Multicomponent Biginelli ’ s Synthesis of 3 , 4-Dihydropyrimidin-2 ( 1 H )-ones Promoted by SnCl 2 . 2 H 2 O

Neste trabalho é descrita a habilidade do SnCl 2 .2H 2 O como catalisador na reação de Biginelli tricomponente. Uma variedade de aldeídos aromáticos monoe dissubstituidos foi utilizada na condensação com acetoacetato de etila e uréia ou tiouréia. A reação foi efetuada em etanol ou acetonitrila como solventes em meio neutro e os resultados representam um melhoramento com relação ao procedimento clássico de Biginelli e uma vantagem com relação ao uso de FeCl 3 .6H 2 O, NiCl 2 .6H 2 O e CoCl 2 .6H 2 O que são utilizados juntamente com HCl como co-catalisador. A síntese das 3,4-diidropirimidinonas foi conseguida em bons rendimentos.


Introduction
The multicomponent reactions (MCRs) are one of the most important protocols in organic synthesis and medicinal chemistry. 1The diversity, efficiency and rapid access to small and highly functionalized organic molecules makes this approach of central current interest in the construction of combinatorial libraries and optimization in drug discovery process. 2 The 3,4-dihydropyrimidin-2(1H)-ones (DHPMs-1, Figure 1) have recently emerged as important target molecules due to their therapeutic and pharmacological properties 3 such as antiviral, 4 antimitotic, 5 anticarcinogenic, 6 antihypertensive 7 and noteworthy, as calcium channel modulators. 8Additionally, their particular structure has been found in natural marine alkaloid batzelladine A and B which are the first low molecular weight natural products reported in the literature to inhibit the binding of HIV gp-120 to CD4 cells, so disclosing a new field towards the development of AIDS therapy. 9Also, due to the close related structure of DHPMs with the known dihydropyridine calcium channel modulators of the Hantzsch-type (DHPs -2, Figure 1), an intensive research has been devoted to synthesize the dihydropyrimidinone nucleus and this subject was recently reviewed. 10e original one-pot synthesis of 3,4-dihydropyrimidin-2-(1H)-ones was firstly reported by Pietro Biginelli in 1893 performing the three-component cyclocondensation reaction of ethyl acetoacetate, benzaldehyde and urea under Brönsted acid catalysis. 11However, this reaction suffers from the harsh conditions, high reaction times and frequently low yields.Among the diversity of available methodologies in the literature that use lithium salts, 12 TMSI, 13 reactions performed under ionic liquids, 14 solid phase, 15 polymer-supported, 16 heterogeneous catalysis by silicas 17 and montmorillonites 18 or activation by ultrasound 19 and microwave 20 energies as synthetic protocols to prepare DHPMs, special attention has been dedicated to Lewis acids catalysis.

Results and Discussion
In connection with our research on the use of SnCl 2 .2H 2 O in multicomponent Mannich reaction, 34 we would like to disclose here our preliminary results employing this catalyst as a new and mild Lewis acid which, to our best knowledge, has not yet been reported promote the multicomponent Biginelli reaction (Scheme 1, Table 1).It should be noted, that SnCl 2 .2H 2 O was used as the sole promoter agent in neutral media while for the others previously reported hydrates of metallic halides such as Fe(III), Ni(II) and Co(II) a catalytic amount of conc.HCl was needed as a Brönsted acid co-catalyst.
To evaluate the ability of SnCl 2 .2H 2 O as catalyst in this reaction, we performed the three component condensation reaction of benzaldehyde (3a), ethyl acetoacetate (4) and urea (5a) in EtOH and CH 3 CN as solvents.To establish the optimal conditions, we carried out a set of experiments varying the reaction time, amounts of the catalysts and the quantities of urea.
The best condition to prepare the dihydropyrimidinone 6a were achieved when 20 mol% of SnCl 2 .2H 2 O, 1 equivalent of both aldehyde 3a and ethyl acetoacetate (4) and 1.2 equivalents of urea (5a) were mixed under reflux for 6 hours, affording the desired product in good yield (>90%, Entry 1, Table 1).This condition was applied to a series of substituted aromatic aldehydes 3b-m with urea (5a) affording the desired products 6b-m.
The ability of SnCl 2 .2H 2 O to promote the Biginelli reaction in EtOH was comparable to those performed in CH 3 CN, affording good yields in all cases (Entries 2-26).The reactions of aldehydes 3a and 3d with thiourea (5b) also afforded the desired products in good yields for both the solvents (entries 27-30).Apparently, for the employed rection conditions (reflux for 6 hours) the nature of the substituents does not affect significantly the yield of the reactions.The product 6c, which has an electron-donanting substituent attached at C-4 position of the aromatic ring was produced in 98% yield while the dihydropyrimidinone 6l with an electron-withdrawing group yielded 96% (see entries 6 and 24, respectively).
The 1 H NMR and 13 C NMR data of compounds 6a-o were compatible with the proposed structures as well as the melting points were in accordance with those reported in the literature.
A general procedure for the synthesis of 3,4dihydropyrimidinones is described as follow: a 50 cm 3 round-bottom flask was charged with 3.6 mmol of urea or thiourea, 3.0 mmol of the aldehyde, 3.0 mmol of ethyl acetoacetate, 0.6 mmol of SnCl 2 .2H 2 O and 4.0 cm 3 of ethanol (or acetonitrile).The mixture was heated to reflux for 6 hours period under magnetic stirrer.The solution was cooled to room temperature and 10 cm 3 of cold water was added, the mixture was additionally stirred for 15 minutes.The resulting solid was filtered under suction, washed with cold ethanol (3 cm 3 ) and recrystalized from hot ethanol to afford the product.
In some cases (compounds 6c, 6d and 6g, entries 5, 7 and 13, respectively), the crude isolated solid compound was dried under vacuum pump and shown essentially the same purity as the recrystallized sample.
Although different mechanistic pathways have been previously proposed, 35,36 we believe that the reaction may Scheme 1.The multicomponent Biginelli reaction.
The coordination of the lone-pair of the nitrogen atom in the N-acylimine 7 with the Lewis acid could lead to the Spectroscopic evidences for such mechanism from 1 H NMR and 13 C NMR studies were reported by Kappe, supporting the intervenience of a N-carbamoyliminium ion as a possible intermediate. 37

Conclusion
In summary, we have demonstrated the ability of SnCl 2 .2H 2 O as a new and mild Lewis acid promoter in the multicomponent Biginelli reaction.Besides its simplicity, neutral reaction conditions and use of commercial solvents without previous purifications or drying, this method was effective with a variety of substituted aromatic aldehydes independently of the nature of the substituents in the aromatic ring, representing an improvement to the classical Biginelli's methodology.
a Literature reported mp values.Scheme 2.