Reaction three-component Biginelli

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... 

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]. 

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). 

Dong F, Zhang DZ, Liu ZL (2010) One-pot three-component Biginelli-type reaction catalyzed by ionic liquids in aqueous media. Monatsh fUr Chem 141 419-423... 

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. 

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. ... 

BR0NSTED BASE-CATALYZED ONE-POT THREE-COMPONENT BIGINELLI-TYPE REACTIONS... 

Table 13.23 Catalytic asymmetric three component biginelli reactions promoted by chiral Yb catalyst...

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. 

I. Sehout, R. Boulcina, B. Boumormd, F. Berree, B. Carboni, A. Debache, Ascorbic acid-catalyzed one-pot three-component Biginelli reaction a practical and green approach towards synthesis of 3,4-dlhydropyrimldin-2(lfl)-ones/thiones, Lett. Org. Chem. 10 (2013) 463 67. 

Scheme 22.18 [HPro]2S04-catalyzed three-component Biginelli reactions.

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],... 

Using a similar format, dihydropyrimidines were obtained in a microwave-expedited version of the classical Biginelli three-component condensation (Scheme 12.24) [73]. Neat mixtures of /i-kctocstcrs, aryl aldehydes and (thio)ureas with polyphosphate ester (PPE) as reaction mediator were irradiated in a domestic microwave oven for 1.5 min. The desired dihydropyrimidines were obtained in 61-95% yield after aqu-... 

Biginelli reactions, using microwave irradiation, 16 579-580 Biginelli three-component condensation products, 16 550... 

When R2 substituent is flourocontaining alkyl group, the transformation 17 18 becomes hindered and its proceeding requires some special methods. For example, in [48] Biginelli-like cyclocondensations based on three-component treatment of 3-amino-l,2,4-triazole or 5-aminotetrazole with aldehydes and fluorinated 1,3-dicarbonyl compounds were investigated. It was shown that the reaction can directly lead to dihydroazolopyrimidines 20, but in the most cases intermediate tetrahydroderivatives 19 were obtained (Scheme 10). To carry out dehydration reaction, refluxing of tetrahydroderivatives 19 in toluene in the presence of p-TSA with removal of the liberated water by azeotropic distillation was used. The same situation was observed for the linear reaction proceeding via the formation of unsaturated esters 21. 

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]. 

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 . 

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