Synlett 2017; 28(14): 1707-1714
DOI: 10.1055/s-0036-1590888
cluster
© Georg Thieme Verlag Stuttgart · New York

Visible-Light-Mediated Synthesis of Pyrazines from Vinyl Azides Utilizing a Photocascade Process

Asik Hossain, Santosh K. Pagire, Oliver Reiser*
This work was supported by the German Science Foundation (DFG) (GRK 1626, Chemical Photocatalysis)
Further Information

Publication History

Received: 30 June 2017

Accepted after revision: 09 August 2017

Publication Date:
16 August 2017 (eFirst)

Dedicated to Professor Albert Padwa on the occasion of his 80th birthday

Published as part of the ISHC Conference Special Section

Abstract

A convenient method for the synthesis of substituted pyrazines from vinyl azides has been developed. This method is enabled by a dual-energy and electron-transfer strategy by visible-light photocatalysis. Initially, vinyl azides are activated by a triplet sensitization process from an excited ruthenium photocatalyst in the presence of water to form dihydropyrazines, followed by a single-electron-transfer (SET) process under oxygen (air) atmosphere that leads to the tetrasubstituted pyrazines in good to excellent yields.

Supporting Information

 
  • References and Notes

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  • 27 Photochemical Synthesis of Pyrazines: General Procedure An oven-dried Schlenk tube (10 mL size) equipped with a stirring bar was charged with [Ru(bpy)3]Cl2·6H2O (3.7 mg, 0.01 equiv, 1 mol%) followed by 1.60 mL MeCN and 0.40 mL distilled water. The resulting solution was degassed via nitrogen bubbling for 5 min using a syringe needle. Then vinyl azide 2 (0.50 mmol, 1 equiv) was added under nitrogen. Irradiation with a blue LED (λmax = 455 nm) was carried out for 24 h at rt. The reaction mixture was transferred to a separatory funnel containing distilled water, and extracted three times with EtOAc. After drying the combined organic layers (Na2SO4), the resulting solution was concentrated in vacuo. The pure product was obtained either by recrystallization from CH2Cl2/pentane or by silica gel column chromatography using hexanes and EtOAc as eluents. Diethyl 3,6-Diphenylpyrazine-2,5-dicarboxylate (3a) Following the general procedure, 3a was prepared from ethyl (Z)-2-azido-3-phenylacrylate (2a, 109 mg, 0.50 mmol, 1.00 equiv) and [Ru(bpy)3]Cl2·6H2O (3.7 mg, 0.01 equiv, 1 mol%). The crude product was purified by column chromatography (silica gel, hexanes–EtOAc = 9:1, Rf = 0.20) to afford 3a as a white solid (57 mg, 61% yield). 1H NMR (300 MHz, CDCl3): δ = 7.74–7.71 (m, 4 H), 7.49–7.47 (m, 6 H), 4.31 (q, J = 7.1 Hz, 4 H), 1.16 (t, J = 7.1 Hz, 6 H). 13C NMR (75 MHz, CDCl3): δ = 166.2, 149.9, 144.8, 136.2, 130.0, 128.9, 128.7, 62.5, 13.8. ESI-HRMS: m/z calcd for C22H20N2O4 [M + H]+: 377.1423; found: 377.1502. IR (neat): 3059, 2986, 2925, 2854, 1731, 1449, 1405, 1380, 1293, 1173, 1137, 1094, 1057, 1021, 856, 766, 705 cm–1. Diethyl 3,6-Di-p-tolylpyrazine-2,5-dicarboxylate (3b) Following the general procedure, 3b was prepared from ethyl (Z)-2-azido-3-(p-tolyl)acrylate (2b, 115 mg, 0.50 mmol, 1.00 equiv) and [Ru(bpy)3]Cl2·6H2O (3.7 mg, 0.01 equiv, 1 mol%). The crude product was dissolved in a minimum amount of CH2Cl2 followed by the addition of n-pentane to initiate crystallization. After 30 min, the solvent mixture was decanted, and the solid was washed twice with n-pentane. The residual solvents were removed in vacuo which afforded 3b as white solid (83 mg, 82%). 1H NMR (300 MHz, CDCl3): δ = 7.62 (d, J = 8.1 Hz, 4 H), 7.27 (d, J = 7.9 Hz, 4 H), 4.32 (q, J = 7.1 Hz, 4 H), 2.41 (s, 6 H), 1.19 (t, J = 7.1 Hz, 6 H). 13C NMR (75 MHz, CDCl3): δ = 166.4, 149.4, 144.6, 140.2, 133.3, 129.5, 128.7, 62.4, 21.5, 13.9. ESI-HRMS: m/z calcd for C24H24N2O4 [M + H]+: 405.1736; found: 405.1814. IR (neat): 2986, 2871, 1723, 1609, 1462, 1442, 1408, 1292, 1247, 1174, 1137, 1095, 1057, 1012, 853, 828, 775, 700 cm–1. Diethyl 3,6-Di(naphthalen-2-yl)pyrazine-2,5-dicarboxylate (3c) Following the general procedure, 3c was prepared from ethyl (Z)-2-azido-3-(naphthalen-2-yl)acrylate (2c, 134 mg, 0.50 mmol, 1 equiv) and [Ru(bpy)3]Cl2·6H2O (3.7 mg, 0.01 equiv, 1 mol%). The crude product was purified by column chromatography (silica gel, hexanes–EtOAc = 4:1, Rf = 0.30) to afford 3c as a white solid (81 mg, 70% yield). 1H NMR (400 MHz, CDCl3): δ = 8.28 (s, 2 H), 7.97–7.85 (m, 8 H), 7.59–7.53 (m, 4 H), 4.33 (d, J = 7.1 Hz, 4 H), 1.13 (t, J = 7.1 Hz, 6 H). 13C NMR (100 MHz, CDCl3): δ = 166.4, 149.6, 145.1, 134.0, 133.5, 133.2, 129.0, 128.8, 128.6, 127.9, 127.4, 126.8, 125.9, 62.6, 13.9. ESI-HRMS: m/z calcd for C30H24N2O4 [M + H]+: 477.1736; found : 477.1821. IR (neat):3056, 2974, 2927, 2854, 1729, 1686, 1462, 1405, 1381, 1304, 1236, 1169, 1140, 1004, 906, 871, 852, 830, 750 cm–1. Diethyl 3,6-Fis(4-methoxyphenyl)pyrazine-2,5-dicarboxylate (3d) Following the general procedure, 3d was prepared from ethyl (Z)-2-azido-3-(4-methoxyphenyl)acrylate (2d, 124 mg, 0.50 mmol, 1 equiv) and [Ru(bpy)3]Cl2·6H2O (3.7 mg, 0.01 equiv, 1 mol%). The crude product was purified by column chromatography (silica gel, hexanes–EtOAc = 3:1, Rf = 0.28) to afford 3d as a white solid (53 mg, 49% yield). 1H NMR (300 MHz, CDCl3): δ = 7.70–7.67 (m, 4 H), 6.99–6.96 (m, 4 H), 4.33 (q, J = 7.1 Hz, 4 H), 3.85 (s, 6 H), 1.21 (t, J = 7.1 Hz, 6 H). 13C NMR (75 MHz, CDCl3): δ = 166.5, 161.2, 148.5, 144.1, 130.3, 128.5, 114.2, 62.4, 55.5, 13.9. ESI-HRMS: m/z calcd for C24H24N2O6 [M + H]+: 437.1634; found: 437.1740. IR (neat): 2980, 2955, 2926, 2851, 1732, 1607, 1580, 1518, 1414, 1295, 1253, 1177, 1148, 1060, 1017, 841, 811, 786, 752 cm–1. Diethyl 3,6-Bis(2-methoxyphenyl)pyrazine-2,5-dicarboxylate (3e) Following the general procedure, 3e was prepared from ethyl (Z)-2-azido-3-(2-methoxyphenyl)acrylate (2e, 124 mg, 0.50 mmol, 1.00 equiv) and [Ru(bpy)3]Cl2·6H2O(3.7 mg, 0.01 equiv, 1 mol%). The crude product was recrystallized as described for 3b to afford 3e as white solid (86 mg, 79%). 1H NMR (300 MHz, CDCl3): δ = 7.78 (dd, J 1 = 7.5 Hz, J 2 = 1.6 Hz, 2 H), 7.44–7.38 (m, 2 H), 7.14–7.09 (m, 2 H), 6.89 (d, J = 8.2 Hz, 2 H), 4.25 (q, J = 7.1 Hz, 4 H), 3.73 (s, 6 H), 1.14 (t, J = 7.1 Hz, 6 H). 13C NMR (75 MHz, CDCl3): δ = 165.5, 156.5, 147.6, 145.9, 131.4, 131.2, 126.5, 121.4, 110.1, 61.8, 55.1, 13.9. ESI-HRMS: m/z calcd for C24H24N2O6 [M + H]+: 437.1634; found: 437.1739. IR (neat): 2968,2924, 2843, 1733, 1601, 1495, 1465, 1439, 1411, 1390, 1280, 1248, 1226, 1182, 1149, 1111, 1061, 1014, 854, 759, 697 cm–1. Diethyl 3,6-Bis(2-chloro-3,4-dimethoxyphenyl)pyrazine-2,5-dicarboxylate (3f) Following the general procedure, 3f was prepared from ethyl (Z)-2-azido-3-(2-chloro-3,4-dimethoxyphenyl)acrylate (2f, 156 mg, 0.50 mmol, 1.00 equiv) and [Ru(bpy)3]Cl2·6H2O (3.7 mg, 0.01 equiv, 1 mol%). The crude product was recrystallized as described for 3b to afford 3f as white solid (122 mg, 87%). 1H NMR (400 MHz, CDCl3): δ = 7.36 (d, J = 8.5 Hz, 2 H), 6.98 (d, J = 8.6 Hz, 2 H), 4.28 (q, J = 7.1 Hz, 4 H), 3.94 (s, 6 H), 3.87 (s, 6 H), 1.17 (t, J = 7.1 Hz, 6 H). 13C NMR (100 MHz, CDCl3): δ = 164.6, 154.8, 149.8, 145.5, 145.1, 129.5, 127.8, 126.4, 110.9, 62.5, 60.8, 56.3, 13.9. ESI-HRMS: m/z calcd for C26H26Cl2N2O8 [M + H]+: 565.1066; found: 565.1143. IR (neat): 3090, 2980, 2938, 2841, 1735, 1590, 1490, 1447, 1412, 1392, 1293, 1269, 1220, 1202, 1099, 1038, 1003, 819, 790, 778 cm–1. Diethyl 3,6-Bis(4-fluorophenyl)pyrazine-2,5-dicarboxylate (3g) Following the general procedure, 3g was prepared from ethyl (Z)-2-azido-3-(4-fluorophenyl)acrylate (2g, 118 mg, 0.50 mmol, 1.00 equiv) and [Ru(bpy)3]Cl2·6H2O (3.7 mg, 0.01 equiv, 1 mol%). The crude product was recrystallized as described for 3b to afford 3g as white solid (87 mg, 85%). 1H NMR (300 MHz, CDCl3): δ = 7.74–7.70 (m, 4 H), 7.20–7.15 (m, 4 H), 4.33 (q, J = 7.1 Hz, 4 H), 1.20 (t, J = 7.1 Hz, 6H). 13C NMR (75 MHz, CDCl3): δ = 165.9, 164.1 (d, 1 J C–F = 250.6 Hz), 148.8, 144.5, 132.1 (d, 4 J C–F = 3.1 Hz), 130.9 (d, 3 J C–F = 8.6 Hz), 116.0 (d, 2 J C–F = 21.8 Hz), 62.7, 13.9. 19F NMR (282 MHz, CDCl3): δ = –110.9. ESI-HRMS: m/z calcd for C22H18F2N2O4 [M + H]+: 413.1235; found: 413.1320. IR (neat): 3084, 2985, 2925, 2854, 1733, 1599, 1512, 1409, 1383, 1289, 1227, 1179, 1155, 1096, 1053, 1012, 845, 815, 766 cm–1. Diethyl 3,6-Bis(2-fluorophenyl)pyrazine-2,5-dicarboxylate (3h) Following general procedure, 3h was prepared from ethyl (Z)-2-azido-3-(2-fluorophenyl)acrylate (2h, 118 mg, 0.50 mmol, 1.00 equiv) and [Ru(bpy)3]Cl2·6H2O (3.7 mg, 0.01 equiv, 1 mol%). The crude product was recrystallized as described for 3b to afford 3h as white solid (83 mg, 81%). 1H NMR (300 MHz, CDCl3): δ = 7.86–7.80 (m, 2 H), 7.51–7.44 (m, 2 H), 7.35–7.30 (m, 2 H), 7.16–7.09 (m, 2 H), 4.35 (q, J = 7.1 Hz, 4 H), 1.21 (t, J = 7.1 Hz, 6 H). 13C NMR (75 MHz, CDCl3): δ = 164.7, 160.1 (d, 1 J C–F = 248.7 Hz), 146.5, 145.4 (d, J = 1.9 Hz), 132.0 (d, 3 J C–F = 8.5 Hz), 131.7 (d, 4 J C–F = 2.3 Hz), 124.9 (d, 3 J C–F = 3.3 Hz), 124.7, 115.4 (d, 2 J C–F = 21.7 Hz), 62.5, 13.9. 19F NMR (282 MHz, CDCl3): δ = –116.6. ESI-HRMS: m/z calcd for C22H18F2N2O4 [M + H]+: 413.1235; found: 413.1320. IR (neat): 3071, 2985, 2939, 2906, 1730, 1613, 1581, 1490, 1454, 1399, 1384, 1245, 1172, 1140, 1093, 1059, 1014, 859, 757 cm–1. Diethyl 3,6-Bis(4-chlorophenyl)pyrazine-2,5-dicarboxylate (3i) Following the general procedure, 3i was prepared from ethyl (Z)-2-azido-3-(4-chlorophenyl)acrylate (2i, 126 mg, 0.50 mmol, 1.00 equiv) and [Ru(bpy)3]Cl2·6H2O (3.7 mg, 0.01 equiv, 1 mol%). The crude product was recrystallized as described for 3b to afford 3i as white solid (63 mg, 57%). 1H NMR (300 MHz, CDCl3): δ = 7.68–7.66 (m, 4 H), 7.47–7.45 (m, 4 H), 4.34 (q, J = 7.1 Hz, 4 H), 1.22 (t, J = 7.1 Hz, 6 H). 13C NMR (75 MHz, CDCl3): δ = 165.8, 148.9, 144.5, 136.7, 134.4, 130.2, 129.1, 62.8, 13.9. ESI-HRMS: m/z calcd for C22H18Cl2N2O4 [M + H]+: 445.0644; found: 445.0713. IR (neat): 2985, 2937, 1728, 1595, 1494, 1426, 1401, 1378, 1277, 1234, 1187, 1158, 1109, 1090, 1053, 1010, 854, 830, 778, 745 cm–1. Diethyl 3,6-Bis(4-bromophenyl)pyrazine-2,5-dicarboxylate (3j) Following the general procedure, 3j was prepared from ethyl (Z)-2-azido-3-(4-bromophenyl)acrylate (2j, 148 mg, 0.50 mmol, 1 equiv) and [Ru(bpy)3]Cl2·6H2O (3.7 mg, 0.01 equiv, 1 mol%). The crude product was purified by column chromatography (silica gel, hexanes–EtOAc = 3:1, Rf = 0.22) to afford 3j as a white solid (73 mg, 55% yield). 1H NMR (300 MHz, CDCl3): δ = 7.64–7.58 (m, 8 H), 4.34 (q, J = 7.2 Hz, 4 H), 1.22 (t, J = 7.2 Hz, 6 H). 13C NMR (75 MHz, CDCl3): δ = 165.8, 149.0, 144.5, 134.9, 132.0, 130.4, 125.0, 62.8, 13.9. ESI-HRMS: m/z calcd for C22H18Br2N2O4 [M + H]+: 532.9633; found: 532.9708. IR (neat): 2983, 2925, 2854, 1728, 1588, 1474, 1423, 1399, 1376, 1279, 1234, 1186, 1159, 1051, 1006, 854, 826, 776, 734 cm–1. Diethyl 3,6-Bis(4-(trifluoromethyl)phenyl)pyrazine-2,5-dicarboxylate (3k) Following the general procedure, 3k was prepared from ethyl (Z)-2-azido-3-(4-(trifluoromethyl)phenyl)acrylate (2k, 143 mg, 0.50 mmol, 1 equiv) and [Ru(bpy)3]Cl2·6H2O (3.7 mg, 0.01 equiv, 1 mol%). The crude product was purified by column chromatography (silica gel, hexanes–EtOAc = 3:1, Rf = 0.30) to afford 3k as a white solid (48 mg, 38% yield). 1H NMR (300 MHz, CDCl3): δ = 7.86 (d, J = 8.1 Hz, 4 H), 7.76 (d, J = 8.3 Hz, 4 H), 4.34 (q, J = 7.1 Hz, 4 H), 1.20 (t, J = 7.1 Hz, 6 H). 13C NMR (75 MHz, CDCl3): δ = 165.4, 149.4, 144.9, 139.4, 132.1 (q, J = 33.1 Hz), 129.4, 125.7 (q, J = 3.6 Hz), 122.1, 62.9, 13.8. 19F NMR (282 MHz, CDCl3): δ = –63.2. ESI-HRMS: m/z calcd for C24H18F6N2O4 [M + H]+: 513.1171; found: 513.1254. IR (neat): 2982, 2965, 2927, 2856, 1721, 1414, 1324, 1254, 1138, 1105, 1072, 1053, 1016, 858, 832, 790, 717 cm–1. Diethyl 3,6-Bis(4-nitrophenyl)pyrazine-2,5-dicarboxylate (3l) Following the general procedure, 3l was prepared from ethyl (Z)-2-azido-3-(4-nitrophenyl)acrylate (2l, 131 mg, 0.50 mmol, 1.00 equiv) and [Ru(bpy)3]Cl2·6H2O (3.7 mg, 0.01 equiv, 1 mol%). The crude product was recrystallized as described for 3b to afford 3l as yellow solid (99 mg, 86%). 1H NMR (300 MHz, CDCl3): δ = 8.38–8.35 (m, 4 H), 7.93–7.90 (m, 4 H), 4.37 (q, J = 7.1 Hz, 4 H), 1.24 (t, J = 7.1 Hz, 6 H). 13C NMR (75 MHz, CDCl3): δ = 164.9, 149.08, 149.00, 144.8, 141.8, 130.1, 124.0, 63.2, 14.0. ESI-HRMS: m/z calcd for C22H18N4O8 [M + H]+: 467.1125; found: 467.1198. IR (neat): 3110, 2985, 2958, 2919, 2851, 1721, 1601, 1516, 1466, 1408, 1344, 1296, 1259, 1144, 1100, 1009, 850, 800, 749, 689 cm–1. Diethyl 3,6-Di(thiophen-2-yl)pyrazine-2,5-dicarboxylate (3m) Following the general procedure, 3m was prepared from ethyl (Z)-2-azido-3-(thiophen-2-yl)acrylate (2m, 112 mg, 0.50 mmol, 1 equiv) and [Ru(bpy)3]Cl2·6H2O (3.7 mg, 0.01 equiv, 1 mol%). The crude product was purified by column chromatography (silica gel, hexanes–EtOAc = 5:1, Rf = 0.52) to afford 3m as a pale yellow solid (25 mg, 26%). 1H NMR (300 MHz, CDCl3): δ = 7.54–7.50 (m, 4 H), 7.12–7.09 (m, 2 H), 4.48 (q, J = 7.1 Hz, 4 H), 1.37 (t, J = 7.1 Hz, 6 H). 13C NMR (75 MHz, CDCl3): δ = 165.9, 142.5, 141.9, 139.1, 130.4, 128.6, 128.4, 62.8, 14.0. ESI-HRMS: m/z calcd for C18H16N2O4S2 [M + H]+: 389.0551; found: 389.0644. IR (neat): 3097, 2991, 2963, 2924, 2853, 1719, 1531, 1435, 1418, 1381, 1330, 1270, 1145, 1109, 852, 830, 706 cm–1. Diethyl 3-(2-Chloro-3,4-dimethoxyphenyl)-6-(p-tolyl)pyrazine-2,5-dicarboxylate (3fb) Following the general procedure, 3fb was prepared from ethyl (Z)-2-azido-3-(2-chloro-3,4-dimethoxyphenyl)acrylate (2f, 78 mg, 0.25 mmol, 1 equiv), ethyl (Z)-2-azido-3-(p-tolyl)acrylate (2b, 57.7 mg, 0.25 mmol, 1.00 equiv) and [Ru(bpy)3]Cl2·6H2O (3.7 mg, 0.01 equiv, 1 mol%). The crude product was purified by column chromatography (silica gel, hexanes–EtOAc = 3:1, Rf = 0.25) to afford 3fb as a white solid (37 mg, 31% yield). 1H NMR (300 MHz, CDCl3): δ = 7.66 (d, J = 8.1 Hz, 2 H), 7.33–7.27 (m, 3 H), 6.97 (d, J = 8.6 Hz, 1 H), 4.36–4.25 (m, 4 H), 3.93 (s, 3 H), 3.87 (s, 3 H), 2.42 (s, 3 H), 1.22–1.16 (m, 6 H). 13C NMR (75 MHz, CDCl3): δ = 166.2, 164.7, 154.7, 150.5, 148.7, 145.5, 144.9, 144.8, 140.5, 133.2, 129.6, 129.5, 128.9, 127.8, 126.3, 110.8, 62.6, 62.4, 60.8, 56.3, 21.6, 13.97, 13.94. ESI-HRMS: m/z calcd for C25H25ClN2O6 [M + H]+: 485.1401; found: 485.1494. IR (neat): 2982, 2927, 2854, 1739, 1591, 1487, 1450, 1397, 1291, 1277, 1236, 1224, 1198, 1153, 1120, 1077, 1030, 1013, 964, 809, 755 cm–1. Diethyl 3-(2-Chloro-3,4-dimethoxyphenyl)-6-(2-fluorophenyl)pyrazine-2,5-dicarboxylate (3fh) Following the general procedure, 3fh was prepared from ethyl (Z)-2-azido-3-(2-chloro-3,4-dimethoxyphenyl)acrylate (2f, 78 mg, 0.25 mmol, 1 equiv), ethyl (Z)-2-azido-3-(2-fluorophenyl)acrylate (2h, 59 mg, 0.25 mmol, 1 equiv) and [Ru(bpy)3]Cl2·6H2O (3.7 mg, 0.01 equiv, 1 mol%). The crude product was purified by column chromatography (silica gel, hexanes–EtOAc = 3:1, Rf = 0.34) to afford 3fh as a white solid (45 mg, 37% yield). 1H NMR (300 MHz, CDCl3): δ = 7.87–7.82 (m, 1 H), 7.59–7.30 (m, 3 H), 7.16–7.09 (m, 1 H), 6.99–6.97 (m, 1 H), 4.38–4.26 (m, 4 H), 3.93 (s, 3 H), 3.87 (s, 3 H), 1.23–1.16 (m, 6 H). 13C NMR (75 MHz, CDCl3): δ = 164.8, 164.5, 160.1 (d, 1 J C–F = 248.3 Hz), 154.8, 149.7, 146.5, 145.5, 145.1, 132.0 (d, 3 J C–F = 8.5 Hz), 131.7 (d, 4 J C–F = 2.2 Hz), 129.4, 127.7, 126.4, 125.0, 124.9 (d, 3 J C–F = 3.3 Hz), 124.9, 115.4 (d, 2 J C–F = 21.6 Hz), 110.9, 62.5 (2×), 60.8, 56.3, 13.95, 13.92. 19F NMR (282 MHz, CDCl3): δ = –116.6. ESI-HRMS: m/z calcd for C24H22ClFN2O6 [M + H]+: 489.1150; found: 489.1257. IR (neat): 2981, 2934, 2843, 1723, 1616, 1558, 1490, 1450, 1408, 1296, 1269, 1248, 1224, 1173, 1142, 1099, 1075, 1040, 1016, 812, 758 cm–1.