English

• Skeletal editing has emerged as a powerful tool in organic chemistry, enabling the simplification of synthetic routes to complex molecules [1]. Indoles, electron-rich nitrogen-containing building blocks, represent privileged scaffolds prevalent in pharmaceuticals, natural products, and bioactive compounds. The application of skeletal editing strategies to modify such structures is highly valuable and in growing demand. Leveraging the electron-rich nature of indoles at C2 and C3, single-carbon atom insertion using cationic carbyne equivalents offers an efficient approach for indole ring expansion to quinoline (Scheme 1a). However, existing methods predominantly rely on halocarbene precursors, which restricts the functional groups of ring-expanded products to halogen [2], alkyl, aryl, heteroaryl and ester moieties [3]. This limitation hinders their utility in late-stage skeletal modifications of complex targets.

  Scheme 1

  

  Scheme 1.  Skeletal editing of indole to quinoline via single-carbon atom insertion.

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  Recent advance in skeletal ring expansion of indoles, using α-halogen-free carbenes generated in situ from N-triftosylhydrazones and developed by Bi, Liu and Anderson, improved the traditional Ciamician-Dennstedt reaction [4]. However, the requirement of N-TBS protected indoles and two-step procedures makes this strategy inconvenient to some extent. To solve these problems, Han and co-workers prepared an α-diazotrifluoroethyl sulfonium salt, and it was magically utilized as a trifluoromethyl cationic carbyne (CF₃C⁺: ) precursor toward the indole-quinoline transmutation, affording a series of 3-trifluoromethyl quinolines in up to 91% yield (Scheme 1b) [5]. The utilization of this specific sulfonium reagent for the synthesis of 3-trifluoromethyl quinolines offers three key advantages: (1) The α-diazotrifluoroethyl sulfonium salt, readily prepared from iodobenzene via a concise three-step protocol, exhibits excellent stability and can be stored at room temperature for one month without decomposition; (2) This reagent, featuring a cleavable C-S(IV) bond, serves as a halogen-free cationic carbyne precursor in indole skeletal editing. Dimethyl sulfide (Me₂S) and trifluoromethanesulfonic acid (TfOH), the generated byproducts, are easily removed using standard purification methods; (3) The Rh-catalyzed one-step procedure demonstrates remarkable tolerance for both N-unprotected and 2-nonsubstituted indoles, obviating the need for high-temperature conditions or additional chemical transformations to forge the quinoline core.

  The authors have demonstrated that the indole-quinoline transmutation was sensitive toward moisture and high substrate concentration, whereas the concentration of oxygen, low substrate concentration, large scale, catalyst loading, and temperature had only weak effects on the reactivity. They further investigaged the compatibility of substrates in two models, the first operation was conducted in glove box, the second operation was prerformed with Schlenk technology. Compared to indoles bearing electron-donating groups, relatively low isolated yields were obtained for electron-withdrawing substituents, most likely because indoles with electron-rich substituents favored the electrophilic cycloaddition of formal trifluoromethyl Rh-carbynoids to increase their reactivity and efficiency.

  To demonstrate its practicality, late-stage skeletal editing of pharmaceuticals and natural products, preparation of adapalene analogs, scaled-up synthesis, and transformations of products were explored.

  The authors proposed that the trifluoromethyl Rh-carbynoid (CF₃C⁺=Rh), a trifluoromethyl cationic carbyne (CF₃C⁺: ) equivalent, in situ generated from α-diazotrifluoroethyl sulfonium salt 2a and dirhodium complex Rh₂(esp)₂ would be engaged in the skeletal editing of indole 1a by single-carbon atom insertion into the C₂(sp²)-C₃(sp²) bond to yield the endo-cyclopropane intermediate, which further gives 3-trifluoromethylquinoline 3a via a TfO^--promoted aromatization-driven rearrangement process (Scheme 2).

  Scheme 2

  

  Scheme 2.  Proposed mechanism.

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  In summary, Han et al. have developed an indole-quinoline transmutation using α-diazo sulfonium salt as a cationic carbyne precursor via a rhodium-catalyzed [2 + 1] cycloaddition and intramolecular rearrangement cascade. DFT calculations further supported the proposed single-atom insertion and ring expansion pathways, suggesting that the mechanism presumably proceeds via the electrophilic cycloaddition of a formal trifluoromethyl Rh-carbynoid to indole, yielding an endo-cyclopropane intermediate. Given that both N-unprotected and 2-nonsubstituted indoles were well tolerated in this reaction, this one-step procedure holds significant application prospects in the fields of organic synthesis and medicinal chemistry.

  Declaration of competing interest

  The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

  CRediT authorship contribution statement

  Cui Xin: Writing – original draft. Zi-Jian Zhao: Writing – original draft. Wei-Min He: Writing – review & editing.

  
  
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  Scheme 1  Skeletal editing of indole to quinoline via single-carbon atom insertion.

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  Scheme 2  Proposed mechanism.

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