C-H (radio)fluorination of hydroxamides via strained and electronically tunable α-lactams enabled by N-O scission

Positron emission tomography (PET) fluorine-18 radiosynthesis primarily relies on operationally robust, albeit scope-limited methodologies. Therefore, a marked scientific need remains for new PET-compatible labelling protocols to expand radiochemical space. In this context, α-fluoroamides are a well-established motif in drug molecules that have yet to be extensively adopted for fluorine-18 PET. Accordingly, this Article describes the nucleophilic substitution of amide α-C-H bonds with (radio)fluoride via base-mediated cyclisation of N-sulphonyloxyamides under conditions conducive to PET production. Radiolabelling proceeds with excellent radiochemical conversions (RCC, up to 91%), radiochemical purities (RCP, up to >99%), isolated radiochemical yields (RCY, up to 23%), and molar activities (A_m, up to 85.1 GBq/μmol) under manual and fully automated conditions. Divergent access to ¹⁹F-standards for imaging agent characterisation is efficiently realised under an analogous protocol, which was modified to selectively deliver α-lactams (aziridinones) with unprecedented resistance to decomposition. A fluorination mechanism involving NO scission, lactamisation, and strain-release-driven CN ionisation is proposed. These protocols provide a versatile platform for the radiosynthesis of fluoroamides with high PET production utility.