Copper(II)-Catalyzed Amination of Aryl Chlorides in Aqueous Ammonia

Abstract

Anilines are ubiquitous in bio-active compounds and their synthesis can be achieved via metal-catalyzed cross-coupling reactions involving aryl halides. We describe an unusual, yet simple, Cu^II-catalyzed system for the amination of aryl chlorides in pure aqueous ammonia with 2.5 mol % catalyst loading under non-inert conditions. Different from previous systems, the reaction proceeds even without an additional organic solvent. Copper(II) sulfate in combination with 4,7-dimethoxy-1,10-phenanthroline enabled the amination of several aryl chlorides containing electron-neutral, -donating and -withdrawing groups to the corresponding anilines with good to excellent yields. The upscaling potential of the procedure has been shown by the synthesis at 50 mmol scale. The reaction proceeds as one of the rare cases of a Cu^II-assisted coupling, in contrast to the typical Cu^I-Cu^III intermediates postulated for most Ullmann-type coupling reactions. The copper(II) center allows for a nucleophilic substitution pathway, enabled by the deprotonation of coordinated ammonia.

Keywords: Amination; Aniline synthesis; Copper catalysis; Cross-coupling; Nucleophilic aromatic substitution.