# Copper-mediated electrophilic trifluoromethylation of amines

Lucile Anthore-Dalion, Alexandre Touron, Uros Todorovic, Laurent Severy, T Cantat, Emmanuel Nicolas

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Lucile Anthore-Dalion, Alexandre Touron, Uros Todorovic, Laurent Severy, T Cantat, et al. Copper-mediated electrophilic trifluoromethylation of amines. EuCOMC 2025 - XXVI European Conference on Organometallic Chemistry, Jul 2025, Berne, Switzerland. hal-05537844

HAL Id: hal-05537844

https://hal.science/hal-05537844v1

Submitted on 5 Mar 2026

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Distributed under a Creative Commons CC BY 4.0 - Attribution - International License
Copper-Mediated Electrophilic Trifluoromethylation of Amines

L. Anthore-Dalion¹, A. Touron¹, U. Todorovic¹, L. Severy¹, T. Cantat¹, E. Nicolas¹

¹Université Paris-Saclay, CEA, CNRS, NIMBE, 91191 Gif-sur-Yvette, France

Introducing trifluoromethyl groups into bioactive molecules often has a dramatic effect on their properties, which is demonstrated by the increasing number of fluorinated-approved drugs.[1] Trifluoromethyl groups are mainly introduced as C–CF₃ linkages, but O–CF₃ and S–CF₃ linkages are also found. In contrast, N-trifluoromethyl amines are rarely studied, despite the ubiquity of nitrogen-containing compounds in the pharmaceutical industry. Historically, the lack of easy-to-implement synthetic pathways toward N–CF₃ bonds partly accounted for this absence, hampering more systematic studies of their reactivity, toxicity, and degradation pathways.[2]

In this work, we took advantage of a *Umpolung* strategy, by *in situ* converting the nucleophilic amine into its corresponding electrophilic chloramine, able to react with nucleophilic sources of CF₃. While the use of the Ruppert-Prakash reagent Me₃SiCF₃[3] led only to CF₃Cl, we have demonstrated that the well-defined copper(I) complex [(phen)CuCF₃] (phen=1,10-phenanthroline), developed by the group of Hartwig as trifluoromethylating reagent,[4] formed the targeted N-trifluoromethyl amines. Experimental mechanistic studies coupled with DFT computations have explained chloramines' ambident reactivity and the intriguing regioselectivity switch observed with [(phen)CuCF₃]. These insights unveiled that single electron transfers are the key players in activating the N-Cl bond.

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<footnote>[1] Jiang Wang, Maria Sánchez-Roselló, José Luis Aceña, Carlos del Pozo, Alexander E. Sorochinsky, Santos Fustero, Vadim A. Soloshonok, Hong Liu, *Chemical Reviews* **2014**, *114*, 2432–2506.</footnote>

<footnote>[2] Stefan Schiesser, Hanna Chepliaka, Johanna Kollback, Thibaut Quennesson, Werngard Czechtizky, Rhona J. Cox, *Journal of Medicinal Chemistry* **2020**, *63*, 13076–13089.</footnote>

<footnote>[3] G. K. Surya Prakash, Andrei K. Yudin, *Chemical Reviews*, **1997**, *97*, 757-786.</footnote>

<footnote>[4] Hiroyuki Morimoto, Tetsu Tsubogo, Nichole D. Litvinas, John F. Hartwig, *Angewandte Chemie International Edition*, **2011**, *50*, 3793–3798.</footnote>