Asymmetric Allylic C-H Amination Cross-Coupling by Palladium-Catalyzed 1,3 Migratory Carboamination of 1,4-Unconjugated Dienes

Asymmetric Allylic C-H Amination Cross-Coupling by Palladium-Catalyzed 1,3 Migratory Carboamination of 1,4-Unconjugated Dienes | 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 Asymmetric Allylic C-H Amination Cross-Coupling by Palladium-Catalyzed 1,3 Migratory Carboamination of 1,4-Unconjugated Dienes Zhan-Ming Zhang, Chen-Yu Ge, Bing Xu, Yi-Hao Li, Junliang Zhang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7867414/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Chiral allylic amines are prominent structural motifs in natural products, pharmaceuticals and agrochemicals. Moreover, they serve as synthetically valuable intermediates for the construction of complex organic molecules. However, amines, especially aliphatic and aromatic amines with free N-H bonds, tend to coordinate with transition metals and deactivate the catalyst, posing a tremendous challenge to applying Lewis basic amines in the amination of olefins. Herein, we present the first example of synthesizing chiral allylamine via the Pd-catalyzed asymmetric 1,3-carboamination of acyclic 1,4-unconjugated dienes through the chain-walking process. The combination of a palladium catalyst, newly synthesized TY-Phos ligand enables the efficient reaction of aryl bromides, 1,4-unconjugated dienes, and aryl primary amines, affording chiral allylamines with excellent chemo-, regio-, and enantioselectivity (up to 94% ee). Remarkably, the 1,3-carboamination cyclization between 2-iodoaniline and acyclic 1,4-unconjugated dienes to synthesize chiral tetrahydroquinoline derivatives was also realized (up to 92% ee) via Pd/Ming-Phos catalytic system. The synthetic utility of this method is exemplified in the enantioselective synthesis of the alkaloids (-)-Cuspareine and (-)-Galipinine. Mechanistic investigations reveal that the reaction via a chain-walking process. Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology Physical sciences/Chemistry/Catalysis/Asymmetric catalysis Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SI.docx supporting information Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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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-7867414","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":547729609,"identity":"b2ba557e-f7b8-46c3-b3d3-4c3288ee90bc","order_by":0,"name":"Zhan-Ming Zhang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCElEQVRIiWNgGAWjYDACCRBhAGNUyDEwHAAx2IjWcsaYWC0wBmMbEVrkZzc/e3Sj4I7dfCDj4dd5Bol9x88eYPhQdpiBf3YDVi2Mc46ZG+cYPEtuBDFktxkkzjyTl8A449xhBok7B7BqYZZIMJPOMTicDGZIbvuTuOFAjgEzb9thBgOJBKxa2CTSv4G1gBmScwwSN5x/Y8D8F48WHokcsC12IIbkxwaglhtAWxjxaJGQyCkDaUkAMxiOGRjPvPHG4GDPuXQeiRvYtcjPSN8mnfPnsD2IIfmjxkC273yO4YMfZdZy/DOwa4GBxAZQWPBAeQdATsarHgjsQQTjD0LKRsEoGAWjYEQCANBFX2XwZQlbAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0009-0008-8902-2527","institution":"Fudan University","correspondingAuthor":true,"prefix":"","firstName":"Zhan-Ming","middleName":"","lastName":"Zhang","suffix":""},{"id":547729610,"identity":"2b1b1b85-ce50-44ad-9c73-b778c8f3d16e","order_by":1,"name":"Chen-Yu Ge","email":"","orcid":"","institution":"Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Chen-Yu","middleName":"","lastName":"Ge","suffix":""},{"id":547729611,"identity":"fa84398c-cfc7-4d42-9c40-c128b69e0d13","order_by":2,"name":"Bing Xu","email":"","orcid":"","institution":"Naval Medical University","correspondingAuthor":false,"prefix":"","firstName":"Bing","middleName":"","lastName":"Xu","suffix":""},{"id":547729612,"identity":"099afb3d-14a7-4dba-ab74-b39faa47071e","order_by":3,"name":"Yi-Hao Li","email":"","orcid":"","institution":"Soochow University","correspondingAuthor":false,"prefix":"","firstName":"Yi-Hao","middleName":"","lastName":"Li","suffix":""},{"id":547729613,"identity":"192ea046-1af7-42dc-b4a8-28b5bb349442","order_by":4,"name":"Junliang Zhang","email":"","orcid":"https://orcid.org/0000-0002-4636-2846","institution":"Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Junliang","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2025-10-15 11:10:42","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7867414/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7867414/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":98624880,"identity":"5d634672-baef-4e38-bfd8-d14002e7b167","added_by":"auto","created_at":"2025-12-19 17:08:47","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2308965,"visible":true,"origin":"","legend":"Article File","description":"","filename":"Manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7867414/v1_covered_f3a52979-14e0-445a-b647-570a41d66b09.pdf"},{"id":96428677,"identity":"63572d0b-e442-468d-b1b3-ccac825e4466","added_by":"auto","created_at":"2025-11-21 03:15:41","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":131009723,"visible":true,"origin":"","legend":"supporting information","description":"","filename":"SI.docx","url":"https://assets-eu.researchsquare.com/files/rs-7867414/v1/96509095deff5616469d809d.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Asymmetric Allylic C-H Amination Cross-Coupling by Palladium-Catalyzed 1,3\r\nMigratory Carboamination of 1,4-Unconjugated Dienes","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7867414/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7867414/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Chiral allylic amines are prominent structural motifs in natural products, pharmaceuticals and agrochemicals. Moreover, they serve as synthetically valuable intermediates for the construction of complex organic molecules. However, amines, especially aliphatic and aromatic amines with free N-H bonds, tend to coordinate with transition metals and deactivate the catalyst, posing a tremendous challenge to applying Lewis basic amines in the amination of olefins. Herein, we present the first example of synthesizing chiral allylamine via the Pd-catalyzed asymmetric 1,3-carboamination of acyclic 1,4-unconjugated dienes through the chain-walking process. The combination of a palladium catalyst, newly synthesized TY-Phos ligand enables the efficient reaction of aryl bromides, 1,4-unconjugated dienes, and aryl primary amines, affording chiral allylamines with excellent chemo-, regio-, and enantioselectivity (up to 94% ee). Remarkably, the 1,3-carboamination cyclization between 2-iodoaniline and acyclic 1,4-unconjugated dienes to synthesize chiral tetrahydroquinoline derivatives was also realized (up to 92% ee) via Pd/Ming-Phos catalytic system. The synthetic utility of this method is exemplified in the enantioselective synthesis of the alkaloids (-)-Cuspareine and (-)-Galipinine. 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