1. Introduction
Thiourea has great medicinal applications promising bactericidal [1], fungicidal [2] and anti-inflammatory drugs [3], as well as non-medicinal activities in the industry [4], analytical chemistry and metallurgy [5]. It is known that the replacement of the oxygen heteroatom by sulfur leads to a significant change in the spectrum of the biological activity of compounds [6]. Carbohydrate derivatives of thiourea can be obtained by the thionization of glycosyl ureas. In addition, thionization of glycosyl urea derivatives is a practically unexplored area. The most common method for synthesis of glycosyl thiourea by isothiocyanate method was developed in 1914 by E. Fischer, which has several significant drawbacks, namely a multi-stage process, the use of expensive reagents (silver salt), the use of an expensive catalyst (platinum dioxide), aggressive and toxic reagents (sodium azide, bromine), deficient isothiocyanate, high pressure and reaction time [7]. We have developed a modified method for obtaining the Lawessons reagent, distinguished by its simplicity and accessibility [8], compared with the previous preparation method [9].
In this regard, it was of interest for us to develop a simplified and accessible method for obtaining of glycosyl thiourea derivatives. For these purposes, we have used the Lawessons reagent (2,4-bis(p-methoxyphenyl)-1,3-dithiadiphos-phetan-2,4-disulfide) for thionization which allows us to eliminate the above-mentioned disadvantages of the isothiocyanate method of thionization as shown in Figure 1.
2. Experimental
A general method for thionization of sugar ureas conducted as following: 0.2 mmol of carbamide sugars, 0.2 mmol of Lawessons reagent, and 3 ml of abs. pyridine placed into the flask then boiled under reflux with the potassium chloride tube for 45 minutes. Then the solution evaporated under vacuum at the temperature of 50˚C - 60˚C until dryness. 3 ml of distilled water was added to this residue and refluxed for five minutes. Then the solution filtered and the filtrate evaporated. The residue recrystallized from alcohol: benzene mixture. Then precipitated crystals separated by filtration and dried in the air. Product yield was about 56% - 60%.
Sample Characterizations
Identification of the synthesized compounds carried out by using thin-layer chromatography on Silufol, IR-, NMR-13C, 1H-spectroscopy, and elemental analysis. The 13C NMR spectra were taken on a Bruker AM-300, SF = 75.47 MHz instruments with an operating frequency of 126 MG at a temperature of 2950 K, where TMS was used as an internal standard. The spectra taken in deuterated solvents—DMSO-d6. H1 NMR spectra were taken on a Bruker AM-300, SF = 300.13 MHz instruments with an operating frequency of 500 MHz at a temperature of 2930 K, where TMS was used as an internal standard. The spectra taken
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Figure 1. Simplified and accessible method for obtaining of glycosyl thiourea derivatives by the Lawessons reagent.
in deuterated solvents—DMSO-d6. The IR spectra of the compounds obtained were obtained on spectrophotometers IKS-29, SpecordM-80 with the program “Soft Spectra”, “SpectrumBXII” Fourier-IR spectrometer “NicoletAvatar 370” DTGS company Electron Corporation in the region of 500 - 4000 cm−1 (pressing with KBr). The melting point of the synthesized compounds measured on a microheater Boetuis. The rate of temperature rise on the table was 4˚C per minute. Elemental analysis of synthesized compounds was determined by colorimetric method Dyumo-Pregl and Schöniger on the device VM-20 (VLM-20g-M), SMD-1000 (VLM-1g). The control throughout the reaction and the purity of the synthesized compounds carried out using thin-layer chromatography (TLC) on SilufolUV-254 plates (sorbent: silica gel). System: chloroform:methanol (3:1), chloroform-ethanol-methyl ethyl ketone (1:2:1).
3. Results and Discussions
3.1. Thionization of Glycosyl Urea
We then applied the synthesized Lawessons reagent to the thionization of glycosylurea derivatives. The proposed method of thionization was based on the interaction of N-methyl-N1-(β-D-glycopyranosyl)-urea (2 - 4) with the Lawessons (1) reagent at a 1:1 ratio of reagents in pyridine, where is formed N-methyl-N1-(β-D-glycopyranosyl)-thioureas (8 - 10) (Figure 2) [10]. This reaction proceeds quickly, so we could not fix the intermediate formation of the corresponding
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Figure 2. The thionization mechanism for glycosylurea (where Ry = xylose, glucose, and galactose).
products. This is most likely due to the decomposition of the Lawessons (1) reagent into dithiometaphosphonate (1a), which has a resonant structure. The interaction of dithiometaphosphonate with glycosylmethyl urea (2-4) leads to the formation of intermediate cyclic thioketals (5 - 7), with the subsequent decomposition, which produces the final products (8 - 10).
The advantage of this method is the simplicity, acceleration of the process, and elimination from the use of high-pressure technological processes and expensive platinum dioxide, poisonous sodium azide, and bromine reagents. Compounds synthesized by the new method are crystalline substances possessing chemical stability. They can be stored without decomposition at room temperature, stable under thin-layer chromatography (TLC) conditions. The individuality and structure of the target products were confirmed by the methods of nuclear magnetic resonance 13С (NMR), 1Н NMR, infrared (IR)-spectroscopy, also elemental analysis. In the 13C NMR and 1H NMR spectra of as-synthesized compounds, we observed nuclei signals belonging to all presenting compounds (Table 1).
In the IR spectra, in particular of N-methyl-N1-(β-D-glucopyranosyl)-thiourea, a broadband was observed in the region of 3000 - 3550 cm−1, which is characteristic of the stretching vibrations of the OH- and NH- groups. Absorption bands in the regions of 1024 and 1108 cm−1 are related to the stretching vibrations of the carbohydrate ring. The presence of signals at 926 cm−1 is indicating β-position of the pyranotic ring. Oscillations in the region of 1256 - 1441 cm−1 can be attributed to the valence vibrations of the group (C=S). Peaks in the region of 2836 cm−1 are attributing to CH3 group vibrations.
Important structural information was obtained by the 1H NMR spectra. According to the proton magnetic resonance (PMR) spectrum, the structures of the products obtained are compounds formed from the glycosylamine bond with the β-arrangement of glucosyl methylthiourea. The low-field part of the PMR spectrum for the N-methyl-N1-(β-D-glucopyranosyl)-thiourea contains signals that appearing as a multiplet centered at 3.6 ppm - 3.8 ppm, respectively, belonging to the fifth axial and the fifth equatorial hydrogen atom of the carbon-water ring. The equatorial hydrogen atom at C-2 appears as a doublet with a chemical shift at 3.8 ppm. A signal in the form of a broadened singlet, belonging to the protons of the methyl group CH3, is observed in the region of 2.7 ppm. The signal in the region of 4.6 ppm - 4.85 ppm refers to carbohydrate rings.
13C NMR spectra of N-methyl-N1-(β-D-glucopyranosyl) thiourea, the anomeric carbon atoms were found in the range of δ 60.69 - 81.09 ppm, which also testifies favor for the β-configuration of the glyosidic bond. Signals in the region of 60.69 ppm and δ 69.42 suggest that the glucoside residue in the compounds under discussion is in the pyranose form. Signals in the region of δ 26.28 ppm belonging to the methyl group, C=S signals were observed in the field of ≈160.13 ppm. The set of spectral characteristics of the synthesized compounds do not doubt that all the substances obtained are individual compounds.
3.2. Synthesis of 2,4-Bis(p-methoxyphenyl)-1,3- dithiadiphosphetan-2,4-disulfide
In a flask equipped with a reflux condenser and a calcium chloride tube, 3.661 g (0.114 mol) of sulfur and 1.4 g (0.045 mol) of red phosphorus placed and boiled. The reaction mass was then cooled, 12 ml (0.11 mol) of anisole was added and boiled. After cooling up to the room temperature, the precipitated crystals filtered and washed with absolute ether and benzene, and then recrystallized from absolute toluene. Product yield: 4.36 g, (47.8%), Tmelt = 228˚C - 229˚C. IR spectrum (KBr, v, cm−1): 689 (P = S), 615 (P = C), 1022, 1095, 1180 (R-O-CH3), 1267, 1294, 1308, 1458, 1493, 1592 (arom.). C14H14O2P2S4 404.475 Calculated %: C-41.57; H-3.49; P-15.32; S-31.71. Found %: C-41.95; H-3.78; R-15.1; S-32.0.
3.3. Thionization of Carbamide Sugars
Lawessons reagent was used by us for thionization of carbamide derivatives of sugars to obtain thiocarbamide derivatives, 4-(N-β-D-glycopyranosyl)-thiosemicarbazide [11], previously synthesized by us, N-(β-D-glycopyranosyl) phenylsemicarbazide, 2,3,4,6-tetra-O-acetyl-(β-D-glycopyranosyl)-carbamoyl diethylenediamine, 1-[(N-glycopyranosyl) carbamoyl]-3,5-dimethylpyrazole [10] [12] [13] [14] as shown in Figure 3.
The reaction proceeds smoothly with the interaction of carbamide derivatives of sugars with Lawesson reagent in pyridine, for 20 minutes and leads to the formation of the corresponding 4-(N-β-D-glycopyranosyl)-thiosemicarbazide, N-(β-D-glycopyranosyl) phenylthiosemicarbazides, 1-[(N-β-glycopyranosyl) thiocarbamoyl]-3,5-dimethylpyrazoles, 2,3,4,6-tetra-O-acetyl-(β-D-glycopyranosyl)-thiocarbamoyl diethylenediamine diamine (Figure 4). The course of reactions and compositions of obtained compounds was controlled and carried out using the methods of thin-layer and paper chromatography in the systems: chloroform-ethanol-methyl ethyl ketone (1:2:1).
Compounds synthesized by the method are the crystalline substances possessing chemical stability. They can be stored without decomposition at room temperature, stable under TLC.
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Figure 3. Synthesized samples of the Lawessons reagent and 4-(N-β-D-glycopyranosyl)-thiosemicarbazide.
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Figure 4. Thionization reaction for carbamide derivatives of sugars.
Individuality and structures of the target products confirmed by physicochemical methods of 13С and Н1 NMR, IR spectroscopy analyses. Results were presented in Tables 1-4, characteristic maximums of sugar thiocarbamides in the IR spectrum absorption bands, and chemical shifts for 13C NMR of sugar thiocarbamides in Figure 5, Figure 6.
4. Conclusion
Thionization method of glycosyl urea and carbamide compounds of sugars is presented in this article. Obtained compounds are crystalline substances possessing chemical stability, and open up new ways of synthesizing various carbohydrate derivatives of thiourea. For thionization of carbamide derivatives of sugars, the Lawessons reagent is used to obtain thiocarbamide derivatives, 4-(N-β-D-glycopyranosyl)-semicarbazide which allows eliminating disadvantages of the isothiocyanate use. Obtained experimental data is useful for thionization of sugar derivatives and provides possibilities for the synthesis of various carbohydrate derivatives of thiourea.
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Table 1. Physio-chemical property of thiocarbamide sugars.
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Table 2. Characteristic maximums of sugar thiocarbamides in the IR spectrum absorption bands.
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Table 3. Chemical shifts of thiocarbamide sugar protons.
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Figure 5. Characteristic maximums of sugar thiocarbamide 4-(N-β-D-galactopyranosyl) thiosemicarbazide in the IR spectrum absorption bands.
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Figure 6. Pattern showing the chemical shifts for 13C NMR of sugar thiocarbamides (N-methyl-N1-(β-D-glucopyranosyl)-thiourea).
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Table 4. Chemical shifts for 13C NMR of sugar thiocarbamides.