Biginelli dihydropyrimidines

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). 

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... 

Fig. 4.3 I solated yields of Biginelli dihydropyrimidine products (Scheme 4.24 a) in different reaction vessels of a 36 vessel rotor (Fig. 3.7). Outer ring, vessels 1-20 inner ring, vessels 21-36). Aldehydes a, benzaldehyde b, 2-hydroxybenzaldehyde c, 3,4-dimethoxybenzaldehyde d, 3-nitrobenzaldehyde e, 2-chlorobenzaldehyde f, 4-(N,N-dimethylamino)benzaldehyde. Adapted from [85],...

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.

For example, it was reported in several independent articles that multicomponent treatment of 5-amino-3-methylpyrazles with 1,3-cyclohexandiones and aldehydes under refluxing in EtOH [82, 83], in DMF with methanol [84], or with application of continuous-flow microwave-assisted procedure in DMSO [85] yielded exclusively pyrazoloquinolinones 50 (Scheme 23). On the other hand, the treatment of 3-unsub-stituted 5-aminopyrazoles with cyclic p-diketones or ketosulfones gave mixtures of Hantzsch dihydropyridines 51 and Biginelly dihydropyrimidines 52 in different ratios [86]. 

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. 

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. 

Hosseini-Sarvaria (2011b) reported the synthesis of quinoline derivatives (60) by the condensation of 2-aminoaryl ketones (58) with methylene carbonyl compounds (59) catalyzed by nanoflake ZnO as a reusable heterogeneous catalyst under solvent-free conditions involving Friedlander heteroannulation (Scheme 9.14). The employed catalyst was synthesized from zinc acetate dihydrate and urea. It constitutes a simple, environmentally benign, and cost-effective method for the synthesis of quinolines. Tamaddon and Moradi (2013) reported the application of nano-ZnO as a reusable heterogeneous catalyst for the synthesis of Biginelli dihydropyrimidines... 

Kappe CO (2000) Recent Advances in the Biginelli Dihydropyrimidine Synthesis. New Tricks from an Old Dog. Acc Chem Res 33 879-888... 

Kappe CO (2000) Recent advances in the biginelli dihydropyrimidine synthesis. New tricks... 

Another simple modification of the Biginelli dihydropyrimidines synthesis was developed, using as an efficient Lewis acid, Bi0Cl04 xH20. The products are obtained in high yields and the reaction times were short [33b]. 

Kappe CO (1993) 100 years of the Biginelli dihydropyrimidine synthesis. Tetrahedron... 

Wipl995 Wipf, P. and Cunningham, A., A Solid Phase Protocol of the Biginelli Dihydropyrimidine Synthesis Suitable for Combinatorial Chemistry, Tetrahedron Lett., 36 (1995) 7819-7822. 

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