Synthesis of aryloxyalkylamines through Cu-catalyzed Chan-Lam-Evans coupling of amino acid derivatives

The aryloxyalkylamine (1) motif is widely present in bioactive molecules and active pharmaceutical ingredients, particularly for the treatment of central nervous system disorders and cancer.¹ Conventional methods for the C‒O bond formation in these molecules, such as nucleophilic substitution and Mitsunobu reactions,² often suffer from poor atom economy and significant waste generation. In contrast, transition-metal-catalyzed approaches remain underexplored.³ Among them, the copper-catalyzed Chan-Lam-Evans⁴ (CLE) coupling is an attractive alternative due to the low cost of copper and its ability to promote C‒O bond formation under mild conditions. In this study, aryloxyalkylamines were synthesized through CLE coupling between amino alcohols (2) derived from natural amino acids and arylboronic acids. After optimization of the reaction conditions, Cu-catalyzed CLE coupling was carried out between L- and D-prolinol with different boronic acids, affording the corresponding aryloxyalkylamines in 22-88% isolated yields. Current studies are ongoing to expand the substrate scope to other amino acid derivatives.