Biginelli three-component

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],... 

Scheme 6.246 Biginelli three-component synthesis of dihydropyrimidines.

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... 

Fig. 1. Building blocks and points of diversity in the Biginelli three-component dihydropyrimidine synthesis.

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. 

Despite its extreme simplicity, the original Biginelli three-component reaction suffers from long reaction times and low to moderate yields of the desired DHPMs 26. This is particularly true when substituted aliphatic/aromatic aldehydes or thioureas are used. To overcome this problem, several improved reaction procedures for the synthesis of 26 have been developed either by modification of the classical... 

Yadav, J. S., Reddy, B. V. S., Sreedhar, R, Reddy, J. S. S., Nagaiah, K., Lingaiah, N. and Saiprasad, P. S. 2004c. Green protocol for the Biginelli three-component reaction Ag3PW,204oas a novel, water-tolerant heteropolyacid for the synthesis of 3,4-dihydro-pyrimidinones. Eur. J. Org. Chem. 2004 552-557. 

In 1893 Pietro Biginelli reported the first synthesis of 4-aryl-3,4-dihydropyrimidin-2(l//)-ones (DHPMs) via an one-pot process using three components. Thus, DHPM 7 was synthesized by mixing benzaldehyde (5), ethyl acetoacetate (6), and urea (3a) in ethanol at reflux in the presence of a catalytic amount of HCl. 

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]. 

Scheme 15 Three-component synthesis of spiroheterocyclic Biginelli s products...

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... 

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). 

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). 

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 . 

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]. 

There are alternative solid-phase protocols described in the literature for the generation of DHPMs, not via the classical three-component Biginelli approach but through related modifications [129-131]. Furthermore, there have been reports de-... 

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). 

O-tethered P-keto esters, through the intermediacy of aiylidene keto esters, have been efficiently utilized for the construction of immobilized dihydropyridines. Ceric ammonium nitrate (CAN) oxidation to pyridines followed by acidolytic cleavage provides a facile entry into nicotinic acid derivatives 57 [42], A three-component Biginelli cyclization of ureas on resin with a solution mixture of aldehydes and P-keto esters provides dihydropyrimidines 58 in high yield and purity [43], Heterocycles such as dihydropyridines and pyrimidines have historically proven to be a rich source of antimicrobial, antitumor, antiviral, and cardiovascular agents. 

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. 

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... 

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