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 <i>N</i>¹,<i>N</i>²-diarylbenzene-1,2-diamine ligand, <b>L15</b>. 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 NaO<i>t-</i>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 p<i>K</i>_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.