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Radicals break C–F bonds one at a time

Chemists can stop defluorination of CF3 to make mono- and difluorinated compounds

by Leigh Krietsch Boerner
March 4, 2021 | A version of this story appeared in Volume 99, Issue 8


Reaction of one, then a second boryl radical allows the functionalization of CF bonds with two different alkynes.

Scientists want to be able to easily add fluorines to pharmaceuticals and agrochemicals because F-containing groups can help the molecules slip through cell membranes to where they are needed. Researchers now report that they can better control the synthesis of such mono- and difluorinated molecules, making these important classes of compounds more accessible to medicinal and agricultural chemists. (Science, 2021, DOI: 10.1126/science.abg0781).

Trifluoromethyl compounds are often fluorinating agents of choice because they are inexpensive and readily available. However, past attempts to efficiently swap out just one or two of the F atoms to make mono- and difluorinated compounds with other functional groups have typically failed. Once the first C–F bond is broken, the other two get weaker. As a result, when chemists try to switch out one or two F atoms, they tend to remove all three. In the new work, Yi-Feng Wang and coworkers at the University of Science and Technology and Kendall N. Houk at the University of California Los Angeles found a way to hit the defluorination brakes for two key classes of molecules.

The trick to controlling the reaction was identifying the right radical, one that could selectively attack their trifluoroacetamide and trifluoroacetate starting materials, Wang says. The amino-boryl radical preferentially attacks the starting compound instead of mono- or difluorinated sites, Houk says, since the CF3 carbon is very electron deficient. Unlike with other defluorination reactions, once the radical breaks first C–F bond, it is less attracted to the compound, so the reaction stops before all the fluorines are gone.

The group used a radical generator and an amino borane to replace C–F bonds with C–H or C–C bonds, adding hydrogen or alkyl groups to make more than 110 mono- and difluorinated acetamides and acetates (example shown). The researchers also modified known drug molecules such as vorinostat, used to treat lymphoma, and norethindrone acetate, a treatment for endometriosis.

Precision defluorination is an important and challenging problem, says Véronique Gouverneur, a fluorine chemist at the University of Oxford. The way that Wang and Houk controlled the reaction was clever and impressive, she says.



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