The Reformatsky reaction is a well-established method for the synthesis of γ-hydroxyesters,
a structural motif commonly found in natural products. While continuous flow adaptations
of the traditional Reformatsky reaction that offer improved safety and efficiency
have been reported, related transformations using γ-bromocrotonate estershave not
yet been explored in flow chemistry. Under batch conditions, the corresponding organozinc
reagent can yield both α-and β-adducts, depending on the metal employed and specific
reaction parameters. In this study, we report the first Reformatsky-type reaction
in continuous flow using ethyl γ-bromocrotonate, with conditions optimized to favor
γ-selectivity and the synthesis of homoallylic alcohols. Zinc dust was utilized as
a reagent, and the reaction scope was demonstrated with a variety of carbonyl compounds,
including in a four-step synthesis of piperine. Furthermore, the synthesis of ethyl
γ-bromocrotonate was efficiently accomplished under continuous flow conditions on
a multigram scale via a Wohl-Ziegler bromination.
