阅读说明：本技术 一种异丙烯基硼酸频哪醇酯的合成方法 (Synthetic method of isopropenyl pinacol borate ) 是由 刘经红 刘启宾 郑鹏 于 2021-09-06 设计创作，主要内容包括：本发明公开了一种异丙烯基硼酸频哪醇酯的合成方法,采用丙酮和联硼酸酯在铜卡宾试剂作用下,生成偕二硼化产物,接着在对甲苯磺酸存在下进行消除反应,最后与频哪醇一锅法反应得到异丙烯基硼酸频哪醇酯。该方法操作简单,采用金属铜催化剂作用下直接硼化反应,避免了传统工艺方法中2-溴丙烯的使用,为异丙烯基硼酸频哪醇酯的合成提供了一条新的合成路径。(The invention discloses a synthesis method of isopropenyl boronic acid pinacol ester, which comprises the steps of generating a gem-diboride product by using acetone and diborate under the action of a copper carbene reagent, carrying out elimination reaction in the presence of p-toluenesulfonic acid, and finally reacting with pinacol by a one-pot method to obtain the isopropenyl boronic acid pinacol ester. The method is simple to operate, adopts direct boronization reaction under the action of a metallic copper catalyst, avoids the use of 2-bromopropylene in the traditional process method, and provides a new synthetic path for the synthesis of isopropenyl pinacol borate.)

1. A synthetic method of isopropenyl pinacol borate is characterized by comprising the following steps: using acetone and diborate as raw materials, and reacting in an organic solvent at 70-80 ℃ in the presence of cuprous chloride, 1, 3-dicyclohexyl imidazole chloride, an anion-containing ligand and organic alkali; adding p-toluenesulfonic acid, and controlling the temperature to be 40-50 ℃ for reaction; and after the reaction is finished, cooling to room temperature, adding triethylamine, pinacol and a polymerization inhibitor for reaction, concentrating under reduced pressure to obtain an organic solvent, adding sulfolane, and distilling under reduced pressure to obtain the isopropenyl borate.

2. The method for synthesizing isopropenylboronic acid pinacol ester according to claim 1, wherein: the diboronic acid ester is selected from neopentyl glycol diborate or o-catechol diborate.

3. The method for synthesizing isopropenylboronic acid pinacol ester according to claim 1, wherein: the anionic ligand is selected from BF₄ ^-、PF₆ ^-Or BARF^-。

4. The method for synthesizing isopropenylboronic acid pinacol ester according to claim 1, wherein: the organic base is selected from potassium trimethylsilanolate, potassium tert-butoxide or sodium tert-butoxide.

5. The method for synthesizing isopropenylboronic acid pinacol ester according to claim 1, wherein: the molar ratio of the acetone, the diboronic acid ester, the cuprous chloride, the 1, 3-dicyclohexylimidazole chloride, the anionic ligand and the organic base is 1-1.3: 1: 0.03-0.05: 0.045-0.075: 0.06-0.10: 0.06-0.10.

6. The method for synthesizing isopropenylboronic acid pinacol ester according to claim 1, wherein: the mole ratio of the diboronic acid ester, the p-toluenesulfonic acid, the triethylamine and the pinacol is 1: 2-3: 2-3: 1-1.2.

7. The method for synthesizing isopropenylboronic acid pinacol ester according to claim 1, wherein: the organic solvent is acetonitrile, and the using amount of the acetonitrile is 2-10 times of the weight of the diboronic acid ester.

8. The method for synthesizing isopropenylboronic acid pinacol ester according to claim 1, wherein: the polymerization inhibitor is selected from phenothiazine or 2, 6-di-tert-butyl-4-methylphenol.

9. The method for synthesizing the isopropenylboronic acid pinacol ester according to any one of claims 1 to 8, wherein: the reaction is carried out under the protection of argon or nitrogen.

The technical field is as follows:

the invention belongs to the field of organic chemistry, and particularly relates to a synthetic method of isopropenyl pinacol borate.

Background art:

isopropenyl borate is used as an important coupling assistant for Suzuki coupling to synthesize a pyrimidone amide phosphodiesterase 2 inhibitor for treating central nervous system disorder, and the isopropenyl is an essential raw material in medicine synthesis due to the particularity of the structure of the isopropenyl, and an isopropenyl structural unit is involved in more and more medicine researches, so that the market demand of the compounds is increasing.

The existing synthesis method of isopropenyl pinacol borate mainly comprises the following three methods:

first, pinacol is reacted with isopropenylboronic acid to form an ester. 2-bromopropylene is used as a raw material, a Grignard reagent is prepared firstly, the Grignard reagent reacts with trimethyl borate to generate isopropenylboronic acid, and then the isopropenylboronic acid reacts with pinacol to obtain isopropenylboronic acid pinacol ester (refer to J.Am.chem.Soc.,2006,128, 16384-one 16393). In the synthesis method, the intermediate isopropenyl boric acid is unstable and is easy to deteriorate in the post-treatment process.

And secondly, carrying out Suzuki coupling reaction on the 2-bromopropylene and the double boric acid ester to obtain ester. The formation of isopropenylboronic acid pinacol ester from 2-bromopropene and pinacol ester of boronic acid bis under the catalysis of palladium metal is reported (refer to org. biomol. chem.,2020,18, 4390-one 4394). The yield of the method is only 34 percent, and the used palladium catalyst of the tetratriphenylphosphine is expensive, so that the cost of raw materials is high.

Thirdly, CN105503923 reports a method for synthesizing isopropenyl borate. 2-bromopropylene reacts with metal lithium and diisopropylamino boron chloride to generate diisopropylamino isopropenyl borane firstly, the diisopropylamino isopropenyl borane directly reacts with diol without quenching post-treatment, and isopropenyl borate is obtained by reduced pressure distillation after the reaction is finished. In the method, because the intermediate is not quenched, a large amount of viscous solid lithium salt is separated out in the process of post-processing the vacuum distillation product, and the product is wrapped in the solid and is not easy to evaporate, so that the reproducibility during amplification is difficult to ensure.

The invention content is as follows:

in order to overcome the problems, the invention discloses a method for synthesizing isopropenyl boronic acid pinacol ester. Acetone and diborate ester are adopted to generate a gem-diboron product under the action of a copper carbene reagent, then elimination reaction is carried out under the action of p-toluenesulfonic acid, and the elimination reaction is carried out with pinacol to obtain isopropenyl boronic acid pinacol ester through a one-pot reaction.

The invention provides a synthesis method of isopropenyl pinacol borate, which comprises the following operation steps: using acetone and diborate as raw materials, and reacting in an organic solvent at 70-80 ℃ in the presence of cuprous chloride, 1, 3-dicyclohexyl imidazole chloride, an anion-containing ligand and organic alkali; adding p-toluenesulfonic acid, and controlling the temperature to be 40-50 ℃ for reaction; and after the reaction is finished, cooling to room temperature, adding triethylamine, pinacol and a polymerization inhibitor for reaction, concentrating under reduced pressure to obtain an organic solvent, adding sulfolane, and distilling under reduced pressure to obtain the isopropenyl borate.

The reaction scheme is expressed by the following equation:

1, 3-dicyclohexylimidazolium chloride (ICy). HCl structural formula as follows:

further, the diborate ester is selected from neopentylglycol diborate or orthophthalate diborate.

Further, the anionic ligand is selected from BF₄ ^-、PF₆ ^-Or BARF-, preferably BARF^-。

Further, the organic base is selected from potassium trimethylsilanolate, potassium tert-butoxide or sodium tert-butoxide, preferably potassium trimethylsilanolate.

Further, the molar ratio of the acetone, the diboronic acid ester, the copper salt, the 1, 3-dicyclohexyl imidazole chloride, the anionic ligand and the organic base is 1-1.3: 1: 0.03-0.05: 0.045-0.075: 0.06-0.10: 0.06-0.10.

Further, the mole ratio of the diborate, the p-toluenesulfonic acid, the triethylamine and the pinacol is 1: 2-3: 2-3: 1-1.2.

Further, the reaction solvent is acetonitrile, and the amount of the acetonitrile is 2-10 times, preferably 5-6 times of the weight of the diboronate.

Further, the polymerization inhibitor is selected from phenothiazine or 2, 6-di-tert-butyl-4-methylphenol.

Further, the isolation of air or oxygen is of particular concern during the reaction. Preferably under argon or nitrogen.

The invention has the following advantages:

1. the traditional copper carbene reagent is limited by harsh preparation conditions and instability, and is difficult to prepare. According to the technical scheme, an anion ligand is introduced into a reaction system, the copper carbene reagent is prepared in situ under an alkaline condition by adopting cheap cuprous chloride and carbene salt, and the anion exchange is utilized to improve the stability of the copper carbene reagent, increase the solubility of the copper carbene reagent in an acetonitrile solvent and promote the rapid reaction.

2. The direct boronization avoids the use of 2-bromopropylene in the traditional process method, and provides a new synthetic path for the synthesis of isopropenyl pinacol borate.

3. The preparation of active metal reagents such as Grignard reagents or lithium reagents is avoided, and the potential safety hazard is reduced. The solvent used in the reaction can be recycled and reused, and the amount of the waste solvent is small.

4. The method provided by the invention is a one-pot reaction, is simple and convenient to operate, simple in treatment after the reaction, good in reproducibility and suitable for large-scale production.

Drawings

FIG. 1 is the nuclear magnetic spectrum of pinacol ester isopropenylboronic acid in example 1.

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION

Example 1

1.5L of acetonitrile, acetone (69.6g, 1.20mol), neopentyl glycol diborate (225.9g, 1.00mol), CuCl (4.9g, 0.05mol), ICy. HCl (20.2g, 0.075mol), potassium tert-butoxide (11.2g, 0.10mol) and 1-butyl-3-methylimidazolium hexafluorophosphate (28.4g, 0.10mol) were added to a reaction flask under nitrogen blanket and heated to 70-80 ℃ for 4 hours. GC tests that the raw materials are completely reacted, the reaction temperature is reduced to room temperature, p-toluenesulfonic acid (344.0g, 2.00mol) is added, the reaction is completed after dropwise addition, the reaction is carried out for 7 hours at the temperature of 40-50 ℃, the temperature is reduced to below 20 ℃, triethylamine (202.4g, 2.00mol) is added dropwise, pinacol (130.0g, 1.1mol) and 2, 6-di-tert-butyl-4-methylphenol (5.0g) are added after dropwise addition, the reaction is completed after stirring for 2 hours at the room temperature, acetonitrile is concentrated under reduced pressure, sulfolane (350g) is added, and then reduced pressure distillation is carried out to obtain colorless liquid isopropenylboronic acid pinacol ester 94.7g, the GC purity is 99.6%, and the yield is 56.4%.¹The characterization spectrum of H-NMR is shown in figure 1. The experiment was carried out under the same conditions in an air atmosphere, and the yield was 21.3%.

Example 2

1.5L of acetonitrile, acetone (63.8g, 1.10mol), neopentyl glycol diborate (225.9g, 1.00mol), CuCl (2.9g, 0.03mol), ICy. HCl (12.2g, 0.045mol), potassium trimethylsilanolate (7.7g, 0.06mol) and 1-butyl-3-methylimidazolium tetrafluoroborate (13.6g, 0.06mol) were added to a reaction flask under nitrogen protection and heated to 70-80 ℃ for 3 hours. GC tests that the raw materials are completely reacted, the reaction temperature is reduced to room temperature, p-toluenesulfonic acid (344.0g, 2.00mol) is added, the reaction is completed after dropwise addition, the reaction is carried out for 6 hours at the temperature of 40-50 ℃, the temperature is reduced to below 20 ℃, triethylamine (202.4g, 2.00mol) is added dropwise, pinacol (141.6g, 1.2mol) and 2, 6-di-tert-butyl-4-methylphenol (5.0g) are added after dropwise addition, the reaction is completed after stirring for 2 hours at the room temperature, acetonitrile is concentrated under reduced pressure, sulfolane (350g) is added, and then reduced pressure distillation is carried out to obtain colorless liquid isopropenylboronic acid pinacol ester 108.6g, the GC purity is 99.4%, and the yield is 64.7%. The experiment was carried out under the same conditions in an air atmosphere, and the yield was 25.6%.

Example 3

1.5L of acetonitrile, acetone (75.4g, 1.30mol), neopentyl glycol diborate (225.9g, 1.00mol), CuCl (4.9g, 0.05mol), ICy. HCl (20.2g, 0.075mol), sodium tert-butoxide (9.6g, 0.10mol) and sodium tetrakis {3, 5-bis (trifluoromethyl) phenyl } borate (88.6g, 0.10mol) were added to a reaction flask under nitrogen blanket, heated to 70-80 ℃ and reacted for 4 hours. GC tests that the raw materials are completely reacted, the reaction temperature is reduced to room temperature, p-toluenesulfonic acid (430.0g and 2.50mol) is added, the reaction is completed after dripping, the reaction is carried out for 6 hours at the temperature of 40-50 ℃, the temperature is reduced to below 20 ℃, triethylamine (253.0g and 2.50mol) is added, pinacol (130.0g and 1.1mol) and phenothiazine (5.0g) are added after dripping, the reaction is stirred for 2 hours at the room temperature, acetonitrile is concentrated under reduced pressure after finishing the reaction, sulfolane (450g) is added, and then the reduced pressure distillation is carried out to obtain colorless liquid pinacol isopropenyl borate ester (120.1 g), the GC purity is 99.1%, and the yield is 71.5%. The experiment was carried out under the same conditions in an air atmosphere, and the yield was 70.8%.

Example 4

1.5L of acetonitrile, acetone (63.8g, 1.10mol), neopentyl glycol diborate (225.9g, 1.00mol), CuCl (2.9g, 0.03mol), ICy. HCl (12.2g, 0.045mol), potassium trimethylsilanolate (7.7g, 0.06mol) and sodium tetrakis {3, 5-bis (trifluoromethyl) phenyl } borate (53.1g, 0.06mol) were added to a reaction flask under nitrogen protection and heated to 70-80 ℃ for 3 hours. GC tests that the raw materials completely react, the temperature is reduced to room temperature, p-toluenesulfonic acid (344.0g, 2.00mol) is added, the reaction is completed at 40-50 ℃ for 7 hours, the temperature is reduced to below 20 ℃, triethylamine (202.4g, 2.00mol) is added dropwise, pinacol (129.8g, 1.1mol) and phenothiazine (5.0g) are added after the dropwise addition, the reaction is stirred for 2 hours at room temperature, acetonitrile is concentrated under reduced pressure after the reaction is completed, sulfolane (350g) is added, and then the mixture is distilled under reduced pressure to obtain a colorless liquid, namely isopropenyl pinacol ester of boric acid 140.6g, the GC purity is 99.5%, and the yield is 83.7%. The experiment was carried out under the same conditions in an air atmosphere, and the yield was 82.2%.

Example 5

1.5L of acetonitrile, acetone (63.8g, 1.10mol), catechol diboronate (223.8g, 1.00mol), CuCl (2.9g, 0.03mol), ICy. HCl (12.2g, 0.045mol), potassium trimethylsilanolate (7.7g, 0.06mol) and sodium tetrakis {3, 5-bis (trifluoromethyl) phenyl } borate (53.1g, 0.06mol) were added to a reaction flask under nitrogen protection and heated to 70-80 ℃ for 3 hours. GC tests that the raw materials are completely reacted, the reaction temperature is reduced to room temperature, p-toluenesulfonic acid (344.0g, 2.00mol) is added, the reaction is completed after dropwise addition, the reaction is carried out for 7 hours at the temperature of 40-50 ℃, the temperature is reduced to below 20 ℃, triethylamine (202.4g, 2.00mol) is added dropwise, pinacol (129.8g, 1.1mol) and 2, 6-di-tert-butyl-4-methylphenol (5.0g) are added after dropwise addition, the reaction is completed after stirring for 2 hours at the room temperature, acetonitrile is concentrated under reduced pressure, sulfolane (350g) is added, and then reduced pressure distillation is carried out to obtain colorless liquid isopropenylboronic acid pinacol ester 143.6g, the GC purity is 99.2%, and the yield is 85.5%. The experiment was carried out under the same conditions in an air atmosphere, and the yield was 81.9%.

Example 6

1.5L of acetonitrile, acetone (69.6g, 1.20mol), catechol diboronate (223.8g, 1.00mol), CuCl (2.9g, 0.03mol), ICy. HCl (12.2g, 0.045mol), sodium tert-butoxide (5.8g, 0.06mol) and 1-butyl-3-methylimidazolium tetrafluoroborate (13.6g, 0.06mol) were added to a reaction flask under nitrogen blanket and heated to 70-80 ℃ for 4 hours. GC tests that the raw materials are completely reacted, the reaction temperature is reduced to room temperature, p-toluenesulfonic acid (430.0g and 2.50mol) is added, the reaction is completed after dripping, the reaction is carried out for 8 hours at the temperature of 40-50 ℃, the temperature is reduced to below 20 ℃, triethylamine (253.0g and 2.50mol) is added dropwise, pinacol (141.6g and 1.2mol) and phenothiazine (5.0g) are added after dripping, the reaction is stirred for 2 hours at the room temperature, acetonitrile is concentrated under reduced pressure, sulfolane (450g) is added, then reduced pressure distillation is carried out, colorless liquid pinacol isopropenylborate ester 82.8g is obtained, the GC purity is 99.6%, and the yield is 49.3%. The experiment was carried out under the same conditions in an air atmosphere, and the yield was 13.5%.

Example 7

1.5L of acetonitrile, acetone (75.4g, 1.30mol), catechol diboronate (223.8g, 1.00mol), CuCl (4.9g, 0.05mol), ICy. HCl (12.2g, 0.075mol), potassium tert-butoxide (11.2g, 0.10mol) and sodium tetrakis {3, 5-bis (trifluoromethyl) phenyl } borate (88.6g, 0.10mol) were added to a reaction flask under nitrogen, heated to 70-80 ℃ and reacted for 4 hours. GC tests that the raw materials completely react, the reaction temperature is reduced to room temperature, p-toluenesulfonic acid (344.0g, 2.00mol) is added, the reaction is completed at 40-50 ℃ for 7 hours, the temperature is reduced to below 20 ℃, triethylamine (202.4g, 2.00mol) is added dropwise, pinacol (141.6g, 1.2mol) and phenothiazine (5.0g) are added after the dropwise addition, the reaction is stirred for 2 hours at room temperature, acetonitrile is concentrated under reduced pressure after the reaction is completed, sulfolane (350g) is added, then reduced pressure distillation is carried out to obtain colorless liquid pinacol isopropenyl borate ester 121.3g, the GC purity is 99.2%, and the yield is 72.2%. The experiment was carried out under the same conditions in an air atmosphere, and the yield was 72.8%.

Example 8

1.5L of acetonitrile, acetone (63.8g, 1.10mol), catechol diboronate (223.8g, 1.00mol), CuCl (4.9g, 0.05mol), ICy. HCl (12.2g, 0.075mol), potassium trimethylsilanolate (12.8g, 0.10mol) and 1-butyl-3-methylimidazolium hexafluorophosphate (28.4g, 0.10mol) were charged to a reaction flask under nitrogen blanket and heated to 70-80 ℃ for 3 hours. GC tests that the raw materials are completely reacted, the reaction temperature is reduced to room temperature, p-toluenesulfonic acid (344.0g, 2.00mol) is added, the reaction is completed after dropwise addition, the reaction is carried out for 7 hours at the temperature of 40-50 ℃, the temperature is reduced to below 20 ℃, triethylamine (202.4g, 2.00mol) is added dropwise, pinacol (141.6g, 1.2mol) and 2, 6-di-tert-butyl-4-methylphenol (5.0g) are added after dropwise addition, the reaction is completed after stirring for 2 hours at the room temperature, acetonitrile is concentrated under reduced pressure, sulfolane (350g) is added, and then the mixture is distilled under reduced pressure to obtain colorless liquid isopropenylboronic acid pinacol ester 101.3g, the GC purity is 99.4%, and the yield is 60.3%. The experiment was carried out under the same conditions in an air atmosphere, and the yield was 24.1%.

The foregoing shows and describes the general principles and broad features of the present invention and advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.