Electrophilic Trifluoromethylselenolation of Boronic

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May 19, 2017 - Coupling reaction between CF3SeCl, generated in situ, and boronic acid 3a. ..... Matheis, C.; Wagner, V.; Goossen, L.J. Sandmeyer-Type ...
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Electrophilic Trifluoromethylselenolation of Boronic Acids Clément Ghiazza 1 , Anis Tlili 1 and Thierry Billard 1,2, * 1 2

*

Institute of Chemistry and Biochemistry (ICBMS-UMR CNRS 5246), Université de Lyon, Université Lyon 1, CNRS, F-69622 Lyon, France; [email protected] (C.G.); [email protected] (A.T.) CERMEP—In Vivo Imaging, Groupement Hospitalier Est, F-69677 Lyon, France Correspondence: [email protected]; Tel.: +33-472-448-129

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 CF3 SeCl 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 CF3 O- and CF3 S-molecules [14–18], especially due to their high lipophilicities (Hansch–Leo parameters: πR (OCF3 ) = 1.04, πR (SCF3 ) = 1.44) [19] which contribute to their favoring of membrane permeation and, consequently, increase their bioavailability. In the series of chalcogens, the CF3 Se 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 CF3 Se group has been recently measured to πR (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 CF3 Se− anions using a stoichiometric amount of selenium metal. Electrophilic trifluoromethylselenolations have been less described. The only available reagent for such reactions is CF3 SeCl, 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

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been applied to electrophilic aromatic substitutions [67] and reactions with Grignard reagents and applied to electrophilic aromatic substitutions [67] and reactions with Grignard reagents and lithium lithium alkynides [36]. alkynides [36]. 2. 2. Results Results and and Discussion Discussion In In our our objective objective to to extend extend the the scope scope of of the the reactivity reactivity of of CF CF33SeCl, SeCl,following followingour ourone-pot one-potstrategy, strategy, we decided to study the trifluoromethylselenolation of boronic acids. we decided to study the trifluoromethylselenolation of boronic acids. The boronic acid acid (2a). (2a). All The reaction reaction was was first first optimized optimized with with biphenyl biphenyl boronic All the the attempts attempts are are summarized summarized in Table 1. in Table 1. Table 1. Coupling reaction between CF33SeCl, generated in situ, and boronic acid 3a.

Base Solvent 3a (%) b Entry [Cu] Ligand a a Entry [Cu] Ligand Base Solvent 3a (%) b L1 (2 eq.) 1 CuI (1 eq.) K2CO3 (1 eq.) CH3CN 5 1 CuI (1 eq.) L1 (2 eq.) K2 CO3 (1 eq.) CH3 CN 5 L1 (2 eq.) 2 Cu(OAc) 2 (1 eq.) K2CO3 (1 eq.) CHCH 3CN 23 2 Cu(OAc)2 (1 eq.) L1 (2 eq.) K2 CO3 (1 eq.) 23 3 CN L1 (2 eq.) 3 Cu(OAc) 2 (1 eq.) CH 3 CN 3 Cu(OAc)2 (1 eq.) L1 (2 eq.) CH3 CN 0 0 4Cu(OAc) Cu(OAc) (1 eq.) K CO (1 eq.) CH CN 4 4 4 2 (1 eq.) K 2 CO 3 (1 eq.) CH 3 CN 2 2 3 3 5 Cu(OAc) (1 eq.) L1 (1 eq.) K CO (1 eq.) CH CN 40 3 3CN L1 (1 eq.) 5 Cu(OAc)2 (1 eq.)2 K22CO33 (1 eq.) CH 40 6 Cu(OAc) (1 eq.) L2 (1 eq.) K2 CO3 (1 eq.) CH3 CN 14 L2 (1 eq.) 6 Cu(OAc)2 (1 eq.)2 K2CO3 (1 eq.) CH3CN 14 7 Cu(OAc)2 (1 eq.) L3 (1 eq.) K2 CO3 (1 eq.) CH3 CN 3 L3 PPh (1 eq.) 7 2 (1 eq.) CO33(1(1eq.) eq.) CHCH 3CN 8Cu(OAc) Cu(OAc) KK22CO 0 3 3 (1 eq.) 2 (1 eq.) 3 CN PPh 3 (1 eq.) 8 2 (1 eq.) 2 CO 3 (1 eq.) CH 3 CN K 9Cu(OAc) Cu(OAc) (1 eq.) L4 (1 eq.) K CO (1 eq.) CH CN 6 0 2 2 3 3 10Cu(OAc) Cu(OAc) L5eq.) (1 eq.) KK22CO 3 6 2 (1 eq.) L4 (1 3 CN 9 2 (1 eq.) CO33(1(1eq.) eq.) CHCH 3CN 11 Cu(OAc) (1 eq.) L6 (1 eq.) K CO (1 eq.) CH CN 0 3 2 2 3 3 L5 (1 eq.) 10 Cu(OAc)2 (1 eq.) K2CO3 (1 eq.) CH3CN 12 Cu(OAc)2 (1 eq.) L7 (1 eq.) K2 CO3 (1 eq.) CH3 CN 0 L6 (1 eq.) 11 2 (1 eq.) K2CO CO3 (1 (1 eq.) eq.) CHCH 3CN 0 13Cu(OAc) Cu(OAc) (1 eq.) L1 (1 eq.) Cs CN 70 2 2 3 3 L7 (1 eq.) 12 Cu(OAc) 2 (1 eq.) K 2 CO 3 (1 eq.) CH 3 CN 14 Cu(OAc)2 (1 eq.) L1 (1 eq.) K3 PO4 (1 eq.) CH3 CN 48 0 15Cu(OAc) Cu(OAc) L1eq.) (1 eq.) CsF (13 eq.) 6 70 13 2 (1 eq.) Cs 2CO (1 eq.) CHCH 3CN 2 (1 eq.) L1 (1 3 CN 16Cu(OAc) Cu(OAc) L1eq.) (1 eq.) Et33PO N (1 eq.) CH 0 48 2 (1 eq.) L1 (1 3 CN 14 2 (1 eq.) K 4 (1 eq.) CH 3CN 17 Cu(OAc)2 (1 eq.) L1 (1 eq.) Pyridine (1 eq.) CH3 CN 0 L1 (1 eq.) 15 Cu(OAc)2 (1 eq.) CsF (1 eq.) CH3CN 6 18 c Cu(OAc)2 (1 eq.) L1 (1 eq.) Cs2 CO3 (1 eq.) CH3 CN 37 L1 (1 eq.) 16 Cu(OAc) 2 (1 eq.) Et 3 N (1 eq.) CH 3 CN 19 Cu(OAc)2 (0.2 eq.) L1 (0.2 eq.) Cs2 CO3 (1 eq.) CH3 CN 56 0 L1 (1 eq.) 17 2 (1 eq.) Pyridine (1 eq.) CH 3 CN 20Cu(OAc) Cu(OAc) (0.2 eq.) L1 (0.4 eq.) Cs CO (1 eq.) CH CN 50 0 2 2 3 3 c c 21 Cu(OAc) (0.2 eq.) L1 (0.2 eq.) Cs CO (1 eq.) CH CN - 37 2 3 3CN L1 (1 eq.) 18 Cu(OAc)2 (1 eq.) Cs22CO33 (1 eq.) CH d Cu(OAc) (0.2 eq.) L1 (0.2 eq.) Cs CO (1 eq.) CH CN 60 22 2 2 3 3 L1 (0.2 eq.) 19 Cu(OAc)2 (0.2 eq.) Cs2CO3 (1 eq.) CH3CN 56 a See Figure 1 for ligand structures. b Yield was determined by 19 F-NMR spectroscopy by using PhOCF as L1 (0.4 eq.) 20 Cu(OAc)c 2 (0.2 eq.) Cs 2CO3 (1 eq.) CH 3CN 50 3 an internal standard. 50 ◦ C instead of r.t. d Addition of 7 eq. of H2 O. c L1 (0.2 eq.) 21 Cu(OAc)2 (0.2 eq.) Cs2CO3 (1 eq.) CH3CN L1 (0.2 eq.) 22 d Cu(OAc)2 (0.2 eq.) Cs2CO3 (1 eq.) CH3CN 60 use of CuI as a catalyst with bipyridine L1 led to the expected compounds with a very low aThe See Figure 1 for ligand structures. b Yield was determined by 19F-NMR spectroscopy by using PhOCF3 yieldas(Entry 1). With Cu(OAc)2 , ainstead betterofyield was observed, but was still low (Entry 2). In order to r.t. d Addition of 7 eq. of H2O. an internal standard. c 50 °C improve this encouraging result, the base or ligand first had to be removed. Without the base, the reaction a small with amount of 3a was L1compounds (Entries 3–4). This led us to The failed, use of although CuI as a catalyst bipyridine L1observed led to thewithout expected with a very low reduce the quantity of the ligand, and 40% of 3a was then formed (Entry 5). Next, various other ligands yield (Entry 1). With Cu(OAc)2, a better yield was observed, but was still low (Entry 2). In order to (Figure 1)this were screened without 6–12); remained the more improve encouraging result, success the base(Entries or ligand firstbipyridine had to beL1 removed. Without theefficient. 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.

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Figure 1. Ligands used in Table 1.

Figure 1. Ligands used in Table 1. The influence of the nature of the base was then explored. A good yield was obtained with Figure 1. Ligands used in Table 1.

The of the nature ofa the baseresult wasto then A good yieldSurprisingly, was obtained with Cs2 CO3 , Cs2influence CO3, whereas K3PO 4 led to similar thatexplored. of K3CO3 (Entries 13–14). CsF, often used in cross-coupling reactions with boronic acid, provided a low yield (Entry 15). Organic nitrogen whereas KThe result that of was K3 CO 13–14). Surprisingly, CsF, often used in 3 POinfluence 4 led to aofsimilar 3 (Entries the nature ofto the base then explored. A good yield was obtained with appeared bewith deleterious for the provided reaction (Entries 16–17). This could be explained a bases cross-coupling reactions boronic acid, a 3low yield (Entry 15). Organic nitrogen Csbases 2CO3, whereas Kto3PO 4 led to a similar result to that of K CO3 (Entries 13–14). Surprisingly, CsF,by often competitive copper coordination between these bases and L1. At higher temperatures, no improvement appeared tocross-coupling be deleteriousreactions for the with reaction (Entries 16–17). This be explained by anitrogen competitive used in boronic acid, provided a lowcould yield (Entry 15). Organic was observed but, on contrary, this resulted in a decrease of yield (Entry 18). This may be due to the bases appeared to be deleterious for the reaction (Entries 16–17). This could be explained by a was copper coordination between these bases and L1. At higher temperatures, no improvement outgassing of the highly volatile CF3SeCl reagent. competitive copper coordination between these bases and L1. At higher temperatures, no improvement observed but, on contrary, this resulted in ligand a decrease of yield 18).yields This were mayobserved be due to the Catalytic amounts of copper (II) and were then tested,(Entry but lower was observed but, on contrary, this resulted in a decrease of yield (Entry 18). This may be due to the outgassing of 19–20). the highly volatile 3 SeCl (Entries Again, heating CF proved to reagent. be deleterious (Entry 21). Inspired by our previous work with outgassing of the highly volatile CF3SeCl reagent. Catalytic amounts of copper andwas ligand then in tested, butinlower yields were observed a sulfur series [68], some water (II) (7 eq.) addedwere resulting, this case, a non-significant effect Catalytic amounts of copper (II) and ligand were then tested, but lower yields were observed (Entry 22). Consequently, stoichiometric (Entry (Entry 13) remained the betterby ones. (Entries 19–20). Again, heating proved to conditions be deleterious 21). Inspired our previous work (Entries 19–20). Again, heating proved to be deleterious (Entry 21). Inspired by our previous work with These conditions werewater applied to other aromatic boronic acids 1). a non-significant effect with aa sulfur sulfur series [68],some some eq.) was added resulting, in(Scheme this series [68], water (7(7 eq.) was added resulting, in this case,case, in a in non-significant effect (Entry 22). Consequently, stoichiometric 13)remained remained better ones. (Entry 22). Consequently, stoichiometricconditions conditions (Entry (Entry 13) thethe better ones. These conditions were applied to other aromatic boronic acids (Scheme 1). These conditions were applied to other aromatic boronic acids (Scheme 1).

Scheme 1. Trifluoromethylselenolation of aromatic boronic acids. Yields shown are those of the isolated products.

Only moderate yields were obtained with substituted aromatic compounds, whatever the donor Scheme 1. Trifluoromethylselenolation of of aromatic aromatic boronic acids. shown are those of theof the Scheme 1. Trifluoromethylselenolation boronic acids.Yields Yields shown are those or acceptor electronic character of the substituents. In heteroaromatic series, the same moderate isolated products. isolated resultsproducts. were observed.

Only moderate yields were obtained with substituted aromatic compounds, whatever the donor

Only moderate yieldscharacter were obtained with substituted aromatic compounds, the donor or acceptor electronic of the substituents. In heteroaromatic series, the whatever same moderate or acceptor electronic character of the substituents. In heteroaromatic series, the same moderate results results were observed. were observed. When these lukewarm results were obtained, some amounts of CF3 SeSeCF3 were detected as well as homocoupling products from the boronic reagents. This could be rationalized by the high reactivity

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of CF3 SeCl, which leads to a competition between the kinetically low coupling reaction and the more Molecules 2017, 22, 833 4 of 8 rapid dimerization. The homocoupling reaction could then come from the lack of CF3 SeCl for the expected reaction. Despite the use of an excess of preformed CF3 SeCl, no3SeSeCF better 3results were observed. When these lukewarm results were obtained, some amounts of CF were detected as well as homocoupling products from the boronic This could be rationalized by the high Furthermore, during the preliminary formation of CFreagents. SeCl, one equivalent of benzyl chloride was also 3 reactivity CF3SeCl, which disturb leads to athe competition between the kinetically low coupling reaction and formed, whichofcould possibly cross-coupling reaction. 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 3. Materials and Methods observed. Furthermore, during the preliminary formation of CF3SeCl, one equivalent of benzyl

Commercial reagents were used as possibly supplied. Reagent 1 was synthesized following procedures chloride was also formed, which could disturb the cross-coupling reaction. described in the literature [36,67]. Anhydrous solvents were used as supplied. NMR spectra were 3. Materials and Methods recorded on a Bruker AV 400 (Billerica, MA, USA) spectrometer at 400 MHz (1 H-NMR), 101 MHz 13 ( C-NMR), and 376 reagents MHz (19were F-NMR), or supplied. on a Bruker AV 1300 at 300 MHz (1 H-NMR) Commercial used as Reagent wasspectrometer synthesized following procedures and 282 MHz in (19the F-NMR). Multiplicities are indicated follows: s (singlet), d (doublet), (triplet), described literature [36,67]. Anhydrous solventsas were used as supplied. NMR spectra twere q (quartet), p (quintet), sext (sextet), m (multiplet), b (broad). All coupling constants are reported recorded on a Bruker AV 400 (Billerica, MA, USA) spectrometer at 400 MHz (1H-NMR), 101 MHzin Hz. (13C-NMR), and 376 MHz (19F-NMR), or on a Bruker AV 300 spectrometer at 300 MHz (1H-NMR) and

3.1. Synthesis Benzyl Trifluoromethyl Selenide (1)as follows: s (singlet), d (doublet), t (triplet), q (quartet), 282 MHz of (19F-NMR). Multiplicities are indicated p (quintet), sext (sextet), m (multiplet), b (broad). All coupling constants are reported in Hz.

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) wereSelenide added. 3.1. Synthesis of Benzyl Trifluoromethyl (1)The flask was evacuated and refilled with nitrogen three times, and then trifluoromethyl trimethylsilane (TMSCF3 ) (20.7 mL, 140 mmol, 2.0 equiv.) was To a dry round-bottom flask equipped with a magnetic stirrer, benzylselanocyanate (13.7 g, added. The reaction mixture was cooled to 0 ◦ C, and then tetrabutylammonium fluoride (TBAF) in 70.0 mmol, 1.0 equiv.) and dry THF (140 mL) were added. The flask was evacuated and refilled with THF 1 M (14.0 mL, 14.0 mmol, 0.2 equiv.) was added dropwise. After 10 min at 0 ◦ C under nitrogen, the nitrogen three times, and then◦ trifluoromethyl trimethylsilane (TMSCF3) (20.7 mL, 140 mmol, 19 F-NMR reaction was allowed to warm to 23 Cmixture and was stirred h. The was checked by 2.0 equiv.) was added. The reaction was cooledfor to 07 °C, and conversion then tetrabutylammonium fluoride with (TBAF) PhOCFin an1internal standard. The0.2 reaction was then partitioned between water and 3 as THF M (14.0 mL, 14.0 mmol, equiv.)mixture was added dropwise. After 10 min at 0 °C under pentane, and the aqueous layer was extracted with pentane. The combined organic layers were washed nitrogen, the reaction was allowed to warm to 23 °C and was stirred for 7 h. The conversion was 19 with brine, dried over MgSO , filtered through a pad of silica (rinsed with pentane) and concentrated checked by F-NMR with4PhOCF 3 as an internal standard. The reaction mixture was then partitioned to between water and pentane, andThe thecrude aqueous layerwas waspurified extractedbywith pentane. The combined dryness (under moderate vacuum). residue chromatography (pentane: 100) 1 H-NMR organic were washed with brine, dried over(11.7 MgSO filtered through a pad of silica (rinsed to afford thelayers desired product 1 as a colorless liquid g,4, 70% yield). (300 MHz, CDCl3 ): with pentane) and concentrated to dryness (under moderate vacuum). The crude residue was 19 δ = 7.37−7.27 (massif, 5H), 4.26 (s, 2H). F-NMR (282 MHz, CDCl3 ): δ = −34.47 (s, 3F). The results are purified by chromatography (pentane: 100) to afford the desired product 1 as a colorless liquid (11.7 in accordance with the literature [38]. 1 19 g, 70% yield). H-NMR (300 MHz, CDCl3): δ = 7.37−7.27 (massif, 5H), 4.26 (s, 2H). F-NMR (282 MHz, CDCl δ = −34.47 (s, 3F). The results are in accordance with the literature [38]. 3.2. Typical3):Procedure

3.2. Typical Solution A:Procedure To a flame-dried flask equipped with a magnetic stirrer, BnSeCF3 (1) (0.40 mmol, 1.1 equiv.), SO Cl mmol, 1.1 flask equiv.) and anhydrous acetonitrile (1 mL)3 were added under 2 A: 2 (0.40 Solution To a flame-dried equipped with a magnetic stirrer, BnSeCF (1) (0.40 mmol, ◦ nitrogen. The reaction was1.1 stirred forand 6 h anhydrous at 20 C. acetonitrile (1 mL) were added under 1.1 equiv.), SO2Cl2 mixture (0.40 mmol, equiv.) Solution a flame-dried flask equipped nitrogen. B: TheTo reaction mixture was stirred for 6 h atwith 20 °C.a magnetic stirrer, biphenylboronic acid 2 Solution B: Tocopper a flame-dried flask (0.36 equipped with a magnetic stirrer, biphenylboronic acid 2 (0.36 mmol, 1 equiv.), (II) acetate mmol, 1 equiv.), bypirydine (L1) (0.36 mmol, 1 equiv.) (0.36 mmol, 1 equiv.), copper (II) acetate (0.36 mmol, 1 equiv.), bypirydine (L1) (0.36 mmol, 1 equiv.) and cesium carbonate (0.36 mmol, 1 equiv.) were added under nitrogen. and cesium carbonate (0.36 mmol, equiv.) were under nitrogen. Solution A was then poured into 1solution B by added syringe and the mixture was stirred at 20 ◦ C for 16 h. Solution A was then poured into solution B by syringe and the mixture was stirred at 20 °C for Conversion was checked by 19 F-NMR with PhOCF3 as an internal standard. The reaction mixture 16 h. Conversion was checked by 19F-NMR with PhOCF3 as an internal standard. The reaction mixture was partitioned between CH2 Cl2 and water. The aqueous layer was extracted with CH2 Cl2 and the was partitioned between CH2Cl2 and water. The aqueous layer was extracted with CH2Cl2 and the combined organic layers were washed with brine, dried over MgSO , filtered and concentrated to combined organic layers were washed with brine, dried over MgSO4, 4filtered and concentrated to dryness. The The crude residue was purified afford desired product dryness. crude residue was purifiedby byflash flash chromatography chromatography totoafford thethe desired product 3. 3.

Synthesis of 4-[(trifluoromethyl)selanyl]-1,1′-biphenyl (3a). Eluent chromatography: cyclohexane/ 0 -biphenyl (3a). Synthesis of 4-[(trifluoromethyl)selanyl]-1,1 Eluentfor forflash flash chromatography: cyclohexane/ 1H-NMR (300 MHz, CDCl3) δ = 7.83 (m, 2H), 7.65−7.60 (massif, 4H), 7.50 (m, 2H), 7.42 (m, AcOEt 98:2. 1 AcOEt 98:2. H-NMR (300 MHz, CDCl ) δ = 7.83 (m, 2H), 7.65 − 7.60 (massif, 4H), 7.50 (m, 2H), 3 1H). 19F-NMR (282 MHz, CDCl3) δ = −36.05 (s, 3F). The results are in accordance with the literature [57]. 7.42 (m, 1H). 19 F-NMR (282 MHz, CDCl3 ) δ = −36.05 (s, 3F). The results are in accordance with the literature [57].

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Synthesis of 1-bromo-4-[(trifluoromethyl)selanyl]benzene (3b). Eluent for flash chromatography: pentane Synthesis of 1-bromo-4-[(trifluoromethyl)selanyl]benzene (3b).Eluent Eluentfor for flash chromatography: pentane Synthesis of 1-bromo-4-[(trifluoromethyl)selanyl]benzene (3b). flash chromatography: pentane 1H-NMR (300 MHz, CDCl3) δ = 7.60 (m, 2H), 7.53 (m, 2H). 19F-NMR (282 MHz, CDCl3) δ = −36.03 100%. 1 19 Synthesis of 1-bromo-4-[(trifluoromethyl)selanyl]benzene (3b). Eluent for flash chromatography: pentane 1H-NMR 19 100%.100%. H-NMR (300 MHz, CDCl ) δ = 7.60 (m, 2H), 7.53 (m, 2H). F-NMR (282 MHz, CDCl3 ) (300 MHz, CDCl3)3 δ = 7.60 (m, 2H), 7.53(3b). (m, Eluent 2H). F-NMR (282 MHz, CDCl3) δ pentane = −36.03 Synthesis of 1-bromo-4-[(trifluoromethyl)selanyl]benzene for flash chromatography: 19F-NMR (s, 3F).1H-NMR The results are in accordance the 2H), literature [61]. 100%. (300 MHz, CDCl 3) δ =with 7.60 (m, 7.53 (m, 2H). (282 MHz, CDCl 3) δ = −36.03 δ = −100%. 36.03 The results are in accordance with the[61]. literature [61]. (s, 3F).1(s, The3F). results in accordance with the literature H-NMR (300are MHz, CDCl 3) δ = 7.60 (m, 2H), 7.53 (m, 2H). 19F-NMR (282 MHz, CDCl3) δ = −36.03 Synthesis of results 1-bromo-4-[(trifluoromethyl)selanyl]benzene (3b). Eluent for flash chromatography: pentane (s, 3F). The are in accordance with the literature [61]. (s, 3F).1H-NMR The results are in accordance the 2H), literature [61]. 100%. (300 MHz, CDCl3) δ =with 7.60 (m, 7.53 (m, 2H). 19F-NMR (282 MHz, CDCl3) δ = −36.03 (s, 3F). The results are in accordance with the literature [61].

Synthesis of 1-methoxy-4-[(trifluoromethyl)selanyl]benzene (3c). Eluent for flash chromatography:

Synthesis of 1-methoxy-4-[(trifluoromethyl)selanyl]benzene (3c). forfor flash chromatography: Synthesis of 1-methoxy-4-[(trifluoromethyl)selanyl]benzene (3c).Eluent Eluent flash chromatography: 7.66 (m, 2H),for 6.91flash (m, 2H), 3.83 (s, 3H). cyclohexane/toluene 9:1. 11H-NMR (300 MHz, CDCl3) δ =(3c). Synthesis of 1-methoxy-4-[(trifluoromethyl)selanyl]benzene Eluent chromatography: H-NMR (300 MHz, CDCl 3) δ = 7.66 (m, 2H), 6.91 (m, 2H), 3.83 (s, 3H). cyclohexane/toluene 9:1. 1 Synthesis of 1-methoxy-4-[(trifluoromethyl)selanyl]benzene (3c). Eluent for flash chromatography: 19F-NMR (282 1 cyclohexane/toluene 9:1. H-NMR (300 MHz, CDCl ) δ = 7.66 (m, 2H), 6.91 (m, 2H), (s, 3H). MHz, CDCl 3 ) δ = −37.18 (s, 3F). The results are in accordance with the literature [61]. (s, 3H). cyclohexane/toluene 9:1. H-NMR (300 MHz, CDCl3) 3δ = 7.66 (m, 2H), 6.91 (m, 2H), 3.83 3.83 19 F-NMR (282 MHz, CDCl ) δ = −37.18 (s,MHz, 3F). The results are7.66 in accordance with the2H), literature [61]. 13H-NMR 19 F-NMR (300 CDCl 3) δ =(3c). (m, 2H), 6.91 (m, 3.83 (s, 3H). cyclohexane/toluene 9:1. 19F-NMR Synthesis of 1-methoxy-4-[(trifluoromethyl)selanyl]benzene Eluent for flash chromatography: (282(282 MHz, CDCl = =−−37.18 37.18 (s, (s,3F). 3F).The Theresults results in accordance the literature MHz, CDCl areare in accordance withwith the literature [61]. [61]. 3 ) 3δ) δ F-NMR (282 MHz, CDCl ) δ = −37.18 (s,MHz, 3F). The results in accordance with the2H), literature [61]. (300 CDCl 3) δ are = 7.66 (m, 2H), 6.91 (m, 3.83 (s, 3H). cyclohexane/toluene 9:1. 13H-NMR 19F-NMR (282 MHz, CDCl3) δ = −37.18 (s, 3F). The results are in accordance with the literature [61].

19

Synthesis of methyl 4-[(trifluoromethyl)selanyl]benzoate (3d). Eluent for flash chromatography: cyclohexane/ Synthesis of methyl 4-[(trifluoromethyl)selanyl]benzoate (3d). Eluent for flash chromatography: cyclohexane/ 1H-NMR (300 MHz, CDCl3) δ = 8.04 (m, 2H), 7.81 (m, 2H), 3.94 (s, 3H). 19F-NMR EtOAc 97:3 to 95:5. Synthesis ofmethyl methyl 4-[(trifluoromethyl)selanyl]benzoate (3d). Eluent for flash chromatography: cyclohexane/ 1H-NMR (300 MHz, CDCl3) δ = 19F-NMR Synthesis of 4-[(trifluoromethyl)selanyl]benzoate (3d). for 3.94 flash chromatography: EtOAc 97:3 to 95:5. 8.04Eluent (m, 2H), 7.81 (m, 2H), (s, 3H). Synthesis of CDCl methyl (3d). for Eluent flash chromatography: cyclohexane/ 19F-NMR (282 MHz, 3)4-[(trifluoromethyl)selanyl]benzoate δ1=H-NMR −35.21 (s, 3F). The results are in accordance with the literature [57]. EtOAc 97:3 to 95:5. (300 MHz, CDCl 3 ) δ = 8.04 (m, 2H), 7.81 (m, 2H), 3.94 (s, 3H). 1 (282 MHz, CDCl 3 ) δ = −35.21 (s, 3F). The results are in accordance with the literature [57]. cyclohexane/EtOAc 97:3 to 95:5.(300 H-NMR (300 MHz, CDCl δfor = 8.04 (m, 2H),3.94 7.81(s, (m, 2H), 3.94 (s, 3H). 1H-NMR 19F-NMR EtOAc 97:3 to 95:5. MHz, CDCl 3) δ = 8.04 (m,3 )2H), 7.81 (m, 2H), 3H). Synthesis of CDCl methyl (3d). Eluent flash chromatography: cyclohexane/ (282 MHz, 3)4-[(trifluoromethyl)selanyl]benzoate δ = −35.21 (s, 3F). The results are in accordance with the literature [57]. 19 F-NMR (282 MHz, CDCl ) δ = −35.21 (s, 3F). The results are in accordance with the literature [57]. (282 MHz, CDCl 3 ) δ = −35.21 (s, 3F). The results are in accordance with the literature [57]. 1 19 3 EtOAc 97:3 to 95:5. H-NMR (300 MHz, CDCl3) δ = 8.04 (m, 2H), 7.81 (m, 2H), 3.94 (s, 3H). F-NMR (282 MHz, CDCl3) δ = −35.21 (s, 3F). The results are in accordance with the literature [57]. Synthesis of 3-[(trifluoromethyl)selanyl]quinoline (3e). Eluent for flash chromatography: cyclohexane/ Synthesis 1of 3-[(trifluoromethyl)selanyl]quinoline (3e). Eluent for flash chromatography: cyclohexane/ 2O 8:2. of H-NMR (300 MHz, CDCl3) δ = 9.14 (s,(3e). 1H),Eluent 8.65 (d, 1.8 Hz, 1H), 8.21 (d, J =cyclohexane/ 8.7 Hz, 1H), Et Synthesis 3-[(trifluoromethyl)selanyl]quinoline forJ =flash chromatography: 2O 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), Et Synthesis 3-[(trifluoromethyl)selanyl]quinoline (3e). Eluent forJ =flash chromatography: cyclohexane/ 19F-NMR (282 MHz, CDCl 1of 7.86 7.67 (m, 1H). 3)8.65 δ = −35.50 (s, 3F). The results are in accordance 2O(m, 8:2.2H), H-NMR (300 MHz, CDCl 3 ) δ = 9.14 (s, 1H), (d, 1.8 Hz, 1H), 8.21 (d, J = Hz, 1H), Et 19F-NMR (282 MHz, CDCl3) δ = −35.50 (s, 3F). The results are in8.7 7.86 (m, 2H), 7.67 (m, 1H). accordance Synthesis 3-[(trifluoromethyl)selanyl]quinoline (3e). Eluent for flash chromatography: cyclohexane/ 1H-NMR 2O of 8:2. (300 MHz, CDCl3(282 ) δ = MHz, 9.14 (s, 1H),Eluent 8.65 (d, 1.83F). Hz, 1H),results 8.21 (d, J =in 8.7 Hz, 1H), Et 19F-NMR with the2H), literature [53]. Synthesis of 3-[(trifluoromethyl)selanyl]quinoline (3e). forJ =flash chromatography: cyclohexane/ 7.86 (m, 7.67 (m, 1H). CDCl 3) δ = −35.50 (s, The are accordance 1the with literature [53]. 19F-NMR Et2 O7.86 8:2. H-NMR (300 MHz, CDCl 9.14 (s, 1H), (d,J =J (s, = 1.8 1H), J =Hz, 8.71H), Hz, 1H), 7.67 (m, 1H). CDCl 3)8.65 δ8.65 = −35.50 3F). The results areJ(d, in accordance 1H-NMR 3 )3(282 2O(m, 8:2. (300 MHz, CDCl )δδ==MHz, 9.14 (s, 1H), (d, 1.8 Hz,Hz, 1H), 8.218.21 (d, = 8.7 Et with the2H), literature [53]. 19 F-NMR with the literature [53]. 19 7.86 (m, 2H), 7.67 (m, 1H). (282 MHz, CDCl ) δ = − 35.50 (s, 3F). The results are in accordance 7.86 (m, 2H), 7.67 (m, 1H). F-NMR (282 MHz, CDCl33) δ = −35.50 (s, 3F). The results are in accordance with with the literature [53].[53]. the literature Synthesis of 3-[(trifluoromethyl)selanyl]-1-benzothiophene (3f). Eluent for flash chromatography: Synthesis of 3-[(trifluoromethyl)selanyl]-1-benzothiophene (3f). Eluent for flash chromatography: cyclohexane/toluene 98:2. 11H-NMR (300 MHz, CDCl3) δ =(3f). 8.02 Eluent (d, J = 7.7 1H), chromatography: 7.96 (s, 1H), 7.92 Synthesis of 3-[(trifluoromethyl)selanyl]-1-benzothiophene forHz, flash cyclohexane/toluene 98:2. H-NMR (300 MHz, CDCl 3) δ = 8.02 (d, J = 7.7 Hz, 1H), 7.96 (s, 1H), 7.92 19F-NMR (282 MHz, CDCl Synthesis of 3-[(trifluoromethyl)selanyl]-1-benzothiophene (3f). Eluent for flash chromatography: 1 (m, 1H), 7.51 (m, 1H), 7.44 (m, 1H). 3 ) δ = −35.66 (s, 3F). The in cyclohexane/toluene 98:2. H-NMR (300 MHz, CDCl3) δ = 8.02 (d, J = 7.7 Hz, 1H), 7.96results (s, 1H),are 7.92 19F-NMR (m, 1H), 7.51 (m, 1H),98:2. 7.441H-NMR (m, 1H). (300 (282 MHz, CDCl 3) δ = −35.66 (s, 3F). The results are in cyclohexane/toluene MHz, CDCl 3) δ =(3f). 8.02 (d, J = 7.7 Hz, 1H), 7.96 (s, 1H), 7.92 19 accordance with the literature [57]. Synthesis of 3-[(trifluoromethyl)selanyl]-1-benzothiophene Eluent for flash chromatography: (m, 1H), 7.51 (m, 1H), 7.44 (m, 1H). F-NMR (282 MHz, CDCl3) δ = −35.66 (s, 3F). The results are in accordance with literature [57]. 19F-NMR (282 MHz, CDCl Synthesis of 7.51 3-[(trifluoromethyl)selanyl]-1-benzothiophene for flash (m, 1H), (m,the 1H), 7.441(m, 1H). (300 δEluent =J −35.66 (s, 3F). The results are in cyclohexane/toluene 98:2. H-NMR MHz, CDCl3) δ = (3f). 8.023)(d, = 7.7 Hz, 1H), 7.96chromatography: (s, 1H), 7.92 accordance with the literature [57]. 1 accordance with literature 4. Conclusions cyclohexane/toluene 98:2. MHz, δ = 3)8.02 (d, J =(s,7.7 7.96 (m, 1H), 7.51 (m,the 1H), 7.44H-NMR (m,[57]. 1H). 19(300 F-NMR (282CDCl MHz,3 )CDCl δ = −35.66 3F).Hz, The1H), results are(s, in 1H), 4. Conclusions 19 accordance with the literature [57]. 7.92 (m, 1H), 7.51 (m,of 1H), 7.44 (m, 1H). F-NMR (282 MHz, CDCl = −35.66 (s, 3F). The results are 4. Conclusions 3) δ In our study its reactivity scope, we have demonstrated that CF 3SeCl, in situ preformed, could 4. Conclusions In ourwith studythe of its reactivity scope, we have demonstrated that CF3SeCl, in situ preformed, could in accordance literature [57]. reactInwith boronic acids to perform trifluoromethylselenolation of3SeCl, aromatic heteroaromatic our study of its reactivity scope, we have demonstrated that CF in situorpreformed, could react with boronic acids to perform trifluoromethylselenolation of3SeCl, aromatic heteroaromatic 4. Conclusions our study of its reactivity scope, have demonstrated thatdue CF situor preformed, could compounds. However, moderate yieldswe were generally observed the in overly high reactivity of reactInwith boronic acids to perform trifluoromethylselenolation oftoaromatic or heteroaromatic compounds. However, moderate yieldstrifluoromethylselenolation were generally observed dueoftoaromatic the overlyorhigh reactivity of 4. Conclusions react boronic acids perform heteroaromatic CF 3SeCl andstudy the presence oftogenerated chloride. This points out major issue of reactivity this one-pot Inwith our of its reactivity scope, we have demonstrated thatdue CFto 3the SeCl, in situ preformed, could compounds. However, moderate yieldsbenzyl were generally observed the overly high of CF3SeCl and the presence of generated benzyl chloride. This pointsdue outto the major issue of reactivity this one-pot compounds. However, moderate yields were generally observed the overly high of strategy; the subsequently formed benzyl chloride may limit this approach by inducing side-reactions. react with boronic acids to perform trifluoromethylselenolation of aromatic or heteroaromatic CF 3 SeCl and the presence of generated benzyl chloride. This points out the major issue of this one-pot In our study of its reactivity scope, we have demonstrated that by CFinducing situ preformed, 3 SeCl, in strategy; the subsequently formed benzyl chloride may limit this approach side-reactions. CF 3SeCl and the of generated benzyl This points outto thethe major issue of this one-pot Furthermore, thepresence high moderate reactivity of CF 3chloride SeCl,chloride. which can easily dimerize, could also constitute compounds. However, yields were generally observed due overly high reactivity ofa strategy; the subsequently formed benzyl may limit this approach by inducing side-reactions. couldstrategy; react with boronic acids to perform trifluoromethylselenolation of aromatic or heteroaromatic Furthermore, the high reactivity of CF 3SeCl, which can easily dimerize, could also constitute a the subsequently formed benzyl chloride may limit this approach by inducing side-reactions. drawback with reactions which areofkinetically too low.can This underlines necessity of constitute developing CF 3SeCl and the presence of generated benzyl This points out thethe major issue of this one-pota Furthermore, the high reactivity CF 3SeCl,chloride. which easily dimerize, could also drawback with reactions which are kinetically too low. This underlines the necessity of developing compounds. However, moderate yields were generally observed due to the overly high reactivity of Furthermore, the high reactivity ofkinetically 3SeCl, which easily dimerize, a new reagents, that are isolable, easy toCF handle and have aThis modular reactivity that isalso easier to control. strategy; the subsequently formed benzyl chloride limit this approach by could inducing side-reactions. drawback with reactions which are toomay low.can underlines the necessity ofconstitute developing new reagents, that are isolable, easy to handle and have a modular reactivity that is easier to control. CF3 SeCl and the presence ofreactivity generated benzyl chloride. This points out the the necessity majoralso issue of this one-pot drawback with reactions which areofkinetically too low.can underlines of constitute developing Furthermore, the high 3SeCl, and which easily dimerize, could a new reagents, that are isolable, easy toCF handle have aThis modular reactivity that is easier to control. Acknowledgments: Clément Ghiazza held a doctoral fellowship from la Région Rhône Alpes. The authors are strategy; the subsequently formed benzyl chloride may limit this approach by inducing side-reactions. new reagents, that are isolable, easy to handle and have a modular reactivity that is easier to control. Acknowledgments: Clémentwhich Ghiazza held a doctoral fellowship from la Région the Rhône Alpes. The authors are drawback with reactions are kinetically too low. This underlines necessity of developing grateful to the CNRSClément and the Ghiazza French Ministry of Research for financial support. The French Fluorine Network Acknowledgments: held a doctoral fellowship from lasupport. Région The Rhône Alpes. The authors are grateful tothe the high CNRS andisolable, the French of Research for French Fluorine Furthermore, reactivity ofeasy CFMinistry which can easily dimerize, could also a drawback new that Clément are to handle and have afinancial modular reactivity that isconstitute easier toNetwork control. 3 SeCl, is alsoreagents, acknowledged for its support. Acknowledgments: 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 forkinetically its support. too low. This underlines the necessity of developing new reagents, with grateful reactions which are to the CNRS and thesupport. French Ministry of Research for financial French Fluorine Network is also acknowledged for its Acknowledgments: Clément Ghiazza held a doctoral fellowship from lasupport. Région The Rhône Alpes. The authors are is also acknowledged for its support. that are isolable, easy to handle and have a modular reactivity that is easier to control. grateful to the CNRS and the French Ministry of Research for financial support. The French Fluorine Network is also acknowledged for its support.

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.

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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. 2. 3. 4. 5. 6. 7. 8.

9.

10.

11. 12. 13. 14. 15.

16. 17. 18. 19. 20. 21. 22.

Smart, B.E. Fluorine substituent effects (on bioactivity). J. Fluor. Chem. 2001, 109, 3–11. [CrossRef] Becker, A. Inventory of Industrial Fluoro-Biochemicals; Eyrolles: Paris, France, 1996. Fujiwara, T.; O’Hagan, D. Successful fluorine-containing herbicide agrochemicals. J. Fluor. Chem. 2014, 167, 16–29. [CrossRef] 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] Hagmann, W.K. The Many Roles for Fluorine in Medicinal Chemistry. J. Med. Chem. 2008, 51, 4359–4369. [CrossRef] [PubMed] Hird, M. Fluorinated liquid crystals—Properties and applications. Chem. Soc. Rev. 2007, 36, 2070–2095. [CrossRef] [PubMed] Pagliaro, M.; Ciriminna, R. New fluorinated functional materials. J. Mater. Chem. 2005, 15, 4981–4991. [CrossRef] 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. 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] 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] Jeschke, P. The unique role of halogen substituents in the design of modern agrochemicals. Pest Manag. Sci. 2010, 66, 10–27. [CrossRef] [PubMed] Chopra, D.; Row, T.N.G. Role of organic fluorine in crystal engineering. CrystEngComm 2011, 13, 2175–2186. [CrossRef] 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] Toulgoat, F.; Alazet, S.; Billard, T. Direct Trifluoromethylthiolation Reactions: The “Renaissance” of an Old Concept. Eur. J. Org. Chem. 2014, 2415–2428. [CrossRef] 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] Tlili, A.; Toulgoat, F.; Billard, T. Synthetic Approaches to Trifluoromethoxy-Substituted Compounds. Angew. Chem. Int. Ed. 2016, 55, 11726–11735. [CrossRef] 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] 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] Leo, A.; Hansch, C.; Elkins, D. Partition coefficients and their uses. Chem. Rev. 1971, 71, 525–616. [CrossRef] 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] 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] Brown, K.M.; Arhur, J.R. Selenium, selenoproteins and human health: A review. Public Health Nutr. 2001, 4, 593–599. [CrossRef]

Molecules 2017, 22, 833

23. 24. 25. 26. 27. 28. 29. 30.

31.

32. 33.

34. 35.

36. 37. 38. 39. 40. 41. 42.

43. 44. 45. 46. 47.

7 of 8

Combs, G.F.; Gray, W.P. Chemopreventive agents: Selenium. Pharmacol. Therap. 1998, 79, 179–192. [CrossRef] Holben, D.H.; Smith, A.M. The diverse role of selenium within selenoproteins: A review. J. Am. Diet. Assoc. 1999, 99, 836–843. [CrossRef] Kyriakopoulos, A.; Behne, D. Selenium-containing proteins in mammals and other forms of life. Rev. Physiol. Biochem. Pharmacol. 2002, 145, 1–46. Lu, J.; Holmgren, A. Selenoproteins. J. Biol. Chem. 2009, 284, 723–727. [CrossRef] Rayman, M.P. The importance of selenium to human health. Lancet. 2000, 356, 233–241. [CrossRef] 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] 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] 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] ´ Pacuła, A.J.; Kaczor, K.B.; Wojtowicz, A.; Antosiewicz, J.; Janecka, A.; Długosz, A.; Janecki, T.; Scianowski, J. New glutathione peroxidase mimetics—Insights into antioxidant and cytotoxic activity. Bioorg. Med. Chem. 2017, 25, 126–131. [CrossRef] [PubMed] 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] 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] Thangamani, S.; Younis, W.; Seleem, M.N. Repurposing ebselen for treatment of multidrug-resistant staphylococcal infections. Sci. Rep. 2015, 5, 11596. [CrossRef] [PubMed] 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] Glenadel, Q.; Ismalaj, E.; Billard, T. Electrophilic Trifluoromethyl- and Fluoroalkylselenolation of Organometallic Reagents. Eur. J. Org. Chem. 2017, 2017, 530–533. [CrossRef] 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] 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] Billard, T.; Langlois, B.R.; Large, S. Synthesis of Trifluoromethyl Selenides. Phosphorus Sulfur Silicon Relat. Elem. 1998, 136, 521–524. [CrossRef] 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] 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] 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] Magnier, E.; Vit, E.; Wakselman, C. A Convenient Access to Perfluoroalkyl Selenoethers and Selenyl Chlorides. Synlett 2001, 1260–1262. [CrossRef] 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] Pooput, C.; Dolbier, W.R.; Médebielle, M. Nucleophilic Perfluoroalkylation of Aldehydes, Ketones, Imines, Disulfides, and Diselenides. J. Org. Chem. 2006, 71, 3564–3568. [CrossRef] Cherkupally, P.; Beier, P. Alkoxide-induced nucleophilic trifluoromethylation using diethyl trifluoromethylphosphonate. Tetrahedron Lett. 2010, 51, 252–255. [CrossRef] Potash, S.; Rozen, S. General Synthesis of Trifluoromethyl Selenides Utilizing Selenocyanates and Fluoroform. J. Org. Chem. 2014, 79, 11205–11208. [CrossRef]

Molecules 2017, 22, 833

48. 49.

50. 51. 52.

53. 54. 55. 56. 57.

58.

59. 60. 61. 62. 63.

64. 65. 66. 67. 68.

8 of 8

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] 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] 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] Zhu, P.; He, X.; Chen, X.; You, Y.; Yuan, Y.; Weng, Z. Copper-mediated synthesis of α-trifluoromethylthioand seleno-α,β-unsaturated carbonyl compounds. Tetrahedron 2014, 70, 672–677. [CrossRef] 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] 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] 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] Wu, C.; Huang, Y.; Chen, Z.; Weng, Z. Synthesis of vinyl trifluoromethyl selenoethers. Tetrahedron Lett. 2015, 56, 3838–3841. [CrossRef] Wang, Y.; You, Y.; Weng, Z. Alkynyl trifluoromethyl selenide synthesis via oxidative trifluoromethylselenolation of terminal alkynes. Org. Chem. Front. 2015, 2, 574–577. [CrossRef] 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] Hou, C.; Lin, X.; Huang, Y.; Chen, Z.; Weng, Z. Synthesis of β-Trifluoromethylthio- and β-Trifluoromethylselenoα,β-unsaturated Ketones through Copper-Mediated Trifluoromethylthio(seleno)lation. Synthesis 2015, 47, 969–975. [CrossRef] 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] Tian, Q.; Weng, Z. A Convenient Process for the Preparation of Heteroaryl Trifluoromethyl Selenoethers. Chin. J. Chem. 2016, 34, 505–510. [CrossRef] 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] 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] 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] 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] 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] 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. 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] 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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