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Journal of Chemistry
Volume 2013, Article ID 176213, 6 pages
http://dx.doi.org/10.1155/2013/176213
Research Article

Synthesis of 2,3-Dihydro-6-methyl-2-thiopyrimidin-4(1H)-one (6-Methylthiouracil) Derivatives and Their Reactions

1Faculty of Chemistry, North Tehran Branch, Islamic Azad University, Tehran, Iran
2Department of Chemistry, Baku State University, Baku, Azerbaijan

Received 21 August 2011; Accepted 9 November 2011

Academic Editor: N. A. Mohamed Farook

Copyright © 2013 Mohammad Barmaki 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.

Abstract

The synthesis and characterization of 2,3-dihydro-6-methyl-2-thioxopyrimidin-(1H)-one (I) and some of its derivatives has been performed in our lab. Ring-closing cyclization, as a result of the condensation of ethyl-3-oxobutanoate with thiourea in KOH in an ethanol medium produced 2,3-dihydro-6-methy -2-thioxopyrimidin-(1H)-one (I). The reaction of compound (I) with 2- chloroacetic acid in an alkaline KOH solution produced the carboxylate derivative, 2-(2,6-dihydro-4-methyl-6-oxopyrimidin-2-yl-thio)ethanoic acid (II). The reaction of the resulted derivative of carboxylate (II) with the salt of copper sulphate, produced a new copper salt (III). A substitution reaction between synthesized compound (I) and 2-chloroethanol in an aqueous solution of KOH, created 2-(2-hydroxyethylthio)-6-methylpyrimidin-4(3H)-one (IV). The reaction of compound (I) with 2-(chloromethyl)oxirane in the presence of an aqueous solution of KOH, resulted yielded 2-(3-chloro-2-hydroxy-propylthio)-6-methylpyrimidin-4(3H)-one (V). Sodium mercaptide compound (VI), was produced by the reaction of (I) with NaOH and then the sodium salt of 2,3-dihydro-6-methyl-2-thioxopyrimidin-(1H)-one (VI) was reacted with 2-(chloromethyl)oxirane to result in 2-((oxiran-2-yl) methyl-thio)-6-methyl-pyrimidin-4(3H)-one (VII). Different acylation reagents (acetyl chloride, benzoyl chloride) were reacted with compound (I), in dimethylformamide, acylation happens on sulfur and furnished S-acylified derivatives of (VIII-IX). All the synthesized and obtained products were confirmed by IR, 1H, and 13C NMR and elemental analysis.

1. Introduction

Among hexagonal heterocycles, pyrimidine has extensive and special applications in chemistry and biochemistry. The structure of pyrimidine is used in medical compounds. For example, Vitamin B1 or thiamin has the pyrimidine ring in its structure [1]. Synthesized derivatives of barbituric acid and sleep-inducing medications like Luminal and veronal (Barbitone) are also from this category of compounds.

Moreover pyrimidines generally have attracted much interest for their widespread potential in biological activities and medicinal applications, thus their chemistry has been investigated extensively [2, 3]. In particular, various analogues of pyrimidine-thiones possess effective antibacterial, antifungal, antiviral, anti-AIDS, insecticidal and medicinal applications [4, 5].

Furthermore many condensed heterocyclic systems, especially when they are linked to a pyrimidine ring, play an important role as analgesic, antihypertensive [6], antipyretic and anti-inflammatory drugs [7, 8]. They also find use as pesticides, herbicides, and plant growth regulators [9]. Among pyrimidines derivatives, uracil is one of the important bases which can be found in nucleic acids and has different efficient derivatives with broad effects.

The importance of uracil and its annealed derivatives is well recognized by synthetic [10], as well as biological [11], chemists. For example, pyrazolo[3,4-d]pyrimidines constitute a class of naturally occurring fused uracils that possess diverse biological activities [12].

5-Flourouracil itself is used in the biosynthesis of the molecular structure of RNA [13]. 5-Bromouracil alternates’ hereditary information carries the chemical properties of mutants at high speed and in mutant parts affect alkaline changes of amines.

According to scientific studies [14], thiouracil derivatives are tranquilizers of the nervous system; they also play protective roles in human immunity against viruses. Other uracil derivatives such as 5-oximethyl-4-methyluracil (Pentoil) and 4-methyluracil (Metoil) are quite effective against colds.

Pentoil, metoil, and uracil play very important roles in anemia, nucleic acid synthesis, and biosynthesis of blood proteins. Derivatives of thiouracil have extended applications in the treatment of nervous disorders. These compounds can also be used for the treatment of Alzheimer’s disease, Parkinson’s disease, migraines, depression and amnesia.

Nowadays, uracil derivatives are successfully applied in immunotherapy and as an implement to show the stability of the properties of the cell membrane [15]. Uracil derivatives are also useful in the biosynthesis of xanthines [16].

Herein, some of the synthesized derivatives of compounds, 6-amino-4-hydroxy-2-mercaptopyrimidine [17], synthesis of uracil derivatives and some of their reactions have been reported alongside our previous investigations [18].

The purpose of this paper in the context of organic chemistry is the “synthesis, cyclization and reactions of given reactants,” which plays an important role in this branch of chemistry. Moreover, uracil derivatives have important usages in medical sciences, as mentioned above. It seems self-evident that these synthesized compounds have also been investigated from a biological point of view and are being studied by biologists and will be presented in a separate paper.

The most available routes for the synthesis of 1-aryl- or 1-heteroaryl-5-substituted uracil derivatives involve condensation reactions [19]. In an effort to increase the molecular structures, that is, in the synthesis of uracil and its derivatives, we have developed a novel synthesis method by applying Diels-Alder reactions [20] and an efficient synthesis by using catalytic material [21].

2. Experimental

1H and 13C NMR spectra of all synthesized compounds were obtained using a Bruker ABM-300 spectrometer. Chemical shifts (δ) are given in ppm using TMS as an internal reference. IR spectra were recorded on Spekord 75-IR. Thin Layer Chromatography (TLC) was performed on silica gel plates. Silufol UV-254 nm in chloroform-methanol (20 : 1 V/V) and chloroform-methanol (9 : 1 V/V) were used as solvent systems. Plates were visualized with iodine vapor under UV light.

2.1. 2,3-Dihydro-6-methyl-2-thioxopyrimidin-(1H)-one (I)

KOH along with ethanol are mixed with ethylacetoacetate and thiourea in a three-necked round-bottomed flask with thermometer and a back flow condenser on the magnetic stirrer. The required amount of each compound is as follows: ethyl-3-oxobutanoate 28.0 g (0.2 mL), thiourea 15.2 g (0.2 mL), KOH 9.0 g (0.16 mL) and ethanol 15.0 mL. The solution is stirred in a hot water bath for 12 h at 50°C until it turns orange. The solution is then added to a small beaker after it has cooled down and is then washed with 20.0 mL of double-distilled water, then 16.0 mL of HCl is added to it, the product first becomes foam and then changes to white crystals.

The solution is filtrated with a water suction pump, it changes to light yellow precipitation as the final product, which is insoluble in benzene but dissolves in 2-propanol. The amount of produced 2,3-dihydro-6-methyl-2-thioxopyrimidin-(1H)-one (I) 18.2 g in 64% yield with m.p. 235°C.

Rate of Flow in TLC (Rf) = 0.27, Anal. Calcd (%) for C5H6N2OS, C, 42.53; H, 4.03; N, 19.54; S, 22.76, found: (%) C, 42.24; H, 4.23; N, 19.27; S, 22.54.

2.2. 2-(2,6-Dihydro-4-methyl-6-oxopyrimidin-2-ylthio)ethanoic Acid (II)

A three-necked round-bottomed flask with a thermometer, a back flow condenser along with a magnetic stirrer are prepared for the experiment; 2,3-dihydro-6-methyl-2-thioxopyrimidin-(1H)-one (I) 3.55 g (0.025 mL), 2-chloroacetic acid 2.4 g (0.25 mL) and dimethyl sulfoxide (DMSO) 20.0 mL as a solvent are added to the flask and heated up to 60–65°C.

Light yellow-colored crystals, which are insoluble in propanone but soluble in water, are formed if the flask is put in ice. Product (II) is 3.0 g, in 61.50% yield with m.p. 220°C. Rf = 0.49, Anal. Calcd. (%) for C7H8N2O3S, C, 41.03; H, 4.04; N, 14.11; S, 16.01, found: (%) C, 42.00; H, 4.00; N, 14.00; S, 16.00

2.3. Copper Di(2(-1,6-dihydro-4-methyl-6-oxopyrimidin-2-yl-thio)ethanoate (III)

A three-necked round-bottomed flask with a thermometer, a back flow condenser along with a magnetic stirrer are prepared for the experiment; 2-(2,6-dihydro-4-methyl-6-oxopyrimidin-2-ylthio)ethanoic acid (II) 3.0 g (0.02 mL), copper sulphate 3.2 g (0.02 mL), and 15.0 mL distilled water are added to the flask and stirred fast. The reaction continues for 5 h at 60–70°C. Then it is cooled down to room temperature. 3.44 g copper salt (III) in 80% yield with m.p. 270°C is separated from the rest of the solution in the form of precipitated crystals. Rf = 0.38 Anal. Calcd. (%) for CuC14H16N4O6S2, C, 36.47; H, 3.23; N, 12.34; S, 13.52, found: (%) C, 36.36; H, 3.03; N, 12.12; S, 13.85.

2.4. 2-(2-Hydroxyethylthio)-6-methylpyrimidin-4(3H)-one (IV)

A three-necked round-bottomed flask with a thermometer, a back flow condenser and a magnetic stirrer are prepared for the experiment. 2,3-Dihydro-6-methyl-2-thioxopyrimidin-(1H)-one (I) 4.26 g (0.02 mL), 2-chloroethanol 1.8 g (0.02 mL), DMSO 10 mL and K2CO3 8.28 g (0.06 mL) are added to the flask and stirred at room temperature. The solution in the flask alongside ethanol converts to precipitate in four hours. Dark yellow crystals are recrystallized by hexane and then filtered, the product is free from chlorine which is insoluble in DMSO, ethanol, buthanol and benzene, but soluble in water. The product (IV) in 69% yield and has m.p. 210°C. Rf = 0.58, Anal. Calcd. (%) for C7H10N2O2S, C, 45.02; H, 5.54; N, 15.28; S, 16.89, found: (%) C, 45.16; H, 5.38; N, 15.05; S, 17.20.

2.5. 2-(3-Chloro-2-hydroxypropylthio)-6-methylpyrimidin-4(3H)-one (V)

A three-necked round-bottomed flask with a thermometer, a back flow condenser and a magnetic stirrer are prepared for the experiment. 2,3-Dihydro-6-methyl-2-thioxopyrimidin-(1H)-one (I) 3.33 g (0.02 mL), Na2CO3 2.0 g (0.02 mL) and ethanol (20.0 mL) are added to the flask and stirred fast. 2-(Chloromethyl)oxirane is added to the flask drop wise and is stirred at room temperature for 5 h. The mixture of the reaction is extracted by ester and it has separated in the form of white precipitates by a water suction pump. Crystals are 200°C. Rf = 0.48, Anal. Calcd. (%) for C6H11N2O2SCl, C, 40.72; H, 4.81; N, 11.75; S, 13.48, found: (%) C, 40.94; H, 4.69; N, 11.94; S, 13.65.

2.6. Sodium Salt of 2,3-Dihydro-6-methyl-2-thioxopyrimidin-(1H)-one (VI)

A mixture of 2,3-dihydro-6-methyl-2-thioxopyrimidin-(1H)-one (I) 1.5 g (0.01 mL), NaOH 0.40 g and H2O 7.0 mL was added to a small beaker and mixed together. After 4-5 h of stirring precipitation in the form of crystals appear on the magnetic stirrer. Crystals are filtered, separated and are recrystallized by ethanol. The white crystals are in 100% yield with m.p. 340°C. Rf = 0.59, Anal. Calcd. (%) for NaC5H5N2OS, C, 36.28; H, 3.23; N, 17.29; S, 19.28, found: (%) C, 36.59; H, 3.05; N, 17.07; S, 19.51.

2.7. 2-((Oxiran-2-yl)methylthio)-6-methylpyrimidin-4(3H)-one (VII)

A three-necked round-bottomed flask, a back flow condenser, a thermometer and a magnetic stirrer are prepared. Sodium salt of 2,3-dihydro-6-methyl-2-thioxopyrimidin-(1H)-one (VI) 3.3 g (0.02 mL) and NaOH 0.8 g (0.02 mL) are dissolved in 15.0 mL of distilled water and are added to the flask and then stirred fast. Initially there is no change, but after 10 h, white precipitate is formed. This precipitation is insoluble in water, but it dissolves in 2-propanol by heating and it precipitates after cooling down again.

It can be recrystallized by 2-propanol after filtration, the final product as a crystals (VII) 2.7 g in 67% yield with m.p. 210°C is collected. Rf = 0.59, Anal. Calcd (%) for C8H10N2O2S, C, 48.22; H, 5.16; N, 14.35; S, 16.47, found: (%) C, 48.48; H, 5.05; N, 14.14; S, 16.16.

2.8. S-1,6-Dihydro-4-methyl-6-oxopyrimidin-2-yl-ethanethioate (VIII)

For this reaction 2,3-dihydro-6-methyl-2-thioxopyrimidin-(1H)-one (I) 1.24 g (0.01 mL), acetyl chloride 0.8 g (0.01 mL) and benzene 5.0 mL as a solvent are added to a small beaker and stirred for 8 h by a magnetic stirrer. The produced compound is insoluble in water, ethanol, and CCl4 even by heating, but it dissolves well in DMSO.

The produced precipitation (VIII) 1.2 g in 63.5% yield with m.p. 240°C recovered. Rf = 0.782, Anal. Calcd. (%) for C7H8N2O2S, C, 45.36; H, 4.63; N, 15.03; S, 17.55, found: (%) C, 45.65; H, 4.34; N, 15.22; S, 17.30.

2.9. S-1,6-Dihydro-4-methyl-6-oxopyrimidin-2-yl-benzothioate (IX)

A mixture of 2,3-dihydro-6-methyl-2-thioxopyrimidin-(1H)-one (I) 1.4 g (0.01 mL), benzoyl chloride 1.4 g (0.01 mL) and benzene 5.0 mL was stirred for 5 h at room temperature. The collected precipitation is washed with EtOH and then filtered. The product (IX) is insoluble in propanone and benzene. It is 1.3 g in 57% yield with m.p. 215°C. Anal. Calcd. (%) for C12H10N2O2S, C, 58.72; H, 4.18; N, 11.14; S, 13.25, found: (%) C, 58.54; H, 4.07; N, 11.38; S, 13.01.

3. Results and Discussion

As a result of the condensation of ethyl-3-oxobutanoate with thiourea in a KOH and ethanol medium, in a hot water bath while evaporation of ethanol is in progress, the rest compound dissolved in water. Afterwards, the neutralization is done by HCl or CH3COOH 10%. The result of the reaction is as follow and it produces 2,3-dihydro-6-methyl-2-thioxopyrimidin-(1H)-one (I), (Figure 1). 2,3-Dihydro-6-methyl-2-thioxopyrimidin-(1H)-one (I) reacts with 2-chloroacetic acid in alkaline KOH solution at room temperature after 20 h. Then it is acidified by acetic acid and produces the derivative of carboxylate (II), (Figure 2). The resulting derivative of carboxylate (II) produced a new copper salt (III) in the reaction with the salt of copper sulphate (Figure 3). According to the following reaction, 2,3-dihydro-6-methyl-2-thioxopyrimidin-(1H)-one (I) in KOH aqueous solution reacts with 2-chloroethanol after 6–8 h in a hot water bath and produces compound (IV), (Figure 4). In the next step, the reaction of 2,3-dihydro-6-methyl-2-thioxopyrimidin-(1H)-one with 2-(chloromethyl)oxirane in the presence of KOH aqueous solution the product will be 2-(3-chloro-2-hydroxypropylthio)-6-methylpyrimidin-4(3H)-one (V) and the reaction is as follows (Figure 5). According to obtained reactions, if 2,3-dihydro-6-methyl-2-thioxopyrimidin-(1H)-one (I) reacts with NaOH compound (VI) is produced, (Figure 6) and then (VI) reacts with 2-(chloromethyl)oxirane and results in a substituted derivative of oxiranyl (VII), (Figure 7).

176213.fig.001
Figure 1: Syntheses of 2,3-dihydro-6-methyl-2-thioxopyrimidin-(1H)-one (I).
176213.fig.002
Figure 2: Syntheses of 2-(2,6-dihydro-4-methyl-6-oxopyrimidin-2-ylthio)ethanoic acid (II).
176213.fig.003
Figure 3: Syntheses of copper di(2(-1,6-dihydro-4-methyl-6-oxopyrimidin-2-yl-thio)ethanoate (III).
176213.fig.004
Figure 4: Syntheses of 2-(2-hydroxyethylthio)-6-methylpyrimidin-4(3H)-one (IV).
176213.fig.005
Figure 5: Syntheses of 2-(3-chloro-2-hydroxypropylthio)-6-methylpyrimidin-4(3H)-one (V).
176213.fig.006
Figure 6: Syntheses of sodium salt of 2,3-dihydro-6-methyl-2-thioxopyrimidin-(1H)-one (VI).
176213.fig.007
Figure 7: Syntheses of 2-((oxiran-2-yl)methylthio)-6-methylpyrimidin-4(3H)-one (VII).

Different acylation reagents (acetyl chloride, benzoyl chloride) in reaction with 2,3-dihydro-6-methyl-2-thioxopyrimidin-(1H)-one (I), in DMF at 20°C were studied. In this reaction acylation happens on sulfur and produces S-acylified derivatives (VIII-IX), (Figure 8).

176213.fig.008
Figure 8: Syntheses of S-1,6-dihydro-4-methyl-6-oxopyrimidin-2-yl-ethanethioate (VIII) and S-1.6-dihydro-4-methyl-6-oxopyrimidin-2-yl-benzothioate (IX).

In the IR spectrum, the absorption band characteristics of the synthesized derivatives of 2,3-dihydro-6-methyl-2-thioxopyrimidin-(1H)-one (I–IX), appear in the range of 1630–1720 cm−1. This range belongs to the bands of pyrimidine fragments [C=O, =N–C=O].

In this spectroscopy N–H stretching will be at 3300–3400 cm−1; furthermore absorption bands at the region of 3090–3100 cm−1 characterize the interior hydrogen of νNH. The intensity of the band at 1715 cm−1 reveals the existence of ν(C=O) functional group which itself is evidence of the presence of a carboxyl group in the 2,3-dihydro-6-methyl-2-thioxopyrimidin-(1H)-one molecule.

Acetyl and benzoyl groups in (VIII-IX) molecules do not cause any differences in the spectrums of IR. It is more probable that stretching νC=O functional group in the region of 1620 cm−1 characterizes the band of νC=O group of pyrimidine. Some compounds have different molecular structures; and their IR spectrums appear in 1170–1180 cm−1 region.

In the spectroscopy of 1H NMR of 2,3-dihydro-6-methyl-2-thioxopyrimidin-(1H)-one, the signals of the three protons of the methyl group at a high field 2.1 MHz are observed as a singlet. The single protons of the methine (CH) group in 6.7 MHz and that of amino (NH) group in 12.3 MHz appeared as singlet.

The molecular structure of 2,3-dihydro-6-methyl-2-thioxopyrimidin-(1H)-one in 13C NMR spectrum has also been proved. The carbon of the methyl group appeared in a strong field of 19 MHz and the splitting carbon of hydrogen double bond group appeared at the 104 MHz field.

Signals of carbon atoms existing in uracil groups in 13C NMR spectrum appeared at 153 and 162 MHz fields and the signals of the carbon atom of thion- (C=S) group appears at a downfield of 178 MHz. In all of the synthesized and obtained compounds, signals of carbon atoms’ in 13C NMR spectra of pyrimidin-4(3H)-one molecule were 164 (C4), 157 (C2), 153 (C6), and 98–102 MHz (C5). The physical-chemical constants and yields of synthesized derivatives of 2,3-dihydro-6-methyl-2-thioxopyrimidin-(1H)-one (I–IX) are given in Table 1.

tab1
Table 1: The physicochemical characteristics of synthesized derivatives of 2,3-dihydro-6-methyl-2-thioxopyrimidin-(1H)-one, (I–IX).

4. Conclusion

In this paper we have presented methods for the synthesis and cyclization reactions based on a strategy to access and produce the heterocyclic compounds. In this state some of their remarkable reactions were also demonstrated.

The first synthesis is based on the reaction of ethyl cyanoacetate and thiocarbamide in the presence of sodium acetate, and produced 2,3-dihydro-6-methyl-2-thioxopyrimidin-4(1H)-one (I).

The cyclized product (I), in different reaction conditions afforded different types of products (II–IX). The synthesized products were confirmed by IR, 1H 13C NMR, and element analysis.

References

  1. Ch. T. Jurgenson, T. P. Begley, and S. E. Ealick, “The structural and biochemical foundations of thiamin biosynthesis,” Annual Review of Biochemistry, vol. 78, pp. 569–603, 2009. View at Publisher · View at Google Scholar · View at Scopus
  2. E. Cb. Taylor, The Chemistry of Heterocyclic Compounds, Interscience, New York, NY, USA, 1985.
  3. T. J. Lomis, J. F. Suida, and R. E. Shepherd, “Bleomycin metal site models with apical imidazole or sulphydryl donors,” Journal of the Chemical Society, Chemical Communications, no. 4, pp. 290–292, 1988. View at Publisher · View at Google Scholar
  4. I. Yildirim, I. Koca, M. Dincer, and N. O. Andac, “Crystal and molecular structure of 1-allyl-5-(4-methylbenzoyl)-4-(4-methylphenyl)pyrimidine-2(1H)-thione,” Crystal Research and Technology, vol. 41, no. 12, pp. 1236–1241, 2006. View at Publisher · View at Google Scholar
  5. E. De Clercq and R. T. Walker, Eds., Targets for the Design of Antiviral Agents, Plenum, New York, NY, USA, 1984.
  6. A. Camito, M. Perrissin, and C. Luu-Due, “Synthesis and pharmacological activities of some 3-substituted thienopyrimidin-4-one-2-thiones,” European Journal of Medicinal Chemistry, vol. 25, no. 8, pp. 635–639, 1990. View at Publisher · View at Google Scholar
  7. E. S. Badawey and and A. M. El-Ashanawey, “Nonsteroidal antiinflammatory agents—part 1: antiinflammatory, analgesic and antipyretic activity of some new 1-(pyrimidin-2-yl)-3-pyrazolin-5-ones and 2-(pyrimidin-2-yl)-1,2,4,5,6,7-hexahydro-3H-indazol-3-ones,” European Journal of Medicinal Chemistry, vol. 33, no. 5, pp. 349–361, 1998. View at Publisher · View at Google Scholar
  8. S. Vega, J. Aonso, J. A. Diaz, and F. Junquera, “Synthesis of 3-substituted-4-phenyl-2-thioxo-1,2,3,4,5,6,7,8-octahydrobenzo[4,5]thieno[2,3-á]pyrimidines,” Journal of Heterocyclic Chemistry, vol. 27, no. 2, pp. 269–273, 1990. View at Publisher · View at Google Scholar
  9. J. Satow, Y. Kondo, Y. Kudo et al., “Pyrimidine derivatives, herbicides and plant growth regulators,” Patent 5773388, Assignee: Nissan Chemical Industries, June 1998, US Patent Application: 08/592,298. View at Google Scholar
  10. P. J. Bhuyan, H. N. Borah, and J. S. Sandhu, “Studies on uracils: an efficient method for the synthesis of novel 1-alIyl-6-(1′,2′,3′-triazolyl) analogues of KEPT,” Journal of the Chemical Society—Perkin Transactions 1, no. 21, pp. 3083–3084, 1999. View at Google Scholar · View at Scopus
  11. R. Pantikis and C. Monneret, “Synthesis of deoxy analogs of HEPT involving a palladium (0) catalyzed coupling,” Tetrahedron Letters, vol. 34, no. 25, pp. 4351–4354, 1994. View at Publisher · View at Google Scholar
  12. E. Y. Sutcliffe, K. Y. Zee-Cheng, C. C. Cheng, and R. K. Robins, “Potential purine antagonists. XXXII. The synthesis and antitumor activity of certain compounds related to 4-aminopyrazolo [3,4-d] pyrimidine,” Journal of Medicinal and Pharmaceutical Chemistry, vol. 5, no. 3, pp. 588–607, 1962. View at Google Scholar · View at Scopus
  13. V. I. Ivanskiy, Chemistry of Heterocyclic Compounds, Visshaya Shkola, Moscow, Russia, 1978.
  14. A. T. Soldateukov, N. M. kolyadina, and I. V. Shendrik, Eds., Fundamentals of Chemistry, Organic drugs, Moscow, Russia, 2003.
  15. V. P. Krivonogov, G. A. Tolstikov, and U. I. Murinor, Pharmaceutical Chemistry Journal, vol. 31, article 24, 1997.
  16. S. H. Youssif, B. Bayoumy, B. Bayoumy, and S. El-Bahaie, “A novel synthesis of 3,9-dialkyl and 8-Aryl-3,9-dimethylxanthines,” Bulletin of the Korean Chemical Society, vol. 23, no. 3, pp. 374–380, 2003. View at Publisher · View at Google Scholar
  17. M. Barmaki, A. M. Maharramov, and M. A. Allahverdiyev, Eds., Kimya Problemlǝri, Baku State University Press, Baku, Azerbaijan, 2007.
  18. M. Barmaki, A. M. Maharramov, and M. A. Allahverdiyev, “Synthesis of uracil derivatives and some of their reactions,” Asian Journal of Chemistry, vol. 20, no. 7, pp. 5277–5281, 2008. View at Google Scholar · View at Scopus
  19. A. Gondela and K. Walczak, “New approach for the synthesis of 1-aryl- and 1-heteroaryl-5-nitrouracil derivatives,” Tetrahedron, vol. 63, no. 13, pp. 2859–2864, 2007. View at Publisher · View at Google Scholar · View at Scopus
  20. R. Chioua, F. Benabdelouahab, M. Chioua, R. Martínez-Alvarez, and A. Herrera Fernández, “Synthesis of novel quinazoline derivatives via pyrimidine ortho-quinodimethane,” Molecules, vol. 7, no. 7, pp. 507–510, 2002. View at Google Scholar · View at Scopus
  21. D. Prajapati and M. Gohain, “An efficient synthesis of novel pyrano[2,3-d]- and furopyrano[2,3-d]pyrimidines via indium-catalyzed multi-component domino reaction,” Beilstein Journal of Organic Chemistry, vol. 2, no. 11, pp. 11–14, 2006. View at Publisher · View at Google Scholar