Three Component Reaction: An Efficient Synthesis and Reactions of 3,4-Dihydropyrimidin-2(1H)-Ones and Thiones Using New Natural Catalyst

Synthesis of 3,4-dihydropyrimidin-2(1H)-one and 3,4-dihydropyrimidin-2(1H)-thione derivatives from aldehydes, 1,3-dicarbonyl derivatives and urea or thiourea using granite and quartz as new, natural and reusable catalysts. Some of the 3,4-dihydropyrimidin-2(1H)-thione derivatives were used to prepare new heterocyclic compounds. The antimicrobial activity of selected examples of the synthesized compounds was tested and showed moderate activity.


Introduction
Aryl-3,4-dihydropyrimidines derivatives have recently received great attention because of their wide range of therapeutic and pharmacological properties, such as antiviral [1], antitumor, antibacterial and antifungal [2], anti-inflammatory [3], antihypertensive agents, and neuropeptide Y (NPY) antagonists [4]. Furthermore, these compounds have emerged as the integral backbones of several calcium-channel blockers [5]. Also, several alkaloids containing the dihydropyrimidine were isolated from marine sources, for example, of these are the batzelladine alkaloids, which are found to be potent HIVgp-120-CD4 inhibitors [6,7].
In general, the classic Biginelli approach to 3,4-dihydropyrimidinones is based on the condensation of ethyl acetoacetate, aromatic aldehyde, and urea under strong acidic conditions; this suffers, however, from low yields of products, particularly in case of substituted aromatic and aliphatic aldehydes [8,9]. This problem has led to the development of multistep synthetic strategies that produce relatively higher yields, but lack the simplicity of the original one-pot-Biginelli protocol. Thus, the Biginelli reaction has received renewed interest from researchers interested in discovering milder and more efficient procedures that are applicable to a wide range of substituents in all three components and proceed in better yields. So, the one-pot-Biginelli protocol for 3,4-dihydropyrimidines synthesis was explored by varying all components and catalysts [10][11][12][13][14][15][16][17][18] in protic, aprotic solvents, and solvent free conditions [19] using either classical heating, microwave [20,21], ultrasound [22,23], and visible light (100 W Lamp, THF) irradiations [24]. Also several improved procedures have been reported recently using not only acidic media such as Lewis acids, protic acids, and ionic liquids as promoters [25,26] but also nonacidic substances such as baker's yeast [27], graphite [28], and iodine [29,30]. Heterogeneous solid acids are used also; however, these are advantageous over conventional homogeneous acid catalysts as they can be easily recovered from the reaction mixture by simple filtration and can be reused after activation or without activation, thereby making the process economically viable [31]. Bakibaev and Filimonov [32] reported that piperidine as a base catalyst can promote the Biginelli protocol also, to afford the corresponding 3,4-dihydropyrimidines along with Hantzsch 1,4dihydropyridines which may form in spite of urea decomposition in the reaction media, releasing ammonia. We would like to propose a new naturally and very cheap catalysts granite and quartz for the synthesis of 3,4-dihydropyrimidinones and 3,4-dihydropyrimidenthiones, using one-pot-Biginelli protocol, in refluxing ethanol.

Result and Discussion
It is interesting to report that the one pot reaction of a mixture of benzaldehyde, ethyl acetoacetate, and urea in the presence of granite or quartz as a catalyst in refluxing ethanol resulted in the formation of 4-phenyl-3,4-dihydropyrimidinone Ia, Table 1 in 64% or 68% yield according to the catalyst (Scheme 1). In a similar way, urea was condensed smoothly with variety of aromatic or heterocyclic aldehydes and variety of 1,3-dicarbonyl compounds in the presence of granite or quartz in refluxing ethanol as one pot reaction to afford the corresponding 3,4-dihydropyrimidines Ib-q (Table 1) whose composition and structures were confirmed by elemental analysis, Mass, IR, and 1 H NMR spectra of the isolated products (cf. experimental section).
In generality of this process, various 1,3-diketones and aldehydes were reacted with thiourea in refluxing ethanol using granite or quartz as the reaction catalyst to give the corresponding 3,4-dihydropyrimidin-2(1H)-thione derivatives IV (Table 2) which their structures were confirmed on the bases of the analytical and spectral data of the isolated products (cf. experimental section) (Scheme 3). On reading of the experimental results, we noted that aromatic aldehydes carrying either electron-donating or electron-withdrawing substituents reacted well under the reaction conditions to give the corresponding products in moderate to good yields high purity in case of granite or quartz. However, the obtained yields on using quartz are higher than granite either in case of urea or thiourea. This may be due to the high percentage of SiO 2 in quartz. This procedure not only preserves the simplicity of the Biginelli reaction but also produces good yields of the products with high purity. Also, the catalyst was recovered by simple filtration and reused in subsequent reactions with consistent activity.
We can use the prepared 3,4-dihydropyrimidenthiones IVa-c to synthesize newly derivatives. Thus, heating of IVa-c with methyl iodide in dry acetone in the presence of anhydrous potassium carbonate afforded the S-CH 3 derivatives Va-c which was confirmed by using elemental analysis and spectral data. The 1 H NMR illustrated the presence of singlet S-CH 3 protons.
On the other hand, heating of IVa-c in acetic anhydride afforded the corresponding 3-N-acetyl derivatives VIa-c. Structure VIc was deduced from elemental and spectral data. The mass spectrum showed the molecular ion peak at / (%) = 378 (M + , 48.03), for molecular formula C 18 H 22 N 2 O 5 S. The 1 H NMR illustrated the presence singlet N-COCH 3 protons at = 2.60 ppm, in addition to other singlet peaks at = 2.27, 3.67, and 3.77 ppm for methyl and two methoxy groups, respectively, and the absence of the NH proton at = 7.27.
In the same time, we can use the same conditions to prepare VIa,b which was elucidated by correct elemental analysis and spectral data (cf. experimental data). Also VIa-c was synthesized by the reaction of IVa-c with acetyl chloride in DMF (melting and mixed melting point) (Scheme 4).
In the same time, the pyrimidine derivatives VIIa,b can be synthesized via acetylation of the corresponding S-CH 3 derivatives Va,b using acetic anhydride. Also, it can be prepared via methylation of the N-acetyl derivatives VIa,b.  spectral data. The mass spectrum for VIIa showed the molecular ion peak at m/z (%) = 394 (M + , 12.51), while VIIb illustrated the molecular ion peak at / (%) = 332 (M + , 43.22). The 1 H NMR revealed the presence of singlet peak at = 2.50 ppm for COCH 3 protons and the absence of the singlet peak at = 7.27 ppm for NH proton. Also IR spectrum showed the absence of NH peak (Scheme 4).
Methylation of Va was carried out in methyl iodide in DMF in the presence of K 2 CO 3 anhydrous that yielded VIIIa which was confirmed by correct elemental analysis as well as spectral data. The 1 H NMR showed the absence of singlet peak at = 7.27 ppm for NH proton and the appearance of a singlet peak at = 3.33 ppm for N-CH 3 protons (Scheme 4).
Heating of IVa with ethylchloroacetate in ethanol and sodium acetate afforded ethyl 3-oxo-5,7-diphenyl-3,5,8,8atetrahydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate Xa over the unisolated intermediate ethyl 2-(2-ethoxy-2-oxoethylthio)-4,6-diphenyl-1,6 dihydropyrimidine-5-carboxylate IXa as shown in elemental analysis as well as spectral data. The mass spectrum showed the molecular ion peak at m/z (%) = 378 (M + , 60.03) for molecular formula C 21 H 18 N 2 O 3 S. The 1 H NMR revealed also the presence of one only ethyl ester group, at = 0.85 for CH 3 protons (t) and 3.85 for CH 2 (q), and also the absence of NH proton at = 7.27 ppm. The IR spectrum showed absorption bands at 1752, 1675, and 1589 cm −1 for carbonyl ester, amidic carbonyl Scheme 5 groups, and C=N, respectively. Also, the isolated product Xa was obtained via the reaction of IVa with chloroacetyl chloride or bromoacetyl bromide in benzene and drops of triethylamine as catalyst. In the same time, compound Xa can be isolated from the reaction of IVa with chloroor bromoacetic acid in acetic acid and acetic anhydride mixture in presence of anhydrous sodium acetate. Similarly, compound Xb was prepared from the reaction of IVb with ethylchloroacetate, chloroacetic acid, or chloroacetylchloride as shown in previous conditions (Scheme 5).
Compound Xa was condensed with different aromatic aldehydes in refluxing ethanolic pipredine solution to give the corresponding arylidene derivatives XIa-c. Structures XIa-c were deduced from its elemental analysis and spectral data. The 1 H NMR showed the absence of singlet peak for CH 2 protons at = 3.88 ppm and the appearance of singlet peak for =CH proton at = 7.74 ppm (Scheme 5).
On the other hand, compound Va,b was reacted with thiosemicarbazide in refluxing ethanol to give the corresponding carbazide XIVa,b instead of the corresponding

Antimicrobial Activity
There are 5 compounds (III, IVg, IVf, IVh, and IVc) that were tested and showed promising positive antibacterial activity.
All the compounds showed activity against bacteria such as Staphylococcus aureus and Escherichia coli. The IVh & IVc compounds showed positive antibacterial against S. aureus which are 14.5 mm and 14 mm, respectively, which are 0.25 and 0.75 mm less than the zone around Streptomphenicol disc. This may be due the presence of sulfur atomand pyrimidine ring.
The other three most active compounds tested are compounds IVg, IVf, and III. The activity of these compounds against Staphylococcus aureus showed positive reactions, 12.75, 12.5, and 12 mm of inhibition zones, respectively, compared to the inhibition zone of antibiotic used, as indicated in  (Table 3); this may be due to sulfur atom, two chlorine atoms, and triazine ring, respectively. All the compounds have approximately the same effect against Escherichia coli bacteria as indicated by the zone of inhibition (Table 3). In case of using these compounds as antimicrobial cytotoxicity, effect of these compounds must be examined.

Conclusion
In summary, we have found that quartz and granite are extremely useful and highly efficient new natural, solids for the synthesis of biologically potent aryl 3,4-dihydropyrimidines by means of three-component condensations of an aldehyde, 1,3-dicarbonyl compound, and urea or thiourea in a one-pot operation. This method is applicable to a wide range of substrates, including aromatic and heterocyclic aldehydes, and provides a variety of biologically relevant 3,4dihydropyrimidinones and 3,4-dihydropyrimidinthiones in high yields after short reaction times. Chemical shifts were related to that of the solvent. Mass spectra were measured on a GCMS-QP1000 EX spectrometer at 70 eV. TLC was conducted on 0.25 mm precoated silica gel plates (60F-254). Elemental analyses were carried out at the Microanalytical Center of Cairo University, Giza, Egypt. The catalyst is ground until it became fine powder. Dihydropyrimidinones (Io,p,q) and 3,4-Dihydropyrimidinthiones (IVc,h,g,f). A mixture of aldehyde (1 mmol), 1,3dicarbonyl compounds (1 mmol), urea or thiourea (1 mmol), and granite or quartz (0.5 g) in ethanol (15 mL) was heated under reflux for the required time. After completion of the reaction as monitored by T.L.C., the reaction mixture was filtered to separate the catalyst. Keep the reaction mixture overnight. The solid product was filtered under suction then recrystallized from ethanol to afford pure product.

General Procedure of Methylation of Compounds IVac.
A mixture of IVa-c (0.005 mol) and methyl iodide (0.005 mol) was dissolved in dry acetone in the presence of pot. Carbonate anhydrous was refluxed in water bath for 5 hours. The reaction mixture was filtered on hot then kept for overnight. The formed solid was filtered off and crystallized from an appropriate solvent to give Va,b,c.

Method (A).
A mixture of IVa-c (0.005 mol) and acetyl chloride (0.01 mol) was refluxed in DMF (15 mL) as a solvent containing (5 drops) of triethylamine (TEA) for 1 hour and then stirred at room temperature for overnight, and then the solution was poured into ice with vigorous stirring, and then the solid product was filtered off and recrystallized from suitable solvent to afford compounds VIa,b,c.

Method (B).
A solution of IVa-c (0.01 mol) in 15 mL of acetic anhydride was heated under reflux for 1.30 hour. The solution was then poured into 150 mL of ice-water and stirred for several hours until crystallization was complete. The precipitate was filtered and crystallized from suitable solvent to afford compounds VIa,b,c.    (VIIa,b). A solution of Va,b (0.01 mol) in 15 mL of acetic anhydride was heated under reflux for one hour. The solution was then poured into 150 mL of ice-water and stirred for several hours until crystallization was complete. The precipitate was filtered off and washed with water then crystallized from an appropriate solvent to afford VIIa,b.

Reaction of Compounds Va,b with Thiosemicarbazide.
A mixture of Va,b (0.005 mol) and thiosemicarbazide (0.07 mol) was refluxed in ethanol (20 mL) for 7 hours in a water bath, then the reaction mixture was allowed to stand for several hours at room temperature, then the solid product was filtered off and recrystallized from ethanol to formed compounds XIVa,b. (0.005 mol) was heated under reflux in (10 mL) of methanol, containing acetic acid (2.5 mL) and water (2.5 mL). After reflux for 25 hours, methanol was distilled off and the remaining solution was treated portionwise with water until precipitation was completed. After standing for several hours at room temperature, the solid product was removed by filteration to yield XVIIa,b which crystallized from ethanol.