Synthesis of coumarin derivative using polymer supported reagents European Journal of Chemistry 9 (2) (2018) 89-91 European Journal of Chemistry View Journal Online View Article Online Synthesis of coumarin derivative using polymer supported reagents Chiheb Mhiri 1, Riadh Ternane 1, Naceur Hamdi 2 and Lassaad Baklouti 1,2,* 1 Laboratory of Applied Chemistry and Natural Substances Resources and Environment, Faculty of Sciences, University of Carthage, Zarzouna‐Bizerta, 7021, Tunisia chiheb.mhiri@gmail.com (C.M.), rternane@yahoo.fr (R.T.) 2 Chemistry Department, College of Science and Arts, Qassim University, Al‐Rass, 51921, Kingdom of Saudi Arabia naceur.hamdi@isste.rnu.tn (N.H.), blkoty@qu.edu.sa (L.B.) * Corresponding author at: Chemistry Department, College of Science and Arts, Qassim University, Al‐Rass, 51921, Kingdom of Saudi Arabia. Tel: +966.53.2056252 Fax: +966.16.3332515 e‐mail: blkoty@qu.edu.sa (L. Baklouti). 10.5155/eurjchem.9.2.89-91.1691 Received: 01 March 2018 Received in revised form: 25 March 2018 Accepted: 31 March 2018 Published online: 30 June 2018 Printed: 30 June 2018 Recently, there has been a surge in use of polymer-supported reagents and catalysts become common tools for organic synthesis in what is known as polymer-assisted synthesis since they can simplify product isolation and purification. In this context, coumarin derivative 3 was prepared in good yield and high purity, starting from 3-methoxy salicylaldehyde, using reagents supported on a macroporous ion exchange resin. For this purpose, iminocoumarin and unsaturated nitrile were used as starting materials. The synthesized compounds were characterized by IR, NMR and mass spectrometry. Iminocoumarin Selective synthesis Unsaturated nitrile Knoevenagel condensation 3-Methoxy salicylaldehyde Polymer supported reagent Cite this: Eur. J. Chem. 2018, 9(2), 89-91 Journal website: www.eurjchem.com 1. Introduction Solution-phase synthesis using solid-phase reagents or scavengers has been termed polymer-assisted solution phase synthesis, and the developments in this field have been subject of several reviews [1]. The interest in this field has caused a recent explosion in the number of scientific papers describing the development of novel support bound reagents, catalysts and methods for purification. Supported reagents are reactive species, which are associated with a support material. The most important advantage in using a polymer-supported reagent in an organic reaction is the simplification of reaction workup, i.e. product separation and isolation. In the case of an insoluble polymeric reagent, filtration and repeated washing with suitable solvents can be generally used at the end of the reaction to isolate the product and therefore the need for complex chromatographic techniques can be avoided [2]. Monitoring the progress of the reactions is easy by applying TLC, NMR or LC/MS techniques. The use of an excess of reagent is also allowed without the need for additional purification steps [3]. Regeneration and reuse of the recovered polymer supported reagents are possible, thus providing an environmentally benign system [4]. On the other hand, the synthesis, characterization, and properties of 2-imino- coumarin derivatives have been studied intensively. This considerable attention of investigators to these products is connected on the one hand to their high reactivity toward both electrophiles and nucleophiles and on the other hand to their many applications in agricultural and pharmacological industries. For example, some 3-hetaryl coumarins and imino- coumarins have been proposed as anticancer [5], anti- asthmatic [6], antibacterial [7], and antiallergic [8-12] agents. They exhibit strong fluorescence in the UV-VIS region that makes them suitable to use as colorants, dye laser media and nonlinear optical chromophore. Taking these facts into consideration, we were interested in developing an efficient synthetic route to iminocoumarins (1) and activated nitrile (2) by the extension of our preceding strategy [13] (Scheme 1). Herein, we report firstly a successful utilization of 3-methoxy salicylaldehyde as a convenient starting material for a synthesis of novel iminocoumarin derivative (1) and unsaturated nitrile (2) then the hydrolysis of the obtained compounds 1 and 2 afforded the coumarin derivative 3. ABSTRACT RESEARCH ARTICLE KEYWORDS European Journal of Chemistry ISSN 2153-2249 (Print) / ISSN 2153-2257 (Online) – Copyright © 2018 The Authors – Atlanta Publishing House LLC – Printed in the USA. This work is published and licensed by Atlanta Publishing House LLC – CC BY NC – Some Rights Reserved. http://dx.doi.org/10.5155/eurjchem.9.2.89-91.1691 http://dx.doi.org/10.5155/eurjchem.9.2.89-91.1691 https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.9.2.89-91.1691&domain=pdf&date_stamp=2018-06-30 http://www.eurjchem.com/ http://dx.doi.org/10.5155/eurjchem.9.2.89-91.1691 mailto:chiheb.mhiri@gmail.com mailto:rternane@yahoo.fr mailto:naceur.hamdi@isste.rnu.tn mailto:blkoty@qu.edu.sa mailto:blkoty@qu.edu.sa http://www.eurjchem.com/ https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.9.2.89-91.1691&domain=pdf&date_stamp=2018-06-30� 90 Mhiri et al. / European Journal of Chemistry 9 (2) (2018) 89‐91 O O Ph OMe (3) OHN MeO OH CN Ph (1) (2) OMe Ph Scheme 1. Structures of iminocoumarins (1), unsaturated nitrile (2) and hydrolysis product (3). P N OH OMe OH CHO -H2O OHC O MeO (II) P: Polymer P N 1st step - Preparation of polymer supported phenate anions (II) P N OHC O MeO (II) P N Cyclohexane Reflux ON (III) OMe Ph OMe O NC Ph (IV) N P N 2nd step - Reaction of phenylacetonitrile with polymer supported reagents (II). P N ON (III) OMe Ph OMe O NC Ph (IV) P N OMe Ph HN + (1) O OMe OH Ph NC (2) CHCl3 P N OH- Yield: 90% Yield: 10% 3rd Step: Deablock of iminocoumarin (1) and unsaturated nitrile (2) from the resin. Scheme 2. Selective synthesis of iminocoumarin (1) and unsaturated nitrile (2) from the resin using 3-methoxy salicylaldehyde and phenylacetonitrile as starting materials. 2. Experimental 2.1. Instrumentation Chemicals and solvents were purchased from Sigma- Aldrich. 1H NMR and 13C NMR spectra were recorded at 200 MHz for (1H) and 50 MHz for (13C), respectively, in CDCl3 with TMS as an internal reference. The melting points of the compounds were determined using Stuart automatic melting point apparatus (SMP-40). Mass spectra were measured on a DI analysis Shimadzu Qp-2010 plus spectrometer; IR spectra were recorded with a Perkin Elmer Spectrum 100 Gladi ATR FT/IR spectrophotometer. 2.2. Synthesis 2.2.1. General procedure for the selective synthesis of iminocoumarin (1) and unsaturated nitrile (2) Under nitrogen atmosphere, a mixture of the 3-methoxy salicylaldehyde (0.02 mol), Amberlite IRA 900 resin (0.02 mol) and cyclohexane (25 mL) was refluxed with the use of a Dean- Stark water separator. Acid-base reaction progress between Amberlite IRA 900 resin and aldehyde. It was monitored by GC technique. After completion of this reaction, the phenyl- acetonitrile (0.02 mol) was added and the mechanically stirred mixture was refluxed during 8 hours. After that, the reaction mixture was separated from the solid catalyst. Treatment of the resin beads by elution with chloroform, allows the recuperation of 90% from the synthesized iminocoumarin (1) and unsaturated nitrile (2). The organic phase was then evaporated under reduced pressure, leading to the recupe- ration of the resting iminocoumarin (1) and unsaturated nitrile (2) (10%). Finally, the obtained iminocoumarin (1) and unsaturated nitrile (2) were purified by crystallization with hexane. The purity of the synthesized compounds was examined by spectroscopic investigations. 8‐Methoxy‐3‐phenyl‐2H‐chromen‐2‐imine (1): FT-IR (KBr, ν, cm-1): 3330-3300 (NH), 1600 (C=C), 1640 (C=N). 1H NMR (200 MHz, CDCl3, δ, ppm): 6.91-7.97 (m, 8H, Ar-H + H5,6,7), 7.16 (s, 1H, H4), 3.94 (s, 3H, OCH3), 3.25 (s, 1H, NH). 13C NMR (50 MHz, CDCl3, δ, ppm): 112.4 (1C, C7), 119.4 (1C, C5), 123.3 (1C, C6), 133.5 (1C, C4), 128.0-129.0 (5C, Ci (3-Ph)), 56.3 (3C, OCH3), 120.6, 131.0, 136.3, 142.6, 146.5 (Cq). MS (EI, m/z (%)): 251 (M+, 100). 3‐(2‐Hydroxy‐3‐methoxyphenyl)‐2‐phenylacrylonitrile (2): FT-IR (KBr, ν, cm-1): 3530 (OH), 2215(CN), 1600 (C=C). 1H NMR (200 MHz, CDCl3, δ, ppm): 7.98 (s, 1H, H4), 6.91-7.97 (m, 8H, Ar-H + H5,6,7), 3.90 (s, 3H, OCH3). 13C NMR (50 MHz, CDCl3, δ, ppm): 112.9 (1C, C7), 119.9 (1C, C6), 126.1 (1C, C5), 136.4 (1C, C4), 128.0-129.0 (5C, Ci (3-Ph)), 56.3 (3C, OCH3), 113.5, 116.3, 120.7, 134.8, 145.2, 146.6 (Cq). 2018 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.9.2.89-91.1691 Mhiri et al. / European Journal of Chemistry 9 (2) (2018) 89‐91 91 2.2.2. Synthesis of 8-methoxy-3-phenyl-2H-chromen-2-one (3) The acid hydrolysis of the mixture of compound 1 and 2 in ethanol leads to the corresponding coumarin derivative (3). 8‐Methoxy‐3‐phenyl‐2H‐chromen‐2‐one (3): Color: Yellow. Yield: 95%. FT-IR (KBr, ν, cm-1): 1727 (C=O), 1610 (C=C). 1H NMR (300 MHz, CDCl3, δ, ppm): 7.78 (s, 1H, H4), 7.73-7.38 (m, 5H, Ar-H), 7.19 (t, 1H, H6), 7.11 (dd, 1H, H5), 7.09 (dd, 1H, H7), 3.97 (s, 3H, OCH3). 13C NMR (50 MHz, CDCl3, δ, ppm): 113.3 (1C, C7), 119.4 (1C, C5), 124.4 (1C, C6), 128.5-128.9 (5C, Ci (3- Ph)), 140.0 (1C, C4), 56.3 (3C, OCH3), 120.3, 128.57, 134.7, 143.5, 147.0, 160.0 (Cq). 3. Results and discussion The synthetic procedure was accomplished in three-steps as given in Scheme 2. Step 1, Preparation of polymer suppor- ted phenate anions (II): Treatment of 3-methoxy salicylal- dehyde with Amberlite IRA 900 (under its OH form) in cyclo- hexane solvent by the use of a Dean-Stark water separator, afforded the polymer supported phenate anions. Step 2, Reaction of phenylacetonitrile with polymer supported reagents (II): Phenylacetonitrile was combined with phenate resin beads, under reflux conditions, leading to the polymer supported anions (III) and (IV). Step 3, Deblock of the iminocoumarin (1) from the resin: Treatment of resin beads by elution with chloroform, afforded the iminocoumarins (1) and unsaturated nitrile (2). Standard spectroscopic data of each compound are consistent with the proposed structures. The FT-IR spectrum of compound 1 showed absorption bands in 3330-3300 cm−1 (NH) and 1640 cm−1 (-C=N str.). The mass spectra of com- pounds 1 and 2 confirmed the proposed structure by the presence of molecular ion peaks [M] at m/z 251. The use of Amberlite IRA 900 resin beads as a solid support offers a practical alternative to the classical Knoevenagel methods. Using our procedure, the iminocoumarin (1) is generated in situ with no presence of free water and their hydrolyze does not take place. The key feature of this strategy is the use of strong anion exchange resin as a polymeric solid support [14,15]. The acid hydrolysis of the mixture of compound 1 and 2 in ethanol leads to the corresponding coumarin derivative (3) according to Scheme 3. The characterization of compound 3 was confirmed by different spectroscopic methods, 1H NMR: the proton H4 appears around δ 7.78 ppm; FT-IR: the carbonyl group absorbs was observed at 1727 cm-1. O Ph NH OMe OH MeO Ph CN O O Ph OMe EtOH AcOH 50°C (1) (2) (3) Scheme 3. The acid hydrolysis of the reaction mixture of compound 1 and 2 in ethanol. 4. Conclusion In summary, we have used a supported polymer that can serve as a foundation for the preparation of iminocoumarin (1) and unsaturated nitrile (2). The acid hydrolysis of compounds 1 and 2 afforded the correspondent coumarin derivative (3) with high purity. The method developed in this work is particularly interesting for the simplicity of providing this iminocoumarin compounds in good yield. Disclosure statement Conflict of interests: The authors declare that they have no conflict of interest. Author contributions: All authors contributed equally to this work. Ethical approval: All ethical guidelines have been adhered. Sample availability: Samples of the compounds are available from the author. ORCID Naceur Hamdi http://orcid.org/0000-0003-0110-9588 Lasaad Baklouti http://orcid.org/0000-0002-5142-7501 Chiheb Mhiri http://orcid.org/0000-0001-6331-6393 Riadh Ternane http://orcid.org/0000-0003-3557-7558 References [1]. Brahnbhatt, D. I.; Gajera, J. M.; Pandya, V. P.; Patel, M. A. Ind. J. Chem. 2007, 46(B), 869-871. [2]. Murrey, R. D. H.; Medez, D.; Brown, S. A. The Natural coumarins occurences. Chemistry and Biochemistry, John Wiley Interscience, New York, 1982. [3]. Bourinbaiar, A. S.; Tan, X.; Nagomy, R. Acta. Virol. 1993, 37, 241-250. [4]. Venugopala, K. N.; Jayashree, B. S. Asian. J. Chem. 2004, 16(1), 407- 411. [5]. Luo, X.; Song, J.; Cheng, L.; Huang, D. Sci. China, Ser. B Chem. 2001, 44, 532-539. [6]. 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Permissions for commercial use of this work beyond the scope of the License (http://www.eurjchem.com/index.php/eurjchem/pages/view/terms) are administered by Atlanta Publishing House LLC (European Journal of Chemistry). 2018 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.9.2.89-91.1691 http://orcid.org/0000-0003-0110-9588 http://orcid.org/0000-0002-5142-7501 http://orcid.org/0000-0001-6331-6393 http://orcid.org/0000-0003-3557-7558 http://www.eurjchem.com/index.php/eurjchem/pages/view/terms http://creativecommons.org/licenses/by-nc/4.0 http://www.eurjchem.com/index.php/eurjchem/pages/view/terms 1. Introduction 2. Experimental 2.1. Instrumentation 2.2. Synthesis 2.2.1. General procedure for the selective synthesis of iminocoumarin (1) and unsaturated nitrile (2) 2.2.2. Synthesis of 8-methoxy-3-phenyl-2H-chromen-2-one (3) 3. Results and discussion 4. Conclusion Disclosure statement ORCID References PrintField10: PrintField11: PrintField12: PrintField20: PrintField21: PrintField22: