Fluorine-containing compounds are useful, e.g., in pharmaceutical and materials chemistry. Often, trifluoromethyl (CF₃) groups are used. C(sp²)–H trifluoromethylation reactions, for example, can be used to introduce CF₃ groups into aromatic compounds. This type of reaction can be performed using trifluoromethyl radicals, but this approach generally has a low regioselectivity. Nucleophilic reactions could offer an alternative pathway. For pyridine derivatives, for example, there are methods for 2- and 4-position-selective nucleophilic trifluoromethylations. Trifluoromethylation at the C3 position of pyridines had remained challenging.

Yoichiro Kuninobu, Kyushu University, Fukuoka, Japan, and colleagues have developed a 3-position-selective C(sp²)–H trifluoromethylation of pyridine derivatives. The team used a hydrosilylation reaction to activate the substrates, followed by a reaction with nucleophilic CF₃ sources such as Togni Reagent I. They functionalized a variety of quinoline and pyridine derivatives by first reacting them with methylphenylsilane in the presence of tris(pentafluorophenyl)borane in 1,2-dichloroethane at 65 °C. Then the hydrosilylated intermediates were reacted with Togni Reagent I at 0–25 °C and with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) at 25 °C to give the desired products.

The 3-trifluoromethylated products were obtained in moderate to high yields and with high regioselectivity. This method was also used for the introduction of perfluoroalkyl groups at the 3 position of pyridine derivatives and for the late-stage trifluoromethylation of a bioactive compound.

• 3-Position-Selective C–H Trifluoromethylation of Pyridine Rings Based on Nucleophilic Activation,
  Ryuhei Muta, Takeru Torigoe, Yoichiro Kuninobu,
  Org. Lett. 2022.
  https://doi.org/10.1021/acs.orglett.2c03327