CC BY
3
ISSN 2310-5607
r
ppublishing.org
PREMIER
Publishing
DOI:10.29013/AJT-24-5.6-28-32
SYNTHESIS OF UREA DERIVATIVES BASED ON SUBSTITUTED2-AMINOTHIAZOLES AND SOME AROMATIC ISOCYANATES
Kudratov G.N.1, Ortikov I.S.1, Elmuradov B. J.1, Saitkulov F.E.1
1 Yunusov Institute of the Chemistry of Plant Substances, Academy of Sciences of the Republic of Uzbekistan
Cite: Kudratov G. N, Ortikov I. S, Elmuradov B. J., Saitkulov F. E. (2024). Synthesis of Urea Derivatives Based on Substituted2-Aminothiazoles and Some Aromatic Isocyanates. Austrian Journal ofTechnical and Natural Sciences 2024, No 3 - 4. https://doi.org/10.29013/ AJT-24-5.6-28-32
Abstract
Synthesis of 1,3-substituted urea derivatives based on m-toluyl isocyanate and 2-amino-thiazoles with different functional groups. Analysis of the structure of the obtained substances in modern physical research methods. 1,3-substituted urea derivatives were synthesized based on m-toluyl isocyanate and 2-aminothiazoles. The structure of the synthesized substances was proved by IR, 1H NMR, 13C NMR, spectral analysis.
Keywords: m-Toluyl isocyanate, DMFA, K2CO3, 2-(3-(m-tolyl)urea)-4,5-dihydrothi-azole-4-carboxylic acid, 1-(benzo[d]thiazol-2-yl)-3-(m-tolyl)urea
Introduction
Modern search in the currently intensively developing chemistry and properties of urea compounds attract the attention of many researchers both in Uzbekistan and abroad (Suresh, G., Nadh, R.V., Sriniva-su, N., Yennity, D., 2018; Das, D., Sikdar, P., Bairagi, M., 2016; Alexandra, M.-G., Velickovic, T. C., Jitaru, I., Grguric-Sipka, S., Draghici, C., 2010). This is due, on the one hand, to those rich capabilities of di-phenyl, azo-diphenyl, bis-urea, polyhydro-carbon groups in molecules of organic mac-rocompounds, and on the other hand, with valuable practical using the properties of organic substances themselves compounds diphenyl, azodiphenyl groups, as well as bis-urea bonds. There are many examples where
the introduction of azo-, phenyl, diphenyl bridging bonds would lead to the emergence of various kinds of biological, pharmacological, physiological activity, as well as the ability to inhibit corrosion of metals, coatings, and stabilizers for halogen-containing polymers, impregnations, and also as an anti-aging vulcanization of rubbers, the creation of solvation theories for intensifying the processes of dyeing and printing fabrics from natural and chemical fibers in liquid ammonia and organic solvents.
At present, the synthesis of urea derivatives kept by various pharmacophoric groups and the study of their biological activities are important tasks. Because among the compounds of this class there are many drugs against diabetes, cancer, hepatitis and
many other diseases, as well as substances with high fungicidal and herbicidal activity in agro-industry. That is why the synthesis of 1,3-substituted ureas, determination of their structure by physico-chemical methods and study of their biological activity are considered urgent issues.
Method and Results
Interest in the chemistry of 2-amino-thiazole in recent years is explained by the discovery of a wide spectrum of biological activity in a number of its derivatives. In addition, the 2-aminothiazole molecule, which has a large number of reaction centers, cannot but interest chemists (Décor, A., Grand-Maître, C., Hucke, O., O'Meara, J., Kuhn, C., Constantineau-Forget, L., Bro-chu, C., Malenfant, E., Bertrand-Laperle, M., Bordeleau, J. 2013; Jalani, H. B., Pan-dya, A. N., Pandya, D. H., Sharma, J. A., Su-
darsanam, V., Vasu, K. K., 2013; Stefanska, J., Nowicka, G., Struga, M., Szulczyk, D., Koziol, A. E., Augustynowicz-Kopec, E., Napiorkowska, A., Bielenica, A., Filipowski, W., Filipowska, A., 2015; Elshaarawy, R. F., Mustafa, F. H., Sofy, A. R., Hmed, A. A., Ja-niak, C., 2019; Chen, Y.-Y., Gopala, L., Bhee-manaboina, R. R. Y., Liu, H.-B., Cheng, Y., Geng, R.-X., Zhou, C.-H., 2017; Prakash, A., Malhotra, R. 2018; Cordeiro, Y., Ferreira, N. C., 2015). Therefore, the goal of our work was to obtain new heterocyclic compounds based on 2-aminothiazole using the halo-cyclization reactionBased on the following reactions, 1,3-substituted urea derivatives were synthesized based on m-toluyl isocy-anate and 2-aminothiazoles with different functional groups. As a result of the action of molecules of substances 2, 3, 4, 5 of raw material 1, corresponding products 6, 7, 8, 9 were synthesized in high yield.
Figure 1.
O
n
h c
h
\ /
no,
h3c
nh
n^xs
ö 5
O
n—v
h c j~\ h
nh2 i a
s^n
\=j
nh
nco
h3c
s ^n
Lio
O
3
ho h c
h
nh
o
h3c
4
h O r
h
h3c
oh
6
2
1
9
7
8
m-Toluyl isocyanate and 2-aminothi-azoles 1,3-substituted urea derivatives were synthesized. Potash was used as a catalyst in the reaction. Factors affecting the course of the reaction were determined.
1,3-substituted aryl-heteryl urea derivatives were synthesized in good yields. -IK, 1H-NMR, 13S-NMR spectra of the obtained substances were analyzed.
Experimental Part
1-(THIAZOL-2-YL)-3-(M-TOLYL) UREA. 0.71 ml (5.48 mmol, 0.73 g, p = = 1.033 g/ml) of m-toluyl isocyanate (1), 0.55 g (5.49 mmol) of 2-aminothiazole (2) were taken in a 100 ml round-bottom flask. 10 mL of DMFA was added to the flask and mixed on a magnetic stirrer. After the substances were completely dissolved, 0.83 g (6 mmol) of potash was added and mixed. The flask was stirred on a magnetic stirrer connected to a reflux condenser for 4-8 hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was left at room temperature overnight. The precipitate was filtered off, extracted with K2SO3 and dried to give 1.08 g. (84%) product (6) was obtained. Rf =0.62 (benzene: methanol - 5:1). 1N YaMR (m.u CD3OD): 10.03 (1H, с, NH-), 7.70 (1H, с, Ar-H-2), 7.62 (1H, д, J=5,72, Ar-H-6), 7.48 (1H, д, J=3.64, Het Н-4), 7.20 (1H, т, J=7.80, HAr-5), 6.98 (1H, д, J=3,64, HHet-5), 6.83 (1H, д, J=7.54, HAr-4), 2.15 (3H, c, Alk-CH3). 13C NMR (CD3OD): 162.7 (CHet-2), 153.9 (C=O C), 140.5 (Ar-C-3), 139.6 (C^-1), 138.3 (CHet-4), 129.8 (CAT-5), 124.7 ^-4), 121.0 (CAr-4), 117.0 (CAr-6), 112.7 (CHet-5), 21.4 (Cchs).
2-(3-(M-TO L Y L)UREA)THI-AZOLE-4-CARBOXYLIC ACID. 0.45 ml (3.5 mmol, 0.46 g. p =1,033 g/ml) m-tolu-ene isocyanate (1), 0.46 g (3.19 mmol) 2-ami-nothiazole-4-carboxylic acid (3), 10 ml DMFA and 0.45 g (3.26 mmol) of K2CO3 was obtained. 0.31 g of product (7) was obtained in 62% yield. . Rf = 0.77 (бензол: метанол -5:1). 1Н NMR (8, м.у., CD3OD): 10.74 (1H,-COOH-H), 8.49 (1H,-NH-H), 7.69 (1H, c, HHet-4), 7.25 (1H, c, Hat-6), 7.19 (1H, д, J=9.22, HAr-2), 7.09 (1H, т, J=7.80, HAr-5), 6.76 (1H, д, J=7.80, HAr-4), 2.30 (3H, HCH3). 13C NMR(CD3OD): 162.03 (C COOH), 160.66
(CHet-2), 152.56 (C_c_0), 142.46 (CHet-4), 139.57 (CAr-3), 139.08 (CAr-1), 129.56 (CAr-5), 124.50 (CAr-2), 122.13 (CAr-4), 120.33 (CAr-6),
116.91 (C^-5), 21.89 (CA!k_CH3). IR (v, cm -1): 3114 (C-H apun), 2977 (CH2 rypy^ ynyH), 676, 694 (C-S-C), 1614 (-C=N-), 1681 (>C=0), 676 (Ar (=C-H ge^opM.T.), 1379 (-C-CH3), 1121, 1107 (-C-OH).
1-(BENZO[d]THIAZOL-2-YL)-3-(M-TOLYL)UREA. 0.7 ml (5.4 mmol, 0.72 g, p =1.033 g/ml) of m-toluyl isocyanate (1), 0.81 g (5.4 mmol) of 2-aminobenzothiazole (4), 10 ml of DMFA and 0, 77 g (5.6 mmol) of ^C03 were obtained. 1.27 g of product (8) was obtained in 83% yield. Liq-uid=340-342oC. Rf =0.76 (benzene: methanol - 5:1). 1HYaMR (m.u., CD30D): 10.58 (1H, c, -NH), 8.82 (1H, c, -NH), 7.74 (1H, c, Het-H-4), 7.57 (1H, d, J=6.49, HAr -7), 7.28 (2H, m, HHet -5.6), 7.23 (1H, d, ^-3), 7.13 (2H, m, HAr -2,6), 6.77 (1H, d, J=7,53, HAr -4), 2.32 (3H, c, HA1k_CH3). 13C NMR (CD3OD): 160.73 (CHet-1), 152.26 (C-C=O), 139.66 (CAr-3), 139.13 (CAr-1), 132.78 (CHet-7a), 1229.60 (CAr-5), 126.54 (CAr-2), 124.53 (C-5), 120.70 (CAr-6), 120.32 (CHet-4),
116.92 (C -7), 21.91 (). IR (v, cm -1):
v reTepun y 7 vy v ~ '
IR-(v, sm -1): 3049 (C-H aryl), 728 (C-S-C), 1725 (>C=0), 690 (Ar (=C-H), 1451 (-C-CH3), 1194, 1194 (-C-OH).
1-(6-NITROBENZO[d]THIAZOL-2-YL)-3-(m-TOLYL)UREA. 0.26 ml (2.03 mmol, 0.27 g., p =1.033 g/ml) m-toluyl isocyanate (1), 0.4 g (2.05 mmol) 2-ami-no-6-nitrobenzothiazole (5), 10 ml DMFmA and 0.304 g (2.2 mmol) of K,C03 were obtained. 0.4 g of product (9) was obtained in (59%) yield. Liquid=240-242oC. Rf =0.65 (benzene: methanol - 5:1). 1H NMR(m.u., CD30D): 10.23 (1H, c, NH-), 8.86 (1H, g, J=2,47, H -4), 8.22 (1H, gg, J=8.90, J=2.40, reTepu^-6), 7.74 (1H, c, HreTepiM-7), 7.66 (2H, T, J=8.51, HAr-2,6), 7.24reT(i!H, T, J=7.80, HAr-5), 6.89 (1H, g, J=7.54, HAr-4), 2.18 (3H, c, HAlkCH3). 13C NMR (CD3OD): 167.3 (C-1), 154.5 (Cc=0), 144.0 (C -3a), 140.1 (C^-5), 139.7 (CAr-7a), 133.3 (Cgetr-7), 129.9 (CAr-1), 125.3 (CAr-5), 122.7 (CAr-2), 121.5 (CAr-4), 119.7 ^-6), 119.3
(CAr-6), 117.9 (Cgetr-4), 21.3 (CCH3-C). IR (v,
sm-1): 3130 (C-H aryl), 747 (C-S-C), 1685 (>C=0), 642 (Ar (=C-H 1447 (-C-CH3), 1549 (-C-N02).
Consulsion
The heterocycles of 2-aminothiazole scaffolds occupy a dominant part in organic/medicinal chemistry in relation to their reactivity and biological activity and mostly act as pharmacophores. The present review summarizes the literature reports of the various synthetic routes for 2-aminothiazole-con-taining molecules with four different biological activities (namely, anticancer, antioxidant, antimicrobial and anti-inflammatory activities). The presented information in this review is valuable for future innovation.
This review highlighted the recently synthesized 2-aminothiazole-containing com-
pounds within the last thirteen years ago. Further, the synthetic strategies developed for the admission of the recent 2-aminothi-azole derivatives (N-substituted, 3-substi-tuted, 4-substituted, multi-substituted, aryl/ alkyl substituents or acyl/other substituents) were presented. The reported literature revealed several synthetic pathways of those 2-aminothiazoles related to four different biological activities (anticancer, antioxidant, antimicrobial and anti-inflammatory activities). It is hoped that this review will be useful in displaying the rationalistic designs of 2-aminothiazole-based medical synthetic pathways.
References
Suresh, G., Nadh, R. V., Srinivasu, N., Yennity, D. Synthesis and Antitumor Activity Evaluation of 2-Aminothiazoles Appended 5-methylisoxazoline and Pyridine-piperazine Hybrid Molecules. Lett. Org. Chem. 2018.- 15.- P. 1070-1077.
Das, D., Sikdar, P., Bairagi, M. Recent developments of 2-aminothiazoles in medicinal chemistry. Eur. J. Med. Chem. 2016.- 109.- P. 89-98.
Alexandru, M.-G., Velickovic, T.C., Jitaru, I., Grguric-Sipka, S., Draghici, C. Synthesis, characterization and antitumor activity of Cu (II), Co (II), Zn (II) and Mn (II) complex compounds with aminothiazole acetate derivative. Cent.Eur. J. Chem. 2010.- 8.- P. 639-645.
Décor, A., Grand-Maître, C., Hucke, O., O'Meara, J., Kuhn, C., Constantineau-Forget, L., Bro-chu, C., Malenfant, E., Bertrand-Laperle, M., Bordeleau, J. Design, synthesis and biological evaluation of novel aminothiazoles as antiviral compounds acting against human rhi-novirus. Bioorg. Med. Chem. Lett. 2013.- 23.- P. 3841-3847.
Jalani, H. B., Pandya, A. N., Pandya, D. H., Sharma, J. A., Sudarsanam, V., Vasu, K. K. An efficient one-pot synthesis of functionally diverse 2-aminothiazoles from isothiocy-anates, amidines/guanidines and halomethylenes. Tetrahedron Lett. 2013.- 54.-P. 5403-5406.
Stefanska, J., Nowicka, G., Struga, M., Szulczyk, D., Koziol, A. E., Augustynowicz-Kopec, E., Napiorkowska, A., Bielenica, A., Filipowski, W., Filipowska, A. Antimicrobial and anti-biofilm activity of thiourea derivatives incorporating a 2-aminothiazole scaffold. Chem. Pharm. Bull. 2015.- 63.- P. 225-236.
Elshaarawy, R. F., Mustafa, F. H., Sofy, A. R., Hmed, A. A., Janiak, C. A new synthetic anti-fouling coatings integrated novel aminothiazole-functionalized ionic liquids motifs with enhanced antibacterial performance. J. Environ. Chem. Eng. 2019.- 7.- 102800 p.
Chen, Y.-Y., Gopala, L., Bheemanaboina, R. R. Y., Liu, H.-B., Cheng, Y., Geng, R.-X., Zhou, C.-H. Novel naphthalimide aminothiazoles as potential multitargeting antimicrobial agents. ACSMed. Chem. Lett. 2017.- 8.- P. 1331-1335.
Prakash, A., Malhotra, R. Co (II), Ni (II), Cu (II) and Zn (II) complexes of aminothiazole-de-rived Schiff base ligands: Synthesis, characterization, antibacterial and cytotoxicity evaluation, bovine serum albumin binding and density functional theory studies. Appl. Or-ganomet. Chem. 2018.- 32.- e4098 p.
Cordeiro, Y., Ferreira, N. C. New approaches for the selection and evaluation of anti-prion organic compounds. Mini Rev. Med. Chem. 2015.- 15.- P. 84-92.
Patil, R., Chavan, J., Beldar, A. Synthesis of aminothiazoles: Polymer-supported approaches. RSCAdv. 2017.- 7.- P. 23765-23778.
Alaraidh, I. A., Okla, M. K., Alamri, S. A., Abdullah, A., Soufan, W. H., Allam, A. A., Fou-da, M.M., Gaffer, H. E. Synthesis of Bis-(2-thiazolyl) amine Analogues and Evaluation of Their Antibacterial, Antioxidant and Cytotoxic Activities. Chemistry Select 2019.- 4.-P. 11726-11734.
submitted 22.05.2024;
accepted for publication 05.06.2024;
published 30.07.2024
© Kudratov G. N., Ortikov I. S., Elmuradov B. J., Saitkulov F. E. Contact: fsaitkulov@bk.ru
