Formal C─H Functionalization of Quinolines at the C7 Position Through a Traceless Directing Strategy
Kun Zhou1, Ni Zhang2, Xin-Rou Zhong1
1Catalytic Hydrogenation Research Center, State Key Laboratory of Green Chemical Synthesis and Conversion, Key Laboratory of Green Pesticides and Cleaner Production Technology of Zhejiang Province, Zhejiang University of Technology, Hangzhou, 310014, P.R. China.
Angewandte Chemie (International Ed. in English)
|September 15, 2025
Summary
Researchers developed a new copper-catalyzed method for C7-H functionalization of quinolines. This method achieves high selectivity and broad scope, enabling efficient synthesis of valuable C7-substituted quinoline derivatives.
Area of Science:
- Organic Chemistry
- Catalysis
- Medicinal Chemistry
Background:
- Precise C─H functionalization of quinolines is crucial for organic synthesis and drug discovery.
- Selective functionalization at the C7 position of quinolines is challenging due to geometric and electronic factors.
Purpose of the Study:
- To develop a facile and selective method for remote C─H functionalization of quinolines at the C7 position.
- To explore the application of this method in synthesizing C7-substituted quinolines and related compounds.
Main Methods:
- Copper-catalyzed formal C─H arylation and alkenylation of quinolines using iodonium triflates.
- Utilizing a traceless directing strategy involving in situ removal of an N-acyl directing group.
- Employing experimental studies and density functional theory (DFT) calculations to elucidate the reaction mechanism.
Main Results:
- Achieved exclusive C7-selectivity in the functionalization of quinolines.
- Demonstrated a broad substrate scope and short reaction times.
- Successfully applied the protocol to tetrahydroquinolines and for further C7-elaboration of quinolines.
Conclusions:
- The developed protocol provides a practical and efficient route to C7-substituted neutral quinolines.
- The ring-size-induced removal of the N-acyl directing group is key to the C7-selectivity.
- This method offers a valuable tool for accessing diverse quinoline derivatives in drug discovery and organic synthesis.
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