A method for highly regioselective bromination of phenolic compounds

Abstract

The invention discloses a method for highly regioselective bromination of phenolic compounds. In the method, trimethylbromosilane is used as a brominating agent, aryl sulfoxide is used as an activator, and phenolic compounds are mixed at 0-50°C. Stirring and reacting in a solvent and nitrogen atmosphere for 1 to 12 hours to achieve high regioselective bromination of phenolic compounds, and obtaining brominated phenolic compounds through filtration, extraction or separation and purification by column chromatography. The present invention adopts aryl sulfoxide as the activator, and the sulfoxide substituent is large, so that on the one hand, the regioselectivity of the bromination reaction of the phenolic compound is relatively high, and when the phenolic compound has no substituent at the para-position of the hydroxyl group, the regioselectivity is obtained. The product of para-bromo, and when the phenolic compound hydroxyl has a substituent at the para-position, the regioselectivity obtains the product of ortho-bromo; on the other hand, if it is separated and purified by filtration and extraction, the separation and purification of by-products can be realized simultaneously. Recycling, compared with column chromatography, reduces the cost of separation and purification.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a method for highly regioselective bromination of phenolic compounds. Background technique [0002] Phenols are important synthetic intermediates and are widely used in organic synthesis. At the same time, there are also structural units of phenolic compounds in many active pharmaceutical molecules, so it is of great value to carry out research on the synthesis of phenol derivatives. Brominated phenol can undergo Heck reaction, Suzuki coupling reaction, Ullmann coupling reaction, etc., and can be further converted into structural units with more complex and diverse structures. However, the bromination reaction of phenol still has low regioselectivity and unsatisfactory reaction yields. However, there is still an urgent need to develop a highly regioselective phenol bromination reaction method. [0003] The synthesis methods reported in the literature main...

AI Technical Summary

Problems solved by technology

Brominated phenol can undergo Heck reaction, Suzuki coupling reaction, Ullmann coupling reaction, etc., and can be further converted into structural units with more complex and diverse structures. However, the bromination reaction of phenol still has low regioselectivity and unsatisfactory reaction yields. However, there is still an urgent need to develop a highly regioselective phenol bromination reaction method, etc.

[0003] The synthesis methods reported in the literature mainly include: (1) The electrophilic substitution reaction of aromatic rings between phenol and bromine electrophiles (such as: liquid bromine, nitrogen-bromobutadiene amine imine, etc.) occurs, but usually 2-bromine Phenol, a mixture of 4-bromophenol and 2,-4-dibromophenol, low selectivity, difficult separation and purification ( Org. Biomol. Chem., 2003, 1, 2506; Tetrahedron ,2010, 66, 6928; J. Org. Chem. , 2018, 83, 930); (2) phenol reacts with bromide (such as potassium bromide, ammonium bromide, etc.) under the action of excess oxidant ( J. Org. Chem. , 1999, 64, 1191; J. Org. Chem., 2002,67 , 4487; Tetrahedron Lett. , 2008, 49 1729)

Since the reaction mechanism is that bromide and oxidant are converted into bromine electrophile in the reaction system and then participate in the reaction, the above problems still exist and the use of excessive oxidant leads to many by-products and great environmental pollution.

In 2017, Togni reported the regioselective bromination reaction of phenolic compounds using trimethylbromosilane as bromination reagent and dimethyl sulfoxide as activator, but the selectivity of the reaction was not high (88 / 12 ), separation and purification are difficult, and the by-product of the reaction, dimethyl sulfide, has a di-odor smell, which is inconvenient to recycle

Therefore, due to the limitation of the mechanism, the existing methods still have many shortcomings, which need to be improved urgently.