Aerobic oxidative bromination and iodination enabled by alloxan and ascorbic acid to mimic flavin-dependent halogenases

This is the authors' abstract. We don't add key points for this paper.

The fundamentally significant halogenation processes in organic synthesis heavily depend on the use of hazardous and toxic elemental halogens directly or indirectly, inevitably increasing environmental burden and leading to various production problems. Flavin-dependent halogenases (FDHs) in nature produce organic halides under benign conditions, yet their practical application remained elusive and difficult to scale up. Inspired by FDHs, here we develop a mild and eco-friendly biomimetic aerobic oxidative halogenation strategy that utilizes O2 from the air to oxidize non-toxic halide salts as a safer alternative. Using simple alloxan as catalyst and low-cost ascorbic acid as reductant, we successfully emulate the challenging flavoenzymatic aerobic halogenation cycle without requiring light activation. This approach yields various important monobromide and iodide products with high efficiency, excellent selectivity, and good functional group tolerance. Moreover, its successful application in late-stage bromination of complex bioactive molecules, operational ease at the gram scale, and use of cost-effective, unpurified primary raw materials all indicate significant potential for green industrial production. Flavin-dependent halogenases (FDHs) in nature produce organic halides under benign conditions, yet their practical application remains elusive and difficult to scale up. Inspired by FDHs, here the authors develop a biomimetic aerobic oxidative halogenation strategy that uses oxygen from the air to oxidize non-toxic halide salts.