Synthesis and reactivity of organozinc reagents derived from γ-bromocrotonate ester in continuous flow

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.