DDQ-mediated direct cross-dehydrogenative-coupling (CDC) reaction of thiols with isochroman: A serendipitous metal-free route to C-S bond formation

DDQ-mediated direct cross-dehydrogenative-coupling (CDC) reaction of thiols with isochroman: A serendipitous metal-free route to C-S bond formation | 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 Article DDQ-mediated direct cross-dehydrogenative-coupling (CDC) reaction of thiols with isochroman: A serendipitous metal-free route to C-S bond formation Soraya Rezaei, Abdolhamid Alizadeh, Gisya Abdi This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2609405/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 A direct and efficient carbon-sulfur bond formation method was developed. For the first time, cross-dehydrogenative-coupling (CDC) reaction of an especial type of benzyl ethers (isochroman) and a variety of thiols was investigated. 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) without using any metal catalyst provides a simple and efficient method to construct C-S bond leading to the library of sulfur-containing hetrocyclic compounds. Indeed, we can directly functionalize C sp3 -H bond by S-H bond without requiring pre-activation. As a result, this method will increase synthetic efficiency at the most fundamental level of organic synthesis. Physical sciences/Chemistry/Organic chemistry/Methodology Physical sciences/Chemistry/Organic chemistry/Reaction mechanisms Physical sciences/Chemistry/Organic chemistry Physical sciences/Chemistry/Synthesis Figures Figure 1 Figure 2 Figure 3 1. Introduction Carbon–sulfur bond formation is one of the main topics among methodologist in organic synthesis 1 , 2 in terms of preparation many sulfur-containing natural and pharmaceutical products, which reveal potent antibiotic, antimicrobial, analgesic, anti-inflammatory, antipsychotic, anti-HIV, and anti-tumor activities 3 – 6 . Michael addition of a thiol as a nucleophile, to an acceptor such as activated alkene or alkyne by an electron-withdrawing group (e.g., ketone, ester, amide, nitrile, nitro, sulfonate, or phosphonate), results in one of the most efficient C–S bond-forming strategies in synthetic organic chemistry 7 . Besides, Xinping and Jimmy utilized the direct displacement of alcohols with sulfur nucleophiles in carbon − sulfur bond formation 8 . There are also some examples of cross-coupling reactions that use aryl halides with Aromatic and alkyl thiols with different catalysts, for example, palladium complexes of the bisphosphine ligand CyPF- t Bu 9 , CoI 2 (dppe) and Zn, 10 CuO on mesoporous silica 11 , combining FeCl 3 and N,N ′-dimethylethylenediamine 12 , ligand-free copper iodide salt 13 , catalytic amount of nanocrystalline indium oxide as a recyclable catalyst with KOH as the base in DMSO 14 . Social, economic, and environmental concerns about chemical production have been increasing. These concerns all originate from the inefficiency of conventional chemical syntheses. In classical organic transformations develop new chemical reactivity that can greatly shorten functional group is required. Cross-dehydrogenative-coupling (CDC) reaction, namely, the cross coupling of two different C–H bonds of pro-nucleophiles and pro-electrophiles, will avoid the preparation of functional groups and thus make synthetic approaches more efficient (Fig. 1) 15 . Therefore, the development of CDC reactions is highly desirable 16–20 and from a practical point of view, highly efficient CDC reactions under mild reaction conditions are greatly needed for synthesis. To realize CDC reactions, it is a prerequisite to activate the C–H bonds in both the pro-nuleophile and the pro-electrophile in situ and selectively, while avoiding homocoupling. CDCs are the most persuasive tool for carrying out number of organic and organometallic reactions, thus they are of great interest for chemists. CDCs allows the selective formation of new C-C bonds without the formation of any metal salts as a byproducts and also without any need to functionalize the starting materials into organohalides or organometallic species to facilitate such reactions. Therefore, CDCs can be environmental friendly as they can help reduce environmental cost of organic and organometallic chemistry. To carry out such reactions hydrogen acceptors such as oxygen, hydrogen peroxide, organic peroxides [tert-butyl hydrogen peroxide (TBHP) or tert-butyl peroxide (TBP)], and N-halosuccinimides [N-bromosuccinimide (NBS) and N-chlorosuccinimide (NCS)] are required. On the other hand CDCs can be performed without the metal catalysts and in the presence of different metal catalysts (Cu, Fe, and Pd), which can lead to the activation of electrophilic coupling partner 21 . However, it was also reported that CDCs can also be carried out in examples of CDCs developed in water 22 . A few factors have to be considered when choosing substrates for CDCs. In addition, there should be no direct functionalization of the C-H bond to be coupled to electrophile. Another crucial factor includes the presence of heteroatoms such as nitrogen, oxygen and sulfur to the adjacent carbon or elsewhere in the molecule acting as directing group for the coupling with electrophilic reactive component. A variety of cross-dehydrogenative coupling (CDC) protocols have been reported in which the sp 3 -hybridized C–H bond adjacent to a heteroatom can be functionalized with a variety of pronucleophiles in the presence of an oxidant, for example, the CDC reaction of tetrahydroisoquinoline with p -methoxyphenylacetylene, 2-naphthol 23 , various dialkyl malonates 24 , and CDC reaction of isochroman with dimethyl malonate 25 . CDC reactions are not limited to the development of C-C bond formations. Indeed, efficient cross-dehydrogenative-coupling methods have been reported to create carbon-phosphor, carbon-nitrogen and carbon - oxygen bonds in recent years. There are some methods to synthesize C-P bond formation through cross-dehydrogenative-coupling reactions: (1) phosphonation of the benzylic position in N -aryltetrahydroisoquinolines (MeOH 60°C) with dialkyl H -phosphonates 26 , (2) the synthesis of α-aminophosphonates by selective oxidation of N,N -dimethylanilines in the presence of iron salts as catalysts and dialkyl H -phosphonates 27 , (3) the formation of C-P bond using diethylphosphite as nucleophile in an ionic liquid as solvent and electrolyte via electrochemical method 27 , (4) electrochemical cross-coupling of tertiary amines with diethyl H-phosphonate (supporting electrolyte: collidine-H + ClO 4 − ) 28 . A hetero-CDC reaction using simple aldehydes and either secondary or tertiary amides as the coupling partners, 29 a hetero-CDC of C-H bond, adjacent to a nitrogen atom, with amide 30 , and a hetero-CDC between a nitroarene and a cycloalkane 29 have been reported for the generation of C-N bonds. Yoo and co-workers have showed that the acyl C–H bond can be selectively functionalized with alcohols 31 to generate the corresponding esters using copper salts and they have also developed an oxidative esterification reaction between aldehydes and alcohols catalyzed by a combination of Cu(ClO 4 ) 2 .6H 2 O and InBr 3 32 . Herein, we report a new method to create C-S bond. For the first time, through cross-dehydrogenative-coupling (CDC) reaction between a sp 3 C-H adjacent to an oxygen and H-S bond. 2. Results And Discussion Our initial effort on investigation of coupling reaction was focused on the reaction of isochroman with cyclohexanthiol (Table 1 , entry 1) mediated by 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) without using any solvent. We were pleased to observe the excellent efficiency of the desired reaction catalyzed by DDQ under an atmosphere of nitrogen. DDQ is a well-known oxidant in organic chemistry 33 . DDQ was initially used for the CDC between benzyl ethers and ketones giving the cross-coupled products in low to moderate yields 34 . Furthermore, Cheng and Bao have developed an efficient coupling reaction between diarylpropargylic compounds and active methylenes using DDQ as a promoter 35 ,36 . The reaction of isochroman and cyclohexanthiol was studied under various temperatures such as 25°C, 65°C, and 100°C. Among these different system setups, it was found that the DDQ/neat/100°C condition (Table 1 , entry 1) was the best reaction condition (no reaction was observed at the first two temperatures). We also continued our investigation on CDC reactions of isochroman with thiols choosing thiophenol as an aromatic thiol (Table 1 , entry 4). Again, the desired product was obtained in an easy and solvent-free procedure and only TLC separation and purification led to the final product in high yield (70%). To examine the generality of this method, we tested other pro-nucleophiles which include various aliphatic and aromatic thiols. The obtained products are collected in Table 1 . Additionally, we continued our investigation using benzyl mercaptane and furfuryl mercaptane. Again, the desired products were obtained easily under solvent-free conditions in high yields (Table 1 , entries 8 and 9). A tentative mechanism, based on the obtained results, was proposed and shown in Fig. 2 , for the CDC reaction of aliphatic and aromatic thiols with isochroman mediated by DDQ. First, an electron transfer (redox) reaction occurs between isochroman and DDQ resulting in a cation-radical of isochroman and an anion-radical of DDQ. Then, the anionic oxygen of DDQ radical-anion abstracts hydrogen from the thiol (pro-nucleophile) to generate a nucleophile. Later, attack of the nucleophile on the benzoxy cation generates the CDC product and the hydroquinone derivative. Furthermore, the CDC reaction of isochroman and the other type of sulphur containing compounds such as 4-toluen-sulfinic acid sodium salt (pro-nucleophile) mediated by DDQ in acetonitrile as solvent was also investigated (Fig. 3 ). 1 H-NMR spectra helped us to monitor two possible structures (1a and 2a) of coupling products (Table 2 , entries 1 and 2). 3. Methods 2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ), 4-toluen-sulfinic acid sodium salt, isochroman, and all kinds of thiols were purchased from Sigma-Aldrich. n-Hexane, dichloromethane, and TLC Silica gel 60 F 254 were procured from Merck. All applied reagents in this study were analytical grade, and Milli-Q water was used. 1 H NMR spectra were recorded on a Bruker spectrometers operating at 200 MHz, chemical shifts were reported with respect to chloroform peaks at 7.26 (CDCl 3 as the internal standard). 3.1. General procedure for the DDQ-mediated carbon–sulfur cross-dehydrogenative-coupling reactions To a mixture of DDQ (2 mmol) and isochroman (2 mmol), a thiol (6 mmol) was added under nitrogen at room temperature. The reaction mixture was stirred for 2 h at 100°C, progress of the reaction was followed by TLC plates. The resulting mixture purified by thin layer chromatography with (n-hexane/dicholoromethane = 5:5); then 1 H NMR spectroscopy was applied to characterize the structure of the separated compound. 4. Conclusion This work represents a novel strategy for the construction of variety of new carbon-sulfur bonds through cross-dehydrogenative-coupling reactions without the use of any metal catalyst. Various sulfur-containing compounds were obtained efficiently through CDC reactions under mild reaction conditions. CDC reactions represent the most direct and efficient methods for C–S bond formations and provide the pillar for the next-generation chemical synthesis with an eye on green chemistry. Declarations Data availability All data generated or analysed during this study are included in this published article [and its supplementary information files]. Acknowledgments The authors are grateful to Alzahra University and Garmian University for their financial support for accomplishment of the work and providing necessary facilities. References Kondo, T. & Mitsudo, T.-a. J. C. r. Metal-catalyzed carbon− sulfur bond formation. 100 , 3205-3220 (2000). TL, G. (Prentice Hall, 1997). Hosseinzadeh, Z., Ramazani, A. & Razzaghi-Asl, N. J. C. O. C. Anti-cancer nitrogen-containing heterocyclic compounds. 22 , 2256-2279 (2018). Ashizawa, T. et al. Antitumor activity of KF22678, a novel thioester derivative of leinamycin. 10 , 829-836 (1999). Wink, M. (Urban & Fischer, 1999). Vardanyan, R. & Hruby, V. Synthesis of essential drugs . (Elsevier, 2006). Oskouie, A. A., Taheri, S., Mamani, L. & Heydari, A. J. C. C. Thiourea-functionalized magnetic hydroxyapatite as a recyclable inorganic–organic hybrid nanocatalyst for conjugate hydrocyanation of chalcones with TMSCN. 72 , 6-10 (2015). Han, X. & Wu, J. J. O. L. Ga (OTf) 3-Catalyzed direct substitution of alcohols with sulfur nucleophiles. 12 , 5780-5782 (2010). Fernandez-Rodriguez, M. A. & Hartwig, J. F. J. T. J. o. o. c. A general, efficient, and functional-group-tolerant catalyst system for the palladium-catalyzed thioetherification of aryl bromides and iodides. 74 , 1663-1672 (2009). Wong, Y.-C., Jayanth, T. T. & Cheng, C.-H. J. O. l. Cobalt-catalyzed aryl− sulfur bond formation. 8 , 5613-5616 (2006). Chen, C.-K., Chen, Y.-W., Lin, C.-H., Lin, H.-P. & Lee, C.-F. J. C. c. Synthesis of CuO on mesoporous silica and its applications for coupling reactions of thiols with aryl iodides. 46 , 282-284 (2010). Correa, A., Carril, M. & Bolm, C. J. A. C. I. E. Iron‐catalyzed S‐Arylation of thiols with aryl iodides. 47 , 2880-2883 (2008). Sperotto, E., van Klink, G. P., de Vries, J. G. & van Koten, G. J. T. J. o. o. c. Ligand-free copper-catalyzed C− S coupling of aryl iodides and thiols. 73 , 5625-5628 (2008). Reddy, V. P., Kumar, A. V., Swapna, K. & Rao, K. R. J. O. l. Nano indium oxide as a recyclable catalyst for C− S cross-coupling of thiols with aryl halides under ligand free conditions. 11 , 1697-1700 (2009). Li, Z. & Li, C.-J. J. J. o. t. A. C. S. Highly efficient copper-catalyzed nitro-Mannich type reaction: cross-dehydrogenative-coupling between sp3 C− H bond and sp3 C− H bond. 127 , 3672-3673 (2005). Murahashi, S.-I., Komiya, N., Terai, H. & Nakae, T. J. J. o. t. A. C. S. Aerobic ruthenium-catalyzed oxidative cyanation of tertiary amines with sodium cyanide. 125 , 15312-15313 (2003). Hatamoto, Y., Sakaguchi, S. & Ishii, Y. J. O. L. Oxidative cross-coupling of acrylates with vinyl carboxylates catalyzed by a Pd (OAc) 2/HPMoV/O2 system. 6 , 4623-4625 (2004). Yokota, T., Tani, M., Sakaguchi, S. & Ishii, Y. J. J. o. t. A. C. S. Direct coupling of benzene with olefin catalyzed by Pd (OAc) 2 combined with heteropolyoxometalate under dioxygen. 125 , 1476-1477 (2003). Tsuji, J. & Nagashima, H. J. T. Palladium-catalyzed oxidative coupling of aromatic compounds with olefins using t-butyl perbenzoate as a hydrogen accepter. 40 , 2699-2702 (1984). DeBoef, B., Pastine, S. J. & Sames, D. J. J. o. t. A. C. S. Cross-Coupling of sp3 C− H Bonds and Alkenes: Catalytic Cyclization of Alkene− Amide Substrates. 126 , 6556-6557 (2004). Shen, Y. et al. An efficient copper-catalyzed oxidative Mannich reaction between tertiary amines and methyl ketones. 953-955 (2009). Lin, Y.-m., Lu, G.-p., Cai, C. & Yi, W.-b. J. O. l. Odorless, one-pot regio-and stereoselective iodothiolation of alkynes with sodium arenesulfinates under metal-free conditions in water. 17 , 3310-3313 (2015). Li, Z., Bohle, D. S. & Li, C.-J. J. P. o. t. N. A. o. S. Cu-catalyzed cross-dehydrogenative coupling: A versatile strategy for C–C bond formations via the oxidative activation of sp3 C–H bonds. 103 , 8928-8933 (2006). Li, Z. & Li, C.-J. J. J. o. t. A. C. S. Catalytic allylic alkylation via the cross-dehydrogenative-coupling reaction between allylic sp3 C− H and methylenic sp3 C− H bonds. 128 , 56-57 (2006). Zhang, Y. & Li, C. J. J. A. C. Highly Efficient Cross‐Dehydrogenative‐Coupling between Ethers and Active Methylene Compounds. 118 , 1983-1986 (2006). Baslé, O. & Li, C.-J. J. C. c. Copper-catalyzed aerobic phosphonation of sp 3 C–H bonds. 4124-4126 (2009). Baslé, O. et al. Aerobic and Electrochemical Oxidative Cross‐Dehydrogenative‐Coupling (CDC) Reaction in an Imidazolium‐Based Ionic Liquid. 16 , 8162-8166 (2010). Bidan, G., Geniès, M. & Renaud, R. J. E. A. Etude electrochimique de la N, N-dimethyl-mesidine en milieu organique. Oxydation electrochimique en presence de phosphonate de diethyle. 26 , 275-282 (1981). Scheuermann, C. J. J. C. A. A. J. Beyond traditional cross couplings: the scope of the cross dehydrogenative coupling reaction. 5 , 436-451 (2010). Zhang, Y., Fu, H., Jiang, Y. & Zhao, Y. J. O. l. Copper-Catalyzed Amidation of sp3 C− H Bonds Adjacent to a Nitrogen Atom. 9 , 3813-3816 (2007). Yoo, W.-J. & Li, C.-J. J. T. J. o. O. C. Highly stereoselective oxidative esterification of aldehydes with β-dicarbonyl compounds. 71 , 6266-6268 (2006). Yoo, W.-J. & Li, C.-J. J. T. l. Copper-catalyzed oxidative esterification of alcohols with aldehydes activated by Lewis acids. 48 , 1033-1035 (2007). Ying, B.-P., Trogden, B. G., Kohlman, D. T., Liang, S. X. & Xu, Y.-C. J. O. l. Oxidative C− C Bond-Forming Reaction of Electron-Rich Alkylbenzyl Ether with Trimethylvinyloxysilane. 6 , 1523-1526 (2004). Zhang, Y. & Li, C.-J. J. J. o. t. A. C. S. DDQ-mediated direct cross-dehydrogenative-coupling (CDC) between benzyl ethers and simple ketones. 128 , 4242-4243 (2006). Cheng, D. & Bao, W. J. T. J. o. O. C. Propargylation of 1, 3-Dicarbonyl Compounds with 1, 3-Diarylpropynes via Oxidative Cross-Coupling between sp3 C− H and sp3 C− H. 73 , 6881-6883 (2008). Ramesh, D., Ramulu, U., Rajaram, S., Prabhakar, P. & Venkateswarlu, Y. J. T. L. Metal-free oxidative C–C bond formation of active methylenic sp3 C–H bonds with benzylic sp3 C–H and allylic sp3 C–H bonds mediated by DDQ. 51 , 4898-4903 (2010). tables Tables 1 and 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Tables1and2.docx SuppInfo20022023AAlizadeh.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. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2609405","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":184802856,"identity":"e7507a8d-194b-44b9-8ce1-6430a87beb2f","order_by":0,"name":"Soraya Rezaei","email":"","orcid":"","institution":"University of Garmian","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Soraya","middleName":"","lastName":"Rezaei","suffix":""},{"id":184802857,"identity":"2302a703-4a34-46c8-b306-bbaae84c88da","order_by":1,"name":"Abdolhamid 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bonds.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-2609405/v1/65678d3374c180c492f792e4.png"},{"id":34653644,"identity":"b6c4f365-b566-4dbf-a85e-c3c783d6e451","added_by":"auto","created_at":"2023-03-22 14:37:30","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":93295,"visible":true,"origin":"","legend":"\u003cp\u003eTentative mechanism for the CDC reaction of thiols with isochroman in the presence of DDQ\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-2609405/v1/96f6090cf7959473147a2631.png"},{"id":34654878,"identity":"a7c14f66-e893-4349-a5b0-8191d845e1e5","added_by":"auto","created_at":"2023-03-22 14:45:30","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":176188,"visible":true,"origin":"","legend":"\u003cp\u003ePlausible mechanism for the CDC reaction of 4-toluen-sulfinic acid sodium salt with isochroman in the presence of DDQ\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-2609405/v1/f53a35d675823e60ed9792b5.png"},{"id":36555250,"identity":"899ec406-f85c-45c5-ac7e-401aba052a8e","added_by":"auto","created_at":"2023-05-03 04:44:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":469949,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2609405/v1/46e117f8-a09b-46be-a01f-706a2782a7ca.pdf"},{"id":34653643,"identity":"7ba6450b-da0f-44e6-a34e-fc7a712ced2a","added_by":"auto","created_at":"2023-03-22 14:37:30","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":198696,"visible":true,"origin":"","legend":"","description":"","filename":"Tables1and2.docx","url":"https://assets-eu.researchsquare.com/files/rs-2609405/v1/dccebb4a35f7ecbd688df556.docx"},{"id":34653645,"identity":"f9055954-c4fd-4ce2-bcef-d75bad4c0fa5","added_by":"auto","created_at":"2023-03-22 14:37:30","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":2101317,"visible":true,"origin":"","legend":"","description":"","filename":"SuppInfo20022023AAlizadeh.docx","url":"https://assets-eu.researchsquare.com/files/rs-2609405/v1/abe81e0c06be48f609648065.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"DDQ-mediated direct cross-dehydrogenative-coupling (CDC) reaction of thiols with isochroman: A serendipitous metal-free route to C-S bond formation","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eCarbon\u0026ndash;sulfur bond formation is one of the main topics among methodologist in organic synthesis \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e in terms of preparation many sulfur-containing natural and pharmaceutical products, which reveal potent antibiotic, antimicrobial, analgesic, anti-inflammatory, antipsychotic, anti-HIV, and anti-tumor activities \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Michael addition of a thiol as a nucleophile, to an acceptor such as activated alkene or alkyne by an electron-withdrawing group (e.g., ketone, ester, amide, nitrile, nitro, sulfonate, or phosphonate), results in one of the most efficient C\u0026ndash;S bond-forming strategies in synthetic organic chemistry \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Besides, Xinping and Jimmy utilized the direct displacement of alcohols with sulfur nucleophiles in carbon\u0026thinsp;\u0026minus;\u0026thinsp;sulfur bond formation \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. There are also some examples of cross-coupling reactions that use aryl halides with Aromatic and alkyl thiols with different catalysts, for example, palladium complexes of the bisphosphine ligand CyPF-\u003cem\u003et\u003c/em\u003eBu \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e, CoI\u003csub\u003e2\u003c/sub\u003e(dppe) and Zn,\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e CuO on mesoporous silica \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e, combining FeCl\u003csub\u003e3\u003c/sub\u003e and \u003cem\u003eN,N\u003c/em\u003e\u0026prime;-dimethylethylenediamine \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e, ligand-free copper iodide salt \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e, catalytic amount of nanocrystalline indium oxide as a recyclable catalyst with KOH as the base in DMSO \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eSocial, economic, and environmental concerns about chemical production have been increasing. These concerns all originate from the inefficiency of conventional chemical syntheses. In classical organic transformations develop new chemical reactivity that can greatly shorten functional group is required.\u003c/p\u003e\n\u003cp\u003eCross-dehydrogenative-coupling (CDC) reaction, namely, the cross coupling of two different C\u0026ndash;H bonds of pro-nucleophiles and pro-electrophiles, will avoid the preparation of functional groups and thus make synthetic approaches more efficient (Fig.\u0026nbsp;1) \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. Therefore, the development of CDC reactions is highly desirable \u003csup\u003e16\u0026ndash;20\u003c/sup\u003e and from a practical point of view, highly efficient CDC reactions under mild reaction conditions are greatly needed for synthesis. To realize CDC reactions, it is a prerequisite to activate the C\u0026ndash;H bonds in both the pro-nuleophile and the pro-electrophile in situ and selectively, while avoiding homocoupling.\u003c/p\u003e\n\u003cp\u003eCDCs are the most persuasive tool for carrying out number of organic and organometallic reactions, thus they are of great interest for chemists. CDCs allows the selective formation of new C-C bonds without the formation of any metal salts as a byproducts and also without any need to functionalize the starting materials into organohalides or organometallic species to facilitate such reactions. Therefore, CDCs can be environmental friendly as they can help reduce environmental cost of organic and organometallic chemistry.\u003c/p\u003e\n\u003cp\u003eTo carry out such reactions hydrogen acceptors such as oxygen, hydrogen peroxide, organic peroxides [tert-butyl hydrogen peroxide (TBHP) or tert-butyl peroxide (TBP)], and N-halosuccinimides [N-bromosuccinimide (NBS) and N-chlorosuccinimide (NCS)] are required. On the other hand CDCs can be performed without the metal catalysts and in the presence of different metal catalysts (Cu, Fe, and Pd), which can lead to the activation of electrophilic coupling partner \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. However, it was also reported that CDCs can also be carried out in examples of CDCs developed in water \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. A few factors have to be considered when choosing substrates for CDCs. In addition, there should be no direct functionalization of the C-H bond to be coupled to electrophile. Another crucial factor includes the presence of heteroatoms such as nitrogen, oxygen and sulfur to the adjacent carbon or elsewhere in the molecule acting as directing group for the coupling with electrophilic reactive component. A variety of cross-dehydrogenative coupling (CDC) protocols have been reported in which the sp\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e-hybridized C\u0026ndash;H bond adjacent to a heteroatom can be functionalized with a variety of pronucleophiles in the presence of an oxidant, for example, the CDC reaction of tetrahydroisoquinoline with \u003cem\u003ep\u003c/em\u003e-methoxyphenylacetylene, 2-naphthol \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e, various dialkyl malonates \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e, and CDC reaction of isochroman with dimethyl malonate \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. CDC reactions are not limited to the development of C-C bond formations. Indeed, efficient cross-dehydrogenative-coupling methods have been reported to create carbon-phosphor, carbon-nitrogen and carbon\u003cstrong\u003e-\u003c/strong\u003eoxygen bonds in recent years.\u003c/p\u003e\n\u003cp\u003eThere are some methods to synthesize C-P bond formation through cross-dehydrogenative-coupling reactions: (1) phosphonation of the benzylic position in \u003cem\u003eN\u003c/em\u003e-aryltetrahydroisoquinolines (MeOH 60\u0026deg;C) with dialkyl \u003cem\u003eH\u003c/em\u003e-phosphonates \u003csup\u003e26\u003c/sup\u003e, (2) the synthesis of \u0026alpha;-aminophosphonates by selective oxidation of \u003cem\u003eN,N\u003c/em\u003e-dimethylanilines in the presence of iron salts as catalysts and dialkyl \u003cem\u003eH\u003c/em\u003e-phosphonates \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e, (3) the formation of C-P bond using diethylphosphite as nucleophile in an ionic liquid as solvent and electrolyte via electrochemical method \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e, (4) electrochemical cross-coupling of tertiary amines with diethyl H-phosphonate (supporting electrolyte: collidine-H\u003csup\u003e+\u003c/sup\u003e ClO\u003csub\u003e4\u003c/sub\u003e\u003csup\u003e\u0026minus;\u003c/sup\u003e ) \u003csup\u003e28\u003c/sup\u003e. A hetero-CDC reaction using simple aldehydes and either secondary or tertiary amides as the coupling partners, \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e a hetero-CDC of C-H bond, adjacent to a nitrogen atom, with amide \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e, and a hetero-CDC between a nitroarene and a cycloalkane \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e have been reported for the generation of C-N bonds. Yoo and co-workers have showed that the acyl C\u0026ndash;H bond can be selectively functionalized with alcohols \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e to generate the corresponding esters using copper salts and they have also developed an oxidative esterification reaction between aldehydes and alcohols catalyzed by a combination of Cu(ClO\u003csub\u003e4\u003c/sub\u003e)\u003csub\u003e2\u003c/sub\u003e.6H\u003csub\u003e2\u003c/sub\u003eO and InBr\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e32\u003c/sup\u003e. Herein, we report a new method to create C-S bond. For the first time, through cross-dehydrogenative-coupling (CDC) reaction between a sp\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e C-H adjacent to an oxygen and H-S bond.\u003c/p\u003e"},{"header":"2. Results And Discussion","content":"\u003cp\u003eOur initial effort on investigation of coupling reaction was focused on the reaction of isochroman with cyclohexanthiol (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, entry 1) mediated by 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) without using any solvent. We were pleased to observe the excellent efficiency of the desired reaction catalyzed by DDQ under an atmosphere of nitrogen. DDQ is a well-known oxidant in organic chemistry \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. DDQ was initially used for the CDC between benzyl ethers and ketones giving the cross-coupled products in low to moderate yields \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. Furthermore, Cheng and Bao have developed an efficient coupling reaction between diarylpropargylic compounds and active methylenes using DDQ as a promoter \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e,36\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eThe reaction of isochroman and cyclohexanthiol was studied under various temperatures such as 25\u0026deg;C, 65\u0026deg;C, and 100\u0026deg;C. Among these different system setups, it was found that the DDQ/neat/100\u0026deg;C condition (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, entry 1) was the best reaction condition (no reaction was observed at the first two temperatures). We also continued our investigation on CDC reactions of isochroman with thiols choosing thiophenol as an aromatic thiol (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, entry 4). Again, the desired product was obtained in an easy and solvent-free procedure and only TLC separation and purification led to the final product in high yield (70%). To examine the generality of this method, we tested other pro-nucleophiles which include various aliphatic and aromatic thiols. The obtained products are collected in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. Additionally, we continued our investigation using benzyl mercaptane and furfuryl mercaptane. Again, the desired products were obtained easily under solvent-free conditions in high yields (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, entries 8 and 9).\u003c/p\u003e\n\u003cp\u003eA tentative mechanism, based on the obtained results, was proposed and shown in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, for the CDC reaction of aliphatic and aromatic thiols with isochroman mediated by DDQ. First, an electron transfer (redox) reaction occurs between isochroman and DDQ resulting in a cation-radical of isochroman and an anion-radical of DDQ. Then, the anionic oxygen of DDQ radical-anion abstracts hydrogen from the thiol (pro-nucleophile) to generate a nucleophile. Later, attack of the nucleophile on the benzoxy cation generates the CDC product and the hydroquinone derivative.\u003c/p\u003e\n\u003cp\u003eFurthermore, the CDC reaction of isochroman and the other type of sulphur containing compounds such as 4-toluen-sulfinic acid sodium salt (pro-nucleophile) mediated by DDQ in acetonitrile as solvent was also investigated (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). \u003csup\u003e1\u003c/sup\u003eH-NMR spectra helped us to monitor two possible structures (1a and 2a) of coupling products (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, entries 1 and 2).\u003c/p\u003e"},{"header":"3. Methods","content":"\u003cp\u003e2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ), 4-toluen-sulfinic acid sodium salt, isochroman, and all kinds of thiols were purchased from Sigma-Aldrich. n-Hexane, dichloromethane, and TLC Silica gel 60 F\u003csub\u003e254\u003c/sub\u003e were procured from Merck. All applied reagents in this study were analytical grade, and Milli-Q water was used. \u003csup\u003e1\u003c/sup\u003eH NMR spectra were recorded on a Bruker spectrometers operating at 200 MHz, chemical shifts were reported with respect to chloroform peaks at 7.26 (CDCl\u003csub\u003e3\u003c/sub\u003e as the internal standard).\u003c/p\u003e\n\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n\u003ch2\u003e3.1. General procedure for the DDQ-mediated carbon\u0026ndash;sulfur cross-dehydrogenative-coupling reactions\u003c/h2\u003e\n\u003cp\u003eTo a mixture of DDQ (2 mmol) and isochroman (2 mmol), a thiol (6 mmol) was added under nitrogen at room\u0026nbsp;temperature. The reaction mixture was stirred for 2 h at 100\u0026deg;C, progress of the reaction was followed by TLC plates. The resulting mixture purified by thin layer chromatography with (n-hexane/dicholoromethane\u0026thinsp;=\u0026thinsp;5:5); then \u003csup\u003e1\u003c/sup\u003eH NMR spectroscopy was applied to characterize the structure of the separated compound.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"4. Conclusion","content":"\u003cp\u003eThis work represents a novel strategy for the construction of variety of new carbon-sulfur bonds through cross-dehydrogenative-coupling reactions without the use of any metal catalyst. Various sulfur-containing compounds were obtained efficiently through CDC reactions under mild reaction conditions. CDC reactions represent the most direct and efficient methods for C\u0026ndash;S bond formations and provide the pillar for the next-generation chemical synthesis with an eye on green chemistry.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analysed during this study are included in this published article [and its supplementary information files].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are grateful to Alzahra University and Garmian University for their financial support for accomplishment of the work and providing necessary facilities.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKondo, T. \u0026amp; Mitsudo, T.-a. J. C. r. Metal-catalyzed carbon\u0026minus; sulfur bond formation. \u003cstrong\u003e100\u003c/strong\u003e, 3205-3220 (2000).\u003c/li\u003e\n\u003cli\u003eTL, G. (Prentice Hall, 1997).\u003c/li\u003e\n\u003cli\u003eHosseinzadeh, Z., Ramazani, A. \u0026amp; Razzaghi-Asl, N. J. C. O. C. Anti-cancer nitrogen-containing heterocyclic compounds. \u003cstrong\u003e22\u003c/strong\u003e, 2256-2279 (2018).\u003c/li\u003e\n\u003cli\u003eAshizawa, T.\u003cem\u003e et al.\u003c/em\u003e Antitumor activity of KF22678, a novel thioester derivative of leinamycin. \u003cstrong\u003e10\u003c/strong\u003e, 829-836 (1999).\u003c/li\u003e\n\u003cli\u003eWink, M. (Urban \u0026amp; Fischer, 1999).\u003c/li\u003e\n\u003cli\u003eVardanyan, R. \u0026amp; Hruby, V. \u003cem\u003eSynthesis of essential drugs\u003c/em\u003e. (Elsevier, 2006).\u003c/li\u003e\n\u003cli\u003eOskouie, A. A., Taheri, S., Mamani, L. \u0026amp; Heydari, A. J. C. C. Thiourea-functionalized magnetic hydroxyapatite as a recyclable inorganic\u0026ndash;organic hybrid nanocatalyst for conjugate hydrocyanation of chalcones with TMSCN. \u003cstrong\u003e72\u003c/strong\u003e, 6-10 (2015).\u003c/li\u003e\n\u003cli\u003eHan, X. \u0026amp; Wu, J. J. O. L. Ga (OTf) 3-Catalyzed direct substitution of alcohols with sulfur nucleophiles. \u003cstrong\u003e12\u003c/strong\u003e, 5780-5782 (2010).\u003c/li\u003e\n\u003cli\u003eFernandez-Rodriguez, M. A. \u0026amp; Hartwig, J. F. J. T. J. o. o. c. A general, efficient, and functional-group-tolerant catalyst system for the palladium-catalyzed thioetherification of aryl bromides and iodides. \u003cstrong\u003e74\u003c/strong\u003e, 1663-1672 (2009).\u003c/li\u003e\n\u003cli\u003eWong, Y.-C., Jayanth, T. T. \u0026amp; Cheng, C.-H. J. O. l. Cobalt-catalyzed aryl\u0026minus; sulfur bond formation. \u003cstrong\u003e8\u003c/strong\u003e, 5613-5616 (2006).\u003c/li\u003e\n\u003cli\u003eChen, C.-K., Chen, Y.-W., Lin, C.-H., Lin, H.-P. \u0026amp; Lee, C.-F. J. C. c. Synthesis of CuO on mesoporous silica and its applications for coupling reactions of thiols with aryl iodides. \u003cstrong\u003e46\u003c/strong\u003e, 282-284 (2010).\u003c/li\u003e\n\u003cli\u003eCorrea, A., Carril, M. \u0026amp; Bolm, C. J. A. C. I. E. Iron‐catalyzed S‐Arylation of thiols with aryl iodides. \u003cstrong\u003e47\u003c/strong\u003e, 2880-2883 (2008).\u003c/li\u003e\n\u003cli\u003eSperotto, E., van Klink, G. P., de Vries, J. G. \u0026amp; van Koten, G. J. T. J. o. o. c. Ligand-free copper-catalyzed C\u0026minus; S coupling of aryl iodides and thiols. \u003cstrong\u003e73\u003c/strong\u003e, 5625-5628 (2008).\u003c/li\u003e\n\u003cli\u003eReddy, V. P., Kumar, A. V., Swapna, K. \u0026amp; Rao, K. R. J. O. l. Nano indium oxide as a recyclable catalyst for C\u0026minus; S cross-coupling of thiols with aryl halides under ligand free conditions. \u003cstrong\u003e11\u003c/strong\u003e, 1697-1700 (2009).\u003c/li\u003e\n\u003cli\u003eLi, Z. \u0026amp; Li, C.-J. J. J. o. t. A. C. S. Highly efficient copper-catalyzed nitro-Mannich type reaction: cross-dehydrogenative-coupling between sp3 C\u0026minus; H bond and sp3 C\u0026minus; H bond. \u003cstrong\u003e127\u003c/strong\u003e, 3672-3673 (2005).\u003c/li\u003e\n\u003cli\u003eMurahashi, S.-I., Komiya, N., Terai, H. \u0026amp; Nakae, T. J. J. o. t. A. C. S. Aerobic ruthenium-catalyzed oxidative cyanation of tertiary amines with sodium cyanide. \u003cstrong\u003e125\u003c/strong\u003e, 15312-15313 (2003).\u003c/li\u003e\n\u003cli\u003eHatamoto, Y., Sakaguchi, S. \u0026amp; Ishii, Y. J. O. L. Oxidative cross-coupling of acrylates with vinyl carboxylates catalyzed by a Pd (OAc) 2/HPMoV/O2 system. \u003cstrong\u003e6\u003c/strong\u003e, 4623-4625 (2004).\u003c/li\u003e\n\u003cli\u003eYokota, T., Tani, M., Sakaguchi, S. \u0026amp; Ishii, Y. J. J. o. t. A. C. S. Direct coupling of benzene with olefin catalyzed by Pd (OAc) 2 combined with heteropolyoxometalate under dioxygen. \u003cstrong\u003e125\u003c/strong\u003e, 1476-1477 (2003).\u003c/li\u003e\n\u003cli\u003eTsuji, J. \u0026amp; Nagashima, H. J. T. Palladium-catalyzed oxidative coupling of aromatic compounds with olefins using t-butyl perbenzoate as a hydrogen accepter. \u003cstrong\u003e40\u003c/strong\u003e, 2699-2702 (1984).\u003c/li\u003e\n\u003cli\u003eDeBoef, B., Pastine, S. J. \u0026amp; Sames, D. J. J. o. t. A. C. S. Cross-Coupling of sp3 C\u0026minus; H Bonds and Alkenes: Catalytic Cyclization of Alkene\u0026minus; Amide Substrates. \u003cstrong\u003e126\u003c/strong\u003e, 6556-6557 (2004).\u003c/li\u003e\n\u003cli\u003eShen, Y.\u003cem\u003e et al.\u003c/em\u003e An efficient copper-catalyzed oxidative Mannich reaction between tertiary amines and methyl ketones. 953-955 (2009).\u003c/li\u003e\n\u003cli\u003eLin, Y.-m., Lu, G.-p., Cai, C. \u0026amp; Yi, W.-b. J. O. l. Odorless, one-pot regio-and stereoselective iodothiolation of alkynes with sodium arenesulfinates under metal-free conditions in water. \u003cstrong\u003e17\u003c/strong\u003e, 3310-3313 (2015).\u003c/li\u003e\n\u003cli\u003eLi, Z., Bohle, D. S. \u0026amp; Li, C.-J. J. P. o. t. N. A. o. S. Cu-catalyzed cross-dehydrogenative coupling: A versatile strategy for C\u0026ndash;C bond formations via the oxidative activation of sp3 C\u0026ndash;H bonds. \u003cstrong\u003e103\u003c/strong\u003e, 8928-8933 (2006).\u003c/li\u003e\n\u003cli\u003eLi, Z. \u0026amp; Li, C.-J. J. J. o. t. A. C. S. Catalytic allylic alkylation via the cross-dehydrogenative-coupling reaction between allylic sp3 C\u0026minus; H and methylenic sp3 C\u0026minus; H bonds. \u003cstrong\u003e128\u003c/strong\u003e, 56-57 (2006).\u003c/li\u003e\n\u003cli\u003eZhang, Y. \u0026amp; Li, C. J. J. A. C. Highly Efficient Cross‐Dehydrogenative‐Coupling between Ethers and Active Methylene Compounds. \u003cstrong\u003e118\u003c/strong\u003e, 1983-1986 (2006).\u003c/li\u003e\n\u003cli\u003eBasl\u0026eacute;, O. \u0026amp; Li, C.-J. J. C. c. Copper-catalyzed aerobic phosphonation of sp 3 C\u0026ndash;H bonds. 4124-4126 (2009).\u003c/li\u003e\n\u003cli\u003eBasl\u0026eacute;, O.\u003cem\u003e et al.\u003c/em\u003e Aerobic and Electrochemical Oxidative Cross‐Dehydrogenative‐Coupling (CDC) Reaction in an Imidazolium‐Based Ionic Liquid. \u003cstrong\u003e16\u003c/strong\u003e, 8162-8166 (2010).\u003c/li\u003e\n\u003cli\u003eBidan, G., Geni\u0026egrave;s, M. \u0026amp; Renaud, R. J. E. A. Etude electrochimique de la N, N-dimethyl-mesidine en milieu organique. Oxydation electrochimique en presence de phosphonate de diethyle. \u003cstrong\u003e26\u003c/strong\u003e, 275-282 (1981).\u003c/li\u003e\n\u003cli\u003eScheuermann, C. J. J. C. A. A. J. Beyond traditional cross couplings: the scope of the cross dehydrogenative coupling reaction. \u003cstrong\u003e5\u003c/strong\u003e, 436-451 (2010).\u003c/li\u003e\n\u003cli\u003eZhang, Y., Fu, H., Jiang, Y. \u0026amp; Zhao, Y. J. O. l. Copper-Catalyzed Amidation of sp3 C\u0026minus; H Bonds Adjacent to a Nitrogen Atom. \u003cstrong\u003e9\u003c/strong\u003e, 3813-3816 (2007).\u003c/li\u003e\n\u003cli\u003eYoo, W.-J. \u0026amp; Li, C.-J. J. T. J. o. O. C. Highly stereoselective oxidative esterification of aldehydes with \u0026beta;-dicarbonyl compounds. \u003cstrong\u003e71\u003c/strong\u003e, 6266-6268 (2006).\u003c/li\u003e\n\u003cli\u003eYoo, W.-J. \u0026amp; Li, C.-J. J. T. l. Copper-catalyzed oxidative esterification of alcohols with aldehydes activated by Lewis acids. \u003cstrong\u003e48\u003c/strong\u003e, 1033-1035 (2007).\u003c/li\u003e\n\u003cli\u003eYing, B.-P., Trogden, B. G., Kohlman, D. T., Liang, S. X. \u0026amp; Xu, Y.-C. J. O. l. Oxidative C\u0026minus; C Bond-Forming Reaction of Electron-Rich Alkylbenzyl Ether with Trimethylvinyloxysilane. \u003cstrong\u003e6\u003c/strong\u003e, 1523-1526 (2004).\u003c/li\u003e\n\u003cli\u003eZhang, Y. \u0026amp; Li, C.-J. J. J. o. t. A. C. S. DDQ-mediated direct cross-dehydrogenative-coupling (CDC) between benzyl ethers and simple ketones. \u003cstrong\u003e128\u003c/strong\u003e, 4242-4243 (2006).\u003c/li\u003e\n\u003cli\u003eCheng, D. \u0026amp; Bao, W. J. T. J. o. O. C. Propargylation of 1, 3-Dicarbonyl Compounds with 1, 3-Diarylpropynes via Oxidative Cross-Coupling between sp3 C\u0026minus; H and sp3 C\u0026minus; H. \u003cstrong\u003e73\u003c/strong\u003e, 6881-6883 (2008).\u003c/li\u003e\n\u003cli\u003eRamesh, D., Ramulu, U., Rajaram, S., Prabhakar, P. \u0026amp; Venkateswarlu, Y. J. T. L. Metal-free oxidative C\u0026ndash;C bond formation of active methylenic sp3 C\u0026ndash;H bonds with benzylic sp3 C\u0026ndash;H and allylic sp3 C\u0026ndash;H bonds mediated by DDQ. \u003cstrong\u003e51\u003c/strong\u003e, 4898-4903 (2010).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"tables","content":"\u003cp\u003eTables 1 and 2 are available in the Supplementary Files section.\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":"","lastPublishedDoi":"10.21203/rs.3.rs-2609405/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2609405/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eA direct and efficient carbon-sulfur bond formation method was developed. For the first time, cross-dehydrogenative-coupling (CDC) reaction of an especial type of benzyl ethers (isochroman) and a variety of thiols was investigated. 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) without using any metal catalyst provides a simple and efficient method to construct C-S bond leading to the library of sulfur-containing hetrocyclic compounds. Indeed, we can directly functionalize C\u003csub\u003esp3\u003c/sub\u003e-H bond by S-H bond without requiring pre-activation. As a result, this method will increase synthetic efficiency at the most fundamental level of organic synthesis.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e","manuscriptTitle":"DDQ-mediated direct cross-dehydrogenative-coupling (CDC) reaction of thiols with isochroman: A serendipitous metal-free route to C-S bond formation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-03-22 14:37:25","doi":"10.21203/rs.3.rs-2609405/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":"055111b5-0922-414f-9021-9b12c42b914e","owner":[],"postedDate":"March 22nd, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":20039818,"name":"Physical sciences/Chemistry/Organic chemistry/Methodology"},{"id":20039819,"name":"Physical sciences/Chemistry/Organic chemistry/Reaction mechanisms"},{"id":20039820,"name":"Physical sciences/Chemistry/Organic chemistry"},{"id":20039821,"name":"Physical sciences/Chemistry/Synthesis"}],"tags":[],"updatedAt":"2023-05-03T04:44:25+00:00","versionOfRecord":[],"versionCreatedAt":"2023-03-22 14:37:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2609405","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2609405","identity":"rs-2609405","version":["v1"]},"buildId":"-HB7Z8yhvgn0wM9Nzuekk","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}