Reaction 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). 

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. 

Since the 1930s several mechanistic pathways have been proposed for the Biginelli In 1933, Folkers and Johnson reported that one of three intermediates 

was likely present in this reaction. These included bisureide 8 which was formed by a condensation reaction between the aryl aldehyde and the urea followed by subsequent 

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. 

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. 

The only way to realize an enantioselective Biginelli reaction is to conduct it intramolecularly where the enantiopure urea and aldehyde portions are tethered. This reaction was the key step in L.E. Overman s total synthesis of guanidine alkaloid 13,14,15-lsocrambescidin 800. An optically active guanidine aminal was reacted with an enantiopure (3-keto ester in trifluoroethanol to afford 1-iminohexahydropyrrolo[1,2-c]pyrimidine carboxylic ester with a 7 1 trans selectivity between CIO and Cl3 positions. 

The traditional intermolecular three-component version of the Biginelli reaction was utilized for the improved synthesis of racemic monastrol by A. Dondoni and co-workers. The one-pot Yb(OTf)3 catalyzed reaction took place between 3-hydroxybenzaldehyde, ethyl acetoacetate, and thiourea. Racemic monastrol was isolated in 95% yield and was resolved on a preparative scale using diastereomeric A/-3-ribofuranosyl amides. 

A wider range of aldehydes and P-keto esters were then employed in this organo-catalytic asymmetric Biginelli reaction by the same group, which enantioselectively 

SCHEME 2.7 Phosphoric acid-catalyzed asymmetric BiginelU reaction. 

SCHEME 2.8 Phosphoric acid-catalyzed asymmetric BigineUi-type reaction. 

During their studies on the Biginelli reactions of para-nitrobenzaldehyde, thiourea, and ethyl acetoacetate with the promotion of 10mol% of the nonenantiopure 3,3 -ditriphenylsilyl binol-derived phosphoric acid 5c in toluene, a strong positive nonlinear effect was observed. The asymmetric amplification was also found to occur in several other phosphoric acid-catalyzed reactions [14]. 

Also known as Biginelli pyrimidone synthesis. One-pot condensation of an aromatic aldehyde, urea, and p-dicarbonyl compound in acidic ethanolic solution and expansion of such a condensation thereof It belongs to a class of transformations called multiconqtonent reactions (MCRs). 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications DOI 10.1007/978-3-319-03979-4 24, Springer International Publishing Switzerland 2014 

Biginelli, P. Ber. 1891, 24, 1317. Pietro BigineUi was at Lab. chim. della Sanita pubbl. in Roma, Italy when this paper was published. 

Limberakis, C. Biginelli Pyrimidone Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J., Ed. Wiley Hoboken, NJ, 2005, pp 509-520. (Review). 

Nasr-Esfahani, M. Diab, L. Smejkal, T. Breit, B. Synlett 2013, 24, 1657-1662. 

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When the aromatic aldehyde is omitted from a Biginelli reaction mixture, a dihydropyrimidine is still formed. Thus, for example, phenylacetaldehyde (2 mol) and urea (1 mol) react to give 4-benzyl-5-phenyl-3,4-dihydropyrimidin-2(li/)-one (676) (33JA3361). 

If one replaces one of the two equivalents of P-dicarbonyl with urea, such that the reaction is now carried out with one equivalent of aldehyde 123, one equivalent of P-dicarbonyl 124 and an equivalent of urea 125 in acidic ethanol solution, then dihydropyrimidines 126 are formed. This class of reactions has been named Biginelli reactions and are reviewed in section 10.6... 

The mechanism was then reexamined 25 years later in 1997 by Kappe. Kappe used H and C spectroscopy to support the argument that the key intermediate in the Biginelli reaction was iminium species 16. In the event, 5 reacted with 3a to form an intermediate hemiaminal 17 which subsequently dehydrated to deliver 16. Iminium cation 16 then reacted with 6 to give 14, which underwent facile cyclodehydration to give 15. Kappe also noted that in the absence of 6, bisureide 8 was afforded as a consequence of nueleophilic attack of 16 by urea (3a). This discovery confirmed the conclusion of Folkers and Johnson in 1933. As far as the proposal from 25 years earlier by Sweet and Fissekis, Kappe saw no evidenee by H and NMR spectroscopy that a carbenium ion was a required species in the Biginelli reaetion. When benzaldehyde (5) and ethyl... 

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. 

Overman has extended his tethered Biginelli reaction to include alkenes and dienes instead of p-keto esters to deliver 51 diastereoselectively over 52 in the presence of Cu(OT02. 

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. ... 

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... 

Deng and Peng have found that certain ionic liquids catalyze the Biginelli reaction [62]. Usually, this reaction is catalyzed by Lewis acids such as InCl3, [Fe(H20)6]Cl3, or BF3.0(C2H5)2, or by acid catalysts such as Nafion-H. The reaction was found to give yields in the 77-99 % range in the ionic liquids [BMIM][PF6] or [BMIM][BF4] for the examples in Scheme 5.1-34. The reaction fails if there is no ionic liquid present or in the presence of tetrabutylammonium chloride. 

In 1997, the controversial mechanism of the Biginelli reaction was reinveshgated by Kappe using NMR spectroscopy and trapping experiments [94], and the current generally accepted process was elucidated (see Scheme 9.23). The N-acyliminium ion 9-112 is proposed as key intermediate this is formed by an acid-catalyzed reaction of an aldehyde with urea or thiourea via the semiaminal 9-111. Intercephon of 9-112 by the enol form of the 1,3-dicarbonyl compound 9-113 produces the open-chain ureide 9-114, which cyclizes to the hexahydropyrimidine 9-115. There follows an elimination to give the final product 9-116. 

A general method for the guanidine analogue of the Biginelli reaction has been developed using the two reagents 25 and 26, which overcome some of the limitations of the direct... 

A number of alternative preparations of Biginelli-type compounds and similar dihydropyrimidines have been described. A route to N-l-substituted compounds 27, which are difficult to make by the standard Biginelli reaction, involved reaction of an a-chlorobenzyl isocyanate with A-substituted aminocrotonates <06SL375>. 

Similar results were achieved when Biginelli reactions in acetic acid/ethanol (3 1) as solvent (120 °C, 20 min) were run in parallel in an eight-vessel rotor system (see Fig. 3.17) on an 8 x 80 mmol scale [87]. Here, the temperature in one reference vessel was monitored with the aid of a suitable probe, while the surface temperature of all eight quartz reaction vessels was also monitored (deviation less than 10 °C Fig. 4.4). The yield in all eight vessels was nearly identical and the same set-up was also used to perform a variety of different chemistries in parallel mode [87]. Various other parallel multivessel systems are commercially available for use in different multimode microwave reactors. These are presented in detail in Chapter 3. 

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

Synthesis of 2,3-dihydroimidazo-[l,2-c]-pyrimidines 283 Microwave-mediated Biginelli reactions 283... 

Six-membered cyclic guanidine 197 was transformed into the corresponding bicyclic guanidine hemiaminal after deprotection of the Cbz and contemporary cyclization on the masked aldehyde function (Equation 4). This product, 198, was then employed in a Biginelli reaction to form a precursor of alkaloid batzelladine F <1999JOC1512>. 

A double tethered Biginelli reaction was carried out on the simple five-membered urea aldehyde 305 that reacted with the aliphatic and aromatic bis-ketoesters 306 and 307 giving compounds 308 and 309, respectively, in good yield, albeit with a diasteromeric ratio of 1 3. A series of different polycyclic bis-guanidines resembling betzelladine alkaloids were prepared <2003OL4485>. 

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

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