Atroposelective Synthesis of N‐Arylated Quinoids by Organocatalytic Tandem N‐Arylation/Oxidation

Abstract

Diarylamines and related scaffolds are ubiquitous atropisomeric chemotypes in biologically active natural products. However, the catalytic asymmetric synthesis of these axially chiral compounds remains largely unexplored. Herein, we report that a BINOL‐derived chiral phosphoric acid (CPA) successfully catalyzed the atroposelective coupling of quinone esters and anilines through direct C−N bond formation to afford N‐aryl quinone atropisomers with an unprecedented intramolecular N−H−O hydrogen bond within a six‐membered ring in good yields and enantioselectivities with the quinone ester as both the electrophile and the oxidant. A gram‐scale experiment demonstrated the utility of this synthetic protocol. Moreover, this methodology provides a platform for the synthesis of structurally diverse secondary amine atropisomers by nucleophilic addition.

A Dynamic Kinetic Resolution Approach to Axially Chiral Diaryl Ethers by Catalytic Atroposelective Transfer Hydrogenation

“…Later on, a chiral phosphoric acid catalyzed hydrogen bonding assisted atroposelective electrophilic halogenation of N ‐aryl quinoids was reported by the same group, in which an intramolecular hydrogen‐bonding between O⋅⋅⋅H⋅⋅⋅N network was introduced to lock the rotation of the quinoid ring, the desired diarylamine‐like atropisomeric scaffold could be formed in excellent yield and atroposelectivity [15] . These positive results reveal that the organocatalytic asymmetric methodologies might provide excellent tools for atroposelective synthesis of axially chiral compounds, several works were reported by Chen, [16a] Liu [16b] and Zhong's [16c] group successively.…”

Synthetic Strategies to Control C–N Atropisomerism in Acyclic Amines and Amides

“…Liu and co-workers have reported an interesting Nfunctionalization reaction to access N-aryl quinone atropisomers (Scheme 20). 46 In the presence of the commerically available chiral phosphoric acid catalyst (R)-TRIP (90), primary anilines 87 could react with quinone esters 88 to afford axially chiral products 89 in high yields and excellent enantioselectivities (up to 99.5:0.5 e.r.). The mechanism of this process is believed to proceed via an initial enantioselective conjugate addition reaction of the amine to form a hydroquinone intermediate, which is then oxidised by a second equivalent of quinone ester (present in excess) to generate the corresponding quinone product 89.…”

“…Liu and co-workers have reported an interesting Nfunctionalization reaction to access N-aryl quinone atropisomers (Scheme 20). 46 In the presence of the commercially available chiral phosphoric acid catalyst (R)-TRIP (90), primary anilines 87 reacted with quinone esters 88 to afford axially chiral products 89 in high yields and excellent enan-…”

“…For example, in 2020, Hong, Shi and coworkers reported an elegant approach in which configurationally unstable anilides 44 bearing a single ortho-substituent (R 2 ) could undergo highly enantioselective Pd-catalyzed C-H olefination to form products 45 displaying robust axial chirality (ΔG ‡ up to 33.5 kcal/mol) (Scheme 11A). 27 The optimal ligand for this process proved to be commercially available L-pyroglutamic acid (46), and on the basis of a detailed experimental and computational studies it was proposed that the enantiodetermining step involves concerted-metalation deprotonation directed by the picolinamide group via transition state TS-49. Subsequently, the Shi group were able to expand upon this approach to develop Pd-catalyzed C-H alkynylation and allylation reactions, targeting atropisomeric N-aryl peptoids 48a and 48b, respectively (Scheme 11B).…”

Organocatalytic atroposelective synthesis of naphthoquinone thioglycosides from aryl-naphthoquinones and thiosugars

“…5 b The second strategy involves the atroposelective functionalization of N -aryl aminoquinone (Scheme 1B). 6 Gustafson reported the first catalytic atroposelective synthesis of N -aryl quinoid compounds in 2020 through phosphoric acid-catalyzed halogenation. 6 a Recently, Chen et al achieved atroposelective sulfenylation of N -aryl aminoquinone using a new chiral SPINOL-derived sulfide catalyst.…”