Abstract
Reactions of 6-amino-2-methylquinolin-4-ol with salicylaldehyde, phthalic anhydride, phenyl isothiocyanate, and ammonium thiocyanate afforded 6-[(2-hydroxybenzylidene)amino]-2-methylquinolin-4-ol, 2-(4-hydroxy-2-methylquinolin-6-yl)-1H-isoindole-1,3(2H)-dione, N-(4-hydroxy-2-methylquinolin-6-yl)-N′-phenylthiourea, and 1-(4-hydroxy-2-methylquinolin-6-yl)thiourea, respectively. Heterocyclizations of the latter with ethyl bromoacetate and bromacetophenone led to the formation of 2-[(4-hydroxy-2-methylquinolin-6-yl)imino]-1,3-thiazolidin-4-one and 2-methyl-6-[(4-phenyl-1,3-thiazol-2(3H)-ylidene)amino]quinolin-4-ol, respectively.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
INTRODUCTION
Quinoline and its derivatives constitute an important class heterocyclic compounds that are promising for the design of new drugs, including those for the treatment of COVID-19 [1–6]. The quinoline scaffold could give rise to a broad spectrum of biological activity [7–9], such as antimicrobial, antiviral, antiprotozoal, antimalarial, antitumor, cardiovascular, psychotropic, antioxidant, anticonvulsant, analgesic, anti-inflammatory, anthelminthic, etc. [8]. Numerous methods have been developed for the synthesis of quinoline and its derivatives. The goal of the present work was to synthesize new quinoline derivatives containing five-membered heterocyclic fragments starting from 6-amino-2-methylquinolin-4-ol.
RESULTS AND DISCUSSION
In continuation of our studies on the synthesis of biologically active compounds, herein we report the synthesis of new Schiff bases and isoindole-1,3-dione and thiazole derivatives containing a quinoline ring using 6-amino-2-methylquinolin-4-ol (1) as starting material. The reaction of aminoquinoline 1 with salicylaldehyde in boiling ethanol gave 6-[(2-hydroxybenzylidene)amino]-2-methylquinolin-4-ol (2). Compound 1 reacted with phthalic anhydride in dioxane–acetic acid (5:1) under reflux conditions to produce 2-(4-hydroxy-2-methylquinolin-6-yl)-1H-isoindole-1,3(2H)-dione (3). N-(4-Hydroxy-2-methylquinolin-6-yl)-N′-phenylthiourea (4) was synthesized in a good yield by the reaction of aminoquinoline 1 with an equimolar amount of phenyl isothiocyanate in boiling ethanol. The reaction of 1 with ammonium thiocyanate in aqueous medium in the presence of concentrated aqueous HCl at 150°C for 5–6 h afforded N-(4-hydroxy-2-methylquinolin-6-yl)thiourea (5) (Scheme 1).
Taking into account functional potential of thiourea 5, it was reacted with ethyl bromoacetate and bromoacetophenone in the presence of sodium acetate in anhydrous ethanol. These reactions led to the formation of 2-[(4-hydroxy-2-methylquinolin-6-yl)imino]-1,3-thiazolidin-4-one (6) and 2-methyl-6-{[4-phenyl-1,3-thiazol-2(3H)-ylidene]amino}quinolin-4-one (7), respectively (Scheme 2).
EXPERIMENTAL
The 1H and 13C NMR spectra were recorded on a Varian Mercury-300 spectrometer (Germany) in DMSO-d6–CCl4 (1:3). The progress of reactions and the purity of the isolated compounds were monitored by TLC on Alugram® XtraSIL G UV254 plates (Germany) using iodine vapor for visualization. All solvents were distilled just before use, and commercially available reagents were purchased from Merck (Darmshtadt, Germany) and/or its branches.
6-[(2-Hydroxybenzylidene)amino]-2-methylquinolin-4-ol (2). A mixture of 0.174 g (1 mmol) of compound 1 [10], 10 mL of methanol, 0.122 g (1 mmol) of salicylaldehyde, and one drop of concentrated aqueous HCl was refluxed with stirring for 7 h. The solvent was distilled off, the residue was dissolved in a dilute alkali solution, the solution was filtered, and the filtrate was acidified to pH 5.0–5.5. The precipitate was filtered off and washed with water. Yield 0.20 g (72%), mp 326–327°C, Rf 0.52 (EtOH–xylene, 1:1). 1H NMR spectrum, δ, ppm: 2.63 s (3H, CH3), 6.73 s (1H, Harom), 7.11–7.16 m (2H, Harom), 7.34 d (1H, Harom, J = 2.4 Hz), 7.43 d.d (1H, Harom, J = 9.0, 2.5 Hz), 7.51–7.59 m (2H, Harom), 7.88 d (1H, Harom, J = 9.0 Hz), 8.01 d (1H, Harom, J = 8.3 Hz), 9.82 s (1H, NH), 10.83 br.s (1H, OH). Found, %: C 73.20; H 5.14.; N 10.23. C17H14N2O2. Calculated, %: C 73.38; H 5.04; N 10.07.
2-(4-Hydroxy-2-methylquinolin-6-yl)-1H-isoindole-1,3(2H)-dione (3) was synthesized according to the procedure described in [11]. A mixture of 0.174 g (1 mmol) of compound 1 [10], 10 mL of dioxane, 2 mL of acetic acid, and 0.18 g (1.2 mmol) of phthalic anhydride was refluxed with stirring for 3 h. After cooling, the precipitate was filtered off and washed with dioxane. Yield 0.27 g (89%), mp 350°C (decomp.), Rf 0.57 (EtOH–xylene, 1:1.5). 1H NMR spectrum, δ, ppm: 2.29 s (3H, CH3), 5.92 s (1H, Harom), 7.36 d (1H, Harom, J = 8.9 Hz), 7.43 d.d (2H, Harom, J = 11.1, 3.9 Hz), 7.74–7.87 m (2H, Harom), 7.97 s (1H, Harom), 8.41 d (1H, Harom, J = 2.3 Hz), 11.89 br.s (1H, OH). Found, %: C 71.18; H 3.79; N 9.37. C18H12N2O3. Calculated, %: C 71.05; H 3.95; N 9.21.
N-(4-Hydroxy-2-methylquinolin-6-yl)-N′-phenylthiourea (4). A mixture of 0.87 g (5 mmol) of compound 1 [10], 10 mL of ethanol, and 0.675 g (0.6 mL, 5 mmol) of phenyl isothiocyanate was refluxed with stirring for 6 h. After cooling, the precipitate was filtered off and washed with ethanol. Yield 1.30 g (85%), mp 325°C (decomp.), Rf 0.60 (EtOH–xylene, 1:2.5). 1H NMR spectrum, δ, ppm: 2.35 d (3H, CH3, J = 0.7 Hz), 5.81 s (1H, Harom), 7.06–7.12 m (1H, Harom), 7.26–7.34 m (2H, Harom), 7.43 d (1H, Harom, J = 8.8 Hz), 7.52–7.57 m (2H, Harom), 7.88 d.d (2H, Harom, J = 8.8, 2.2 Hz), 7.97 d (1H, Harom, J = 2.5 Hz), 9.87 br.s (2H, NH), 11.39 br.s (1H, OH). 13C NMR spectrum, δC, ppm: 19.23, 39.49, 107.67, 117.16, 118.42, 123.13, 123.69, 124.50, 127.81, 128.26, 134.39, 137.07, 139.30, 148.25, 176.09, 179.43. Found, %: C 66.18; H 4.71; N 13.43; S 10.20. C17H15N3OS. Calculated, %: C 66.02; H 4.85; N 13.59; S 10.36.
N-(4-Hydroxy-2-methylquinolin-6-yl)thiourea (5). A mixture of 1.74 g (10 mmol) of compound 1 [10], 30 mL of water, 2.5 mL of aqueous HCl (pH ~ 2.0), and 2.28 g (30 mmol) of ammonium thiocyanate was heated with stirring at ~150°C for 5–6 h. After cooling, the precipitate was filtered off and washed with water. Yield 1.51 g (65%), mp 242–243°C, Rf 0.52 (EtOH–xylene, 1:2). 1H NMR spectrum, δ, ppm: 2.74 s (3H, CH3), 6.95 s (1H, Harom), 7.62 br.s (2H, NH2), 7.99 d (1H, Harom, J = 9.1 Hz), 8.16 d.d (1H, Harom, J = 9.1, 2.5 Hz), 8.52 d (1H, Harom, J = 2.5 Hz), 10.50 s (1H, NH), 14.72 br.s (1H, OH). 13C NMR spectrum, δC, ppm: 19.59, 39.39, 39.78, 40.06, 40.33, 95.45, 105.54, 113.44, 118.95, 119.72, 129.42, 135.85, 138.25. Found, %: C 56.78; H 4.69; N 18.12; S 13.87. C11H11N3OS: Calculated, %: C 56.65; H 4.72; N 18.03; S 13.73.
2-[(4-Hydroxy-2-methylquinolin-6-yl)imino]-1,3-thiazolidin-4-one (6). A mixture of 0.233 g (1 mmol) of compound 5, 10 mL of anhydrous ethanol, 0.246 g (3 mmol) of anhydrous sodium acetate, and 0.22 g (0.15 mL, 1.3 mmol) of ethyl bromoacetate was refluxed with stirring for 5–6 h. After cooling, the precipitate was filtered off, washed with ethanol, and dried. Yield 0.23 g (85%), mp 375°C (decomp.), Rf 0.50 (EtOH–xylene, 1:3). 1H NMR spectrum, δ, ppm: 2.31 s (3H, CH3), 3.96 t (2H, CH2, J = 19.1 Hz), 5.89 s (1H, Harom), 7.20–7.70 m (2H, Harom), 7.93 d (1H, Harom, J = 8.4 Hz), 11.26 br.s (1H, NH), 11.60 br.s (1H, OH). Found, %: C 57.26; H 4.89; N 15.23; S 11.59. C13H11N3O2S. Calculated, %: C 57.14; H 4.72; N 15.38; S 11.72.
2-Methyl-6-{[4-phenyl-1,3-thiazol-2(3H)ylidene]amino}quinolin-4-ol (7). A mixture of 0.233 g (1 mmol) of compound 5, 10 mL of anhydrous ethanol, 0.246 g (3 mmol) of anhydrous sodium acetate, and 0.199 g (1 mmol) of bromoacetophenone was refluxed with stirring for 6–7 h. After cooling, the precipitate was filtered off, washed with ethanol, and dried. Yield 0.31 g (93%), mp 305–306°C, Rf 0.67 (EtOH–PhMe, 1:1). 1H NMR spectrum, δ, ppm: 2.30 s (3H, CH3), 5.82 s (1H, Harom), 7.25–7.34 m (2H, Harom), 7.40 d.d (2H, Harom, J = 10.3, 4.7 Hz), 7.49 d (1H, Harom, J = 8.9 Hz), 7.89 d.d (1H, Harom, J = 8.9, 2.7 Hz), 7.92–7.97 m (2H, Harom), 8.46 d (1H, Harom, J = 2.6 Hz), 10.41 s (1H, NH), 11.58 br.s (1H, OH). 13C NMR spectrum, δC, ppm: 19.26, 39.23, 40.06, 40.33, 102.85, 107.45, 110.46, 118.54, 122.29, 125.23, 125.66, 127.50, 128.53, 134.50, 135.07, 136.72, 148.52, 149.99, 162.94, 176.21. Found, %: C 68.32; H 4.68; N 12.49; S 9.72. C19H15N3OS. Calculated, %: C 68.48; H 4.50; N 12.61; S 9.61.
CONCLUSIONS
The reactions of 6-amino-2-methylquinolin-4-ol with salicylaldehyde, phthalic anhydride, phenyl isothiocyanate, and ammonium thiocyanate have been found to produce 6-[(2-hydroxybenzylidene)amino]-2-methylquinolin-4-ol, 2-(4-hydroxy-2-methylquinolin-6-yl)-1H-isoindole-1,3(2H)-dione, N-(4-hydroxy-2-methylquinolin-6-yl)-N′-phenylthiourea, and N-(4-hydroxy-2-methylquinolin-6-yl)thiourea, respectively. Methods have been developed for the synthesis of 2-[(4-hydroxy-2-methylquinolin-6-yl)imino]-1,3-thiazolidin-4-one and 2-methyl-6-{[4-phenyl-1,3-thiazol-2(3H)-ylidene]amino}quinolin-4-ol via heterocyclizations of N-(4-hydroxy-2-methylquinolin-6-yl)thiourea with ethyl bromoacetate and bromoacetophenone, respectively.
REFERENCES
Man, R.-J., Jeelani, N., Zhou, Ch., and Yang, Y.-Sh., Anti-Cancer Agents Med. Chem., 2021, vol. 21, no. 7, p. 825. https://doi.org/10.2174/1871520620666200516150345
Zhou, W., Wang, H., Yang, Y., Chen, Z.S., Zou, C., and Zhang, J., Drug Discovery Today, 2020, vol. 25, no. 11, p. 2012. https://doi.org/10.1016/j.drudis.2020.09.010
De Barros, C.M., Almeida, C.A.F., Pereira, B., Costa, K.C.M., Pinheiro, F.A., Maia, L.D.B., Trindade, C.M., Garcia, R.C.T., Torres, L.H., and Diwan, S., Pain Physician, 2020, vol. 23, no. 4S, p. S351.
Shah, S., Das, S., Jain, A., Misra, D.P., and Negi, V.S., Int. J. Rheum. Dis., 2020, vol. 23, no. 5, p. 613. https://doi.org/10.1111/1756-185X.13842
Adeel, A.A., Sudan J. Paediatr., 2020, vol. 20, no. 1, p. 4. https://doi.org/10.24911/SJP.106-1587122398
Halcrow, P.W., Geiger, J.D., and Chen, X., Front. Cell. Dev. Biol., 2021, vol. 9, article ID 627639. https://doi.org/10.3389/fcell.2021.627639
Matada, B.S., Pattanashettar, R., and Yernale, N.G., Bioorg. Med. Chem., 2021, vol. 32, article ID 115973. https://doi.org/10.1016/j.bmc.2020.115973
Radini, I.A.M., Khidre, R.E., and El-Telbani, E.M., Lett. Drug Des. Discovery, 2016, vol. 13, no. 9, p. 921. https://doi.org/10.2174/1570180813666160712234454
Suresh, N., Nagesh, H.N., Sekhar, K.V., Kumar, A., Shirazi, A.N., and Parang, K., Bioorg. Med. Chem. Lett., 2013, vol. 23, p. 6292. https://doi.org/10.1016/j.bmcl.2013.09.077
Rubtsov, M.B. and Bunina, V.I., Zh. Obshch. Khim., 1944, vol. 14, p. 1129.
Aleksanyan, I.L. and Hambardzumyan, L.P., Russ. J. Org. Chem., 2020, vol. 56, p. 2114. https://doi.org/10.1134/S1070428020120118
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
The authors declare the absence of conflict of interest.
Additional information
Translated from Zhurnal Organicheskoi Khimii, 2022, Vol. 58, No. 10, pp. 1103–1107 https://doi.org/10.31857/S0514749222100081.
Rights and permissions
About this article
Cite this article
Aleqsanyan, I.L., Hambardzumyan, L.P. Synthesis of Schiff Bases and Isoindolyl- and Thiazolyl-Substituted Quinolines from 6-Amino-2-methylquinolin-4-ol. Russ J Org Chem 58, 1434–1437 (2022). https://doi.org/10.1134/S1070428022100086
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1134/S1070428022100086