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2.6.2.1 Palladium-Catalyzed Fluorination of Aryl Trifluoromethanesulfonates

DOI: 10.1055/sos-SD-208-00368

McMurtrey, K. B.; Sanford, M. S.Science of Synthesis: Cross Coupling and Heck-Type Reactions, (20132562.

The palladium-catalyzed nucleophilic fluorination of aryl trifluoromethanesulfonates with cesium fluoride has recently been achieved. The key to the success of this transformation (where numerous related reactions have failed) is the use of the biaryl monophosphine ligand t-BuBrettPhos, in conjunction with a palladium(II) precatalyst (Scheme 8).[‌11‌] Fluorination proceeds smoothly in the presence of a number of common functional groups, including ketones, amines, nitro groups, and esters. Hetaryl trifluoromethanesulfonates derived from pyridine, quinoline, indole, and flavone are also effective substrates. Interestingly, under the standard reaction conditions (with toluene as solvent) aryl trifluoromethanesulfonates containing electron-donating methyl or methoxy substituents react to afford mixtures of regioisomeric fluorinated products. Selectivity for the desired product 15 (in which fluorine is installed at the site originally occupied by the trifluoromethanesulfonate) is enhanced dramatically by the use of less polar cyclohexane as solvent in place of toluene. This method has also been applied to a microflow packed-bed reactor, which alleviates challenges associated with the low solubility of cesium fluoride.[‌12‌]

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