Pd-Catalyzed O-Arylation of Phenols Mediated by a Weak, Soluble Organic Base: Methodology, Mechanism, and Compatibility with Enabling Technologies

The low nucleophilicity of phenols represents a major obstacle to the Pd-catalyzed synthesis of diaryl ethers. This inherent challenge is typically exacerbated by the reliance of C-O couplings on an insoluble, inorganic base: the resulting reaction heterogeneity leads to irreproducibility across scales and between laboratories, and incompatibility with common enabling technologies. In this <i>Article</i>, we report the development and mechanistic interrogation of an homogeneous, Pd-catalyzed C-O coupling between phenols and aryl triflates that uses a weak, soluble tertiary amine as base. We show that the choice of ligand, aryl electrophile, and base is crucial if side reactions and catalyst poisoning are to be avoided, and productive catalysis achieved. Investigation of reaction kinetics and linear free energy relationships has revealed the identity of both the catalyst resting state and the turnover-limiting step. The combined mechanistic insight allows qualitative <i>a priori</i> prediction of reaction outcome as a function of substrate electronics, and provides an intuitive guide as to how diaryl ether targets should be disconnected. The resulting methodology exhibits broad substrate scope, with yields reproducible across both preparative 'singleton' scales and high throughput formats. The homogeneous nature of the couplings allows their safe execution under microwave heating, with elevated temperatures allowing for short reaction times even in the presence of air, and their facile translation to scale-up in continuous flow.