Penta- versus hexa-coordinated iridium catalysts control the reactivity of the direct reductive amination between aliphatic amines and aliphatic ketones: a DFT-guided mechanism

Understanding reaction mechanisms of metal-catalyzed processes is of paramount importance for the design of superior catalysts that circumvent unproductive pathways, while accelerating catalyst discovery. In this respect, gaining mechanistic understanding for reactions carried out at high pressures of gas reagents remains a major limitation because special setups are typically required, which is the case for metal-catalyzed direct reductive aminations (DRA) under high H-2 pressure. To overcome this issue, extensive computational calculations have been herein conducted for the iridium-catalyzed DRA between aliphatic ketones and aliphatic secondary amines. This highly atom-economic reaction delivers only water as side-product and it is relevant for the identification of active pharmaceutical ingredients. In this contribution, we highlight that the excellent reactivity encountered with very different P,P-chelating ligands results from the fact that two different mechanistic pathways operate for each system. In addition, we found that the key hydride transfer step is more accessible with a penta-coordinated iridium complex rather than with the expected hexa-coordinated iridium species using a Josiphos-type ligand when compared to the large bite-angle Xantphos. For comparison purposes, we also evaluated a related Josiphos-type ligand and a small bite-angle diphosphane.