Dihydropyrimidine synthesis

The Biginelli reaction involves an one-pot reaction between aldehyde 1, 1,3-dicarbonyl 2, and urea 3a or thiourea 3b in the presence of an acidic catalyst to afford 3,4-dihydropyrimidin-2(l//)-one (DHPM) 4. This reaction is also referred to as the Biginelli condensation and Biginelli dihydropyrimidine synthesis. It belongs to a class of transformations called multi-component reactions (MCRs). 

Kappe, C.O. (2000) Recent Advances in the BigineUi Dihydropyrimidine Synthesis. New Tricks from an Old Dog. Accounts of Chemical Research, 33, 879-888. 

A classical non-isocyanide-based multicomponent process is the Biginelli dihydropyrimidine synthesis from 3-keto esters, aldehydes and urea or thiourea [63], The transformation was first reported in 1893 [64], but during the early part of the... 

More recently [29] the microwave-mediated Biginelli dihydropyrimidine synthesis (Eq. 2) was reinvestigated using a purpose-built commercial microwave reactor with on-line temperature, pressure, and microwave power control. Transformations performed with microwave heating at atmospheric pressure in ethanol solution resulted in neither a rate increase nor an increase in yield when the temperature was identical to that used for conventional thermal heating. The only significant rate and yield enhancements were found when the reaction was performed under solvent-free conditions in an open system. 

Scheme 12.24 Microwave-assisted Biginelli dihydropyrimidine synthesis.

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 . 

Wipf, P., Cunningham, A. A solid phase protocol of the Biginelli dihydropyrimidine synthesis suitable for combinatorial chemistry. Tetrahedron Lett. 1995, 36, 7819-7822. 

Barbituric acids, 5-ylidene derivatives of 83WCH479. Dihydropyrimidines, synthesis, structure, tautomerism of 86H(24)1433, Hydrazinopyrimidines, advances in chemistry of 82KGS579. 

Multicomponent reactions, although fashionable these days, have in fact a long history. Indeed, many important reactions such as the Strecker amino acid synthesis (1850)[6], the Hantsch dihydropyridine synthesis (1882) [7], the Biginelli dihydropyrimidine synthesis (1891)[8], the Mannich reaction (1912) [9], and the isocyanide-based Passerini reactions (1921) (Scheme 5.1) [10], among others, are all... 

Recent advances in the Biginelly dihydropyrimidine synthesis 00ACR879. 

TheBiginelli dihydropyrimidine synthesis o is another relevant multicomponent condensation reaction that has been recently adapted to the solid phase by Wipf et to prepare a small library... 

The Biginelli reaction A green perspective 12COC507. Dihydropyrimidines (synthesis, tautomerism, reactivity, skeleton types, including mono-, hi-, tri-, tetracyclic, bicyclo-, and spirocompounds, and biological activities) 13H(87)1441. 

---