Nucleophilic ¹⁸F-Fluorination of Heteroaromatic Iodonium Salts with No-Carrier-Added [¹⁸F]Fluoride

Abstract

Diaryliodonium salts containing the 2-thienyl group as an example of an electron-rich heteroaromatic moiety proved to be very potent precursors for the nucleophilic, regioselective no-carrier-added (nca) radiofluorination of various arenes. It even allowed the nucleophilic introduction of nca [18F]fluoride into electron-rich arene compounds in one step. The influences of the substitution pattern, of counteranions, and of different reaction conditions were studied. Effects of counterions could be explained by the influence of solvent on ion pair separation of precursor salts. Different aryl(2-thienyl)iodonium salts were used as precursors, where the homoaromatic group systematically varied from bearing electron-deficient to electron-rich substituents. Relative rates of exchange kinetics correlated linearly with Hammett constants of the appropriate substituents confirming a nucleophilic aromatic substitution reaction of high reactivity and low selectivity.

Spirocyclic hypervalent iodine(III)-mediated radiofluorination of non-activated and hindered aromatics

“…1a, 3) [15][16][17] has been recently reviewed 18,19 . This technology has been successfully used to prepare PET radiopharmaceuticals.…”

“…However, 18 F-incorporation into the relatively electron-deficient (activated) arene is accompanied by production of undesired radioactive byproducts arising from the electron-rich aryl auxiliary. 17,20 Although diaryliodonium salts represent the most investigated class of hypervalent iodine(III) compounds in PET, there is scant patent literature 21 on how one might achieve the desired regiospecific radiofluorination based on the use of aryliodonium ylides (ArI ¼ CX 2 ; X¼ electron-deficient substituent) as precursors with Meldrum's acid auxiliaries.…”

Recent Trends in the Nucleophilic [18F]-radiolabeling Method with No-carrier-added [18F]fluoride

“…8 [36, 37]. Ross et al [38] developed heteroaromatic iodonium salts, such as aryl-(2-thienyl)iodonium salt derivatives, as precursors for regioselective nucleophilic [ 18 F]flurorination. In this report, the highly electron-rich heteroaromatic 2-thienyl group made the no-carrier-added [ 18 (Fig.…”

Mn–salen catalysed benzylic C–H activation for the synthesis of aryl [18F]CF3-containing PET probes

“…[1][2][3][4] While there has been an increase in the number of 18 F-containing pre-clinical radiotracers and new methods for the attachment of 18 F-containing prosthetic groups to target molecules, the initial incorporation of [ 18 F]fluoride is in most cases still achieved by classical nucleophilic substitution reactions (i.e., via S N 2 or S N Ar mechanisms). Recently however, protocols for the preparation of [ 18 F] aryl fluorides from aryl iodoniumsalts, [5], [6] and by the use of Pd(IV) and Ni(II) complexes, [7] [ 18 F]allylic fluorides by Pd-catalysed substitution, [ 18 F]4-fluorophenols by oxidative fluorination, [8] and [ 18 F]trifluoromethyl aromatics catalysed by copper, [9] have been described that bypass these traditional radiofluorination paradigms. Moreover, Groves et al have very recently disclosed an appealing method for direct oxidative [ 18 F]fluorination at benzylic methylene C-H positions using [ 18 F]fluoride using a Mn(salen)OTs pre-catalyst.…”