Site-Selective Staudinger Conjugation of Aryl Azides Driven by Intramolecular Hydrogen Bonding

Site-selective conjugation on aryl azides is hampered by a fundamental trade-off: electron-withdrawing groups that promote the reaction often preclude further functionalization, while versatile electron-donating groups suppress reactivity. We report a strategy that resolves this by using an ortho-amido group to activate an electron-rich aryl azide via an intramolecular hydrogen bond. This non-covalent interaction renders the ortho-amidoaryl azide significantly more reactive than its para-isomer and even activated alkyl azides, although competition experiments revealed that steric hindrance presents a counteracting effect. The principle was successfully applied to achieve excellent site-selectivity in a diazide molecule, favoring reaction at the aryl position. Its utility was further demonstrated in a highly selective classical Staudinger-Bertozzi ligation. This work establishes the ortho-amido group as a powerful controlling element, offering a new click conjugation platform that enables ready functionalization.