# Electrophilic Trifluoromethylselenolation of Boronic Acids

Clément Ghiazza, Anis Tlili, Thierry Billard

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Clément Ghiazza, Anis Tlili, Thierry Billard. Electrophilic Trifluoromethylselenolation of Boronic Acids. Molecules, 2017, Tri- and Di-Fluoromethylation and Tri- and Di-Fluoromethylchalcogenation Reactions, 22 (5), pp.833. 10.3390/molecules22050833. hal-04409404

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Article

# Electrophilic Trifluoromethylselenolation of Boronic Acids

Clément Ghiazza<fnref n="1" />, Anis Tlili<fnref n="1" /> and Thierry Billard <fnref n="1" />,<fnref n="2" />,*

Academic Editor: Derek J. McPhee

Received: 1 May 2017; Accepted: 15 May 2017; Published: 19 May 2017

**Abstract:** Trifluoromethylselenylated compounds are emergent compounds with interesting physicochemical properties that still suffer from a lack of efficient synthetic methods. We recently developed an efficient one-pot strategy to generate in situ CF₃SeCl and use it in various reactions. Herein, we continue our study of the reactivity scope of this preformed reagent. Cross-coupling reactions with aromatic and heteroaromatic boronic acids have been investigated. The expected products have been obtained, using a stoichiometric amount of copper, with moderate yields.

**Keywords:** trifluoromethylselenolation; boronic acids; trifluoromethylselenyl chloride; fluorine; selenium

## 1. Introduction

Fluorinated compounds play a more and more important role in various fields of application. Among all the fluorinated substituents, the CF₃ group occupies a particular place due to its specific properties [1–13]. Furthermore, the association of this CF₃ moiety with chalcogens leads to new fluorinated substituents with very interesting electronic and physicochemical properties. This has been well illustrated by CF₃O- and CF₃S-molecules [14–18], especially due to their high lipophilicities (Hansch–Leo parameters: π<sub>R</sub>(OCF₃) = 1.04, π<sub>R</sub>(SCF₃) = 1.44) [19] which contribute to their favoring of membrane permeation and, consequently, increase their bioavailability. In the series of chalcogens, the CF₃Se group has been less investigated. However, selenylated compounds also play an important role in various fields of application, from materials to life sciences [20–31]. This is illustrated, for example, by the drug Ebselen [32–35]. Furthermore, the Hansch–Leo lipophilicity parameter of the CF₃Se group has been recently measured to π<sub>R</sub>(SeCF₃) = 1.29 [36].

Despite the strong interest in this group, synthetic methods to obtain trifluoromethylselenylated molecules are still limited. Trifluoromethylation of selenylated compounds has recently been investigated for the first time [37–49]. Although this strategy gave good results, the preliminary preparation of selenylated adducts can be a drawback. Late stage direct trifluoromethylselenolation appears to be the most versatile approach. Nucleophilic reactions have been the most investigated, with a large panel of organic compounds from nucleophilic substitutions onto halogen compounds or diazonium salts, to cross-coupling reactions with halogen substrates or boronic acids [50–64]. Nevertheless, this approach required the preparation of CF₃Se⁻ anions using a stoichiometric amount of selenium metal. Electrophilic trifluoromethylselenolations have been less described. The only available reagent for such reactions is CF₃SeCl, which is volatile, potentially toxic and, until recently, difficult to synthesize [65,66].

To favor a safe and easy handling of this reagent, we have recently described an efficient procedure to generate in situ this species from benzyl trifluoromethyl selenide (1). This strategy has already been

<footnote n="1">¹ Institute of Chemistry and Biochemistry (ICBMS-UMR CNRS 5246), Université de Lyon, Université Lyon 1, CNRS, F-69622 Lyon, France; clementghiazza@gmail.com (C.G.); anis tlili@univ-lyon1.fr (A.T.)</footnote>

<footnote n="2">² CERMEP—In Vivo Imaging, Groupement Hospitalier Est, F-69677 Lyon, France</footnote>

<footnote>* Correspondence: Thierry.billard@univ-lyon1.fr; Tel.: +33-472-448-129</footnote>
applied to electrophilic aromatic substitutions [67] and reactions with Grignard reagents and lithium alkynides [36].

## 2. Results and Discussion

In our objective to extend the scope of the reactivity of $CF_3SeCl$, following our one-pot strategy, we decided to study the trifluoromethylselenolation of boronic acids.

The reaction was first optimized with biphenyl boronic acid (2a). All the attempts are summarized in Table 1.

<table><caption>**Table 1.** Coupling reaction between $CF_3SeCl$, generated in situ, and boronic acid 3a.</caption><thead><tr><th>Entry</th><th>[Cu]</th><th>Ligand <sup>a</sup></th><th>Base</th><th>Solvent</th><th>3a (%) <sup>b</sup></th></tr></thead><tbody><tr><td>1</td><td>CuI (1 eq.)</td><td>L1 (2 eq.)</td><td>K<sub>2</sub>CO<sub>3</sub> (1 eq.)</td><td>CH<sub>3</sub>CN</td><td>5</td></tr><tr><td>2</td><td>Cu(OAc)<sub>2</sub> (1 eq.)</td><td>L1 (2 eq.)</td><td>K<sub>2</sub>CO<sub>3</sub> (1 eq.)</td><td>CH<sub>3</sub>CN</td><td>23</td></tr><tr><td>3</td><td>Cu(OAc)<sub>2</sub> (1 eq.)</td><td>L1 (2 eq.)</td><td>-</td><td>CH<sub>3</sub>CN</td><td>0</td></tr><tr><td>4</td><td>Cu(OAc)<sub>2</sub> (1 eq.)</td><td>-</td><td>K<sub>2</sub>CO<sub>3</sub> (1 eq.)</td><td>CH<sub>3</sub>CN</td><td>4</td></tr><tr><td>5</td><td>Cu(OAc)<sub>2</sub> (1 eq.)</td><td>L1 (1 eq.)</td><td>K<sub>2</sub>CO<sub>3</sub> (1 eq.)</td><td>CH<sub>3</sub>CN</td><td>40</td></tr><tr><td>6</td><td>Cu(OAc)<sub>2</sub> (1 eq.)</td><td>L2 (1 eq.)</td><td>K<sub>2</sub>CO<sub>3</sub> (1 eq.)</td><td>CH<sub>3</sub>CN</td><td>14</td></tr><tr><td>7</td><td>Cu(OAc)<sub>2</sub> (1 eq.)</td><td>L3 (1 eq.)</td><td>K<sub>2</sub>CO<sub>3</sub> (1 eq.)</td><td>CH<sub>3</sub>CN</td><td>3</td></tr><tr><td>8</td><td>Cu(OAc)<sub>2</sub> (1 eq.)</td><td>PPh<sub>3</sub> (1 eq.)</td><td>K<sub>2</sub>CO<sub>3</sub> (1 eq.)</td><td>CH<sub>3</sub>CN</td><td>0</td></tr><tr><td>9</td><td>Cu(OAc)<sub>2</sub> (1 eq.)</td><td>L4 (1 eq.)</td><td>K<sub>2</sub>CO<sub>3</sub> (1 eq.)</td><td>CH<sub>3</sub>CN</td><td>6</td></tr><tr><td>10</td><td>Cu(OAc)<sub>2</sub> (1 eq.)</td><td>L5 (1 eq.)</td><td>K<sub>2</sub>CO<sub>3</sub> (1 eq.)</td><td>CH<sub>3</sub>CN</td><td>3</td></tr><tr><td>11</td><td>Cu(OAc)<sub>2</sub> (1 eq.)</td><td>L6 (1 eq.)</td><td>K<sub>2</sub>CO<sub>3</sub> (1 eq.)</td><td>CH<sub>3</sub>CN</td><td>0</td></tr><tr><td>12</td><td>Cu(OAc)<sub>2</sub> (1 eq.)</td><td>L7 (1 eq.)</td><td>K<sub>2</sub>CO<sub>3</sub> (1 eq.)</td><td>CH<sub>3</sub>CN</td><td>0</td></tr><tr><td>13</td><td>Cu(OAc)<sub>2</sub> (1 eq.)</td><td>L1 (1 eq.)</td><td>Cs<sub>2</sub>CO<sub>3</sub> (1 eq.)</td><td>CH<sub>3</sub>CN</td><td>70</td></tr><tr><td>14</td><td>Cu(OAc)<sub>2</sub> (1 eq.)</td><td>L1 (1 eq.)</td><td>K<sub>3</sub>PO<sub>4</sub> (1 eq.)</td><td>CH<sub>3</sub>CN</td><td>48</td></tr><tr><td>15</td><td>Cu(OAc)<sub>2</sub> (1 eq.)</td><td>L1 (1 eq.)</td><td>CsF (1 eq.)</td><td>CH<sub>3</sub>CN</td><td>6</td></tr><tr><td>16</td><td>Cu(OAc)<sub>2</sub> (1 eq.)</td><td>L1 (1 eq.)</td><td>Et<sub>3</sub>N (1 eq.)</td><td>CH<sub>3</sub>CN</td><td>0</td></tr><tr><td>17</td><td>Cu(OAc)<sub>2</sub> (1 eq.)</td><td>L1 (1 eq.)</td><td>Pyridine (1 eq.)</td><td>CH<sub>3</sub>CN</td><td>0</td></tr><tr><td>18 <sup>c</sup></td><td>Cu(OAc)<sub>2</sub> (1 eq.)</td><td>L1 (1 eq.)</td><td>Cs<sub>2</sub>CO<sub>3</sub> (1 eq.)</td><td>CH<sub>3</sub>CN</td><td>37</td></tr><tr><td>19</td><td>Cu(OAc)<sub>2</sub> (0.2 eq.)</td><td>L1 (0.2 eq.)</td><td>Cs<sub>2</sub>CO<sub>3</sub> (1 eq.)</td><td>CH<sub>3</sub>CN</td><td>56</td></tr><tr><td>20</td><td>Cu(OAc)<sub>2</sub> (0.2 eq.)</td><td>L1 (0.4 eq.)</td><td>Cs<sub>2</sub>CO<sub>3</sub> (1 eq.)</td><td>CH<sub>3</sub>CN</td><td>50</td></tr><tr><td>21 <sup>c</sup></td><td>Cu(OAc)<sub>2</sub> (0.2 eq.)</td><td>L1 (0.2 eq.)</td><td>Cs<sub>2</sub>CO<sub>3</sub> (1 eq.)</td><td>CH<sub>3</sub>CN</td><td>-</td></tr><tr><td>22 <sup>d</sup></td><td>Cu(OAc)<sub>2</sub> (0.2 eq.)</td><td>L1 (0.2 eq.)</td><td>Cs<sub>2</sub>CO<sub>3</sub> (1 eq.)</td><td>CH<sub>3</sub>CN</td><td>60</td></tr></tbody></table>

The use of CuI as a catalyst with bipyridine L1 led to the expected compounds with a very low yield (Entry 1). With $Cu(OAc)_2$, a better yield was observed, but was still low (Entry 2). In order to improve this encouraging result, the base or ligand first had to be removed. Without the base, the reaction failed, although a small amount of 3a was observed without L1 (Entries 3–4). This led us to reduce the quantity of the ligand, and 40% of 3a was then formed (Entry 5). Next, various other ligands (Figure 1) were screened without success (Entries 6–12); bipyridine L1 remained the more efficient.

<footnote><sup>a</sup> See Figure 1 for ligand structures. <sup>b</sup> Yield was determined by <sup>19</sup>F-NMR spectroscopy by using $PhOCF_3$ as an internal standard. <sup>c</sup> 50 °C instead of r.t. <sup>d</sup> Addition of 7 eq. of $H_2O$.</footnote>
<figure><img src="image_2.png" /><figcaption>**Figure 1.** Ligands used in Table 1.</figcaption></figure>

The influence of the nature of the base was then explored. A good yield was obtained with $Cs_2CO_3$, whereas $K_3PO_4$ led to a similar result to that of $K_3CO_3$ (Entries 13–14). Surprisingly, CsF, often used in cross-coupling reactions with boronic acid, provided a low yield (Entry 15). Organic nitrogen bases appeared to be deleterious for the reaction (Entries 16–17). This could be explained by a competitive copper coordination between these bases and **L1**. At higher temperatures, no improvement was observed but, on contrary, this resulted in a decrease of yield (Entry 18). This may be due to the outgassing of the highly volatile $CF_3SeCl$ reagent.

Catalytic amounts of copper (II) and ligand were then tested, but lower yields were observed (Entries 19–20). Again, heating proved to be deleterious (Entry 21). Inspired by our previous work with a sulfur series [68], some water (7 eq.) was added resulting, in this case, in a non-significant effect (Entry 22). Consequently, stoichiometric conditions (Entry 13) remained the better ones.

These conditions were applied to other aromatic boronic acids (Scheme 1).

<figure><img src="image_3.png" /><figcaption>**Scheme 1.** Trifluoromethylselenolation of aromatic boronic acids. Yields shown are those of the isolated products.</figcaption></figure>

Only moderate yields were obtained with substituted aromatic compounds, whatever the donor or acceptor electronic character of the substituents. In heteroaromatic series, the same moderate results were observed.

When these lukewarm results were obtained, some amounts of $CF_3SeSeCF_3$ were detected as well as homocoupling products from the boronic reagents. This could be rationalized by the high reactivity
of CF₃SeCl, which leads to a competition between the kinetically low coupling reaction and the more rapid dimerization. The homocoupling reaction could then come from the lack of CF₃SeCl for the expected reaction. Despite the use of an excess of preformed CF₃SeCl, no better results were observed. Furthermore, during the preliminary formation of CF₃SeCl, one equivalent of benzyl chloride was also formed, which could possibly disturb the cross-coupling reaction.

### 3. Materials and Methods

Commercial reagents were used as supplied. Reagent **1** was synthesized following procedures described in the literature [36,67]. Anhydrous solvents were used as supplied. NMR spectra were recorded on a Bruker AV 400 (Billerica, MA, USA) spectrometer at 400 MHz (¹H-NMR), 101 MHz (¹³C-NMR), and 376 MHz (¹⁹F-NMR), or on a Bruker AV 300 spectrometer at 300 MHz (¹H-NMR) and 282 MHz (¹⁹F-NMR). Multiplicities are indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), p (quintet), sext (sextet), m (multiplet), b (broad). All coupling constants are reported in Hz.

#### 3.1. Synthesis of Benzyl Trifluoromethyl Selenide (**1**)

To a dry round-bottom flask equipped with a magnetic stirrer, benzylselanocyanate (13.7 g, 70.0 mmol, 1.0 equiv.) and dry THF (140 mL) were added. The flask was evacuated and refilled with nitrogen three times, and then trifluoromethyl trimethylsilane (TMSCF₃) (20.7 mL, 140 mmol, 2.0 equiv.) was added. The reaction mixture was cooled to 0 °C, and then tetrabutylammonium fluoride (TBAF) in THF 1 M (14.0 mL, 14.0 mmol, 0.2 equiv.) was added dropwise. After 10 min at 0 °C under nitrogen, the reaction was allowed to warm to 23 °C and was stirred for 7 h. The conversion was checked by ¹⁹F-NMR with PhOCF₃ as an internal standard. The reaction mixture was then partitioned between water and pentane, and the aqueous layer was extracted with pentane. The combined organic layers were washed with brine, dried over MgSO₄, filtered through a pad of silica (rinsed with pentane) and concentrated to dryness (under moderate vacuum). The crude residue was purified by chromatography (pentane: 100) to afford the desired product **1** as a colorless liquid (11.7 g, 70% yield). ¹H-NMR (300 MHz, CDCl₃): δ = 7.37–7.27 (massif, 5H), 4.26 (s, 2H). ¹⁹F-NMR (282 MHz, CDCl₃): δ = −34.47 (s, 3F). The results are in accordance with the literature [38].

#### 3.2. Typical Procedure

**Solution A:** To a flame-dried flask equipped with a magnetic stirrer, BnSeCF₃ (**1**) (0.40 mmol, 1.1 equiv.), SO₂Cl₂ (0.40 mmol, 1.1 equiv.) and anhydrous acetonitrile (1 mL) were added under nitrogen. The reaction mixture was stirred for 6 h at 20 °C.

**Solution B:** To a flame-dried flask equipped with a magnetic stirrer, biphenylboronic acid **2** (0.36 mmol, 1 equiv.), copper (II) acetate (0.36 mmol, 1 equiv.), bypyrydine (**L1**) (0.36 mmol, 1 equiv.) and cesium carbonate (0.36 mmol, 1 equiv.) were added under nitrogen.

Solution A was then poured into solution B by syringe and the mixture was stirred at 20 °C for 16 h. Conversion was checked by ¹⁹F-NMR with PhOCF₃ as an internal standard. The reaction mixture was partitioned between CH₂Cl₂ and water. The aqueous layer was extracted with CH₂Cl₂ and the combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated to dryness. The crude residue was purified by flash chromatography to afford the desired product **3**.

<figure><img src="image_4.png" /></figure>

*Synthesis of 4-[(trifluoromethyl)selanyl]-1,1'-biphenyl (3a).* Eluent for flash chromatography: cyclohexane/ AcOEt 98:2. ¹H-NMR (300 MHz, CDCl₃) δ = 7.83 (m, 2H), 7.65–7.60 (massif, 4H), 7.50 (m, 2H), 7.42 (m, 1H). ¹⁹F-NMR (282 MHz, CDCl₃) δ = −36.05 (s, 3F). The results are in accordance with the literature [57].
<figure><img src="image_5.png" /></figure>

*Synthesis of 1-bromo-4-[(trifluoromethyl)selanyl]benzene (3b).* Eluent for flash chromatography: pentane 100%. ¹H-NMR (300 MHz, CDCl₃) δ = 7.60 (m, 2H), 7.53 (m, 2H). ¹⁹F-NMR (282 MHz, CDCl₃) δ = -36.03 (s, 3F). The results are in accordance with the literature [61].

<figure><img src="image_6.png" /></figure>

*Synthesis of 1-methoxy-4-[(trifluoromethyl)selanyl]benzene (3c).* Eluent for flash chromatography: cyclohexane/toluene 9:1. ¹H-NMR (300 MHz, CDCl₃) δ = 7.66 (m, 2H), 6.91 (m, 2H), 3.83 (s, 3H). ¹⁹F-NMR (282 MHz, CDCl₃) δ = -37.18 (s, 3F). The results are in accordance with the literature [61].

<figure><img src="image_7.png" /></figure>

*Synthesis of methyl 4-[(trifluoromethyl)selanyl]benzoate (3d).* Eluent for flash chromatography: cyclohexane/EtOAc 97:3 to 95:5. ¹H-NMR (300 MHz, CDCl₃) δ = 8.04 (m, 2H), 7.81 (m, 2H), 3.94 (s, 3H). ¹⁹F-NMR (282 MHz, CDCl₃) δ = -35.21 (s, 3F). The results are in accordance with the literature [57].

<figure><img src="image_8.png" /></figure>

*Synthesis of 3-[(trifluoromethyl)selanyl]quinoline (3e).* Eluent for flash chromatography: cyclohexane/Et₂O 8:2. ¹H-NMR (300 MHz, CDCl₃) δ = 9.14 (s, 1H), 8.65 (d, *J* = 1.8 Hz, 1H), 8.21 (d, *J* = 8.7 Hz, 1H), 7.86 (m, 2H), 7.67 (m, 1H). ¹⁹F-NMR (282 MHz, CDCl₃) δ = -35.50 (s, 3F). The results are in accordance with the literature [53].

<figure><img src="image_9.png" /></figure>

*Synthesis of 3-[(trifluoromethyl)selanyl]-1-benzothiophene (3f).* Eluent for flash chromatography: cyclohexane/toluene 98:2. ¹H-NMR (300 MHz, CDCl₃) δ = 8.02 (d, *J* = 7.7 Hz, 1H), 7.96 (s, 1H), 7.92 (m, 1H), 7.51 (m, 1H), 7.44 (m, 1H). ¹⁹F-NMR (282 MHz, CDCl₃) δ = -35.66 (s, 3F). The results are in accordance with the literature [57].

4. Conclusions

In our study of its reactivity scope, we have demonstrated that CF₃SeCl, in situ preformed, could react with boronic acids to perform trifluoromethylselenolation of aromatic or heteroaromatic compounds. However, moderate yields were generally observed due to the overly high reactivity of CF₃SeCl and the presence of generated benzyl chloride. This points out the major issue of this one-pot strategy; the subsequently formed benzyl chloride may limit this approach by inducing side-reactions. Furthermore, the high reactivity of CF₃SeCl, which can easily dimerize, could also constitute a drawback with reactions which are kinetically too low. This underlines the necessity of developing new reagents, that are isolable, easy to handle and have a modular reactivity that is easier to control.

**Acknowledgments:** Clément Ghiazza held a doctoral fellowship from la Région Rhône Alpes. The authors are grateful to the CNRS and the French Ministry of Research for financial support. The French Fluorine Network is also acknowledged for its support.
**Author Contributions:** All the experiments have been performed by Clément Ghiazza. Anis Tlili and Thierry Billard have supervised and discussed this research. Thierry Billard has written this manuscript. All authors are aware of this manuscript and have agreed for its publication.

**Conflicts of Interest:** The authors declare no conflicts of interest.

## References

1. Smart, B.E. Fluorine substituent effects (on bioactivity). *J. Fluor. Chem.* **2001**, *109*, 3–11. [CrossRef]

2. Becker, A. *Inventory of Industrial Fluoro-Biochemicals*; Eyrolles: Paris, France, 1996.

3. Fujiwara, T.; O'Hagan, D. Successful fluorine-containing herbicide agrochemicals. *J. Fluor. Chem.* **2014**, *167*, 16–29. [CrossRef]

4. Gillis, E.P.; Eastman, K.J.; Hill, M.D.; Donnelly, D.J.; Meanwell, N.A. Applications of Fluorine in Medicinal Chemistry. *J. Med. Chem.* **2015**, *58*, 8315–8359. [CrossRef]

5. Hagmann, W.K. The Many Roles for Fluorine in Medicinal Chemistry. *J. Med. Chem.* **2008**, *51*, 4359–4369. [CrossRef] [PubMed]

6. Hird, M. Fluorinated liquid crystals—Properties and applications. *Chem. Soc. Rev.* **2007**, *36*, 2070–2095. [CrossRef] [PubMed]

7. Pagliaro, M.; Ciriminna, R. New fluorinated functional materials. *J. Mater. Chem.* **2005**, *15*, 4981–4991. [CrossRef]

8. Theodoridis, G. Chapter 4 Fluorine-Containing Agrochemicals: An Overview of Recent Developments. In *Advances in Fluorine Science*; Tressaud, A., Ed.; Elsevier: Amsterdam, The Netherlands, 2006; Volume 2, pp. 121–175.

9. Wang, J.; Sánchez-Roselló, M.; Aceña, J.L.; del Pozo, C.; Sorochinsky, A.E.; Fustero, S.; Soloshonok, V.A.; Liu, H. Fluorine in Pharmaceutical Industry: Fluorine-Containing Drugs Introduced to the Market in the Last Decade (2001–2011). *Chem. Rev.* **2014**, *114*, 2432–2506. [CrossRef] [PubMed]

10. Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Aceña, J.L.; Soloshonok, V.A.; Izawa, K.; Liu, H. Next Generation of Fluorine-Containing Pharmaceuticals, Compounds Currently in Phase II–III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas. *Chem. Rev.* **2016**, *116*, 422–518. [CrossRef] [PubMed]

11. Jeschke, P. The unique role of halogen substituents in the design of modern agrochemicals. *Pest Manag. Sci.* **2010**, *66*, 10–27. [CrossRef] [PubMed]

12. Chopra, D.; Row, T.N.G. Role of organic fluorine in crystal engineering. *CrystEngComm* **2011**, *13*, 2175–2186. [CrossRef]

13. Berger, R.; Resnati, G.; Metrangolo, P.; Weber, E.; Hulliger, J. Organic fluorine compounds: A great opportunity for enhanced materials properties. *Chem. Soc. Rev.* **2011**, *40*, 3496–3508. [CrossRef] [PubMed]

14. Toulgoat, F.; Alazet, S.; Billard, T. Direct Trifluoromethylthiolation Reactions: The “Renaissance” of an Old Concept. *Eur. J. Org. Chem.* **2014**, 2415–2428. [CrossRef]

15. Xu, X.-H.; Matsuzaki, K.; Shibata, N. Synthetic Methods for Compounds Having CF₃–S Units on Carbon by Trifluoromethylation, Trifluoromethylthiolation, Triflylation, and Related Reactions. *Chem. Rev.* **2015**, *115*, 731–764. [CrossRef]

16. Tlili, A.; Toulgoat, F.; Billard, T. Synthetic Approaches to Trifluoromethoxy-Substituted Compounds. *Angew. Chem. Int. Ed.* **2016**, *55*, 11726–11735. [CrossRef]

17. Leroux, F.R.; Manteau, B.; Vors, J.-P.; Pazenok, S. Trifluoromethyl ethers—Synthesis and properties of an unusual substituent. *Beilstein J. Org. Chem.* **2008**, *4*, 13. [CrossRef]

18. Ben-David, I.; Rechavi, D.; Mishani, E.; Rozen, S. A novel synthesis of trifluoromethyl ethers via xanthates, utilizing BrF₃. *J. Fluor. Chem.* **1999**, *97*, 75–78. [CrossRef]

19. Leo, A.; Hansch, C.; Elkins, D. Partition coefficients and their uses. *Chem. Rev.* **1971**, *71*, 525–616. [CrossRef]

20. Abdulah, R.; Miyazaki, K.; Nakazawa, M.; Koyama, H. Chemical forms of selenium for cancer prevention. *J. Trace Elem. Med. Biol.* **2005**, *19*, 141–150. [CrossRef]

21. Bodnar, M.; Konieczka, P.; Namiesnik, J. The Properties, Functions, and Use of Selenium Compounds in Living Organisms. *J. Environ. Sci. Health C Environ. Carcinog. Ecotoxicol. Rev.* **2012**, *30*, 225–252. [CrossRef]

22. Brown, K.M.; Arhur, J.R. Selenium, selenoproteins and human health: A review. *Public Health Nutr.* **2001**, *4*, 593–599. [CrossRef]
23. Combs, G.F.; Gray, W.P. Chemopreventive agents: Selenium. *Pharmacol. Therap.* **1998**, *79*, 179–192. [CrossRef]

24. Holben, D.H.; Smith, A.M. The diverse role of selenium within selenoproteins: A review. *J. Am. Diet. Assoc.* **1999**, *99*, 836–843. [CrossRef]

25. Kyriakopoulos, A.; Behne, D. Selenium-containing proteins in mammals and other forms of life. *Rev. Physiol. Biochem. Pharmacol.* **2002**, *145*, 1–46.

26. Lu, J.; Holmgren, A. Selenoproteins. *J. Biol. Chem.* **2009**, *284*, 723–727. [CrossRef]

27. Rayman, M.P. The importance of selenium to human health. *Lancet.* **2000**, *356*, 233–241. [CrossRef]

28. Romashov, L.V.; Ananikov, V.P. Self-Assembled Selenium Monolayers: From Nanotechnology to Materials Science and Adaptive Catalysis. *Chem. Eur. J.* **2013**, *19*, 17640–17660. [CrossRef]

29. Wessjohann, L.A.; Schneider, A.; Abbas, M.; Brandt, W. Selenium in chemistry and biochemistry in comparison to sulfur. *Biol. Chem.* **2007**, *388*, 997–1006. [CrossRef]

30. Angeli, A.; Tanini, D.; Viglianisi, C.; Panzella, L.; Capperucci, A.; Menichetti, S.; Supuran, C.T. Evaluation of selenide, diselenide and selenoheterocycle derivatives as carbonic anhydrase I, II, IV, VII and IX inhibitors. *Bioorg. Med. Chem.* **2017**, *25*, 2518–2523. [CrossRef]

31. Pacuła, A.J.; Kaczor, K.B.; Wojtowicz, A.; Antosiewicz, J.; Janecka, A.; Długosz, A.; Janecki, T.; Ścianowski, J. New glutathione peroxidase mimetics—Insights into antioxidant and cytotoxic activity. *Bioorg. Med. Chem.* **2017**, *25*, 126–131. [CrossRef] [PubMed]

32. Lynch, E.D.; Gu, R.; Pierce, C.; Kil, J. Reduction of acute cisplatin ototoxicity and nephrotoxicity in rats by oral administration of allopurinol and ebselen. *Hear. Res.* **2005**, *201*, 81–89. [CrossRef]

33. Singh, N.; Sharpley, A.L.; Emir, U.E.; Masaki, C.; Herzallah, M.M.; Gluck, M.A.; Sharp, T.; Harmer, C.J.; Vasudevan, S.R.; Cowen, P.J.; et al. Effect of the Putative Lithium Mimetic Ebselen on Brain Myo-Inositol, Sleep, and Emotional Processing in Humans. *Neuropsychopharmacology* **2016**, *41*, 1768–1778. [CrossRef]

34. Thangamani, S.; Younis, W.; Seleem, M.N. Repurposing ebselen for treatment of multidrug-resistant staphylococcal infections. *Sci. Rep.* **2015**, *5*, 11596. [CrossRef] [PubMed]

35. Singh, N.; Halliday, A.C.; Thomas, J.M.; Kuznetsova, O.V.; Baldwin, R.; Woon, E.C.Y.; Aley, P.K.; Antoniadou, I.; Sharp, T.; Vasudevan, S.R.; et al. A safe lithium mimetic for bipolar disorder. *Nat. Commun.* **2013**, *4*, 1332. [CrossRef]

36. Glenadel, Q.; Ismalaj, E.; Billard, T. Electrophilic Trifluoromethyl- and Fluoroalkylselenolation of Organometallic Reagents. *Eur. J. Org. Chem.* **2017**, *2017*, 530–533. [CrossRef]

37. Billard, T.; Langlois, B.R. A new simple access to trifluoromethyl thioethers or selenoethers from trifluoromethyl trimethylsilane and disulfides or diselenides. *Tetrahedron Lett.* **1996**, *37*, 6865–6868. [CrossRef]

38. Billard, T.; Large, S.; Langlois, B.R. Preparation of trifluoromethyl sulfides or selenides from trifluoromethyl trimethylsilane and thiocyanates or selenocyanates. *Tetrahedron Lett.* **1997**, *38*, 65–68. [CrossRef]

39. Billard, T.; Langlois, B.R.; Large, S. Synthesis of Trifluoromethyl Selenides. *Phosphorus Sulfur Silicon Relat. Elem.* **1998**, *136*, 521–524. [CrossRef]

40. Billard, T.; Roques, N.; Langlois, B.R. Synthetic Uses of Thio- and Selenoesters of Trifluoromethylated Acids. 1. Preparation of Trifluoromethyl Sulfides and Selenides. *J. Org. Chem.* **1999**, *64*, 3813–3820. [CrossRef]

41. Large, S.; Roques, N.; Langlois, B.R. Nucleophilic Trifluoromethylation of Carbonyl Compounds and Disulfides with Trifluoromethane and Silicon-Containing Bases. *J. Org. Chem.* **2000**, *65*, 8848–8856. [CrossRef]

42. Blond, G.; Billard, T.; Langlois, B.R. New stable reagents for the nucleophilic trifluoromethylation. Part 4: Trifluoromethylation of disulfides and diselenides with hemiaminals of trifluoroacetaldehyde. *Tetrahedron Lett.* **2001**, *42*, 2473–2475. [CrossRef]

43. Magnier, E.; Vit, E.; Wakselman, C. A Convenient Access to Perfluoroalkyl Selenoethers and Selenyl Chlorides. *Synlett* **2001**, 1260–1262. [CrossRef]

44. Pooput, C.; Medebielle, M.; Dolbier, W.R. A New and Efficient Method for the Synthesis of Trifluoromethylthio- and Selenoethers. *Org. Lett.* **2004**, *6*, 301–303. [CrossRef]

45. Pooput, C.; Dolbier, W.R.; Médebielle, M. Nucleophilic Perfluoroalkylation of Aldehydes, Ketones, Imines, Disulfides, and Diselenides. *J. Org. Chem.* **2006**, *71*, 3564–3568. [CrossRef]

46. Cherkupally, P.; Beier, P. Alkoxide-induced nucleophilic trifluoromethylation using diethyl trifluoromethylphosphonate. *Tetrahedron Lett.* **2010**, *51*, 252–255. [CrossRef]

47. Potash, S.; Rozen, S. General Synthesis of Trifluoromethyl Selenides Utilizing Selenocyanates and Fluoroform. *J. Org. Chem.* **2014**, *79*, 11205–11208. [CrossRef]
48. Ma, J.-J.; Yi, W.-B.; Lu, G.-P.; Cai, C. Trifluoromethylation of thiophenols and thiols with sodium trifluoromethanesulfinate and iodine pentoxide. *Catal. Sci. Technol.* **2016**, *6*, 417-421. [CrossRef]

49. Nikolaienko, P.; Rueping, M. Trifluoromethylselenolation of Aryldiazonium Salts: A Mild and Convenient Copper-Catalyzed Procedure for the Introduction of the SeCF₃ Group. *Chem. Eur. J.* **2016**, *22*, 2620–2623. [CrossRef]

50. Kondratenko, N.V.; Kolomeytsev, A.A.; Popov, V.I.; Yagupolskii, L.M. Synthesis and Reactions of Trifluoromethylthio(seleno)- and Pentafluorophenylthio(seleno)-copper. *Synthesis* **1985**, 667–669. [CrossRef]

51. Zhu, P.; He, X.; Chen, X.; You, Y.; Yuan, Y.; Weng, Z. Copper-mediated synthesis of α-trifluoromethylthio- and seleno-α,β-unsaturated carbonyl compounds. *Tetrahedron* **2014**, *70*, 672–677. [CrossRef]

52. Rong, M.; Huang, R.; You, Y.; Weng, Z. Synthesis of propargylic and allylic trifluoromethyl selenoethers by copper-mediated trifluoromethylselenolation of propargylic chlorides and allylic bromides. *Tetrahedron* **2014**, *70*, 8872–8878. [CrossRef]

53. Chen, C.; Ouyang, L.; Lin, Q.; Liu, Y.; Hou, C.; Yuan, Y.; Weng, Z. Synthesis of CuI Trifluoromethylselenates for Trifluoromethylselenolation of Aryl and Alkyl Halides. *Chem. Eur. J.* **2014**, *20*, 657–661. [CrossRef]

54. Chen, C.; Hou, C.; Wang, Y.; Hor, T.S.A.; Weng, Z. Copper-Catalyzed Trifluoromethylselenolation of Aryl and Alkyl Halides: The Silver Effect in Transmetalation. *Org. Lett.* **2014**, *16*, 524–527. [CrossRef]

55. Wu, C.; Huang, Y.; Chen, Z.; Weng, Z. Synthesis of vinyl trifluoromethyl selenoethers. *Tetrahedron Lett.* **2015**, *56*, 3838–3841. [CrossRef]

56. Wang, Y.; You, Y.; Weng, Z. Alkynyl trifluoromethyl selenide synthesis via oxidative trifluoromethylselenolation of terminal alkynes. *Org. Chem. Front.* **2015**, *2*, 574–577. [CrossRef]

57. Lefebvre, Q.; Pluta, R.; Rueping, M. Copper catalyzed oxidative coupling reactions for trifluoromethylselenolations
—Synthesis of R-SeCF₃ compounds using air stable tetramethylammonium trifluoromethylselenate.
*Chem. Commun.* **2015**, *51*, 4394–4397. [CrossRef]

58. Hou, C.; Lin, X.; Huang, Y.; Chen, Z.; Weng, Z. Synthesis of β-Trifluoromethylthio- and β-Trifluoromethylseleno-α,β-unsaturated Ketones through Copper-Mediated Trifluoromethylthio(seleno)lation. *Synthesis* **2015**, *47*, 969–975. [CrossRef]

59. Aufiero, M.; Sperger, T.; Tsang, A.S.K.; Schoenebeck, F. Highly Efficient C-SeCF₃ Coupling of Aryl Iodides Enabled by an Air-Stable Dinuclear PdI Catalyst. *Angew. Chem. Int. Ed.* **2015**, *54*, 10322–10326. [CrossRef]

60. Tian, Q.; Weng, Z. A Convenient Process for the Preparation of Heteroaryl Trifluoromethyl Selenoethers. *Chin. J. Chem.* **2016**, *34*, 505–510. [CrossRef]

61. Matheis, C.; Wagner, V.; Goossen, L.J. Sandmeyer-Type Trifluoromethylthiolation and Trifluoromethylselenolation of (Hetero)Aromatic Amines Catalyzed by Copper. *Chem. Eur. J.* **2016**, *22*, 79–82. [CrossRef]

62. Matheis, C.; Krause, T.; Bragoni, V.; Goossen, L.J. Trifluoromethylthiolation and Trifluoromethylselenolation of α-Diazo Esters Catalyzed by Copper. *Chem. Eur. J.* **2016**, *22*, 12270–12273. [CrossRef]

63. Fang, W.-Y.; Dong, T.; Han, J.-B.; Zha, G.-F.; Zhang, C.-P. Expeditious trifluoromethylthiolation and trifluoromethylselenolation of alkynyl(phenyl)iodoniums by [XCF₃]⁻ (X = S, Se) anions. *Org. Biomol. Chem.* **2016**, *14*, 11502–11509. [CrossRef]

64. Wang, J.; Zhang, M.; Weng, Z. A general method for synthesis of Se-trifluoromethyl esters through Iron-catalyzed trifluoromethylselenolation of acid chlorides. *J. Fluor. Chem.* **2017**, *193*, 24–32. [CrossRef]

65. Dale, J.W.; Emeleus, H.J.; Haszeldine, R.N. Organometallic and organometalloidal fluorine compounds. Part XIV. Trifluoromethyl derivatives of selenium. *J. Chem. Soc.* **1958**, 2939–2945. [CrossRef]

66. Yarovenko, N.N.; Shemanina, V.N.; Gazieva, G.B. Preparation of hexafluorodimethyl diselenide from salts of trifluoroacetic acid, and some of its properties. *Russ. J. Gen. Chem.* **1959**, *29*, 924–927.

67. Glenadel, Q.; Ismalaj, E.; Billard, T. Benzyltrifluoromethyl (or Fluoroalkyl) Selenide: Reagent for Electrophilic Trifluoromethyl (or Fluoroalkyl) Selenolation. *J. Org. Chem.* **2016**, *81*, 8268–8275. [CrossRef]

68. Glenadel, Q.; Alazet, S.; Tlili, A.; Billard, T. Mild and Soft Catalyzed Trifluoromethylthiolation of Boronic Acids: The Crucial Role of Water. *Chem. Eur. J.* **2015**, *21*, 14694–14698. [CrossRef]

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