Chemoenzymatic Synthesis of 3‐Halochromones via Oxidative α‐Halogenation of Enaminones in TPGS‐750‐M Micelles

Synthesis strategies of chromones have been widely investigated due to the abundance of chromone moiety in bioactive compounds and natural products. Of which, 3‐halochromones are a versatile set of precursors to synthetically access valuable compounds with chromone frameworks. Generally, 3‐halochromones are synthesized from o ‐hydroxy enaminones through oxidative α‐halogenation, a process that often uses toxic and corrosive chemicals. Herein, an alternative strategy is presented for oxidative α‐halogenation catalyzed by vanadium‐dependent chloroperoxidase from Curvularia inaequalis ( Ci VCPO) with H 2 O 2 /KX (X = Cl, Br, and I) in an aqueous medium. With a micellar system from a surfactant TPGS‐750‐M, substrate concentration can be increased to 50 mM without compromising the yield, thereby, significantly reducing the use of organic solvents. Substrate scope investigation reveals that bromination and chlorination processes prefer electron‐donating substituents although moderate electron‐withdrawing groups are tolerated (20 examples). Additionally, iodination processes can be performed under the optimized condition. However, slow conversion indicates that further optimization is needed. It is also found that iodination can occur without Ci VCPO, albeit at a lower conversion. Further investigation suggests that such a conversion took place via I 2 generated in situ. Overall, this chemoenzymatic method can offer an environmentally friendly approach to access a variety of 3‐bromo or 3‐chlorochromones.