Unexpected Ethyltellurenylation of Epoxides with Elemental Tellurium under Lithium Triethylborohydride Conditions

: The one-pot multistep ethyltellurenylation reaction of epoxides with elemental tellurium and lithium triethylborohydride is described. The reaction mechanism was experimentally investigated. Dilithium ditelluride and triethyl borane, formed from elemental tellurium and lithium triethylborohydride, were shown to be the key species involved in the reaction mechanism. Epoxides undergo ring-opening reaction with dilithium ditelluride to a ﬀ ord β -hydroxy ditellurides, which are sequentially converted into the corresponding β -hydroxy-alkyl ethyl tellurides by transmetalation with triethyl borane, reasonably proceeding through the S H 2 mechanism.

The development of new, reliable, and general methodologies towards these chalcogen-containing organic molecules is thus highly sought after in organic synthesis. Particularly, the possibility to access densely functionalised and sp 3 -rich compounds, characterised by high molecular complexity, enables the possibility to define and explore new chemical space and plays a key role in terms of successfully developing new catalysts and drug candidates [32,33]. Furthermore, sp 3 -rich organochalcogens bearing O-and N-containing functionalities have been demonstrated to possess improved catalytic and pharmacological properties [15][16][17]20,23,34]. However, although a number of methods for the synthesis of selenides and tellurides have been reported, a number of limitations remain, including functional-group compatibility and the harsh reaction conditions. Therefore, the development of mild procedures for the synthesis of densely functionalised molecules still remains challenging. Part a. A: a tellurium-containing biopolimeric nanogel for anticancer therapy [11]; B: telluriumcontaining carbonic anhydrases inhibitors with anticancer activity [15]; LQ7: a ditelluride active as antiparasitic agent [29]; ent-nakamurol A: an organotelluride is involved in the key step of its total synthesis [35]. Part b. Functionalization of organotellurium compounds [29,31].
Three-membered heterocycles such as epoxides and aziridines, often undergoing regioselective nucleophilic ring-opening reactions (NRORs), represent convenient starting materials for the synthesis of functionalised chalcogen-containing systems [36]. A number of ring-opening-based procedures for the synthesis of hydroxy-and amino-substituted selenides and tellurides have been developed over the last decade [37][38][39][40][41][42]. Such functionalised chalcogenides have also been employed as intermediates for the synthesis of valuable compounds [35,43,44] and as organocatalysts for the asymmetric addition of diethylzinc to aldehydes [45].
In this communication, as a part of our growing interest in the study of the chemistry of organotellurium compounds, we report a study on the mechanism of an unexpected reaction of epoxides with elemental tellurium and lithium triethylborohydride, leading to the formation of βhydroxy-alkyl ethyl tellurides.

Experimental Section
All reactions were carried out in an oven-dried glassware. Solvents were dried using a solvent purification system (Pure-Solv™, Darmstadt, Germany). All commercial materials were purchased from various commercial sources and used as received, without further purification. Flash column chromatography purifications were performed with Silica gel 60 (230-400 mesh). Thin layer chromatography was performed with TLC plates Silica gel 60 F254, which was visualised under UV Biological and synthetic applications of organotellurium compounds (selected examples). Part a. A: a tellurium-containing biopolimeric nanogel for anticancer therapy [11]; B: tellurium-containing carbonic anhydrases inhibitors with anticancer activity [15]; LQ7: a ditelluride active as antiparasitic agent [29]; ent-nakamurol A: an organotelluride is involved in the key step of its total synthesis [35]. Part b. Functionalization of organotellurium compounds [29,31].
Three-membered heterocycles such as epoxides and aziridines, often undergoing regioselective nucleophilic ring-opening reactions (NRORs), represent convenient starting materials for the synthesis of functionalised chalcogen-containing systems [36]. A number of ring-opening-based procedures for the synthesis of hydroxy-and amino-substituted selenides and tellurides have been developed over the last decade [37][38][39][40][41][42]. Such functionalised chalcogenides have also been employed as intermediates for the synthesis of valuable compounds [35,43,44] and as organocatalysts for the asymmetric addition of diethylzinc to aldehydes [45].
In this communication, as a part of our growing interest in the study of the chemistry of organotellurium compounds, we report a study on the mechanism of an unexpected reaction of epoxides with elemental tellurium and lithium triethylborohydride, leading to the formation of β-hydroxy-alkyl ethyl tellurides.

Experimental Section
All reactions were carried out in an oven-dried glassware. Solvents were dried using a solvent purification system (Pure-Solv™, Darmstadt, Germany). All commercial materials were purchased from various commercial sources and used as received, without further purification. Flash column chromatography purifications were performed with Silica gel 60 (230-400 mesh). Thin layer chromatography was performed with TLC plates Silica gel 60 F 254 , which was visualised under UV light, or by staining with an ethanolic acid solution of p-anisaldehyde followed by heating. High resolution mass spectra (HRMS) were recorded by electrospray ionization (ESI). In the control experiment with degassed solvent, tetrahydrofuran (THF) was degassed by freeze-pump-thaw cycles (×3) on the high vacuum line.
The 1 H and 13 C-NMR spectra were recorded in CDCl 3 with Mercury 400, Bruker 400 Ultrashield (Bruker, Milan, Italy), and Varian Gemini 200 spectrometers operating at 400 MHz for 1 H and 100 MHz for 13 C. NMR signals were referenced to nondeuterated residual solvent signals: 7.26 ppm for 1 H and 77.0 ppm for 13 C. The 125 Te-NMR spectra were recorded in CDCl 3 at 126 MHz with a Bruker Ultrashield 400 Plus instrument (Bruker, Milan, Italy). (PhTe) 2 was used as an external reference (δ = 420 ppm). Chemical shifts (δ) are given in parts per million (ppm), and coupling constants (J) are given in Hertz (Hz), rounded to the nearest 0.1 Hz. The 1 H-NMR data are reported as follows: chemical shift, integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublet, bs = broad singlet, ap = apparent), coupling constant (J), and assignment. Mass spectra (MS) were determined by ESI (Thermo Fisher Scientific, Milan, Italy).

General Procedure for the Synthesis of β-Hydroxy-alkyl Ethyl Tellurides 2
Li 2 Te 2 was generated according to the literature [48,49] from 1.0 mL of a 1 M THF solution of LiEt 3 BH (1.0 mmol, 1.0 eq.) and elemental tellurium powder (128 mg, 1.0 mmol, 1.0 eq.), stirred at ambient temperature under inert atmosphere (N 2 ) for 6 h. The dark red suspension of Li 2 Te 2 in THF was treated with the epoxide (1.0 mmol, 1.0 eq.) and the reaction was stirred for 6 h at ambient temperature. Afterwards, the mixture was diluted with Et 2 O (10 mL), filtered through a short pad of celite, and washed with saturated aq. NH 4 Cl and then with H 2 O (2 × 5 mL). The organic phase was dried over Na 2 SO 4 , filtered and evaporated under reduced pressure. The crude residue was then purified by flash chromatography (Et 2 O/petroleum ether) to yield β-hydroxy-alkyl ethyl tellurides 2.

Results
During the course of our studies on the reactivity of strained heterocycles with selenium-centered nucleophiles we developed convenient routes towards generating a variety of hydroxy-, amino-, and mercapto-substituted Se-containing systems [50][51][52][53]. For example, through the tuning of the stoichiometry and the conditions of the reaction of (Me 3 Si) 2 Se [(bis(trimethylsilyl)selenide, a synthetic equivalent of hydrogen selenide] with epoxides, thiiranes, and aziridines, we were able to successfully achieve a range of functionalised selenols [50], selenides, and diselenides [47].
Attracted by the synthetic utility and versatility of organotellurium compounds, we recently moved to evaluate the chemistry of tellurium-centered nucleophiles with strained heterocycles [46,49]. The poor stability of (Me 3 Si) 2 Te [48,49] prompted us to employ dilithium telluride and dilithium ditelluride, generated from elemental tellurium and lithium triethylborohydride (superhydride), as tellurenylation reagents for the NRORs of epoxides and aziridines [49]. However, while the ring-opening of epoxides with Li 2 Te provided access to symmetrical β-hydroxy-tellurides 1 (Scheme 1, part a), the reaction with Li 2 Te 2 gave almost exclusively β-hydroxy-alkyl ethyl tellurides 2 instead of the expected β-hydroxy-ditellurides 3, which were isolated only in trace amounts (Scheme 1, part b). Intrigued by this result, we wished to deeper investigate such a transformation in order to establish the mechanism involved in the formation of asymmetrical β-hydroxy-alkyl ethyl tellurides 2.  Copy of 1 H-NMR, 13 C-NMR, and 125 Te-NMR spectra can be found in Supplementary Materials.

Results
During the course of our studies on the reactivity of strained heterocycles with seleniumcentered nucleophiles we developed convenient routes towards generating a variety of hydroxy-, amino-, and mercapto-substituted Se-containing systems [50][51][52][53]. For example, through the tuning of the stoichiometry and the conditions of the reaction of (Me3Si)2Se [(bis(trimethylsilyl)selenide, a synthetic equivalent of hydrogen selenide] with epoxides, thiiranes, and aziridines, we were able to successfully achieve a range of functionalised selenols [50], selenides, and diselenides [47].
Attracted by the synthetic utility and versatility of organotellurium compounds, we recently moved to evaluate the chemistry of tellurium-centered nucleophiles with strained heterocycles [46,49]. The poor stability of (Me3Si)2Te [48,49] prompted us to employ dilithium telluride and dilithium ditelluride, generated from elemental tellurium and lithium triethylborohydride (superhydride), as tellurenylation reagents for the NRORs of epoxides and aziridines [49]. However, while the ring-opening of epoxides with Li2Te provided access to symmetrical β-hydroxy-tellurides 1 (Scheme 1, part a), the reaction with Li2Te2 gave almost exclusively β-hydroxy-alkyl ethyl tellurides 2 instead of the expected β-hydroxy-ditellurides 3, which were isolated only in trace amounts (Scheme 1, part b). Intrigued by this result, we wished to deeper investigate such a transformation in order to establish the mechanism involved in the formation of asymmetrical β-hydroxy-alkyl ethyl tellurides 2.  Notably, this ethyltellurenylation reaction proved to be general and differently substituted epoxides could be smoothly converted into the corresponding β-hydroxy-alkyl ethyl tellurides through this one-pot multistep procedure (Scheme 2).
Notably, this ethyltellurenylation reaction proved to be general and differently substituted epoxides could be smoothly converted into the corresponding β-hydroxy-alkyl ethyl tellurides through this one-pot multistep procedure (Scheme 2). Scheme 2. One-pot ethyltellurenylation of epoxides. Traces of ditellurides 3a-d (3%-7%) were detected in the crude material. Isolated yields are reported.
A plausible explanation for the formation of unsymmetrical tellurides 2 involves the transmetalation of triethylborane with β-hydroxy-ditellurides 3. However, an alternative path could proceed through the ring-opening of epoxides with tris(ethyltelluro)borane 4 (Scheme 3) which, in principle, could be generated from dilithium ditelluride and triethyl borane. A series of control experiments were therefore undertaken in order to test these hypotheses.
We initially evaluated whether tris(ethyltelluro)borane 4 could be generated upon the treatment of elemental tellurium with lithium triethylborohydride. However, the formation of 4 was not observed under the standard reaction conditions (Scheme 3, reaction a). Traces of 4 were not detected performing the reaction in a coaxial NMR tube and monitoring its progress over the time.
On the basis of these results, we next turned our attention to evaluating whether under the studied conditions ditellurides 3 could behave as precursors of β-hydroxy-alkyl ethyl tellurides 2. We recently developed an on-water methodology to access functionalised dialkyl ditellurides from elemental tellurium, sodium hydroxymethanesulfinate, and strained heterocycles [46]. Therefore, we employed this route to prepare β-hydroxy-ditelluride 3a and then we studied its reactivity with organoboranes. As a result, 3a was thus treated with lithium triethylborohydride and, pleasingly, βhydroxy-alkyl ethyl telluride 2a was formed in 42% yield (Scheme 3, reaction b). However, under these conditions the alkyltellurolate 5a, arising from the LiBEt3H-induced reduction of the ditelluride 3a, could be the species actually involved in the formation of 2a. Unequivocal proof for the direct involvement of ditelluride 3a and triethylborane was obtained by the reaction of these two compounds which, in the absence of hydrides, afforded 2a in 48% yield (Scheme 3, reaction c). Notably, related diselenide 6a reacted slowly with triethylborane under the same conditions and only traces (<5%) of unsymmetrical ethyl-selenide 7a were detected after 6 h (Scheme 3, reaction d).
Trialkyl boranes readily undergo radical reactions generating alkyl radicals. Such processes can be initiated by oxygen, light or radical initiators, such as AIBN (Azobisisobutyronitrile) [54,55]. Additionally, ditellurides have been demonstrated to easily react with alkyl radicals, exhibiting remarkable radical-trapping activity [56]. On the basis of these considerations and supported by a literature precedent describing the reactivity of diphenyl ditelluride with organoboranes [57], we hypothesised a radical process involving ditellurides 3 and ethyl radicals. Control experiments performed using 3,5-di-tert-butyl-4-hydroxytoluene (BHT) as a radical inhibitor further demonstrated a radical pathway. Additionally, performing reactions b and c (Scheme 3) in the dark had no significant effect on the reaction outcome, showing that light was not required for the process leading to 2a. On the other hand, when degassed tetrahydrofuran (THF) was used as the solvent, the ethyltellurenylation reaction was strongly inhibited and only traces of 2a (<10%) were isolated. Scheme 2. One-pot ethyltellurenylation of epoxides. Traces of ditellurides 3a-d (3%-7%) were detected in the crude material. Isolated yields are reported.
A plausible explanation for the formation of unsymmetrical tellurides 2 involves the transmetalation of triethylborane with β-hydroxy-ditellurides 3. However, an alternative path could proceed through the ring-opening of epoxides with tris(ethyltelluro)borane 4 (Scheme 3) which, in principle, could be generated from dilithium ditelluride and triethyl borane. A series of control experiments were therefore undertaken in order to test these hypotheses.
We initially evaluated whether tris(ethyltelluro)borane 4 could be generated upon the treatment of elemental tellurium with lithium triethylborohydride. However, the formation of 4 was not observed under the standard reaction conditions (Scheme 3, reaction a). Traces of 4 were not detected performing the reaction in a coaxial NMR tube and monitoring its progress over the time.
On the basis of these results, we next turned our attention to evaluating whether under the studied conditions ditellurides 3 could behave as precursors of β-hydroxy-alkyl ethyl tellurides 2. We recently developed an on-water methodology to access functionalised dialkyl ditellurides from elemental tellurium, sodium hydroxymethanesulfinate, and strained heterocycles [46]. Therefore, we employed this route to prepare β-hydroxy-ditelluride 3a and then we studied its reactivity with organoboranes. As a result, 3a was thus treated with lithium triethylborohydride and, pleasingly, β-hydroxy-alkyl ethyl telluride 2a was formed in 42% yield (Scheme 3, reaction b). However, under these conditions the alkyltellurolate 5a, arising from the LiBEt 3 H-induced reduction of the ditelluride 3a, could be the species actually involved in the formation of 2a. Unequivocal proof for the direct involvement of ditelluride 3a and triethylborane was obtained by the reaction of these two compounds which, in the absence of hydrides, afforded 2a in 48% yield (Scheme 3, reaction c). Notably, related diselenide 6a reacted slowly with triethylborane under the same conditions and only traces (<5%) of unsymmetrical ethyl-selenide 7a were detected after 6 h (Scheme 3, reaction d).
Trialkyl boranes readily undergo radical reactions generating alkyl radicals. Such processes can be initiated by oxygen, light or radical initiators, such as AIBN (Azobisisobutyronitrile) [54,55]. Additionally, ditellurides have been demonstrated to easily react with alkyl radicals, exhibiting remarkable radical-trapping activity [56]. On the basis of these considerations and supported by a literature precedent describing the reactivity of diphenyl ditelluride with organoboranes [57], we hypothesised a radical process involving ditellurides 3 and ethyl radicals. Control experiments performed using 3,5-di-tert-butyl-4-hydroxytoluene (BHT) as a radical inhibitor further demonstrated a radical pathway. Additionally, performing reactions b and c (Scheme 3) in the dark had no significant effect on the reaction outcome, showing that light was not required for the process leading to 2a. On the other hand, when degassed tetrahydrofuran (THF) was used as the solvent, the ethyltellurenylation reaction was strongly inhibited and only traces of 2a (<10%) were isolated. On the basis of the control experiments and previous reports, a proposed reaction mechanism is reported in Scheme 4. The first step (I) involves the reduction of elemental tellurium with lithium triethylborohydride, leading to the formation of dilithium ditelluride and triethylborane [58]. Subsequently (II), Li2Te2 reacts with two equivalents of epoxide to afford the corresponding ditelluride 3 through a regioselective nucleophilic ring-opening reaction. The following transmetalation of Et3B with 3 reasonably proceeds through the oxygen-mediated formation of ethyl radicals (III) [54,55] which, in turn, react with ditelluride 3 providing unsymmetrical β-hydroxy-alkyl ethyl telluride 2 through an SH2 process (IV) [59,60]. The tellurium-centered radical 8, formed in the SH2 reaction, undergoes typical propagation and termination processes, including the recombination with a second equivalent of 8 providing ditelluride 3 [61]. Furthermore, the reaction of 8 with oxygen or borylperoxyl radicals (V) would afford reactive tellurenyl peroxides which plausibly decompose, thus explaining the rather low yield of the transmetalation reaction and the absence of ditelluride 3, or unreacted epoxide in the crude mixture. On the basis of the control experiments and previous reports, a proposed reaction mechanism is reported in Scheme 4. The first step (I) involves the reduction of elemental tellurium with lithium triethylborohydride, leading to the formation of dilithium ditelluride and triethylborane [58]. Subsequently (II), Li 2 Te 2 reacts with two equivalents of epoxide to afford the corresponding ditelluride 3 through a regioselective nucleophilic ring-opening reaction. The following transmetalation of Et 3 B with 3 reasonably proceeds through the oxygen-mediated formation of ethyl radicals (III) [54,55] which, in turn, react with ditelluride 3 providing unsymmetrical β-hydroxy-alkyl ethyl telluride 2 through an S H 2 process (IV) [59,60]. The tellurium-centered radical 8, formed in the S H 2 reaction, undergoes typical propagation and termination processes, including the recombination with a second equivalent of 8 providing ditelluride 3 [61]. Furthermore, the reaction of 8 with oxygen or borylperoxyl radicals (V) would afford reactive tellurenyl peroxides which plausibly decompose, thus explaining the rather low yield of the transmetalation reaction and the absence of ditelluride 3, or unreacted epoxide in the crude mixture. On the basis of the control experiments and previous reports, a proposed reaction mechanism is reported in Scheme 4. The first step (I) involves the reduction of elemental tellurium with lithium triethylborohydride, leading to the formation of dilithium ditelluride and triethylborane [58]. Subsequently (II), Li2Te2 reacts with two equivalents of epoxide to afford the corresponding ditelluride 3 through a regioselective nucleophilic ring-opening reaction. The following transmetalation of Et3B with 3 reasonably proceeds through the oxygen-mediated formation of ethyl radicals (III) [54,55] which, in turn, react with ditelluride 3 providing unsymmetrical β-hydroxy-alkyl ethyl telluride 2 through an SH2 process (IV) [59,60]. The tellurium-centered radical 8, formed in the SH2 reaction, undergoes typical propagation and termination processes, including the recombination with a second equivalent of 8 providing ditelluride 3 [61]. Furthermore, the reaction of 8 with oxygen or borylperoxyl radicals (V) would afford reactive tellurenyl peroxides which plausibly decompose, thus explaining the rather low yield of the transmetalation reaction and the absence of ditelluride 3, or unreacted epoxide in the crude mixture.

Conclusions
In conclusion, we have described a one-pot multistep reaction in which epoxides are converted into the corresponding unsymmetrical β-hydroxy-alkyl ethyl tellurides upon treatment with elemental tellurium under lithium triethylborohydride-reducing conditions. The reaction mechanism was experimentally investigated; β-hydroxy ditellurides and triethyl borane were demonstrated to be the key species involved in this one-pot ethyltellurenylation reaction. The transmetalation of triethyl borane with hydroxy-dialkyl ditellurides, reasonably occurring through an oxygen-induced S H 2 mechanism, represents the key step of the process. The findings here described can be exploited for the development of novel general methodologies towards the synthesis of synthetically and biologically valuable complex sp 3 -rich unsymmetrical tellurides. Further studies on the application of this reaction to functionalised boranes (and boronic esters) for the preparation and the elaboration of poly-functionalised unsymmetrical tellurides are currently ongoing in our laboratories.
Funding: This research received no external funding.