A Convergent, Modular Approach to Trifluoromethyl-Bearing 5-Membered Rings via Catalytic C(sp3 )-H Activation
Kai Wu1, Xuyang Zhang1,2, Liang-Liang Wu1
1State Key Laboratory of Synthetic Chemistry, Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, China.
Angewandte Chemie (International Ed. in English)
|January 3, 2023
Summary
This study introduces a new rhodium-catalyzed method for directly functionalizing C-H bonds to create trifluoromethylated (CF3) 5-membered rings. This approach offers precise control for synthesizing complex CF3-containing molecules.
Area of Science:
- Organic Chemistry
- Catalysis
- Medicinal Chemistry
Background:
- Trifluoromethyl (CF3)-bearing 5-membered rings are crucial motifs in many bioactive compounds.
- Developing modular and selective methods for synthesizing these structures via C(sp3)-H bond functionalization remains a significant challenge.
Purpose of the Study:
- To develop a novel rhodium-catalyzed approach for the direct and selective functionalization of C(sp3)-H bonds.
- To synthesize a diverse range of trifluoromethylated (CF3) saturated 5-membered carbo- and heterocycles.
Main Methods:
- Rhodium-catalyzed carbene insertion of α-CF3-α-alkyl carbene precursors into C(sp3)-H bonds.
- Utilized a broad scope of substrates for C-H functionalization.
- Employed Density Functional Theory (DFT) calculations to investigate reaction mechanisms and selectivity.
Main Results:
- Successfully synthesized 7 distinct types of CF3-bearing saturated 5-membered carbo- and heterocycles.
- Demonstrated high site-, diastereoselectivity, and enantioselectivity, particularly for benzylic C-H insertion.
- The method is applicable to the synthesis of chiral CF3-analogues of bioactive molecules.
- Stoichiometric reactions with ruthenium complexes provided evidence for metal-carbene intermediates.
Conclusions:
- Developed a versatile and efficient rhodium-catalyzed method for constructing CF3-containing 5-membered rings.
- The study elucidates the origin of selectivity in benzylic C-H insertion through computational analysis.
- This work provides a valuable tool for medicinal chemistry and drug discovery efforts.
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