Triple-Click Chemistry of Selenium Dihalides: Catalytic Regioselective and Highly Efﬁcient Synthesis of Bis-1,2,3-Triazole Derivatives of 9-Selenabicyclo[3.3.1]nonane

: The catalytic regioselective and highly efﬁcient synthesis of bis-1,2,3-triazole derivatives of 9-selenabicyclo[3.3.1]nonane was developed. The 1,3-dipolar cycloaddition reaction of 2,6-diazido-9-selenabicyclo[3.3.1]nonane with a variety of terminal acetylenes catalyzed by a copper acetate/sodium ascorbate system proceeded in a regioselective fashion, affording 2,6-bis(4-organyl-1,2,3-triazole)-9-selenabicyclo[3.3.1]nonanes in high yields (93–98%). The reaction of 2,6-diazido-9-selenabicyclo[3.3.1]nonane with dimethyl and diethyl acetylenedicarboxylates was carried out as thermal 1,3-dipolar Huisgen cycloaddition giving the corresponding 4,5-disubstituted 1,2,3-triazole derivatives of 9-selenabicyclo[3.3.1]nonane in high yields. The obtained products are potentially bioactive compounds and ﬁrst representatives of selenium heterocycles combined with two 1,2,3-triazole moieties. 2.6-Diazido-9-selenabicyclo[3.3.1]nonane was obtained in quantitative yield via the reaction of sodium azide with 2,6-dibromo-9-selenabicyclo[3.3.1]nonane at room temperature. The latter compound was synthesized by stereoselective transannular addition of selenium dibromide to cis, cis-1,5-cyclooctadiene.


Introduction
Heterocycles can be regarded as the most common and important structural components of pharmaceuticals [1]. Nitrogen heterocycles are integral parts of the vast majority of modern widely used drugs [2], and 1,2,3-trizoles are among the most useful heterocyclic scaffolds for pharmaceutical application [3][4][5].
Since the discovery of the copper-catalyzed 1,3-dipolar cycloadditions of azides to alkynes independently by Sharpless et al. [20] and Meldal et al. [21], research on the synthesis and application of 1,4-substituted 1,2,3-triazoles has been intensively developed. The reaction is termed the copper(I)-catalyzed azide-alkyne cycloaddition (Cu-AAC). This reaction represents one example of click chemistry, a term introduced in 2001 by Sharpless [22]. The modified CuAAC version of this reaction is completely regioselective and provides only one regioisomer in contrast with the mixture of regioisomers usually obtained under classical thermal conditions [23]. The application of this methodology has made great contribution to the fields of drug discovery, pharmaceutical chemistry, polymer chemistry, medicinal, biological and materials sciences [24][25][26][27].
Recent publications and comprehensive reviews discussed different aspects of the CuAAC reactions [28][29][30][31][32][33][34][35] including reaction conditions, catalytic systems, ligands, mechanistic features and the nature of the Cu-intermediates [28], recoverable and recyclable catalytic systems [29], and systems under continuous flow conditions [30]. The catalytic Cu(I) species may either be introduced as preformed complexes, or otherwise generated in situ from various copper sources. Although some reactions can be carried out using usual copper(I) sources such as copper iodide or copper bromide, the CuAAC process often proceeds much better using a mixture of copper(II) salt and a reducing agent for in situ generation of Cu(I) intermediates [31]. Many modifications to this Cu-based protocol were developed by using copper(II) acetate/sodium ascorbate, CuI/Et3N, CuSO4/sodium ascorbate, Cu(II) salts/Cu wire, CuI/sodium ascorbate, ionic Recent publications and comprehensive reviews discussed different aspects of the CuAAC reactions [28][29][30][31][32][33][34][35] including reaction conditions, catalytic systems, ligands, mechanistic features and the nature of the Cu-intermediates [28], recoverable and recyclable catalytic systems [29], and systems under continuous flow conditions [30]. The catalytic Cu(I) species may either be introduced as preformed complexes, or otherwise generated in situ from various copper sources. Although some reactions can be carried out using usual copper(I) sources such as copper iodide or copper bromide, the CuAAC process often proceeds much better using a mixture of copper(II) salt and a reducing agent for in situ generation of Cu(I) intermediates [31]. Many modifications to this Cu-based protocol were developed by using copper(II) acetate/sodium ascorbate, CuI/Et 3 N, CuSO 4 /sodium ascorbate, Cu(II) salts/Cu wire, CuI/sodium ascorbate, ionic liquids, polymers as copper support, or alternative energy sources, such as microwave or ultrasounds irradiation [28][29][30][31][32][33][34][35].
To date, a number of works on the synthesis of selenium-containing 1,2,3-triazole derivatives have been described in the literature. These works include cycloadditions of azides and selenium-containing acetylenes [54,55], reactions of selenium-containing azides to alkynes [56,57], and introduction of elemental selenium into the 1,2,3-triazole system [58,59]. The three-component reaction of ribosyl azides, terminal alkynes, and phenylselanyl bromide in the presence of CuI and N, N-diisopropylethylamine should be noted [60]. The interesting reaction of benzyl azide, terminal alkynes, and phenylselanyl benzenesulfonate in the presence of CuI and t-BuOLi has been carried out [61]. It is important that 5-arylselanyl-1,2,3-triazoles exhibit anticancer activity [54].
Diazido derivative 3 was obtained in quantitative yield by the nucleophilic substitution reaction of 2,6-dibromo-9-selenabicyclo[3.3.1]nonane (2) with sodium azide (Scheme 2). This is the second step (the second efficient "click") of the triple-click chemistry of selenium dihalides. It was found that the reaction of dibromo derivative 2 with sodium azide proceeded efficiently in a mixture of acetonitrile and water, and the excess of sodium azide was necessary to use. A solution of sodium azide was added dropwise to a mixture of compound 2 and acetonitrile (20 mL), with stirring at room temperature, and the reaction mixture was stirred overnight at room temperature. After removing acetonitrile by a rotary evaporator, the residue was extracted with methylene chloride. Pure product 3 in quantitative yield was obtained by removing methylene chloride from the extract, and drying the residue under a vacuum. It is important that the product 3 did not require additional purification.
Compound 3 was also obtained in 91% yield from dichloro derivative 1 and sodium azide under similar conditions. The prepared diazido derivative 3 was used in cycloaddition reactions with various acetylenes: 1-pentyne (4a), 1-hexyne (4b), 1-heptyne (4c), 1-octyne (4d), phenylacetylene (4e), trimethylethynylsilane (4f), dimethylethynylcarbinol (4g), phenylpropargyl ether (4h), methyl and ethyl propiolates (4i,j), dimethyl and diethyl acetylenedicarboxilates It was found that the reaction of dibromo derivative 2 with sodium azide proceeded efficiently in a mixture of acetonitrile and water, and the excess of sodium azide was necessary to use. A solution of sodium azide was added dropwise to a mixture of compound 2 and acetonitrile (20 mL), with stirring at room temperature, and the reaction mixture was stirred overnight at room temperature. After removing acetonitrile by a rotary evaporator, the residue was extracted with methylene chloride. Pure product 3 in quantitative yield was obtained by removing methylene chloride from the extract, and drying the residue under a vacuum. It is important that the product 3 did not require additional purification.
It is known that the cycloaddition reaction often proceeds much better using a mixture of copper(II) salt and a reducing agent (e.g., sodium ascorbate) for in situ generation of Cu(I) intermediates [31]. The catalytic system of Cu(OAc) 2 ·H 2 O and sodium ascorbate was chosen to carry out cycloaddition reactions. This system was found to be very efficient in the reactions of selenium-containing organic azides with terminal acetylenes [56,57]. In this case, the active Cu(I) catalyst was generated in situ from the Cu(II) salt via reduction of copper acetate with sodium ascorbate. Addition of a slight excess of sodium ascorbate prevents the formation of oxidative homocoupling products. It was also shown that increasing the loading of copper acetate in the reaction from 0.5 to 5 mol % led to a significant increase in the yield of target 1,2,3-triazoles [56].
The amounts of the catalytic system reactants, sodium ascorbate and copper acetate (20% mol in respect to compound 3), were used taking into account the presence of two diazide groups in compound 3. A slight excess of alkynes 4a-f compared to the stoichiometric amount of these acetylenes was found to help obtaining high yields of the desired products.
Acetylene, containing heteroatom at the triple bond, trimethylethynylsilane was involved in the 1,3-dipolar cycloaddition reaction with diazido derivative 3. A specific feature of this compound is that it can be hydrolyzed in the presence of water with the rupture of the carbon-silicon bond. However, the formation of side products by hydrolysis was not observed under these reaction conditions. The target product, 2,6-bis(4-trimethylsilyl-1H-1,2,3-triazol-1-yl)-9-selenabicyclo[3.3.1]nonane (5f), was obtained in 93% yield as white flakes.
When the 1,3-dipolar cycloaddition of diazido derivative 3 with dimethylethynylcarbinol (4g) and phenylpropargyl ether (4h) was studied under the same conditions, it was found that the reactions proceeded more slowly compared to the processes presented in Scheme 3. The higher amounts of the catalyst, copper acetate and sodium ascorbate, were taken, as well as the reaction duration was increased in order to obtain the product in high yield. Also, when the reaction with dimethylethynylcarbinol was finished, first it was necessary to distill off methanol from the reaction mixture and then to carry out the extraction of the residue with methylene chloride in order to avoid the loss of the product, containing the hydroxyl groups, and to obtain compound 5g in 96% yield (Scheme 4). Scheme 3. Synthesis of 2,6-bis(4-organyl-1H-1,2,3-triazol-1-yl)-9-selenabicyclo[3.3.1]nonanes 5a-f by the 1,3-dipolar cycloaddition reaction of diazido derivative 3 with 1-alkynes 4a-f (1-pentyne, 1-hexyne, 1-heptyne, 1-octyne), phenylacetylene (4e), and trimethylethynylsilane (4f).
The amounts of the catalytic system reactants, sodium ascorbate and copper acetate (20% mol in respect to compound 3), were used taking into account the presence of two diazide groups in compound 3. A slight excess of alkynes 4a-f compared to the stoichiometric amount of these acetylenes was found to help obtaining high yields of the desired products.
Acetylene, containing heteroatom at the triple bond, trimethylethynylsilane was involved in the 1,3-dipolar cycloaddition reaction with diazido derivative 3. A specific feature of this compound is that it can be hydrolyzed in the presence of water with the rupture of the carbon-silicon bond. However, the formation of side products by hydrolysis was not observed under these reaction conditions. The target product, 2,6-bis(4-trimethylsilyl-1H-1,2,3-triazol-1-yl)-9-selenabicyclo[3.3.1]nonane (5f), was obtained in 93% yield as white flakes.
When the 1,3-dipolar cycloaddition of diazido derivative 3 with dimethylethynylcarbinol (4g) and phenylpropargyl ether (4h) was studied under the same conditions, it was found that the reactions proceeded more slowly compared to the processes presented in Scheme 3. The higher amounts of the catalyst, copper acetate and sodium ascorbate, were taken, as well as the reaction duration was increased in order to obtain the product in high yield. Also, when the reaction with dimethylethynylcarbinol was finished, first it was necessary to distill off methanol from the reaction mixture and then to carry out the extraction of the residue with methylene chloride in order to avoid the loss of the product, containing the hydroxyl groups, and to obtain compound 5g in 96% yield (Scheme 4). Phenylpropargyl ether 4h has a relatively high boiling point (~202 °C) and it is difficult to remove an excess of this reagent under the reduced pressure after finishing the reaction. Therefore, stoichiometric amounts of the reagents were used in the reaction, but the reaction duration was increased to 28 h in order to obtain the high yield (95%) of 2,6-bis(4-phenyloxymethyl-1H-1,2,3-triazol-1-yl)-9-selenabicyclo[3.3.1]nonane (5h) (Scheme 5). Phenylpropargyl ether 4h has a relatively high boiling point (~202 • C) and it is difficult to remove an excess of this reagent under the reduced pressure after finishing the reaction. Therefore, stoichiometric amounts of the reagents were used in the reaction, but the reaction duration was increased to 28 h in order to obtain the high yield (95%) of 2,6bis(4-phenyloxymethyl-1H-1,2,3-triazol-1-yl)-9-selenabicyclo[3.3.1]nonane (5h) (Scheme 5).
Dimethyl and diethyl acetylenedicarboxilates 6a,b have no the terminal CH group, which is able to coordinate with the formation of intermediate acetylide species. In order to carry out the 1,3-dipolar cycloaddition reaction of diazido derivative 3 with acetylenedicarboxilates 6a,b, the thermal conditions were used without the copper catalyst.
The heating dimethyl and diethyl acetylenedicarboxilates 6a,b with diazido derivative 3 in toluene solution up to reflux for 8 h afforded the target products 7a and 7b in 92% and 90% yields, respectively (Scheme 7). The thermal reaction is less efficient compared to the copper-catalyzed process (Schemes 3-6).
which is able to coordinate with the formation of intermediate acetylide species. In order to carry out the 1,3-dipolar cycloaddition reaction of diazido derivative 3 with acetylenedicarboxilates 6a,b, the thermal conditions were used without the copper catalyst.
which is able to coordinate with the formation of intermediate acetylide species. In order to carry out the 1,3-dipolar cycloaddition reaction of diazido derivative 3 with acetylenedicarboxilates 6a,b, the thermal conditions were used without the copper catalyst.
The heating dimethyl and diethyl acetylenedicarboxilates 6a,b with diazido derivative 3 in toluene solution up to reflux for 8 h afforded the target products 7a and 7b in 92% and 90% yields, respectively (Scheme 7). The thermal reaction is less efficient compared to the copper-catalyzed process (Schemes 3-6). Thus, the regioselective and highly efficient synthesis of bis-1,2,3-triazole derivatives of 9-selenabicyclo[3.3.1]nonane 5a-j (93-98% yields) and 7a,b (90-92% yields) was developed by the cycloaddition reaction of 2,6-diazido-9-selenabicyclo[3.3.1]nonane with a variety of acetylenes (Scheme 8).  obtained products 2, 3, 5a-j, and 7a,b.  Scheme 8. The obtained products 2, 3, 5a-j, and 7a,b. A mechanistic scheme that includes the interaction of two copper centers, with one or two alkyne/acetylide units and one azide, has been proposed based on kinetics measurements of the Cu-catalyzed cycloaddition reaction of 1,3-diazidoalkyl derivatives [77]. We suppose that the two azide groups in compound 3 are further apart than in ordinary 1,3-diazidoalkyl derivatives and interaction between the two centers is less possible. The possible reaction pathway of the Cu-catalyzed formation of the products 5a-j is outlined in Scheme 9. Water and methanol may play the role of ligands in this catalytic reaction.
A mechanistic scheme that includes the interaction of two copper centers, with one or two alkyne/acetylide units and one azide, has been proposed based on kinetics measurements of the Cu-catalyzed cycloaddition reaction of 1,3-diazidoalkyl derivatives [77]. We suppose that the two azide groups in compound 3 are further apart than in ordinary 1,3-diazidoalkyl derivatives and interaction between the two centers is less possible. The possible reaction pathway of the Cu-catalyzed formation of the products 5a-j is outlined in Scheme 9. Water and methanol may play the role of ligands in this catalytic reaction. The structural assignments of synthesized compounds were made using 1 H and 13 C-NMR spectroscopy including two-dimensional experiments and confirmed by elemental analysis.
The signals of the carbon atoms of the CH group, which is bonded to the nitrogen atom, are observed in the 61-64 ppm region in the 13 C-NMR spectra of the obtained compounds. The carbon atoms of the SeCH group exhibit the direct spin-spin coupling constants ( 1 JSe-C), which are about 51-56 Hz in the 13 C-NMR spectra of the obtained compounds.
The NMR spectra of the products 5a-e contains singlets at 7.38−7.43 ppm ( 1 H-NMR) and signals at 119.4-119.8 ppm ( 13 C-NMR spectra) corresponding to the olefinic CH= group of the triazole ring. The signals of the olefinic CH= group of compounds 5i and 5j are observed at lower field at 8.23−8.25 ppm in the 1 H-NMR spectra and at 126.4-126.9 ppm in the 13 C-NMR spectra due to high electron-withdrawing effect of the alkoxycarbonyl group.
Compounds 5g,h, obtained from propargyl alcohol 4g and propargyl ether 4h, are poorly soluble in CDCl3 and their spectra are recorded in DMSO-d6.

General Information
The 1 Н (400.1 MHz) and 13 C (100.6 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 or DMSO-d6 solutions and referred to Scheme 9. The possible reaction pathway of the Cu-catalyzed formation of the products 5a-j.
The structural assignments of synthesized compounds were made using 1 H and 13 C-NMR spectroscopy including two-dimensional experiments and confirmed by elemental analysis.
The signals of the carbon atoms of the CH group, which is bonded to the nitrogen atom, are observed in the 61-64 ppm region in the 13 C-NMR spectra of the obtained compounds. The carbon atoms of the SeCH group exhibit the direct spin-spin coupling constants ( 1 J Se-C ), which are about 51-56 Hz in the 13 C-NMR spectra of the obtained compounds.
The NMR spectra of the products 5a-e contains singlets at 7.38−7.43 ppm ( 1 H-NMR) and signals at 119.4-119.8 ppm ( 13 C-NMR spectra) corresponding to the olefinic CH= group of the triazole ring. The signals of the olefinic CH= group of compounds 5i and 5j are observed at lower field at 8.23−8.25 ppm in the 1 H-NMR spectra and at 126.4-126.9 ppm in the 13 C-NMR spectra due to high electron-withdrawing effect of the alkoxycarbonyl group.
Compounds 5g,h, obtained from propargyl alcohol 4g and propargyl ether 4h, are poorly soluble in CDCl 3 and their spectra are recorded in DMSO-d 6 .

General Information
The 1 H (400.1 MHz) and 13 C (100.6 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 CDCl 3 or DMSO-d 6 solutions and referred to the residual solvent peaks of CDCl 3 (δ = 7.27 and 77.16 ppm) and DMSO-d 6 (δ = 2.50 and 39.50 ppm) for 1 H-and 13 C-NMR, respectively.
Elemental analysis was performed on a Thermo Scientific Flash 2000 Elemental Analyzer (Thermo Fisher Scientific Inc., Milan, Italy). Melting points were determined on a Kofler Hot-Stage Microscope PolyTherm A apparatus Wagner & Munz GmbH, München, Germany). The distilled organic solvents and degassed water were used in syntheses.

Synthesis of Starting Compound 3
2,6-Diazido-9-selenabicyclo[3.3.1]nonane (3). A solution of sodium azide (1.5 g, 23 mmol) in water (12 mL) was added dropwise to a mixture of compound 2 (0.75 g, 2.16 mmol) and acetonitrile (20 mL) with stirring at room temperature. The reaction mixture was stirred Catalysts 2022, 12, 1032 9 of 15 overnight (16 h) at room temperature. Acetonitrile was removed by a rotary evaporator and the residue was extracted with methylene chloride (2 × 20 mL). The organic phase was dried over CaCl 2 , the solvent was removed by a rotary evaporator and the residue was dried in, vacuum giving a compound 3 (586 mg, quantitative yield) as a grey oil. 1