3. Synthesis of aryloxy phenols by reaction between aryl halides and resorcinol

The reaction between aryl halides and resorcinol involves a nucleophilic aromatic substitution mechanism. In this mechanism, resorcinol undergoes deprotonation under basic conditions and subsequently acts as a nucleophile on the aromatic ring of the aryl halide. This results in the formation of an intermediate, in which the nucleophile attacks the ring, leading to the substitution of the halide group. The intermediate species contains an oxide anion, which is formed due to the loss of a proton. The final product of the reaction is an aryloxy phenol, which can be obtained in good yield under appropriate reaction conditions [22].

In 2010, Vagin and colleagues published a study detailing the synthesis of 5-(3-hydroxyphenoxy)-2-nitroaniline from 5-chloro-2-nitroaniline and resorcinol. The reaction was performed using sodium hydride as a base and DMF as a solvent and was carried out under an argon atmosphere by heating the reaction mixture at 125°C for 24 hours. They then used a hydrogenation reaction with a Pd/C catalyst to obtain 4-(3-hydroxyphenoxy)-1,2-benzyldiamine (Scheme 4) [23].

4. Sonogashira Coupling: A Copper-Catalyzed Method for Biaryl Synthesis

The Sonogashira coupling reaction represents a variation of cross-coupling, wherein the interaction between aryl boronic acids and phenols is facilitated by the presence of a copper catalyst and a base. Copper (II) acetate (Cu(OAc)₂) serves as a typical example of a copper catalyst for this reaction, while potassium carbonate (K₂CO₃) is commonly used as the base. The reaction mechanism involves the formation of a complex between the copper and phenol, which subsequently reacts with the aryl boronic acid to form an intermediate. This intermediate undergoes transmetallation to furnish the final biaryl product. Due to its high efficiency and versatility, the Sonogashira coupling reaction has gained widespread use in the synthesis of pharmaceuticals and agrochemicals, among other applications [69,70]

The report by Bryan and colleagues in 2015 summarizes research endeavors centered on forming new carbon-heteroatom bonds using organoboron reagents through copper acetate-mediated reactions under ultrasound irradiation (Scheme 23). The methodology involves incorporating ultrasound irradiation in the Chan-Evans-Lam reaction to achieve the O-arylation of phenols, N-arylation of anilines and indoles, and S-arylation of thiols. The utilization of ultrasound irradiation was discovered to significantly reduce reaction times from 72 hours to 4 hours while increasing product yields by an average of 20% [71].

5. Synthesis of m-Aryloxy phenols using Grignard Reagents

The utilization of Grignard reagents, a type of organometallic compound, in the synthesis of aryloxy phenols via reaction with aldehydes or ketones has received widespread attention in the field of organic chemistry. Through interaction with a carbonyl compound, a complex intermediate is formed, which upon treatment with acidic conditions, gives rise to the corresponding alcohol. The alcohol can then be oxidized through the use of oxidation reagents such as hydrogen peroxide (H₂O₂) or sodium hypochlorite (NaClO) to produce the desired aryloxy phenol.

It is important to note that the reaction conditions, such as the choice of solvent and the presence of catalysts or bases, have a significant impact on the reactivity, selectivity, yield, and stereochemistry of the Grignard reaction and the final product [73].

In 2012, researchers led by Pidathala used 4-(3-methoxyphenoxy)benzaldehyde in a Grignard reaction to produce an intermediate alcohol (Scheme 25). 

6. Hydrolysis of Diazonium Salts Using a Two-Phase System

In 2015, Taniguchi et al. published findings on the synthesis of 3-phenoxyphenol and 3-(4-nitrophenoxy)phenol (Scheme 27). The method involved the hydrolysis of intermediate diazonium salts derived from anilines in a two-phase system of cyclopentyl methyl ether (CPME) and water, resulting in high yields of the desired compounds. These products were found to be key components for the production of raw materials for functional plastics, specifically polyimide resin [77].

7. Synthesis of 3-aryloxyphenols from 3-chlorocyclohex-2-en-1-one

In 2023, a chemical reaction was reported by Clive's group wherein 3-chlorocyclohex-2-en-1-one was treated with phenols in the presence of K₂CO₃ resulting in the formation of 3-(aryloxy)cyclohex-2-en-1-ones . The synthesized products were then subjected to bromination at the C(2) position using NBS in DMF, ultimately forming the brominated products. Subsequently, the brominated compounds were aromatized to form 3-(aryloxy)phenols through treatment with DBU in PhMe or MeCN. This multi-step reaction sequence necessitated the use of several reagents and conditions to generate the final compounds (Scheme 28). The method presently utilized operates at ambient temperature, and does not employ any heavy metals or ligands. Moreover, it circumvents the procedural steps required to overcome the o,p-directing effect of oxygen, owing to the readily available 1,3-functional group relationship inherent in the starting material, namely cyclohexane-1,3-dione [78].

8. Conclusion

In summary, the past decade has witnessed remarkable advances in the synthesis and utilization of m-aryloxy phenols. The implementation of various synthetic methodologies has resulted in the preparation of structurally diverse m-aryloxy phenols, including biologically active compounds with promising pharmacological applications. Moreover, m-aryloxy phenols have demonstrated versatility in the fields of materials science and organic electronics. These achievements have propelled further research towards the synthesis, characterization, and application of m-aryloxy phenols, and it is anticipated that this research area will continue to expand in the foreseeable future. The growing interest in m-aryloxy phenols underscores their potential to emerge as key compounds in the field of synthetic organic chemistry and their relevance to a diverse range of technological applications.