Switchable skeletal editing of quinolines enabled by cyclizative sequential rearrangements

Area of Science:

• Organic Chemistry
• Medicinal Chemistry

Background:

• Diversifying molecular structures is key in drug discovery.
• Controlling chemical modifications of azaarene frameworks remains challenging.

Purpose of the Study:

• To develop a tunable method for skeletal editing of quinolines.
• To generate diverse nitrogen-containing heteroaromatic and linear compounds.

Main Methods:

• Utilized Brønsted acid-catalyzed multicomponent reactions of quinoline N-oxides, dialkyl acetylenedicarboxylates, and water.
• Employed a one-pot procedure involving cyclization and rearrangement.
• Demonstrated catalytic asymmetric skeletal editing.

Main Results:

• Successfully converted quinoline N-oxides into 2-substituted indolines, indoles, 2-alkenylanilines, and isoquinolinones.
• Achieved modular synthesis of diverse nitrogen-containing compounds.
• Generated enantioenriched benzazepines with quaternary stereocenters.
• Showcased late-stage skeletal modification of drug molecules.

Conclusions:

• The developed method offers a versatile platform for skeletal editing of quinolines.
• This approach enhances structural diversity for drug discovery.
• The methodology is applicable to complex molecules and drug scaffolds.