Synthesis of 3,4-Bis(Butylselanyl)Selenophenes and 4-Alkoxyselenophenes Promoted by Oxone®

We describe herein an alternative transition-metal-free procedure to access 3,4-bis(butylselanyl)selenophenes and the so far unprecedented 3-(butylselanyl)-4-alkoxyselenophenes. The protocol involves the 5-endo-dig electrophilic cyclization of 1,3-diynes promoted by electrophilic organoselenium species, generated in situ through the oxidative cleavage of the Se-Se bond of dibutyl diselenide using Oxone® as a green oxidant. The selective formation of the title products was achieved by controlling the solvent identity and the amount of dibutyl diselenide. By using 4.0 equiv of dibutyl diselenide and acetonitrile as solvent at 80 °C, four examples of 3,4-bis(butylselanyl)selenophenes were obtained in moderate to good yields (40–78%). When 3.0 equiv of dibutyl diselenide were used, in the presence of aliphatic alcohols as solvent/nucleophiles under reflux, 10 3-(butylselanyl)-4-alkoxyselenophenes were selectively obtained in low to good yields (15–80%).

Considering the growing potential utility of selenophenes in pharmaceutical, materials science, and organic synthesis, different methodologies have been reported for the preparation of this class of compounds [51]. Among these protocols, a general approach for the synthesis of 3-substituted selenophenes is the electrophilic cyclization of (Z)-selenoenynes with different electrophiles, such as I 2 , ICl, PhSeBr, and PhSeCl (Scheme 1a, path i) [52] or with electrophilic selenium species generated in situ from diorganyl dichalcogenides in the presence of FeCl 3 [5] or Oxone ® [53] (Scheme 1a, path ii). In addition, in 2017 the electrophilic cyclization of selenoenynes in the presence of an appropriate nucleophile, affording 3-iodo-selenophenes and 3-organoselanyl-selenophenes (Scheme 1b), was reported [54]. The Bu 2 Se 2 /FeCl 3 combination was also used in the cyclization of 1,3-diynes for the synthesis of 3,4-bis(butylselanyl)selenophenes (Scheme 1c) [55]. More recently this year, a three-component approach involving dialkyl acetylenedicarboxylate, ethyl 2-cyano-3-arylacrylates, and KSeCN was described to access functionalized selenophenes [56]. Scheme 1. Previously reported methods for the synthesis of selenophenes and derivatives (a-c) and our general protocol for the synthesis of selenophenes promoted by Oxone ® (d).

Results and Discussion
To start our studies, 1,4-diphenylbuta-1,3-diyne 1a and dibutyl diselenide 2a were chosen as model substrates in the reaction with Oxone ® . The reactions were monitored by TLC until total disappearance of the 1,3-diyne 1a. Firstly, a mixture of 1a (0.25 mmol), 2a (0.50 mmol), and Oxone ® (0.50 mmol) in acetonitrile (3.0 mL) was stirred at 80 • C for 72 h in a conventional system under nitrogen atmosphere, affording the 3,4-bis(butylselanyl)-2,5diphenylselenophene 3a in 58% yield (Table 1, entry 1). Interested in reducing the reaction time and increasing the yield of the product 3a, we decided to perform a reaction under ultrasonic irradiation (US, 20 kHz, 60% of amplitude) and, unfortunately, the expected product 3a was obtained in only 15% yield after 2 h (Table 1, entry 2). Thus, studies using this energy were abandoned. Based on this, the conventional heating system (oil bath) was utilized in the following experiments to verify the influence of different solvents in the reaction (Table 1, entries 3-6). In the reactions using dimethylformamide, PEG-400, and glycerol as solvents, the desired product 3a was not obtained, as observed by GC/MS analysis, and the starting materials were recovered (Table 1, entries [3][4][5]. Surprisingly, when ethanol was used as a solvent, after 24 h we observed the total consumption of 1,3-diyne 1a by TLC, and the expected product 3a was obtained in only 15% yield, combined with 43% yield of 3-(butylselanyl)-4ethoxy-2,5-diphenylselenophene 4a (Table 1, entry 6). Focused on selectively preparing selenophene 3a, acetonitrile was set as the best solvent. Subsequently, the effect of using different quantities of Oxone ® was evaluated (Table 1, entries 7-10). When the amount of Oxone ® was increased to 0.75 mmol, product 3a was obtained in 78% yield after 48 h of reaction (Table 1, entry 7). Lower yields were obtained with larger (1.0 mmol) or smaller amounts (0.25 mmol or 0.38 mmol) of Oxone ® , affording the desired compound 3a in 75%, 38%, and 50% yield, respectively ( Table 1, entries 8-10).
Once the best conditions were determined for the synthesis of 3,4-bis(butylselanyl)-2,5-diphenylselenophene 3a, the scope and limitations of the methodology were explored by reacting different 1,3-diynes 1b-f with dibutyl diselenide 2a, and the results are shown in Table 2. Firstly, the effect of electron donating groups (EDGs) and electron withdrawing groups (EWGs) bonded in the aromatic rings of 1,3-diyne 1 was examined in the reaction with 2a. Thus, when the electron-rich 1,3-diynes 1b (R = 4-CH 3 OC 6 H 4 ) and 1c (R = 4-CH 3 C 6 H 4 ) were used, the corresponding products, 3b and 3c, were obtained in 50% and 70% yield after 2.5 h and 4 h of reaction, respectively ( Table 2, compounds 3b and 3c). However, the presence of the EWG chlorine in the para-position of the phenyl ring negatively affected the reaction, and compounds 3d (R = 4-ClC 6 H 4 ) could not be obtained, even after refluxing for 72 h, as indicated by GC/MS analysis. The starting materials, 1d and 2a, were recovered ( Table 2, compound 3d). Table 2. Synthesis of 3,4-bis(butylselanyl)selenophenes 3 a,b . a Reaction conditions: A mixture of diyne 1 (0.25 mmol), dialkyl dichalcogenide 2 (0.50 mmol), and Oxone ® (0.75 mmol) in acetonitrile (3.0 mL) under nitrogen atmosphere was stirred at 80 • C by the time indicated. The progress of the reaction was monitored by TLC. b Isolated yields after purification by preparative thin-layer chromatography. c No product was detected and the starting materials were recovered. d The starting materials were completely consumed and a complex mixture of decomposition products was formed.
Next, the versatility and limitations of this protocol for accessing the new 4-alkoxyselen ophenes 4 was evaluated by reacting several 1,3-diynes 1a-j with dialkyl dichalcogenide 2 in the presence of different solvents/nucleophiles (Table 3). In general, we observed that the reactivity was affected both by electronic and steric effects in the 1,3-diynes and in the solvent. 1,4-diphenylbuta-1,3-diyne 1a reacted with dibutyl diselenide 2a in methanol as the solvent, affording the respective 4-methoxyselenophene 4b in 75% yield after 24 h (Table 3, compound 4b). When the secondary alcohol iso-propanol was used instead of methanol, the alkoxy derivative 4c was obtained in only 35% yield, while the products' derivative of tert-butanol 4d and phenol 4e were not observed under the optimal conditions, even after 72 h of reaction, as indicated by GC/MS analysis (Table 3, compounds 4c-e). The lower reactivity of iso-propanol and tert-butanol can be explained by steric effects, while phenol was not sufficiently nucleophilic to form the reactive intermediate in the reaction (see below a plausible mechanism). Next, the same reaction was performed in the presence of thiols and amines, aiming to verify the possibility of preparing thio-and amino-substituted selenophenes through the cyclization of 1,3-diyne 1a. Unfortunately, the limitation of this protocol was observed when aryl and alkyl thiols and amines (2 equiv) were used in the presence of acetonitrile as solvent (3.0 mL). In these cases, the starting materials were not consumed, even after 48 h of reaction, as indicated by GC/MS analysis.
In the sequence, we investigated the reactivity of several symmetrical 1,3-diynes 1 with dibutyl diselenide 2a in the presence of ethanol or methanol. Similar to what we observed in the synthesis of selenophenes 3 (Table 2), the presence of EDGs and EWGs at the para-position of the pendant phenyl ring of the diyne remarkably influenced the reactivity. Accordingly, selenophenes 4f (R = 4-CH 3 OC 6 H 4 , R 1 = C 2 H 5 ), 4g (R = 4-CH 3 OC 6 H 4 , R 1 = CH 3 ), and 4h (R = 4-CH 3 C 6 H 4 , R 1 = C 2 H 5 ) were obtained in 35%, 40%, and 80% yield, respectively, while 4i (R = 4-ClC 6 H 4 , R 1 = C 2 H 5 ) was not observed (Table 3, compounds 4f-i). The lack of reactivity of 1,4-bis(4-chlorophenyl)buta-1,3-diyne 1d was probably due to the low stability of the intermediate involved in the cyclization to form the 4-alcoxyselenophene 4i. The structure of compound 4h was confirmed by an additional NMR analysis, which is available in the SI (Figures S25-S27). The presence of the 2-naphthyl groups in diyne 1e negatively influenced the reaction, and the respective product, 4j, did not form, even after 48 h, presumably due to the steric congestion around the triple bonds (Table 3, compound 4j). Additionally, we investigated the reactivity of the alkyl-substituted dodeca-5,7-diyne 1f and of the propargyl alcohol derivative 1g. In these cases, despite the starting materials being totally consumed, the corresponding selenophenes, 4k and 4l, were not observed, and a complex mixture of compounds was formed (Table 3, compounds 4k and 4l). In contrast, when sterically hindered ortho-substituted 1,4-diaryl diynes were used, a similar reactivity was observed when EDG (1h, R = 2-CH 3 C 6 H 4 ) or EWG (1i, R = 2-ClC 6 H 4 ) groups were present, and the respective 4-ethoxyselenophenes, 4m and 4o, were obtained, both in 15% yield after 72 h of reaction (Table 3, compounds 4m and 4o). When methanol was used instead of ethanol, the 4-methoxyselenophenes 4n and 4p were obtained, both in 25% yield after 60 h (Table 3, compounds 4n and 4p). As observed in the reactions in CH 3 CN, dibutyl ditelluride 2b and dimethyl disulfide 2c were not suitable substrates in the reaction. After 48 h of refluxing in ethanol, no products were observed and the starting materials were recovered (Table 3, compounds 4q and 4r). The progress of the reaction was monitored by TLC. b Isolated yields after purification by preparative thin-layer chromatography. c No product was detected, and the starting materials were recovered. d Reaction performed using acetonitrile (3.0 mL) as solvent and 0.50 mmol of phenol. e The starting materials were completely consumed, providing a complex mixture of products. f Conversion determined by 1 H NMR.
In order to collect data to elucidate the mechanism of the synthesis of 3,4-bis(butylselan yl)selenophenes 3 and 3-(butylselanyl)-4-alkoxy-selenophenes 4, some control experiments were conducted (Scheme 2). Thus, the reaction between 1,4-bis-4-tolylbuta-1,3-diyne 1c and dibutyl diselenide 2a was conducted in the presence of 3.0 equiv of the radical scavenger benzene-1,4-diol (hydroquinone) and 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO). In these experiments, after 4 h of reaction the products, 3c and 4h, were obtained in 30% and 25% yield, respectively, when hydroquinone was used. In contrast, the formation of the products 3c and 4h was not observed in the presence of TEMPO. Considering that products 3c and 4h were formed in the presence of hydroquinone, even in lower yields, the reaction could have occurred via ionic and radical pathways. Thus, based on our knowledge and the literature [57][58][59], we believe that the step of formation of the activation can occur by both radical and ionic mechanisms, whereas the cyclization step proceeds via ionic pathway.

Materials and Methods
The reactions were monitored by TLC sheets ALUGRAM ® Xtra SIL G/UV 254 . For visualization, TLC plates were either placed under UV light or stained with iodine vapor and 5% vanillin in 10% H 2 SO 4 and heat. Preparative layer with UV 254 (20 × 20 cm-500 microns) was used in the chromatographic purification of compounds 3 and 4. Hydrogen nuclear magnetic resonance spectra ( 1 H NMR) were obtained on Bruker Avance III HD 400 MHz employing a direct broadband probe at 400 MHz. The spectra were recorded in CDCl 3 solutions. The chemical shifts are reported in ppm, referenced to tetramethylsilane (TMS) as the internal reference. Coupling constants (J) are reported in Hertz. Abbreviations to denote the multiplicity of a particular signal are s (singlet), d (doublet), dd (doublet of doublet), t (triplet), quint (quintet), sext (sextet), sept (septet), and m (multiplet). Carbon-13 nuclear magnetic resonance spectra ( 13 C NMR) were obtained on Bruker Avance III HD 400 MHz employing a direct broadband probe at 100 MHz. The chemical shifts are reported in ppm, referenced to the solvent peak of CDCl 3 (δ 77.0 ppm). Selenium-77 nuclear magnetic resonance ( 77 Se NMR) spectra were obtained at 76 MHz, using (PhSe) 2 as an internal standard. Low-resolution mass spectra (MS) were measured on a Shimadzu GC-MS-QP2010 mass spectrometer. The high-resolution atmospheric pressure chemical ionization (APCI-QTOF) analyses were performed on a Bruker Daltonics micrOTOF-Q II instrument operating in the positive ion detection mode. For data acquisition and processing, Compass 1.3 for micrOTOF-Q II software (Bruker Daltonics, Billerica, MA, USA) was used. Melting point (m.p.) values were measured in a Marte PFD III instrument with a 0.1 • C precision. Oxone ® was purchased from Sigma-Aldrich. The 1,3-diynes 1 were prepared as described in the Supplementary Materials. To work safely with selenium compounds, these must be handled carefully in a chemical fume hood, and gloves and goggles should be worn. No other special lab practice is required.

Conclusions
In this work, we developed an alternative and transition-metal-free procedure for accessing 3,4-bis(butylselanyl)selenophenes by the electrophilic cyclization of 1,3-diynes with dibutyl diselenide using Oxone ® as a green oxidant and acetonitrile as solvent. In addition, we demonstrated for the first time the synthesis of 3-(butylselanyl)-4-alkoxyselenophenes starting from several 1,3-diynes and dibutyl diselenide in the presence of Oxone ® using aliphatic alcohols as solvent/nucleophiles. This protocol was sensitive to electronic effect in the 1,3-diynes, as well as to steric effects of the alkyl chain of the alcohols.

Data Availability Statement:
The data presented in this study are available on request from the corresponding authors.