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

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

Keywords

visible-light photocatalysis - pyrazines - synthetic methods - vinyl azides - photocascade process

• References and Notes

• 1a Narayanam JM. R. Stephenson CR. J. Chem. Soc. Rev. 2011; 40: 102
• 1b Majek M. Jacobi von Wangelin A. Acc. Chem. Res. 2016; 49: 2316
• 1c Skubi KL. Blum TR. Yoon TP. Chem. Rev. 2016; 116: 10035
• 1d Hopkinson MN. Tlahuext-Aca A. Glorius F. Acc. Chem. Res. 2016; 49: 2261
• 1e Tellis JC. Kelly CB. Primer DN. Jouffroy M. Patel NR. Molander GA. Acc. Chem. Res. 2016; 49: 1429
• 1f Shaw MH. Twilton J. MacMillan DW. C. J. Org. Chem. 2016; 81: 6898
• 1g Zeitler K. Angew. Chem. Int. Ed. 2009; 48: 9785
• 2 Prier CK. Rankic DA. MacMillan DW. C. Chem. Rev. 2013; 113: 5322
• 3a Lu Z. Yoon TP. Angew. Chem. Int. Ed. 2012; 51: 10329
• 3b Welin ER. Le C. Arias-Rotondo DM. McCusker JK. MacMillan DW. C. Science 2017; 355: 380
• 3c Brachet E. Ghosh T. Ghosh I. König B. Chem. Sci. 2015; 6: 987
• 3d Heitz DR. Tellis JC. Molander GA. J. Am. Chem. Soc. 2016; 138: 12715
• 4 Farney EP. Yoon TP. Angew. Chem. Int. Ed. 2014; 53: 793
• 5 Bagal DB. Kachkovskyi G. Knorn M. Rawner T. Bhanage BM. Reiser O. Angew. Chem. Int. Ed. 2015; 54: 6999
• 6a Ghosh I. König B. Angew. Chem. Int. Ed. 2016; 55: 7676
• 6b Pandey G. Laha R. Singh D. J. Org. Chem. 2016; 81: 7161
• 6c Lenhart D. Bauer A. Pöthig A. Bach T. Chem. Eur. J. 2016; 22: 6519
• 6d Zhang P. Xiao T. Xiong S. Dong X. Zhou L. Org. Lett. 2014; 16: 3264
• 7a Kachkovskyi G. Faderl C. Reiser O. Adv. Synth. Catal. 2013; 355: 2240
• 7b Kohls P. Jadhav D. Pandey G. Reiser O. Org. Lett. 2012; 14: 672
• 7c Pagire SK. Reiser O. Green. Chem. 2017; 19: 1721
• 7d Paria S. Kais V. Reiser O. Adv. Synth. Catal. 2014; 356: 2853
• 7e Paria S. Reiser O. Adv. Synth. Catal. 2014; 356: 557
• 7f Murphy JJ. Bastida D. Paria S. Fagnoni M. Melchiorre P. Nature 2016; 532: 218
• 7g Perkowski AJ. Cruz CL. Nicewicz DA. J. Am. Chem. Soc. 2015; 137: 15684
• 7h Shu X.-Z. Zhang M. He Y. Frei H. Toste FD. J. Am. Chem. Soc. 2014; 136: 5844
• 7i Sun Z. Kumagai N. Shibasaki M. Org. Lett. 2017; 19: 3727
• 7j Huff CA. Cohen RD. Dykstra KD. Streckfuss E. DiRocco DA. Krska SW. J. Org. Chem. 2016; 81: 6980
• 8a Borra S. Chandrasekhar D. Adhikary S. Rasala S. Gokulnath S. Maurya RA. J. Org. Chem. 2017; 82: 2249
• 8b Chandrasekhar D. Borra S. Nanubolu JB. Maurya RA. Org. Lett. 2016; 18: 2974
• 8c Chen J.-R. Yan D.-M. Wei Q. Xiao W.-J. ChemPhotoChem 2017; 1: 148
• 8d Metternich JB. Gilmour R. J. Am. Chem. Soc. 2016; 138: 1040
• 9 Xuan J. Xia X.-D. Zeng T.-T. Feng Z.-J. Chen J.-R. Lu L.-Q. Xiao W.-J. Angew. Chem. Int. Ed. 2014; 53: 5653
• 10 Pagire SK. Kreitmeier P. Reiser O. Angew. Chem. Int. Ed. 2017; DOI: 10.1002/anie.201702953.
• 11 Fahy E. Potts BC. M. Faulkner DJ. Smith K. J. Nat. Prod. 1991; 54: 564
• 12 Morris SA. Andersen RJ. Tetrahedron 1990; 46: 715
• 13a Miniyar P. Murumkar P. Patil P. Barmade M. Bothara K. Mini. Rev. Med. Chem. 2013; 13: 1607
• 13b Loffing J. Kaissling B. Am. J. Physiol. Renal Physiol. 2003; 284: F628
• 13c Cavalier J.-F. Burton M. Dussart F. Marchand C. Rees J.-F. Marchand-Brynaert J. Bioorg. Med. Chem. 2001; 9: 1037
• 14 Miyake FY. Yakushijin K. Horne DA. Org. Lett. 2000; 2: 3185
• 15a Palacios F. Ochoa de Retana AM. Gil JI. Lopez de Munain R. Org. Lett. 2002; 4: 2405
• 15b Aparicio D. Attanasi OA. Filippone P. Ignacio R. Lillini S. Mantellini F. Palacios F. Los Santos JM. J. Org. Chem. 2006; 71: 5897
• 15c Gnanaprakasam B. Balaraman E. Ben-David Y. Milstein D. Angew. Chem. Int. Ed. 2011; 50: 12240
• 15d Viswanadham KK. D. R. Prathap Reddy M. Sathyanarayana P. Ravi O. Kant R. Bathula SR. Chem. Commun. 2014; 50: 13517
• 15e Pandit RP. Kim SH. Lee YR. Adv. Synth. Catal. 2016; 358: 3586
• 15f Modha SG. Trivedi JC. Mehta VP. Ermolat’ev DS. van der Eycken EV. J. Org. Chem. 2011; 76: 846
• 15g Ryu T. Baek Y. Lee PH. J. Org. Chem. 2015; 80: 2376
• 15h Loy NS. Y. Kim S. Park C.-M. Org. Lett. 2015; 17: 395
• 15i Wu K. Huang Z. Qi X. Li Y. Zhang G. Liu C. Yi H. Meng L. Bunel EE. Miller JT. Pao C.-W. Lee J.-F. Lan Y. Lei A. Sci. Adv. 2015; 1: e1500656
• 16a Zhang Y. Liu S. Yu W. Hu M. Zhang G. Yu Y. Tetrahedron 2013; 69: 2070
• 16b Hong D. Chen Z. Lin X. Wang Y. Org. Lett. 2010; 12: 4608
• 16c Bonnamour J. Bolm C. Org. Lett. 2011; 13: 2012
• 16d Stokes BJ. Dong H. Leslie BE. Pumphrey AL. Driver TG. J. Am. Chem. Soc. 2007; 129: 7500
• 17a Suresh R. Muthusubramanian S. Nagaraj M. Manickam G. Tetrahedron Lett. 2013; 54: 1779
• 17b Wang Y.-F. Toh KK. Chiba S. Narasaka K. Org. Lett. 2008; 10: 5019
• 17c Chiba S. Wang Y.-F. Lapointe G. Narasaka K. Org. Lett. 2008; 10: 313
• 17d Chen F. Shen T. Cui Y. Jiao N. Org. Lett. 2012; 14: 4926
• 18a Chen Z.-B. Hong D. Wang Y.-G. J. Org. Chem. 2009; 74: 903
• 18b Wang Y.-F. Chiba S. J. Am. Chem. Soc. 2009; 131: 12570
• 19 Sun X. Yu S. Chem. Commun. 2016; 52: 10898
• 20a Yang Y.-Y. Shou W.-G. Chen Z.-B. Hong D. Wang Y.-G. J. Org. Chem. 2008; 73: 3928
• 20b Wang Y.-F. Toh KK. Lee J.-Y. Chiba S. Angew. Chem. Int. Ed. 2011; 50: 5927
• 21a Hu B. DiMagno SG. Org. Biomol. Chem. 2015; 13: 3844
• 21b Driver TG. Org. Biomol. Chem. 2010; 8: 3831
• 22 Hari DP. König B. Chem. Commun. 2014; 50: 6688
• 23 Reiser O. Acc. Chem. Res. 2016; 49: 1990
• 24a Paria S. Reiser O. ChemCatChem 2014; 6: 2477
• 24b Pirtsch M. Paria S. Matsuno T. Isobe H. Reiser O. Chem. Eur. J. 2012; 18: 7336
• 24c Pagire SK. Paria S. Reiser O. Org. Lett. 2016; 18: 2106
• 24d Rawner T. Knorn M. Lutsker E. Hossain A. Reiser O. J. Org. Chem. 2016; 81: 7139
• 25 Lu Z. Yang Y.-Q. Li H.-X. Synthesis 2016; 48: 4221
• 26a Smith HE. Hicks AA. J. Org. Chem. 1971; 36: 3659
• 26b Knittel D. Synthesis 1985; 186
• 26c Banert K. Meier B. Angew. Chem. Int. Ed. 2006; 45: 4015
• 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 (λ_max = 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, R_f = 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, R_f = 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, R_f = 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, R_f = 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, R_f = 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, R_f = 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, R_f = 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, R_f = 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.