Dearomatization of Biaryls through Polarity Mismatched Radical Spirocyclization

Abstract

Dearomatization reactions involving radical cyclizations can facilitate the synthesis of complex polycyclic systems that find applications in medicinal chemistry and natural product synthesis. Here we employ redox-neutral photocatalysis to affect a radical spirocyclization that transforms biaryls into spirocyclic cyclohexadienones under mild reaction conditions. In a departure from previously reported methods, our work demonstrates the polarity mismatched addition of a nucleophilic radical to an electron rich arene, and allows the regioselective synthesis of 2,4-or 2,5-cyclohexadienones with broad functional group tolerance. By transforming biaryls into spirocycles, our methodology accesses underexplored three-dimensional chemical space, and provides an efficient means of creating quaternary spirocenters that we apply to the first synthesis of the cytotoxic plant metabolite denobilone A.

Mechanisms for radical reactions initiating from N-hydroxyphthalimide esters

“…While many reports, including Okada's original work, have suggested that a proton donor can accelerate the fragmentation rate of RAEs [29,49,53], specific values comparing the fragmentation rate constants or the N-O bond dissociation energies of radical anions and neutral radicals derived from RAEs are not available in the literature. Lumb and co-workers recently published a study on the conversion of biaryl-derived NHPI esters into spirocyclic cyclohexadienones through a photocatalytic radical-mediated dearomatization, with H 2 O serving as the nucleophile [54] (Scheme 9A). Despite the presence of H 2 O in the reaction, the reduction of 38 to its corresponding radical anion 39 could occur without the need for hydrogen-bonding (Scheme 9B NHPI esters can also engage in π-π interactions with electronrich species to generate charge-transfer complexes that can absorb light in the visible region.…”