Abstract
The copper-catalyzed click reaction of organic azides with acetylene gas to give 1,2,3-triazoles using water as solvent was studied. The best yields are obtained in the presence of 10 mol% of CuI and 20 mol% of Et3N. Several 1-substituted triazoles were prepared in the yields of 29–96%.
Introduction
1,2,3-Triazoles exhibit important biological activities such as antiviral, antibacterial, antiepileptic, and antiallergic behaviors and are important industrial compounds. Their synthetic strategies have received broad attention [1, 2]. In numerous methods, thermal 1,3-dipolar cycloaddition of azides and alkynes is the most utilitarian one [3]. However, elevated temperature and long reaction time are obligatory in the thermal cycloaddition. In 2002, the Meldal group [4] and the Sharpless group [5] independently reported Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction to construct 1,4-disubstituted 1,2,3-triazoles. Because of its mild conditions, high yield and high regioselectivity, the CuAAC reaction has become the most widely used reaction in ‘click chemistry’ [6–8].
1-Monosubstituted 1,2,3-triazoles play an important role in some biologically active molecules [9–13] and such molecules are normally synthesized by high-temperature cycloaddition reaction [14, 15]. It is an attractive research to develop milder conditions for the synthesis. Recently, several groups have focused on the synthesis of 1-monosubstituted triazoles via click chemistry from acetylene gas [16] or some acetylenic surrogates such as trimethylsilyl acetylene [17], calcium carbide [18–20], and sodium acetylide [21]. Although good results have been achieved, organic solvents are necessary in these preparations. Influenced by increasing environmental consciousness, the use of water as a green medium has attracted considerable attention in chemical society in the past decades [22–24]. It is fascinating to establish novel methods for the synthesis of 1-monosubstituted 1,2,3-triazoles via a green process (for the selected examples for click reaction in water, see [25–33]). Herein, we wish to report an efficient and green synthesis method of 1,2,3-triazoles from organic azides with acetylene gas in water under CuI catalysis.
Results and discussion
In continuation of our previous research [16] and taking into account other reports on the CuAAC reaction [6–8], the initial studies were conducted using phenyl azide (1a, 1.0 mmol), water (1 mL), base (0.2 mmol), and Cu(I) salt (0.1 mmol) under the atmosphere of acetylene (1 atm) at room temperature for 24 h, as shown in Scheme 1.
Previously, our group and the Kuang group found that high water content in organic solvents was disadvantageous in the click chemistry of organic azide with acetylene gas or calcium carbide. Surprisingly, the reaction of Scheme 1 underwent smoothly and afforded the desired triazole 2a in 90% yield in the presence of 10 mol% of CuI and 20 mol% of Et3N. Encouraged by this positive result, optimization of the reaction conditions was carried out using different amines. Et3N proved to be the best catalyst, and in the absence of Et3N the yield decreased to 29%. Subsequently, when Et3N was dosed to 10 mol%, the yield increased to 69%. Many different nitrogen-containing bases were employed in the dosage of 20 mol%. No significant difference was observed when 2,6-lutidine or iPr2EtN was used as the base. When changing to pyridine, NH3‧H2O, Et2NH, and ethane-1,2-diamine as the base, 2a was obtained in 63%, 82%, 85%, and 29% yield, respectively. In further studies, we chose 20 mol% Et3N as the standard base. Different commercially available and inexpensive copper(I) salts such as CuCl and CuBr were used for the reaction, and the results showed that CuCl and CuBr exhibited relatively low activity as catalysts. When the dosage of CuI was reduced to 5 mol%, the reaction yield decreased considerably to 75%. Without CuI as a catalyst, no desired product was observed. The reaction under solvent-free conditions with 10 mol% of CuI and 20 mol% of Et3N yielded 73% of 2a.
Under the optimized conditions, a variety of azides were employed to demonstrate the efficiency and generality of this green process on a 1.0 mmol scale. As summarized in Scheme 2, both aryl azides and alkyl azides were successfully examined. In general, the reactions of electron-rich and electron-poor aromatic azides proceed efficiently in good to excellent yields except the aromatic azides bearing ortho-substituents. Compared with other click processes in organic solvents [16, 18–20], it was found that the efficiency of this green process in water is slightly lower or equivalent to that of the former processes. The desired triazole 2k was not obtained in the attempted reaction of p-nitrophenyl azide, for which heterogeneous conditions were observed. However, the triazole 2k was synthesized in 78% yield after a small amount of toluene (0.8 mmol) was added to make a homogeneous solution. Under the same conditions, triazole 2l was obtained from 3-azidobenzonitrile in 95% yield. Benzyl derivative 2n and octyl derivative 2o were obtained in 67% and 41% yields, respectively, when using water as solvent.
The synthesis of different triazoles under the optimal conditions in water.
Conclusion
In summary, the CuAAC reaction of organic azides with acetylene gas using water as solvent was developed. The use of 10 mol% CuI with 20 mol% Et3N catalyzed the click reaction with good results. This green process provides a simple and practical method to synthesize 1-substituted 1,2,3-triazoles.
Experimental
Melting points were measured using a Beijing-Taike X-4 apparatus without correction. NMR spectra were recorded on Bruker DRX-400 spectrometer (400 MHz for 1H and 100 MHz for 13C). IR analyses were performed with a Bruker FT-IR spectrophotometer. Elemental analyses were performed at Midwest Microlabs. Column chromatography was carried out on silica gel (200–300 mesh). All azides 1a–o were prepared from arylamines [34] or organic bromides [35] according to the literature procedures.
General procedure for synthesis of 1,2,3-triazoles 2a–o
To a flask equipped with a stirring bar, azide (1.0 mmol), Et3N (0.2 mmol), water (1 mL), and CuI (0.1 mmol) were added successively. After the atmosphere was excluded using a vacuum pump, acetylene gas was introduced from a balloon and the mixture was stirred at room temperature for 24 h. After completion of the reaction, ethyl acetate (25 mL) was added to dissolve the product and the mixture was washed with brine (10 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. After the solvent was removed under reduced pressure, the residue was purified by flash chromatography to give the 1,2,3-triazole product. Warning: organic azides are potentially explosive substances and should be handled with great care.
1-Phenyl-1H-1,2,3-triazole (2a)
Yield 90% (lit. [18] yield 85%); white solid; mp 52–53°C (lit. [16] mp 52–53°C); 1H NMR (CDCl3): δ 8.04 (s, 1H), 7.82 (s, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.52 (m, 3H); 13C NMR (CDCl3): δ 136.8, 134.2, 129.5, 128.5, 121.7, 120.4.
1-p-Tolyl-1H-1,2,3-triazole (2b)
Yield 85% (lit. [18] yield 88%); white solid; mp 85–86°C (lit. [16] mp 86°C); 1H NMR (CDCl3): δ 7.98 (s, 1H), 7.82 (s, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 2.41 (s, 3H); 13C NMR (CDCl3): δ 138.8, 134.7, 134.3, 130.2, 121.7, 120.5, 21.0.
1-o-Tolyl-1H-1,2,3-triazole (2c)
Yield 29% (lit. [16] yield 45%); yellow oil; 1H NMR (CDCl3): δ 7.85 (s, 1H), 7.78 (s, 1H), 7.39 (m, 4H), 2.20 (s, 3H); 13C NMR (CDCl3): δ 136.3, 133.6, 133.5, 131.4, 129.8, 126.7, 125.9, 125.0, 17.7.
1-(4-Methoxyphenyl)-1H-1,2,3-triazole (2d)
Yield 82% (lit. [19] yield 64%); white solid; mp 77–79°C (lit.[16] mp 78–80°C); 1H NMR (CDCl3): δ 7.98 (s, 1H), 7.80 (s, 1H), 7.62 (d, J = 7.6 Hz, 2H), 6.99 (d, J = 7.6 Hz, 2H), 3.83 (s, 3H); 13C NMR (CDCl3): δ 159.4, 133.9, 130.0, 121.9, 121.7, 114.4, 55.3.
1-(4-Chlorophenyl)-1H-1,2,3-triazole (2e)
Yield 86% (lit. [16] yield 92%); pale yellow solid; mp 111–113°C (lit. [16] mp 111–113°C); 1H NMR (CDCl3): δ 7.98 (s, 1H), 7.85 (s, 1H), 7.80 (d, J = 7.6 Hz, 2H), 7.50 (d, J = 7.6 Hz, 2H); 13C NMR (CDCl3): δ 135.5, 134.6, 134.5, 129.9, 121.8, 121.6.
1-(2-Chlorophenyl)-1H-1,2,3-triazole (2f)
Yield 54% (lit. [16] yield 54%); yellow oil; 1H NMR (CDCl3): δ 8.02 (s, 1H), 7.87 (s, 1H), 7.68–7.60 (m, 2H), 7.50 (m, 2H); 13C NMR (CDCl3): δ 134.8, 133.5, 130.7, 128.6, 127.9, 127.8, 125.6.
1-m-Tolyl-1H-1,2,3-triazole (2g)
Yield 86% (lit. [16] yield 93%); yellow oil; 1H NMR (CDCl3): δ 8.00 (s, 1H), 7.80 (m, 1H), 7.57 (s, 1H), 7.50 (s, 1H), 7.38 (d, J = 7.2 Hz, 1H), 7.23 (s, 1H), 2.43 (s, 3H); 13C NMR (CDCl3): δ 139.8, 136.8, 134.2, 129.4, 121.7, 121.1, 117.5, 21.2.
1-(4-Bromophenyl)-1H-1,2,3-triazole (2h)
Yield 84% (lit. [16] yield 89%); white solid; mp 145–146°C (lit.[16] mp 145–146°C); 1H NMR (CDCl3): δ 7.98 (s, 1H), 7.85 (s, 1H), 7.73–7.65 (m, 4H); 13C NMR (CDCl3): δ 136.0, 134.7, 132.9, 122.4, 122.0, 121.5.
1-(3-Chlorophenyl)-1H-1,2,3-triazole (2i)
Yield 86% (lit. [16] yield 93%); pale yellow solid; mp 91–93°C (lit.[16] mp 91–93°C); 1H NMR (CDCl3): δ 8.02 (s, 1H), 7.87 (s, 1H), 7.80 (s, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.52–7.40 (m, 2H); 13C NMR (CDCl3): δ 137.8, 135.6, 134.7, 130.8, 128.8, 121.6, 120.9, 118.6.
Ethyl 4-(1H-1,2,3-triazol-1-yl)benzoate (2j)
Yield 96% (lit. [16] yield 90%); yellow solid; mp 94–96°C (lit.[16] mp 94–96°C); 1H NMR (CDCl3): δ 8.22 (d, J = 7.6 Hz, 2H), 8.10 (s, 1H), 7.87 (d, J = 9.6 Hz, 3H), 4.42 (q, J = 6.8 Hz, 2H), 1.43 (t, J = 6.8 Hz, 3H); 13C NMR (CDCl3): δ 165.4, 139.9, 134.8, 131.3, 130.6, 121.6, 119.9, 61.4, 14.3.
1-(4-Nitrophenyl)-1H-1,2,3-triazole (2k)
Yield 78% (lit. [16] yield 91%); yellow solid; mp 202–205°C (lit.[16] mp 202–205°C); 1H NMR (DMSO-d6): δ 9.06 (s, 1H), 8.47 (d, J = 8.8 Hz, 2H), 8.25 (d, J = 8.8 Hz, 2H), 8.01 (s, 1H); 13C NMR (DMSO-d6): δ 146.6, 140.9, 135.0, 125.5, 123.8, 120.6.
3-(1H-1,2,3-triazol-1-yl)benzonitrile (2l)
Yield 95%; pale yellow solid; mp 130.5–132°C; 1H NMR (CDCl3): δ 8.08 (s, 2H), 8.05 (d, J = 8.0 Hz, 1H), 7.89 (s, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.68 (dd, J = 7.6 Hz, 1H); 13C NMR (CDCl3): δ 137.5, 132.0, 130.9, 124.6, 123.7, 121.6, 114.1. Anal. Calcd for C9H6N4: C, 63.52; H, 3.55; N, 23.92. Found: C, 63.55; H, 3.52; N, 23.89. IR (KBr, cm-1): 3107, 2098, 1601, 1457, 1215.
2-(1H-1,2,3-triazol-1-yl)phenol (2m)
Yield 40%; pale reddish solid; mp 150–151°C; 1H NMR (CDCl3): δ 9.86 (s, 1H), 8.13 (s, 1H), 7.91 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.21(d, J = 8.0 Hz, 1H), 7.01(t, J = 7.6 Hz, 1H); 13C NMR (DMSO-d6): 149.3, 133.8, 129.8, 122.7, 121.6, 120.3, 119.6, 119.5; IR (KBr, cm-1): 3436, 3125, 1643, 1397, 1044.
Anal. Calcd for C8H7N3O: C, 59.62; H, 4.38; N, 26.07. Found: C, 59.68; H, 4.34; N, 26.04.
1-Benzyl-1H-1,2,3-triazole (2n)
Yield 67% (lit. [16] yield 85%); white solid; mp 51–53°C (lit. [16] mp 51–53°C); 1H NMR (CDCl3): δ 7.68 (s, 1H), 7.50 (s, 1H), 7.34 (m, 3H), 7.26 (m, 2H), 5.55 (s, 2H); 13C NMR (CDCl3): 134.6, 134.0, 128.9, 127.8, 128.5, 123.3, 53.7.
1-Octyl-1H-1,2,3-triazole (2o)
Yield 41% (lit. [16] yield 97%); pale yellow oil (lit. [16] mp 18–20°C); 1H NMR (CDCl3): δ 7.71 (s, 1H), 7.56 (s, 1H), 4.39 (t, J = 7.2 Hz, 2H), 1.91 (t, J = 6.4 Hz, 2H), 1.27 (m, 10H), 0.85(t, J = 6.4 Hz, 3H). 13C NMR (CDCl3): δ 133.7, 123.1, 50.1, 31.6, 30.3, 29.0, 28.9, 26.4, 22.5, 14.0.
The authors are grateful for the support of the Natural Science Foundation of Hainan Province (No. 211017).
References
[1] Wamhoff, H. 1,2,3-Triazoles in Comprehensive Heterocyclic Chemistry. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds. Pergamon: Oxford, 1984; Vol. 5, pp. 669–732.10.1016/B978-008096519-2.00079-5Search in Google Scholar
[2] Fan, W. Q.; Katritzky, A. R. 1,2,3-Triazoles in Comprehesive Heterocyclic Chemistry II. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds. Pergamon Science: Oxford, 1996; Vol. 4. pp. 1–126.10.1016/B978-008096518-5.00079-4Search in Google Scholar
[3] Huisgen, R. 1,3-dipolar cycloaddition- Introduction, survey, mechanism. In 1,3-Dipolar Cycloadition Chemistry. In 1,3-Dipolar Cycloadition Chemistry; Padwa, A., Ed. Wiley: New York, 1984; Vol. 1, pp. 1–176.Search in Google Scholar
[4] Tornøe, C. W.; Christensen, C.; Meldal, M. Peptidotriazoles on solid phase: [1,2,3]-triazoles by regiospecific copper(I)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides. J. Org. Chem. 2002, 67, 3057–3064.Search in Google Scholar
[5] Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. A stepwise Huisgen cycloaddition process: copper(I)-catalyzed regioselective ligation of azides and terminal alkynes. Angew. Chem. Int. Ed. 2002, 41, 2596–2599.Search in Google Scholar
[6] Bock, V. D.; Hiemstra, H.; van Maarseveen, J. H. CuI-catalyzed alkyne-azide “click” cycloadditions from a mechanistic and synthetic perspective. Eur. J. Org. Chem. 2006, 2006, 51–68.Search in Google Scholar
[7] Meldal, M.; Tornøe, C. W. Cu-Catalyzed azide-alkyne cycloaddition. Chem. Rev. 2008, 108, 2952–3015.Search in Google Scholar
[8] Alonso, F.; Moglie, Y.; Radivoy, G.; Yus, M. Unsupported copper nanoparticles in the 1,3-dipolar cycloaddition of terminal alkynes and azides. Eur. J. Org. Chem. 2010, 2010, 1875–1884.Search in Google Scholar
[9] Micetich, R. G.; Maiti, S. N.; Spevak, P.; Hall, T. W.; Yamabe, S.; Ishida, N.; Tanaka, M.; Yamazaki, T.; Nakai, A.; Ogawa, K. Synthesis and β-lactamase inhibitory properties of 2β-[(1,2,3-triazol-1-yl) methyl-2α-methylpenam-3α-carboxyic acid 1,1-dioxide and related triazolyl derivatives. J. Med. Chem. 1987, 30, 1469–1474.Search in Google Scholar
[10] Fan, H.; Xu, G.; Chen, Y.; Jiang, Z.; Zhang, S.; Yang, Y.; Ji, R. Synthesis and antibacterial activity of oxazolidinones containing triazolyl group. Eur. J. Med. Chem. 2007, 42, 1137–1143.Search in Google Scholar
[11] Kim, J.-Y.; Boyer, F.-E.; Choy, A. L.; Huband, M. D.; Pagano, P. J.; Prasad, J. V. N. V. Synthesis and structure-activity studies of novel homomorpholine oxazolidinone antibacterial agents. Bioorg. Med. Chem. Lett. 2009, 19, 550–553.Search in Google Scholar
[12] Komine, T.; Kojima, A; Asahina, Y.; Saito, T.; Takano, H.; Shibue, T.; Fukuda, Y. Synthesis and structure-activity relationship studies of highly potent novel oxazolidinone antibacterials. J. Med. Chem. 2008, 51, 6558–6562.Search in Google Scholar
[13] Reck, F.; Zhou, F.; Eyermann, C. J.; Kern, G.; Carcanague, D.; Loannidis, G.; Illingworth, R.; Poon, G.; Gravestock, M. B. Novel substituted (pyridin-3-yl)phenyloxazolidinones: antibacterial agents with reduced activity against monoamine oxidase A and increased solubility. J. Med. Chem. 2007, 50, 4868–4881.Search in Google Scholar
[14] Kauer, J. C.; Carboni, R. A. Aromatic azapentalenes. III. 1,3a,6,6a-Tetraazapentalenes. J. Am. Chem. Soc. 1966, 89, 2633–2637.Search in Google Scholar
[15] Biagi, G.; Livi, O.; Scartoni, V. Studies on 1,2,3-triazole derivatives as potential inhibitors of the cyclooxygenase. Farmaco Sci. 1988, 43, 597–611.Search in Google Scholar
[16] Wu, L. Y.; Xie, Y. X.; Chen, Z. S.; Niu, Y. N.; Liang, Y. M. A convenient synthesis of 1-substituted 1,2,3-triazoles via CuI/Et3N catalyzed ‘click chemistry’ from azides and acetylene gas. Synlett 2009, 1453–1456.10.1055/s-0029-1216745Search in Google Scholar
[17] Fletcher, J. T.; Walz, S. E.; Keeney, M. E. Monosubstituted 1,2,3-triazoles from two-step one-pot deprotection/click additions of trimethylsilylacetylene. Tetrahedron Lett. 2008, 49, 7030–7032.Search in Google Scholar
[18] Jiang, Y. B.; Kuang, C. X.; Yang, Q. The use of calcium carbide in the synthesis of 1-monosubstituted aryl 1,2,3-triazole via click chemistry. Synlett 2009, 3163–3166.10.1055/s-0029-1218346Search in Google Scholar
[19] Gonda, Z.; Lőrincz, K.; Novák, Z. Efficient synthesis of deuterated 1,2,3-triazoles. Tetrahedron Lett. 2010, 51, 6275–6277.Search in Google Scholar
[20] Yang, Q.; Jiang, Y.; Kuang, C. Facile one-pot synthesis of monosubstituted 1-aryl-1H-1,2,3-triazoles from arylboronic acids and arop-2-ynoic acid (=propiolic acid) or calcium acetylide (=calcium carbide) as acetylene source. Helv. Chim. Acta 2012, 95, 448–454.Search in Google Scholar
[21] Jiang, Y. B.; Kuang, C. X.; Yang, Q. Facile and quick synthesis of 1-monosubstituted aryl 1,2,3-triazoles: a copper-free [3+2] cycloaddition. Tetrahedron 2011, 67, 289–292.Search in Google Scholar
[22] Lindstrom, U. M. Organic Reactions in Water: Principles, Strategies and Applications; Wiley-Blackwell: Oxford, UK, 2007.10.1002/9780470988817Search in Google Scholar
[23] Hailes, H. C. Reaction solvent selection: the potential of water as a solvent for organic transformations. Org. Process Res. Dev. 2007, 11, 114–120.Search in Google Scholar
[24] Simon, M. O.; Li, C. J. Green chemistry oriented organic synthesis in water. Chem. Soc. Rev. 2012, 41, 1415–1427.Search in Google Scholar
[25] Alonso, F.; Moglie, Y.; Radivoy, G.; Yus, M. Multicomponent synthesis of 1,2,3-triazoles in water catalyzed by copper nanoparticles on activated carbon. Adv. Synth. Catal. 2010, 352, 3208–3214.Search in Google Scholar
[26] Wang, K.; Bi, X.; Xing, S.; Liao, P.; Fang, Z.; Meng, X.; Zhang, Q.; Liu, Q.; Ji, Y. Cu2O acting as a robust catalyst in CuAAC reactions: water is the required medium. Green Chem. 2011, 13, 562–565.Search in Google Scholar
[27] Alonso, F.; Moglie, Y.; Radivoy, G.; Yus, M. Click chemistry from organic halides, diazonium salts and anilines in water catalysed by copper nanoparticles on activated carbon. Org. Biomol. Chem. 2011, 9, 6385–6395.Search in Google Scholar
[28] Alonso, F.; Moglie, Y.; Radivoy, G.; Yus, M. Multicomponent click synthesis of 1,2,3-triazoles from epoxides in water catalyzed by copper nanoparticles on activated carbon. J. Org. Chem. 2011, 76, 8394–8405.Search in Google Scholar
[29] Liu, M.; Reiser, O. A copper(I) isonitrile complex as a heterogeneous catalyst for azide-alkyne cycloaddition in water. Org. Lett. 2011, 13, 1102–1105.Search in Google Scholar
[30] Wang, Y.; Liu, J.; Xia, C. Insights into supported copper(II)-catalyzed azide-alkyne cycloaddition in water. Adv. Synth. Catal. 2011, 353, 1534–1542.Search in Google Scholar
[31] Hudson, R.; Li, C.-J.; Moores, A. Magnetic copper-iron nanoparticles as simple heterogeneous catalysts for the azide-alkyne click reaction in water. Green Chem. 2012, 14, 622–624.Search in Google Scholar
[32] Suzuka, T.; Kawahara, Y.; Ooshiro, K.; Nagamine, T.; Ogihara, K.; Higa, M. Reusable polymer-supported 2,2′-biarylpyridine-copper complexes for Huisgen [3+2] cycloaddition in water. Heterocycles 2012, 85, 615–626.Search in Google Scholar
[33] Alonso, F.; Moglie,Y.; Radivoy, G.; Yus, M. Multicomponent click synthesis of potentially biologically active triazoles catalysed by copper nanoparticles on activated carbon in water. Heterocycles 2012, 84, 1033–1044.Search in Google Scholar
[34] Kwok, S. W.; Fotsing, J. R.; Fraser, R. J.; Rodionov, V. O.; Fokin, V. V. Transition-metal-free catalytic synthesis of 1,5-diaryl-1,2,3-triazoles. Org. Lett. 2010, 12, 4217–4219.Search in Google Scholar
[35] Alvarez, S. G.; Alvarez, M. T. A practical procedure for the synthesis of alkyl azides at ambient temperature in dimethyl sulfoxide in high purity and yield. Synthesis 1997, 4, 413–414.Search in Google Scholar
©2013 by Walter de Gruyter Berlin Boston
This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
