Trifluoromethylated heteroatoms go with the flow

Connecting a trifluoromethyl group to an organic compound through a heteroatom such as nitrogen, oxygen, or sulfur can help chemists get the properties they want when designing small-molecule drugs or agrochemicals. But the leading methods for making those connections tend to rely on reagents that are expensive, atom inefficient, and difficult to scale up.

Timothy Noël and his team at the University of Amsterdam wanted to fix that. They developed a flow-chemistry approach to making trifluoromethylated nitrogen, oxygen, and sulfur anions from widely available precursors and attaching them to organic molecules (Science 2024, DOI: 10.1126/science.adq2954). Because the method creates the reactive fluorinated species as needed, Noël says, it cuts down on waste. “You can just make it on demand in your environment, and you’re ready to go.”

It also doesn’t use any reagents that could be considered per- and polyfluoroalkyl substances (PFAS) under proposed European Union regulations that would tightly restrict their use. Noël says this wasn’t something he and his team were specifically aiming for, but it’s “a nice collateral effect.”

The researchers started with commercially available or easy-to-make chlorinated precursors and passed them through a packed column of cesium fluoride to generate reactive trifluoromethylated anions. They then channeled the anions directly into nucleophilic substitution reactions to furnish a wide range of organic products bearing trifluoromethylated nitrogen, oxygen, or sulfur atoms. Collaborators at AstraZeneca provided the team with derivatives of drug molecules to test the new method on and make sure it would be suitable for late-stage functionalization.

The chlorinated precursors are derivatives of phosgene, a toxic gas used to manufacture plastics and pesticides, but Noël says there’s little need for alarm. These chemicals are liquids and already used in process chemistry, so chemists already know how to mitigate the risks they carry. The flow system makes it easier to manage them safely.

Fluorine chemist Tobias Ritter of the Max Planck Institute for Kohlenforschung, who was not involved in the work, calls it “an elegant solution to access valuable molecules.” He adds that it’s a great example of using flow chemistry to streamline tricky synthesis.