Catalytic Aerobic Cross-Coupling of Indoles and Urazoles

Abstract

TAD-indole adducts, serving as stable surrogates for reactive triazolinediones (TADs), are pivotal in bioconjugation and polymer chemistry but remain limited by cumbersome synthesis. Current methods rely on preformed TADs or stoichiometric oxidants, posing practical and environmental challenges. Herein, we report a sustainable catalytic cross-coupling protocol to directly synthesize TAD-indole adducts from indoles and urazoles via Ma's oxidation. This one-step method employs the Fe(NO₃)₃·9H₂O/TEMPO/NaCl system with air as the terminal oxidant, achieving high efficiency (up to 86% yield), broad substrate scope (electron-rich/-deficient indoles/urazoles), and mild conditions. The protocol's practicality is demonstrated through gram-scale synthesis and the preparation of blocked TAD cross-linkers for temperature-controlled polymer networks. By circumventing traditional TAD-handling limitations and eliminating excess oxidants, this strategy establishes a green, scalable platform for advancing TAD chemistry in materials and bioconjugation.

Keywords

TAD-indole adduct / Cross-coupling / Oxidation / Blocked TAD cross-linker / Green synthesis / Nitrogen heterocycles

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2025 SIOC, CAS, Shanghai, & WILEY-VCH GmbH