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Article

Quantum Chemical and Experimental Studies of an Unprecedented Reaction Pathway of Nucleophilic Substitution of 2-Bromomethyl-1,3-thiaselenole with 1,3-Benzothiazole-2-thiol Proceeding Stepwise at Three Different Centers of Seleniranium Intermediates

by
Svetlana V. Amosova
*,
Vladimir A. Shagun
,
Nataliya A. Makhaeva
,
Irina A. Novokshonova
and
Vladimir A. Potapov
Siberian Division of the Russian Academy of Sciences, A.E. Favorsky Irkutsk Institute of Chemistry, Favorsky Str. 1, 664033 Irkutsk, Russia
*
Author to whom correspondence should be addressed.
Molecules 2021, 26(21), 6685; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26216685
Submission received: 29 September 2021 / Revised: 28 October 2021 / Accepted: 2 November 2021 / Published: 4 November 2021
(This article belongs to the Special Issue Novel Organic Heteroatom Compounds: Synthesis Design and Theoretical Studies)
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Abstract

:
The results of quantum chemical and experimental studies of the reaction of 2-bromomethyl-1,3-thiaselenole with 1,3-benzothiazole-2-thiol made it possible to discover the unprecedented pathway of this reaction, which proceeds stepwise at three different centers of seleniranium intermediates. The first stage includes an attack of thiolate anion at the selenium atom of the seleniranium cation accompanied by ring opening with the formation of (Z)-2-[(1,3-benzothiazol-2-ylsulfanyl)selanyl]ethenyl vinyl sulfide, which is converted to six-membered heterocycle, 2-(2,3-dihydro-1,4-thiaselenin-2-ylsulfanyl)-1,3-benzothiazole, in a 99% yield. The latter compound undergoes rearrangement with ring contraction producing five-membered heterocycle, 2-[(1,3-thiaselenol-2-ylmethyl)sulfanyl]-1,3-benzothiazole, in a 99% yield (the thermodynamic product). The formation of 1,2-bis[(Z)-2-(vinylsulfanyl)ethenyl] diselenide is the result of the disproportionation of (Z)-2-[(1,3-benzothiazol-2-ylsulfanyl)selanyl]ethenyl vinyl sulfide. Thus, based on the quantum chemical and experimental studies, a regioselective synthesis of the reaction products in high yields was developed.

1. Introduction

More than 80% of modern drugs contain heterocyclic fragments in their structures [1]. Nitrogen heterocycles are among the most significant structural components of pharmaceuticals. Analysis of the database of U.S. FDA-approved drugs reveals that 59% of unique small-molecule drugs contain a nitrogen heterocycle [1]. The 1,3-thiazole ring is one of most important scaffolds for medicinal chemistry and many 1,3-thiazole derivatives exhibit high biological activity. Thiazole ranks sixth among the 27 classes of the most used nitrogen-containing heterocycles [2]. The thiazole ring is a structural component of more then 30 modern drugs including very significant anti-HIV drugs such as ritonavir and cobicistat, each of which contains two thiazole heterocycles with different functional environments [2]. Besides, the thiazole cycle is a chemically active center of the very important coenzyme thiamine (vitamin B1), antibacterial sulfathiazole, and many other natural and synthetic drugs (Figure 1) [3,4]. Compounds containing a condensed thiazole ring, 2,3-dihydro[1,3]thiazolo[3,2-a]pyridines and [1,3]thiazolo[3,2-a]quinolines, show high antibacterial [5,6,7,8] and antitumor activity [9,10,11,12]. Platinum group metal complexes containing a benzothiazole moiety exhibit antibacterial [13] and antimicrobial [14] activity.
Sulfur continues to maintain its status as the dominating heteroatom, integrated into a set of 362 sulfur-containing FDA-approved drugs [15]. Application of organoselenium compounds is one of modern trends in bioorganic chemistry. Organoselenium compounds show wide spectrum of biological activities [16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31]. Functionalized selenides containing benzenesulfonamide moieties were found to inhibit five human isoforms of zinc enzyme carbonic anhydrase. These enzymes are implicated in a variety of diseases, including glaucoma, retinitis pigmentosa, epilepsy, arthritis, and tumors [32]. The chemistry of selenium-containing five- and six-membered heterocycles is rapidly developing, and these compounds show various types of biological activities [33,34,35,36,37].
Selenium-containing electrophilic reagents play one of the main roles in the development of chemo-, regio-, and stereoselective methods for the synthesis of functionalized organoselenium compounds by selenofunctionalization reactions [38,39,40,41,42,43,44,45]. We were the first to use selenium dichloride and dibromide for the synthesis of organoselenium compounds [46,47], and these electrophilic reagents sufficiently expanded the possibilities of selenofunctionalization reactions, demonstrating high efficiency and selectivity [48,49,50,51,52,53].
The anchimeric effect of the selenium atom was quantitatively evaluated by estimation of the rates of nucleophilic substitution reactions in 2,6-dichloro-9-selena[3.3.1]bicyclononane, which was obtained by the addution of selenium dichloride to 1,5-cyclooctadiene [54].
A novel methodology for the synthesis of condensed selenium heterocycles based on the annulation and annulation–methoxylation reactions of selenium dihalides with natural compounds was developed [55]. The complexes of selenium dihalides with 2,6-dihalo-9-selenabicyclo[3.3.1]nonanes, which are the first representatives of coordination compounds with the Se–Se–Se bond, were obtained [56].
The starting compound, 2-bromomethyl-1,3-thiaselenole, was obtained with high selectivity by one-pot synthesis based on the reaction of divinyl sulfide with selenium dibromide [57]. 2-Bromomethyl-1,3-thiaselenole is a unique reagent demonstrating unusual reactivity in nucleophilic substitution reactions as a result of high anchimeric assistance of selenium [54].
2-Bromomethyl-1,3-thiaselenole (1) in solutions exists in equilibrium with intermediate seleniranium cation, which determines its unusual chemical properties [57,58,59,60,61] (Scheme 1). The formation of intermediate seleniranium cation in nucleophilic substitution reactions of thiaselenole 1 with dithiocarbamates was supported by quantum chemical calculations [59]. Nucleophilic attack on seleniranium cation can occur at three electrophilic centers of the seleniranium cation (two carbon atoms and the selenium atom) determining three possible directions of the reaction (Scheme 1).

2. Results and Discussion

The present work is a necessary continuation of pioneering studies of the new methodology of nucleophilic substitution at three different centers of seleniranium intermediates in reactions of 2-bromomethyl-1,3-thiaselenole (1) with nucleophilic reagents (Scheme 1) [57,58,59,60,61]. The analysis of the data includes a comparison with the previously obtained results on the reactions of 2-bromomethyl-1,3-thiaselenole with sulfur-centered nucleophiles [57,58,59,60]. The reactions of thiaselenole 1 with sulfur-centered nucleophiles with the formation of compounds with the sulfur–selenium bond are of great scientific interest since they include the nucleophilic attack of thiols or thiolate anions at the selenium atom of seleniranium cations. It should be emphasized that the reactions of nucleophilic substitution at the selenium atom of seleniranium cations were unknown before our investigations. However, compounds with the sulfur–selenium bond often play the role of intermediates, which underwent conversion into thermodynamically more stable products.
Depending on the conditions, the reaction of thiaselenole 1 with 1,3-benzothiazole-2-thiol (2) leads to the formation of products 3–6 (Scheme 2): (Z)-2-[(1,3-benzothiazol-2-ylsulfanyl)selanyl]ethenyl vinyl sulfide (3), 2-(2,3-dihydro-1,4-thiaselenin-2-ylsulfanyl)-1,3-benzothiazole (4), 2-[(1,3-thiaselenol-2-ylmethyl)sulfanyl]-1,3-benzothiazole (5), and 1,2-bis[(Z)-2-(vinylsulfanyl)ethenyl] diselenide (6a).
The formation of compound 3 with the sulfur–selenium bond is the result of a nucleophilic attack of thiol or thiolate anion at the selenium atom of seleniranium cation (Scheme 3).
We found the reaction of thiaselenole 1 with benzothiazole-2-thiol 2 very promising for advanced experimental and theoretical studies and carried out quantum chemical calculations and optimization of the reaction conditions. The obtained results are discussed in the present article.
Quantum chemical calculations and analysis of the thermodynamic characteristics of the multichannel interaction of thiaselenole 1 with thiol 2 were carried out (Scheme 4). The first stage of reaction channels 1–3 leads to the formation of the ion pair (1+−2−). This process proceeds via the TS1 transition state overcoming a 30.3 kcal/mol barrier (Figure 2). A cleavage of the C–Br bond in thiaselenole 1 leads to the formation of a new C–Se bond and seleniranium cation (1+). Hydrogen bromide, which released in the reaction, forms a donor–acceptor bond (2.127 Å) with 1,3-benzothiazole-2-thiolate anion (2−). As a result, the molecular system (1+−2−) + HBr is stabilized in a potential well, the depth of which from the side of the reverse transition (1+−2−) + HBr → (1−2) is 4.2 kcal/mol, and the total thermal effect of endothermic rearrangement [(1−2) → (1+−2−) + HBr] is 26.1 kcal/mol (Figure 2).
Based on these studies (Scheme 4, Figure 2), two important conclusions can be drawn: the reaction proceeds via the formation of seleniranium cation and the channel with a nucleophilic attack of the thiolate anion 2− at the selenium atom of the intermediate seleniranium cation is kinetically preferable, with the formation of selanyl sulfide 3 [(1+−2−) + HBr → 3 + HBr] (Scheme 4, channel 1). Channel 1 is energetically superior compared to the channels leading to the formation of 2-(2,3-dihydro-1,4-thiaselenin-2-ylsulfanyl)-1,3-benzothiazole (4) and 2-[(1,3-thiaselenol-2-ylmethyl)sulfanyl]-1,3-benzothiazole (5) by nucleophilic attacks at the carbon atoms C-2 and C-3 of the intermediate seleniranium cation (Scheme 4, channels 2 and 3). The ring opening of thiaselenole 1 proceeds via the TS2 transition state (Figure 2, channel 1) overcoming the 3.2 kcal/mol barrier. The heat effect of the reaction is 29.9 kcal/mol. The two channels, 4 and 5, or [(1+−2−) + HBr → 4 + HBr] and [(1+−2−) + HBr → 5 + HBr], respectively, are unable to compete with channel 1 (Figure 2), and the main product of the reaction of thiaselenole 1 with thiol 2 is linear selanyl sulfide 3.
The obtained data allowed us to direct our investigations towards the search for new reaction conditions in order to increase the yield of selanyl sulfide 3 (varying temperature, the nature of a solvent, the presence of a base, the nature of a base, and concentration of reagents under homogeneous or heterogeneous conditions). An alternative pathway for the formation of six-membered thiaselenine heterocycle 4 from selanyl sulfide 3 by acid-catalyzed cyclization (Figure 3) with the participation of hydrogen bromide, which is released with the formation of selanyl sulfide 3, was considered. Previously, we studied acid-catalyzed cyclization of a wide range of functionalized selanyl sulfides affording 2,3-dihydro-1,4-thiaselenines in up to 96% yields [60]. It was shown that the cyclization is catalyzed by a number of acids (HClO4, CF3COOH, and AcOH).
It has been experimentally proven by 1H−NMR monitoring that the reaction of thiaselenole 1 with thiol 2 is accompanied by rearrangement of 4 into 5 (acetonitrile, Li2CO3, r.t.), which proceeds via the intermediate seleniranium cation (Figure 4) [58]. Similarly, the reaction thiaselenole 1 with potassium selenocyanate proceeds via a rearrangement with ring expansion leading to six-membered 2,3-dihydro-1,4-thiaselenin-2-yl selenocyanate (the kinetic product), which in turn undergoes rearrangement with ring contraction into 1,3-thiaselenol-2-ylmethyl selenocyanate (the thermodynamic product) [61].
The reaction of disproportionation of selanyl sulfide 3 with the formation of two symmetrical products, 1,2-bis[(Z)-2-(vinylsulfanyl)ethenyl] diselenide (6a) and bis(1,3-benzothiazol-2-yl) disulfide (6b), was studied (Figure 5). Similar reactions of the disproportionation of compounds with the sulfur–selenium bond are known [62,63]. They are accelerated under the action of basic or acidic catalysts [63].
It was found that the reaction of thiaselenole 1 with thiol 2 can be carried out without a base in such aprotic bipolar solvent as DMF, which is able to bind evolved hydrogen bromide. Six-membered heterocycle 4 as a major product and five-membered heterocycle 5 as a minor product were formed in 1–1.5 h (Table 1, Runs 1, 2). The latter compound became the major product in 24 h (Table 1, Run 3). The six-membered product 4 was completely rearranged into five-membered heterocycle 5 in a 99% yield (Table 1, Run 4). Thus, new regioselective conditions for the quantitative preparation of heterocycle 5 were found.
Carrying out the reaction in the presence of an equimolar amount of NaHCO3 for 1 h made it possible to prevent the rearrangement and to direct the reaction to the formation of the six-membered heterocycle 4 in a 99% yield with high regioselectivity (Table 1, Run 5). These reaction conditions are very convenient (room temperature, 1 h), and the reaction regioselectively led to the desired product 4 in a quantitative yield. Increasing the reaction time under these conditions led to the partial rearrangement of product 4 into five-membered heterocycle 5 (Table 1, Run 6). Thus, the quantum chemical calculations assisted to find new reaction conditions that provided highly regioselective methods for the preparation of heterocycles 4 and 5 in quantitative yields, which did not require additional purification.
Further studies of the reaction were conducted out in acetonitrile. When the reaction was carried out in the presence of equimolar amounts of K2CO3 at 0 °C for 5 h, it was possible for the first time to detect the target selanyl sulfide 3 in a 9% yield along with the product of its disproportionation 6a (46% yield) and heterocycle 4 (27% yield) (Table 1, Run 7). It is worth reminding that quantum chemical studies indicate the formation of selanyl sulfide 3 as the kinetic product (Scheme 4, Figure 2).
In the presence of pyridine as a base (0 °C, 3 h), the reaction led to products 4 and 5 in 25% and 61% yields, respectively (Table 1, Run 8). Even when using an equimolar amount of pyridine with respect to thiaselenole 1, no traces of the pyridine quaternization product with thiaselenole were detected. The reaction of pyridine with thiaselenole 1 was studied by us previously and it was found that the quaternization was accompanied by rearrangement with the ring expansion of thiaselenole with the formation of (2,3-dihydro-1,4-thiaselenin-2-yl)pyridinium bromide [65].
A series of experiments on the reaction of thiaselenole 1 with sodium 1,3-benzothiazole-2-thiolate (anion 2−) was carried out under homogeneous conditions in acetonitrile, varying the concentration of reagents, reaction time, and the method of the reaction mixture treatment (Table 1, Runs 9–12).
The most representative results are included in Table 1 (Runs 9–12). When the treatment consisted of dilution with water and extraction, the reaction mixture contained mainly thiaselenine 4 (45% yield) along with selanyl sulfide 3 (8% yield) and the product of its disproportionation diselenide 6a (14% yield) with a complete conversion of thiaselenole 1 (Table 1, Run 9).
When another method of the reaction mixture treatment (filtering and acetonitrile removing) was used (Table 1, Run 10), the major product was diselenide 6a (60% yield), the yield of thiaselenine 4 dropped from 45% to 8%, and the yield of selanyl sulfide 3 increased slightly to 11%. We assumed that increasing the yield of diselenide 6a occurred on the stage of concentration of products upon removing acetonitrile under reduced pressure (Table 1, Run 10). Traces of sodium 1,3-benzothiazole-2-thiolate can present in the reaction mixture and act as the catalyst of the disproportionation reaction. This was confirmed by the experiment under the same conditions, when the resulted reaction mixture was divided into two equal parts, which were treated in a different mode. When the solvent was removed under reduced pressure from the first part, the 87% conversion of thiaselenole 1 and the formation of products 3, 4, and 6a in 13%, 13%, and 54% yields, respectively, were observed (Table 1, Run 11). Thus, it made it possible to direct the reaction towards the preferential formation of selanyl sulfide 3 and the product of its disproportionation 6a under these conditions. In the second half of the mixture, the reaction was stopped by dilution with water and extraction with CCl4 followed by the solvent removing under reduced pressure. The formation of products 4 (40% yield) and 6a (30% yield) with a complete conversion of thiaselenole 1 was detected (Table 1, Run 12). Besides, 2,3-dihydro-1,4-thiaselenin-2-ol, the product of the competitive reaction of thiaselenole 1 with water in aqueous acetonitrile, was unexpectedly formed in a 10% yield. We previously obtained this compound by the reaction of thiaselenole 1 with water [64].
Based on the obtained results (Table 1, Runs 11, 12), it can be concluded that the initial reaction mixture contained diselenide 6a (30% yield), which cannot be converted into other reaction products, and the formation of an additional amount of this compound (54% yield) is the result of disproportionation of selanyl sulfide 3 upon concentration of the solution by removing acetonitrile. The main product of the untreated reaction mixture is believed to be selanyl sulfide 3, which is converted to thiaselenine 4 in aqueous acetonitrile. This is in good agreement with quantum chemical calculations (Figure 3).
The simplified reaction pathway of multichannel regioselective reaction of thiaselenole 1 with thiol 2 based on the experimental data and quantum chemical calculations is presented in Scheme 5. The reaction of nucleophilic substitution in thiaselenole 1 with thiol 2 proceeds stepwise at three different centers of seleniranium intermediates. The first stage: the attack of thiolate anion at the selenium atom of the seleniranium cation generated from thiaselenole 1 proceeds with ring opening and the formation of selanyl sulfide 3. It is important that the selenium atom conjugated with the sulfanylethenyl fragment is a soft electrophile, its reaction with thiolate anion 2− (which is a soft nucleophile) proceeds with minimal energy consumption, and the formation of selanyl sulfide 3 as a kinetic product. On the second stage, the nucleophilic attack of thiolate anion occurs at the carbon atom of the CH group of seleniranium cation B+, which is generated from selanyl sulfide 3. Seleniranium cation B+ is characterized by the elongation of the Se–CH bond (2.73 Å) as compared to the 1+ cation (2.21 Å), which leads to its rupture by the nucleophilic attack and the formation of heterocycle 4. The third stage: the attack of thiolate anion at the carbon atom of the CH2 group of the seleniranium cation (transition state S8) generated from six-membered thiaselenine 4. The third stage is accompanied by rearrangement, which proceeds with the ring contraction producing five-membered thermodynamic product 5.
The stages were optimized and heterocycles 4 and 5 were obtained in quantitative yields. Increasing the concentration of selanyl sulfide 3 in solution led to its disproportionation and the formation of symmetric products 6a and 6b. The experimental data are in good agreement with quantum chemical calculations including the analysis of the thermodynamic characteristics of the reaction.

3. Materials and Methods

3.1. Computational Analysis

The potential energy surface of the reaction of thiaselenole 1 with thiol 2 in the framework of the GAUSSIAN 09 software package was investigated using the basic set 6-311 + G (d, p) [66]. The calculations of molecular structures and the study of the gradient channels connecting them (Scheme 4) were carried out using the density functional theory (DFT) with the three-parameter B3LYP functional [67]. Stationary points were identified by the analysis of the Hessian matrices. The search and localization of transient states (TS) was carried out by the method of synchronous transit QST [68]. All the results obtained refer to the gas phase. The analysis of vibration frequencies at the saddle point was carried out and the correspondence of the critical points to the gradient line was proved.

3.2. General Information

1H (400.1 MHz), 13C (100.6 MHz), 15N (40.56 MHz), and 77Se (76.3 MHz) NMR spectra were recorded on a Bruker DPX-400 spectrometer (Bruker BioSpin GmbH, Rheinstetten, Germany) in 5%–10% solution in CDCl3 referenced to HMDS (1H−NMR, internal), the residual CDCl3 peak (77.00 ppm for 13C−NMR), MeNO2 (15N−NMR, external), and Me2Se (77Se−NMR, external). Mass spectra were recorded on an Agilent 5975 Series Gas Chromatograph/Mass Selective Detector (GC/MSD) system (Agilent Technologies, Inc., Santa Clara, CA, USA) with electron impact (EI) ionization at 70 eV. The C, H, N, and S elemental analyses were performed on a Thermo Scientific FLASH 2000 Organic Elemental Analyzer (Thermo Fisher Scientific Inc., Milan, Italy). The content of selenium was assessed by iodometric titration. Melting points were determined on a Kofler Hot-Stage Microscope PolyTherm A apparatus (Wagner and Munz GmbH, München, Germany) and uncorrected.
To start, 2-bromomethyl-1,3-thiaselenole 1 was prepared from divinyl sulfide and SeBr2 according to the previously described procedure [57]. A commercial 1,3-benzothiazole-2-thiol (2) (Sigma-Aldrich, St. Louis, MO, USA) and dried, freshly distilled solvents were used in the reactions. All syntheses using acetonitrile were carried out under an argon atmosphere. Acetonitrile was degassed with argon before the use.

3.3. General Procedure for the Reaction of Thiaselenole 1 with Thiol 2 in DMF

3.3.1. Without Base

A solution of thiol 2 (334 mg, 2 mmol) in DMF (3 mL) was added to a solution of thiaselenole 1 (488 mg, 2 mmol) in DMF (3 mL). The mixture was stirred at room temperature for the prescribed time (Table 1, Runs 1–4), diluted with cold water (40 mL), and extracted with EtOAc (5 × 5 mL). The organic phase was washed with water (5 × 5 mL) and dried over CaCl2. After removing the solvent in a vacuum, the residue (a yellow powder) was analyzed by 1H−NMR (Table 1). Analysis examples can be found in the Supplementary Materials, Figures S14–S19.

3.3.2. In the Presence of NaHCO3

A solution of thiol 2 (167 mg, 1 mmol) in DMF (2 mL) and NaHCO3 (84 mg, 1 mmol) were added to a solution of thiaselenole 1 (244 mg, 1 mmol) in DMF (2 mL). The mixture was stirred at room temperature for the prescribed time (Table 1, Runs 5, 6), diluted with cold water (20 mL), and extracted with EtOAc (3 × 5 mL). The organic phase was washed with water (3 × 5 mL) and dried over CaCl2. After removing the solvent in a vacuum, the residue (a yellow powder) was analyzed by 1H−NMR (Table 1). Analysis examples can be found in the Supplementary Materials, Figures S14–S19.

3.4. 2-(2,3-Dihydro-1,4-thiaselenin-2-ylsulfanyl)-1,3-benzothiazole 4

A solution of thiol 2 (167 mg, 1 mmol) in DMF (2 mL) and NaHCO3 (84 mg, 1 mmol) were added to a solution of thiaselenole 1 (244 mg, 1 mmol) in DMF (2 mL) (Table 1, Run 5). The mixture was stirred at room temperature for 1 h, diluted with cold water (20 mL), and extracted with EtOAc (3 × 5 mL). The organic phase was washed with water (3 × 5 mL) and dried over CaCl2. Removing the solvent in vacuum led to compound 4 as a yellow powder. Yield: 327 mg (99%). M.p. 90–91 °C. The NMR data can be found in the Supplementary Materials.

3.5. 2-[(1,3-Thiaselenol-2-ylmethyl)sulfanyl]-1,3-benzothiazole 5

A solution of thiol 2 (334 mg, 2 mmol) in DMF (3 mL) was added to a solution of thiaselenole 1 (488 mg, 2 mmol) in DMF (3 mL) (Table 1, Run 4). The mixture was stirred at room temperature for 48 h, diluted with cold water (40 mL), and extracted with EtOAc (5 × 5 mL). The organic phase was washed with water (5 × 5 mL) and dried over CaCl2. After removing the solvent in a vacuum, compound 5 was obtained as a white-yellow powder. Yield: 653 mg (99%). M.p. 109–110 °C. The NMR data can be found in the Supplementary Materials.

3.6. Reaction of Thiaselenole 1 with Benzothiazole 2 in Acetonitrile in the Presence of K2CO3

Thiol 2 (302 mg, 1.81 mmol) and K2CO3 (250 mg, 1.81 mmol) were added to a solution of thiaselenole 1 (442 mg, 1.81 mmol) in acetonitrile (10 mL) (Table 1, Run 7). The mixture was stirred at 0 °C for 5 h. The mixture was filtered, and the solvent was removed in a vacuum. The residue (355 mg, a yellow oil) contained (according to 1H−NMR data) product 3 (54 mg, 9% yields), product 4 (164 mg, 27% yields), and product 6a (137 mg, 46% yields) (a 15:46:39 molar ratio of compounds 3, 4, and 6a). Compounds 3, 4, and 6a were identified by 1H−NMR (the analysis of the reaction mixture can be found in the Supplementary Materials, Figures S14–S16).

3.7. Reaction of Thiaselenole 1 with Benzothiazole 2 in Acetonitrile in the Presence of Pyridine

Pyridine (111 mg, 1.41 mmol) was added to a solution of thiaselenole 1 (344 mg, 1.41 mmol) in acetonitrile (8 mL) (Table 1, Run 8). The mixture was cooled to 0 °C and thiol 2 (235 mg, 1.41 mmol) was added. The mixture was stirred at 0 °C for 3 h, diluted with cold water (10 mL), and extracted with chloroform (3 × 5 mL). The organic phase was dried over CaCl2 and the solvent was removed in a vacuum. The residue (397 mg, a yellow powder) contained (according to 1H−NMR data) products 4 (115 mg, 25% yield) and 5 (282 mg, 61% yield) (a 29:71 molar ratio of compounds 4 and 5).

3.8. Sodium 1,3-Benzothiazole-2-thiolate (Sodium Thiolate of Benzothiazole 2)

Powdered NaOH (80%, 300 mg, 6.00 mmol) was added to a solution of thiol 2 (1002 mg, 6.00 mmol) in dry EtOH (60 mL). The mixture was stirred at room temperature for 0.5 h and the solvent was removed in a vacuum. Sodium 1,3-benzothiazole-2-thiolate was obtained as a light-yellow powder. Yield: 1134 mg (~100%). M.p. 327–328 °C.

3.9. Reaction of Thiaselenole 1 with Sodium 1,3-Benzothiazole-2-thiolate

A solution of thiaselenole 1 (244 mg, 1 mmol) in acetonitrile (6 mL) was added to sodium 1,3-benzothiazole-2-thiolate (189 mg, 1.00 mmol). The mixture was stirred at room temperature for 10 min, diluted with cold water (20 mL), and extracted with chloroform (3 × 10 mL). The organic phase was filtered, washed with water, dried over CaCl2, and the solvent was removed in a vacuum. The residue (224 mg, a yellow oil) contained (according to 1H−NMR data) compounds 3 (27 mg, 8% yield), 4 (150 mg, 45% yield), and 6a (47 mg, 14% yield) (a 12:67:21 molar ratio of compounds 3, 4, and 6a).
  • 1,2-Bis[(Z)-2-(Vinylsulfanyl)ethenyl] Diselenide 6 (Table 1, Run 10)
A solution of sodium 1,3-benzothiazole-2-thiolate (189 mg, 1 mmol) in acetonitrile (3 mL) was added to a solution of thiaselenole 1 (244 mg, 1 mmol) in acetonitrile (3 mL). The mixture was stirred at room temperature for 0.5 h. The mixture was filtered, and the solvent was removed in a vacuum. The residue (162 mg, a yellow oil) contained (according to 1H−NMR data) compounds 3 (37 mg, 11% yield), 4 (26 mg, 8% yield), and 6a (99 mg, 60% yield) (a 23:16:61 molar ratio of compounds 3, 4, and 6a). Compound 6a (91 mg, 55% yield) was isolated by column chromatography on silica gel (eluent: hexane). 1H−NMR (400 MHz, CDCl3), δ: 7.04 (d, 3J = 7.9 Hz, 2H, SCH=CHSe), 6.63 (d, 3J = 7.9 Hz, 2H, SCH=CHSe), 6.42 (dd, 3Jcis = 9.8 Hz, 3Jtrans = 16.4 Hz, 2H, H2C=CHS), 5.33 (d, 3Jcis = 9.8 Hz, 1H, H2C=CHS), 5.28 (d, 3Jtrans = 16.4 Hz, 1H, H2C=CHS). 13C−NMR (100 MHz, CDCl3) δ: 114.37 (H2C=CHS), 124.95 (SCH=CHSe), 127.72 (SCH=CHSe), 129.61 (H2C=CHS). 77Se−NMR (76 MHz, CDCl3): δ 418.9 ppm. MS (EI) m/z: 330 (6%) [M]+, 165 (75%), 151 (32%), 133 (6%), 85 (100%), 58 (51%), 45 (59%). Found, %: C 29.47; H 2.95, S 19.39, Se 47.87. C8H10S2Se2. Calculated, %: C 29.28; H 3.07, S 19.54, Se 48.11.

3.10. Reaction of Thiaselenole 1 with Sodium 1,3-Benzothiazole-2-thiolate in Acetonitrile at High Dilution. Synthesis of (Z)-2-[(1,3-Benzothiazol-2-ylsulfanyl)selanyl]ethenyl Vinyl Sulfide (3)

A solution of sodium 1,3-benzothiazole-2-thiolate (280 mg, 1.48 mmol) in acetonitrile (13 mL) was added to a solution of thiaselenole 1 (361 mg, 1.48 mmol) in acetonitrile (14 mL). The mixture was stirred at room temperature for 10 min. The mixture was filtered and divided into two equal parts (Table 1, Runs 11, 12).
The solvent from the first part of the mixture was removed in a vacuum. The residue (153 mg, a yellow oil) contained (according to 1H−NMR data) thiaselenole 1 (23 mg, 87% conversion), and compounds 3 (32 mg, 13% yield), 4 (32 mg, 13% yield), and 6a (66 mg, 54% yield) (a 19:20:20:41 molar ratio of compounds 1, 3, 4, and 6a). Compounds 1, 3, 4, and 6a were identified by 1H−NMR (the analysis of the reaction mixture can be found in the Supplementary Materials, Figures S17 and S18).
The second part of the mixture was diluted with cold water (7 mL) and extracted with CCl4 (7 mL). The organic phase was dried over MgSO4 and the solvent was removed in a vacuum. The residue (147 mg, a yellow oil) contained (according to 1H−NMR data) products 4 (98 mg, 40% yield), 6a (36 mg, 30% yield), and 2,3-dihydro-1,4-thiaselenin-2-ol (13 mg, 10% yield) (a 63:23:14 molar ratio of compounds 4, 6a, and 2,3-dihydro-1,4-thiaselenin-2-ol). Compounds 4, 6a, and 2,3-dihydro-1,4-thiaselenin-2-ol [64] were identified by 1H−NMR (the analysis of the reaction mixture can be found in the Supplementary Materials, Figure S19).

4. Conclusions

Three successive stages of nucleophilic substitution reaction of thiol 2 with thiaselenole 1 proceeding via the generation of seleniranium cation were optimized. This determines the ease of ring opening on attacking the soft nucleophile 2 at the soft electrophile—the selenium atom in seleniranium cation with the formation of labile selanyl sulfide 3. The subsequent stage is accompanied by the generation of seleniranium cation from selanyl sulfide 3 by the nucleophilic attack at the carbon atom of the CH group, leading to six-membered thiaselenine 4. The five-membered thiaselenole 5 is formed by the nucleophilic attack at the carbon atom of the CH2 group of the seleniranium cation generated from thiaselenine 4. The results of quantum chemical studies of these unprecedented reactions are in good agreement with the experimental data.
Based on obtained results, regioselective methods for preparation of heterocycles 4 and 5 in quantitative yields at room temperature were developed. Due to the disproportionation of product 3, a symmetric highly unsaturated diselenide of (Z,Z)-stereochemistry 6a is formed. Compound 6a is the promising reagent for organoselenium chemistry. The reduction of diselenide 6a leads to the generation of (Z)-vinylsulfanylethenylselenide anion, which can be involved in further nucleophilic reactions.
The reaction products combine sulfur/selenium- and nitrogen-containing heterocycles, and these combinations represent new scaffolds, which can find applications in organochalcogen and medicinal chemistry. For example, the selenium moiety of the obtained compounds can bring glutathione peroxidase-like activity to the products. It is known that a number of organic selenides exhibit high glutathione peroxidase-like activity [17,18,19,20].

Supplementary Materials

The following are available online, synthesis and 1H−, 13C−, and 77Se−NMR spectra of 2-bromomethyl-1,3-thiaselenole (1), 1H−, 13C−, 15N−, and 77Se−NMR spectra of the obtained compounds (Figures S1–S13) and 1H NMR spectra of the reaction mixtures (Table 1, Runs 7, 11, 12, Figures S14–S19) and results of quantum chemical calculations (Tables S1–S25).

Author Contributions

Conceptualization and the paper preparation, S.V.A.; quantum chemical calculations and their interpretation, V.A.S.; methodology and research experiments, N.A.M. and I.A.N.; the data curation and supervision, V.A.P. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data is available in this article and Supplementary Materials.

Acknowledgments

The authors thank Baikal Analytical Center SB RAS for providing the instrumental equipment for structural investigations.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Gomtsyan, A. Heterocycles in drugs and drug discovery. Chem. Heterocycl. Compd. 2012, 48, 7–10. [Google Scholar] [CrossRef]
  2. Vitaku, E.; Smith, D.T.; Njardarson, J.T. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA Approved Pharmaceuticals. J. Med. Chem. 2014, 57, 10257–10274. [Google Scholar] [CrossRef] [PubMed]
  3. Joule, J.A.; Smith, G.F. Heterocyclic Chemistry; Van Nostrand Reinhold: London, UK, 1972; ISBN 978-0442078102. [Google Scholar]
  4. Nora de Souza, M.V. Synthesis and biological activity of natural thiazoles: An important class of heterocyclic compounds. J. Sulfur Chem. 2005, 26, 429–449. [Google Scholar] [CrossRef]
  5. Cegelski, L.; Pinkner, J.S.; Hammer, N.D.; Cusumano, C.K.; Hung, C.S.; Chorell, E.; Åberg, V.; Walker, J.N.; Seed, P.C.; Almqvist, F.; et al. Small-molecule inhibitors target Escherichia coli amyloid biogenesis and biofilm formation. Nat. Chem. Biol. 2009, 5, 913–919. [Google Scholar] [CrossRef] [Green Version]
  6. Bengtsson, C.; Lindgren, A.E.G.; Uvell, H.; Almqvist, F. Design, synthesis and evaluation of triazole functionalized ring-fused 2-pyridones as antibacterial agents. Eur. J. Med. Chem. 2012, 54, 637–646. [Google Scholar] [CrossRef] [Green Version]
  7. Piatek, R.; Zalewska-Piatek, B.; Dzierzbicka, K.; Makowiec, S.; Pilipczuk, J.; Szemiako, K.; Cyranka-Czaja, A.; Wojciechowski, M. Pilicides inhibit the FGL chaperone/usher assisted biogenesis of the Dr fimbrial polyadhesin from uropathogenic Escherichia coli. BMC Microbiol. 2013, 13, 131. [Google Scholar] [CrossRef] [Green Version]
  8. Good, J.A.D.; Silver, J.; Núñez-Otero, C.; Bahnan, W.; Krishnan, K.S.; Salin, O.; Engström, P.; Svensson, R.; Artursson, P.; Gylfe, Å.; et al. Thiazolino 2-Pyridone Amide Inhibitors of Chlamydia trachomatis Infectivity. J. Med. Chem. 2016, 59, 2094–2108. [Google Scholar] [CrossRef]
  9. Youssef, A.M.; Malki, A.; Badr, M.H.; Elbayaa, R.Y.; Sultan, A.S. Synthesis and anticancer activity of novel benzimidazole and benzothiazole Derivatives against HepG2 liver cancer cells. Med. Chem. 2012, 8, 151–162. [Google Scholar] [CrossRef]
  10. Bywater, M.J.; Poortinga, G.; Sanij, E.; Hein, N.; Peck, A.; Cullinane, C.; Wall, M.; Cluse, L.; Drygin, D.; Anderes, K.; et al. Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53. Cancer Cell 2012, 22, 51–56. [Google Scholar] [CrossRef] [Green Version]
  11. Azam, S.S.; Abro, A.; Tanvir, F.; Parvaiz, N. Identification of unique binding site and molecular docking studies for structurally diverse Bcl-xL inhibitors. Med. Chem. Res. 2014, 23, 3765–3783. [Google Scholar] [CrossRef]
  12. Devlin, J.R.; Hannan, K.M.; Hein, N.; Cullinane, C.; Kusnadi, E.; Ng, P.Y.; George, A.J.; Shortt, J.; Bywater, M.J.; Poortinga, G.; et al. Combination therapy targeting ribosome biogenesis and mRNA translation synergistically extends survival in MYC-driven lymphoma. Cancer Discov. 2016, 6, 59–70. [Google Scholar] [CrossRef] [Green Version]
  13. Shadap, L.; Diamai, S.; Banothu, V.; Negi, D.P.S.; Adepally, U.; Kaminsky, W.; Kollipara, M.R. Half sandwich platinum group metal complexes of thiourea derivative ligands with benzothiazole moiety possessing anti-bacterial activity and colorimetric sensing: Synthesis and characterization. J. Organomet. Chem. 2019, 884, 44–54. [Google Scholar] [CrossRef]
  14. Dkhar, L.; Banothu, V.; Kaminsky, W.; Kollipara, M.R. Synthesis of half sandwich platinum group metal complexes containing pyridyl benzothiazole hydrazones: Study of bonding modes and antimicrobial activity. J. Organomet. Chem. 2020, 914, 121225. [Google Scholar] [CrossRef]
  15. Feng, M.; Tang, B.; Liang, S.H.; Jiang, X. Sulfur containing scaffolds in drugs: Synthesis and application in medicinal chemistry. Curr. Top. Med. Chem. 2016, 16, 1200–1216. [Google Scholar] [CrossRef]
  16. Nogueira, C.W.; Zeni, G.; Rocha, J.B.T. Organoselenium and organotellurium compounds:  Toxicology and pharmacology. Chem. Rev. 2004, 104, 6255–6286. [Google Scholar] [CrossRef]
  17. Wirth, T. Small Organoselenium compounds: More than just glutathione peroxidase mimics. Angew. Chem. Int. Ed. 2015, 54, 10074–10076. [Google Scholar] [CrossRef]
  18. Fonseca, S.F.; Lima, D.B.; Alves, D.; Jacob, R.G.; Perin, G.; Lenardão, E.J.; Savegnago, L. Synthesis, characterization and antioxidant activity of organoselenium and organotellurium compound derivatives of chrysin. New J. Chem. 2015, 39, 3043–3050. [Google Scholar] [CrossRef]
  19. Mugesh, G.; du Mont, W.-W.; Sies, H. Chemistry of biologically important synthetic organoselenium compounds. Chem. Rev. 2001, 101, 2125–2180. [Google Scholar] [CrossRef]
  20. McNeil, N.M.R.; Press, D.J.; Mayder, D.M.; Garnica, P.; Doyle, L.M.; Back, T.G. Enhanced glutathione peroxidase activity of water-soluble and polyethylene glycol-supported selenides, related spirodioxyselenuranes, and pincer selenuranes. J. Org. Chem. 2016, 81, 7884–7897. [Google Scholar] [CrossRef]
  21. Potapov, V.A.; Ishigeev, R.S.; Amosova, S.V.; Borodina, T.N. Synthesis of a novel family of water-soluble 2H,3H-[1,3]thia- and -selenazolo[3,2-a]pyridin-4-ium heterocycles by annulation reactions. Tetrahedron Lett. 2019, 60, 475–479. [Google Scholar] [CrossRef]
  22. Frizon, T.E.; Rafique, J.; Saba, S.; Bechtold, I.H.; Gallardo, H.; Braga, A.L. Synthesis of functionalized organoselenium materials: Selenides and diselenides containing cholesterol. Eur. J. Org. Chem. 2015, 2015, 3470–3476. [Google Scholar] [CrossRef]
  23. Bortoli, M.; Torsello, M.; Bickelhaupt, F.M.; Orian, L. Role of the chalcogen (S, Se, Te) in the oxidation mechanism of the glutathione peroxidase active site. Chemphyschem 2017, 18, 2990–2998. [Google Scholar] [CrossRef]
  24. Jain, V.K. An Overview of organoselenium chemistry: From fundamentals to synthesis. In Organoselenium Compounds in Biology and Medicine: Synthesis, Biological and Therapeutic Treatments; Jain, V.K., Priyadarsini, K.I., Eds.; Royal Society of Chemistry: London, UK, 2017; pp. 1–33. [Google Scholar]
  25. May, S.W. Selenium-based drug design. In Topics in Medicinal Chemistry. Atypical Elements in Drug Design; Schwarz, J., Ed.; Springer International Publishing: Cham, Switzerland, 2016; pp. 87–118. [Google Scholar]
  26. Angeli, A.; Tanini, D.; Nocentini, A.; Capperucci, A.; Ferraroni, M.; Gratteri, P.; Supuran, C.T. Selenols: A new class of carbonic anhydrase inhibitors. Chem. Commun. 2019, 55, 648–651. [Google Scholar] [CrossRef]
  27. Yu, S.-C.; Ri, D.-M.; Kühn, H. Hydrophobicity and glutathione peroxidase-like activity of substituted salicyloyl-5-seleninic acids: Re-investigations on aromatic selenium compounds based on their hydrophobicity. J. Organomet. Chem. 2018, 862, 86–94. [Google Scholar] [CrossRef]
  28. Panaka, S.; Trivedi, R.; Jaipal, K.; Giribabu, L.; Sujitha, P.; Kumar, C.G.; Sridhar, B. Ferrocenyl chalcogeno (sugar) triazole conjugates: Synthesis, characterization and anticancer properties. J. Organomet. Chem. 2016, 813, 125–130. [Google Scholar] [CrossRef]
  29. Seliman, A.A.A.; Altaf, M.; Onawole, A.T.; Ahmad, S.; Ahmed, M.Y.; Al-Saadi, A.A.; Altuwaijri, S.; Bhatia, G.; Singh, J.; Isab, A.A. Synthesis, X-ray structures and anticancer activity of gold(I)-carbene complexes with selenones as co-ligands and their molecular docking studies with thioredoxin reductase. J. Organomet. Chem. 2017, 848, 175–183. [Google Scholar] [CrossRef]
  30. Al-Rubaie, A.Z.; Al-Jadaan, S.A.S.; Muslim, S.K.; Saeed, E.A.; Ali, E.T.; Al-Hasani, A.K.J.; Al-Salman, H.N.K.; Al-Fadal, S.A.M. Synthesis, characterization and antibacterial activity of some new ferrocenyl selenazoles and 3,5-diferrocenyl-1,2,4-selenadiazole. J. Organomet. Chem. 2014, 774, 43–47. [Google Scholar] [CrossRef]
  31. Dhau, J.S.; Singh, A.; Singh, A.; Sooch, B.S.; Brandão, P.; Félix, V. Synthesis and antibacterial activity of pyridylselenium compounds: Self-assembly of bis(3-bromo-2-pyridyl)diselenide via intermolecular secondary and π-π stacking interactions. J. Organomet. Chem. 2014, 766, 57–66. [Google Scholar] [CrossRef]
  32. Angeli, A.; Tanini, D.; Capperucci, A.; Supuran, C.T. Synthesis of novel selenides bearing benzenesulfonamide moieties as carbonic anhydrase I, II, IV, VII, and IX inhibitors. ASC Med. Chem. Lett. 2017, 8, 1213–1217. [Google Scholar] [CrossRef]
  33. Banerjee, B.; Koketsy, M. Recent developments in the synthesis of biologically relevant selenium-containing scaffolds. Coord. Chem. Rev. 2017, 339, 104–127. [Google Scholar] [CrossRef]
  34. Elsherbini, M.; Hamama, W.S.; Zoorob, H.H. Recent advances in the chemistry of selenium-containing heterocycles: Five-membered ring systems. Coord. Chem. Rev. 2016, 312, 149–177. [Google Scholar] [CrossRef]
  35. Ninomiya, M.; Garud, D.R.; Koketsu, M. Biologically significant selenium-containing heterocycles. Coord. Chem. Rev. 2011, 255, 2968–2990. [Google Scholar] [CrossRef]
  36. Sonawane, A.D.; Sonawane, R.A.; Ninomiya, M.N.; Koketsu, M. Synthesis of seleno-heterocycles via electrophilic/radical cyclization of alkyne containing heteroatoms. Adv. Synth. Catal. 2020, 362, 3485–3515. [Google Scholar] [CrossRef]
  37. Potapov, V.A.; Ishigeev, R.S.; Shkurchenko, I.V.; Zinchenko, S.V.; Amosova, S.V. Natural compounds and their structural analogs in regio- and stereoselective synthesis of new families of water-soluble 2H,3H-[1,3]thia- and -selenazolo[3,2-a]pyridin-4-ium heterocycles by annulation reactions. Molecules 2020, 25, 376. [Google Scholar] [CrossRef] [Green Version]
  38. Potapov, V.A.; Musalov, M.V.; Kurkutov, E.O.; Yakimov, V.A.; Khabibulina, A.G.; Musalova, M.V.; Amosova, S.V.; Borodina, T.N.; Albanov, A.I. Remarkable alkene-to-alkene and alkene-to-alkyne transfer reactions of selenium dibromide and PhSeBr. Stereoselective addition of selenium dihalides to cycloalkenes. Molecules 2020, 25, 194. [Google Scholar] [CrossRef] [Green Version]
  39. Santi, C.; Santoro, S. Electrophilic selenium. In Organoselenium Chemistry: Synthesis and Reactions; Wirth, T., Ed.; Wiley-VCH: Weinheim, Germany, 2012; pp. 1–53. [Google Scholar]
  40. Freudendahl, D.M.; Wirth, T. New selenium electrophiles and their reactivity. In New Selenium and Tellurium Chemistry. From Small Molecules to Biomolecules and Materials; Woollins, J.D., Laitinen, R.S., Eds.; Springer: Berlin/Heidelberg, Germany, 2011; pp. 41–55. [Google Scholar]
  41. Dutton, J.L.; Ragogna, P.J. Recent developments in the Lewis acidic chemistry of selenium and tellurium halides and pseudo-halides. In New Selenium and Tellurium Chemistry. From Small Molecules to Biomolecules and Materials; Woollins, J.D., Laitinen, R.S., Eds.; Springer: Berlin/Heidelberg, Germany, 2011; pp. 179–199. [Google Scholar]
  42. Denmark, S.E.; Collins, W.R.; Cullen, M.D. Observation of direct sulfenium and selenenium group transfer from thiiranium and seleniranium ions to alkenes. J. Am. Chem. Soc. 2009, 131, 3490–3492. [Google Scholar] [CrossRef]
  43. Ścianowski, J.; Rafiński, Z. Electrophilic selenium reagents: Addition reactions to double bonds and selenocyclizations. In Organoselenium Chemistry: Between Synthesis and Biochemistry; Santi, C., Ed.; Bentham Science Publishers: Sharjah, United Arab Emirates, 2014; pp. 8–60. [Google Scholar]
  44. Lenardão, E.J.; Santi, C.; Sancineto, L. New Frontiers in Organoselenium Compounds; Springer International Publishing: Cham, Switzerland, 2018. [Google Scholar]
  45. Sancineto, L.; Palomba, M.; Bagnoli, L.; Marini, F.; Santi, C. Advances in electrophilic organochalcogen reagents. Curr. Org. Chem. 2016, 20, 122–135. [Google Scholar] [CrossRef]
  46. Potapov, V.A.; Amosova, S.V.; Belozerova, O.V.; Albanov, A.I.; Yarosh, O.G.; Voronkov, M.G. Synthesis of 3,6-dihalo-4,4-dimethyl-1,4-selenasilafulvenes. Chem. Heterocycl. Compd. 2003, 39, 549–550. [Google Scholar] [CrossRef]
  47. Potapov, V.A.; Amosova, S.V. New methods for preparation of organoselenium and organotellurium compounds from elemental chalcogens. Russ. J. Org. Chem. 2003, 39, 1373–1380. [Google Scholar] [CrossRef]
  48. Abakumov, G.A.; Piskunov, A.V.; Cherkasov, V.K.; Fedushkin, I.L.; Ananikov, V.P.; Eremin, D.B.; Gordeev, E.G.; Beletskaya, I.P.; Averin, A.D.; Bochkarev, M.N.; et al. Organoelement chemistry: Promising growth areas and challenges. Russ. Chem. Rev. 2018, 87, 393–507. [Google Scholar] [CrossRef]
  49. Amosova, S.V.; Penzik, M.V.; Albanov, A.I.; Potapov, V.A. Addition of selenium dibromide to divinyl sulfide: Spontaneous rearrangement of 2,6-dibromo-1,4-thiaselenane to 5-bromo-2-bromomethyl-1,3-thiaselenolane. Tetrahedron Lett. 2009, 50, 306–308. [Google Scholar] [CrossRef]
  50. Amosova, S.V.; Penzik, M.V.; Albanov, A.I.; Potapov, V.A. The reaction of selenium dichloride with divinyl sulfide. J. Organomet. Chem. 2009, 694, 3369–3372. [Google Scholar] [CrossRef]
  51. Potapov, V.A.; Amosova, S.V.; Volkova, K.A.; Penzik, M.V.; Albanov, A.I. Reactions of selenium dichloride and dibromide with divinyl selenide: Synthesis of novel selenium heterocycles and rearrangement of 2,6-dihalo-1,4-diselenanes. Tetrahedron Lett. 2010, 51, 89–92. [Google Scholar] [CrossRef]
  52. Chirkina, E.A.; Chernyshev, K.A.; Krivdin, L.B.; Potapov, V.A.; Amosova, S.V. Quantum-chemical study of organic reaction mechanisms. Part 2. Addition of selenium dichloride to acetylene. J. Organomet. Chem. 2014, 766, 49–56. [Google Scholar] [CrossRef]
  53. Potapov, V.A.; Musalov, M.V.; Musalova, M.V.; Rusakov, Y.Y.; Khabibulina, A.G.; Rusakova, I.L.; Amosova, S.V. Stereoselective synthesis of E-2-halovinyl tellanes, ditellanes and selenides based on tellurium tetrahalides, selenium dihalides and internal alkynes. J. Organomet. Chem. 2018, 867, 300–305. [Google Scholar] [CrossRef]
  54. Accurso, A.A.; Cho, S.-H.; Amin, A.; Potapov, V.A.; Amosova, S.V.; Finn, M.G. Thia-, aza-, and selena[3.3.1]bicyclononane dichlorides: Rates vs internal nucleophile in anchimeric assistance. J. Org. Chem. 2011, 76, 4392–4395. [Google Scholar] [CrossRef]
  55. Musalov, M.V.; Yakimov, V.A.; Potapov, V.A.; Amosova, S.V.; Borodina, T.N.; Zinchenko, S.V. A novel methodology for the synthesis of condensed selenium heterocycles based on the annulation and annulation–methoxylation reactions of selenium dihalides. New J. Chem. 2019, 43, 18476–18483. [Google Scholar] [CrossRef]
  56. Potapov, V.A.; Amosova, S.V.; Abramova, E.V.; Musalov, M.V.; Lyssenko, K.A.; Finn, M.G. 2,6-Dihalo-9-selenabicyclo[3.3.1]nonanes and their complexes with selenium dihalides: Synthesis and structural characterisation. New J. Chem. 2015, 39, 8055–8059. [Google Scholar] [CrossRef]
  57. Amosova, S.V.; Novokshonova, I.A.; Penzik, M.V.; Filippov, A.S.; Albanov, A.I.; Potapov, V.A. Reaction of 2-bromomethyl-1,3-thiaselenole with thiourea: En route to the first representatives of 2-(organylsulfanyl)-2,3-dihydro-1,4-thiaselenines. Tetrahedron Lett. 2017, 58, 4381–4383. [Google Scholar] [CrossRef]
  58. Amosova, S.V.; Filippov, A.S.; Makhaeva, N.A.; Albanov, A.I.; Potapov, V.A. New methodology of nucleophilic substitution at three different centers of a seleniranium intermediate in reactions of 2-bromomethyl-1,3-thiaselenole with mercapto benzazoles. New. J. Chem. 2019, 43, 11189–11199. [Google Scholar] [CrossRef]
  59. Amosova, S.V.; Penzik, M.V.; Potapov, V.A.; Filippov, A.S.; Shagun, V.A.; Albanov, A.I.; Borodina, T.N.; Smirnov, V.I. Unexpected Regioselective Reactions of 2-Bromomethyl-1,3-thiaselenole with Dithiocarbamates: The First Example of nucleophilic attack at selenium atom of seleniranium intermediate. Synlett 2016, 27, 1653–1658. [Google Scholar] [CrossRef]
  60. Amosova, S.V.; Filippov, A.S.; Potapov, V.A.; Penzik, M.V.; Makhaeva, N.A.; Albanov, A.I. Regio- and stereoselective synthesis of a novel family of unsaturated compounds with the S–Se bond and their cyclization to 2,3-dihydro-1,4-thiaselenines. Synthesis 2019, 8, 1832–1840. [Google Scholar] [CrossRef] [Green Version]
  61. Amosova, S.V.; Filippov, A.A.; Makhaeva, N.A.; Albanov, A.I.; Potapov, V.A. Regio- and stereoselective synthesis of new ensembles of diversely functionalized 1,3-thiaselenol-2-ylmethyl selenides by a double rearrangement reaction. Beilstein J. Org. Chem. 2020, 16, 515–523. [Google Scholar] [CrossRef]
  62. Braga, A.L.; Rafique, J. Synthesis of biologically relevant small molecules containing selenium. Part A. Antioxidant compounds. In Patai’s Chemistry of Functional Groups. Organic Selenium and Tellurium; Rappoport, Z., Ed.; John Wiley and Sons: Chichester, UK, 2013; pp. 1–64. [Google Scholar]
  63. Potapov, V.A.; Amosova, S.V.; Petrov, P.A.; Romanenko, L.S.; Keiko, V.V. The exchange reaction of dialkyl dichalcogenids. Sulfur Lett. 1992, 15, 121–126. [Google Scholar]
  64. Amosova, S.V.; Rykunova, Y.I.; Filippov, A.S.; Penzik, M.V.; Makhaeva, N.A.; Albanov, A.I.; Potapov, V.A. Cascade regio- and stereoselective reactions of 2-bromomethyl-1,3-thiaselenole with water and ethylene glycol: En roote to the first representatives of polyfunctional 2,3-dihydro-1,4-thiaselenines. J. Organomet. Chem. 2018, 867, 398–403. [Google Scholar] [CrossRef]
  65. Amosova, S.V.; Penzik, M.V.; Rykunova, Y.I.; Potapov, V.A.; Albanov, A.I. Uncommon reaction of 2-bromomethyl-1,3-thiaselenole with pyridine and its derivatives. Russ. J. Org. Chem. 2017, 53, 1691–1695. [Google Scholar] [CrossRef]
  66. Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G.A.; et al. Gaussian 09, Revision A.01; Gaussian, Inc.: Wallingford, CT, USA, 2009. [Google Scholar]
  67. Becke, A.D. Density-functional thermochemistry. III. The role of exact exchange. J. Chem. Phys. 1993, 98, 5648–5652. [Google Scholar] [CrossRef] [Green Version]
  68. Peng, C.; Ayala, P.Y.; Schlegal, H.B.; Frisch, M.J. Using redundant internal coordinates to optimize equilibrium geometries and transition states. J. Comput. Chem. 1996, 17, 49–56. [Google Scholar] [CrossRef]
Molecules 26 06685 g001 550
Figure 1. Natural and synthetic drugs containing thiazole ring.
Figure 1. Natural and synthetic drugs containing thiazole ring.
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Molecules 26 06685 sch001 550
Scheme 1. The generation of intermediate seleniranium cation in nucleophilic substitution reactions of thiaselenole 1, and three possible directions of the reaction by nucleophilic attack at electrophilic centers of the seleniranium cation.
Scheme 1. The generation of intermediate seleniranium cation in nucleophilic substitution reactions of thiaselenole 1, and three possible directions of the reaction by nucleophilic attack at electrophilic centers of the seleniranium cation.
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Molecules 26 06685 sch002 550
Scheme 2. Products of the reaction of thiaselenole 1 with 1,3-benzimidazole-2-thiol 2.
Scheme 2. Products of the reaction of thiaselenole 1 with 1,3-benzimidazole-2-thiol 2.
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Molecules 26 06685 sch003 550
Scheme 3. A pathway of the reaction of thiaselenole 1 with thiol 2 with the formation of (Z)-2-[(1,3-benzothiazol-2-ylsulfanyl)selanyl]ethenyl vinyl sulfide (3).
Scheme 3. A pathway of the reaction of thiaselenole 1 with thiol 2 with the formation of (Z)-2-[(1,3-benzothiazol-2-ylsulfanyl)selanyl]ethenyl vinyl sulfide (3).
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Molecules 26 06685 sch004 550
Scheme 4. Quantum chemical calculations and analysis of thermodynamic characteristics of multichannel interaction of thiaselenole 1 with thiol 2.
Scheme 4. Quantum chemical calculations and analysis of thermodynamic characteristics of multichannel interaction of thiaselenole 1 with thiol 2.
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Figure 2. Schematic representations of processes of the formation of selanyl sulfide 3, six-membered product 4, and five-membered heterocycle 5 according to B3LYP/6-311+G(d,p).
Figure 2. Schematic representations of processes of the formation of selanyl sulfide 3, six-membered product 4, and five-membered heterocycle 5 according to B3LYP/6-311+G(d,p).
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Molecules 26 06685 g003 550
Figure 3. Schematic representation of the process of intramolecular rearrangement 3·H+ → 4·H+ according to B3LYP/6-311+G(d,p).
Figure 3. Schematic representation of the process of intramolecular rearrangement 3·H+ → 4·H+ according to B3LYP/6-311+G(d,p).
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Figure 4. Schematic representation of the process of intramolecular rearrangement 4 → 5 according to B3LYP/6-311+G(d,p).
Figure 4. Schematic representation of the process of intramolecular rearrangement 4 → 5 according to B3LYP/6-311+G(d,p).
Molecules 26 06685 g004
Molecules 26 06685 g005 550
Figure 5. Schematic representation of the disproportionation reaction 3–3 → 6a–6b.
Figure 5. Schematic representation of the disproportionation reaction 3–3 → 6a–6b.
Molecules 26 06685 g005
Molecules 26 06685 sch005 550
Scheme 5. The simplified reaction pathway of multichannel regioselective nucleophilic substitution in thiaselenole 1 by thiol 2 proceeding via three centers of seleniranium intermediates based on the experimental data and quantum chemical calculations (bond lengths (in angstroms) are presented for the selected intermediates and transition states).
Scheme 5. The simplified reaction pathway of multichannel regioselective nucleophilic substitution in thiaselenole 1 by thiol 2 proceeding via three centers of seleniranium intermediates based on the experimental data and quantum chemical calculations (bond lengths (in angstroms) are presented for the selected intermediates and transition states).
Molecules 26 06685 sch005
Table
Table 1. The influence of conditions on the yields and the ratio of products in the reaction of thiaselenole 1 with thiol 2 (or thiolate).
Table 1. The influence of conditions on the yields and the ratio of products in the reaction of thiaselenole 1 with thiol 2 (or thiolate).
Molecules 26 06685 i001
RunSolventBase, 1 EqT, °CTime, hMolar Ratio a
1:4:5:3:6a		Yield a of 4, %Yield a of 5, %Yield a of 3, %Yield a of 6a, %Conversion a of 1, %
1DMF−2510:96:4:0:0914−−100
2DMF−251.50:85:15:0:08114−−100
3DMF−25240:5:95:0:0592−−100
4DMF−25480:0:100:0:0−99−−100
5DMFNaHCO32510:100:0:0:099−−−100
6DMFNaHCO325240:39:61:0:03960−−100
7MeCNK2CO3050:46:0:15:3927−946100
8MeCNC5H5N030:29:71:0:02561−−100
9 bMeCNRSNac250.170:67:0:12:2145−814100
10dMeCNRSNac250.50:16:0:23:618−1160100
11eMeCNRSNac250.1719:20:0:20:4113−135487
12 eMeCNRSNac250.170:63:0:0:2340−−30100
a Due to the lability of intermediate compounds, the ratio and yields of products 1, 3–6 were determined by NMR in the reaction mixture. b A solution of thiaselenole 1 in acetonitrile (6 mL) was added to a solution of sodium 1,3-benzothiazole-2-thiolate. The reaction mixture was diluted with water and extracted with chloroform. c Sodium 1,3-benzothiazole-2-thiolate was used as a reagent instead of 1,3-benzothiazole-2-thiol. d A solution of sodium 1,3-benzothiazole-2-thiolate in acetonitrile (3 mL) was added to a solution of thiaselenole 1 in acetonitrile (3 mL). The reaction mixture was stirred for 0.5 h and the solvent was removed in vacuum. e The reaction was carried out with 1.48 mmol of the reagents in 27 mL of acetonitrile. The reaction mixture was divided into two equal parts. From one of them the solvent was removed in a vacuum, and unconverted thiaselenole 1 (13% yield, Run 11) was detected along with the reaction products. The second part was diluted with water followed by extraction with CCl4, drying and removing the solvent in vacuum (Run 12). The reaction mixture contained 2,3-dihydro-1,4-thiaselenin-2-ol (10% yield) [64].
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Amosova, S.V.; Shagun, V.A.; Makhaeva, N.A.; Novokshonova, I.A.; Potapov, V.A. Quantum Chemical and Experimental Studies of an Unprecedented Reaction Pathway of Nucleophilic Substitution of 2-Bromomethyl-1,3-thiaselenole with 1,3-Benzothiazole-2-thiol Proceeding Stepwise at Three Different Centers of Seleniranium Intermediates. Molecules 2021, 26, 6685. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26216685

AMA Style

Amosova SV, Shagun VA, Makhaeva NA, Novokshonova IA, Potapov VA. Quantum Chemical and Experimental Studies of an Unprecedented Reaction Pathway of Nucleophilic Substitution of 2-Bromomethyl-1,3-thiaselenole with 1,3-Benzothiazole-2-thiol Proceeding Stepwise at Three Different Centers of Seleniranium Intermediates. Molecules. 2021; 26(21):6685. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26216685

Chicago/Turabian Style

Amosova, Svetlana V., Vladimir A. Shagun, Nataliya A. Makhaeva, Irina A. Novokshonova, and Vladimir A. Potapov. 2021. "Quantum Chemical and Experimental Studies of an Unprecedented Reaction Pathway of Nucleophilic Substitution of 2-Bromomethyl-1,3-thiaselenole with 1,3-Benzothiazole-2-thiol Proceeding Stepwise at Three Different Centers of Seleniranium Intermediates" Molecules 26, no. 21: 6685. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26216685

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