Table of Contents  
ORIGINAL ARTICLE
Year : 2013  |  Volume : 12  |  Issue : 2  |  Page : 186-192

Synthesis of new sulfanyl pyrimidin-4(3H)-one and ethyl-2-(pyridin-4yl) methoxy-1,2-dihydro-6-methyl-pyrimidine derivatives under conventional and heterogeneous conditions


1 Chemistry of Natural and Microbial Products Department and Pharmaceutical Research Group, Center of Excellence for Advanced Sciences, National Research Centre, Cairo, Egypt
2 Department of Medicinal Chemistry, National Research Centre, Cairo, Egypt

Date of Submission09-May-2013
Date of Acceptance18-Aug-2013
Date of Web Publication31-Dec-2013

Correspondence Address:
Fatma A Bassyouni
Chemistry of Natural and Microbial Products Department and Pharmaceutical Research Group, Center of Excellence for Advanced Sciences, National Research Centre, 12311 Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1687-4315.124047

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  Abstract 

Background and objectives
Heterocyclic systems with a pyrimidine nucleus display a wide spectrum of biological activities, such as antimicrobial, antiviral, anticancer, antidepressive, anti-inflammatory, antitubercular, diuretic, and anticoagulant. The aim of the present study was the synthesis of new heterocyclic sulfanylpyrimidin-4(3H)-one derivatives by adopting simple and efficient methods, in addition to ethyl-2-(pyridin-4-yl) methoxy-1,2-dihydro-6-methyl-pyrimidine derivatives in excellent yields.
Materials and methods
The synthesis of the titled sulfanyl pyrimidin-4(3H)-one derivatives was achieved by the reaction of compounds 1a-c with phenacyl bromide, 4-methyl phenacyl bromide, or 4-nitrophenacyl bromide to give 5-(morpholin-4-ylmethyl)-2-oxoethylphenyl-sulfanyl-pyrimidin-4(3H)-ones (2a-c), [(4-methylpiperazin-1-yl) methyl]-2-oxoethylphenyl-sulfanyl-pyrimidin-4(3H)-ones (3a-c), or piperidin-1-yl) methyl]sulfanyl-pyrimidin-4(3H)-ones (4a-c), respectively. In addition, several heterocyclic pyrimidine derivatives such as ethyl-2-((pyridin-4-yl)methoxy-1,2-dihydro-6-methyl-pyrimidine derivatives 6a-h were prepared by the reaction of 1,2 dihydropyrimidone derivatives 5a-h with picolyl chloride using conventional and heterogeneous catalysts such as silica sulfuric acid and CuY-Zeolite. The structures of the synthesized compounds were confirmed by elemental analyses and spectroscopic methods.
Results and conclusion
A simple and efficient method was used for the synthesis of sulfanyl pyrimidin-4(3H)-one derivatives through reaction with different reagents. Also, ethyl-2-((pyridin-4-yl)methoxy-1,2-dihydro-6-methyl-pyrimidine derivatives were obtained using conventional and heterogeneous conditions in excellent yields.

Keywords: dihydropyrimidines, heterogeneous catalyst, pyrimidines, sulfany pyrimidines, synthesis


How to cite this article:
Bassyouni FA, Fathalla OA. Synthesis of new sulfanyl pyrimidin-4(3H)-one and ethyl-2-(pyridin-4yl) methoxy-1,2-dihydro-6-methyl-pyrimidine derivatives under conventional and heterogeneous conditions. Egypt Pharmaceut J 2013;12:186-92

How to cite this URL:
Bassyouni FA, Fathalla OA. Synthesis of new sulfanyl pyrimidin-4(3H)-one and ethyl-2-(pyridin-4yl) methoxy-1,2-dihydro-6-methyl-pyrimidine derivatives under conventional and heterogeneous conditions. Egypt Pharmaceut J [serial online] 2013 [cited 2020 Apr 1];12:186-92. Available from: http://www.epj.eg.net/text.asp?2013/12/2/186/124047


  Introduction Top


Since many decades, bioactive heterocyclic compounds have been one of the main topics of interest among medicinal chemists as it displays a number of pharmacological activities. These compounds are used as a starting point to prepare complex heterocyclic scaffolds with numerous pharmacological properties [1],[2] . Pyrimidine derivatives form a component in a number of useful drugs such as nifedipine for the treatment of cardiovascular diseases, fluorouracil and monastrol for treatment of cancer, flucytosine as antimycotic, and bosentan for the treatment of pulmonary artery hypertension [3] . Moreover, several pyrimidine derivatives are associated with many biological activities such as antitumoral [4] , anti-HIV‐1 [5] , analgesic [6] , antidepressive [7] , anticonvulsant [8] , antimicrobial [9] , herbicidal [10] , anti-inflammatory, antioxidant [11],[12] , in-vitro COX-1 and COX-2 inhibition activity [13] , antitubercular [14] , and diuretic [15] . In addition, pyrimidine compounds are also used as hypnotic drugs for the nervous system [16] , for calcium-sensing receptor antagonists [17] , and for antagonists of the human A2A adenosine receptor [18] . Furthermore, the synthesis and chemistry of sulfanyl pyrimidines have recently been reported by a vast number of papers for the synthesis of different biological activities such as anti-HIV and antimicrobial, and as a new class of antifilarial agents [19],[20],[21],[22] .

In view of these points and as a part of our research interest in heterocyclic pyrimidine derivatives, this work involves the development of new methods for the synthesis of heterocyclic sulfanyl pyrimidin-4(3H)-one derivatives and ethyl-2-((pyridin-4-yl)methoxy-1,2-dihydro-6-methyl-pyrimidine derivatives under conventional and heterogeneous conditions.


  Experimental Top


Chemistry

Melting points were determined in open capillary tubes on an Electro thermal digital melting point apparatus (SMP30; Stuart, StaffordShire, ST150SA, UK) and reported uncorrected. IR spectra were recorded on a Jasco FT/IR Fourier transform infrared spectrophotometer ( South san Francisco, CA 94080, USA) using KBr discs. 1 H-NMR spectra were determined on a JEOL 500 MHz spectrometer (Tokyo, Japan) in DMSO-d 6 using TMS as the internal reference. Mass spectra were recorded on mass spectrometer JEOL (Japan) at 70 eV. Elemental analyses were performed at the Micro analytical Laboratory, Cairo University, and the results were found to be in agreement (±0.4%) with the calculated values. Purity of the synthesized compounds was checked by thin-layer chromatography (TLC) silica-gel alumina sheet-Merck 60-F254 precoated sheets (Merck, Darmstadt, Germany).


  Synthesis of 2-thioxo-2,3-dihydropyrimidin-4 (1H)-one derivatives (1a-c) Top
[23]

A mixture of paraformaldehyde (0.005 mol), mopholine or N-methylpiprazine or pipridine (0.005 mol) in absolute ethanol (25 ml) was heated under reflux with stirring for 1 h, followed by addition of (0.005 mol) 2-thiouracil in absolute ethanol (25 ml). The reaction mixture was then refluxed with stirring for 8-10 h. The progress of the reaction was monitored by TLC (eluent: chloroform-methanol 3 : 1). After cooling, the precipitated solid product was collected by filtration, washed with water, dried under vacuum, and crystallized from absolute ethanol to give compounds 1a-c. Compounds 1a-c were synthesized as reported in the literature [23] . Their molecular structure and purity were confirmed by spectroscopic analysis.


  General procedure for the synthesis of 5-(morpholin-4-ylmethyl)-2-oxoethylphenyl-sulfanyl pyrimidin-4 (3H)-one derivatives (2a-c) Top


Sodium metal (1 g) was dissolved in absolute ethanol (50 ml) and left to cool to room temperature. Thereafter, sodium ethoxide solution (15 ml) was added to compound 1a (0.01 mol) and then phenacyl bromide or 4-methyl phenacyl bromide or 4-nitrophenacyl bromide (0.01 mol) was added dropwise and heated under reflux with stirring for 5-6 h. During the procedure the reaction progress was monitored by TLC (eluent: chloroform-methanol 3 : 1). The products were neutralized, and the precipitated solid was filtered, washed several times with ice water, dried under vacuum, and crystallized from 95% acetic acid to afford compounds 2a-c.

5-(Morpholin-4-yl-methyl)-2-[(2-oxo-2-phenylethyl)sulfanyl]pyrimidin-4(3H)-one (2a), 69% yield, m.p.>300°C. Anal. calcd. for C 17 H 19 N 3 O 3 S (345.41): C, 59.41; H, 5.54; N, 12.17. Found: C, 59.38; H, 5.51; N, 12.11. IR (KBr, cm -1 ): 3350 (NH), 3160 (CH-aromatic), 2970 (CH-aliphatic), 1675, 1680 (2C=O), 1629 (C=C), 1270 (C=S of thiouracil). 1 H-NMR (500 MHz, DMSO-d 6 , d ppm): 2.10-2.30 (4H, m, CH 2 -N-CH 2 ), 3.60-3.79 (4H, m, CH 2 -O-CH 2 ), 4.30 (2H, s, CH 2 ), 4.45 (2H, s, CH 2 ), 7.10-7.40 (4H, m, CH-aromatic), 8.10 (1H, s, CH-thiouracil), 10.20 (1H, s, NH exchangeable with D 2 O).

2-{[2-(4-Methylphenyl)-2-oxoethyl]sulfanyl}-5-(morpholin-4-ylmethyl)pyrimidin-4(3H)-one (2b), 67% yield, m.p. 267-269°C. Anal. calcd. for C 18 H 21 N 3 O 3 S (359.44): C, 60.15; H, 5.89; N, 11.69. Found: C, 60.10; H, 5.83; N, 11.65. IR (KBr, cm -1 ): 3340 (NH), 3174 (CH-aromatic), 2960 (CH-aliphatic), 1678, 1685 (2C=O), 1630 (C=C), 1275 (C=S of thiouracil). 1 H-NMR (500 MHz, DMSO-d 6 , d ppm): 2.00 (3H, s, CH 3 ), 2.15-2.30 (4H, m, CH 2 -N-CH 2 ), 3.35-3.45 (4H, m, CH 2 -O-CH 2 ), 4.35 (2H, s, CH 2 ), 4.50 (2H, s,CH 2 ), 7.25-7.55 (4H, m, CH-aromatic), 8.20 (1H, s, CH-thiouracil), 10.00 (1H, s, NH exchangeable with D 2 O).

5-(Morpholin-4-ylmethyl)-2-{[2-(4-nitrophenyl)-2-oxoethyl]sulfanyl}pyrimidin-4(3H)-one (2c), 74% yield, m.p. 245-247°C. Anal. calcd. for C 17 H 18 N 4 O 4 S (390.41): C, 52.30; H, 4.65; N, 14.35. Found: C, 52.26; H, 4.59; N, 14.31. IR (KBr, cm -1 ): 3342 (NH), 3274 (CH-aromatic), 2968 (CH-aliphatic), 1670, 1680 (2C=O), 1636 (C=C), 1278 (C=S of thiouracil). 1 H-NMR (500 MHz, DMSO-d 6 , d ppm): 2.20-2.40 (4H, m, CH 2 -N-CH 2 ), 3.50-3.65 (4H, m, CH 2 -O-CH 2 ), 4.25 (2H, s, CH 2 ), 4.45 (2H, s, CH 2 ), 7.30-7.50 (4H, m, CH-aromatic), 8.25 (1H, s, CH-thiouracil), 10.40 (1H, s, NH exchangeable with D 2 O).


  General procedure for the synthesis of 5-[(4-methylpiperazin-1-yl)methyl]-2-oxoethylphenyl-sulfanyl-pyrimidin-4(3H)-one derivatives (3a-c) Top


These compounds were synthesized using the same procedure as described for synthesis of compounds 2a-c by using compound 1b with phenacyl bromide, 4-methyl phenacyl bromide, or 4-nitrophenacyl bromide to give compounds 3a-c, respectively.

5-[(4-Methylpiperazin-1-yl)methyl]-2-[(2-oxo-2-phenylethyl)sulfanyl]pyrimidin-4(3H)-one (3a), 67% yield, m.p. 285-287°C. Anal. calcd. for C 18 H 22 N 4 O 2 S (358.46): C, 60.31; H, 6.19; N, 15.63. Found: C, 60.25; H, 6.16; N, 15.57. IR (KBr, cm -1 ): 3345 (NH), 3167 (CH-aromatic), 2972 (CH-aliphatic), 1679, 1689 (2C=O),1630 (C=C), 1274 (C=S of thiouracil). 1 H-NMR (500 MHz, DMSO-d 6 , d ppm): 2.30 (3H, s, N-CH 3 ), 2.60-2.80 (4H, m, CH 2 -N-CH 2 ), 3.60-3.78 (4H, m, CH 2 -N-CH 2 ), 4.40 (2H, s,CH 2 ), 4.55 (2H, s, CH 2 ), 7.30-7.55 (5H, m, CH-aromatic), 8.15 (1H, s, CH-thiouracil), 10.10 (1H, s, NH exchangeable with D 2 O).

2-{[2-(4-Methylphenyl)-2-oxoethyl]-sulfanyl}-5-[(4-methylpiperazin-1-yl)methyl]pyrimidin-4(3H)-one (3b), 72% yield, m.p. 235-237°C. Anal. calcd. for C 19 H 24 N 4 O 2 S (372.48): C, 61.27; H, 6.49; N, 15.04. Found: C, 61.23; H, 6.46; N, 15.00. IR (KBr, cm -1 ): 3340 (NH), 3174 (CH-aromatic), 2960 (CH-aliphatic), 1670, 1680 (2C=O), 1635 (C=C), 1275 (C=S of thiouracil). 1 H-NMR (500 MHz, DMSO-d 6 , d ppm): 2.10 (3H, s, CH 3 ), 2.35 (3H, s, N-CH 3 ), 2.60-2.85 (4H, m, CH 2 -N-CH 2 ), 3.65-3.80 (4H, m, CH 2 -N-CH 2 ), 4.30 (2H, s, CH 2 ), 4.50 (2H, s, CH 2 ), 7.15-7.45 (4H, m, CH-aromatic), 8.20 (1H, s, CH-thiouracil), 9.95 (1H, s, NH exchangeable with D 2 O).

5-[(4-Methylpiperazin-1-yl)methyl]-2-{[2-(4-nitrophenyl)-2-oxoethyl]sulfanyl}pyrimidin-4(3H)-one (3c), 70% yield, m.p. 215-217°C. Anal. calcd. for C 18 H 21 N 5 O 4 S (403.46): C, 53.59; H, 5.25; N, 17.36. Found: C, 53.56; H, 5.20; N, 17.30. IR (KBr, cm -1 ): 3350 (NH), 3260 (CH-aromatic), 2955 (CH-aliphatic), 1675, 1680 (2C=O), 1638 (C=C), 1270 (C=S of thiouracil). 1 H-NMR (500 MHz, DMSO-d 6 , d ppm): 2.30 (3H, s, N-CH 3 ), 2.40-2.55 (4H, m, CH 2 -N-CH 2 ), 3.65-3.85 (4H, m, CH 2 -N-CH 2 ), 4.35 (2H, s, CH 2 ), 4.55 (2H, s, CH 2 ), 7.10-7.40 (4H, m, CH-aromatic), 8.16 (1H, s, CH-thiouracil), 10.25 (1H, s, NH exchangeable with D 2 O).

General procedure for the synthesis of 5-[(piperidin-1-yl)methyl]sulfanyl-pyrimidin-4(3H)-one derivatives (4a-c)

These compounds were synthesized using the same procedure as that described for synthesis of compounds 2a-c by using compound 1c with phenacyl bromide, 4-methyl phenacyl bromide, or 4-nitrophenacyl bromide to give compounds 4a-c, respectively.

2-[(2-Oxo-2-phenylethyl) sulfanyl]-5-(piperidin-1-yl)methyl)]pyrimidin-4(3H)-one (4a), 68% yield, m.p. 274-276°C. Anal. calcd. for C 18 H 21 N 3 O 2 S (343.44): C, 62.95; H, 6.16; N, 12.23. Found: C, 62.90; H, 6.13; N, 12.19. IR (KBr, cm -1 ): 3355 (NH), 3160 (CH-aromatic), 2970 (CH-aliphatic), 1675, 1680 (2C=O), 1628 (C=C), 1279 (C=S of thiouracil). 1 H-NMR (500 MHz, DMSO-d 6 , d ppm): 2.15-2.35 (4H, m, CH 2 -N-CH 2 ), 3.60-3.90 (4H, m, 2CH 2 ), 4.28 (2H, s, CH 2 ), 4.40 (2H, s, CH 2 ), 4.55 (2H, s, CH 2 ), 7.10-7.45 (4H, m, CH-aromatic), 8.26 (1H, s, CH-thiouracil), 9.85 (1H, s, NH exchangeable with D 2 O).

2-{[2-(4-Methylphenyl)-2-oxoethyl]sulfanyl}-5-(piperidin-1-yl)methyl]pyrimidin-4(3H)-one (4b), 71% yield, m.p. 215-217°C. Anal. calcd. for C 19 H 23 N 3 O 2 S (357.47): C, 63.49; H, 6.49; N, 11.75. Found: C, 63.43; H, 6.45; N, 11.70. IR (KBr, cm -1 ): 3340 (NH), 3174 (CH-aromatic), 2960 (CH-aliphatic) 1670, 1680 (2C=O), 1635 (C=C), 1270 (C=S of thiouracil). 1 H-NMR (500 MHz, DMSO-d 6 , d ppm): 2.15 (3H, s, CH 3 ), 2.30-2.45 (4H, m, CH 2 -N-CH 2 ),), 3.55-3.80 (4H, m, 2CH 2 ), 4.20 (2H, s, CH 2 ), 4.35 (2H, s, CH 2 ), 4.50 (2H, s, CH 2 ), 7.20-7.50 (4H, m, CH-aromatic), 8.22 (1H, s, CH-thiouracil), 10.20 (1H, s, NH exchangeable with D 2 O).

2-{[2-(4-Nitrophenyl)-2-oxoethyl]sulfanyl}-5-(piperidin-1-yl)methyl]pyrimidin-4(3H)-one (4c), 68% yield, dark brown crystals m.p. 145-147°C. Anal. calcd. for C 18 H 20 N 4 O 4 S (388.44): C, 55.66; H, 5.19; N, 14.42. Found: C, 53.62; H, 5.14; N, 14.36. IR (KBr, cm -1 ): 3348 (NH), 3174 (CH-aromatic), 2966 (CH-aliphatic), 1679, 1685 (2C=O), 1630 (C=C), 1268 (C=S of thiouracil). 1 H-NMR (DMSO-d 6 , d ppm): 2.36 (4H, m, CH 2 -N-CH 2 ), 3.60-3.80 (4H, m, 2CH 2 ), 4.20 (2H, s,CH 2 ), 4.45 (2H, s, CH 2 ), 4.55 (2H, s, CH 2 ), 7.20-7.45 (4H, m, CH-aromatic), 8.16 (1H, s, CH-thiouracil), 9.90 (1H, s, NH exchangeable with D 2 O).


  General procedure for the synthesis of 1,2 dihydropyrimidone derivatives (5a-h) Top


Method A

A mixture of urea or thiourea (1 mmol), benzaldehyde derivatives such as 4-flourobenzaldehyde, 4-chlorobenzaldehyde, 2-thiophene aldehyde, or 2-furfuraldehyde (1 mmol), and ketoester (1.1 mmol), silica sulfuric acid (SSA; 0.06 g equal to 0.15 mmol), silica gel (0.06 g), and P-toluenesulfonic acid (0.06 g) in ethanol (25 ml) was stirred at 100°C for 3-5 h. After completion of the reaction, which was confirmed by TLC (eluent: n-hexane/ethyl acetate: 2 : 1), hot ethanol (20 ml) was added to the residue, which was then filtered. The resulting solution was condensed under reduced pressure. Finally, the precipitate product was recrystallized from ethanol to give compounds 5a-h in excellent yields of 86-885%.

Method B

A mixture of urea or thiourea (0.5 mmol), benzaldehyde derivatives such as 4-flourobenzaldehyde, 4-chlorobenzaldehyde, 2-thiophene aldehyde, or 2-furfuraldehyde (0.5 mmol), and ketoester (0.55 mmol) in ethanol (20 ml) and nano-CuY-Zeolite (0.005 g) was stirred at room temperature for 2-3 h. The progress of the reaction was monitored by TLC (eluent: n-hexane/ethyl acetate: 2/1). After completion of the reaction, the used catalyst was collected by filtration using cold water (20 ml) to produce the products and then washed with water/ethanol (70 : 30). The solvent was evaporated under vacuum, and the product was recrystallized from absolute ethanol to form compounds 5a-h in excellent yields of 88-90%.


  General procedure for the synthesis of compounds ethyl-2-((pyridin-4-yl)methoxy-1,2-dihydro-6-methyl-pyrimidine derivatives (6a-h) Top


Method C

A mixture of compounds 5a-h (0.1 mmol) and potassium carbonate (0.138 g, 1 mmol) in DMF (5 ml) and picolyl chloride (0.1 mmol) was stirred at room temperature for 7-8 h. The progress of the reaction was monitored by TLC (eluent: n-hexane/ethyl acetate: 2/1). The solvent was removed under vacuum, and the products were washed with ice water (25 ml). The precipitated product was filtered and dried and then recrystallized from ethanol to form compounds 6a-h in yields of 74-77%.

Method D

A mixture of compounds 5a-h (0.1 mmol), picolyl chloride (0.1 mmol), and SSA (0.1 g) in 20 ml ethanol was stirred at 110°C for 3-5 h. After completion of the reaction, which was confirmed by TLC (eluent: n-hexane/ethyl acetate: 2/1), hot ethanol (20 ml) was added to the residue, which was then filtered. The solvent was evaporated under vacuum and the product was dried. The precipitate was recrystallized from ethanol to give compounds 6a-h in excellent yields of 83-86%.

Ethyl-2-((pyridin-4-yl)methylthio)-4-(4-fluorophenyl)-1,2-dihydro-6-methylpyrimidine-5-carboxylate (6a), 84% yield, m.p. 201-203°C. Anal. calcd. for C 20 H 20 FN 3 O 2 S (385.12): C, 62.32; H, 5.23; N, 10.90. Found: C, 62.29; H, 5.19; N, 10.85. IR (KBr, cm -1 ): 3345 (NH), 1720 (CO ester), 1270 (C-S), 1100 (C-F). 1 H-NMR (DMSO-d 6 , d ppm): 1.98 (3H, s, CH 3 ), 2.15 (3H, t, COOCH 2 CH 3 ), 3.85 (2H, q, COOCH 2 CH 3 ), 3.90 (2H, s, CH 2 S), 5.60 (1H, s, CH), 6.80-7.10 (4H, m, CH-aromatic), 7.20-7.35 (4H, m, CH-aromatic pyridine), 9.75 (1H, s, NH exchangeable with D 2 O). MS: m/z=385 [M + ].

Ethyl-2-((pyridin-4-yl)methylthio)-4-(4-chlorophenyl)-1,2-dihydro-6-methylpyrimidine-5-carboxylate (6b), 83% yield, m.p. 223-225°C. Anal. calcd. for C 20 H 20 ClN 3 O 2 S (401.91): C, 59.77; H, 8.82; N, 10.46; S, 7.98, 5.02, Cl. Found: C, 59.73; H, 7.78; N, 10.41; S, 7.94, 4.49, Cl. IR (KBr, cm -1 ): 3355 (NH), 1725 (CO ester), 1267 (C-S), 1090 (C-Cl). 1 H-NMR (DMSO-d 6 , d ppm): 2.00 (3H, s, CH 3 ), 2.20 (3H, t, COOCH 2 CH 3 ), 3.80 (2H, q, COOCH 2 CH 3 ), 4.10 (2H, s, CH 2 S), 5.75 (1H, s, CH), 6.90-7.20 (4H, m, CH-aromatic), 7.30-7.45 (4H, m, CH-aromatic pyridine), 9.65 (1H, s, NH exchangeable with D 2 O). MS: m/z=401 [M + ] and 403 [M + +2].

Ethyl-2-((pyridin-4-yl)methylthio)-1,2-dihydro-6-methyl-4-(4-(thiophen-2yl)phenyl)pyrimidine-5-carboxylate (6c), 85% yield, m.p. 229-231°C. Anal. calcd. for C 24 H 23 N 3 O 2 S 2 (449.123): C, 64.12; H, 5.16; N, 9.35; S, 14.26. Found: C, 64.10; H, 5.14; N, 9.32. IR (KBr, cm -1 ): 3340 (NH), 1700 (CO ester), 1269-1275 (C-S). 1 H-NMR (DMSO-d 6 , d ppm): 2.15 (3H, s, CH 3 ), 2.30 (3H, t, COOCH 2 CH 3 ), 3.90 (2H, q, COOCH 2 CH 3 ), 4.20 (2H, s, CH 2 S), 5.85 (1H, s, CH), 6.20-6.40 (3H, m, CH-thiophene), 7.20-7.35 (4H, m, CH-aromatic pyridine), 9.55 (1H, s, NH exchangeable with D 2 O).

Ethyl-2-((pyridin-4-yl)methylthio)-4-(4-(furan-2-yl)phenyl)-1,2-dihydro-6-methylpyrimidine-5-carboxylate (6d), 84% yield, m.p. 255-257°C. Anal. calcd. for C 24 H 23 N 3 O 3 S (433.146): C, 66.49; H, 5.35; N, 9.69; S, 7.40. Found: C, 66.46; H, 5.30; N, 9.63; S, 7.37. IR (KBr, cm -1 ): 3350 (NH), 1715 (CO ester), 1270 (C-S), 1110 (C-F). 1 H-NMR (DMSO-d 6 , d ppm): 2.20 (3H, s, CH 3 ), 2.35 (3H, t, COOCH 2 CH 3 ), 3.85 (2H, q, COOCH 2 CH 3 ), 3.98 (2H, s, CH 2 S), 5.78 (1H, s, CH), 6.28-6.46 (3H, m, CH-furan), 7.30-7.45 (4H, m, CH-aromatic pyridine), 9.85 (1H, s, NH exchangeable with D 2 O).

Ethyl-2-((pyridin-4-yl)methoxy)-4-(4-fluorophenyl)-1,2-dihydro-6-methylpyrimidine-5-carboxylate (6e), 83% yield, m.p. 245-247°C. Anal. calcd. for C 20 H 20 FN 3 O 3 (369.149): C, 65.03; H, 5.46; F, 5.14; N, 11.38. Found: C, 65.00; H, 5.42; N, 11.35. IR (KBr, cm -1 ): 3340 (NH), 1719 (CO ester), 1640 (C=N), 1260 (C-S), 1120 (C-F). 1 H-NMR (DMSO-d 6 , d ppm): 1.90 (3H, s, CH 3 ), 2.25 (3H, t, COOCH 2 CH 3 ), 3.98 (2H, q, COOCH 2 CH 3 ), 4.59 (2H, s, CH 2 O), 5.70 (1H, s, CH), 6.80-7.00 (4H, m, CH-aromatic), 7.15-7.35 (4H, m, CH-aromatic pyridine), 8.95 (1H, s, NH exchangeable with D 2 O). MS: m/z=369 [M + ].

Ethyl-2-((pyridin-4-yl)methoxy)-4-(4-chlorophenyl)-1,2-dihydro-6-methylpyrimidine-5-carboxylate (6f), 83% yield, m.p. 260-262°C. Anal. calcd. for C 20 H 20 ClN 3 O 3 (385.119): C, 62.26; H, 5.22; Cl, 9.19; N, 10.89. Found: C, 62.21; H, 5.18; Cl, 9.15; N, 10.86. IR (KBr, cm -1 ): 3345 (NH), 1725 (CO ester), 1626 (C=N), 1265 (C-S), 1080 (C-Cl). 1 H-NMR (DMSO-d 6 , d ppm): 1.95 (3H, t, CH 3 ), 2.30 (3H, t, COOCH 2 CH 3 ), 3.95 (2H, q, COOCH 2 CH 3 ), 4.55 (2H, s, CH 2 O), 5.85 (1H, s, CH), 6.80-7.00 (4H, m, CH-aromatic), 7.15-7.35 (4H, m, CH-aromatic pyridine), 8.89 (1H, s, NH exchangeable with D 2 O). MS: m/z=385 [M + ] and 387 [M + +2].

Ethyl-2-((pyridin-4-yl)methoxy)-1,2-dihydro-6-methyl-4-(4-(thiophen-2-yl)phenyl)pyrimidine-5-carboxylate (6g), 85% yield, m.p. 209-211°C. Anal. calcd. for C 24 H 23 N 3 O 3 S (433.146): C, 66.49; H, 5.35; N, 9.69; S, 7.40. Found: C, 66.46; H, 5.30; N, 9.64; S, 7.36. IR (KBr, cm -1 ): 3338 (NH), 1700 (CO ester), 1630 (C=N), 1257 (C-S). 1 H-NMR (DMSO-d 6 , d ppm): 1.80 (3H, s, CH 3 ), 2.25 (3H, t, COOCH 2 CH 3 ), 3.95 (2H, q, COOCH 2 CH 3 ), 4.50 (2H, s, CH 2 O), 5.75 (1H, s, CH), 6.10-6.35 (3H, m, CH-thiophene), 7.20-7.40 (4H, m, CH-aromatic pyridine), 8.85 (1H, s, NH exchangeable with D 2 O).

Ethyl-2-((pyridin-4-yl)methoxy)-4-(4-(furan-2-yl)phenyl)-1,2-dihydro-6-methylpyrimidine-5-carboxylate (6h), 86% yield, m.p. 236-238 °C. Anal. calcd. for C 24 H 23 N 3 O 4 (417.169): C, 69.05; H, 5.55; N, 10.07. Found: C, 69.02; H, 5.50; N, 10.04. IR (KBr, cm -1 ): 3348 (NH), 1718 (CO ester), 1640 (C=N), 1269 (C-S). 1 H-NMR (DMSO-d 6 , d ppm): 1.50 (3H, s, CH 3 ), 2.10 (3H, t, COOCH 2 CH 3 ), 4.00(2H, q, COOCH 2 CH 3 ), 4.70 (2H, s, CH 2 O), 5.60 (1H, s, CH), 6.00-6.20 (3H, m, CH-furan), 7.15-7.35 (4H, m, CH-aromatic pyridine), 8.75 (1H, s, NH exchangeable with D 2 O).


  Results and discussion Top


The reaction routes for the synthesis of the title compounds are described in Schemes 1 and 2. [Additional file 1] [Additional file 2]

Compounds 2-thioxo-2,3-dihydropyrimidin-4(1H)-one derivatives 1a-c were synthesized by adopting the procedure reported in the study by Singh et al. [23] by the reaction of 2-thiouracil with mopholine or N-methylpiprazine or pipyridine under reflux. Compounds 1a-c were allowed to react with phenacyl bromide or 4-methyl phenacyl bromide or 4-nitrophenacyl bromide in the presence of sodium ethoxide under reflux to give the corresponding products 5-[(morpholin-4-ylmethyl)]-2-oxoethyl-sulfanyl pyrimidin-4(3H)-one derivatives (2a-c), 5-[(4-methylpiperazin-1-yl)]methyl sulfanyl-pyrimidin-4(3H)-one derivatives (3a-c), and 5-[(piperidin-1-yl)methyl]sulfanyl-pyrimidin-4(3H)-one derivatives (4a-c), respectively (Scheme 1). The spectral data of all the synthesized compounds 2a-c, 3a-c, and 4a-c were established on the basis of elemental analysis and spectral data (c.f. experimental data). The IR spectra of compounds 2a-c revealed the absorption bands at 3340-3350 cm -1 (NH), 1670-1685 cm -1 (C=O groups), and 1270-1278 cm -1 corresponding to C=S groups, respectively. The IR spectra of compounds 3a-c indicated the presence of NH absorption bands at 3340-3350 cm -1 in addition to C=O bands at 1670-1689 cm -1 . The IR spectra of compounds 4a-c showed absorption bands at 3340-3355 cm -1 (NH) and at 1675-1685 cm -1 (carbonyl groups).

Compounds 5a-h were previously prepared according to Biginelli reaction [24],[25],[26],[27] . To improve the yield, the reaction was carried out in the presence of catalytic amount of silica sulfuric acid (SSA) and para toluene sulfonic acid (P-TSA) as heteroogeneous catalyst. SSA is an inorganic acidic catalyst that has recently attracted some interest in organic reactions [28],[29] . The yield was improved to 88%.

Heterogeneous reagent systems have many advantages such as simplicity of use, mild reaction conditions, minimization of chemical waste, and good yields. In contrast, the use of heterogeneous solid catalysts in the organic synthesis and industrial manufacture of chemicals is interesting and of value because of their suitable acidity, insolubility to all organic solvents, thermal stability, and low cost; they also provide an eco-friendly [30],[31] .

However, the best result was obtained when the reaction was carried out in the presence of 5wt% of nano-copper Y Zeolite in ethanol, encouraged by the above result and the development and generality of this simple method as a fairly good catalyst for this reaction. The method is associated with several advantages such as simplicity of use, milder conditions, short reaction times, excellent yields, and reusability of the catalyst. Transition CuY-Zeolite is an efficient nanocatalyst that is clean and eco-friendly [32],[33],[34],[35],[36] .

When compounds 5a-h were reacted with 4-picolyl chloride under basic conditions and in the presence of potassium carbonate in DMF or SSA in ethanol, the corresponding products ethyl-2-((pyridin-4-yl)methoxy-1,2-dihydro-6-methyl-pyrimidine derivatives 6a-h were obtained (Scheme 2). The structures of compounds 6a-d were established on the basis of elemental analysis and spectral data. The IR spectrum of 6a revealed absorption bands at 3345 cm -1 attributed to the NH group, at 1720 cm -1 for the CO ester group, and at 1100 cm -1 for the C-F group. In addition, the mass spectrum showed ion peak [M + ] at m/z=385, which was in agreement with the calculated molecular weight. In a similar manner, the IR spectrum of compound 6b showed absorption bands at 3355 cm -1 for NH, at 1725 cm -1 for the CO ester group, and at 1090 cm -1 for C-Cl. The mass spectrum revealed ion peak [M + ] at m/z=401 and 403/3 : 1 abundance, which was in agreement with the calculated molecular weight of compound 6b. The IR spectrum of compound 6c showed absorption band due to the NH group at 3340 cm -1 and the presence of CO ester group at 1700 cm -1 , and its 1 H-NMR spectrum displayed signals at 2.15 (CH 3 ), 4.20 (CH 2 S), 7.20-7.35 (CH-aromatic proton), and 9.55 (NH) ppm, respectively. The IR spectrum of compound 6d revealed absorption bands at 3350 cm -1 for NH and at 1715 cm -1 for the CO ester group. The 1 H-NMR spectrum of compound 6d showed signals due to 2.20 (CH 3 ), 3.98 (CH 2 S), 7.30-7.45 (CH-aromatic proton), and 9.85 (NH) ppm, which supported the suggested structures (c.f. experimental data).

The structure of compounds 6e-h was assigned on the basis of their elemental analyses and spectral data. The IR spectra of 6e-h revealed absorption bands at 3338-3348 cm -1 (NH groups) and 1718-1725 cm -1 (CO ester groups), in addition to at 1260-1269 cm -1 (C-S groups), 1120 cm -1 (C-F), and 1080 cm -1 (C-Cl). In addition, the mass spectrum of compound 6e showed ion peak [M + ] at m/z=369 and the mass spectrum of compound 6f revealed ion peak [M + ] at m/z=385 and 387/3 : 1 abundance, which supported the structure of compound 6f (c.f. experimental data).


  Conclusion Top


The synthesis of new heterocyclic pyrimidines was performed in good yields. These compounds could be considered as interesting analogs of pyrimidines used in biological applications. A series of sulfanylpyrimidin-4(3H)-one derivatives have been prepared in good yield. Sulfanylpyrimidin-4(3H)-one derivatives were incorporated into a ring of morpholine, methylpiprazine, and piperidin through a sulfanyl bridge at position 5 to form compounds (2a-c), (3a-c), and (4a-c). Ethyl-2-((pyridin-4-yl)methoxy-1,2-dihydro-6-methyl-pyrimidine derivatives 6a-h were prepared using conventional and heterogeneous conditions such as SSA as an efficient catalyst for the preparation of pyrimidine derivatives and nano-copper Y Zeolite to improve the yield to optimize the reaction conditions. We believe that the present method would be an important addition to existing methodologies.


  Acknowledgements Top


The authors are grateful to the National Research Center for supporting this work.

Conflicts of interest

None declared.

 
  References Top

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