Stereospecific fluorination of bioactive N-heterocycles

Prior investigations on deoxyfluorination reactions of N-heterocyclic azepanes have led to the observation of unusual C-F bond epimerisation. It was hypothesised that a complex aziridinium-based intermediate involving both nitrogen and fluorine neighbouring group participation maybe responsible for the observed stereochemical outcomes. Experimental evidence suggested the formation of this complex intermediate is sensitive to the electron density on the nitrogen atom and the type of N-protecting group used. In this work a new, N-Benzyl protected azepane was prepared and deoxyfluorinated in order to test the validity of the hypothesized complex aziridinium-fluoronium intermediate. In the case of this N-Benzyl azepane, the deoxyfluorination proceeded through an aziridinium that does not require fluorine participation and led to the complete suppression of the C-F epimerised product. This confirms the hypothesis that the formation of the complex aziridinium-fluoronium intermediate is dependent on the nitrogen electron density. The investigation also resulted in the synthesis of a new N-Boc fluorohydrin azepane which will serve as an interesting test case for future deoxyfluorination investigations.