Electrochemical Radiofluorination of Small Molecules: New Advances

Abstract

The development of new 18F‐based radiopharmaceuticals constantly demands innovations in the search for new radiofluorination methods. [18F]fluoride is the simplest and most convenient chemical form of the isotope for the synthesis of 18F‐based radiopharmaceuticals. The ease of production and handling, as well as the possibility of obtaining high molar activities, makes it the preferred choice for radiofluorination. However, the use of [18F]fluoride in late‐stage radiofluorination comes with challenges, especially for the radiolabeling of electron‐rich molecules where SN2 and SNAr reactions are not suitable. New developments in fluorination chemistry have been extensively studied to overcome these difficulties. Selective electrochemical oxidation of precursors, using a controlled potential, is one method to create reactive intermediates and overcome the activation energy required for nucleophilic fluorination of electron‐rich moieties. This method has been used for years in cold fluorination of organic molecules and more recently has been adapted as an alternative to traditional radiofluorination methods. Although relatively young, this field stands out as a promising route for the synthesis of new PET probes as well as fluorinated pharmaceuticals. This review focuses on recent advances in electrochemical radiofluorination as an alternative for the late‐stage radiolabeling of organic molecules.

The 18F‐Difluoromethyl Group: Challenges, Impact and Outlook

“…The advent of new solutions, either using new classes of substrates or novel activation strategies will continue to impact the field and emerging technologies, such as photochemistry and electrochemistry, may also play a role in future. [48] As 18 F-fluorination plays an instrumental role in the radiosynthesis of reagents for 18 F-difluoromethylation, further advances in this area have benefits across the field. Meanwhile, 18 F-difluoromethylation offers radiochemists the opportunity to exploit the large number of 19 F-difluoromethylation conditions reported in the literature.…”

“…[29] A cross-coupling of aryl boronic acids and ethyl bromofluoroacetate (5) using a Cu(I) and terpyridine (46) catalyst system was developed to prepare the α-fluoro carboxylic acid labelling precursors in a single step. The radiofluorination of such substrates (47) then proceeded with prior formation of the iodine(III) carboxylate intermediate (48) in MeCN, followed by a solvent exchange to DMF, where [ 18 F]fluoride and 45 were added. A key 18 FÀ Mn complex is proposed to form, capable of an 18 F-atom transfer to alkyl radicals generated by decarboxylation (Scheme 10b).…”

Recent Advances in Synthetic Methodologies to Form C-18F Bonds

“…The introduction of 18F into organic compounds via Photo- and Electro-catalytic methods under mind conditions is a very attractive topic ( Bui and Kim, 2021 ; Hernández-Valdés and Sadeghi, 2021 ). Using cationic organic dye 15 as a photoredox catalyst, Nicewicz and colleagues developed a series of photoredox catalytic methods to form C- 18 F bonds.…”

“…Research on 18 F-labeling by electrosynthesis provides a new direction for investigations into radiofluorination ( Waldmann et al, 2017 ; Hernández-Valdés and Sadeghi, 2021 ). Professor Sadeghi’s group studied the electrochemical fluorination of di- tert -butyl-(4- tert -butyl-1,2-phenylene)-dicarbonate ( He et al, 2015 ) and methyl (phenylthio)acetate ( Balandeh et al, 2017 ; Balandeh et al, 2018 ).…”

Electrochemical Fluorination Functionalization of gem-Difluoroalkenes with CsF as a Fluorine Source: Access to Fluoroalkyl Building Blocks

“…The convenience of adjusting electric current or potential allows electrochemical methods to achieve transformations in a short time and simple reaction system, which is highly preferred to prepare useful fluorinated/radiofluorinated precursors. However, current electrochemical fluorination mainly followed Funchigami and Inagi’s seminal work using ionic liquid fluoride (toxic and corrosive) as the electrolyte and fluorine source, which usually suffers from poor substrate scope and is hard to apply in 18 F labeling chemistry . Until now, very limited examples of electrochemical fluorination using simple fluoride salts have been achieved.…”