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Blue-light special on perfluoroalkylations

Combining photochemical synthesis with a continuous-flow reactor leads to practical kilogram-scale arene trifluoromethylations

by Stephen K. Ritter
September 26, 2016 | A version of this story appeared in Volume 94, Issue 38

Direct trifluoromethylation of aromatic rings is an important synthetic tool for chemists. Although an abundance of new methods that use less harsh reagents, have improved product selectivity, and minimize waste have been reported during the past decade, cost-effective scalable processes have remained underdeveloped. Corey R. J. Stephenson and his coworkers at the University of Michigan in collaboration with process chemistry researchers at Eli Lilly & Co. may have found a solution. The team has designed a scaled up photochemical flow reactor that employs an inexpensive reagent combination under mild conditions to produce kilogram amounts of trifluoromethylated arenes and heteroarenes (Chem 2016, DOI: 10.1016/j.chempr.2016.08.002). The researchers use 4-phenylpyridine N-oxide as a redox trigger that is activated by a blue light-absorbing ruthenium bipyridine catalyst. This photoredox system decarboxylates trifluoroacetic anhydride to generate a trifluoromethyl radical that reacts with an arene or heteroarene. Stephenson and his colleagues are able to recrystallize the crude reaction products to high purity and they have extended the reaction scope to include perfluoroethyl and perfluoropropyl products.

Reaction scheme shows trifluoromethylation of a pyrrole in a flow reactor.
Credit: Adapted from Chem


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