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

Elmaghraby, A. M.; Mousa, I. A.; Harb, A. A.; Mahgoub, M. Y.

doi:https://doi.org/10.1155/2013/706437

International Scholarly Research Notices

On this page

Abstract Introduction Discussion Conclusion References Copyright Related Articles

Research Article | Open Access

Volume 2013 | Article ID 706437 | https://doi.org/10.1155/2013/706437

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

A. M. Elmaghraby,¹I. A. Mousa,¹A. A. Harb,¹and M. Y. Mahgoub¹

Academic Editor: T. C. Dinadayalane, D. K. Chand, J. Wu, S. Bellemin-Laponnaz

Received28 May 2013

Accepted01 Jul 2013

Published18 Aug 2013

Abstract

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.

1. 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 [10–18] 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 1,4-dihydropyridines 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.

2. 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 ¹H NMR spectra of the isolated products (cf. experimental section).

On the other hand, carrying out of the above reaction using of 3-benzyloxybenzaldehyde, acetyl acetone, and urea in refluxing ethanol using granite as catalyst, the corresponding 5-acetyl-4-(3-(benzyloxy)phenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one Io was isolated. However, on carrying the above reaction using quartz as a catalyst, beside the proposed 3,4-dihydropyrimidinone Io, another product with molecular formula (C₁₆H₁₆N₄O₂), was isolated from the reaction media in 25% yield. This product can be identified as 4-amino-6-(3-(benzyloxy)phenyl)-5,6-dihydro-1,3,5-triazin-2(1H)-one III based on the analytical and the spectral data of the isolated product, which revealed the presence of characteristic stretching vibrations due to NH, NH₂, and amidic CO at , 3300, and 1640 cm⁻¹ regions, respectively, in the IR spectrum. Also, the ¹H-NMR spectrum of the isolated product shows signals at (s, 2H, –CH₂–), 5.43 (s, 1H, –CH–), 5.68 (s, 2H, –NH₂), 6.70–7.46 (m, 9H, Ar), and 10.0 (s, 1H, NH) ppm. The ¹³C-NMR spectrum of the isolated product shows signals at (CH aliphatic), 62.32 (CH₂ aliphatic), 165.3 (C triazine ring), 190.4 (C=O amidic), and 111–160 (Benzene rings). This expectation is based on the observation that the 3-benzyloxybenzaldehyde condensed with two moles of urea to give the corresponding bis-ureide II as key intermediate which cyclized via elimination of H₂O to give the extremely low yield triazine derivative III [44] (Scheme 2).

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 SiO₂ 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–CH₃ derivatives Va–c which was confirmed by using elemental analysis and spectral data. The ¹H NMR illustrated the presence of singlet S–CH₃ 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 C₁₈H₂₂N₂O₅S. The ¹H NMR illustrated the presence singlet N–COCH₃ protons at ppm, in addition to other singlet peaks at , 3.67, and 3.77 ppm for methyl and two methoxy groups, respectively, and the absence of the NH proton at .

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–CH₃ derivatives Va,b using acetic anhydride. Also, it can be prepared via methylation of the N-acetyl derivatives VIa,b. Structures VIIa,b were elucidated by elemental analysis and 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 ¹H NMR revealed the presence of singlet peak at ppm for COCH₃ protons and the absence of the singlet peak at 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 K₂CO₃ anhydrous that yielded VIIIa which was confirmed by correct elemental analysis as well as spectral data. The ¹H NMR showed the absence of singlet peak at ppm for NH proton and the appearance of a singlet peak at ppm for N–CH₃ protons (Scheme 4).

Heating of IVa with ethylchloroacetate in ethanol and sodium acetate afforded ethyl 3-oxo-5,7-diphenyl-3,5,8,8a-tetrahydro-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 C₂₁H₁₈N₂O₃S. The ¹H NMR revealed also the presence of one only ethyl ester group, at for CH₃ protons (t) and 3.85 for CH₂ (q), and also the absence of NH proton at ppm. The IR spectrum showed absorption bands at 1752, 1675, and 1589 cm⁻¹ for carbonyl ester, amidic carbonyl 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 chloro- or 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 chloroacetyl-chloride 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 ¹H NMR showed the absence of singlet peak for CH₂ protons at ppm and the appearance of singlet peak for =CH proton at ppm (Scheme 5).

Aiming to the synthesizing of thiazolopyrimidine XII, we refluxed IVb with chloroacetone in ethanolic piperidine solution. However the corresponding 1-(5-acetyl-6-(4-methoxyphenyl)-4-methyl-1,6-dihydropyrimidin-2-ylthio)propan-2-one XIII was formed which was identified by elemental analysis as well as spectral data. The mass spectrum showed the molecular ion peak at (%) = 332 (M⁺, 5.30) for molecular formula C₁₇H₂₀N₂O₃S. The ¹H NMR confirmed the presence of only one NH proton at ppm and singlet peak at ppm due to CH₂ protons (Scheme 6).

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 fused pyrimidinotriazoles XV and XVI. Structures XIVa,b were established by elemental analysis and spectral data where the mass spectrum showed the molecular ion peak at (%) = 395 (M⁺, 24.13) for XIVa and at m/z (%) = 333 (M⁺, 12.18) for XIVb (Scheme 7).

On the other hand, refluxing of IVa,b in methyl alcohol in the presence of acetic acid and water (4 : 1 : 1) afforded 3,4-dihydropyrimidinone derivatives XVIIa,b. Compound XVIIa was confirmed by compare mp. (Found) = 160°C, mp. (Reported) = 158°C [48]. Also, compound XVIIb was established by compare mp. (Found) = 164–166°C; mp. (Reported) = 166-167°C [48] (Scheme 8).

3. 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.

4. 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 3,4-dihydropyrimidinones and 3,4-dihydropyrimidinthiones in high yields after short reaction times.

5. Experimental Section

5.1. General

All melting points were measured with a Gallenkamp apparatus. The IR spectra of samples were recorded in KBr via a Shimadzu FT-IR 8101 PC infrared spectrophotometer. ¹H NMR spectra were run at 300 MHz and recorded in CDCl₃/[D6] DMSO using TMS as the internal standard. 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.

5.1.1. General Procedure for the Synthesis of the Newly 3,4-Dihydropyrimidinones (Io,p,q) and 3,4-Dihydropyrimidinthiones (IVc,h,g,f)

A mixture of aldehyde (1 mmol), 1,3-dicarbonyl 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.

Ethyl-4-(3-(benzyloxy)phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Io). mp. 178–180°C. I.R (KBr): , 3100, 2950, 1700, 1630 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): (t, Hz, 3H, –O–CH₂–CH₃), 2.33 (s, 3H, CH₃), 4.08 (q, 2H, –O–CH₂–CH₃), 5.03 (s, 2H, –O–CH₂–Ph), 5.37 (s, 1H, –CH–), 5.92 (s, 1H, –NH), 6.85–6.94 (m, 4H, Ar), 7.19–7.39 (m, 5H, Ar), 8.31 (s, 1H, –NH) ppm. Mass: m/z (%): 366 (M⁺, 6.31), 275 (22.72), 183 (24.94), 91 (100.0). C₂₁H₂₂N₂O₄ (366): calculated, %: C 68.84, H 6.05, N 7.65, O 17.47; found, %: C 68.82, H 6.10, N 7.55, O 17.46. Yield quartz (65%), granite (62%).

5-Acetyl-4-(3-(benzyloxy)phenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one (Ip). mp. 192–194°C. I.R (KBr): , 3200, 2950, 1640, 1590 cm⁻¹. ¹H NMR (300 MHz, DMSO): (s, 3H, CH₃), 2.27 (s, 3H, –COCH₃), 5.05 (s, 2H, –O–CH₂–Ph), 5.20 (s, 1H, –CH–), 6.81–6.92 (m, 4H, Ar), 7.21–7.45 (m, 5H, Ar), 7.81 (s, 1H, –NH), 9.17 (s, 1H, –NH) ppm. Mass: (%): 336 (M⁺, 1.6), 293 (1.9), 245 (33), 153 (14.6), 91 (100.0). C₂₀H₂₀N₂O₃ (336): calculated, %: C 71.41, H 5.99, N 8.33, O 14.27; found, %: C 71.40, H 6.0, N 8.30, O 14.21. Yield quartz (40%), granite (63%).

Ethyl-4-(2,3-dimethoxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Iq). mp. 178–180°C. I.R (KBr): , 3100, 2950, 1700, 1640 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): (t, Hz, 3H, –O–CH₂–CH₃), 2.40 (s, 3H, CH₃), 3.87 (s, 3H, –OCH₃), 3.92 (s, 3H, –OCH₃), 4.06 (q, 2H, –O–CH₂–CH₃), 5.71 (s, 1H, –CH–), 5.72 (s, 1H, –NH), 6.73 (d, 1H, Ar), 6.87 (d, 1H, Ar), 6.98 (t, 1H, Ar), 7.27 (s, 1H, –NH) ppm. Mass: m/z (%): 320 (M⁺, 13.7), 288 (100.0), 243 (55.2), 183 (94.9), 155 (68.9), 137 (60.1), 77 (47.3). C₁₆H₂₀N₂O₅ (320): calculated, %: C 59.99, H 6.29, N 8.74, O 24.97; found, %: C 59.95, H 6.22, N 8.70, O 24.99. Yield quartz (63%), granite (60%).

Ethyl-4-(3-(benzyloxy)phenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (IVg). mp. = 180–182°C. I.R (KBr): , 3150, 2950, 1650 cm⁻¹. ¹H NMR (300 MHz, DMSO): (t, Hz, 3H, –O–CH₂–CH₃), 2.27 (s, 3H, CH₃), 4.01 (q, 2H, –O–CH₂–CH₃), 5.05 (s, 2H, –O–CH₂–Ph), 5.15 (s, 1H, –CH–), 6.80 (m, 4H, Ar), 7.23–7.42 (m, 5H, Ar), 9.60 (s, 1H, –NH), 10.30 (s, 1H, –NH) ppm. Mass: m/z (%): 382 (M⁺, 17.6), 199 (12.2), 91 (100.0). C₂₁H₂₂N₂O₃S (382): calculated, %: C 65.95, H 5.80, N 7.32, O 12.55, S 8.38; found, %: C 65.89, H 5.60, N 7.35, O 17.46, S 8.36. Yield quartz (66%), granite (60%).

Ethyl-4-(2,3-dimethoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (IVc). mp. 181–183°C. I.R (KBr): , 3100, 2950, 1705 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): (t, Hz, 3H, –O–CH₂–CH₃), 2.42 (s, 3H, CH₃), 3.86 (s, 3H, –OCH₃), 3.93 (s, 3H, –OCH₃), 4.05 (q, 2H, –O–CH₂–CH₃), 5.71 (s, 1H, –CH–), 6.68 (d, 1H, Ar), 6.88 (d, 1H, Ar), 6.99 (t, 1H, Ar), 7.26 (s, 1H, –NH), 8.10 (s, 1H, –NH) ppm. Mass: (%): 336 (M⁺, 76.4), 305 (86.1), 289 (81.5), 263 (100.0), 199 (87.7), 171 (63.3), 153 (31.5), 77 (44.6). C₁₆H₂₀N₂O₄S (336): calculated, %: C 57.12, H 5.99, N 8.33, O 19.02, S 9.53; found, %: C 57.13, H 5.96, N 8.35, O 19.06, S 9.51. Yield quartz (64%), granite (63%).

Ethyl-4-(2,5-dimethoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (IVh). mp. 188–190°C. I.R (KBr): , 3100, 2940, 1700 cm⁻¹. ¹H NMR (300 MHz, DMSO): (t, Hz, 3H, –O–CH₂–CH₃), 2.27 (s, 3H, CH₃), 3.65 (s, 3H, –OCH₃), 3.72 (s, 3H, –OCH₃), 3.96 (q, 2H, –O–CH₂–CH₃), 5.44 (s, 1H, –CH–), 6.57 (s, 1H, Ar), 6.83 (d, 1H, Ar), 6.94 (d, 1H, Ar), 9.24 (s, 1H, –NH), 10.24 (s, 1H, –NH) ppm. Mass: m/z (%): 338 (M⁺, 10.97), 279 (10.49), 256 (19.23), 166 (45.38), 149 (100.0), 105 (28.13), 69 (90.57). C₁₆H₂₀N₂O₄S (336): calculated, %: C 57.12, H 5.99, N 8.33, O 19.02, S 9.53; found, %: C 57.14, H 5.96, N 8.30, O 19.04, S 9.56. Yield quartz (64%), granite (60%).

Ethyl-4-(2,6-dichlorophenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (IVf). mp. 222–224°C. I.R (KBr): , 3000, 2900, 1750, 1640 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): (t, Hz, 3H, –O–CH₂–CH₃), 2.23 (s, 3H, CH₃), 3.91 (q, 2H, –O–CH₂–CH₃), 6.28 (s, 1H, –CH–), 7.05–7.23 (m, 3H, Ar), 7.94 (s, 1H, –NH), 8.32 (s, 1H, –NH) ppm. Mass: m/z (%): 344 (M⁺, 23.9), 348 (M⁺⁴, 7.6), 315 (34.5), 199 (100.0), 171 (36.4), 153 (16.2). C₁₄H₁₄Cl₂N₂O₂S (344): calculated, %: C 48.70, H 4.09, Cl 20.54, N 8.11, O 9.27, S 9.29; found, %: C 48.72, H 4.04, Cl 20.50, N 8.13, O 9.29, S 9.30. Yield quartz (55%), granite (60%).

4-Amino-6-(3-(benzyloxy)phenyl)-5,6-dihydro-1,3,5-triazin-2(1H)-one (III). mp. 172–174°C I.R (KBr): , 3300, 1640 cm⁻¹. ¹H NMR (300 MHz, DMSO): (s, 2H, –CH₂–), 5.43 (s, 1H, –CH–), 5.68 (s, 2H, –NH₂), 6.70–6.92 (m, 4H, Ar), 6.98 (s, 1H, NH), 7.23–7.46 (m, 5H, Ar), 10.0 (s, 1H, NH) ppm. The ¹³C-NMR (300 MHz, DMSO) (CH aliphatic), 62.32 (CH₂ aliphatic), 165.3 (C triazine ring), 190.4 (C=O amidic), 111–160 (benzene rings). Mass: m/z (%): 296 (M⁺, 54.58), 294 (82.76), 253 (57.20), 227 (63.30), 203 (100.0), 182 (31.01), 171 (55.77), 131 (99.09), 104 (29.73). C₁₆H₁₆N₄O₂ (296): calculated, %: C 64.85, H 5.44, N 18.91, O 10.80; found, %: C 64.82, H 5.40, N 18.93, O 10.82. Yield quartz (25%).

5.1.2. General Procedure of Methylation of Compounds IVa–c

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.

Ethyl-2-(methylthio)-4,6-diphenyl-1,6-dihydropyrimidine-5-carboxylate (Va). The formed solid was crystallized from petroleum ether/benzene 2 : 1; mp. = 158–160°C; I.R (KBr): , 2982, 2807, 1676, 1614, 1493 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): (t, Hz, 3H, –O–CH₂–CH₃), 2.49 (s, 3H, –SCH₃), 3.86 (q, 2H, –O–CH₂–CH₃), 5.74 (s, 1H, –CH–), 7.27 (s, 1H, NH), 7.28–7.48 (m, 10H, Ar) ppm; mass: (%): 352 (M⁺, 23.35), 337 (33.58), 323 (68.32), 275 (100.0), 77 (25.52); C₂₀H₂₀N₂O₂S (352): calculated, %: C 68.16, H 5.72, N 7.95, O 9.08, S 9.10; Found, %: C 68.13, H 5.75, N 7.97, O 9.10, S 9.12; yield (77%).

1-(6-(4-Methoxyphenyl)-4-methyl-2-(methylthio)-1,6-dihydropyrimidin-5-yl)ethanone (Vb). The formed solid was crystallized from petroleum ether/ethanol 1 : 1; mp. = 126–128°C; I.R (KBr): , 2950, 2928, 1639, 1594 cm⁻¹; ¹H NMR (300 MHz, DMSO): (s, 3H, –CH₃), 2.23 (s, 3H, –SCH₃), 2.28 (s, 3H, –COCH₃), 3.70 (s, 3H, –OCH₃), 5.54 (s, 1H, –CH–), 6.82–7.15 (d, d, 4H, Ar), 9.57 (s, 1H, –NH) ppm; mass: (%): 288 (M⁺, 29.40), 250 (22.10), 183 (19.10), 73 (67.60), 57 (100.0); C₁₅H₁₈N₂O₂S (290): calculated, %: C 62.04, H 6.25, N 9.65, O 11.02, S 11.04; found, %: C 62.03, H 6.26, N 9.65, O 11.04, S 11.03; yield (86%).

Ethyl-6-(2,3-dimethoxyphenyl)-4-methyl-2-(methylthio)-1,6-dihydropyrimidine-5-carboxylate (Vc). The solid product was crystallized from petroleum ether (60–80); mp. = 140°C; I.R (KBr): , 2935, 2832, 1706, 1669, 1594 cm⁻¹; ¹H NMR (300 MHz, DMSO): (t, Hz, 3H, CH₃CH₂O–), 2.39 (s, 3H, –CH₃), 2.45 (s, 3H, –SCH₃), 3.87 (s, 3H, –OCH₃), 3.93 (s, 3H, –OCH₃), 4.06 (q, 2H, CH₃CH₂O–), 5.85 (s, 1H, –CH), 6.77–7.02 (m, 3H, Ar), 7.27 (s, 1H, –NH) ppm; mass: m/z (%): 350 (M⁺, 20.56), 335 (36.97), 321 (64.29), 303 (40.44), 213 (100.0), 77 (23.14); C₁₇H₂₂N₂O₄S (350): calculated, %: C 58.27, H 6.33, N 7.99, O 18.26, S 9.15; found, %: C 58.26, H 6.33, N 7.97, O 18.27, S 9.16; yield (74%).

5.1.3. Acylation of Compounds IVa–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.

Ethyl 3-acetyl-4-(2,3-dimethoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (VIc). The solid product was recrystallized from ethanol; method (A): yield (81%). method (B): yield (78%); mp. = 186°C; I.R (KBr): , 2996, 2944, 2837, 1702, 1671 cm⁻¹; ¹H NMR (300 MHz, DMSO): (t, Hz, 3H, CH₃CH₂O–), 2.27 (s, 3H, –CH₃), 2.60 (s, 3H, –COCH₃), 3.67 (s, 3H, –OCH₃), 3.77 (s, 3H, –OCH₃), 4.08 (q, 2H, CH₃CH₂O–), 5.50 (s, 1H, –CH), 6.68–7.0 (m, 3H, Ar), 11.6 (s, 1H, –NH) ppm; mass: (%): 378 (M⁺, 48.03), 335 (96.81), 289 (100.0), 263 (45.57), 199 (33.62), 77 (22.44); C₁₈H₂₂N₂O₅S (378): calculated, %: C 57.13, H 5.86, N 7.40, O 21.14, S 8.47; found, %: C 57.14, H 5.85, N 7.41, O 21.13, S 8.45.

Ethyl 3-acetyl-4,6-diphenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (VIa). The solid product was recrystallized from benzene; method (A): yield (80%); method (B): yield (85%). mp. 136°C; I.R (KBr): , 2986, 1642, 1599, 1494 cm⁻¹; mass: (%): 380 (M⁺, 37.39), 337 (100.0), 307 (25.7), 265 (57.72), 104 (65.03); C₂₁H₂₀N₂O₃S (380): calculated, %: C 66.29, H 5.30, N 7.36, O 12.62, S 8.43; found, %: C 66.28, H 5.31, N 7.35, O 12.63, S 8.42.

1,1 ′ -(6-(4-Methoxyphenyl)-4-methyl-2-thioxo-2,3-dihydropyrimidine-1,5(6H)-diyl)diethanone (VIb). The solid product was recrystallized from ethanol; method (A): yield (65%); method (B): yield (70%). mp. = 130°C; I.R (KBr): , 2962, 1698, 1609, 1509 cm⁻¹.

5.1.4. Synthesis of Compounds (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.

Ethyl 1-acetyl-2-(methylthio)-4,6-diphenyl-1,6-dihydropyrimidine-5-carboxylate (VIIa). The solid product crystallized from petroleum ether (60–80); yield (90%); mp. = 102°C; I.R (KBr): , 1697, 1601, 1533 cm⁻¹; ¹H NMR (300 MHz,CDCl₃): 0.97 (t, Hz, 3H, CH₃CH₂O–), 2.50 (s, 3H, –SCH₃), 2.50 (s, 3H, –COCH₃), 4.02 (q, 2H, CH₃CH₂O–), 6.66 (s, 1H, –CH), 7.27–7.60 (m, 10H, Ar) ppm; mass: (%): 394 (M⁺, 12.51), 351 (100.0), 337 (10.86), 323 (28.06), 275 (84.24), 129 (18.40), 77 (29.31); C₂₂H₂₂N₂O₃S (394): calculated, %: C 66.98, H 5.62, N 7.10, O 12.17, S 8.13; found, %: C 66.97, H 5.63, N 7.09, O 12.18, S 8.12.

1,1 ′ -(6-(4-Methoxyphenyl)-4-methyl-2-(methylthio)pyrimidine-1,5(6H)-diyl)diethanone (VIIb). The precipitated product was crystallized from benzene; yield (86%); mp. = 180°C. I.R (KBr): , 1675, 1568 cm⁻¹; mass: (%): 332 (M⁺, 43.22), 312 (39.56), 278 (51.28), 100 (100.0), 67 (50.55); C₁₇H₂₀N₂O₃S (332): calculated, %: C 61.42, H 6.06, N 8.43, O 14.44, S 9.65; found, %: C 61.43, H 6.04, N 8.46, O 14.45, S 9.66.

Synthesis of Ethyl 1-Methyl-2-(methylthio)-4,6-diphenyl-1,6-dihydro-pyrimidine-5-carboxylate (VIIIa). A mixture of Va (0.005 mol) and methyl iodide (0.005 mol) was dissolved in DMF in the presence of pot. Carbonate anhydrous was refluxed in water bath for 4 hours. The reaction mixture was filtered on hot then the filtrate was cooled and poured onto cold water with stirring; the formed solid was filtered off and crystallized from ethanol : benzene (3 : 1); mp. = 92°C; I.R (KBr): , 2977, 2932, 1717, 1580 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): (t, Hz, 3H, –O–CH₂–CH₃), 2.57 (s, 3H, –SCH₃), 3.33 (s, 3H, –NCH₃), 4.01 (q, 2H, –O–CH₂–CH₃), 5.74 (s, 1H, –CH–), 7.49–7.64 (m, 10H, Ar) ppm; mass: (%): 366 (M⁺, 5.21), 350 (100.0), 321 (28.48), 129 (30.96), 77 (15.87); C₂₁H₂₂N₂O₂S (366): calculated, %: C 68.82, H 6.05, N 7.64, O 8.73, S 8.75; found, %: C 68.81, H 6.04, N 7.65, O 8.73, S 8.75; yield (25%).

5.1.5. General Procedure for the Preparation of Compounds (Xa,b)

Method (A). A mixture of IVa,b (1 mmol) and chloroacetic acid (1 mmol) was dissolved in 40 mL of a mixture of (AC)₂O/ACOH (1 : 3) in the presence of 3 gm anhydrous sodium acetate that was refluxed for 4 hours. The reaction mixture was cold and poured onto cold water with stirring; the solid formation was filtered off and crystallized from benzene/ethanol (3 : 1) to give Xa,b.

Method (B). A mixture of IVa,b (0.005 mol) and chloroacetyl chloride with 2 drops of T.E.A was refluxed in benzene for 3 hours. Then the reaction mixture was filtered off through heating then dried and crystallized from benzene/ethanol (3 : 1) to give Xa,b.

Method (C). A mixture of IVa,b (0.005 mol), ethylchloro acetate (0.005 mol), and sodium acetate trihydrate (1 gm) was refluxed in ethanol for 5 hours. The reaction mixture was filtered and kept for overnight. The solid formation was filtered off then dried and crystallized from benzene/ethanol 3/1 to afforded Xa,b.

Ethyl 3-oxo-5,7-diphenyl-3,5,8,8a-tetrahydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate (Xa). The formed solid was crystallized from benzene/ethanol (3 : 1); method (A): yield (72%); method (B): yield (75%); method (C): yield (84%). mp. = 136–8°C; I.R (KBr): , 2931, 2900, 1752, 1675, 1589 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): (t, Hz, 3H, –O–CH₂–CH₃), 3.85 (q, 2H, –O–CH₂–CH₃), 3.88 (s, 2H, –CH₂CO–), 6.19 (s, 1H, –CH–), 7.27–7.51 (m, 10H, Ar) ppm; mass: (%): 378 (M⁺, 60.03), 350 (16.30), 301 (100.0), 273 (35.62), 129 (25.11), 77 (35.57); C₂₁H₁₈N₂O₃S (378): calculated, %: C 66.65, H 4.79, N 7.40, O 12.68, S 8.47; found, %: C 66.65, H 4.78, N 7.41, O 12.67, S 8.47.

6-Acetyl-5-(4-methoxyphenyl)-7-methyl-8,8a-dihydro-2H-thiazolo[3,2-a]pyrimidin-3(5H)-one (Xb). The formed solid was crystallized from benzene and drops of ethanol; method (A): yield (42%). method (B): yield (34%). method (C): yield (40%). mp. = 160–162°C; I.R (KBr): , 2936, 2876, 1756, 1655, 1612 cm⁻¹; ¹H NMR (300 MHz, DMSO): (s, 3H, CH₃), 2.34 (s, 3H, –COCH₃), 3.70 (s, 3H, OCH₃), 4.15 (s, 2H, –CH₂CO–), 5.98 (s, 1H, –CH–), 6.86–7.21 (d, d, 4H, Ar) ppm; mass: (%): 316 (M⁺, 35.08), 301 (5.32), 273 (100.0), 245 (28.08), 230 (4.72), 181 (19.36), 115 (25.14), 77 (26.0); C₁₆H₁₈N₂O₃S (316): calculated, %: C 60.36, H 5.70, N 8.80, O 15.08, S 10.07; found, %: C 60.35, H 5.70, N 8.81, O 15.06, S 10.08.

5.1.6. Synthesis of Compounds (XIa,b,c)

A mixture of compound Xa (1 mmol), aromatic aldehyde (1 mmol), and 2 drops of piperidine was refluxed in ethanol for 2 hours. The reaction mixture kept overnight, then the solid product was filtered off and crystallized from EtOH to afford compound XI.

(E)-Ethyl 2-(4-chlorobenzylidene)-3-oxo-5,7-diphenyl-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate (XIa). mp. = 164–6°C; I.R (KBr): , 1721, 1620, 1559 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): (t, Hz, 3H, –O–CH₂–CH₃), 3.89 (q, 2H, –O–CH₂–CH₃), 6.34 (s, 1H, –CH–), 7.27–7.54 (m, 14H, Ar), 7.74 (s, 1H, =CH–) ppm; mass: (%): 500 (M⁺², 45.80), 503 (M⁺⁴, 9.82), 423 (67.99), 168 (100.0), 77 (77.69); C₂₈H₂₁ClN₂O₃S (500): calculated, %: C 67.13, H 4.22, Cl 7.08, N 5.59, O 9.58, S 6.40; found, %: C 67.14, H 4.24, Cl 7.07, N 5.60, O 9.59, S 6.42; yield (88%).

(E)-Ethyl 2-(2,3-dimethoxybenzylidene)-3-oxo-5,7-diphenyl-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate (XIb). mp. = 148°C; I.R (KBr): , 1712, 1630, 1581 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): (t, Hz, 3H, –O–CH₂–CH₃), 3.77 (s, 3H, –OCH₃), 3.85 (s, 3H, –OCH₃), 6.34 (s, 1H, –CH–), 6.84 (d, 1H Ar), 6.96 (s, 1H, Ar), 6.98 (d, 1H, Ar), 7.35–7.55 (m, 10H, Ar), 8.09 (s, 1H, =CH–) ppm; mass: (%): 526 (M⁺¹, 42.98), 449 (100.0), 363 (27.0), 77 (5.37); C₃₀H₂₆N₂O₅S (526): calculated, %: C 68.42, H 4.98, N 5.32, O 15.19, S 6.09; found, %: C 68.43, H 4.99, N 5.33, O 15.20, S 6.10; Yield (85%).

(E)-Ethyl2-(3-nitrobenzylidene)-3-oxo-5,7-diphenyl-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate (XIc). mp. = 158–160°C; I.R (KBr): , 2998, 1716, 1617, 1557, 1563, 1530 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): (t, Hz, 3H, –O–CH₂–CH₃), 3.86 (q, 2H, –O–CH₂–CH₃), 6.31 (s, 1H, –CH–), 7.20–7.75 (m, 14H, Ar), 8.31 (s, 1H, =CH–) ppm; C₂₈H₂₁N₃O₅S (511): calculated, %: C 65.74, H 4.14, N 8.21, O 15.64, S 6.27; found, %: C 65.75, H 4.13, N 8.22, O 15.63, S 6.28; yield (92%).

Synthesis of 1-[5-Acetyl-6-(4-methoxy-phenyl)-4-methyl-1,6-dihydro-pyrimidin-2-ylsulfanyl]-propan-2-one (XIII). A mixture of IVb (0.005 mol), chloroacetone (0.005 mol), and 2 drops of piperidine was refluxed in ethanol for 6 hours. The reaction mixture was kept for overnight. The solid formation was filtered off then dried and crystallized from benzene/ethanol (1 : 1); mp. = 215°C; I.R (KBr): , 3004, 1644, 1608, 1524 cm⁻¹; ¹H NMR (300 MHz, DMSO): (s, 3H, –CH₃), 2.26 (s, 3H, –COCH₃), 2.30 (s, 3H, –COCH₃), 2.46 (s, 2H, CH₂), 3.71 (s, 3H, –OCH₃), 6.44 (s, 1H, –CH), 6.90–7.28 (d, d, 4H, Ar), 7.11 (s, 1H, –NH); mass: (%): 332 (M⁺, 5.30), 298 (5.30), 270 (33.60), 245 (25.7), 91 (100.0); C₁₇H₂₀N₂O₃S (332): calculated, %: C 61.42, H 6.06, N 8.43, O 14.44, S 9.65; found, %: C 61.43, H 6.05, N 8.43, O 14.42, S 9.66; yield (48%).

5.1.7. 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.

Ethyl 2-(2-carbamothioylhydrazinyl)-4,6-diphenyl-1,6-dihydro-pyrimidine-5-carboxylate (XIVa). Method (A): yield (51%); method (B): yield (46%); mp. = 170–172°C I.R (KBr): , 3262, 3175, 1644, 1620 cm⁻¹. ¹H NMR (300 MHz, DMSO): (t, Hz, 3H, OCH₂CH₃), 3.74 (q, 2H, OCH₂CH₃), 4.50 (s, 2H, –NH₂), 5.26 (s, –CH), 7.19–7.58 (m, 10H, Ar), 8.65 (s, 1H, –NH), 9.78 (s, 1H, –NH), 10.51 (s, 1H, –NH) ppm; mass: (%): 395 (M⁺, 24.13), 379 (21.13), 368 (49.20), 352 (76.97), 105 (86.51), 55 (100.0); C₂₀H₂₁N₅O₂S (395): calculated, %: C 60.74, H 5.35, N 17.71, O 8.09, S 8.11; found, %: C 60.73, H 5.36, N 17.71, O 8.08.

2-(5-Acetyl-6-(4-methoxyphenyl)-4-methyl-1,6-dihydropyrimidin-2-yl)hydrazinecarbothioamide (XIVb). Method (A): yield (64%); method (B): yield (48%); mp. = 92°C; I.R (KBr): , 3145, 2049, 1604, 1510 cm⁻¹; mass: (%): 333 (M⁺, 12.18), 274 (14.92), 233 (27.31), 215 (84.93), 178 (90.61), 136 (100.0), 76 (65.0), 51 (23.07); C₁₅H₁₉N₅O₂S (333): calculated, %: C 54.04, H 5.74, N 21.01, O 9.60, S 9.62; found, %: C 54.05, H 5.74, N 21.0, O 9.61, S 9.62.

5.1.8. Synthesis of Compounds XVIIa,b

Compound IVa,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.

Ethyl 2-oxo-4,6-diphenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (XVIIa). mp. (found) = 160°C, mp. (reported) = 158°C [48]; yield (77%).

5-Acetyl-4-(4-methoxyphenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one (XVIIb). mp. (found) = 164–166°C; mp. (reported) = 166-167°C [48]; yield (71%).

References

E. W. Hurst and R. Hull, “Two new synthetic substances active against viruses of the psittacosis-lymphogranuloma- trachoma group,” Journal of Medicinal Chemistry, vol. 3, no. 2, pp. 215–229, 1961.
View at: Publisher Site | Google Scholar
M. Ashok, B. S. Holla, and N. S. Kumari, “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,” European Journal of Medicinal Chemistry, vol. 42, no. 3, pp. 380–385, 2007.
View at: Publisher Site | Google Scholar
S. S. Bahekar and D. B. Shinde, “Synthesis and anti-inflammatory activity of some [4,6-(4-substituted aryl)-2-thioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-acetic acid derivatives,” Bioorganic & Medicinal Chemistry Letters, vol. 14, no. 7, pp. 1733–1736, 2004.
View at: Publisher Site | Google Scholar
T. U. Mayer, T. M. Kapoor, S. J. Haggarty, R. W. King, S. L. Schreiber, and T. J. Mitchison, “Smart molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen,” Science, vol. 286, no. 5441, pp. 971–974, 1999.
View at: Publisher Site | Google Scholar
C. O. Kappe, “Recent advances in the Biginelli dihydropyrimidine synthesis. New tricks from an old dog,” Accounts of Chemical Research, vol. 33, no. 12, pp. 879–888, 2000.
View at: Publisher Site | Google Scholar
A. D. Patil, N. V. Kumar, W. C. Kokke et al., “Novel alkaloids from the sponge Batzella sp.: inhibitors of HIV gp120-human CD4 binding,” Journal of Organic Chemistry, vol. 60, no. 5, pp. 1182–1188, 1995.
View at: Google Scholar
B. B. Snider, J. Chen, A. D. Patil, and A. J. Freyer, “Synthesis of the tricyclic portions of batzelladines A, B and D. Revision of the stereochemistry of batzelladines A and D,” Tetrahedron Letters, vol. 37, no. 39, pp. 6977–6980, 1996.
View at: Publisher Site | Google Scholar
P. Biginelli, “Derivati aldeidureidici degli eteri acetil-ed ossalacetico,” Gazzetta Chimica Italiana, vol. 23, pp. 360–416, 1893.
View at: Google Scholar
P. Wipf and A. Cunningham, “A solid phase protocol of the Biginelli dihydropyrimidine synthesis suitable for combinatorial chemistry,” Tetrahedron Letters, vol. 36, no. 43, pp. 7819–7822, 1995.
View at: Publisher Site | Google Scholar
C. O. Kappe, “100 years of the Biginelli dihydropyrimidine synthesis,” Tetrahedron, vol. 49, no. 32, pp. 6937–6963, 1993.
View at: Publisher Site | Google Scholar
D. Dallinger, A. Stadler, and C. O. Kappe, “Solid- and solution-phase synthesis of bioactive dihydropyrimidines,” Pure and Applied Chemistry, vol. 76, no. 5, pp. 1017–1024, 2004.
View at: Google Scholar
C. O. Kappe, “4-aryldihydropyrimidines via the Biginelli condensation: aza-analogs of nifedipine-type calcium channel modulators,” Molecules, vol. 3, no. 1, pp. 1–9, 1998.
View at: Publisher Site | Google Scholar
C. O. Kappe and A. Stadler, “The Biginelli dihydropyrimidine synthesis,” Organic Reactions, vol. 63, pp. 1–116, 2004.
View at: Google Scholar
C. Simon, T. Constantieux, and J. Rodriguez, “Utilisation of 1,3-dicarbonyl derivatives in multicomponent reactions,” European Journal of Organic Chemistry, no. 24, pp. 4957–4980, 2004.
View at: Publisher Site | Google Scholar
C. O. Kappe, “The generation of dihydropyrimidine libraries utilizing Biginelli multicomponent chemistry,” QSAR and Combinatorial Science, vol. 22, no. 6, pp. 630–645, 2003.
View at: Google Scholar
H. E. Zaugg and W. B. Martin, “α-amidoalkylations at carbon,” in Organic Reactions, vol. 14, pp. 88–90, John Wiley & Sons, New York, NY, USA, 1965.
View at: Publisher Site | Google Scholar
C. O. Kappe, “The Biginelli reaction,” in Multicomponent Reactions, pp. 95–120, John Wiley & Sons, New York, NY, USA, 2005.
View at: Google Scholar
L. Z. Gong, X. H. Chen, and X. Y. Xu, “Asymmetric organocatalytic biginelli reactions: a new approach to quickly access optically active 3,4-dihydropyrimidin-2-(1H)-ones,” Chemistry—A European Journal, vol. 13, no. 32, pp. 8920–8926, 2007.
View at: Publisher Site | Google Scholar
A. Dondoni and A. Massi, “Parallel synthesis of dihydropyrimidinones using Yb(III)-resin and polymer-supported scavengers under solvent-free conditions. A green chemistry approach to the Biginelli reaction,” Tetrahedron Letters, vol. 42, no. 45, pp. 7975–7978, 2001.
View at: Publisher Site | Google Scholar
A. Shaabani and A. Bazgir, “Microwave-assisted efficient synthesis of spiro-fused heterocycles under solvent-free conditions,” Tetrahedron Letters, vol. 45, no. 12, pp. 2575–2577, 2004.
View at: Publisher Site | Google Scholar
B. J. Ahn, M. S. Gang, K. Chae, Y. Oh, J. Shin, and W. Chalg, “A microwave-assisted synthesis of 3,4-dihydro-pyrimidin-2-(1H)-ones catalyzed by FeCl₃-supported Nanopore Silica under solvent-free conditions,” Journal of Industrial and Engineering Chemistry, vol. 14, no. 3, pp. 401–405, 2008.
View at: Publisher Site | Google Scholar
X. Zhang, Y. Li, C. Liu, and J. Wang, “An efficient synthesis of 4-substituted pyrazolyl-3,4-dihydropyrimidin-2(1H)-(thio)ones catalyzed by Mg(ClO₄)₂ under ultrasound irradiation,” Journal of Molecular Catalysis A, vol. 253, no. 1-2, pp. 207–211, 2006.
View at: Publisher Site | Google Scholar
J. T. Li, J. F. Han, J. H. Yang, and T. S. Li, “An efficient synthesis of 3,4-dihydropyrimidin-2-ones catalyzed by NH₂SO₃H under ultrasound irradiation,” Ultrasonics Sonochemistry, vol. 10, no. 3, pp. 119–122, 2003.
View at: Publisher Site | Google Scholar
N. Foroughifar, A. Mobinikhaledi, and H. Fathinejad Jirandehi, “Synthesis of some biginelli compounds in solvent medium using a photochemistry method,” Phosphorus, Sulfur and Silicon and the Related Elements, vol. 178, no. 3, pp. 495–500, 2003.
View at: Publisher Site | Google Scholar
E. H. Hu, D. R. Sidler, and U. H. Dolling, “Unprecedented catalytic three component one-pot condensation reaction: an efficient synthesis of 5-alkoxycarbonyl-4-aryl-3,4-dihydropyrimidin- 2(1H)-ones,” Journal of Organic Chemistry, vol. 63, no. 10, pp. 3454–3457, 1998.
View at: Publisher Site | Google Scholar
C. V. Reddy, M. Mahesh, P. V. K. Raju, T. R. Babu, and V. V. N. Reddy, “Zirconium(IV) chloride catalyzed one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones,” Tetrahedron Letters, vol. 43, no. 14, pp. 2657–2659, 2002.
View at: Publisher Site | Google Scholar
A. Kumar and R. A. Maurya, “An efficient bakers' yeast catalyzed synthesis of 3,4-dihydropyrimidin-2-(1H)-ones,” Tetrahedron Letters, vol. 48, no. 26, pp. 4569–4571, 2007.
View at: Publisher Site | Google Scholar
Y. Q. Zhang, C. Wang, G. S. Li, J. C. Li, H. M. Liu, and Q. H. Wu, “One-pot Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones Catalyzed by Expandable Graphite,” Chinese Journal of Organic Chemistry, vol. 25, pp. 1265–1267, 2005.
View at: Google Scholar
R. V. Yarapathi, S. Kurva, and S. Tammishetti, “Synthesis of 3,4-dihydropyrimidin-2(1H)ones using reusable poly(4-vinylpyridine-co-divinylbenzene)-Cu(II)complex,” Catalysis Communications, vol. 5, no. 9, pp. 511–513, 2004.
View at: Publisher Site | Google Scholar
J. Azizian, A. A. Mohammadi, A. R. Karimi, and M. R. Mohammadizadeh, “KAl(SO₄)₂·12H₂O supported on silica gel as a novel heterogeneous system catalyzed biginelli reaction: one-pot synthesis of di-hydropyrimidinones under solvent-free conditions,” Applied Catalysis A, vol. 300, no. 1, pp. 85–88, 2006.
View at: Publisher Site | Google Scholar
N. Mizuno and M. Misono, “Heterogeneous catalysis,” Chemical Reviews, vol. 98, no. 1, pp. 199–217, 1998.
View at: Google Scholar
A. A. Bakibaev and V. D. Filimonov, “Synthesis of hydrogenated acridine-1,8-diones & 1,4-dihydropyrimidines by reaction of urea with 1,3-dicarbonyl compounds,” Russian Journal of Organic Chemistry, vol. 27, pp. 854–859, 1991.
View at: Google Scholar
Y. Yu, D. Liu, C. Liu, and G. Luo, “One-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones using chloroacetic acid as catalyst,” Bioorganic & Medicinal Chemistry Letters, vol. 17, no. 12, pp. 3508–3510, 2007.
View at: Publisher Site | Google Scholar
A. S. Paraskar, G. K. Dewkar, and A. Sudalai, “Cu(OTf)₂: a reusable catalyst for high-yield synthesis of 3,4-dihydropyrimidin-2(1H)-ones,” Tetrahedron Letters, vol. 44, no. 16, pp. 3305–3308, 2003.
View at: Publisher Site | Google Scholar
M. Gohain, D. Prajapati, and S. Sandhub, “A novel Cu-catalysed three-component one-pot synthesis of dihydropyrimidin-2(1H)-ones using microwaves under solvent free conditions,” Synlett, p. 235, 2004.
View at: Google Scholar
Y. Ma, C. Qian, L. Wang, and M. Yang, “Lanthanide triflate catalyzed Biginelli reaction. one-pot synthesis of dihydropyrimidinones under solvent-free conditions,” The Journal of Organic Chemistry, vol. 65, no. 12, pp. 3864–3868, 2000.
View at: Publisher Site | Google Scholar
V. T. Kamble, D. B. Muley, S. T. Atkore, and S. D. Dakore, “Three component reaction: an efficient synthesis of 3,4-dihydropyrimidin-2(1H)-ones and thiones using heterogeneous catalyst,” Chinese Journal of Chemistry, vol. 28, no. 3, pp. 388–392, 2010.
View at: Publisher Site | Google Scholar
B. Gangadasu, S. Palaniappan, and V. J. Rao, “One-pot synthesis of dihydropyrimidinones using polyaniline-bismoclite complex. A facile and reusable catalyst for the biginelli reaction,” Synlett, no. 7, pp. 1285–1287, 2004.
View at: Google Scholar
A. K. Mitra and K. Banerjee, “Clay catalysed synthesis of dihydropyrimidinones under solvent-free conditions,” Synlett, no. 10, pp. 1509–1511, 2003.
View at: Google Scholar
J. Mabry and B. Ganem, “Studies on the Biginelli reaction: a mild and selective route to 3,4-dihydropyrimidin-2(1H)-ones via enamine intermediates,” Tetrahedron Letters, vol. 47, no. 1, pp. 55–56, 2006.
View at: Publisher Site | Google Scholar
T. Ghorge, R. Tahilramani, and D. V. Mehta, “Condensed heterocycles from 5-ethoxycarbonyl-6-methyltetrahydropyrimidin-2-ones,” Communications, pp. 405–407, 1975.
View at: Google Scholar
N.-Y. Fu, Y.-F. Yuan, Z. Cao, S.-W. Wang, J.-T. Wang, and C. Peppe, “Indium(III) bromide-catalyzed preparation of dihydropyrimidinones: improved protocol conditions for the Biginelli reaction,” Tetrahedron, vol. 58, no. 24, pp. 4801–4807, 2002.
View at: Publisher Site | Google Scholar
J. S. Yadav, B. V. S. Reddy, P. Sridhar et al., “Green protocol for the biginelli three-component reaction: Ag 3PW₁₂O₄₀ as a novel, water-tolerant heteropolyacid for the synthesis of 3,4-dihydropyrimidinones,” European Journal of Organic Chemistry, no. 3, pp. 552–557, 2004.
View at: Google Scholar
K. Folkers and T. B. Johnson, “Researches on pyrimidines. CXXXVI. The mechanism of formation of tetrahydropyrimidines by the Biginelli reaction,” Journal of the American Chemical Society, vol. 55, no. 9, pp. 3784–3791, 1933.
View at: Google Scholar
R. D. Carlos, D. Bernardi, and G. Kirsch, “ZrCl₄ or ZrOCl₂ under neat conditions: optimized green alternatives for the Biginelli reaction,” Tetrahedron Letters, vol. 48, no. 33, pp. 5777–5780, 2007.
View at: Publisher Site | Google Scholar
N. Foroughifar, A. Mobinikhaledi, H. F. Jirandehi, and S. Memar, “Microwave-assisted synthesis of some BI- and tricyclic pyrimidine derivatives,” Phosphorus, Sulfur and Silicon and the Related Elements, vol. 178, no. 6, pp. 1269–1276, 2003.
View at: Publisher Site | Google Scholar
B. Ahmed, R. A. Khan, Habibullah, and M. Keshari, “An improved synthesis of Biginelli-type compounds via phase-transfer catalysis,” Tetrahedron Letters, vol. 50, no. 24, pp. 2889–2892, 2009.
View at: Publisher Site | Google Scholar
E. Ramu, V. Kotra, N. Bansal, R. Varala, and S. R. Adapa, “Green approach for the efficient synthesis of Biginelli compounds promoted by citric acid under solvent-free conditions,” RASĀYAN Journal of Chemistry, vol. 1, no. 1, pp. 188–194, 2008.
View at: Google Scholar

Copyright

Copyright © 2013 A. M. Elmaghraby et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

10570

Downloads

2706

Citations