Electrochemical Hydroxylation of Electron‐Rich Arenes in Continuous Flow

Abstract

Dedicated to Laura Ošeka, who was born during the preparation of the manuscript for this article and helped to write it.Electrochemical hydroxylation of arenes by trifluoroacetic acid provides a straightforward access to aryl oxygen compounds under the mild and environmental benign reaction conditions. Harmful and pollutant stoichiometric amounts of oxidation reagents and the use of metal-catalysts can be avoided. Herein, we present a novel method for the synthesis of hydroxylated products from electron-rich arenes that was achieved by the implementation of a continuous-flow setup. The continuous nature of the process allowed to fine-tune the reactions conditions in order to prevent the decomposition of the sensitive products expanding the reaction scope beyond electron-poor and neutral arenes that were previously reported in the batch processes. Thus, synthetically valuable hydroxylated arenes were obtained in good yields with the residence time just over a minute. In order to demonstrate the reliability and the efficiency of the electrochemical flow setup, a scale up experiment was also performed.

Electrochemical aromatic C–H hydroxylation in continuous flow

“…The electrochemical hydroxylation reaction was compatible with anisoles substituted at the 4-position with functionalities of various electronic properties such as electron-donating OMe ( 3 ), halogens (Cl, Br; 4 and 5 ) and electron-withdrawing COOH ( 6 ), CO 2 Me ( 7 ), COMe ( 8 ), CONEt 2 ( 9 ), and CN ( 10 ). In contrast, 1,3-dimethoxybenzene failed completely and 4-methoxybenzonitrile afforded a low yield of 20% under Ošeka’s conditions 49 . Anisole derivatives bearing a substituent at the 2 or 3 position were also suitable substrates but afforded regioisomers ( 11 – 13 ).…”

“…5c . Anodic oxidation of the arene generates its corresponding radical cation, which reacts with trifluoroacetate to produce a cyclohexadienyl radical 49 , 59 . Further one-electron oxidation followed by proton loss generates the aryl trifluoroacetate intermediate, which has been observed experimentally (Supplementary Fig.…”

“…Very recently, Ošeka and coworkers reported an intriguing electrochemical hydroxylation of electron-rich arenes but are limited to certain electron-rich arenes (Fig. 1d , bottom) 49 . Benzene and electron-deficient arenes failed completely.…”

Continuous Flow Electrochemistry Enables Practical and Site‐Selective C−H Oxidation

“…We have been interested in the development of electrooxidative synthetic methods with continuous flow electrochemistry [31][32][33][34] and have achieved arene C(sp 2 )À H hydroxylation to produce phenols. [34,35] Herein, we report a practical electrochemical method for the highly selective monooxidation of benzylic C(sp 3 )À H bonds in continuous flow (Figure 1c). This electrochemical method offers several advantages, including an exceptionally broad scope (compatible with alkylarenes of a wide range of electronic properties and applicable to 1°, 2°, and 3°benzylic C(sp 3 )À H bonds), high site selectivity, excellent scalability, and the absence of any catalysts or chemical oxidants, enabling not only the efficient and cost-effective conversion of feedstock chemicals to value-added benzyl alcohols but also the late-stage oxygenation of drug molecules and natural products.…”

α-Carbonyl Radicals from N-Enoxybenzotriazoles: De Novo Synthesis of 9-Phenanthrols

“…Phenanthrene scaffolds are found in the expanding group of natural products, the core of chiral polycyclic aromatic hydrocarbons (PAHs), and optoelectric materials . Previous syntheses of 9-phenanthrols have involved C–H hydroxylation at the K-region of phenanthrenes, albeit with poor selectivity because of facile oxidation of 9-phenanthrols to 9,10-diones and to dimeric 10,10-diols. De novo syntheses of 9-phenanthrols have been relatively scarce, and notable exceptions include directed remote metalation/cyclization, Au­(I)-catalyzed alkyne oxidation/cyclization, photoinduced S RN 1 reaction of ketone enolates, Friedel–Crafts acylation, pinacol coupling, and diazo insertion…”