Condensations Biginelli

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). 

Fig. 4.4 Temperature and power profiles for a Biginelli condensation (Scheme 4.24.a) under sealed quartz vessel/microwave irradiation conditions (see Fig. 3.17). Linear heating ramp to 120 °C (3 min), temperature control using the feedback from the reference vessel temperature measurement (constant 120 °C, 20 min), and forced air cooling (20 min). The reaction was performed in eight quartz vessels...

Fig. 5.3 Heating profile for a typical Biginelli condensation in AcOH/EtOH (3 1) under sealed-vessel microwave irradiation conditions microwave flash heating (300 W, 0-40 s), temperature control using the feedback from IR thermography (constant 120 °C, 40-600 s), and active cooling (600-660 s).

The yields for the optimized microwave-assisted Biginelli condensations are in general comparable to or higher than those obtained using the standard reflux conditions. More importantly, however, reaction times have been brought down from several hours (4—12 h) under reflux conditions to 10-20 min employing microwave... 

A similar strategy has been used for the Biginelli condensation reaction to synthesize a set of pyrimidinones (65-95%) in a household MW oven [152]. This MW approach has been successfully applied to combinatorial synthesis [153]. Yet another example is the convenient synthesis of pyrroles (60-72 %) on silica gel using readily available enones, amines and nitro compounds [154]. 

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... 

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). 

Fig. 2. Solid-phase Biginelli condensation using 7-aminobutyric acid -derived urea on Wang resin.

Fig. 3. Solid-phase Biginelli condensations using Wang resin-bound acetoacetates.

In addition to the methods described above where the urea component is linked to a solid (or fluorous) support, it is also possible to link instead the acetoacetate building block to the solid support as shown in the example in Fig. 3.25 Thus, Biginelli condensation of Wang-bound acetoacetates with excess aldehydes (such as 2-trifluoromethylbenzaldehyde, Fig. 3) and urea/thiourea provides the desired DHPMs on solid support. Subsequent cleavage with trifluoroacetic acid furnishes the free carboxylic acids in high overall yields. 

The Biginelli condensation strongly depends on the amount of acidic catalyst present in the reaction medium. Traditionally, strong Brpnsted acids such as hydrochloric or sulfuric acid have been employed, but today the use Lewis acids such as BF3OEt2, LaCl3, FeCl3, Yb(OTf)3, InCl3,... 

Fig. 5. The influence of the catalyst on the Biginelli condensation involving ethyl acetoacetate, benzaldehyde, and urea [see Eq. (1)] in a 3 1 AcOH/EtOH solvent mixture under microwave irradiation (120°, 10 min).

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 . 

Today there is a great variety of suitable reaction conditions for Biginelli condensations. For the condensation of ethyl acetoacetate with benzaldehyde and urea, at... 

Fig. 4.5. Combinatorial diversity in dihydropyrimidines synthesized via Biginelli condensation.

Scheme 4.9. Biginelli condensations with the Garner aldehyde.

As mentioned above, cyclic / -diketones such as cyclohexane-1,3-dione and other cyclic / -dicarbonyl compounds are known to function well in Biginelli condensations (see Figure 4.3). However, for tetronic acid the reaction takes an entirely different course, following a pseudo-four-component pathway to furnish spiro het-erobicydic products in good yields (Scheme 4.11) [158], The reaction proceeds by a regiospecific condensation of two molecules of aldehyde with the other reagents... 

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