Synthesis of (3-Methoxycarbonyl)coumarin in an Ionic Liquid: An

Laboratory Experiment pubs.acs.org/jchemeduc

Synthesis of (3-Methoxycarbonyl)coumarin in an Ionic Liquid: An Advanced Undergraduate Project for Green Chemistry Pedro Verdía, Francisco Santamarta, and Emilia Tojo* Department of Organic Chemistry, University of Vigo, Marcosende, Vigo 36310, Pontevedra, Spain S Supporting Information *

ABSTRACT: An experiment for an undergraduate organic chemistry class based on the application of an ionic liquid as solvent and catalyst of an organic reaction is reported. The whole experiment requires three 3-h lab sessions. First, students prepare the ionic liquid dimethylimidazolium methylsulfate, which is then used as a recyclable catalyst/ reaction medium for the Knoevenagel condensation between benzaldehyde and malononitrile. Finally, in the third session, the application of the ionic liquid is extended to the preparation of 3-(methoxycarbonyl)coumarin. This project provides a valuable opportunity for undergraduates within the last 2 years of the chemistry degree to experience the latest innovative ideas in chemical research and green chemistry. KEYWORDS: Upper-Division Undergraduate, Organic Chemistry, Hands-On Learning/Manipulatives, Aldehydes/Ketones, Catalysis, Green Chemistry, Heterocycles, NMR Spectroscopy, Natural Products, Laboratory Instruction

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INTRODUCTION Nowadays, the implementation and design of chemical compounds and processes that can eliminate or, at least, reduce the environmental impact is one of the main concerns of chemists and the main goal of green chemistry. It involves the use and production of less hazardous reagents and products, the improvement of the efficiency of the processes (both energy and atom efficiency), the recoverability of the chemicals, the reduction of waste production and its proper disposal, and the elimination of the hazards associated with the processes. Over the past decade, ionic liquids (ILs) have been proposed as a promising and “greener” alternative to the use of the hazardous conventional organic molecular solvents in reactions and separation processes. As an arbitrary convention, ILs are defined as salts that melt below 100 °C,1 which in many cases are known to possess a series of unique properties, such as high thermal stability, wide liquid range, nonflammability, and negligible vapor pressure. They are usually composed of large organic cations with bulky substituents or with the positive charge delocalized, such as the imidazolium, pyridinium, ammonium, or phosphonium cations (Figure 1). In recent years they have been used in a number of organic reactions as solvents and/or catalysts with considerable success, often accelerating the reaction, making workup easier, and allowing their own recycling.2 The Knoevenagel condensation3 is one of the most common organic reactions used to form CC bonds.4 The resulting α,β-unsaturated products have been widely used in the synthesis of drugs, 5 natural products, 6 polymers, 7 fine chemicals,8 herbicides,9,10 and insecticides.11 The classical © XXXX American Chemical Society and Division of Chemical Education, Inc.

methods to perform this reaction are associated with disadvantages such as hazardous and carcinogenic solvents and unrecoverability of the catalysts, with the use of ILs as solvents/catalysts being one of the most successful alternatives. In recent years, a series of ILs have been applied in the Knoevenagel reaction with great success,12 allowing the synthesis of 3-substituted coumarins when using o-hydroxybenzaldehydes as starting materials.13 Coumarins are naturally occurring phytochemicals with a wide range of pharmacological activities, such as antitumor,14 anti-inflammatory, antiallergic, and anti-HIV.15 Among them, 3-substitued coumarins are of special interest due to their potential applications for the treatment of Chagas or Alzeimer’s disease.16 The increasing popularity that ionic liquids have reached in the past years is accelerating the need for incorporating this topic into the undergraduate curriculum. However, only four articles describing laboratory experiments for undergraduate courses related to the synthesis and applications of ILs have been reported; these explore the synthesis of ionic liquids17,18 and their application to the Mannich reaction as reaction medium19 and as catalysts for the PET depolymerization.20 Also, ILs have a dedicated chapter in the first published book oriented toward the introduction of green chemistry and sustainability in laboratory and experimental teaching. Examples for the preparation of an IL and its use in dissolution and precipitation of cellulose and its further acetylation, olefin selfReceived: June 7, 2016 Revised: December 21, 2016

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DOI: 10.1021/acs.jchemed.6b00148 J. Chem. Educ. XXXX, XXX, XXX−XXX

Journal of Chemical Education

Laboratory Experiment

Figure 1. Common structures of cations and anions in ionic liquids.

Scheme 1. First Session: Preparation of the IL 1,3-Dimethylimidazolium Methylsulfate, [MMIm][MSO4]

Scheme 2. Second Session: Application of [MMIm][MSO4], 1, as a Solvent and Catalyst in the Knoevenagel Reaction between Benzaldehyde and Malononitrile

Scheme 3. Third Session: Synthesis of 3-(Methoxycarbonyl)coumarin, 3, in [MMIm][MSO4], 1, Using L-Proline as Promoter

cross metathesis in an IL, and the cleavage of anisole in a protic IL and the reduction of benzophenone in a Lewis acidic IL are described.21 Due to its great interest in organic synthesis, some laboratory experiments applying the Knoevenagel reaction have also been reported in this Journal, but none of them with the use of ionic liquids. It has been employed for example to prepare aphenylcinnamonitriles,22 to use for annulation reactions,23 to produce trans-cinnamic acid,24 as well as to study the charge distribution in 1,1-dicyano-2-arylethenes.25 Regarding the synthesis of coumarins,26−29 only four lab experiments were described in this Journal, and none of them use ILs. Due to awareness of the growing interest of ionic liquids in green chemistry both in industry and academia, the experiment presented here was designed for and tested in a fourth-year organic chemistry laboratory; our main goal was to make students aware of the high interest in these peculiar compounds. This project allows them to synthesize an ionic

liquid and to apply it as the reaction medium/catalyst for the Knoevenagel reaction and for the synthesis of coumarins. This experience helps students to get some sustainability criteria, at the same time that it reinforces laboratory skills and organic chemistry concepts such as nucleophilic substitution, catalysis, and addition and intramolecular reactions. In this laboratory experiment, an IL with low toxicity is used: 1,3-dimethylimidazolium methyl sulfate ([MMIm][MSO4]), 1 (Scheme 1). It is considered not dangerous according with the Directives CE 67/548/CEE30 or 1999/45/CE.31 This IL acts efficiently as both solvent and catalyst of the Knoevenagel condensation reaction between benzaldehyde and malonotrile, and when L-proline is used as an additional promoter, 3(methoxycarbonyl)coumarin is obtained from o-hydroxybenzaldehyde and diethyl malonate in high yield and with short reaction time. L-Proline is also considered nondangerous according to the Directives CE 67/548/CEE30 or 1999/45/ CE.31 B



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EXPERIMENTAL OVERVIEW This laboratory experiment has been carried out for the last 7 years by fourth-year undergraduate students within an advanced organic chemistry course divided into three sessions of 3 h. The first of them involves the preparation of the IL 1,3dimethylimidazolium methylsulfate, [MMIm][MSO4]. In the second session the synthesized [MMIm][MSO4], 1, is applied as solvent and catalyst in the Knoevenagel reaction between benzahaldehyde and manolonitrile (Scheme 2). Finally, in the last session, the IL is employed as reaction medium for the synthesis of 3-(methoxycarbonyl)coumarin 3 (Scheme 3).

organic solvents and liquids should be used under a fume hood. The synthesis of [MMIm][MSO4] is a highly exothermic reaction, and dimethylsulfate is suspected of being carcinogenic and mutagenic. Therefore, dimethylsulfate needs to be collected from a sealed bottle containing an inert atmosphere, employing a glass syringe and a metallic needle to transfer. The receiving flask will be placed over an ice bath, sealed with a rubber septum, containing an inert atmosphere, and connected to a balloon in order to avoid the generation of overpressure when performing the addition. The addition will be performed drop by drop to avoid overheating. If the safety measures related with dimethylsulfate handling are not possible, the students should not perform the synthesis of [MMIm][MSO4]. In this case, the first step of the experiment would be eliminated, and commercially available [MMIm][MSO4] would be used for the next steps. 1-Methylimidazole is corrosive to skin and eyes; is hazardous via skin or eye contact, inhalation, and ingestion; and can cause skin burns and eye damage. Dimethylsulfate is corrosive to skin and eyes; is hazardous via skin or eye contact, inhalation, and ingestion; and can cause skin burns and eye damage. It may also cause an allergic skin reaction. It is also a possible carcinogen and mutagenic compound. Toluene is flammable; irritating to eyes and skin; and hazardous via skin or eye contact, inhalation, and ingestion, and it a possible carcinogen and mutagenic compound. Benzaldehyde is harmful if swallowed. Malononitrile is toxic if swallowed, if in contact with skin, and if inhaled, and it is very toxic to aquatic life with long-lasting effects. Salicylaldehyde is toxic via skin or eye contact, inhalation, and ingestion and harmful if swallowed, and it can cause skin and serious eye corrosion and irritation. Dimethyl malonate is toxic via skin or eye contact, inhalation, and ingestion, and can cause skin and serious eye corrosion and irritation. Also, it is irritating to the respiratory tract. Ethyl acetate is highly flammable, can cause serious eye irritation and damage, and may cause drowsiness or dizziness. It presents specific target organ toxicity and narcotic effects. Heptane is a highly flammable liquid and vapor, may be fatal if swallowed and enters airways, causes skin irritation, may cause drowsiness or dizziness, and is very toxic to aquatic life with long-lasting effects. 2-(Phenylmethylene)malononitrile is harmful if swallowed, if in contact with skin, and if inhaled; it causes skin irritation and serious eye irritation and may cause respiratory irritation. 3-(Methoxycarbonyl)coumarin causes skin and eye irritation and may cause respiratory irritation. Deuterated chloroform is harmful if swallowed, causes skin irritation, causes serious eye irritation, is toxic if inhaled, is suspected of causing cancer, is suspected of damaging the unborn child, and can cause damage to organs through prolonged or repeated exposure.

First Session

1,3-Dimethylimidazolium methylsulfate, [MMIm][MSO4], is prepared by the addition of dimethylsulfate over a solution of 1methylimidazolium (Scheme 1). Because the reaction is highly exothermic, the addition needs to be carried out drop by drop, over an ice bath under an inert atmosphere. The employment of a solvent such as toluene to act as a heat disperser is also highly recommended. In this case, the synthesized [MMIm][MSO4] separates from the toluene as a second layer. Once the reaction is finished, the toluene is decanted and the reaction product washed with ethyl acetate. Finally, the remaining solvent is evaporated at low pressure using a rotary evaporator, to afford the desired IL 1. Second Session

The second step involves the application of the IL as solvent and catalyst for the Knoevenagel reaction (Scheme 2). The experimental procedure is very simple: a mixture of benzaldehyde, malononitrile, and the IL is stirred at room temperature for 10 min. The completion of the reaction is indicated by TLC. The product is then extracted from the reaction medium with ethyl acetate, and the solvent is evaporated; the Knoevenagel product 2-(phenylmethylene)malononitrile, 2, is obtained as a white solid with high yield and purity. Its melting point is measured, and their 1H NMR and 13 C NMR spectra are recorded and found to be in total agreement with those previously reported.12 Third Session

Dimethyl malonate and salicylaldehyde are added over a solution of L-proline in [MMIm][MSO4] (Scheme 3). The reaction mixture is stirred at 90 °C for approximately 1 h until the completion of the reaction is indicated by TLC. The reaction product is then allowed to cool at room temperature, and the desired 3-(methoxycarbonyl)coumarin 3 is isolated by liquid−liquid extraction as a yellow crystalline solid with good yield. Its melting point is measured, and their 1H NMR, 13C NMR, and mass spectra are recorded and found in total agreement with those previously reported.13 All chemicals are commercially available, and the experiments can be carried out with standard laboratory equipment. Experimental procedure details and spectroscopic data (1H, 13 C NMR) of all obtained compounds, as well as the most significant MS spectra and their interpretation, are provided in Supporting Information.

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DISCUSSION Students were generally able to perform and work up reactions without significant problems. The synthesis of [MMIm][MSO4], 1, was performed via a nucleophilic substitution (SN2). No byproducts were formed, and most students were able to obtain [MMIm][MSO4], 1, in high yield (90−99%). The Knoevenagel reaction between benzaldehyde and malononitrile was performed employing the [MMIm][MSO4], 1, synthesized in the previous step. This IL was selected to be used as reaction medium because it presents a series of advantages: it is halogen free, easy to prepare, easy to handle, and inexpensive, and it presents low viscosity,32 low cytotoxic effect,33 and high solvent ability for organic compounds. In

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HAZARDS Students should be aware of the necessary precautions and safety instructions. Although the hazards associated with the reactants and solvents are significantly reduced by the very small quantities employed, students should avoid exposure. Laboratory coats, safety goggles, and gloves must be worn. All C




This project can be carried out in different versions of various lengths depending on the available time and situations. Instead of developing the whole experiment in 3 days, the students can synthesize the ionic liquid and use it only for the Knoevenagel condensation, or the instructor may provide them with the ionic liquid and let them work on the condensation and/or the coumarin synthesis.

addition, [MMIm][MSO4], 1, is able to promote the Knoevenagel reaction due the catalytic effect produced by the hydrogen-bond donating character of imidazolium H-2, which forms hydrogen bonds with the carbonyl group of benzaldehyde34,35 (a more detailed discussion about proposed mechanisms is provided in Supporting Information). It has also been proven that the best performance for this reaction happens when the IL contains some amount of water13 (preferably 2 wt %). Taking into account that [MMIm][MSO4], 1, absorbs around 2.16 wt % of water when exposed to the atmosphere, it can be used in the Knoevenagel reaction without drying and without adding any other promoter. Most students were capable of completing the reaction in a few minutes with high yield (90−98%) and of obtaining reaction product 2 with high purity after its extraction from the reaction medium with ethyl acetate. The synthesis of 3-(methoxycarbonyl)coumarin 3 was achieved by the reaction of salicylaldehyde and dimethyl malonate in [MMIm][MSO4] 1, employing L-proline as promoter. The reaction proceeded very efficiently via a Knoevenagel reaction followed by an intramolecular transesterification. Under these conditions, the reaction was complete after 1 h when heated at 90 °C. Workup was very simple, and 3-(methoxycarbonyl)coumarin, 3, was obtained by the students without the need of further purification with a slightly lower yield (80−85%) than the previous reactions; it can be attributed to the formation of some emulsions during the extraction process. In general, students were able to confirm that the reactions were successful by analyzing the NMR and MS spectra, and the melting point measurements produced melting point ranges within 1−2 °C of that in literature reports. Representative student NMR and MS spectra for each step are in Supporting Information. For seven years, this experiment has been carried out by fourth-year undergraduate students (between 20 and 35 students each year) obtaining good yields in all steps. Several pedagogical goals can be described for this laboratory activity. On one hand, students will be able to understand the importance of using environmentally friendly solvents and catalysts. In addition, this experience will increase a student’s ability to carry on an organic reaction, as well as to isolate the reaction product and assess its degree of purity by TLC. Besides, students will get more experience identifying organic compounds (by analyzing their NMR and MS spectra) and describing laboratory procedures and results in a lab notebook. These pedagogical goals were assessed by different means: instructor observation of practical laboratory skills and aptitude, answers to pre- and postlab questions, participation in mechanism and spectra discussions, the lab report, and a written exam (more detailed information about assessment is provided in S15 of the Supporting Information).

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available on the ACS Publications website at DOI: 10.1021/acs.jchemed.6b00148. Instructor notes, student handout, and detailed experimental procedures, as well as detailed spectroscopic information (PDF, DOCX)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors are grateful to Ministerio de Economiá y Competitividad of the Spanish Government (ref DPI201238841-C02-02), the Xunta de Galicia (projects CN 2012/184 and CN 2012/120), and the Galician Network on Ionic Liquids (ReGaLis REGALIs CN 2014/015) for their financial support.

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REFERENCES

(1) Plechkova, N. V.; Seddon, K. Applications of ionic liquids in the chemical industry. Chem. Soc. Rev. 2008, 37 (1), 123−150. (2) Welton, T.; Wassercheid, P. Ionic Liquids in Synthesis; WileyVCH: Weinheim, 2003. (3) Freeman, F. Properties and reactions of ylidenemalononitriles. Chem. Rev. 1980, 80 (4), 329−350. (4) Tietze, L. F. Domino Reactions in Organic Synthesis. Chem. Rev. 1996, 96 (1), 115−136. (5) Kraus, G. A.; Krolski, M. E. Synthesis of a precursor to quassimarin. J. Org. Chem. 1986, 51 (17), 3347−3350. (6) Tietze, L. F.; Rackelmann, N. Domino reactions in the synthesis of heterocyclic natural products and analogs. Pure Appl. Chem. 2004, 76 (11), 1967−1983. (7) Liang, F.-J.; Pu, Y.; Kurata, T.; Kido, J.; Nishide, H. Synthesis and electroluminescent property of poly(p-phenylenevinylene)s bearing triarylamine pendants. Polymer 2005, 46 (11), 3767−3775. (8) Zahouily, M.; Salah, M.; Bahlaouane, B.; Rayadh, A.; Houmam, A.; Hamed, E. A.; Sebti, S. Solid catalysts for the production of fine chemicals: The use of natural phosphate alone and doped base catalysts for the synthesis of unsaturated arylsulfones. Tetrahedron 2004, 60 (7), 1631−1635. (9) Ahn, S. C.; Kim, S. H.; Kadivendi, S.; Lee, S. Y.; Kim, K. D.; Ryu, I. A. Method for preparation of 3-alkylthio-2-bromopyridine as key intermediate for producing flucetosulfuron with superior herbicidal activity. PCT Int. Appl. 2015, WO2015053576A1 20150416. (10) Miao, L.; Cai, P.; Lai, H.-q.; Yang, Z.-x.; Ding, C.-r.; Qu, J.; Li, F.-y. Synthesis of 3-methyl-7-nitrophthalide. Zhejiang Gongye Daxue Xuebao 2013, 41 (2), 195−198. (11) Chyan, M.-K.; Norton, S. J. Synthesis and Biological Evaluation of New Pyrethroids Having Halogen, Keto, or Nitro GroupContaining Substituents. J. Agric. Food Chem. 1995, 43 (8), 2286− 2290.

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CONCLUSION This laboratory experiment involved the synthesis of an ionic liquid and its application as solvent/catalyst for the Knoevenagel reaction and later preparation of a coumarin derivative. It was developed for advanced undergraduate students to be introduced to the chemistry of ionic liquids, their application in organic synthesis, and the meaning of green chemistry. It also provided an opportunity to discuss the SN2, Knoevenagel condensation, and intramolecular esterification mechanisms as well as the catalytic effect of the ionic liquid. D




(12) Santamarta, F.; Verdía, P.; Tojo, E. A simple, efficient and green procedure for Knoevenagel reaction in [MMIm][MSO4] ionic liquid. Catal. Commun. 2008, 9 (8), 1779−1781. (13) Verdía, P.; Santamarta, F.; Tojo, E. Knoevenagel reaction in [MMIm][MSO4]. Molecules 2011, 16 (6), 4379−4388. (14) Thakur, A.; Singla, R.; Jaitak, V. Coumarins as anticancer agents: A review on synthetic strategies, mechanism of action and SAR studies. Eur. J. Med. Chem. 2015, 101, 476−495. (15) Yu, D.; Suzuki, M.; Morris-Natschke, S. L.; Lee, K. H.; Xie, L. Recent progress in the development of coumarin derivatives as potent anti-HIV agents. Med. Res. Rev. 2003, 23 (3), 322−345. (16) Viña, D.; Matos, M. J.; Yáñez, M.; Santana, L.; Uriarte, E. Substituted coumarins as dual inhibitors of AChE and MAO for the treatment of Alzheimer’s disease. MedChemComm 2012, 3 (2), 213− 218. (17) Dzyuba, S. V.; Kollar, K. D.; Sabnis, S. S. Synthesis of imidazolium Room-Temperature Ionic Liquids: exploring green chemistry and click chemistry paradigms in undergraduate organic chemistry laboratory. J. Chem. Educ. 2009, 86 (7), 856−858. (18) Stark, A.; Ott, D.; Kralisch, D.; Kreisel, G.; Ondruschka, B. Ionic Liquids and Green Chemistry: a Lab Experiment. J. Chem. Educ. 2010, 87 (2), 196−201. (19) Mak, K. K. W.; Siu, J.; Lai, Y. M.; Chan, P. Mannich Reactions in Room Temperature Ionic Liquids (RTILs): and advanced undergraduate project of green chemistry and structural elucidation. J. Chem. Educ. 2006, 83 (6), 943−946. (20) Kamber, N. E.; Tsujii, Y.; Keets, K.; Waymouth, R. M.; Pratt, R. C.; Nyce, G. W.; Hedrick, J. L. The Depolimerization of Poly(ethyleneterephthalate) (PET) using N-Heterocyclic Carbenes from Ionic Liquids. J. Chem. Educ. 2010, 87 (5), 519−521. (21) Roesky, H.; Kennepohl, D. Experiments in Green and Sustainable Chemistry; Wiley-VCH: Weinheim, 2009; pp 118−127. (22) Kulp, S. S. Knoevenagel condensation to alpha-phenylcinnamonitriles: NaBH4 reduction to propanenitriles. J. Chem. Educ. 1988, 65 (8), 742−742. (23) Cook, A. G. A Knoevenagel Initiated Annulation Reaction Using Room Temperature or Microwave Conditions. J. Chem. Educ. 2007, 84 (9), 1477−1479. (24) Kolb, K. E.; Field, K. W.; Schatz, P. F. A One-Step Synthesis of Cinnamic Acids Using Malonic Acid: The Verley-Doebner Modification of the Knoevenagel Condensation. J. Chem. Educ. 1990, 67 (12), A304. (25) Rowland, A. T. Charge Distribution in 1,1-Dicyano-2Arylethenes: An Undergraduate Organic Experiment Utilizing the Knoevenagel Condensation and NMR Spectroscopy. J. Chem. Educ. 1995, 72 (6), 548−549. (26) Aktoudianakis, E.; Dicks, A. P. Convenient Microscale Synthesis of a Coumarin Laser Dye Analog. J. Chem. Educ. 2006, 83 (2), 287− 289. (27) Holden, M. S.; Crouch, R. D. The Pechmann Reaction. J. Chem. Educ. 1998, 75 (12), 1631. (28) Young, D. M.; Welker, J. J. C.; Doxsee, K. M. Green Synthesis of a Fluorescent Natural Product. J. Chem. Educ. 2011, 88 (3), 319−332. (29) Fringuelli, F.; Piermatti, O.; Pizzo, F. One-Pot Synthesis of 7Hydroxy-3-carboxycoumarin in Water. J. Chem. Educ. 2004, 81 (6), 874−876. (30) EUR-Lex Access to European Union law, http://eur-lex.europa. eu/legal-content/ES/TXT/?uri=celex:31967L0548 (accessed Nov 2016). (31) EUR-Lex Access to European Union law, http://eur-lex.europa. eu/legal-content/ES/TXT/?uri=celex:31999L0045 (accessed Nov 2016). (32) Pereiro, A. B.; Santamarta, F.; Tojo, E.; Rodríguez, A.; Tojo, J. Temperature dependence of physical properties of ionic liquid 1,3dimethylimidazolium methyl sulfate. J. Chem. Eng. Data 2006, 51 (3), 952−954. (33) García-Lorenzo, A.; Tojo, E.; Tojo, J.; Teijeira, M.; RodríguezBerrocal, F. J.; González, M. P.; Martínez-Zorzano, V. S. Cytotoxicity of selected imidazolium-derived ionic liquids in the human Caco-2cell

line. Sub-structural toxicological interpretation through a QSAR study. Green Chem. 2008, 10 (5), 508−516. (34) Aggarwal, A.; Lancaster, N. L.; Sethi, A. R.; Welton, T. The role of hydrogen bonding in controlling the selectivity of Diels−Alder reactions in room-temperature ionic liquids. Green Chem. 2002, 4 (5), 517−520. (35) Roy, S. R.; Chakraborti, A. K. Supramolecular Assemblies in Ionic Liquid Catalysis for Aza-Michael Reaction. Org. Lett. 2010, 12 (17), 3866−3869.

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Synthesis of (3-Methoxycarbonyl)coumarin in an Ionic Liquid: An

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