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Molbank 2018, 2018(3), 1001; https://doi.org/10.3390/M1001

Short Note
(E)-3-[3-(2-Butoxyquinolin-3-yl)acryloyl]-2-hydroxy-4H-chromen-4-one
Department of Chemistry, Universidad del Valle, A. A. 25360 Santiago de Cali, Colombia
*
Author to whom correspondence should be addressed.
Received: 25 May 2018 / Accepted: 18 June 2018 / Published: 21 June 2018

Abstract

:
The coumarinyl-quinolinylchalcone hybrid (E)-3-[3-(2-butoxyquinolin-3-yl)acryloyl]-2-hydroxy-4H-chromen-4-one 3b was prepared in good yield from a Claisen-Schmidt condensation reaction between 3-acetyl-4-hydroxy-2H-chromen-2-one 1 and 2-butoxyquinoline-3-carbaldehyde 2 in methanol at reflux and catalyzed by KOH pellets. The structure of the synthesized compound 3b was fully confirmed by FTIR-ATR, (1D and 2D) NMR experiments, EIMS and elemental analysis.
Keywords:
coumarinyl-quinolinylchalcone hybrid; Claisen-Schmidt condensation
PACS:
J0101

1. Introduction

Chalcones are synthetic and naturally occurring α,β-unsaturated diaryl ketones that have shown a wide spectrum of biological activities, and can act as anti-tubercular [1], anti-inflammatory [2], antimalarial [3], antibacterial [4], antifungal [5], and mainly as antitumor agents [6]. Another important class of heterocyclic system is the coumarin, which consists of a benzene ring fused to a 2-pyrone skeleton, which is present in various natural and synthetic compounds [7]. Molecules based on the coumarin moiety have been extensively studied as pharmacophore agents because of their interesting medical properties, such as their antioxidant [8], antitumor [9], or antimalarial effects [10], among others. On the other hand, quinolines have attracted considerable interest for many years due to their presence in the skeletons of a large number of pharmacologically active substances and natural products (mainly alkaloids) [11]. Quinoline-based chalcones have been found to display antitumor [12], antibacterial [13], and antiulcer activity [14]. Due to the diverse range of biological activities that these three pharmacophores possess, we hypothesized a novel molecular hybrid incorporating chalcone, coumarinyl, and quinolinyl moieties in the structure of product 3b, as a starting point for a future project in the searching for new molecules of therapeutic potential.

2. Results and Discussion

Continuing with our studies on the synthetic utility of chalcones, as key precursors for the synthesis of diverse derivatives with interesting biological properties [15,16,17], herein, we report an efficient synthesis of a novel coumarinyl-quinolinylchalcone hybrid 3 in good yield. Product 3 was obtained from a mixture of 3-acetyl-4-hydroxy-2H-chromen-2-one 1 and 2-butoxyquinoline-3-carbaldehyde 2 via a Claisen-Schmidt condensation reaction as shown in Scheme 1. The reaction proceeded in methanol at reflux and was catalyzed by a KOH pellet. Upon consumption of the starting materials 1 and 2, after 4 h of heating (monitored by TLC), the obtained solution was neutralized with acetic acid and isolated by filtration, affording a yellow solid as the new product.
It is well known that the 2,4-dioxocoumarin exist as an equilibrium mixture of their 2,4-dioxo- (a), 2-hydroxy-4-oxo- (b) and 4-hydroxy-2-oxo- (c) forms, being this latter the main component of the mixture [18]. In consequence, it is expected that its 3-acetyl derivative 1 should exist as the same type of mixtures with the tautomer 1c as the main component [19]. In principle, the IR, 1D NMR, mass spectrum and microanalyses data suggested that effectively the structure of the isolated yellow solid corresponded to the chalcone isomer 3c, taking into account that it proceeded from the majority isomer 1c. Nevertheless, as a challenge, we attempted to assign all protons and carbon atoms from the NMR spectra and mainly by using the 2D HSQC and HMBC experiments, but some drawbacks with structure 3c were found.
Thus, the most relevant spectroscopic features for the isolated product corresponded to a molecular ion with m/z 415 and a base peak with m/z 170, in the mass spectrum, which agree with all three expected isomers 3ac. The presence of broad absorption bands at 3401 cm−1 and 1735, 1711 cm−1 assigned to the OH and two C=O functionalities, respectively, are the most relevant features of the IR spectrum. (Isomers 3b and 3c matches with this spectral finding). The presence of a very low field OH signal at 18.9 ppm, as well as, two doublets at 8.37 (J = 15.9 Hz, 1H) and 8.74 (J = 15.9 Hz, 1H) ppm associated with the α,β-vinylic protons 10 and 11 in E configuration of the new C=C bond formed, and the absence of a 8-H aliphatic proton, are the most relevant features of the 1H-NMR spectrum (just isomers 3b, and c match with this finding). The presence of ten quaternary Cq carbon atoms involving two C=O functionalities at 181.6 and 192.6 ppm are the most relevant features of the 13C-NMR spectrum. A signal at 192.6 ppm was assigned without doubt to the C=C-C=O carbonyl moiety. In Addition, only isomers 3b,c matched with this finding.
Finally, the proposal of the tautomer 3b as the true obtained product helped us to solve the above drawbacks. A three bonding correlation of H-2 with the C=O functionality at 181.6 ppm and a complete agreement of the remaining 2D NMR correlations in the HMBC experiment confirmed the above. Hence, the signal at 181.6 ppm is associated with the ketonic C-1 carbon atom, indicating that the OH group is effectively located on C-7 (see 3b), and not on C-1 as it would have happened if isomer 3c would have been obtained. Thus, after a complete study by analytical and spectroscopic techniques, the formation of chalcone 3b in 75% yield (but not their isomers 3a, 3c), was determined. Moreover, 1D and 2D NMR experiments permitted us the assignment of all proton and carbon atoms (see experimental), confirming the proposed structure for 3b without ambiguity. A comparison of our carbon atom assignment with the Automatic Evaluation Report from CSEARCH [20] also matched quite well (see Supplementary Materials).

3. Materials and Methods

3.1. General Information

Melting point was determined on a Büchi melting point B-450 apparatus (Instrumart, South Burlington, VT, USA) and is uncorrected. The IR spectrum was recorded on a Shimadzu FTIR 8400 spectrophotometer by ATR technique (Scientific Instruments Inc., Seattle, WA, USA). 1H and 13C-NMR spectra were recorded on a Bruker Avance 400 spectrophotometer (Bruker BioSpin GmbH, Rheinstetten, Germany), operating at 400 MHz and 100 MHz, respectively, while using CDCl3 as solvent and tetramethylsilane as the internal standard. Mass spectrum was run on a SHIMADZU-GCMS 2010-DI-2010 spectrometer (Scientific Instruments Inc., Columbia, WA, USA) (equipped with a direct inlet probe) operating at 70 eV. Microanalyses was performed on an Agilent CHNS elemental analyzer (Thermo Fischer Scientific Inc., Madison, WI, USA) and the values are within ±0.4% of the theoretical values.

3.2. Synthesis of ((E)-3-(3-(2-Butoxyquinolin-3-yl)acryloyl)-2-hydroxy-4H-chromen-4-one (3b)

A mixture of acetyl-4-hydroxy-2H-chromen-2-one 1 (0.1 g, 1.0 mmol), 2-butoxyquinoline-3-carbaldehyde 2 (1.1 mmol) and a KOH pellet in methanol (5 mL) was heated to reflux for 4 h. After disappearance of the starting materials, as monitored by TLC, acetic acid was added portion-wise with stirring, to the reaction mixture until formation of a precipitate. The solid was collected by filtration and washed with cold methanol (2 × 0.5 mL) to afford 3b (75% yield, yellow solid, m.p. 180–182 °C). FTIR-ATR: ν = 3401 br (OH), 2961, 1735 (C=O), 1711 (C=O), 1603 (C=N), 1565 (C=C), 1489, 1424, (1305, 1257, 1220, 1176, 1098) (C-O), 989 cm−1. 1H-NMR (400 MHz, CDCl3): δ = 1.08 (t, J = 7.4 Hz, 3H, H-24), 1.59–1.66 (m, 2H, H-23), 1.95–2.03 (m, 2H, H-22), 4.63 (t, J = 6.7 Hz, 2H, H-21), 7.30–7.40 (m, 3H, H-15, H-3, H-5), 7.62–7.70 (m, 2H, H-4, H-16), 7.77–7.81 (m, 2H, H-14, H-17), 8.10 (dd, J = 7.9, 1.7 Hz, 1H, H-2), 8.33 (d, J = 15.9 Hz, 1H, H-11), 8.38 (s, 1H, H-13), 8.70 (d, J = 15.9 Hz, 1H, H-10), 18.90 (s, 1H, OH) ppm. 13C-NMR (100 MHz, CDCl3): δ = 13.9 (C-24), 19.5 (C-23), 30.9 (C-22), 66.6 (C-21), 100.9 (C-8), 116.3 (C-1a), 117.0 (C-5), 120.0 (C-12), 124.4 (C-3), 124.6 (C-15), 124.9 (C-13a), 125.1 (C-10), 125.8 (C-2), 127.0 (C-17), 128.4 (C-14), 131.2 (C-16), 136.0 (C-4), 139.5 (C-13), 141.6 (C-11), 147.6 (C-17a), 154.8 (C-5a), 160.1 (C-19, C-7), 181.6 (C-1), 192.6 (C-9) ppm. Anal. calcd. for C25H21NO5 (415.44): C, 72.28; H, 5.10; N, 3.37. Found: C, 72.05; H, 4.98; N, 3.51. MS (EI, 70 eV) m/z (%): 415 (26) [M+], 397 (17), 386 (9), 359 (29), 226 (19), 170 (100), 121 (14), 41 (26).

Supplementary Materials

The following are available online. Figure S1: 1H-NMR spectrum of compound 3b in CDCl3, Figure S2: 13C-NMR spectrum of compound 3b in CDCl3, Figure S3: DEPT-135 experiment of compound 3b, Figure S4: HMBC experiment of compound 3b in CDCl3, Figure S5: Expansion 1 of HMBC experiment of compound 3b in CDCl3, Figure S6: Expansion 2 of HMBC experiment of compound 3b in CDCl3, Figure S7: Expansion 3 of HMBC experiment of compound 3b in CDCl3, Figure S8: HSQC experiment of compound 3b in CDCl3, Figure S9: Expansion of HSQC experiment of compound 3b in CDCl3, Figure S10: COSY experiment of compound 3b in CDCl3, Figure S11: Expansion of COSY experiment of compound 3b in CDCl3, Figure S12: Mass spectrum of compound 3b (EI technique), Figure S13: IR spectrum of compound 3b (ATR technique).

Author Contributions

R.A. designed the experiments; L.G. performed the experiments; R.A., L.G., J.Q. and B.I. analyzed the IR, MS and NMR spectral data and wrote the manuscript. All authors read and approved the final manuscript.

Funding

This research was funded by COLCIENCIAS, grant number 110665842661. APC was sponsored by MDPI.

Acknowledgments

Authors thank COLCIENCIAS and Universidad del Valle for financial support—Project Number CI-7907. L.G. specially thank COLCIENCIAS for her “Joven Investigador” fellowship assigned.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Lin, Y.M.; Zhou, Y.; Flavin, M.T.; Zhou, I.M.; Nie, W.; Chen, F.C. Chalcones and flavonoids as anti-tuberculosis agents. Bioorg. Med. Chem. 2002, 10, 2795–2802. [Google Scholar] [CrossRef]
  2. Won, S.-J.; Liu, C.-T.; Tsao, L.-T.; Weng, J.-R.; Ko, H.-H.; Wang, J.-P.; Lin, C.-N. Synthetic chalcones as potential anti-inflammatory and cancer chemopreventive agents. Eur. J. Med. Chem. 2005, 40, 103–112. [Google Scholar] [CrossRef] [PubMed]
  3. Liu, M.; Wilairat, P.; Go, M.-L. Antimalarial alkoxylated and hydroxylated chalcones:  Structure−activity relationship analysis. J. Med. Chem. 2001, 44, 4443–4452. [Google Scholar] [CrossRef] [PubMed]
  4. Ávila, H.P.; Smânia, E.D.F.A.; Delle-Monache, F.; Júnior, A.S. Structure-activity relationship of antibacterial chalcones. Bioorg. Med. Chem. 2008, 16, 9790–9794. [Google Scholar] [CrossRef] [PubMed]
  5. Sivakumar, P.M.; Muthu-Kumar, T.; Doble, M. Antifungal activity, mechanism and QSAR studies on chalcones. Chem. Biol. Drug Des. 2009, 74, 68–79. [Google Scholar] [CrossRef] [PubMed]
  6. Modzelewska, A.; Pettit, C.; Achanta, G.; Davidson, N.E.; Huang, P.; Khan, S.R. Anticancer activities of novel chalcone and bis-chalcone derivatives. Bioorg. Med. Chem. 2006, 14, 3491–3495. [Google Scholar] [CrossRef] [PubMed]
  7. Wei, H.; Ruan, J.; Zhang, X. Coumarin–chalcone hybrids: Promising agents with diverse pharmacological properties. RSC Adv. 2016, 6, 10846–10860. [Google Scholar] [CrossRef]
  8. Xi, G.-L.; Liu, Z.-Q. Coumarin moiety can enhance abilities of chalcones to inhibit DNA oxidation and to scavenge radicals. Tetrahedron 2014, 70, 8397–8404. [Google Scholar] [CrossRef]
  9. Emami, S.; Dadashpour, S. Current developments of coumarin-based anti-cancer agents in medicinal chemistry. Eur. J. Med. Chem. 2015, 102, 611–630. [Google Scholar] [CrossRef] [PubMed]
  10. Sashidhara, K.; Kumar, A.; Dodda, R.; Krishna, N.; Agarwal, P.; Srivastava, K.; Puri, S. Coumarin–trioxane hybrids: Synthesis and evaluation as a new class of antimalarial scaffolds. Bioorg. Med. Chem. Lett. 2012, 22, 3926–3930. [Google Scholar] [CrossRef] [PubMed]
  11. Marella, A.; Tanwar, O.; Saha, R.; Ali, M.; Srivastava, S.; Akhter, M.; Shaquiquzzaman, M.; Alam, M. Quinoline: A versatile heterocyclic. Saudi Pharm. J. 2013, 21, 1–12. [Google Scholar] [CrossRef] [PubMed]
  12. Kotra, V.; Ganapaty, S.; Adapa, S. Synthesis of a new series of quinolinyl chalcones as anticancer and anti-inflammatory agents. Indian J. Chem. 2010, 49, 1109–1116. [Google Scholar]
  13. Abdullah, M.; Mahmood, A.; Madni, M.; Masood, S.; Kashif, M. Synthesis, characterization, theoretical, anti-bacterial and molecular docking studies of quinoline based chalcones as a DNA gyrase inhibitor. Bioorg. Chem. 2014, 54, 31–37. [Google Scholar] [CrossRef] [PubMed]
  14. Sashidhara, K.; Avula, S.; Mishra, V.; Palnati, G.; Singh, L.; Singh, N.; Chhonker, Y.; Swami, P.; Bhatta, R.; Palit, G. Identification of quinoline-chalcone hybrids as potential antiulcer agents. Eur. J. Med. Chem. 2015, 89, 638–653. [Google Scholar] [CrossRef] [PubMed]
  15. Abonia, R.; Cuervo, P.; Insuasty, B.; Quiroga, J.; Nogueras, M.; Cobo, J.; Meier, H.; Lotero, E. An Amberlyst-15® mediated synthesis of new functionalized dioxoloquinolinone derivatives. Open Org. Chem. J. 2008, 2, 26–34. [Google Scholar] [CrossRef]
  16. Abonia, R.; Cuervo, P.; Insuasty, B.; Quiroga, J.; Nogueras, M.; Cobo, J. A simple two-step sequence for the synthesis of novel 3-aryl[1,3]dioxolobenzo[f]pyrrolo[1,2-a]azepin-11-ones from 6-amino-3,4-methylenedioxyacetophenone. Eur. J. Org. Chem. 2008, 2008, 4684–4689. [Google Scholar] [CrossRef]
  17. Abonia, R.; Insuasty, D.; Castillo, J.; Insuasty, B.; Quiroga, J.; Nogueras, M.; Cobo, J. Synthesis of novel quinoline-2-one based chalcones of potential anti-tumor activity. Eur. J. Med. Chem. 2012, 57, 29–40. [Google Scholar] [CrossRef] [PubMed]
  18. Abdou, M.; El-Saeed, R.; Bondock, S. Recent advances in 4-hydroxycoumarin chemistry. Part 1: Synthesis and reactions. Arab. J. Chem. 2015. [Google Scholar] [CrossRef]
  19. Abdou, M. 3-Acetyl-4-hydroxycoumarin: Synthesis, reactions and applications. Arab. J. Chem. 2017, 10, S3664–S3675. [Google Scholar] [CrossRef]
  20. Please See CSEARCH-Robot-Referee by Haider, N.; Robien, W. Available online: http://nmrpredict.orc.univie.ac.at/c13robot/robot.php (accessed on 15 June 2018).
Scheme 1. Synthesis of the coumarinyl-quinolinylchalcone hybrid 3b.
Scheme 1. Synthesis of the coumarinyl-quinolinylchalcone hybrid 3b.
Molbank 2018 01001 sch001

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