Dehydrogenative synthesis of N-functionalized 2-aminophenols from cyclohexanones and amines: Molecular complexities via one-shot assembly

Abstract

Polyfunctionalized arenes are privileged structural motifs in both academic and industrial chemistry. Conventional methods for accessing this class of chemicals usually involve stepwise modification of phenyl rings, often necessitating expensive noble metal catalysts and suffering from low reactivity and selectivity when introducing multiple functionalities. We herein report dehydrogenative synthesis of N-functionalized 2-aminophenols from cyclohexanones and amines. The developed reaction system enables incorporating amino and hydroxyl groups into aromatic rings in a one-shot fashion, which simplifies polyfunctionalized 2-aminophenol synthesis by circumventing issues associated with traditional arene modifications. The wide substrate scope and excellent functional group tolerance are exemplified by late-stage modification of complex natural products and pharmaceuticals that are unattainable by existing methods. This dehydrogenative protocol benefits from using 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) as oxidant that offers interesting chemo- and regio-selective oxidation processes. More notably, the essential role of in situ generated water is disclosed, which protects aliphatic amine moieties from overoxidation via hydrogen bond-enabled interaction.

Fig. 1.. Significance and development of the methods for syntheses of N-functionalized 2-aminophenols via transformation of C─H bond.

(A) The examples of the functional compounds synthesized from reactions of N-functionalized 2-aminophenols. (B) The conventional route to syntheses of N-functionalized 2-aminophenols. (C) The recently developed methods for construction of 2-aminophenols. (D) This work: the dehydrogenation-driven reaction of amines with cyclohexanones to construct N-functionalized 2-aminophenols.

Fig. 2.. Substrate scope for syntheses of 2-(alkylamino)phenols from cyclohexanones and aliphatic amines.

Reaction conditions: aliphatic amines (0.2 mmol, 1.0 equiv), cyclohexanone (1.5 equiv), TEMPO (3.8 equiv), 1,4-dioxane (0.4 ml), 120°C, 36 hours, under N₂ atmosphere. Yields are the yields of isolated products. ^aThe corresponding benzoxazole was isolated in 8% yield.

Fig. 3.. Substrate scope for syntheses of 2-(arylamino)phenols from cyclohexanones and anilines.

Reaction conditions: anilines (0.2 mmol), cyclohexanone (1.5 equiv), 3,5-diaminobenzoic acid (5 mol %), TEMPO (2.8 equiv), 4-Å MS (200 mg), 1,4-dioxane (0.4 ml), 120°C, N₂, 36 hours. Yields are the yields of isolated products.

Fig. 4.. Synthetic applications of the dehydrogenation-driven cross-coupling between cyclohexanones and primary amines.

(A) Scale-up syntheses of naturally occurring carbazoles in 10 mmol scale. (B) Late-stage diversification of bioactive and medicinally relevant compounds. ^aThe corresponding benzoxazole was isolated in 7% yield. ^bThe corresponding benzoxazole was isolated in 5% yield. TBS, tert-butyldimethylsily.

Fig. 5.. Mechanistic investigations and the proposed reaction pathway.

(A) Validation of α-enaminone as possible reaction intermediate. (B) Investigation on the effect of water. (C) Investigation on the source of oxygen atom in 2-aminophenol product. (D) Proposed plausible reaction mechanism.