Biginelli synthesis of dihydropyrimidines

The ever-popular Biginelli synthesis of dihydropyrimidines, by condensation of urea with a keto ester and an aldehyde, and variations on it, has been applied in a number of areas. 

Substantial MW rate enhancements have been reported in the Biginelli synthesis of dihydropyrimidines [50, 51] under homogeneous conditions. The synthesis involves a one-pot cyclocondensation of a /i-ketoester with an aryl aldehyde and urea or thiourea in the presence of a catalytic amount of HC1 in ethanol solution. An example of this synthesis is shown in Scheme 4.17. 

The microwave-assisted Biginelli synthesis of dihydropyrimidine was investigated in open vessels as well as sealed reaction vessels. The reaction carried out at atmospheric pressure under microwave irradiation in a solution showed no rate increase compared to... 

An MS investigation of the three-component base-mediated Biginelli synthesis of dihydropyrimidines has found evidence for a hemiacetal intermediate (117), but no sign of a bis-ureide (118). ° A prolinamide gives up to 99% ee in Biginelli cyclocondensations of urea, aldehyde, and ethyl acetoacetate. ... 

An important multicomponent transformation for the synthesis of dihydropyrimidines is the Biginelli reaction, which involves the acid-catalyzed condensation... 

Scheme 6.246 Biginelli three-component synthesis of dihydropyrimidines.

Bahrami K, Khodaei MM, Farrokhi A (2009) Highly efficient solvent-free synthesis of dihydropyrimidinones catalyzed by zinc oxide. Synth Commun 39 1801-1808 74. Gross GA, Wurziger H, Schober A (2006) Solid-phase synthesis of 4,6-diaryl-3,4-dihydro-pyrimidine-2(lH)-one-5-carboxylic acid amide derivatives a Biginelli three-component-condensation protocol based on immobilized beta-ketoamides. J Comb Chem 8 153-155 Desai B, Dallinger D, Kappe CO (2006) Microwave-assisted solution phase synthesis of dihydropyrimidine C5 amides and esters. Tetrahedron 62 4651 664 Kumar A, Maurya RA (2007) An efficient bakers yeast catalyzed synthesis of 3,4-dihydro-pyrimidin-2-(lH)-ones. Tetrahedron Lett 48 4569-4571 77. Zalavadiya P, Tala S, Akbari J, Joshi H (2009) Multi-component synthesis of dihydropyrimidines by iodine catalyst at ambient temperature and in-vitro anti mycobacterial activity. Arch Pharm 342 469-475... 

Huang YJ, Yang FY, Zhu CJ (2005) Highly enantioseletive biginelli reaction using a new chiral ytterbium catalyst Asymmetric synthesis of dihydropyrimidines. J Am Chem Soc 127 16386-16387... 

The Biginelli procedure is amenable to microwave technology, and several microwave-assisted procedures have now been published <2002SC147, 2004SL235>. An example is the microwave-assisted solution-phase synthesis of dihydropyrimidine C-5 amides and esters 723 using ytterbium triflate as the Lewis acid catalyst <2006T4651>. 

Yaddav, J.S., Reddy, B.V.S., Reddy, E.J. and Ramalingam, T., Microwave-assisted efficient synthesis of dihydropyrimidines improved high yielding protocol for the Biginelli reaction,/. Chem.Res. (S), 2000,354-355. 

Biginelli synthesis of 3,4-dihydropyrimidin-2( 1 //)-oncs (99) from an aldehyde, a /3-diketone, and urea is catalysed by L-proline methyl ester hydrochloride.276 Although evidence strongly supports an enamine mechanism, the products were essentially racemic. 

Kappe, C. O., Falsone, S. F. Synthesis and reactions of Biginelli compounds. Part 12. Polyphosphate ester-mediated synthesis of dihydropyrimidines. Improved conditions for the Biginelli reaction. Synlett 1998, 718-720. 

In 1893, Pietro Biginelli published his pioneering findings on a threereaction that has become known as the Biginelli reaction. This three-component one-pot reaction leads to the synthesis of dihydropyrimidines (130), typically via the reaction of a benzaldehyde (131), an acetoacetate (132), and a (thio)urea (133) under acid catalysis [73]. The Biginelli reaction is quite versatile since it can be performed with variations in all three components, leading therefore to a myriad of dihydropyrimidines (Scheme 3.33). 

Y. Huang, F. Yang, C. Zhu, J. Am. Chem. Soc. 2005, 127, 16386-16387. Highly enantioselective Biginelli reaction using a new chiral ytterbium catalyst asymmetric synthesis of dihydropyrimidines. 

Bigi F, Carloni S, Erullanti B, Maggi R, Sartori S (1999) A revision of the Biginelli reaction under solid acid catalysis. Solvent-free synthesis of dihydropyrimidines over montmorilion-ite KSF. Tetrahedron Lett 40 3465-3468... 

Liu Q, Pan N, Xu J, Zhang W, Kong F (2013) Microwave-assisted and iodine-catalyzed synthesis of dihydropyrimidin-2-thiones via biginelli reaction under solvent-fiee conditions. Synth Commun 43 139-146... 

D.Z. Xu, H. Li, Y. Wang, Highly enantioselective Biginelli reaction catalyzed by a simple chiral primary amine catalyst asymmetric synthesis of dihydropyrimidines. Tetrahedron 68 (2012) 7867-7872. 

W. Y. Chen, S. D. Qin and J. R. Jin, HBF4-catalyzed Biginelly Reaction One-pot synthesis of dihydropyrimidin-2(lH)-ones under solvent-free conditions . Catalysis Communications, 8(2), 123 (2007). 

In 1893 Pietro Biginelli reported the first synthesis of 4-aryl-3,4-dihydropyrimidin-2(l//)-ones (DHPMs) via an one-pot process using three components. Thus, DHPM 7 was synthesized by mixing benzaldehyde (5), ethyl acetoacetate (6), and urea (3a) in ethanol at reflux in the presence of a catalytic amount of HCl. 

As a suitable model reaction to highlight the steps necessary to successfully translate thermal conditions to microwave conditions, and to outline the general workflow associated with any microwave-assisted reaction sequence, in this section we describe the complete protocol from reaction optimization through to the production of an automated library by sequential microwave-assisted synthesis for the case of the Biginelli three-component dihydropyrimidine condensation (Scheme 5.1) [2, 3],... 

It is very important that this preparative procedure allowed selective synthesis of Biginelli-like fused dihydropyrimidines of type 69 having angular stmcture. As everyone can see from the other publications cited above in other cases, these heterocycles were usually minor reaction by-products. The third direction discovered in [97-99] led to acridinediones 70 (Scheme 30). 

Comas H, Buisson DA, Najman R, Kozielski F, Rousseau B, Lopez R (2009) Synthesis of 5-Acyl-3,4-dihydropyrimidine-2-thiones via solvent-free, solution-phase and solid-phase Biginelli procedures. Synlett 1737-1740... 

Joseph JK, Jain SL, Sain B (2006) Ion exchange resins as recyclable and heterogeneous solid acid catalysts for the Biginelli condensation an improved protocol for the synthesis of 3,4-dihydropyrimidin-2-ones. J Mol Catal A Chem 247 99-102... 

The Biginelli synthesis (Scheme 3) is an important route to dihydropyrimidines, e.g. (25),46a with many variants of the original reactants now established. The mechanism has now been re-investigated using H- and 13C-NMR.46b The first step does not appear to involve aldol condensation or a carbenium-ion intermediate rather, condensation of benzaldehyde and urea gives an A -acyliminium ion intermediate (26), which then goes on to react with ethyl acetoacetate. 

Fig. 1. Building blocks and points of diversity in the Biginelli three-component dihydropyrimidine synthesis.

In 1893, the Italian chemist Pietro Biginelli (University of Florence) for the first time reported on the acid-catalyzed cyclocondensation reaction of ethyl acetoacetate 1, benzaldehyde 2, and urea 3 [1], The reaction was carried out by simply heating a mixture of the three components dissolved in ethanol with a catalytic amount of HC1 at reflux temperature. The product of this novel one-pot, three-component synthesis that precipitated on cooling the reaction mixture was identified as 3,4-dihydropyrimidin-2(lH)-one 4 (Scheme 4.1) [2]. This reaction is nowadays referred to as the Biginelli reaction , Biginelli condensation or as the Biginelli dihydropyrimidine synthesis . 

In 1893 the Italian chemist Pietro Biginelli [2] reported the one-pot synthesis of 4-aryl-3, 4-dihydropyrimidin-2(lff)-ones (DHPMs 1) by a three-component condensation reaction of aromatic aldehydes, urea and ethylacetoacetate (Scheme 11.1). 

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