HETEROCYCLES

Short Paper | Regular issue | Vol. 87, No. 4, 2013, pp. 869-876
Received, 19th January, 2013, Accepted, 5th February, 2013, Published online, 22nd February, 2013.
DOI: 10.3987/COM-13-12670

■ A New Method for the Synthesis of [1,2,4]Triazolo[1,5-a]pyridine Derivatives

Wei-Ming Zhao, Yan-Qing Ge,* Wei-Ren Xu, Gui-Long Zhao, Jiong Jia, and Jian-Wu Wang*

School of Chemistry and Chemical Engineering, Shandong University, 27 Shanda Nanlu, Jinan,Shandong, 250100, China

Abstract

[1,2,4]triazolo[1,5-a]pyridine derivatives were conveniently synthesized by tandem reaction under mild conditions. The reaction mechanism was also proposed.

The [1,2,4]triazolo[1,5-a]pyridine derivatives are a kind of important heterocyclic compounds which exhibit antifungal, anticancer and anti-inflammatory activity.1-3 Despite possessing outstanding biological activities, only a few [1,2,4]triazolo[1,5-a]pyridines are known. Some commonly used synthetic methods are the annulation of 1,2,4-triazole ring starting with amino substituted pyridines by a multistep procedure.4 Previously, imidazo[1,5-a]pyridines, pyrazolo[1,5-a]pyridines, imidazo[1,2-a]pyridines and indolizines had been synthesized by a novel tandem reaction in our group.5-8 Herein we are interested to extend the reaction to synthesize the [1,2,4]triazolo[1,5-a]pyridine heterocycles.
1,2,4-Triazoles 1a-f were prepared according to a literature method (Scheme 1)9 only that we used different reactant. The expected [1,2,4]triazolo[1,5-a]pyridine 3a-l were obtained by the reactions of 1,2,4-triazoles 1a-f and α,β-unsaturated esters 2a-b in the presence of K2CO3 in dry DMF at room temperature for 6-10 h. The experimental results are collected in Table 1. As observed in Table 1, a variety of substituted 5-benzoyl-1,2,4-triazoles 1 afforded good yields of these products including a variety of electron-donating and electron-withdrawing substituents.

The structures of products 3 were characterized by spectroscopic methods (1H and 13C NMR, IR, and MS). The structure of 3k was further confirmed by X-ray crystallographic analysis as shown in Figure 1.
In consideration of the result, we proposed the reaction mechanism as follows: Firstly, there would be an intermolecular SN2 reaction between 1 and α,β-unsaturated esters 2, through which intermediate 3 was formed. Afterwards, in the presence of K2CO3, intermediate 4 was deprotonated to form a γ-carbanion of the ester. In order to be more stable, it would transform to α-carbanion of the ester 5. Then by intramolecular nucleophilic addition, the α-carbanion reacted with the aldehyde group to obtain intermediate 6. Afterwards our target product would be gained from 6 by eliminating water. The entire process is shown in Scheme 2.

In summary, we described a novel tandem reaction to synthesize [1,2,4]triazolo[1,5-a]pyridine derivatives under mild conditions in good yields. The reaction mechanism was also proposed. The compounds are particularly interesting molecules due to their biological activity, which will be presented in due course.

EXPERIMENTAL
All reagents and solvents were purchased from Sinopharm Chemical Reagent Co. Ltd and used without further purification unless otherwise noted. Starting materials were prepared according to literatures.9 Thin-layer chromatography (TLC) was conducted on silica gel 60 F254 plates (Merck KGaA). 1H NMR spectra were recorded on a Bruker Avance 300 (300 MHz) spectrometer, using CDCl3 or DMSO-d6 as solvents and tetramethylsilane (TMS) as an internal standard. Melting points were determined on an XD-4 digital micro-melting point apparatus and are uncorrected. IR spectra were recorded with an IR spectrophotometer Avtar 370 FT-IR (Termo Nicolet). MS spectra were recorded on a Trace DSQ mass spectrometer. Elemental analyses were performed on a Vario EL III (Elementar Analysensysteme GmbH) spectroanalyzer.
General procedure for the synthesis and analytical data of 1a-1f
To a 250 mL three-necked, round-bottomed flask, 3.45 g (0.05 mol)1,2,4-triazole and triethylamine (7 mL) were dissolved in pyridine (30 mL) at 0 °C under nitrogen. Then benzoyl chloride (0.1 mol) was added dropwise to the flask. The mixture was stirred for 6 h at rt. After that, sodium hydroxide (0.15 mol) dissolved in 20 mL water was added in the mixture, refluxing for 1.5 h. Then this system was cooled to room temperature and added in water (150 mL), adjusted PH value to 5-6 by using diluted hydrochloric acid. It would precipitate solid compounds. After that, it was filtered and washed with water and ice-cold EtOAc. The crude intermediates were depurated by column chromatography.
Phenyl(1H-1,2,4-triazol-5-yl)methanone (1a)10
1H NMR (300 MHz, CDCl3): δ 14.83 (s, 1H), 8.83 (s, 1H), 7.57-7.84 (m, 5H). ESI-MS m/z Calcd: 173.1. Found: 174.1 [M++1].
p-Tolyl(1H-1,2,4-triazol-5-yl)methanone (1b)
1H NMR (300 MHz, CDCl3): δ 14.82 (s, 1H), 8.81 (s, 1H), 7.82-7.85 (m, 2H), 7.29-7.32 (m, 2H), 2.37 (s, 3H). ESI-MS m/z Calcd: 187.1. Found: 188.1 [M++1]. Anal. Calcd for C10H9N3O: C, 64.16; H, 4.85; N, 22.45. Found: C, 64.22; H, 4.91; N, 22.49.
(4-Methoxyphenyl)(1H-1,2,4-triazol-5-yl)methanone (1c)10
1H NMR (300 MHz, CDCl3): δ 14.80 (s, 1H), 8.80 (s, 1H), 7.87-7.92 (m, 2H), 7.00-7.03 (m, 2H), 3.82 (s, H). ESI-MS m/z Calcd: 203.1. Found: 204.1 [M++1].
(4-Fluorophenyl)(1H-1,2,4-triazol-5-yl)methanone (1d)
1H NMR (300 MHz, CDCl3): δ 14.93 (s, 1H), 8.71 (s, 1H), 8.39-8.43 (m, 2H), 7.38-7.45 (m, 2H). ESI-MS m/z Calcd: 191.1. Found: 192.1 [M++1]. Anal. Calcd for C9H6FN3O: C, 56.55; H, 3.16; N, 21.98. Found: C, 56.59; H, 3.20; N, 21.98.
(2-Fluorophenyl)(1H-1,2,4-triazol-5-yl)methanone (1e)
1H NMR (300 MHz, CDCl3): δ 14.86 (s, 1H), 8.74 (s, 1H), 7.70-7.81 (m, 1H), 7.67-7.69 (m, 1H), 7.33-7.39 (m, 2H). ESI-MS m/z Calcd: 191.1. Found: 192.1 [M++1]. Anal. Calcd for C9H6FN3O: C, 56.55; H, 3.16; N, 21.98. Found: C, 56.57; H, 3.22; N, 22.04.
(2,4-Dichlorophenyl)(1H-1,2,4-triazol-5-yl)methanone (1f)10
1H NMR (300 MHz, CDCl3): δ 14.89 (s, 1H), 8.76 (s, 1H), 7.78-7.79 (m, 1H), 7.69-7.71 (m, 1H), 7.57-7.60 (m, 1H). ESI-MS m/z Calcd: 241.0. Found: 242.0 [M++1].

General procedure for the synthesis and analytical data of 3a-3l
Intermediate 1 (6 mmol), α,β-unsaturated esters (12 mmol), potassium carbonate (1.8 g, 13.2 mmol) and DMF (30 mL) were added to a 100 mL round-bottomed flask. The reaction system was stirred for 6-10 h. Then the mixture was poured into water (200 mL) and extracted with CH2Cl2 (3 x 50 mL). Organic layers were combined and dried over anhydrous Na2SO4, then filtered. By rotary evaporation, the mixture was concentrated. After that, these crude products were depurated by using column chromatography.
Ethyl 8-phenyl[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (3a)
Yellow solid: mp 77-79 °C. 1H NMR (300 MHz, CDCl3): δ 8.64 (d, 1H, J = 6.9 Hz), 8.41 (s, 1H), 7.48-7.50 (m, 6H), 4.10-4.17 (q, 2H, J = 7.2 Hz), 0.98-1.02 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 166.9, 155.6, 150.9, 134.6, 131.4, 129.7, 129.4, 128.8, 127.6, 114.8, 77.9, 77.5, 77.1, 62.3, 14.0. IR (KBr) ν = 3112, 3068, 2925, 1712, 1536, 1486, 1366, 1324, 1257, 1183, 1124, 767, 657 cm-1. ESI-MS m/z Calcd: 267.1. Found: 268.1 [M++1]. Anal. Calcd for C15H13N3O2: C, 67.40; H, 4.90; N, 15.72. Found: C, 67.38; H, 4.94; N, 15.74.
Ethyl 6-methyl-8-phenyl[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (3b)
Yellow oil. 1H NMR (300 MHz, CDCl3): δ 8.45 (s, 1H), 8.33 (s, 1H), 7.55-7.59 (m, 2H), 7.44-7.51 (m, 3H), 4.10-4.17 (q, 2H, J = 7.2 Hz), 2.44 (s, 3H), 0.97-1.02 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 167.0, 154.4, 148.8, 135.1, 133.3, 129.1, 128.5, 128.3, 126.1, 121.4, 77.4, 77.0, 76.6, 61.8, 16.7, 13.6. IR (KBr) ν = 3101, 3061, 2981, 2928, 1229, 1498, 1323, 1241, 1185, 1141, 788, 699 cm-1. ESI-MS m/z Calcd: 281.1. Found: 282.1 [M++1]. Anal. Calcd for C16H15N3O2: C, 68.31; H, 5.37; N, 14.94. Found: C, 68.34; H, 5.35; N, 14.99.
Ethyl 8-p-tolyl[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (3c)
Yellow oil. 1H NMR (300MHz, CDCl3): δ 8.61 (d, 1H, J = 7.2 Hz), 8.39 (s, H), 7.46 (d, 1H, J = 7.2 Hz), 7.39-7.41 (m, 2H), 7.27-7.31 (m, 2H), 4.13-4.20 (q, 2H, J = 7.2 Hz), 2.43 (s, 3H), 1.03-1.08 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 166.5, 155.0, 150.5, 138.8, 131.9, 131.1, 130.6, 129.1, 126.9, 114.3, 77.4, 77.0, 76.6, 61.8, 21.4, 13.6. IR (KBr) ν = 3110, 2981, 2922, 1718, 1492, 1324, 1258, 1180, 1134, 820, 758 cm-1. ESI-MS m/z Calcd: 281.1. Found: 282.1 [M++1]. Anal. Calcd for C16H15N3O2: C, 68.31; H, 5.37; N, 14.94. Found: C, 68.30; H, 5.35; N, 14.98.
Ethyl 6-methyl-8-p-tolyl[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (3d)
Yellow solid: mp 115-117 °C. 1H NMR (300 MHz, CDCl3): δ 8.42 (s, 1H), 8.31 (s, 1H), 7.46-7.49 (m, 2H), 7.27-7.30 (m, 2H), 4.13-4.20 (q, 2H, J = 7.2 Hz), 2.41-2.43 (m, 6H), 1.03-1.08 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 167.1, 154.4, 149.0, 139.0, 134.8, 130.6, 129.1, 128.3, 125.9, 121.4, 77.5, 77.0, 76.6, 61.8, 21.4, 16.7, 13.7. IR (KBr) ν = 3103, 2963, 2926, 1727, 1609, 1500, 1434, 1322, 1250, 1181, 1140, 831, 665 cm-1. ESI-MS m/z Calcd: 295.1. Found: 296.1 [M++1]. Anal. Calcd for C17H17N3O2: C, 69.14; H, 5.80; N, 14.23. Found: C, 69.20; H, 5.85; N, 14.29.
Ethyl 8-(4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (3e)
Yellow solid: mp 99-101 °C. 1H NMR (300 MHz, CDCl3): δ 8.60 (d, H, J = 6.9 Hz), 8.41 (s, 1H), 7.44-7.49 (m, 3H), 7.02-7.05 (m, 2H), 4.15-4.22 (q, 2H, J = 7.2 Hz), 3.87 (s, 3H), 1.06-1.11 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 167.2, 160.7, 155.4, 151.0, 131.8, 131.2, 131.1, 127.2, 126.6, 114.6, 77.9, 77.5, 77.1, 62.3, 55.9, 14.2. IR (KBr) ν = 3747, 3674, 2922, 2850, 1716, 1650, 1558, 1509, 1458, 1385, 1325, 1116, 839, 760 cm-1. ESI-MS m/z Calcd: 297.1. Found: 298.1 [M++1]. Anal. Calcd for C16H15N3O3: C, 64.64; H, 5.09; N, 14.13. Found: C, 64.67; H, 5.12; N, 14.19.
Ethyl 8-(4-methoxyphenyl)-6-methyl[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (3f)
Yellow oil. 1H NMR (300 MHz, CDCl3): δ 8.41 (s, 1H), 8.32 (s, 1H), 7.52-7.57 (m, 2H), 6.99-7.04 (m, 2H), 4.16-4.22 (q, 2H, J = 7.2 Hz), 3.86 (s, 3H), 2.42 (s, 3H), 1.06-1.11 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 167.2, 160.2, 154.3, 149.0, 134.7, 130.6, 127.9, 125.8, 121.4, 114.1, 77.4, 77.0, 76.6, 61.8, 55.4, 16.7, 13.8. IR (KBr) ν = 3748, 3673, 2824, 2854, 1717, 1650, 1558, 1506, 1459, 1385, 1324, 1117, 720 cm-1. ESI-MS m/z Calcd: 311.1. Found: 312.1 [M++1]. Anal. Calcd for C17H17N3O3: C, 65.58; H, 5.50; N, 13.50. Found: C, 65.54; H, 5.52; N, 13.56.
Ethyl 8-(4-fluorophenyl)[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (3g)
Yellow oil. 1H NMR (300 MHz, CDCl3): δ 8.64 (d, 1H, J = 7.2 Hz), 8.40 (s, 1H), 7.47-7.52 (m, 3H), 7.17-7.23 (m, 3H), 4.14-4.21 (q, 2H, J = 7.2 Hz), 1.05-1.10 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 167.8, 161.5, 155.1, 150.5, 131.5, 131.1, 130.7, 130.4, 127.3, 114.3, 77.4, 77.0, 76.6, 61.9, 13.8. IR (KBr) ν = 3112, 2925, 2853, 1719, 1603, 1493, 1368, 1326, 1233, 1180, 839, 760 cm-1. ESI-MS m/z Calcd: 285.1. Found: 286.1 [M++1]. Anal. Calcd for C15H12FN3O2: C, 63.15; H, 4.24; N, 14.73. Found: C, 63.14; H, 4.30; N, 14.79.
Ethyl 8-(4-fluorophenyl)-6-methyl[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (3h)
Yellow oil. 1H NMR (300 MHz, CDCl3): δ 8.41 (s, 1H), 8.32 (s, 1H), 7.52-7.57 (m, 2H), 6.99-7.04 (m, 2H), 4.15-4.22 (q, 2H, J = 7.2 Hz), 3.86 (s, 3H), 1.06-1.11 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 167.2, 160.2, 154.3, 149.0, 134.7, 130.6, 127.9, 125.8, 121.4, 114.1, 77.4, 77.0, 76.6, 61.8, 16.7, 12.9. IR (KBr) ν = 2924, 2854, 1721, 1602, 1495, 1458, 1321, 1246, 1142, 841 cm-1. ESI-MS m/z Calcd: 299.1. Found: 300.1 [M++1]. Anal. Calcd for C16H14FN3O2: C, 64.21; H, 4.71; N, 14.04. Found: C, 64.24; H, 4.70; N, 14.09.
Ethyl 8-(2-fluorophenyl)[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (3i)
Yellow solid: mp 120-122 °C. 1H NMR (300 MHz, CDCl3): δ 8.68 (d, 1H, J = 7.2 Hz), 8.43 (s, 1H), 7.40 (d, 1H, J = 7.2 Hz), 7.45-7.54 (m, 2H), 7.17-7.34 (m, 2H), 4.17-4.24 (q, 2H, J = 7.2 Hz), 1.05-1.10 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 165.7, 161.8, 158.5, 155.7, 150.8, 131.4, 126.5, 124.5, 122.6, 115.8, 77.9, 77.5, 77.1, 62.4, 14.0. IR (KBr) ν = 3446, 2925, 2853, 1702, 1651, 1540, 1457, 1324, 1254, 757 cm-1. ESI-MS m/z Calcd: 285.1. Found: 286.1 [M++1]. Anal. Calcd for C15H12FN3O2: C, 63.15; H, 4.24; N, 14.73. Found: C, 63.17; H, 4.20; N, 14.79.
Ethyl 8-(2-fluorophenyl)-6-methyl[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (3j)
Yellow solid: mp 135-137 °C. 1H NMR (300 MHz, CDCl3): δ 8.50 (s, 1H), 8.33 (s, 1H), 7.39-7.50 (m, 2H), 7.18-7.28 (m, 2H), 4.10-4.17 (q, 2H, J = 7.2 Hz), 2.47 (s, 3H), 0.97-1.02 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 166.2, 161.6, 158.3, 154.6, 148.6, 131.1, 127.0, 124.2, 121.6, 115.9, 77.4, 77.0, 76.6, 61.8, 16.9, 13.6. IR (KBr) ν = 3443, 2924, 2854, 1718, 1651, 1540, 1500, 1457, 1328, 1260, 758 cm-1. ESI-MS m/z Calcd: 299.1. Found: 300.1 [M++1]. Anal. Calcd for C16H14FN3O2: C, 64.21; H, 4.71; N, 14.04. Found: C, 64.23; H, 4.74; N, 14.05.
Ethyl 8-(2,4-dichlorophenyl)[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (3k)
Yellow solid: mp 96-98 °C. 1H NMR (300 MHz, CDCl3): δ 8.70 (d, 1H, J = 7.2 Hz), 8.40 (s, 1H), 7.68-7.71 (d, 1H, J = 7.2 Hz), 7.55-7.60 (m, 1H), 7.39-7.42 (m, 1H), 7.26-7.32 (m, 1H), 4.26-4.33 (q, 2H, J = 7.2 Hz), 1.08-1.13 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 164.5, 155.3, 150.1, 135.4, 134.0, 132.3, 131.3, 129.5, 127.2, 114.3, 77.4, 77.0, 76.6, 62.1, 13.6. IR (KBr) ν = 3119, 2982, 1724, 1588, 1467, 1322, 1240, 1120, 863, 751 cm-1. ESI-MS m/z Calcd: 335.0. Found: 336.0 [M++1]. Anal. Calcd for C15H11Cl2N3O2: C, 53.59; H, 3.30; N, 12.50. Found: C, 53.64; H, 3.33; N, 12.54.
Ethyl 8-(2,4-dichlorophenyl)-6-methyl[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (3l)
Yellow oil. 1H NMR (300 MHz, CDCl3): δ 8.52 (s, 1H), 8.32 (s, 1H), 7.56-7.57 (m, 1H), 7.34-7.38 (m, 1H), 7.27-7.30 (m,1H), 4.11-4.18 ( q, 2H, J = 7.2 Hz), 2.48 (s, 3H), 1.01-1.06 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 165.8, 154.7, 148.2, 135.8, 134.8, 131.8, 131.4, 129.7, 127.2, 121.5, 77.5, 77.1, 76.7, 61.9, 17.0, 13.7. IR (KBr) ν = 3093, 2918, 1729, 1589, 1501, 1322, 1241, 1142, 863, 781 cm-1. ESI-MS m/z Calcd: 349.0. Found: 350.0 [M++1]. Anal. Calcd for C16H13Cl2N3O2: C, 54.87; H, 3.74; N, 12.00. Found: C, 54.84; H, 3.76; N, 12.05.

ACKNOWLEDGEMENTS
The authors gratefully acknowledge the Science and Technology Special Major Project for Significant New Drugs Formulation (2011ZX09401-009), the Natural Science Foundation of Shandong Province (No. ZR2012BL04) for financial support of this work.

References

1. Y. Luo and Y. Hu, Arch. Pharm. Chem. Life Sci., 2006, 339, 262. CrossRef
2. T. Liu and Y. Hu, Bioorg. Med. Chem. Lett., 2002, 12, 2411. CrossRef
3. S. P. East, C. B. White, O. Barker, S. Barker, J. Bennett, D. Brown, E. A. Boyd, C. Brennan, C. Chowdhury, I. Collins, E. Convers-Reignier, B. W. Dymock, R.Fletcher, D. J. Haydon, M. Gardiner, S. Hatcher, P. Ingram, P. Lancett, P. Mortenson, K. Papadopoulos, C. Smee, H. B. Thomaides-Brears, H. Tye, J. Workman, and L. G. Czaplewski, Bioorg. Med. Chem. Lett., 2009, 19, 894. CrossRef
4. G. Jones and D. R. Sliskovic, Adv. Heterocycl. Chem., 1983, 34, 86. CrossRef
5. J. W. Wang, J. Jia, D. J. Hou, H. M. Li, and J. Yin, Chin. J. Org. Chem., 2003, 23, 173.
6. Y. Q. Ge, J. Jia, Y. Li, L. Yin, and J. W. Wang, Heterocycles, 2009, 78, 197. CrossRef
7. Y. Q. Ge, J. Jia, H. Yang, G. L. Zhao, F. X. Zhan, and J. W. Wang, Heterocycles, 2009, 78, 725. CrossRef
8. J. Jia, Y. Q. Ge, X. T. Tao, and J. W. Wang, Heterocycles, 2010, 81, 185. CrossRef
9. L. A. M. Bastiaansen and E. F. Godefroi, Synthesis, 1978, 675. CrossRef
10. S. Ohta, I. Kawasaki, A. Fukuno, M. Yamashita, T. Tada, and T. Kawabata, Chem. Pharm. Bull., 1993, 41, 1226. CrossRef