Letter Cite This: Org. Lett. 2019, 21, 60−64
pubs.acs.org/OrgLett
Iridium-Catalyzed Radiosynthesis of Branched Allylic [18F]Fluorides Jason C. Mixdorf,∥,‡ Alexandre M. Sorlin,∥,‡ David W. Dick,*,§ and Hien M. Nguyen*,† †
Department of Chemistry, Wayne State University, Detroit, Michigan 48202, United States Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, United States § University of Iowa Hospitals and Clinics, University of Iowa, Iowa City, Iowa 52242, United States ‡
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ABSTRACT: The rapid and operationally simple radiosynthesis of branched allylic [18F]fluorides bearing a variety of functional groups, via iridium-catalyzed nucleophilic substitution reaction utilizing allylic trichloroacetimidates and [18F]KF·Kryptofix[2.2.2] complex in 5−15 min at room temperature, is reported. The versatility of the allyl functional group of the resulting radiofluorinated products offers the benefit of being subsequently available for further functionalization.
M
ethods that enable the rapid and efficient introduction of fluorine-18 into molecules are powerful applications in positron emission tomography (PET). Radiotracer-based imaging for qualitative and quantitative assessment of disease state is one of the most rapidly growing areas of noninvasive medical imaging.1−5 Presently, PET has been used in diagnosis of various cancers, cardiovascular diseases, and early stage neurological disorders.2−5 Measuring physiochemical and biochemical processes with PET requires radiotracers labeled with a positron-emitting radionuclide. Commonly used radioisotopes are carbon-11 and fluorine-18.6 Although the ubiquitous presence of carbon in many molecules makes carbon-11 an attractive isotope, its 20 min half-life and complicated radiometabolite analysis limits its clinical utility.6 Alternatively, fluorine-18 is an equally ideal isotope due to its low positron emission energy, 110 min half-life, and its ability to serve as an isostere for hydrogen or hydroxyl group. Furthermore, a considerable portion of drugs in clinical and preclinical trials contain a carbon−fluorine (C−F) bond, making fluorine-18 an ideal choice for imaging applications.7 The use of transition metals and new [18F] reagents has proven to be a powerful technique to expand the substrate scope, including [18F]aryl,8−21 [18F]benzylic,22,23 and [18F]aliphatic fluorides.18−21,24,25 Despite these advances, allylic C[18F] bond formation via transition metal catalysis remains challenging.26 This is likely because metals are known to insert onto the allylic fluorides,27 a major concern in radiofluorination when metal content is in 100−1000-fold excess over the allylic [18F]fluoride product. Not surprisingly, there are only two reports on the synthesis of allylic [18F]fluorides utilizing allylic carbonates as electrophilic partners under palladium- and iridium-mediated fluorination (Figure 1a− b).28,29 The scope of these two methods has only been investigated with four allylic carbonates, demonstrating the difficulty forming allylic [18F]fluorides. The broad success of the transition-metal-catalyzed formation of allylic [18F]fluorides has hinged on the ability to © 2018 American Chemical Society
Figure 1. Transition-metal-mediated allylic radiofluorination
identify suitable electrophilic partners to enable radiofluorination in high efficiency. An attractive option is to use a trichloroacetimidate leaving group whose nitrogen functionality can be exploited as a directing group in transition-metalcatalyzed allylic substitution.30 We discovered that combining allylic trichloroacetimidates as electrophiles, Et3N·3HF as a fluoride source, and iridium complexes led to the production of the branched allylic fluorides in good yields and excellent selectivity.31−33 We hypothesize that this method can be adapted with the radioisotope fluorine-18. Herein, we report an operationally simple, rapid, and stable procedure for the synthesis of allylic [18F]fluorides (Figure 1c) in 5−15 min at 25 °C utilizing [IrMeO(COD)]2 as a catalyst. The significance of this catalytic protocol allows rapid access to numerous allylic [18F]fluorides bearing a variety of functional groups and overcomes the limitations previously associated with the radiosynthesis of this [18F]fluoride motif. Received: November 1, 2018 Published: December 21, 2018 60
DOI: 10.1021/acs.orglett.8b03496 Org. Lett. 2019, 21, 60−64
Letter
Organic Letters Table 1. Optimized Reaction Conditionsa
entry
catalyst
catalyst loading (mol %)
solvent
temp (°C)
time (min)
RCC %b
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
[IrCl(COD)]2 [RhCl(COD)]2 [RhCl(NBD)]2 [IrMeO(COD)]2 None [IrMeO(COD)]2 [IrMeO(COD)]2 [IrMeO(COD)]2 [IrMeO(COD)]2 [IrMeO(COD)]2 [IrMeO(COD)]2 [IrMeO(COD)]2 [IrMeO(COD)]2 [IrMeO(COD)]2 [IrMeO(COD)]2
15 15 15 15 15 15 15 15 15 7.5 22.5 30 15 15 15
THF THF THF THF THF CPME MTBE CH3CN THF THF THF THF THF THF THF
25 25 25 25 25 25 25 25 25 25 25 25 25 25 40
10 5 5 5 5 5 5 5 5 5 5 5 15 25 5
5−12c 0c 2.5 ± 0.5d 33 ± 1d 0c 26 ± 6d 29 ± 5d
