Construction 7-Membered Ring via Ni-Al Bimetal-Enabled C-H Cyclization for Synthesis of Tricyclic Imidazoles

Construction 7-Membered Ring via Ni-Al Bimetal-Enabled C-H Cyclization for Synthesis of Tricyclic Imidazoles | 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 Construction 7-Membered Ring via Ni-Al Bimetal-Enabled C-H Cyclization for Synthesis of Tricyclic Imidazoles Mengchun Ye, Jiang-Fei Li, Wei-Wei Xu, Rong-Hua Wang, Yue Li, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-198647/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 May, 2021 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract The construction of 7-membered ring via direct C7−H cyclization of benzoimidazoles with alkenes would provide a more atom- and step economical route to tricyclic imidazoles and derivatives that widely exist in a broad range of bioactive molecules. However, transition metal-catalyzed C−H cyclization for medium-ring synthesis has been limited to reactive C−H bonds, instead, the activation of unreactive C−H bonds towards medium synthesis still remains an elusive challenge. Herein, we report a direct construction of 7-membered rings via Ni−Al co-catalyzed unreactive C7−H cyclization of benzoimidazoles with alkenes, providing a series of tricyclic imidazoles in 40−98% yield and with up to 95:5 er. Catalysis Organic Chemistry synthesis catalysis organic chemistry Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Introduction Tricyclic imidazoles and derivatives bearing a 7-membered ring are an important class of structural motifs that widely exit in diverse range of bioactive and material molecules (Fig. 1 a). 1−7 However, due to the difficulty in construction of medium rings that requires overcoming unfavorable entropy and transannular strain, 8−10 synthetic routes of such tricyclic imidazoles are quite limited. A typical method relies on Friedel-Crafts acylation for cyclization, often requiring multiple synthetic steps and stoichiometric amounts of AlCl 3 catalyst (Fig. 1 b). 11−14 Another alternative is use alkene metathesis to form 7-membered rings, generally needing lengthy routes for both starting material preparation and final product formation (Fig. 1 c). 15 Thereby, direct construction of 7-membered ring via C7−H cyclization of benzoimidazoles with alkenes would provide a more straightforward, atom- and step-economical access to tricyclic imidazoles from more easily-accessible substrates (Fig. 1 d). On the other hand, transition metal-catalyzed C−H cyclization for medium-ring synthesis has become an important endeavor and attracted considerable interests during the past two decades, 16 , 17 because such methods can not only allow using more readily available starting materials, but also provide more atom- and step-economical routes (Fig. 2 a). Early efforts focused on the cyclization of reactive formyl C−H bonds with alkenes via rhodium catalysis. 18−28 Until recent years, non-formyl C−H bonds were also able to be activated via nickel catalysis to form 7-membered rings (Fig. 2 a). 29−34 However, these examples were still limited to reactive C−H bonds such as heterocyclic and polyfluoro-aromatic C−H bonds, and moreover, only scattered substrates were reported with in general low to moderate yield and ee. In contrast, the activation of prevalent and unreactive aromatic C−H bonds towards 7-membered ring synthesis still remains an elusive challenge. The difficulty was ascribed to the fact that unreactive aromatic C−H bonds are often more reluctant to be activated by low-valent metals owing to their higher bond strength and weaker acidity. 35 To achieve unreactive C7−H bond activation, we envisioned to use a Ni−Al bimetallic synergistic catalysis instead of traditional mono-metal catalysis (Fig. 2 b), 36−44 hoping that the coordination of Al-Lewis acid to the N atom of imidazoles would contribute to decreasing electron density of the aromatic ring, thus promoting C−H bond activation, and as well as proper steric hindrance from C2 substituent of benzoimidazolse could reduce unfavorable entropy effect, favoring the formation of medium rings. Herein, we report our latest result: the construction of 7-membered ring via Ni−Al bimetal-catalyzed unreactive C7−H bond cyclization of benzoimidazoles with alkenes was achieved for the first time, providing a series of tricyclic imidazoles in 40−98% yield and with exclusively endo selectivity and up to 95:5 er and (Fig. 2 b). Results Reaction optimization . We commenced our study by selecting benzoimidazole 1a as a model substrate, nickel as a catalyst and Al-Lewis acid as a co-catalyst (Fig. 3 ). A systematic survey on Ni metals, Al Lewis acids, ligands, bases, and other reaction parameters led to the optimal conditions: 10 mol% of Ni(cod) 2 , 10 mol% of IPr·HCl, 10 mol% of AlMe 3 and 40 mol% of t BuOK in toluene at 130 °C, under which an endo cyclization was exclusively achieved, providing tricyclic imidazole 2a bearing a 7-membered ring in 98% yield (Fig. 3 , entry 1). Control experiments showed that the combination of Ni, IPr, AlMe 3 and t BuOK is critical, and the removal of any of them would greatly reduce the yield (entries 2−5). Traditional phosphine ligands such as monophosphines and bidentate phosphines were all ineffective (entries 6 and 7), whereas other N-heterocyclic carbenes were still compatible, albeit with a little lower yields (entries 8 and 9). In addition, in situ formed Ni(0) was also an effective catalyst, yet providing only 42% yield (entry 10). Base acted as another critical role in the reaction. t BuOLi was inefficient, whereas t BuONa worked well, affording a comparable result to that of t BuOK (entries 11 and 12). Notably, more than 10 mol% of t BuOK was essential to the reactivity (entries 13−15). The use of 10 mol% of t BuOK gave no products (entry 13), instead, leading to an imidazole with free NH group in 5% yield, which was formed from the decomposition of alkene-isomerization substrate. We reasoned that excess t BuOK could suppress the isomerization of the terminal alkene as the literature proposed. 45 Scope of imidazoles and alkenes. With the optimized conditions in hand, various benzoimidazole motifs bearing different substituents on the aromatic ring were investigated first (Fig. 4 ). Results showed that either electron-donating groups such as methyl ( 2b ) and tert -butyl ( 2c ) or electron-withdrawing groups such as CF 3 O ( 2d ), F ( 2e to 2h ), CF 3 ( 2i ) and carboxylate ( 2j ) were well compatible with the reaction, providing the corresponding products in 80−98% yield. Notably, C2 substituents of benzoimidazoles proved critical to the reactivity. Without C2 substituents, C2−H cyclization would dominate to form a 6-memebered ring as we previously reported, 41 further suggesting that C7−H bond was quite unreactive towards Ni catalysis. In general, electron-deficient CF 3 group on C2 position can ensure high reactivity with using only 10 mol% of AlMe 3 co-catalyst, while CF 3 group was not indispensable, and it can be replaced by a broad range of other substituents such as alkyl ( 2k and 2l ), (hetero)aryl ( 2m and 2n ), carbamoyl ( 2o and 2p ), alkoxy ( 2q ) and amino ( 2r ) groups, providing the corresponding products in 40−79% yield by tuning the amount of AlMe 3 . Pleasingly, imidazole-2-ones, which also widely exist in numerous bioactive compounds, were well compatible with the current reaction. When N-protecting groups varied from Me ( 2s ), Bn ( 2t ), PMP ( 2u ) to Ph ( 2v ), the corresponding products can be smoothly obtained in 64−90% yield. In consideration of two symmetrical N atoms in the molecule, dual C−H annulation was then investigated and a tetracyclic product ( 2w ) bearing two 7-membered rings can be smoothly achieved, which is not easily accessed by traditional Friedel-Crafts reaction because the second acylation would be quite difficult. Besides simple aryl and alkyl groups, carboxylate group was also tolerated, providing a translocator protein inhibitor ( 2x ) in 60% yield. 1 Next, the compatibility of alkene motifs were investigated (Fig. 5 ). Although internal alkenes were ineffective because of big steric hindrance, various 1,1-disubstituted terminal alkenes proved to be effective. Different types of alkyls such as methyl ( 3a ), linear n -butyl ( 3b ), branched cyclohexyl ( 3c ) and functionalized alkyl ( 3d ) were well tolerated, delivering the corresponding products in 82−96% yield. Considering that the incorporation of aryl motifs can significantly increase the complexity of molecules, we examined various aryl substituted alkenes ( 3e to 3p ). Results showed that these aryl alkenes bearing either electron-rich groups such as methyl ( 3f to 3h ), t Bu ( 3i ), Ph ( 3j ), methoxy ( 3k ), and naphthyl ( 3l ) or electron-deficient groups such as CF 3 O ( 3m ) and F ( 3n to 3p ) at different positions of the aryl ring all proceeded smoothly, providing the corresponding products in 50−90% yield. Enantioselective attempts. For the synthesis of medium ring, a flexible large ring transition state would be involved, rendering the enantioselective control of such a reaction quite challenging. 29−34 By surveying a wide range of chiral carbenes, we found that bulky AnIPE was the optimal ligand (see the Supporting Information for details). 46−48 With this ligand, a series of substrates with various alkene motifs were then tested (Fig. 6 ). In general, various aryl groups were well compatible with the current reaction, providing the corresponding products in good yields and with 91.5:8.5 to 95:5 er ( 3e to 3q ). However, alkyl groups, albeit still with good yields, would result in slightly decreased ee ( 3a , 3d , 3r and 3s ) owing to bigger structural flexibility. The absolute configuration of major enantiomer of the product was assigned to be ( R ) by single crystal X-ray diffraction. Reaction utility and mechanistic discussion. To demonstrate the utility of the current method, a gram-scale reaction of 1a was conducted, and a comparable yield was obtained under the standard conditions (Fig. 7 a). In addition, tricyclic imidazole derivative 2s can be easily oxidized at the benzylic position to produce an intermediate 4 in 62% yield, which can be further transformed into various bioactive molecules such as β-2-adrenergic agonists and zilpaterol (Fig. 7 b). 11−14 To gain more insights into the reaction, relevant mechanistic experiments were conducted. Deuterium-labeling experiment showed that C7-D on the aromatic ring was completely transferred to the 7-membered ring, and moreover, no deuterium scrambling was observed at other positions (Fig. 7 c), which suggested that an endo -insertion of alkene to Ni−H bond could proceed via an irreversible step. Both competitive experiment between equivalent moles of 1a and d 4 - 1a and parallel reactions revealed significant kinetic isotope effect ( k H / k D = 5.75, 4.81, respectively), indicating that the C−H cleavage could be the rate-determining step (Fig. 7 d), and it could proceed via oxidative addition mechanism because direct H transfer pathway in general gives low kinetic isotope effect. 35 In addition, 19 F NMR spectra of stoichiometric reactions suggested that nickel could rapidly coordinate to the alkene motif of substrate 1a , and then initiate next C−H cleavage and alkene insertion (see the Supporting Information). On the basis of these facts, a plausible mechanism was proposed as below (Fig. 7 e): substrate 1a coordinates with AlMe 3 and nickel first, and then facilitates Ni-catalyzed C7−H bond cleavage via oxidative addition process. Subsequent irreversible endo -type alkene migratory insertion and reductive elimination generates the Al-coordinated product, which exchanges with another substrate 1a to initiate a next cycle. Conclusions In summary, we have developed a unreactive C7−H bond cyclization of benzoimidazoles with alkenes via Ni−Al bimetallic catalysis, providing a series of tricyclic imidazoles and derivatives bearing a 7-membered ring in 40−98% yield and with up to 95:5 er. The coordination of Al co-catalyst contributes to reduce the electron density of aromatic ring, favoring the activation of unreactive C7−H bond. The development of other C−H cyclization for medium ring synthesis via Ni−Al bimetallic catalysis is underway in our lab. Methods General Procedure for Ni-Catalyzed C7–H Cyclization. To a 15 mL oven dried tube in glove box were added Ni(cod) 2 (5.5 mg, 10 mol%), IPr•HCl (8.6 mg, 10 mol%), t BuOK (9 mg, 0.08 mmol, 40 mol%), benzoimidazole 1 (0.2 mmol), dry degassed toluene (2.0 mL), and AlMe 3 (1.0 M/hexane, 10 mol% or 60 mol% or 200 mol%). The tube was capped, taken outside the glove box, and stirred at 130 °C for 3 h. After that, the mixture was cooled to r.t., quenched with 2 mL of 5% EDTA disodium salt solution, and filtered through a short plug of silica gel, eluting with EtOAc. The filtration was concentrated in vacuo to afford the crude product, which was further purified by flash column chromatography on silica gel (EtOAc/hexanes). Declarations Acknowledgments We thank the National Natural Science Foundation of China (21871145 and 91856104), the Tianjin Applied Basic Research Project and Cutting-Edge Technology Research Plan (19JCZDJC37900) and “the Fundamental Research Funds for the Central Universities” (63191601) for financial support for financial support. Author contributions J.-F. L. discovered and developed the reactions. W.-W. X., R.-H. W., Y. L., G. Y. performed part of synthetic experiments. M.Y. conceived, designed the investigations and wrote the manuscript. J.-F. L. wrote the Supplementary Information. Additional information Supplementary information and chemical compound information are available in the online version of the paper. Reprints and permissions information is available online at www.nature.com/reprints. Correspondence and requests for materials should be addressed to M.Y. Competing financial interests The authors declare no competing financial interests. 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Cai, Y.; Yang, X.-T.; Zhang, S.-Q.; Li, F.; Li, Y.-Q.; Ruan, L.-X.; Hong, X.; Shi, S.-L. Copper-Catalyzed Enantioselective Markovnikov Protoboration of α-Olefins Enabled by a Buttressed N−Heterocyclic Carbene Ligand. Angew. Chem., Int. Ed. 57 , 1376−1380 (2018). Cai, Y.; Zhang, J.-W.; Li, F.; Liu, J.-M.; Shi, S.-L. Nickel/N-Heterocyclic Carbene Complex-Catalyzed Enantioselective Redox-Neutral Coupling of Benzyl Alcohols and Alkynes to Allylic Alcohols. ACS Catal. 9 , 1−6 (2019). Additional Declarations There is NO Competing Interest. Supplementary Files SIimidazole21.pdf p20181121b.cif GraphicalAbstract.jpg Cite Share Download PDF Status: Published Journal Publication published 24 May, 2021 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. 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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-198647","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":10971340,"identity":"adad4a60-3e99-4d1b-8503-c992afc8129f","order_by":0,"name":"Mengchun Ye","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0klEQVRIiWNgGAWjYLCCD0AswcDYwMDARqQOxhkka2HmAWsBAWK06LafMXxsu8MuT7L9cAPDh7LDDPyzG/BrMTuTY2yceya5WJonsYFxxrnDDBJ3DhDQcoPHTDq3jTlxHkNiAzNv22EGA4kEglrMf1u21SfO43/YwPyXSC1mzIxthxNnSwBtYSRKy5m0YsnetuOJM2c8bDjYcy6dR+IGIS3HD2/88LOtOnHG+fSHD36UWcvxzyCghYGBwwDOPADEPITUAwH7AyIUjYJRMApGwYgGAAaAQ3+0uPwSAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-2019-5365","institution":"Nankai University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Mengchun","middleName":"","lastName":"Ye","suffix":""},{"id":10971341,"identity":"be40e0ac-399c-4235-add2-439aa1d923cd","order_by":1,"name":"Jiang-Fei Li","email":"","orcid":"","institution":"Nankai University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jiang-Fei","middleName":"","lastName":"Li","suffix":""},{"id":10971342,"identity":"a7dc3a91-309e-444e-b320-4929be730099","order_by":2,"name":"Wei-Wei Xu","email":"","orcid":"","institution":"Nankai University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Wei-Wei","middleName":"","lastName":"Xu","suffix":""},{"id":10971343,"identity":"48242f45-4d3e-4a80-b2b6-2206433c633b","order_by":3,"name":"Rong-Hua Wang","email":"","orcid":"","institution":"Nankai University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Rong-Hua","middleName":"","lastName":"Wang","suffix":""},{"id":10971344,"identity":"ea0388f0-8966-445b-8efc-89c0463293af","order_by":4,"name":"Yue Li","email":"","orcid":"","institution":"Nankai University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yue","middleName":"","lastName":"Li","suffix":""},{"id":10971345,"identity":"8ca97ee8-0aa9-4ae7-b30d-f8651d0a3510","order_by":5,"name":"Ge Yin","email":"","orcid":"","institution":"Nankai University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ge","middleName":"","lastName":"Yin","suffix":""}],"badges":[],"createdAt":"2021-02-01 15:16:01","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-198647/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-198647/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41467-021-23371-x","type":"published","date":"2021-05-24T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":5802460,"identity":"a8148e09-7496-49e0-9aa9-7cefcf6f9d3b","added_by":"auto","created_at":"2021-02-09 22:03:18","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":26311,"visible":true,"origin":"","legend":"Synthesis of tricyclic imidazoles and derivatives bearing a 7-membered ring. a, Tricyclic imidazoles bearing a 7-member ring in bioactive molecules and materials. b, Typical method I: Friedel-Crafts reaction. c, Typical method II: alkene metathesis reaction. d, Proposed direct C-H cyclization.","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-198647/v1/129f07a08f12dce020e6368e.png"},{"id":5802461,"identity":"8b53ffa1-268c-47a2-884b-169728da6987","added_by":"auto","created_at":"2021-02-09 22:03:18","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":27268,"visible":true,"origin":"","legend":"Transition metal-catalyzed C-H cyclization for medium ring synthesis. a, Reactive C-H bond activation. b, Our proposed Ni-Al bimetallic catalysis and direct C7-H cyclization for synthesis of tricyclic imidazoles bearing a 7-membered ring (this work).","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-198647/v1/91442a42343f1df7a1f4470e.png"},{"id":5802547,"identity":"c6010eff-bf52-4bac-8d5f-cd26f129fd4f","added_by":"auto","created_at":"2021-02-09 22:06:19","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":19452,"visible":true,"origin":"","legend":"Reaction optimization. Reaction conditions: 1a (0.20 mmol), toluene (1.0 mL), under N2 for 3 h. Yield was determined by 1H NMR analysis with CH2Br2 as the internal standard.","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-198647/v1/6904359c0d0034602493f8da.png"},{"id":5802544,"identity":"2074a877-32c0-4826-9c77-6d1d56db0b13","added_by":"auto","created_at":"2021-02-09 22:06:18","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":45344,"visible":true,"origin":"","legend":"Scope of imidazoles. Reaction conditions: 1 (0.20 mmol), toluene (1.0 mL) under N2 for 3 h. Yield of isolated products. *AlMe3 (200 mol%) was used. †AlMe3 (60 mol%) was used. ‡AlMe3 (100 mol%) and tBuOK (80 mol%) were used.","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-198647/v1/f747ba1a16aabd2374ca371e.png"},{"id":5802466,"identity":"d193cc00-bb81-4dab-86b7-8d5934d176f5","added_by":"auto","created_at":"2021-02-09 22:03:19","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":33163,"visible":true,"origin":"","legend":"Scope of alkynes. Reaction conditions: 1 (0.2 mmol), toluene (1.0 mL) under N2 for 3 h. Yield of isolated products.","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-198647/v1/e74d816daa0a099edc074bb7.png"},{"id":5802469,"identity":"a19e1fb9-c081-4dbc-82e9-0b68acf0a9ce","added_by":"auto","created_at":"2021-02-09 22:03:19","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":41646,"visible":true,"origin":"","legend":"Enantioselective control. Reaction conditions: 1 (0.20 mmol), Ni(cod)2 (10 mol%), AnIPE·HCl (10 mol%), AlMe3 (80 mol%), tBuOK (40 mol%), toluene (1.0 mL) at 130 °C under N2 for 3 h. Yield of isolated products. Ee was determined by chiral HPLC.","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-198647/v1/495799ca400ecb364e495944.png"},{"id":5802549,"identity":"4ccb3cbf-a0ec-4c83-b2d2-313c034fdf2d","added_by":"auto","created_at":"2021-02-09 22:06:19","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":34618,"visible":true,"origin":"","legend":"Synthetic utility and mechanistic experiments. a, Gram-scale reaction b, product transformation. c, Deuterium labeling experiments d, Kinetic isotope effect. e, Proposed mechanism ","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-198647/v1/edf88077f9d5038ec480255d.png"},{"id":15783872,"identity":"67d99b1b-a714-4756-bd74-b646ec63ceca","added_by":"auto","created_at":"2021-11-22 15:49:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":627278,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-198647/v1/67f8f341-f857-4ae8-bfc3-e3596da2371c.pdf"},{"id":5802545,"identity":"0eb9ff39-7674-4a1e-ac0b-65ad89154f47","added_by":"auto","created_at":"2021-02-09 22:06:19","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":4847734,"visible":true,"origin":"","legend":"","description":"","filename":"SIimidazole21.pdf","url":"https://assets-eu.researchsquare.com/files/rs-198647/v1/25b644281fdc7da594e7a786.pdf"},{"id":5802592,"identity":"a40f3abc-1cf2-477b-9e84-8f11e2e4fbf4","added_by":"auto","created_at":"2021-02-09 22:09:19","extension":"cif","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":308608,"visible":true,"origin":"","legend":"","description":"","filename":"p20181121b.cif","url":"https://assets-eu.researchsquare.com/files/rs-198647/v1/c6b6cb7537f93e25c4967c8f.cif"},{"id":5802623,"identity":"29568c66-8b61-4d16-b31c-2438a68c14d9","added_by":"auto","created_at":"2021-02-09 22:12:19","extension":"jpg","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":14914,"visible":true,"origin":"","legend":"","description":"","filename":"GraphicalAbstract.jpg","url":"https://assets-eu.researchsquare.com/files/rs-198647/v1/5a4c7d0f72e314d4f78abd4b.jpg"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Construction 7-Membered Ring via Ni-Al Bimetal-Enabled C-H Cyclization for Synthesis of Tricyclic Imidazoles","fulltext":[{"header":"Introduction","content":"\u003cp\u003eTricyclic imidazoles and derivatives bearing a 7-membered ring are an important class of structural motifs that widely exit in diverse range of bioactive and material molecules (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ea).\u003csup\u003e1\u0026minus;7\u003c/sup\u003e However, due to the difficulty in construction of medium rings that requires overcoming unfavorable entropy and transannular strain,\u003csup\u003e8\u0026minus;10\u003c/sup\u003e synthetic routes of such tricyclic imidazoles are quite limited. A typical method relies on Friedel-Crafts acylation for cyclization, often requiring multiple synthetic steps and stoichiometric amounts of AlCl\u003csub\u003e3\u003c/sub\u003e catalyst (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eb).\u003csup\u003e11\u0026minus;14\u003c/sup\u003e Another alternative is use alkene metathesis to form 7-membered rings, generally needing lengthy routes for both starting material preparation and final product formation (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ec).\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e Thereby, direct construction of 7-membered ring via C7\u0026minus;H cyclization of benzoimidazoles with alkenes would provide a more straightforward, atom- and step-economical access to tricyclic imidazoles from more easily-accessible substrates (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ed).\u003c/p\u003e\n\u003cp\u003eOn the other hand, transition metal-catalyzed C\u0026minus;H cyclization for medium-ring synthesis has become an important endeavor and attracted considerable interests during the past two decades,\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e because such methods can not only allow using more readily available starting materials, but also provide more atom- and step-economical routes (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ea). Early efforts focused on the cyclization of reactive formyl C\u0026minus;H bonds with alkenes via rhodium catalysis.\u003csup\u003e18\u0026minus;28\u003c/sup\u003e Until recent years, non-formyl C\u0026minus;H bonds were also able to be activated via nickel catalysis to form 7-membered rings (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ea).\u003csup\u003e29\u0026minus;34\u003c/sup\u003e However, these examples were still limited to reactive C\u0026minus;H bonds such as heterocyclic and polyfluoro-aromatic C\u0026minus;H bonds, and moreover, only scattered substrates were reported with in general low to moderate yield and ee. In contrast, the activation of prevalent and unreactive aromatic C\u0026minus;H bonds towards 7-membered ring synthesis still remains an elusive challenge. The difficulty was ascribed to the fact that unreactive aromatic C\u0026minus;H bonds are often more reluctant to be activated by low-valent metals owing to their higher bond strength and weaker acidity.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e To achieve unreactive C7\u0026minus;H bond activation, we envisioned to use a Ni\u0026minus;Al bimetallic synergistic catalysis instead of traditional mono-metal catalysis (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eb),\u003csup\u003e36\u0026minus;44\u003c/sup\u003e hoping that the coordination of Al-Lewis acid to the N atom of imidazoles would contribute to decreasing electron density of the aromatic ring, thus promoting C\u0026minus;H bond activation, and as well as proper steric hindrance from C2 substituent of benzoimidazolse could reduce unfavorable entropy effect, favoring the formation of medium rings. Herein, we report our latest result: the construction of 7-membered ring via Ni\u0026minus;Al bimetal-catalyzed unreactive C7\u0026minus;H bond cyclization of benzoimidazoles with alkenes was achieved for the first time, providing a series of tricyclic imidazoles in 40\u0026minus;98% yield and with exclusively \u003cem\u003eendo\u003c/em\u003e selectivity and up to 95:5 er and (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eb).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eReaction optimization\u003c/strong\u003e. We commenced our study by selecting benzoimidazole \u003cstrong\u003e1a\u003c/strong\u003e as a model substrate, nickel as a catalyst and Al-Lewis acid as a co-catalyst (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). A systematic survey on Ni metals, Al Lewis acids, ligands, bases, and other reaction parameters led to the optimal conditions: 10 mol% of Ni(cod)\u003csub\u003e2\u003c/sub\u003e, 10 mol% of IPr\u0026middot;HCl, 10 mol% of AlMe\u003csub\u003e3\u003c/sub\u003e and 40 mol% of \u003csup\u003e\u003cem\u003et\u003c/em\u003e\u003c/sup\u003eBuOK in toluene at 130 \u0026deg;C, under which an \u003cem\u003eendo\u003c/em\u003e cyclization was exclusively achieved, providing tricyclic imidazole \u003cstrong\u003e2a\u003c/strong\u003e bearing a 7-membered ring in 98% yield (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e, entry 1).\u003c/p\u003e\n\u003cp\u003eControl experiments showed that the combination of Ni, IPr, AlMe\u003csub\u003e3\u003c/sub\u003e and \u003csup\u003e\u003cem\u003et\u003c/em\u003e\u003c/sup\u003eBuOK is critical, and the removal of any of them would greatly reduce the yield (entries 2\u0026minus;5). Traditional phosphine ligands such as monophosphines and bidentate phosphines were all ineffective (entries 6 and 7), whereas other N-heterocyclic carbenes were still compatible, albeit with a little lower yields (entries 8 and 9). In addition, in situ formed Ni(0) was also an effective catalyst, yet providing only 42% yield (entry 10). Base acted as another critical role in the reaction. \u003csup\u003e\u003cem\u003et\u003c/em\u003e\u003c/sup\u003eBuOLi was inefficient, whereas \u003csup\u003e\u003cem\u003et\u003c/em\u003e\u003c/sup\u003eBuONa worked well, affording a comparable result to that of \u003csup\u003e\u003cem\u003et\u003c/em\u003e\u003c/sup\u003eBuOK (entries 11 and 12). Notably, more than 10 mol% of \u003csup\u003e\u003cem\u003et\u003c/em\u003e\u003c/sup\u003eBuOK was essential to the reactivity (entries 13\u0026minus;15). The use of 10 mol% of \u003csup\u003e\u003cem\u003et\u003c/em\u003e\u003c/sup\u003eBuOK gave no products (entry 13), instead, leading to an imidazole with free NH group in 5% yield, which was formed from the decomposition of alkene-isomerization substrate. We reasoned that excess \u003csup\u003e\u003cem\u003et\u003c/em\u003e\u003c/sup\u003eBuOK could suppress the isomerization of the terminal alkene as the literature proposed.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eScope of imidazoles and alkenes.\u003c/strong\u003e With the optimized conditions in hand, various benzoimidazole motifs bearing different substituents on the aromatic ring were investigated first (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). Results showed that either electron-donating groups such as methyl (\u003cstrong\u003e2b\u003c/strong\u003e) and \u003cem\u003etert\u003c/em\u003e-butyl (\u003cstrong\u003e2c\u003c/strong\u003e) or electron-withdrawing groups such as CF\u003csub\u003e3\u003c/sub\u003eO (\u003cstrong\u003e2d\u003c/strong\u003e), F (\u003cstrong\u003e2e\u003c/strong\u003e to \u003cstrong\u003e2h\u003c/strong\u003e), CF\u003csub\u003e3\u003c/sub\u003e (\u003cstrong\u003e2i\u003c/strong\u003e) and carboxylate (\u003cstrong\u003e2j\u003c/strong\u003e) were well compatible with the reaction, providing the corresponding products in 80\u0026minus;98% yield.\u003c/p\u003e\n\u003cp\u003eNotably, C2 substituents of benzoimidazoles proved critical to the reactivity. Without C2 substituents, C2\u0026minus;H cyclization would dominate to form a 6-memebered ring as we previously reported,\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e further suggesting that C7\u0026minus;H bond was quite unreactive towards Ni catalysis. In general, electron-deficient CF\u003csub\u003e3\u003c/sub\u003e group on C2 position can ensure high reactivity with using only 10 mol% of AlMe\u003csub\u003e3\u003c/sub\u003e co-catalyst, while CF\u003csub\u003e3\u003c/sub\u003e group was not indispensable, and it can be replaced by a broad range of other substituents such as alkyl (\u003cstrong\u003e2k\u003c/strong\u003e and \u003cstrong\u003e2l\u003c/strong\u003e), (hetero)aryl (\u003cstrong\u003e2m\u003c/strong\u003e and \u003cstrong\u003e2n\u003c/strong\u003e), carbamoyl (\u003cstrong\u003e2o\u003c/strong\u003e and \u003cstrong\u003e2p\u003c/strong\u003e), alkoxy (\u003cstrong\u003e2q\u003c/strong\u003e) and amino (\u003cstrong\u003e2r\u003c/strong\u003e) groups, providing the corresponding products in 40\u0026minus;79% yield by tuning the amount of AlMe\u003csub\u003e3\u003c/sub\u003e. Pleasingly, imidazole-2-ones, which also widely exist in numerous bioactive compounds, were well compatible with the current reaction. When N-protecting groups varied from Me (\u003cstrong\u003e2s\u003c/strong\u003e), Bn (\u003cstrong\u003e2t\u003c/strong\u003e), PMP (\u003cstrong\u003e2u\u003c/strong\u003e) to Ph (\u003cstrong\u003e2v\u003c/strong\u003e), the corresponding products can be smoothly obtained in 64\u0026minus;90% yield. In consideration of two symmetrical N atoms in the molecule, dual C\u0026minus;H annulation was then investigated and a tetracyclic product (\u003cstrong\u003e2w\u003c/strong\u003e) bearing two 7-membered rings can be smoothly achieved, which is not easily accessed by traditional Friedel-Crafts reaction because the second acylation would be quite difficult. Besides simple aryl and alkyl groups, carboxylate group was also tolerated, providing a translocator protein inhibitor (\u003cstrong\u003e2x\u003c/strong\u003e) in 60% yield.\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eNext, the compatibility of alkene motifs were investigated (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e). Although internal alkenes were ineffective because of big steric hindrance, various 1,1-disubstituted terminal alkenes proved to be effective. Different types of alkyls such as methyl (\u003cstrong\u003e3a\u003c/strong\u003e), linear \u003cem\u003en\u003c/em\u003e-butyl (\u003cstrong\u003e3b\u003c/strong\u003e), branched cyclohexyl (\u003cstrong\u003e3c\u003c/strong\u003e) and functionalized alkyl (\u003cstrong\u003e3d\u003c/strong\u003e) were well tolerated, delivering the corresponding products in 82\u0026minus;96% yield. Considering that the incorporation of aryl motifs can significantly increase the complexity of molecules, we examined various aryl substituted alkenes (\u003cstrong\u003e3e\u003c/strong\u003e to \u003cstrong\u003e3p\u003c/strong\u003e). Results showed that these aryl alkenes bearing either electron-rich groups such as methyl (\u003cstrong\u003e3f\u003c/strong\u003e to \u003cstrong\u003e3h\u003c/strong\u003e), \u003csup\u003e\u003cem\u003et\u003c/em\u003e\u003c/sup\u003eBu (\u003cstrong\u003e3i\u003c/strong\u003e), Ph (\u003cstrong\u003e3j\u003c/strong\u003e), methoxy (\u003cstrong\u003e3k\u003c/strong\u003e), and naphthyl (\u003cstrong\u003e3l\u003c/strong\u003e) or electron-deficient groups such as CF\u003csub\u003e3\u003c/sub\u003eO (\u003cstrong\u003e3m\u003c/strong\u003e) and F (\u003cstrong\u003e3n\u003c/strong\u003e to \u003cstrong\u003e3p\u003c/strong\u003e) at different positions of the aryl ring all proceeded smoothly, providing the corresponding products in 50\u0026minus;90% yield.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEnantioselective attempts.\u003c/strong\u003e For the synthesis of medium ring, a flexible large ring transition state would be involved, rendering the enantioselective control of such a reaction quite challenging.\u003csup\u003e29\u0026minus;34\u003c/sup\u003e By surveying a wide range of chiral carbenes, we found that bulky AnIPE was the optimal ligand (see the Supporting Information for details).\u003csup\u003e46\u0026minus;48\u003c/sup\u003e With this ligand, a series of substrates with various alkene motifs were then tested (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e). In general, various aryl groups were well compatible with the current reaction, providing the corresponding products in good yields and with 91.5:8.5 to 95:5 er (\u003cstrong\u003e3e\u003c/strong\u003e to \u003cstrong\u003e3q\u003c/strong\u003e). However, alkyl groups, albeit still with good yields, would result in slightly decreased ee (\u003cstrong\u003e3a\u003c/strong\u003e, \u003cstrong\u003e3d\u003c/strong\u003e, \u003cstrong\u003e3r\u003c/strong\u003e and \u003cstrong\u003e3s\u003c/strong\u003e) owing to bigger structural flexibility. The absolute configuration of major enantiomer of the product was assigned to be (\u003cem\u003eR\u003c/em\u003e) by single crystal X-ray diffraction.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eReaction utility and mechanistic discussion.\u003c/strong\u003e To demonstrate the utility of the current method, a gram-scale reaction of \u003cstrong\u003e1a\u003c/strong\u003e was conducted, and a comparable yield was obtained under the standard conditions (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e7\u003c/span\u003ea). In addition, tricyclic imidazole derivative \u003cstrong\u003e2s\u003c/strong\u003e can be easily oxidized at the benzylic position to produce an intermediate \u003cstrong\u003e4\u003c/strong\u003e in 62% yield, which can be further transformed into various bioactive molecules such as \u0026beta;-2-adrenergic agonists and zilpaterol (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e7\u003c/span\u003eb).\u003csup\u003e11\u0026minus;14\u003c/sup\u003e To gain more insights into the reaction, relevant mechanistic experiments were conducted. Deuterium-labeling experiment showed that C7-D on the aromatic ring was completely transferred to the 7-membered ring, and moreover, no deuterium scrambling was observed at other positions (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e7\u003c/span\u003ec), which suggested that an \u003cem\u003eendo\u003c/em\u003e-insertion of alkene to Ni\u0026minus;H bond could proceed via an irreversible step. Both competitive experiment between equivalent moles of \u003cstrong\u003e1a\u003c/strong\u003e and \u003cem\u003ed\u003c/em\u003e\u003csub\u003e\u003cem\u003e4\u003c/em\u003e\u003c/sub\u003e-\u003cstrong\u003e1a\u003c/strong\u003e and parallel reactions revealed significant kinetic isotope effect (\u003cem\u003ek\u003c/em\u003e\u003csub\u003eH\u003c/sub\u003e/\u003cem\u003ek\u003c/em\u003e\u003csub\u003eD\u003c/sub\u003e = 5.75, 4.81, respectively), indicating that the C\u0026minus;H cleavage could be the rate-determining step (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e7\u003c/span\u003ed), and it could proceed via oxidative addition mechanism because direct H transfer pathway in general gives low kinetic isotope effect.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e In addition, \u003csup\u003e19\u003c/sup\u003eF NMR spectra of stoichiometric reactions suggested that nickel could rapidly coordinate to the alkene motif of substrate \u003cstrong\u003e1a\u003c/strong\u003e, and then initiate next C\u0026minus;H cleavage and alkene insertion (see the Supporting Information). On the basis of these facts, a plausible mechanism was proposed as below (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e7\u003c/span\u003ee): substrate \u003cstrong\u003e1a\u003c/strong\u003e coordinates with AlMe\u003csub\u003e3\u003c/sub\u003e and nickel first, and then facilitates Ni-catalyzed C7\u0026minus;H bond cleavage via oxidative addition process. Subsequent irreversible \u003cem\u003eendo\u003c/em\u003e-type alkene migratory insertion and reductive elimination generates the Al-coordinated product, which exchanges with another substrate \u003cstrong\u003e1a\u003c/strong\u003e to initiate a next cycle.\u003c/p\u003e"},{"header":"Conclusions","content":" \u003cp\u003eIn summary, we have developed a unreactive C7\u0026minus;H bond cyclization of benzoimidazoles with alkenes via Ni\u0026minus;Al bimetallic catalysis, providing a series of tricyclic imidazoles and derivatives bearing a 7-membered ring in 40\u0026minus;98% yield and with up to 95:5 er. The coordination of Al co-catalyst contributes to reduce the electron density of aromatic ring, favoring the activation of unreactive C7\u0026minus;H bond. The development of other C\u0026minus;H cyclization for medium ring synthesis via Ni\u0026minus;Al bimetallic catalysis is underway in our lab.\u003c/p\u003e "},{"header":"Methods","content":" \u003cp\u003e \u003cb\u003eGeneral Procedure for Ni-Catalyzed C7\u0026ndash;H Cyclization.\u003c/b\u003e To a 15 mL oven dried tube in glove box were added Ni(cod)\u003csub\u003e2\u003c/sub\u003e (5.5 mg, 10 mol%), IPr\u0026#149;HCl (8.6 mg, 10 mol%), \u003csup\u003e\u003cem\u003et\u003c/em\u003e\u003c/sup\u003eBuOK (9 mg, 0.08 mmol, 40 mol%), benzoimidazole \u003cb\u003e1\u003c/b\u003e (0.2 mmol), dry degassed toluene (2.0 mL), and AlMe\u003csub\u003e3\u003c/sub\u003e (1.0 M/hexane, 10 mol% or 60 mol% or 200 mol%). The tube was capped, taken outside the glove box, and stirred at 130 \u0026deg;C for 3 h. After that, the mixture was cooled to r.t., quenched with 2 mL of 5% EDTA disodium salt solution, and filtered through a short plug of silica gel, eluting with EtOAc. The filtration was concentrated in \u003cem\u003evacuo\u003c/em\u003e to afford the crude product, which was further purified by flash column chromatography on silica gel (EtOAc/hexanes).\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the National Natural Science Foundation of China (21871145 and 91856104), the Tianjin Applied Basic Research Project and Cutting-Edge Technology Research Plan (19JCZDJC37900) and \u0026ldquo;the Fundamental Research Funds for the Central Universities\u0026rdquo; (63191601) for financial support for financial support.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJ.-F. L. discovered and developed the reactions. W.-W. X., R.-H. W., Y. L., G. Y. performed part of synthetic experiments. M.Y. conceived, designed the investigations and wrote the manuscript. J.-F. L. wrote the Supplementary Information.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSupplementary information and chemical compound information are available in the online version of the paper. Reprints and permissions information is available online at www.nature.com/reprints. Correspondence and requests for materials should be addressed to M.Y.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting financial interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing financial interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFukaya, T.,\u0026nbsp;Kodo, T.,\u0026nbsp;Ishiyama, T.,\u0026nbsp;Nishikawa, H.,\u0026nbsp;Baba, S.,\u0026nbsp;Masumoto, S. 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NHC ligand-enabled Ni-catalyzed reductive coupling of alkynes and imines using isopropanol as a reductant. \u003cem\u003eGreen Chem\u003c/em\u003e. \u003cstrong\u003e21\u003c/strong\u003e, 2240\u0026minus;2244 (2019).\u003c/li\u003e\n\u003cli\u003eCai, Y.; Yang, X.-T.; Zhang, S.-Q.; Li, F.; Li, Y.-Q.; Ruan, L.-X.; Hong, X.; Shi, S.-L. Copper-Catalyzed Enantioselective Markovnikov Protoboration of \u0026alpha;-Olefins Enabled by a Buttressed N\u0026minus;Heterocyclic Carbene Ligand. \u003cem\u003eAngew. Chem., Int. Ed.\u003c/em\u003e \u003cstrong\u003e57\u003c/strong\u003e, 1376\u0026minus;1380 (2018).\u003c/li\u003e\n\u003cli\u003eCai, Y.; Zhang, J.-W.; Li, F.; Liu, J.-M.; Shi, S.-L. Nickel/N-Heterocyclic Carbene Complex-Catalyzed Enantioselective Redox-Neutral Coupling of Benzyl Alcohols and Alkynes to Allylic Alcohols. \u003cem\u003eACS Catal.\u003c/em\u003e \u003cstrong\u003e9\u003c/strong\u003e, 1\u0026minus;6 (2019).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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":"synthesis, catalysis, organic chemistry","lastPublishedDoi":"10.21203/rs.3.rs-198647/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-198647/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe construction of 7-membered ring via direct C7\u0026minus;H cyclization of benzoimidazoles with alkenes would provide a more atom- and step economical route to tricyclic imidazoles and derivatives that widely exist in a broad range of bioactive molecules. However, transition metal-catalyzed C\u0026minus;H cyclization for medium-ring synthesis has been limited to reactive C\u0026minus;H bonds, instead, the activation of unreactive C\u0026minus;H bonds towards medium synthesis still remains an elusive challenge. Herein, we report a direct construction of 7-membered rings via Ni\u0026minus;Al co-catalyzed unreactive C7\u0026minus;H cyclization of benzoimidazoles with alkenes, providing a series of tricyclic imidazoles in 40\u0026minus;98% yield and with up to 95:5 er.\u003c/p\u003e","manuscriptTitle":"Construction 7-Membered Ring via Ni-Al Bimetal-Enabled C-H Cyclization for Synthesis of Tricyclic Imidazoles","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-02-09 22:03:17","doi":"10.21203/rs.3.rs-198647/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":"26a07b17-028f-419b-93d9-c63a2956e23a","owner":[],"postedDate":"February 9th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":2334059,"name":"Catalysis"},{"id":2334060,"name":"Organic Chemistry"}],"tags":[],"updatedAt":"2021-11-22T15:42:51+00:00","versionOfRecord":{"articleIdentity":"rs-198647","link":"https://doi.org/10.1038/s41467-021-23371-x","journal":{"identity":"nature-communications","isVorOnly":false,"title":"Nature Communications"},"publishedOn":"2021-05-24 04:00:00","publishedOnDateReadable":"May 24th, 2021"},"versionCreatedAt":"2021-02-09 22:03:17","video":"","vorDoi":"10.1038/s41467-021-23371-x","vorDoiUrl":"https://doi.org/10.1038/s41467-021-23371-x","workflowStages":[]},"version":"v1","identity":"rs-198647","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-198647","identity":"rs-198647","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}