Zn(II)-Catalyzed Selective N-Alkylation of Amines with Alcohols Using Redox Noninnocent Azo-Aromatic Ligand as Electron and Hydrogen Reservoir

We report a sustainable and eco-friendly approach for selective Nalkylation of various amines by alcohols, catalyzed by a well-defined Zn(II)-catalyst, Zn(La)Cl2 (1a), bearing a tridentate arylazo scaffold. A total of 57 N-alkylated amines were prepared in good to excellent yields, out of which 17 examples are new. The Zn(II)catalyst shows wide functional group tolerance, is compatible with the synthesis of dialkylated amines via double N-alkylation of diamines, and produces the precursors in high yields for the marketed drugs tripelennamine and thonzonium bromide in gram scale reactions. Control reactions and DFT studies indicate that electron transfer events occur at the azo-chromophore throughout the catalytic process, which shuttles between neutral azo, one-electron reduced azo-anion radical, and two-electron reduced hydrazo forms acting both as electron and hydrogen reservoir, enabling the Zn(II)-catalyst for Nalkylation reaction.

Automated summary

We developed a sustainable and eco-friendly method for selective N-alkylation of various amines using a well-defined Zn(II)-catalyst with a tridentate arylazo scaffold. A total of 57 N-alkylated amines were synthesized with good to excellent yields, including 17 new examples. The Zn(II)-catalyst demonstrated wide functional group tolerance and compatibility for the synthesis of dialkylated amines, providing high yields for the precursors of tripelennamine and thonzonium bromide drugs.