Palladium catalysis

Facile fluorination

The palladium-catalysed conversion of aryl bromides and triflates into aryl fluorides has been achieved.

Credit: © 2009 AAAS

Fluorinating organic molecules improves many of their properties, including solubility, bioavailability and metabolic stability, and is therefore of great importance in pharmaceuticals. Traditional methods for introducing fluorine to a molecule often require harsh conditions and electrophilic reagents, which have poor functional-group tolerance. Metal-catalysed processes using nucleophilic fluorine sources, although desirable, are hindered by the high barrier to reductive elimination for the formation of an aryl–fluoride bond. Side reactions involving the phosphine ligands and formation of stable metal dimers contribute to the difficulty of achieving aryl fluorination.

Now, Stephen Buchwald and colleagues at the Massachusetts Institute of Technology have found1 conditions suitable for aryl–fluoride bond formation by reductive elimination from a palladium(II) complex. This allowed them to develop a palladium-catalysed conversion of aryl bromides and triflates into aryl fluorides. The key finding was that sterically demanding, electron-rich monophosphines were required to promote the reaction and prevent the formation of Pd dimers.

The reaction uses nucleophilic sources of fluorine, such as CsF, and has a broad scope, including heterocycles that are of particular importance to drug development. This methodology also has the potential to be used to make radioactive 18F-labelled organic compounds that serve as contrast agents for positron emission tomography.

References

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    Watson, D. A. et al. Formation of ArF from LPdAr(F): catalytic conversion of aryl triflates to aryl bromides. Science 10.1126/science.1178239 (2009).

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Croft, L. Facile fluorination. Nature Chem (2009). https://doi.org/10.1038/nchem.389

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