转自：康龙化成

Switchable Skeletal Editing of Quinolines Enabled by Cyclizative Sequential Rearrangements

Di Tian, Yu-Ping He, Lu-Sen Yang, Zhuo-Chen Li, Hua Wu*

Shanghai Frontiers Science Center for Drug Target Identification and Delivery, Laboratory of Innovative Immunotherapy, and Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, China; 

Department of Chemistry, College of Sciences, Shanghai University, Shanghai, China.

—Nat. Chem., 2025, doi:https://doi.org/10.1038/s41557-025-01793-0

Recommended by Yuting Gao_MC3

KEY WORDS: skeletal editing, chiral phosphoric acid catalysis (反应类型), quinoline N-oxides, dimethyl acetylenedicarboxylate(DMAD), dialkyl acetylene dicarboxylates(原料), 2-substituted indolines,indoles, 2-alkenylanilines, isoquinolinones(产物)

ABSTRACT: Wu’s group reported the tunable skeletal editing of quinolines through Brønsted acid-catalysedmulticomponent reactions of quinoline N-oxides, dialkyl acetylenedicarboxylates and water to generate nitrogen-containing heteroaromatic compounds together with linear compounds in a modular fashion. Specifically, in a one-pot procedure, after cyclization and sequential rearrangement processes, the quinoline N-oxides are easily converted into unique 2-substituted indolines. These then undergo acid-promoted fragmentation to give indoles, base-facilitated ring-opening to afford 2-alkenylanilines and oxidative cyclization to yield isoquinolinones. Catalytic asymmetric skeletal editing of quinolines is also realized, providing enantioenriched benzazepines bearing quaternary stereocentres, and late-stage skeletal modification of quinoline cores in several drugs is demonstrated.

Skeletal editing of heterocycles. a, Conceptual outline of the divergent skeletal editing of heteroaromatic compounds. b, Recent advances in skeletal editing of quinolines and pyridines.c, Tunable and chemodivergent skeletal editing of quinolines, enabling efficient construction of indoles, 2-alkenylanilines, isoquinolinones and enantioenriched benzazepines (This work). 

Proposed Reaction Pathways

Substrates Scope of Quinolines to Indoles (selected)

Substrates Scope of Quinolines to 2-Alkenylanilines

Substrates Scope of Quinolines to Isoquinolinones

Substrates Scope of Quinolines to Benzazepines

The Group of Prof. Hua Wuhas developed a cyclizative sequential rearrangement strategy for the chemodivergent skeletal editing of quinolines. In this case, a variety of structurally diverse indoles, 2-alkenylanilines and fused isoquinolinones are efficiently constructed in one pot through single carbon hopping, deconstructive carbon grafting and aza-arene reconstruction, respectively. Furthermore, based on chiral phosphoric acid catalysis, the catalytic enantioselective skeletal editing of quinolines via carbon atom insertion was also achieved. These reactions are scalable and powerful, take place in the presence of readily available starting materials and a cheap catalyst, are insensitive to air and moisture and show broad substrate scope with adequate complexity. The practicality of the strategy has also been demonstrated by successful late-stage application to drug modification. These intermolecular multicomponent cyclizativerea rrangements enable the tunable and enantioselective editing of aromatic heterocycles and should attract more interest in this frontier.

（转自：康龙化成）