A highly selective and efficient method for the synthesis of 3,3’(5,5’)-polymethylene-bis(1H1,2,4-triazol-5(3)-amines)

was developed using the reaction of dicarboxylic acids and

aminoguanidine in an aqueous medium. This one-pot, microwave-promoted method was proved to be scalable affording the desired products in good yields and purity. The scope of the method was successfully explored by the preparation of a small library of polymethylene-bis(1H-1,2,4-triazol-5(3)-amines) with different alkyl chain linkers. The annular prototropic tautomerism in the prepared compounds was studied using NMR spectroscopy and X-ray crystallography

Dolzhenko, Anton V

Lee, Ming Hu

Phei, Felicia Lin Lim

Tiekink, Edward R. T. *

Sunway Institutional Repository

Graphical Abstract To create your abstract, type over the instructions in the template box below. Fonts or abstract dimensions should not be changed or altered. One-pot, microwave-assisted synthesis of polymethylene-bridged bis(1H-1,2,4-triazol-5(3)-amines) and their tautomerism  Felicia Phei Lin Lim, Lee Ming Hu, Edward R. T. Tiekink and Anton V. Dolzhenko   Leave this area blank for abstract info.  1   Tetrahedron Letters journal  homepage:  www.e lsevier .com   One-pot, microwave-assisted synthesis of polymethylene-bridged bis(1H-1,2,4-triazol-5(3)-amines) and their tautomerism Felicia Phei Lin Lima, Lee Ming Hua, Edward R. T. Tiekinkb  and Anton V. Dolzhenkoa,c  a School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Selangor Darul Ehsan 47500, Malaysia b Research Centre for Crystalline Materials, School of Science and Technology, Sunway University, Bandar Sunway, Selangor Darul Ehsan 47500, Malaysia c School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Faculty of Health Sciences, Curtin University, GPO Box U1987 Perth, Western Australia 6845, Australia  ——— * Corresponding author. Tel.: +60 3 5514 5867; fax: +60 3 5514 6364; e-mail addresses: dolzhenkoav@gmail.com, anton.dolzhenko@monash.edu (A.V. Dolzhenko).  The twin-drugs strategy involves linking two identical pharmacophores in one molecule by a chemically and pharmacologically inert bridge. It is one of the efficient approaches to significantly improve effectiveness of bioactive agents. A polymethylene chain is often used as a link between pharmacophores in twin-drugs and the length of this chain is adjusted to achieve optimal therapeutic properties.  Many symmetrical polymethylene-bridged diamines, their derivatives and analogues, including bis(N-heterocycles), have been found to possess antiparasitic,1 antibacterial,2 and anticancer3 properties. Some notable recent examples of these bioactive compounds include highly potent antimalarial diamine 1;1d bis-thiourea 2 inhibiting soluble epoxide hydrolase at a low nanomolar concentration range;4 bis-imidazoles 3 and 4 possessing strong anti-biofilm activity against Staphylococcus aureus and Pseudomonas aeruginosa, respectively;2c compound 5 effectively bis-intercalating into the tatelomeric DNA/RNA duplex;3e and bis(1H-1,2,4-triazol-5-amine) 6 possessing anticancer properties3f (Fig. 1). Bis-triazole 6 was synthesized using the reaction of the corresponding bis-urea 8 or bis-thiourea 9, which were prepared from sebacoyl chloride (7), with hydrazine (Scheme 1).3f This two-step process produced 6 in 59-61% overall yield. However, using a relatively unstable acid chloride and extended reaction times (4-8 h for each step) makes this process less practical. Moreover, the selectivity of all steps is questionable as confirmed by the low purity of products (by reported elemental analysis data for 6, 8, and 9).3f ART ICLE  INFO  AB ST R ACT  Article history: Received Received in revised form Accepted Available online A highly selective and efficient method for the synthesis of 3,3’(5,5’)-polymethylene-bis(1H-1,2,4-triazol-5(3)-amines) was developed using the reaction of dicarboxylic acids and aminoguanidine in an aqueous medium. This one-pot, microwave-promoted method was proved to be scalable affording the desired products in good yields and purity. The scope of the method was successfully explored by the preparation of a small library of polymethylene-bis(1H-1,2,4-triazol-5(3)-amines) with different alkyl chain linkers. The annular prototropic tautomerism in the prepared compounds was studied using NMR spectroscopy and X-ray crystallography.   2018 Elsevier Ltd. All rights reserved.  Keywords: Triazole Dicarboxylic acid Microwave-assisted synthesis One-pot synthesis Tautomerism  Figure 1. Selected bioactive symmetrical polymethylene-bridged compounds.  Tetrahedron Letters 2  A homologue of compound 6, decamethylene-bis(1H-1,2,4-triazol-5-amine) (11) was prepared via the intramolecular cyclization of bis-amidoguanidine 10 (Scheme 2).5 This reaction required heating at high temperature (160-180 °C) for 3 h but afforded 11 in rather modest yield (26%). Previously, we developed an effective method for the cyclization of amidoguanidines in water under microwave irradiation affording the corresponding aminotriazoles in excellent yields.6 This approach was further elaborated for the synthesis of more complex compounds in a one-pot manner.7 Therefore, we decided to adopt a similar microwave-assisted methodology to prepare 3,3’(5,5’)-polymethylene-bis(1H-1,2,4-triazol-5(3)-amines). Furthermore, we attempted to carry out the synthesis in one-pot starting from readily available dicarboxylic acids.  As the model reaction, we decided to use condensation of succcinic acid with aminoguanidine. This reaction under conventional heating was reported to suffer from a lack of selectivity resulting in the formation of a mixture of products, from which pure ethylene-bis(1H-1,2,4-triazol-5-amine) 12 was isolated in 8-11% yield only.8 To overcome this problem, we optimized the reaction conditions under microwave irradiation.  Initially, using the Discover SP (CEM) microwave synthesizer, succinic acid was heated with aminoguanidine hydrochloride in water at 200 °C for 15 min. After cooling, an aqueous solution of potassium carbonate was added to the reaction mixture and heating was continued at 200 °C for 5 min. To our satisfaction, we observed the formation of ethylene-bis(1H-1,2,4-triazol-5-amine) 12, which was isolated in pure form via filtration (Entry 1). To further improve the reaction yield, we continued the optimization process and found that increasing the amount of potassium carbonate led to a slight increase in product yield (Entry 2). However, a further optimization of the reaction conditions, particularly increase of the temperature, was limited due to exessive pressure generated in the reaction vessel. Screening other bases for the reaction (Entries 3-4), we identified that under similar conditions sodium hydroxide was equally efficient as a base in terms of yield. Hence, the optimization was continued using sodium hydroxide as a base. Further variations in the reaction parameters revealed that 12 could be obtained in good yield by heating succinic acid and aminoguanidine hydrochloride in water at 220 °C for 15 min followed by the addition of an aqueous solution of sodium hydroxide and further microwave irradiation at 200 °C for 5 min (Entry 16). It should be noted that the exclusive presence of ethylene-bis(1H-1,2,4-triazol-5-amine) 12 was observed in the crude product isolated from the reactions.  To explore the scope of the method, various dicarboxylic acids were used as substrates in the reaction with aminoguanidine hydrochloride to produce polymethylene-bis(1H-1,2,4-triazol-5(3)-amines). The optimized conditions9 were found to be sufficiently general and suitable for the synthesis of compounds 6, 11-17 in good yields (Table 2). In all cases, the reaction was selective and only polymethylene-bis(1H-1,2,4-triazol-5(3)-amines) were isolated in high purity via filtration. The reaction was also effectively performed on 3.4 mmol and 17 mmol scales with similar outcomes.  It should also be noted that the developed method was successfully tested using another microwave reactor Monowave 450 (Anton Paar) microwave synthesizer for the synthesis of 12 under the conditions optimized using the Discover SP (CEM). The outcome was satisfactory affording 12 in 91% yield, therefore confirming the reproducibility of the method in different microwave reactors.  Scheme 1. Synthesis of octamethylene-bis(1H-1,2,4-triazol-5-amine) (6).3f Scheme 2. Synthesis of decamethylene-bis(1H-1,2,4-triazol-5-amine) (11).5  3 Table 1. Optimization of the reaction conditions for the synthesis of ethylene-bis(1H-1,2,4-triazol-5(3)-amine) 12a  Entry Molar ratio of succinic acid: aminoguanidine Conditions Isolated yield of 12 (%) 1 1: 2 i: water, 200 °C, 15 min; ii: K2CO3 (0.5 equiv.), water, 200 °C, 5 min 33 2 1: 2 i: water, 200 °C, 15 min; ii: K2CO3 (1.0 equiv.), water, 200 °C, 5 min 37 3 1: 2 i: water, 200 °C, 15 min; ii: NaHCO3 (1.0 equiv.), water, 200 °C, 5 min 27 4 1: 2 i: water, 200 °C, 15 min; ii: NaOH (1.0 equiv.), water, 200 °C, 5 min 36 5 1: 3 i: water, 200 °C, 15 min; ii: NaOH (1.0 equiv.), water, 200 °C, 5 min  58 6 1: 4 i: water, 200 °C, 15 min; ii: NaOH (1.0 equiv.), water, 200 °C, 5 min,  66 7 1: 5 i: water, 200 °C, 15 min; ii: NaOH (1.0 equiv.), water, 200 °C, 5 min  79 8 1: 6 i: water, 200 °C, 15 min; ii: NaOH (1.0 equiv.), water, 200 °C, 5 min  74 9 1: 7 i: water, 200 °C, 15 min; ii: NaOH (1.0 equiv.), water, 200 °C, 5 min  71 10 1: 5 i: water, 200 °C, 10 min; ii: NaOH (1.0 equiv.), water, 200 °C, 5 min  58 11 1: 5 i: water, 180 °C, 30 min; ii: NaOH (1.0 equiv.), 200 °C, 5 min 58 12 1: 5 i: water, 200 °C, 15 min; ii: NaOH (1.0 equiv.), 180 °C, 5 min 68 13 1: 5 i: water, 180 °C, 15 min; ii: NaOH (1.0 equiv.), 200 °C, 5 min 46 14 1: 5 i: water, 190 °C, 15 min; ii: NaOH (1.0 equiv.), 200 °C, 5 min 54 15 1: 5 i: water, 210 °C, 15 min; ii: NaOH (1.0 equiv.), 200 °C, 5 min 79 16 1: 5 i: water, 220 °C, 15 min; ii: NaOH (1.0 equiv.), 200 °C, 5 min 85 17 1: 5 i: water, 230 °C, 15 min; ii: NaOH (1.0 equiv.), 200 °C, 5 min 77 a The reaction was performed using the Discover SP (CEM) microwave synthesizer on a 3.4 mmol scale (succinic acid) using 2 mL of water in the first step, followed by the addition of 1 mL of the specified aqueous base in the second step.  Tetrahedron Letters 4  Table 2. One-pot synthesis of polymethylene-bis(1H-1,2,4-triazol-5(3)-amines)a   Compound Structure Scale (mmol) Yield (%) 12  3.4  17  85 88 13  3.4  17  58 63 14  3.4  17  77 66 15  3.4  17  52 56 16  3.4  17  72 65 17  3.4  17  57 54 6  3.4  17  63 63 11  3.4  17  72 67 a The reaction was performed using a Discover SP CEM microwave synthesizer at 220 °C for 15 min in water followed by addition of aq. NaOH and heating at 200 °C for 5 min. The annular prototropic tautomerism, possible in both triazole rings of the prepared compounds, might result in six different tautomers representing different combinations of the 5-amino-1H-1,2,4-triazole, 3-amino-1H-1,2,4-triazole, and 5-amino-4H-1,2,4-triazole rings (Scheme 3). These three principal forms of the 1,2,4-triazole ring can be distinguished on the basis of NMR spectroscopy data (though without allowing assigning the presence of individual tautomers). The 1H NMR spectra of the products in DMSO-d6 gave two sets of signals for the protons for the primary amino group and the triazole ring. These signals together with two sets of signals for the triazole ring carbon atoms in the 13C NMR spectra served for the assignments of two main forms (A and B) of the triazole ring (three potential tautomers). The assignments were confirmed with the literature data,6-8,10 and the equilibrium constant (KT) and corresponding Gibbs free energy (ΔG300) values were estimated (Table 3). Scheme 3. Theoretically possible tautomers of polymethylene-bis(1H-1,2,4-triazol-5(3)-amines).  5  Table 3. Tautomeric composition polymethylene-bis(1,2,4-triazol-5(3)-amines) in DMSO-d6 solutiona Compounds n Composition (%) KT -ΔG300 (kJmol-1) A B 12 2 72 28 2.57 2.35 13 3 68 32 2.13 1.89 14 4 67 33 2.03 1.77 15 5 66 34 1.94 1.65 16 6 66 34 1.94 1.65 17 7 65 35 1.86 1.55 6 8 65 35 1.86 1.55 11 10 65 35 1.86 1.55 a Assigned by the NMR spectroscopy performed at 27 °C.In DMSO-d6 solution, the tautomeric equilibria was shifted mainly towards the 5-amino-1H-form (A) of the triazole ring with the 3-amino-1H-form (B) being less prominent and the 4H-form (C) undetectable. The expansion of the polymethylene link between the triazole rings led to some increase in the 3-amino-1H-form (B) presence in the equilibrium. This trend can be explained by the diminishing distance electron-withdrawing effect of one triazole ring on another. However, for compounds possessing seven or more methylenic groups in the linking chain, the equilibrium constant remained the same. It should be noted that the tautomer signals were indistinguishable when the NMR spectra of the compounds were recorded in CDCl3. In crystals, the tautomerizable 5(3)-amino-1,2,4-triazoles usually appear in the 5-amino-1H-tautomer form.11 An example of 5-amino-1H- and 3-amino-1H-tautomers crystallising together has also been reported.12 With the objective to investigate the tautomeric preference in crystals of the prepared compounds, we performed single crystal X-ray crystallography for representative compound 14.13 The molecular structure of 14, shown in Fig. 2(a), revealed that this compound crystallised with the 3-amino-1H-1,2,4-triazole rings on both sides of the molecule.  This tautomeric form is not typical for crystals of tautomerizable 5(3)-amino-1,2,4-triazoles and represents a rather unique case of finding 3-amino-1H-1,2,4-triazoles in crystals.   In conclusion, we have developed an efficient and practical one-pot microwave-promoted synthesis of polymethylene-bis(1H-1,2,4-triazol-5(3)-amines) from readily available dicarboxylic acids. The method was found to be scalable and transferable to another microwave reactor. The tautomeric preferences in the products were determined in solution (by NMR spectroscopy) and solid state (X-ray crystallography). The tautomeric equilibrium in the solution depended on the length of the chain connecting the triazole rings. A unique crystallisation of the 5-substituted 3-amino-1H-1,2,4-triazole tautomeric form was also observed.  Acknowledgments The Research Centre for Crystalline Materials (Sunway University) is thanked for the X-ray intensity data. This work is supported by the Ministry of Higher Education, Malaysia under Fundamental Research Grant Scheme, grant number FRGS/1/2015/SG01/MUSM/03/1.  References and notes 1. (a) Venkatraj, M.; Salado, I. G.; Heeres, J.; Joossens, J.; Lewi, P. J.; Caljon, G.; Maes, L.; Van der Veken, P.; Augustyns, K. Eur. J. Med. Chem. 2018, 143, 306-319; (b) Schmidt, I.; Pradel, G.; Sologub, L.; Golzmann, A.; Ngwa, C. J.; Kucharski, A.; Schirmeister, T.; Holzgrabe, U. Bioorg. Med. Chem. 2016, 24, 3636-3642; (c) Fielding, A. J.; Lukinović, V.; Evans, P. G.; Alizadeh-Shekalgourabi, S.; Bisby, R. H.; Drew, M. G. B.; Male, V.; Del Casino, A.; Dunn, J. F.; Randle, L. E.; Dempster, N. M.; Nahar, L.; Sarker, S. D.; Cantú Reinhard, F. G.; de Visser, S. P.;  Dascombe, M. J.; Ismail, F. M. D. Chem. - Eur. J. 2017, 23, 6811-6828; (d) Panozzo-Zénere, E. A.; Porta, E. O. J.; Arrizabalaga, G.; Fargnoli, L.; Khan, S. I.; Tekwani, B. L.; Labadie, G. R. Eur. J. Med. Chem. 2018, 143, 866-880. 2. (a) Suzuki, K.; Nomura, I.; Ninomiya, M.; Tanaka, K.; Koketsu, M. Bioorg. Med. Chem. Lett. 2018, in press, doi: 10.1016/j.bmcl.2018.06.050; (b) Hua, X.; Zhang, G.; Zhang, D.; Wu, Y. J. Heterocycl. Chem. 2018, 55, 1504-1508; (c) Trang, T. T. T.; Dieltjens, L.; Hooyberghs, G.; Waldrant, K.; Ermolat'ev, D. S.; Van der Eycken, E. V.; Steenackers, H. P. L. Bioorg. Med. Chem. 2018, 26, 1470-1480. Figure 2. Molecular structure of 14 showing atom labelling and 70% probability displacement ellipsoids; unlabelled atoms are related by the symmetry operation -x, 2-y, -z. Tetrahedron Letters 6 3. (a) Kumar, A.; Banerjee, S.; Roy, P.; Sondhi, S. M.; Sharma, A. Bioorg. Med. Chem. Lett. 2017, 27, 501-504; (b) Kopsida, M.; Barron, G. A.; Bermano, G.; Kong Thoo Lin, P.; Goua, M. Org. Biomol. Chem. 2016, 14, 9780-9789; (c) Sosic, A.; Zuravka, I.; Schmitt, N.-K.; Miola, A.; Goettlich, R.; Fabris, D.; Gatto, B. ChemMedChem 2017, 12, 1471-1479; (d) Santiago-Vazquez, Y.; Das, S.; Das, U.; Robles-Escajeda, E.; Ortega, N. M.; Lema, C.; Varela-Ramirez, A.; Aguilera, R. J.; Balzarini, J.; De Clercq, E.; Dimmock, S. G.; Gorecki, D. K. J.; Dimmock, J. R. Eur. J. Med. Chem. 2014, 77, 315-322; (e) Islam, M. K.; Jackson, P. J. M.; Thurston, D. E.; Rahman, K. M. Org. Biomol. Chem. 2018, 16, 4424-4428; (f) I El Azab, I. H.; Elkanzi, N. A. A. Curr. Org. Synth. 2017, 14, 309-320. 4. Burmistrov, V.; Morisseau, C.; Pitushkin, D.; Karlov, D.; Fayzullin, R. R.; Butov, G. M.; Hammock, B. D. Bioorg. Med. Chem. Lett. 2018, 28, 2302-2313. 5. Fujisaki, F.; Usami, H.; Nakashima, S.; Nishida, S.; Fujioka, T.; Kashige, N.; Miake, F.; Sumoto, K. Heterocycles 2013, 87, 665-675 6. Dolzhenko, A. V.; Pastorin, G.; Dolzhenko, A. V.; Chui, W. K. Tetrahedron Lett. 2009, 50, 2124-2128. 7. Lim, F. P. L.; Tan, L. Y.; Tiekink, E. R. T.; Dolzhenko, A. V. RSC Adv. 2018, 8, 22351-22360. 8. Chernyshev, V. M.; Chernysheva, A. V.; Starikova, Z. A. Heterocycles 2010, 81, 2291-2311. 9. General method for the microwave-assisted synthesis of bis(5(3)-amino-1,2,4-triazol-3(5)-yl)polymethylenes (6, 11-17).  A mixture of the corresponding dicarboxylic acids (3.4 mmol) and aminoguanidine hydrochloride (1.88 g, 17 mmol) in water (2 mL) was irradiated in a 10 mL seamless pressure vial using the microwave system operating at maximum microwave power (up to 300 W) at 220 °C for 15 min. After cooling to ambient temperature, 17 M aq. NaOH (1 mL) was added to the vial and the reaction mixture was irradiated again at 200 °C for 10 min. After cooling to ambient temperature, the precipitated solid was filtered, washed with cold water and recrystalised from water to give desired product. The reaction was also replicated on an increased scale of the dicarboxylic acids (17 mmol) and aminoguanidine hydrochloride (9.40 g, 85 mmol) in water (10 mL). 10. Buzykin, B. I.; Mironova, E. V.; Nabiullin, V. N.; Gubaidullin, A. T.; Litvinov, I. A. Russ. J. Gen. Chem. 2006, 76, 1471-1486.  11. (a) Garcia, E.; Lee, K. Y. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1992, C48, 1682-1683; (b) Borbulevych, O. Y.; Shishkin, O. V.; Desenko, S. M.; Chernenko, V. N.; Orlov, V. D. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1998, C54, 442-444; (c) Dolzhenko, A. V.; Tan, G. K.; Koh, L. L.; Dolzhenko, A. V.; Chui, W. K. Acta Crystallogr., Sect. E: Struct. Rep. Online 2009, 65, o125; (d) Zhang, S.; Liu, P.-J.; Ma, D.-S.; Hou, G.-F. Acta Crystallogr., Sect. E: Struct. Rep. Online 2012, 68, o83; (e) Liu, B.; Tome, J. P. C.; Cunha-Silva, L.; Almeida Paz, F. A. Acta Crystallogr., Sect. E: Struct. Rep. Online 2012, 68, o2700-o2701; (f) Hernandez-Gil, J.; Ferrer, S.; Ballesteros, R.; Castineiras, A. Acta Crystallogr., Sect. E: Struct. Rep. Online 2013, 69, o227-o228. 12. Dolzhenko, A. V.; Tan, G. K.; Koh, L. L.; Dolzhenko, A. V.; Chui, W. K. Acta Crystallogr., Sect. E: Struct. Rep. Online 2009, 65, o126.  13. Crystal data for C8H14N8 (14): M = 222.27, monoclinic, P21/n, a = 5.00860(10), b = 5.1190(2), c = 19.5646(6) Å, β= 93.306(3)˚, V = 500.78(3) Å3, Z = 2, Dx = 1.474 g cm-3, F(000) = 236, µ = 0.844 mm-1. CCDC 1851291.  Supplementary Material Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2018.XX.XXX. These data include experimental details, copies of 1H and 13C NMR spectra of the prepared compounds, and X-ray crystallography data for compound 14.   

One-pot, microwave-assisted synthesis of polymethylene-bridged bis(1H-1,2,4triazol-5(3)-amines) and their tautomerism

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One-pot, microwave-assisted synthesis of polymethylene-bridged bis(1H-1,2,4triazol-5(3)-amines) and their tautomerism

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