The hydrogenation side-reaction in copper-mediated radiofluorination

Copper-mediated radiofluorination (CMRF) is a breakthrough in ¹⁸F-radiochemistry, enabling ¹⁸F incorporation into molecules even at electron-rich aromatic positions. In recent years, several improved protocols have been reported to advance the application of CMRF. These advancements primarily focus on improving radiochemical conversion, expanding substrate scope, and enabling scalability for remote-controlled radiotracer production. Despite these improvements, one major challenge remains: the protodemetallation. Protodemetallation is a common side reaction in transition metal-mediated cross-couplings that takes place by a mechanism that is not yet fully elucidated. In ¹⁸F-chemistry, the formation of the hydrogenated side product (HSP) can interfere with the chromatographic purification of the desired radiotracer, resulting in complex radiotracer production.

The present work investigates the factors influencing the rate of the hydrogenation reaction as well as the source of hydrogen in the CMRF by use of model precursors bearing -B(OH)₂, -Bpin, -BEpin and -SnBu₃ as leaving groups. While the CMRF reactions are usually carried out under anhydrous conditions, the formation rate of the HSP was evaluated by controlling the chemical constituents (type and molarity of reagents) as well as the physical parameters (time and temperature). Moreover, experiments with deuterated reagents complemented by high-resolution mass spectrometry (HRMS) analysis were carried out to identify the source of hydrogen for the reductive elimination step.

This study identifies reaction parameters that influence hydrogenation side reactions in CMRF, enabling high RCC with minimal HSP formation. The optimal reaction conditions include low temperature, short reaction time, and minimal amount of precursor, copper, and ideally no base and alcohols as solvents. Among the evaluated precursors, -BEpin afforded the lowest HSP formation, while -B(OH)₂ afforded the highest. Overall, this study showed that the selection of proper reaction reagents and the fine-tuning of reaction parameters can substantially reduce the HSP formation while maintaining optimal radiochemical conversion.