Minimalist approach meets green chemistry: Synthesis of¹⁸F‐ labeled (hetero)aromatics in pure ethanol

Abstract

The application of toxic solvents and additives is inevitable for most of the described protocols for 18F‐labeling. Herein, a novel “green” procedure for nucleophilic aromatic radiofluorination of highly activated (hetero)aromatic substrates in pure EtOH is described. Using this method a series of 18F‐labeled (hetero)arenes have been synthesized in radiochemical yields (RCYs) of up to 97%.

Late-Stage Copper-Catalyzed Radiofluorination of an Arylboronic Ester Derivative of Atorvastatin

“…Additionally, it is also beneficial to not let the [(Krypt-2.2.2)K + ][ 18 F]F − solution completely evaporate (3 azeotropic drying cycles with 0.5 mL anhydrous acetonitrile, each one starting after the previous volume has almost vanished, followed by the dilution with 100 µl of anhydrous DMA immediately after the last cycle has nearly evaporated completely and the further addition of the remaining solvent with the precursor ( 6 ) and [Cu(OTf) 2 (py) 4 ]). To circumvent the downsides of azeotropic evaporation, especially when automated where manipulation and close control of the conditions are challenging, a few solid-phase extraction (SPE) drying procedures have been rising in the literature [21,27,28,30], some even able to avoid the use of bases [29]. However, being very recent, they still lack a proper multicentre evaluation and assessment into more than just simple (hetero)arenes, as some authors claim not being able to reproduce them [38] and when attempted by us for the 18 F-fluorination of the arylboronic ester derivative of atorvastatin ( 6 ), invariably led to no detectable [ 18 F]F − conversion (despite shown to be successful when tested first in some of the same simple aryl boronic acid esters used in our previous work [39]).…”

“…Therefore, a case-by-case optimization still seems to be necessary, being extremely difficult to reach a standardized procedure for every labeling precursor, which might explain the reason why the exact same methodology has been very rarely repeated in the literature. An analysis through the Cu-mediated works published, and hereby referenced [15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39], shows that [Cu(OTf) 2 (py) 4 ] is still by far the most common catalyst used (against other options such as Cu(OTf) 2 , Cu(OTf) 2 (associated with diverse pyridine derivatives), or Cu(CF 3 SO 3 ) 2 ), and the typical amounts for all of them are between 5 to 30 µmol while the Bpin labeling precursor may vary from 4 to 60 µmol. The reaction temperatures are usually kept around 120 °C ± 10 °C while anhydrous DMA and dimethylformamide (DMF) are the solvents almost exclusively reported, with the first one having the propensity for better conversion efficacies [39] which can arguably be due to its higher boiling point and resistance to bases.…”

“…One of these strategies, the late-stage copper-mediated oxidative 18 F-fluorination of arylboronic ester and acid derivatives, has received great attention from radiochemistry research groups but is still not routinely applied in the production of clinical PET radiopharmaceuticals. Numerous basic-research proposals for improving this Cu-catalyzed reaction have been successfully reported and conceptualized with simple heteroaromatic groups [15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33], but advanced applications to more complex molecules with potential clinical value are sparse and generally reveal very fluctuating 18 F-fluorination efficiencies [33,34,35,36,37,38]. Following previous work from our group [39], where we applied this Cu-mediated strategy to several structurally different drug-like molecules and investigated the influence of a range of temperature, solvents, catalyst, and precursor amounts, we aimed to go up in terms of complexity, applicability, and relevance.…”

Strained Ammonium Precursors for Radiofluorinations

“…The combination of using azetidinium salts as precursors and the minimalist approach for radiofluorinations was highlighted in a work of Omrane [103] . This approach is based on the use of ammonium salts as precursors to avoid phase transfer catalysts and additives like Kryptofix K222 for the radiolabelling process with fluorine‐18 [104] . spiro ‐Ammonium salts are therefore the ideal precursors.…”

Alcohol-Supported Cu-Mediated 18F-Fluorination of Iodonium Salts under “Minimalist” Conditions

“…The efficacy of Cu-mediated 18 F-fluorination in alcoholic media markedly contradicted previous observations concerning the deleterious effect of protic solvents, including alcohols, on S n Ar fluorination. Noteworthy, quite recently the efficient metal-free 18 F-fluorination of electron-deficient (hetero)aromatics in pure EtOH was published [24]. Herein, we disclose a novel evaporation step free protocol for Cu-mediated radiofluorination of (aryl)(mesityl)iodonium salts which combines advantages of the “alcohol-enhanced” with the “minimalist” approach.…”