Room-Temperature Cu-Catalyzed Etherification of Aryl Bromides

Transition-metal-catalyzed C–O coupling reactions of aryl halides and alcohols represent a useful alternative to classical aromatic substitution methods due to their improved functional group tolerance and substrate scope. Despite these benefits, many existing protocols rely on harsh reaction conditions or necessitate the use of a significant molar excess of alcohol to facilitate efficient C–O bond formation, thereby limiting their utility with complex substrates. Herein, we disclose the development of a Cu-catalyzed C–O coupling method utilizing a new N1,N2-diarylbenzene-1,2-diamine ligand, L8. Under optimized reaction conditions, a structurally diverse set of aryl and heteroaryl bromides underwent efficient coupling with a variety of alcohols at room temperature using an L8-based catalyst. Notably, the L8-derived catalyst exhibited enhanced activity when compared to the L4-based system previously disclosed for C–N coupling, most notably including the ability to functionalize aryl bromides containing acidic functional groups. Mechanistic studies demonstrate that C–O coupling utilizing the catalyst derived from L8 involves rate-limiting alkoxide transmetallation, resulting in a mechanism of C–O bond formation that is distinct from previously described Pd-, Cu-, or Ni-based systems. Consequently, this lower energy pathway leads to rapid C–O bond formation; a 7-fold increase relative to what it seen with other ligands. The results presented in this report overcome limitations in previously described transition-metal-catalyzed C–O coupling methods, expand the utility of this ligand family, and introduce a new ligand that we anticipate may be useful in other Cu-catalyzed C–heteroatom and C–C bond-forming reactions.