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A milder, more general approach to deoxyfluorinations

Latest method converts phenols to aryl fluorides, with benefits for pharmaceuticals and agrochemicals

by Stephen K. Ritter
January 25, 2017 | A version of this story appeared in Volume 95, Issue 5

A reaction scheme shows deoxyfluorination of phenols via aryl fluorosulfonate intermediates.
This one-pot deoxyfluorination method generates a diverse range of aryl fluorides.

It’s no secret that adding fluorine to bioactive molecules such as pharmaceuticals and agrochemicals can enhance their effectiveness. The trick for chemists has been to fluorinate molecules using inexpensive reagents that operate under mild conditions and to do so on a useful scale.

A research team including Sydonie D. Schimler, Megan A. Cismesia, and Melanie S. Sanford at the University of Michigan, working in collaboration with process chemists at Dow Chemical, is now reporting success in meeting all those goals for the deoxyfluorination of phenols, an important reaction for making aryl fluorides (J. Am. Chem. Soc. 2017, DOI: 10.1021/jacs.6b12911).

“Plenty of interesting and useful arene fluorination reactions have recently been developed,” says Tobias Ritter of Harvard University and the Max Planck Institute for Kohlenforschung. Ritter’s group, for instance, has developed the PhenoFluor family of fluoroimidazole deoxyfluorinating reagents. “But this new one stands out by its simplicity and also the low cost of the fluorinating reagents, which will make it very useful,” he says.

Other methods chemists use for preparing aryl fluorides are aromatic substitution of aryl chlorides with metal fluorides, palladium-catalyzed fluorination of aryl triflates, and treatment of phenols with deoxyfluorinating reagents such as phenylsulfur fluorides or fluoroimidazoles. But those methods each have limitations, including cost, low stability, poor functional group selectivity, and the need for an auxiliary reagent such as a base.

The Michigan-Dow team continued looking for a better way, which they found via aryl fluorosulfonate intermediates. The team first discovered that treating aryl fluorosulfonates bearing either electron-withdrawing or electron-donating substituents with tetramethylammonium fluoride, (CH3)4NF, is a straightforward way to prepare a broad array of fluoride derivatives, often at room temperature.

Taking a step back, the researchers then found that the aryl fluorosulfonates could be generated and fluorinated in the same reaction vessel by treating phenols with sulfuryl fluoride, SO2F2, and then (CH3)4NF. The end result is a one-pot, catalyst-free deoxyfluorination process to convert phenols to aryl and heteroaryl fluorides, including analogs of commercial drugs and herbicides.

“The partnership with Melanie has been an excellent example of how academia and industry are able to collaborate to develop a simple, novel, and effective solution to a long-standing problem in fluorination chemistry,” says James W. Ringer, operations and R&D lead technology director for Dow Chemical.

“This approach to deoxyfluorination of phenols from the Sanford lab represents a major advance in that it enables access to electronically diverse aryl fluorides from simple, commodity chemicals under mild conditions,” adds Abigail G. Doyle of Princeton University, whose group developed the pyridinesulfonyl fluoride deoxyfluorinating reagent called PyFluor. Doyle notes that one limitation of the new approach could be the sensitivity of the reaction to moisture. “Nevertheless, the method has significant industrial relevance given its scalability.”



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