Iodine-Mediated Alkoxyselenylation of Alkenes and Dienes with Elemental Selenium

A one-pot synthesis of linear and cyclic β-alkoxyselenides is developed through the iodine-mediated three-component reaction of elemental selenium with alkenes (dienes) and alcohols. Selenylation of 1,5-hexadiene gives 2,5-di(methoxymethyl)tetrahydroselenophene and 2-methoxy-6-(methoxymethyl)tetrahydro-2H-selenopyran via the 5-exo-trig and 6-endo-trig cyclization. 1,7-Octadiene affords only linear 1:2 adduct with two terminal double bonds. 1,5-Cyclooctadiene results in one diastereomer of 2,6-dialkoxy-9-selenabicyclo [3.3.1]nonanes via 6-exo-trig cyclization. With 1,3-diethenyl-1,1,3,3-tetramethyldisiloxane, the first ring-substituted representative of a very rare class of heterocycles, 1,4,2,6-oxaselenadisilinanes, was obtained at a high yield.


Introduction
Organoselenium compounds are valuable reagents in organic and organoelement synthesis [1][2][3][4] and demonstrate diverse biological activities [5][6][7][8][9]. For example, 4-phenylselenyl-7-chloroquinoline (4-PSQ) exerts acute anti-inflammatory effects on apar with the widely used drug Meloxicam [10]. Some organoselenium compounds affect mood and exhibit high antidepressant activity [11,12]. They possess powerful radical scavenging and broad anti-HIV activity [13] and are capable of blocking the replication of SARS-CoV-2 [14][15][16]. One of the actively studied properties of organoselenium compounds is their glutathione peroxidase activity, [17,18] protecting living organisms against oxidative stress. All of this shows that organoselenium compounds are good candidates for the medicines of the future and promotes the search for new methods of their synthesis and investigation.
Nowadays, the iodine-mediated reactions of alkene functionalization are actively used in organic synthesis [19][20][21] since molecular iodine is non-toxic, inexpensive, safe, and easy to use in the handling of reagents. These reactions are employed in the synthesis of organoselenium compounds, for example, for selenylation of alkenes with organic diselenides via the formation of a Se-C bond, Scheme 1 [22][23][24]. The method is promising, although the scope of the substrates was limited to alkenes and did not include other unsaturated substrates. The drawbacks of this method are the impossibility to obtain the Se-containing heterocycles and the use, as a rule, of only diphenyl (or diaryl) diselenides. The main methods of the synthesis of symmetrical difunctionalized and cyclic selenides are based on the reactions of nucleophilic selenium reagents (selenolates and selenols) with electrophiles such as epoxides [25][26][27]. An alternative approach is the electrophilic addition of inorganic selenium halides to alkenes [28][29][30], leading to β-haloselenides (mustard gas analogs).
The drawbacks of such selenium-containing reagents as organic diselenides, organoselenyl halides, inorganic selenium halides, selenols, etc., are their high toxicity, low stability and inability to store for a long time. In contrast, elemental selenium is low-toxic and easy to store, transport and handle and thus has significant advantages as a reagent for the synthesis of organoselenium compounds [4,31].
Recently, we first reported the possibility of introducing a selenium atom into the organic chain by using molecular iodine in the reaction of hydroxyselenylation of alkenes with elemental selenium in an aqueous organic medium, resulting in the formation of bifunctionalized symmetrical β,β-dihydroxyselenides [32]. The reaction with cycloalkenes was shown to proceed stereoselectively as anti-addition, resulting exclusively in the trans,transdiastereomers [32,33]. In distinction to that, in dry acetonitrile the iodine-mediated reaction of elemental selenium with alkenes proceeded as a Ritter-type reaction with an interception of the solvent (acetonitrile) and resulted in assembling the 1,3-selenazoline ring, Scheme 2 [34]. [32,34].

Scheme 2. Previous works
Here, we report a one-pot procedure for the three-component synthesis of cyclic and linear β,β-alkoxyselenides based on the iodine-mediated alkoxyselenylation of alkenes and dienes with elemental selenium and alcohols. The method takes advantage of using elemental selenium and alcohols as the reagents and allows the selective synthesis of selenium-containing compounds; possible structures are presented in Figure 1. The novelty of the present study is not only in extending the reaction of hydroxyselenylation [32] to alkoxyselenylation but also in including, in addition to alkenes, the earlier not-studied dienes as the substrates, which can (and do) result in the formation of novel selenium heterocycles (vide infra).

Results and Discussion
The investigated alkenes 1a-e and dienes 2a-d are depicted in Figure 2. The reaction of alkenes 1a-e with selenium in alcohols proceeded under mild conditions in one preparative step to give β,β-dialkoxyselenides 3a-g at good yields, taking into account the conversion (Scheme 3, Table 1). The conversion was estimated by subtracting the amount of unreacted (filtered off) selenium from that taken in the reaction. The reaction was highly regioselective; with unsymmetrical alkenes 1a-d, only selenides 3 with the selenium atom at the terminal olefinic carbons were formed. Selenides 3a-f have two chiral centers which were formed as mixtures of diastereomers in the ratio of ca. 1:1, as proved by the presence of two 77 Se NMR signals of equal intensity and the doubled sets of signals in the 13 C NMR spectra. With cyclohexene, only two diastereomers were formed in the ratio of 1:1, although molecule 3g has four asymmetric centers allowing four diastereomers to be formed. Based on our previous results on the exclusive formation of the trans-products of hydroselenylation of cycloalkenes, we assumed stereoselective anti-addition and formation of product 3c as the d,l and meso diastereomers with trans-arrangement of the methoxy groups and the selenium atom. The yields of compounds 3 are given in Figure 3. 1 H NMR spectroscopy revealed the formation of trace amounts of by-products of iodomethoxylation 4, which can easily be separated by eluting with CCl 4 . Independently synthesized compounds 4 do not react with selenium under the conditions of the reaction; so, they are not intermediates on the way to the target products 3.

Scheme 3. Synthesis of selenides 3a-g.
Optimization of the reaction conditions was performed by varying the solvent, the iodine source and its amount, temperature and reaction time for the reaction of heptene-1 with methanol (Table 1). With 1 or 1.5 equivalents of iodine, the conversion is incomplete (entries 1-4) but increases with time. With two equivalents of iodine, the conversion is complete in 40 h (entry 5) without an increase in the number of by-products 4. When using five equivalents of methanol (2.5 molar excess), selenide 3a is formed selectively at a 79% yield (entry 10), but the conversion is rather low. A high conversion of 86% was achieved when using methanol as the solvent (entry 4). The use of catalytic amounts of iodine in combination with DMSO is known [21,22] when iodine is recycled by oxidation of the formed hydrogen iodide with DMSO. However, in our case, the use of DMSO shows low conversion and selectivity affording a mixture of adducts (entry 9). The increase in the temperature to 50 • C lowers the yield (entry 7). Since molecular iodine acts as an oxidant, we tried to replace it with N-iodosuccinimide; indeed, the rate of the reaction increased, but simultaneously increased the number of by-products 4, up to 30% (NIS, entry 8). No reaction occurs in the absence of iodine or its substitute. To summarize, the most favorable condition is the use of a two-fold excess of iodine in methanol at room temperature. Alkoxyselenylation of alkenes 1a-e was performed under the conditions providing the highest yield of the target selenides (entries 2 and 5) in spite of incomplete conversion, which can be increased by prolonging the reaction time (entry 3).  With the results for alkenes 1a-e in mind, one can expect the formation of various products of methoxyselenylation of dienes 2a-d via addition to one or both double bonds of the diene, or the reaction with two diene molecules, or even the products of cyclization or oligomerization. The unpredictability of the reaction is exacerbated by the fact that it is very poorly studied, and the nature of active intermediates is not clear, taking into account that elemental selenium exists as a mixture of single chains, Se 8 cyclic molecules, or polymer nanoparticles [35] and can form a mixture of iodides of general formula Se n I 2 . However, to our surprise and delight, the reaction of methoxyselenylation of 1,5-hexadiene 2a led selectively to the isomeric products of cyclization, 2,5-di(methoxymethyl)tetrahydroselenophene 5 and its six-membered isomer, 5-methoxy-2-(methoxymethyl)tetrahydro-2H-selenopyran 6 in the ratio of 1:2 and an 86% total yield, Scheme 4. Compounds 5 and 6 are formed as two diastereomers in the ratio of ca. 1:1, as proved by the presence of doubled signals in the 13 C and 77 Se NMR spectra of the products. The products could not be completely separated into pure diastereomers, but we succeeded in the isolation of the fractions of compound 6 enriched with diastereomer 1 (80:20) or diastereomer 2 (35:65), which allowed the assignment of the signals to specific diastereomers (see spectra S26-S32 in the Supplementary Materials).
Note that no linear adducts were formed, even with a large excess of diene 2a. Remarkably, while the formation of products 3 in Scheme 1 obeys the Markovnikov rule (addition of MeO nucleophile to the internal olefinic carbon), the reaction with 1,5-hexadiene 2a proceeded as an anti-Markovnikov addition. Apparently, this is due to the effect of the second double bond, which can interact with the selenium atom in the intermediate seleniranium cation with a subsequent opening by methanol via the 5-exo-trig or 6-endo-trig mode, both of which are favorable according to Baldwin's rules [36], Scheme 5. In contrast, with a higher homologue of diene 2a and 1,7-octadiene 2b, the reaction proceeded with the formation of 1:2 linear adduct, 8,8 -selenobis(7-methoxyoct-1-ene) 7, with two terminal double bonds being retained, and 2:3 linear adduct, 3,16-dihex-5-en-1-yl-7,12-dimethoxy-2,17-dioxa-5,14-diselenaoctadecane 8. As with alkenes 1a-d, the addition follows the Markovnikov rule, probably due to a more remote second double bond than in the case of diene 2a, Scheme 6. No cyclic products were detected in the reaction mixture. With a large excess of the diene (Se:2b = 1:3), selenide 7 is practically the only product of the reaction. For the equimolar ratio, it still is the main product, but a fraction enriched with compound 8 was also isolated via column chromatography. The structure of 8 was validated through 1 H NMR spectroscopy and mass spectrometry. The relative intensity of the methylene proton signals with respect to olefinic protons is notably larger than for monoselenide 7, and the mass spectrum contains a peak with m/z 614, corresponding to the molecular ion [C 28 H 54 O 4 Se 2 ] + .
For comparison, the reaction with 1,5-cyclooctadiene was investigated. The reaction proceeds regioselectively to give only one diastereomer of 2,6-dialkoxy-9-selenabicyclo [3.3.1]nonanes 9a-c, apparently via alkoxyselenylation at one double bond followed by the 6-exo-trig cyclization [36]. Based on the common mechanism of anti-addition via the ring opening of the intermediate seleniranium cation and the earlier proved trans structure of the products of hydroxyselenylation of cyclohexene [32,33], it is reasonable to assume that the selenium atom in 9 is in the trans position to the alkoxy groups, Scheme 7. Under the same conditions, the iodine-mediated reaction of elemental selenium with 1,3-diethenyl-1,1,3,3-tetramethyldisiloxane and methanol affords 3,5-bis(methoxymethyl)-2,2,6,6-tetramethyl-1,4,2,6-oxaselenadisilinane 10, Scheme 8. The structure of compound 10 and, hence, the anti-Markovnikov regioselectivity of addition is proved through the presence of SeCH signals at 22-25 ppm in the 13 C j-mod NMR spectrum ( Figure S47) as well as the value of the 1 J C-Se direct constant of~58 Hz on the satellites of this signal ( Figure S48). Heterocycle 10 is representative of a very rare class of 1,4,2,6-oxaselenadisilinanes and is the first one with substituents in the ring. It is formed of a 2:1 mixture of diastereomers generated by the methanol attack on the re or si faces of the double bond during the 6-exo-trig cyclization. Judging from theoretical calculations, the prevalent diastereomer has both substituents equatorial and is more stable than the ax-eq diastereomer by 1.24 kcal/mol in total energy ∆E and by 1.52 kcal/mol in free energy ∆G. The formula of compound 10 is proved by the presence of a fragment ion with m/z 297 corresponding to a fragment ion [M + H − MeOH] + formed by protonation and elimination of methanol from 10. This ion can exist as two diastereomers, each as a carbocation or seleniranium cation. Interestingly, while seleniranium cations 10a + and 10b + are the minima on the MP2 potential energy surface, the six-membered carbocations undergo ring expansion upon geometry optimization to 10c or 10d. The relative total and free energies of all cations are given in Figure 4 relative to the most stable seven-membered cyclic cation 10d [37]. This result raises the question of the manner and relative ability of different substituents to stabilize the adjacent carbocationic center; however, it is beyond the scope of our paper.
Unlike chlorides or bromides, selenium iodides Se n I 2 were not isolated as individuals, but registered in a solution via 77 Se NMR spectroscopy, the major constituent being Se 2 I 2 [38]. Based on these data, we assume that the mechanism of hydroxyselenylation is similar to that described in [32], which includes the electrophilic addition of selenium iodides, successive Se-Se bonds rupture via their iodination and, finally, the formation of selenides. This is proved through mass spectrometric detection of di-and triselenides 11 and 12 in the reaction mixture with cyclohexene, as shown in Figure 5. Therefore, a variety of transformations occur in the system elemental selenium-iodinealcohol-alkene(diene), opening the way to different selenium-containing linear and heterocyclic compounds, which is illustrated in Figure 6.

General Procedure for the Preparation of Selenides 3a-g and 7
Alkene 1a-e (or diene 2b) (3.5 mmol) and alcohol (1 mL) were added to a mixture of fine-ground elemental Se (0.079 g, 1 mmol) and I 2 (0.508 g, 2 mmol for 3a-c or 1 mmol, 0.254 g for 3d-g and 7), and the mixture was stirred for 40 h at room temperature. Then, a saturated solution of Na 2 S 2 O 3 (2 mL) was added, stirred for 10 min, the mixture was diluted with water (10 mL), and Et 2 O (10 mL) was added. The unreacted selenium was filtered off, the water layer extracted with Et 2 O (3 × 10 mL), and the extract was washed with H 2 O (2 × 5 mL), dried with CaCl 2 , and filtered. The solvent was removed in a vacuum to give the crude product, which was purified on silica gel via successive eluting with CCl 4 and CHCl 3 to give the corresponding selenide 3a-g and 7.
3.3. General Procedure for the Preparation of Selenides 5, 6, 9a-c, and 10 Diene 2a, 2c or 2d (1.5 mmol) and alcohol (1 mL) were added to a mixture of fineground elemental Se (0.079 g, 1 mmol) and I 2 (0.254 g, 1 mmol), and the mixture was stirred for 40 h at room temperature. Then, a saturated solution of Na 2 S 2 O 3 (2 mL) was added, stirred for 10 min, the mixture was diluted with water (5 mL), and Et 2 O (EtOAc for 5,6) (10 mL) was added. The unreacted selenium was filtered off, the water layer extracted with Et 2 O (EtOAc for 5,6) (3 × 10 mL), and the extract was washed with H 2 O (2 × 5 mL), dried with CaCl 2 , and filtered. The solvent was removed in a vacuum to give the crude product, which was purified on silica gel via successive eluting with CCl 4 and CHCl 3 to give products 9, 10. Isomers 5 and 6 were obtained at an 86% total yield (selenium conversion 79%) as mixtures of regioisomers in the ratio of 2:1.

Conclusions
To summarize, a one-pot procedure for the synthesis of linear and cyclic alkoxyfunctionalized organoselenium compounds is proposed, based on the iodine-mediated reaction of elemental selenium with alkenes and dienes in alcohols.
The method has significant advantages over the existing procedures, such as the use of simple and low-toxic reagents, mild conditions, and a diversity of synthesized products.