OBTAINING α-CHLORO-DERIVATIVES AND α-AMINO-KETONES FROM ACETYLTHIOIN AND ACETYLTHIOCHROMAN MOLECULES

ABSTRACT

This article presents methods for obtaining α-chloro derivatives and α-aminoketones of acetylthiaindene and acetylthiochroman molecules. During the research, the reaction of acetylthiaindene and acetylthiochroman with molecular chlorine in a dioxane medium was carried out, resulting in the synthesis of α-chloroacetyl compounds. The structures of the obtained products were confirmed by elemental analysis, infrared (IR), and proton magnetic resonance (PMR) spectroscopy. The results indicate that the reactions proceed via an SN₂ mechanism. Based on the synthesized α-chloro derivatives, nucleophilic substitution reactions with piperidine and morpholine were performed, leading to the formation of new α-aminoketones.

АННОТАЦИЯ

В данной статье описаны методы получения α-хлорпроизводных и α-аминокетоновацетилтиаиндена и ацетилтиохромана. В ходе исследования проведена реакция ацетилтиаиндена и ацетилтиохромана с молекулярным хлором в среде диоксана, в результате чего были синтезированы α-хлорацетильные соединения. Строение полученных веществ подтверждено методами элементного анализа, инфракрасной (ИК) и протонной магнитно-резонансной (ПМР) спектроскопии. Установлено, что реакции протекают по механизму SN₂. На основе синтезированных α-хлорпроизводных изучены реакции нуклеофильного замещения с пиперидином и морфолином, в результате чего получены новые α-аминокетоны.

Keywords: acetylthiaindene, acetylthiochroman, α-chloro derivatives, dioxane, nucleophilic substitution, SN₂ mechanism, α-aminoketone, spectroscopy.

Ключевые слова: ацетилтиаинден, ацетилтиохроман, α-хлорпроизводные, диоксан, нуклеофильное замещение, механизм SN₂, α-аминокетон, спектроскопия.

Introduction. In recent years, sulfur-containing heterocyclic compounds — in particular, thiainide and thiochroman derivatives — have gained significant importance in the fields of organic synthesis, pharmaceuticals, catalysis, and corrosion inhibitors. Compounds of this class are characterized by high biological activity, electron-donating properties, and aromatic stability. In particular, thiainide and thiochroman derivatives containing an acetyl group are of great scientific importance due to their reactivity properties. Under the influence of the carbonyl oxygen of the acetyl group, the mobility of hydrogen atoms in the α-position increases, which allows them to be converted into halogenated derivatives to obtain intermediates convenient for subsequent syntheses. Therefore, the formation of α-chloro derivatives from acetylthiainide and acetylthiochroman molecules and the study of the synthesis of new α-aminoketones based on them are of scientific and practical importance.

Scientific research on thiain and thiochroman derivatives has been one of the most relevant areas of organic synthetic chemistry for many years. The use of this class of compounds as important intermediates in the synthesis of oxidizing, reducing and biologically active substances is widely covered in the literature [1,p.427-440]. There is information that the α-aminoketones formed as a result of these processes are widely used in the synthesis of antibiotics, antimicrobial and antitumor agents in the pharmaceutical industry [2,p.66-68]. Studies in recent years have shown that sulfur-containing aromatic systems exhibit high reactivity due to the uneven distribution of electron density [3,p.82-86]. Therefore, the reaction of acetylthiainden and acetylthiochroman with halogen in the α-position is of scientific interest both in determining their structural properties and in the synthesis of new functional derivatives. The research conducted in this article is a logical continuation of work in this direction and is aimed at obtaining a new class of compounds containing α-chloro and α-aminoketone derivatives of thiainden and thiochroman, and determining their structure based on spectral analysis [4,p.7322-7328].Condensation reactions of aliphatic and aromatic aldehydes with 6-acetyl-1-thiachroman yielded α- and β-unsaturated thiachroman ketones. It was determined that the reaction of acetyl-1-thiachroman with aliphatic and aromatic aldehydes yields a relatively high product yield, ranging from 78% to 95% [5,p.120-123].

Materials and methods. The hydrogen atoms belonging to the acetyl group in the side chain of the acetylthione and acetylthiochroman molecules become slightly mobile due to the action of the carbonyl group. It becomes possible to transfer such mobile hydrogen atoms to halogenated derivatives used as intermediates and to carry out targeted syntheses based on them. To carry out studies aimed at this goal, it was first necessary to switch to one of the active derivatives of the substrate containing the thiane and thiochroman fragment, which react easily with secondary amines. For these reactions, it was necessary to obtain α-halogen-containing derivatives in the side chain of acetylthione and acetylthiochromans. To obtain such compounds, the reaction of acetylthione and acetylthiochromans with molecular chlorine was carried out. To prepare α-chloroacetylthione and α-chloroacetylthiochroman molecules, acetylthione and acetylthiochroman (0.01 mol) were first dissolved in dioxane (10 ml). The resulting solution was cooled with ice, stirred using a magnetic stirrer, and 5 ml of chlorine (0.01 mol) dissolved in ether was added dropwise to the solution. After the addition of the chlorine solution, an ice bath was installed and the reaction mixture was stirred at 20 0C for 2 hours. After the reaction was completed, crystals were precipitated by adding cold water to the mixture. As we all know, there are lone pairs of electrons on the two oxygen atoms in the dioxane molecule, which increases the nucleophilicity of the dioxane molecule. The reaction of dioxane with molecular chlorine forms a complex dioxane dichloride, which polarizes the chlorine-chlorine bond of molecular chlorine, and the resulting complex nucleophilically attacks the α-carbon atom in the aliphatic part of the acyl derivatives of thiain and thiochroman. This is because the carbon atom in the α-position relative to the carbonyl group in the acetyl group experiences a partial electron deficiency, which leads to the appearance of a partial positive charge on this carbon atom. As a result, the attack of dioxane dichloride on the α-carbon atom leads to the formation of α-chloroacetylthiain and α-chloroacetylthiochromans and their α-chloro derivatives, respectively. As a result of the reaction, the corresponding α-chloroacetyl derivatives were obtained. The conditions for the course of this reaction can be represented by the following eaction scheme:

The hydrogen ion released during the reaction reacts with a second chlorine ion to form hydrogen chloride. This is confirmed by the fact that the hydrogen chloride gas released during the reaction turns litmus paper red.

PMR spectra were obtained on an 80 MHz “TESLA-487 C” device with GMDS as the internal standard and operating with CF₃COOH, CCl₄ and CD₃OH as solvents.

The purity of the products and the course of the reaction were monitored by thin layer chromatography (TLC) on a “Silufol UV-254” plate in a system of various solvents. Iodine vapor and UV light were used as decolorizers. The liquefaction temperature of the obtained substances was determined using a Boethius device.

Discussion of the results. The structure and composition of the obtained α-chloroacetylthiain and α-chloroacetylthiochromans were confirmed by elemental analysis, IR and PMR spectroscopic methods. When analyzing the IR spectra of the obtained products, it was found that the stretching vibrations of the carbon-carbon bond belonging to the aromatic ring give rise to specific absorption lines in the region of 1600-1610 cm^-1. It was also found that the stretching vibrations of the СH=СH bonds in the aromatic ring appear in the region of 800-815 cm^-1, and the stretching vibrations of the carbon-hydrogen bonds in the aromatic ring appear in the region of 940-950 cm^-1. The absorption lines characteristic of the carbonyl group show specific absorption lines in the region of 1700-1710 cm^-1. It was found that the absorption lines in the region of 1380-1400 cm^-1, which are characteristic of the methyl group of the acetyl group in the side chain of acetylthiochroman and acetylthiochroman, were not present in the newly formed compounds. It was also found that the absorption lines of the new valence vibrations of the CH₂Cl group belonging to the newly formed α-chloroacetylthiochroman and α-chloroacetylthiochroman molecules appeared in the region of 655-640 cm^-1.

Figure 1. IR spectrum of α-chloro-6-acetyl-1-thiochroman

When comparing the PMR spectra of the resulting α-chloroacetyl-1-thiaine and α-chloroacetyl-1-thiochromans with the PMR spectra of the original acetylthiaine and acetylthiochromans, it was found that the signals of the protons belonging to the aromatic ring of the molecule and the signals of the protons belonging to the heteroring remained practically unchanged. However, in the PMR spectra of acetyl-1-thiaine and acetyl-1-thiochromans, the signals of the methyl group belonging to the acetyl group of the molecule at 2.54 m.p., which appeared, disappeared, and instead of them, new signals belonging to CH₂Cl at 4.25-4.40 m.h., which appeared, were observed. In particular, in the PMR spectrum of α-chloroacetyl-1-thiochroman, it was found that the signals of the methylene groups belonging to the heterocycle appear in the form of a triplet at 2.03 m.h., 2.76 m.h., and 3.00 m.h. It was found that the spin-spin interaction constant of all SN₂ groups in the molecule is equal to 3 Gs. The protons of the aromatic ring appear at 7.12 m.h., and 7.56 m.h. The signals of the two protons in the СH₂-Cl bond in the molecule are observed in the form of a singlet at 4.28 m.h. It was determined that the spin-spin interaction constants of the hydrogen atoms at the sixth and seventh carbon atoms in the aromatic ring of the α-chloroacetyl 1-thiochroman molecule are JH₆ H₇ = 0 Gs., JH₇H ₈ = 13 Gs.,. while the spin-spin interaction constants of the hydrogen atoms at the seventh and eighth carbon atoms of this substance are

Figure 2. PMR spectrum of α-chloro-6-acetyl-1-thiochroman

Thus, the results of the reactions of acetylthione and acetylthiochroman and their derivatives in dioxane at room temperature confirmed the conversion of the saturated acetyl moiety to the α-state. The reaction yield, physicochemical constants and elemental analysis data of the obtained substances are presented in

Table 1.

Physicochemical data of α-chloroacyl-1-thiainand and α-chloroacyl-1-thiochroman

The ease of displacement of the chlorine atom in the α-chloroacylthione and α-chloroacylthiochroman molecules depends on the presence of a partial positive charge on the attacked carbon atom and the strength of the nucleophilic reagent. The greater the positive charge on the attacked carbon atom, the easier nucleophilic displacement reactions will occur under the same conditions. The value of this charge depends on the electronegativity of the atom directly bonded to the attacked carbon atom. Although halide ions are weak nucleophiles among anions, they significantly create a partial positive charge on the attacked carbon atom in the substrate, i.e., they reduce the electron density. Also, if the carbon atom adjacent to the halogen atom has electron-withdrawing substituents, the rate of the nucleophilic displacement reaction, which proceeds according to the SN₂ mechanism, increases in the reaction process.

IR spectra of the obtained substances were obtained in the range of 3600-400 cm^-1 on a VR-20 spectrophotometer. The samples were prepared in the form of tablets pressed into KBr salt. The thickness of the tablet layer was selected depending on the ability of the studied substance to transmit IR radiation.

Conclusion. The results of these reactions allowed us to deeply study the reactivity, electron distribution, and the effect of substituents of thiamine and thiochroman derivatives. The obtained results can be recommended as one of the effective ways to synthesize new amine organic compounds based on α-halogen derivatives. The results of the research can be practically applied in pharmaceuticals, organic synthesis, and the chemistry of modified sulfur compounds.

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