Mild Trifluoromethylation of Alkyl Iodides

Trifluoromethyl groups can be useful, e.g., in pharmaceutical chemistry to tune the properties of drug candidates. The trifluoromethylation of arenes and activated aliphatic compounds such as benzyl-, allyl-, and carbonyl compounds is well studied. In contrast, introducing –CF₃ groups into unactivated alkanes is considerably more challenging.

Yanchi Chen, Guobin Ma, and Hegui Gong, Shanghai University, China, have developed a cross-electrophile coupling between an alkyl electrophile and an electrophilic CF₃ species under mild conditions. The team used alkyl iodides as substrates, Togni's reagent II (pictured) as a CF₃ source, CuCl and NiCl₂glyme (glyme = dimethoxyethane) as catalysts, pyrrolidinone as an additive, B₂(nep)₂/LiOMe (B₂(nep)₂ = bis(neopentyl glycolato)diboron) as a reductant, and dimethylformamide (DMF) as the solvent. The reaction gives the desired alkyl–CF₃ products in moderate to good yields.

The reaction tolerates a variety of functional groups and has a broad substrate scope. The researchers propose a reaction mechanism involving both alkyl and CF₃ radicals, with the reaction of an alkyl–Cu complex with Togni’s reagent as a key step. According to the team, the reaction represents one of the first catalytic processes for the cross-electrophile trifluoromethylation of alkyl electrophiles.

• Copper-Catalyzed Reductive Trifluoromethylation of Alkyl Iodides with Togni's Reagent,
  Yanchi Chen, Guobin Ma, Hegui Gong,
  Org. Lett. 2018.
  https://doi.org/10.1021/acs.orglett.8b02005

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