Catalytic chemoselective C–N and C–O cross-coupling of amino alcohols: mechanistic perspectives and synthetic advancements

Abstract

The development of sustainable and selective cross-coupling strategies for arylation of bifunctional substrates containing both amine and alcohol groups remains a central challenge in modern cross-coupling chemistry. Among these, amino alcohols represent a particularly valuable yet underutilized class of ubiquitous building blocks, frequently encountered in active pharmaceutical ingredients and fine chemicals. However, their dual nucleophilicity often complicates selective C–O versus C–N bond formation. In this study, we critically examine recent advances in environmentally benign arylation methodologies that enable site-selective functionalization of amino alcohols using non-precious, Earth-abundant metal catalysts under mild conditions. Special focus is placed on copper-, nickel-, palladium- and microwave-catalyzed systems that avoid the use of protecting groups, operate in green solvents, and exhibit high atom economy. We explore key mechanistic factors such as differential coordination behavior, ligand-enabled control of reductive elimination, and electronic and steric influences that govern selectivity. Emphasis is also placed on solvent effects, reaction scalability, and the integration of computational tools to guide catalyst design and predict reactivity trends. By consolidating both experimental and theoretical insights, this review offers a roadmap for the rational design of green and efficient synthesis of next-generation C–O and C–N cross-coupling protocols.