Synthesis of Alkynylselenides under Visible-Light Irradiation Using the Ionic Liquid [BMIm]BF4 as a Solvent

In this work, a visible-light-driven synthesis of alkynyl selenides using [BMIm]BF4 as an environmentally friendly solvent and without the addition of metal catalysts, photosensitizers, directing-groups, or bases is reported. The target compounds were obtained in moderate to good yields with good functional group tolerance by the reaction of diorganoyldiselenides with 1-bromoalkynes proceeding through a radical mechanism.


Introduction
Visible-light promoted reactions have emerged as a remarkable and powerful tool to provide greener and milder transformations in organic synthesis, leading to a wide range of organic reactions that are conducted at room temperature and easily operated. 1Moreover, the light-emitting diodes that are able to promote photochemical reactions under visiblelight are inexpensive, sustainable lighting sources with broad commercial availability, 2 which makes this approach very attractive from an environmental and economic perspective.
In this context, the continuous search for new synthetic routes that can reduce/minimize the generation of waste and side-products and that, in some way, fit within the principles of green chemistry is necessary. 3In this way, for a long time, ionic liquids have attracted the interest of the scientific community and even industry, 4 as these organic salts can exhibit several applications in organic synthesis, 5 CO 2 capture, 6 catalysis, 7 biochemistry, 8 and others.In particular, they have often been used to replace conventional solvents in organic reactions 9 due to their unique physical properties such as high thermal stability, low volatility, low flammability, and negligible vapor pressure. 10In addition, the fundamental structure of ionic liquids has offered many combinations of organic cations and organic or inorganic anions in order to specifically model them for different sustainable applications. 11 part of the sophisticated organochalcogen chemistry found in biological 12 and materials sciences, 13 alkynyl chalcogenides are useful and versatile synthetic intermediates in hydrohalogenation, 14 cycloaddition, 15 cross coupling, 16 A 3 -coupling, 17 chalcogenoesters synthesis, 18 and cyclization reactions, 19 playing an important role in the synthesis of bioactive heterocyclic compounds described as anti-cancer, 15 anti-alzheimer's, 19 and antioxidant 19 agents (Scheme 1).
A convenient method for the synthesis of alkynyl chalcogenides involves the reaction between diorganoyl dichalcogenides and terminal alkynes.However, this approach often requires reducing agents 20 or metal catalysts, such as copper, 21 iron, 22 or silver 23 (Scheme 2a,i).Recently, some metal-free strategies under base-catalyzed conditions (catalytic K 3 PO 4 or CsOH) were described, 24 but these methodologies are restricted to the synthesis of alkynyl tellurides (Scheme 2a, ii).Alternatively, considering the number of works about carbon-chalcogen bond formation under visible light irradiation, 25 photochemistry becomes a promising tool to expand the synthesis of alkynyl chalcogenides in an eco-friendly pathway.The first step toward the photoinduced synthesis of alkynyl chalcogenides was taken by Collins and co-workers, 26 who reported an elegant transition-metal photoredox catalysis for the synthesis of alkynyl sulfides using thiols and 1-bromoalkynes in the presence of a nickel catalyst and 4CzIPN as a photosensitizer under blue light emitting diode (LED) irradiation (Scheme 2b).Interestingly, the use of 1-bromoalkynes in this methodology was essential to avoid the reduction of the C≡C bond and the subsequent formation of vinyl chalcogenides as side-products, which are usually observed in previous photoinduced reactions of terminal alkynes with thiols 19 or diorganoyl dichalcogenides under visible light irradiation. 27More recently, the amino group ortho-assisted synthesis of alkynyl sulfides using 2,2'-diaminodisulfides and terminal alkynes or 1-bromoalkynes proved to be an efficient strategy towards the formation of the Csp-S bond under visible light (Scheme 2c). 28n this context, considering the well-established homolytic cleavage of diorganoyl dichalcogenides under visible light to produce chalcogen centered-radicals 29 and the use of 1-bromoalkynes in order to maintain the valuable C≡C bond in photoinduced processes, herein, we report the synthesis of alkynylselenides under visible-light irradiation using the ionic liquid [BMIm]BF 4 as an environmentally friendly solvent (Scheme 2d).The developed methodology avoided the requirement of directing-group strategies and allowed the synthesis of alkynyl selenides in moderate to good yields.Furthermore, [BMIm]BF 4 played a crucial role as the reaction media to convert vinylic side-products into the desired alkynyl selenides.

Results and Discussion
Our reaction study started by using (bromoethynyl) benzene (1a) and diphenyldiselenide (2a) as model substrates and the reaction was carefully monitored by gas chromatography mass spectrometry (GC-MS).Initially, the stoichiometric relationship between 1a and 2a was evaluated (for details, see Supplementary Information (SI) section, Table S1).The best condition was found when 3.0 equivalents of 1a and 1.0 equivalent of 2a reacted under blue LED irradiation (100 W) in dichloromethane (DCM) after 1 h, with 68% conversion of 2a into the desired product phenyl(phenylethynyl)selane (3a) along with the vinylic side-product 4 (m/z = 418) in a 69:31 ratio, respectively (Table 1, entry 1).To improve the conversion of 2a and the reaction selectivity, other lightning sources were evaluated (Table 1, entries 2-4), but unsatisfactory conversions of 2a were obtained.Next, the reaction was performed under blue LED (100 W) irradiation in other polar aprotic solvents (Table 1, entries 5-9), such as tetrahydrofuran (THF), dimethylformamide (DMF), and dimethylsulfoxide (DMSO).A moderate conversion of 2a was observed in DMF, with a good ratio of the desired product 3a and the vinylic side-product 4 (Table 1, entry 5).Alternatively, the reaction performed in THF showed an excellent conversion of 2a, but the reaction was not selective ( of ionic liquids could effectively act as a catalyst and solvent in debromination reactions of alkyl and alkenyl vicinal-dibromides, affording the respective alkenes and alkynes in high yields. 31With this in mind, and in order to convert the undesired vinylic side-product 4 into 3a by debromination, we performed a reaction in the ionic liquid [BMIm]BF 4 , which gratifyingly led to an excellent conversion of 2a with high selectivity for the desired product 3a (Table 1, entry 10).Furthermore, the use of the ionic liquid [BMIm]PF 6 as the solvent did not favor the reaction selectivity (Table 1, entry 11), indicating an important role of the BF 4 anion in our methodology.Finally, lower or higher amounts of [BMIm]BF 4 did not improve the reaction efficiency (Table 1, entries 12 and 13).
With the optimized reaction conditions in hand (Table 1, entry 10), we then evaluated the reaction scope of this photoinduced process.Unfortunately, although high conversion and selectivity were achieved during the reaction optimization study for the synthesis of 3a, this compound could not be cleanly isolated by column chromatography from the remaining mixture of diphenyldiselenide 2a and the vinylic side-product 4, so we decided to use methoxy-substituted diaryl diselenides 2 during the reaction scope to benefit the purification processes (Scheme 3).Initially, bromoethynylbenzene (1a) and arylbromoalkyne derivatives bearing electrondonating or electron-withdrawing groups on the benzene ring successfully reacted with 1,2-bis(4-methoxyphenyl) diselane (2b), affording the respective alkynylselenides 3b-3h in moderate to good yields.The reaction also tolerated bromoalkynes containing naphtalene derivatives or heteroaromatic groups in comparable yields (Scheme 3, 3i and 3j).Sterically hindered 1,2-bis(2-methoxyphenyl) diselane (2c) also proved to be a suitable reaction partner in this transformation (Scheme 3, 3k).Also, vinyl or alkyl bromoalkyne derivatives were well tolerated, but modest yields and longer reaction times were required, which was probably related to a weakly radical stabilization on these substrates (Scheme 3, 3l-3n).It is noteworthy that an alkynylsulfide derivative could also be synthesized through this photoinduced process (Scheme 3, 3o).This reaction required the use of a 200 W blue LED to proceed well, which is a reasonable result considering the higher relative energy of the S-S bond in comparison to the Se-Se bond. 31inally, it is important to mention that the reaction did not work for bromoalkynes containing strong electron-donating or withdrawing groups such as amino, nitro, cyano, and pyridyl (Scheme 3, 3p-3s). 32n order to give insights about the reaction mechanism, some control experiments were performed under the optimized reaction conditions for the synthesis of 3a (Scheme 4).The addition of the radical inhibitor (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) almost completely inhibited the reaction, indicating a radical mechanism (Scheme 4a).Moreover, a reaction performed in the dark did not produce 3a, which confirmed the fundamental effect of light irradiation in our methodology (Scheme 4b).
Based on these results, we proposed a plausible mechanism for the photoinduced synthesis of alkynylselenides 3 in [BMIm]BF 4 (Scheme 5).Initially, diaryldiselenide 2 undergoes a reversible Se-Se bond homolytic cleavage due to the light irradiation. 29Then, a radical addition between arylselenium radical species and bromoalkyne 1 takes place to produce a vinylic radical intermediate 5.At this point, the desired product 3 can be directly obtained by bromine radical elimination 31

Conclusions
In conclusion, a low-cost, environmentally benign and easily workable methodology for the photoinduced synthesis of selenoalkynes was developed.Even if moderate to good yields were obtained in the reaction scope investigation, we highlight that this methodology benefits from mild conditions and the inherent absence of transitionmetals, photosensitizers, or directing-groups to promote a challenging photoinduced Csp-Se bond formation.We also hope that this work may provide useful insights into the use of ionic liquids as sustainable catalysts/reaction media in organochalcogen chemistry.

Experimental
Unless otherwise stated, all reagents were purchased from commercial suppliers (Sigma-Aldrich, Steinheim, Germany) and used without further purification.DMF (N,N-dimethylformamide), DMSO (dimethyl sulfoxide), MeCN (acetonitrile), THF (tetrahydrofuran) and DCM (dichloromethane) were purified and dried under classical General procedure for the synthesis of alkynylselenides 3a-3n and alkynylsulfide 3o In a dried glass tube under argon atmosphere, [BMIm]BF 4 (1.0 g) was added and degassed for 20 min at room temperature.After this time, bromoalkyne 1 (0.3 mmol) and diaryldichalcogenide 2 (0.1 mmol) were added.Under argon atmosphere, the reaction mixture was stirred in the photoreactor (blue LED, 100 W) at room temperature for 24 h for the synthesis of 3a-3j, 3l and 3m and 48 h for the synthesis of 3k, 3n and 3o (the respective synthesis of alkynylsulfide 3o was performed using a blue LED 200 W).
After the completion of the reaction, hexane/ethyl acetate (90:10 v:v, 5.0 mL) was added to the glass tube.After vigorous stirring, two layers were generated, and the upper layer containing the organic solvents was collected and this process was repeated until complete extraction of the desired product 3 (monitored by TLC).The collected organic phase was concentrated under reduced pressure and further purified by preparative thin layer chromatography on silica gel to give the desired products 3b-3o.

from intermediate 5 (
Scheme 5, pathway A).Conversely, this intermediate can undergo a bromine radical addition to generate the respective vinylic dibromide side-product 4 (Scheme 5, pathway B).Based on previous literature,30 a debromination reaction can occur from 4 in the presence of [BMIm]BF 4 , leading to vinylic carbanion species 6, which is able to produce 3 with concomitant regeneration of [BMIm]BF 4 .

Table 1
-) anion could serve as an ideal reaction media in our methodology.In 2005, Ranu and Jana 30 demonstrated that this class Scheme 1. Selected synthetic applications of alkynyl chalcogenides.