Differentiating Catalysis in the Dearomative [4 + 2]-Cycloaddition Involving Enals and Heteroaromatic Aldehydes

Abstract

In this paper, the application of differentiating catalysis in the [4 + 2]-cycloaddition between 2-alkyl-3-formylheteroarenes and α,β-unsaturated aldehydes is described. Within the developed approach, the same aminocatalyst is employed for the independent activation of both starting materials, differentiating their properties via LUMO-lowering and HOMO-rising principles. By the combination of dearomative dienamine activation with iminium ion chemistry high enantio- and diastereoselectivity of the doubly asymmetric process was accomplished. Selected transformations of products were also demonstrated.

Turning the Imidazole Core into Three‐Dimensional Ring Systems: Mild Organocatalytic Entry to Enantiopure 6,7‐Dihydrobenzimidazoles

“…A similar retrosynthesis plan, indeed, has been successfully employed in recent years by several research groups, including ours, [8] during the asymmetric synthesis of cyclohexene‐ (or cyclohexane)‐fused heteroaromatic ring systems and exploiting in situ‐formed heterocyclic o QDMs from indole, [9] benzofuran, [9b,d,g,10] benzothiophene, [9b,d,g,10a–b] uracil, [11] and furan, [10c,12] in productive organocatalyzed [4+2] cycloadditions reactions (Figure 3b). Importantly, in those instances, the use of benzofused starting heterocycles (e. g. indoles, benzofurans, and benzothiophenes), or poorly aromatic rings (e. g. uracil, furan) was key for the successful generation of the o QDM intermediates, due to low energy gap between the starting aromatic substrate and the HOMO‐activated diene species [13]…”

Synergistic Strategies in Aminocatalysis

“…[21] Recently, Albrecht et al applied this concepts to the asymmetric [4 + 2] cycloaddition β-enals 35 and 2-alkyl-3formylheteroarenes 50 (Scheme 9. [22] Cycloadducts 51 are forged in outstanding stereoselectivities upon reaction with 52 that has a dichotomous role: it catalyzes the dearomatization of 50 through dienamine formation and it activates the dienophile 35 through iminium ion formation. In 2021, Luo et al designed an elegant αoxidation of β-ketoester 28 relying also on differentiating catalysis.…”

“…Recently, Albrecht et al. applied this concepts to the asymmetric [4+2] cycloaddition β‐enals 35 and 2‐alkyl‐3‐formylheteroarenes 50 (Scheme 9 [22] …”

Iron-catalyzed cascade C–C/C–O bond formation of 2,4-dienals with donor–acceptor cyclopropanes: access to functionalized hexahydrocyclopentapyrans

“…Despite these advances, selective coupling at the C2–C3 backbone is quite challenging due to the competing 1,2- and 1,4-additions in 2,4-dienal. 6 Furthermore, DAC has emerged as a versatile building block for the construction of five-membered cyclic scaffolds. 7,8…”