Synthesis and characterization of new pyrimidine-based 1,3,4-oxa(thia)diazoles, 1,2,4-triazoles and 4-thiazolidinones

New 1,2,4-triazoles 3a , b , 4a , b , 1,3,4-oxadiazoles 5a , b , 1,3,4-thiadiazoles 6a , b and 4-thiazolidinones 7a , b were synthesized by cyclization of N-substituted 2-[2-(6-methyl-2-morpholinopyrimidin-4-ylthio)acetyl]hydrazinecarbothioamides 2a , b under different conditions. The starting 2a , b were readily obtained by acylation of 2-(6-methyl-2-morpholinopyrimidin-4-ylthio)acetohydrazide ( 1 ) with cyclohexyl or phenyl isothiocyanate. All new compounds were characterized by 1 H, 13 C NMR, IR spectroscopy and elemental analysis.


Introduction
Heterocyclic structures, in particular azoles and azines, form the basis of many pharmaceutical and agrochemical products.Publications devoted to the chemistry of azoles in recent decade refer to the synthesis of 1,2,4-triazoles, 1,3,4-oxa(thia)diazoles and thiazolidines.Different approaches have been reported for the preparation of such heterocycles. 1,2Their significance deals with a broad spectrum of biological activity and technological interest.The efficacy of clinical use of antiviral, anticancer and antifungal drugs (Ribavirin, Anastrozole, Fluconazole, Voriconazole etc.) led to intense investigation of 1,2,4-triazole derivatives.1,2,4-Triazole containing molecules have increasing interest as anticancer, 3 fungicidal, antimicrobial, 4 antitubercular 5 or anti-inflammatory 6 agents.They also are significant in agrochemical industry as plant protecting materials. 7][10] Moreover, ionic liquidcrystalline compounds bearing 1,3,4-oxadiazole moiety are of interest in emerging organic electronics OLED technologies. 11hiazolidine is a biologically important scaffold and numerous pharmacological activities of 4-thiazolidinone are revealed and well documented. 12,13

Results and Discussion
Our earlier studies involved synthesis of heterocyclic compounds containing in their structure both the pyrimidine and azole, in particular 1,2,4-triazole, rings. 14In consideration of diverse biological properties of this type of compounds and in continuation of our interest in the synthesis of biologically active heterocycles, the aim of the present work was to develop simple and efficient procedures for the preparation of new 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4thiadiazole and 4-thiazolidinone derivatives bearing substituted pyrimidine moiety.As a core structure for these reactions (6-methyl-2-morpholinopyrimidin-4-ylthio)acetohydrazide (1) was exploited. 15Its derivatives were found to show significant anti-inflammatory activity and this was the reason of our choice to use hydrazide 1 as a starting compound.Reaction of hydrazide 1 with cyclohexyl or phenyl isothiocyanate in absolute ethanol at reflux produced the corresponding hydrazinecarbothioamides 2a,b with good yields (Scheme 1).The structure of hydrazinecarbothioamides 2a,b was confirmed by the spectral data.The IR spectra of componds 2a,b displayed characteristic absorption bands in a region of 3235-3127 cm - 1 for NH, at 1700-1692 cm -1 for C=O and in the region of 1348-1335 cm -1 corresponding to C=S vibrations.In the 1 H NMR spectra three sets of NH group proton singlets as well as signals of cyclohexyl or phenyl group protons were observed confirming 2a and 2b formation.The cyclization of hydrazinecarbothioamides is an excellent strategy for the synthesis of different heterocycles. 16he starting hydrazinecarbothioamides 2a,b on treatment with 10% sodium hydroxide solution at reflux undergo cyclodehydration to give 1,2,4-triazole-3-thiones 3a,b.The structure was evident from spectral data.The IR spectra displayed absorption bands at 3235-3127 cm -1 for NH, 1605-1595 cm -1 due C=N group and at 1332-1330 cm -1 corresponding to C=S stretch vibrations.The C=O group absorption was absent.The 1 H NMR spectra revealed far downfield signal of triazole NH proton at 13.89-13.60ppm.
Hydrazinecarbothioamides 2a,b were treated with iodomethane to give compound A. The intermediate A was expected to cyclize to form either 1,2,4-triazole 4 (dehydration) or 1,3,4oxadiazole 5 (loss of CH 3 SH).Reaction of 2a,b with iodomethane in the presence of sodium hydroxide as a base did not proceed at room temperature, while at reflux heterocyclization to 1,2,4-triazoles 4a,b took place.The same methylthio derivatives 4a,b were synthesized by the direct alkylation of triazoles 3a,b with iodomethane in analogous conditions.The structure assignment was made by spectral data.In the 1 H NMR spectra of triazoles 4a,b singlets observed at 2.65 ppm (4a) and 2.59 ppm (4b) were attributed to SCH 3 protons and a signal for NH proton was absent.In the IR spectra characteristic NH group absorption was not found.
There are different methods to generate 2-amino substituted 1,3,4-oxadiazoles by oxidative cyclization of acylhydrazinecarbothioamides.16b,17 Reactions with hydrazinecarbothioamides 2a,b to give 1,3,4-oxadiazoles 5a,b were carried out either using iodine/potassium iodide in sodium hydroxide solution or mercury (II) acetate in abs.ethanol.The latter method appeared to be much more convenient because of shorter reaction time, ease of work-up procedure and slightly higher yields of products 5a,b.
The acid catalyzed cyclization of hydrazinecarbothioamides 2a,b afforded thiadiazoles 6a,b.Compounds 2a,b were reacted with conc.sulfuric acid at 0 °C to give moderate yields of 6a,b.
Reaction of starting 2a,b with ethyl bromoacetate in abs.ethanol in the presence of anhydrous sodium acetate as a base resulted in the formation of 4-thiazolidinones 7a,b.The spectral data were in accordance with given structures.Thiazolidinones 7a,b show absorption bands for ring C=O in the region of 1720-1760 cm -1 together with amide C=O absorption at ~ 1670 cm -1 .The 1 H NMR spectra revealed the presence of two singlets for thiomethylene protons.Another pair of singlets equivalent to two protons at 4.02, 4.05 (for 7a) and 4.10, 4.07 ppm (for 7b) correspond to C-5 protons of the 4-thiazolidinone ring.Peaks resonated at 28.3 and 30.6 ppm in the 13 C NMR were assigned to thiazolidinone C-5, while at 158.5 and 148.2 ppm were attributed to C-2 of the 4-thiazolidinone ring.

Experimental Section
General.Melting points were determined in open capillaries and are uncorrected.The IR spectra were recorded on a Spectrum BX FT-IR (Perkin-Elmer, Sweden) as potassium bromide pellets.The NMR spectra were recorded on a Unity Varian Inova spectrometer at 300 MHz for H and 75 MHz for C, chemical shifts (δ) are reported in ppm relative to TMS.The course of reactions and purity of compounds was controlled by TLC on Alugram Sil G/UV plates (ethyl acetate/hexane = 3/1).Elemental analyses were performed at the Microanalytical Laboratory of the Department of Organic Chemistry of Vilnius University.Chemicals were purchased from Sigma-Aldrich.All solvents were dried and distilled before use.General procedure for the synthesis of 2a,b A mixture of hydrazide 1 (2.83 g, 10 mmol) and cyclohexyl (or phenyl) isothiocyanate (11 mmol) in abs.ethanol (50 ml) was refluxed for 3 h and then cooled to room temperature.The resultant white solid was collected by filtration, dried and crystallized from ethanol.

General procedure for the synthesis of 3a,b
A mixture of compound 2a or 2b (1 mmol) and 10% sodium hydroxide solution (20 ml) was heated at reflux for 3 h, cooled to room temperature, poured over crushed ice and acidified with conc.HCl to pH 5. The precipitate was collected by filtration, washed with water, dried and crystallized from ethanol.

Method B.
A solution of sodium hydroxide (0.04 g, 1 mmol) in methanol (5 ml) was added dropwise at room temperature to a stirred mixture of hydrazinecarbothioamide 2a (0.42 g, 1 mmol) and iodomethane (0.185 g, 1.3 mmol) in methanol (10 ml).The reaction mixture was then heated at reflux for 1 h and the solvent was removed under reduced pressure.The residue was dissolved in water, neutralized with diluted HCl and extracted with chloroform.The extracts were dried under Na 2 SO 4 and evaporated to give 4a, 0.28 g (67%), mp 178-180 °C (from 2propanol).