Eleni Kavetsou, Anastasia Detsi


Coumarins are extremely vital in pharmaceuticals and industry therefore the development of mild, efficient, and ecofriendly benign synthetic methodology is necessary. Ionic liquids (ILs) are environmentally friendly with green chemistry credentials and can be regarded as greener alternatives for conventional organic solvents. The present review focuses on the synthetic approaches toward coumarin analogues that use ILs as a solvent and/or as a catalyst. The review includes the literature after 2005, with the exception of some important historic articles on coumarin derivatives. 

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Borges F, Roleira F, Milhazes N, Santana L, Uriarte E. Simple Coumarins and Analogues in Medicinal Chemistry: Occurrence, Synthesis and Biological Activity. Curr Med Chem 2005;12:887.

Roussaki M, Zelianaios K, Kavetsou E, Hamilakis S, Hadjipavlou-Litina D, Kontogiorgis C, Liargkova T, Detsi A. Structural modifications of coumarin derivatives: Determination of antioxidant and lipoxygenase (LOX) inhibitory activity. Bioorg Med Chem 2014;6586–6594.

Roussaki M , Kontogiorgis CA, Hadjipavlou-Litina D, Hamilakis S, Detsi A. A novel synthesis of 3-aryl coumarins and evaluation of their antioxidant and lipoxygenase inhibitory activity. Bioorg Med Chem Lett 2010;20: 3889-3892.

Huang GJ, Deng JS, Liao JC, Hou WC, Wang SY, Sung PJ, et al. Inducible nitric oxide synthase and cyclooxygenase-2 participate in antiinflammatory activity of imperatorin from Glehnia littoralis. J Agric Food Chem 2012;60:1673–1681.

Khaghanzadeh N, Mojtahedi Z, Ramezani M, Erfani N and Ghader A. Umbelliprenin is cytotoxic against QU-DB large cell lung cancer cell line but anti-proliferative against A549 adenocarcinoma cellsDARU. J Pharm Sci 2012;20:69-75.

Shikishima Y, Takaishi Y, Honda G, Ito M, Takfda Y, Kodzhimatov OK, Ashurmetov O, Lee KH. Chemical constituents of Prangos tschiniganica, structure elucidation and absolute configuration of coumarin and furanocoumarin derivatives with anti-HIV activity. Chem Pharm Bull 2001;49:877-880.

Rosselli S, Maggio AM, Faraone N, Spadaro V, Morris-Natschke SL, Bastow KF, Lee KH, Bruno M. The cytotoxic properties of natural coumarins isolated from roots of Ferulago campestris (Apiaceae) and of synthetic ester derivatives of aegelinol. Nat Prod Commun 2009;4:1701–1706.

Luszczki JJ, Wojda E, Andres-Mach M, Cisowski W, Glensk M, Glowniak K, Czuczwar SJ. Anticonvulsant and acute neurotoxic effects of imperatorin, osthole and valproate in the maximal electroshock seizure and chimney tests in mice: a comparative study. Epilepsy Res 2009;85:293–299.

Kennedy RO, Thornes RD, Coumarins: Biology, Applications and Mode of Action, John Wiley and Sons, Chichester; 1997.

Maeda M, Laser Dyes. Academic Press. New York;1984.

(a) Raad I, Darouiche R, Hachem R, Sacilowski M, Bodey GP. Antibiotics and prevention of microbial colonization of catheters. Antimicrob Agents Chemother 1995;39:2397–2400; (b) Raad II, Hachem RY, Abi-Said D, Rolston KVI, Whimbey E, Buzaid AC, et al. A prospective crossover randomized trial of novobiocin and rifampin prophylaxis for the prevention of intravascular catheter infections in cancer patients treated with interleukin-2. Cancer 1998;82:403–411; (c) Walsh TJ, Standiford HC, Reboli AC, John JF, Mulligan ME, Ribner BS, et al. Randomized Double-Blinded Trial of Rifampin with Either Novobiocin or Trimethoprim-Sulfamethoxazole against Methicillin-Resistant Staphylococcus aureus Colonization: Prevention of Antimicrobial Resistance and Effect of Host Factors on Outcome. Antimicrob Agents Chemother 1993;37:1334–1342.

Anderle C, Stieger M, Burrell M, Reinelt S, Maxwell A, Page M, et al. Biological activities of novel gyrase inhibitors of the aminocoumarin class. Antimicrob Agents Chemother 2008;52:1982–1990.

(a) Janin YL. Heat Shock Protein 90 Inhibitors. A Text Book Example of Medicinal Chemistry?. J Med Chem 2005;48:7503–7512;(b) Burlison JA, Neckers L, Smith AB, Maxwell A, Blagg BSJ. Novobiocin: Redesigning a DNA gyrase inhibitor for selective inhibition of Hsp90. J Am Chem Soc 2006;128:15529–15536.

Heide L. The aminocoumarins: biosynthesis and biology. Nat Prod Rep 2009; 26:1241-1250.

Bansal Y, Silakari O. Multifunctional compounds: smart molecules for multifactorial diseases. Eur J Med Chem 2014;76:31-42.

Witaicenis A, Seito LN, Di Stasi LC. Intestinal antiinflammatory activity of esculetin and 4-methylesculetin in the trinitrobenzenesulphonic acid model of rat colitis. Chem Biol Interact 2010;186:211–218.

Chiang CC, Cheng MJ, Peng CF, Huang HY, Chen IS. A novel dimeric coumarin analog and antimycobacterial constituents from Fatoua pilosa. Chem Biodivers 2010;7:1728–1736.

Ramalingam R, Vaiyapuri M. Effects of umbelliferone on lipid peroxidation and antioxidant status in diethylnitrosamine-induced hepatocellular carcinoma. J Acute Med2 013;3:73-82.

Valizadeh H, Shockravi A. An efficient procedure for the synthesis of coumarin derivatives using TiCl4 as catalyst under solvent-free conditions. Tetrahedron Lett 2005;46:3501–3503.

Donnelly BJ, Donnelly DMX, Sullivan AMO. Dalbergia species—VI: The occurrence of melannein in the genus Dalbergia. Tetrahedron 1968;24:2617–2622.

Bigi F, Chesini L, Maggi R, Sartori G. Montmorillonite KSF as an inorganic, water stable, and reusable catalyst for the Knoevenagel synthesis of coumarin-3-carboxylic acids. J Org Chem 1999;64:1033–1035.

Shirner RL. The Reformatsky reaction. Org React 1942;1:1-35.

Yavari I, Hekmat-shoar R, Zonuzi A. A new and efficient route to 4-carboxymethylcoumarins mediated by vinyltriphenylphosphonium salt. Tetrahedron Lett 1998;39:2391–2392.

Shockravi, A.; Valizadeh, H.; Heravi, M. M. A one-pot and convenient synthesis of coumarins in solventless system. Phosphorus, Sulfur Silicon Relat Elem 2003;178: 501–504.

Wasserscheid P, Welton T, Eds. Ionic Liquids in Synthesis. Wiley-VCH, Verlag GmbH & Co.: Weinheim 2002.

Yue C, Fang D, Liu L, Yi TF. Synthesis and application of task-specific ionic liquids used as catalysts and/or solvents in organic unit reactions. J Mol Liq 2011;163: 99−121.

Tzani A, Douka A, Papadopoulos A, Pavlatou EA, Voutsas E and Detsi A. Synthesis of Biscoumarins Using Recyclable and Biodegradable Task-Specific Ionic Liquids. ACS Sustainable Chem Eng 2013;1:1180-1185.

Tsanas C, Tzani A, Papadopoulos A, Detsi A, Voutsas E. Ionic liquids as entrainers for the separation of the ethanol/water system. Fluid Phase Equilibria 2014;379:148–156.

Gjineci N, Boli E, Tzani A , Detsi A, Voutsas E. Separation of the Ethanol/Water Azeotropic Mixture using Ionic Liquids and Deep Eutectic Solvents. Fluid Phase Equilibria 2015;DOI:10.1016/j.fluid.2015.07.048.

Gu Y, Zhang J, Duan Z, Deng Y. Pechmann Reaction in Non-Chloroaluminate Acidic Ionic Liquids under Solvent-Free Conditions. Adv Synth Catal 2005;347:512– 516.

Potdar MK, Rasalkar MS, Mohile SS, Salunkhe MM. Convenient and efficient protocols for coumarin synthesis via Pechmann condensation in neutral ionic liquids. J Mol Catalysis A: Chemical 2005;235:249–252.

Ranu BC and Jana R. Ionic Liquid as Catalyst and Reaction Medium – A Simple, Efficient and Green Procedure for Knoevenagel Condensation of Aliphatic and Aromatic Carbonyl Compounds Using a Task-Specific Basic Ionic Liquid. Eur J Org Chem 2006;3767–3770.

Dong F, Jian C, Kai G, Qunrong S, Zuliang L. Synthesis of Coumarins via Pechmann Reaction in Water Catalyzed by Acyclic Acidic Ionic Liquids. Catal Lett 2008;121:255–259.

Liu X-H, Fan J-C, Liu Y, Shang Z-C. L-Proline as an efficient and reusable promoter for the synthesis of coumarins in ionic liquid, J Zhejiang Univ Sci B 2008;9:990-995.

Darvatkar NB, Deorukhkar AR, Bhilare SV, Raut DG, Salunkhe MM. Ionic Liquid–Mediated Synthesis of Coumarin-3-carboxylic Acids via Knoevenagel Condensation of Meldrum's Acid with ortho-Hydroxyaryl Aldehydes. Synth Commun 2008;38:3508-3513.

Kumar V, Tomar S, Patel R, Yousaf A, Parmar VS, Malhotra SV. FeCl3-Catalyzed Pechmann Synthesis of Coumarins in Ionic Liquids. Synth Commun 2008;38:2646-2654.

Yadav LDS, Singh S, Rai VK. A one-pot [Bmim]OH-mediated synthesis of 3-benzamidocoumarins. Tetrahedron Lett 2009;50:2208–2212.

Shi D-Q, Zhou Y, Rong S-F. Ionic Liquid, [bmim]Br, as an Efficient Promoting Medium for Synthesis of 3-Acetoacetylcoumarin Derivatives Without the Use of Any Catalyst. Synth Commun 2009;39:3500-3508.

Valizadeh H, Vaghefi S. One-Pot Wittig and Knoevenagel Reactions in Ionic Liquid as Convenient Methods for the Synthesis of Coumarin Derivatives. Synth Commun 2009;39:1666-1678.

Valizadeh H, Gholipour H. Imidazolium-Based Phosphinite Ionic Liquid (IL-OPPh2) as Reusable Catalyst and Solvent for the Knoevenagel Condensation Reaction. Synth Commun 2010;40:1477-1485.

Das S, Majee A, Hajra A. A convenient synthesis of coumarins using reusable ionic liquid as catalyst. Green Chem Lett and Reviews 2011;4:349-353.

Harishkumar HN, Mahadevan KM, Kumar HCK and Satyanarayan ND. A facile, choline chloride/urea catalyzed solid phase synthesis of coumarins via Knoevenagel condensation. Org Commun 2011;4:26-32.

Valizadeh H, Mahmoodian M and Gholipour H. ZrCl4/[bmim]BF4-Catalyzed Condensation of Salicylaldehydes and Malononitrile: Single-Step Synthesis of 3-Cyanocoumarin Derivatives. J Heterocyclic Chem 2011;48:799-802.

Khaligh NG. Synthesis of coumarins via Pechmann reaction catalyzed by 3-methyl-1-sulfonic acid imidazolium hydrogen sulfate as an efficient, halogen-free and reusable acidic ionic liquid. Catal Sci Technol 2012;2:1633–1636.

Zhang Y, Zhu A, Li Q, Li L, Zhao Y, Wang J. Cholinium ionic liquids as cheap and reusable catalysts for the synthesis of coumarins via Pechmann reaction under solvent-free conditions. RSC Adv 2014;4:22946-22950.

Shirini F, Yahyazadeh A, Mohammadi K. A solvent-free synthesis of coumarins using 1,3-disulfonic acid imidazolium hydrogen sulfate as a reusable and effective ionic liquid catalyst. Res Chem Intermed 2015;41:6207-6218.

Singh V, Kaur S, Sapehiyia V, Singh J, Kad GL. Microwave accelerated preparation of [bmim][HSO4] ionic liquid: an acid catalyst for improved synthesis of coumarins. Catalysis Communications 2005; 6:57–60.

Valizadeh H, Shockravi A and Gholipur H. Microwave Assisted Synthesis of Coumarins via Potassium Carbonate Catalyzed Knoevenagel Condensation in 1-n-Butyl-3-methylimidazolium Bromide Ionic Liquid. J. Heterocyclic Chem 2007;44:867-870.

Shaabani A, Ghadari R, Rahmati A and Rezayan AH. Coumarin Synthesis via Knoevenagel Condensation Reaction in 1,1,3,3-N,N,N',N'- Tetramethylguanidinium Trifluoroacetate Ionic Liquid. J Iran Chem Soc 2009;6:710-714.

Valizadeh H and Shockravi A. Task-Specific Ionic Liquid as Reagent and Reaction Medium for the One-Pot Horner–Wadsworth–Emmons–Type Reaction Under Microwave Irradiation. Synthetic Communications 2009;39:4341–4349.

Valizadeh H, Gholipour H and Mahmoudian M. Phosphinite Ionic Liquid (IL-OPPh2) as a Recyclable Reagent for the Efficient Synthesis of Coumarins under Microwave Irradiation Conditions. J Iran Chem Soc 2011;8:862-871.

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Journal of Critical Reviews
Vol 3, Issue 3, 2016 Page: 50-55

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Authors & Affiliations

Eleni Kavetsou

Anastasia Detsi
Laboratory of Organic Chemistry, School of Chemical Engineering, National Technical University of Athens, Zografou Campus, 15780 Athens, Greece


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