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Short Note

(E)-2-(2-Oxo-4-phenylbut-3-en-1-yl)benzo[d]thiazole-3(2H)-carboxylates

Department of Organic Chemistry, University of Plovdiv Paisii Hilendarski, 24 Tsar Asen Str., 4000 Plovdiv, Bulgaria
*
Author to whom correspondence should be addressed.
Academic Editor: Oleg A. Rakitin
Molbank 2021, 2021(2), M1236; https://doi.org/10.3390/M1236
Received: 25 May 2021 / Revised: 8 June 2021 / Accepted: 9 June 2021 / Published: 13 June 2021
(This article belongs to the Section Organic Synthesis)

Abstract

An convenient one-pot approach for the synthesis of new (E)-2-(2-oxo-4-phenylbut-3-en-1-yl)benzo[d]thiazole-3(2H)-carboxylates is demonstrated. The method is based on a three-component reaction of benzylideneacetone with electrophilic N-alkoxycarbonylbenzothiazolium species formed in situ. The newly synthesized compounds were fully characterized by 1D 1H, 13C- NMR, IR and MS.
Keywords: benzothiazole; benzylideneacetone; α-amidoalkylation; multicomponent reaction benzothiazole; benzylideneacetone; α-amidoalkylation; multicomponent reaction

1. Introduction

Cancer is one of the most prevalent lethal diseases worldwide, and is a serious concern of modern medicine. It is of great attention to the scientific community for drug development and precision therapy [1,2]. Benzothiazole (BT) (1) is a privileged heterocycle structure with significant pharmacological applications [3]. In this regard, during the last ten years, the functionalization of BT scaffold has modulated a broad range of anticancer activities [4,5,6,7]. The interest drawn by a BT moiety has led to the preparation of many 2-substituted derivatives, with proven antiproliferative effects [8,9]. In this context, various (E)-2-benzothiazole hydrazones have been described as actual active structures [10,11]. The α,β-unsaturated ketones are subject to scientific interest [12] and are present in many bioactive heterocycle hybrids [13,14,15]. In a previously published paper, we demonstrated the effective application of α-amidoalkylation for the synthesis of 1,2,3-substituted benzimidazoles containing benzylidenacetonyl fragments [16]. One of the obtained compounds (Figure 1) showed selective antiproliferative activity in vitro against the human metastatic melanoma cells—inhibition by 93% after 96 h treatment at 10−4 M [17]. Considering the existing interest in the structure–activity relationship of various benzothiazoles, we saw an opportunity to apply this convenient approach for the synthesis of some novel, structurally similar derivatives. In recent scientific research, we successfully functionalized indole and some hydroxyarenes to 2-substituted benzothiazoles with bioactive profiles [18,19].

2. Results

Here, we report the investigations on the application of adducts obtained from benzothiazole (1) with alkyl chloroformates (2) in a one-pot α-amidoalkylation reaction with benzylideneacetone (3). The above-mentioned adducts react successfully with the α,β-unsaturated ketone to form products (4a,b, Scheme 1).
The reaction conditions were optimized by varying the solvent, temperature, and time (Table 1).
The three-component reactions were successfully completed under mild reaction conditions for 5–80 h at room temperature. The reactions were initially carried out in acetonitrile for 5 h at room temperature to result in products 4a and b with low yields (24%, 4a) and (28%, 4b). It was found that 1,2-dichloroethane performed better than acetonitrile and led to a higher yield of products (4a,b, Table 1).
The best yields of products were obtained with twofold excess of benzothiazole and alkyl chloroformates in 1,2-dichloroethane at 25 °C for 80 h (70%, 4a; 76%, 4b). Analytically pure samples were isolated by column chromatography on silica, using a mixture of petroleum/diethyl ether as eluents and the yields indicated in Table 1.
The 1H-NMR spectra of compounds (4a,b), indicated (E)-trans configuration, exhibiting two characteristic doublets in the range of δ = 6.83–6.85, 7.64–7.70 ppm with coupling constant (J = 16.4 Hz) for vinyl protons.
The resulting products were structurally characterized by 1H, 13C-NMR, IR, and MS spectra (copies can be found via “Supplementary Materials” section).

3. Materials and Methods

All reagents and solvents were purchased from commercial suppliers (Sigma-Aldrich or Merck) and were used without further purification. NMR spectra were run on a Bruker Avance AV600 (600/150 MHz 1H/13C) spectrometer at BAS-IOCCP—Sofia, and chemical shifts (δ, ppm) were downfield from TMS. To average out the rotamers observed, the spectrum of compound (4a) was measured at 80 °C, as indicated in the text below. High-resolution mass spectral measurements were performed on a Thermo Scientific Q Exactive hybrid quadrupole-orbitrap mass spectrometer. IR spectra were measured on a VERTEX 70 FT-IR spectrometer (Bruker Optics, Germany). TLC was performed on aluminium-backed silica gel 60 sheets (Merck) with cerium sulfate staining. Melting points were measured on Boetius hot stage apparatus and were not corrected.

Synthetic Procedures

Synthesis of (E)-2-(2-oxo-4-phenylbut-3-en-1-yl)benzo[d]thiazole-3(2H)-carboxylates (4a,b), general procedure: ethyl chlorofomate (0.217 g, 2 mmol, 0.19 mL) or methyl chloroformate (0.189 g, 2 mmol, 0.16 mL) was added dropwise to a magnetically stirred solution of benzothiazole (0.270 g, 2 mmol, 0.22 mL) in 1,2-dichloroethane (5 mL/mmol), followed immediately by the benzylideneacetone (0.292 g, 2 mmol). The stirring was then continued under the conditions indicated in Table 1. After completion of the reaction (monitored by TLC), the mixture was transferred to a separatory funnel with dichloromethane (10 mL/mmol) and consecutively washed with 50 mL water. For the reactions with acetonitrile, we first proceeded with solvent evaporation under reduced pressure, before the following work-up. The organic layer was dried (Na2SO4), and the crude mixture was dry-loaded onto silica gel. The products were isolated by column chromatography on silica gel with mixtures of petroleum/diethyl ether as the eluents and successfully crystallized.
Ethyl (E)-2-(2-oxo-4-phenylbut-3-en-1-yl)benzo[d]thiazole-3(2H)-carboxylate (4a): white solid; isolated with petroleum/diethyl ether (8:1 increasing polarity to 4:1); Rf = 0.61 (petroleum:diethyl ether 2:1); yield:50%, 70%; mp: 85–87 °C.
Results of 1H-NMR (600 MHz, 80 °C, DMSO-d6, δ ppm): 1.29 (t, J = 7.0 Hz, 3H, -COOCH2CH3), 3.37 (dd, 2J = 16.4 Hz, 3J = 4.7 Hz, 1H, -CH2-), 3.42 (dd, 2J = 16.4 Hz, 3J = 9.4 Hz, 1H, -CH2-), 4.22–4.30 (m, 2H, -COOCH2CH3), 6.14 (dd, 2J = 8.8 Hz, 3J = 4.7 Hz, 1H, -CH*), 6.83 (d, J = 16.4 Hz, 1H, -CH=CH-), 7.02 (t, J = 7.6 Hz, 1H, Ar), 7.13 (t, J = 7 Hz, 1H, Ar), 7.25 (d, J = 7.6 Hz, 1H, Ar), 7.42–7.43 (m, 3H, Ar), 7.64 (d, J = 16.4 Hz, 1H, -CH=CH-), 7.66–7.68 (m, 3H, Ar).
Results of 13C-NMR (150 MHz, 80 °C, DMSO-d6, δ ppm): 14.6 (-COOCH2CH3), 48.1 (-CH2), 62.1 (-CH*), 62.7 (-COOCH2CH3), 117.8 (-CH), 123.0 (-CH), 124.7 (-CH), 125.7 (-CH), 127.0 (-CH), 128.9 (-CH), 129.0 (-CH), 129.4 (-CH), 131.0 (-CH), 134.9 (-CH), 137.7 (-CH), 143.9 (-CH), 152.3 (-COO), 197.2 (-CO).
IR (KBr, cm−1): 3057 ν(C-sp2-H), 2980 νas(C-sp3-H, > sp2), 2911 νs(C-sp3-H, > sp2), 1700 ν(C=O, α,β-unsaturated ketone), 1653 ν(C=O, ester), 1580, 1471 ν(C=C, Ph), 1377 δs(CH3), 1256, 1183 ν(C-N), 752 γ(C-sp2-H), 692, 580, 459 δ(C-N-C);
HRMS m/z (ESI): calcd for C20H19NNaO3S+ [M + Na]+ 376.0978, found 376.0988; calcd for C40H38N2NaO6S2+ [2M + Na]+ 729.2063, found 729.2057.
Methyl (E)-2-(2-oxo-4-phenylbut-3-en-1-yl)benzo[d]thiazole-3(2H)-carboxylate (4b): pale yellow solid; isolated with petroleum/diethyl ether (8:1 increasing polarity to 4:1); Rf = 0.48 (petroleum:diethyl ether 2:1); yield: 55%, 76%; mp: 136–137 °C.
Results of 1H-NMR (600 MHz, 20 °C, DMSO-d6, δ ppm): 3.40 (dd, 2J = 17.6 Hz, 3J = 3.5 Hz, 1H, -CH2-), 3.49 (dd, 2J = 17.6 Hz, 3J = 10.0 Hz, 1H, -CH2-), 3.78 (s, 3H, -COOCH3), 6.08 (dd, 2J = 10 Hz, 3J = 3.5 Hz, 1H, -CH*), 6.85 (d, J = 16.4 Hz, 1H, -CH=CH-), 7.03 (t, J = 7.6 Hz, 1H, Ar), 7.13 (t, J = 7.6 Hz, 1H, Ar), 7.27 (d, J = 7.6 Hz, 1H, Ar), 7.42–7.44 (m, 3H, Ar), 7.70 (d, J = 16.4 Hz, 1H, -CH=CH-), 7.69–7.71 (m, 3H, Ar).
Results of 13C-NMR (150 MHz, 20 °C, DMSO-d6, δ ppm): 47.5 (-CH2), 53.8 (-COOCH3), 61.9 (-CH*), 117.6 (-CH), 121.7 (-CH), 123.1 (-CH), 124.8 (-CH), 125.8 (-CH), 126.7 (-CH), 129.0 (-CH), 129.5 (-CH), 131.2 (-CH), 134.5 (-CH), 134.7 (-CH), 144.5 (-CH), 152.7 (-COO), 197.9 (-CO).
IR (KBr, cm−1): 3019 ν(C-sp2-H), 2958 νas(C-sp3-H, > sp2), 2900 νs(C-sp3-H, > sp2), 1717 ν(C=O, α,β-unsaturated ketone), 1649 ν(C=O, ester), 1576, 1474 ν(C=C, Ph), 1361 δs(CH3), 1259, 1181 ν(C-N), 759 γ(C-sp2-H), 684, 576, 433 δ(C-N-C).
HRMS m/z (ESI): calcd for C19H17NNaO3S+ [M + Na]+ 362.0821, found 362.0819; calcd for C38H34N2NaO6S2+ [2M + Na]+ 701.1750, found 701.1756.

4. Conclusions

We have successfully prepared two new 2-(benzylideneacetonyl)benzothiazoles via an efficient one-pot approach. The applied three-component reactions offer several advantages, such as a simple procedure, clean reaction conditions, and good yields. The obtained compounds are of interest due to their potential cytotoxic activities.

Supplementary Materials

The following are available online, S1. PDF—processed 1H, 13C-NMR, MS, IR spectra and TLC separation of (4a,b), S2.zip—Raw NMR data, S3.zip—mol files.

Author Contributions

Visualization, Y.S.; conceptualization and supervision, S.S.-A.; chemical synthesis and spectral characteristics: Y.S. and S.S.-A.; writing—original draft preparation, Y.S.; review and editing, Y.S and S.S.-A. All authors have read and agreed to the published version of the manuscript.

Funding

Y.S. thanks the Ministry of Education and Science for financial support under the National Program “Young Scientists and Postdoctoral Researchers” (PMC 577/2018).

Data Availability Statement

The data presented in this study are available in this article and supplementary information.

Acknowledgments

The authors are grateful to the Faculty of Biology, Department of Plant Physiology and Molecular Biology for access to the high-resolution mass spectrometer, provided under the EC FP7/REGPOT-2009-1/BioSupport project.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Denny, W.A. The contribution of synthetic organic chemistry to anticancer drug development. Anticancer Drug Dev. 2002, 11, 187–202. [Google Scholar] [CrossRef]
  2. Liang, G.; Fan, W.; Luo, H.; Zhu, X. The emerging roles of artificial intelligence in cancer drug development and precision therapy. Biomed. Pharmacother. 2020, 128, 110255. [Google Scholar] [CrossRef] [PubMed]
  3. Gill, R.K.; Rawal, R.K.; Bariwal, J. Recent Advances in the Chemistry and Biology of Benzothiazoles. Arch. Pharm. (Weinh.) 2015, 348, 155–178. [Google Scholar] [CrossRef] [PubMed]
  4. Irfan, A.; Batool, F.; Naqvi, S.A.Z.; Islam, A.; Osman, S.M.; Nocentini, A.; Alissa, S.A.; Supuran, C.T. Benzothiazole derivatives as anticancer agents. J. Enzyme Inhib. Med. Chem. 2020, 35, 265–279. [Google Scholar] [CrossRef] [PubMed]
  5. Akhtar, J.; Khan, A.A.; Ali, Z.; Haider, R.; Yar, M.S. Structure-activity relationship (SAR) study and design strategies of nitrogen-containing heterocyclic moieties for their anticancer activities. Eur. J. Med. Chem. 2017, 125, 143–148. [Google Scholar] [CrossRef] [PubMed]
  6. Sharma, P.C.; Sharma, D.; Sharma, A.; Bansal, K.K.; Rajak, H.; Sharma, S.; Thakur, V.K. New horizons in benzothiazole scaffold for cancer therapy: Advances in bioactivity, functionality, and chemistry. Appl. Mater. Today 2020, 20, 100783. [Google Scholar] [CrossRef]
  7. Singh, M.; Singh, S. Benzothiazoles: How Relevant in Cancer Drug Design Strategy? Anticancer Agents Med. Chem. 2014, 14, 127–146. [Google Scholar] [CrossRef] [PubMed]
  8. Ammazzalorso, A.; Carradori, S.; Amoroso, R.; Fernández, I.F. 2-substituted benzothiazoles as antiproliferative agents: Novel insights on structure-activity relationships. Eur. J. Med. Chem. 2020, 207, 112762. [Google Scholar] [CrossRef] [PubMed]
  9. Uremis, N.; Uremis, M.M.; Tolun, F.I.; Ceylan, M.; Doganer, A.; Kurt, A.H. Synthesis of 2-Substituted Benzothiazole Derivatives and Their In Vitro Anticancer Effects and Antioxidant Activities Against Pancreatic Cancer Cells. Anticancer Res. 2017, 37, 6381–6389. [Google Scholar] [CrossRef] [PubMed]
  10. Lindgren, E.B.; de Brito, M.A.; Vasconcelos, T.R.A.; de Moraes, M.O.; Montenegro, R.C.; Yoneda, J.D.; Leal, K.Z. Synthesis and anticancer activity of (E)-2-benzothiazole hydrazones. Eur. J. Med. Chem. 2014, 86, 12–16. [Google Scholar] [CrossRef] [PubMed]
  11. Osmaniye, D.; Levent, S.; Karaduman, A.B.; Ilgın, S.; Özkay, Y.; Kaplancikli, Z.A. Synthesis of New Benzothiazole Acylhydrazones as Anticancer Agents. Molecules 2018, 23, 1054. [Google Scholar] [CrossRef] [PubMed]
  12. Liu, G.G.; Zhao, H.; Lan, Y.B.; Wu, B.; Huang, X.F.; Chen, J.; Tao, J.C.; Wang, X.W. Asymmetric cross aldol addition of isatins with α,β-unsaturated ketones catalyzed by a bifunctional Brønsted acid–Brønsted base organocatalyst. Tetrahedron 2012, 68, 3843–3850. [Google Scholar] [CrossRef]
  13. Eberle, M.; Bachmann, F.; Strebel, A.; Roy, S.; Srivastava, S.; Saha, G. Furazanobenzimidazoles. Patent WO2004103994A1. Available online: https://patents.google.com/patent/WO2004103994A1 (accessed on 2 December 2004).
  14. Cao, B.; Wang, Y.; Ding, K.; Neamati, N.; Long, Y.Q. Synthesis of the pyridinyl analogues of dibenzylideneacetone (pyr-dba) via an improved Claisen–Schmidt condensation, displaying diverse biological activities as curcumin analogues. Org. Biomol. Chem. 2012, 10, 1239–1245. [Google Scholar] [CrossRef] [PubMed]
  15. Kumar, D.; Reddy, V.B.; Kumar, A.; Mandal, D.; Tiwari, R.; Parang, K. Click chemistry inspired one-pot synthesis of 1,4-disubstituted 1,2,3-triazoles and their Src kinase inhibitory activity. Bioorganic Med. Chem. Lett. 2011, 21, 449–452. [Google Scholar] [CrossRef] [PubMed]
  16. Venkov, A.P.; Statkova-Abeghe, S. α-Amidoalkylation Reactions and Oxidation of Adducts of Benzimidazoles and Acyl Chlorides. Synth. Commun. 1998, 28, 1857–1864. [Google Scholar] [CrossRef]
  17. Statkova-Abeghe, S.; Ivanov, I.; Daskalova, S.; Dzhambazov, B. Synthesis and Cytotoxic Evaluation of 1,2,3-Trisubstituted 2-(2-Oxoalkyl)-2,3-dihydrobenzimidazoles. Med. Chem. Res. 2005, 14, 429–439. [Google Scholar] [CrossRef]
  18. Stremski, Y.; Statkova-Abeghe, S.; Angelov, P.; Ivanov, I. Synthesis of Camalexin and Related Analogues. J. Heterocycl. Chem. 2018, 55, 1589–1595. [Google Scholar] [CrossRef]
  19. Stremski, Y.; Kirkova, D.; Statkova-Abeghe, S.; Angelov, P.; Ivanov, I.; Georgiev, D. Synthesis and antibacterial activity of hydroxylated 2-arylbenzothiazole derivatives. Synth. Commun. 2020, 50, 3007–3015. [Google Scholar] [CrossRef]
Figure 1. Benzylidenacetonyl substituted heterocyclic compounds.
Figure 1. Benzylidenacetonyl substituted heterocyclic compounds.
Molbank 2021 m1236 g001
Scheme 1. Synthesis of (E)-2-(2-oxo-4-phenylbut-3-en-1-yl)benzo[d]thiazole-3(2H)-carboxylates (4a,b).
Scheme 1. Synthesis of (E)-2-(2-oxo-4-phenylbut-3-en-1-yl)benzo[d]thiazole-3(2H)-carboxylates (4a,b).
Molbank 2021 m1236 sch001
Table 1. The optimized reaction conditions and yields of products 4, prepared according to Scheme 1.
Table 1. The optimized reaction conditions and yields of products 4, prepared according to Scheme 1.
Product 4RTime, hT, °CYield, %
a−Et80255070 *
b−Me80255576 *
* Obtained with benzothiazole (2 mmol), alkyl chloroformates (2 mmol) and benzylidenacetone (1 mmol).
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