A reaction mode of carbene-catalysed aryl aldehyde activation and induced phenol OH functionalization

Abstract

The research in the field of asymmetric carbene organic catalysis has primarily focused on the activation of carbon atoms in non-aromatic scaffolds. Here we report a reaction mode of carbene catalysis that allows for aromatic aldehyde activation and remote oxygen atom functionalization. The addition of a carbene catalyst to the aldehyde moiety of 2-hydroxyl aryl aldehyde eventually enables dearomatization and remote OH activation. The catalytic process generates a type of carbene-derived intermediate with an oxygen atom as the reactive centre. Inexpensive achiral urea co-catalyst works cooperatively with the carbene catalyst, leading to consistent enhancement of the reaction enantioselectivity. Given the wide presence of aromatic moieties and heteroatoms in natural products and synthetic functional molecules, we expect our reaction mode to significantly expand the power of carbene catalysis in asymmetric chemical synthesis.

Carbene‐Catalyzed Enantioselective Decarboxylative Annulations to Access Dihydrobenzoxazinones and Quinolones

“…[11b] Following these studies,s everal approaches to extend this reactivity to carbocyclic aromatic systems have emerged. [13] These contributions have expanded the scope of carbene catalysis,w hile simultaneously presenting opportunities to develop new and complementary methods employing NHC-bound o-QDMlike nucleophiles.H erein, we report ad ecarboxylative transformation proceeding via an NHC-bound aza-o-QM intermediate to access enantioenriched dihydrobenzoxazin-4-ones (Scheme 1c). There have been significantly fewer developments employing oquinone methides (o-QMs) or aza-o-quinone methides (azao-QMs) as nucleophiles in NHC catalysis.Anotable recent advance by Chi employed salicylaldehydes in the presence of stoichiometric oxidant and base to generate an NHC-bound o-QM, which participated in an annulation with trifluoromethyl ketone electrophiles (Scheme 1b).…”

Carbene‐Catalyzed Enantioselective Aromatic N‐Nucleophilic Addition of Heteroarenes to Ketones

“…Lewis acids have been shown to be promising co‐catalysts that can enhance stereoselective control in multiple NHC‐catalytic reactions . We therefore examined Lewis acids as co‐catalysts (entries 5–7) and found that the addition of urea molecule G could succefully enhance the reaction er from 86:14 (entry 4) to 90:10 (entry 7). Organic or inorganic bases with strong basicities resulted in a decomposition of the N , O ‐acetal products (entry 8).…”

“…The carbon atoms were activated as either nucleophilic or electrophilic reactive centers. In 2017, Chi and co‐workers found that through the addition of a carbene to the aldehyde moiety of a 2‐hydroxyl benzaldehyde under oxidative conditions, the phenol oxygen atom could be activated for enantioselective reactions . This activation converted the acylazolium to an ortho ‐quinone methide ( o ‐QM) intermediate with the oxygen as the reactive center (Scheme b, left).…”

N‐Heterocyclic Carbene‐Catalyzed Formal [6+2] Annulation Reaction via Cross‐Conjugated Aza‐Trienolate Intermediates

“…When the reaction of 1 a and 2 a was performed in the absence of NHC pre‐catalyst 4 , the desired product 3 a was not formed indicating the role of NHC in this [6+2] annulation (Scheme , eq 6). Moreover, the acetal 10 a (likely formed by the N−H addition of 1 a to 2 a followed by intramolecular cyclization) was not observed under these conditions showing that the direct N−H addition of initially formed acylazolium and cyclization in a [3+2] pathway is not operating in this case . In addition, when the reaction was performed using N ‐Boc protected aldehyde 11 a , the product 3 a was not formed signifying the role of N−H moiety in forming the NHC‐bound cross‐conjugated aza‐trienolates (eq 7).…”