction was then reheated to 165 C for a further 16 hours, by microwaves. After cooling, thesolvent was removed under a stream of nitrogen and the crude redissolved in dichloromethane (20mL). Water (25 mL) was added and the mixture basified to pHl4 using sodium hydroxide solution(18 N). The organic layer was removed and the aqueous layer extracted with dichloromethane (5 x25 mL). The organic phases were combined and dried using a hydrophobic frit, then evaporated invacuoto give the title product (109 mg). This was used directly in the next step with no furtherpurification. LCMS (2 mm, high pH) Rt 0.47 mi m/z (ESj 124 (M+H).1H NMR (400 MHz, CHLOROFORM-o) O ppm 7.73 (5, 1 H), 4.42 (br. s., 2 H), 2.37 (5, 3 H), 2.35 (5, 3H). |
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