Hydrophobic Deep Eutectic Solvents Unlock Green Palladium-Catalyzed N-Alkylation via Hydrogen Borrowing

The borrowing hydrogen (BH) strategy represents a powerful and sustainable alternative to classical Nalkylation methods for C–N bond formation, eliminating the need for mutagenic alkyl halides and improving atom economy. Traditionally, BH N-alkylations have been conducted under homogeneous or heterogeneous catalytic conditions, using transition metals in organic solvents such as toluene, o-xylene, or THF, typically at elevated temperatures. In an effort to design greener protocols, Azumaya et al. developed a Pd-catalyzed N-benzylation of electron-deficient anilines in water, using tris(m-sulfophenyl)phosphine (TPPTS) as a watersoluble ligand. However, under these same aqueous conditions, C-benzylation was observed with simple or electron-rich anilines, highlighting the challenge of achieving chemoselectivity in this substrate class. To address this limitation and expand the scope of the BH reaction toward selective N-alkylation of electron-rich anilines, we explored the use of Hydrophobic Deep Eutectic Solvents (HDESs) as both reaction media and ligand-like components. HDESs–emerging, bio-based solvents composed of hydrogen bond donors and acceptors–form eutectic mixtures with melting points significantly lower than those of their individual components, and offer tunable physicochemical properties. While hydrophilic DESs have been widely used in green chemistry, the potential of hydrophobic eutectic mixtures remains largely underexplored, especially in the context of transition-metal catalysis. In this communication, we report a novel application of reusable HDESs in Pd-catalyzed N-alkylation via HB, enabling a more sustainable, selective, and broadly applicable approach to C–N bond formation.