Efficient Synthesis of a New Family of 2,6-Disulfanyl-9-selenabicyclo[3.3.1]nonanes

The efficient synthesis of a new family of 2,6-disulfanyl-9-selenabicyclo[3.3.1]nonanes in high yields has been developed based on 9-selenabicyclo[3.3.1]nonane-2,6-dithiolate anion generated from bis-isothiouronium salt of 2,6-dibromo-9-selenabicyclo[3.3.1]nonane. The derivatives of 2,6-disulfanyl-9-selenabicyclo[3.3.1]nonane containing alkyl, allyl and benzyl moieties have been prepared in 90–99% yields by nucleophilic substitution of 9-selenabicyclo[3.3.1]nonane-2,6-dithiolate anion with alkyl, allyl and benzyl halides. The reaction of nucleophilic addition of 9-selenabicyclo[3.3.1]nonane-2,6-dithiolate anion to alkyl propiolates afforded 2,6-di(vinylsulfanyl)-9-selenabicyclo[3.3.1]nonanes. The conditions for regio- and stereoselective addition of 9-selenabicyclo[3.3.1]nonane-2,6-dithiolate anion to a triple bond of alkyl propiolates have been found. To date, not a single representative of 2,6-disulfanyl-9-selenabicyclo[3.3.1]nonanes has been described in the literature.


Introduction
The importance of chemistry of heterocyclic compounds for the development of organic medicinal and pharmaceutical chemistry is difficult to overestimate. A lion's share of modern drugs contains heterocyclic moieties in their structures [1,2]. The discovery of many novel drugs is closely related to the development of chemistry of heterocyclic compounds. Heterocyclic derivatives exhibit various types of biological activity [1,2]. Many distinguished scientists have made important contributions to modern chemistry of heterocyclic compounds [1][2][3][4].
Selenium heterocyclic compound Ebselen shows anti-inflammatory, neuroprotective and glutathione peroxidase-like activities [13][14][15]. This compound finds application as an anti-inflammatory agent. Ebselen is also used for the treatment and prevention of cardiovascular diseases and ischemic stroke.

Results and Discussion
Nucleophilic substitution reactions of bromine in compound 2 by sulfur-centered nucleophiles have not been studied and not a single representative of 2,6-disulfanyl-9-selenabicyclo[3.3.1]nonanes has been described in the literature.

Results and Discussion
Nucleophilic substitution reactions of bromine in compound 2 by sulfur-centered nucleophiles have not been studied and not a single representative of 2,6-disulfanyl-9-selenabicyclo[3.3.1]nonanes has been described in the literature.

Results and Discussion
Nucleophilic substitution reactions of bromine in compound 2 by sulfur-centered nucleophiles have not been studied and not a single representative of 2,6-disulfanyl-9selenabicyclo[3.3.1]nonanes has been described in the literature.
The efficient synthesis of a new family of 2,6-diorganylsulfanyl-9-selenabicyclo[3.3.1] nonanes has been developed in the present work ( Figure 2). Theoretically, these compounds can be obtained by nucleophilic substitution reactions of bromine in compound 2 by organylthiols. However, we found a more efficient approach to 2,6-diorganylsulfanyl-9selenabicyclo[3.3.1]nonanes, which includes the preparation of bis-isothiouronium salt from compound 2 and thiourea. This approach opens up more synthetic possibilities and allows obtaining not only nucleophilic substitution products but also products of nucleophilic addition to a triple bond. possibilities and allows obtaining not only nucleophilic substitution products but also products of nucleophilic addition to a triple bond.   Bis-isothiouronium salt 3 was prepared in 95% yield by the reaction of thiourea with compound 2 in acetonitrile under reflux. Bis-isothiouronium salt 3 precipitated under the reaction conditions and can be easily isolated (Scheme 2). The action of alkalis on bis-isothiouronium salt 3 led to generation of 9-selenabicyclo[3.3.1]nonane-2,6-dithiolate anion 4, which was involved in nucleophilic substitution reactions with a variety of alkylating reagents (Scheme 3). The conditions for efficient synthesis of 2,6-dialkylsulfanyl-9-selenabicyclo[3.3.1]nonanes have been found. In a typical   Bis-isothiouronium salt 3 was prepared in 95% yield by the reaction of thiourea with compound 2 in acetonitrile under reflux. Bis-isothiouronium salt 3 precipitated under the reaction conditions and can be easily isolated (Scheme 2). The action of alkalis on bis-isothiouronium salt 3 led to generation of 9-selenabicyclo[3.3.1]nonane-2,6-dithiolate anion 4, which was involved in nucleophilic substitution reactions with a variety of alkylating reagents (Scheme 3). The conditions for efficient synthesis of 2,6-dialkylsulfanyl-9-selenabicyclo[3.3.1]nonanes have been found. In a typical The action of alkalis on bis-isothiouronium salt 3 led to generation of 9-selenabicyclo[3.3.1] nonane-2,6-dithiolate anion 4, which was involved in nucleophilic substitution reactions with a variety of alkylating reagents (Scheme 3). The conditions for efficient synthesis of 2,6-dialkylsulfanyl-9-selenabicyclo[3.3.1]nonanes have been found. In a typical procedure, sodium hydroxide was added to a methanol or ethanol solution containing alkylating reagent (MeI, EtBr, PrBr, BuBr, i-BuBr). procedure, sodium hydroxide was added to a methanol or ethanol solution containing alkylating reagent (MeI, EtBr, PrBr, BuBr, i-BuBr). The reaction proceeded under mild condition at room temperature in such "green solvents" as methanol or ethanol affording the target product 5-9 in 94-99% yields without additional purification (Scheme 3).
In the case of the reaction of dithiolate anion 4 with isopropyl bromide at room temperature, the corresponding product 10 was formed only in 52% yield. However, carrying out the process under reflux made it possible to accelerate this reaction and to obtain isopropyl derivative 10 in 90% yield after purification on a short column with silica gel (Scheme 3).
Although chlorine is usually displaced more slowly than bromine in nucleophilic substitution, the reactions of bis-isothiouronium salt 3 with benzyl and 4-fluorobenzyl chlorides proceeded smoothly at room temperature leading to 2,6-di(benzylsulfanyl)-9selenabicyclo[3.3.1]nonanes 11, 12 in 90-92% yields (Scheme 4). It is worth noting that introduction of fluorine to organic molecules is usually favorable from the viewpoint of possible manifestation of biological activity and a number of modern important drugs contain the fluorine atom [71].
Allyl bromide easily reacted with bis-isothiouronium salt 3 at room temperature, leading to 2,6-di(allylsulfanyl)-9-selenabicyclo[3.3.1]nonane 13 in 96% yields (Scheme 4). However, in the case of the reactions of bis-isothiouronium salt 3 with substituted allyl chlorides (3-chloro-2-methyl-1-propene, 2,3-dichloro-1-propene, E-3-chloro-1-propenylbenzene) under the same conditions at room temperature, corresponding products were obtained in 60-72% yields. In order to increase the yields of the products, the reactions of bis-isothiouronium salt 3 with substituted allyl chlorides were carried out with heating (50-60 °C). This made it possible to accelerate the reaction and to obtain compounds 14-16, which were isolated in 90-94% yields by purification on a short column with silica gel (Scheme 5). The reaction proceeded under mild condition at room temperature in such "green solvents" as methanol or ethanol affording the target product 5-9 in 94-99% yields without additional purification (Scheme 3).
In the case of the reaction of dithiolate anion 4 with isopropyl bromide at room temperature, the corresponding product 10 was formed only in 52% yield. However, carrying out the process under reflux made it possible to accelerate this reaction and to obtain isopropyl derivative 10 in 90% yield after purification on a short column with silica gel (Scheme 3).
Although chlorine is usually displaced more slowly than bromine in nucleophilic substitution, the reactions of bis-isothiouronium salt 3 with benzyl and 4-fluorobenzyl chlorides proceeded smoothly at room temperature leading to 2,6-di(benzylsulfanyl)-9selenabicyclo[3.3.1]nonanes 11, 12 in 90-92% yields (Scheme 4). It is worth noting that introduction of fluorine to organic molecules is usually favorable from the viewpoint of possible manifestation of biological activity and a number of modern important drugs contain the fluorine atom [71].
We found that it is advisable to carry out the reaction of bis-isothiouronium salt 3 with methyl propiolate in methanol and the process with ethyl propiolate advantageously to conduct in ethanol. Otherwise, the formation of some by-products derived from the interconversion of methyl and ethyl esters (the transesterification reaction in the presence of bases). Besides, the amount of alkali should be reduced by 2 times in comparison with the previous conditions for nucleophilic substitution reactions.
We found that it is advisable to carry out the reaction of bis-isothiouronium salt 3 with methyl propiolate in methanol and the process with ethyl propiolate advantageously to conduct in ethanol. Otherwise, the formation of some by-products derived from the interconversion of methyl and ethyl esters (the transesterification reaction in the presence of bases). Besides, the amount of alkali should be reduced by 2 times in comparison with the previous conditions for nucleophilic substitution reactions.
We found that it is advisable to carry out the reaction of bis-isothiouronium salt 3 with methyl propiolate in methanol and the process with ethyl propiolate advantageously to conduct in ethanol. Otherwise, the formation of some by-products derived from the interconversion of methyl and ethyl esters (the transesterification reaction in the presence of bases). Besides, the amount of alkali should be reduced by 2 times in comparison with the previous conditions for nucleophilic substitution reactions.

Synthesis of Compounds 5-18
2,6-Bis(methylsulfanyl)-9-selenabicyclo[3.3.1]nonane (5). A solution of methyl iodide (0.26 g, 1.8 mmol) in ethanol (1 mL) was added to a solution of bis-isothiouronium salt 3 (0.35 g, 0.7 mmol) in ethanol (4 mL). Then a solution of sodium hydroxide (80%, 0.2 g, 4 mmol) in ethanol (3 mL) was added dropwise to the reaction mixture. The mixture was stirred for 8 h at room temperature. Methylene chloride (15 mL) and cold water (15 mL) were added to the reaction mixture. The mixture was transferred to a separatory funnel and the organic layer was separated. The mixture was additionally extracted with methylene chloride (2 × 10 mL), the organic phase was dried over CaCl 2 and the solvent was removed by a rotary evaporator. The residue was dried in vacuum, giving product 5 (0.195 g, 99% yield) as a white powder; mp 64-65 • C. 1 (6). A solution of ethyl bromide (0.28 g, 2.6 mmol) in methanol (1 mL) was added to a solution of bis-isothiouronium salt 3 (0.43 g, 0.86 mmol) in methanol (5 mL). Then, a solution of sodium hydroxide (80%, 0.25 g, 5 mmol) in methanol (4 mL) was added dropwise to the reaction mixture. The mixture was stirred overnight (14 h) at room temperature. Methylene chloride (20 mL) and cold water (20 mL) were added to the reaction mixture. The mixture was transferred to a separatory funnel and the organic layer was separated. The mixture was additionally extracted with methylene chloride (2 × 10 mL), the organic phase was dried over CaCl 2 and the solvent was removed by a rotary evaporator. The residue was dried in vacuum, giving product 6 (0.26 g, 98% yield) as a white powder; mp 59-60 • C. 1  Anal. calcd for C 16 (10). A solution of isopropyl bromide (0.32 g, 2.6 mmol) in methanol (1 mL) was added to a solution of compound 3 (0.43 g, 0.86 mmol) in methanol (5 mL). Then a solution of sodium hydroxide (80%, 0.25 g, 5 mmol) in methanol (4 mL) was added dropwise and the mixture was refluxed for 3 h. Methylene chloride (20 mL) and cold water (20 mL) were added to the reaction mixture. The mixture was transferred to a separatory funnel and the organic layer was separated. The mixture was additionally extracted with methylene chloride (2 × 10 mL), the organic phase was dried over CaCl 2 and the solvent was removed by a rotary evaporator. The residue was subjected to column chromatography on silica gel (eluent: hexane, then hexane/chloroform 1:10). Compound 10 (0.262 g, 90% yield) was isolated as a colourless viscous oil. 1 (14). A solution of 2,3dichloro-1-propene (0.289 g, 2.6 mmol) in methanol (1 mL) was added to a solution of compound 3 (0.43 g, 0.86 mmol) in methanol (5 mL). Then, a solution of sodium hydroxide (80%, 0.25 g, 5 mmol) in methanol (4 mL) was added dropwise and the mixture was heated at 50-60 • C with stirring for 7 h. Methylene chloride (20 mL) and cold water (20 mL) were added to the reaction mixture. The mixture was transferred to a separatory funnel and the organic layer was separated. The mixture was additionally extracted with methylene chloride (2 × 10 mL), the organic phase was dried over CaCl 2 and the solvent was removed by a rotary evaporator. The residue was subjected to column chromatography on silica gel (eluent: hexane, then hexane/chloroform 1:10). Compound 14 (0.325 g, 94% yield) was isolated as a colourless viscous oil. 1 (15) was obtained from bis-isothiouronium salt 3 (0.43 g, 0.86 mmol), 3-chloro-2-methyl-1-propene, (0.313 g, 2.5 mmol) and sodium hydroxide (80%, 0.25 g, 5 mmol) in methanol under the same conditions as compound 14. The product was purified by column chromatography on silica gel (eluent: hexane, then hexane/chloroform 1:10). Compound 15 (0.283 g, 91% yield) was isolated as a white powder; mp 52-53 • C. 1