Trifluoromethylation of Aryl and Heteroaryl Halides with Fluoroform-Derived CuCF3: Scope, Limitations, and Mechanistic Features
2013
Lishchynskyi, Anton | Novikov, Maxim A. | Martin, Eddy | Escudero-Adán, Eduardo C. | Novák, Petr | Grushin, Vladimir V.
Fluoroform-derived CuCF₃ recently discovered in our group exhibits remarkably high reactivity toward aryl and heteroaryl halides, performing best in the absence of extra ligands. A broad variety of iodoarenes undergo smooth trifluoromethylation with the “ligandless” CuCF₃ at 23–50 °C to give the corresponding benzotrifluorides in nearly quantitative yield. A number of much less reactive aromatic bromides also have been trifluoromethylated, including pyridine, pyrimidine, pyrazine, and thiazole derivatives as well as aryl bromides bearing electron-withdrawing groups and/or ortho substituents. Only the most electrophilic chloroarenes can be trifluoromethylated, e.g., 2-chloronicotinic acid. Exceptionally high chemoselectivity of the reactions (no side-formation of arenes, biaryls, and C₂F₅ derivatives) has allowed for the isolation of a large number of trifluoromethylated products in high yield on a gram scale (up to 20 mmol). The CuCF₃ reagent is destabilized by CuX coproduced in the reaction, the magnitude of the effect paralleling the Lewis acidity of CuX: CuCl > CuBr > CuI. While SNAr and SRN1 mechanisms are not operational, there is a well-pronounced ortho effect, i.e., the enhanced reactivity of ortho-substituted aryl halides 2-RC₆H₄X toward CuCF₃. Intriguingly, this ortho-effect is observed for R = NO₂, COOH, CHO, COOEt, COCH₃, OCH₃, and even CH₃, but not for R = CN. The fluoroform-derived CuCF₃ reagent and its reactions with haloarenes provide an unmatched combination of reactivity, selectivity, and low cost.
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