Harnessing the Reactivity of Sulfamate Esters and Sulfamides to Enable Position-Selective C-H Halogenation Processes

Synthetic technologies that enable transformation of typically inert carbon–hydrogen (C–H) bonds into diverse functional groups have streamlined access to complex molecules. These processes, defined as C–H functionalization reactions, remain challenging as traditionally unreactive C–H bonds have high bond dissociation energies (90–105 kcal•mol–1), are not acidic (pKa ≥ 50), and do not incorporate more polarizable and electronically accessible π-orbitals. In addition, the ubiquity of C–H bonds within organic molecules requires methods to predictably and selectivity control the site of functionalization.

Some of the most effective strategies for controlling the position of C–H functionalization employ directing groups to guide a reaction to a particular site within a molecule. Herein disclosed are investigations into position-selective C–H halogenation reactions mediated by sulfamate ester and sulfamide directing groups. We have demonstrated that these substrates guide rare, 1,6-hydrogen-atom transfer (1,6-HAT) processes to dictate the position of halogen installation with specific focus on chlorination and fluorination reactions.

Through this research, we have developed methods to prepare sulfamate esters and sulfamides from readily available starting materials via activation of sulfamic acid salts. Additionally, we have utilized these substrates to guide position-selective chlorine- and fluorine-transfer reactions, enabling access to alkyl halide products with complementary selectivity to that achieved with other known halogenation technologies.