Synthesis: Copper-mediated trifluoromethylation


The introduction of fluorine in the course of a lead optimisation programme has become a key tool in the medicinal chemist’s armoury and many drug candidates incorporate one or more fluorine atoms.  Two reviews published in 2008 in J.Med.Chem. and Chem.Soc.Rev. nicely summarise many of the key aspects attributed to the use of fluorine in drug design.

Trifluoromethyl groups, being strongly electron-withdrawing and also often resistant to oxidative metabolism, can have dramatic effects on the properties of bioactive molecules.  Until recently no general, mild methodology for the direct introduction of these groups was available and more often than not they were introduced by using appropriately substituted building blocks.  Last year, Buchwald’s group published the first example of a palladium catalysed trifluoromethylation of aryl chlorides which went some way to addressing this deficit and now Xiao’s group in Shanghai have published an alternative complementary method in which aryl iodides are readily converted to the corresponding trifluoromethyl derivatives using the combination of a (trifluoromethyl)diphenylsulfonium salt and copper.

The reactions proceed under mild conditions and the trifluoromethylated products are obtained in high yields.  The methodology appears to be tolerant of a range of functionality and works well on heterocyclic systems (see examples above).  The authors propose that CuCF3 is the active intermediate in these reactions and outline a possible mechanism for its production (see below) under the reaction conditions.

Update (13/3/2011): A more recent protocol from Buchwald also makes use of a copper catalyst to promote room temperature aryl trifluoromethylation of boronic acids.

Update (30/3/2011): Hartwig has now also published on the use of another copper-based reagent for the trifluoromethylation and perfluoroalkylation of aryl iodides and bromides.

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2 Responses to Synthesis: Copper-mediated trifluoromethylation

  1. The Hartwig trifluoromethylation reagent described above is being developed by Catylix, Inc. and is now available commercially: http://www.catylix.com/catylix-licenses-hartwig-trifluoromethylation-technology.html

  2. Aldrich has a Technology Spotlight page now up providing more information about the HArtwig trifluoromethylation reagent: (Phen)Cu-CF3. The reagent is shelf-stable and shows exceptional functional group compatibility. Here is the link to the Tech Spotlight page at Aldrich: http://www.sigmaaldrich.com/chemistry/chemical-synthesis/technology-spotlights/trifluoromethylation.html

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