This acid-catalyzed, three-component reaction between an aldehyde, a ß-ketoester and urea constitutes a rapid and facile synthesis of dihydropyrimidones, which are interesting compounds with a potential for pharmaceutical application.
Mechanism of the Biginelli Reaction
The first step in the mechanism is believed to be the condensation between the aldehyde and urea, with some similarities to the Mannich Condensation. The iminium intermediate generated acts as an electrophile for the nucleophilic addition of the ketoester enol, and the ketone carbonyl of the resulting adduct undergoes condensation with the urea NH2 to give the cyclized product.
Combined Role of the Asymmetric Counteranion-Directed Catalysis (ACDC) and Ionic Liquid Effect for the Enantioselective Biginelli Multicomponent Reaction
H. G. O. Alvim D. L. J. Pinheiro, V. H. Carvalho-Silva, M. Fioramonte, F. C. Gozzo, W. A. da Silva, G. W. Amarante, B. A. D. Neto, J. Org. Chem., 2018, 83, 12143-12153.
By using Yb(OTf)3 as a catalyst and under solvent-free reaction conditions, the yields of the one-pot Biginelli reaction can be increased while the reaction time was shortened. In addition, the catalyst can be easily recovered and reused. It not only led to economical automation but also reduces hazardous pollution to achieve environmentally friendly processes.
Y. Ma, C. Qian, L. Wang, M. Yang, J. Org. Chem., 2000, 65, 3864-3868.
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
B. C. Ranu, A. Hajra, U. Jana, J. Org. Chem., 2000, 65, 6270-6272.
A New Substrate for the Biginelli Cyclocondensation: Direct Preparation of 5-Unsubstituted 3,4-Dihydropyrimidin-2(1H)-ones from a β-Keto Carboxylic Acid
J. C. Bussolari, P. A. McDonell, J. Org. Chem., 2000, 65, 6777-6779.
N-Substituted Ureas and Thioureas in Biginelli Reaction Promoted by Chlorotrimethylsilane: Convenient Synthesis of N1-Alkyl-, N1-Aryl-, and N1,N3-Dialkyl-3,4-Dihydropyrimidin-2(1H)-(thi)ones
S. V. Ryabukhin, A. S. Plaskon, E. N. Ostapchuk, D. M. Volochnyuk, A. A. Tolmachev, Synthesis, 2007, 417-427.
Organocatalytic Application of Ionic Liquids: [bmim][MeSO4] as a Recyclable Organocatalyst in the Multicomponent Reaction for the Preparation of Dihydropyrimidinones and -thiones
S. R. Roy, P. S. Jadhavar, K. Seth, K. K. Sharma, A. K. Chakraborti, Synthesis, 2011, 2261-2267.
Ferric chloride/tetraethyl orthosilicate as an efficient system for synthesis of dihydropyrimidinones by Biginelli reaction
I. Cepanec, M. Litvić, A. Bartolinčić, M. Lovrić, Tetrahedron, 2005, 61, 4275-4280.
Ruthenium(III) Chloride-Catalyzed One-Pot Synthesis of 3,4-Dihydropyrimidin-2-(1H)-ones under Solvent-Free Conditions
J. H. Schauble, E. A. Trauffer, P. P. Deshpande, R. D. Evans, Synthesis, 2005, 1333-1339.