Evaluation of Titanium Oxo Clusters as Catalysts for Direct Amidations

Abstract The direct amidation between carboxylic acids and amines is highly relevant for the pharmaceutical industry, also because of its high atom economy, as water is the sole byproduct. However, achieving synthetically useful yields in this condensation reaction typically requires a stoichiometric coupling reagent or a metal catalyst. Many of the catalysts reported to date rely on noble metals or complex ligands, making them costly and limiting their large-scale applicability. In this work, we evaluated mixed heteronuclear oxo clusters based on Ti(IV) and Zr(IV) as catalysts for the direct amidation. Despite the challenging stability of Ti complexes in the presence of water, we succeeded in synthesizing a significant range of amides under comparatively mild conditions. To achieve this, we sought to modulate metal oxo clusters’ reactivity through addition of zirconium in the inorganic core as second metal species. Finally, incorporation of titanium oxo clusters in a polymer matrix reduced their sensitivity toward water, allowing direct amidations to occur without water scavenging, and enabling catalyst recycling. Overall, these results showcase titanium oxo clusters as viable alternatives for the development of recyclable and cheap catalysts for atom-economic direct amidation reactions.