title: Trifluoromethylation of aryl and heteroaryl halides with fluoroform-derived CuCF3: scope, limitations, and mechanistic features.
abstract: 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 S(N)Ar and S(RN)1 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.
authors: Institute of Chemical Research of Catalonia (ICIQ), Tarragona 43007, Spain.
authors: Anton
authors: A
authors: Lishchynskyi
authors: Maxim A
authors: MA
authors: Novikov
authors: Eddy
authors: E
authors: Martin
authors: Eduardo C
authors: EC
authors: Escudero-Adán
authors: Petr
authors: P
authors: Novák
authors: Vladimir V
authors: VV
authors: Grushin
mesh_terms: D005617:Chlorofluorocarbons, Methane / Q000737:chemistry*; D003300:Copper / Q000737:chemistry*; D006846:Hydrocarbons, Halogenated / Q000138:chemical synthesis* / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry*
chemical_list: D005617:Chlorofluorocarbons, Methane; D006846:Hydrocarbons, Halogenated; D009942:Organometallic Compounds; D003300:Copper; C009554:fluoroform