CC BY
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CHEMICAL SCIENCES
Samandarov N. Yu., Makhkamova B.Kh., Kadyrov A.Kh., Rakhimova Kh.S.
Institute of Chemistry after the name V.I. Nikitina, Sciences Academy of the Republic of Tajikistan, Tajik National University,
Avicenna Tajik State Medical University DOI: 10.24411/2520-6990-2019-10185 INVESTIGATION OBTAIN REACTION OF N - (5-ALKYL-1, 3, 4-TIADIZOLSUBS TITUTED)-3-CHLORBENZO /B/ TIOPHEN -2-CARBOXYIMIDES AND THEIR OXIDATION
Самандаров Н.Ю., Махкамова Б.Х., Кадыров А.Х., Рахимова Х. С.
Институт химии им. В.И. Никитиной, Академия наук РТ, Таджикский национальный университет, Авиценна Таджикский государственный медицинский университет
ИССЛЕДОВАНИЕ ПОЛУЧЕНИЯ РЕАКЦИИ N- (5-АЛКИЛ-1, 3, 4-ТИАДИЗОЛЗАМЕЩЕННЫХ) -3-ХЛОРБЕНЗО / B / ТИОФЕН-2-КАРБОКСИМИДОВ И ИХ ОКИСЛЕНИЯ
Abstract.
This paper presents the results of studying reaction of the acid chloride-3-chlorobenzo / b / thiophene-2-carboxylic acid by reacting it with some amino-derived thioadisols, which led the synthesis of new biologically active substances and compounds with a complex of practically valuable properties.
The optimal conditions for the synthesis of N- (5-alkyl-1,3,4-thiadisole-substituted) -3-chlorobenzo / b / thio-phene-2-carboxyimides were found. It has been established that the chlorine atom in the oxychloride group is highly reactive ability.
The oxidation reaction of some synthesized 3-chlorobenzo / b / thiophene-2-carboxylic acid amides was studied; as a result, a number of corresponding imidosulfones were obtained. It has been comprehensively confirmed that in this case only the acyclic sulfur atom is oxidized.
Key words. Synthesis, acid chloride-3-chlorobenzo / b / thiophene-2-carboxylic acid, N- (5-alkyl-1,3,4-thia-disole) -3-chlorobenzo / b / thiophene-2-carboxyimides, sulfones
Relevance. In recent years, the number of studies devoted to the development of methods for the synthesis and the actual synthesis of highly effective preparations based on synthetic analogues of natural physiological active substances exhibiting large-scale biological activity has been steadily increasing.
In some studied reactions of amines and N-amino derivatives of nitrogen and sulfur-containing bicyclic compounds should be noted that they are the least represented in the literature [9,10, 1].
From other sources it is clear that among the derivatives of amino-substituted 1,2,4-thiadisols, substances with antimicrobial, antitumor immuno-stimu-lating and anti-allergic activity have been found [2].
A fragment of thiadizole was found in composition of many drugs [3-4].
In this connection, we are interested in introducing the thiadizole fragment in reaction of interaction with the benzo / b / thiophene system [5].
The aim of the work is to search the optimal conditions for obtaining a number of imides 3-chlorobenzo / b / thiophene-2-carboxylic acid having an N-1,3,4-thi-adiazole moiety, studying their oxidation reaction, investigate the structure of the obtained compounds, as well as identifying their beneficial properties.
Results descussions. To solve this problem, we have used a number of derivatives of 2-aminothi-adizole.
In order to obtain more complete information about the nature of the original bicycle in nucleophilic substitution reactions, we attempted to react the 3-chlo-robenzo /b/ diophene-2-carboxylic acid chloride with 2-aminothiadizole derivatives in ethyl alcohol. The optimal condition for carrying out this reaction showed that it is better to hold it at a temperature of 75-800C for 5-6 hours. The reactants ratio is 1:1. Dry pyridine was used as a catalyst.
<<C®yL®qUQUM~J®U©MaL>>#8I12)),2(
25
+
COCIH2
N-N
C2H5OH
C5H5N
S CO-NH
N-N
JL-A,
S
I. R = H ; II. R = CF3 ; III. R = - (C^SCsHv; IV. R = - (C^SC^; V. R = - (C^SCsHis; VI. R =-
(CH2)2SCBHI7;
VII R = CH3; VIII. R = C2H5; IX. R = C3H7
It could be seen from the nucleophilic substitution reaction scheme of various derivatives thiadizole with acid chloride-3-chlorobenzo / b / thiophene-2-carbox-ylic acid, and as a result were synthesized N- (1,3,4-thiadizol) -3-chlorobenzo / b / thiophene -2-carboxy-imide - (I); N- (5-tifluoromethyl -1,3,4-thiadizol) -3-chlorobenzo /b / thiophene-2-carboxyimide - (II); N-(5-propyl-ethylsulfide-1,3,4-thiadizol) -3 -chlorobenzo / b / thiophene-carboxyimide- (III); N- (5-butylethyl-sulfide-1,3,4-thiadizol) -3-chlorobenzo / b / thiophene-2-carboxy-imide- (IV); N- (5-hexyl ethyl sulphide-1,3,4-thiadizol) -3-chlorobenzo / b / thiophene -2-car-boxyimide - (V); 5- (N-octylethylsulfide-1,3,4-thia-disol) -3-chloro-benzo [b] thiophene-2-carboxyimide-(VI); N - (5-methyl-1,3,4-thiadizol) -3-chlorobenzo / b / thiophene-2-carboxyimide - (VII); N - (5-ethyl-1,3,4-
thiadizol) -3-chlorobenzo / b / thiophene-2-carboxy-imide - (VIII); and 5- (N-propyl-1,3,4-thiadisol) -3-chlorobenzo /b/ thiophene-2-carboxyimide - (IX), see Table 1.
Continuing the work based on synthesis of 3 -chlo-robenzo / b / thiophene-2-carboxylic acid amides, we attempted to replace one hydrogen atom of the amino group in m-3-fluoromethylphenylaniline molecule. As a result, amide-21-threefluoromethylphenyl-3-chloro-benzo / b / thiophene-2-carboxyimide- (X) was synthesized. For this purpose, acid-3-chlorobenzo / b / thio-phene-2-carboxylic acid is treated with m-three-fluoro-methyl-phenyl-aniline in absolute ethanol. In this case, firstly the reaction was carried out with presence of pyr-idine, which is an acceptor of hydrochloric acid, accelerates the reaction.
Table 1
№ comp. Yield % Mel. temp.,°C % C Found Calculated %HFound Calculated Gross formula
I 85 180-181 44,55 44,67 2.15 2,03 C11H6CIN3OS2
I I 96 200-201 38,48 38.61 1.43 1,37 C12H5 F3QN3OS2
I I I 97 119-120 48.41 48,30 3.93 4,02 C16H16QN3OS3
IV 85 176-177 50.05 49,86 4.94 5,17 C17H18QN3OS3
V 96 166-167 52,10 51,88 5,12 5,00 C19H22ClN3OS3
VI 97 158-159 53,77 53,90 3,69 3,56 C21H26CIN3OS3
VII 81 216-217 43,06 42,92 2,29 2,38 C12H8ClN3OS2
VIII 87 178-179 44,72 44,63 2,97 2,86 C13H10QN3OS2
IX 88 164-165 46,15 46,22 3,17 3,30 C14H12ClN3OS2
X 84 150-151 54,93 55,01 2,74 2,57 C16H9F3QNOS
The obtained compound has pronounced bactero-cidal effect on sexually transmitted staphylococcal, no-cardia, corinbacterium and pastareml strains.
More detailed study of the compound (X) may be used as an antibacterial drug for the treatment of animal's respiratory diseases.
To confirm the structure of the synthesized compound (X), we used HMR spectroscopy.
As an example, the HMR spectrum of N- (31-tri-fluoro-methylphenyl) -imide-3-chlorobenzo / b / thio-phene-2-carboxylic acid (X) was selected.
Fig. HMR spectrum of N- (31-trifluoromethylphenyl) -imide-3-chlorobenzo / b / thiophene-2-carboxylic acid (X).
In the HMR spectrum of compound (X), signals are detected in multiplets in the regions of 6.75 ppm. to 7.86 ppm, and the proton of the NH- group appears in the region of 8.75 ppm. The HMR spectrum was taken in solution (CF3 COOH) trifluoroacetic acid.
The structure of the synthesized compounds (I-X) are confirmed by the data of IR, HMR spectroscopy and elemental analysis. In the IR spectra, intense absorption bands are observed in the region of 2250-3320 cm - 1, 1670-1690 cm - 1, which characterize the presence of the NH and >C = O groups in the molecules of the heterocyclic compound. The yield and the results of the elemental analysis are given in Table 1.
To determine the purity of the synthesized imides used thin-layer chromatography. A mixture of diisopro-pyl ether and isooctane (8: 2), developer-iodine pairs was used as eluents.
Having disposal the above-listed imides (III-VI), we have proceeded the synthesis of their amidosul-fones, which are particular interest as potential biologically active compounds.
Thus, optimal conditions for the synthesis of N-(5-alkyl-1,3,4-thiadisole-substituted) -3-chlorobenzo / b / thiophene-2-carboxyimide were developed and it was established that the chlorine atom in the chloroxymethyl group is highly reactive in terms of nu-cleophilic reagents.
Many researchers were engaged reaction processes of benzo / b / thiophenes and their 2,3-dihydro-benzo / b / thiophenes oxidation [6-8]. The authors show that these bicyclic organo-sulfur compounds under mild conditions are almost quantitatively oxidized with hydrogen peroxide in acetic acid with the corresponding 1,1-dioxides.
Starting the search, more effective oxidizing agent for the oxidation of sulfur atoms in the molecules of the synthesized imides we again turned to a mixture of hydrogen peroxide in ice-cold acetic acid solution. It would be interesting to consider the behavior of three sulfur atoms in the molecules of the synthesized imides - (III-VI), in oxidation reactions.
As the result of various experiments, it was revealed that the calculated amount of 30% hydrogen peroxide in a solution of glacial acetic acid at 8500C oxidizes the sulfide sulfur atom for 3-4 hours.
The oxidation process results of the studied im-ides- (III-VI) showed that during the experiment it was evident that the sulfur atoms are not oxidized in the benzo / b / thiophenic and thiadisole parts of the molecules.
We reproduced this reaction using the most varied ratios of the reactants, with the excess of hydrogen peroxide being varied within two and three times from calculated amount. However, in all cases, sulfide sulfur atoms in molecules of the synthesized imides were subjected to oxidation.
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N-N
HO
2O2
CH3COOH
"CONH
s' N (CH2)2SR
CI
CONH
N-N
O
^ N (CH2)2"S"R
O
where XI. R=C3Ht; XII. R= C4H9;XIII. R= C6Hi3;XIV. R= CsHxt.
It is clear from the reaction scheme that the sulfur atoms in benzo / b / thiophene and thiadazole moieties are not affected by oxidation. The characteristics of all obtained imidosulfones are given in Table 2.
Table 2.
Characterization of imidosulfone 1,3,4-thiadisole containing-3-chlorobenzo / b /
№ comp. Yield % Mel. temp.,°C % C Found Calculated %H Found Calculated Gross formula
XI 80 281-282 44,89 44,70 3,56 3,72 C16H16QN3O3S3
XII 75 209-210 46,15 45,99 4,12 4,07 C17H18QN3O3S3
XIII 74 205-206 46,15 45,99 4,80 4,66 C19H22ClN3O3S3
XIV 69 200-201 50,27 50,45 5,31 5,20 C21H26QN3O3S3
S
S
From here, N- (5-propylethylsulfide-1,3,4-thia-disol) -3-chlorobenzo / b / thiophene-2-carboxyimide -(XI); N- (5-Butylethyl sulfide, 1,3,4-thiadisol) -3-chlo-robenzo / b / thiophene-2-carboxyamide (XII); N- (5-hexyl ethyl sulfide 1, 3,4-thiadisol) -3-chlorobenzo / b / thiophene-2 carboxyamide (XIII) and N- (5-octylethyl sulfide 1,3,4-thiadizole) -3-chlorobenzo / b / thiophene -2-carboxyimide (XIV) were subjected to oxidation.
The individual synthesized iimidosulfones was checked by analytical thin-layer chromatography on a thin non-fixed layer of ASK silica gel. Chromatography conditions: acetone - chloroform system (2: 1), iodine vapor developer.
The presence of SO2 - group and its location in obtained compound (XI-XIV) were established using infrared spectral and elemental analysis.
In IR compounds spectra (XI-XIV), intense absorption bands were found in the region of 3375-3415 cm - 1, 1135-1290 cm - 1, and 1650-1780 cm - 1 characterizing the presence of NH, SO2, and >C=O groups in studied molecules.
Thus, the oxidation reaction of some imides of 3-chlorobenzo /b / thiophene-2-carboxylic acid was studied and it was shown that in this case only the acyclic sulfur atom is oxidized.
Experimental part
Synthesis of 31-trifluoromethylphenyl-3-chlo-robenzo | b | thiophene 2-carboxyimide (X)
9 g (0.0389mol) of 3-chlorobenzo-1-thiophene-2-carboxylic acid chloride and 6.2 g (0.0389 mol) of 3-fluoromethyl-phenylaniline were mixed in a round-bottomed flask, and then 4 ml of pyridine in 150 ml of absolute ethyl alcohol were added.
The reaction mixture was boiled under reflux for 5 hours. Upon completion of the reaction, the mixture was poured into a glass with cold water, the precipitation was filtered, washed with dilute hydrochloric acid and then with water convert to neutral medium, dried and recrystallized from ethyl alcohol.
Yield 11.5 g (84.6%). Melt. Temp. 150-151 ° C.
Found % : C - 54,93; H - 2,74;
Calculated %: C^FsClNOS %:C - 55,01; H -
2,57.
NMR (CF3 COOH) 5 =CH 6.75; CH. 7,33; CH. 7,78: CH. 7,86: NH. 8.75. CH, 7.24 CH, 6.75. CH, 74. ppm.
In a similar manner, other thiadisole-substituted-3-chlorobenzo / b / thiophene-2-carboxylic acid (I-IX) was also prepared. See Table 1.
References
1. Кадыров А. Х., Каримов Г. К., Махкамова Б. Х. Амиды 3-хлор-бензо|в|тиофен-2-карбоновой кислоты. // Республ. науч.-прак. конференция «Роль экомониторинга в улучшении окружающей среды» ГКООС и ЛХ, Душанбе, май 2005.
2. Заявка 64-6264 Япония, МКИ СО7Д 277/40, Заявл. 30.03.88. Т. 63-77916. производные гетероциклическх аминов / Исода С., Мива Т., Фуд-зивара Х., РЖ хим. - 1991. ч. 2. 2048 п.
3. Cафаров С.Ш. Синтез превращения и свойства 2-бром -5метил-7-оксо-7Н-1,3,4-тиади-золо(3,2-а) примидина. Дис ... к.х.н. Душанбе, 2006-с 3-6,
4. Сангов З. Г., Синтез и антимикробная активность некоторых производных 1,3,4-тиадиазоло [3.2-a] пиримидина. Дисс. канд. хим. наук. - Душанбе, 2004. - С. 42-46
5. Заявка 57-142982 Япония, МКИ СО7Д 513/40, Заявл. 27,02,81. Т. 56-27864. Производные тиадиазол примидина /Исода С., Цикада Ц. С. Суд-зуки и др. РЖ хим. - 1984. ч. 10. 129 п.
6. Махкамова Б. Х., Кадыров А. Х., Каримов Г. К. Некоторые реакции хлорангидрида 3-хлор-бензо|в|тиофен-2-карбоновой кислоты. // Докл. АН РТ. - 2004, т. XLVII, № 1-2. - с. 19-22.
7. КадыровА.Х., Нитро-, амино- и N-аминопроизводные бензо|в|тиофен- и 2,3-дигид-робензо|в|тиофен-1,1-диоксидов. / КадыровА.Х., Бобогарибов Б.М. // Изд. «Дониш», Душанбе, 2001. - С. 26-27.
8. Табаров А. К. Синтез, свойства некоторых аминов бициклических азот- и серосодержащих соединений // Дисс. к.х.н., Душанбе, 2003. - С. 52-55.
References in English
9. Katritzky A.R., Wang Z., OtfermanR. J. S. S' andS,N-disubstitute-dderivativesof 1,3,4-thiadia-zolethiones. // J. Heterociclic Chem. 1990 vol. 27. - p. 139-142.
10. Jddon B., Recent advonces in the chemistry of benzo|в|thiofenes / Jddon B., Schrovston R.M., // Av-rances in heterocyclic chemistry. Nev. York Academic Press, 1970. v. 11. p. 177-380.
