Late-Stage Fluorination
Late-stage fluorination is particularly important for the synthesis of positron-emission tomography (PET) tracers that are often similar in structure to pharmaceuticals. Aryl fluorides are prevalent in active pharmaceuticals; yet, late-stage site-selective C–F bond formation still remains a challenge. We have described a new approach to catalysis that has enabled the first undirected transition metal catalyzed method for aromatic C–H fluorination with mild electrophilic fluorinating reagents. The reaction is enabled by a mode of catalysis that is unusual in aromatic C–H functionalization, in which a reactive transition metal fluoride electrophile is generated catalytically for controlled fluorination of arenes that do not otherwise react with mild fluorinating reagents. The scope and functional group tolerance enables the exploration of functional fluorinated molecules in pharmaceutical and agrochemical development that would otherwise not be readily accessible. Our program is characterized by careful catalyst design of novel transition metal ligand structures that combine deductive analysis with desired reactivity. Within the program, we have been able to achieve several milestones for the field, such as the first reductive elimination of a C–F bond from a transition metal complex, the first conversion of nucleophilic fluoride to an electrophilic fluorination reagent, and the application of novel transition metal fluoride complexes to the field of 18F radiochemistry. In collaborations with radiochemists and physicians, we have successfully translated our methods to hospital settings, and obtained in vivo PET images in non-human primates, as well as even validated our methods for human use at US hospitals.
Select publications:
K. Yamamoto, J. Li, J. A. O. Garber, J. D. Rolfes, G. B. Boursalian, J. C. Borghs, C. Genicot, J. Jacq, M. van Gastel, F. Neese, T. Ritter “Palladium-catalysed electrophilic aromatic C–H fluorination” Nature 2018, 554, 511–514.
C. N. Neumann, J. M. Hooker, T. Ritter “Concerted nucleophilic aromatic substitution (CSNAr) with 19F− and 18F−” Nature 2016, 534, 369–373.
E. Lee, A. S. Kamlet, D. C. Powers, C. N. Neumann, G. B. Boursalian, T. Furuya, D. C. Choi, J. M. Hooker, T. Ritter “A fluoride-derived electrophilic late-stage fluorination reagent for PET imaging” Science 2011, 334, 639–642.
M. G. Strebl, A. J. Campbell, W.-N. Zhao, F. A. Schroeder, M. M. Riley, P. S. Chindavong, T. M. Morin, S. J. Haggarty, F. F. Wagner, T. Ritter, J. M. Hooker “HDAC6 brain mapping with [18F]Bavarostat enabled by a Ru-mediated deoxyfluorination” ACS Cent. Sci. 2017, 3, 1006–1014.
DOI: 10.1021/acscentsci.7b00274
M. H. Beyzavi, D. Mandal, M. G. Strebl, C. N. Neumann, E. M. D’Amato, J. Chen, J. M. Hooker, T. Ritter “18F‑Deoxyfluorination of phenols via Ru π‑complexes” ACS Cent. Sci. 2017, 3, 944–948.
DOI: 10.1021/acscentsci.7b00195
T. Furuya, D. Benitez, E. Tkatchouk, A. E. Strom, P. Tang, W. A. Goddard, III, T. Ritter “Mechanism of C−F Reductive Elimination from Palladium(IV) Fluorides” J. Am. Chem. Soc. 2010, 132, 3793–3807.