Grignard Reagents Unlock 3D Nitrogen Heterocycles via Single Carbon Ring Insertion

Grignard Reagents Unlock 3D Nitrogen Heterocycles via Single Carbon Ring Insertion | 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 Physical Sciences - Article Grignard Reagents Unlock 3D Nitrogen Heterocycles via Single Carbon Ring Insertion Mark Gandelman, Aleksandr Koronatov, Pavel Sakharov, Alexander Kaushansky, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8560979/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 Nitrogen heterocycles are integral part of pharmaceuticals, catalysts, and materials, yet most accessible molecular scaffolds remain flat, aromatic rings with limited three-dimensionality. As medicinal chemistry increasingly seeks non-planar, sp3-rich architectures to improve molecular performance and to expand underexplored chemical space, methods that can remodel existing heterocycles into new 3D frameworks are urgently needed. Here we introduce a fundamentally new strategy for ring insertion that uses simple nucleophilic reagents - most notably, Grignard reagents - to introduce one-carbon into azolium rings. This unprecedented nucleophilic rearrangement converts planar triazolium salts, derived from alkenes, into a previously inaccessible family of saturated, three-dimensional 1,2,4-triazinanes. These underexplored compounds are 3D counterparts of planar 1,2,4-triazines well represented in pharmaceuticals and bioactive molecules. The method is operationally simple, broadly applicable to cyclic, acyclic, natural, and highly functionalized alkenes, and remarkably tolerant of sensitive groups including esters, amides, sulfonamides, acetals, phosphates, and alkynes. Mechanistic experiments and density functional theory computations reveal a unique nitrenium-centered pathway that enables this umpolung reactivity. By transforming readily available olefins into complex, non-planar nitrogen heterocycles in just two steps, this work provides a powerful entry into new heterocyclic space and opens opportunities for late-stage diversification relevant to drug discovery, catalysis, and molecular design. Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology Physical sciences/Chemistry/Chemical synthesis/Diversity-oriented synthesis Full Text Additional Declarations There is NO Competing Interest. Supplementary Files supplementaryinformation.pdf Supplementary Information NMRdata.pdf NMR Data 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-8560979","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Physical Sciences - Article","associatedPublications":[],"authors":[{"id":572833131,"identity":"f93f607e-199c-4c8e-aa42-8ba530e748b8","order_by":0,"name":"Mark Gandelman","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8klEQVRIiWNgGAWjYDACCRBxwAbCYWxg4IGJyxDQkgakmFG18BDQchiuBQ5wauGf3Z34ueLM+TqDA/wHH/zccUeGX7qB8cMPBgucWiTunN0seebGbQnJBmZmw94zz3gk5xxgluzB4zADidwNkg0fbkvwMzCzSTO2HeYxuJHAII3PL0Atm382fDgnwcbAzP4bqoX5NwEt2yQbbhwA28IM1cKG1xaJG7nbLBvOJEvObGY2luwFapGckdhm2WOAWwv/jNzNNxuO2fEbHG98+OFn22F7fonkwzd+VNTJ4dKCAMxwFih2DAhrGAWjYBSMglGAGwAA56ZOVhaK3TMAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-9651-2902","institution":"Technion - 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As medicinal chemistry increasingly seeks non-planar, sp3-rich architectures to improve molecular performance and to expand underexplored chemical space, methods that can remodel existing heterocycles into new 3D frameworks are urgently needed. Here we introduce a fundamentally new strategy for ring insertion that uses simple nucleophilic reagents - most notably, Grignard reagents - to introduce one-carbon into azolium rings. This unprecedented nucleophilic rearrangement converts planar triazolium salts, derived from alkenes, into a previously inaccessible family of saturated, three-dimensional 1,2,4-triazinanes. These underexplored compounds are 3D counterparts of planar 1,2,4-triazines well represented in pharmaceuticals and bioactive molecules. The method is operationally simple, broadly applicable to cyclic, acyclic, natural, and highly functionalized alkenes, and remarkably tolerant of sensitive groups including esters, amides, sulfonamides, acetals, phosphates, and alkynes. Mechanistic experiments and density functional theory computations reveal a unique nitrenium-centered pathway that enables this umpolung reactivity. 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