The structural complexity and diversity of organic molecules play a pivotal role in the advancement of drug discovery, offering promising avenues for the development of therapeutics with improved efficacy and selectivity. Central to these efforts is the ability to manipulate core ring systems within heteroaromatic compounds, which are ubiquitous in pharmaceutical agents due to their unique chemical and biological properties. Among these, quinolines stand out as privileged scaffolds but have long posed challenges for controlled structural modification, particularly through methods that allow the selective alteration of their skeletons. Addressing this, recent research has now introduced a breakthrough approach that leverages switchable skeletal editing via cyclizative sequential rearrangements, unveiling a versatile platform for the generation of diverse nitrogen-containing heteroaromatic architectures.
This innovative methodology exploits the inherent reactivity of quinoline N-oxides, dialkyl acetylenedicarboxylates, and water under Brønsted acid catalysis to orchestrate a multicomponent reaction sequence that goes beyond traditional functionalization. What sets this approach apart is its tunability, enabling practitioners to direct the molecular framework along different pathways with high precision, producing an array of structurally distinct products from common substrates. Such controllability in the skeletal editing of azaarene frameworks represents a significant stride forward, given the previously limited toolkit for chemically divergent modifications within this class of compounds.
At the heart of the process is a one-pot procedure that initiates with the formation of cyclized intermediates through the reaction of quinoline N-oxides with dialkyl acetylenedicarboxylates and water. This cyclization is promptly followed by sequential rearrangement steps, which efficiently convert the quinoline N-oxide starting materials into unique 2-substituted indoline derivatives. The efficient synthesis of these indolines in a modular fashion not only underscores the versatility of the reaction but also highlights the strategic innovation in skeletal editing, wherein ring frameworks are rearranged and functionalized in a choreographed sequence rather than through stepwise, isolated transformations.
These 2-substituted indolines serve as critical branching points for further transformations, with the reaction conditions dictating divergent outcomes via selective skeletal rearrangements and fragmentation. For example, under acidic conditions, these indolines undergo a notable acid-promoted fragmentation that results in the formation of indoles — a class of heterocycles highly prized for their biological activity. This control over ring system disassembly and reconstruction exemplifies the mastery of skeletal editing achieved in this work, showcasing how subtle shifts in reaction conditions can pivot the molecular fate toward distinct heteroaromatic nuclei.
Alternatively, the reaction environment can be adjusted to favor base-induced ring-opening reactions of the indoline intermediates, yielding linear 2-alkenylanilines. Such a transformation is particularly compelling, as it offers access to open-chain derivatives from cyclic precursors in a controlled manner, expanding the chemical space accessible from a common framework. The ability to interconvert between ring-closed and ring-opened structures demonstrates the synthetic flexibility embedded in this multicomponent system, enhancing the prospects for downstream modifications and biological evaluation.
Further illustrating the versatility of this reaction platform is the oxidative cyclization pathway leading to isoquinolinones. Through oxidative conditions, the evolving intermediates undergo cyclization to yield these nitrogen-containing bicyclic compounds, which are structurally related to quinolines yet possess distinct electronic and steric environments. Isoquinolinones are notable for their presence in various bioactive natural products and pharmaceuticals, and their efficient synthesis from quinoline derivatives marks a valuable addition to the synthetic chemist’s arsenal.
Beyond the synthetic versatility, this research ventures into asymmetric skeletal editing, introducing an enantioselective catalytic system that affords benzazepines bearing quaternary stereocenters. The formation of such complex, chiral molecules with high enantiomeric enrichment is a notable achievement, addressing a long-standing challenge in the construction of structurally intricate heterocycles with stereochemical control. This asymmetric variant broadens the applicability of skeletal editing strategies to the synthesis of chiral drug scaffolds, thereby enhancing their potential for therapeutic innovation.
Late-stage skeletal modification of quinoline cores in existing drugs is another compelling demonstration of the power of this methodology. By applying these switchable skeletal editing protocols, the research team showcased the ability to tune the molecular architectures of known pharmaceuticals, potentially altering their biological properties and expanding their utility. This capability is particularly valuable for drug discovery and development, where rapid diversification of lead compounds can accelerate the identification of candidates with optimized pharmacological profiles.
Mechanistically, the reactions proceed via initial nucleophilic attack on the activated acetylenic ester substrates, followed by intramolecular cyclization events. The sequential rearrangements involve well-orchestrated bond cleavage and formation steps, underpinning the dynamic reorganization of carbon and nitrogen frameworks. The involvement of Brønsted acid catalysis is crucial, modulating the reaction pathway by facilitating protonation events that lower activation barriers and direct skeletal rearrangements, effectively tuning the reaction landscape toward desired products.
The study offers profound insights into the design of multicomponent reactions for skeletal editing, revealing how the combination of commonly available substrates can yield substantial molecular complexity through controlled reaction sequences. Such multicomponent reactions not only streamline synthetic processes but also embody principles of green chemistry by minimizing steps and waste, aligning well with contemporary demands for sustainable chemical synthesis.
Importantly, this approach addresses a notable gap in the field of heteroaromatic chemistry. While prior techniques have enabled functionalization at peripheral positions of azaarenes, their core skeletons often remained refractory to selective and divergent modification. By enabling switchable and modular editing of quinoline cores, this work paves the way for the rational design of new heterocyclic entities, with potential ripple effects spanning medicinal chemistry, materials science, and chemical biology.
The adaptability of the method is enhanced by its compatibility with various substituents and functional groups on the quinoline nucleus, allowing for the derivation of structurally diverse scaffolds from a common precursor. Such substrate scope breadth underscores the practicality of the technique and its suitability for complex molecule synthesis, evincing potential adoption across academic and industrial laboratories.
Furthermore, the seamless integration of cyclization, rearrangement, and fragmentation within a single operational setup amplifies the synthetic efficiency, reducing the need for isolation and purification of intermediates. This modularity and operational simplicity alleviate synthetic bottlenecks, facilitating rapid access to complex molecules that might otherwise require multi-step synthetic routes.
In the broader context, skeletal editing as exemplified by this quinoline platform represents an emergent paradigm in molecular synthesis, shifting the focus from functional group interconversions to direct architectural transformations of molecular skeletons. Such transformations afford access to chemical landscapes that are difficult to explore through classical synthetic methodologies, enabling the discovery of novel molecular entities with unprecedented structures and functions.
As the demand for structural innovation in drug discovery intensifies, methodologies that provide controlled, switchable, and asymmetric transformation routes hold immense promise. By demonstrating these capabilities on quinoline frameworks, a backbone prevalent in therapeutic chemistry, this work is poised to catalyze further exploration and application of skeletal editing techniques, potentially reshaping synthetic strategies in pharmaceutical research.
In sum, the reported switchable skeletal editing of quinolines through cyclizative sequential rearrangements represents a landmark advance with wide-reaching implications. It unlocks new chemical space by converting readily accessible substrates into a spectrum of valuable heterocyclic structures, all under tunable reaction conditions within a streamlined, one-pot protocol. With its combination of mechanistic sophistication, synthetic versatility, and enantioselective capability, this approach sets a new benchmark for skeletal editing technologies and their role in modern organic synthesis.
Subject of Research: Skeletal editing of quinoline cores via Brønsted acid-catalyzed multicomponent reactions enabling tunable structural diversification of nitrogen-containing heteroaromatic compounds.
Article Title: Switchable skeletal editing of quinolines enabled by cyclizative sequential rearrangements.
Article References:
Tian, D., He, YP., Yang, LS. et al. Switchable skeletal editing of quinolines enabled by cyclizative sequential rearrangements. Nat. Chem. (2025). https://doi.org/10.1038/s41557-025-01793-0
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