Trifluoromethyl-substituted saturated five-membered rings are important motifs widely present in a large number of bioactive molecules and drugs, and are becoming increasingly popular in newly designed drugs. Therefore, it is very attractive to develop a modular approach to the synthesis of such compounds. But developing a modular approach by manipulating different types of C(sp3)–H bonds, especially reactions with good site and stereoselectivity, remains very challenging.
In recent years, metal-catalyzed α-trifluoromethylcarbene transfer reactions have received increasing attention in synthetic chemistry, which provides a promising tool for obtaining structurally diverse trifluoromethyl-containing bioactive molecules. Recently, some researchers used chiral dirhodium(II) complexes as catalysts to generate α-trifluoromethyl-α-alkyldiazo compounds in situ from a new class of stable and atom-economical amine hydrochlorides. The extensive C(sp3)–H bond insertion of intramolecular carbene was achieved for the first time, and seven classes of trifluoromethyl-containing five-membered carbocyclic and heterocyclic compounds were obtained in a site- and stereoselective manner.
In recent years, metal-catalyzed α-trifluoromethylcarbene transfer reactions have received increasing attention in synthetic chemistry, which provides a promising strategy for obtaining structurally diverse trifluoromethyl-containing bioactive molecules. tool. Recently, some researchers used chiral dirhodium(II) complexes as catalysts to generate α-trifluoromethyl-α-alkyldiazo compounds in situ from a new class of stable and atom-economical amine hydrochlorides. For the first time, the extensive C(sp3)–H bond insertion of intramolecular carbene was achieved, and five-membered carbocyclic and heterocyclic compounds containing trifluoromethyl groups were obtained in a site- and stereoselective manner.
The researchers first screened and optimized the reaction conditions, investigated the effects of a series of metal catalysts and temperature on the reaction efficiency, site, and diastereoselectivity, and found that the dirhodium (II) complex is the most suitable catalyst. The researchers further screened dirhodium(II) complexes to investigate their impact on enantioselectivity, and finally determined the optimal reaction conditions.
Under optimal conditions, this method is particularly efficient for C-H bond insertion at the benzylic position, including benzene arenes and heteroarenes with different substituents, showing good site, diastereo, and enantioselectivity control. Complex natural products and drug molecules also showed good compatibility.
In addition, there are also very good results for the carbon-hydrogen bond insertion of aliphatic, oxygen and nitrogen, and a series of trifluoromethyl-containing cyclopentane, 2,3-dihydroindene, tetrahydrofuran, pyrrolidine and pyrrolidone, etc. and exert good control of site and diastereoselectivity.
Since active biomolecules in nature rarely contain fluorine atoms, and considering the increasing importance of fluorinated molecules in drug discovery. Through the derivatization of the products, the researchers realized the efficient synthesis of a variety of chiral small molecule drugs containing trifluoromethylcyclopentane fragments, natural products and fluorine-labeled peptides.
Computational studies reveal that site-, diastereo- and enantio-control of C–H bond insertion at the benzylic position originates from strong π•••π attraction and intracarbene C–H•••F hydrogen bonds. Additionally, for the first time, active ruthenium porphyrin-α-trifluoromethyl-α-alkylcarbene complexes were isolated and spectroscopically characterized. These data provide evidence for the involvement of a rhodium α-trifluoromethyl-α-alkylcarbene intermediate in the transformation.
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Reference
- A Convergent, Modular Approach to Trifluoromethyl-Bearing 5-Membered Rings via Catalytic C(sp3)–H Activation
Kai Wu, Xuyang Zhang, Liang-Liang Wu, Jie-Sheng Huang, Chi-Ming Che
