New reaction creates elusive N-trifluoromethyl carbonyl compounds

There’s a silver lining for chemists trying to make N-trifluoromethyl carbonyl compounds. Using silver fluoride as a key reagent, a team at RWTH Aachen University has developed a general method for making these elusive compounds, including N-trifluoromethyl amides, carbamates, thiocarbamates, and ureas (Nature 2019, DOI: 10.1038/s41586-019-1518-3).

The reaction could help medicinal chemists on the hunt for new drugs. These chemists often incorporate amides into their drug candidates because the motif can help a compound bind to its biological target. As a result, amides show up frequently in best-selling small-molecule drugs. But amides are also sites where the body’s enzymes can metabolize drug molecules. If chemists could add a trifluoromethyl group—which tends to resist biological breakdown—to an amide’s nitrogen, they might be able to make a drug last longer in the body.

Until now, making these N-trifluoromethyl amides has been tricky. Such reactions required toxic or extremely reactive reagents, like BrF₃. Also, the reactions couldn’t be performed on compounds containing reactive functional groups or stereocenters, which are common in pharmaceuticals.

The new synthetic method, developed by Franziska Schoenebeck, Thomas Scattolin, and Samir Bouayad-Gervais, uses AgF to combine an isothiocyanate with bis(trichloromethyl) carbonate. The AgF plucks the sulfur from the isothiocyanate and adds three fluorines to its carbon atom. Another AgF-catalyzed reaction with bis(trichloromethyl) carbonate forms an N-trifluoromethyl carbamoyl fluoride. Subsequent reaction of these stable N-trifluoromethyl carbonyl compounds with nucleophiles forms a range of complex N-trifluoromethyl carbonyl compounds (example shown).

“The clever combination of reagents and diverse range of targets makes this an appealing route,” says Jonathan Clayden, an expert in organic synthesis at the University of Bristol.

The challenge, he says, comes in scaling up the reaction should a drug candidate made in this manner make it to clinical trials. The large excess of silver salts used would need to be recycled efficiently. Schoenebeck points out that silver metal has a high recycling rate, which might be applied to the by-products of this reaction.