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Golden ticket to trifluoromethylations

Borane catalyst and gold reagent forge C–CF3 bonds, opening another route to radiotracers

by Bethany Halford
June 22, 2017 | A version of this story appeared in Volume 95, Issue 26

An illustration of the multistep synthesis of leflunomide.
Synthesis of the rheumatoid arthritis drug leflunomide (Arava) features a new trifluoromethylation reaction.

Medicinal chemists love to add trifluoromethyl groups to drug candidates. The substituents are roughly the size of a milquetoast methyl, but the C–F bonds make the moieties resistant to metabolism, helping compounds to circulate longer in the body.

Now, chemists led by F. Dean Toste at the University of California, Berkeley, report a new method for adding trifluoromethyl substituents to molecules. Working in collaboration with researchers at Lawrence Berkeley National Laboratory, led by James P. O’Neil, the chemists adapted the reaction to make molecules with one 18F in the trifluoromethyl group, creating a new method for making radiolabeled compounds for positron emission tomography (PET).

The reaction uses a tris(pentafluorophenyl)borane catalyst and stoichiometric amounts of a gold complex to generate the trifluoromethylated product (Science 2017, DOI: 10.1126/science.aan1411). The gold complex tolerates a wide range of reactions, including aluminum hydride reduction, Simmons-Smith cyclopropanation, osmium-catalyzed dihydroxylation, periodate-mediated diol cleavage, and palladium-catalyzed cross-coupling—all without rupturing the Au–C bond. The complex even withstands the harsh reaction conditions of aromatic nitration when used to synthesize the rheumatoid arthritis drug leflunomide (Arava).

The Berkeley chemists discovered the trifluoromethylation serendipitously when they were trying to do a different reaction. Observing that they’d made a trifluoromethylated product, they decided to look into the mechanism of this unexpected transformation. They figured out that the trifluoromethyl group loses and regains a fluoride during the course of the reaction—a so-called fluoride rebound mechanism.

“The fluoride rebound made it clear that we had an opportunity to do something new in the radiochemical arena,” says the report’s first author Mark D. Levin. Working with O’Neil’s team, they determined they could use radiolabeled potassium fluoride and a cryptand to swap the 18F into their trifluoromethylated products. At the moment, the radiolabeling reaction is limited to trifluoromethylating sp3 carbons, but the chemists hope to make it work for radiolabeling aromatic trifluoromethyl compounds as well.

“None of us started this project with PET in mind,” Levin says. “But now, because we stopped to investigate an unexpected result, we have a platform from which we can start to develop new tracers, not to mention a new mechanism to help us think about synthetic problems.”

“The paper is a beautiful combination of novel reactivity and useful application,” comments Tobias Ritter, an organofluorine chemistry expert at the Max Planck Institute for Kohlenforschung. It’s “a great example of how an unusual discovery can open the doors for valuable reaction chemistry, if you think carefully about it.”

This article has been translated into Spanish by and can be found here.



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