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Article

Green Organoselenium Chemistry: Selective Syntheses of New 1,4-Thiaselenine Derivatives Based on Reactions of Thiaselenole Reagent with Alcohols and Water

by
Svetlana V. Amosova
*,
Andrey S. Filippov
,
Nataliya A. Makhaeva
,
Alexander I. Albanov
and
Vladimir A. Potapov
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Division of The Russian Academy of Sciences, 1 Favorsky Str., Irkutsk 664033, Russia
*
Author to whom correspondence should be addressed.
Inorganics 2023, 11(7), 281; https://doi.org/10.3390/inorganics11070281
Submission received: 1 June 2023 / Revised: 26 June 2023 / Accepted: 27 June 2023 / Published: 29 June 2023
(This article belongs to the Special Issue Selective Synthesis of New Organometallic and Organochalcogen Compounds Based on Inorganic Reagents)
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Abstract

:
Environmentally friendly synthetic methods were developed for the selective preparation of new 2,3-dihydro-1,4-thiaselenine derivatives in high yields based on the reactions of 2-bromomethyl-1,3-thiaselenole with alcohols and water at room temperature. The reaction of 2-bromomethyl-1,3-thiaselenole with alcohols was accompanied by a rearrangement with ring extension, leading to six-membered heterocyclic compounds, a new family of 2-organyloxy-2,3-dihydro-1,4-thiaselenines, in 80–96% yields. The remarkable cascade reactions of 2-bromomethyl-1,3-thiaselenole with water afforded 2,3-dihydro-1,4-thiaselenines functionalized with the (Z)-S-CH=CH-Se fragment and one or two highly reactive aldehyde groups. The latter aldehydes were functionalized by the reactions with alcohols and glycols to give new polyfunctionalized compounds, containing two double bonds, two sulfur atoms, two selenium atoms, and two or four oxygen atoms, in high yields.

Graphical Abstract

1. Introduction

It is known that selenium is an indispensable trace element for humans and mammals [1,2,3,4]. After the discovery of the important biological role of selenium [4], organoselenium chemistry developed rapidly [5,6,7,8]. It has been established that organoselenium compounds exhibit various types of biological activities [9,10,11,12,13,14,15,16,17,18] including antitumor [9,10,11,12], antibacterial [12,13], antiviral [14,15], and glutathione peroxidase-like properties [16,17,18]. Selenium heterocycles are very important compounds with respect to their practical application [18,19,20,21,22,23,24]. The most studied organoselenium compound in terms of biological activity is heterocyclic ebselen, which is undergoing clinical trials as a therapeutic agent in the treatment of COVID-19, bipolar disorder, and Meniere’s disease [18].
It has been found that 1,4-thiaselenines and their analogs exhibit antitumor, antibacterial, and antifungal activities [25,26]. It is worth noting that dihydro-1,4-thiaselenines are a very rare class of organoselenium heterocycles. Only two representatives of this class were obtained [27] before our investigations in this field [28,29,30,31,32]. 5-Methyl- and 5-ethyl-2,3-dihydro-1,4-thiaselenines were synthesized in 60% and 64% yields, respectively, by the nucleophilic reaction of lithium selenide with 1-(2-chloroethylsulfanyl)-1-alkynes [27].
Examples of selenium heterocycles with biological activity, including compounds structurally related to 1,4-thiaselenines, are shown in Figure 1.
Previously, we developed the selective one-pot synthesis of 2-bromomethyl-1,3-thiaselenole (1) in 80% yield based on the reaction of selenium dibromide with divinyl sulfide [28,32]. All stages of this synthesis, including the formation of five-membered 5-bromo-2-bromomethyl-1,3-thiaselenole followed by dehydrobromination, were realized as a one-pot procedure (Scheme 1). This method made it possible to obtain this reagent with a high purity without using additional purification such as column chromatography [28,32].
Thiaselenole 1 is a remarkable highly reactive reagent in which the bromine atom is activated by the strong anchimeric assistance effect of the selenium atom [33]. The chemical properties of this reagent show that it exists in equilibrium with seleniranium cation A (Scheme 1) [28,29,30,31], and this is confirmed by quantum chemical calculations [32]. The attack of the nucleophiles can proceed at three centers of seleniranium intermediate A [32].
The development of selective syntheses of new 1,4-thiaselenine derivatives using principles of green chemistry and studying chemical properties of these compounds is an important task.
The goal of this research is to develop efficient regioselective syntheses of new 1,4-thiaselenine derivatives based on the reactions of thiaselenole 1 with alcohols and water. The use of green chemistry principles and carrying out reactions under mild conditions (at room temperature) are important features of this research. Some chemical properties of the obtained compounds were also studied.
Along with 1,4-thiaselenine derivatives, compounds with the (Z)-Se-CH=CH-S group were obtained from the studied reactions. It is worth noting that vinyl selenides are versatile intermediates and synthons for the synthesis of both selenium-containing and selenium-free organic compounds [34,35,36,37]. Vinyl selenides were used in cross-coupling reactions with terminal alkynes to afford (Z)- and (E)-enyne derivatives in good yields with the retention of the stereoconfiguration of vinyl selenides [38]. These compounds were also used in the synthesis of functionalized allyl alcohols and unsaturated aldehydes and ketones [39]. Functionalized vinyl selenides show hepatoprotective [40], antinociceptive [41], and antioxidant [42] properties. The synthesis of resveratrol and its derivatives, which exhibit anti-inflammatory, anticancer, antibacterial, and neuroprotective activities, was developed based on vinyl selenides [43].

2. Results and Discussion

The nucleophilic substitution reaction of thiaselenole 1 with a wide range of alcohols was systematically studied. Alcohols were also used as a reaction medium; they played the role of not only a reagent, but also of a solvent. The reaction proceeded chemo- and regioselectively at room temperature in the presence of sodium bicarbonate for 1–2 h. The reaction was accompanied by a rearrangement with ring extension affording six-membered heterocyclic compounds, a new family of 2-organyloxy-2,3-dihydro-1,4-thiaselenines 2a–k, in high yields (Scheme 2). Sodium bicarbonate acted as a base in this reaction, neutralizing the evolved hydrogen bromide with the formation of sodium bromide.
Methoxy and ethoxy derivatives 2a and 2b were obtained in 96% yield in pure form and did not require additional purification. With an increase in the length and branching of the carbon chains of the alcohols, a slight decrease in the yield (84–91%) of the products (2c–g) was observed: the reaction of thiaselenole 1 with less nucleophilic benzyl, allyl and propargyl alcohols was carried out for 2 h (instead of the 1 h reaction for compounds 2a–g) affording the products 2i–k in 80–82% yields (Scheme 2).
The reaction is highly regioselective and proceeds via the formation of the intermediate seleniranium cation A, in which the nucleophilic attack of the alkoxide anion at the C2 carbon atom occurs with the cleavage of the C2–Se bond (Scheme 3). The rearrangement with the expansion of a five-membered ring to a six-membered cycle affording only 2-organyloxy-2,3-dihydro-1,4-thiaselenines takes place. The formation of five-membered 1,3-thiaselenole derivatives was not observed. Thus, the nucleophilic attack of the alkoxide anion does not occur at the C3 carbon atom, which is bound to the bromine atom in thiaselenole 1, and the reaction does not follow the classical pathway.
The 77Se NMR data of compounds 2a–k are presented in Table 1. A slight downfield shift of the 77Se NMR signal is observed with an increase in the length of the carbon chain and branching of the alkyl substituent in the alkoxy group (compounds 2a–d).
Increasing the length of the carbon chain from an ethyl to a hexyl substituent has no noticeable effect on the chemical shift (Table 1, products 2b,c,e,g,h).
The bromine atom is in the β-position in respect to both chalcogens, the selenium and sulfur atoms, in thiaselenole 1. Theoretically, a thiiranium cation can be also formed from thiaselenole 1. In this case, the nucleophilic substitution reaction at the carbon atom of the thiiranium cation with the cleavage of the C–S bond would give other products, 3-alkoxy-2,3-dihydro-1,4-thiaselenoles. However, the formation of these products was not observed, even in traces.
It is worth noting that a quantitative assessment of the anchimeric effect of the selenium atom in comparison with the sulfur atom was previously developed [33]. It was shown that the anchimeric assistance effect of the selenium atom is more than one order of magnitude higher than the anchimeric effect of the sulfur atom [33].
A remarkable cascade reaction of thiaselenole 1 with water in aqueous DMSO was found (Scheme 4). The reaction of thiaselenole 1 in DMSO containing 4% of water afforded O/S/Se unsaturated compounds with an aldehyde function: bis[(Z)-2-(2-oxoethylselanyl)ethenyl]disulfane (3) and 2-[(Z)-2-(2-oxoethylselanyl)ethenylsulfanyl]-1,4-thiaselenine (4) in 40% and 32% yields, respectively.
The supposed reaction pathways for the formation of compounds 3 and 4 are depicted in Scheme 5. It is known that thiaselenole 1 generates seleniranium cation A, which acts as the intermediate in reactions with nucleophiles [28,29,30,31,32]. The reaction of seleniranium intermediate A with water starts as the nucleophilic attack at the carbon atom of the CH-group of cation A and is accompanied by a rearrangement with ring expansion of the five-membered thiaselenole to the six-membered 1,4-thiaselenine heterocycle. The reaction of thiol B with seleniranium cation A leads to compound 4 and hydrogen bromide, which can act as a catalyst for some of these transformations, e.g., for the oxidation of thiol B to disulfane 3.
It was found that the content of compound 4 in the reaction product mixture increases with increasing the water content. It was revealed that 19% of water in DMSO is close to the optimal water content for efficient selective synthesis of compound 4. Under these conditions, product 4 was obtained in 80% yield and did not require additional purification. The formation of dialdehyde compound 3 was not observed in this case (Scheme 6).
Thus, simple and environmentally friendly synthetic methods were developed for the preparation of the new 2,3-dihydro-1,4-thiaselenine derivatives 3 and 4 functionalized with the (Z)-S-CH=CH-Se fragment and one or two highly reactive aldehyde groups by the cascade reaction of thiaselenole 1 with water at room temperature.
Mild reaction conditions (room temperature, 2 h) and the ease of carrying out these cascade reactions with the formation of polyfunctional O/S/Se-containing products 3 and 4 functionalized with the (Z)-S-CH=CH-Se fragment and a highly reactive aldehyde group makes these compounds promising reagents. The application of these multifunctional reagents can open up new possibilities in the synthesis of O/S/Se-containing linear compounds and heterocycles.
In the present work, the reagents 3 and 4 were used in the synthesis of novel organoselenium compounds by the reactions with alcohols and glycols.
Compound 4 was involved in the reaction with alcohols: methanol, ethanol, butanol and propargyl alcohol. The reaction was carried out in methylene chloride at room temperature in the presence of a catalytic amount of hydrochloric acid. 2-[(Z)-2-(2,2-Dialkoxyethylselanyl)ethenylsulfanyl]-2,3-dihydro-1,4-thiaselenines 5a–d, new compounds containing two oxygen, two sulfur, and two selenium atoms, were obtained in 94–97% yield (Scheme 7).
It is worth noting that the pure products 5a–d were isolated from the reaction mixture and did not require additional purification.
Glycols such as 1,3-propandiol, 2,3-butandiol, and (Z)-2-butene-1,4-diol were reacted with aldehyde 4 in the presence of hydrochloric acid in methylene chloride at room temperature to give bicyclic acetals 6a–c in 83%, 80% and 83% yields, respectively (Scheme 8).
Compound 6b, containing two methyl groups in the dioxane cycle, consists of two diastereomers (cis/trans ~7:5) according to the NMR data. The assignment of cis- and trans-diastereomers was developed and the spectral data for each diastereomer were presented in the experimental part.
The assignment of cis- and trans-diastereomers was carried out based on the NMR investigations. Inter alia, the vicinal coupling constant (3JHH) between CH-protons in the trans-diastereomer is greater (7.8 Hz) than in the cis-product (4.4 Hz). The difference in chemical shifts of both methyl and CH protons is larger in trans-diastereomer than in the cis-product.
Compound 3, bearing two aldehyde groups, was involved in the reaction with alcohols and glycols at room temperature affording new unsaturated polyfunctionalized compounds containing two double bonds, two sulfur atoms, two selenium atoms, and four oxygen atoms (Scheme 9 and Scheme 10).
The reaction of compound 3 with methanol led to diacetal compound 7 in 86% yield (Scheme 9).
Bicyclic unsaturated diacetals 8a,b were obtained in 80% and 85% yields, respectively, by the reaction of dialdehyde 3 with 1,3-propandiol and 2,3-butandiol in the presence of hydrochloric acid at room temperature (Scheme 10).
The developed reactions proceeded with high selectivity under mild reaction conditions (at room temperature) to afford target products in high yields.
The structural assignment of the obtained compounds 2a–k, 3, 4, 5a–d, 6a–c, 7 and 8a,b was carried out based on the NMR investigations and mass spectrometry data and confirmed by an elemental analysis. Molecular ions were observed in the mass spectra of the obtained compounds.
The (Z)-configuration of the S-CH=CH-Se fragment remained unchanged in the studied reactions. The spin–spin coupling constants (3JH-H) of protons in the linear S-CH=CH-Se group of compounds 3–8 is about 8 Hz. In the 1,4-thiaselenine ring, the values of the spin–spin coupling constants of protons in the S-CH=CH-Se fragment of compounds 2 and 4–6 is about 10 Hz.
The replacement of the organyloxy substituent in position 2 of the 1,4-thiaselenine ring by the organylsulfanyl group leads to a downfield shift of the 77Se NMR signal of the selenium atom in the cycle from 128–154 ppm (compounds 2a–k) to 221–225 ppm (compounds 3–6a–c).

3. Materials and Methods

3.1. General Information

The 1H (400.1 MHz), 13C (100.6 MHz), and 77Se (76.3 MHz) NMR spectra (the spectra can be found in Supplementary Materials) were recorded on a Bruker DPX-400 spectrometer (Bruker BioSpin GmbH, Rheinstetten, Germany) in CDCl3 solutions and referred to the residual solvent peaks (CDCl3, δ = 7.27 and 77.0 ppm for 1H- and 13C-NMR, respectively), and dimethyl selenide (77Se).
Mass spectra were recorded on a Shimadzu GCMS-QP5050A (Shimadzu Corporation, Kyoto, Japan) with electron impact (EI) ionization (70 eV).
Elemental analysis was performed on a Thermo Scientific Flash 2000 Elemental Analyzer (Thermo Fisher Scientific Inc., Milan, Italy). The distilled organic solvents and degassed water were used in syntheses.

3.2. General Procedure for the Synthesis of 2-Alkoxy-2,3-Dihydro-1,4-Thiaselenines 2a–k

Sodium hydrocarbonate (0.168 g, 2.0 mmol) was added to a solution of thiaselenole 1 (0.244 g, 1.0 mmol) in alcohol (5 mL) and the mixture was stirred for 1–3 h at room temperature. The mixture was filtered and alcohol excess was removed in vacuum. Compounds 2c–k were isolated by column chromatography (silica gel 60, 70–230 mesh, eluent: hexane, then chloroform–hexane 1:4). Compounds 2a and 2b were obtained in pure form without the use of column chromatography and did not require additional purification.
2-Methoxy-2,3-dihydro-1,4-thiaselenine (2a). Yield: 96%, yellow oil. Reaction time is 1 h.
1H NMR (400 MHz, CDCl3): δ 1.25 (t, 3H,CH3), 3.08 (dd, 2J 12.1 Hz, 3J 5.6 Hz, 1H, SeCH2), 3.28 (dd, 2J 12.1 Hz, 3J 2.0 Hz, 1H, SeCH2), 3.59 (dq, 2J 9.5 Hz, 3J 7.0 Hz, 1H, OCH2), 3.93 (dq, 2J 9.5 Hz, 3J 7.0 Hz, 1H, OCH2), 4.97 (d, 3J 5.6 Hz, 3J 2.1 Hz, 1H, SCHO), 6.38 (d, 3J 9.9 Hz, 1H, =CHS), 6.49 (d, 3J 9.9 Hz, 1H, =CHSe).
13C NMR (100 MHz, CDCl3): δ 14.71 (CH3), 25.12 (CH2Se, 1JC-Se 63.8 Hz), 64.30 (OCH2), 76.03 (SCHO), 110.64 (=CHSe, 1JC-Se 116.6 Hz), 117.88 (=CHS).
77Se NMR (76 MHz, CDCl3): δ 140.5.
MS (EI), m/z (%): 210 (69) [M]+, 164 (8), 149 (14), 101 (100), 84 (20).
Anal. Calcd for C6H10OSSe (209.17): C, 34.45; H, 4.82; S, 15.33; Se, 37.75. Found: C, 34.28; H, 4.77; S, 15.29; Se, 37.89.
2-Ethoxy-2,3-dihydro-1,4-thiaselenine (2b). Yield: 96%, yellow oil. Reaction time is 1 h.
1H NMR (400 MHz, CDCl3): δ 1.25 (t, 3H,CH3), 3.08 (dd, 2J 12.1 Hz, 3J 5.6 Hz, 1H, SeCH2), 3.28 (dd, 2J 12.1 Hz, 3J 2.0 Hz, 1H, SeCH2), 3.59 (dq, 2J 9.5 Hz, 3J 7.0 Hz, 1H, OCH2), 3.93 (dq, 2J 9.5 Hz, 3J 7.0 Hz, 1H, OCH2), 4.97 (d, 3J 5.6 Hz, 3J 2.1 Hz, 1H, SCHO), 6.38 (d, 3J 9.9 Hz, 1H, =CHS), 6.49 (d, 3J 9.9 Hz, 1H, =CHSe).
13C NMR (100 MHz, CDCl3): δ 14.71 (CH3), 25.12 (CH2Se, 1JC-Se 63.8 Hz), 64.30 (OCH2), 76.03 (SCHO), 110.64 (=CHSe, 1JC-Se 116.6 Hz), 117.88 (=CHS).
77Se NMR (76 MHz, CDCl3): δ 140.5.
MS (EI), m/z (%): 210 (69) [M]+, 164 (8), 149 (14), 101 (100), 84 (20).
Anal. Calcd for C6H10OSSe (209.17): C, 34.45; H, 4.82; S, 15.33; Se, 37.75. Found: C, 34.28; H, 4.77; S, 15.29; Se, 37.89.
2-Propoxy-2,3-dihydro-1,4-thiaselenine (2c). Yield: 91%, light yellow oil. Reaction time is 1 h.
1H NMR (400 MHz, CDCl3): δ 0.94 (t, 3J 6.9 Hz, 3H, CH3), 1.66 (m, 2H, CH2CH3), 3.10 (dd, 2J 11.9 Hz, 3J 5.5 Hz, 1H, SeCH2), 3.31 (dd, 2J 11.9 Hz, 3J 2.1 Hz, 1H, SeCH2), 3.50 (dt, 2J 9.2 Hz, 3J 5.6 Hz, 1H, OCH2), 3.83 (dt, 2J 9.2 Hz, 3J 5.6 Hz, 1H, OCH2), 4.96 (d, 3J 5.5 Hz, 3J 2.1 Hz, 1H, SCHO), 6.39 (d, 3J 9.8 Hz, 1H, =CHS), 6.50 (d, 3J 9.8 Hz, 1H, =CHSe).
13C NMR (100 MHz, CDCl3): δ 10.50 (CH3), 22.44 (CH3CH2), 25.19 (CH2Se, 1JC-Se 63.7 Hz), 70.51 (OCH2), 76.16 (SCHO), 110.71 (=CHSe, 1JC-Se 116.6 Hz), 117.85 (=CHS).
77Se NMR (76 MHz, CDCl3): δ 143.1.
MS (EI), m/z (%): 224 (60) [M]+, 164 (18), 149 (13), 101 (100), 84 (20).
Anal. Calcd for C7H12OSSe (223.20): C, 37.63; H, 5.42; S, 14.37; Se,35.38. Found: C, 37.58; H, 5.61; S, 14.31; Se, 35.62.
2-Isopropoxy-2,3-dihydro-1,4-thiaselenine (2d). Yield: 84%, yellow oil. Reaction time is 1 h.
1H NMR (400 MHz, CDCl3): δ 1.24 (s, 6H, CH3), 3.09 (dd, 2J 11.8 Hz, 3J 6.3 Hz, 1H, SeCH2), 3.29 (dd, 2J 11.8 Hz, 3J 2.2 Hz, 1H, SeCH2), 3.50 (m, 1H, OCH), 5.11 (d, 3J 6.3 Hz, 3J 2.2 Hz, 1H, SCHO), 6.43 (d, 3J 9.8 Hz, 1H, =CHS), 6.50 (d, 3J 9.8 Hz, 1H, =CHSe).
13C NMR (100 MHz, CDCl3): δ 21.29, 22.93 (CH3), 25.77 (CH2Se, 1JC-Se 62.3 Hz), 70.22 (OCH(CH3)2), 74.43 (SCHO), 110.56 (=CHSe, 1JC-Se 116.4 Hz), 118.58 (=CHS).
77Se NMR (76 MHz, CDCl3): δ 154.6.
MS (EI), m/z (%): 224 (51) [M]+, 164 (16), 149 (10), 101 (100), 84 (20).
Anal. Calcd for C7H12OSSe (223.20): C, 37.63; H, 5.42; S, 14.37; Se, 35.38. Found: C, 37.81; H, 5.28; S, 14.44; Se, 35.28.
2-Butoxy-2,3-dihydro-1,4-thiaselenine (2e). Yield: 90%, light yellow oil. Reaction time is 1 h.
1H NMR (400 MHz, CDCl3): δ 0.93 (t, 3J 7.4 Hz, 3H, CH3), 1.40 (m, 2H, CH2CH2CH3), 1.63 (m, 2H, CH2CH2CH3), 3.10 (dd, 2J 11.8 Hz, 3J 5.6 Hz, 1H, SeCH2), 3.30 (dd, 2J 11.8 Hz, 3J 2.1 Hz, 1H, SeCH2), 3.54 (dq, 2J 9.2 Hz, 3J 5.6 Hz, 1H, OCH2), 3.89 (dt, 2J 9.2 Hz, 3J 5.6 Hz, 1H, OCH2), 4.97 (d, 3J 5.5 Hz, 3J 2.1 Hz, 1H, SCHO), 6.40 (d, 3J 9.8 Hz, 1H, =CHS), 6.51 (d, 3J 9.8 Hz, 1H, =CHSe).
13C NMR (100 MHz, CDCl3): δ 13.81 (CH3), 19.27 (CH3CH2), 25.26 (CH2Se, 1JC-Se 63.7 Hz), 31.26 (CH3CH2CH2), 68.74 (OCH2), 76.24 (SCHO), 110.77 (=CHSe, 1JC-Se 116.6 Hz), 117.93 (=CHS).
77Se NMR (76 MHz, CDCl3): δ 142.8.
MS (EI), m/z (%): 238 (58) [M]+, 164 (22), 149 (23), 101 (100), 84 (16).
Anal. Calcd for C8H14OSSe (237.22): C, 40.50; H, 5.95; S, 13.52; Se, 33.29. Found: C, 40.67; H, 5.91; S, 13.35; Se, 33.51.
2-Isobutoxy-2,3-dihydro-1,4-thiaselenine (2f). Yield: 86%, yellow oil. Reaction time is 1 h.
1H NMR (400 MHz, CDCl3): δ 0.91 (dd, 3J 6.6 Hz, 6H, CH3), 1.90 (n, 3J 6.6 Hz, 1H, CH(CH3)2), 3.08 (dd, 2J 11.8 Hz, 3J 6.1 Hz, 1H, SeCH2), 3.28 (dq, 2J 9.0 Hz, 3J 7.0 Hz, 1H, OCH2), 3.29 (dd, 2J 11.8 Hz, 3J 2.1 Hz, 1H, SeCH2), 3.61 (dq, 2J 9.5 Hz, 3J 7.0 Hz, 1H, OCH2), 4.92 (d, 3J 6.3 Hz, 3J 2.2 Hz, 1H, SCHO), 6.36 (d, 3J 9.8 Hz, 1H, =CHS), 6.48 (d, 3J 9.8 Hz, 1H, =CHSe).
13C NMR (100 MHz, CDCl3): δ 19.20 (CH3), 25.20 (CH2Se, 1JC-Se 62.3 Hz), 28.04 (CH2), 75.37 (OCH2), 76.31 (SCHO), 110.80 (=CHSe, 1JC-Se 116.8 Hz), 117.74 (=CHS).
77Se NMR (76 MHz, CDCl3): δ 146.3.
MS (EI), m/z (%): 238 (42) [M]+, 164 (28), 149 (21), 101 (100), 84 (10).
Anal. Calcd for C8H14OSSe (237.22): C, 40.50; H, 5.95; S, 13.52; Se, 33.29. Found: C, 40.28; H, 5.78; S, 13.59; Se, 33.57.
2-Pentyloxy-2,3-dihydro-1,4-thiaselenine (2g). Yield: 87%, yellow oil. Reaction time is 1 h.
1H NMR (400 MHz, CDCl3): δ 0.90 (t, 3J 5.6 Hz, 3H, CH3), 1.35 (m, 4H, CH2CH2CH2CH3), 1.64 (m, 2H, CH2CH2CH2CH3), 3.10 (dd, 2J 12.0 Hz, 3J 5.7 Hz, 1H, SeCH2), 3.31 (dd, 2J 12.0 Hz, 3J 2.2 Hz, 1H, SeCH2), 3.53 (dt, 2J 9.2 Hz, 3J 7.0 Hz, 1H, OCH2), 3.87 (dt, 2J 9.2 Hz, 3J 7.0 Hz, 1H, OCH2), 4.97 (d, 3J 5.7 Hz, 3J 2.2 Hz, 1H, SCHO), 6.40 (d, 3J 9.8 Hz, 1H, =CHS), 6.50 (d, 3J 9.8 Hz, 1H, =CHSe).
13C NMR (100 MHz, CDCl3): δ 13.95 (CH3), 19.27 (CH3CH2), 22.35 (CH2CH2CH2CH3), 25.24 (CH2Se, 1JC-Se 63.8 Hz), 28.17 (CH2CH2CH2CH3), 28.88 (CH2CH2CH2CH3), 69.04 (OCH2), 76.35 (SCHO), 110.78 (=CHSe, 1JC-Se 116.4 Hz), 117.98 (=CHS).
77Se NMR (76 MHz, CDCl3): δ 143.1.
MS (EI), m/z (%): 252 (33) [M]+, 164 (10), 149 (65), 101 (100), 84 (8).
Anal. Calcd for C9H16OSSe (251.25): C, 43.02; H, 6.42; S, 12.76; Se, 31.43. Found: C, 43.21; H, 6.38; S, 12.69; Se, 31.50.
2-Hexyloxy-2,3-dihydro-1,4-thiaselenine (2h). Yield: 85%, yellow oil. Reaction time is 1 h.
1H NMR (400 MHz, CDCl3): δ 0.89 (t, 3J 6.7 Hz, 3H, CH3), 1.34 (m, 6H, CH2CH2CH2CH2CH3), 1.64 (m, 2H, CH2CH2CH2CH2CH3), 3.11 (dd, 2J 11.8 Hz, 3J 5.6 Hz, 1H, SeCH2), 3.32 (dd, 2J 11.8 Hz, 3J 2.1 Hz, 1H, SeCH2), 3.54 (dq, 2J 9.2 Hz, 3J 6.9 Hz, 1H, OCH2), 3.88 (dq, 2J 9.2 Hz, 3J 6.9 Hz, 1H, OCH2), 4.97 (d, 3J 5.7 Hz, 3J 2.2 Hz, 1H, SCHO), 6.40 (d, 3J 9.8 Hz, 1H, =CHS), 6.51 (d, 3J 9.8 Hz, 1H, =CHSe).
13C NMR (100 MHz, CDCl3): δ 14.00 (CH3), 22.54 (CH3CH2), 25.25 (CH2Se, 1JC-Se 63.9 Hz), 25.69 (CH2CH2 CH2CH2CH3), 29.14 (CH2CH2CH2CH2CH3), 31.50 (CH2CH2CH2CH2CH3), 69.06 (OCH2), 76.25 (SCHO), 110.75 (=CHSe, 1JC-Se 116.5 Hz), 117.94 (=CHS).
77Se NMR (76 MHz, CDCl3): δ 143.1.
MS (EI), m/z (%): 266 (51) [M]+, 164 (12), 149 (45), 101 (100), 84 (10).
Anal. Calcd for C10H18OSSe (265.28): C, 45.28; H, 6.84; S, 12.09; Se, 29.77. Found: C, 45.21; H, 6.75; S, 12.49; Se, 29.84.
2-Benzyloxy-2,3-dihydro-1,4-thiaselenine (2i). Yield: 82%, yellow oil. Reaction time is 2 h.
1H NMR (400 MHz, CDCl3): δ 3.00 (dd, 2J 12.2 Hz, 3J 4.9 Hz, 1H, SeCH2), 3.26 (dd, 2J 12.2 Hz, 3J 1.5 Hz, 1H, SeCH2), 4.62 (d, 2J 12.1 Hz, 1H, OCH2), 4.84 (d, 3J 4.9 Hz, 3J 1.5 Hz, 1H, SCHO), 4.89 (d, 2J 12.1 Hz, 1H, OCH2), 6.31 (d, 3J 9.8 Hz, 1H, =CHS), 6.47 (d, 3J 9.8 Hz, 1H, =CHSe), 7.22–7.29 (7.26) (m, 5H, C6H5).
13C NMR (100 MHz, CDCl3): δ 25.22 (CH2Se, 1JC-Se 62.7 Hz), 69.64 (OCH2), 73.85 (SCHO), 111.19 (=CHSe, 1JC-Se 117.5 Hz), 117.02 (=CHS), 127.84 (Cp), 127.97 (Co), 128.41 (Cm), 136.93 (Ci).
77Se NMR (76 MHz, CDCl3): δ 135.7.
MS (EI), m/z (%): 272 (50) [M]+, 164 (11), 149 (47), 101 (100), 84 (10).
Anal. Calcd for C11H12OSSe (271.24): C, 48.71; H, 4.46; S, 11.82; Se, 29.11. Found: C, 48.90; H, 4.48; S, 11.74; Se, 29.05.
2-Allyloxy-2,3-dihydro-1,4-thiaselenine (2j). Yield: 80%, light yellow oil. Reaction time is 2 h.
1H NMR (400 MHz, CDCl3): δ 3.07 (dd, 2J 12.0 Hz, 3J 5.3 Hz, 1H, SeCH2), 3.32 (dd, 2J 12.0 Hz, 3J 2.2 Hz, 1H, SeCH2), 4.15 (dd, 2J 12.9 Hz, 3J 6.7 Hz, 1H, OCH2), 4.37 (dd, 2J 12.9 Hz, 3J 4.4 Hz, 1H, OCH2), 4.97 (d, 3J 5.3 Hz, 3J 2.2 Hz, 1H, SCHO), 5.23 (dd, 3Jcis 10.2 Hz, 1H, =CH2), 5.33 (dd, 3Jtrans 17.3 Hz, 1H, =CH2), 5.91 (m, 3Jcis 10.2 Hz, 3Jtrans 17.3 Hz, 3J 6.7 Hz, 3J 4.4 Hz, 1H, =CH), 6.35 (d, 3J 9.8 Hz, 1H, =CHS), 6.49 (d, 3J 9.8 Hz, 1H, =CHSe).
13C NMR (100 MHz, CDCl3): δ 25.01 (CH2Se, 1JC-Se 64.2 Hz), 68.93 (OCH2), 74.38 (SCHO), 110.81 (=CHSe, 1JC-Se 117.0 Hz), 117.23 (=CHS), 118.18 (=CH2), 133.42(=CH).
77Se NMR (76 MHz, CDCl3): δ 135.3.
MS (EI), m/z (%): 222 (54) [M]+, 164 (12), 149 (13), 101 (100), 84 (12).
Anal. Calcd for C7H10OSSe (221.18): C, 38.01; H, 4.56; S, 14.50; Se, 35.70. Found: C, 37.82; H, 5.60; S, 14.31; Se, 35.73.
2-Propynyloxy-2,3-dihydro-1,4-thiaselenine (2k). Yield: 81%, yellow oil. Reaction time is 2 h.
1H NMR (400 MHz, CDCl3): δ 2.48 (s, 1H, ≡CH), 3.12 (dd, 2J 12.1 Hz, 3J 5.0 Hz, 1H, SeCH2), 3.44 (dd, 2J 12.1 Hz, 3J 1.9 Hz, 1H, SeCH2), 4.49 (dd, 2J 16.1 Hz, 3J 2.3 Hz, 2H, OCH2), 5.23 (d, 3J 5.0 Hz, 3J 1.9 Hz, 1H, SCHO), 5.23 (dd, 3Jcis 10.2 Hz, 1H, =CH2), 5.33 (dd, 3Jtrans 17.3 Hz, 1H, =CH2), 5.91 (dd, 3Jcis 10.2 Hz, 3Jtrans 17.3 Hz, 3J 6.7 Hz, 3J 4.4 Hz, 1H, =CH2), 6.32 (d, 3J 10.1 Hz, 1H, =CHS), 6.53 (d, 3J 10.1 Hz, 1H, =CHSe).
13C NMR (100 MHz, CDCl3): δ 24.78 (CH2Se, 1JC-Se 64.9 Hz), 54.90 (C≡CH), 72.65 (OCH2), 75.41 (SCHO), 78.59 (C≡CH), 111.26 (=CHSe, 1JC-Se 118.3 Hz), 116.27 (=CHS).
77Se NMR (76 MHz, CDCl3): δ 126.5.
MS (EI), m/z (%): 220 (44) [M]+, 164 (12), 149 (11), 101 (100), 84 (21).
Anal. Calcd for C7H8OSSe (219.16): C, 38.36; H, 3.68; S, 14.63; Se, 36.03. Found: C, 38.26; H, 3.61; S, 14.71; Se, 36.10.

3.3. The Procedure for Synthesis of Bis[(Z)-2-(2-Oxoethylselanyl)ethenyl]Disulfane 3

Thiaselenole 1 (1.530 g, 6.27 mmol) was added to a solution of water (4%) in DMSO (20 mL) and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (4 × 20 mL). The organic phase was washed with water (2 × 40 mL), dried with Na2SO4, and filtered. The solvent was removed in vacuum to give a mixture of compound 3 (0.457 g, 40% yield) and compound 4 (0.344 g, 32% yield). Compounds 3 and 4 were isolated by column chromatography (silica gel 60, 70–230 mesh, eluent: hexane, then chloroform–hexane 1:9).
Bis[(Z)-2-(2-oxoethylselanyl)ethenyl]disulfane (3).
1H NMR (400 MHz, CDCl3): δ 3.41 (d, 3J 4.0 Hz, 2JSe-H 15.2 Hz, 2H, SeCH2), 6.48 (d, 3J = 8.0 Hz, 1H, SeCH=), 6.75 (d, 3J 8.0 Hz, 1H, SCH=), 9.46 (t, 3J 4.0 Hz, 1H, O=C-H).
13C NMR (100 MHz, CDCl3): δ 35.13 (CH2Se, 1JC-Se 61.5 Hz), 122.17 (=CHSe, 1JC-Se 106.8 Hz), 132.78 (=CHS), 191.73 (O=C-H).
77Se NMR (CDCl3, 76.3 MHz): δ 198.7.
MS (EI), m/z (%): 362 [M]+· (15), 302 (3), 218 (21), 181 (12), 151(41), 116 (71), 84 (48), 58 (100), 41 (70).
Anal. Calcd for C8H10O2S2Se2 (360.22): C, 26.67; H, 2.80; S, 17.80; Se, 43.84. Found: C, 26.59; H, 2.78; S, 17.61; Se, 43.68.

3.4. The Procedure for Synthesis of 2-{[(Z)-2-(2,3-Dihydro-1,4-Thiaselenin-2-Ylsulfanyl)Ethenyl]Selanyl}Acetaldehyde 4

Thiaselenole 1 (0.780 g, 3.20 mmol) was added to a solution of water (19%) in DMSO (10 mL) and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (4 × 10 mL). The organic phase was washed with water (2 × 20 mL), dried with Na2SO4, and filtered. The solvent was removed in vacuum to give compound 4 (0.442 g, 80% yield) as a brownish oil.
1H NMR (400 MHz, CDCl3): δ 3.22 (dd, 2J 11.9 Hz, 3J 9.2 Hz, 1H, SeCH2), 3.36 (d, 3J 4.1 Hz, 2H, SeCH2), 3.41 (dd, 2J 11.9 Hz, 3J 2.5 Hz, 1H, CH2Se cyclic), 4.60 (dd, 3J 9.2 Hz, 3J 2.5 Hz, 1H, SCHS), 6.44 (d, 3J 9.8 Hz, 1H, =CHS cyclic), 6.46 (d, 3J 9.8 Hz, 2JSeH 54.8 Hz 1H, =CHSe cyclic), 6.48 (d, 3J 8.1 Hz, 1H, SeCH=), 6.77 (d, 3J 8.1 Hz, 1H, SCH=), 9.44 (t, 3J 4.1 Hz, 1H, O=C-H).
13C NMR (100 MHz, CDCl3): δ 24.69 (CH2Se cyclic, 1JSeC 64.4 Hz), 34.86 (CH2Se), 45.84 (SCHS), 109.79 (=CHSe cyclic, 1JSeC 116.6 Hz), 119.66 (=CHS cyclic), 121.20 (=CHSe), 125.98 (=CHS), 191.80 (O=C-H).
77Se NMR (CDCl3, 76.3 MHz): δ 221.0 (cyclic), 200.4.
MS (EI), m/z (%): 346 (11) [M]+·, 300 (8), 223 (5), 165 (37), 84 (25), 45 (14).
Anal. Calcd for C8H10OS2Se2 (344.22): C, 27.91; H, 2.93; S, 18.63; Se, 45.88. Found: C, 27.59; H, 3.08; S, 18.91; Se, 46.01.

3.5. Typical Procedure for the Synthesis of 2-([(Z)-2-[(2,2-Dialkoxyethylselanyl)Ethenyl]Sulfanyl)-2,3-Dihydro-1,4-Thiaselenines 5a–d

2-([(Z)-2-[(2,2-dimethoxyethylselanyl)ethenyl]sulfanyl)-2,3-dihydro-1,4-thiaselenine (5a). One drop of concentrated hydrochloric acid (0.016 g, 0.17 mmol) was added to a solution of aldehyde 4 (0.083 g, 0.24 mmol) in a mixture of methylene chloride (1 mL) and methanol (1 mL) and the reaction mixture was stirred at room temperature overnight (18 h). Methylene chloride (7 mL) was added and the reaction mixture was washed with water (3 × 5 mL). The organic phase was dried over Na2SO4, filtered, and the solvent was removed in vacuum. Product 5a was obtained as brownish oil (0.091 g, 97%).
1H NMR (400 MHz, CDCl3): δ 2.89 (d, 3J 5.2 Hz 2H, O2CHCH2Se), 3.24 (dd, 2J 12.0 Hz, 3J 9.4 Hz 1H, CH2Se-cyclic), 3.37 (s, 6H, 2CH3), 3.39 (dd, 2J 12.0 Hz, 3J 2.6 Hz, 1H, CH2Se-cyclic), 4.56 (t, 3J 5.2 Hz, 1H, OCHO), 4.60 (dd, 3J 9.4 Hz, 3J 2.6 Hz, 1H, SCHS), 6.45 (s, 2H, SCH=CHSe-cyclic), 6.62 (d, 3J 8.1 Hz, 1H, SeCH=, 6.81 (d, 3J 8.1 Hz, 1H, SCH=).
13C NMR (100 MHz, CDCl3): δ 24.62 (CH2Se-cyclic, 1JSeC 63.8 Hz), 28.84 (O2CHCH2Se, 1JSeC 65.3 Hz), 45.78 (SCHS), 53.85 (OCH3), 104.72 (OCHO), 109.44 (=CHSe-cyclic, 1JSeC 115.8 Hz), 120.02 (=CHS-cyclic, 2JSeC 8.4 Hz), 121.35 (=CHS, 2JSeC 14.0 Hz), 125.90 (=CHSe, 1JSeC 106.9 Hz).
77Se NMR (CDCl3, 76.3 MHz): δ 223.9 (cyclic), 228.4.
MS (EI), m/z (%): 392 (2) [M]+·, 303(1), 223 (10), 196 (2), 165 (56), 151 (16), 103 (1), 87 (71), 75 (100) 58 (19).
Anal. Calcd for C10H16O2S2Se2 (390.28): C, 30.77; H, 4.13; S, 16.43; Se, 40.46. Found: C, 31.00; H, 4.18; S, 16.33; Se, 40.64.
2-[(Z)-2-[(2,2-diethoxyethylselanyl)ethenylsulfanyl]-2,3-dihydro-1,4-thiaselenine (5b). Yield: 96%, brownish oil.
1H NMR (400 MHz, CDCl3): δ 1.23 (t, 3J 7.1 Hz, 6H, CH3), 2.92 (d, 3J 5.6 Hz, 2H, O2CHCH2Se), 3.25 (dd, 2J 11.9 Hz, 3J 9.4 Hz, 1H, CH2Se-cyclic), 3.41 (dd, 2J 12.1 Hz, 3J 2.8 Hz, 1H, CH2Se-cyclic), 3.56 (dq, 2J 9.3 Hz, 3J 7.1 Hz, 2H, OCH2), 3.69 (dq, 2J 9.3 Hz, 3J 7.1 Hz, 2H, OCH2), 4.62 (dd, 3J 9.4 Hz, 3J 2.8 Hz, 1H, SCHS), 4.68 (t, 3J 5.6 Hz 1H, OCHO), 6.47 (s, 2H, SCH=CHSe-cyclic), 6.61 (d, 3J 8.1 Hz, 1H, SeCH=), 6.88 (d, 3J 8.1 Hz, 1H, SCH=).
13C NMR (100 MHz, CDCl3): δ 15.26 (CH3), 24.64 (CH2Se-cyclic, 1JSeC 64.4 Hz), 29.91 (O2CHCH2Se, 1JSeC 64.4 Hz), 45.83 (SCHS), 62.43 (OCH2), 103.17 (OCHO),109.42 (=CHSe-cyclic, 1JSeC 116.6 Hz), 120.11 (=CHS-cyclic), 120.72 (=CHSe), 126.68 (=CHS).
77Se NMR (CDCl3, 76.3 MHz): δ 224.7 (cyclic), 232.7.
MS (EI), m/z (%): 418 (3) [M]+·, 223 (9), 196 (2), 165 (78), 103 (100), 87 (71), 75 (75) 47 (75).
Anal. Calcd for C12H20O2S2Se2 (418.34): C, 34.45; H, 4.82; S, 15.33; Se, 37.75. Found: C, 34.12; H, 4.83; S, 15.21; Se, 37.71.
2-[(Z)-2-[(2,2-dibutoxyethylselanyl)ethenylsulfanyl]-2,3-dihydro-1,4-thiaselenine (5c). Yield: 94%, brownish oil.
1H NMR (400 MHz, CDCl3): δ 0.92 (t, 3J 7.3 Hz, 6H, 2CH3), 1.34–1.43 (m, 4H, 2CH3CH2), 1.52–1.59 (m, 4H, 2CH3CH2CH2), 2.91 (d, 3J 5.7 Hz, 2H, O2CHCH2Se), 3.24 (dd, 2J 12.0 Hz, 3J 9.4 Hz, 1H, CH2Se-cyclic), 3.40 (dd, 2J 12.0 Hz, 3J 2.6 Hz, 1H, CH2Se-cyclic), 3.47 (dt, 2J 9.3 Hz, 3J 6.6 Hz, 2H, OCH2), 3.62 (dt, 2J 9.3 Hz, 3J 6.6 Hz, 2H, OCH2), 4.61 (dd, 3J 9.4 Hz, 3J 2.6 Hz, 1H, SCHS), 4.66 (t, 3J 5.7 Hz, 1H, OCHO), 6.46 (s, 2H, SCH=CHSe cyclic), 6.60 (d, 3J 8.1 Hz, 1H, SeCH=), 6.87 (d, 3J 8.1 Hz, 1H, SCH=).
13C NMR (100 MHz, CDCl3): δ 13.84 (CH3), 19.28 (CH3CH2), 24.63 (CH2Se-cyclic, 1JSeC 64.2 Hz), 29.81 (O2CHCH2Se, 1JSeC 64.6 Hz), 31.80 (CH3CH2CH2), 45.83 (SCHS), 66.53 (OCH2), 103.31 (OCHO), 109.38 (=CHSe-cyclic, 1JSeC 115.5 Hz), 120.10 (=CHS-cyclic), 120.52 (=CHS), 126.95 (=CHSe, 1JSeC 107.8 Hz).
77Se NMR (CDCl3, 76.3 MHz): δ 224.2 (cyclic), 232.9.
MS (EI), m/z (%): 476 (3) [M]+·, 396 (2), 223 (3), 197 (2), 165 (75), 103 (50), 85 (51), 75 (23) 57 (100).
Anal. Calcd for C16H28O2S2Se2 (474.44): C, 40.50; H, 5.95; S, 13.52; Se, 33.29. Found: C, 40.38; H, 5.83; S, 13.38; Se, 33.10.
2-[(Z)-2-[(2,2-dipropargyloxyethylselanyl)ethenylsulfanyl]-2,3-dihydro-1,4-thiaselenine (5d). Yield: 94%, brownish oil.
1H NMR (400 MHz, CDCl3): δ 2.37 (t, 4J 2.3 Hz, 2H, 2≡CH,), 2.92 (d, 3J 6.9 Hz, 2H, O2CHCH2Se), 3.24 (dd, 2J 12.2 Hz, 3J 10.0 Hz, 1H, CH2Se-cyclic), 3.37 (dd, 2J 12.2 Hz, 3J 2.1 Hz, 1H, CH2Se-cyclic), 4.23 (d, 4J 2.3 Hz, 4H, OCH2), 4.57 (dd, 3J 10.0 Hz, 3J 2.1 Hz, 1H, SCHS), 4.97 (t, 3J 6.9 Hz, 1H, OCHO), 6.39 (d, 3J 9.8 Hz, 2JSe-H 50.2 Hz, 1H, SCH=CHSe-cyclic), 6.43 (d, 3J 9.8 Hz, 1H, SCH=CHSe-cyclic), 6.60 (d, 3J 8.1 Hz, 1H, SeCH=), 6.85 (d, 3J 8.1 Hz, 1H, SCH=).
13C NMR (100 MHz, CDCl3): δ 24.66 (CH2Se-cyclic, 1JSeC 64.4 Hz), 29.36 (O2CHCH2Se, 1JSeC 65.7 Hz), 45.81 (SCHS), 54.40 (OCH2), 74.94 (≡CH), 79.16 (≡C-), 101.39 (OCHO), 109.49 (=CHSe-cyclic, 1JSeC 115.8 Hz), 120.00 (=CHS-cyclic), 121.68 (=CHSe), 125.94 (=CHS, 1JSeC 106.7 Hz).
77Se NMR (CDCl3, 76.3 MHz): δ 223.6 (cyclic), 229.9.
MS (EI), m/z (%): 440 (3) [M]+·, 223 (12), 196 (3), 165 (100), 123 (22), 97 (10), 85 (82), 58 (31).
Anal. Calcd for C14H16O2S2Se2 (438.33): C, 38.36; H, 3.68; S, 14.63; Se, 36.03. Found: C, 38.25; H, 3.59; S, 15.01; Se, 36.12.

3.6. Typical Procedure for the Synthesis of Compounds 6a–c

2-{[(Z)-2-(2,3-dihydro-1,4-thiaselenin-2-ylsulfanyl)ethenyl]selanylmethyl}-1,3-dioxane (6a). A solution of aldehyde 4 (0.165 g, 0.48 mmol) in methylene chloride (2 mL) was added to a solution of 1,3-propanediol (0.076 g, 1.00 mmol) in methylene chloride (2 mL) followed by a drop of concentrated hydrochloric acid (0.016 g, 0.17 mmol) and the reaction mixture was stirred at room temperature for 16 h. Methylene chloride (5 mL) was added and the reaction mixture was washed with water (3 × 5 mL). The organic phase was dried over Na2SO4, filtered, and the solvent was removed in vacuum. Product 6a (0.159 g, 83%, beige oil) was purified by column chromatography (silica gel 60, 70–230 mesh, eluent: hexane, then chloroform–hexane 1:8).
1H NMR (400 MHz, CDCl3): δ 1.35 (d, 2J 13.5 Hz, 1H, OCH2CH2CH2O), 2.03–2.13 (m, 1H, OCH2CH2CH2O), 2.89 (d, 3J 5.0 Hz, 2H, O2CHCH2Se), 3.25 (dd, 2J 12.1 Hz, 3J 9.5 Hz, 1H, CH2Se-cyclic), 3.41 (dd, 2J 12.1 Hz, 3J 2.6 Hz, 1H, CH2Se-cyclic), 3.77–3.83 (m, 2H, OCH2), 4.10–4.14 (m, 2H, OCH2), 4.61 (dd, 3J 9.5 Hz, 3J 2.6 Hz 1H, SCHS), 4.75 (t, 3J 5.0 Hz, 1H, OCHO), 6.46 (s, 2H, SCH=CHSe-cyclic), 6.61 (d, 3J 8.1 Hz, 1H, SeCH=), 6.88 (d, 3J 8.1 Hz, 1H, SCH=).
13C NMR (100 MHz, CDCl3): δ 24.65 (CH2Se-cyclic, 1JSeC 64.4 Hz), 25.40 (O2CHCH2Se, 1JSeC 64.4 Hz), 30.19 (OCH2CH2CH2O), 45.84 (SCHS), 66.97 (OCH2), 101.58 (OCHO), 109.40 (=CHSe-cyclic, 1JSeC 116.6 Hz), 120.12 (=CHS-cyclic), 120.68 (=CHSe), 127.06 (=CHS).
77Se NMR (CDCl3, 76.3 MHz): δ 224.7 (cyclic), 229.4.
MS (EI), m/z (%): 403 (5) [M]+·, 223 (7), 196 (3), 165 (38), 87 (100), 59 (40).
Anal. Calcd for C11H16O2S2Se2 (402.30): C, 32.84; H, 4.01; S, 15.94; Se, 39.25. Found: C, 33.01; H, 3.93; S, 16.02; Se, 39.12.
2-{[(Z)-2-(2,3-dihydro-1,4-thioselenine-2-ylsulfanyl)ethenyl]selanylmethyl}-4,5-dimethyl-1,3-dioxalane (6b) obtained in 80% yield as beige oil from 2,3-butandiol. The product was purified by column chromatography (silica gel 60, 70–230 mesh, eluent: hexane, then chloroform–hexane 1:7) and isolated as a mixture of cis and trans-diastereomers in a 7:5 ratio.
Anal. Calcd for C12H18O2S2Se2 (416.32): C, 34.62; H, 4.36; S, 15.40; Se, 37.93. Found: C, 34.78; H, 4.22; S, 15.49; Se, 38.01.
MS (EI), m/z (%): 418 (2) [M]+· (2), 165 (7), 116 (3), 165 (38), 101 (100), 73 (60), 41 (48).
cis-Diastereomer. 1H NMR (400 MHz, CDCl3): δ 1.18 (d, 3J 6.1 Hz, 6H, 2CH3), 2.93 (d, 3J 4.4 Hz, 2H, O2CHCH2Se), 3.25 (dd, 2J 12.1 Hz, 3J 9.5 Hz, 1H, CH2Se-cyclic), 3.41 (dd, 2J 12.1 Hz, 3J 2.7 Hz, 1H, CH2Se-cyclic), 4.18 (AB-dq, 3J 6.1 Hz, 3J 4.4 Hz, 1H, CHCH3), 4.20 (AB-dq, 3J 6.1 Hz, 3J 4.4 Hz, 1H, CHCH3), 4.61 (dd, 3J 9.5 Hz, 3J 2.7 Hz, 1H, SCHS), 5.11 (t, 3J 4.4 Hz, 1H, OCHO), 6.47 (s, 2JSe-H 54.0 Hz, 2H, SCH=CHSe-cyclic), 6.61 (d, 3J 8.1 Hz, 1H, SeCH=, 6.92 (d, 3J 8.1 Hz 1H, SCH=).
13C NMR (100 MHz, CDCl3): δ 15.41, (2CH3), 24.68 (CH2Se-cyclic, 1JSeC 64.0 Hz), 30.24 (O2CHCH2Se, 1JSeC 64.8 Hz), 45.88 (SCHS), 75.04 (2CHCH3), 102.37 (OCHO), 109.47 (=CHSe-cyclic, 1JSeC 115.7 Hz), 120.17 (=CHS-cyclic), 120.47 (=CHS, 2JSeC 14.0 Hz), 127.18 (=CHSe, 1JSeC 107.2 Hz).
77Se NMR (CDCl3, 76.3 MHz): δ 218.7, 224.5 (cyclic).
trans-Diastereomer. 1H NMR (400 MHz, CDCl3): δ 1.25 (d, 3H, CH3, 3J = 5.8 Hz), 1.30 (d, 3J 5.8 Hz 3H, CH3), 2.94 (d, 3J 4.0 Hz, 2H, O2CHCH2Se), 3.25 (dd, 2J 12.1 Hz, 3J 9.5 Hz, 1H, CH2Se-cyclic), 3.41 (dd, 2J 12.1 Hz, 3J 2.7 Hz, 1H, CH2Se-cyclic), 3.66 (AB-dq, 3J 7.8 Hz, 3J 5.8 Hz 1H, CHCH3), 3.72 (AB-dq, 3J 7.8 Hz, 3J 5.8 Hz, 1H, CHCH3), 4.61 (dd, 3J 9.5 Hz, 3J 2.7 Hz, 1H, SCHS), 5.31 (t, 3J 4.0 Hz, 1H, OCHO), 6.47 (s, 2JSe-H 54.0 Hz, 2H, SCH=CHSe-cyclic), 6.61 (d, 3J 8.1 Hz, 1H, SeCH=), 6.92 (d, 3J 8.1 Hz, 1H, SCH=).
13C NMR (100 MHz, CDCl3): δ 16.58, (CH3), 16.96 (CH3), 24.68 (CH2Se-cyclic, 1JSeC 64.0 Hz), 30.94 (O2CHCH2Se, 1JSeC 65.2 Hz), 45.88 (SCHS), 78.79 (CHCH3), 80.17 (CHCH3), 102.22 (OCHO), 109.41 (=CHSe-cyclic, 1JSeC 115.7 Hz), 120.17 (=CHS-cyclic), 120.47 (=CHS, 2JSeC 14.0 Hz), 127.20 (=CHSe, 1JSeC 107.2 Hz).
77Se NMR (CDCl3, 76.3 MHz): δ 218.8, 224.5 (cyclic).
2-{[(Z)-2-(2,3-dihydro-1,4-thiaselenin-2-ylsulfanyl)ethenyl]selanylmethyl}-4,7-dihydro-1,3-dioxepine (6c) obtained in 84% yield as beige oil from (Z)-2-butene-1,4-diol.
1H NMR (400 MHz, CDCl3): δ 2.86 (d, 3J 5.6 Hz, 2H, O2CHCH2Se), 3.24 (dd, 2J 11.8 Hz, 3J 9.3 Hz, 1H, CH2Se-cyclic), 3.37 (dd, 2J 11.8 Hz, 3J 2.7 Hz, 1H, CH2Se-cyclic), 4.14 (dm, 2H, OCH2), 4.40 (dm, 2H, OCH2) 4.57 (dd, 3J 9.3 Hz, 3J 2.7 Hz, 1H, SCHS), 4.95 (t, 3J 5.6 Hz, 1H, OCHO), 5.67 (brt, 2H, CH=CH dioxepine), 6.46–6.48 (m, 2H, SCH=CHSe-cyclic), 6.57 (d, 3J 8.1 Hz, 1H, SeCH=), 6.83 (d, 3J 8.1 Hz, 1H, SCH=).
13C NMR (100 MHz, CDCl3): δ 24.64 (CH2Se-cyclic, 1JSeC 64.4 Hz), 29.54 (O2CHCH2Se, 1JSeC 64.4 Hz), 45.81 (SCHS), 65.70 (CH2OCH2), 104.04 (OCHO), 109.45 (=CHSe-cyclic, 1JSeC 116.6 Hz), 120.05 (=CHS-cyclic), 121.29 (=CHSe), 126.15 (=CHS), 129.33 (CH=CH, dioxepine).
77Se NMR (CDCl3, 76.3 MHz): δ 224.5 (cyclic), 232.0.
MS (EI), m/z (%): 415 (5) [M]+, 223 (19), 165 (100), 85 (87), 43 (100).
Anal. Calcd for C12H16O2S2Se2: C, 36.45; H, 4.24; S, 14.97; Se, 36.87. Found: C, 36.41; H, 4.40; S, 15.05; Se, 36.98.

3.7. The Synthesis of Compounds 7–8a,b

1,2-Bis[(Z)-2-(2,2-dimethoxyethylselanyl)ethenyl]disulfane (7)
One drop of concentrated hydrochloric acid (0.016 g, 0.17 mmol) was added to a solution of 0.083 g (0.24 mmol) of dialdehyde 3 in a mixture of methylene chloride (1 mL) and methanol (1 mL) and the reaction mixture was stirred at room temperature for 16 h. Methylene chloride (5 mL) was added and the reaction mixture was washed with water (3 × 5 mL). The organic phase was dried over Na2SO4, filtered, and the solvent was removed in vacuum. The product was obtained as brownish oil (0.07 g, 86%).
1,2-Bis[(Z)-2-(1,3-dioxane-2-ylmethylselanyl)ethenyl]disulfane (8a)
A solution of propanediol-1,3 (0.100 g, 1.32 mmol) in methylene chloride (1 mL) was added to a solution of dialdehyde 3 (0.095 g, 0.26 mmol) in methylene chloride (2 mL) followed by a drop of concentrated hydrochloric acid (0.016 g, 0.17 mmol). The reaction mixture was stirred at room temperature for 16 h. Methylene chloride (5 mL) was added and the reaction mixture was washed with water (3 × 5 mL). The organic phase was dried over Na2SO4, filtered, and the solvent was removed in vacuum. Product 8a (1.0 g, 80%) was obtained as brownish oil.
1H NMR (CDCl3, 400 MHz): δ 1.33 (brd, 1H (eq), 2J 13.7 Hz, OCH2CH2CH2O), 2.05 (dtt, 2J 13.7 Hz, 3Jax-ax 12.4 Hz, 3Jax-eq 5.1 Hz, 1H (ax), OCH2CH2CH2O), 2.86 (d, 2H, 3J 4.7 Hz, O2CHCH2Se), 3.77 (dd, 2J 11.5 Hz, 3Jax-ax 12.4 Hz, 2H (ax), OCH2), 4.09 (dd, 2J 11.5 Hz, 3Jax-eq 5.1 Hz, 2H, OCH2 (eq)), 4.71 (t, 3J 4.7 Hz, 1H, OCHO), 6.60 (d, 3J 8.1 Hz 1H, SeCH=), 6.74 (d, 3J 8.1 Hz, 1H, SCH=).
13C NMR (CDCl3, 100.6 MHz): δ 25.33 (O2(CH2)2CH2), 30.46 (O2CHCH2Se, 1JSeC 65.1 Hz), 66.86 (OCH2), 101.39 (OCHO), 125.87 (=CHSe, 1JSeC 107.7 Hz), 128.88 (=CHS, 2JSeC 12.4 Hz).
77Se NMR (CDCl3, 76.3 MHz): δ 223.4.
MS (EI), m/z (%): 478 (2) [M]+·, 420 (7), 362 (3), 265 (4), 239 (2), 180 (3), 100 (5), 87 (100), 59 (33), 43 (31).
Anal. Calcd for C14H22O4S2Se2 (476.37): C, 35.30; H, 4.65; S, 13.46; Se, 33.15. Found: C, 35.21; H, 4.59; S, 13.42; Se, 33.37.
1,2-Bis[(Z)-2-(4,5-dimethyldioxalane-2-ylmethylselanyl)ethenyl]disulfane (8b) was obtained in 85% yield (brownish oil) as a mixture of major and minor diastereomers in a 8:5 ratio.
MS (EI), m/z (%): 506 (2) [M]+·, 448 (2), 390 (2), 194 (5), 151 (5), 116 (3), 101 (100), 73 (81), 41 (51).
Anal. Calcd for C16H26O4S2Se2 (504.43): C, 38.10; H, 5.20; S, 12.69; Se, 31.31. Found: C, 38.18; H, 5.12; S, 12.79; Se, 31.38.
Major diastereomer.
1H NMR (CDCl3, 400 MHz): δ 1.16 (d, 3J 5.9 Hz, 6H, 2CH3), 2.92 (d, 3J 4.2 Hz, 2H, O2CHCH2Se), 4.16 (AB-m, 1H, CHCH3), 4.20 (AB-m, 1H, CHCH3), 5.10 (t, 3J 4.2 Hz, 1H, OCHO), 6.62 (d, 3J 8.0 Hz, 1H, SeCH=), 6.80 (d, 3J 8.0 Hz 1H, SCH=).
13C NMR (CDCl3, 100.6 MHz): δ 15.38, (2CH3), 30.58 (O2CHCH2Se, 1JSeC 65.3 Hz), 75.05 (2CHCH3), 102.27 (OCHO), 126.06 (=CHSe, 1JSeC 107.2 Hz), 128.80 (=CHS).
77Se NMR (CDCl3, 76.3 MHz): δ 217.9.
Minor diastereomer.
1H NMR (CDCl3, 400 MHz): δ 1.24 (d, 3J 5.8 Hz, 3H, CH3), 1.30 (d, 3J 5.8 Hz, 3H, CH3), 2.92 (d, 3J 4.0 Hz, 2H, O2CHCH2Se), 3.65 (AB-dq, 3J 7.8 Hz, 3J 5.8 Hz, 1H, CHCH3), 3.71 (AB-dq, 3J 7.8 Hz, 3J 5.8 Hz, 1H, CHCH3), 5.30 (t, 3J 4.0 Hz, 1H, OCHO), 6.62 (d, 3J 8.0 Hz, 1H, SeCH=), 6.80 (d, 3J 8.0 Hz, 1H, SCH=).
13C NMR (CDCl3, 100.6 MHz): δ 16.58, (CH3), 16.94 (CH3), 31.29 (O2CHCH2Se, 1JSeC 65.3 Hz), 78.80 (CHCH3), 80.18 (CHCH3), 102.15 (OCHO), 126.13 (=CHSe, 1JSeC 107.7 Hz), 128.80 (=CHS).
77Se NMR (CDCl3, 76.3 MHz): δ 217.9.

4. Conclusions

The remarkable cascade reactions of 2-bromomethyl-1,3-thiaselenole with water at room temperature were developed to afford compounds 3 and 4—new promising semi-products for organic synthesis, containing the (Z)-S-CH=CH-Se fragment and one or two highly reactive aldehyde groups. The application of these multifunctional reagents can open up new possibilities in the synthesis of O/S/Se-containing heterocyclic and linear products. Dialdehyde 3 and aldehyde 4 were used for the preparation of a number of new polyfunctional compounds 5–8, containing from six to eight chalcogen heteroatoms (selenium, sulfur and oxygen) and the (Z)-S-CH=CH-Se fragment.
A new ensemble of 2-organyloxy-2,3-dihydro-1,4-thiaselenines was obtained in 80–96% yields by the reaction of 2-bromomethyl-1,3-thiaselenole with alcohols at room temperature.
Thus, efficient and environmentally friendly synthetic methods were developed for the synthesis of new compounds 2–8 based on the reactions of 2-bromomethyl-1,3-thiaselenole with alcohols and water. The reactions proceeded with high selectivity under mild reaction conditions to afford the target products in high yield.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/inorganics11070281/s1: 1H, 13C and 77Se NMR spectra of the obtained compounds.

Author Contributions

Methodology and the paper preparation, S.V.A.; investigation and research experiments, A.S.F. and N.A.M.; NMR investigation, A.I.A.; conceptualization and the paper preparation, V.A.P. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

Not applicable.

Acknowledgments

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

Conflicts of Interest

The authors declare no conflict of interest.

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Inorganics 11 00281 g001 550
Figure 1. Examples of selenium heterocycles with biological activity including compounds structurally related to 1,4-thiaselenines.
Figure 1. Examples of selenium heterocycles with biological activity including compounds structurally related to 1,4-thiaselenines.
Inorganics 11 00281 g001
Inorganics 11 00281 sch001 550
Scheme 1. The one-pot synthesis of thiaselenole 1 and the equilibrium of thiaselenole 1 with seleniranium cation A.
Scheme 1. The one-pot synthesis of thiaselenole 1 and the equilibrium of thiaselenole 1 with seleniranium cation A.
Inorganics 11 00281 sch001
Inorganics 11 00281 sch002 550
Scheme 2. The synthesis of a new family of 2-organyloxy-2,3-dihydro-1,4-thiaselenines 2a–k.
Scheme 2. The synthesis of a new family of 2-organyloxy-2,3-dihydro-1,4-thiaselenines 2a–k.
Inorganics 11 00281 sch002
Inorganics 11 00281 sch003 550
Scheme 3. The reaction pathway of the formation of compounds 2a–k.
Scheme 3. The reaction pathway of the formation of compounds 2a–k.
Inorganics 11 00281 sch003
Inorganics 11 00281 sch004 550
Scheme 4. The cascade reaction of thiaselenole 1 with water in aqueous DMSO (77Se NMR data are included).
Scheme 4. The cascade reaction of thiaselenole 1 with water in aqueous DMSO (77Se NMR data are included).
Inorganics 11 00281 sch004
Inorganics 11 00281 sch005 550
Scheme 5. The supposed reaction pathways for the formation of compounds 3 and 4.
Scheme 5. The supposed reaction pathways for the formation of compounds 3 and 4.
Inorganics 11 00281 sch005
Inorganics 11 00281 sch006 550
Scheme 6. The selective synthesis of compound 4 (77Se NMR data are included).
Scheme 6. The selective synthesis of compound 4 (77Se NMR data are included).
Inorganics 11 00281 sch006
Inorganics 11 00281 sch007 550
Scheme 7. The efficient synthesis of thiaselenines 5a–d (77Se NMR data are included).
Scheme 7. The efficient synthesis of thiaselenines 5a–d (77Se NMR data are included).
Inorganics 11 00281 sch007
Inorganics 11 00281 sch008 550
Scheme 8. The efficient synthesis of thiaselenines 6a–c (77Se NMR data are included).
Scheme 8. The efficient synthesis of thiaselenines 6a–c (77Se NMR data are included).
Inorganics 11 00281 sch008
Inorganics 11 00281 sch009 550
Scheme 9. The efficient synthesis of compound 7 (77Se NMR data are included).
Scheme 9. The efficient synthesis of compound 7 (77Se NMR data are included).
Inorganics 11 00281 sch009
Inorganics 11 00281 sch010 550
Scheme 10. The synthesis of compounds 8a,b (77Se NMR data are included).
Scheme 10. The synthesis of compounds 8a,b (77Se NMR data are included).
Inorganics 11 00281 sch010
Table
Table 1. 77Se NMR data of the compounds 2a–k.
Table 1. 77Se NMR data of the compounds 2a–k.
CompoundStructure77Se NMR,
ppm
2aInorganics 11 00281 i001127.9
2bInorganics 11 00281 i002140.5
2cInorganics 11 00281 i003143.1
2dInorganics 11 00281 i004154.6
2eInorganics 11 00281 i005142.8
2fInorganics 11 00281 i006146.3
2gInorganics 11 00281 i007143.1
2hInorganics 11 00281 i008143.1
2iInorganics 11 00281 i009135.7
2jInorganics 11 00281 i010135.3
2kInorganics 11 00281 i011126.5
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Amosova, S.V.; Filippov, A.S.; Makhaeva, N.A.; Albanov, A.I.; Potapov, V.A. Green Organoselenium Chemistry: Selective Syntheses of New 1,4-Thiaselenine Derivatives Based on Reactions of Thiaselenole Reagent with Alcohols and Water. Inorganics 2023, 11, 281. https://doi.org/10.3390/inorganics11070281

AMA Style

Amosova SV, Filippov AS, Makhaeva NA, Albanov AI, Potapov VA. Green Organoselenium Chemistry: Selective Syntheses of New 1,4-Thiaselenine Derivatives Based on Reactions of Thiaselenole Reagent with Alcohols and Water. Inorganics. 2023; 11(7):281. https://doi.org/10.3390/inorganics11070281

Chicago/Turabian Style

Amosova, Svetlana V., Andrey S. Filippov, Nataliya A. Makhaeva, Alexander I. Albanov, and Vladimir A. Potapov. 2023. "Green Organoselenium Chemistry: Selective Syntheses of New 1,4-Thiaselenine Derivatives Based on Reactions of Thiaselenole Reagent with Alcohols and Water" Inorganics 11, no. 7: 281. https://doi.org/10.3390/inorganics11070281

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