Skeletal Editing of Pyridines and Pyrimidines via ANRORC Mechanism

ConspectusSkeletal editing has emerged as a transformative strategy in synthetic chemistry, providing a direct route to modify molecular frameworks that are challenging to access by conventional methods. This approach is particularly valuable for privileged, electron-deficient heteroarenes such as pyridines and pyrimidines─scaffolds ubiquitous in pharmaceuticals and functional materials. The inherent aromatic stability and electron-deficient nature of these compounds pose significant challenges to skeletal modification. Current methodologies address these challenges through dearomatization to access activated intermediates for subsequent skeletal restructuring. These strategies can be broadly divided into three categories. The first involves the photochemical activation of pyridine N-oxides or N-ylides to generate high-energy intermediates, such as 1,3-oxazepines and 1,2-diazepines. The second approach employs a dearomative addition to convert electron-deficient pyridines into electron-rich cyclic dieneamine intermediates. The third approach is the quaternization-facilitated ANRORC (Addition of the Nucleophile, Ring Opening, and Ring Closure) pathway, wherein N-activated pyridinium salts undergo nucleophilic ring-opening to form Zincke-type intermediates that exhibit versatile reactivity. Through these reactive intermediates, various skeletal editing systems for pyridines and pyrimidines have been developed. Among them, the Zincke intermediate involved in the ANRORC strategy provides exceptional tunability via systematic variation of three key elements: activators, nucleophiles, and functional modifiers, enabling precise control over the editing outcomes while maintaining excellent functional group compatibility. Our research program has systematically advanced the ANRORC process into a powerful strategy for skeletal editing of the electron-deficient N-heteroarenes. Through the rational design of activators (including alkyl, vinyl, benzyl, dinitrophenyl and Tf groups) and the incorporation of diverse nucleophiles (O-, C-, and N-based), we have established a modular system capable of generating a range of key open-chain intermediates such as Zincke aldehydes, azatrienes (including Zincke imines), streptocyanines, and vinamidinium salts. Strategic modification of these versatile intermediates using a wide range of electrophilic, amphiphilic, or dipolar reagents enables multiple editing paradigms, including efficient pyridine ring contractions to functionalized pyrroles, degenerate ring transformations of pyridines with concurrent core functionalization, and denitrogenative annulation of pyridine to arene dialdehydes or thiophene motifs. Moreover, it facilitates the transformation of pyrimidines into diverse nitrogen-containing heterocycles via vinamidinium salt intermediates. In this Account, we systematically summarize our work on skeletal editing using tunable Zincke intermediates generated via the ANRORC pathway, with particular emphasis on mechanistic understanding, substrate scope, and synthetic applications. By outlining prospective research directions, we anticipate this Account will set the stage for future exploration of the ANRORC strategy in skeletal editing of heterocycles, promote the discovery of novel reactivity patterns, and thereby contribute to further progress in this dynamic field.