Mild and Efficient Palladium‐Catalyzed Direct Trifluoroethylation of Aromatic Systems by C−H Activation

Abstract

The introduction of trifluoroalkyl groups into aromatic molecules is an important transformation in the field of organic and medicinal chemistry. However, the direct installation of fluoroalkyl groups onto aromatic molecules still represents a challenging and highly demanding synthetic task. Herein, a simple trifluoroethylation process that relies on the palladium-catalyzed C-H activation of aromatic compounds is described. With the utilization of a highly active trifluoroethyl(mesityl)iodonium salt, the developed catalytic method enables the first highly efficient and selective trifluoroethylation of aromatic compounds. The robust catalytic procedure provides the desired products in up to 95 % yield at 25 °C in 1.5 to 3 hours and tolerates a broad range of functional groups. The utilization of hypervalent reagents opens new synthetic possibilities for direct alkylations and fluoroalkylations in the field of transition-metal-catalyzed C-H activation.

A comprehensive overview of directing groups applied in metal-catalysed C–H functionalisation chemistry

“…The group of Novak disclosed a Pd catalysed protocol for the trifluoroethylation of N -aryl-anilides with an iodonium salt ( Scheme 24G ). 200 The introduction of fluorine moieties onto molecules is of course highly interesting in context of medicinal chemistry projects and drug development. The protocol showed high yields (typically >70% and up to 95%) and remarkable FG tolerance.…”

Progress on Trifluoroethylation Reactions Using Aryl(trifluoroethyl)iodonium Salts

“…[22] A simple Pd-catalyzed C-H trifluoroethylation of anilides using mesityl(trifluoroethyl)iodonium triflate as CH 2 CF 3 reagent was described by Novák and coworkers (Scheme 21). [23] The preliminary study showed that the stoichiometric reaction of mesityl(trifluoroethyl)iodonium triflate with the trifluoroacetate-bridged dimeric complex of 2-methylacetanilide and palladium rapidly formed the ortho-trifluoroethylated product in 76% yield. [23] Based on this, the catalytic procedures were investigated.…”

“…[23] The preliminary study showed that the stoichiometric reaction of mesityl(trifluoroethyl)iodonium triflate with the trifluoroacetate-bridged dimeric complex of 2-methylacetanilide and palladium rapidly formed the ortho-trifluoroethylated product in 76% yield. [23] Based on this, the catalytic procedures were investigated. Various anilides reacted with [MesICH 2 CF 3 ][OTf] at 25 ℃ for 1.5～3 h in the presence of 1～3 equivalents of 2,2,2-trifluoroacetic acid (TFA) to afford the desired ortho-trifluoroethylated products in good yields.…”

Mild Palladium Catalyzed ortho C‐H Bond Functionalizations of Aniline Derivatives

“…Recently, we developed a novel, effective and mild method for trifluoroethylation on N ‐aryl amide derivatives in ortho position with the aid of simple palladium acetate. (Scheme ) …”