A Mild Intramolecular Cyclization for the Synthesis of N–O Heterocycles and Unlocked Nucleic Acid Analogs

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N–O heterocycles are privileged scaffolds in medicinal chemistry and materials science, yet their synthesis often requires harsh conditions or metal catalysts, limiting functional group compatibility. Herein, we report a mild, metal‐free intramolecular cyclization strategy for the efficient assembly of diverse N–O heterocycles (4‐ to 8‐membered rings). A sequential optimization approach employing definitive screening, steepest ascent, and full factorial designs significantly enhanced the reaction yield up to 95%. The method exhibits broad substrate scope, tolerating halogens, alkyl/aryl groups, and sensitive functionalities, and enables the synthesis of complex fused and nucleic acid‐derived heterocycles. Its utility is demonstrated through the efficient preparation of unprotected unlocked nucleic acid (UNA) analogs, underscoring potential for therapeutic oligonucleotide development.