2.2. General Procedure for the Synthesis of Pyrazine Derivatives (RB1–RB9)
Triethylamine (1.5 mmol) was added to a suspension of 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-α]pyrazine hydrochloride (1 mmol) in DCM (dichloro methane) (10 mL) in RT (retention time), followed by the addition of isocyanates (1.2 mmol). The reaction mixture was stirred at room temperature for 5 h and the progress of the reaction was monitored by TLC (Thin layer chromatography). Upon completion of the reaction, the solvent was removed under reduced pressure and the residue obtained was added to water and extracted with ethyl acetate. The organic layer was washed with a brine solution and dried over anhydrous Na
2SO
4. The solvent was evaporated and the crude product was purified by column chromatography over silica gel using chloroform: methanol (9:1) as an eluent to afford the anticipated products (RB1–RB9) (
Supplementary Materials).
N-[4-(chloromethyl)phenyl]-3-(trifluromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-α]pyrazine-7(8H)-carboxamide (RB1): (92%, off-white solid), m.p 178.8–183.6 °C 1H-NMR (CDCL3, 400 MHz) δ: 4.00 (t, 2H, J = 5.6 Hz), 4.21 (t, 2H, J = 5.2 Hz), 4.46 (d, 2H, J = 5.6 Hz),4.88 (s, 2H), 5.66 (d, 1H, J = 4.8 Hz), 7.28–7.32 (m,4H). LCMS for C14H13ClF3N5O (ESI + ion): m/z = 360 [M + H]+. IR (KBr, cm−1): 3356.2, 1736, 1621, 1041.
N-[3-methyl-(1,11-biphenyl)-4-yl]-3-(trifluromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-α]pyrazine-7(8H)-carboxamide (RB2): (95%, off-white-solid), 188.6–205.9 °C, 1H-NMR (CDCl3, 400 MHz) δ: 4.07 (t, 2H, J = 5.6 Hz), 4.27 (t, 2H, J = 5.6 Hz), 5.02 (s, 2H), 6.90–7.58 (m, 10H). LCMS for C19H16F3N5O MS (ESI + ion): m/z = 388 [M + H]+. IR (KBr, cm−1): 3429, 3030, 1654, 1283, 1078, 981.
N-(2-fluoro-5-methylphenyl)-3-(trifluromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-α]pyrazine-7(8H)-carboxamide (RB3): (90%, off-white-solid), 196.7–201.7 °C, 1H-NMR (CDCl3, 400 MHz) δ: 2.32 (s, 3H), 4.05 (t, 2H, J = 6 Hz), 4.27 (t, 2H, J = 4.8 Hz), 4.99 (s, 2H), 6.78–7.76 (m, 4H) LCMS for C14H13F4N5O MS (ESI + ion): m/z = 344 [M + H]+. IR (KBr, cm−1): 3240, 2926, 1638, 1498, 1042, 939, 871.
N-(3-methylbenzene)-3-(trifluromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-α]pyrazine-7(8H)-carboxamide (RB4): (87%, white-solid), 178.3, 185.1 °C, 1H-NMR (CDCl3, 400 MHz) δ: 2.35 (d, 2H, J = 8 Hz), 3.99 (t, 2H, J = 6.8 Hz), 4.20 (t, 2H, J = 6.8 Hz), 4.43(d, 2H, J = 7.2 Hz), 4.84 (s, 2H), 5.22 (s, 1H), 7.11–7.28 (m, 3H). LCMS for C15H16F3N5O MS (ESI + ion): m/z = 341 [M + H]+. IR (KBr, cm−1): 3354, 2919, 1629, 1535, 1498, 1138, 1011, 947.
N-(2-methoxyphenyl)-3-(trifluromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-α]pyrazine-7(8H)-carboxamide (RB5): (90%, white-solid), 142.4, 149.9 °C, 1H-NMR (CDCl3, 400 MHz) δ: 2.43 (s, 3H), 4.09 (t, 2H, J = 5.6 Hz), 4.29 (t, 2H, J = 5.2 Hz), 5.06 (s, 2H), 7.06–8.11 (m, 5H). LCMS for C14H14F3N5O2 MS (ESI + ion): m/z = 342 [M + H]+. IR (KBr, cm−1): 3309, 2962, 1662, 1600, 1389, 1012, 939, 747.
N-(2-isopropylyphenyl)-3-(trifluromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-α]pyrazine-7(8H)-carboxamide (RB6): (95%, Off-white-solid), 168.1–172.9 °C. 1H-NMR (CDCl3, 400 MHz) δ: 1.26 (d, 6H, J = 6.8 Hz), 3.05 (t, 1H, J = 6.8 Hz), 4.02 (t, 2H, J = 5.6 Hz), 4.23 (t, 3H, J = 5.2 Hz), 4.92 (s, 2H), 6.44–7.42 (m, 5H). LCMS for C16H18F3N5O MS (ESI + ion): m/z = 355 [M + H]+. IR (KBr, cm−1): 3290, 2958, 1636, 1521, 1389, 1246, 1122, 1032, 940.
N-(2-fluoro-4-trifluoromethylphenyl-3-(trifluromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-α]pyrazine-7(8H)-carboxamide (RB7): (88%, off-white-solid), 171.4–176.4 °C, 1H-NMR (CDCl3, 400 MHz) δ: 4.10 (t, 2H, J = 7.6 Hz), 4.31 (t, 2H, J = 6.8 Hz), 5.04 (d, 2H, J = 12 Hz), 6.94–8.41 (m, 4H). LCMS for C14H10Cl2F7N5O MS (ESI + ion): m/z = 398 [M + H]+. IR (KBr, cm−1): 3342, 646, 1501, 1335, 1277, 1121, 1014, 894.
N-(benzyl)-3-(trifluromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-α]pyrazine7(8H)-carboxamide (RB8): (96%, white-solid), 194.4–199.3 °C. 1H-NMR (CDCl3, 400 MHz) δ: 3.99 (t, 2H, J = 5.6 Hz), 4.20 (t, 2H, J = 5.2 Hz), 4.48 (d, 2H, J = 5.6 Hz), 5.39 (s, 1H), 7.28–7.36 (m, 5H). LCMS for C14H14F3N5O MS (ESI + ion): m/z = 326 [M + H]+. IR (KBr, cm−1): 3325, 2924, 1626, 1543, 1280, 1046, 938.
N-[2-(methylthio)phenyl]-3-(trifluromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-α]pyrazine7(8H)carboxamide (RB9): (94%, off-white-solid), 191.9–197.3 °C. 1H-NMR (CDCl3, 400 MHz) δ: 2.41 (d, 3H, J = 10.8 Hz), 4.08 (t, 2H, J = 7.6 Hz), 4.29 (t, 2H, J = 6.8 Hz), 5.04 (s, 2H), 7.05–8.10 (m, 5H) LCMS for C14H14F3N5O5 MS (ESI + ion): m/z = 358 [M + H]+. IR (KBr, cm−1): 3299, 2930, 1644, 1398, 1039, 943.