A method for highly regioselective bromination of phenolic compounds

A phenolic compound and selective technology, which is applied in the field of high regioselective bromination of phenolic compounds, can solve the problems of inconvenient recovery, unsatisfactory reaction yield, difficulty in separation and purification, etc., so as to reduce the cost of separation and purification, and improve the availability of raw materials. The effect of a wide range and wide application prospects

Active Publication Date: 2021-08-27
XINYANG NORMAL UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

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.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Embodiment 1 phenol and bromotrimethylsilane prepare 4-bromophenol

[0020] Phenol (47.0 mg, 0.50 mmol), trimethylbromosilane (84.2 mg, 0.55 mmol, 1.1 equiv.), bis-(4-chlorophenyl) sulfoxide (148.5 mg, 0.55 mol) and acetonitrile (1.0 mL), then evacuated, under nitrogen protection, and reacted at 25 °C for 6 h. After the completion of the reaction monitored by GC-MS, filter and wash the filter cake with a small amount of cold acetonitrile, and recover the filter cake as bis-(4-chlorophenyl)sulfide. Add 1M sodium hydroxide (0.6 mL) to the filtrate, then transfer to a separatory funnel and extract with ethyl acetate 5 mL*3, combine the organic layers, spin dry and combine with the filter cake bis-(4-chlorophenyl) obtained above The thioether is combined, that is, a mixture of bis-(4-chlorophenyl)sulfoxide (residue from the reaction) and bis-(4-chlorophenyl)sulfide (reaction product), and then the mixture is completely converted to di- (4-Chlorophenyl) sulfoxide can be us...

Embodiment 2

[0024] Embodiment 2 phenol and bromotrimethylsilane prepare 4-bromophenol

[0025] Phenol (47.0 mg, 0.50 mmol), bromotrimethylsilane (84.2 mg, 0.55 mmol, 1.1 equiv.), bis-(4-methylphenyl)sulfoxide (126.5 mg, 0.55 mol ) and acetonitrile (1.0 mL), then evacuated, under nitrogen protection, and reacted at 25°C for 6 h. After the completion of the reaction was monitored by GC-MS, 1M sodium hydroxide (0.6mL) was added to the solution, then transferred to a separatory funnel and extracted with ethyl acetate 5 mL*3, the organic layers were combined, and the obtained filter cake di-(4 -Tolyl)sulfide and bis-(4-tolyl)sulfoxide (residue from the reaction). The mixture was then completely converted to bis-(4-tolyl)sulfoxide by oxidation, which could be used as an activator in the next bromination reaction of phenolic compounds (90% overall recovery). Add 1M dilute hydrochloric acid to the extracted aqueous phase to adjust the pH to 1, then add 5 mL*3 ethyl acetate again for extraction,...

Embodiment 3

[0028] Embodiment 3 phenol and bromotrimethylsilane prepare 4-bromophenol

[0029] Phenol (47.0 mg, 0.50 mmol), trimethylbromosilane (84.2 mg, 0.55 mmol, 1.1 equiv.), bis-(4-chlorophenyl) sulfoxide (148.5 mg, 0.55 mol) and acetonitrile (1.0 mL), then evacuated, under nitrogen protection, and reacted at 25 °C for 6 h. After the completion of the reaction was monitored by GC-MS, the product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 30 / 1). The separation yield was 90% (selectivity 97 / 3).

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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...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C37/62C07C39/27C07C41/22C07C43/253C07C231/12C07C233/25C07C67/307C07C69/84C07C39/38C07C45/63C07C47/565
Inventor 马献涛于静江梦园唐林周秋菊
Owner XINYANG NORMAL UNIVERSITY
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