THE STUDY OF THE THREE-COMPONENT INTERACTION BETWEEN 1-ETHYL-1 Н-2 , 1-BENZOTHIAZIN-4 ( 3 Н )-ONE 2 , 2-DIOXIDE , HETERYLCARBALDEHYDES AND ACTIVE METHYLENE NITRILES

Some peculiarities of the three-component interaction of 1-ethyl-1H-2,1-benzothiazin-4(3H)-one 2,2-dioxide with active methylene nitriles and heterylcarbaldehydes have been described in this article. It has been found that if malononitrile is used, the products of the three-component reaction are 2-amino-4-heteryl-3-cyano-6-ethyl-4,6dihydropyrano[3,2-c][2,1]benzothiazine 5,5-dioxides irrespective of the heteryl fragment nature in the initial aldehyde. When using ethyl cyanoacetate (as the active methylene nitrile) in the three-component interaction instead malononitrile the reaction lost its selectivity. In this case, depending on the heterylcarbaldehyde, three different types of products were obtained, namely 2-amino-3-alkoxycarbonyl-4-heteryl-4H-pyranes (for pyridine-3-, pyridine-4-carbaldehydes and furan-2-carbaldehyde), thriethylammonium salt of bis(1-ethyl-1H-2,1-benzothiazin-2,2dioxo-4-ol-3-yl)(2-thienyl)methane (for thiophen-2-carbaldehyde) or ethyl 2-cyano-3-(1H-indol-3-yl)acrylate (for indol-3-carbaldehyde). Formation of a stable triethylammonium salts was considered as the process competitive with formation of 2-amino-4H-pyranes. It has allowed to propose the modified mechanism of 2-amino-4H-pyranes formation. This mechanism includes the stage of forming triethylammonium salts of bis-adducts. According to this mechanism 2-amino-3-ethoxycarbonyl-4-(2-thienyl)-4H-pyrane without any impurity of bis-adduct could be selectively obtained using the three-component interaction. Triethylammonium salts of bis-adducts were obtained by direct interaction of 1-ethyl-1H-2,1-benzothiazin-4(3H)-one 2,2-dioxide with heterylcarbaldehydes in the presence of equimolar amounts of triethylamine. It has been shown that the three-component interaction of 1-ethyl-1H-2,1-benzothiazin-4(3H)-one 2,2-dioxide with active methylene nitriles and heterylcarbaldehydes is a more effective tool in order to obtain condensed 2-amino-4-heteryl-4H-pyranes compared to the stepwise approach.

In contrast to the latter, 1Н-2,1-benzothiazin-4 (3Н)-one 2,2-dioxide is characterized by special structural and reactivity features.In spite of the expected properties of ketones, 1Н-2,1-benzothiazin-4(3Н)-one 2,2-dioxide can not be reduced to the alcohol either by catalytic reduction (hydrogenation in various solvents using platinum or nickel catalysts at various temperatures and pressures) or chemical means (borohydride, lithium aluminum hydride, or sodium and alcohol).It also fails to form oximes and semicarbazones, and it does not form enamines in reactions with the secondary amines [4,16].
The first stage of our studies was dedicated to the use of malononitrile as an active methylene nitrile in the three-component one-pot interaction.
As the result of high reactivity of pyridine-3-carbaldehyde (4а) and pyridine-4-carbaldehyde (4b) the interaction in these cases proceeded in ethanol at the room temperature for 10 min with almost quantitative yields of the target products (4a,b) (Table 1, Method А).In general, such interactions need a base as a catalyst of the reaction.When pyridinecarbaldehydes (4a,b) are used, it is not necessary to use the base, and it can be explained by autocatalytic effect of the pyridine ring.
A gradual decrease in the yields of the target pyranes (4) and a gradual increase of the reaction time was observed in the case of thiophene-2-carbaldehyde (2c), furan-2-carbaldehyde (2d) and indol-3-carbaldehyde (2e).This can happen because of the influence of the electron-rich heterocyclic system on the activity of the aldehyde group.In this case, the interaction was carried out in refluxed ethanol for 2-13 h in the presence of the catalytic amounts of triethylamine (Table 1, Method А).When the reaction mixtures were refluxed for less time than required, the reaction was not completed and the target 2-amino-4H-pyranes (4с-е) were contaminated with the intermediate 2-cyano-3-heterylacrylonitriles.The use of the equimolar amounts of triethylamine did not lead to increase of the interaction efficiency and decrease of the reaction time.
The products (4а-е) precipitated from the reaction mixture were recrystallized from ethanol.
Our attempts to use pyridine-2-carbaldehyde in such three-component interaction (Scheme 2, Method A) under conditions common for pyridinecarbaldehydes (2a,b) (EtOH, rt, 10 min) led to isolation of an unidentified black coal-like product.Variation of the solvents used, thermal conditions, the reaction time, as well as the presence or absence of a catalyst did not give any positive results.
Due to the lower reactivity of ethyl cyanoacetate compared to malononitrile the three-component interaction (Scheme 3, Method A) involving pyridinecarbaldehydes (2a,b) needed the catalytic amounts of triethylamine as the base and heating.The interaction in these cases was carried out in refluxing ethanol for 7 h.If methanol was used as a solvent, the interaction was accompanied by the transesterification and the products obtained were the corresponding methyl esters -2-amino-3-methoxycarbonyl-4H-pyranes (7aa and 7bb) (Scheme 3, Method A).
To obtain 2-amino-4H-pyrane (7d) in the case of furan-2-carbaldehyde (2d) it was necessary to reflux the reaction mixture in ethanol for 10 h and use equimolar amounts of 4-dimethylaminopyridine, as a catalyst instead triethylamine (in the case of triethylamine any product of the three-component reaction was not isolated).
ISSN 2308-8303 lecule of ethyl cyanoacetate (6) and forms enone (11c).The last one acting as a Michael acceptor reacts with another molecule of 1-ethyl-1Н-2,1-benzothiazin-4 (3Н)-one 2,2-dioxide (1) with formation of dienol (12).Intermediate (12) possesses the increased OH-acidic properties due to the electron-withdrawing effect of SO 2 -groups.Moreover, in product (8c) formation of the intramolecular hydrogen bond, which stabilizes the structure of enolate anion, is possible.As the result, intermediate (12) reacts with triethylamine giving triethylammonium salt (8с).We have not found any literature data about formation of such bis-adducts salts that are similar to (8с).At the same time there are many examples of symmetrical bis-adducts as dienols, which can be easily obtained by the interaction of different 1,3-dicarbonyl compounds with aldehydes under the base catalysis [23,24].
Enone (11с) is the key intermediate in the mechanism (Scheme 4) since it can be transformed either into bis-adduct (8c) or into the target 2-amino-4Hpyrane (7c) (through formation of Michael adduct (10c)).These processes are competitive and each can prevail under certain conditions.According to the literature data about reversibility of enone (11c) formation we tried to direct the transformation of enone (11c) towards 2-amino-4H-pyran (7c) using an excess of ethyl cyanoacetate (6).When 3.0 equiv of (6) was used, the isolated mixture contained the target 2-amino-4Hpyrane (7с) and bis-adduct (8с) in the molar ratio of 1:0.4 (based on the 1 Н NMR spectroscopy data).Application of 7.0 equiv of (6) allowed to obtain compound (7c) in the yield of 53% without any impurity of bis-adduct (8с).
As in the case of malononitrile (3), the use of pyridine-2-carbaldehyde in the three-component reaction with (1) and ( 6) led to isolation of an unidentified black coal-like product.
We also attempted to obtain the triethylammonium salts of bis-adducts by direct interaction of 1-ethyl-1Н-2,1-benzothiazin-4(3Н)-one 2,2-dioxide (1) with heterylcarbaldehydes (2).This interaction may proceed through formation of highly reactive enone (11) (Table 3).The last one, as a Michael acceptor, reacts in the presence of triethylamine with the second molecule of (1) resulting in formation of salts (8).The reaction, in general, is carried out by the interaction of compounds ( 1) and (2) (the molar ratio -2:1) in ethanol in the presence of equimolar amounts of triethylamine.When aldehydes (2b,e) were used, the reaction was carried out under conditions of heating (without heating the reaction was not complete as it was confirmed by 1 H NMR-spectra).It allowed to  obtain the corresponding triethylammonium salts (8а-e) (Table 3).
If aldehyde (2b) was used in this reaction, triethylammonium salt (8b) was obtained.In the 1 H NMR spectrum of (8b) (Fig. 5) protons corresponding to two enolic OH-groups, two bridged methyne CH-groups and the triethylammonium cation can be observed.According to this spectrum the molar ratio of the enolate anion and the triethylammonium cation is 2:1.Conducting the reaction in the presence of more than equimolar amounts of triethylamine led to the same result.
In accordance with these data we suggested that compound (8b) represents a peculiar double salt, in which triethylammonium and pyridinium cations are present.This is more interesting due to the less basic properties of the pyridine ring compared to triethylamine.Such "dimeric" structure can be stable due to the presence of hydrogen bonds, but it is required the additional study to determine the structure of (8b).The yields of the compounds (8a-e) synthesized are presented in Table 3.
The structures of all compounds synthesized were confirmed by the data of 1 Н NMR spectroscopy and elemental analysis. 1Н NMR-spectra of compounds ( 4) are characterized by the presence of the narrow highintensity in position 4 of the 4H-pyran ring in the range of 4.78-5.06ppm, as well as the singlet of the 2-amino group, which can be observed in the range of 7.23-7.47ppm.In 1 Н NMR-spectra of compounds (7) the singlet in position 4 of the 4H-pyran ring can be found in the region of 4.83-5.17ppm, the signal of the 2-amino group is situated in the range of 7.80-7.90ppm.The 1 H NMR-spectra of bis-adducts (8) are characterized by the presence of the singlet of the benzothiazine OH-group at 17.13-17.49ppm and the CH-group bridge at 5.62-5.91ppm.The signals of the triethylammonium NH-group and pyridinium of the NH-group (for 8b) are not found in the 1 H NMR-spectra probably due to the fast deutero exchange.
After heating cool the mixture to the room temperature.Filter the resulting precipitates of (4c-e), wash with ethanol, then dry on air and recrystallize from ethanol.
In the case of malononitrile the three-component condensation provides exclusively formation of 2amino-3-cyano-4H-pyranes in high yields.When ethyl cyanoacetate is used, the interaction results in formation of three different products depending on the heteryl fragment in the initial aldehyde, namely the expected 2-amino-3-ethoxycarbonyl-4H-pyranes, the triethylammonium salt of bis-adducts or ethyl 2-cyanoacrylates.
The modified mechanism for the synthesis of 2amino-4H-pyranes has been proposed.It has allowed to synthesize selectively 2-aminopyranes and avoid formation of the triethylammonium salt of bis-adducts.

Table 2
Yields of products of three-component reactionswith ethyl cyanoacetate (Scheme 3)