Dihydropyrimidin-2

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). 

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. 

The following syntheses all proceeded regioselectively 4,6-diaryl-3,4-dihydropyrimidine-2-thiones with 3-bromopropionic acid in a Ac20/AcOH system <2001MI407, 2000IJH49>, or with acrylonitrile in pyridine followed by hydrolysis <1996IJB915> resulted 6,8-diaryl-2,3-dihydro+//,6//-pyrirnido[2,l+][l,3]thiazin-4-ones in good yield 4-phenyl-5-carbethoxy-3,4-dihydropyrimidine-2-thiones with benzylidenemalonitrile in a NaOAc/AcOH system... 

Cyclocondensation of l,6-dimethyl 4-phenyl-5-carbethoxy-3,4-dihydropyrimidine-2-thione with ClCO-Ph-Cl I—(—() in alcohol-free chloroform or with 2-methylmalonyl dichloride in DCM resulted in the thiazinium... 

The cyclizations to obtain cyclic thioureas have been performed using thiocarbonyldiimidazole.232 Reaction of methyl acetoacetate, thiourea and an aliphatic aldehyde in the presence of the zinc iodide (Znl2) was studied. Under the normal pressure, reaction has not been occurred whereas at high pressure (300 MPa) conditions 3,4-dihydropyrimidine-2-thione was obtained only in 10% yield.233 The same one-pot three-component cyclocondensation reaction in the presence of iodide (I2) provides a variety of 3,4-dihydropyrimi-dine-2-thione in high yields.234 Condensation reaction of thioureas with a,p-unsaturated ketones in the presence of the sodium methoxide in methanol affords 3,4-dihydropyrimidine-2-thione derivatives.235,236 Acylation of N,N -disubstituted thioureas with methyl malonyl chloride followed by base-catalysed cyclization leads in the formation of l,3-disubstituted-2-thiobarbituric acids (Scheme 78).237... 

Sabitha G, Reddy KB, Yadav JS, Shailaja D, Sivudu KS (2005) Ceria/vinylpyridine polymer nanocomposite an ecofriendly catalyst for the synthesis of 3,4-dihydropyrimidin-2(lH)-ones. Tetrahedron Lett 46 8221-8224... 

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... 

Gui JZ, Liu D, Wang C, Lu F, Lian JZ, Jiang H, Sun ZL (2009) One-Pot Synthesis of 3,4-Dihydropyrimidin-2(lH)-ones Catalyzed by Acidic Ionic Liquids Under Solvent-Free Conditions. Synth Commun 39 3436-3443... 

Comas H, Buisson DA, Najman R, Kozielski F, Rousseau B, Lopez R (2009) Synthesis of 5-Acyl-3,4-dihydropyrimidine-2-thiones via solvent-free, solution-phase and solid-phase Biginelli procedures. Synlett 1737-1740... 

Hegedus A, Hell Z, Vigh I (2006) Convenient one-pot heterogeneous catalytic method for the preparation of 3,4-dihydropyrimidin-2(lH)-ones. Synth Commun 36 129-136... 

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... 

Gong LZ, Chen XH, Xu XY (2007) Asymmetric organocatalytic biginelli reactions a new approach to quickly access optically active 3,4-dihydropyrimidin-2-(lH)-ones. Chem Eur J 13 8920-8926... 

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. 

Bazureau s group reported extensive work with TSILs for synthesis of various 4-thiazolidinones, 1,4-dihydropyridines, 3,4-dihydropyrimidin-2(lH)-ones and polyhydroquinones. They functionalized imidazole compounds with esters, which were then reacted with reagents to afford the target compound. They report that microwave dielectric heating is a useful aid to rapidly produce the desired product in high yields. 

A Pd(0)-catalyzed/Cu(l)-mediated carbon-carbon cross-coupling of 3,4-dihydropyrimidine-2-thiones 520 and boronic acids occurs under microwave-assisted conditions to give 2-aryl-l,4-dihydropyrimidines 521 in moderate to high yield <20040L771>. In contrast, Gu(ll)-mediated reaction of the same substrates leads to carbon-sulfur cross-coupling. 

Shaabani, A., Bazgir, A. and Teimouri, F., Ammonium chloride-catalyzed one-pot synthesis of 3,4-dihydropyrimidin-2-(liT)-ones under solvent-free conditions, Tetrahedron Lett., 2003, 857—859. 

Biginelli synthesis of 3,4-dihydropyrimidin-2( 1 //)-oncs (99) from an aldehyde, a /3-diketone, and urea is catalysed by L-proline methyl ester hydrochloride.276 Although evidence strongly supports an enamine mechanism, the products were essentially racemic. 

Oxidation of 3,4-dihydropyrimidin-2(l //)-oncs (DHPMs) with ceric ammonium nitrate (CAN) in acetic acid resulted in ethyl 2,4-dioxo-6-phenyltetrahydropyrimidin-5-carboxylates as the major product. However, DHPMs undergo a regioselective oxidation with CAN in the presence of sodium hydrogencarbonate in neutral aqueous acetone solution to yield ethyl 6-meihyl-4-aryl(alkyl)pyrimidin-2(l //)-one-5-carboxylates. A mechanism involving a nitrolic acid intermediate has been suggested.72... 

As already mentioned at the beginning of this chapter, one of the facile methods for the synthesis of dihydropyrimidine derivatives is the treatment of oc,(3-unsaturated carbonyls with urea and its analogues—thiourea, guanidine and amidines. However, the majority of the publications have dealt with syntheses involving thiourea. Most likely is the possibility of the modification of 3,4-dihydropyrimidine-2-thiones or their heteroaromatized analogues, which produces a diverse class of heterocycles. The reagent involved in this modification process can act like a,(3-unsaturated carbonyls [16] (Scheme 3.9). 

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 . 

In 1893 the Italian chemist Pietro Biginelli [2] reported the one-pot synthesis of 4-aryl-3, 4-dihydropyrimidin-2(lff)-ones (DHPMs 1) by a three-component condensation reaction of aromatic aldehydes, urea and ethylacetoacetate (Scheme 11.1). 

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. 

Nanosized sulfated tin oxide (STO) particles dispersed in the micropores of Al-pillared clay (STO/Al-P), were used by Mishra and co-workers [91] as an environmentally benign, recyclable and efficient catalyst for the solvent-free synthesis of 3,4-dihydropyrimidin-2(l//)-ones 42 using a domestic microwave oven. The protocol offers advantages in terms of simple experimentation, reusable catalyst, excellent yields, short reaction times, and preclusion of toxic solvents (Scheme 31). 

A novel and efficient ionic liquid synthesis of DHPMs has been developed by Bazureau and co-workers [92] in which ionic liquid-phase bound acetoacetate was reacted with (thio)urea and a suitable aldehyde in the presence of HCl affording ionic liquid-phase supported 3,4-dihydropyrimidine-2-(thi)ones 43. The desired 3,4-dihydropyriinidme-2-(thi)one was easily cleaved from the ionic liquid-phase by transesterification under mild conditions in good yield and with high purity. Advantageously, the ionic liquid-phase linked DHPM could be crystallized from the excess of (thio)urea (Scheme 32). 

Liang B, Wang X, Wang JX et al (2007) New three component cyclocondensation micro-wave assisted one-pot synthesis of 5-unsubistutited-3,4-dihydropyrimidin-2(lH)-ones under solvent-free conditions. Tetrahedron 63 1981-1986... 

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