Arylboronic Acid Catalyzed Reductive Alkylation of Azoarenes to N-Alkylated Hydrazines

Hydrazine derivatives are generally difficult to prepare despite their appealing structural simplicity. The synthetic challenge may arise from either the similar reactivity or the relatively low activity of the two nitrogen atoms in a hydrazine precursor. The former would lead to severe selectivity issues while the latter would require harsh reaction conditions. Herein we report a facile method for the synthesis of N-alkyl-N, N'-diarylhydrazines by boronic acid-catalyzed one-pot tandem reduction of azoarene to hydrazoarene followed by reductive alkylation with the aldehyde. The mild reaction conditions suppress N-N cleaved products and selectively provide trisubstituted hydrazine derivatives. The reaction is highly chemoselective and tolerates various hydrogenation-sensitive functional groups. The method has been successfully utilized in the late-stage functionalization and diversification of pharmaceuticals. A series of control experiments with boronic acids, boronic ester, and Brønsted acids were interpreted. The study suggests the mode of boronic catalysis involves both Brønsted acid and H-bond donor catalysis. Based on the thermodynamic activation parameters, kinetic Hammett studies, and competitive reaction on the substrate, it has been postulated that the iminium formation step is likely to be the rate-limiting step.