From rod to reactor – a new continuous approach to the Simmons-Smith reaction

Organozinc chemistry is fundamental in the synthesis of highly functionalized molecules, e.g., pharmaceuticals. However, its adaptation to continuous flow has been hindered by an intricate challenge: Reactions involving metallic zinc rely on the presence of an activated metal surface. Conventional protocols depend on chemical zinc activation and, with a few exceptions only, showcase closed processes where redosing the metal, which is consumed in the reaction, is not possible. Here, we present a continuous process that overcomes these limitations by integrating on-demand mechanical surface activation with a continuous flow reactor. A zinc rod is abraded inside a sealed chamber, delivering zinc shavings directly into the reactor under inert conditions. This “from-rod-to-reactor” approach eliminates the need for chemical pre-activation and maintains a reactive surface throughout operation. To demonstrate the viability of this new proposed setup, the Simmons-Smith synthesis, which is used to form cyclopropanes from double bonds, using activated zinc and a dihalomethane as a carbon source, is demonstrated. Using only green solvents and cinnamyl alcohol as a model substrate, we show that the process enables cyclopropanation with high conversion and yield under stable, continuous conditions. Additionally, this study could provide a scalable framework to conduct other stochiometric organometallic reactions, which rely on non-passivated metal surfaces. Continuous flow processing is highly advantageous for managing hazardous, exothermic reactions that utilize reactive starting materials. The classical Simmons-Smith synthesis, a reliable and often used method for the cyclopropanation of alkenes using activated zinc and a dihalomethane, is an ideal candidate for such continuous operations. Furthermore, the economically favorable standard in industrial settings utilizes a Zn/Cu couple, which subsequently requires a cumbersome post-reaction filtration step. This new proposed method uses a novel activation protocol that shifts from chemical to mechanical activation of the zinc, rendering the filtration step unnecessary. Additionally, this approach eliminates the need for copper and avoids the use of large quantities of pyrophoric chemical activators, such as trimethylsilyl chloride (TMSCl). This means that overall, changing from batch to this type of operation eliminates heat transfer limitations, the use of toxic chemicals, as well as the necessity of a downstream operated filtration unit operation.