Biginelli catalysts

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). 

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. 

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. 

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. 

Kolosov MA, Orlov VD, Beloborodov DA, Dotsenko VV (2009) A chemical placebo NaCl as an effective, cheapest, non-acidic and greener catalyst for Biginelli-type 3,4-dihydropy-rimidin-2(lH)-ones (-thiones) synthesis. Mol Divers 13 5-25... 

Bahrami K, Khodaei MM, Farrokhi A (2009) Highly efficient solvent-free synthesis of dihydropyrimidinones catalyzed by zinc oxide. Synth Commun 39 1801-1808 74. Gross GA, Wurziger H, Schober A (2006) Solid-phase synthesis of 4,6-diaryl-3,4-dihydro-pyrimidine-2(lH)-one-5-carboxylic acid amide derivatives a Biginelli three-component-condensation protocol based on immobilized beta-ketoamides. J Comb Chem 8 153-155 Desai B, Dallinger D, Kappe CO (2006) Microwave-assisted solution phase synthesis of dihydropyrimidine C5 amides and esters. Tetrahedron 62 4651 664 Kumar A, Maurya RA (2007) An efficient bakers yeast catalyzed synthesis of 3,4-dihydro-pyrimidin-2-(lH)-ones. Tetrahedron Lett 48 4569-4571 77. Zalavadiya P, Tala S, Akbari J, Joshi H (2009) Multi-component synthesis of dihydropyrimidines by iodine catalyst at ambient temperature and in-vitro anti mycobacterial activity. Arch Pharm 342 469-475... 

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... 

Huang YJ, Yang FY, Zhu CJ (2005) Highly enantioseletive biginelli reaction using a new chiral ytterbium catalyst Asymmetric synthesis of dihydropyrimidines. J Am Chem Soc 127 16386-16387... 

The Gong group utilized 2a in the multicomponent Biginelli reaction to provide structurally diverse 3,4-dihydropyrimidin-2(lH)-ones in high yields and ee s (Scheme 5.19) [33]. Notably, the authors found that bulky 3,3 subshtuents on the catalyst had a deleterious effect with respect to yields and enantioselectivities. 

The Biginelli procedure is amenable to microwave technology, and several microwave-assisted procedures have now been published <2002SC147, 2004SL235>. An example is the microwave-assisted solution-phase synthesis of dihydropyrimidine C-5 amides and esters 723 using ytterbium triflate as the Lewis acid catalyst <2006T4651>. 

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).

Aliphatic aldehydes typically provide only moderate yields in the Biginelli reaction unless special reaction conditions are employed, such as Lewis-acid catalysts or solvent-free methods, or the aldehydes are used in protected form [96]. The C4-unsubstituted DHPM can be prepared in a similar manner employing suitable formaldehyde synthons [96]. Of particular interest are reactions where the aldehyde component is derived from a carbohydrate. In such transformations, DHPMs having a sugar-like moiety in position 4 (C-nucleoside analogues) are obtained (see Section 4.7) [97-106]. Also of interest is the use of masked amino acids as building blocks [107, 108]. In a few cases, bisaldehydes have been used as synthons in Biginelli reactions [89, 109, 110]. 

As a final example it should be mentioned that precondensed enones, prepared by standard Knoevenagel condensation of the aldehyde with the CH-acidic carbonyl component, when reacted with thioureas provided 1,3-thiazines 37, which are isomeric to thio-Biginelli compounds of the general formula 14 (see Figure 4.5). A published report describes the combinatorial synthesis of a library of 29 derivatives of thiazines 37 utilizing polymer-supported reagents and catalysts [168]. 

Bismuth(m) nitrate catalyzes Michael addition of a,/Yunsaturated ketones with amines, thiols, and carbamates, although the promoting role of Bi(N03)3 is not fully understood (Equation (91)).100 The Biginelli cyclocondensation of a mixture of (3-keto esters, aldehydes, and urea is mediated by BiCl3, affording 3,4-dihydropyrimidin-2(lH)-ones (Equation (92)).149 Bi(OCOCF3)3 is an efficient catalyst for the regio- and chemoselective synthesis of /3-enaminones in water.150... 

Heravi, M.M., Bakhtiari, K., and Bamoharram, F.F. 2006a. 12-Molybdophosphoric acid A recyclable catalyst for the synthesis of Biginelli-type 3,4-dihydropyrimidine-2(lH)-ones. Catalysis Communications, 7 373-76. 

To create stereochemical diversity within MCRs there is need for stereoselective (or -specific) reactions. Since many MCRs involve flat intermediates, like imines and a,p-unsaturated ketones, they result in the formation of racemic products. Moreover, often mixtures of diastereomers are obtained if more than one stereo-genic centre is formed. However, there are several examples known of asymmetric induction, by the use of chiral building blocks (diastereoselective reactions). For example, it has been successfully applied to the Strecker, Mannich, Biginelli, Petasis, Passerini, Ugi, and many other MCRs, which has been excellently reviewed by Yus and coworkers [33]. Enantioselective MCRs, which generally proved to be much harder, have been performed with organometaUic chiral catalysts and orga-nocatalysts [33, 34]. 

Copper (II) chloride proved to be a very efficient catalyst for the Biginelli reaction in the absence of solvent [27]. When ethyl acetoacetate, aldehydes and urea or thiourea were heated neat in the presence of copper (11) chloride, the Biginelli products were isolated, after recrystallization from hot ethanol, in high yields and purities (Scheme 7). 

Figure 2.7 Solvent and catalyst free Biginelli condensation of a 1,3-dicarbonyl compound, an aldehyde and urea.

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