Efﬁcient Regioselective Synthesis of Novel Ensembles of Organylselanyl-Functionalized Divinyl Sulﬁdes and 1,3-Thiaselenoles under Phase Transfer Catalysis Conditions

: Efﬁcient regioselective synthesis of novel ensembles of organylselanyl-functionalized 1,3-thiaselenoles and divinyl sulﬁdes in high yields under phase transfer catalysis conditions was developed. The methodology is based on the generation of sodium [( Z )-2-(vinylsulfanyl)ethenyl]selenolate and 1,3-thiaselenol-2-ylmethylselenolate, which were involved in a nucleophilic addition reaction with activated alkenes such as acrylonitrile, acrylamide, methyl vinyl ketone, methyl, and ethyl acrylates. In the case of methyl vinyl ketone, the reaction was accompanied by the hydrogenation of the carbonyl group. Methylene chloride was involved in the nucleophilic substitution reaction with sodium [( Z )-2-(vinylsulfanyl)ethenyl]selenolate and 1,3-thiaselenol-2-ylmethylselenolate to afford new polyunsaturated compounds with several sulfur and selenium atoms.


Introduction
Selenium had previously been considered a poison for many years until Schwartz and Foltz found that this element is an important micronutrient for humans and animals [1].Since then, interest in the chemistry of organoselenium compounds has sharply increased, and multifaceted studies of these compounds gave impetus to the development of bioorganic chemistry, enzymology, and medicine [2][3][4][5][6][7].
Ebselen (2-phenyl-1,2-benzoselenazol-3(2H)-one) is a well-known selenium-containing heterocyclic compound, an anti-inflammatory drug with neuroprotective and glutathione peroxidase-like properties [23][24][25].Ebselen can be used for the prevention and treatment of cardiovascular diseases including ischemic stroke and reperfusion injury.It is worth noting that ebselen was found to inhibit SARS-CoV2 viral replication [24,25].Recently, this compound has been undergoing evaluation as a therapeutic agent in clinical trials in the treatment of COVID-19, Meniere's disease, hearing loss, and bipolar disorder [23].
Functionalized divinyl sulfides and (4-tert-butylcyclohexylidene)methyl styryl sulfides, show antioxidant, antinociceptive, and glutathione peroxidase-like properties (Figure 1) [43,44].The potential of vinyl sulfides with respect to biological activity can be demonstrated by the example of a cyclic peptide with the vinyl sulfide group (Figure 1), which is an angiotensin II analog, exhibiting high affinity and agonist activity at the AT1 receptor [45].
Earlier, we developed the efficient one-pot synthesis of 2-bromomethyl-1,3-thiaselenole in high yield from selenium dibromide with divinyl sulfide [46].2-Bromomethyl-1,3thiaselenole is a unique reagent for organic synthesis, which exhibits unusual behavior in nucleophilic substitution reactions [46][47][48].The bromine atom in 2-bromomethyl-1,3-thiaselenole is highly activated by the strong anchimeric assistance effect of the selenium atom [49].Quantum chemical calculations show that this reagent exists in equilibrium Organylselanyl-functionalized divinyl sulfides are very rare compounds.However, divinyl sulfides, and especially the first representative of this series, unsubstituted divinyl sulfide, are promising starting compounds for the synthesis of polyfunctional sulfides and heterocycles [42].Divinyl sulfide exhibits very useful properties as a highly reactive monomer for the preparation of various valuable polymeric materials by polymerization and copolymerization reactions, as well as an effective crosslinking agent (Figure 1) [42].
Functionalized divinyl sulfides and (4-tert-butylcyclohexylidene)methyl styryl sulfides, show antioxidant, antinociceptive, and glutathione peroxidase-like properties (Figure 1) [43,44].The potential of vinyl sulfides with respect to biological activity can be demonstrated by the example of a cyclic peptide with the vinyl sulfide group (Figure 1), which is an angiotensin II analog, exhibiting high affinity and agonist activity at the AT1 receptor [45].
Earlier, we developed the efficient one-pot synthesis of 2-bromomethyl-1,3-thiaselenole in high yield from selenium dibromide with divinyl sulfide [46].2-Bromomethyl-1,3thiaselenole is a unique reagent for organic synthesis, which exhibits unusual behavior in nucleophilic substitution reactions [46][47][48].The bromine atom in 2-bromomethyl-1,3thiaselenole is highly activated by the strong anchimeric assistance effect of the selenium atom [49].Quantum chemical calculations show that this reagent exists in equilibrium with corresponding three-membered seleniranium cation and nucleophilic reactions that proceed at three different centers of the seleniranium intermediate [46].
with corresponding three-membered seleniranium cation and nucleophilic reactions that proceed at three different centers of the seleniranium intermediate [46].

Se
Compounds 1 and 2 were used as starting materials for the development of efficient synthetic methods for the preparation of novel ensembles of unsaturated sulfur/selenium products.
Compounds 1 and 2 were used as starting materials for the development of efficient synthetic methods for the preparation of novel ensembles of unsaturated sulfur/selenium products.
with corresponding three-membered seleniranium cation and nucleophilic reactions that proceed at three different centers of the seleniranium intermediate [46].

Se
Compounds 1 and 2 were used as starting materials for the development of efficient synthetic methods for the preparation of novel ensembles of unsaturated sulfur/selenium products.

Results and Discussion
A goal of this work is to develop efficient regioselective syntheses of novel families of organylselanyl-functionalized 1,3-thiaselenoles and divinyl sulfides based on addition reactions of sodium [(Z)-2-(vinylsulfanyl)ethenyl]selenolate and 1,3-thiaselenol-2-ylmethylselenolate, generated from compounds 1 and 2, to activated alkenes (Scheme 2).The treatment of compounds 1 and 2 with sodium borohydride (NaBH4) led to the generation of corresponding sodium selenolates, which were involved in the nucleophilic addition reaction with activated alkenes such as acrylonitrile, methyl and ethyl acrylates, acrylamide, and methyl vinyl ketone.The treatment of compounds 1 and 2 with sodium borohydride (NaBH 4 ) led to the generation of corresponding sodium selenolates, which were involved in the nucleophilic addition reaction with activated alkenes such as acrylonitrile, methyl and ethyl acrylates, acrylamide, and methyl vinyl ketone.
We found that phase transfer catalysis conditions using triethylbenzylammonium chloride (TEBAC) as a phase transfer catalyst made it possible to realize this addition reaction in a chemo-and regioselective fashion and obtain the target products in high yields.The reactions were carried out by adding an aqueous solution of NaBH 4 to a solution of compounds 1 or 2 in methylene chloride or chloroform under argon followed by stirring for 1-3 h at room temperature.
The reaction of selenocyanate 2 with activated alkenes (acrylonitrile, methyl and ethyl acrylates, acrylamide, and methyl vinyl ketone) was carried out in the two-phase system NaBH 4 /H 2 O/TEBAC/chloroform under argon with stirring at room temperature for 3 h (Scheme 3).
We found that phase transfer catalysis conditions using triethylbenzylammonium chloride (TEBAC) as a phase transfer catalyst made it possible to realize this addition reaction in a chemo-and regioselective fashion and obtain the target products in high yields.The reactions were carried out by adding an aqueous solution of NaBH4 to a solution of compounds 1 or 2 in methylene chloride or chloroform under argon followed by stirring for 1-3 h at room temperature.
The reaction of selenocyanate 2 with activated alkenes (acrylonitrile, methyl and ethyl acrylates, acrylamide, and methyl vinyl ketone) was carried out in the two-phase system NaBH4/H2O/TEBAC/chloroform under argon with stirring at room temperature for 3 h (Scheme 3).The efficient synthesis of compounds 3a-e from selenocyanate 2 and activated alkenes (the 77 Se NMR data are included).
Methyl and ethyl acrylates and acrylamide were involved in the reaction with compound 2 affording the corresponding addition products 3b,c,d in 93%, 95%, and 93% yields, respectively (Scheme 3).
In order to find out whether the hydrogenation would occur in another solvent, chloroform was replaced with methylene chloride.The reaction of compound 2 with methyl vinyl ketone under similar conditions in methylene chloride gave, along with hydrogenated product 3e (yield 59%), a very interesting compound 4, containing four selenium atoms, in 25% yield (Scheme 4).Scheme 3. The efficient synthesis of compounds 3a-e from selenocyanate 2 and activated alkenes (the 77 Se NMR data are included).
Methyl and ethyl acrylates and acrylamide were involved in the reaction with compound 2 affording the corresponding addition products 3b,c,d in 93%, 95%, and 93% yields, respectively (Scheme 3).
In order to find out whether the hydrogenation would occur in another solvent, chloroform was replaced with methylene chloride.The reaction of compound 2 with methyl vinyl ketone under similar conditions in methylene chloride gave, along with hydrogenated product 3e (yield 59%), a very interesting compound 4, containing four selenium atoms, in 25% yield (Scheme 4).  7Se NMR data are included).
Compound 4 is formed by the nucleophilic substitution of two chlorine atoms in methylene chloride with sodium 1,3-thiaselenol-2-ylmethylselenolate.The formation of the nucleophilic substitution products with chloroform was not observed in the system NaBH4/H2O/TEBAC/chloroform (Scheme 3).The ease of product formation by the nucleophilic substitution of two chlorine atoms in methylene chloride with selenium-centered nucleophiles was noted in the literature [50].
Compound 4 is a symmetrical molecule, which has two asymmetric carbon centers Scheme 4. The reaction of compound 2 with methyl vinyl ketone in methylene chloride (the 77 Se NMR data are included).
Compound 4 is formed by the nucleophilic substitution of two chlorine atoms in methylene chloride with sodium 1,3-thiaselenol-2-ylmethylselenolate.The formation of the nucleophilic substitution products with chloroform was not observed in the system NaBH 4 /H 2 O/TEBAC/chloroform (Scheme 3).The ease of product formation by the nucleophilic substitution of two chlorine atoms in methylene chloride with seleniumcentered nucleophiles was noted in the literature [50].
Compound 4 is a symmetrical molecule, which has two asymmetric carbon centers in the cycles.It consists of two diastereomers, which manifest themselves in the NMR spectra.For example, two signals of the selenium atom in the ring were observed in the 77 Se NMR spectrum of this compound (Scheme 4).
The reaction of polyunsaturated diselenide 1 with activated alkenes in the system NaBH 4 /H 2 O/TEBAC/chloroform was studied.The reaction of diselenide 1 with methyl and ethyl acrylates and acrylamide afforded the addition of products 5a,b in 83-85% yields taking into account that one molecule of diselenide 1 gives two molecules of the target products (Scheme 5).  7Se NMR data are included).

OH
Compound 4 is formed by the nucleophilic substitution of two chlorine atoms in methylene chloride with sodium 1,3-thiaselenol-2-ylmethylselenolate.The formation of the nucleophilic substitution products with chloroform was not observed in the system NaBH4/H2O/TEBAC/chloroform (Scheme 3).The ease of product formation by the nucleophilic substitution of two chlorine atoms in methylene chloride with selenium-centered nucleophiles was noted in the literature [50].
Compound 4 is a symmetrical molecule, which has two asymmetric carbon centers in the cycles.It consists of two diastereomers, which manifest themselves in the NMR spectra.For example, two signals of the selenium atom in the ring were observed in the 77 Se NMR spectrum of this compound (Scheme 4).
The reaction of polyunsaturated diselenide 1 with activated alkenes in the system NaBH4/H2O/TEBAC/chloroform was studied.The reaction of diselenide 1 with methyl and ethyl acrylates and acrylamide afforded the addition of products 5a,b in 83-85% yields taking into account that one molecule of diselenide 1 gives two molecules of the target products (Scheme 5).The efficient synthesis of compounds 5a-c from diselenide 1 and activated alkenes (the 77 Se NMR data are included).
In the case of using methyl vinyl ketone as an activated alkene in the reaction with diselenide 1, the suggested addition product was not obtained.As in the reaction with compound 2 (Scheme 3), the process was accompanied by hydrogenation of the carbonyl group of methyl vinyl ketone, leading to 4-{[(Z)-2-(vinylsulfanyl)ethenyl]selanyl}-2-butanol (5c) in 87% yield (Scheme 5).
In the case of using methyl vinyl ketone as an activated alkene in the reaction with diselenide 1, the suggested addition product was not obtained.As in the reaction with compound 2 (Scheme 3), the process was accompanied by hydrogenation of the carbonyl group of methyl vinyl ketone, leading to 4-{[(Z)-2-(vinylsulfanyl)ethenyl]selanyl}-2-butanol (5c) in 87% yield (Scheme 5).
When methylene chloride was used instead of chloroform in the reaction of diselenide 1 with methyl vinyl ketone under similar conditions, three compounds 5c, 7, and 8 were obtained in 41%, 9%, and 24% yields, respectively (Scheme 7).  7Se NMR data are included).
Under the same conditions, the reaction of sodium [(Z)-2-(vinylsulfanyl)ethenyl]selenolate and 1,3-thiaselenol-2-ylmethylselenolate with divinyl sulfone led to a complex mixture containing ethyl vinyl sulfone as the major product.The possibility of the hydrogenation reaction of divinyl sulfone to ethyl vinyl sulfone under the action of NaBH 4 under phase transfer catalysis conditions was confirmed by an additional experiment.
When methylene chloride was used instead of chloroform in the reaction of diselenide 1 with methyl vinyl ketone under similar conditions, three compounds 5c, 7, and 8 were obtained in 41%, 9%, and 24% yields, respectively (Scheme 7).
nolate and 1,3-thiaselenol-2-ylmethylselenolate with divinyl sulfone led to a complex mixture containing ethyl vinyl sulfone as the major product.The possibility of the hydrogenation reaction of divinyl sulfone to ethyl vinyl sulfone under the action of NaBH4 under phase transfer catalysis conditions was confirmed by an additional experiment.
When methylene chloride was used instead of chloroform in the reaction of diselenide 1 with methyl vinyl ketone under similar conditions, three compounds 5c, 7, and 8 were obtained in 41%, 9%, and 24% yields, respectively (Scheme 7).  7Se NMR data are included).
The formation of compounds 7 and 8 can be considered as the result of nucleophilic substitution of one or two chlorine atoms in methylene chloride by sodium [(Z)-2-(vinylsulfanyl)ethenyl]selenolate.Taking into account the formation of bis(selanyl)methane compounds 4 and 8 from methylene chloride, we suggest that this method can be used for the preparation of other bis(organylselanyl)methane derivatives by the reactions of organylselenolate anions with methylene chloride under phase transfer catalysis conditions.
We have shown the possibility of obtaining other 3-hydroxybutyl selenides from methyl vinyl ketone by this method using diphenyl diselenide as an example.When diphenyl diselenide was involved in the reaction with methyl vinyl ketone under the same conditions as the reaction of diselenide 1 (Scheme 5), 3-hydroxybutyl phenyl selenide was obtained with an 81% yield (Scheme 8).It should be noted that alkyl and aryl 3-hydroxybutyl selenides are rare compounds, and only butyl and phenyl 3-hydroxybutyl selenides have been previously obtained [51][52][53][54].Butyl and phenyl 3-hydroxybutyl selenides were synthesized in three stages starting Scheme 7. The reaction of compound 1 with methyl vinyl ketone in methylene chloride (the 77 Se NMR data are included).
The formation of compounds 7 and 8 can be considered as the result of nucleophilic substitution of one or two chlorine atoms in methylene chloride by sodium [(Z)-2-(vinylsulfanyl)-ethenyl]selenolate.Taking into account the formation of bis(selanyl)methane compounds 4 and 8 from methylene chloride, suggest that this method can be used for the preparation of other bis(organylselanyl)methane derivatives by the reactions of organylselenolate anions with methylene chloride under phase transfer catalysis conditions.
We have shown the possibility of obtaining other 3-hydroxybutyl selenides from methyl vinyl ketone by this method using diphenyl diselenide as an example.When diphenyl diselenide was involved in the reaction with methyl vinyl ketone under the same conditions as the reaction of diselenide 1 (Scheme 5), 3-hydroxybutyl phenyl selenide was obtained with an 81% yield (Scheme 8).
nolate and 1,3-thiaselenol-2-ylmethylselenolate with divinyl sulfone led to a complex mixture containing ethyl vinyl sulfone as the major product.The possibility of the hydrogenation reaction of divinyl sulfone to ethyl vinyl sulfone under the action of NaBH4 under phase transfer catalysis conditions was confirmed by an additional experiment.
When methylene chloride was used instead of chloroform in the reaction of diselenide 1 with methyl vinyl ketone under similar conditions, three compounds 5c, 7, and 8 were obtained in 41%, 9%, and 24% yields, respectively (Scheme 7).  7Se NMR data are included).
The formation of compounds 7 and 8 can be considered as the result of nucleophilic substitution of one or two chlorine atoms in methylene chloride by sodium [(Z)-2-(vinylsulfanyl)ethenyl]selenolate.Taking into account the formation of bis(selanyl)methane compounds 4 and 8 from methylene chloride, we suggest that this method can be used for the preparation of other bis(organylselanyl)methane derivatives by the reactions of organylselenolate anions with methylene chloride under phase transfer catalysis conditions.
We have shown the possibility of obtaining other 3-hydroxybutyl selenides from methyl vinyl ketone by this method using diphenyl diselenide as an example.When diphenyl diselenide was involved in the reaction with methyl vinyl ketone under the same conditions as the reaction of diselenide 1 (Scheme 5), 3-hydroxybutyl phenyl selenide was obtained with an 81% yield (Scheme 8).It should be noted that alkyl and aryl 3-hydroxybutyl selenides are rare compounds, and only butyl and phenyl 3-hydroxybutyl selenides have been previously obtained [51][52][53][54].Butyl and phenyl 3-hydroxybutyl selenides were synthesized in three stages starting Scheme 8.The reaction of diphenyl diselenide with methyl vinyl ketone and sodium borohydride under phase transfer catalysis conditions.
Hydroxyorganyl selenides are a very important family of organoselenium compounds, many of which exhibit glutathione peroxidase mimetic properties and also serve as intermediates for organic synthesis [55][56][57][58].For example, a novel cyclic seleninate ester with high glutathione peroxidase-like activity was obtained from allyl 3-hydroxypropyl selenide [56].
It is worth noting that the nucleophilic addition reactions of sodium [(Z)-2-(vinylsulfanyl)ethenyl]selenolate and 1,3-thiaselenol-2-ylmethylselenolate to the activated alkenes acrylonitrile, acrylamide, methyl vinyl ketone, methyl, and ethyl acrylates proceed in a regioselective fashion exclusively at the terminal carbon atom of the double bond.
The structural assignment of the obtained compounds was carried out based on the NMR investigations and mass spectrometry data and confirmed by elemental analysis.Molecular ions were observed in the mass spectra of the obtained compounds.
Mass spectra were recorded on a Shimadzu GCMS-QP5050A (Shimadzu Corporation, Kyoto, Japan) with electron impact (EI) ionization (70 eV).The data of mass spectra are given in the experimental part regarding the maximum isotope of selenium ( 80 Se).
Elemental analysis was performed on a Thermo Scientific Flash 2000 Elemental Analyzer (Thermo Fisher Scientific Inc., Milan, Italy).Distilled organic solvents and degassed water were used in syntheses.The spectral characteristics of obtained 3-hydroxybutyl phenyl selenide correspond to the data of the known sample [51].
Scheme 3. The efficient synthesis of compounds 3a-e from selenocyanate 2 and activated alkenes (the77 Se NMR data are included).
Scheme 5.The efficient synthesis of compounds 5a-c from diselenide 1 and activated alkenes (the77 Se NMR data are included).

Scheme 6 .
Scheme 6.The reaction of compound 1 with acrylonitrile (the77 Se NMR data are included).

Scheme 8 .
Scheme 8.The reaction of diphenyl diselenide with methyl vinyl ketone and sodium borohydride under phase transfer catalysis conditions.

Scheme 8 .
Scheme 8.The reaction of diphenyl diselenide with methyl vinyl ketone and sodium borohydride under phase transfer catalysis conditions.