Dihydropyrimidine synthesis, condensation

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). 

The ever-popular Biginelli synthesis of dihydropyrimidines, by condensation of urea with a keto ester and an aldehyde, and variations on it, has been applied in a number of areas. 

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 . 

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... 

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],... 

An important multicomponent transformation for the synthesis of dihydropyrimidines is the Biginelli reaction, which involves the acid-catalyzed condensation... 

The readily prepared support was then used for dihydropyrimidine and chalcone synthesis (Scheme 7.29). Thus, the modified support was activated prior to reaction by treatment with tosyl chloride. Solutions of the appropriate acetophenones were then spotted onto the membrane and the support was submitted to microwave irradiation for 10 min [45]. In the next step, several aryl aldehydes were attached under microwave irradiation to form a set of corresponding chalcones through a Claisen-Schmidt condensation. 

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... 

Joseph JK, Jain SL, Sain B (2006) Ion exchange resins as recyclable and heterogeneous solid acid catalysts for the Biginelli condensation an improved protocol for the synthesis of 3,4-dihydropyrimidin-2-ones. J Mol Catal A Chem 247 99-102... 

The Biginelli synthesis (Scheme 3) is an important route to dihydropyrimidines, e.g. (25),46a with many variants of the original reactants now established. The mechanism has now been re-investigated using H- and 13C-NMR.46b The first step does not appear to involve aldol condensation or a carbenium-ion intermediate rather, condensation of benzaldehyde and urea gives an A -acyliminium ion intermediate (26), which then goes on to react with ethyl acetoacetate. 

A conceptually different approach to dihydropyrimidine analogues was developed by Kishi and co-workers (Scheme 4.8) [137, 138], The trimolecular room-temperature condensation of an enamine, acetaldehyde, and isocyanic acid provides the bicyclic dihydropyrimidine derivative 21. With some modification, this strategy was initially employed toward a stereospecific [138, 139] and later an enan-tioselective [140] synthesis of the natural product saxitoxin. Recent investigations by Elliott and coworkers have shown that substituted isocyanates can also be employed in this method [141-146], but a more general modification of this trimolecular condensation towards monocyclic dihydropyrimidine derivatives of the Bigi-nelli type has not yet been reported. 

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). 

The synthesis of small arrays of organic compounds derived from multicomponent condensations was recently reported by Studer et al. (119). A 10-member amino acid amide library L7 (Fig. 8.21) was prepared using the fluorous Ugi ( Flugi ) condensation, and another 10-member dihydropyrimidine library L8 (Fig. 8.21) was prepared using the Biginelli ( Fluginelli ) condensation adapted to the fluorous phase. The key intermediates for library preparation were the silyl bromide 8.36, prepared from a fluorous iodide (120), and the acyl bromide 8.37 and the acid 8.38, prepared from an orthothiobenzoate (121), as shown in Fig 8.21. The structure of the fluorous tag was... 

Trimethyl-l,6-dihydropyrimidine-2-thione (113), on condensation with aromatic aldehydes in ethanolic KOH, gives arylidene derivatives 114 which react with chloroacetic acid in the presence of anhydrous sodium acetate in acetic anhydride to afford a cyclized product formulated as 115 (81 Mil) that can also be represented by the alternate structure 116 (Scheme 25). Similarly, the thione 113 reacts with chloroacetic acid and aromatic aldehydes in the presence of anhydrous sodium acetate in acetic acid and acetic anhydride to furnish a cyclized product for which structure 117 has been assigned without any evidence (81 Mil). The cyclized product can also be represented by the other isomeric structure 118. The bicyclic compound (115 or 116) condenses with aromatic aldehydes to give arylidene derivatives that are also obtained in a single-step synthesis involving the reaction of 114 with chloroacetic acid and aromatic aldehydes in the presence of anhydrous sodium acetate in acetic acid and acetic anhydride. 

Bose, D. S., Fatima, L., Mereyala, H. B. Green Chemistry Approaches to the Synthesis of 5-Alkoxycarbonyl-4-aryl-3,4- dihydropyrimidin-2(1 H)-ones by a Three-Component Coupling of One-Pot Condensation Reaction Comparison of Ethanol, Water, and Solvent-free Conditions. J. Org. Chem. 2003, 68, 587-590. 

Legeay JC, Eynde JJV, Toupet L, Bazureau IP (2007) A three-component condensation protocol based on ionic liquid phase bound acetoacetate for the synthesis of Biginelh 3,4-dihydropyrimidine-2(177)- ones. Arkivociti 13-28... 

This very old synthesis of l,4-dihydropyrimidin-2-ones, which is analogous to the Hantzsch pyridine synthesis (8.14.1.2), is much used, particularly for library synthesis, and many variants of the reaction conditions have been described most often the condensation is acid or Lewis-acid catalysed. The products are important in their own right, but can also be dehydrogenated to give pyrimidin-2-ones. If guanidine is used instead of the urea component, 2-amino-1,4-dihydropyrimidines result. ... 

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