Electrophilic Trifluoromethylselenolation of Boronic Acids

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.

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 applied to electrophilic aromatic substitutions [67] and reactions with Grignard reagents and lithium alkynides [36].

Results and Discussion
In our objective to extend the scope of the reactivity of CF 3 SeCl, 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. been applied to electrophilic aromatic substitutions [67] and reactions with Grignard reagents and lithium alkynides [36].

Results and Discussion
In our objective to extend the scope of the reactivity of CF3SeCl, 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 1. Coupling reaction between CF3SeCl, generated in situ, and boronic acid 3a.

Entry
[Cu] Ligand a Base Solvent 3a (%) b 1 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.
The influence of the nature of the base was then explored. A good yield was obtained with Cs2CO3, whereas K3PO4 led to a similar result to that of K3CO3 (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 CF3SeCl 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).

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 or acceptor electronic character of the substituents. In heteroaromatic series, the same moderate results were observed.  Table 1.
The influence of the nature of the base was then explored. A good yield was obtained with Cs 2 CO 3 , whereas K 3 PO 4 led to a similar result to that of K 3 CO 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 3 SeCl 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).  Table 1.
The influence of the nature of the base was then explored. A good yield was obtained with Cs2CO3, whereas K3PO4 led to a similar result to that of K3CO3 (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 CF3SeCl 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).

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 or acceptor electronic character of the substituents. In heteroaromatic series, the same moderate results were observed. 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 3 SeSeCF 3 were detected as well as homocoupling products from the boronic reagents. This could be rationalized by the high reactivity of CF 3 SeCl, 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 CF 3 SeCl for the expected reaction. Despite the use of an excess of preformed CF 3 SeCl, no better results were observed. Furthermore, during the preliminary formation of CF 3 SeCl, one equivalent of benzyl chloride was also formed, which could possibly disturb the cross-coupling reaction.

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 ( 1 H-NMR), 101 MHz ( 13 C-NMR), and 376 MHz ( 19 F-NMR), or on a Bruker AV 300 spectrometer at 300 MHz ( 1 H-NMR) and 282 MHz ( 19 F-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. (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 (TMSCF 3 ) (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 19 F-NMR with PhOCF 3 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 MgSO 4 , 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). 1
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 19 F-NMR with PhOCF 3 as an internal standard. The reaction mixture was partitioned between CH 2 Cl 2 and water. The aqueous layer was extracted with CH 2 Cl 2 and the combined organic layers were washed with brine, dried over MgSO 4 , filtered and concentrated to dryness. The crude residue was purified by flash chromatography to afford the desired product 3. When these lukewarm results were obtained, some amounts of CF3SeSeCF3 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.

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 ( 1 H-NMR), 101 MHz ( 13 C-NMR), and 376 MHz ( 19 F-NMR), or on a Bruker AV 300 spectrometer at 300 MHz ( 1 H-NMR) and 282 MHz ( 19 F-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. (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 19 F-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). 1
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 19 F-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.

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.

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.

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.

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.