One-pot microwave-assisted synthesis of 2 , 5-bis ( pyrazol-4-yl ) [ 1 , 3 ] thiazolo [ 5 , 4-d ] [ 1 , 3 ] thiazoles from pyrazole-4-carbaldehydes and dithiooxamide

An efficient one-pot method for the synthesis of previously unknown of 2,5-bis(pyrazol-4yl)[1,3]thiazolo[5,4-d][1,3]thiazoles has been developed. The method comprises the microwaveassisted reaction of dithiooxamide with pyrazole-4-carbaldehydes followed by oxidation of the initially formed 2,5-dihydro[1,3]thiazolo[5,4-d][1,3]thiazoles with selenium dioxide. 2,5Bis(pyrazol-4-yl)[1,3]thiazolo[5,4-d][1,3]thiazoles were characterized by 1H, 13C and 15N NMR, IR spectroscopy and X-ray diffraction data.

5][26] Pyrazoles are used in supramolecular and polymer chemistry, 27 as cosmetic colorings and UV stabilizers. 19,28They are also used to design of complexes with unusual magnetic properties. 29ynthetic approaches to 2,5-disubstituted thiazolo [5,4-d]thiazoles are limited in number, laborious and require harsh reaction conditions.A popular method for the preparation of diarylsubstituted thiazolo [5,4-d]thiazole, reported for the first time, 30 is based on the condensation of dithiooxamide with excess aromatic aldehydes (10-12-fold molar excess), which is used for oxidation of the initially formed products.This reaction is carried out in diverse solvents, 10,[31][32][33][34] or without solvent. 6,15,16,18However, the harsh reaction conditions and duration of the process (24 h) lead to resinification and formation of the side products.The developed alternative approaches to the synthesis of diarylthiazolo [5,4-d]thiazoles such as treatment of 2,5-bis(acetylamino)thiazole with sodium thiocyanate in the presence of bromine followed by thermal cyclization, 35 acidcatalyzed reaction of 5-amino-2-aryl-4-mercaptothiazole with orthoether 36 and others 1 are of limited utility.
In 2014, a method for the preparation of 2,5-disubstituted [1,3]thiazolo [5,4-d][1,3]-thiazoles was elaborated (yields 6-81%). 37The method comprises the interaction of a diverse range of aldehydes with dithiooxamides in nitrobenzene at 4:1 or 2:1 reagents ratio.Also, the first stage of the process involves microwave activation to obtain the intermediate nonaromatic thiazolinothiazolines.For the synthesis of the target thiazolothiazoles, oxidation of the intermediate heterocycles with chloroanil or DDQ is employed at the second stage of the process.The two-stage character of the reaction and the application the aforementioned expensive toxic oxidizing agents, hinders isolation and purification of the target thiazolothiazoles.

Results and Discussion
Recently, we developed a one-pot microwave-assisted method for the synthesis of 2,5bisarylthiazolo [5,4-d]thiazoles from benzaldehydes and dithiooxamide. 38The reaction is carried out under microwave activation at both steps (condensation of dithiooxamide with aromatic aldehydes and oxidative aromatization of intermediate 2,5-dihydrothiazolo [5,4-d]thiazoles with SeO2).We have employed for the first time SeO2 as an oxidizing agent.Unlike chloroanil and DDQ, SeO2 in the course of the process is transformed to the low toxic elemental selenium, which is not dissolved in reaction mixtures and easily separated from reaction products.
The elemental selenium, which formed during the reaction, was easily separated allowing the facile isolation of thiazolo [5,4-d]thiazoles 2a-d.Unlike the known procedure, 37 this protocol did not require additional purification of the products on chromatographic column.
It should be noted that while diarylthiazolothiazoles can be synthesized by the reaction of the corresponding benzaldehydes with dithiooxamide without microwave irradiation, the interaction of pyrazole-4-carbaldehydes with dithiooxamide affording bispyrazolyl-thiazolo [5,4-d]thiazoles cannot be implemented without microwave activation.Under the conditions reported in literature 18,30,34 or upon the reagents heating at 130 °C for 3 h in DMSO, the reaction mixture darkens and resinifies, only the initial aldehyde being detected among the reaction products.
The 2,5-bispyrazolyl [1,3]thiazolo [5,4-d][1,3]thiazoles 2a-d obtained are high-melting lightcolored compounds, which are poorly soluble in organic solvents.The structure and composition of thiazolo [5,4-d]thiazoles 2a-d have been supported by IR, 1 Н, 13 С, and 15 N NMR spectroscopy and elemental analysis.In the IR spectrum of compounds 2a-d, characteristic absorption bands of the carbonyl groups of the initial aldehydes 1a-d are absent.In the 1  To investigate the molecular structure and intermolecular interactions in the solid state, X-ray structure analysis of the single crystal of compound 2c was carried out.The single crystals of 2c were obtained by slow evaporation from dimethylformamide.The molecular structure of thiazolothiazole 2c is depicted in Figure 1.  1a).Compound 2c have simple stacking structure where all molecular planes are parallel to each other.They form columnar structures with intermolecular short S … S contacts between the thiazolothiazole rings equal 3.379 Å (Figure 1b).In addition there are short C-H … S contacts between methyl groups and sulfur atoms of neighboring molecules (Figure 1c).In contrast to pyridine or phenyl structures with thiazolo-thiazole fragment where pyridine 12 or phenyl 10,31 ring does not exceed 5.5°, angle between pyrazole and thiazolothiazole planes in compound 2c consists 16.83°.

Conclusions
A facile and efficient one-pot method for the synthesis of 2,5-bispyrazol-4-yl-thiazolo [5,4d]thiazoles has been developed.The method comprises the microwave-assisted reaction of dithiooxamide with pyrazole-4-carbaldehydes followed by oxidation of the initially formed bispyrazolothiazolinothiazolines with SeO2.The protocol does not require the use of excess aldehyde and is less laborious compared to the known syntheses of thiazolo [5,4-d]thiazoles.

Experimental Section
General.The 1 H, 13 C, 15 N NMR spectra were recorded on Bruker DPX-400 (400.13,100.62 and 40.55 MHz, respectively) from solutions in (DMSO-d6) and СDСl3 relative to HMDS ( 1 Н, 13 C) and СН3NO2 ( 15 N).Chemical shifts are reported in ppm values (δ) and coupling constants (J) in Hz.The IR spectra were taken in KBr on a Bruker Vertex 70 instrument.The elemental analyses were obtained on a Thermo Scientific Flash 2000 CHNS analyzer.The melting points were determined on a PolyTherm A micro hot stage.Starting dithiooxamide was taken from commercial suppliers and used without further purification.Pyrazole-4-carbaldehydes 1a-d were synthesized according to the literature. 39Reactions were carried out in the microwave reactor Anton Paar Monowave 300 under inert atmosphere at fixed temperature (control external surface sensor) and variable power (maximum power 400 W).