Heteroaromatic Swapping in Aromatic Ketones

Heteroaromatic Swapping in Aromatic Ketones | 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 Heteroaromatic Swapping in Aromatic Ketones Junichiro Yamaguchi, Hikaru Nakahara, Ryotaro Shirai, Yoshio Nishimoto, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5583133/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 09 Oct, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract The modification of aromatic rings to heteroaromatic rings is a widely employed strategy in medicinal chemistry, often used to modulate lipophilicity and improve metabolic stability. However, achieving a one-step, generalizable transformation of aromatic rings into diverse heteroaromatic rings—termed "heteroaromatic swapping"—remains a persistent challenge. Existing methods, such as skeletal editing and transition-metal-catalyzed aromatic ring exchange, are limited in substrate scope and efficiency. Here, we present an efficient strategy for heteroaromatic swapping via a Claisen/retro-Claisen mechanism, utilizing heteroaryl esters and aromatic ketones. This approach enables the selective exchange of aromatic rings with heteroaromatic rings across a broad substrate range, overcoming the limitations of existing techniques. Notably, it achieves high-yield conversions of bioactive aromatic ketones into their heteroaromatic counterparts. This method expands the molecular editing toolkit, offering a practical and versatile platform for synthesizing bioactive compounds with enhanced physicochemical properties. Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology Physical sciences/Chemistry/Organic chemistry/Reaction mechanisms Full Text Additional Declarations There is NO Competing Interest. Supplementary Files HN2980.cif CIF file HN2980checkCIF.pdf CheckCIF SInakaharaswappingNaturerevfinal.pdf Supplementary Information Cite Share Download PDF Status: Published Journal Publication published 09 Oct, 2025 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. 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