The NCF₃ and SCF₃ fluorinated motifs have attracted increasing interest in medicinal and agrochemical chemistry, but methods for introducing them at a late stage remain scarce. In their JACS paper, the researchers present how this can be achieved by combining the on-demand generation of NCF₃ and SCF₃ anions in flow, with the copper-mediated photocatalytic coupling of aryl thianthrenium salts. By generating the highly reactive fluorinated intermediates only when needed, they can be handled safely while also minimising fluorinated waste.

The study brings together the areas that have been central to the research of the Flow Chemistry group over the past years: flow chemistry, fluorine chemistry, photocatalysis, and late-stage functionalisation.

Abstract, as published with the paper

The incorporation of heteroatom-linked trifluoromethyl groups, such as N-trifluoromethyl (NCF₃) and trifluoromethylthio (SCF₃) motifs, remains challenging, particularly in the context of late-stage aryl functionalisation. Herein, we report a flow-enabled platform that allows for the late-stage installation of NCF₃ and SCF₃ groups onto aryl frameworks through the coupling of flow-generated nucleophilic heteroatom–CF₃ anions with aryl thianthrenium salts. In this strategy, readily available organic precursors are converted on demand into NCF₃ and SCF₃ anions using a CsF-packed bed reactor, allowing safe handling of highly reactive fluorinated intermediates while minimising fluorinated waste. The resulting anions are subsequently engaged in a copper-mediated, photocatalytic cross-coupling, enabling efficient formation of aryl–NCF₃ and aryl–SCF₃ bonds under mild conditions. The method exhibits broad substrate scope and functional group tolerance, and is applicable to the late-stage diversification of medicinally and agrochemically relevant molecules. Overall, this work expands the scope of nucleophilic CF₃X anions as viable partners in late-stage aryl functionalisation and provides a modular platform for the discovery-oriented synthesis of fluorinated molecules.

Paper details

Dmitrii Nagornîi, Álvaro Valdés-Maqueda, Sara Stocchetti, Nikolaos Kaplaneris, Zhen He, Jasper H.A. Schuurmans, and Timothy Noël: Late-Stage Aryl NCF₃ and SCF₃ Installation Enabled by Coupling Flow-Generated Anions with Aryl Thianthrenium Salts. Journal of the American Chemical Society, Article ASAP, DOI: 10.1021/jacs.6c04790

See also

Research group Flow Chemistry