Reductive Allylic Defluorinative Cross-Coupling Enabled by Ni/Ti Cooperative Catalysis
Zhiyang Lin1, Yun Lan1, Chuan Wang1
1Hefei National Laboratory for Physical Science at the Microscale, Department of Chemistry, Center for Excellence in Molecular Synthesis , University of Science and Technology of China , 96 Jinzhai Road , Hefei , Anhui 230026 , P. R. China.
Organic Letters
|October 2, 2019
Summary
This study introduces a new method for synthesizing gem-difluoroalkenes using nickel/titanium-cocatalyzed cross-coupling reactions. The process efficiently couples readily available alkyl chlorides and bromides with trifluoromethyl alkenes.
Area of Science:
- Organic Chemistry
- Catalysis
- Synthetic Methodology
Background:
- Unactivated alkyl chlorides are common synthetic precursors but are underutilized in cross-electrophile coupling reactions.
- Developing efficient methods for synthesizing gem-difluoroalkenes is crucial for medicinal chemistry and materials science.
Purpose of the Study:
- To develop a novel Ni/Ti-cocatalyzed reductive allylic defluorinative cross-coupling reaction.
- To enable the synthesis of diverse and functional-group-rich gem-difluoroalkenes from unactivated alkyl halides and trifluoromethyl alkenes.
Main Methods:
- Utilized a dual catalytic system of Nickel (Ni) and Titanium (Ti) for reductive cross-coupling.
- Employed trifluoromethyl alkenes and unactivated alkyl chlorides or bromides as coupling partners.
- Investigated the scope and limitations of the developed synthetic methodology.
Main Results:
- Successfully achieved reductive allylic defluorinative cross-coupling between trifluoromethyl alkenes and unactivated alkyl chlorides/bromides.
- Demonstrated the efficient preparation of a wide range of functional-group-rich gem-difluoroalkenes.
- Synthesized gem-difluoroalkene analogues of important pharmaceutical compounds like azaperone, haloperidol, and benperidol.
Conclusions:
- The developed Ni/Ti-cocatalyzed method provides a powerful new route to gem-difluoroalkenes.
- This approach expands the utility of unactivated alkyl halides in cross-coupling reactions.
- The methodology offers a valuable tool for accessing complex fluorinated molecules, including drug analogues.
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