CF3- (trifluoromethyl negative ion) tends to be unstable when detached from other molecules, so the catalyst must act quickly to transfer the CF3 group before it decomposes. The MIT team chose to use a catalyst built from palladium, a silvery-white metal commonly used in catalytic converters. The MIT team is not the first to try palladium catalysis for this reaction, but the key to their success was the use of a ligand (a molecule that binds to the metal to stabilize it and hasten the reaction) called BrettPhos, which they had previously developed for other purposes.

Coming up with a useful reaction required much testing of different combinations of palladium, ligand, CF3 source, temperature and other factors. "Everything had to match up," says Senecal.

During the reaction, a CF3 group is transferred from a silicon carrier to the palladium, displacing a chlorine atom. Subsequently, the aryl-CF3 unit is released and the catalytic cycle begins anew. The researchers tried the synthesis with a variety of aryl compounds and achieved yields ranging from 70 to 94 percent of the trifluoromethylated products.

In its current state, the process is too expensive for manufacturing use. For drug discovery, however, it may lower overall costs because it streamlines the entire synthesis process. "For discovery chemistry, the price of the metal is much less important," says Kinzel.

All of the reaction components are commercially available, so pharmaceutical and other companies will immediately be able to use this method.

"This versatile new methodology is directly applicable to drug development," says John Schwab, a program director at the National Institute of Health's National Institute of General Medical Sciences, which partially funded the research. "This is a terrific example of how U.S. healthcare consumers are benefiting from their investment in NIH and in basic, biomedical research."

Source: Massachusetts Institute of Technology