(446a) Continuous Ligand-Free Suzuki-Miyaura Cross-Coupling Reactions in a Packed Bed Flow Reactor Using an Easily Synthesized Siloxane Network-Supported Palladium Catalyst

Synthesis of fine chemicals is traditionally performed in a series of batch reactions, that possess certain limitations at process scale, including lower transport rates, safety hazards related to large quantities of material, and purification steps that are both labor-intensive and costly. The Suzuki-Miyaura cross-coupling reaction is one of the most important reactions for pharmaceutical and fine chemical synthesis. Homogeneous catalysis, although very effective, has the disadvantage of requiring a post-reaction catalyst separation step, and traditional heterogeneous catalysis suffers from lower reproducibility and activity. In response, we have developed a new catalytic microreactor using a readily accessible polymer network-supported, ligand-free palladium catalyst for continuous flow Suzuki-Miyaura cross-coupling reactions integrated with an automated online sampling for reaction analysis.

In this work, we crosslink poly(methylhydrosiloxane) (PMHS) with tri(ethylene glycol divinyl ether) (VTEG) to form a simple and easy to synthesize gel catalyst support. The Si-H units present on the PMHS backbone act both as the crosslink site with vinyl the vinyl end groups of VTEG and the reducing agent to anchor and reduce palladium (II) acetate to active palladium (0). These catalytic particles are then packed into stainless steel tubing for the continuous flow exemplary Suzuki-Miyaura reaction of 4-iodotoluene, phenylboronic acid, and potassium carbonate through the flow reactor. The start-up and steady-state yields are obtained via automated sampling using an on-line HPLC. A series of systematic optimization experiments testing reaction temperature, Pd loading, crosslink density, and gel particle size were conducted for accelerated reaction optimization in flow and obtained a yield of 97% at 25 min nominal reaction time at 95°C. This catalyst also experienced no noticeable leaching after flushing of the cartridge flow reactor. The cartridge flow reactor developed in this work has certain advantages over both batch and homogeneous Suzuki-Miyaura cross-coupling reactions, including increased safety, and lower cost of catalyst recovery.