Synthesis and Derivatization of 1,1‐[¹⁸F]Difluorinated Alkenes

Abstract

Ag eneral method for the synthesis of 1,1-[ 18 F]difluorinated alkenes from [ 18 F]fluoride is reported. This transformation is highly regioselective giving the desired 18 Ffluoroalkenes with radiochemical purities of up to 77 %within 20 minutes and am olar activity (A m )o f1GBq mmol À1 .T he transformations are operationally simple to perform and were readily translated onto acommercial automated synthesis unit. The resultant 1,1-[ 18 F]difluorinated alkene motif is prevalent in numerous drug molecules,a nd this is the first general method to synthesize this motif with fluorine-18. 18 F-fluorinated alkenes are excellent building blocks and participate in an umber of post-labeling transformations to access ar ange of 18 F-perfluorinated functional groups that have never before been radiolabeled with non-carrier-added [ 18 F]fluoride.T his method considerably expands the range of 18 F-motifs accessible to radiochemists.

Closing the gap between 19F and 18F chemistry

“…This radiochemistry underwent various improvements (Kramer et al 2020). In 2020, Riss and Scott implemented this protocol for the synthesis [ 18 F]N-methyl lansoprazole ([ 18 F]NML) (4.6% RCY and A m = 120.1 GBq/μmol), a candidate for Alzheimer's Tau imaging (Frost et al 2019). In 2019, Tredwell reported that 1,1-[ 18 F]difluoroalkenes (up to 77% RCY) are accessible upon 18 F-fluorination of fluoroalkenyl(aryl) iodonium triflates with [ 18 F]KF/Kryptofix ® (Fig.…”

Expanding the 18F-Radiochemical Space: Synthesis and Applications of 1,1-18F-Difluorinated Alkenes

“…identity of the aryl group. 5 Of the groups tested 4methoxyphenyl was found to give the desired 1,1-18 Fdifluoroalkene selectively with no formation of 4-[ 18 F]fluoroanisole. Addition of (2,2,6,6-tetramethylpiperodone-1yl)oxidanyl (TEMPO) was found to significantly improve the reaction (Scheme 5a).…”

“…The reduction of the 1,1-18 F-difluorinated alkene was also possible within 5 minutes at room temperature, to yield (4) in 49 ± 4 % (n = 3) RCP. Treatment of (1) with Selectfluor in water/CH3CN gave (5) in 61 ± 4 % (n = 3) RCP. The 1,3-dipolar cycloaddition of (1) with an in-situ generated azomethine, gave the 3,3-[ 18 F]difluoropyrrolidine (6) in 92 ± 3 % (n = 3) RCP.…”

“…The continued expansion in the variety of transformations with fluorine-18 available to radiochemists to include a wide range of perfluorinated motifs will help to maintain the development and increase the potential of 18 F-PET ( 18 Fpositron emission tomography) for molecular imaging applications. 4 This Synpacts article highlights our recent work detailing the synthesis and derivatization of 1,1-18 F-difluorinated alkenes 5 in the context of current methods to synthesize 18 F-perfluorinated compounds.…”

Cobalt-Catalyzed Selective Unsymmetrical Dioxidation of gem-Difluoroalkenes

“…This substructure displays unique reactivity relative to typical alkenes; specifically, the distinct electronic character of the termini enables differential functionalization of each carbon atom . Transition-metal-free and transition-metal-catalyzed reactions exploit this reactivity through selective addition of nucleophiles to the difluorinated position over the nonfluorinated position, to generate β-fluoroanionic , or β-fluoroorganometallic intermediates, which readily undergo β-fluoride elimination to generate monofluorinated products (Figure a), even under biological conditions . Though this facile β-fluoride elimination under both basic and transition-metal-catalyzed conditions enables access to monofluoroalkene-based products, the elimination reduces the synthetic utility of gem -difluoroalkenes toward accessing difluorinated products.…”