Biginelli reaction building blocks

The Biginelli reaction has also been extended to solid phase and combinatorial synthesis. In a recent combinatorial approach Kappe and coworkers used 4-chloroacetoacetate as a building block to create a library of diverse DHPMs under... 

In order to make the Biginelli protocol amenable to an automated library generation format, utilizing the integrated robotic interface of the instrument, attempts were made to dissolve most of the building blocks used in solvents compatible with the reaction conditions. Since many of the published protocols employ either ethanol or acetic acid as solvents in Biginelli-type condensations, a 3 1 mixture of acetic acid... 

As far as the molar ratio of building blocks is concerned, Biginelli reactions generally employ an excess of the CH-acidic carbonyl or urea components, and not of the aldehyde. Since the resulting DHPM products of a Biginelli-type condensation are usually only sparingly soluble in solvents such as methanol or ethanol at room temperature, in many cases workup involves only isolation of the formed product by a simple filtration. Alternatively, it is also possible to precipitate the products by addition of water. 

While the early examples of this cyclocondensation process typically involved a / -ketoester, aromatic aldehyde and urea, the scope of this heterocycle synthesis has now been extended considerably by variation of all three building blocks, allowing access to a large number of multifunctionalized pyrimidine derivatives. For this particular heterocyclic scaffold the acronym DHPM has been adopted in the literature and is also used throughout this chapter. Owing to the importance of multi-component reactions in combinatorial chemistry there has been renewed interest in the Biginelli reaction, and the number of publications and patents describing... 

Fig. 4.2. Aldehyde building blocks used in the Biginelli reaction.

Aliphatic aldehydes typically provide only moderate yields in the Biginelli reaction unless special reaction conditions are employed, such as Lewis-acid catalysts or solvent-free methods, or the aldehydes are used in protected form [96]. The C4-unsubstituted DHPM can be prepared in a similar manner employing suitable formaldehyde synthons [96]. Of particular interest are reactions where the aldehyde component is derived from a carbohydrate. In such transformations, DHPMs having a sugar-like moiety in position 4 (C-nucleoside analogues) are obtained (see Section 4.7) [97-106]. Also of interest is the use of masked amino acids as building blocks [107, 108]. In a few cases, bisaldehydes have been used as synthons in Biginelli reactions [89, 109, 110]. 

The urea is the component in the Biginelli reaction that faces the most restrictions in terms of allowed structural diversity (Figure 4.4). Therefore, most of the published examples involve urea itself as a building block. However, simple mono-substituted alkyl ureas generally react equally well, in a regiospecific manner (see above), to provide good yields of N1-substituted DHPMs. Thiourea and substituted... 

To create stereochemical diversity within MCRs there is need for stereoselective (or -specific) reactions. Since many MCRs involve flat intermediates, like imines and a,p-unsaturated ketones, they result in the formation of racemic products. Moreover, often mixtures of diastereomers are obtained if more than one stereo-genic centre is formed. However, there are several examples known of asymmetric induction, by the use of chiral building blocks (diastereoselective reactions). For example, it has been successfully applied to the Strecker, Mannich, Biginelli, Petasis, Passerini, Ugi, and many other MCRs, which has been excellently reviewed by Yus and coworkers [33]. Enantioselective MCRs, which generally proved to be much harder, have been performed with organometaUic chiral catalysts and orga-nocatalysts [33, 34]. 

A new microwave-assisted protocol for the generation of diversely substituted 3,4-dihydropyrimidine-5-carboxylic acid esters 40 has been developed by Kappe and co-workers [88, 89] using trimethylsilyl chloride (TMSCl) as a mediator for the Biginelli MCR. This involved the reaction of S-ethyl acetothioacetate or ethyl acetoacetate, an aromatic aldehyde and (monosubstituted) urea or thiourea as building blocks. Also sterically hindered aromatic and heterocyclic aldehydes... 

Past, present and future of the Biginelli reaction 12ARK(1)66. Pyrimidine ring as building block for the synthesis of fxmctionalized Tc-conjugated materials 12COS163. 

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). 

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