On the Halogenation of Tyrosine N-Oxime Methyl Ester

Abstract

Efficient syntheses of mono-, di-, and heterodihalogenated derivatives of tyrosine N-oxime methyl ester are reported. Monohalogenation with N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS) or N-iodosuccinimide (NIS) was optimized by addition of acid to suppress dihalogenation, affording bromo, chloro, and iodo derivatives in 71%, 50-53%, and 78-80% yields, respectively. Homodihalogenation utilized a two-step, one-flask process via a spirocyclic intermediate, yielding dibromo, dichloro, and diiodo analogues, respectively (75-76%, 54-56%, 79-80%). This strategy was extended to synthesize heterodihalogenated bromochloro, bromoiodo, and chloroiodo derivatives from monohalogenated analogues (50-77%). Key to this approach was the formation of an oxidized spirocyclic intermediate using excess N-halosuccinimide, followed by Na₂S₂O₄ reduction. This method ensures complete conversion and simplifies purification. Nine halogenated building blocks were prepared. These methods provide practical access to versatile precursors for natural product synthesis and derivatization, offering potential for diverse synthetic applications including regioselective palladium-catalyzed couplings.