Synthesis and some reactions of 5-carbmethoxymethylidene-4-oxo-1,3-thiazol-2-ylguanidine

Methyl (2 Z )-[2[(diaminomethylene)amino]-4-oxothiazol-5(4 H )-ylidene]acetate was obtained by the reaction of N -amidinothiourea and dimethyl acetylenedicarboxylate (DMAD) under various conditions: methanol, ethanol, acetonitrile, ethyl acetate, dioxane, acetic acid, ethanol/TsOH. The structure of the product has been proven by X-ray diffraction analysis. A series of new N -(5-R -1,3,5-triazinan-2-ylidene)- N -1,3-thiazol-2-amines was obtained as a result of the multicomponent condensation of methyl (2 Z )-[2[(diaminomethylene)amino]-4- oxothiazol-5(4 H )-ylidene]acetate with alkylamines and formaldehyde.


Introduction
1] Thieno [2,3-d]thiazole-6-carboxylic acid derivatives are potential inducers of systemic resistance in plants. 12In this regard, the synthesis of new thiazole derivatives, including those with additional reactive groups in their structure, is an important task.

Results and Discussion
Based on the literature data, the formation of compounds 9-13 during the interaction of amidinothiourea with DMAD can be assumed (Scheme 4).As noted above, there are reports in the literature 34 on the formation of 1,3-thiazinone 10 in an ethanol/p-TsOH medium.We carried out this reaction under the same conditions and obtained a product with characteristics (melting point) and spectral analysis data identical to those described by El-Shaieb et al. 34 However, by X-ray diffraction analysis (Figure 1) we proved the actual formation of 1,3-thiazole 9.This suggests an error was made by the authors 34 in the structure of the reaction product of N-amidinothiourea with DMAD.
The structure of compound 9 was also confirmed by further 1 H NMR spectroscopic analysis.The spectrum contains a methyl group singlet at 3.76 ppm, a CH-proton singlet at 6.61 ppm, and two broadened amino group singlets at 7.58 and 8.59 ppm.The 13 C NMR spectrum shows signals of the carbon of the methyl group at 52.63 ppm, CH at 113.84 ppm, as well as signals of 5 carbon atoms for the carbonyl and imino groups in the range of 149.36-181.09ppm.It should be noted that one cannot assume that 9 or 10 has been be formed based on the spectral data alone.
X-ray diffraction analysis showed that 1,3-thiazole 9 forms a solvate with a solvent molecule, DMF.A detailed description of the X-ray structural analysis data is presented in the Supplementary Material.In order to study the possibility of obtaining alternative products 10-13, we also studied the interaction of N-amidinothiourea and DMAD under other catalytic and non-catalytic conditions, which are presented in Table 1.A complex of physicochemical methods of analysis ( 1 H NMR spectroscopy, HPLC-MS) established that regardless of the reaction conditions, methyl (2Z)-[2[(diaminomethylene)amino]-4-oxothiazol-5(4H)ylidene]acetate 9 is formed as the main product.There are known examples of isomerization of 1,3-thiazoles similar in structure to compound 9 to the corresponding 1,3-thiazines upon heating in methanol 27 or in an aqueous solution of NaOH. 35Our attempts to extend these reactions to guanidine 9 were unsuccessful.In both cases, only the starting 1,3-thiazolone 9 was isolated.
Methyl (2Z)-[2[(diaminomethylene)amino]-4-oxothiazol-5-(4H)-ylidene]acetate 9 is a convenient substrate for the preparation of new heterocyclic compounds.This is due to the presence of nucleophilic (guanidine fragment) and electrophilic (carbonyl and carbmethoxy groups) centers in its structure.In this work, we studied the condensation of 9 with both alkylamines and formaldehyde (Scheme 5).It is known that such reactions with 1,3-N,N-binucleophiles lead to the formation of hydrogenated 1,3,5-triazines. 36 1,3,5-Triazinanes 17 a-f with exocyclic multiple bonds are formed as a result of reaction 9 with primary aliphatic amines and formaldehyde.The formation of products 14-16 can be excluded based on 1 H NMR and 13 C NMR spectroscopy data.Thus, in the 1 H NMR spectra, two CH2-groups and two NH-groups are seen as singlets in the range of 4.27-4.41and 9.01-9.14ppm, respectively.This is due to the fact that the protons of the two NH groups and the two CH2 groups are magnetically equivalent.In the 13 C NMR spectra, both carbons of the CH2 groups of the triazine ring are seen as one signal at 57.5-60.6 ppm.For alternative regioisomers 14-15 and tautomers 16, the form of the spectra would be different.Thus, for compound 14, the signals of the protons of methylene groups should have the form of two singletons.For compounds 15 and 16, the signals of the protons of secondary amino groups and CH2 groups should have an even more complex character.The ester and carbonyl groups do not react with amines.This is proved by the presence of a methoxy group singlet in the 3.71-3.75ppm region in the 1 H NMR. Additionally, the structure of products of 17 is supported by the LCMS and IR spectroscopy.

Experimental Section
General.IR spectra were registered on a Vertex 70 Fourier transform spectrometer. 1H and 13 C NMR spectra were acquired on a Bruker DRX-500 spectrometer (500 and 125 MHz, respectively ) in DMSO-d6 at 30°С with TMS as internal standard.High resolution mass spectra were recorded on an Agilent Technologies LCMS 6230B spectrometer (electrospray ionization).Melting points were determined on a Stuart SMP30 apparatus.Assaying of the purity of the starting materials and the synthesized compounds, as well as the analysis of reaction mixtures was done by TLC on Merck TLC Silica gel 60 F254 plates; eluents: MeOH, CHCl3, and their mixtures in different ratios.Visualization of TLC plates was done under UV light or in iodine vapor.Namidinothiourea, dimethyl acetylenedicarboxylate and alkylamine were supplied by Acros.

Table 1 .
Conditions for the reaction of N-amidinothiourea with DMAD and yields of product 9