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

Authors

Soichiro Mori, Cunyuan Zhao, Tenghui Wang, Yuankai Wang, Yu Nishio, Matthew D Disney, Masayuki Wasa

Published in

Angewandte Chemie (International ed. in English). Pages e6711809. Sep 02, 2026. Epub Sep 02, 2026.

Abstract

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.

PMID:
42683765
Bibliographic data and abstract were imported from PubMed on 02 Sep 2026.

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