Bis(phenolate)–Titanium(IV) Catalysts for Efficient and Sustainable Direct Amide Bond Formation

Amides are fundamental and hugely widespread functional groups in key bioactive and industrially relevant molecules. However, conventional methods for amide bond formation, particularly in peptide synthesis, are challenging in terms of environmental impact, waste, and production costs. The most commonly used method for amide bond formation involves activating carboxylic acids with excess coupling agents, heavily affecting the atom economy of the process. Despite the need for more sustainable alternatives, research on catalytic methodologies to minimize such drawbacks remains limited. In this study, we explored the use of titanium alkoxides of general formula Ti(OAr)2(OiPr)2, as efficient and environmentally friendly catalysts for amide bond formation. Our results indicated that the replacement of isopropoxide ligands with the less basic phenolates 2,4-dimethylphenolate and 2,6-dimethylphenolate significantly improved the reactivity of the Ti-center. Indeed, by using 5% mol of titanium bis(2,6-dimethylphenoxy)diisopropoxy (Ti2), or 10% mol of titanium bis(2,4-dimethylphenoxy)diisopropoxy (Ti1), we achieved efficient direct amidation between benzylamine and various carboxylic acids, including N-protected amino acids for which limited data are available in the literature. This work highlights the potential of titanium-based catalysis as a sustainable and effective solution for amide bond formation, particularly in peptide synthesis.