Abstract
The oxidation of 1,4-diacetylbenzene using several oxidizing agents gave 1,4-phenylene-bis-glyoxal in 61–85% yields. A convenient and efficient synthesis of bis-quinoxaline and bis-pyrido[2,3-b]pyrazine derivatives involves the double condensation of 1,2-diamines with 1,4-phenylene-bis-glyoxal in ethanol under reflux conditions. The structures of the new products were defined by proton nuclear magnetic resonance (1H NMR), carbon-13 nuclear magnetic resonance (13C NMR), Fourier-transform infrared spectroscopy (FT-IR) and mass spectrometry (MS).
Introduction
Glyoxals are important building blocks in organic synthesis, particularly in the synthesis of biologically active heterocyclic compounds [1], [2], [3], [4], [5], [6], [7], [8], [9] including quinoxaline derivatives [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26]. Synthesis of a quinoxaline by the reaction of a glyoxal with a 1,2-diamine is part of the general strategy involving the reaction of 1,2-dicarbonyl compounds with 1,2-diamines [27], [28], [29], [30]. In continuation of our studies on the development of new synthetic routes to heterocyclic compounds using arylglyoxals, herein we report the synthesis of new bis-quinoxaline derivatives 3a–f in a 68–94% yield via condensation of 1,4-phenylene-bis-glyoxal as its hydrate 1 (structure in Scheme 1) and 1,2-diamines 2a–f in ethanol under reflux conditions.
Results and discussion
The glyoxal hydrate 1 was synthesized by oxidation of 1,4-diacetylbenzene using different oxidizing agents in a 61–85% yield. The SeO2/dioxane/H2O system is preferred to other oxidizing agents as its use provides product 1 in an 85% yield after crystallization from water. The use of other oxidizing systems described in the literature, namely HBr/DMSO/H2O, CuCl2/DMSO/H2O and I2/CuO/DMSO, furnished compound 1 in the respective yields of 73%, 65% and 61%.
The condensation of compound 1 with 1,2-diamines 2a–f in ethanol under reflux gave the desired bis-quinoxalines and bis-pyrido[2,3-b]pyrazines under catalyst-free conditions in a 68–89% yield (Scheme 1). The use of unsymmetrical aromatic diamines 2b, 2e and 2f could in principle lead to isomeric products, but the formation of a single product in each case shows that the reactions are regioselective. As can be seen, in the condensation of bis-glyoxal 1 with 4-nitro-1,2-diaminobenzene (2b) and aminopyridines 2e or 2f, the more nucleophilic 1-amino group attacks the formyl group in the first step, and the condensation of the less reactive 2-amino group with the keto groups occurs in the second step, leading to the formation of bis-quinoxaline 3b. The reactions of aminopyridines 2e and 2f with 1 follow a similar pattern and furnish regioselectively the respective bis-pyrido[2,3-b]pyrazines 3e and 3f. This reactivity pattern is in full agreement with previous mechanistic studies on the construction of fused pyrazines [27], [28], [29], [30].
Conclusion
A double condensation of 1,4-phenylene-bis-glyoxal with various 1,2-diamines furnished bis-quinoxaline derivatives 3a–f in high to excellent yields. The simplicity of operation, high yields and regioselectivity are the key advantages of this method.
Experimental
Melting points were measured on an Electrothermal 9200 apparatus and are uncorrected. Infrared spectra were measured on a Spectrum RXI, Perkin Elmer, UK Fourier-transform infrared (FT-IR) instrument using KBr disks. The 1H (300 MHz) and 13C (75 MHz) nuclear magnetic resonance (NMR) spectra were recorded on a Bruker DRX-300 Avance spectrometer in DMSO-d6, CDCl3 and C6D6 relative to tetramethylsilane (TMS) as the internal reference. Thin layer chromatography (TLC) was carried out on a pre-coated aluminum sheet with silica gel 60F 254 obtained from Merck, and detection was made with the help of an ultraviolet (UV) lamp (λ 254 nm). Mass analysis was performed on an Agilent Technology (HP) 5973 Network Mass Selective Detector and high-resolution mass spectra were recorded on a Kratos mass spectrometry (MS) 25RF spectrometer.
Synthesis of 1,1′-(1,4-phenylene)bis(2,2-dihydroxyethanone) (1)
A solution of selenium dioxide (1.55 g, 14 mmol) in 90% aqueous dioxane (10 mL) was treated at 100°C with a solution of 1,4-diacetylbenzene (1.62 g, 10 mmol) in dioxane (12 mL). The mixture was heated under reflux for 14 h and the precipitated selenium was removed by filtration. The solution was cooled and the resultant pale yellow precipitate of product 1 was collected and crystallized from water: yield 1.92 g (85%); mp 141–142°C; IR: νmax 3428, 3377, 2975, 1670, 1505, 1446, 1407, 1297, 1121, 1037, 962, 873, 801, 696, 584, 517 cm−1; 1H NMR (DMSO-d6): δ 8.15 (s, 4H), 6.90 (d, J=7.2 Hz, 4H, 4×OH, exchanged by D2O addition), 5.68 (bt, J=7.2 Hz, 2H, changed to a singlet after D2O addition); 13C NMR (DMSO-d6): δ 196.5, 137.4, 129.7, 89.9; MS: m/z (%) 226 ([M]+, 59), 184 (100), 163 (58), 149 (65), 133 (76), 105 (59), 91 (52), 77 (56), 55 (75). ESI-HRMS: Calcd. for C10H10O6, [M]+: m/z 226.0477. Found: m/z 226.0462.
General procedure for the synthesis of bis-quinoxalines and bis-pyrido[2,3-b]pyrazines (3a–f)
A mixture of 1,4-phenylene-bis-glyoxal (1, 1 mmol) and a 1,2-diamine (2a–f, 2 mmol) in absolute ethanol (10 mL) was heated under reflux for 10–15 h, then cooled and the resultant precipitate of 3a–f was filtered, washed with ethanol and crystallized from ethanol.
1,4-Bis-(quinoxalin-2-yl)benzene (3a)
Reaction time 12 h; yield 82% of light yellow powder; mp 264–266°C; IR: νmax 3054, 1678, 1609, 1574, 1545, 1490, 1462, 1426, 1370, 1320, 1262, 1231, 1208, 1130, 1054, 1014, 956, 847, 756, 674, 630, 601, 566 cm−1; 1H NMR (CDCl3): δ 9.45 (s, 2H), 8.45 (s, 4H), 8.24–8.16 (m, 4H), 7.85–7.80 (m, 4H); 13C NMR (CDCl3): δ 150.9, 142.4, 141.8, 138.3, 130.5, 129.9, 129.7, 129.2, 128.2; EI-MS: m/z (%) 335 ([M+1]+, 28), 334 [M]+ (100), 307 (11), 306 (17), 204 (12), 76 (19). ESI-HRMS. Calcd. for C22H14N4, [M]+: 334.1218. Found: m/z 334.1205.
1,4-Bis(6-nitroquinoxalin-2-yl)benzene (3b)
Reaction time 15 h; yield 68% of orange powder; mp 235–236°C; IR: νmax 3047, 1578, 1554, 1348, 1320, 1280, 1193, 1078, 1050, 964, 844, 831, 792, 742 cm−1; 1H NMR (C6D6): δ 9.16 (s, 1H), 9.13 (s, 1H), 8.20 (s, 4H), 8.10 (d, J=9 Hz, 2H), 7.98 (d, J=9 Hz, 2H), 7.10 (bs, 2H); 13C NMR (C6D6): δ 138.5, 137.7, 136.1, 135.7, 133.7, 127.6, 126.9, 124.6, 124.0, 123.8; EI-MS: m/z (%) 425 ([M+1]+, 27), 424 ([M]+, 100), 394 (25), 382 (11), 351 (14), 75 (13). ESI-HRMS. Calcd. for C22H12N6O4, [M]+: m/z 424.0920. Found: m/z 424.0907.
1,4-Bis(6-methoxyquinolin-2-yl)benzene (3c)
Reaction time 10 h; yield 89% of brown powder; mp 267–268°C; IR: νmax 3047, 1616, 1498, 1374, 1321, 1261, 1217, 1201, 1173, 1122, 1060, 1026, 958, 846, 830, 779 cm−1; 1H NMR (DMSO-d6): δ 9.52 (s, 2H), 8.55(s, 4H), 8.03 (d, J=8.7 Hz, 2H), 7.54 (s, 2H), 7.51 (d, J=8.7 Hz, 2H), 3.86 (s, 6H); 13C NMR spectrum could not be recorded due to low solubility of the sample; EI-MS: m/z (%) 395 ([M+1]+, 29), 394 ([M]+, 100), 262 (10), 197 (7), 106 (12), 63 (10). ESI-HRMS. Calcd. for C24H18N4O2, [M]+: m/z 394.1430. Found: m/z 394.1416.
1,4-Bis(6,7-dichloroquinoxalin-2-yl)benzene (3d)
Reaction time 12 h; yield 78% of gray powder; mp 190–191°C; the 1H NMR and 13C NMR spectra could not be recorded due to low solubility of the sample; IR: νmax 3066, 3045, 1544, 1459, 1418, 1317, 1274, 1177, 1111, 1058, 1016, 945, 928, 900, 878, 840, 810, 660, 624 cm−1; EI-MS: m/z (%) 478 ([M+6]+, 14), 474 ([M+4]+, 52), 472 ([M+2]+, 100), 470 ([M]+, 80), 300 (17), 272 (15), 237 (11), 170 (13), 146 (32), 144 (50), 109 (30), 74 (12). ESI-HRMS. Calcd. for C22H10Cl4N4, [M]+: m/z 469.9660. Found: m/z 469.9648.
1,4-Bis(pyrido[2,3-b]pyrazine-2-yl)benzene (3e)
Reaction time 10 h; yield 80% of brown powder; mp 320–321°C; IR: νmax 3413, 3067, 2372, 1546, 1461, 1310, 209, 1125, 1061, 952, 848, 794 cm−1; 1H NMR (CDCl3): δ 9.29 (s, 2H), 9.25 (bs, 2H) 8.82 (s, 4H), 8.54 (d, J=7.8 Hz, 2H), 7.77 (dd, J1=8.4 Hz, J2=4.5 Hz, 2H); 13C NMR spectrum could not be recorded due to low solubility of the sample; EI-MS: m/z (%) 337 ([M+1]+, 24), 336 ([M]+, 100), 308 (9), 233 (20), 205 (9), 104 (10), 77 (14). ESI-HRMS. Calcd. for C20H12N6, [M]+m/z 336.1123. Found: m/z 336.1111.
1,4-Bis(pyrido[3,4-b]pyrazine-2-yl)benzene (3f)
Reaction time 10 h; yield 78% of creamy powder; mp 248–249°C; IR: νmax 3216, 2373, 1547, 1419, 1317, 1235, 1054, 960, 854, 837, 584 cm−1; 1H NMR (CDCl3): δ 9.62 (s, 2H), 9.55 (s, 2H), 8.90 (d, J=5.7 Hz, 2H), 8.52 (s, 4H), 8.04 (d, J=6 Hz, 2H); 13C NMR (CDCl3+DMSO-d6): δ 154.2, 147.7, 145.2, 144.8, 136.8, 128.9, 128.5, 121.9, 121.5; EI-MS: m/z (%) 337 ([M+1]+, 22), 336 ([M]+, 100), 309 (13), 308 (15), 233 (11), 77 (11), 50 (32). ESI-HRMS. Calcd. for C20H12N6, [M]+: m/z 336.1123. Found: m/z 336.111.
Acknowledgments
We are grateful to Urmia University for the financial support and we also thank Professor R. H. Prager (Flinders University, Australia) for language editing and proofreading of this article.
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