Drug-Derived Tetrahydropyrazines for Late-Stage α- and β-Functionalization of Piperazine-Based Pharmaceuticals.

Piperazine is one of the most prevalent saturated nitrogen heterocycles in pharmaceuticals, yet late-stage access to α- and β-substituted piperazine analogues remains challenging. Here, we report a flavin-photocatalyzed platform that converts complex piperazine-containing drugs into persistent tetrahydropyrazine intermediates that serve as versatile branch points for downstream functionalization. Under blue-light irradiation, riboflavin tetraacetate (RFTA) promotes sequential α- and β-C─H bond cleavage of N-alkyl, N-aryl, and N-heteroaryl piperazines under mild conditions and with tolerance of diverse functional groups. The resulting drug-derived tetrahydropyrazines can be isolated or directly telescoped into reactions with electrophiles and nucleophiles, enabling late-stage access to cyclopropyl-, trifluoromethyl-, carbonyl-, amide-, and cyano-substituted piperazine analogues. By decoupling C─H oxidation from subsequent bond construction, this two-stage strategy enables transformations that would otherwise be incompatible with flavin-mediated oxidation. The utility of this approach is demonstrated through the rapid preparation of diverse analogues of piperazine-based pharmaceuticals and a preliminary structure-activity relationship (SAR) study of erastin, which reveals that piperazine-core substitution and stereochemistry can substantially influence cellular activity. Stern-Volmer quenching experiments, cyclic voltammetry, and characterization of intermediates formed under photoirradiation provide insight into the reaction mechanism. This work establishes drug-derived tetrahydropyrazines as practical late-stage intermediates for expanding medicinally relevant chemical space around piperazine-containing drug leads.