A Photochemical Strategy for ortho-Aminophenol Synthesis via Dearomative-Rearomative Coupling Between Aryl Azides and...

ortho-Aminophenols are aromatic derivatives featuring vicinal N- and O-based functionalities commonly found in the structures of many high-value materials. These molecules are generally prepared using multistep strategies that follow the rules of electrophilic aromatic substitution (S_E Ar) chemistry. Despite their high fidelity, such approaches cannot target substrates featuring a "contra-S_E Ar" arrangement of N- and O-groups. Here we report an alternative strategy for the preparation of such ortho-aminophenols using aryl azides as the precursors. The process utilizes low-energy photoexcitation to trigger the decomposition of aryl azides into singlet nitrenes that undergo a dearomative-rearomative sequence. This allows the incorporation of alcoholic nucleophiles into a seven-membered ring azepine intermediate via temporary disruption of aromaticity, followed by electrophile-induced re-aromatization. The net retrosynthetic logic is that the alcohol displaces the azide, which, in turn, moves to its ortho position and furthermore is converted into an amide. The synthetic value and complementarity of this strategy has been demonstrated by the coupling of aryl azides with complex, drug-like alcohols and phenols as well as amines, thiols and thiophenols, which provides a general platform for the fast and selective heterofunctionalization of aromatics.