Reaction Biginelli condensation

EAN IL was used in various reactions such as Biginelli reaction, condensation reaction, nitration of phenol, synthesis of P-amino ketone, ete. Nitration of phenol using ferric nitrate and clayfen in the IL, EAN, has been reported imder irltrasound irradiation [102]. Jaeger and Tucker in 1989 reported the Diels-Alder reaction involving EAN IL [ 103], IL EAN was prepared as per the literature method. EAN was found to be a more suitable solvent and catalyst for these reactions. In the presence of EAN, the reactions proceed in a shorter time, under milder conditions, and with excellent yield of products. EAN is liqttid at room temperature and is miscible with water thus, the separation and isolation of the product becomes easier. Its autoprotolysis constant is high, and the large electroactivity area and conductivity allow it to be used as a potential solvent. Araos et al. [104] reported the stability of a variety of lyotropic liquid crystals formed by a nttmber of polyoxyethylene nonionic surfactants in the room-temperature IL EAN. 

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). 

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... 

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

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

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... 

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. 

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 . 

Nearly a century later with the recognition that DHPMs possessed similar pharmacological profiles to the Nifedipine class [9a] of DHP calcium channel modulators 2 (formed via the Hantzsch condensation 1882, Scheme 11.2 [9b]), the Biginelli reaction witnessed a dramatic upsurge in popularity [10],... 

The first important MCR was developed by Strecker in 1850 (Scheme 1) [20]. In this reaction ammonia, an aldehyde and hydrogen cyanide combine to form a-cyano amines 1, which upon hydrolysis form a-amino acids 2. Also, heterocyclic compounds were obtained using MCRs. An example of this is the Hantzsch reaction, discovered in 1882 [21]. This reaction is a condensation of an aldehyde with two equivalents of a (3-ketoester in the presence of ammonia resulting in the formation of dihydropyridines 3. A comparable reaction is the Biginelli reaction, founded in 1893 ([22] and see for review [23]). This reaction is a 3-component reaction (3CR) between an aldehyde, a (3-ketoester and urea to afford dihydropyrimidines 4. 

The first step in the mechanism of the Biginelli reaction is the acid-catalyzed condensation of the urea with the aldehyde affording an aminal, which dehydrates to an A/-acyliminium ion intermediate. Subsequently, the end form of the 3-keto ester attacks the A/-acyliminium ion to generate an open chain ureide, which readily cyclizes to a hexahydropyrimidine derivative. 

Biginelli reaction. Synthesis of tetrahydropyri-midinones by the acid-catalyzed condensation of an aldehyde, a (i-keto ester, and urea. 

Heterocyclic chemistry has been a major beneficiary of MW-expedited solvent-lfee chemistry utilizing mineral supported reagents. It has been exploited for parallel synthesis, a strategy that is adaptable for multicomponent reactions, such as Ugi " and Biginelli reactions " , for rapid assembly of a library of compoimds. A representative multi-component condensation reaction to create a small-molecule library of imidazo[l,2-a]pyridines, imidazo[l,2-a] pyrazines, and imidazo[l,2-a]pyrimidines is depicted in Scheme 3. 

Potentially useful heterocyclic libraries can also be prepared by the application of solution-phase combinatorial chemistry. Although multiple reactions in solution have often been complicated by the difficulties with liquid-liquid extractions the introduction of solid scavengers and equipment to automate these extraction processes allows hundreds of reactions to be managed simultaneously. A typical example is a series of aminothiazole derivatives which has been prepared starting from acyclic precursors (Scheme 3.9). Naturally one-pot multicomponent condensations such as the Ugi (library 84) [332], Passerini or Biginelli reactions present one of the simplest... 

Scheme 10.8 Aldol condensation (top) and Biginelli reaction (bottom) catalyzed by Nation.

For Biginelli Reaction. TMSI (in situ generated from TM-SCl and Nal) is an excellent promoter for the one-pot synthesis of dihydropyrimidinones via the Biginelli reaction (eq 51), which involves the condensation of an aldehyde, a 8-ketoester and urea (or thiourea). The traditional Biginelli reaction commonly proceeds under strongly acidic conditions, and this protocol often... 

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