Diversification of Pharmaceuticals via Late-Stage Hydrazination

Developments in organic synthesis over the past century have greatly enabled the discovery of life-saving medicines. In this context, over the past two decades, palladium-catalyzed cross-coupling reactions have transformed the exploration of emerging therapeutics. However, the cross-coupling between aryl halides and hydrazine, NH2NH2, the smallest bis-nitrogen nucleophile, has been a long-standing challenge due to the reducing capacity of hydrazine and the presence of multiple N-H bonds. These advances have significantly lagged behind modern cross-coupling technologies despite the broad utility of arylhydrazines to serve as a springboard for the discovery of innovative medicines. Herein, we report a general platform for the diversification of pharmaceuticals by late-stage hydrazination. By designing biaryl, sterically demanding biaryl and flexible N-heterocyclic carbene ligands with strong σ-donation and controlled architecture of the catalytic pocket, we have established selective palladium-catalyzed cross-coupling of aryl halides with hydrazine to give highly valuable arylhydrazines. By using this method, we have achieved direct cross-coupling of a variety of complex pharmaceuticals covering various metabolic diseases ranging from life-changing anticancer to blockbuster antiallergic drugs to give broadly useful arylhydrazines that can be converted in situ into heterocyclic frameworks. The developed class of ligands shows notably high %Vbur, while retaining the full flexibility of the catalytic pocket. In this catalysis approach, a remarkably broad range of aryl chlorides and aryl bromides can be systematically applied as cross-coupling partners using mild carbonate bases. The developed ligands feature biaryl-controlled steric environment of the catalytic pocket in combination with strong σ-donicity, which facilitates and integrates individual elementary steps of the catalytic cycle, such as oxidative addition, reductive elimination from Pd center, as well as protection of Pd-(II) intermediate from overreduction. Extensive computational studies have been conducted to gain insight into the mechanism of the coupling and elucidate the key role of biaryl and sterically flexible N-heterocyclic carbene ligands. The presented reactivity establishes a powerful entry into the late-stage cross-coupling with challenging nucleophiles for drug discovery and development.