Electrophilic aromatic substitution (EAS) reaction is one of the basic reactions in chemical synthesis. One-third of the approximately 10 million compounds synthesized today are functionalized on benzene rings by EAS. However, the application of EAS is still limited, and it is urgent to develop a strategy to overcome the rigid regioselectivity of EAS in order to accelerate the preparation of benzene series that cannot be synthesized by existing methods.
Some research groups imagined that if the regiochemically favorable σ-complexes could be prevented from directly converting into the expected EAS products, migration via 1,2-electrophiles would lead to a completely new σ-complex that cannot be obtained by other synthetic methods. The complex, a product of electrophilic substitution with different regioselectivity, can be generated by re-aromatization. However, the synthesis and subsequent rearrangement and rearomatization of 2,4-cyclohexadienone are not easy. Recently, researchers report the successful overcoming of the inherent regioselectivity of electrophilic aromatic substitutions by transferring key σ-complex intermediates to otherwise difficult-to-synthesize substitution products. This transfer strategy (consisting of Bi(V)-mediated electrophilic arylation followed by aryl migration/re-aromatization) can be used for the meta-selective C–H bond arylation of sterically crowded phenolic compounds. Furthermore, this approach also yields highly functionalized, sequentially substituted aromatic building blocks that cannot be synthesized by existing methods.
First, the researchers optimized the conditions of the bismuth oxide-mediated electrophilic arylation reaction, and the results showed that dienone could be obtained in excellent isolated yield (93%). Subsequently, the researchers found that Lewis acids (such as Bi(OTf)3 and Sc(OTf)3) can promote the rearrangement of dienone, and after increasing the temperature and prolonging the reaction time, the desired m-arylphenol can be obtained compounds can be obtained in >95% yield.
Under the optimal conditions, the researchers investigated the range of substrates, and the results showed that a series of aryl boric acid and heteroaryl boric acid with donor/acceptor groups or ortho-substituted in the intermediate/para-position can be converted into the desired products with good yields. Secondly, 2,6-dimethylphenol with different groups can be effectively dearomatized and aryl transferred, and polysubstituted phenol can be obtained with excellent yield. In summary, this method has the following advantages: 1) The interrupted arylation - migration process eliminates the polyarylation of the substrate, so it can achieve high yield; 2) The bicyclic group has complete ortho selectivity for the initial arylation of phenol substrate, and has regional specificity for the transferred aryl group; 3) Although the m-arylation of 2,6-unsubstituted phenol can not be realized, this method is compatible with the previous ortho and para substitutions, thus speeding up the synthesis of multi-functional phenol and providing a supplement for the Pd-catalytic method.
Next, the researchers carried out a series of derivatization of the product: 1) The analogues of the antiarrhythmic drug metoprolol were obtained by O-alkylation and reductive amination of phenol in 75% yield; 2) The product is deoxidized to obtain m-aryl aniline, which can then be further converted into the anesthetic lidocaine analogues and the herbicide dimethylchlor analogues; 3) Using this method, asymmetric 3,5-diarylphenol, which is a dimethyl analogue of the key block for the synthesis of LTB4 receptor antagonist RO5101576, was synthesized in a modular manner; 4) Starting from the same substrate, two regioisomers of bisphenol can be selectively prepared by selecting different arylation reagents.
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Reference
- meta-Selective C–H arylation of phenols via regiodiversion of electrophilic aromatic substitution
Aaron Senior, Katie Ruffell, Liam T. Ball.
