Radical–Radical Cross-Coupling Assisted N–S Bond Formation Using Alternating Current Protocol

Open AccessCCS ChemistryRESEARCH ARTICLE5 Aug 2022Radical–Radical Cross-Coupling Assisted N–S Bond Formation Using Alternating Current Protocol Yong Yuan†, Jun-Chao Qi†, Dao-Xin Wang, Ziyue Chen, Hao Wan, Jing-Yun Zhu, Hong Yi, Abhishek Dutta Chowdhury and Aiwen Lei Yong Yuan† National Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang 330022 College of Chemistry and Molecular Sciences, Institute for Advanced Studies (IAS), Engineering Research Center of Organosilicon Compounds m-CPBA, 3-chloroperoxybenzoic acid; NFSI, N-fluorobenzenesulfonimide. aReaction conditions: AC (50 Hz), two platinum plates as the electrodes, 5 V, 10 h, nBu4NBF4 (0.2 mmol), 1 (0.3 mmol), 2 (0.6 mmol), DCE (3 mL), HFIP (8 mL), RT, isolated yields. After the initial optimization, the substrate scope of this AC-promoted cross-coupling reaction has been evaluated (Table 2). First, a wide range of thiols was investigated. Thiophenols bearing either weak electron-withdrawing or -donating substituents delivered corresponding N–S coupled products in high to excellent yields (Table 2, 3–14). In contrast, thiophenols with strong electron-donating or -withdrawing group led to expected cross-coupling product in moderate to good yields (Table 2, 15 and 16). Note that halogen substituents, such as F, Cl, and Br, were well tolerated under the conditions of AC electrolysis (Table 2, 3–9), providing useful functionality for further modifications. Using unsubstituted thiophenol as the substrate, 93% yield of N–S coupled product could be provided (Table 2, 17). In addition to thiophenol derivatives, 2-naphthalenethiol was also tolerated, generating corresponding N–S bonds containing compounds in 81% yield (Table 2, 18). It is worth noting that the substrate scope of thiols could also be extended to aliphatic thiols. For example, using 2-propanethiol, 2-phenylethanethiol, 1-butanethiol, 3-methyl-2-butanethiol, cyclopentanethiol, or cyclohexanethiol as the reaction partners, the corresponding cross-coupling products could be obtained in 62–78% yields (Table 2, 19–24). Table 2 | Substrate Scope of Thiols and Aminesa aReaction conditions: AC (50 Hz), two platinum plates as the electrodes, 5 V, 10 h, nBu4NBF4 (0.2 mmol), thiols (0.3 mmol), amines (0.6 mmol), DCE (3 mL), HFIP (8 mL), RT, isolated yields. Next, various amines were employed to react with 4-chlorothiophenol. N–Ts substituted anilines bearing electron-donating groups (such as phenoxyl, methyl, and tert-butyl) delivered corresponding N–S coupled products in high to excellent yields (Table 2, 25–27). In contrast, when an electron-withdrawing group-substituted aniline was used as the coupling partner, the corresponding cross-coupling product was afforded in decreased yield (Table 2, 28). Ortho- and meta-substituted anilines were also compatible with the reaction conditions, generating corresponding cross-coupling products in 77–90% yields (Table 2, 30–32). Note that when N–Ts substituted aniline was used in the reaction, the corresponding cross-coupling product could be afforded in 65% yield (Table 2, 33). The benzenesulfonyl protecting groups were found to be important for developing desired products in high yields (Table 2, 34–37). For example, using 4-tert-butylbenzenesulfonyl, 4-methoxybenzenesulfonyl, 4-chlorobenzenesulfonyl, and benzenesulfonyl substituted aniline derivatives as the coupling partners, the corresponding cross-coupling reactions occurred smoothly and led to desired products in 78–83% yields (Table 2, 34–37). Note that besides sulfonyl groups, acyl-protecting groups were also tolerated. Either using aromatic or aliphatic acyl-protected anilines as reaction partners, the corresponding cross-coupling reactions occurred successfully and led to desired products in 60–81% yields (Table 2, 38–42). It is worth noting that the AC-promoted radical–radical cross-coupling reaction could be easily scaled up to a gram. For example, when the AC electrolysis of 1 and 2 on a 10 mmol scale was carried out with 2.0 mmol of nBu4NBF4 as the electrolyte and a mixture of DCE and HFIP (DCE/HFIP = 30/80) as the co-solvent, the desired N–S coupled product 3 could be isolated in 82% yield (Figure 3a, see details in Supporting Information Sections S2 and S3). Figure 3 | The utility of the AC-promoted radical–radical cross-coupling method. (a) Gram-scale synthesis. (b) The reaction of product 3 with GSH (43). Download figure Download PowerPoint As mentioned at the beginning of this research article, sulfonamides are valuable structural motifs in drugs. To further demonstrate the versatility of this AC promoted radical–radical cross-coupling reaction, the reaction of N–S coupled product 3 with glutathione (GSH) 43 (an abundant thiol in vivo) was conducted (Figure 3b). To our delight, both S–S coupled product 44, and the released sulfonamide product 2 could be detected (see details in Supporting Information Section S66). This result indicated that the N–S coupled products could react with GSH to release important sulfonamides into the blood using this method.26,32 That is, the prepared N–S coupled products may be used as potential prodrugs. To gain insight into the electrolysis of this AC promoted cross-coupling reaction, numerous experiments were planned (Figure 4). First, performing the electrolysis of 4-fluorothiophenol ( 45) in the absence of N-Ts-4-methoxyaniline ( 2) delivered the corresponding homo-coupling product 46 in 95% yield (Figure 4a). Second, using disulfide intermediate 46 as the cross-coupling partner to replace 4-fluorothiophenol ( 45) to react with N-Ts-4-methoxyaniline ( 2), the corresponding AC electrolysis occurred smoothly and led to desired cross-coupling product 5 in 74% yield (Figure 4b). These results suggest that disulfide might be the key intermediate for N–S bond formation. Third, running the electrolysis of N-Ts-4-methoxyaniline ( 2) in the absence of 4-chlorothiophenol ( 1) delivered the corresponding homo-coupling product 47 in 18% yield (Figure 4c). In addition, when 1.0 mmol of 1,1-diphenylethylene was added into the model reaction, 12% yield of intermolecular radical 3 + 2 annulation product 48 was afforded (Figure 4d).55 These results confirmed the formation of nitrogen radical intermediate. Cyclic voltammetry (CV) experiments were also carried out to clarify which substrate is preferentially oxidized (see details in Supporting Information Section S3). The first oxidation peak of 4-chlorothiophenol ( 1) was observed at 1.52 V, whereas N-Ts-4-methoxyaniline ( 2) showed the oxidation peak at 2.14 V. These results indicated that thiophenols are more easily oxidized than substituted anilines. Figure 4 | (a–d) Control experiments. Download figure Download PowerPoint Next, reactions between 4-fluorothiophenol ( 45) and N-Ts-4-methoxyaniline ( 2) with different reaction times were conducted. As shown in Figure 5, performing the electrolysis with an output voltage of 5 V for 2.5 h, product 5 could not be detected. Instead, disulfide intermediate 46 was obtained with 82% NMR yield (Figure 5a). Prolonging the electrolysis time to 5.0 h, in addition to 47% yield of 46, 36% yield of product 5 was also afforded (Figure 5b). Further prolonging the reaction time to 7.5 h, the yield of target product 5 increased to 85%, whereas the yield of disulfide intermediate 46 decreased to 3% (Figure 5c). It was found that when the electrolysis of 45 and 2 was conducted under an output voltage of 5 V for 10 h, the highest concentration of product 5 (91%) was obtained while disulfide intermediate 46 was hardly detected (Figure 5d). All together, these results indicated that disulfide is the key intermediate in this AC promoted radical–radical cross-coupling reaction. Figure 5 | (a–d) Electrolysis process studies. Reaction conditions: AC (50 Hz), two platinum plates as the electrodes, 5 V, 2.5–10 h, nBu4NBF4 (0.2 mmol), 45 (0.3 mmol), 2 (0.6 mmol), DCE (3 mL), HFIP (8 mL), RT, and the yields were determined by 19F NMR spectroscopy, with 1-fluoronaphthalene (49) as the internal standard. Download figure Download PowerPoint Control experiments were also conducted to explore the effect of frequency (f) on reaction. The experimental results are shown in Figure 6. Increasing the frequency to 75 or 100 Hz delivered desired product 5 in decreased yields (56% or 12%, Figures 6b and 6c). Moreover, controlling the frequency at 500 Hz, product 5 could not even be detected (Figure 6a). In contrast, the cross-coupling reaction took place smoothly at 25 Hz and gave a corresponding N–S coupled product in 85% yield (Figure 6e). Even when the reaction time was shortened to 9 h, product 5 could be produced with a 90% NMR yield (Figure 6f). Although 25 Hz showed a faster reaction rate than 50 Hz (Figure 6d), 50 Hz AC power supply is much cheaper and easier to obtain. In addition, decreasing the frequency to 0 Hz, that is, performing the reaction with a DC, only 39% yield of disulfide intermediate 46 was obtained (Figure 6g), indicating that AC is essential to obtain the desired product. Figure 6 | (a–g) The effect of frequency on the reaction. Reaction conditions: AC (25–500 Hz), two platinum plates as the electrodes, 5 V, 9–10 h, nBu4NBF4 (0.2 mmol), 45 (0.3 mmol), 2 (0.6 mmol), DCE (3 mL), HFIP (8 mL), RT, the yields were determined by 19F NMR spectroscopy, with 1-fluoronaphthalene (49) as the internal standard. Download figure Download PowerPoint Based on experimental outcomes and literature reports,51 a possible mechanism for this N–H/S–H cross-coupling reaction is proposed in Figure 7. In the beginning, the electrochemical oxidation and following deprotonation of thiol (R1SH) lead to the formation of thiyl radical (R1S•), which is unstable and then quickly dimerized to produce disulfide (R1SSR1) intermediate. Upon the voltage polarity reversal, H+ is reduced at the same electrode to give H2. Accompanied by the continuous accumulation of disulfide (R1SSR1) and the release of H2, the electrolysis reaches the next stage. When the potential of electrode is negative enough to reduce the disulfide (R1SSR1), the disulfide intermediate will be reduced to access the corresponding disulfide radical anion and then thiyl radical (R1S•) and thiolate anion (R1S−). Upon the voltage polarity reversal, the electrochemical oxidation and following deprotonation of amine (R2R3NH) result in the formation of a nitrogen-centered radical (R2R3N•). The radical–radical cross-coupling of thiyl radical (R1S•) with nitrogen radical (R2R3N•) finally produces the N–S coupled product. Note that for the electrolysis with an AC, there is no difference between two electrodes and the same reaction also takes place on the other electrode. In addition, the generated thiolate anion (R1S−) is not a by-product, but an intermediate, and will be converted to the corresponding thiyl radical (R1S•) after losing an electron. Figure 7 | Proposed mechanism. Download figure Download PowerPoint Conclusions An AC-promoted N–H/S–H radical–radical cross-coupling reaction has been successfully developed. Mechanistic investigations indicated that disulfide is the crucial intermediate in this AC promoted cross-coupling reaction. The N–H/S–H cross-coupling method described herein reveals the unique advantages of AC electrolysis in realizing the reactions that cannot occur through DC electrolysis. We anticipate this work will stimulate research interest of chemists and pave new avenues to innovation in organic electrosynthesis. Footnote a During the preparation of this manuscript, Phil S. Baran, Yu Kawamata and and co-workers uploaded to ChemRxiv a manuscript also using the strategy of AC electrolysis. See ref 24. Supporting Information Supporting Information is available and includes the general information, experimental procedure, analytical data of products, references, and NMR spectra of products. Conflict of Interest There is no conflict of interest to report. Acknowledgments This work was supported by the National Natural Science Foundation of China (no. 22031008) and the Science Foundation of Wuhan (no. by and to Molecular the between Organic and with via of and of in the of 6. Kawamata Organic Methods the of a 7. Yu Wang for of of under Cross-Coupling of to and of with Wang and of for the Formation of of via of by and the of a Chemical of by and and Bond of by S. for Current Electrolysis for the of via Bond Electrolysis for the of from Current Electrolysis of of with Alternating Electrolysis of Organic Compounds with Alternating Current Electrolysis for Organic of 24. Kawamata Using Alternating ChemRxiv 1 and Studies of 2, V. 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