Synthetic method of arylboronic acid

Abstract

The invention belongs to the field of synthesis process and production application, and relates to a synthesis process for preparing arylboronic acid by taking aryl halogen as a raw material. The method comprises the following steps: S1, preparing aryl lithium salt, namely adding n-butyllithium into an ether solvent of aryl halogen at low temperature; s2, synthesizing arylboronic acid, namely adding alkyl borate serving as a raw material into the prepared aryl lithium salt solution, and optimizing a reaction process to obtain high-yield and high-purity arylboronic acid. The production method provided by the invention has the advantages of simple steps, few reaction byproducts, high yield of the obtained arylboronic acid, and great cost saving, and is suitable for large-scale industrial production, and the used solvents can be recycled.

Description

Technical Field

[0001] The invention belongs to the technical field of production of arylboronic acid, and specifically relates to a process of lithiation of halogenated aromatic hydrocarbons and hydrolysis of alkyl borate to generate boric acid. Background Art

[0002] Arylboronic acid is a boron-containing organic compound. Since the discovery of the Suzuki–Miyaura reaction in 1979, arylboronic acid has been used more and more widely in organic synthesis, and organic boronic acid compounds have become very important intermediates. In addition to the Suzuki–Miyaura reaction, Chan–Lam C–X coupling reaction, Liebeskind coupling reaction, Petasis reaction, and Minisci reaction of boronic acid and heterocyclic aromatic hydrocarbons under oxygen conditions, boronic acid is also used as a substrate. In addition, arylboronic acid can also be oxidized to prepare phenols. Its unique chemical properties make it play a key role in a variety of reactions and are widely used in organic synthesis, materials science, and drug development.

[0003] The synthesis method of aryl boronic acid is mainly to generate aryl boronic acid by reacting Grignard reagent or lithium reagent with boric acid ester. The first Grignard reagent method mainly uses aryl halogen as raw material, adds magnesium chips to generate Grignard reagent, and the generated Grignard reagent undergoes substitution reaction with alkyl borate, and then hydrolyzes to generate aryl boronic acid. Organic Letters, 13 (17), 4479-4481, 2011; Organic & Biomolecular Chemistry, 10 (24), 4704-4711; 2012;; WO2009054202; CN 104119367 A. This method is mature, but the yield is low, and the reproducibility is poor, which has caused certain limitations on large-scale production; the second method is to use aryl halogen as raw material, add n-butyl lithium and other lithium reagents to generate aryl lithium salt, and then undergo substitution reaction with alkyl borate, and then hydrolyze to obtain aryl boronic acid. J.Am.Chem.Soc.119(20),4578-4593;1997;J.Org.Chem.67(15),5394-5397,2002;J.Org.Chem.72(16),5960-5967,2007;CN101481380;WO2009092278. This method has good selectivity, high yield, and few side reactions, but the low reaction temperature imposes certain limitations on the large-scale production of this reaction. With the development of science, there are also transition metal-catalyzed borylation reactions to generate boric acid and its derivatives, but the use of transition metals as catalysts has caused a certain increase in cost, which has limited large-scale production. ACS Catal.,2022,12,8904-8910, Org.Lett.2022,24,17,3227–3231. Summary of the invention

[0004] In order to solve the above problems, the present invention discloses a method for synthesizing aryl boronic acid, which uses halogenated aromatic hydrocarbon as raw material to prepare aryl boronic acid. The halogenated aromatic hydrocarbon first reacts with n-butyl lithium to generate aryl lithium salt, then reacts with alkyl borate, and then hydrolyzes to obtain aryl boronic acid by adjusting pH. The preparation method has high yield, simple operation and low cost.

[0005] The invention provides a method for preparing an aryl boronic acid, comprising the following steps: (1) dissolving a halogenated aromatic hydrocarbon in an ether solvent under the protection of an inert gas, adding n-butyl lithium dropwise to the halogenated aromatic hydrocarbon solution at a low temperature of -78°C, slowly heating the temperature to room temperature after the addition is complete, reacting at room temperature for 2-10 hours, and generating an aryl lithium salt; (2) dissolving an alkyl borate in an ether solvent, and dropwise adding the ether solution of the alkyl borate into the aryl lithium salt solution at -78°C; (3) slowly heating the temperature to room temperature after the addition is complete, reacting at room temperature for 3-12 hours, adding acid to adjust the pH value to acidic after the reaction is complete, and generating a white solid; and (4) adding an organic solvent to the reaction solution of the white solid for extraction, separating an organic phase and an aqueous phase, combining all organic phases, and recovering the solvent by reduced pressure distillation, and beating the remaining white solid to obtain the aryl boronic acid.

[0006] The inert gas in the above scheme is nitrogen, the reaction conditions in step (1) and step (2) are anhydrous and oxygen-free, and the halogen substituent in the halogenated aromatic hydrocarbon is selected from Cl, Br or I.

[0007] The ether solvent in the above scheme is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, diethyl ether, and methyl tert-butyl ether.

[0008] In the above scheme, the molar ratio of the halogenated aromatic hydrocarbon to n-butyl lithium is 1:1-1.1; the molar ratio of the aryl lithium salt to the alkyl borate is 1:1.0-1.3; the molar ratio of the aryl halogen to the ether solvent is 1:5-10; the molar ratio of the alkyl borate to the ether solvent is 1:3-5.

[0009] In the above scheme, the alkyl borate is selected from one or more of trimethyl borate, triethyl borate, tripropyl borate, tributyl borate, triisopropyl borate, triisobutyl borate and tripentyl borate.

[0010] In the above scheme, the acid is selected from sulfuric acid, hydrochloric acid, hydrobromic acid, and phosphoric acid, and the acid is added to adjust the pH value to 2-5.

[0011] In the above scheme, the organic solvent added in step (4) is selected from one or more of ethyl acetate, benzene, toluene, dichloromethane, chloroform and n-hexane.

[0012] Beneficial effects of the present invention

[0013] (1) The present invention uses halogenated aromatic hydrocarbons as raw materials and adopts organic lithium to replace the Grignard reagent to prepare the intermediate, which has the advantages of high synthesis yield and less by-products.

[0014] (2) The present invention uses halogenated aromatic hydrocarbons as raw materials, which are low in cost and readily available, and are suitable for industrial production. DETAILED DESCRIPTION

[0015] For a better understanding of the present invention, the present invention is illustrated by the following examples. It should be clear to those skilled in the art that the examples are only to help understand the present invention and should not be regarded as specific limitations of the present invention. The raw materials involved in the embodiments of the present invention, unless otherwise specified, can be obtained from commercial sources or synthesized using commercially available starting materials and reagents by conventional methods in the art.

[0016] Example 1

[0017] Preparation of phenyl lithium salt: Take a dry 250ml three-necked flask, a 100mL constant pressure funnel, a thermometer, and a low temperature device. Add 20.0g bromobenzene dissolved in 50ml THF dehydrated into the three-necked flask under N2 protection, weigh 53.5mL of 2.5M n-butyl lithium n-hexane solution under nitrogen atmosphere protection, add dropwise to the three-necked flask at -76°C, slowly warm to room temperature after addition, react at room temperature for 5 hours, and obtain phenyl lithium salt for the next reaction.

[0018] Preparation of phenylboronic acid: Take a dry 250mL three-necked flask, a 100ml constant pressure funnel, a thermometer, a mechanical stirring device, and a low temperature device. Under N2 protection, add 50ml THF and 25.16g tributyl borate to the three-necked flask, cool to -78°C, slowly add the above-prepared phenyl lithium salt dropwise to the three-necked flask through the constant pressure funnel, and complete the dropwise addition in about 2 hours, slowly warm to room temperature, react at room temperature for 6 hours, add 10% sulfuric acid dropwise in an ice bath until the pH of the mixed solution is about 3-4, and a white precipitate is generated in the bottle at this time, filter, distill the organic phase under reduced pressure, recover the solvent, and wash the solid phase with ethyl acetate 30mL×3 times, distill all the organic phases under reduced pressure, recover all the ethyl acetate, and then continue to distill under reduced pressure to obtain a large amount of white solid, dry to obtain 14.19g of crude product, the purity of which is 98.4% after HPLC, and the yield is 94%, and the pure product of LC>99% is obtained by beating with water-ethanol solvent.

[0019] Example 2

[0020] Preparation of phenyl lithium salt: Take a dry 250mL three-necked flask, a 100mL constant pressure funnel, a thermometer, and a low temperature device. Add 20.0g of chlorobenzene dissolved in 50mL of THF dehydrated to the three-necked flask under N2 protection, weigh 74.6mL of 2.5M n-butyl lithium n-hexane solution under nitrogen atmosphere protection, add it dropwise to the three-necked flask at -76°C, slowly warm to room temperature after adding, react at room temperature for 5 hours, and obtain phenyl lithium salt for the next step reaction.

[0021] Preparation of phenylboric acid: take a dry 250mL three-necked flask, a 100mL constant pressure funnel, a thermometer, a mechanical stirring device, a low temperature device. Under N2 protection, add 50mLTHF and 35.25g tributyl borate of dehydration in the three-necked flask, cool to-78 ℃, slowly the phenyl lithium salt prepared above is added dropwise to the three-necked flask by constant pressure funnel, dropwise addition is completed in about 2 hours, slowly warm to room temperature, react at room temperature for 6 hours, dropwise add 10% sulfuric acid to the pH of mixed solution in an ice bath to about 3-4, now there is white precipitate in the bottle, filter, organic phase under reduced pressure distillation, reclaim solvent, solid phase is also washed with ethyl acetate 30mL × 3 times, all organic phases are under reduced pressure distilled, reclaim all ethyl acetate, then continue under reduced pressure distillation, obtain a large amount of white solid, dry crude product 19.71g, through HPLC purity is 97.4%, productive rate is 91%, and the pure product of LC>99% is obtained by beating with water-ethanol solvent.

[0022] For any technician familiar with the art, without departing from the scope of the technical solution of the present invention, the technical content disclosed above can be used to make many possible changes and modifications to the technical solution of the present invention, or modified into equivalent embodiments with equivalent changes. Therefore, any simple modification, equivalent change and modification made to the above embodiments according to the technical essence of the present invention without departing from the content of the technical solution of the present invention should still fall within the scope of protection of the technical solution of the present invention.

Claims

1. A method for preparing an arylboronic acid, characterized in that: The method comprises the following steps: (1) Under the protection of inert gas, the halogenated aromatic hydrocarbon is dissolved in an ether solvent, and n-butyl lithium is added dropwise to the halogenated aromatic hydrocarbon solution at a low temperature of -78°C. After the addition is completed, the temperature is slowly raised to room temperature, and the reaction is carried out at room temperature for 2-10 hours to generate an aryl lithium salt; (2) dissolving an alkyl borate in an ether solvent, and adding the ether solution of the alkyl borate dropwise into the aryl lithium salt solution at -78°C; (3) After the addition is completed, the temperature is slowly raised to room temperature and the reaction is allowed to react for 3-12 hours at room temperature. After the reaction is completed, acid is added to adjust the pH value to acidic, and a white solid appears; (4) The reaction solution of the white solid is added with an organic solvent for extraction, the organic phase and the aqueous phase are separated, all the organic phases are combined and the solvent is recovered by vacuum distillation, and the remaining white solid is recrystallized to obtain an arylboronic acid.

2. The preparation method according to claim 1, characterized in that: The inert gas in step (1) is nitrogen, and both steps (1) and (2) are carried out under anhydrous and oxygen-free conditions.

3. The preparation method according to claim 1, characterized in that: The halogen substituent in the halogenated aromatic hydrocarbon is Cl, Br or I.

4. The preparation method according to claim 1, characterized in that: The ether solvent in step (1) is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, diethyl ether, and methyl tert-butyl ether.

5. The preparation method according to claim 1, wherein the molar ratio of the halogenated aromatic hydrocarbon to n-butyl lithium is 1:1-1.1; the molar ratio of the aryl lithium salt to the alkyl borate is 1:1.0-1.3; the molar ratio of the aryl halogen to the ether solvent is 1:5-10; and the molar ratio of the alkyl borate to the ether solvent is 1:3-5.

6. The preparation method according to claim 1, characterized in that: The alkyl borate is selected from one or more of trimethyl borate, triethyl borate, tripropyl borate, tributyl borate, triisopropyl borate, triisobutyl borate and tripentyl borate.

7. The preparation method according to claim 1, characterized in that: The acid is selected from sulfuric acid, hydrochloric acid, hydrobromic acid or phosphoric acid, and the pH value is adjusted to 2-5 by adding acid.

8. The preparation method according to claim 1, characterized in that: The organic solvent added in step (1) is selected from one or more of ethyl acetate, benzene, toluene, dichloromethane, chloroform and n-hexane.