Late-Stage C(sp³)–H Functionalization of Bioactive Piperazines

We describe a late-stage C–H functionalization strategy that enables rapid access to α- and/or β-substituted analogues of piperazine-based pharmaceuticals. Despite significant advances in C(sp³)–H functionalization of saturated N-heterocycles, selective transformation of piperazine C–H bonds remains challenging due to the presence of two Lewis-basic nitrogen centers. Here, we show that a photoexcited flavin analogue under blue-LED irradiation promotes sequential α- and β-C–H bond cleavage in both N-alkyl and N-aryl piperazines. The resulting alkene intermediates can be intercepted by a range of electrophiles and/or nucleophiles to deliver diverse structural derivatizations. This operationally simple protocol operates under mild, pH-neutral conditions and tolerates Lewis acid- and base-sensitive functionalities, making it broadly applicable to the late-stage oxidation of piperazine-based drugs. Mechanistic insights gleaned from spectroscopic studies shed light on the photoexcited flavin-catalyzed C–H oxidation pathway.