P 2 O 5 / SiO 2 as an Efficient , Green and Heterogeneous Catalytic System for the Solvent-Free Synthesis of 3 , 4-Dihydropyrimidin-2-( 1 H )-ones ( and-Thiones )

A simple, green and efficient solventless procedure for the synthesis of 3,4-dihydropyrimidin-2-(1H)-ones (and -thiones) from aldehydes, β-ketoesters and urea or thiourea in the presence of catalytic amount of silica-supported P2O5 (P2O5/SiO2) at 85 C is described. Using this method, the title compounds were produced in high yields.


Introduction
Multicomponent reactions have been used as an important method for the preparation of potential biologically active substances 1 .For instance, 3,4-dihydropyrimidin-2-(1H)-ones (and -thiones) (Biginelli products) are very important heterocyclic motif in the realm of natural and synthetic organic chemistry due to possessing some biological and pharmacological activities such as antitumor 2 , antibacterial 3 , and antiviral properties 4,5 .They have also emerged as integral backbones of several calcium channel blockers 6 , vasorelaxants 7 , and antimitotic agents 8 .One of the most efficient methods for the synthesis of these compounds is one step three-component the condensation of aldehydes with βketoesters and urea or thiourea derivatives, which was discovered by Biginelli as early as 1893 9 .The major drawback associated with this protocol is low yields, particularly for substituted aromatic and aliphatic aldehydes 10,11 .Because of high importance of Biginelli reaction products, several reagents and catalysts have been used for this transformation, including ytterbium(III) resin 12 , 12-molybdophosphoric acid 13 , Zn(OTf) 2 14 , N-butyl-N,Ndimethyl-α-phenyl ethyl ammonium bromide 15 , Fe(HSO 4 ) 3 16 , H 3 BO 3 17 , various lanthanide trifluoromethanesulfonates (Ln(OTf) 3 , Ln = Yb, Sc, La) 18 , alumina sulfuric acid 19 , ZrCl 4 20 , Sm(NO 3 ) 3 21 , TMSCl 22 , ionic liquid 23 , and InCl 3 24 .Nevertheless, many of the reported methods are associated with one or more of the following drawbacks: (i) the use of expensive reagents, (ii) unsatisfactory yield, (iii) long reaction time, (iv) the use of catalysts that are difficult to their handling, and (v) no agreement with the green chemistry protocols.Thus, development of a cheap, green and efficient catalyst for the synthesis of substituted 3,4-dihydropyrimidin-2-(1H)-ones (and -thiones) would be desirable.
Phosphorus pentoxide/silica gel is an inexpensive, green, commercially available and heterogeneous catalytic system which has been used in several organic transformations, such as synthesis of N-sulfonyl imines 25 , condensation of indoles with carbonyl compounds 26 , esterification 27 , oxidation of sulfides to sulfoxides 28 , Schmidt reaction 29 , Fries rearrangement 30 , direct sulfonylation of aromatic rings 31 , oxime preparation 32 , conversion of aldehydes to acylals 33 , selective deprotection of 1,1-diacetals 34 , and acetalization of carbonyl compounds 35 .
Solvent-free organic reactions have been applied as an useful protocol in organic synthesis 36,37 .Solvent-free conditions often lead to shorter reaction times, increased yields, easier workup, matches with green chemistry protocols, and may enhance the regio-and stereoselectivity of reactions 36,37 .

Scheme 1 Experimental
All chemicals were purchased from Merck or Fluka Chemical Companies.Silica gel 60, 0.063-0.200mm (70-230 mesh ASTM) was used as support.Spectra were recorded on the following apparatus: IR spectra on a Shimadzu FTIR-8300 spectrophotometer; 1 H NMR (250 MHz) and 13 C NMR (62.5 MHz) on a Bruker Avance DPX-250, FT-NMR spectrometer (δ in ppm); Microanalyses on a Perkin-Elmer 240-B microanalyzer; Melting points on a Büchi B-545 apparatus in open capillary tubes.

Preparation of P 2 O 5 /SiO 2 catalytic system
A mixture of SiO 2 (3.5 g) and P 2 O 5 (1.5 g) was ground vigorously to give P 2 O 5 /SiO 2 (30% w/w) catalytic system as a white powder (5 g).

General procedure for the synthesis of 3,4-dihydropyrimidin-2-(1H)-ones (and -thiones)
To a mixture of compounds consisting of aldehyde (1 m mol), βketoester (1 m mol) and urea or thiourea (1.5 m mol) in a 10 mL round-bottomed flask connected to a reflux

Result and Discussion
To optimize reaction conditions, the reaction of benzaldehyde (1 m mol), ethyl acetoacetate (1 m mol) and urea (1.5 mmol) was selected as a model reaction to provide the desired dihydropyrimidin-2-(1H)-one (Scheme 1).At first, the reaction was examined using various amounts of P 2 O 5 /SiO 2 (30% w/w) at different temperatures.The results are displayed in Table 1.As Table 1 indicates, higher yield and shorter reaction time were obtained when the reaction was carried out in the presence of 1 g catalyst at 85 ºC.Thus, we applied these optimal conditions for all other reactions.The model reaction was also tested in the presence of only P 2 O 5 or only SiO 2 at 85 °C under solvent-free conditions; however, these reagents were not efficient separately.P 2 O 5 afforded the Biginelli product in 61% yield after 4 h and SiO 2 gave the product in 65% after 7 h (Table 1, entries 11 and 12).Thus, it is necessary to support P 2 O 5 on SiO 2 .
In order to compare the efficiency as well as capacity of the solvent-free procedure with respect to solution conditions, the condensation of benzaldehyde with ethyl acetoacetate and urea was examined in the presence of silica-supported P 2 O 5 in several solvents (Table 2).As it can be seen from Table 2, the solvent-free method is more efficient.a Isolated pure product.b The Solvent-free conditions.
After optimization of the reaction conditions, the Biginelli reaction was examined with structurally diverse aldehydes, β-ketoesters and urea or thiourea.The results are summarized in Table 3.As it is clear from Table 3, all reaction proceeded efficiently and the desired 3,4-dihydropyrimidin-2-(1H)-ones (and -thiones) were produced in high to excellent yields.The influence of electron-releasing and electron-withdrawing substituents on the aromatic ring of aldehydes upon results of the reaction was investigated.The results showed that both electron-donating and electron-withdrawing substituents had no significant effect on the reaction yields; however, these groups increased the reaction times (Table 3).Thiourea was also used as one of the ingredients with similar success to provide the corresponding 3,4-dihydropyrimidin-2-(1H)-thiones, which are also of interest for their biological activities 6 (Table 3, entries 3, 4, 6, 9, 13 and  15).In all cases, 3,4-dihydropyrimidin-2(1H)-ones (and -thiones) were the sole products and no by-products were observed.a Isolated pure product.b All compounds are known and their structures were identified by comparison of their melting points and spectral data with those in the authentic samples.

Conclusions
In summary, we have developed a new solvent-free strategy for the preparation of 3,4dihydropyrimidin-2-(1H)-ones (and -thiones) as biologically interesting compounds via the condensation of aldehyde with β-ketoesters and urea or thiourea.The advantages of this method are high yields, relatively short reaction times, low cost, simple experimental and as isolation procedures, and finally, it is in agreement with the green chemistry protocols.

Table 1 .
Optimization of reaction conditions relative to amount of P 2 O 5 /SiO 2 and temperature.
a Isolated pure product.

Table 3 .
Preparation of Biginelli compounds in the presence of P 2 O 5 /SiO 2 at 85 ºC under solvent-free conditions.