3.1. Chemistry
Chemicals such as 2-aminopyrazine, aldehydes, and isocyanides were obtained from TCI and Alderich Chemical Companies. The measurement of melting points was conducted using the electrothermal melting point apparatus (UK), and the results were not corrected. NMR spectra data were obtained using Bruker Ascend 700 NMR spectrometer (Fällanden, Switzerland) at 700.17 MHz for proton NMR and 176.08 MHz for carbon NMR, and DMSO-d6 was used as a solvent in all samples. Thin-layer chromatography (TLC) technique was used as a monitoring technique to check the reaction progression using silica-gel-precoated aluminum sheets (60 F254, Merck) and visualize it under UV at 365 and 254 nm wavelength. The reactions were carried out in a microwave using Biotage, Initiator Sweden AB using vial size 2.0–5.0 mL and normal absorption level.
General procedure:
2-Aminopyrazine (0.52 mmol, 1.3 equiv.), required aldehyde (0.4 mmol, 1 equiv.), required isocyanide (0.52 mmol, 1.3 equiv.), and scandium(III)-trifluoromethanesulfonate (0.015 mmol, 10%) were placed in a microwave vial, and then 2 mL of DCM:MeOH (3:1) was added. The reaction mixture then heated in the microwave to 150 °C, low-boiling solvents for 30 min. After cooling to ambient temperature, the reaction solvent was evaporated, and the residue was extracted with DCM (3 × 5 mL). The combined organic layers were dried with MgSO4 and then concentrated. The residue was purified by column chromatography using hexane:EtOAc.
N-(Tert-butyl)-2-phenylimidazo[1,2-a]pyrazin-3-amine (1a)
Yield: 88.7%; yellow oil. 1H NMR (700 MHz, DMSO-d6) δ ppm 1.01 (s, 9H) 4.83 (s, 1H) 7.35 (t, J = 7.42 Hz, 1H) 7.45 (t, J = 7.74 Hz, 2H) 7.87 (d, J = 4.52 Hz, 1H) 8.21 (d, J = 8.17 Hz, 2H) 8.43 (dd, J = 4.52, 1.51 Hz, 1H) 8.94 (d, J = 1.51 Hz, 1H). 13C NMR (176 MHz, DMSO-d6) δ ppm 30.46, 56.67, 117.68, 126.06, 128.22, 128.33, 128.57, 128.87, 134.93, 135.06, 137.06, 142.99. m/z (ESI-MS) [M]+ 267.15 (100%), [phenyl]+ 78.96 (20%), [M-tert-butyl]+ 209.21 (2%)
N-Cyclohexyl-2-phenylimidazo[1,2-a]pyrazin-3-amine (1b)
Yield: 92.3%; white solid. (MP: 145–146 °C). 1H NMR (700 MHz, DMSO-d6) δ ppm 1.05–1.13 (m, 3H) 1.24–1.33 (m, 2H) 1.50 (br. s., 1H) 1.64 (d, J = 9.68 Hz, 2H) 1.72 (d, J = 12.91 Hz, 2H) 2.83–2.91 (m, 1H) 5.09 (d, J = 6.88 Hz, 1H) 7.34–7.37 (m, 1H) 7.48 (t, J = 7.74 Hz, 2H) 7.86 (d, J = 4.52 Hz, 1H) 8.23 (dd, J = 8.28, 1.18 Hz, 2H) 8.38 (dd, J = 4.73, 1.51 Hz, 1H) 8.94 (d, J = 1.51 Hz, 1H). 13C NMR (176 MHz, DMSO-d6) δ ppm 25.00, 25.78, 34.06, 56.91, 116.85, 127.17, 128.09, 128.17, 128.74, 128.95, 134.27, 136.27, 136.98.142.97. m/z (ESI-MS) [M]+ 293.22 (100%), [phenyl]+ 78.96 (50%), [M-cyclohexyl]+ 209.21 (5%).
N-Benzyl-2-phenylimidazo[1,2-a]pyrazin-3-amine (1c)
Yield: 96.1%; yellow oil. 1H NMR (700 MHz, DMSO-d6) δ ppm 4.15 (d, J = 6.45 Hz, 2H) 5.73 (t, J = 6.35 Hz, 1H) 7.24 (s, 5H) 7.35–7.39 (m, 1H) 7.49 (t, J = 7.53 Hz, 2H) 7.76 (d, J = 4.52 Hz, 1H) 8.15 (d, J = 7.74 Hz, 2H) 8.20 (d, J = 4.52 Hz, 1H) 8.89 (s, 1H). 13C NMR (176 MHz, DMSO-d6) δ ppm 51.19, 116.56,127.35, 127.62, 128.19, 12852, 128.73, 129.00, 134.20, 136.17, 136.45, 140.00, 142.33, 142.93. m/z (ESI-MS) [M]+ 301.13 (100%), [phenyl]+ 78.96 (70%), [M-benzyl]+ 209.21 (5%).
N-(4-Methoxyphenyl)-2-phenylimidazo[1,2-a]pyrazin-3-amine(1d)
Yield: 91.0%; yellow oil. 1H NMR (700 MHz, DMSO-d6) δ ppm 3.64 (s, 3H) 6.48 (m, J = 9.03 Hz, 2H) 6.77 (m, J = 9.03 Hz, 2H) 7.43 (t, J = 7.64 Hz, 2H) 7.51 (d, J = 3.87 Hz, 1H) 7.86–7.91 (m, 1H) 7.92 (s, 1H) 8.01 (dd, J = 4.63, 1.40 Hz, 1H) 8.09 (dd, J = 8.39, 1.29 Hz, 2H) 8.12 (s, 1H). 13C NMR (176 MHz, DMSO-d6) δ ppm 55.68, 114.66, 114.88, 115.53, 116.88, 122.88, 127.22, 129.08, 129.63, 133.35, 135.06, 137.51, 138.86, 143.39, 153.10. m/z (ESI-MS) [M-Me]+ 302.10.
4-(3-(Tert-butylamino)imidazo[1,2-a]pyrazin-2-yl)benzene-1,2-diol (2a)
Yield: 84.1%; white solid. (MP: 270–272 °C). 1H NMR (700 MHz, DMSO-d6) δ ppm 1.03 (s, 9H) 4.65 (s, 1H) 6.77 (d, J = 8.17 Hz, 1H) 7.53 (dd, J = 8.17, 1.94 Hz, 1H) 7.65 (d, J = 2.58 Hz, 1H) 7.82 (d, J = 4.52 Hz, 1H) 8.37 (dd, J = 4.63, 1.40 Hz, 1H) 8.86 (d, J = 1.29 Hz, 1H) 8.96 (br. s., 1H) 9.04 (br. s., 1H). 13C NMR (176 MHz, DMSO-d6) δ ppm 30.54, 56.63, 115.60, 115.97, 117.42, 119.92, 125.03, 126.18, 128.64, 136.79, 141.51, 142.35, 145.29, 145.79. m/z (ESI-MS) [M]+ 299.10.
4-(3-(Cyclohexylamino)imidazo[1,2-a]pyrazin-2-yl)benzene-1,2-diol (2b)
Yield: 75.6%; white solid. (MP: 296–298 °C). 1H NMR (700 MHz, DMSO-d6) δ ppm 1.07–1.14 (m, 3H) 1.25–1.32 (m, 2H) 1.51 (br. s., 1H) 1.62–1.67 (m, 2H) 1.71 (d, J = 12.26 Hz, 2H) 2.83–2.92 (m, 1H) 4.86 (d, J = 6.88 Hz, 1H) 6.80 (d, J = 8.17 Hz, 1H) 7.54 (dd, J = 8.17, 2.15 Hz, 1H) 7.68 (d, J = 2.15 Hz, 1H) 7.81 (d, J = 4.73 Hz, 1H) 8.31 (dd, J = 4.52, 1.29 Hz, 1H) 8.84 (d, J = 1.29 Hz, 1H) 9.00 (s, 1H) 9.07 (s, 1H)13C NMR (176 MHz, DMSO-d6) δ ppm 25.03, 25.84, 34.03, 56.75, 114.92, 115.99, 116.51, 118.78, 125.68, 126.69, 128.76, 136.09, 137.76, 142.26, 145.59, 145.81 m/z (ESI-MS) [M]+ 325.12 (100%), [cyclohexyl]+ 83.10 (10%).
4-(3-(Benzylamino)imidazo[1,2-a]pyrazin-2-yl)benzene-1,2-diol (2c)
Yield: 84.9%; white solid. (MP: 118–220 °C). 1H NMR (700 MHz, DMSO-d6) δ ppm 4.13 (br. s., 2H) 5.55 (br. s., 1H) 6.84 (br. s., 1H) 7.25 (br. s., 5H) 7.49 (br. s., 1H) 7.64 (br. s., 1H) 7.70 (br. s., 1H) 8.11 (br. s., 1H) 8.81 (br. s., 1H) 9.06 (br. s., 1H) 9.12 (br. s., 1H).13C NMR (176 MHz, DMSO-d6) δ ppm 51.10, 115.08, 116.10, 116.22, 118.93, 125.57, 127.32, 127.58, 128.53, 128.59, 128.71, 135.91, 137.34, 140.19, 142.24, 145.73, 145.92 m/z (ESI-MS) 331.06.
4-(3-((4-Methoxyphenyl)amino)imidazo[1,2-a]pyrazin-2-yl)benzene-1,2-diol (2d)
Yield: 91.4%; white solid. (MP: 150–152 °C). 1H NMR (700 MHz, DMSO-d6) δ ppm 3.64 (s, 3H) 6.44 (d, J = 8.82 Hz, 2H) 6.75 (d, J = 8.17 Hz, 1H) 6.77 (d, J = 8.82 Hz, 2H) 7.39 (dd, J = 8.28, 2.04 Hz, 1H) 7.59 (d, J = 2.15 Hz, 1H) 7.84 (d, J = 4.52 Hz, 1H) 7.92 (dd, J = 4.52, 1.51 Hz, 1H) 7.97 (s, 1H) 9.00 (d, J = 1.29 Hz, 1H) 7.91 (m, 1H) 7.92 (s, 1H) 8.01 (dd, J = 4.63, 1.40 Hz, 1H) 8.09 (dd, J = 8.39, 1.29 Hz, 2H) 8.12 (s, 1H). 13C NMR (176 MHz, DMSO-d6) δ ppm 55.69, 114.59, 114.96, 115.50, 116.03, 116.60, 118.91, 120.52, 124.74, 129.40, 137.27, 139.02, 140.69, 142.70, 145.68, 146.37, 152.97 m/z (ESI-MS) [M]+ 349.23.
N-(Tert-butyl)-2-(pyridin-4-yl)imidazo[1,2-a]pyrazin-3-amine (3a)
Yield: 91.3%; dark viscous oil. 1H NMR (700 MHz, DMSO-d6) δ ppm 1.05 (br. s., 9H) 5.00 (br. s., 1H) 7.91 (br. s., 1H) 8.19 (br. s., 2H) 8.47 (br. s., 1H) 8.65 (br. s., 2H) 9.01 (br. s., 1H). 13C NMR (176 MHz, DMSO-d6) δ ppm 30.40, 57.08, 117.94, 122.35, 122.99, 127.76, 129.10, 137.35, 137.81, 143.76, 150.16. m/z (ESI-MS) [M]+ 268.15N-Cyclohexyl-2-(pyridin-4-yl)imidazo[1,2-a]pyrazin-3-amine (3b).
Yield: 97.0%; yellow oil.1H NMR (700 MHz, DMSO-d6) δ ppm 1.11 (br. s., 3H) 1.32 (d, J = 10.11 Hz, 2H) 1.51 (br. s., 1H) 1.64 (br. s., 2H) 1.75 (d, J = 11.83 Hz, 2H) 3.27 (br. s., 1H) 5.27 (br. s., 1H) 7.89 (br. s., 1H) 8.16 (br. s., 2H) 8.41 (br. s., 1H) 8.67 (br. s., 2H) 9.00 (br. s., 1H).13C NMR (176 MHz, DMSO-d6) δ ppm 25.05, 25.72, 34.08, 57.39, 117.09, 121.18, 122.00, 129.14, 130.16, 132.89, 136.63, 143.87, 150.17. m/z (ESI-MS) [M]+ 294.40 (100%), [M-cyclohexyl]+ 211.08 (10%).
N-Benzyl-2-(pyridin-4-yl)imidazo[1,2-a]pyrazin-3-amine (3c)
Yield: 88.6%; yellow oil.1H NMR (700 MHz, DMSO-d6) δ ppm 4.19 (d, J = 6.02 Hz, 2H) 5.96 (t, J = 6.24 Hz, 1H) 7.23 (s, 5H) 7.80 (d, J = 4.09 Hz, 1H) 8.09 (d, J = 4.52 Hz, 2H) 8.23 (d, J = 4.30 Hz, 1H) 8.67 (d, J = 4.30 Hz, 2H) 8.96 (s, 1H).13C NMR (176 MHz, DMSO-d6) δ ppm 51.39, 116.88, 121.43, 127.74, 128.61, 128.78, 130.71, 132.04, 136.49, 139.70, 141.91, 143.84, 149.82, 151.25. m/z (ESI-MS) [M]+ 302.08 (100%), [M-benzyl]+ 211.05 (80%).
N-(4-Methoxyphenyl)-2-(pyridin-4-yl)imidazo[1,2-a]pyrazin-3-amine (3d)
Yield: 95.6%; yellow oil.1H NMR (700 MHz, DMSO-d6) δ ppm 3.66 (br. s., 3H) 6.54 (br. s., 1H) 6.80 (br. s., 1H) 7.89 (br. s., 1H) 7.95 (br. s., 1H) 8.09 (br. s., 1H) 8.37 (br. s., 1H) 8.65 (br. s., 1H) 8.69 (br. s., 2H) 8.83 (br. s., 2H) 9.19 (br. s., 1H). 13C NMR (176 MHz, DMSO-d6) δ ppm 55.71, 115.07, 115.57, 121.58, 123.02, 129.90, 132.03, 132.97, 142.23, 144.36, 149.17, 151.25, 153.42, 156.50. m/z (ESI-MS) [M]+ 318.04 (100%), [M-Me]+ 302.08 (15%), [M-methoxyphenyl]+ 211.05 (10%).
N-(Tert-butyl)-2-(thiophen-3-yl)imidazo[1,2-a]pyrazin-3-amine (4a)
Yield: 90.7%; yellow oil.1H NMR (700 MHz, DMSO-d6) δ ppm 1.06 (br. s., 9H) 4.84 (s, 1H) 7.62 (br. s., 1H) 7.85 (br. s., 2H) 8.17 (br. s., 1H) 8.41 (br. s., 1H) 8.91 (s, 1H).13C NMR (176 MHz, DMSO-d6) δ ppm 30.49, 56.69, 117.70, 124.03, 125.54, 126.18, 128.02, 128.87, 135.91, 137.02, 138.13, 142.73. m/z (ESI-MS) [M]+ 273.10.
N-Cyclohexyl-2-(thiophen-3-yl)imidazo[1,2-a]pyrazin-3-amine (4b)
Yield: 85.6%; white solid. (MP: 170–172 °C). 1H NMR (700 MHz, DMSO-d6) δ ppm 1.09–1.15 (m, 3H) 1.29–1.33 (m, 2H) 1.51–1.54 (m, 1H) 1.64–1.68 (m, 2H) 1.75 (d, J = 12.48 Hz, 2H) 2.85–2.95 (m, 1H) 5.04 (d, J = 6.67 Hz, 1H) 7.66 (dd, J = 4.95, 2.80 Hz, 1H) 7.82–7.84 (m, 1H) 7.86 (d, J = 4.52 Hz, 1H) 8.10 (d, J = 2.80 Hz, 1H) 8.34 (dd, J = 4.52, 1.29 Hz, 1H) 8.89–8.94 (m, 1H). 13C NMR (176 MHz, DMSO-d6) δ ppm 25.07, 25.80, 34.14, 56.98, 116.90, 123.08, 126.76, 127.19, 127.35, 128.76, 135.03, 135.47, 136.27, 142.47. m/z (ESI-MS) [M]+ 299.12.
N-Benzyl-2-(thiophen-3-yl)imidazo[1,2-a]pyrazin-3-amine (4c)
Yield: 89.3%; yellow oil.1H NMR (700 MHz, DMSO-d6) δ ppm 4.17 (d, J = 6.02 Hz, 2H) 5.65 (t, J = 6.13 Hz, 1H) 7.20–7.29 (m, 5H) 7.66 (br. s., 1H) 7.75 (d, J = 3.87 Hz, 1H) 7.79 (d, J = 4.73 Hz, 1H) 8.06 (br. s., 1H) 8.11–8.15 (m, 1H) 8.87 (s, 1H). 13C NMR (176 MHz, DMSO-d6) δ ppm 51.30, 116.59, 123.06, 126.81, 127.23, 127.64, 127.82, 128.63, 128.76, 134.42, 135.38, 136.17, 140.08, 142.67. m/z (ESI-MS) [M]+ 307.04 (100%), [M-benzyl]+ 216.02 (30%).
N-(4-Methoxyphenyl)-2-(thiophen-3-yl)imidazo[1,2-a]pyrazin-3-amine (4d)
Yield: 88.6%; yellow oil.1H NMR (700 MHz, DMSO-d6) δ ppm 3.64 (br. s., 3H) 6.48 (d, J = 7.10 Hz, 2H) 6.77 (d, J = 7.31 Hz, 2H) 7.63 (d, J = 2.58 Hz, 1H) 7.66–7.69 (m, 1H) 7.89 (br. s., 1H) 7.95 (br. s., 1H) 8.03 (br. s., 1H) 8.06 (br. s., 1H) 9.06 (br. s., 1H). 13C NMR (176 MHz, DMSO-d6) δ ppm 55.69, 114.69, 115.52, 116.85, 121.26, 123.77, 126.93, 127.14, 129.64, 134.73, 137.33, 137.47, 138.95, 143.10, 153.12. m/z (ESI-MS) [M-Me]+ 307.07 (100%), [M-methoxyphenyl]+ 2016.02 (20%).