Ortho-C–H Methoxylation of Aryl Halides Enabled by a Polarity Reversed N–O Reagent

Oxygen-substituted arenes not only commonly exist in biologically important molecules, but also serve as a versatile handle to install other functional groups. However, to date it remains challenging to install oxygen groups directly and site-selectively to common aromatic compounds, especially when additional arene functionalization is simultaneously required. Current arene C−H oxidation strategies generally require directing groups to control site-selectivity and/or use strong oxidants, whereas other approaches need precisely pre-functionalized substrates. While the palladium/norbornene (Pd/NBE) cooperative catalysis is promising for site-specific arene vicinal difunctionalization through simultaneous reactions with an electrophile and a nucleophile, respectively, at the ortho and ipso positions, the electrophile scope has been limited to species based on relatively “soft” elements, such as carbon, nitrogen, and sulfur. To shift the Pd/NBE-catalysis paradigm, here we report the development of an ortho oxygenation reaction with readily available aryl halides to rapidly deliver diverse methyl aryl ethers. The coupling of the “hard” oxygen-electrophile is enabled by a stable, polarity reversed, conformationally pre-distorted N−O reagent and facilitated by a C7-bromo-substituted NBE mediator. Mechanistic studies reveal a unique SN2-type pathway between the N−O reagent as the oxygen electrophile and an electron-rich Pd(II) nucleophile. This new C−H oxygenation reaction allows streamlined synthesis of complex bioactive compounds containing methyl aryl ethers and provides an efficient modular approach to access underrepresented benzenoid substitution patterns that are challenging to prepare otherwise.