Domino-reactions of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide, hetarenecarbaldehydes and active methylene nitriles in the construction of new 2-amino-4H-pyrans and the study of their antimicrobial properties

Multicomponent domino reactions are an effective modern approach in the synthesis of different types of organic compounds, including biologically active pyrans. Aim. To study the three-component interaction of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide with different hetarenecarbaldehydes and active methylene nitriles in order to synthesize new 2-amino-4H-pyran derivatives, as well as the antimicrobial activity of the compounds obtained. Results and discussion. 2-Amino-4-heteryl-4,6-dihydropyrano[3,2-c][2,1]benzoxathiin-3-carbonitrile 5,5-dioxides were obtained by stepwise and multicomponent reactions of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide with hetarenecarbaldehydes and malononitrile. For the same interaction with ethyl cyanoacetate the reaction selectivity decreased and not only target ethyl 2-amino-4H-pyran-3-carboxylates were obtained, but also triethylammonium salts of bis(1,2-benzoxathiin-2,2-dioxo-4-ol-3-yl)(heteryl)methane. The latter were also purposefully synthesized by the two-component reaction of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide with hetarenecarbaldehydes in the presence of triethylamine. The compounds obtained revealed a higher antimicrobial activity against gram-positive bacteria and fungi compared to the reference drugs. Experimental part. 3-Amino-4-heteryl-4,6-dihydropyrano[3,2-c][2,1]benzoxathiin-3-carbonitrile 5,5-dioxides and triethylammonium 3-[1-(4-hydroxy-2,2-dioxido-1,2-benzoxathiin-3-yl)heteryl]-1,2-benzoxathiin-4-olate 2,2-dioxides were synthesized. The antimicrobial activity of the compounds synthesized was studied by the agar diffusion method. Conclusions. It has been proven that the multicomponent format for the three-component interaction of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide with hetarenecarbaldehydes and active methylene nitriles is more favorable and convenient than the stepwise approach to obtain new derivatives of 2-amino-4H-pyrans. Triethylammonium 3-[(4-hydroxy-2,2-dioxido-2,1-benzoxathiin-3-yl)heteryl]-2,1-benzoxathiin-5-olate 2,2-dioxides have been also synthesized. The antimicrobial properties of the compounds obtained are higher than in the reference drugs, especially against gram-positive bacteria and fungi.

Ключевые слова: 1,2-бензоксатиин-4(3H)-он 2,2-диоксид; домино-реакции; 2-амино-4H-пиран; триэтиламмониевая соль; антимикробная активность When planning the synthesis of any organic compound it is important to determine all possible synthetic paths. After choosing a clearly defined pathway among this set the paramount attention is paid to the number of stages and the final yield of the product. Considering that organic reactions always occur with less than 100 % yield the synthesis becomes more valuable if it contains fewer stages with a high yield at each of them. Even such acceptable organic yield as 75 % at the 5-th stage gives the total yield of approximately 24 %, for 50 % yield it turns out to be about 3 % [1].
The first way to solve this synthetic problem is to increase the yield of each stage. However, this path is not always successful [2].
The second route relies on utilization of cascade transformations that are known as domino-reactions representing a one-pot process with construction of two or more bonds in one step in order to obtain a complex compound without isolation of intermediates. Domino reactions can take place as the one-component, two-component or multicomponent processes by the number of starting compounds. This approach turned out to be very effective, so it is not surprising that domino interactions gained popularity among synthetic chemists. Moreover, sometimes domino reactions lead to formation of the unexpected reaction products, so they are considered as an instru-ment for new types of the synthesis of organic compounds [3].
To date a huge variety of domino-reactions has been studied, and it gives the possibility to construct different types of organic compounds, including heterocyclic frames. One of such heterocyclic systems are pyrans, a well-known group with many biologically active representatives, including antimicrobial [4] and antitumor [5] agents. Therefore, one-pot multicomponent reactions in the case of the pyran synthesis can be considered as a useful tool for creating new bioactive substances.
The two-step approach towards 2-amino-4H-pyrans with the preliminary obtaining of α,β-unsaturated nitriles 5a-h was also performed (Scheme 2, Path B). It was found that this reaction pathway resulted in the lower yields of target compounds compared to those obtained by three-component reactions. Thereby, the multicomponent format for the 2-amino-4H-pyrans synthesis is more favorable. It is also worth noting that the two-step format in the case of 3e and 3h also gave no target products 4e and 4h and resulted in the starting hetarylidenes. Considering such result the triethylammonium salt for indol-3-carbaldehyde 3h in the three-component reaction was probably formed due to the direct interaction of 1,2-benzoxathiin-4 (3H)-one 2,2-dioxide 1 and aldehyde 3h.
At the next stage of our research ethyl cyanoacetate 7 was used instead malononitrile in the threecomponent interaction studied (Scheme 3) in order to obtain the corresponding ethyl 2-amino-4H-pyran- 3-carboxylates. According to the previous research data [6] the common conditions for similar reactions include reflux for 7 h in the presence of the catalytic amount of triethylamine. However, in this case the reaction selectivity significantly decreased and three types of products were obtained: the target 2-amino-3-ethoxycarbonyl-4H-pyrans 8a and 8f, α,β-unsaturated nitriles 10d and 10g and triethylammonium salts of bis(1,2-benzoxathiine-2,2-dioxo-4-ol-3-yl)(heteryl) methane 6c and 6h. The interaction with 4-pyridinecarbaldehyde 3b led to isolation of an unidentified product. Any product was not isolated for N-methylpyrrol-2-carbaldehyde 3e. Formation of triethylammonium salts 6c and 6h can be explained by two possible reaction pathways. The first one presumes that Michael adduct A initially formed does not undergo the intramolecular hetero-Thorpe-Ziegler cyclization, but eliminates the molecule of ethyl cyanoacetate with formation of enone B. The latter as a Michael acceptor reacted with another molecule of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide 1 with formation of the bis-adduct isolated as a triethylammonium salt. The second route supposed the direct interaction of 1,2-benzoxathiin-4(3H)-one 2,2dioxide 1 with hetarencarbaldehydes 3.
Considering this probable reaction pathways we performed the same interaction for thiophen-2-carbaldehyde 3c with the 3-fold and 7-fold excess of ethyl cyanoacetate 7 in order to shift the equilibrium towards 2-amino-4H-pyran 8c and to avoid salt 6c formation. However, according to 1 H NMR the mixture of the corresponding α,β-unsaturated nitrile and triethylammonium salt was obtained. Furthermore, application of the two-step approach as an interaction of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide 1 and Knoevenagel products for aldehydes 3c and 3h also resulted in forming triethylammonium salts 6c and 6h.
These results proved the proposed mechanism of retro-Michael cleavage for the two-component reaction described and gave the opportunity to consider the similar mechanism for the three-component reaction along with a direct interaction of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide 1 with hetarencarbaldehydes 3.
It is interesting that the triethylammonium salt similar to 6c was obtained in the previous studies of 1H-2,1-benzothiazin-4-one 2,2-dioxide in the same reaction [6]. Considering the assumption that formation of salt 6c proceeds through enone B we tried to obtain the similar triethylammonium salts of bisadducts by a direct interaction of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide 1 with hetarenecarbaldehydes 3 (Scheme 4). The reaction was performed in the molar ratio of compounds 1 and 3 2:1 in propan-2-ol in the presence of the equimolar amount of triethylamine.
The structures of all compounds synthesized were confirmed by 1 Н NMR-spectroscopy and elemental analysis. The 1 Н NMR-spectra of compounds 4a-d, 4f, 4g are characterized by the presence of the narrow high intensity singlet of a proton in position 4 of the 4Hpyran ring in the range of 4.85-5.32 ppm, the singlet of the 2-amino group can be observed in the spectral region of 7.30-7.63 ppm. In 1 Н NMR-spectra of compounds 8a and 8f the singlet in position 4 of the 4Hpyran ring is situated at 4.83 ppm and 4.90 ppm, respectively, the signal of the 2-NH 2 group is shifted to downfield compared to 4a and 4f. The last fact can be explained by formation of the intramolecular hydrogen bond between NH 2 and carbonyl oxygen of the ester fragment. The 1 H NMR-spectra of bis-adducts 6a-d, 6g, 6h are characterized by the presence of the singlets of the benzoxathiine OH-group at 16.78-17.53 ppm and the bridging CH-group at 5.45-5.84 ppm. There are no signals of the triethylammonium NH-group in the 1 H NMR-spectra probably due to the fast deutero exchange.
The study of the antimicrobial activity of the compounds synthesized was performed according to the international standards [9,10] by the agar diffusion method against the standard test-strains of gram-positive and gram-negative bacteria, as well as against fungi of C. albicans. The results showed a higher antimicrobial activity compared to the reference drugs (Table). The moderate activity revealed was higher in the case of gram-positive strains than for gramnegative bacteria and fungi. The most active were triethylammonium salts corresponding to 2-amino-4Hpyran-3-carbonitriles. Therefore, the synthesis of such ammonium salts with other amines may be considered as a promising way for further creation of antimicrobials with the narrow spectrum.

Experimental Chemical Part
Starting aldehydes and active methylene nitriles were obtained from commercial sources and used without further purification. Melting points were determined on a Gallenkamp melting point apparatus, Model MFB-595 in open capillary tubes. The 1 H NMRspectra were recorded on a Varian WXR-400 spectrometer using DMSO-d 6 as a solvent and TMS as an in-ternal standard. Elemental analyses were carried out using a Carlo Erba CHNS-O EA 1108 analyzer.