Catalytic S_NAr Hydroxylation and Alkoxylation of Aryl Fluorides

Abstract

Nucleophilic aromatic substitution (SNAr) is a powerful strategy for incorporating a heteroatom into an aromatic ring by displacement of a leaving group with a nucleophile, but this method is limited to electron‐deficient arenes. We have now established a reliable method for accessing phenols and phenyl alkyl ethers via catalytic SNAr reactions. The method is applicable to a broad array of electron‐rich and neutral aryl fluorides, which are inert under classical SNAr conditions. Although the mechanism of SNAr reactions involving metal arene complexes is hypothesized to involve a stepwise pathway (addition followed by elimination), experimental data that support this hypothesis is still under exploration. Mechanistic studies and DFT calculations suggest either a stepwise or stepwise‐like energy profile. Notably, we isolated a rhodium η5‐cyclohexadienyl complex intermediate with an sp3‐hybridized carbon bearing both a nucleophile and a leaving group.

Synthesis of Phenols from Aryl Ammonium Salts under Mild Conditions

“…All spectral data match those previously reported. 21 Synthesis of 4′-Hydroxyacetophenone (5). Following the general procedure, the crude product was purified using silica gel column chromatography (hexane−AcOEt = 8:1) to produce the desired product 5; 5 was isolated as a white solid (139 mg, 85% yield); 1 H NMR 6).…”

“…The nucleophilic aromatic substitution (S N Ar) of aryl fluorides bearing strongly electron-withdrawing substituents is also effective to prepare phenols . In 2021, Shi and co-workers developed a remarkable strategy for the hydroxylation of electron-rich and neutral aryl fluorides via Rh-catalyzed S N Ar reaction …”

“…4 In 2021, Shi and co-workers developed a remarkable strategy for the hydroxylation of electron-rich and neutral aryl fluorides via Rh-catalyzed S N Ar reaction. 5 The direct oxidation of arylboronic acids 6 or the one-pot C(sp 2 )−H activation/borylation/oxidation strategy 7 of the arenes are also common methods of hydroxylation, which were limited to substrates that are not sensitive to oxidation conditions (Scheme 1B). In addition, direct hydroxylation of the simple arenes is a straightforward and effective strategy for the synthesis of phenols with high atom economy.…”

Radicals as Exceptional Electron-Withdrawing Groups: Nucleophilic Aromatic Substitution of Halophenols Via Homolysis-Enabled Electronic Activation

“…This limitation has drawn the interest of many laboratories in recent years, and a number of elegant methods have been developed to achieve S N Ar of unactivated electrophiles, including the use of alkali hydrides for concerted substitution, 21,22 the development of pre-functionalization reagents for deoxyfluorination, 23,24 the application of singleelectron oxidation, 25−27 and η 6 -coordination with a rhodium catalyst. 28 However, direct S N Ar with many electron-rich arenes remains a general challenge. With a σ p − (OH) value as low as −0.37, 3 fluorophenols are prohibitively electron-rich to serve as electrophiles in S N Ar reactions.…”

One-step hydroxylation of aryl and heteroaryl fluorides using mechanochemistry

“…Very recently, assisted S N Ar through the formation of a complex with the use of a Rh catalyst and an Ag base, has also allowed the introduction of electron-rich aromatic rings as reactants. 7…”