Pd-Catalyzed Fluorination

Mechanism + Description

Catalytic cycle proceeds through three fundamental steps. Whereas oxidative addition and halide exchange readily proceed in this cycle, reductive elimination is challenging for this transformation owing to, i) the nature of the catalyst species in solution, ii) the high energy required to generate the C-F bond, and iii) the preference of fluoride to bond with phosphorus, which is typically present on the ligand backbone.

General comments

Some success has been reported for this transformation with the key being the use of sterically-hindered ligands to facilitate the reductive elimination, and to prevent aggregation of the catalytically-active species in solution. Initial results utilized aryl triflates as substrates with the conditions being extended to flow. Modification of the ligand enabled highly electron-rich and heteroaryl substrates to be tolerated as substrates. In-depth mechanistic studies revealed a complicated situation involving dearomative rearrangement of the catalysts taking place prior to oxidative addition. This allowed the fluorination of heteroaryl halides to be realized using a rationally designed catalyst system.

Key references

Milner, P. J.; Maimone, T. J.; Su, M.; Chen, J.; Müller, P.; Buchwald, S. L. Investigating the Dearomative Rearrangement of Biaryl Phosphine-Ligated Pd(II) Complexes. J. Am. Chem. Soc. 2012, 134, 19922-19934.

Lee, H. G.; Milner, P. J.; Buchwald, S. L. Pd-Catalyzed Nucleophilic Fluorination of Aryl Bromides. J. Am. Chem. Soc. 2014, 136, 3792-3795.

Sather, A. C.; Lee, H. G.; De La Rosa, V. Y.; Yang, Y.; Müller, P.; Buchwald, S. L. A Fluorinated Ligand Enables Room-Temperature and RegioselectivePd-Catalyzed Fluorination of Aryl Triflates and Bromides. J. Am. Chem. Soc. 2015, 137, 13433-13437.

Watson, D. A.; Su, M.; Teverovskiy, G.; Zhang, Y.; García-Fortanet, J.; Kinzel, T.; Buchwald, S. L. Formation of ArF from LPdAr(F): Catalytic Conversion of Aryl Triflates to Aryl Fluorides. Science 2009, 325, 1661-1664.

Noël, T.; Maimone, T. J.; Buchwald, S. L. Accelerating Palladium‐Catalyzed C-F Bond Formation: Use of a Microflow Packed‐Bed Reactor. Angew. Chem., Int. Ed. 2011, 50, 8900-8903.

Lee, H. G.; Milner, P. J.; Buchwald, S. L. An Improved Catalyst System for the Pd-Catalyzed Fluorination of (Hetero)Aryl Triflates. Org. Lett. 2013, 15, 5602-5605.

 

Relevant scale up examples

None found.

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