Direct Oxygen Insertion into C-C Bond of Styrenes with Air

Direct Oxygen Insertion into C-C Bond of Styrenes with Air | 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 Direct Oxygen Insertion into C-C Bond of Styrenes with Air Ning Jiao, Qixue Qin, Liang Zhang, Jialiang Wei, Xu Qiu, Shuanghong Hao, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4706612/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 18 Oct, 2024 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract Skeletal editing of single-atom insertion to basic chemicals has been demonstrated as efficient strategy for the discovery of structurally novel compounds. Previous endeavors in skeletal editing have successfully facilitated the insertion of boron, nitrogen, and carbon atoms. Given the prevalence of oxygen atoms in biologically active molecules, the direct oxygenation of C-C bonds through single-oxygen-atom insertion like Baeyer-Villiger reaction is of particular significance. Herein, we present a novel approach for the skeletal modification of styrenes using O2 via oxygen insertion into Ar-C(sp2) σ-bond, resulting in the formation of corresponding aryl ether frameworks under mild reaction conditions. The broad functional-group tolerance and the excellent chemo- and regioselectivity were demonstrated in this protocol. A preliminary mechanistic study indicated the potential involvement of 1,2-aryl radical migration in this reaction. Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology Physical sciences/Chemistry/Photochemistry/Photocatalysis Physical sciences/Chemistry/Catalysis/Photocatalysis Physical sciences/Chemistry/Green chemistry Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Over the past few years, molecular skeletal editing has emerged as a potent tool, facilitating the construction of structurally novel molecules derived from common synthetic scaffolds 1 . Compared with the traditional de novo synthesis approach, direct modification of the molecular structure obviates the resource and time-consuming of construction a library of complex molecular and may extremely extend the chemical space 2–9 . However, it is still a challenging issue because the selective modification of inert C-C bonds is required in complicated reaction system. Despite these challenges, some significant achievements have been reported in the context of formal-single-atom skeletal editing including boron 10,11 , carbon 12–17 , or nitrogen 18–21 atom insertion and deletion reaction 22–28 (Fig. 1a). Considering the prevalence of oxygen atoms in biologically active molecules, the direct oxygenation of C-C bonds through single-oxygen-atom insertion holds particular significance, which is also very important for bioactive compound modification and drug discovery 29–32 . One classic reaction fitting this description is the Baeyer-Villiger reaction, which has been widely used in organic synthesis to convert ketones into esters or lactones through a single-oxygen-atom insertion process (Fig. 1b) 33,34 . Notably, a formal oxygen insertion into C-C bond of arenes through cascade reactions of arenophile-based cycloaddition, epoxidation, and cycloreversion was recently reported by Sarlah and colleagues (Fig. 1c) 35 . Despite previous significant progress, there is room for expanding the concept of single-oxygen-atom insertion into other types of C-C bonds, particularly through the utilization of O 2 or even air as a green and ideal oxygen source 36–40 . Alkene is one of the most important classes of chemicals in chemical industry and synthetic community 41–43 . Significant oxygenation of olefins at the relatively active C = C double bond and allylic C-H bond including classical Wacker oxidation 44,45 , epoxidation 46–49 , oxidative cleavage of alkene 50,51 , and C-H bond oxygenation 52–59 have been developed and widely used in synthetic chemistry. Despite these notable achievements, no new oxygenation pathway for olefins has been disclosed in recent decades. Although some novel Ar-C(sp 2 ) bond functionalization transformations have been elegantly realized by the groups such as Youn 60 , Schoenebeck and Lautens 61 , Wei and Duan 62 , and our own group 63 . Herein, we present a novel and efficient skeletal editing of alkenes through Ar-C(sp 2 ) σ-bond oxygenation of alkene for the synthesis of highly value-added ether products (Fig. 1d), which are widely exist in natural products, pharmaceuticals and agrochemicals 29,30 . By utilizing air or dioxygen as the O-source, this chemistry provides a new and alternative approach to aryl ether synthesis under metal-free and mild reaction conditions. The new mode of C-C bond activation would open new avenues for future research in alkene chemistry. Results and Discussion To implement this concept, we conducted a preliminary investigation using 4-methylstyrene 1a and Tosyl chloride (TsCl) 2a as the model substrates for the reaction discovery and optimization. To our delight, the desired Ar-C(sp 2 ) σ-bond oxygen atom insertion reaction proceeded smoothly in the presence of a photoredox catalyst (2.0 mol%), DIPEA (1.5 equiv) and Na 3 PO 4 .12H 2 O (1.0 equiv) in CH 3 CN at 35℃, upon exposure to a 90 W white LED for 24 h. Further experiments revealed that the photoredox catalyst was not essential for this transformation (see SI). Subsequent comprehensive optimization led to the identification of standard conditions that provided 63% isolated yield of the desired product (Table 1, entry 1). DIPEA proved crucial for this reaction, as there was no reaction in its absence (entry 2). We speculated that DIPEA could act as an electron donor and an Electron-Donor-Acceptor (EDA) complex may be occurred between the TsCl and DIPEA (see SI) 64 . Other electron donors such as Et 3 N, DABCO or PPh 3 showed lower efficiencies (entry 3–4). Na 3 PO 4 .12H 2 O is critical for the reaction efficiency, and the yield of 3a decreased to 35% in the absence of the base (entry 5). Other inorganic base such as NaH 2 PO 4 and K 2 CO 3 , could be used, but they afforded lower yields (entry 6–7). Different solvents were also screened, and DCM was found to be the optimal choice (entry 8–10). Not surprisingly, a control experiment verified the necessity of light for the success of the reaction (entry 11). It is worth to mention that thermal conditions showed lower efficiency than light in this process (entry 12). With the optimized conditions in hand, we next studied the generality of this transformation by exploring the scope of styrenes (Table 2). Styrenes with variety of substituents at the para -, meta -, and ortho -position, such as alkyl-, cycloalkyl-, aryl-, ester-, aryl ether-, amide- and alkoxy groups were compatible in this transformation and gave the corresponding ether products 3a - 3l in moderate to good yields (39–72%). The reaction of 2-vinylnaphthalene delivered 3m in 43% yield. Furthermore, vinylheteroarenes substrates also performed well and produced products 3n - 3p in 52–70% yields. Notably, a range of complex alkenes, such as derivatives of estrone, oxaprozin and ibuprofen were also found to perform well yielding the corresponding products 3q - 3t . Unfortunately, the reactivity of 1,1- and 1,2-disubstituted styrenes ( 1u , 1v ) was found to be lower under these oxygenation conditions probably due to the steric effect. The presence of strong electron-withdrawing groups ( 1w , 1x ) were not tolerated, resulting in no desired products detected. In these cases, significant decomposition of most sulfonyl chlorides occurred during the reactions. Next, attention was turned to exploring the functional group tolerance of the sulfonyl chloride yielding the vinyl aryl ether products. As depicted in Table 2, both electron-donating and electron-withdrawing substituents at the phenyl group in benzenesulfonyl chloride were found to tolerate the reaction conditions well, giving rise to the desired products in acceptable yields ( 4a - o ). Comparatively, toluene sulfonyl chlorides with halogen groups at the para -, meta -, and ortho - positions of the phenyl group afforded the corresponding products 4k - o in yields of 40–52%. The lower yield of the ortho -substituted product may be due to the steric effect. Naphthalene-1-sulfonyl chloride and naphthalene-2-sulfonyl chloride were converted to the desired products 4p and 4q in 43% and 51% yields, respectively. In addition, the disubstituted as well as trisubstituted phenyl groups of sulfonyl chloride also delivered the desired products in acceptable yields ( 4r , 4s ). In particular, sulfonyl chloride containing heterocycles such as dihydrobenzofura and 1,4-benzodioxan, commonly found in medicinally relevant compounds, all performed well and gave the desired product 4t - u in yields of 30–59%. Thiophene-2-sulfonyl chloride ( 4w ) was also competent under this protocol. Moreover, complex sulfonyl chloride was also applied in this oxygenation reaction, and potentially bioactive compound 4z was obtained in a reasonable yield. To gain insight into the mechanism, several control experiments were extensively carried out (Fig. 2). 19 F NMR titration experiments and UV-Vis spectrum (see SI) indicated weak interactions between DIPEA and sulfonyl chloride 2p occurred in solution (Fig. 2a) 65 . The reaction was significantly inhibited in the presence of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) as a radical scavenger. Furthermore, a radical clock experiment using substrate 1y formed the ring-opening product 5 in 7% yield along with 47% β -hydroxysulfone compound 5' (Fig. 2c). These experiments suggest a radical mechanism may be involved in this reaction. Moreover, 18 O-labeling experiments were conducted (Fig. 2d). When the reaction was carried out in the presence of 5.0 equiv of H 2 18 O, no 18 O labelled product was detected. In contrast, the oxygenation product was obtained in 60% yield with 80% 18 O-labeled [ 18 O]- 3a’ in the presence of 18 O 2 (the formation of 3a is probably due to the impurity of 18 O 2 gas), which demonstrates that the oxygen atom of the aryl ether products was derived from molecular oxygen. We also performed several further transformations to demonstrate the synthetic application of the vinyl aryl ether products in forming useful molecular scaffolds (Fig. 3). For instance, enamine 6 , a high-valued synthetic block, can be readily prepared in high yield using vinyl aryl ether 3a and pyrrolidine as the starting material. Moreover, thioether 7 was constructed in 76% yield by a simple Michael addition reaction of benzenemethanethiol with vinyl sulfones 3a . Radical substitution of 3a with silicon reagent in the presence of AIBN could afford the product 8 in 56% yield. In addition, the Ts group can be readily removed by treating with magnesium in MeOH to give the desired product 9a-9c in moderate to good yields. Although the mechanism, including the photoexcitation process, is not entirely clear yet, a potential mechanism is outlined in Fig. 4 based on mechanistic studies and literature reports 64,66,67 . Photoexcitation or thermally activation of EDA complex generates sulfonyl radical I . The subsequent radical addition of I to 4-methylstyrene 2a produces the secondary alkyl radical II , which could be trapped by an oxygen molecule to form peroxyl radical III . Radical cross-coupling of peroxyl radical III with radical II yields intermediate IV . Alternatively, the intermediate IV could also be generated by the homocoupling of III followed by the release of dioxygen. Then, the O-O bond homolysis of the species IV produces radical V , which undergoes concerted [ 1 , 2 ]-aryl shift through a spiro-cyclohexadienyl radical VII 68–70 , forming the more stable phenoxymethyl radical intermediate VII . Ultimately, a Cl-atom transfer from 2a to radical intermediate VII regenerates the sulfonyl radical I , delivering the desired product 3a after β-H elimination of VIII . Conclusion In summary, we have developed a novel method for the skeletal editing of styrenes, achieving oxygen atom insertion into the Ar-C(sp 2 ) σ-bond and facilitating the creation of corresponding aryl ether scaffolds under mild reaction conditions. The versatility of this reaction is evident in its tolerance towards a diverse range of functional groups, making it adaptable for late-stage modifications of complex molecules. Preliminary mechanistic studies indicated that a radical-induced 1,2-aryl migration is key to the success of this process. This innovative strategy not only expands the synthetic toolbox but also may promote the development of novel transformations of alkenes through C-C σ-bond cleavage. Methods General procedure for direct oxygenation of alkenes A 25 mL quartz tube was equipped with a rubber septum and magnetic stir bar and was charged with benzenesulfonyl chloride derivatives 2 (0.4 mmol, 2.0 equiv or 0.5 mmol, 2.5 equiv), Na 3 PO 4 .12H 2 O (0.2 mmol, 1.0 equiv). Then alkenes 1 (0.2 mmol, 1.0 equiv), DIPEA (0.4 mmol, 2.0 equiv or 0.5 mmol, 2.5 equiv) and DCM (1.0 mL, 0.20 M) were added with syringe. The mixture was stirred and irradiated by a 90 W white LED from 6 cm distance at ambient temperature for specific time (24 h-48 h). After the reaction was complete (as judged by TLC analysis), the mixture was poured into a separatory funnel containing 10 mL H 2 O and 10 mL DCM. The layer was separated and the aqueous layer was extracted with DCM (2×10 mL). The combined organic layers were dried with Na 2 SO 4 and concentrated under reduced pressure after filtration. The crude product was purified by flash chromatography on silica gel to afford the desired product 3 or 4 . For complete experimental details, including Photochemical instrumentation, related detection, procedures and full characterization ( 1 H and 13 C NMR, HRMS spectrometry) of all new compounds, see Supplementary Information. Declarations Acknowledgements The authors acknowledge the National Key R&D Program of China (No. 2021YFA1501700), the NSFC (Nos. 22293014, 22131002, 22161142019, 21901010), the Natural Science Foundation of Shandong Province (ZR2023MB071, ZR2021MC022), the Tencent Foundation and the Doctorial Fund of Qingdao Agriculture University (665-1120030), the New Cornerstone Science Foundation through the New Cornerstone Investigator Program and the XPLORER PRIZE for financial support. We also thank Shouyun Yu from Nanjing University and Hua Yang from Central South University for helpful discussion. Author Contributions Q.Q. and N.J. conceived and designed the experiments; Q.Q. and L.Z. carried out most of experiments; Q.Q., L.Z., J.W., X.Q., S.H., X.A., and N.J. analyzed data; Q.Q. and N.J. wrote the paper; N.J. directed the project. Competing interests The authors declare no competing interests. Author Information : 1 College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Chang Cheng Rd. 700, Qingdao, Shandong 266109, China. 2 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Chemical Biology Center, Peking University, Xue Yuan Rd. 38, Beijing 100191, China. # these authors contributed equally: Qixue Qin, Liang Zhang. Correspondence and requests for materials should be addressed to Qixue Qin ( [email protected] ) and Ning Jiao ( [email protected] ). References Jurczyk J, Woo J, Kim SF, Dherange BD, Sarpong R, Levin MD (2022) Single-Atom Logic for Heterocycle Editing. 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J Org Chem 72:4520–4523 Salamone M, Bietti M, Calcagni A, Gente G (2009) Phenyl Bridging in Ring-Substituted Cumyloxyl Radicals. A Product and Time-Resolved Kinetic Study. Org Lett 11:2453–2456 Bietti M, Calcagni A, Cicero DO, Martella R, Salamone M (2010) The O-neophyl rearrangement of 1,1-diarylalkoxyl radicals. Experimental evidence for the formation of an intermediate 1-oxaspiro[2,5]octadienyl radical. Tetrahedron Lett 51:4129–4131 Tables Tables 1 and 2 are available in the Supplementary Files section. Additional Declarations There is NO Competing Interest. Supplementary Files 4y.cif QinSupplementaryInformation.pdf checkCIFPLATONreport.pdf Tables.docx Cite Share Download PDF Status: Published Journal Publication published 18 Oct, 2024 Read the published version in Nature Communications → 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-4706612","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":326954624,"identity":"5dc5b9a8-c00f-4749-bc68-bfde0d105a69","order_by":0,"name":"Ning Jiao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3ElEQVRIiWNgGAWjYBACxmYQacDAwC/BkAAWaCBai+QMYrXAgcENqBkEtTC3Mz98XFBwx27z7Yanm3kYbGQ3HGB+9gC/w9iMjWcYPEvedudA2m0ehjTjDQfYzA3wa2Ewk+YxOJxsdiMBpOVw4oYDPGwS+LWwfwNrMZ4B1vKfGC08YFvsDCTAWg4QpaXYGKglQQLol5tzDJKNZx5mM8OrxbD/+MbHPH8O2/PP7km78abCTrbvePMz/FoaIHRiAwNPAjhOGZjxqQcCeShtz8DAfoCA2lEwCkbBKBipAABWl0k9F/sHXwAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0003-0290-9034","institution":"Peking University","correspondingAuthor":true,"prefix":"","firstName":"Ning","middleName":"","lastName":"Jiao","suffix":""},{"id":326954625,"identity":"d6cc49ba-ad6b-446d-beb0-7e156e6f68af","order_by":1,"name":"Qixue Qin","email":"","orcid":"","institution":"Qingdao Agricultural University","correspondingAuthor":false,"prefix":"","firstName":"Qixue","middleName":"","lastName":"Qin","suffix":""},{"id":326954626,"identity":"8345748d-450c-4a09-8f3a-55ca206bb4e1","order_by":2,"name":"Liang Zhang","email":"","orcid":"","institution":"Qingdao Agricultural University","correspondingAuthor":false,"prefix":"","firstName":"Liang","middleName":"","lastName":"Zhang","suffix":""},{"id":326954627,"identity":"abd65bc6-f9f4-43bf-9275-8ecdfac28e79","order_by":3,"name":"Jialiang Wei","email":"","orcid":"","institution":"Peking University","correspondingAuthor":false,"prefix":"","firstName":"Jialiang","middleName":"","lastName":"Wei","suffix":""},{"id":326954628,"identity":"88529393-a7ef-4cb4-8223-5dd335fa6cfd","order_by":4,"name":"Xu Qiu","email":"","orcid":"https://orcid.org/0000-0002-9559-3624","institution":"Peking University","correspondingAuthor":false,"prefix":"","firstName":"Xu","middleName":"","lastName":"Qiu","suffix":""},{"id":326954629,"identity":"e12b0238-babd-46aa-a861-aa93bc3bc529","order_by":5,"name":"Shuanghong Hao","email":"","orcid":"","institution":"Qingdao Agricultural University","correspondingAuthor":false,"prefix":"","firstName":"Shuanghong","middleName":"","lastName":"Hao","suffix":""},{"id":326954630,"identity":"b3848f96-315f-48a9-9c14-d052b5bc3763","order_by":6,"name":"Xiao-De An","email":"","orcid":"","institution":"Qingdao Agricultural University","correspondingAuthor":false,"prefix":"","firstName":"Xiao-De","middleName":"","lastName":"An","suffix":""}],"badges":[],"createdAt":"2024-07-08 15:20:58","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4706612/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4706612/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41467-024-53266-6","type":"published","date":"2024-10-18T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":60395430,"identity":"01e62c47-9e7a-4afc-85be-1605248212e1","added_by":"auto","created_at":"2024-07-16 09:50:39","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":63248,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eInsertion of single-atom into organic scaffold. (a) \u003c/strong\u003eskeletal editing through direct boron, carbon and nitrogen insertion. \u003cstrong\u003e(b)\u003c/strong\u003e single-oxygen-atom insertion through Baeyer-Villiger reaction. \u003cstrong\u003e(c)\u003c/strong\u003e two step formal oxygen-atom insertion of arene. \u003cstrong\u003e(d)\u003c/strong\u003e direct oxygen insertion into Ar-C(sp\u003csup\u003e2\u003c/sup\u003e) σ-bond.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4706612/v1/7448ac0a742449f682c554c1.png"},{"id":60396969,"identity":"bbf2eb5d-b410-4a08-aa6e-07ae15cc03f8","added_by":"auto","created_at":"2024-07-16 10:06:39","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":66050,"visible":true,"origin":"","legend":"\u003cp\u003ePreliminary Mechanistic Studies. (a) \u003csup\u003e19\u003c/sup\u003eF NMR titration experiments. (b) Radical trapping experiment. (c) Radical clock experiment. (d) \u003csup\u003e18\u003c/sup\u003eO-Labelling experiments.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4706612/v1/ccee67e237188cbc7d883055.png"},{"id":60396360,"identity":"3c47d5a2-b1c9-4989-aa14-8190e7d07445","added_by":"auto","created_at":"2024-07-16 09:58:39","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":38666,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSynthetic Applications.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4706612/v1/e4f5199b87969b1375885798.png"},{"id":60396362,"identity":"235445af-4f30-46c3-866b-eb7fa9b3156f","added_by":"auto","created_at":"2024-07-16 09:58:39","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":52550,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eProposed Mechanism.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4706612/v1/ada8f43b19b3391cc89da187.png"},{"id":67002824,"identity":"fbf4e9b8-109f-4451-889c-25ea036766ac","added_by":"auto","created_at":"2024-10-19 07:05:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":599004,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4706612/v1/411dd381-c51d-4032-8ecc-6d87a966abdc.pdf"},{"id":60395434,"identity":"6f949e93-095a-461f-a890-3dccb4aa42f3","added_by":"auto","created_at":"2024-07-16 09:50:39","extension":"cif","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":869663,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"4y.cif","url":"https://assets-eu.researchsquare.com/files/rs-4706612/v1/d8e8380a84f2ca341d687568.cif"},{"id":60395437,"identity":"ee4bff6d-bfaa-41b1-9d41-b0a66326b6f1","added_by":"auto","created_at":"2024-07-16 09:50:39","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":9836035,"visible":true,"origin":"","legend":"","description":"","filename":"QinSupplementaryInformation.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4706612/v1/0f01dafe7a886eabfc31c3c9.pdf"},{"id":60395438,"identity":"12efea00-61b3-44d5-b717-b6a7ceeb79bb","added_by":"auto","created_at":"2024-07-16 09:50:39","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":166348,"visible":true,"origin":"","legend":"","description":"","filename":"checkCIFPLATONreport.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4706612/v1/5af994cd5ee156c4bda06a9b.pdf"},{"id":60395436,"identity":"fc98e408-962f-410b-8059-7e33cda0dba0","added_by":"auto","created_at":"2024-07-16 09:50:39","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":506530,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-4706612/v1/35c016fa54c67461a7fdc8d6.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Direct Oxygen Insertion into C-C Bond of Styrenes with Air","fulltext":[{"header":"Introduction","content":"\u003cp\u003eOver the past few years, molecular skeletal editing has emerged as a potent tool, facilitating the construction of structurally novel molecules derived from common synthetic scaffolds\u003csup\u003e1\u003c/sup\u003e. Compared with the traditional de novo synthesis approach, direct modification of the molecular structure obviates the resource and time-consuming of construction a library of complex molecular and may extremely extend the chemical space\u003csup\u003e2\u0026ndash;9\u003c/sup\u003e. However, it is still a challenging issue because the selective modification of inert C-C bonds is required in complicated reaction system. Despite these challenges, some significant achievements have been reported in the context of formal-single-atom skeletal editing including boron\u003csup\u003e10,11\u003c/sup\u003e, carbon\u003csup\u003e12\u0026ndash;17\u003c/sup\u003e, or nitrogen\u003csup\u003e18\u0026ndash;21\u003c/sup\u003e atom insertion and deletion reaction\u003csup\u003e22\u0026ndash;28\u003c/sup\u003e (Fig.\u0026nbsp;1a). Considering the prevalence of oxygen atoms in biologically active molecules, the direct oxygenation of C-C bonds through single-oxygen-atom insertion holds particular significance, which is also very important for bioactive compound modification and drug discovery\u003csup\u003e29\u0026ndash;32\u003c/sup\u003e. One classic reaction fitting this description is the Baeyer-Villiger reaction, which has been widely used in organic synthesis to convert ketones into esters or lactones through a single-oxygen-atom insertion process (Fig.\u0026nbsp;1b)\u003csup\u003e33,34\u003c/sup\u003e. Notably, a formal oxygen insertion into C-C bond of arenes through cascade reactions of arenophile-based cycloaddition, epoxidation, and cycloreversion was recently reported by Sarlah and colleagues (Fig.\u0026nbsp;1c)\u003csup\u003e35\u003c/sup\u003e. Despite previous significant progress, there is room for expanding the concept of single-oxygen-atom insertion into other types of C-C bonds, particularly through the utilization of O\u003csub\u003e2\u003c/sub\u003e or even air as a green and ideal oxygen source\u003csup\u003e36\u0026ndash;40\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eAlkene is one of the most important classes of chemicals in chemical industry and synthetic community\u003csup\u003e41\u0026ndash;43\u003c/sup\u003e. Significant oxygenation of olefins at the relatively active C\u0026thinsp;=\u0026thinsp;C double bond and allylic C-H bond including classical Wacker oxidation\u003csup\u003e44,45\u003c/sup\u003e, epoxidation\u003csup\u003e46\u0026ndash;49\u003c/sup\u003e, oxidative cleavage of alkene\u003csup\u003e50,51\u003c/sup\u003e, and C-H bond oxygenation\u003csup\u003e52\u0026ndash;59\u003c/sup\u003e have been developed and widely used in synthetic chemistry. Despite these notable achievements, no new oxygenation pathway for olefins has been disclosed in recent decades. Although some novel Ar-C(sp\u003csup\u003e2\u003c/sup\u003e) bond functionalization transformations have been elegantly realized by the groups such as Youn\u003csup\u003e60\u003c/sup\u003e, Schoenebeck and Lautens\u003csup\u003e61\u003c/sup\u003e, Wei and Duan\u003csup\u003e62\u003c/sup\u003e, and our own group\u003csup\u003e63\u003c/sup\u003e. Herein, we present a novel and efficient skeletal editing of alkenes through Ar-C(sp\u003csup\u003e2\u003c/sup\u003e) σ-bond oxygenation of alkene for the synthesis of highly value-added ether products (Fig.\u0026nbsp;1d), which are widely exist in natural products, pharmaceuticals and agrochemicals\u003csup\u003e29,30\u003c/sup\u003e. By utilizing air or dioxygen as the O-source, this chemistry provides a new and alternative approach to aryl ether synthesis under metal-free and mild reaction conditions. The new mode of C-C bond activation would open new avenues for future research in alkene chemistry.\u003c/p\u003e"},{"header":"Results and Discussion","content":"\u003cp\u003eTo implement this concept, we conducted a preliminary investigation using 4-methylstyrene \u003cstrong\u003e1a\u003c/strong\u003e and Tosyl chloride (TsCl) \u003cstrong\u003e2a\u003c/strong\u003e as the model substrates for the reaction discovery and optimization. To our delight, the desired Ar-C(sp\u003csup\u003e2\u003c/sup\u003e) \u0026sigma;-bond oxygen atom insertion reaction proceeded smoothly in the presence of a photoredox catalyst (2.0 mol%), DIPEA (1.5 equiv) and Na\u003csub\u003e3\u003c/sub\u003ePO\u003csub\u003e4\u003c/sub\u003e.12H\u003csub\u003e2\u003c/sub\u003eO (1.0 equiv) in CH\u003csub\u003e3\u003c/sub\u003eCN at 35℃, upon exposure to a 90 W white LED for 24 h. Further experiments revealed that the photoredox catalyst was not essential for this transformation (see SI). Subsequent comprehensive optimization led to the identification of standard conditions that provided 63% isolated yield of the desired product (Table\u0026nbsp;1, entry 1). DIPEA proved crucial for this reaction, as there was no reaction in its absence (entry 2). We speculated that DIPEA could act as an electron donor and an Electron-Donor-Acceptor (EDA) complex may be occurred between the TsCl and DIPEA (see SI)\u003csup\u003e64\u003c/sup\u003e. Other electron donors such as Et\u003csub\u003e3\u003c/sub\u003eN, DABCO or PPh\u003csub\u003e3\u003c/sub\u003e showed lower efficiencies (entry 3\u0026ndash;4). Na\u003csub\u003e3\u003c/sub\u003ePO\u003csub\u003e4\u003c/sub\u003e.12H\u003csub\u003e2\u003c/sub\u003eO is critical for the reaction efficiency, and the yield of \u003cstrong\u003e3a\u003c/strong\u003e decreased to 35% in the absence of the base (entry 5). Other inorganic base such as NaH\u003csub\u003e2\u003c/sub\u003ePO\u003csub\u003e4\u003c/sub\u003e and K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e, could be used, but they afforded lower yields (entry 6\u0026ndash;7). Different solvents were also screened, and DCM was found to be the optimal choice (entry 8\u0026ndash;10). Not surprisingly, a control experiment verified the necessity of light for the success of the reaction (entry 11). It is worth to mention that thermal conditions showed lower efficiency than light in this process (entry 12).\u003c/p\u003e\n\u003cp\u003eWith the optimized conditions in hand, we next studied the generality of this transformation by exploring the scope of styrenes (Table 2). Styrenes with variety of substituents at the \u003cem\u003epara\u003c/em\u003e-, \u003cem\u003emeta\u003c/em\u003e-, and \u003cem\u003eortho\u003c/em\u003e-position, such as alkyl-, cycloalkyl-, aryl-, ester-, aryl ether-, amide- and alkoxy groups were compatible in this transformation and gave the corresponding ether products \u003cstrong\u003e3a\u003c/strong\u003e-\u003cstrong\u003e3l\u003c/strong\u003e in moderate to good yields (39\u0026ndash;72%). The reaction of 2-vinylnaphthalene delivered \u003cstrong\u003e3m\u003c/strong\u003e in 43% yield. Furthermore, vinylheteroarenes substrates also performed well and produced products \u003cstrong\u003e3n\u003c/strong\u003e-\u003cstrong\u003e3p\u003c/strong\u003e in 52\u0026ndash;70% yields. Notably, a range of complex alkenes, such as derivatives of estrone, oxaprozin and ibuprofen were also found to perform well yielding the corresponding products \u003cstrong\u003e3q\u003c/strong\u003e-\u003cstrong\u003e3t\u003c/strong\u003e. Unfortunately, the reactivity of 1,1- and 1,2-disubstituted styrenes (\u003cstrong\u003e1u\u003c/strong\u003e, \u003cstrong\u003e1v\u003c/strong\u003e) was found to be lower under these oxygenation conditions probably due to the steric effect. The presence of strong electron-withdrawing groups (\u003cstrong\u003e1w\u003c/strong\u003e, \u003cstrong\u003e1x\u003c/strong\u003e) were not tolerated, resulting in no desired products detected. In these cases, significant decomposition of most sulfonyl chlorides occurred during the reactions.\u003c/p\u003e\n\u003cp\u003eNext, attention was turned to exploring the functional group tolerance of the sulfonyl chloride yielding the vinyl aryl ether products. As depicted in Table\u0026nbsp;2, both electron-donating and electron-withdrawing substituents at the phenyl group in benzenesulfonyl chloride were found to tolerate the reaction conditions well, giving rise to the desired products in acceptable yields (\u003cstrong\u003e4a\u003c/strong\u003e-\u003cstrong\u003eo\u003c/strong\u003e). Comparatively, toluene sulfonyl chlorides with halogen groups at the \u003cem\u003epara\u003c/em\u003e-, \u003cem\u003emeta\u003c/em\u003e-, and \u003cem\u003eortho\u003c/em\u003e- positions of the phenyl group afforded the corresponding products \u003cstrong\u003e4k\u003c/strong\u003e-\u003cstrong\u003eo\u003c/strong\u003e in yields of 40\u0026ndash;52%. The lower yield of the \u003cem\u003eortho\u003c/em\u003e-substituted product may be due to the steric effect. Naphthalene-1-sulfonyl chloride and naphthalene-2-sulfonyl chloride were converted to the desired products \u003cstrong\u003e4p\u003c/strong\u003e and \u003cstrong\u003e4q\u003c/strong\u003e in 43% and 51% yields, respectively. In addition, the disubstituted as well as trisubstituted phenyl groups of sulfonyl chloride also delivered the desired products in acceptable yields (\u003cstrong\u003e4r\u003c/strong\u003e, \u003cstrong\u003e4s\u003c/strong\u003e). In particular, sulfonyl chloride containing heterocycles such as dihydrobenzofura and 1,4-benzodioxan, commonly found in medicinally relevant compounds, all performed well and gave the desired product \u003cstrong\u003e4t\u003c/strong\u003e-\u003cstrong\u003eu\u003c/strong\u003e in yields of 30\u0026ndash;59%. Thiophene-2-sulfonyl chloride (\u003cstrong\u003e4w\u003c/strong\u003e) was also competent under this protocol. Moreover, complex sulfonyl chloride was also applied in this oxygenation reaction, and potentially bioactive compound \u003cstrong\u003e4z\u003c/strong\u003e was obtained in a reasonable yield.\u003c/p\u003e\n\u003cp\u003eTo gain insight into the mechanism, several control experiments were extensively carried out (Fig. 2). \u003csup\u003e19\u003c/sup\u003eF NMR titration experiments and UV-Vis spectrum (see SI) indicated weak interactions between DIPEA and sulfonyl chloride \u003cstrong\u003e2p\u003c/strong\u003e occurred in solution (Fig. 2a)\u003csup\u003e65\u003c/sup\u003e. The reaction was significantly inhibited in the presence of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) as a radical scavenger. Furthermore, a radical clock experiment using substrate \u003cstrong\u003e1y\u003c/strong\u003e formed the ring-opening product \u003cstrong\u003e5\u003c/strong\u003e in 7% yield along with 47% \u003cem\u003e\u0026beta;\u003c/em\u003e-hydroxysulfone compound \u003cstrong\u003e5\u0026apos;\u003c/strong\u003e(Fig. 2c). These experiments suggest a radical mechanism may be involved in this reaction. Moreover, \u003csup\u003e18\u003c/sup\u003eO-labeling experiments were conducted (Fig.\u0026nbsp;2d). When the reaction was carried out in the presence of 5.0 equiv of H\u003csub\u003e2\u003c/sub\u003e\u003csup\u003e18\u003c/sup\u003eO, no \u003csup\u003e18\u003c/sup\u003eO labelled product was detected. In contrast, the oxygenation product was obtained in 60% yield with 80% \u003csup\u003e18\u003c/sup\u003eO-labeled [\u003csup\u003e18\u003c/sup\u003eO]-\u003cstrong\u003e3a\u0026rsquo;\u003c/strong\u003e in the presence of \u003csup\u003e18\u003c/sup\u003eO\u003csub\u003e2\u003c/sub\u003e (the formation of \u003cstrong\u003e3a\u003c/strong\u003e is probably due to the impurity of \u003csup\u003e18\u003c/sup\u003eO\u003csub\u003e2\u003c/sub\u003e gas), which demonstrates that the oxygen atom of the aryl ether products was derived from molecular oxygen.\u003c/p\u003e\n\u003cp\u003eWe also performed several further transformations to demonstrate the synthetic application of the vinyl aryl ether products in forming useful molecular scaffolds (Fig. 3). For instance, enamine \u003cstrong\u003e6\u003c/strong\u003e, a high-valued synthetic block, can be readily prepared in high yield using vinyl aryl ether \u003cstrong\u003e3a\u003c/strong\u003e and pyrrolidine as the starting material. Moreover, thioether \u003cstrong\u003e7\u003c/strong\u003e was constructed in 76% yield by a simple Michael addition reaction of benzenemethanethiol with vinyl sulfones \u003cstrong\u003e3a\u003c/strong\u003e. Radical substitution of \u003cstrong\u003e3a\u003c/strong\u003e with silicon reagent in the presence of AIBN could afford the product \u003cstrong\u003e8\u003c/strong\u003e in 56% yield. In addition, the Ts group can be readily removed by treating with magnesium in MeOH to give the desired product \u003cstrong\u003e9a-9c\u003c/strong\u003e in moderate to good yields.\u003c/p\u003e\n\u003cp\u003eAlthough the mechanism, including the photoexcitation process, is not entirely clear yet, a potential mechanism is outlined in Fig.\u0026nbsp;4 based on mechanistic studies and literature reports\u003csup\u003e64,66,67\u003c/sup\u003e. Photoexcitation or thermally activation of EDA complex generates sulfonyl radical \u003cstrong\u003eI\u003c/strong\u003e. The subsequent radical addition of \u003cstrong\u003eI\u003c/strong\u003e to 4-methylstyrene \u003cstrong\u003e2a\u003c/strong\u003e produces the secondary alkyl radical \u003cstrong\u003eII\u003c/strong\u003e, which could be trapped by an oxygen molecule to form peroxyl radical \u003cstrong\u003eIII\u003c/strong\u003e. Radical cross-coupling of peroxyl radical \u003cstrong\u003eIII\u003c/strong\u003e with radical \u003cstrong\u003eII\u003c/strong\u003e yields intermediate \u003cstrong\u003eIV\u003c/strong\u003e. Alternatively, the intermediate \u003cstrong\u003eIV\u003c/strong\u003e could also be generated by the homocoupling of \u003cstrong\u003eIII\u003c/strong\u003e followed by the release of dioxygen. Then, the O-O bond homolysis of the species \u003cstrong\u003eIV\u003c/strong\u003e produces radical \u003cstrong\u003eV\u003c/strong\u003e, which undergoes concerted [\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e]-aryl shift through a spiro-cyclohexadienyl radical \u003cstrong\u003eVII\u003c/strong\u003e\u003csup\u003e68\u0026ndash;70\u003c/sup\u003e, forming the more stable phenoxymethyl radical intermediate \u003cstrong\u003eVII\u003c/strong\u003e. Ultimately, a Cl-atom transfer from \u003cstrong\u003e2a\u003c/strong\u003e to radical intermediate \u003cstrong\u003eVII\u003c/strong\u003e regenerates the sulfonyl radical \u003cstrong\u003eI\u003c/strong\u003e, delivering the desired product \u003cstrong\u003e3a\u003c/strong\u003e after \u0026beta;-H elimination of \u003cstrong\u003eVIII\u003c/strong\u003e.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, we have developed a novel method for the skeletal editing of styrenes, achieving oxygen atom insertion into the Ar-C(sp\u003csup\u003e2\u003c/sup\u003e) σ-bond and facilitating the creation of corresponding aryl ether scaffolds under mild reaction conditions. The versatility of this reaction is evident in its tolerance towards a diverse range of functional groups, making it adaptable for late-stage modifications of complex molecules. Preliminary mechanistic studies indicated that a radical-induced 1,2-aryl migration is key to the success of this process. This innovative strategy not only expands the synthetic toolbox but also may promote the development of novel transformations of alkenes through C-C σ-bond cleavage.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eGeneral procedure for direct oxygenation of alkenes\u003c/strong\u003e \u003cp\u003eA 25 mL quartz tube was equipped with a rubber septum and magnetic stir bar and was charged with benzenesulfonyl chloride derivatives \u003cb\u003e2\u003c/b\u003e (0.4 mmol, 2.0 equiv or 0.5 mmol, 2.5 equiv), Na\u003csub\u003e3\u003c/sub\u003ePO\u003csub\u003e4\u003c/sub\u003e.12H\u003csub\u003e2\u003c/sub\u003eO (0.2 mmol, 1.0 equiv). Then alkenes \u003cb\u003e1\u003c/b\u003e (0.2 mmol, 1.0 equiv), DIPEA (0.4 mmol, 2.0 equiv or 0.5 mmol, 2.5 equiv) and DCM (1.0 mL, 0.20 M) were added with syringe. The mixture was stirred and irradiated by a 90 W white LED from 6 cm distance at ambient temperature for specific time (24 h-48 h). After the reaction was complete (as judged by TLC analysis), the mixture was poured into a separatory funnel containing 10 mL H\u003csub\u003e2\u003c/sub\u003eO and 10 mL DCM. The layer was separated and the aqueous layer was extracted with DCM (2\u0026times;10 mL). The combined organic layers were dried with Na\u003csub\u003e2\u003c/sub\u003eSO\u003csub\u003e4\u003c/sub\u003e and concentrated under reduced pressure after filtration. The crude product was purified by flash chromatography on silica gel to afford the desired product \u003cb\u003e3\u003c/b\u003e or \u003cb\u003e4\u003c/b\u003e. For complete experimental details, including Photochemical instrumentation, related detection, procedures and full characterization (\u003csup\u003e1\u003c/sup\u003eH and \u003csup\u003e13\u003c/sup\u003eC NMR, HRMS spectrometry) of all new compounds, see Supplementary Information.\u003c/p\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors acknowledge the National Key R\u0026amp;D Program of China (No. 2021YFA1501700), the NSFC (Nos. 22293014, 22131002, 22161142019, 21901010), the Natural Science Foundation of Shandong Province (ZR2023MB071, ZR2021MC022), the Tencent Foundation and the Doctorial Fund of Qingdao Agriculture University (665-1120030), the New Cornerstone Science Foundation through the New Cornerstone Investigator Program and the XPLORER PRIZE for financial support. We also thank Shouyun Yu from Nanjing University and Hua Yang from\u0026nbsp;Central South University\u0026nbsp;for helpful discussion.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eQ.Q. and N.J. conceived and designed the experiments; Q.Q. and L.Z. carried out most of experiments; Q.Q., L.Z., J.W., X.Q., S.H., X.A., and N.J. analyzed data; Q.Q. and N.J. wrote the paper; N.J. directed the project.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Information\u003c/strong\u003e:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eCollege of Chemistry and Pharmaceutical Sciences,\u0026nbsp;Qingdao Agricultural University,\u0026nbsp;Chang Cheng Rd. 700,\u0026nbsp;Qingdao, Shandong 266109, China.\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003csup\u003e2\u003c/sup\u003eState Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Chemical Biology Center, Peking University, Xue Yuan Rd. 38, Beijing 100191, China. \u003csup\u003e#\u003c/sup\u003ethese authors contributed equally: Qixue Qin, Liang Zhang. Correspondence and requests for materials should be addressed to Qixue Qin ([email protected]) and Ning Jiao ([email protected]).\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eJurczyk J, Woo J, Kim SF, Dherange BD, Sarpong R, Levin MD (2022) Single-Atom Logic for Heterocycle Editing. Nat Synth 1:352\u0026ndash;364\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang H, Shao H, Das A, Dutta S, Chan HT, Daniliuc C, Houk KN, Glorius F (2023) Dearomative ring expansion of thiophenes by bicyclobutane insertion. Science 381:75\u0026ndash;81\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePatel SC, Burns NZ (2022) Conversion of Aryl Azides to Aminopyridines. J Am Chem Soc 144:17797\u0026ndash;17802\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePearson TJ, Shimazumi R, Driscoll JL, Dherange BD, Park D-I, Levin MD (2023) Aromatic nitrogen scanning by ipso-selective nitrene internalization. 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Tetrahedron Lett 51:4129\u0026ndash;4131\u003c/span\u003e\u003c/li\u003e\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":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4706612/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4706612/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Skeletal editing of single-atom insertion to basic chemicals has been demonstrated as efficient strategy for the discovery of structurally novel compounds. Previous endeavors in skeletal editing have successfully facilitated the insertion of boron, nitrogen, and carbon atoms. Given the prevalence of oxygen atoms in biologically active molecules, the direct oxygenation of C-C bonds through single-oxygen-atom insertion like Baeyer-Villiger reaction is of particular significance. Herein, we present a novel approach for the skeletal modification of styrenes using O2 via oxygen insertion into Ar-C(sp2) σ-bond, resulting in the formation of corresponding aryl ether frameworks under mild reaction conditions. The broad functional-group tolerance and the excellent chemo- and regioselectivity were demonstrated in this protocol. A preliminary mechanistic study indicated the potential involvement of 1,2-aryl radical migration in this reaction.","manuscriptTitle":"Direct Oxygen Insertion into C-C Bond of Styrenes with Air","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-16 09:50:34","doi":"10.21203/rs.3.rs-4706612/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"b5a61d16-c8fe-4d22-8b49-4827dd332025","owner":[],"postedDate":"July 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":34592737,"name":"Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology"},{"id":34592738,"name":"Physical sciences/Chemistry/Photochemistry/Photocatalysis"},{"id":34592739,"name":"Physical sciences/Chemistry/Catalysis/Photocatalysis"},{"id":34592740,"name":"Physical sciences/Chemistry/Green chemistry"}],"tags":[],"updatedAt":"2024-10-19T07:05:48+00:00","versionOfRecord":{"articleIdentity":"rs-4706612","link":"https://doi.org/10.1038/s41467-024-53266-6","journal":{"identity":"nature-communications","isVorOnly":false,"title":"Nature Communications"},"publishedOn":"2024-10-18 04:00:00","publishedOnDateReadable":"October 18th, 2024"},"versionCreatedAt":"2024-07-16 09:50:34","video":"","vorDoi":"10.1038/s41467-024-53266-6","vorDoiUrl":"https://doi.org/10.1038/s41467-024-53266-6","workflowStages":[]},"version":"v1","identity":"rs-4706612","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4706612","identity":"rs-4706612","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}