Palladium-Catalyzed Dearomative syn-1,4-Carboamination with Grignard Reagents

Abstract

A protocol for palladium-catalyzed dearomative functionalization of simple, non-activated arenes with Grignard reagents has been established. This one-pot method features a visible-light-mediated [4+2] cycloaddition between an arene and an arenophile, and subsequent palladium-catalyzed allylic substitution of the resulting cycloadduct with Grignard reagent. A variety of arenes and Grignard reagents can participate in this process, forming carboaminated products with exclusive syn-1,4-selectivity. Moreover, the dearomatized products are amenable to further elaborations, providing functionalized alicyclic motifs and pharmacophores. For example, naphthalene was converted to sertraline, one of the most prescribed antidepressants, in only four operations. Finally, this process could also be conducted in an enantioselective fashion, as demonstrated with the desymmetrization of naphthalene.

A novel dearomative process is described using arenophile-based chemistry and Pd catalysis. A range of arenes were readily converted into the corresponding syn-1,4-carboaminated products using Grignard reagents as nucleophiles. The synthetic value of this transformation was demonstrated by several elaborations of products, including short synthesis of sertraline from naphthalene.

Graphical Abstract