Suppressing Protodeboronation in Cu-Mediated 19F/18F-Fluorination of Arylboronic Acids: A Mechanistically Guided Approach Towards Optimized PET Probe Development.

ABSTRACT

Fluorinated arenes play a crucial role in drug discovery, specialty materials, and medical imaging. Although several variants for Cu-mediated nucleophilic fluorination of arylboronic acids and derivatives have been developed, these protocols rarely address the occurrence and control of protodeboronation, which greatly complicates product separation and can compromise the effectiveness of a radiotracer for in vivo imaging. Consequently, simpler and more efficient procedures are needed to allow rapid 18F/19F-fluorination of both arylboronic acids and esters while minimizing protodeboronation. Mechanistic controls revealed that in addition to a high temperature, strong donor ligands such as acetonitrile and pyridine accentuate a Cu-mediated protodeboronation. This observation guided the optimization of a ligandless procedure with t-BuOH as solvent to enhance the nucleophilicity of fluoride under milder conditions at lower temperatures minimizing protodeboronation. Additionally, a new copper salt, Cu(ONf)2 was employed to further improve the fluorination efficiency. A large range of functional groups are tolerated under the new procedure, which is complete within 30 minutes at a temperature of 60 °C, and affords fluorinated arenes and heteroarenes in 39% to 84% yield. With minimal modifications, the protocol can also be applied in 18F-radiofluorination, affording radiochemical conversions (RCCs) between 17-54% with minimal protodeboronation compared to previously established protocols.