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

ConspectusLate-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.With the long-term goal of achieving selective halogenation of complex molecules, we summarize herein three complementary research topics in our group: (1) Efficient oxidative halogenations: Taking inspiration from naturally occurring enzyme-catalyzed oxidative halogenation reactions, we focused on developing cost-effective oxidative halogenation reactions. We found the combination of dimethyl sulfoxide (DMSO) and HX (X = Cl, Br, I) efficient for the oxidative halogenation of aromatic compounds and alkenes. Additionally, we developed electrochemical oxidative halogenation using DCE as a practical chlorinating reagent for chlorination of (hetero)arenes. (2) Halenium reagent activation: Direct electrophilic halogenation using halenium reagents is a reliable method for obtaining organohalides. However, compared to highly reactive reagents, the common and readily available NXS and dihalodimethylhydantoin (DXDMH) demonstrate relatively lower reactivity. Therefore, we focused on developing oxygen-centered Lewis base catalysts such as DMSO, 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) and nitromethane to activate NXS or DXDMH, enabling selective halogenation of bioactive substrates. (3) Halogenation of inert substrates: Some substrates, such as electron-poor arenes and pyridines, are inert toward electrophilic functionalization reactions. We devised several strategies to enhance the reactivity of these molecules. These strategies, characterized by mild reaction conditions, the ready availability and stability of catalysts and reagents, and excellent tolerance for various functional groups, have emerged as versatile protocols for the late-stage aromatic halogenation of drugs, natural products, and peptides. By harnessing the versatility and selectivity of these catalysts and methodologies, synthetic chemists can unlock new possibilities in the synthesis of halogenated compounds, paving the way for the development of novel functional materials and biologically active molecules.