62. Photoredox-Catalyzed Nucleophilic Aromatic Substitution of Halophenols with Azoles via Oligomeric Phenylene Oxide Radicals

Jan Seliger, Lydia R. Fries, Jonathan M. Meinhardt, Robert R. Knowles

J. Am. Chem. Soc. 2025, 147, 9931–9938. DOI: 10.1021/jacs.5c01012

https://pubs.acs.org/doi/10.1021/jacs.5c01012

Abstract: Nucleophilic aromatic substitution (S_NAr) reactions are widely employed in organic synthesis yet typically require the use of electron-deficient arenes for efficient reactivity. Herein, we report a photocatalytic protocol for formal S_NAr of electron-rich 4-halophenols with azole nucleophiles under mild, redox-neutral conditions. The transformation proceeds via a two-stage mechanism consisting of initial halophenol oligomerization to produce a key oligo(phenylene oxide) intermediate and its subsequent breakdown through S_NAr with the azole enabled by photoredox-catalyzed arene umpolung. Reaction monitoring, stoichiometric control experiments, and luminescence quenching data implicate phenoxyl radicals and Brønsted acid-activated oligo(phenylene oxide) radicals as the reactive species in the oligomerization and the S_NAr stages, respectively. The synthetic utility of this method is demonstrated across 17 (pseudo)halophenols bearing a variety of leaving groups (F, Cl, Br, OMs, and OTs) and 22 azole examples.