Palladium‐Catalyzed [4 + 4] Cycloaddition of Homo‐TMM All‐Carbon 1,4‐Dipole Precursors for Construction of Benzofuro[3,2‐b]azocines and Furo[3,2‐b]azocines

Abstract

Comprehensive SummaryWe developed a novel Pd‐catalyzed [4 + 4] cycloaddition of (benzo)furan‐derived azadienes with homo‐TMM all‐carbon 1,4‐dipoles in situ generated from α‐allyl malonate derivatives, affording an array of benzofuro[3,2‐b]azocines and furo[3,2‐b]azocines with good to excellent yields (up to 96%) and exclusive regioselectivities. This methodology featured mild reaction conditions and good functional group tolerance. The synthetic utility was demonstrated by a gram‐scale reaction. Furthermore, the catalytic asymmetric [4 + 4] cycloaddition version has also been explored.

Recent advances in [4 + 4] annulation of conjugated heterodienes with 1,4-dipolar species for the synthesis of eight-membered heterocycles

“…25 In recent years, the assembly of the azocine skeleton through cascade transformations based on [4 + 4] annulation has evolved as a facile and powerful strategy for access to the related useful medium-sized N-heterocyclic molecules. 31,33,35,38,41,44,45,47,49,53…”

“…In recent years, enyne-amides have been employed as a class of precursors of furan- or pyrrole-fused conjugated heterodienes, which have been extensively applied as robust 4-atom annulation synthons for the assembly of various bicyclic heterocycles through [4 + n ] cycloaddition. 39,41,44,45…”

“…Inspired by Trost's work and in combination with their efforts in the synthesis of medium-sized rings, the Deng and Luo group developed a Pd-catalyzed [4 + 4] cycloaddition of (benzo)furan-derived 1-azadienes with homo-TMM 1,4-dipoles, in 2023. 44 Using benzofuran-derived 1-azadienes or enyne-amides and α-allyl malonate derivatives 86 as starting materials, a broad range of functionalized benzofuro[3,2- b ]azocines 87 and furo[3,2- b ]azocines 88 were facilely assembled in moderate to excellent yields with exclusive regioselectivities through the [4 + 4] annulation reactions under Pd catalysis (Scheme 11). The annulation of benzofuran-derived 1-azadienes 40 proceeded effectively without the use of a ligand, while a racemic monophosphine ligand ( L2 ) was required to facilitate the reactions with enyne-amides 72 .…”

Recent progress in the construction of eight-membered nitrogen-heterocycles

“…Recently, Deng and co-workers reported that in situ -generated homo-TMM (trimethylenemethane) all-carbon 1,4-dipoles participated in the [4+4] cycloaddition reaction and afforded furo[3,2- b ]azocines containing an eight-membered N-heterocycle skeleton in good to excellent yields. 42 Zhou and co-workers further developed an enantioselective [4+4] cycloaddition reaction using similar substrates, which was the first catalytic asymmetric [4+4] cyclization of aliphatic 1,4-dipoles. 43…”

Kinetic resolution of 1-(1-alkynyl)cyclopropyl ketones via gold-catalyzed divergent (4 + 4) cycloadditions: stereoselective access to furan fused eight-membered heterocycles

“… 4 However, these dipolar species often lack structural diversity and heterocyclic 1,4-dipoles are seldom studied, hampering the exploration of the (4 + 4) strategy in a broader manner. 5 To address this long-standing challenge, we wondered whether TM-based furyl species could serve as heterocyclic 1,4-dipoles, which would furnish challenging eight-membered cycloadducts with tetrasubstituted furan scaffolds ( Scheme 1c ). In 2008, Zhang and co-workers presented one remarkable study of Au-catalyzed racemic (4 + 2) cycloaddition of 1-(1-alkynyl)-cyclopropyl ketones with indoles, where the alkynyl cyclopropyl ketones serve as the Au-furyl 1,4-dipole precursors.…”