The synthesis of dihydropyrimidinones is of interest due to their biological activities. A common method for their synthesis is the Biginelli reaction, which is a one-pot multicomponent reaction of an aldehyde, urea and a β-ketoester. The Biginelli reaction is typically catalyzed by a Br?nsted or Lewis acid. However, many of these catalysts, such as BF3?Et2O and AlCl3 are corrosive and/or toxic. Herein, we report the iron(II) triflate-catalyzed (10.0 mol%, 22 - 24 h) synthesis of dihydropyrimidinones via the Biginelli reaction in isopropanol as a solvent. The reaction is also reported in two other solvents, benzotrifluoride (a useful replacement for CH2Cl2) and 2-methyltetrahydrofuran, a bio-derived solvent. Iron(II) salts are attractive catalysts because of their low cost, low toxicity, and ease of handling.
References
[1]
Atwal, K.S., Swanson, B.N., Unger, S.E., Floyd, D.M., Moreland, S., Hedberg, A., et al. (1991) Dihydropyrimidine Calcium Channel Blockers. 3. 3-Carbamoyl-4-aryl-1,2,3,4-tetrahydro-6-methyl-5-pyrimidinecarboxylic Acid Esters as Orally Effective Antihypertensive Agents. Journal of Medicinal Chemistry, 34, 806-811. https://doi.org/10.1021/jm00106a048
[2]
Mayer, T.U., Kapoor, T.M., Haggarty, S.J., King, R.W., Schreiber, S.L. and Mitchison, T.J. (1999) Small Molecule Inhibitor of Mitotic Spindle Bipolarity Identified in a Phenotype-Based Screen. Science, 286, 971-974. https://doi.org/10.1126/science.286.5441.971
[3]
Stefani, H.A., Oliveira, C.B., Almeida, R.B., Pereira, C.M.P., Braga, R.C., Cella, R., et al. (2006) Dihydropyrimidin-(2H)-ones Obtained by Ultrasound Irradiation: A New Class of Potential Antioxidant Agents. European Journal of Medicinal Chemistry, 41, 513-518. https://doi.org/10.1016/j.ejmech.2006.01.007
[4]
Brands, M., Endermann, R., Gahlmann, R., Krüger, J. and Raddatz, S. (2003) Dihydropyrimidinones—A New Class of Anti-Staphylococcal Antibiotics. Bioorganic & Medicinal Chemistry Letters, 13, 241-245. https://doi.org/10.1016/s0960-894x(02)00880-6
[5]
Biginelli, P. (1893) Derivati aldeidureidici degli eteri acetile dossal-acetico. Gazzetta Chimica Italiana, 23, 360-413.
[6]
Touré, B.B. and Hall, D.G. (2009) Natural Product Synthesis Using Multicomponent Reaction Strategies. Chemical Reviews, 109, 4439-4486. https://doi.org/10.1021/cr800296p
[7]
Tietze, L.F. (1996) Domino Reactions in Organic Synthesis. Chemical Reviews, 96, 115-136. https://doi.org/10.1021/cr950027e
[8]
Kappe, C.O. (2000) Recent Advances in the Biginelli Dihydropyrimidine Synthesis. New Tricks from an Old Dog. Accounts of Chemical Research, 33, 879-888. https://doi.org/10.1021/ar000048h
[9]
Kappe, C.O. (1997) A Reexamination of the Mechanism of the Biginelli Dihydropyrimidine Synthesis. Support for an n-Acyliminium Ion Intermediate. The Journal of Organic Chemistry, 62, 7201-7204. https://doi.org/10.1021/jo971010u
[10]
Ahmed, B., Khan, R.A., Habibullah, and Keshari, M. (2009) An Improved Synthesis of Biginelli-Type Compounds via Phase-Transfer Catalysis. Tetrahedron Letters, 50, 2889-2892. https://doi.org/10.1016/j.tetlet.2009.03.177
[11]
Chitra, S. and Pandiarajan, K. (2009) Calcium Fluoride: An Efficient and Reusable Catalyst for the Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones and Their Corresponding 2(1H)thione: An Improved High Yielding Protocol for the Biginelli Reaction. Tetrahedron Letters, 50, 2222-2224. https://doi.org/10.1016/j.tetlet.2009.02.162
[12]
Nandurkar, N.S., Bhanushali, M.J., Bhor, M.D. and Bhanage, B.M. (2007) Y(NO3)3·6H2O: A Novel and Reusable Catalyst for One Pot Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones under Solvent-Free Conditions. Journal of Molecular Catalysis A: Chemical, 271, 14-17. https://doi.org/10.1016/j.molcata.2007.02.021
[13]
Adapa, S.R., Varala, R. and Alam, M.M. (2002) Bismuth Triflate Catalyzed One-Pot Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones: An Improved Protocol for the Biginelli Reaction. Synlett, No. 1, 0067-0070. https://doi.org/10.1055/s-2003-36216
[14]
Paraskar, A.S., Dewkar, G.K. and Sudalai, A. (2003) Cu(OTf)2: A Reusable Catalyst for High-Yield Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones. Tetrahedron Letters, 44, 3305-3308. https://doi.org/10.1016/s0040-4039(03)00619-1
[15]
Ranu, B.C., Hajra, A. and Jana, U. (2000) Indium(III) Chloride-Catalyzed One-Pot Synthesis of Dihydropyrimidinones by a Three-Component Coupling of 1,3-Dicarbonyl Compounds, Aldehydes, and Urea: An Improved Procedure for the Biginelli Reaction. The Journal of Organic Chemistry, 65, 6270-6272. https://doi.org/10.1021/jo000711f
[16]
Bigi, F., Carloni, S., Frullanti, B., Maggi, R. and Sartori, G. (1999) A Revision of the Biginelli Reaction under Solid Acid Catalysis. Solvent-Free Synthesis of Dihydropyrimidines over Montmorillonite KSF. Tetrahedron Letters, 40, 3465-3468. https://doi.org/10.1016/s0040-4039(99)00424-4
[17]
Tamaddon, F., Razmi, Z. and Jafari, A.A. (2010) Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones and 1,4-Dihydropyridines Using Ammonium Carbonate in Water. Tetrahedron Letters, 51, 1187-1189. https://doi.org/10.1016/j.tetlet.2009.12.098
[18]
Debache, A., Amimour, M., Belfaitah, A., Rhouati, S. and Carboni, B. (2008) A One-Pot Biginelli Synthesis of 3,4-Dihydropyrimidin-2-(1H)-ones/thiones Catalyzed by Triphenylphosphine as Lewis Base. Tetrahedron Letters, 49, 6119-6121. https://doi.org/10.1016/j.tetlet.2008.08.016
[19]
Shen, Z.-L., Xu, X.-P. and Ji, S.-J. (2010) Br？nsted Base-Catalyzed One-Pot Three-Component Biginelli-Type Reaction: An Efficient Synthesis of 4,5,6-Triaryl-3,4-dihydropyrimidin-2(1H)-one and Mechanistic Study. The Journal of Organic Chemistry, 75, 1162-1167. https://doi.org/10.1021/jo902394y
[20]
Pandey, J., Anand, N. and Tripathi, R.P. (2009) L-Proline Catalyzed Multicomponent Reaction of 3,4-Dihydro-(2H)-pyran, Urea/Thiourea, and Aldehydes: Diastereoselective Synthesis of Hexahydropyrano Pyrimidinones (Thiones). Tetrahedron, 65, 9350-9356. https://doi.org/10.1016/j.tet.2009.09.002
[21]
Heravi, M.M., Moradi, R., Mohammadkhani, L. and Moradi, B. (2018) Current Progress in Asymmetric Biginelli Reaction: An Update. Molecular Diversity, 22, 751-767. https://doi.org/10.1007/s11030-018-9841-4
[22]
Baruah, M.J., Dutta, R., Zaki, M.E.A. and Bania, K.K. (2024) Heterogeneous Iron-Based Catalysts for Organic Transformation Reactions: A Brief Overview. Molecules, 29, Article No. 3177. https://doi.org/10.3390/molecules29133177
[23]
Lu, J. and Ma, H. (2000) Iron(III)-Catalyzed Synthesis of Dihydropyrimidinones: Improved Conditions for the Biginelli Reaction. Synlett, 2000, 63-64. https://doi.org/10.1055/s-2000-6469
[24]
Krishna, T., Laxminarayana, E. and Kalita, D. (2020) FeF3 as a Green Catalyst for the Synthesis of Dihydropyrimidines via Biginelli Reaction. European Journal of Chemistry, 11, 206-212. https://doi.org/10.5155/eurjchem.11.3.206-212.1992
[25]
Adibi, H., Samimi, H.A. and Beygzadeh, M. (2007) Iron(III) Trifluoroacetate and Trifluoromethanesulfonate: Recyclable Lewis Acid Catalysts for One-Pot Synthesis of 3,4-Dihydropyrimidinones or Their Sulfur Analogues and 1,4-Dihydropyridines via Solvent-Free Biginelli and Hantzsch Condensation Protocols. Catalysis Communications, 8, 2119-2124. https://doi.org/10.1016/j.catcom.2007.04.022
[26]
Starcevich, J.T., Laughlin, T.J. and Mohan, R.S. (2013) Iron(III) Tosylate Catalyzed Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones/thiones via the Biginelli Reaction. Tetrahedron Letters, 54, 983-985. https://doi.org/10.1016/j.tetlet.2012.12.032
[27]
Iron Fluoride (FeF3). https://pubchem.ncbi.nlm.nih.gov/compound/Iron-fluoride-_FeF3#section=2D-Structure
[28]
Phukan, M., Kalita, M.K. and Borah, R. (2010) A New Protocol for Biginelli (or like) Reaction under Solvent-Free Grinding Method Using Fe(NO3)3？9H2O as Catalyst. Green Chemistry Letters and Reviews, 3, 329-334. https://doi.org/10.1080/17518253.2010.487841
[29]
Rajni, Sahil, Raghav, N., Bendi, A. and Rao, G.B.D. (2026) Sustainable Biginelli Chemistry: Indian Contributions to Green Multicomponent Synthesis. Discover Chemistry, 3, Article No. 172. https://doi.org/10.1007/s44371-026-00582-z
[30]
Manche？o, O.G., Dallimore, J., Plant, A. and Bolm, C. (2009) Iron(II) Triflate as an Efficient Catalyst for the Imination of Sulfoxides. Organic Letters, 11, 2429-2432. https://doi.org/10.1021/ol900660x
[31]
Bonnamour, J. and Bolm, C. (2011) Iron(II) Triflate as a Catalyst for the Synthesis of Indoles by Intramolecular C-H Amination. Organic Letters, 13, 2012-2014. https://doi.org/10.1021/ol2004066
[32]
Mayer, A.C., Salit, A. and Bolm, C. (2008) Iron-Catalysed Aziridination Reactions Promoted by an Ionic Liquid. Chemical Communications, No. 45, 5975-5977. https://doi.org/10.1039/b813655f
[33]
Kumawat, S. and Natte, K. (2024) Iron(II) Triflate as a Photocatalyst for Trifluoromethylation of Functionalized Arenes under Blue LED Light: Access to Bioactive Compounds. Journal of Catalysis, 434, Article ID: 115506. https://doi.org/10.1016/j.jcat.2024.115506
[34]
Prat, D., Wells, A., Hayler, J., Sneddon, H., McElroy, C.R., Abou-Shehada, S., et al. (2016) CHEM21 Selection Guide of Classical-and Less Classical-Solvents. Green Chemistry, 18, 288-296. https://doi.org/10.1039/c5gc01008j
[35]
Ogawa, A. and Curran, D.P. (1997) Benzotrifluoride: A Useful Alternative Solvent for Organic Reactions Currently Conducted in Dichloromethane and Related Solvents. The Journal of Organic Chemistry, 62, 450-451. https://doi.org/10.1021/jo9620324
[36]
Maul, J.J., Ostrowski, P.J., Ublacker, G.A., Linclau, B. and Curran, D.P. (1999) Benzotrifluoride and Derivatives: Useful Solvents for Organic Synthesis and Fluorous Synthesis. In: Knochel, P., Ed., Modern Solvents in Organic Synthesis, Springer, 79-105. https://doi.org/10.1007/3-540-48664-x_4
[37]
Pace, V., Hoyos, P., Castoldi, L., Domínguez de María, P. and Alcántara, A.R. (2012) 2-Methyltetrahydrofuran (2-MeTHF): A Biomass-Derived Solvent with Broad Application in Organic Chemistry. ChemSusChem, 5, 1369-1379. https://doi.org/10.1002/cssc.201100780
[38]
Fu, N.-Y., Yuan, Y.-F., Cao, Z., Wang, S.-W., Wang, J.-T. and Peppe, C. (2002) Indium(III) Bromide-Catalyzed Preparation of Dihydropyrimidinones: Improved Protocol Conditions for the Biginelli Reaction. Tetrahedron, 58, 4801-4807. https://doi.org/10.1016/s0040-4020(02)00455-6
[39]
Li, P., Regati, S., Butcher, R.J., Arman, H.D., Chen, Z., Xiang, S., et al. (2011) Hydrogen-Bonding 2D Metal-Organic Solids as Highly Robust and Efficient Heterogeneous Green Catalysts for Biginelli Reaction. Tetrahedron Letters, 52, 6220-6222. https://doi.org/10.1016/j.tetlet.2011.09.099
[40]
Ma, Y., Qian, C., Wang, L. and Yang, M. (2000) Lanthanide Triflate Catalyzed Biginelli Reaction. One-Pot Synthesis of Dihydropyrimidinones under Solvent-Free Conditions. The Journal of Organic Chemistry, 65, 3864-3868. https://doi.org/10.1021/jo9919052
[41]
Ghosh, R., Maiti, S. and Chakraborty, A. (2004) In(OTf)3-Catalysed One-Pot Synthesis of 3,4-Dihydropyrimidin-2(lH)-ones. Journal of Molecular Catalysis A: Chemical, 217, 47-50. https://doi.org/10.1016/j.molcata.2004.02.025
![](\"https://html.scirp.org/file/5500509-rId13.jpeg?20260526043912\")
