Electrochemical Synthesis of 4-Sulfenylisocoumarins via Radical Cascade Annulation of o- Alkynylbenzoates with Thiophenols

Electrochemical Synthesis of 4-Sulfenylisocoumarins via Radical Cascade Annulation of o- Alkynylbenzoates with Thiophenols | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Electrochemical Synthesis of 4-Sulfenylisocoumarins via Radical Cascade Annulation of o- Alkynylbenzoates with Thiophenols Chao Ma, Xiaoling Xu, Xiang Luo, Ruijuan Lu, Hualiang Shen, Guoqi Yu, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7188600/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract The first example of directly using abundant, stable, and inexpensive thiophenols as sulfenylating agents for the construction of valuable and structually diverse 4-sulfenylisocoumarins under electrochemical conditions is described. Compared to the existing methods, this approach avoids the use of toxic, moisture-sensitive, pre-functionalized reagents and significantly broadens the substrate scope. Thiophenol 4-sulfenylisocoumarin radical cascade reaction o-alkynylbenzoate electrochemical synthesis Introduction Isocoumarin moieties are important skeletons that have been widely found in natural products, functional materials, as well as pharmaceutical molecules [1]. On the other hand, organochalcogenide compounds have attracted significant interest due to the ability of chalcogen groups to modify the physical, chemical, and biological properties of organic molecules, as well as enabling the introduction of new functionalities through the transformation of carbon–chalcogen bonds [2]. In this context, the synthesis of diverse chalcogenylisocoumarins is highly desirable. However, the reported approaches for the construction of chalcogenylisocoumarins were very limited, much less for 4-sulfenylisocoumarins [3,4]. Among them, the use of stoichiometric amounts of Lewis acids, metal salts, or oxidants as initiators to promote the intramolecular 6- endo - dig cyclization/demethylation reaction of o -alkynylbenzoates with sulfenylating agents (e.g., sulfenylchlorides, disulfides, and N -thiosuccinimides) represents one of the most efficient and powerful ways (Scheme 1A) [4]. In general, these methods are robust because they typically work in very mild or soft reaction conditions with good functional group tolerance; however, the inherent limitations associated with the need for large amounts of initiators and toxic, moisture-sensitive sulfenylating agents make the development of sustainable and alternative synthetic platforms highly desirable. Along this line, recently, Satyanarayana and co-workers disclosed a green electrochemical process for the construction of 4-sulfenylisocoumarins from o -alkynylbenzoates and diaryl disulfides (ArSSAr) without using initiators (Scheme 1B) [5]. Despite the progress made, the toxic and moisture-sensitive nature of disulfide reagents, as well as their limited range of substrates, have been the two main drivers behind the search for alternative precursors. Thiophenols, a class of abundant, stable, and inexpensive reagents, are widely used as building blocks in electrochemically driven organic synthesis via anodic single-electron-transfer (SET) oxidation of the S-H bond to generate a sulfenyl radical [6]. Nevertheless, to the best of our knowledge, the direct use of thiophenols as sulfenylating agents for the construction of 4-sulfenylisocoumarins under electrochemical conditions has not been achieved so far. Retrosynthetic analysis of the 4-sulfenylisocoumarin skeleton indicates that regioselective annulation of o -alkynylbenzoates with thiophenols could offer a more effective and atom-economic alternative to existing methods owing to easy availability of thiophenols (Scheme 1C). However, this hypothesis remains challenging, which may be attributed to the two factors. One is that the resulting sulfenyl radical, stemming from a single-electron-transfer (SET) oxidation of the S-H bond at the anode, could undergo fast dimerization to form a disulfide, which could then further transform into a thiosulfonate product under electrochemical conditions (Scheme 1C, challenge 1) [7]. Another is that the substrate of o -alkynylbenzoate could be easily oxidized to a 1,2-diketone-type product in an air atmosphere under electrochemical conditions (Scheme 1C, challenge 2) [8]. Following our previous research on the synthesis of functionalized polycyclic and heterocyclic compounds [9], we present herein a sustainable and alternative electrochemical method for the synthesis of 4-sulfenylisocoumarins via a radical cascade annulation of o -alkynylbenzoates with thiophenols (Scheme 1D). This approach avoids the use of toxic, moisture-sensitive, pre-functionalized sulfenylating agents and significantly broadens the substrate scope. To test this hypothesis, methyl 2-(phenylethynyl)benzoate 1a and 4-methylbenzenethiol 2a were chosen as model substrates in a 1:4 molar ratio for the optimization of reaction conditions (Table 1). Initially, the reaction was carried out in an undivided three-necked flask, using a 10 x 10 x 1 mm platinum electrode as both the anode and the cathode, Bu 4 NBF 4 (0.067 M) as the electrolyte, and CH 3 CN as the solvent under an N 2 atmosphere at ambient temperature. The result indicated that only trace amounts of the desired product, 3-phenyl-4-(p-tolylthio)-1H-isochromen-1-one 3a, and 1,2-diketone-type byproduct were obtained under 10 mA constant current for 10 h, in contrast, a thiosulfonate-type product, S-(p-tolyl)-4-methylbenzenesulfonothioate, stemming from the cascade oxidation of 4-methylbenzenethiol was obtained in almost quantitative amounts (entry 1). This finding is similar to that reported by Guan, Wu and coworkers, who also obtained thiosulfonate-type products through the electrochemical oxidation of thiols. 7 Subsequently, a combination of various electrode pairs was investigated, to our delight, using a 10x12 mm C200 anode and a platinum cathode gave better results and significantly improved the yield of 3a to 70% (entries 2−8). Since the reaction medium is an important factor in influencing the regioselectivity and yield, we then turned our attention to the screening of different solvent systems. It was found that the yield of the product 3a could be increased to 82% when the use of a mixed solvent system, that is CH 3 CN-HFIP (v/v = 10:1), however, other solvent systems, such as THF, HFIP, EtOH, acetone, DMSO, CH 3 CN-acetone, and CH 3 CN-H 2 O gave poor results (entries 9–16). After that, several common salts, including Bu 4 NClO 4 , Bu 4 NPF 6 , Bu 4 NBr, CF 3 SO 3 Li, and LiClO 4 , were investigated as electrolytes, the results showed that they all displayed diminished efficiency in producing the desired product 3a (entries 17−21). Moreover, decreasing or increasing the electric current to 5 mA and 15 mA, respectively, could not improve the yield of 3a (entries 22, 23). Finally, the air atmosphere resulted in a sharp decrease of the yield of 3a because the concentration of the by-products of S-(p-tolyl)-4-methylbenzenesulfonothioate and methyl 2-(2-oxo-2-phenylacetyl)benzoate increased (entry 24). With the optimized conditions in hand, we then investigated the substrate scope of this electrochemical protocol, and the results were summarized in Table 2. Under the optimized conditions, a wide range of aryl substituents at the terminal of alkynes were first tested. It was found that no matter electron-donating substituents (e.g. -Me, -Et, and -OMe) or electron-withdrawing substituents (e.g. -F, -Cl, and -Br) in different positions of the benzene ring were well tolerated in this transformation, and delivered the desired 4-sulfenylisochromenones 3b – 3j in moderate to good yields, indicating that the electron and steric properties of the substituent have little influence on the reaction. The above results are comparable to those reported in Satyanarayana’s method, which used ArSSAr as a sulfenylating agent, resulting in the production of the corresponding 4-sulfenylisocoumarins 3a , 3c , and 3e with yields of 80%, 79%, and 74%, respectively [5]. Moreover, a substrate with a 2-thienyl group at the terminal of the alkyne could also be smoothly converted into the corresponding product 3k in 50% yield. To demonstrate the generality of this protocol, we then chose 4-methoxybenzenethiol instead of 4-methylbenzenethiol as a sulfenylating agent steering the reaction, as expected, varying the substituents (R and R ’ ) over a wide range (e.g. -Me, -Ph, -CF 3 , -F, -Cl, and -OMe) on different positions of the different benzene ring demonstrated comparable results, leading to the formation of the desired products 3l – 3t in 65%-84% yields. Moreover, substrate with trimethylsilyl (TMS) substituent exhibited good compatibility, affording the corresponding product 3u in 75%- yield. Subsequently, our attention turned to the applicability of other common thiophenols as sulfenylating agents in this electrochemical protocol, the results showed that thiophenols possessing no matter electron-donating groups (e.g. -Et, - t Bu, - i Pr, and -OMe) or electron-withdrawing halogen groups (e.g. -F, -Cl, and -Br) delivered the cross-coupling products 3v - 3aa in moderate to good yields (58−84%) regardless of these substituents at the ortho - or para -position, exhibiting a broader substrate scope than Satyanarayana’s method, in which the scope of diaryl disulfides just limited to (PhS) 2 , (4-Me-PhS) 2 , (4-MeO-PhS) 2 [5]. Unfortunately, no desired products were obtained when substrates with H or n Bu bonding to the C≡C bond were examined. When phenylmethanethiol was used as a sulfenylating agent, only trace amounts of the desired product were detected. To display the feasibility of this protocol, a 10-fold scale-up reaction was also performed with 1a (2 mmol) and 2a (8 mmol, 4 equiv.) under the optimized electrochemical conditions for 10 h, resulting in the synthesis of 3a (0.4 g) in 59% isolated yield, as shown in Table 3, eq.1. This result shows the potential of this electrochemical protocol in practical synthesis. Moreover, the utility of this protocol was further demonstrated by the transformation of 3a into (S)-3-phenyl-4-( p -tolylsulfinyl)-1H-isochromen-1-one 4 in the presence of 1.0 equivalent of m -CPBA, 4a as shown in Table 3, eq.2. To investigate the reaction mechanism, a radical trapping experiment was initially conducted to verify our original design of the radical annulation process. It was found that the reaction was completely repressed when 2.0 equivalents of TEMPO were added to the reaction, and the intermediate 5 was detected by GC−MS (Table 4 i ), which suggested that a radical pathway is probably involved. Subsequently, cyclic voltammetry (CV) experiments were conducted to investigate the redox potential of the substrates. As illustrated in Table 4 ii , the oxidation peaks of methyl 2-(phenylethynyl)benzoate 1a and 4-methoxybenzenethiol 2b were observed at 2.05 V (curve 3, red line), and 1.26 V (curve 1, green line) respectively, indicating that the oxidation of 2b was much easier than 1a at the anode. Furthermore, there were two oxidation peaks of the mixture ( 1a + 2b ) at 1.37 V, and 1.92 V, respectively, in the CV experiment, suggesting that 4-methylbenzenethiol may be firstly oxidized to 4-methoxyphenylsulfenyl radical, which could undergo dimerization to give a disulfide intermediate, followed by further oxidized into 4-methoxyphenylsulfenyl radical and cation species [6b,7]. Based on the preliminary mechanistic experiments and previous reports [6,7], a possible mechanism for this electrochemical transformation was proposed by using substrates 1a and 2b as examples (Table 4ii i ). Initially, 4-methoxybenzenethiol 2b is first oxidized at the anode to give the 4-methoxyphenylsulfenyl radical [6], which then regioselectively attacks the α-position of the C≡C bond in 1a to form a vinyl radical intermediate I , followed by an intramolecular 6- endo - dig cyclization/demethylation reaction to yield the desired product 4-sulfenylisocoumarin 3l . Another possibility is that the initially resulting 4-methoxyphenylsulfenyl radical undergoes dimerization to in situ produce a disulfide intermediate, which then further undergoes oxidation to generate the corresponding radical and the anion, the former reacts with 1a to furnish the final product, and the latter receives an electron at the cathode to regenerate a disulfide species [6b,7]. Conclusions In summary, we have successfully developed an electrochemical protocol for the assembly of valuable 4-sulfenylisocoumarins through a radical cascade annulation of o -alkynylbenzoates with thiophenols. Compared to the existing electrochemical method, this approach avoids the use of toxic, moisture-sensitive and pre-functionalized disulfide reagents and significantly broadens the substrate scope. Declarations Conflicts of interest There are no conflicts to declare. Author Contribution C. Ma wrote the draft manuscript, and performed the experiments, acquired and analysed the original data; X. Xu, X. Luo, R. Lu, and H. Shen conducted the experiments; G. Yu and T. Cai supervised the project, designed the research plan, and revised the manuscript. All authors have read and agreed to the published version of the manuscript. Acknowledgements T. Cai gratefully thanks the Shaoxing Basic Public Welfare Project (No. 2023A11003), as well as the Research Project of Shaoxing University (No. 2023LG003). Data Availability Data is provided within the manuscript or supplementary information files. 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Zhou J, Tao XZ, Dai JJ, et al (2019), Electrochemical synthesis of 1,2-diketones from alkynes under transition-metal-catalyst-free conditions. Chem. Commun. 55: 9208-9211. https://doi.org/10.1039/C9CC03996A. For selected examples see: a) Wei X, Cai T, Zhang ZB, et al (2024), ortho -Alkynyl Benzyl Alcohols as C6 Synthons in Regioselective Construction of Polysubstituted Naphthalenes. J. Org. Chem. 89: 7804-7811. https://doi.org/10.1021/acs.joc.4c00491. b) Zhang ZB, Cai T, Zhan ZH, et al (2022), Assembly of 5H-dibenzo[a,d]cycloheptenes by a formal [5 + 2] annulation of ortho-aryl alkynyl benzyl alcohols with arenes. Org. Biomol. Chem. 20: 7221-7225. https://doi.org/10.1039/D2OB01335E. c) Cai T, Zhang ZB, Li PQ, Sun T, et al (2021), Radical Cascade Bicyclization/Aromatization of 1,7-Enynes with 1,3-Dicarbonyl Compounds towards 2,3-Dihydro-1H-cyclopenta[a]naphthalenes. Adv. Synth. Catal. 363: 3750-3755. https://doi.org/10.1002/adsc.202100678. d) Cai T, Liu J, Zhang H, et al (2019), Ag-Mediated Radical Cyclization of 2-Alkynylthio(seleno)anisoles: Direct Synthesis of 3-Phosphinoylbenzothio(seleno)phenes. Org. Lett. 21: 4605-4608. https://doi.org/10.1021/acs.orglett.9b01510. Tables Tables 1 to 4 are available in the Supplementary Files section Scheme Scheme 1 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files SI20250722.docx Scheme1.docx Tables.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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15:37:34","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":613680,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-7188600/v1/857cf503000537d04ff2ec5e.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Electrochemical Synthesis of 4-Sulfenylisocoumarins via Radical Cascade Annulation of o- Alkynylbenzoates with Thiophenols","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIsocoumarin moieties are important skeletons that have been widely found in natural products, functional materials, as well as pharmaceutical molecules [1]. On the other hand, organochalcogenide compounds have attracted significant interest due to the ability of chalcogen groups to modify the physical, chemical, and biological properties of organic molecules, as well as enabling the introduction of new functionalities through the transformation of carbon\u0026ndash;chalcogen bonds [2]. In this context, the synthesis of diverse chalcogenylisocoumarins is highly desirable. However, the reported approaches for the construction of chalcogenylisocoumarins were very limited, much less for 4-sulfenylisocoumarins [3,4]. Among them, the use of stoichiometric amounts of Lewis acids, metal salts, or oxidants as initiators to promote the intramolecular 6-\u003cem\u003eendo\u003c/em\u003e-\u003cem\u003edig\u003c/em\u003e cyclization/demethylation reaction of \u003cem\u003eo\u003c/em\u003e-alkynylbenzoates with sulfenylating agents (e.g., sulfenylchlorides, disulfides, and \u003cem\u003eN\u003c/em\u003e-thiosuccinimides) represents one of the most efficient and powerful ways (Scheme 1A) [4]. In general, these methods are robust because they typically work in very mild or soft reaction conditions with good functional group tolerance; however, the inherent limitations associated with the need for large amounts of initiators and toxic, moisture-sensitive sulfenylating agents \u0026nbsp;make the development of sustainable and alternative synthetic platforms highly desirable. Along this line, recently, Satyanarayana and co-workers disclosed a green electrochemical process for the construction of 4-sulfenylisocoumarins from \u003cem\u003eo\u003c/em\u003e-alkynylbenzoates and diaryl disulfides (ArSSAr) without using initiators (Scheme 1B) [5]. Despite the progress made, the toxic and moisture-sensitive nature of disulfide reagents, as well as their limited range of substrates, have been the two main drivers behind the search for alternative precursors.\u003c/p\u003e\n\u003cp\u003eThiophenols, a class of abundant, stable, and inexpensive reagents, are widely used as building blocks in electrochemically driven organic synthesis via anodic single-electron-transfer (SET) oxidation of the S-H bond to generate a sulfenyl radical [6]. Nevertheless, to the best of our knowledge, the direct use of thiophenols as sulfenylating agents for the construction of 4-sulfenylisocoumarins under electrochemical conditions has not been achieved so far. Retrosynthetic analysis of the 4-sulfenylisocoumarin skeleton indicates that regioselective annulation of \u003cem\u003eo\u003c/em\u003e-alkynylbenzoates with thiophenols could offer a more effective and atom-economic alternative to existing methods owing to easy availability of thiophenols (Scheme 1C). However, this hypothesis remains challenging, which may be attributed to the two factors. One is that the resulting sulfenyl radical, stemming from a single-electron-transfer (SET) oxidation of the S-H bond at the anode, could undergo fast dimerization to form a disulfide, which could then further transform into a thiosulfonate product under electrochemical conditions (Scheme 1C, challenge 1) [7]. Another is that the substrate of \u003cem\u003eo\u003c/em\u003e-alkynylbenzoate could be easily oxidized to a 1,2-diketone-type product in an air atmosphere under electrochemical conditions (Scheme 1C, challenge 2) [8]. Following our previous research on the synthesis of functionalized polycyclic and heterocyclic compounds [9], we present herein a sustainable and alternative electrochemical method for the synthesis of 4-sulfenylisocoumarins via a radical cascade annulation of \u003cem\u003eo\u003c/em\u003e-alkynylbenzoates with thiophenols (Scheme 1D). This approach avoids the use of toxic, moisture-sensitive, pre-functionalized sulfenylating agents and significantly broadens the substrate scope.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; To test this hypothesis, methyl 2-(phenylethynyl)benzoate 1a and 4-methylbenzenethiol 2a were chosen as model substrates in a 1:4 molar ratio for the optimization of reaction conditions (Table 1). Initially, the reaction was carried out in an undivided three-necked flask, using a 10 x 10 x 1 mm platinum electrode as both the anode and the cathode, Bu\u003csub\u003e4\u003c/sub\u003eNBF\u003csub\u003e4\u003c/sub\u003e (0.067 M) as the electrolyte, and CH\u003csub\u003e3\u003c/sub\u003eCN as the solvent under an N\u003csub\u003e2\u003c/sub\u003e atmosphere at ambient temperature. The result indicated that only trace amounts of the desired product, 3-phenyl-4-(p-tolylthio)-1H-isochromen-1-one 3a, and 1,2-diketone-type byproduct were obtained under 10 mA constant current for 10 h, in contrast, a thiosulfonate-type product, S-(p-tolyl)-4-methylbenzenesulfonothioate, stemming from the cascade oxidation of 4-methylbenzenethiol was obtained in almost quantitative amounts (entry 1). This finding is similar to that reported by Guan, Wu and coworkers, who also obtained thiosulfonate-type products through the electrochemical oxidation of thiols.\u003csup\u003e7\u003c/sup\u003e Subsequently, a combination of various electrode pairs was investigated, to our delight, using a 10x12 mm C200 anode and a platinum cathode gave better results and significantly improved the yield of 3a to 70% (entries 2\u0026minus;8). Since the reaction medium is an important factor in influencing the regioselectivity and yield, we then turned our attention to the screening of different solvent systems. It was found that the yield of the product 3a could be increased to 82% when the use of a mixed solvent system, that is CH\u003csub\u003e3\u003c/sub\u003eCN-HFIP (v/v = 10:1), however,\u0026nbsp;other solvent\u0026nbsp;systems,\u0026nbsp;such as THF,\u0026nbsp;HFIP,\u0026nbsp;EtOH, acetone,\u0026nbsp;DMSO, CH\u003csub\u003e3\u003c/sub\u003eCN-acetone, and CH\u003csub\u003e3\u003c/sub\u003eCN-H\u003csub\u003e2\u003c/sub\u003eO\u0026nbsp;gave poor results\u0026nbsp;(entries\u0026nbsp;9\u0026ndash;16).\u0026nbsp;After that,\u0026nbsp;several common salts, including Bu\u003csub\u003e4\u003c/sub\u003eNClO\u003csub\u003e4\u003c/sub\u003e, Bu\u003csub\u003e4\u003c/sub\u003eNPF\u003csub\u003e6\u003c/sub\u003e, Bu\u003csub\u003e4\u003c/sub\u003eNBr, CF\u003csub\u003e3\u003c/sub\u003eSO\u003csub\u003e3\u003c/sub\u003eLi, and LiClO\u003csub\u003e4\u003c/sub\u003e, were investigated as electrolytes, the results showed that they all displayed diminished efficiency in producing the desired product 3a (entries 17\u0026minus;21). Moreover, decreasing or increasing the electric current to 5 mA and 15 mA, respectively, could not improve the yield of 3a (entries 22, 23). Finally, the air atmosphere resulted in a sharp decrease of the yield of 3a because the concentration of the by-products of S-(p-tolyl)-4-methylbenzenesulfonothioate and methyl 2-(2-oxo-2-phenylacetyl)benzoate increased (entry 24).\u003c/p\u003e\n\u003cp\u003eWith the optimized conditions in hand, we then investigated the substrate scope of this electrochemical protocol, and the results were summarized in Table 2. Under the optimized conditions, a wide range of aryl substituents at the terminal of alkynes were first tested. It was found that no matter electron-donating substituents (e.g. -Me, -Et, and -OMe) or electron-withdrawing substituents (e.g. -F, -Cl, and -Br) in different positions of the benzene ring were well tolerated in this transformation, and delivered the desired 4-sulfenylisochromenones \u003cstrong\u003e3b\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e3j\u003c/strong\u003e in moderate to good yields, indicating that the electron and steric properties of the substituent have little influence on the reaction. The above results are comparable to those reported in Satyanarayana\u0026rsquo;s method, which used ArSSAr as a sulfenylating agent, resulting in the production of the corresponding 4-sulfenylisocoumarins \u003cstrong\u003e3a\u003c/strong\u003e, \u003cstrong\u003e3c\u003c/strong\u003e, and \u003cstrong\u003e3e\u003c/strong\u003e with yields of 80%, 79%, and 74%, respectively [5]. Moreover, a substrate with a 2-thienyl group at the terminal of the alkyne could also be smoothly converted into the corresponding product \u003cstrong\u003e3k\u003c/strong\u003e in 50% yield. To demonstrate the generality of this protocol, we then chose 4-methoxybenzenethiol instead of 4-methylbenzenethiol as a sulfenylating agent steering the reaction, as expected, varying the substituents (R and R\u003csup\u003e\u0026rsquo;\u003c/sup\u003e) over a wide range (e.g. -Me, -Ph, -CF\u003csub\u003e3\u003c/sub\u003e, -F, -Cl, and -OMe) on different positions of the different benzene ring demonstrated comparable results, leading to the formation of the desired products \u003cstrong\u003e3l\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e3t\u003c/strong\u003e in 65%-84% yields. Moreover, substrate with trimethylsilyl (TMS) substituent exhibited good compatibility, affording the corresponding product \u003cstrong\u003e3u\u003c/strong\u003e in 75%- yield. Subsequently, our attention turned to the applicability of other common thiophenols as sulfenylating agents in this electrochemical protocol, the results showed that thiophenols possessing no matter electron-donating groups (e.g. -Et, -\u003cem\u003e\u003csup\u003et\u003c/sup\u003e\u003c/em\u003eBu,\u0026nbsp;-\u003cem\u003e\u003csup\u003ei\u003c/sup\u003e\u003c/em\u003ePr, and -OMe) or electron-withdrawing halogen groups (e.g. -F, -Cl, and -Br) delivered the cross-coupling products \u003cstrong\u003e3v\u003c/strong\u003e-\u003cstrong\u003e3aa\u003c/strong\u003e in moderate to good yields (58\u0026minus;84%) regardless of these substituents at the \u003cem\u003eortho\u003c/em\u003e- or \u003cem\u003epara\u003c/em\u003e-position, exhibiting a broader substrate scope than Satyanarayana\u0026rsquo;s method, in which the scope of diaryl disulfides just limited to (PhS)\u003csub\u003e2\u003c/sub\u003e, (4-Me-PhS)\u003csub\u003e2\u003c/sub\u003e, (4-MeO-PhS)\u003csub\u003e2\u003c/sub\u003e[5]. Unfortunately, no desired products were obtained when substrates with H or \u003cem\u003e\u003csup\u003en\u003c/sup\u003e\u003c/em\u003eBu bonding to the C\u0026equiv;C bond were examined. When phenylmethanethiol was used as a sulfenylating agent, only trace amounts of the desired product were detected.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo display the feasibility of this protocol, a 10-fold scale-up reaction was also performed with \u003cstrong\u003e1a\u003c/strong\u003e (2 mmol) and \u003cstrong\u003e2a\u003c/strong\u003e (8 mmol, 4 equiv.) under the optimized electrochemical conditions for 10 h, resulting in the synthesis of \u003cstrong\u003e3a\u003c/strong\u003e (0.4 g) in 59% isolated yield, as shown in Table 3, eq.1. This result shows the potential of this electrochemical protocol in practical synthesis. Moreover, the utility of this protocol was further demonstrated by the transformation of \u003cstrong\u003e3a\u003c/strong\u003e into (S)-3-phenyl-4-(\u003cem\u003ep\u003c/em\u003e-tolylsulfinyl)-1H-isochromen-1-one \u003cstrong\u003e4\u003c/strong\u003e in the presence of 1.0 equivalent of \u003cem\u003em\u003c/em\u003e-CPBA,\u003csup\u003e4a\u003c/sup\u003e as shown in Table 3, eq.2.\u003c/p\u003e\n\u003cp\u003eTo investigate the reaction mechanism, a radical trapping experiment was initially conducted to verify our original design of the radical annulation process. It was found that the reaction was completely repressed when 2.0 equivalents of TEMPO were added to the reaction, and the intermediate \u003cstrong\u003e5\u003c/strong\u003e was detected by GC\u0026minus;MS (Table 4\u003cstrong\u003ei\u003c/strong\u003e), which\u0026nbsp;suggested\u0026nbsp;that a radical pathway is probably involved.\u0026nbsp;Subsequently,\u0026nbsp;cyclic voltammetry (CV) experiments were\u0026nbsp;conducted\u0026nbsp;to investigate the redox potential of the substrates. As illustrated in Table 4\u003cstrong\u003eii\u003c/strong\u003e, the oxidation peaks of methyl 2-(phenylethynyl)benzoate \u003cstrong\u003e1a\u003c/strong\u003e and 4-methoxybenzenethiol \u003cstrong\u003e2b\u003c/strong\u003e were observed at 2.05 V (curve 3, red line), and 1.26 V (curve 1, green line) respectively, indicating that the oxidation of \u003cstrong\u003e2b\u003c/strong\u003e was much easier than \u003cstrong\u003e1a\u003c/strong\u003e at the anode. Furthermore, there were two oxidation peaks of the mixture (\u003cstrong\u003e1a\u003c/strong\u003e + \u003cstrong\u003e2b\u003c/strong\u003e)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eat 1.37 V, and 1.92 V, respectively, in the CV experiment, suggesting that 4-methylbenzenethiol may be firstly oxidized to 4-methoxyphenylsulfenyl radical, which could undergo dimerization to give a disulfide intermediate, followed by further oxidized into 4-methoxyphenylsulfenyl radical and cation species [6b,7].\u003c/p\u003e\n\u003cp\u003eBased on the preliminary mechanistic experiments and previous reports [6,7], a possible mechanism for this electrochemical transformation was proposed by using substrates \u003cstrong\u003e1a\u003c/strong\u003e and\u0026nbsp;\u003cstrong\u003e2b\u003c/strong\u003e as examples (Table \u003cstrong\u003e4ii\u003c/strong\u003e\u003cstrong\u003ei\u003c/strong\u003e). Initially, 4-methoxybenzenethiol \u003cstrong\u003e2b\u003c/strong\u003e is first oxidized at the anode\u0026nbsp;to\u0026nbsp;give the 4-methoxyphenylsulfenyl\u0026nbsp;radical [6], which then regioselectively attacks the \u0026alpha;-position of the C\u0026equiv;C bond in \u003cstrong\u003e1a\u003c/strong\u003e to form a vinyl radical intermediate \u003cstrong\u003eI\u003c/strong\u003e, followed by an intramolecular 6-\u003cem\u003eendo\u003c/em\u003e-\u003cem\u003edig\u003c/em\u003e cyclization/demethylation reaction to yield the desired product 4-sulfenylisocoumarin \u003cstrong\u003e3l\u003c/strong\u003e. Another possibility is that the initially resulting 4-methoxyphenylsulfenyl\u0026nbsp;radical\u0026nbsp;undergoes dimerization to \u003cem\u003ein situ\u003c/em\u003e produce a disulfide intermediate, which then further undergoes oxidation to generate the corresponding radical and the anion, the former reacts with \u003cstrong\u003e1a\u0026nbsp;\u003c/strong\u003eto\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003efurnish the final product, and the latter receives an electron at the cathode to regenerate a disulfide species [6b,7].\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn summary, we have successfully developed an electrochemical protocol for the assembly of valuable 4-sulfenylisocoumarins through a radical cascade annulation of \u003cem\u003eo\u003c/em\u003e-alkynylbenzoates with thiophenols. Compared to the existing electrochemical method, this approach avoids the use of toxic, moisture-sensitive and pre-functionalized disulfide reagents and significantly broadens the substrate scope.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eConflicts of interest\u003c/h2\u003e\u003cp\u003eThere are no conflicts to declare.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eC. Ma wrote the draft manuscript, and performed the experiments, acquired and analysed the original data; X. Xu, X. Luo, R. Lu, and H. Shen conducted the experiments; G. Yu and T. Cai supervised the project, designed the research plan, and revised the manuscript. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e\u003cp\u003eT. Cai gratefully thanks the Shaoxing Basic Public Welfare Project (No. 2023A11003), as well as the Research Project of Shaoxing University (No. 2023LG003).\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eData is provided within the manuscript or supplementary information files.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eFor selected reviews see: a) Saikia P, Gogoi S (2018), Isocoumarins: General Aspects and Recent Advances in their Synthesis, Adv. Synth. Catal. 360: 2063-2075. https://doi.org/10.1002/adsc.201800019. b) Gogoi N, Parhi R, Tripathi RKP, et al (2024), Recent advances in synthesis of isocoumarins: An overview. Tetrahedron, 150: 133740. https://doi.org/10.1016/j.tet.2023.133740. c) Chutia K, Sarmah M, Gogoi P (2023), Substituted Isocoumarins: An Assemble of Synthetic Strategies Towards 3-Substituted and 3,4-Disubstituted Isocoumarins. Chem. Asian J. 18: e202201240. https://doi.org/10.1002/asia.202201240. 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Catal. 364: 3496-3500. https://doi.org/10.1002/adsc.202200761. b) Speran\u0026ccedil;a A, Godoi B, Pinton S, et al (2011), Regioselective Synthesis of Isochromenones by Iron(III)/PhSeSePh-Mediated Cyclization of 2-Alkynylaryl Esters. J. Org. Chem. 76: 6789-6797. https://doi.org/10.1021/jo201211s. c) Xing L, Zhang Y, Li B, et al (2019), In Situ Formation of RSCl/ArSeCl and Their Application to the Synthesis of 4-Chalcogenylisocumarins/Pyrones from o-(1-Alkynyl)benzoates and (Z)-2-Alken-4-ynoates. Org. Lett. 21: 3620-3624. https://doi.org/10.1021/acs.orglett.9b01046. d) Li Z, Hong J, Weng L, et al (2012), Facile synthesis of sulfenyl-substituted isocoumarins, heterocycle-fused pyrones and 3-(inden-1-ylidene)isobenzofuranones by FeCl\u003csub\u003e3\u003c/sub\u003e-promoted regioselective annulation of o-(1-alkynyl)benzoates and o-(1-alkynyl)heterocyclic carboxylates with disulfides. Tetrahedron, 68: 1552-1559. https://doi.org/10.1016/j.tet.2011.12.003. e) Li Y, Li G, Ding QP (2014), (Trifluoromethyl)thiolation of 2-Alkynylbenzoates: An Efficient Route to 4-[(Trifluoromethyl)thio]-1H-isochromen-1-ones. Eur. J. Org. Chem. 2014: 5017-5022. https://doi.org/10.1002/ejoc.201402629.\u003c/li\u003e\n \u003cli\u003eDapkekar AB, Satyanarayana G (2024), Electrochemically driven regioselective construction of 4-sulfenyl-isochromenones from o-alkynylbenzoates and diaryl disulfides. Org. Biomol. Chem. 22: 7111-7116. https://doi.org/10.1039/D4OB01137F.\u003c/li\u003e\n \u003cli\u003eFor selected examples see: a) Wang Y, Deng L, Mei H, et al (2018), Electrochemical oxidative radical oxysulfuration of styrene derivatives with thiols and nucleophilic oxygen sources. Green Chem. 20: 3444-3449. https://doi.org/10.1039/C8GC01337C. b) Huang P, Wang P, Tang S, et al (2018), Electro-Oxidative S\u0026minus;H/S\u0026minus;H Cross-Coupling with Hydrogen Evolution: Facile Access to Unsymmetrical Disulfides. Angew. Chem. Int. Ed. 57: 8115-8119. https://doi.org/10.1002/anie.201803464. c) Zhang X, Cui T, Zhang Y, et al (2019), Electrochemical Oxidative Cross-Coupling Reaction to Access Unsymmetrical Thiosulfonates and Selenosulfonates. Adv. Synth. Catal. 361: 2014-2019. https://doi.org/10.1002/adsc.201900047.\u003c/li\u003e\n \u003cli\u003eYang Z, Shi Y, Zhan Z, et al (2018), Sustainable Electrocatalytic Oxidant-Free Syntheses of Thiosulfonates from Thiols. ChemElectroChem 5: 3619-3623. https://doi.org/10.1002/celc.201801058.\u003c/li\u003e\n \u003cli\u003eZhou J, Tao XZ, Dai JJ, et al (2019), Electrochemical synthesis of 1,2-diketones from alkynes under transition-metal-catalyst-free conditions. Chem. Commun. 55: 9208-9211. https://doi.org/10.1039/C9CC03996A.\u003c/li\u003e\n \u003cli\u003eFor selected examples see: a) Wei X, Cai T, Zhang ZB, et al (2024), \u003cem\u003eortho\u003c/em\u003e-Alkynyl Benzyl Alcohols as C6 Synthons in Regioselective Construction of Polysubstituted Naphthalenes. J. Org. Chem. 89: 7804-7811. https://doi.org/10.1021/acs.joc.4c00491. b) Zhang ZB, Cai T, Zhan ZH, et al (2022), Assembly of 5H-dibenzo[a,d]cycloheptenes by a formal [5 + 2] annulation of ortho-aryl alkynyl benzyl alcohols with arenes. Org. Biomol. Chem. 20: 7221-7225. https://doi.org/10.1039/D2OB01335E. c) Cai T, Zhang ZB, Li PQ, Sun T, et al (2021), Radical Cascade Bicyclization/Aromatization of 1,7-Enynes with 1,3-Dicarbonyl Compounds towards 2,3-Dihydro-1H-cyclopenta[a]naphthalenes. Adv. Synth. Catal. 363: 3750-3755. https://doi.org/10.1002/adsc.202100678. d) Cai T, Liu J, Zhang H, et al (2019), Ag-Mediated Radical Cyclization of 2-Alkynylthio(seleno)anisoles: Direct Synthesis of 3-Phosphinoylbenzothio(seleno)phenes. Org. Lett. 21: 4605-4608. https://doi.org/10.1021/acs.orglett.9b01510.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 4 are available in the Supplementary Files section\u003c/p\u003e"},{"header":"Scheme","content":"\u003cp\u003eScheme 1 is available in the Supplementary Files section.\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Thiophenol, 4-sulfenylisocoumarin, radical cascade reaction, o-alkynylbenzoate, electrochemical synthesis","lastPublishedDoi":"10.21203/rs.3.rs-7188600/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7188600/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe first example of directly using abundant, stable, and inexpensive thiophenols as sulfenylating agents for the construction of valuable and structually diverse 4-sulfenylisocoumarins under electrochemical conditions is described. Compared to the existing methods, this approach avoids the use of toxic, moisture-sensitive, pre-functionalized reagents and significantly broadens the substrate scope.\u003c/p\u003e","manuscriptTitle":"Electrochemical Synthesis of 4-Sulfenylisocoumarins via Radical Cascade Annulation of o- Alkynylbenzoates with Thiophenols","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-30 15:29:30","doi":"10.21203/rs.3.rs-7188600/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b1ac7de4-51bd-48c7-bef4-0561236c291c","owner":[],"postedDate":"July 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-08-05T16:08:18+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-30 15:29:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7188600","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7188600","identity":"rs-7188600","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}