Dihydropyrimidinone synthesis

Scheme 1 Hantzsch s dihydropyridines and Biginelli s dihydropyrimidinones synthesis...

Kappe CO, Stadler A (2004) The Biginelli dihydropyrimidinone synthesis. Org React 63 1-117... 

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. 

Dabiri M, Salehi P, Baghbanzadeh M, Shakouri M, Otokesh S, Ekrami T, Doosti R (2007) Efficient and eco-friendly synthesis of dihydropyrimidinones, bis(indolyl) methanes, and N-alkyl and N-arylimides in ionic liquids. J Iran Chem Soc 4 393 01 Legeay JC, Eynde JJV, Bazureau JP (2008) Ionic liquid phase organic synthesis (loLiPOS) methodology applied to the preparation of new 3,4-dihydropyrimidine-2(lH)-ones bearing bioisostere group in N-3 position. Tetrahedron 64 5328-5335... 

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... 

Dihydropyrimidinones can be reduced by hydrogenation over palladium on charcoal, as demonstrated by the synthesis of the tetrahydropyrimidinone 534 from the chiral precursor 533 <1996TA2233, 1999JOC8668, 2004HCA1016>. 

Polymer-assisted methodology has been used several times for parallel-array synthesis of libraries involving three to five synthetic steps. Scheme 11 shows a three-step solution-phase synthesis of 2-thioxo-4-dihydro-pyrimid-inones wherein the key purification step involved amine resin 1 to sequester excess aldehydes and isot,hiocyanates from upstream transformations. Thermal cyclization of the purified intermediates gave the desired 2-thioxo-4-dihydropyrimidinones in excellent yields and purities.83... 

Ma Y, Qian C, Wang L, Yang M, Lanthanide triflate catalyzed Biginelli reaction. One-pot synthesis of dihydropyrimidinones under solvent-free conditions, J. Org. Chem., 65 3864-3868, 2000. 

Ashok M, Holla BS, Kumari NS (2007) Convenient one pot synthesis of some novel derivatives of thiazolo[2, 3-b]dihydropyrimidinone possessing 4-methylthiophenyl moiety and evaluation of their antibacterial and antifungal activities. Eur J Med Chem 42 380-385... 

In this context, dihydropyrimidinone (/ )-44 has been exploited by Chu et al. and Konopelski et al. in the enantioselective synthesis of p-alkyl p-amino acids. Furthermore, (V-phenethylperhydropyrimidinone (5)-45, as well as the 6-substituted analogs 46-48 (configuration not indicated) are useful substrates for the asymmetric synthesis of a,p-disubstituted p-amino acids. 

Lu, J., Ma, H. R. lron(lll)-catalyzed synthesis of dihydropyrimidinones. Improved conditions for the Biginelli reaction. Synlett 2000, 63-64. 

Ranu, B. C., Hajra, A., Jana, U. Indium(lll) chloride-catalyzed one-pot synthesis of dihydropyrimidinones by a three-component coupling of 1,3-dicarbonyl compounds, aldehydes, and urea an improved procedure for the Biginelli reaction. J. Org. Cbem. 2000, 65, 6270-6272. 

Yadav, J. S., Reddy, B. V. S., Srinivas, R., Venugopal, C., Ramalingam, T. LiCI04-catalyzed one-pot synthesis of dihydropyrimidinones an improved protocol for the Biginelli reaction. Synthesis 2001,1341-1345. 

Maiti, G., Kundu, P., Guin, C. One-pot synthesis of dihydropyrimidinones catalyzed by lithium bromide an improved procedure for the Biginelli reaction. Tetrahedron Lett. 2003,44, 2757-2758. 

Sabitha, G., Reddy, G. S. K. K., Reddy, C. S., Yadav, J. S. One-pot synthesis of dihydropyrimidinones using iodotrimethylsilane. Facile and new improved protocol for the Biginelli reaction at room temperature. Synlett 2003, 858-860. 

Recently, various scavenger resin approaches have appeared in the literature. For the synthesis of 4000 ureas (400 pools of 10-compound mixtures) [47], a solid-supported amino nucleophile was used to quench the excess of isocyanates, yielding the desired products in good purity. A similar concept has been employed in the synthesis of 2-thioxo-4-dihydropyrimidinones using aminomethylated polystyrene beads to quench isothiocyanates as well as aldehydes [48]. To quench an excess of amine in the synthesis of 2,6,9-trisubstituted purines, formyl polystyrene beads were used to form the corresponding polymer-bound imine, which could be filtered off [49]. 

The classical Biginelli synthesis is a one-pot condensation using P-dicarbonyl compounds with aldehydes (aromatic and aliphatic ones) and urea or thiourea in ethanol solution containing catalytic amounts of acid. Peng et al. for the first time reported a novel method for the synthesis of dihydropyrimidinones by three-component Biginelli condensations of aldehydes with 1,3-dicarbonyl compounds and urea using room temperature ionic liquids based on [bmim][BF ] or [bmim][PFJ as catalyst under solvent-free and neutral conditions (Fig. 12.15) [11]. 

A comprehensive study has investigated multidirectional cyclative cleavage transformations leading to bicyclic dihydropyrimidinones [61]. This approach required synthesis of 4-chloroacetoacetate resin as the key starting material this was prepared by microwave-assisted acetoacetylation of commercial available hydroxymethyl polystyrene resin under open-vessel conditions. This resin precursor was subsequently treated with urea and a variety of aldehydes in a Biginelli-type multi-component reaction, leading to the corresponding resin-bound dihydropyrimidinones (Scheme 16.40). The desired furo[3,4-d]pyrimidine-2,5-dione scaffold was obtained by a novel procedure for cyclative release under the action of micro-wave irradiation in sealed vials at 150 °C for 10 min. 

Selective protection of dihydropyrimidinones has been used in a novel approach to improve the synthesis of valuable Biginelli compounds with different substitution patterns [130]. This procedure has been successfully catalyzed by polymer-supported NjN-dimethylaminopyridine (PS-DMAP) (Scheme 16.85). This micro-... 

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