Indirect Electrochemical‐Induced Trifluoromethylation of Tryptophan Containing Oligopeptides

Abstract Electrochemical synthesis in chemical biology is a milder, biocompatible, and environmentally friendly process for constructing novel types of bioconjugated systems. Herein, we report on the development of an indirect electrochemical strategy that allows a trifluoromethyl group to be incorporated into a tryptophan residue. This protocol allowed fluorinated peptides to be produced, thus allowing their characterization by 19 F‐NMR. Interestingly, the trifluoromethylation of tryptophan did not appear under conditions of direct electrolysis; instead, as we introduced ferrocene as a mediator to allow indirect electrosynthesis, the desired product could be obtained in 67% isolated yield. Furthermore, various oligopeptides are successfully coupled to the Trp residue selectively. Mechanistic studies involving CV and DFT calculations indicated that the transformation proceeds through the homo‐cleavage of CF 3 SO 2 Na via ferrocene‐mediated indirect electrolysis. Subsequently, the addition of a CF 3 radical allowed the labelled Trp to be incorporated into the corresponding products. This electrochemical protocol provides a new toolkit for the trifluoromethylation of peptides that contain tryptophan.