Base-catalysed <sup>18</sup>F-labelling of trifluoromethyl ketones. Application to the synthesis of <sup>18</sup>F-labelled neutrophil elastase inhibitors

Meyer, Denise N.; González, Miguel A. Cortés; Jiang, Xiaoshun; Johansson-Holm, Linus; Lati, Monireh Pourghasemi; Elgland, Mathias; Nordeman, Patrik; Antoni, Gunnar; Szabó, Kálmán J.

doi:10.1039/d1cc03624f

Cited by 14 publications

(21 citation statements)

References 38 publications

(3 reference statements)

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“…The fluorinated silyl enol ether products are useful for further α‐functionalization, including halogenation. A notable application of this sequence by Szabó and co‐workers is the use of 18 F‐substitution of α‐iodo‐polyfluorocarbonyl intermediates to achieve isotopic labeling of trifluoromethyl ketones in bioactive molecules for PET imaging (Scheme 39b) [198] . Recently, Lennox and co‐workers developed an improved hydrodefluorination protocol via an electrochemical strategy; as illustrated in Scheme 39c, this method offers improved yields and substrate tolerance over direct use of reducing metals (e.g., Mg) [199] .…”

Section: α‐Fluorocarbonyl Defluorofunctionalizationmentioning

confidence: 99%

Synthetic Advantages of Defluorinative C−F Bond Functionalization

Hooker,

Bandar

2023

Angew Chem Int Ed

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Much progress has been made in the development of methods to both create compounds that contain C−F bonds and to functionalize C−F bonds. As such, C−F bonds are becoming common and versatile synthetic functional handles. This review summarizes the advantages of defluorinative functionalization reactions for small molecule synthesis. The coverage is organized by the type of carbon framework the fluorine is attached to for mono‐ and polyfluorinated motifs. The main challenges, opportunities and advances of defluorinative functionalization are discussed for each class of organofluorine. Most of the text focuses on case studies that illustrate how defluorofunctionalization can improve routes to synthetic targets or how the properties of C−F bonds enable unique mechanisms and reactions. The broader goal is to showcase the opportunities for incorporating and exploiting C−F bonds in the design of synthetic routes, improvement of specific reactions and advent of new methods.

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Section: α‐Fluorocarbonyl Defluorofunctionalizationmentioning

confidence: 99%

Synthetic Advantages of Defluorinative C−F Bond Functionalization

Hooker,

Bandar

2023

Angew Chem Int Ed

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“…A number of reports have demonstrated incorporation of fluorine‐18 into CF 2 H and CF 3 (Figure 1, A) [5] . For example, halogen exchange (Halex) has been utilized to generate fluorine‐18 labeled CF 2 H and CF 3 groups, most successfully with bromide leaving groups [5a–k] . The harsh reaction conditions required for exchange of C−X bonds greatly limits the scope of this approach.…”

Section: Figurementioning

confidence: 99%

“…The harsh reaction conditions required for exchange of C−X bonds greatly limits the scope of this approach. However, this exchange barrier is reduced in the presence of added Lewis acids [5f–k] . A number of groups have reported on access to copper [ 18 F]trifluoromethyl reagents that can transfer a radiolabeled CF 3 group to aryl and heteroaryl hosts [5m–s] .…”

Section: Figurementioning

confidence: 99%

Fluorine‐18 Labeling of Difluoromethyl and Trifluoromethyl Groups via Monoselective C−F Bond Activation

et al. 2022

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We report a general method for the labeling of both CF 3 and CF 2 H groups in a broad range of chemical settings (aryl, oxide, sulfide). The method utilizes frustrated Lewis pair mediated selective CÀ F activation to formally substitute fluorine-19 with fluorine-18 in a two-step defluorination/radiofluorination process, and as such can utilize the target compounds as starting materials. The radiotracer precursors can be isolated as stable salts prior to radiofluorination. The method delivers good radiochemical yields and molar activities (up to 35.2 � 6.5 % non-decay corrected isolated activity yields and 12.0 � 1.7 GBq μmol À 1 molar activities) and is shown to be applicable to biologically relevant compounds. The ability to utilize the target compound as the starting material and the synthetic simplicity of the method coupled with the ever-increasing use of CF 3 and CF 2 H groups in pharmaceuticals makes this method attractive for drug and radiotracer development.In molecular imaging, fluorine-18 (t 1/2 � 110 min) finds use as the most suitable radionuclide for positron-emission tomography (PET). [1] PET utilizes radiotracers that contain (most commonly) the positron-emitting fluorine-18 to noninvasively image biological tissue and organs in real-time. Most notably, PET is utilized in diagnostic medicine but has also found application in pharmacokinetic studies. [2] Recent attention has turned to the incorporation of fluorine-18 into difluoromethyl and trifluoromethyl groups due to their increasing presence in bioactive molecules as bioisosteres. [3] The ability to readily label CF 3 and CF 2 H groups with fluorine-18 in biologically relevant molecules for use in PET would directly benefit drug development, pharmacokinetic studies and biological imaging. [4] A number of reports have demonstrated incorporation of fluorine-18 into CF 2 H and CF 3 (Figure 1, A). [5] For example, halogen exchange (Halex) has been utilized to generate fluorine-18 labeled CF 2 H and CF 3 groups, most successfully with bromide leaving groups. [5a-k] The harsh reaction conditions required for exchange of CÀ X bonds

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“…The authors reported a moderate molar activity of 8.4 GBq/µmol for the reaction. Meyer and co-workers reported a nucleophilic halex reaction to synthesize α-CF 3 ketones [40]. The reaction used TBD (1,5,7-triazabicyclo-[4.4.0]dec-5-ene) as additive.…”

Section: Aliphatic [ 18 F]cf 3 Compoundsmentioning

confidence: 99%

Advances in [18F]Trifluoromethylation Chemistry for PET Imaging

Francis

Wuest

2021

Molecules

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Positron emission tomography (PET) is a preclinical and clinical imaging technique extensively used to study and visualize biological and physiological processes in vivo. Fluorine-18 (18F) is the most frequently used positron emitter for PET imaging due to its convenient 109.8 min half-life, high yield production on small biomedical cyclotrons, and well-established radiofluorination chemistry. The presence of fluorine atoms in many drugs opens new possibilities for developing radioligands labelled with fluorine-18. The trifluoromethyl group (CF3) represents a versatile structural motif in medicinal and pharmaceutical chemistry to design and synthesize drug molecules with favourable pharmacological properties. This fact also makes CF3 groups an exciting synthesis target from a PET tracer discovery perspective. Early attempts to synthesize [18F]CF3-containing radiotracers were mainly hampered by low radiochemical yields and additional challenges such as low radiochemical purity and molar activity. However, recent innovations in [18F]trifluoromethylation chemistry have significantly expanded the chemical toolbox to synthesize fluorine-18-labelled radiotracers. This review presents the development of significant [18F]trifluoromethylation chemistry strategies to apply [18F]CF3-containing radiotracers in preclinical and clinical PET imaging studies. The continuous growth of PET as a crucial functional imaging technique in biomedical and clinical research and the increasing number of CF3-containing drugs will be the primary drivers for developing novel [18F]trifluoromethylation chemistry strategies in the future.

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Base-catalysed ¹⁸F-labelling of trifluoromethyl ketones. Application to the synthesis of ¹⁸F-labelled neutrophil elastase inhibitors

Abstract: A new method for the fluorine-18 labelling of trifluoromethyl ketones has been developed. This method is based on the conversion of a COCF3 functional group to a difluoro enol silyl...

Cited by 14 publications

References 38 publications

Synthetic Advantages of Defluorinative C−F Bond Functionalization

Synthetic Advantages of Defluorinative C−F Bond Functionalization

Fluorine‐18 Labeling of Difluoromethyl and Trifluoromethyl Groups via Monoselective C−F Bond Activation

Advances in [18F]Trifluoromethylation Chemistry for PET Imaging

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Base-catalysed 18F-labelling of trifluoromethyl ketones. Application to the synthesis of 18F-labelled neutrophil elastase inhibitors

Abstract: A new method for the fluorine-18 labelling of trifluoromethyl ketones has been developed. This method is based on the conversion of a COCF3 functional group to a difluoro enol silyl...

Cited by 14 publications

References 38 publications

Synthetic Advantages of Defluorinative C−F Bond Functionalization

Synthetic Advantages of Defluorinative C−F Bond Functionalization

Fluorine‐18 Labeling of Difluoromethyl and Trifluoromethyl Groups via Monoselective C−F Bond Activation

Advances in [18F]Trifluoromethylation Chemistry for PET Imaging

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Base-catalysed ¹⁸F-labelling of trifluoromethyl ketones. Application to the synthesis of ¹⁸F-labelled neutrophil elastase inhibitors