UDC:54.057.12
SYNTHESIS OF 2-R-AMINO-5,6-ETHYLENE-1,4-DIOXYBENZTHIAZOLANE FROM 6-AMINO-1,4-BENZODIOXANE
Turdialiev M.Z., Pulatov E.Kh.
Institute of Chemistry named after V.I. Nikitin NAS of Tajikistan,
Dushanbe, st. Ayni, 299/This email address is being protected from spambots. You need JavaScript enabled to view it.
It is known that benzo-1,4-dioxane is obtained by the interaction of pyrocatechol with dibromoethane [1] and some of its derivatives are used as medicinal preparations, for example, fluparoxan, domoxin, eltoprazine, imiloxan, piperoxan, proraxan, prosimpal, butyroxan and a number of other preparations with a wide range of biological activity [2-4].
In this regard, the chemistry of 1,4-benzodioxane is currently being intensively developed in theoretical and practical terms, which makes the chemistry of this class of compounds relevant. This is also evidenced by more information in scientific journals, patents and various conference materials, and in the review of Daukshas V.K., Udrenaite E.B., a brief review of Ahmed P. and Khan H., and the review of Pilkinton and Barker is devoted to the synthesis of effective biologically active compounds - natural lignans of this series [5-9].
Literature data have established that when sodium borohydride is applied to 2-cyano-4,5-ethylenedioxybenzophenone, 5,6-ethylenedioxy-3-phenylphthalide is formed in high yield. [10].
The authors showed [11] that during the hydrolysis of 2-cyano-4,5-ethylenedioxybenzophenones under the action of a mixture of sulfuric and trifluoroacetic acids, the corresponding compound 3-hydroxyphthalimidines were formed in high yields.
In this synthesis [12] it was proposed that 2-phenylazo-4,5-ethylenedioxybenzophenone is reduced and undergoes acid-catalyzed cyclization to the corresponding substituted 2H-indazoles.
In the work [13] the synthesis of derivatives of 6,7-ethylenedioxyquinolones, intramolecular Knoevenagal condensation of o-phenacyl-substituted acylbenzenes was carried out. The first substance was obtained by N-acylation with phenylacetic acid chloride.
(1,4-benzodioxan-6-yl)-propynoic acid under the influence of polyphosphoric acid cyclization occurs with the formation of 5,6-ethylenedioxyindanone-1, the obtained compound of the ketone with sodium amalgam gives 5,6-ethylenedioxyindan, with bromine 2-bromo-5,6-ethylenedioxyindanone and secondary amines in under the action of 2-dialkylaminomethyl-5,6-ethylenedioxyindanone [14].
A method for synthesizing a new heterocycle based on benzo-1,4-dioxane was developed by the co-worker G.A. Tashbaev. Thus, by chloromethylation of benzo-1,4-dioxane, 6,7-bischloromethylbenzo-1,4-dioxane was obtained, which with sodium sulfide in an acetone solvent medium gives 5,6-ethylenedioxy-1,3-dihydrobenzo[c]thiophene, which is well oxidized by hydrogen peroxide to form 5,6-ethylenedioxy-1,3-dihydrobenzo[c]thiophene-2,2-dioxide [11,12].
5,6-ethylenedioxy-1,3-dihydrobenzo[c]thiophene-2,2-dioxide under the action of nitric acid in an acetic acid medium forms the compound n-nitro 5,6-ethylenedioxy-1,3-dihydrobenzo[c]thiophene-2,2-dioxide [12].
When heated above the melting point, sulfur dioxide is formed and unstable 4,5-ethylenedioxy-o-quinodimethane is generated, which, with the participation of maleic acid derivatives, forms new compounds corresponding to derivatives of 1,2,3,4-tetrahydro-5,6-ethylenedioxynaphthalene-2,3-dicarboxylic acid [13].
CONSIDERATION
In this research, we present the synthesis of a condensed heterocycle containing a thiazole fragment based on benzo-1,4-dioxane, an analogue of which (fluparoxan) is a very effective α2-adrenoblocker [15].
By reacting 6-aminobenzo-1,4-dioxane (1) with potassium thiocyanate with the participation of sulfuric acid and sequential oxidation with sulfuryl chloride [16], we preliminarily synthesized the tricyclic heterocycle 2-amino-5,6-ethylenedioxy-1,4-benzothiazole (2), according to the scheme:
1
2
According to the final product and the results of the IR and H1NMR spectra, this reaction occurs in the presence of a catalytic amount of sulfuric acid through intermediate-forming stages (as indicated in the scheme), i.e. at the primary stage, benzo-1,4-dioxane is formed with a thiourea fragment, which under the conditions of the reaction medium, the thiourea fragment isomerizes into the thiol form, then the oxidizing agent sulfuryl chloride promotes intramolecular heterocyclization, which then forms a previously undescribed new condensed compound of benzo-1,4-dioxane: 2-amino-5,6-ethylenedioxy-1,4-benzothiazole (2).
In the IR spectrum of compound (2) there are absorption bands in the region of 1620 cm-1 for the endocyclic C=N bond and 3260 cm-1 characteristic of the amino group, and the absorption bands in the region of 870, 890, 910 cm-1 are related to the C=C bond of the aromatic ring.
In the H1NPMR spectrum of compound (2) there are signals of aromatic protons at 7.09 ppm, 7.52 and 7.99 ppm, signals of protons of the methylene group of the 1,4-dioxane part at 4.28 ppm and signals of protons of the exocyclic amino group at 8.25 ppm.
It is known from the literature that acyl and sulfonamide derivatives of heterocyclic compounds have a wide range of biological activities, from this position, on the basis of the obtained compound (2) we carried out reactions of its interaction with electrophilic reagents: acetyl chloride and toluene sulfonic acid chloride.
Thus, the reaction of the interaction of compound (2) with acetyl chloride combines in a medium of dry 1,4-dioxane at the exocyclic nitrogen atom with the formation of 2-acylamido-5,6-ethylenedioxy-1,4-benzothiazole (3), at a temperature of 70 ° C for 3 hours, while triethylamine was used as an acceptor of hydrogen chloride, according to the scheme:
2 3
In the IR spectrum of the substance (3) there are absorption bands in the region of 1730 cm-1, characteristic of C=O bonding, and the absorption bands in the region of 860, 880, 920 cm-1 can be attributed to the C=C bond of the aromatic ring.
The structure of the obtained product 2-acylamino-7-ethylenedioxy-1,4-benzothiazole (3), and is also confirmed by the data of the H1PMR spectrum.
Since in the H1PMR spectrum of compound (3) at 12.53 ppm a signal equivalent to one proton was detected, which can be reduced to the proton of the amide NH group, and the signals of aromatic protons remain at 7.52 and 7.99 ppm, and the last signals of the protons of the methylene group of the 1,4-dioxane part are observed at 4.28 ppm, (Fig. 1.).
Fig. 1. NMR 1H spectrum (400 MHz) of 2-acylamido-5,6-ethylenedioxy-1,4-benzothiazole (3), the solvent of this product CDCl3.
In the case of the possibility of interaction of toluene sulfonyl chloride, the reaction proceeds similarly to the synthesis of compound (3) in the middle of the base used as an acceptor of hydrogen chloride with the formation of 2-(p-tolyl)sulfamido-5,6-ethylenedioxy-1,4-benzothiazole (4) at a temperature of 70 °C for 4 hours with an 85% yield, according to the scheme:
2 4
The structure of compound (4) was determined by IR and NMR 1H spectroscopy. In the IR spectrum of substance (4) there are absorption bands in the region of 1340 cm-1 characteristic of O=S=O bonding, absorption bands in the region of 860, 880, 920 cm-1 characteristic of C=C bonding of aromatic ring.
In the NMR 1H spectrum of compound (4) there is a signal at 12.64 ppm, corresponding to the proton of sulfonamide NH group and signals of protons of aromatic part at 7.52 and 7.99 ppm, signals of protons of methylene group are at 4.28 ppm, and signals of hydrogens of methyl group of toluosulfonamide fragment at 2.43 ppm, (Fig. 2.).
Fig. 2. NMR 1H spectrum (400 MHz) of 2-(p-tolyl)sulfamido-5,6-ethylenedioxy-1,4-benzothiazole (4) in solution CDCl3.
Thus, the signals obtained in the IR and PMR 1H spectra indicate that the reaction of 2-amino-5,6-ethenedioxy-1,4-benzothiazole (2) with electrophilic reagents occurs in the same way, at the exocyclic nitrogen atom.
Aliphatic aminonitrile compounds and new amino acids are of interest from a pharmacological point of view. Amino acids are known to be stimulants and depressants of the central nervous system. Thus, the synthesis and study of new amino acids has an important social focus.
Conducting a study aimed at finding ways to synthesize new amino acid representatives, and thus expanding the database on the biological activity and stereochemistry of these compounds.
In order to find products of alternative biologically active substances in a number of amino acids studied, we synthesized 3-methyl-3-aminopropionitrile using the Strecker method, with subsequent hydrolysis of the resulting aminonitrile to convert it into an amino acid. In this process, 3-methyl-3-aminopropionitrile was obtained in the initial stage by the interaction of ammonia and hydrogen cyanide in dry 1,4-dioxane, in the presence of a catalyst - ammonium hydroxide. Then, during the hydrolysis of the resulting aminonitrile, a new amino acid, 2-amino-2-methylbutanoic acid, was obtained, as shown in the scheme:
After this, the expansion of the reactivity of compound (2) was carried out by the process of addition of 2-amino-2-methylbutanoic acid in the presence of an acidic medium, 2-amino 2-methylbutanamido-5,6-ethylenedioxy-1,4-benzothiazole was obtained according to the following scheme:
2 5
Taking into account the information on the biological activity of 1,4-benzodioxane derivatives [2-9], we, at the Department of Microbiology of the Tajik State Medical University named after Abu Ali ibn Sino, conducted studies of the synthesized 2-acylamino-5,6-ethylenedioxy-1,4-benzothiazole (3) for antimicrobial activity against several types of bacteria grown in nutrient media (meat-peptone agar-MPA): Staphyloagar, Endo medium for enterobacteria, SPA-Medium, Simple Agar and Sabouraud medium for fungi of the genus Candida in the form of a concentrated alcohol and aqueous solution using the disk diffusion method. The bactericidal effect was studied on 4 types of bacterial strains: Staphylococcus aureus (ATCC 4929), Escherichia coli (ATCC 4928), Pseudomonas aeruginosa (ATCC 4930) and Klebsiella pneumoniae (4927), as well as hospital strains of the same bacterial species, i.e. strains isolated from inpatient surgical patients.
It should be noted that in all cases, an aqueous solution of 2-acylamino-5,6-ethylenedioxy-1,4-benzothiazole (3) has antibacterial and antifungal properties against hospital and standard strains of microorganisms.
The strains of microorganisms used in the work were cultured for 18-24 hours on MPA (meat-peptone agar) with the addition of 0.1% glucose. From daily cultures of the studied strains, suspensions (inoculums) were prepared using McFarland 10 ME turbidity, bringing the final concentration of microorganisms to 2∙106 CFU/ml. They were scattered as a lawn over the surface of the corresponding nutrient media in Petri dishes: Staphylococcusaureus - on staphyloagar, Escherichiacoli - on Endo medium, Pseudomonasaeruginosa and Klebsiellapneumoniae - on simple agar. Glass wool disks, pre-impregnated with alcohol and aqueous solutions of 2-acylamino-5,6-ethylenedioxy-1,4-benzothiazole preparation, were dried at room temperature for 5-10 hours. Then the disks were placed on the surface of the nutrient medium with the corresponding strain of microorganism and incubated at t = 37˚C for 18-24 hours.
After incubation, the following results were obtained: in relation to Staphylococcusaureus, Pseudomonasaeruginosa, Klebsiellapneumoniae and Candida. Albicans, this preparation was characterized by high bactericidal activity, while in relation to the representative of enterobacteria Escherichiacoli, only bacteriostatic action.
Conclusion
It should be noted that in all cases the aqueous-alcoholic solution of the drug - 2-acylamino-5,6-ethylenedioxy-1,4-benzothiazole was characterized by antibacterial and antifungal properties and also has these properties in relation to hospital and standard strains of microorganisms.
MATERIAL AND METHODS OF RESEARCH
Instruments and reagents: NMR spectra δ, ppm, on a VARIAN 400-MR device, CHCl3, HMDS-in as an internal standard. IR spectra, ν, cm-1: on a UR-20 device on a KBr tablet. TLC was performed on a Silufol plate by developing with iodine vapor, melting points were measured on a Boethius device.
2-Amino-5,6-ethylenedioxy-1,4-benzothiazole (2). A 100-milliliter conical flask equipped with a magnetic stirrer with a reflux condenser and a dropping funnel is charged with a solution of 4.6 g (0.03 M) 6-aminobenzo-1,4-dioxane in 30 ml chlorobenzene. 1.3 ml of sulfuric acid is added to the solution over 5 min and 6 g of potassium thiocyanate are added, the resulting mixture is heated in an oil bath for 3 hours at a temperature of 100 ° C. After cooling to 25 ° C, 2.4 ml (0.03 M) sulfuryl chloride is added, then ensuring that the temperature does not rise above 50 ° C. The mixture is maintained at this temperature for 2 hours until the hydrogen chloride ceases to evaporate, after which the precipitate is filtered and dissolved in 30 ml of hot water. The solution is filtered from a small amount of solid impurity and alkalized with 25% ammonia to a slightly alkaline medium, the precipitate is filtered and washed with water. The precipitate is dissolved in 10 ml of hot alcohol, 0.5 g of activated carbon is added to the solution and diluted with 15 ml of hot water. The solution is cooled and the precipitate is filtered and dried. Yield of 2-amino-5,6-ethylenedioxybenzthiazole 2 3.2 g (51%), "colorless needles", mp 143-144 ° C. (EtOH), Rf = 0.58. (benzene). Found, %: C 51.71, 51.83; H 3.69, 3.72; N 13.27, 3.34; S 15.22, 15.29, C9H8N2O2S, calculated, %: C 51.92; H 3.85; N 13.46; S 15.38.
IR spectra, (KBr), γ, cm-1: 870, 890, 910 (aromatic), 3060 (NH2) 1H NMR spectra (400, MHz, CDCl3), δ, ppm: 7.52 and 7.99 m d. (2 H, CH), 7.09 ppm (2 H, NH2). 4.28 ppm. (4H, CH2),
2-Acetylamino-5,6-ethylenedioxy-1,4-benzothiazole (3). A 50-milliliter conical flask equipped with a magnetic stirrer with a reflux condenser is charged with a solution of 1.04 g (5 mmol) of 2-amino-6,7-ethylenedioxybenzothiazole (4) in 10 ml of 1,4-dioxane. 1 ml of triethylamine and 0.51 g (5 mmol) of acetic anhydride are added to the solution and the mixture is stirred for 1 hour at a temperature of 5 ° C. Then it is stirred for another 3 hours at a temperature of 70 ° C. After cooling, it is poured into 50 ml of cold water, the crystals are separated, dried and recrystallized from alcohol. Yield (3), 1.15 g (92%), “colorless needles”, mp 137-138 °C (EtOH), Rf = 0.55 (benzene). Found, %: C 52.72, 52.63; H 3.89, 3.92; N 11.07, 10.94; S 12.62, 12.69, C11H10N2O3S, calculated, %: C 52.80; H 4.00;N 11.20; S 12.80.
IR spectra, (KBr), γ, cm-1: 870, 890, 910 (arom), 1550 (C=O).
NMR spectra 1H (400 MHz CDCl3), δ, ppm: 2.23 ppm (3H, CH3), 4.28 ppm (4H, CH2), 7.52 and 7.99 ppm (2 H, CH), 12.53 ppm. (1H, NH).
2-(p-Tolyl)sulfonylamino-5,6-ethylenedioxy-1,4-benzthiazole (4). A solution of 1.04 g (5 mmol) of 2-Amino-5,6-ethylenedioxy-1,4-benzothiazole (2) in 10 ml of 1,4-dioxane is added to a 50-ml conical flask equipped with a magnetic stirrer and reflux condenser. 0.86 g (5 mmol) of toluenesulfonyl chloride are added to the solution and 0.5 ml of triethylamine is added, the mixture is stirred for 1 hour at a temperature of 5 °C and 3 hours at a temperature of 70 °C, cooled, poured into 50 ml of cold water, separated, dried and recrystallized from alcohol. Yield (4) 1.54 g (85%), "colorless needles" mp 147-148 °C (EtOH), Rf = 0.53, (benzene). Found, %: C 52.92, 52.96; H 3.59, 3.62; N 7.57, 10.64; S 17.62, 17.54, C11H10N2O3S, calculated, %: C 53.04; H 3.86; N 7.73; S 17.68.
IR spectra, (KBr), γ, cm-1: 870, 890, 910 (arom.), 1130, 1310 (SO2).
NMR spectra 1H (400, MHz CDCl3), δ, ppm: 2.43 ppm (3H, CH3), 4.28 ppm (4H, CH2), 7.70 (2H, CH), 7.34 (2H, CH). 7.52 (H, CH) and 7.99 ppm (H, CH), 12.64 ppm. (1H, NH).
REVIEWER: Rajabzoda S.I.,
Doctor of Chemical Sciences,
Professor
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SYNTHESIS OF 2-R-AMINO-5,6-ETHYLENE-1,4-DIOXYBENZTHIAZOLE BASED ON 6-AMINO-1,4-BENZODIOXANE
By reacting 6-amino-1,4-benzodioxane with potassium thiocyanate in an acidic medium and subsequent oxidation with sulfuryl chloride, 2-amino-5,6-ethylenedioxy-1,4-benzothiazole was obtained. Further, in reactions with electrophilic reagents: acetic anhydride and toluenesulfonamide, the corresponding acylamide and toluenesulfonamide derivatives of the latter were obtained.An innovative approach to the synthesis of secondary and tertiary carbinols of the 1,4-benzodioxane series is proposed. A new method for the synthesis of a tricyclic heterocycle, 2-amino-6,7-ethylenedioxybenzthiazole, has been proposed.
Key words: 6-amino-1,4-benzodioxane, 2-amino-5,6-ethylenedioxy-1,4-benzothiazole, acylamide and sulfamide.
Information about authors: Turdialiev Murodjon Zokirovich - Institute of Chemistry named after V.I. Nikitin of the National Academy of Sciences of Tajikistan, candidate of chemical sciences, senior researcher. Address: 734063, Dushanbe, Tajikistan, Shokhmansur district, S. Aini Street 299/2. Phone: 930669946. Email: This email address is being protected from spambots. You need JavaScript enabled to view it.
Pulatov Elmurod Kholikulovich - Pulatov Elmurod Kholikulovich - Chemical Institute named after. V.I. Nikitin National Academy of Sciences of Tajikistan, Doctor of Chemical Sciences, senior researcher. Address: 734063, Dushanbe, Tajikistan, Shokhmansur district, S. Aini Street 299/2. Phone: 907851676. Email: This email address is being protected from spambots. You need JavaScript enabled to view it..
Article received 12.02.2024
Approved after review 24.04.2024
Accepted for publication 21.09.2024