Ligand Design Enables Cu-Catalyzed Etherification of Aryl Bromides Using Mild Bases

We report a Cu-catalyzed method for the efficient coupling of base-sensitive aryl bromides and alcohols utilizing a newly developed N¹,N²-diarylbenzene-1,2-diamine ligand, L15. This ligand was developed to increase the Lewis acidity of the Cu center, thereby permitting the use of a substantially milder base (NaOTMS or NaOPh) relative to those required in a previous iteration of this methodology (NaOMe or NaOt-Bu). Under the optimized reaction conditions, several classes of previously incompatible aryl bromides were efficiently transformed, including base-sensitive heterocycles and those containing acidic functional groups. Kinetic analyses support that C-O coupling proceeds via a mechanism involving binding/deprotonation of alcohol nucleophiles, that the pK_a of the base influences the overall rate law, and that substoichiometric quantities of strong base can be utilized to accelerate ligand activation and thereby increase the overall rate of the transformation.