Homocouplings of Sodium Arenesulfinates: Selective Access to Symmetric Diaryl Sulfides and Diaryl Disulfides

Symmetrical diaryl sulfides and diaryl disulfides have been efficiently and selectively constructed via the homocoupling of sodium arenesulfinates. The selectivity of products relied on the different reaction systems: symmetrical diaryl sulfides were predominately obtained under the Pd(OAc)2 catalysis, whereas symmetrical diaryl sulfides were exclusively yielded in the presence of the reductive Fe/HCl system.


Results and Discussion
Our initial study started with sodium phenylsulfinate 1a as the model substrate to explore the formation of diphenylsulfide 2a. First, by screening different solvents, NMP was proven to be the most effective out of the others, such as DMF and DMSO (Table 1, entry 3 vs. 1−2). The catalyst played a decisive role in this reaction: among the common metal catalysts, Pd(OAc) 2 was the best one to afford diphenylsulfide 2a in 47% yield (entry 3 vs. [4][5][6]. With CuI and Ni(OAc) 2 as catalysts, the product 2a was not detected at all (entries 4 and 5). Only a trace amount of 2a was observed when FeCl 3 was employed (entry 6). The yield could be improved to 60% by increasing reaction temperature to 150 • C (entry 7 vs. 3 and 8). Most importantly, a decrease of catalyst loading to 2 mol% could further increase the yield to 89%, and no better result was observed by continuously reducing the catalyst loading (entry 10 vs. 7,[9][10][11]. The desired 2a was not detected when sodium benzenesulfinate was replaced with benzenesulfinic acid in the presence of NaOH under the same conditions (entry 12).

Results and Discussion
Our initial study started with sodium phenylsulfinate 1a as the model substrate to explore the formation of diphenylsulfide 2a. First, by screening different solvents, NMP was proven to be the most effective out of the others, such as DMF and DMSO (Table 1, entry 3 vs. 1−2). The catalyst played a decisive role in this reaction: among the common metal catalysts, Pd(OAc)2 was the best one to afford diphenylsulfide 2a in 47% yield (entry 3 vs. 4-6). With CuI and Ni(OAc)2 as catalysts, the product 2a was not detected at all (entries 4 and 5). Only a trace amount of 2a was observed when FeCl3 was employed (entry 6). The yield could be improved to 60% by increasing reaction temperature to 150 °C (entry 7 vs. 3 and 8). Most importantly, a decrease of catalyst loading to 2 mol% could further increase the yield to 89%, and no better result was observed by continuously reducing the catalyst loading (entry 10 vs. 7,[9][10][11]. The desired 2a was not detected when sodium benzenesulfinate was replaced with benzenesulfinic acid in the presence of NaOH under the same conditions (entry 12). Having built the optimal conditions for the construction of diphenylsulfide 2a, we turned our attention to explore the generality of sodium sulfinates. As shown in Table 2, a variety of substrates could undergo the homocoupling to afford symmetrical diaryl sulfides with high chemoselectivity. It was found that sodium benzenesulfinates with electron-donating groups such as 4-methyl, 3-methyl, 2-methyl, 4-methoxyl, 3-methoxyl, 2-methoxyl, 4-isopropyl, and 4-tert-butyl on the phenyl ring gave the corresponding products 2b-2i in good yields. Electron-withdrawing groups, such as F, Cl, Br, and NO 2 , were also well-tolerated to provide the desired products 2j-2s in moderate to good yields that were somewhat lower than the electron-donating groups offered. To our delight, the intramolecular formation of sulfides was also tried, and the desired dibenzothiophene 2t was produced in a 51% yield. Having built the optimal conditions for the construction of diphenylsulfi we turned our attention to explore the generality of sodium sulfinates. As s in Table 2, a variety of substrates could undergo the homocoupling to afford metrical diaryl sulfides with high chemoselectivity. It was found that sodium zenesulfinates with electron-donating groups such as 4-methyl, 3-methyl, 2-m 4-methoxyl, 3-methoxyl, 2-methoxyl, 4-isopropyl, and 4-tert-butyl on the p ring gave the corresponding products 2b−2i in good yields. Electron-withdr groups, such as F, Cl, Br, and NO2, were also well-tolerated to provide the d products 2j−2s in moderate to good yields that were somewhat lower than th tron-donating groups offered. To our delight, the intramolecular formation fides was also tried, and the desired dibenzothiophene 2t was produced in yield. During our studies on the synthesis of diphenylsulfide 2a, 1,2-dipheny fide 3a was accidentally detected when using CuI as a reductant. This disc encouraged us to search for optimal conditions for the reductive coupling dium benzenesulfinate for 1,2-diphenyldisulfide 3a. Fortunately, using Fe/H the reductive system, diphenyldisulfide 3a was isolated as the major produc sequently, the investigation of the concentration of hydrochloric acid reveale During our studies on the synthesis of diphenylsulfide 2a, 1,2-diphenyldisulfide 3a was accidentally detected when using CuI as a reductant. This discovery encouraged us to search for optimal conditions for the reductive coupling of sodium benzenesulfinate for 1,2diphenyldisulfide 3a. Fortunately, using Fe/HCl as the reductive system, diphenyldisulfide 3a was isolated as the major product. Subsequently, the investigation of the concentration of hydrochloric acid revealed that increasing the concentration led to the higher yield, and 12 mol/L of hydrochloric acid gave up to 96% yield (Table 3, entry 4 vs. 1−3). The highest yield was obtained when 4.0 equiv. of HCl was used ( Table 2, entry 4). Increasing or decreasing the amount resulted in lower yields (entries 5 and 6 vs. 4). It was found that 2.0 equiv. of Fe was suitable for this transformation, and other amounts did not improve the yield further (entry 4 vs. 7 and 8). More notably, the similar high yield was provided when the time was shortened to 9 h (entry 9). However, sodium benzenesulfinate generated in situ by the reaction of NaOH and the equivalent of 4-methylbenzenesulfinic acid only afforded the target product (3b) in a 59% yield (entry 10). Table 3. Optimization of reaction conditions for sodium benzenesulfinate to diphenyldisulfide [a] .
increasing the concentration led to the higher yield, and 12 mol/L of hydrochloric acid gave up to 96% yield (Table 3, entry 4 vs. 1−3). The highest yield was obtained when 4.0 equiv. of HCl was used ( Table 2, entry 4). Increasing or decreasing the amount resulted in lower yields (entries 5 and 6 vs. 4). It was found that 2.0 equiv. of Fe was suitable for this transformation, and other amounts did not improve the yield further (entry 4 vs. 7 and 8). More notably, the similar high yield was provided when the time was shortened to 9 h (entry 9). However, sodium benzenesulfinate generated in situ by the reaction of NaOH and the equivalent of 4-methylbenzenesulfinic acid only afforded the target product (3b) in a 59% yield (entry 10). With the optimized reaction conditions in hand, we next focused on the evaluation of the scope of the coupling partner to symmetric disulfides, and the results are summarized in Table 4. To our delight, it was found that the reaction could be compatible with a broad range of functional groups, furnishing the corresponding products in good to excellent yields. Although various functional groups, including electronically diverse (3a−3u) and sterically hindered (3d, 3g, 3h, 3i, 3l, and 3r) ones are readily tolerated, some substantial influence of electronic properties and steric hindrance of the substituents was observed. The substrates possessing an electronrich group (Me, MeO, i-Pr, and t-Bu) showed higher yields than those bearing an electron-poor group (F, Cl, Br, and CF3) (3b−3i vs. 3j−3l, 3p−3s, and 3u). Among substrates, sodium ortho-substituted arylsulfinates, which are sterically hindered, gave relatively lower yields (3d vs. 3b, 3c, and 3g vs. 3e, 3f, and 3l vs. 3j, 3k, and 3r vs. 3p and 3q). In addition, an 82% yield was obtained when sodium 2-naphthyl- With the optimized reaction conditions in hand, we next focused on the evaluation of the scope of the coupling partner to symmetric disulfides, and the results are summarized in Table 4. To our delight, it was found that the reaction could be compatible with a broad range of functional groups, furnishing the corresponding products in good to excellent yields. Although various functional groups, including electronically diverse (3a-3u) and sterically hindered (3d, 3g, 3h, 3i, 3l, and 3r) ones are readily tolerated, some substantial influence of electronic properties and steric hindrance of the substituents was observed. The substrates possessing an electron-rich group (Me, MeO, i-Pr, and t-Bu) showed higher yields than those bearing an electron-poor group (F, Cl, Br, and CF 3 ) (3b-3i vs. 3j-3l, 3p-3s, and 3u). Among substrates, sodium ortho-substituted arylsulfinates, which are sterically hindered, gave relatively lower yields (3d vs. 3b, 3c, and 3g vs. 3e, 3f, and 3l vs. 3j, 3k, and 3r vs. 3p and 3q). In addition, an 82% yield was obtained when sodium 2-naphthylsulfinate was employed as a substrate (3t). Notably, sodium 3-carboxybenzenesulfinate and sodium thiophene-2-sulfinate could be not transformed into the corresponding disulfides.
To further evaluate the utility of these two protocols, two gram-scale reactions were subsequently carried out (Scheme 2). The corresponding products 2a and 3a could be afforded in 88% and 94% yields in a 10 mmol scale, respectively, demonstrating the practicability of the present methodology.
sulfinate was employed as a substrate (3t). Notably, sodium 3-carboxybenzenesul finate and sodium thiophene-2-sulfinate could be not transformed into the corre sponding disulfides.  To further evaluate the utility of these two protocols, two gram-scale reaction were subsequently carried out (Scheme 2). The corresponding products 2a and 3 could be afforded in 88% and 94% yields in a 10 mmol scale, respectively, demon strating the practicability of the present methodology.  sulfinate was employed as a substrate (3t). Notably, sodium 3-carboxybenzenesul finate and sodium thiophene-2-sulfinate could be not transformed into the corre sponding disulfides. To further evaluate the utility of these two protocols, two gram-scale reaction were subsequently carried out (Scheme 2). The corresponding products 2a and 3a could be afforded in 88% and 94% yields in a 10 mmol scale, respectively, demon strating the practicability of the present methodology.  To elucidate the reaction mechanism for the homocoupling of sodium arylsulfinates, several control experiments were conducted (Scheme 3). The formation of both symmetric diphenyl disulfide 3a and diphenyl sulfide 2a was not detected after the addition of the radical scavenger 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO, 2 equiv.) to the standard reaction systems (Scheme 3a,b), indicating that both of these two transformations underwent a free-radical process. For the synthesis of 2a, the disulfide 3a was detected by mass spectrometry. The preparation of disulfides from sodium arylsulfinates under Pd(OAc) 2 catalysis was also demonstrated by Xiang and co-workers [55]. In addition, the transformation from 3a to 2a could be successfully realized in the presence of a catalytic amount of Pd(OAc) 2 and sodium sulfinate 1a (Scheme 3c,d).
Based on the results of the control experiments and literature reports [64,65], a plausible mechanism for the homocoupling of sodium arylsulfinate 1 to the selective access to symmetric sulfide 2 and disulfide 3 is shown in Scheme 4. First, in the reductive Fe/HCl system, disulfide 3a could be generated via the homocoupling of the thiyl radical A, which comes from the radical reduction of sodium phenylsulfinate 2a (Scheme 4a). Alternatively, disulfide 3a could be also formed in the presence of catalytic Pd(OAc) 2  several control experiments were conducted (Scheme 3). The formation of both symmetric diphenyl disulfide 3a and diphenyl sulfide 2a was not detected after the addition of the radical scavenger 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO, 2 equiv.) to the standard reaction systems (Scheme 3a,b), indicating that both of these two transformations underwent a free-radical process. For the synthesis of 2a, the disulfide 3a was detected by mass spectrometry. The preparation of disulfides from sodium arylsulfinates under Pd(OAc)2 catalysis was also demonstrated by Xiang and co-workers [55]. In addition, the transformation from 3a to 2a could be successfully realized in the presence of a catalytic amount of Pd(OAc)2 and sodium sulfinate 1a (Scheme 3c,d).

Scheme 3. Control experiments for the homocoupling of sodium phenylsulfinate.
Based on the results of the control experiments and literature reports [64,65], a plausible mechanism for the homocoupling of sodium arylsulfinate 1 to the selective access to symmetric sulfide 2 and disulfide 3 is shown in Scheme 4. First, in the reductive Fe/HCl system, disulfide 3a could be generated via the homocoupling of the thiyl radical A, which comes from the radical reduction of sodium phenylsulfinate 2a (Scheme 4a). Alternatively, disulfide 3a could be also formed in the presence of catalytic Pd(OAc)2. After disulfide 3a was formed, the Pd(II)-insertion to the S-S bond produced the metal-intermediate B, which underwent ligand exchange to form intermediate C. The thermal extrusion of SO2 of intermediate C resulted in the formation of intermediate D [66], which underwent the reductive elimination to give the target sulfide 2a and regenerate Pd(0) into the next catalytic cycle (Scheme 4b).

Materials and Methods
Unless otherwise indicated, all reagents and solvents were purchased from commercial sources and used without further purification. Deuterated solvents were purchased from Sigma-Aldrich(Shanghai, China.). Refinement of the mixed system was achieved through column chromatography, which was performed on silica gel (200-300 mesh) with petroleum ether (solvent A)/ethyl acetate (solvent B) gradients as elution. In addition, all yields were referred to the isolated yields (average of two runs) of the compounds, unless otherwise specified. The known compounds were partly characterized by melting points (for solid samples), 1H NMR, and compared to authentic samples or the literature data. Melting points were measured with an RD-II digital melting point apparatus (Henan, China) and were uncorrected. 1 H NMR data were acquired on a Bruker Advance 600 MHz spectrometer (Bruker, Germany). using CDCl 3 as solvent. Chemical shifts are reported in ppm from tetramethylsilane, with the solvent CDCl 3 resonance as the internal standard (CDCl 3 = 7.26). Spectra are reported as follows: chemical shift (δ = ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants (Hz), integration, and assignment. 13 C NMR data were collected at 100 MHz, with complete proton decoupling. The chemical shifts are reported in ppm downfield to the central CDCl 3 resonance (δ = 77.0). High-resolution mass spectra were performed on a micrOTOF-Q II instrument (Bruker, Germany), with an ESI source.

Typical Procedure for Symmetric Diaryl Sulfides 2
The mixture of sodium arylsulfinate 1 (0.4 mmol) and Pd(OAc) 2 (2 mg, 2 mol%) in NMP (1.0 mL) was stirred at 150 • C (oil bath) until the substrate was completely consumed, which was determined by TLC. Finally, the reaction mixture was purified by silica gel column chromatography (PE: EA = 40: 1) to afford the desired coupling product diarylsulfides 2.

Gram-Scale Reaction of Sodium Benzenesulfinate to Diphenylsulfide
The mixture of sodium benzenesulfinate 1a (1.64 g, 10 mmol) and the catalyst, Pd(OAc) 2 (45 mg, 2 mol%) in NMP (10 mL), was stirred at 150 • C (oil bath) until the substrate was completely consumed, which was determined by TLC. Finally, the reaction mixture was purified by silica gel column chromatography to afford the coupling product diphenylsulfide 2a (1.640 g, 88% yield).

Conclusions
In summary, we have developed an efficient protocol for the selective access to symmetrical diaryl sulfides and disulfides using sodium sulfinates as sulfenylation reagents via homocoupling reaction. The utilization of readily available sodium sulfinates as coupling partners and good functional group tolerance with modest to excellent yields for most substrates enable these two types of novel transformations to become attractive alternatives for the preparation of the corresponding sulfur compounds. More importantly, sodium sulfinates were used for the first time to access symmetrical diaryl sulfides. The convinced mechanism, selectivity, and synthetic application of this transformation are still under investigation.