Late-Stage Halogenation of Complex Substrates with Readily Available Halogenating Reagents

Abstract

Late-stage halogenation, targeting specific positions in complex substrates, has gained significant attention due to its potential for diversifying and functionalizing complex molecules such as natural products and pharmaceutical intermediates. Utilizing readily available halogenating reagents, such as hydrogen halides (HX), N-halosuccinimides (NXS), and dichloroethane (DCE) reagents for late-stage halogenation shows great promise for expanding the toolbox of synthetic chemists. However, the reactivity of haleniums (X⁺, X = Cl, Br, I) can be significantly hindered by the presence of various functional groups such as hydroxyl, amine, amide, or carboxylic acid groups. The developed methods of late-stage halogenation often rely on specialized activating reagents and conditions. Recently, our group (among others) has put great efforts into addressing these challenges and unlocking the potential of these readily available HX, NXS, and DCE reagents in complex molecule halogenation. Developing new methodologies, catalyst systems, and reaction conditions further enhanced their utility, enabling the efficient and selective halogenation of intricate substrates.