Photo- and Cu-Mediated ¹¹C Cyanation of (Hetero)Aryl Thianthrenium Salts

Abstract

We present a photo-and Cu-mediated 11 C cyanation of benchstable (hetero)aryl thianthrenium salts via an aryl radical addition pathway. The thianthrenium substrates can be readily accessed via C−H functionalization, and the radiocyanation protocol proceeds under mild conditions (<50 °C, 5 min) and can be automated using open-source, readily accessible augmentations to existing radiochemistry equipment.

Organosilicon Precursors for Efficient Aromatic Copper-Mediated Radiocyanation

“…Indeed, difluoro(methyl)(aryl)silanes have been used as cross-coupling partners in other systems and are readily synthesised from dialkoxy(methyl)(aryl)silanes and HF in EtOH (Scheme 5C). 50,51 Notably, the analytical purity of NMe4F•4H2O was confirmed by 1 H and 19 F NMR in D2O. However, samples dissolved in DMF-d 7 displayed major and minor signals corresponding to NMe 4 HF 2 and NMe 4 F, respectively, demonstrating that HF is feasibly liberated under the reaction conditions.…”

“…For example, the reaction of 1-(OTMS)2Me with NMe4F•4H2O dissolved in DMF-d 7 in a sealed tube at 80 °C for 1 h gave quantitative protodesilylation to benzene (Scheme 5A). Neither FSiMe3 nor F2SiMe3, corresponding to deprotection of the trimethylsilyl groups, were detected by 1 H/ 19 Therefore, it was hypothesised that 1-(OTMS)2Me undergoes substitutive fluorination at the Si(I) atom to form a transmetallation-active intermediate. On this basis, the enhanced activity of 1-(OTMS)2Me vs structurally related silanes that exhibit radiolabelling incorporation, such as may be attributed to the enhanced nucleofugality of trimethylsilanolate (pKa(R3SiOH) ≈ 11) vs aliphatic alcohols (pKa(EtOH) = 16).…”

“…Analysis of the radiolabelling reaction mixture using 1-(OTMS)2Me via rHPLC indicated the formation of an unknown major side-product of comparable polarity to 1- 11 used in other aryl silane cross-coupling reactions, such as KOTMS, were inadequate substitutes for NMe4F•4H2O (Entry 17). Finally, by increasing the temperature to 100 °C, efficient conversions were obtained using 10 µmol 1-(OTMS)2Me, and the addition of Et3SiF provided a modest boost to conversion whilst improving solution homogeneity for improved automation compatibility in DMA or DMF (Entries 18,19).…”

“…However, samples dissolved in DMF-d 7 displayed major and minor signals corresponding to NMe 4 HF 2 and NMe 4 F, respectively, demonstrating that HF is feasibly liberated under the reaction conditions. 52 Although 1-F2Me is a stable compound in solvents like CDCl3, dissolution in anhydrous DMF-d 7 at room temperature immediately initiates slow defluorination observable by 1 H and 19 F NMR. This suggests that 1-F2Me may only be transiently generated under the optimised radiolabelling conditions and, therefore, challenging to detect.…”

“…Still, precursor stability, accessibility, and engineering challenges complicate the clinical adoption of these systems. 18,19 Consequently, the current optimisations, utilisations, and focus of copper-mediated radiolabelling centres on the polar Cu II /Cu III radiolabelling system using transmetallation-active precursors. However, research efforts have yet to address multiple drawbacks that hinder streamlined (pre)clinical utilisation of these procedures.…”