Palladium‐Catalyzed Dearomativesyn‐1,4‐Carboamination with Grignard Reagents

Abstract

A protocol for palladium‐catalyzed dearomative functionalization of simple, nonactivated 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 a 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 into 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.

Diversity-oriented synthesis of nanographenes enabled by dearomative annulative π-extension

“…We began our investigations by establishing conditions for the annulation of cycloadduct 2a, which is readily prepared by the photo-induced [4 + 2] cycloaddition of 1-phenylnaphthalene (1a) with MTAD [24][25][26][27] , to form a precursor of the desired M-APEX products (Fig. 2a).…”

“…We have previously developed several dearomative functionalizations by exploiting the ability of 4-methyl-1,2,4-triazoline-3,5-dione (MTAD) as an arenophile, which can participate in photo-induced [4 + 2] cycloaddition with aromatic compounds [24][25][26] . During the study, we have discovered that the [4 + 2] cycloaddition of polyarenes with MTAD preferentially occurs on a terminal acene-like structure, likely to minimize steric repulsion, and the reaction furnishes an activated olefin moiety on the M-region of the PAH starting materials (Fig.…”

Advances in Catalytic Asymmetric Dearomatization

“…Sarlah and co-workers also developed Pd-catalyzed dearomative syn -1,4-carboamination of naphthalenes with the aryl Grignard reagent. 55 Product 61 could be readily transformed to sertraline in three steps ( Scheme 13 ). It was confirmed that the isolated arene-arenophile adduct 62 underwent an enantioselective ring-opening reaction in the presence of a Pd-catalyst derived from chiral bisphosphine ligand DIFLUORPHOS ( S )- L14 .…”

Shaping Molecular Landscapes: Recent Advances, Opportunities, and Challenges in Dearomatization

“…50 As seen above in the synthesis of pancratistatin (56) (Figure 4), 29 arenophile-arene cycloadducts could also be exposed to transition-metal catalysis, specifically the Ni-catalyzed dearomative trans-1,2-carboamination. Application of other metals can result in a complete change of selectivity; the combination of Pd catalysis and either enolates 51 or Grignard reagents 52 as nucleophiles affords a complementary syn-1,4-carboamination. Heteroatom nucleophiles are compatible as well, as showcased with Pd-catalyzed syn-1,4-diamination of benzene (e.g., 49 / 100).…”