A Pharma-Friendly Fluorination

Tasked with improving the biological profile of drug candidates, medicinal chemists treasure reactions that easily slip a fluorine atom onto a molecule. That’s because the addition of this little electronegative element can keep metabolism in check, facilitate delivery to a drug target, or improve binding to that target.

But fluorination reactions are often unpredictable or impractical, employing harsh reagents that are expensive and don’t work well on large scale. Now, chemists at Massachusetts Institute of Technology have come up with a simple and predictable palladium-catalyzed fluorination reaction that converts aryl bromides and iodides to the corresponding fluorides (J. Am. Chem. Soc. 2014, DOI: 10.1021/ja5009739). The transformation, developed by Stephen L. Buchwald, Hong Geun Lee, and Phillip J. Milner, even works on nitrogen-containing heteroaryl bromides—substrates that have proven especially tough to fluorinate in the past.

The reaction makes use of a Pd catalyst, silver fluoride as a fluorinating reagent, and added potassium fluoride as a base to get the reaction going. Picking the proper ligand for the Pd catalyst is also important, Buch­wald points out. The ligand varies for arenes and heteroarenes. The researchers found a diadamantyl phosphine ligand to be effective for both types of substrates, and adding a 3'-aryl substituent to the ligand turned out to be key for heterocyclic substrates.

“A big advantage of our method is that we see almost no reduction product, that is, aryl bromide converted to arene,” Buchwald notes. “This is important because the aryl fluoride and the corresponding arene are usually impossible to separate.”

This work is a real step toward a practical solution for medicinal chemists who have struggled with fluorination reactions, according to Jin-Quan Yu, an expert in organic synthesis at Scripps Research Institute, La Jolla, Calif. “The use of a range of heteroaryl bromides and a simple fluoride source to perform fluorination is a truly remarkable breakthrough that will impact the whole pharmaceutical industry,” he says.