Metal-Free Oxidative Annulation of Phenols and Amines: A General Synthesis of Benzoxazoles

Abstract

The ubiquity of benzoxazoles in natural products, drugs, and functional materials has stimulated numerous efforts toward their synthesis; however, the developed methods rely on prefunctionalized substrates and lack generality. Under metal-free conditions, a highly general synthesis of benzoxazoles direct from abundant and easily available phenols and amines is developed via a modular phenol functionalization controlled by TEMPO. In the reaction, various phenols and primary amines with a broad range of functional groups are compatible, producing structurally and functionally diverse benzoxazoles (64 examples) without or with trace observation of the byproducts of phenol transformation with amines. The practical synthesis, especially for drug tafamidis, demonstrates decisive advantages in generality, selectivity, efficiency, and atom-and step-economies over traditional methods, even in the cases of low yields. Mechanistically, the radical adducts of TEMPO with ortho-cyclohexa-2,4-dien-1-one radicals rather than the well-recognized cyclohexa-3,5-diene-1,2-diones may serve as intermediates.

Application of Vitreoscilla Hemoglobin as a Green and Efficient Biocatalyst for the Synthesis of Benzoxazoles in Water

“…It is well‐known that hemeproteins catalyze oxidative reactions via a free‐radical pathway involving hydrogen transfer [12] . According to literature reports and the results of this study, [8,9g,13] a plausible mechanism can be proposed on the basis of this series of consecutive oxidation, condensation, cyclization and aromatization (Scheme 2). First, in the presence of TBHP, the heme cofactor of VHb was converted into compound I and then facilitated hydrogen atom transfer from 2,4‐di‐tert‐butylphenol (1a) to the heme cofactor, generating Fe(IV)‐hydroxide species ( compound II ) and phenolic oxygen radical 4 .…”

“…(Figure 1) Moreover, benzoxazole moieties have been used in fluorescent probes, heat‐resistant polymers and other functional materials [3] . In the past few decades, tremendous efforts have been devoted to developing procedures for benzoxazole synthesis, [4] and the most common methods are as follows (Scheme 1, a–d): (a) condensation of o‐aminophenol with aldehydes, which produces imine intermediates that are subsequently cyclized and dehydrogenated; [5] (b) intramolecular C−O coupling of 2‐haloanilides; [6] (c) intramolecular cyclization of aldimines generated from 2‐aminophenols and aromatic aldehydes; [7] and (d) oxidative annulation of phenols and amines [8] . However, these protocols have some drawbacks, such as toxic metal catalysts, high catalyst loading, harsh reaction conditions, long reaction time and non‐environmentally friendly solvents.…”

Oxytrofalcatin Puzzle: Total Synthesis and Structural Revision of Oxytrofalcatins B and C

“…The original possible biogenetic pathway proposed by Shi and co-workers is shown in Scheme A . Oxidative cyclization of 10–11 at the benzene ring through path a could lead to N -benzoyl-3-hydroxyindoline 24 . Dehydrative aromatization of 24 delivers the N -benzoylindole 25 , whose oxyfunctionalization at the C-3 position results in oxytrofalcatins 1–6 .…”

Palladium-Mediated Reductive Heck Cyclization for the Synthesis of Fused Retinoid Derivatives

“…Compound 3 was prepared from phenol according to known procedure. 15 To a stirred solution of compound 3 (2.0 g, 9.7 mmol), in DMF (20 ml) was added N-iodo succinimide (2.40 g, 10.67 mmol) and the reaction mixture was stirred at room temperature for 2 h. After that, the reaction mixture was poured into 100 ml of water and extracted with CHCl3 (100 ml x 3). The combined organic layer was further washed with water (50 ml x 3).…”