Metal-Free Oxidative Fluorination of Phenols with [~(18)F]Fluoride

摘要

Positron emission tomography (PET) is a molecular imaging technique that captures functional or phenotypic changes associated with pathology.This research field is currently fuelled by the need for conceptually new ~(18)F-radiolabeling methods to satisfy clinical demand.~(18)F-labeled aryl derivatives are highly sought after in the context of both drug and radiotracer development because of their advantageous metabolic profile for in vivo applications. The most challenging targets are aryl precursors that are not amenable to nucleophilic aromatic substitution reactions with [~(18)F]fluoride. Electrophilic fluorination is a logical strategy to access electron-rich ~(18)F-labeled aryl fluorides, but this approach is not adopted preferentially, as ~(18)F2 is difficult to handle and produced in low specific activity in comparison with [~(18)F]fluoride.t21 Electrophilic [~(18)F]N-F-type reagents of tamed reactivity have been developed, but to date they do not address the issue of specific activity.[4 The direct coupling of electron-rich aromatic compounds with [~(18)F]fluoride is a conceptually attractive alternative strategy, but notoriously difficult to implement. For reaction discovery, [~(18)F]4-fluoro-phenol is possibly the most archetypical target, as it is a versatile prosthetic group for the synthesis of complex radiopharmaceuticalsJ, and this structural submotif is thus featured in many tracers that are used clinically. Representative examples include [~(18)F]L-6-fluoro-m-tyrosine and [~(18)F]-(1R, 2S)-6-fluorometaraminol (Scheme 1). Ideally, the radi-osynthesis of [~(18)F]fluorophenol from [~(18)F] fluoride should be fast (the half-life of ~(18)F is 109.77 mins), convenient to implement, and include use of a readily accessible or commercially available precursor. A one-step (or one-pot) protocol as simple as the one developed for [~(18)F]fluorodeoxyglucose would be ideal. The methods available to date for accessing [~(18)F]fluorophenol require two steps or more with cartridge purification of intermediates.