DHPMs

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 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. 

Forty years after the initial proposal, Sweet and Fissekis proposed a more detailed pathway involving a carbenium ion species. According to these authors the first step involved an aldol condensation between ethyl acetoacetate (6) and benzaldehyde (5) to deliver the aldol adduct 11. Subsequent dehydration of 11 furnished the key carbenium ion 12 which was in equilibrium with enone 13. Nucleophilic attack of 12 by urea then delivered ureide 14. Intramolecular cyclization produced a hemiaminal which underwent dehydration to afford dihydropyrimidinone 15. These authors demonstrated that the carbenium species was viable through synthesis. After enone 13 was synthesized, it was allowed to react with N-methyl urea to deliver the mono-N-methylated derivative of DHPM 15. 

Although acid catalysis is thought to be necessary for the Biginelli reaction, there has been a report disputing this requirement. Ranu and coworkers surveyed over 20 aldehydes and showed that excellent yields of DHPMs could be achieved at 100-105°C in 1 h in the absence of catalyst and solvent with no by-products formed. In contrast Peng and Deng reported no significant formation of DHPM 15 when a mixture of benzaldehyde (5), ethyl acetoacetate (6), and urea (3a) was heated at 100°C for 30 min. 

Over the last several years research groups have also explored the use of microwaves to increase the reaction rate and efficiency of the Biginelli reaction. In one example, polyphosphate ester (PPE) was used as the promoter under microwave conditions to deliver a variety of DHPMs 38 in yields ranging from 65-95% yield with reaction times typically below 2 minutes. ... 

In addition to modification of the catalyst, several variants of the Biginelli reaction have emerged as viable alternatives however, each method requires pre-formation of intermediates that are normally formed in the one-pot Biginelli reaction. First, Atwal and coworkers reported the reaction between aldol adducts 39 with urea 40a or thiourea 40b in the presence of sodium bicarbonate in dimethylformamide at 70°C to give 1,4-dihydropyrimidines 41. DHPM 42 was then produced by deprotection of 41. 

Since the early 1990s the Biginelli reaction has been utilized to deliver the DHPM core which was further elaborated to the target of interest. These reports are well documented in two reviews by Kappe in 2000. However, this section will address work primarily completed after these comprehensive reviews were published. 

For example, Ghorab and coworkers exploited the classical Biginelli reaction to synthesize a variety of potentially active antifungal agents such as 56 from DHPM 55. ... 

In addition, Namazi and coworkers expanded the DHPM core by constructing pyrrolo[3,4-rf pyrimidines via the classical approach. First, DHPM 59 was delivered in 60% yield using the standard Biginelli conditions. 59 was then brominated in high yield to afford 60. Substitution of bromide 60 with methylamine followed by cyclization of the intermediate amino ester furnished pyrrolo[3,4-rf pyrimidine 61 in 53% yield. 

Dondoni has elaborated this methodology to include C-glycosylated dihydro-pyrimidines/ The sugar residue can be a subunit in the aldehyde, 1,3-dicarbonyl, or urea consequently, substitution of the DHPM ring may occur in one of three places depending on which component originally contains the glycosidic residue. In the example... 

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... 

Scheme 1 Biginelli q clocondensation reaction for the synthesis of DHPMs 4...

Scheme 2 Liquid-phase synthesis of DHPM derivatives 7a-f...

Decarboxylation reactions 26 Dechlorination 277 DHPMs 34 Diazepines 259 Diazines 242... 

With this set of five optimized reaction conditions in hand (Fig. 5.6), the production of a small DHPM library was performed. As a set of structurally diverse representative building blocks, 17 individual CH-acidic carbonyl compounds, 25 aldehydes, and 8 ureas/thioureas were chosen. Combination of all these building blocks would lead to a library of 3400 individual DHPMs. To demonstrate the practicability of the presented concept, a representative subset library of 48 DHPM analogues involving all of the aforementioned building blocks was generated [2],... 

In recent decades, the Biginelli-type dihydropyrimidinones (DHPM) have received considerable attention, because of the interesting pharmacological properties of this heterocydic scaffold [30]. It was soon established that DHPM has a similar pharmacological profile to the well-known dihydropyridine (DHP) caldum-channel modulations of the Hantzsch type [31]. 

Varma and Kappe have developed a method that enables the rapid and parallel synthesis of DHPM 58 (Scheme 8.22) but does not rely on polymer-supported building blocks and therefore does not require the development of solid-phase linkingcleaving chemistry. They showed that polyphosphate ester (PPE) serves as an excel-... 

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