Aqueous Benzylic C-H Trifluoromethylation for Late-Stage Functionalization

Abstract

The installation of trifluoromethyl groups has become an essential step across a number of industries such as agrochemicals, drug discovery, and materials. Consequently, the rapid introduction of this critical functional group in a predictable fashion would benefit current practitioners in those fields. This communication describes a mild trifluoromethylation of benzylic C-H bonds with high selectivity for the least hindered hydrogen atom. The reaction provides monotrifluoromethylation and proceeds in an environmentally friendly acetone/water solvent system. The method can be used to install benzylic trifluoromethyl groups on highly functionalized drug molecules.

Figure 1.

The switch from aromatic bromination (a) to benzylic bromination (b) requires relatively minor changes to the reaction conditions. The modern switch from aromatic trifluoromethylation (c) to benzylic trifluoromethylation (d) has yet to be realized.

Figure 2.

Computed energy profile of C−H selectivity. Bipyridineligated Cu illustrated here possessed the highest energy barriers relative to water- or unligated Cu.

Figure 3.

Mechanistic details.

Scheme 1.. Late-Stage C−H Trifluoromethylation of Bioactive Molecules

^aThe reactions were run on 0.3 mmol scale with substrate (0.6 mmol) and 2a (0.3 mmol) in 3.0 mL of solvent for 18 h unless otherwise noted. Isolated yield.^b10 equiv of TFA was used.