Intramolecular Oxa-Michael Cyclization of 2’-Hydroxychalcones for the Synthesis of Flavanones: A Comparative Study
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Keywords:
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Claisen-Schmidt Condensation, Flavanones, 2’-hydroxychalcones, Oxa-Michael Cyclization
Abstract
In this study, flavanones were synthesized using a two-step reaction process starting from 2’ hydroxyacetophenone and aldehydes. Claisen-Schmidt condensations were carried out on the starting materials to produce 2’-hydroxychalcones with mono-, di-, and tri-substituents on ring B. Subsequently, flavanones were produced via intramolecular oxa-Michael cyclization under three different reaction conditions: methanesulfonic acid in ethanol, sodium acetate in methanol, and piperidine in water. These approaches aimed to investigate the steric and electronic effects to achieve high yields in optimal reaction conditions for flavanone synthesis. Twelve 2’-hydroxychalcones (1a-1l) were successfully synthesized with yields ranging from 17% to 99%. The use of methanesulfonic acid in ethanol resulted in modest flavanone yields (11% for 2a, 13% for 2c). The synthesis of flavanones using sodium acetate was successful for seven 2’-hydroxychalcones (2a-2g), yielding products with varying yields (2-49%). Furthermore, piperidine was effective for three 2’-hydroxychalcones (1a, 1b, 1e), resulting in high flavanone yields (74-93%). These findings indicate that the three reaction conditions are only effective for certain 2’-hydroxychalcones.
References
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Iguchi, D., R. Erra-Balsells, and S. M. Bonesi (2014). Expeditious Photochemical Reaction Toward the Preparation of Substituted Chroman-4-ones. Tetrahedron Letters, 55(33); 4653–4656.
Iwash, T. (2013). Flavonoid Properties of Five Families Newly Incorporated into the Order Caryophyllales (Review). Bull Natl Mus Nat Sci, 39; 25–51.
Jiang, H., X. Zheng, Z. Yin, and J. Xie (2011). An Efficient Catalytic Synthesis of Flavanones Under Green Conditions. Journal of Chemical Research, 35(4); 220–221.
Joglekar, S. J. and S. D. Samant (1988). Abnormal Base Catalysed Reaction of Formaldehyde and Benzaldehydes with 1-(2-hydroxyphenyl)-3-phenyl-1,3-propanedione. Tetrahedron Letters, 29(2); 241–244.
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Kulkarni, P., P. Wagh, and P. Zubaidha (2012). An Improved and Eco-Friendly Method for the Synthesis of Flavanone by the Cyclization of 2’-Hydroxy Chalcone Using Methane Sulphonic Acid as Catalyst. Chemistry Journal, 2(3); 106–101.
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Macquarrie, D. J., R. Nazih, and S. Sebti (2002). KF/Natural Phosphate As an Efficient Catalyst for Synthesis of 2’-hydroxychalcones and Flavanones. Green Chemistry, 4(1); 56–59.
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Pouget, C., C. Fagnere, J.-P. Basly, G. Habrioux, and A.-J. Chulia (2002). New Aromatase Inhibitors Synthesis and Inhibitory Activity of Pyridinyl-Substituted Flavanone Derivatives. Bioorganic & Medicinal Chemistry Letters, 12(7); 1059–1061.
Raj, C. G. D., B. K. Sarojini, S. Hegde, S. Sreenivasa, Y. S. Ravikumar, V. Bhanuprakash, Y. Revanaiah, and R. Ragavendra (2013). In Vitro Biological Activities of New Heterocyclic Chalcone Derivatives. Medicinal Chemistry Research, 22(5); 2079–2087.
Rosa, G. P., A. M. L. Seca, M. d. C. Barreto, A. M. S. Silva, and D. C. G. A. Pinto (2019). Chalcones and Flavanones Bearing Hydroxyl and/or Methoxyl Groups: Synthesis and Biological Assessments. Applied Sciences, 9(14); 2846.
Sagrera, G. J. and G. A. Seoane (2005). Microwave-Accelerated Solvent-Free Synthesis of Flavanones. Journal of the Brazilian Chemical Society, 16(4); 851–856.
Santos, E. L., B. H. L. N. S. Maia, A. P. Ferriani, and S. D. Teixeira (2017). Flavonoids: Classification, Biosynthesis and Chemical Ecology. In Flavonoids - From Biosynthesis to Human Health. InTech.
Sharma, P., S. Kumar, F. Ali, S. Anthal, V. K. Gupta, I. A. Khan, S. Singh, P. L. Sangwan, K. A. Suri, B. D. Gupta, D. K. Gupta, P. Dutt, R. A. Vishwakarma, and N. K. Satti (2013). Synthesis and Biologic Activities of Some Novel Heterocyclic Chalcone Derivatives. Medicinal Chemistry Research, 22(8); 3969–3983.
Shi, L.-P., K.-M. Jiang, J.-J. Jiang, Y. Jin, Y.-H. Tao, K. Li, X.-H. Wang, and J. Lin (2013). Synthesis and Antimicrobial Activity of Polyhalobenzonitrile Quinazolin-4(3H)-one Derivatives. Bioorganic & Medicinal Chemistry Letters, 23(21); 5958–5963.
Sinyeue, C., M. Matsui, M. Oelgemöller, F. Bregier, V. Chaleix, V. Sol, and N. Lebouvier (2022). Synthesis and Investigation of Flavanone Derivatives as Potential New Anti-Inflammatory Agents. Molecules, 27(6); 1781.
Subramanian, R. S. and K. K. Balasubramanian (1990). Mercury(II)trifluoroacetate-mediated Transformation of 3-bromo-1-phenylprop-2-ynyl aryl ethers; A Novel Synthesis of Flavanones. Journal of the Chemical Society, Chemical Communications, 21; 1469.
Syukur, M., M. S. Prahasiwi, N. Nurkhasanah, S. Yuliani, Y. Purwaningsih, and E. Indriyanti (2023). Profiling of Active Compounds of Extract Ethanol, n-Hexane, Ethyl Acetate and Fraction Ethanol of Star Anise (Illicium verum Hook. f.) and Determination of Total Flavonoids, Total Phenolics and Their Potential as Antioxidants. Science and Technology Indonesia, 8(2); 219–226.
Tanaka, K. and T. Sugino (2001). Efficient Conversion of 2’-hydroxychalcones into Flavanones and Flavanols in a Water Suspension Medium. Green Chemistry, 3(3); 133–134.
Vu Nguyen, D., C. Muanprasat, S. Kaewin, K. Hengphasatporn, Y. Shigeta, T. Rungrotmongkol, and W. Chavasiri (2024). Synthesis and Biological Evaluation of 2’-hydroxychalcone Derivatives as AMPK Activators. Bioorganic Chemistry, 143; 107048.
Wang, G., J.-J. Wang, R. Guan, L. Du, J. Gao, and X.-L. Fu (2017). Strategies to Target Glucose Metabolism in Tumor Microenvironment on Cancer by Flavonoids. Nutrition and Cancer, 69(4); 534–554.
Zheng, X., H. Jiang, J. Xie, Z. Yin, and H. Zhang (2013). Highly Efficient and Green Synthesis of Flavanones and Tetrahydroquinolones. Synthetic Communications, 43(7); 1023–1029.
Chandrasekhar, S., K. Vijeender, and K. V. Reddy (2005). New Synthesis of Flavanones Catalyzed by L-Proline. Tetrahedron Letters, 46(41); 6991–6993.
Chen, P., Y. Cao, B. Bao, L. Zhang, and A. Ding (2017). Antioxidant Capacity of Typha angustifolia Extracts and Two Active Flavonoids. Pharmaceutical Biology, 55(1); 1283–1288.
Climent, M. J., A. Corma, S. Iborra, and J. Primo (1995). Base Catalysis for Fine Chemicals Production: Claisen-Schmidt Condensation on Zeolites and Hydrotalcites for the Production of Chalcones and Flavanones of Pharmaceutical Interest. Journal of Catalysis, 151(1); 60–66.
Dauzonne, D. and C. Monneret (1997). A New Synthesis of Flavanones. Synthesis, 1997(11); 1305–1308.
Donaire-Arias, A., M. L. Poulsen, J. Ramón-Costa, A. M. Montagut, R. Estrada-Tejedor, and J. I. Borrell (2023). Synthesis of Chalcones: An Improved High-Yield and Substituent-Independent Protocol for an Old Structure. Molecules, 28(22); 7576.
Geissman, T. A. (1962). The Chemistry of Flavonoid Compounds. Pergamon Press.
Gomes, M., E. Muratov, M. Pereira, J. Peixoto, L. Rosseto, P. Cravo, C. Andrade, and B. Neves (2017). Chalcone Derivatives: Promising Starting Points for Drug Design. Molecules, 22(8); 1210.
Hanáková, Z., J. Hošek, Z. Kutil, V. Temml, P. Landa, T. Vaněk, D. Schuster, S. Dall’Acqua, J. Cvačka, O. Polanský, and K. Šmejkal (2017). Anti-Inflammatory Activity of Natural Geranylated Flavonoids: Cyclooxygenase and Lipoxygenase Inhibitory Properties and Proteomic Analysis. Journal of Natural Products, 80(4); 999–1006.
Iguchi, D., R. Erra-Balsells, and S. M. Bonesi (2014). Expeditious Photochemical Reaction Toward the Preparation of Substituted Chroman-4-ones. Tetrahedron Letters, 55(33); 4653–4656.
Iwash, T. (2013). Flavonoid Properties of Five Families Newly Incorporated into the Order Caryophyllales (Review). Bull Natl Mus Nat Sci, 39; 25–51.
Jiang, H., X. Zheng, Z. Yin, and J. Xie (2011). An Efficient Catalytic Synthesis of Flavanones Under Green Conditions. Journal of Chemical Research, 35(4); 220–221.
Joglekar, S. J. and S. D. Samant (1988). Abnormal Base Catalysed Reaction of Formaldehyde and Benzaldehydes with 1-(2-hydroxyphenyl)-3-phenyl-1,3-propanedione. Tetrahedron Letters, 29(2); 241–244.
Kar Mahapatra, D., V. Asati, and S. K. Bharti (2019). An Updated Patent Review of Therapeutic Applications of Chalcone Derivatives (2014–Present). Expert Opinion on Therapeutic Patents, 29(5); 385–406.
Keane, D. D., K. G. Marathe, W. I. O’Sullivan, E. M. Philbin, R. M. Simons, and P. C. Teague (1970). Configuration and Conformation of 3-arylideneflavanones. The Journal of Organic Chemistry, 35(7); 2286–2290.
Kshatriya, R. B. and G. M. Nazeruddin (2014). Synthesis of Flavanones Using Methane Sulphonic Acid as a Green Catalyst and Comparision Under Different Conditions. Oriental Journal of Chemistry, 30(2); 857–862.
Kulkarni, P. (2015). Methane Sulphonic Acid Is Green Catalyst in Organic Synthesis. Oriental Journal of Chemistry, 31(1).
Kulkarni, P., P. Wagh, and P. Zubaidha (2012). An Improved and Eco-Friendly Method for the Synthesis of Flavanone by the Cyclization of 2’-Hydroxy Chalcone Using Methane Sulphonic Acid as Catalyst. Chemistry Journal, 2(3); 106–101.
Kurniawan, M. F. and M. Audita (2021). Formulation, Evaluation of Physical Properties, Anti-Cholesterol Activity From Ficus carica L. Leaves Extract Tablet. Science and Technology Indonesia, 6(4); 285–295.
Macquarrie, D. J., R. Nazih, and S. Sebti (2002). KF/Natural Phosphate As an Efficient Catalyst for Synthesis of 2’-hydroxychalcones and Flavanones. Green Chemistry, 4(1); 56–59.
Maruyama, K., K. Tamanaka, A. Nishinaga, A. Inada, and T. Nakanishi (1989). Conversion of 2’-hydroxychalcones to Flavanones Catalyzed by Cobalt Schiff Base Complex. Tetrahedron Letters, 30(31); 4145–4148.
Nabaei-Bidhendi, G. and N. R. Bannerjee (1991). ChemInform Abstract: Convenient Synthesis of Polyhydroxy Flavonoids. ChemInform, 22(29); 172.
Pouget, C., C. Fagnere, J.-P. Basly, G. Habrioux, and A.-J. Chulia (2002). New Aromatase Inhibitors Synthesis and Inhibitory Activity of Pyridinyl-Substituted Flavanone Derivatives. Bioorganic & Medicinal Chemistry Letters, 12(7); 1059–1061.
Raj, C. G. D., B. K. Sarojini, S. Hegde, S. Sreenivasa, Y. S. Ravikumar, V. Bhanuprakash, Y. Revanaiah, and R. Ragavendra (2013). In Vitro Biological Activities of New Heterocyclic Chalcone Derivatives. Medicinal Chemistry Research, 22(5); 2079–2087.
Rosa, G. P., A. M. L. Seca, M. d. C. Barreto, A. M. S. Silva, and D. C. G. A. Pinto (2019). Chalcones and Flavanones Bearing Hydroxyl and/or Methoxyl Groups: Synthesis and Biological Assessments. Applied Sciences, 9(14); 2846.
Sagrera, G. J. and G. A. Seoane (2005). Microwave-Accelerated Solvent-Free Synthesis of Flavanones. Journal of the Brazilian Chemical Society, 16(4); 851–856.
Santos, E. L., B. H. L. N. S. Maia, A. P. Ferriani, and S. D. Teixeira (2017). Flavonoids: Classification, Biosynthesis and Chemical Ecology. In Flavonoids - From Biosynthesis to Human Health. InTech.
Sharma, P., S. Kumar, F. Ali, S. Anthal, V. K. Gupta, I. A. Khan, S. Singh, P. L. Sangwan, K. A. Suri, B. D. Gupta, D. K. Gupta, P. Dutt, R. A. Vishwakarma, and N. K. Satti (2013). Synthesis and Biologic Activities of Some Novel Heterocyclic Chalcone Derivatives. Medicinal Chemistry Research, 22(8); 3969–3983.
Shi, L.-P., K.-M. Jiang, J.-J. Jiang, Y. Jin, Y.-H. Tao, K. Li, X.-H. Wang, and J. Lin (2013). Synthesis and Antimicrobial Activity of Polyhalobenzonitrile Quinazolin-4(3H)-one Derivatives. Bioorganic & Medicinal Chemistry Letters, 23(21); 5958–5963.
Sinyeue, C., M. Matsui, M. Oelgemöller, F. Bregier, V. Chaleix, V. Sol, and N. Lebouvier (2022). Synthesis and Investigation of Flavanone Derivatives as Potential New Anti-Inflammatory Agents. Molecules, 27(6); 1781.
Subramanian, R. S. and K. K. Balasubramanian (1990). Mercury(II)trifluoroacetate-mediated Transformation of 3-bromo-1-phenylprop-2-ynyl aryl ethers; A Novel Synthesis of Flavanones. Journal of the Chemical Society, Chemical Communications, 21; 1469.
Syukur, M., M. S. Prahasiwi, N. Nurkhasanah, S. Yuliani, Y. Purwaningsih, and E. Indriyanti (2023). Profiling of Active Compounds of Extract Ethanol, n-Hexane, Ethyl Acetate and Fraction Ethanol of Star Anise (Illicium verum Hook. f.) and Determination of Total Flavonoids, Total Phenolics and Their Potential as Antioxidants. Science and Technology Indonesia, 8(2); 219–226.
Tanaka, K. and T. Sugino (2001). Efficient Conversion of 2’-hydroxychalcones into Flavanones and Flavanols in a Water Suspension Medium. Green Chemistry, 3(3); 133–134.
Vu Nguyen, D., C. Muanprasat, S. Kaewin, K. Hengphasatporn, Y. Shigeta, T. Rungrotmongkol, and W. Chavasiri (2024). Synthesis and Biological Evaluation of 2’-hydroxychalcone Derivatives as AMPK Activators. Bioorganic Chemistry, 143; 107048.
Wang, G., J.-J. Wang, R. Guan, L. Du, J. Gao, and X.-L. Fu (2017). Strategies to Target Glucose Metabolism in Tumor Microenvironment on Cancer by Flavonoids. Nutrition and Cancer, 69(4); 534–554.
Zheng, X., H. Jiang, J. Xie, Z. Yin, and H. Zhang (2013). Highly Efficient and Green Synthesis of Flavanones and Tetrahydroquinolones. Synthetic Communications, 43(7); 1023–1029.
Authors
Ramadhini, R. A., Danova, A., & Roswanda, R. (2025). Intramolecular Oxa-Michael Cyclization of 2’-Hydroxychalcones for the Synthesis of Flavanones: A Comparative Study. Science and Technology Indonesia, 10(4), 1169–1178. https://doi.org/10.26554/sti.2025.10.4.1169-1178
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