A New Metal-Free Strategy for C-N Cross-Coupling of Benzamide and Sulfonamide Enabled Smiles Rearrangement

A New Metal-Free Strategy for C-N Cross-Coupling of Benzamide and Sulfonamide Enabled Smiles Rearrangement | 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 A New Metal-Free Strategy for C-N Cross-Coupling of Benzamide and Sulfonamide Enabled Smiles Rearrangement Srimanta Manna, Sukhendu Pramanick, Sudipta Baur, Ashif Iqubal Ashif Iqubal, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8676133/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 N-substituted anilines and their derivatives are versatile building blocks for synthesizing pharmaceutical molecules, natural products, and functional materials. Given the significant role of biarylamine motifs in modern chemistry, the development of a mild and easily manageable protocol is highly desirable in contemporary organic synthesis. In this context, we develop a transition-metal-free C-N cross-coupling of carboxamides and sulfonamides, resulting in the synthesis of valuable biarylamines and alkylarylamines. This discovery represents an intermolecularly challenging Smiles rearrangement and introduces a novel method for synthesizing N-substituted anilines through the activation of carboxamides derived from carboxylic acids, a previously unexplored approach. The protocol showcases a broad substrate scope with various functional groups and scalability, providing access to key building blocks in medicinal chemistry and drug discovery. Furthermore, the developed protocol was successfully applied to 20 late-stage modifications of drugs and natural products containing primary amides derived from the corresponding acids. Scientific community and society/Scientific community/Education Biological sciences/Drug discovery/Medicinal chemistry/Drug discovery and development Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SICNcouplingSP.pdf A New Metal-Free Strategy for C-N Cross-Coupling of Benzamide and Sulfonamide Enabled Smiles Rearrangement Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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-8676133","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":579355659,"identity":"7d7d9fab-e618-4190-b79b-91713306f079","order_by":0,"name":"Srimanta Manna","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3UlEQVRIie2OsQrCMBCGLwi6VLpWRPsKKa6KzxI6+BoF8bJUXAO+REEQB4eIqzi31KFTNwc3hQrGoigIaUeHfHDcDffd/QAGw19CgrLZ7wE+g1ah0AnqKyUUqKwby13uZ9FtU7iDdIrZZQuuHTQw054/MkzmB+qtTzvuiRw8IQmnWsUiGLeRknXMsGtJIBEQdLTBQoLJHel4JZRSSBhXKnAgmKovLHKUAhJYpUKfSg8HvogZ90Lp+GJfGayVJ2fsjxZikmdXORwtOM/1wb5oqlLLjbr7L8VgMBgMvzwAPDFLDDEUoyoAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-3903-1256","institution":"National Institute of Pharmaceutical Education and Research (NIPER)","correspondingAuthor":true,"prefix":"","firstName":"Srimanta","middleName":"","lastName":"Manna","suffix":""},{"id":579355660,"identity":"9717a6a7-3eac-4980-85c9-c1d2d5997eec","order_by":1,"name":"Sukhendu Pramanick","email":"","orcid":"","institution":"National Institute of Pharmaceutical Education and Research (NIPER)","correspondingAuthor":false,"prefix":"","firstName":"Sukhendu","middleName":"","lastName":"Pramanick","suffix":""},{"id":579355661,"identity":"eecf3078-19a4-4869-951e-f6cbf32e3b68","order_by":2,"name":"Sudipta Baur","email":"","orcid":"","institution":"National Institute of Pharmaceutical Education and Research (NIPER)","correspondingAuthor":false,"prefix":"","firstName":"Sudipta","middleName":"","lastName":"Baur","suffix":""},{"id":579355662,"identity":"e8af2994-cd13-4756-98ce-82edcf6c0021","order_by":3,"name":"Ashif Iqubal Ashif Iqubal","email":"","orcid":"","institution":"Indian Institute of Technology (Indian School of Mines)","correspondingAuthor":false,"prefix":"","firstName":"Ashif","middleName":"Iqubal Ashif","lastName":"Iqubal","suffix":""},{"id":579355663,"identity":"eabaf93a-ef0a-469c-8e92-0a974018bb72","order_by":4,"name":"Joydev Laha","email":"","orcid":"https://orcid.org/0000-0003-0481-5891","institution":"National Institute of Pharmaceutical Education and Research S. A. S. Nagar","correspondingAuthor":false,"prefix":"","firstName":"Joydev","middleName":"","lastName":"Laha","suffix":""}],"badges":[],"createdAt":"2026-01-23 07:24:04","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8676133/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8676133/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105565602,"identity":"4eb6ae5b-bf6d-43ac-b1d8-a7c27c157921","added_by":"auto","created_at":"2026-03-27 12:53:42","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1402380,"visible":true,"origin":"","legend":"Article File","description":"","filename":"ManuscriptCNcouplingSP.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8676133/v1_covered_8a18b1aa-665e-4696-8fd2-9a7500429cb3.pdf"},{"id":101198808,"identity":"8ab70c28-0005-4ffd-b5a1-235ab058f2ac","added_by":"auto","created_at":"2026-01-27 08:43:00","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":11638874,"visible":true,"origin":"","legend":"A New Metal-Free Strategy for C-N Cross-Coupling of Benzamide and Sulfonamide Enabled Smiles Rearrangement","description":"","filename":"SICNcouplingSP.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8676133/v1/811cec679a63f537486ba343.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"A New Metal-Free Strategy for C-N Cross-Coupling of Benzamide and Sulfonamide Enabled Smiles Rearrangement","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-8676133/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8676133/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"N-substituted anilines and their derivatives are versatile building blocks for synthesizing pharmaceutical molecules, natural products, and functional materials. Given the significant role of biarylamine motifs in modern chemistry, the development of a mild and easily manageable protocol is highly desirable in contemporary organic synthesis. In this context, we develop a transition-metal-free C-N cross-coupling of carboxamides and sulfonamides, resulting in the synthesis of valuable biarylamines and alkylarylamines. This discovery represents an intermolecularly challenging Smiles rearrangement and introduces a novel method for synthesizing N-substituted anilines through the activation of carboxamides derived from carboxylic acids, a previously unexplored approach. The protocol showcases a broad substrate scope with various functional groups and scalability, providing access to key building blocks in medicinal chemistry and drug discovery. Furthermore, the developed protocol was successfully applied to 20 late-stage modifications of drugs and natural products containing primary amides derived from the corresponding acids.","manuscriptTitle":"A New Metal-Free Strategy for C-N Cross-Coupling of Benzamide and Sulfonamide Enabled Smiles Rearrangement","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-27 08:42:25","doi":"10.21203/rs.3.rs-8676133/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e90ed8e4-cda2-4963-8a18-c91db7e3b9df","owner":[],"postedDate":"January 27th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":61644624,"name":"Scientific community and society/Scientific community/Education"},{"id":61644625,"name":"Biological sciences/Drug discovery/Medicinal chemistry/Drug discovery and development"}],"tags":[],"updatedAt":"2026-03-25T01:40:30+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-27 08:42:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8676133","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8676133","identity":"rs-8676133","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}