Electric Literature of 7170-01-6, New Advances in Chemical Research in 2021.Reactions catalyzed within inorganic and organic materials and at electrochemical interfaces commonly occur at high coverage and in condensed media, 7170-01-6, name is 3-Methyl-1H-1,2,4-triazole, molecular formula is C3H5N3, its traditional synthetic route has been very mature, but the traditional synthetic route has various shortcomings, below Introduce a new synthetic route.
A mixture of 3 -methyl- IH-1, 2,4-triazole (8.12 g, 98 mmol), l,2,3-trifluoro-5-nitrobenzene (17.3 g, 98 mmol), and sodium bicarbonate (8.21 g, 98 mmol) in DMSO (100 mL) was heated at 800C for 24 h . The reaction mixture was allowed to cool to rt and was poured into water (800 mL). The aqueous mixture was extracted with EtOAc (3 x 200 mL). The combined organic extracts were sequentially washed with water (500 mL) and brine solution (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude reaction mixture was purified using silica gel chromatography (30-80% EtOAc/hexane, linear gradient) to afford a 1.7:1.0 mixture of two regioisomeric products as an orange solid. The orange solid was recrystallized from EtOAc (hot- cold) to provide 4.25 g of l-(2,6-difluoro-4-nitrophenyl)-3-melhyl-lH-l.,2,4-triazole as a white solid. The mother liquor was recrystalized from EtO Ac/Hex (hot-rt) to afford 1.89 g of l-(2,6-difluoro-4-nitrophenyl)-5-methyl-lH-l,2,4-triazole as a light yellow solid. The mother liquor was repeatly chromatographed under the previously stated conditions to provide two samples. One sample was partially enriched in the slightly less polar isomer, l-(2,6-difluoro-4~nitrophenyl)-3-memyl-lH-l,2,4-t?azole. The other sample was partially enriched in the slightly more polar isomer, l-(2,6- difluoro-4-nitrophenyl)-5-methyl-lH-l,2,4~triazoe. Both samples were independently recrystallized from EtO Ac/Hex to provide an additional 1.9 g of 1- (2,6-diiluoro-4-nitrophenyl)-3 -methyl- 1 H- 1 ,2,4-triazole and 1.37 g of l-(2,6- difluoro-4-nitrophenyl)-5-methyl- 1 H- 1 ,2,4-triazole. A combined total of 6.15 g (26 % yield) of 1 -(2,-difluoro-4-nitrophenyl)~3-methyl-l H- 1 ,2,4-triazole and 3.2 g (13% yield) of l-(2,6-difluoro-4-nitrophenyl)-5-methyl- IH-1 ,2,4-triazole was obtained.Data for 1 -(2 s6-difluoro-4-nitrophenyl)-3 -methyl- 1 H- 1 ,2,4-triazole: LC-MS(M+H)+ = 241.0. 1H NMR (500 MHz, CHLOROFORM-d) delta ppm 8.34 (s, 1 H), 8.01- 8.10 (m, 2 H)5 2.54 (s, 3 H). Data for l-(2,6-difluoro-4-nitrophenyl)-5-methyl-lH-l,2,4-triazole: LC-MS(M+H)+ = 241.0. IH NMR (500 MHz, CHLOROFORM-d) delta ppm 8.08 (s, 1 H)5 8.04- 8.08 (m, 2 H), 2.45 (s, 3 H). An X-ray analysis of a single crystal grown from EtOAc/hexanes confirmed the regiochemical assignment of this isomer as the 5- methyl congener.
I am very proud of our efforts over the past few months and hope to 3-Methyl-1H-1,2,4-triazole help many people in the next few years.
Reference:
Patent; BRISTOL-MYERS SQUIBB COMPANY; MARCIN, Lawrence, R.; THOMPSON, Lorin, A., III; BOY, Kenneth, M.; GUERNON, Jason, M.; HIGGINS, Mendi, A.; SHI, Jianliang; WU, Yong-Jin; ZHANG, Yunhui; MACOR, John, E.; WO2010/83141; (2010); A1;,
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