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Flexible Fluorination

Pd-catalyzed reaction adds fluorine to a wide variety of substrates

by Carmen Drahl
August 17, 2009 | A version of this story appeared in Volume 87, Issue 33

Credit: Courtesy of Donald A. Watson
The bulkiness of the phosphine ligand in Buchwald's Pd catalysts is evident in this X-ray structure.
Credit: Courtesy of Donald A. Watson
The bulkiness of the phosphine ligand in Buchwald's Pd catalysts is evident in this X-ray structure.

With the help of a bulky ligand, chemists have devised a versatile new reaction for installing fluorine atoms on aromatic rings. The advance could have a big impact on the synthesis of pharmaceuticals, agrochemicals, and radiolabeled agents for medical imaging applications.

Facile Fluorides
The new reaction works on a wide range of aryl triflates.
The new reaction works on a wide range of aryl triflates.

Fluorine atoms abound in drugs because they can favorably alter compounds’ metabolic stability or other properties in the body. But getting fluorine into a molecule easily, selectively, and safely is often still a challenge.

Now, chemistry professor Stephen L. Buchwald, postdoctoral associate Donald A. Watson, and colleagues at Massachusetts Institute of Technology have developed a palladium-catalyzed reaction that replaces a triflate group on an aromatic ring with a fluorine atom (Science, DOI: 10.1126/science.1178239). The reaction works with catalytic amounts of Pd 
and does not require directing groups. Other metal-mediated routes to aryl fluorides possess just one of those attributes—Buchwald’s is the first to feature both. The procedure works on a range of triflate substrates, including highly functionalized triflates derived from the natural product quinine and the dye fluorescein.

Furthermore, the reaction employs simple, nucleophilic fluorine sources such as cesium fluoride. Some other fluorinations employ electrophilic fluorine sources, which tend to be expensive and unstable, Buchwald explains. “For 18F radiochemists, this is a breakthrough conceptual advance as nucleophilic 18F fluoride is widely available and is the preferred reagent to produce 18F radiotracers,” says Véronique Gouverneur of the University of Oxford, who also develops new tactics for making radiotracers.

Key to the new method is a pair of bulky, electron-rich phosphine-containing ligands developed by the Buchwald group. These ligands are thought to promote efficient carbon-fluorine bond formation from a Pd(II) center. Pioneering work by Vladimir V. Grushin of DuPont has demonstrated that such bond formations are notoriously difficult, Buchwald says. Other groups have tried to use phosphine ligands to promote the reaction without much success or have opted to form C–F bonds via a Pd(IV) center instead.

This work surmounts the challenges and is “a beautiful testament to how ancillary ligands can be exploited to modify the ‘typical’ reactivity of metal complexes,” says organometallic chemist Melanie S. Sanford of the University of Michigan, Ann Arbor.

The new reactions must be set up in a glove box because they are sensitive to water. By exploring other ways to dry the fluorine source, the group hopes to move past that limitation, says Watson, who is now an assistant professor of chemistry at the University of Delaware. It’s not yet clear whether water sensitivity is related to the catalytic reaction. If that turns out to be the case, it may be possible to design ligands that fix the problem, he says. The team has submitted a patent application for the reaction, he adds.

“Over the past several years, the Buchwald group has redefined what is possible in cross-coupling chemistry by developing new classes of ligands for palladium catalysis, and this new carbon-fluorine bond formation is a dramatic example,” says organic chemist Eric N. Jacobsen of Harvard University. “This work is certain to find immediate application in pharmaceutical research,” he adds.


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