The Biginelli Reaction

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 

Multicomponent Reactions. Edited by Jieping Zhu. Hugues Bienayme Copyright 2005 WILEY-VCH Veriag GmbH Co. KGaA, Weinheim ISBN 3-527-30806-7 

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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). 

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. 

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. 

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... 

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

The Biginelli reaction is a cyclocondensation between ethylacetoacetate, an arylal-dehyde and urea derivatives to obtain dihydropyrimidines. Transfer this reaction to the solid-phase chemistry, allow the preparation of libraries of this kind of products (Scheme 3.18) [288]. 

The Biginelli reaction is also known to be catalyzed by the ionic liquids [bmim] [BF ] and [bmim][PFg] under solvent-free conditions [197]. One example is shown in Scheme 75. While a control reaction without ionic liquid gave no product, the addition of just 0.4 mol% afforded a yield of 92% in 30 min. [Bmim][Cl] resulted only in a yield of 56%, while [ Bu N][Cl] gave no yield. This indicated that both the cation and the anion have an influence in catalyzing the reaction. 

Ryabukhin SV, Plaskon AS, Ostapchuk EN, Volochnyuk DM, Shishkin OV, Tolmachev AA (2008) CF3-substituted 1,3-dicarbonyl compounds in the Biginelli reaction promoted by chlorotrimethylsilane. J Fluor Chem 129 625-631... 

Nilsson BL, Overman LE (2006) Concise synthesis of guanidine-containing heterocycles using the Biginelli reaction. J Org Chem 71 7706-7714... 

However, dihydropyrimidinones 524 derived from the Biginelli reaction are less readily oxidized <1997H(45)1967>, and there have been several investigations of oxidation systems that can convert compounds of this class to the fully conjugated pyrimidine derivatives 525. 

The most important synthesis within this subgroup is the Biginelli reaction, which involves reaction between a methylene ketone 715, an aldehyde 716, and either a urea 717 (Z = 0) or thiourea 717 (Z = S) to give a dihydro-2-pyrimidinone 718 (Z = 0) or dihydro-2-pyrimidinethione 718 (Z=S) <1993T6937, 2000ACR879, 20040R1>. 

Scheme 5.1-34 The Biginelli reaction in an ionic liquid. R = CsHs, 4-(H3CO)-C6H4, 4-CI-C6H4, 4-(02N)-C6H4, C5H,. R = OC2H5, CH3.

Yaddav, J.S., Reddy, B.V.S., Reddy, E.J. and Ramalingam, T., Microwave-assisted efficient synthesis of dihydropyrimidines improved high yielding protocol for the Biginelli reaction,/. Chem.Res. (S), 2000,354-355. 

Moreover, the short reaction times open up new approaches for rapid testing of ideas and fast iterations in protocol development as demonstrated here successfully for the Biginelli reaction. While microwave heating is today still considered by some as a laboratory curiosity, we believe that this technology will be used extensively in the future for many... 

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 . 

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

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