Biginelli three-component condensation

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... 

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... 

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... 

Scheme 4.17. Enantioselective variation of the Biginelli three-component condensation.

A novel solid-phase version of the Biginelli three-component condensation has been recently disclosed [359]. Since the reaction proceeds via formation of an N-acyliminium ion intermediate from the aldehyde and the urea precursors, these components were first combined and then reacted with the resin-bound fi-ketoe-ster (454). Highly loaded (2.53 mmol g ) fi-ketoester Wang resin was utilized in order to increase the amount of final product (Scheme 94). Using this strategy, eleven different dihydropyrimidones (458) have been prepared. 

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],... 

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). 

Legeay JC, Eynde JJV, Toupet L et al (2007) A three-component condensation protocol based on ionic liquid phase bound acetoacetate for the synthesis of Biginelli 3,4-dihydropyr-imidine-2(l//)-ones. Arkivoc (iii) 13-28... 

A similar strategy tvas originally used for the Biginelli condensation reaction to synthesize a set of pyrimidinones (65-95%) in a household MW oven [196], an approach that has been successfully applied to combinatorial synthesis [197]. Yet another example is the convenient synthesis of pyrroles (60-72%) on silica gel using readily available enones, amines, and nitro compounds [198]. Three-component condensation of an aldehyde, urea or thiourea, and a dicarbonyl com-... 

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 ability of bismuth(III) nitrate pentahydrate as effective catalyst in the Biginelli reaction was reported, while the oxidative property of this salt has been also investigated. By combining both of these characteristics, the authors developed a convenient alternative method for the Biginelli reaction. The direct synthesis of 3,4-dihydropyrimidin-2(lH)-ones by three-component condensation in one pot, using benzyl halides in place of aldehydes in the presence of bismuth nitrate pentahydrate in tetrabutylammonium fluoride (TBAF), afforded the products in good to excellent yields. Some chemoselectivity was observed, the aliphatic halides gave less than 30% of the respective dihydropyrimidinones under the present reaction conditions (Equation 12) [33a]. 

Apart from the Biginelli reaction, several additional three-component condensations are worth mentioning in this section. In particular, a transformation closely related to Biginelli reaction was described by Shermolovich and coworkers, namely, reaction of p-ketophosphonates 946, urea and orthoformates, which leads to adducts 947 (Scheme 200) [571], The corresponding aromatic compounds 948 were not isolated, presumably due to high electrophilicity of C=N bond in their molecules. Evidently, the reaction occurs via intermediate formation of 946, which has been reported by same scientists in the reaction of 3-arylsulfonyl-l,l,l-trifluoropiopan-2-ones 944 with orthoformates [591]. 

The reaction of dihydropyrimidine-2(lH)-thione (propylenethiourea) 1 with a-halocarboxylic acids gives only the bicyclic thiazolo[3,2-a]pyrimidine. The most convenient procedme for the synthesis of 3,4-dihydropyrimidine-2(l//)-thiones (known as the Biginelli reaction) is based on one-pot three-component condensation of aldehydes with P-keto esters and thiomea. Thiazolopyrimidine derivatives (3, Scheme 1) were obtained by a simple one-pot condensation reaction of 1 and 2-bromopropionic acid (2, R3 = H, bromoacetic acid (2, R3 = H, CH3) imder microwave irradiation and conventional conditions [12, 13]. 

Kappe et al. (103,104) approached dihydropyrimidines, a potent group of calcium channel modulators, through the use of an isomiinchnone-type cyclization. Kappe prepared the cyclization precursor 195 in the course of a three component Biginelli condensation process (Scheme 4.49). 

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 . 

The classical Biginelli synthesis is a one-pot condensation using P-dicarbonyl compounds with aldehydes (aromatic and aliphatic ones) and urea or thiourea in ethanol solution containing catalytic amounts of acid. Peng et al. for the first time reported a novel method for the synthesis of dihydropyrimidinones by three-component Biginelli condensations of aldehydes with 1,3-dicarbonyl compounds and urea using room temperature ionic liquids based on [bmim][BF ] or [bmim][PFJ as catalyst under solvent-free and neutral conditions (Fig. 12.15) [11]. 

Other examples of scale-up involved a triphenylphosphine-free one-pot Wittig olefination, a one-step three-component synthesis of imidazo annulated pyridine and a metal-catalyzed Suzuki coupling. Kappe and co-workers also recently transferred conditions for reactions originally performed on a small scale with a mono-modal system, to scale-up by parallel synthesis in a multimodal batch reactor [13]. Typically, the scale-up was 100-fold, from 1 mmol examples included Biginelli condensations, Heck and Negishi couplings, and Diels-Alder cycloadditions with gaseous reactants. 

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. 

The synthesis of DHPMs linked through C-4 is precursor for supramo-lecular applications. DHPM-based podand 165 was synthesized from diformyl precursor 164, in a three-component Biginelli condensation in ethanol aided with ultrasonication (Scheme 63) (03MI8). 

The three-component Biginelli condensation of pyrazole aldehyde 185 (Ar = CeHs X = CH or CCl = Me, Et), p-ketoesters and urea catalyzed by phosphotungstic acid in methanol (Scheme 70, Method A) (05JHC863)... 

Indium (III) halides catalyzed a three-component Biginelli condensation of ferrocenyl-1,3-diketones 259, aldehydes, and urea (or thiourea) and furnished 5-ferrocenyl-DHPMs 260 (X = O, S) (Scheme 100) (03JOM(672)52). 

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