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

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.

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-9selenabicyclo[3.3.1]nonanes, which are the first representatives of coordination compounds with the Se-Se-Se bond, were obtained [56].

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 (  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).
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 (HClO 4 , CF 3 COOH, and AcOH). It has been experimentally proven by 1 H−NMR monitoring that the reaction of thiaselenole 1 with thiol 2 is accompanied by rearrangement of 4 into 5 (acetonitrile, Li 2 CO 3 , 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(1,3benzothiazol-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 ( 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 CCl 4 , drying and removing the solvent in vacuum (Run 12). The reaction mixture contained 2,3-dihydro-1,4-thiaselenin-2-ol (10% yield) [64].
Carrying out the reaction in the presence of an equimolar amount of NaHCO 3 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 K 2 CO 3 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 CCl 4 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 CH 2 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. 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).
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.

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. To start, 2-bromomethyl-1,3-thiaselenole 1 was prepared from divinyl sulfide and SeBr 2 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.  (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 CaCl 2 . After removing the solvent in a vacuum, the residue (a yellow powder) was analyzed by 1 H−NMR (Table 1). Analysis examples can be found in the Supplementary Materials, Figures S14-S19.

In the Presence of NaHCO 3
A solution of thiol 2 (167 mg, 1 mmol) in DMF (2 mL) and NaHCO 3 (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 CaCl 2 . After removing the solvent in a vacuum, the residue (a yellow powder) was analyzed by 1 H−NMR (Table 1). Analysis examples can be found in the Supplementary Materials, Figures S14-S19.

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 sixmembered thiaselenine 4. The five-membered thiaselenole 5 is formed by the nucleophilic attack at the carbon atom of the CH 2 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].