The Three-Component Biginelli Reaction

Knoevenagel mechanism, evidenced by thedetectionofthe intermediate 136a (detected as its protonated form 143a) after a 24 h reaction period, seems to be feasible but too slow 

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De Souza R, da Penha ET, Milagre HMS, Garden SJ, Esteves PM, Eberlin MN, Antunes OAC (2009) The three-component Biginelli reaction a combined experimental and theoretical mechanistic investigation. Chem Eur J 15 9799-9804... 

In a number of multicomponent condensation reactions, TMSCl has also been utilized to inprove the yield or efficacy of the desired product, or is directly incorporated into the final molecules. Examples include the s)fnthesis of Al-aryl-3-arylamino acids from a three-component reaction of phenols, glyoxylates, and anilines, preparation of 2,4,5-trisuhstituted oxazoles, or 4-cyanooxazoles, and the three-component Biginelli reaction (eq 92) and Biginelli-like Mannich reaction of carhamates, aldehydes, and ketones. 

The manufacturer of the commercially available Syrris Africa system [14] reports on the optimization of several multicomponent reactions Passerini, Biginelli and Ugi reaction. However, only the details of the three-component Passerini reaction were available [15]. 

Solvent-free three-component Biginelli reactions of 2-phenyl-l,3-oxazol-5-one, D-xylose/D-glucose and (thio)ureas 136 in the presence of Ce2(S04)3 salt (10%) under microwave irradiation produced perhydropyrido[l,2-c] pyrimidines 137 and 138 with 94% trans diastereoselectivity (Scheme 3). In the absence of Ce3+ salt no reaction occurred, and without microwave irradiation using conventional heating at 90 °C yields were significantly lower (39-51%) even for longer reaction times (3-5 h). If shorter reaction periods (4-7 min) was applied addition products 139 could be isolated, which then were converted to pyrido[l,2-c]pyrimidines 137 (X = O, R = H) and 138 (X = S, R = Ph) (07SL1905). 

A tabular literature survey with about 650 entries listing all dihydropyrimidine derivatives of type 14 prepared via three-component Biginelli reactions up to the year 2001 has been published [7]. 

Novel boron-containing dihydropyrimidinones 159 are synthesized using boronic acid substituted aldehydes 158, a ketoester and a urea in the traditional three-component Biginelli reaction in the absence of an additional Lewis acid, as the boronic acid group itself acts as a Lewis acid (Scheme 60) (05CJC2052). 

Three-component Condensation Reactions. Cu(OTf)2 catalyzes the three-component syuithesis of 3,4-dihydropyrimidin-2(l/ -ones (eq 31) in high yields via condensation of aldehydes with keto esters and ureas. For the three-component Biginelli condensation involving benzaldehyde, urea, and ethyl acetoac-etate, the reaction proceeds with a low catalyst concentration [0.5 mol % of Cu(OTf)2] at ambient temperature, yielding 3,4-dihydropyrimidin-2(l/ -one. ... 

The DHPMs should be synthesized in solution using standard Biginelli three-component condensation reaction mixtures. Although microwave-assisted Biginelli reactions have been published under solvent-free conditions,46 50 we felt that such methods would... 

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). 

Conversely, neutral and ambient conditions lead to the formation of the kineti-cally controlled Biginelli product 144 (eight examples, 51-70%). The authors found that sonication was required to obtain the final product, since simple stirring of the three components at rt did not result in any desired reaction. They explained this observation by the improved mass transfer through cavitation phenomena. This reaction presumably involves intermediate 143. 

Dong and cowoikers have also reported the preparation of some dicationic acidic ionic liquids as halogen-free TSILs that bear dialkane sulfonic acid groups in acyclic diamine cations (Fig. 12.71) [43] and their application as catalysts in a one-pot three-component Biginelli-type reaction (Fig. 12.72). 

This catalyst also promoted a three-component coupling reaction under improved protocol conditions for the Biginelli reaction. The recovered catalyst, which is washed with acetonitrile and dried at 150°C/0.5 Torr for 1.5 h, can be reused four successive times (Scheme 5.22) [123]. 

A number of high-yielding variants of the traditional three-component Biginelli condensation employing a variety of catalysts, reagents, and reaction conditions/techniques have been developed (09M115) these are beyond the scope of this review. Reference is made to some excellent reviews (Tables 1-4). However, scaffold decoration of Biginelli DHPMs is presented by us. 

Dihydropyridines can be prepared via the three-eomponent coupling of cinnamaldehyde, aniline and p-keto esters under solvent-free conditions by means again of L-Pro as catalyst in the transformation. The three-component reaction of 1,3-indanedione, isatins and enamines as the nucleophiles is also possible in the presence of L-Pro for the one-pot synthesis of highly functionalised spirooxindoles derivatives. While only some examples are highlighted here, ° ° the possibilities of L-Pro in multicomponent reactions are tremendous. It has also shown good catalytie activity in classic multicomponent reactions such as Biginelli reactions and Hantzsch dihydropyridine synthesis. 

Zhidovinova et al. (2003) showed that the classical Biginelli reaction (EtOH and HCl) (Biginelli 1893) is accelerated by a factor of more than 40 times as a result of ultrasonic irradiation. The three-component reaction among aldehydes (96), ethyl ace-toacetate (97), and urea (98) or thiourea (99) in the presence of a catalytic amount of HCl was completed within 2-5 min at room tanperature, and dihydropyrimidin-2-ones (thiones) (DHPM) (100) were obtained in excellent yields (90%-95%) (Scheme 8.30). 

Sc(OTf)3 was found to be a versatile catalyst for multicomponent reactions such as Biginelli condensation [55] for the three-component synthesis of a-amino phosphonates [56], and benzothiazoline [57, 58]. A Catalytic amount of Sc(OTf)3 was sufficient for condensation of o-phenylenediamines with ketones to give 2,3-dihydro-IH-1,5-benzodiazepine derivatives in excellent yields under solvent-free conditions (Scheme 12.26) [59]. 

Abstract The Biginelli reaction, a three-component cyclocondensation reaction, is an important member of the multicomponent reaction (MCR) family. The Biginelli reaction is so efficient and shares many similar properties as the recent click reactions. In this chapter, we summarised the current applications of the Biginelli reaction in polymer chemistry including polymer coupling, post polymer modification, and new functional polymer synthesis. We expect this old reaction (>120 years) can draw attention from polymer chemists and play new roles in the polymer science. 

The Biginelli reaction is a member of the multicomponent reaction (MCR) family. It is a three-component cyclocondensation reaction using aldehyde, 1,3-dione, and urea as building blocks and is particularly useful for synthesis of 3,4-dihydro-2(//)-pyrimidinone (DHPM) compounds in one pot (Scheme 1). 

Urea and its derivatives can form imines when treated with aldehydes. In the presence of [3-ketoesters, these imines are subject to nucleophilic attack followed by intramolecular imine formation. This three-component transformation is known as the Biginelli reaction [94]. The resulting products are dihydropyrimidi-nones, which are compounds of high importance in medicinal chemistry [95]. In 2006, Gong and coworkers reported the first organocatalytic Biginelli reactions. Several different aromatic aldehydes 186, ]3-ketoesters 188, and (thio)urea (187) were successfully coupled in the presence of chiral phosphoric acid catalyst 99a (Scheme 42.43). Whereas aromatic aldehydes delivered the desired Biginelli... 

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