Process Intensification of Continuous-Flow Imine Hydrogenation in Catalyst-Coated Tube Reactors

Hydrogenation of an imine (N-Cyclohexyl(benzylidene)imine) into a secondary amine (N-Benzylcyclohexylamine) was studied in catalyst-coated tube reactors to utilize the advantages of continuous-flow processes. Tetrahydrofuran (THF) was found to be an optimal solvent providing high reaction and low catalyst deactivation rates compared to toluene and isopropanol. Even in THF, however, the deactivation was noticeable, with a decrease in the imine hydrogenation rate of 80 and 47% during 20 h on stream over the Pd/C and Pd/SiO2 catalyst-coated tubes, respectively. After comparing various regeneration methods, we found that washing with isopropanol recovered the catalyst activity. The catalyst support affected regeneration: the Pd/SiO2 catalyst suffered from a permanent degradation, whereas the Pd/C was stable over multiple reaction-regeneration cycles. Process intensification study at a range of reaction temperatures allowed to establish the optimal secondary amine production temperature of 110 °C. The long-term stability test under the optimized conditions allowed reaching a turnover number (TON) of 150 000, an unprecedented value in heterogeneous imine hydrogenation. A reductive amination cascade reaction (aldehyde and amine condensation simultaneously with imine hydrogenation) showed the byproduct yield below 3%. The cascade reaction, however, decreased the reaction throughput by 45% compared to the direct imine hydrogenation still allowing for a throughput of 0.75 kg of product per day in a single 5 m catalyst-coated reactor opening a way for a multikilogram synthesis.