A Greener Approach to Palladium-Catalyzed N-Alkylation of Amines via Hydrogen Borrowing

The borrowing hydrogen (BH) strategy represents a valuable alternative to classical N-alkylation protocols for the formation of C–N bonds, offering significant advantages such as the elimination of mutagenic alkyl halides and enhanced atom economy. This reaction has been extensively investigated under both homogeneous and heterogeneous catalytic conditions, typically employing transition metals as catalysts in organic solvents such as toluene, o-xylene, or THF, and generally requiring elevated temperatures. In the pursuit of more sustainable methodologies, Azumaya et al. reported a Pd-catalyzed N-benzylation of electron-deficient anilines in water, using tris(m-sulfophenyl)phosphine (TPPTS) as a ligand. However, under these same conditions, C-benzylation at the benzylic position was observed when using simple or more electron-rich anilines. To develop a greener, selective, and more versatile approach to the N-alkylation of this latter class of amines, and to broaden the applicability of the hydrogen borrowing reaction, we are currently investigating the use of Hydrophobic Deep Eutectic Solvents (HDESs) as both reaction media and greener ligands. DESs are an emerging class of bio-based, renewable solvents composed of hydrogen bond donors and acceptors, whose eutectic mixtures exhibit melting points significantly lower than those of their individual components, along with tunable physicochemical properties. While hydrophilic DESs have been extensively explored in various fields, applications of HDESs have remained largely limited to natural product extraction. In this communication, we aim to highlight the untapped potential of hydrophobic eutectic mixtures in metal catalysis, paving the way for new sustainable strategies in organic synthesis.